FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Olivieri, LJ Kellman, P McCarter, RJ Cross, RR Hansen, MS Spurney, CF AF Olivieri, Laura J. Kellman, Peter McCarter, Robert J. Cross, Russell R. Hansen, Michael S. Spurney, Christopher F. TI Native T1 values identify myocardial changes and stratify disease severity in patients with Duchenne muscular dystrophy SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Article DE Duchenne muscular dystrophy; Cardiovascular magnetic resonance; Cardiomyopathy; Pediatrics; T1 mapping ID LATE-GADOLINIUM-ENHANCEMENT; CARDIOVASCULAR MAGNETIC-RESONANCE; VENTRICULAR SYSTOLIC DYSFUNCTION; EXTRACELLULAR VOLUME; CARDIOMYOPATHY; PRECISION; POPULATION; PREVALENCE; ACCURACY; RECOVERY AB Background: Duchenne muscular dystrophy (DMD) is an X-linked, inherited disorder causing dilated cardiomyopathy with variable onset and progression. Currently we lack objective markers of the effect of therapies targeted towards preventing progression of subclinical cardiac disease. Thus, our aim was to compare the ability of native T1 and extracellular volume (ECV) measurements to differentiate risk of myocardial disease in DMD and controls. Methods: Twenty boys with DMD and 16 age/gender-matched controls without history predisposing to cardiac fibrosis, but with a clinical indication for cardiovascular magnetic resonance (CMR) evaluation, underwent CMR with contrast. Data points collected include left ventricular ejection fraction (LVEF), left ventricular mass, and presence of late gadolinium enhancement (LGE). Native T1, and ECV regional mapping were obtained using both a modified Look-Locker (MOLLI) and saturation recovery single shot sequence (SASHA) on a 1.5T scanner. Using ordinal logistic regression models, controlling for age and LVEF, LGE-free septal we evaluated the ability native T1 and ECV assessments to differentiate levels of cardiomyopathy. Results: Twenty DMD subjects aged 14.4 +/- 4 years had an LVEF of 56.3 +/- 7.4 %; 12/20 had LGE, all confined to the lateral wall. Sixteen controls aged 16.1 +/- 2.2 years had an LVEF 60.4 +/- 5.1 % and no LGE. Native T1 and ECV values were significantly higher in the DMD group (p < 0.05) with both MOLLI and SASHA imaging techniques. Native T1 demonstrated a 50 % increase in the ability to predict disease state (control, DMD without fibrosis, DMD with fibrosis). ECV demonstrated only the ability to predict presence of LGE, but could not distinguish between controls and DMD without fibrosis. Conclusions: LGE-spared regions of boys with DMD have significantly different native T1 and ECV values compared to controls. Native T1 measurements can identify early changes in DMD patients without the presence of LGE and help predict disease severity more effectively than ECV. Native T1 may be a novel outcome measure for early cardiac therapies in DMD and other cardiomyopathies. C1 [Olivieri, Laura J.; Cross, Russell R.; Spurney, Christopher F.] Childrens Natl Hlth Syst, Div Cardiol, 111 Michigan Ave NW,W3-200, Washington, DC 20010 USA. [Olivieri, Laura J.; Kellman, Peter; Hansen, Michael S.] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [McCarter, Robert J.] Childrens Natl Hlth Syst, Clin & Translat Sci Inst, 111 Michigan Ave NW, Washington, DC 20010 USA. [Spurney, Christopher F.] Childrens Natl Hlth Syst, Med Genet Res Ctr, 111 Michigan Ave NW, Washington, DC 20010 USA. RP Olivieri, LJ (reprint author), Childrens Natl Hlth Syst, Div Cardiol, 111 Michigan Ave NW,W3-200, Washington, DC 20010 USA.; Olivieri, LJ (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. EM lolivier@childrensnational.org FU NHLBI [NHLBI-CSB-(HL)-2014-013-JML]; National Heart, Lung, Blood Institute National Institutes of Health FX This study was funded through NHLBI Intramural grant number NHLBI-CSB-(HL)-2014-013-JML. Several co-authors are employed by the NHLBI Intramural science program, and thus contributed to the study design, analysis and interpretation of data.; National Heart, Lung, Blood Institute; National Institutes of Health; Building 31, Room 5A52; 31 Center Drive, MSC 2486; Bethesda, MD 20892 NR 29 TC 1 Z9 1 U1 3 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1097-6647 EI 1532-429X J9 J CARDIOVASC MAGN R JI J. Cardiov. Magn. Reson. PD OCT 28 PY 2016 VL 18 AR 72 DI 10.1186/s12968-016-0292-8 PG 11 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA EA2ZU UT WOS:000386467500001 PM 27788681 ER PT J AU Axelsen, PH Murphy, RC Igarashi, M Rapoport, SI AF Axelsen, Paul H. Murphy, Robert C. Igarashi, Miki Rapoport, Stanley I. TI Increased omega 6-Containing Phospholipids and Primary omega 6 Oxidation Products in the Brain Tissue of Rats on an omega 3-Deficient Diet SO PLoS One LA English DT Article ID POLYUNSATURATED FATTY-ACIDS; N-3 PUFA DEPRIVATION; ALPHA-LINOLENIC ACID; AMYLOID-BETA PROTEINS; DOCOSAHEXAENOIC ACID; ALZHEIMERS-DISEASE; DOCOSAPENTAENOIC ACID; MOUSE MODEL; ARACHIDONIC-ACID; INFUSED RATS AB Polyunsaturated fatty acyl (PUFA) chains in both the omega 3 and omega 6 series are essential for normal animal brain development, and cannot be interconverted to compensate for a dietary deficiency of one or the other. Paradoxically, a dietary omega 3-PUFA deficiency leads to the accumulation of docosapentaenoate (DPA, 22:5 omega 6), an omega 6-PUFA chain that is normally scarce in the brain. We applied a high-precision LC/MS method to characterize the distribution of DPA chains across phospholipid headgroup classes, the fatty acyl chains with which they were paired, and the extent to which they were oxidatively damaged in the cortical brain of rats on an omega 3-deficient diet. Results indicate that dietary omega 3-PUFA deficiency markedly increased the concentrations of phospholipids with DPA chains across all headgroup subclasses, including plasmalogen species. The concentrations of phospholipids containing docosahexaenoate chains (22:6 omega 3) decreased 20-25%, while the concentrations of phospholipids containing arachidonate chains (20:4 omega 6) did not change significantly. Although DPA chains are more saturated than DHA chains, a larger fraction of DPA chains were monohydroxylated, particularly among diacyl-phosphatidylethanolamines and plasmalogen phosphatidylethanolamines, suggesting that they were disproportionately subjected to oxidative stress. Differences in the pathological significance of omega 3 and omega 6 oxidation products suggest that greater oxidative damage among the omega 6 PUFAs that increase in response to dietary omega 3 deficiency may have pathological significance in Alzheimer's disease. C1 [Axelsen, Paul H.] Univ Penn, Dept Pharmacol, Sch Med, Philadelphia, PA 19104 USA. [Axelsen, Paul H.] Univ Penn, Dept Biochem & Biophys, Sch Med, Philadelphia, PA 19104 USA. [Axelsen, Paul H.] Univ Penn, Dept Med, Sch Med, Philadelphia, PA 19104 USA. [Murphy, Robert C.] Univ Colorado, Denver Hlth Sci Ctr, Dept Pharmacol, Mail Stop 8303, Aurora, CO 80045 USA. [Igarashi, Miki; Rapoport, Stanley I.] NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. [Igarashi, Miki] RIKEN, Yokohama Branch, Ctr Integrat Med Sci, Tsurumi Ku, 1-7-22 Suehiro Cho, Yokohama, Kanagawa 2300045, Japan. RP Axelsen, PH (reprint author), Univ Penn, Dept Pharmacol, Sch Med, Philadelphia, PA 19104 USA.; Axelsen, PH (reprint author), Univ Penn, Dept Biochem & Biophys, Sch Med, Philadelphia, PA 19104 USA.; Axelsen, PH (reprint author), Univ Penn, Dept Med, Sch Med, Philadelphia, PA 19104 USA. EM axe@pharm.med.upenn.edu FU NIH [AG20238, GM76201, NS74178, GM069338]; American Health Assistance Foundation; Glenn Foundation; Alzheimer's Association; Intramural Research Program of the National Institutes on Aging, NIH FX This work was supported by grants from the NIH (AG20238, GM76201, and NS74178), the American Health Assistance Foundation, the Glenn Foundation, and the Alzheimer's Association to PHA, and a large scale collaborative grant from the NIH (GM069338, LipidMaps) to RCM. The work by MI and SIR was supported entirely by the Intramural Research Program of the National Institutes on Aging, NIH. NR 55 TC 0 Z9 0 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 27 PY 2016 VL 11 IS 10 AR e0164326 DI 10.1371/journal.pone.0164326 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE4VY UT WOS:000389604900017 PM 27788153 ER PT J AU Gu, CF Wilson, MSC Jessen, HJ Saiardi, A Shears, SB AF Gu, Chunfang Wilson, Miranda S. C. Jessen, Henning J. Saiardi, Adolfo Shears, Stephen B. TI Inositol Pyrophosphate Profiling of Two HCT116 Cell Lines Uncovers Variation in InsP(8) Levels SO PLoS One LA English DT Article ID BIS-DIPHOSPHOINOSITOL TETRAKISPHOSPHATE; ION CHROMATOGRAPHY; POLYPHOSPHATES; PHOSPHATES; KINASE; INSTABILITY; METABOLISM; TURNOVER; STRESS; GROWTH AB The HCT116 cell line, which has a pseudo-diploid karotype, is a popular model in the fields of cancer cell biology, intestinal immunity, and inflammation. In the current study, we describe two batches of diverged HCT116 cells, which we designate as HCT116(NIH) and HCT116(UCL). Using both gel electrophoresis and HPLC, we show that HCT116(UCL)cells contain 6-fold higher levels of InsP(8) than HCT116(NIH) cells. This observation is significant because InsP(8) is one of a group of molecules collectively known as Inositol pyrophosphates' (PP-InsPs) highly 'energetic' and conserved regulators of cellular and organismal metabolism. Variability in the cellular levels of InsP(8) within divergent HCT116 cell lines could have impacted the phenotypic data obtained in previous studies. This difference in InsP(8) levels is more remarkable for being specific; levels of other inositol phosphates, and notably InsP(6) and 5-InsP(7), are very similar in both HCT116(NIH) and HCT116(UCL)-lines. We also developed a new HPLC procedure to record 1-InsP(7) levels directly (for the first time in any mammalian cell line); 1-InsP(7) comprised <2% of total InsP(7) in HCT116(NIH) and HCT116(UCL) lines. The elevated levels of InsP(8) in the HCT116(UCL) lines were not due to an increase in expression of the PP-InsP kinases (IP6Ks and PPIP5Ks), nor to a decrease in the capacity to dephosphorylate InsP(8). We discuss how the divergent PP-InsP profiles of the newly-designated HCT116(NIH) and HCT116(UCL) lines should be considered an important research opportunity: future studies using these two lines may uncover new features that regulate InsP(8)s turnover, and may also yield new directions for studying InsP(8) function. C1 [Gu, Chunfang; Shears, Stephen B.] NIEHS, Lab Signal Transduct, NIH, 101 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. [Wilson, Miranda S. C.; Saiardi, Adolfo] UCL, Med Res Council Lab Mol Cell Biol, London, England. [Jessen, Henning J.] Albert Ludwigs Univ, Inst Organ Chem, Albertstr 21, D-79104 Freiburg, Germany. RP Shears, SB (reprint author), NIEHS, Lab Signal Transduct, NIH, 101 TW Alexander Dr, Res Triangle Pk, NC 27709 USA.; Saiardi, A (reprint author), UCL, Med Res Council Lab Mol Cell Biol, London, England. EM dmcbado@ucl.ac.uk; shears@niehs.nih.gov RI Jessen, Henning/F-5108-2014 OI Jessen, Henning/0000-0002-1025-9484 FU UK Medical Research Council (MRC) [1201814]; Intramural Research Program of the NIH / National Institute of Environmental Health Sciences; Swiss National Science Foundation [PP00P2_157607] FX This work was supported by the UK Medical Research Council (MRC) core support to the MRC/UCL Laboratory for Molecular Cell Biology University Unit (MC UU 1201814), and by the Intramural Research Program of the NIH / National Institute of Environmental Health Sciences. HJJ acknowledges support from the Swiss National Science Foundation (grant number PP00P2_157607). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 1 Z9 1 U1 3 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 27 PY 2016 VL 11 IS 10 AR e0165286 DI 10.1371/journal.pone.0165286 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE4VY UT WOS:000389604900056 PM 27788189 ER PT J AU Kosoy, R Agashe, C Grishin, A Leung, DY Wood, RA Sicherer, SH Jones, SM Burks, AW Davidson, WF Lindblad, RW Dawson, P Merad, M Kidd, BA Dudley, JT Sampson, HA Berin, MC AF Kosoy, Roman Agashe, Charuta Grishin, Alexander Leung, Donald Y. Wood, Robert A. Sicherer, Scott H. Jones, Stacie M. Burks, A. Wesley Davidson, Wendy F. Lindblad, Robert W. Dawson, Peter Merad, Miriam Kidd, Brian A. Dudley, Joel T. Sampson, Hugh A. Berin, M. Cecilia TI Transcriptional Profiling of Egg Allergy and Relationship to Disease Phenotype SO PLoS One LA English DT Article ID REGULATORY T-CELLS; COWS MILK ALLERGY; FC-EPSILON-RI; PLASMACYTOID DENDRITIC CELLS; FOOD ALLERGY; PEANUT ALLERGY; CHILDREN; RESPONSES; RECEPTOR; TOLERANCE AB Background Egg allergy is one of the most common food allergies of childhood. There is a lack of information on the immunologic basis of egg allergy beyond the role of IgE. Objective To use transcriptional profiling as a novel approach to uncover immunologic processes associated with different phenotypes of egg allergy. Methods Peripheral blood mononuclear cells (PBMCs) were obtained from egg-allergic children who were defined as reactive (BER) or tolerant (BET) to baked egg, and from food allergic controls (AC) who were egg non-allergic. PBMCs were stimulated with egg white protein. Gene transcription was measured by microarray after 24 h, and cytokine secretion by multiplex assay after 5 days. Results The transcriptional response of PBMCs to egg protein differed between BER and BET versus AC subjects. Compared to the AC group, the BER group displayed increased expression of genes associated with allergic inflammation as well as corresponding increased secretion of IL-5, IL-9 and TNF-alpha. A similar pattern was observed for the BET group. Further similarities in gene expression patterns between BER and BET groups, as well as some important differences, were revealed using a novel Immune Annotation resource developed for this project. This approach identified several novel processes not previously associated with egg allergy, including positive associations with TLR4-stimulated myeloid cells and activated NK cells, and negative associations with an induced Treg signature. Further pathway analysis of differentially expressed genes comparing BER to BET subjects showed significant enrichment of IFN-alpha and IFN-gamma response genes, as well as genes associated with virally-infected DCs. Conclusions Transcriptional profiling identified several novel pathways and processes that differed when comparing the response to egg allergen in BET, BER, and AC groups. We conclude that this approach is a useful hypothesis- generating mechanism to identify novel immune processes associated with allergy and tolerance to forms of egg. C1 [Kosoy, Roman; Kidd, Brian A.; Dudley, Joel T.] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Agashe, Charuta; Grishin, Alexander; Sicherer, Scott H.; Sampson, Hugh A.; Berin, M. Cecilia] Icahn Sch Med Mt Sinai, Dept Pediat, New York, NY 10029 USA. [Leung, Donald Y.] Natl Jewish Hlth, Dept Pediat, Denver, CO USA. [Wood, Robert A.] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. [Jones, Stacie M.] Univ Arkansas Med Sci, Dept Pediat, Little Rock, AR 72205 USA. [Jones, Stacie M.] Arkansas Childrens Hosp, 800 Marshall St, Little Rock, AR 72202 USA. [Burks, A. Wesley] Univ N Carolina, Dept Pediat, Chapel Hill, NC USA. [Davidson, Wendy F.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Lindblad, Robert W.; Dawson, Peter] EMMES Corp, Rockville, MD USA. [Merad, Miriam] Icahn Sch Med Mt Sinai, Oncol Sci, New York, NY 10029 USA. RP Berin, MC (reprint author), Icahn Sch Med Mt Sinai, Dept Pediat, New York, NY 10029 USA. EM cecilia.berin@mssm.edu FU National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID) [U19A1066738, U01A1066560, U01A1044236]; National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) [UL1 TR000154, UL1 TR000067, UL1 TR000039, UL1 TR000083, UL1 TR000424] FX Supported by National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID) grants U19A1066738 and U01A1066560, and a supplement to U01A1044236. The project was also supported by grant numbers UL1 TR000154 (National Jewish), UL1 TR000067 (Mount Sinai), UL1 TR000039 (Arkansas), UL1 TR000083 (North Carolina), and UL1 TR000424 (Johns Hopkins) from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH).; We acknowledge the Human Immune Monitoring Center, and the Genomics Core Facility at the Icahn School of Medicine at Mount Sinai for their contribution. We thank the physicians and staff of the Jaffe Food Allergy Institute for their assistance in recruiting atopic controls, and the physicians, research coordinators, and laboratory staff at the 5 CoFAR study sites for their contributions. This work was supported in part through the computational resources and staff expertise provided by the Department of Scientific Computing at the Icahn School of Medicine at Mount Sinai. NR 33 TC 0 Z9 0 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 27 PY 2016 VL 11 IS 10 AR e0163831 DI 10.1371/journal.pone.0163831 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE4VY UT WOS:000389604900010 PM 27788149 ER PT J AU Liu, KD Siew, ED Reeves, WB Himmelfarb, J Go, AS Hsu, CY Bennett, MR Devarajan, P Ikizler, TA Kaufman, JS Kimmel, PL Chinchilli, VM Parikh, CR AF Liu, Kathleen D. Siew, Edward D. Reeves, W. Brian Himmelfarb, Jonathan Go, Alan S. Hsu, Chi-yuan Bennett, Michael R. Devarajan, Prasad Ikizler, T. Alp Kaufman, James S. Kimmel, Paul L. Chinchilli, Vernon M. Parikh, Chirag R. CA ASSESS-AKI Study Investigators TI Storage Time and Urine Biomarker Levels in the ASSESS-AKI Study SO PLoS One LA English DT Article ID ACUTE KIDNEY INJURY; LONG-TERM STORAGE; GELATINASE-ASSOCIATED LIPOCALIN; MOLECULE-1 KIM-1; ALBUMIN; NGAL; DISEASE; SAMPLES; -20-DEGREES-C; PREVALENCE AB Background Although stored urine samples are often used in biomarker studies focused on acute and chronic kidney disease, how storage time impacts biomarker levels is not well understood. Methods 866 subjects enrolled in the NIDDK-sponsored ASsessment, Serial Evaluation, and Subsequent Sequelae in Acute Kidney Injury (ASSESS-AKI) Study were included. Samples were processed under standard conditions and stored at -70 degrees C until analyzed. Kidney injury molecule- 1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), and liver fatty acid binding protein (L-FABP) were measured in urine samples collected during the index hospitalization or an outpatient visit 3 months later. Mixed effects models were used to determine the effect of storage time on biomarker levels and stratified by visit. Results Median storage was 17.8 months (25-75% IQR 10.6-23.7) for samples from the index hospitalization and 14.6 months (IQR 7.3-20.4) for outpatient samples. In the mixed effects models, the only significant association between storage time and biomarker concentration was for KIM-1 in outpatient samples, where each month of storage was associated with a 1.7% decrease (95% CI -3% to -0.3%). There was no relationship between storage time and KIM-1 levels in samples from the index hospitalization. Conclusion There was no significant impact of storage time over a median of 18 months on urine KIM-1, NGAL, IL-18 or L-FABP in hospitalized samples; a statistically significant effect towards a decrease over time was noted for KIM-1 in outpatient samples. Additional studies are needed to determine whether longer periods of storage at -70 degrees C systematically impact levels of these analytes. C1 [Liu, Kathleen D.; Hsu, Chi-yuan] Univ Calif San Francisco, Dept Med, Div Nephrol, San Francisco, CA 94143 USA. [Siew, Edward D.; Ikizler, T. Alp] Vanderbilt Univ, Med Ctr, Dept Med, Div Nephrol & Hypertens, Nashville, TN USA. [Reeves, W. Brian] Penn State Coll Med, Dept Med, Div Nephrol, Hershey, PA USA. [Himmelfarb, Jonathan] Univ Washington, Dept Med, Kidney Res Inst, Seattle, WA USA. [Go, Alan S.; Hsu, Chi-yuan] Kaiser Permanente Northern Calif, Div Res, Oakland, CA USA. [Bennett, Michael R.; Devarajan, Prasad] Cincinnati Childrens Hosp Med Ctr, Div Nephrol, Cincinnati, OH 45229 USA. [Kaufman, James S.] VA New York Harbor Healthcare Syst, Res Serv, New York, NY USA. [Kaufman, James S.] VA New York Harbor Healthcare Syst, Renal Sect, New York, NY USA. [Kaufman, James S.] NYU, Sch Med, New York, NY USA. [Kimmel, Paul L.] NIDDK, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD 20892 USA. [Chinchilli, Vernon M.] Penn State Coll Med, Dept Publ Hlth Sci, Hershey, PA USA. [Parikh, Chirag R.] Yale Univ, Sch Med, Dept Med, Nephrol Sect, New Haven, CT 06510 USA. [Parikh, Chirag R.] Yale Univ, Sch Med, Program Appl Translat Res, New Haven, CT USA. RP Liu, KD (reprint author), Univ Calif San Francisco, Dept Med, Div Nephrol, San Francisco, CA 94143 USA. EM kathleen.liu@ucsf.edu OI Moledina, Dennis/0000-0002-9537-9038 FU Vanderbilt Center for Kidney Disease (VCKD); [U01-DK082223]; [U01-DK082185]; [U01-DK082192]; [P50-DK096418]; [U01-DK082183]; [U01-DK084012]; [R01 DK098233] FX This study was supported by research grants U01-DK082223, U01-DK082185, U01-DK082192, P50-DK096418, U01-DK082183, U01-DK084012 and R01 DK098233. A NIDDK Program Officer was involved in the study design, data collection, and preparation of the manuscript, though decisions were made in collaboration with other authors, and no official approval from NIDDK was required for manuscript submission. From the National Institute of Digestive, Diabetes and Kidney Disease and by UL1-RR024131 from the National Center for Research Resources of the National Institutes of Health, U.S. Department of Health and Human Services. EDS is also supported by the Vanderbilt Center for Kidney Disease (VCKD). NR 26 TC 0 Z9 0 U1 4 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 27 PY 2016 VL 11 IS 10 AR e0164832 DI 10.1371/journal.pone.0164832 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE4VY UT WOS:000389604900027 PM 27788160 ER PT J AU Sicko, RJ Browne, ML Rigler, SL Druschel, CM Liu, G Fan, RZ Romitti, PA Caggana, M Kay, DM Brody, LC Mills, JL AF Sicko, Robert J. Browne, Marilyn L. Rigler, Shannon L. Druschel, Charlotte M. Liu, Gang Fan, Ruzong Romitti, Paul A. Caggana, Michele Kay, Denise M. Brody, Lawrence C. Mills, James L. TI Genetic Variants in Isolated Ebstein Anomaly Implicated in Myocardial Development Pathways SO PLoS One LA English DT Article ID CONGENITAL HEART-DISEASE; COPY-NUMBER VARIATION; MYOSIN HEAVY-CHAIN; TRICUSPID-VALVE; HUMAN GENOME; DE-NOVO; DILATED CARDIOMYOPATHY; SEPTAL-DEFECT; DELETION; MALFORMATION AB Ebstein anomaly ( EA) is a rare heart defect in which the tricuspid valve is malformed and displaced. The tricuspid valve abnormalities can lead to backflow of blood from the right ventricle to the right atrium, preventing proper circulation of blood to the lungs. Although the etiology of EA is largely unresolved, increased prevalence of EA in those with a family history of congenital heart disease suggests EA has a genetic component. Copy number variants (CNVs) are a major source of genetic variation and have been implicated in a range of congenital heart defect phenotypes. We performed a systematic, genome-wide search for CNVs in 47 isolated EA cases using genotyping microarrays. In addition, we used a custom HaloPlex panel to sequence three known EA genes and 47 candidate EA genes. We identified 35 candidate CNVs in 24 (51%) EA cases. Rare sequence variants in genes associated with cardiomyopathy were identified in 11 (23%) EA cases. Two CNVs near the transcriptional repressor HEY1, a member of the NOTCH signaling pathway, were identified in three unrelated cases. All other candidate CNVs were each identified in a single case. At least 11 of 35 candidate CNVs include genes involved in myocardial development or function, including multiple genes in the BMP signaling pathway. We identified enrichment of gene sets involved in histone modification and cardiomyocyte differentiation, supporting the involvement of the developing myocardium in the etiology of EA. Gene set enrichment analysis also identified ribosomal RNA processing, a potentially novel pathway of altered cardiac development in EA. Our results suggest an altered myocardial program may contribute to abnormal tricuspid valve development in EA. Future studies should investigate abnormal differentiation of cardiomyocytes as a potential etiological factor in EA. C1 [Sicko, Robert J.; Caggana, Michele; Kay, Denise M.] New York State Dept Hlth, Wadsworth Ctr, Div Genet, Albany, NY USA. [Browne, Marilyn L.; Druschel, Charlotte M.; Liu, Gang] New York State Dept Hlth, Congenital Malformat Registry, Albany, NY USA. [Browne, Marilyn L.; Druschel, Charlotte M.] SUNY Albany, Sch Publ Hlth, Dept Epidemiol & Biostat, Rensselaer, NY USA. [Rigler, Shannon L.; Fan, Ruzong; Mills, James L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Rigler, Shannon L.] Walter Reed Natl Mil Med Ctr, Dept Neonatol, Bethesda, MD USA. [Romitti, Paul A.] Univ Iowa, Dept Epidemiol, Coll Publ Hlth, Iowa City, IA USA. [Brody, Lawrence C.] NHGRI, Med Genom & Metab Genet Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Mills, JL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM jamesmills@nih.gov OI Sicko, Robert/0000-0001-7521-9742; ROMITTI, PAUL/0000-0001-5393-9984; Browne, Marilyn/0000-0002-1872-2787 FU National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development [HHSN2752011000011, HHSN27500005, N01-DK-73431]; National Human Genome Research Institute; Wellcome Trust FX This work was funded by the Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts HHSN2752011000011 and HHSN27500005; NICHD contract N01-DK-73431) and the National Human Genome Research Institute. Funding for the DECIPHER project was provided by the Wellcome Trust. NR 89 TC 0 Z9 0 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 27 PY 2016 VL 11 IS 10 DI 10.1371/journal.pone.0165174 PG 21 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE4VY UT WOS:000389604900051 ER PT J AU Yang, MQ Elnitski, L AF Yang, Mary Qu Elnitski, Laura TI A Systems Biology Comparison of Ovarian Cancers Implicates Putative Somatic Driver Mutations through Protein-Protein Interaction Models SO PLoS One LA English DT Article ID GRADE SEROUS CARCINOMA; PHOSPHORYLATION-ACETYLATION SWITCH; CANDIDATE MOLECULAR MARKERS; GENE-EXPRESSION PROFILES; BREAST-CANCER; INTERACTION NETWORK; MESSENGER-RNA; 2-TIER SYSTEM; GROWTH-FACTOR; CELL-GROWTH AB Ovarian carcinomas can be aggressive with a high mortality rate (e.g., high-grade serous ovarian carcinomas, or HGSOCs), or indolent with much better long-term outcomes (e.g., low-malignant-potential, or LMP, serous ovarian carcinomas). By comparing LMP and HGSOC tumors, we can gain insight into the mechanisms underlying malignant progression in ovarian cancer. However, previous studies of the two subtypes have been focused on gene expression analysis. Here, we applied a systems biology approach, integrating gene expression profiles derived from two independent data sets containing both LMP and HGSOC tumors with protein-protein interaction data. Genes and related networks implicated by both data sets involved both known and novel disease mechanisms and highlighted the different roles of BRCA1 and CREBBP in the two tumor types. In addition, the incorporation of somatic mutation data revealed that amplification of PAK4 is associated with poor survival in patients with HGSOC. Thus, perturbations in protein interaction networks demonstrate differential trafficking of network information between malignant and benign ovarian cancers. The novel network-based molecular signatures identified here may be used to identify new targets for intervention and to improve the treatment of invasive ovarian cancer as well as early diagnosis. C1 [Yang, Mary Qu] Univ Arkansas, MidSouth Bioinformat Ctr, 2801 S Univ Ave, Little Rock, AR 72204 USA. [Yang, Mary Qu] Univ Arkansas, Joint Bioinformat PhD Program, 2801 S Univ Ave, Little Rock, AR 72204 USA. [Yang, Mary Qu] Univ Arkansas Med Sci, 2801 S Univ Ave, Little Rock, AR 72204 USA. [Elnitski, Laura] NHGRI, NIH, Rockville, MD 20852 USA. RP Yang, MQ (reprint author), Univ Arkansas, MidSouth Bioinformat Ctr, 2801 S Univ Ave, Little Rock, AR 72204 USA.; Yang, MQ (reprint author), Univ Arkansas, Joint Bioinformat PhD Program, 2801 S Univ Ave, Little Rock, AR 72204 USA.; Yang, MQ (reprint author), Univ Arkansas Med Sci, 2801 S Univ Ave, Little Rock, AR 72204 USA.; Elnitski, L (reprint author), NHGRI, NIH, Rockville, MD 20852 USA. EM mqyang@ualr.edu; elnitski@mail.nih.gov FU Intramural Research Program of the National Human Genome Research Institute (NHGRI) at the National Institutes of Health (NIH); NIH Academic Research Enhancement Award [1R15GM114739]; Arkansas Science and Technology Authority (ASTA) Award [15-B-23]; NIH/NHGRI/Division of Intramural Research (DIR) FX This project was supported by the Intramural Research Program of the National Human Genome Research Institute (NHGRI) at the National Institutes of Health (NIH). In addition, we acknowledge the NIH Academic Research Enhancement Award 1R15GM114739 and Arkansas Science and Technology Authority (ASTA) Award # 15-B-23 to MQY. Funding for the publication of the article came from NIH/NHGRI/Division of Intramural Research (DIR). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 90 TC 0 Z9 0 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 27 PY 2016 VL 11 IS 10 AR e0163353 DI 10.1371/journal.pone.0163353 PG 26 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE4VY UT WOS:000389604900006 PM 27788148 ER PT J AU Grazziotin, AL Vidal, NM Palmeiro, JK Dalla-Costa, LM Venancio, TM AF Grazziotin, Ana Laura Vidal, Newton M. Palmeiro, Jussara K. Dalla-Costa, Libera Maria Venancio, Thiago M. TI Genome Sequencing of Four Multidrug-Resistant Enterobacter aerogenes Isolates from Hospitalized Patients in Brazil SO FRONTIERS IN MICROBIOLOGY LA English DT Article DE Brazil; Enterobacter aerogenes; genome sequencing; multidrug resistance; carbapenem resistance ID INTENSIVE-CARE-UNIT; SPECTRUM BETA-LACTAMASE; KLEBSIELLA-PNEUMONIAE; MULTIPLEX PCR; ANTIMICROBIAL RESISTANCE; ANTIBIOTIC-RESISTANCE; CARBAPENEM RESISTANCE; CLONAL DISSEMINATION; PREVALENT CLONE; EFFLUX PUMP C1 [Grazziotin, Ana Laura; Venancio, Thiago M.] Univ Estadual Norte Fluminense, Ctr Biociencias & Biotecnol, Lab Quim & Funcao Prot & Peptideos, Campos Dos Goytacazes, Brazil. [Vidal, Newton M.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. [Palmeiro, Jussara K.; Dalla-Costa, Libera Maria] Univ Fed Parana, Hosp Clin, Unidade Lab Anal Clin, Lab Bacteriol, Curitiba, Parana, Brazil. [Palmeiro, Jussara K.; Dalla-Costa, Libera Maria] Fac & Inst Pesquisa Pele Pequeno Principe, Curitiba, Parana, Brazil. RP Grazziotin, AL; Venancio, TM (reprint author), Univ Estadual Norte Fluminense, Ctr Biociencias & Biotecnol, Lab Quim & Funcao Prot & Peptideos, Campos Dos Goytacazes, Brazil.; Dalla-Costa, LM (reprint author), Univ Fed Parana, Hosp Clin, Unidade Lab Anal Clin, Lab Bacteriol, Curitiba, Parana, Brazil.; Dalla-Costa, LM (reprint author), Fac & Inst Pesquisa Pele Pequeno Principe, Curitiba, Parana, Brazil. EM analauragrazziotin@gmail.com; lmdallacosta@gmail.com; thiago.venancio@gmail.com RI Venancio, Thiago/B-5003-2011 FU Fundacao Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ) [E-26/110.236/2011, E-26/102.259/2013]; Intramural Research Program of the National Library of Medicine (NLM), National Institutes of Health (NIH); CNPq; NIH; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) FX This work was supported by Fundacao Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ; E-26/110.236/2011 and E-26/102.259/2013). This research was partially supported by the Intramural Research Program of the National Library of Medicine (NLM), National Institutes of Health (NIH). NV postdoctoral fellowship is funded by a partnership between CNPq and NIH. TV is a recipient of an established investigator fellowship award from Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq). We thank Bruker Corporation of Brazil for performing the MALDI-TOF assay and the staff of the Life Sciences Core Facility (LaCTAD), from State University of Campinas (UNICAMP), for library preparation and genome sequencing. NR 53 TC 0 Z9 0 U1 3 U2 3 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-302X J9 FRONT MICROBIOL JI Front. Microbiol. PD OCT 27 PY 2016 VL 7 AR 1649 DI 10.3389/fmicb.2016.01649 PG 7 WC Microbiology SC Microbiology GA ED1XW UT WOS:000388639200001 PM 27833588 ER PT J AU Kuhns, DB Fink, DL Choi, U Sweeney, C Lau, K Priel, DL Riva, D Mendez, L Uzel, G Freeman, AF Olivier, KN Anderson, VL Currens, R Mackley, V Kang, A Al-Adeli, M Mace, E Orange, JS Kang, E Lockett, SJ Chen, D Steinbach, PJ Hsu, AP Zarember, KA Malech, HL Gallin, JI Holland, SM AF Kuhns, Douglas B. Fink, Danielle L. Choi, Uimook Sweeney, Colin Lau, Karen Priel, Debra Long Riva, Dara Mendez, Laura Uzel, Gulbu Freeman, Alexandra F. Olivier, Kenneth N. Anderson, Victoria L. Currens, Robin Mackley, Vanessa Kang, Allison Al-Adeli, Mehdi Mace, Emily Orange, Jordan S. Kang, Elizabeth Lockett, Stephen J. Chen, De Steinbach, Peter J. Hsu, Amy P. Zarember, Kol A. Malech, Harry L. Gallin, John I. Holland, Steven M. TI Cytoskeletal abnormalities and neutrophil dysfunction in WDR1 deficiency SO BLOOD LA English DT Article ID LAZY-LEUKOCYTE SYNDROME; ACTIN-DEPOLYMERIZING FACTOR; AUTOINFLAMMATORY DISEASE; PROTEIN; EXOCYTOSIS; DISORDER AB Cell motility, division, and structural integrity depend on dynamic remodeling of the cellular cytoskeleton, which is regulated in part by actin polymerization and depolymerization. In 3 families, we identified 4 children with recurrent infections and varying clinical manifestations including mild neutropenia, impaired wound healing, severe stomatitis with oral stenosis, and death. All patients studied had similar distinctive neutrophil herniation of the nuclear lobes and agranular regions within the cytosol. Chemotaxis and chemokinesis were markedly impaired, but staphylococcal killing was normal, and neutrophil oxidative burst was increased both basally and on stimulation. Neutrophil spreading on glass and cell polarization were also impaired. Neutrophil F-actin was elevated fourfold, suggesting an abnormality in F-actin regulation. Two-dimensional differential in-gel electrophoresis identified abnormal actin-interacting protein 1 (Aip1), encoded by WDR1, in patient samples. Biallelic mutations in WDR1 affecting distinct antiparallel beta-strands of Aip1 were identified in all patients. It has been previously reported that Aip1 regulates cofilin-mediated actin depolymerization, which is required for normal neutrophil function. Heterozygous mutations in clinically normal relatives confirmed that WDR1 deficiency is autosomal recessive. Allogeneic stem cell transplantation corrected the immunologic defect in 1 patient. Mutations in WDR1 affect neutrophil morphology, motility, and function, causing a novel primary immunodeficiency. C1 [Kuhns, Douglas B.; Fink, Danielle L.; Lau, Karen; Priel, Debra Long; Riva, Dara; Mendez, Laura] Leidos Biomed Res Inc, Neutrophil Monitoring Lab, Appl Dev Res Directorate, Frederick Natl Lab Canc Res, Frederick, MD USA. [Choi, Uimook; Sweeney, Colin; Kang, Elizabeth; Zarember, Kol A.; Malech, Harry L.; Gallin, John I.] NIAID, Host Def Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Uzel, Gulbu; Freeman, Alexandra F.; Olivier, Kenneth N.; Anderson, Victoria L.; Hsu, Amy P.; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bldg 10-11N248 MSC 1881, Bethesda, MD 20892 USA. [Currens, Robin; Mackley, Vanessa; Kang, Allison] NCI, Werner H Kirsten Student Internship Program, NIH, Frederick, MD 21701 USA. [Al-Adeli, Mehdi] Hamad Med Corp, Doha, Qatar. [Mace, Emily; Orange, Jordan S.] Baylor Inst Immunol, Dallas, TX USA. [Lockett, Stephen J.; Chen, De] Leidos Biomed Res Inc, Canc Res Technol Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Steinbach, Peter J.] NIH, Ctr Mol Modeling, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. RP Holland, SM (reprint author), NIAID, Lab Clin Infect Dis, NIH, Bldg 10-11N248 MSC 1881, Bethesda, MD 20892 USA. EM smh@nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; federal funds from National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health and has been funded in part with federal funds from National Cancer Institute, National Institutes of Health, contract HHSN261200800001E. NR 18 TC 2 Z9 2 U1 3 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD OCT 27 PY 2016 VL 128 IS 17 BP 2135 EP 2143 DI 10.1182/blood-2016-03-706028 PG 9 WC Hematology SC Hematology GA EC4KT UT WOS:000388098800007 PM 27557945 ER PT J AU Steel, A Silson, EH Stagg, CJ Baker, CI AF Steel, Adam Silson, Edward H. Stagg, Charlotte J. Baker, Chris I. TI The impact of reward and punishment on skill learning depends on task demands SO SCIENTIFIC REPORTS LA English DT Article ID BASAL GANGLIA; MOTOR; IMPLICIT; CONSOLIDATION; MODULATION; NETWORKS; CORTEX; SLEEP; NOISE; TERM AB Reward and punishment motivate behavior, but it is unclear exactly how they impact skill performance and whether the effect varies across skills. The present study investigated the effect of reward and punishment in both a sequencing skill and a motor skill context. Participants trained on either a sequencing skill (serial reaction time task) or a motor skill (force-tracking task). Skill knowledge was tested immediately after training, and again 1 hour, 24-48 hours, and 30 days after training. We found a dissociation of the effects of reward and punishment on the tasks, primarily reflecting the impact of punishment. While punishment improved serial reaction time task performance, it impaired force-tracking task performance. In contrast to prior literature, neither reward nor punishment benefitted memory retention, arguing against the common assumption that reward ubiquitously benefits skill retention. Collectively, these results suggest that punishment impacts skilled behavior more than reward in a complex, task dependent fashion. C1 [Steel, Adam; Stagg, Charlotte J.] Univ Oxford, Nuffield Dept Clin Neurosci, FMRIB Ctr, Oxford, England. [Steel, Adam; Silson, Edward H.; Baker, Chris I.] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20814 USA. [Stagg, Charlotte J.] Univ Oxford, Univ Dept Psychiat, Oxford Ctr Human Brain Act OHBA, Oxford, England. RP Steel, A (reprint author), Univ Oxford, Nuffield Dept Clin Neurosci, FMRIB Ctr, Oxford, England.; Steel, A (reprint author), NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20814 USA. EM adam.steel@nih.gov OI Steel, Adam/0000-0001-8876-933X FU NIH intramural program [ZIA MH002893-10]; Wellcome Trust; Royal Society [102584/Z/13/Z] FX C.I.B. and A.D.S. are funded by NIH intramural program number ZIA MH002893-10. C.J.S. is funded by the Wellcome Trust and the Royal Society 102584/Z/13/Z. NR 29 TC 0 Z9 0 U1 10 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD OCT 27 PY 2016 VL 6 AR 36056 DI 10.1038/srep36056 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EA3PR UT WOS:000386516500001 PM 27786302 ER PT J AU Leang, R Khu, NH Mukaka, M Debackere, M Tripura, R Kheang, ST Chy, S Kak, N Buchy, P Tarantola, A Menard, D Roca-Felterer, A Fairhurst, RM Kheng, S Muth, S Ngak, S Dondorp, AM White, NJ Taylor, WRJ AF Leang, Rithea Khu, Naw Htee Mukaka, Mavuto Debackere, Mark Tripura, Rupam Kheang, Soy Ty Chy, Say Kak, Neeraj Buchy, Philippe Tarantola, Arnaud Menard, Didier Roca-Felterer, Arantxa Fairhurst, Rick M. Kheng, Sim Muth, Sinoun Ngak, Song Dondorp, Arjen M. White, Nicholas J. Taylor, Walter Robert John TI An optimised age-based dosing regimen for single low-dose primaquine for blocking malaria transmission in Cambodia SO BMC MEDICINE LA English DT Article DE Primaquine; Malaria; G6PD deficiency; Dosing; Cambodia ID PLASMODIUM-FALCIPARUM MALARIA; INDUCED HEMOLYTIC-ANEMIA; ANTIMALARIAL-DRUG PRIMAQUINE; ADULT THAI SUBJECTS; VIVAX MALARIA; DIHYDROARTEMISININ-PIPERAQUINE; CYTOCHROME-P450 2D6; WESTERN CAMBODIA; G6PD DEFICIENCY; GLUCOSE-6-PHOSPHATE-DEHYDROGENASE DEFICIENCY AB Background: In 2012, the World Health Organization recommended the addition of single low-dose primaquine (SLDPQ, 0.25 mg base/kg body weight) to artemisinin combination therapies to block the transmission of Plasmodium falciparum without testing for glucose-6-phosphate dehydrogenase deficiency. The targeted group was non-pregnant patients aged >= 1 year (later changed to >= 6 months) with acute uncomplicated falciparum malaria, primarily in countries with artemisinin-resistant P. falciparum (ARPf). No dosing regimen was suggested, leaving malaria control programmes and clinicians in limbo. Therefore, we designed a user-friendly, age-based SLDPQ regimen for Cambodia, the country most affected by ARPf. Methods: By reviewing primaquine's pharmacology, we defined a therapeutic dose range of 0.15-0.38 mg base/kg (9-22.5 mg in a 60-kg adult) for a therapeutic index of 2.5. Primaquine doses (1-20 mg) were tested using a modelled, anthropometric database of 28,138 Cambodian individuals (22,772 healthy, 4119 with malaria and 1247 with other infections); age distributions were: 0.5-4 years (20.0 %, n = 5640), 5-12 years (9.1 %, n = 2559), 13-17 years (9.1 %, n = 2550), and >= 18 years (61.8 %, n = 17,389). Optimal age-dosing groups were selected according to calculated mg base/kg doses and proportions of individuals receiving a therapeutic dose. Results: Four age-dosing bands were defined: (1) 0.5-4 years, (2) 5-9 years, (3) 10-14 years, and (4) >= 15 years to receive 2.5, 5, 7.5, and 15 mg of primaquine base, resulting in therapeutic doses in 97.4 % (5494/5640), 90.5 % (1511/1669), 97.7 % (1473/1508), and 95.7 % (18,489/ 19,321) of individuals, respectively. Corresponding median (1st-99th centiles) mg base/kg doses of primaquine were (1) 0.23 (0.15-0.38), (2) 0.29 (0.18-0.45), (3) 0.27 (0.15-0. 39), and (4) 0.29 (0.20-0.42). Conclusions: This age-based SLDPQ regimen could contribute substantially to malaria elimination and requires urgent evaluation in Cambodia and other countries with similar anthropometric characteristics. It guides primaquine manufacturers on suitable tablet strengths and doses for paediatric-friendly formulations. Development of similar age-based dosing recommendations for Africa is needed. C1 [Leang, Rithea; Kheng, Sim; Muth, Sinoun] Natl Ctr Parasitol Entomol & Malaria Control, Corner St 92, Khan Sen Sok, Phnom Penh, Cambodia. [Khu, Naw Htee; Mukaka, Mavuto; Tripura, Rupam; Dondorp, Arjen M.; White, Nicholas J.; Taylor, Walter Robert John] Mahidol Oxford Trop Med Res Unit MORU, 420-6 Rajvithi Rd, Bangkok 10400, Thailand. [Mukaka, Mavuto; Dondorp, Arjen M.; White, Nicholas J.; Taylor, Walter Robert John] Univ Oxford, Oxford Ctr Trop Med & Global Hlth, Nuffield Dept Med Res Bldg, Old Rd Campus,Roosevelt Dr, Oxford OX3 7FZ, England. [Debackere, Mark] MSF Belgium Cambodia Malaria Program, 19,St 388,POB 1933, Phnom Penh, Cambodia. [Kheang, Soy Ty; Chy, Say] Univ Res Co LLC, MK Bldg,House 10 2nd Floor,St 214, Daun Penh, Phnom Penh, Cambodia. [Kak, Neeraj] Univ Res Co LLC Washington DC, 7200 Wisconsin Ave, Bethesda, MD 20814 USA. [Buchy, Philippe; Tarantola, Arnaud; Menard, Didier] Inst Pasteur Cambodge, 5 Monivong Blvd,POB 983, Phnom Penh 12201, Cambodia. [Roca-Felterer, Arantxa] Malaria Consortium, House 91 St 95, Chamkar Morn, Phnom Penh, Cambodia. [Fairhurst, Rick M.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Ngak, Song] FHI 360 Cambodia Off, 03,St 330 Boeung Keng Kang 3 Khan Chamkamon, Phnom Penh, Cambodia. [Taylor, Walter Robert John] Hop Univ Geneve, Ctr Med Humanitaire, Geneva, Switzerland. RP Taylor, WRJ (reprint author), Mahidol Oxford Trop Med Res Unit MORU, 420-6 Rajvithi Rd, Bangkok 10400, Thailand.; Taylor, WRJ (reprint author), Univ Oxford, Oxford Ctr Trop Med & Global Hlth, Nuffield Dept Med Res Bldg, Old Rd Campus,Roosevelt Dr, Oxford OX3 7FZ, England.; Taylor, WRJ (reprint author), Hop Univ Geneve, Ctr Med Humanitaire, Geneva, Switzerland. EM bob@tropmedres.ac OI Tarantola, Arnaud/0000-0002-6946-7958 FU France Expertise International; Intramural Research Program of the US National Institute of Allergy and Infectious Diseases, National Institutes of Health FX We acknowledge with gratitude the Demographic Health Survey of USAID for permission to download data from their 2014 survey in Cambodia. WRJT was partly supported by France Expertise International through the 5 % initiative as a consultant to Centre National de Malariologie in operational research; he expresses "ses profonds remerciements au peuple francais." NJW is a Wellcome Trust Principal Fellow. Data contributed by RMF were obtained from studies funded by the Intramural Research Program of the US National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 89 TC 2 Z9 2 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7015 J9 BMC MED JI BMC Med. PD OCT 27 PY 2016 VL 14 AR 171 DI 10.1186/s12916-016-0701-8 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA EA1CW UT WOS:000386331100001 PM 27784313 ER PT J AU Gallego-Bustos, F Gotea, V Ramos-Amador, JT Rodriguez-Pena, R Gil-Herrera, J Sastre, A Delmiro, A Rai, G Elnitski, L Gonzalez-Granado, LI Allende, LM AF Gallego-Bustos, Fernando Gotea, Valer Ramos-Amador, Jose T. Rodriguez-Pena, Rebeca Gil-Herrera, Juana Sastre, Ana Delmiro, Aitor Rai, Ghadi Elnitski, Laura Gonzalez-Granado, Luis I. Allende, Luis M. TI A Case of IL-7R Deficiency Caused by a Novel Synonymous Mutation and Implications for Mutation Screening in SCID Diagnosis SO FRONTIERS IN IMMUNOLOGY LA English DT Article DE IL-7R; primary immunodeficiency; SCID; splicing; synonymous substitutions ID SEVERE COMBINED IMMUNODEFICIENCY; TRANSPLANTATION AB Reported synonymous substitutions are generally non-pathogenic, and rare pathogenic synonymous variants may be disregarded unless there is a high index of suspicion. In a case of IL7 receptor deficiency severe combined immunodeficiency (SCID), the relevance of a non-reported synonymous variant was only suspected through the use of additional in silico computational tools, which focused on the impact of mutations on gene splicing. The pathogenic nature of the variant was confirmed using experimental validation of the effect on mRNA splicing and IL7 pathway function. This case reinforces the need to use additional experimental methods to establish the functional impact of specific mutations, in particular for cases such as SCID where prompt diagnosis can greatly impact on diagnosis, treatment, and survival. C1 [Gallego-Bustos, Fernando; Allende, Luis M.] Hosp Univ 12 Octubre, Serv Inmunol, Madrid, Spain. [Gotea, Valer; Elnitski, Laura] NHGRI, Translat & Funct Genom Branch, NIH, Rockville, MD USA. [Ramos-Amador, Jose T.] Hosp Univ Clin, Serv Pediat, Madrid, Spain. [Rodriguez-Pena, Rebeca] Hosp Univ La Paz, Unidad Inmunol, Madrid, Spain. [Gil-Herrera, Juana] Univ Hosp, Serv Inmunol, Madrid, Spain. [Gil-Herrera, Juana] Inst Invest Sanitaria Gregorio Maranon, Madrid, Spain. [Sastre, Ana] Hosp Univ La Paz, Serv Hematol Oncol, Madrid, Spain. [Delmiro, Aitor; Gonzalez-Granado, Luis I.; Allende, Luis M.] Inst Invest I 12, Madrid, Spain. [Rai, Ghadi] Aix Marseille Univ, GMGF, Marseille, France. [Rai, Ghadi] INSERM, UMR S 910, Marseille, France. [Gonzalez-Granado, Luis I.] Hosp Univ 12 Octubre, Unidad Inmunodeficiencias, Pediat, Madrid, Spain. RP Allende, LM (reprint author), Hosp Univ 12 Octubre, Serv Inmunol, Madrid, Spain.; Allende, LM (reprint author), Inst Invest I 12, Madrid, Spain. EM luis.allende@salud.madrid.org OI Gotea, Valer/0000-0001-7857-3309 FU Spanish Health Research Fund [FIS PI11/1591, FIS PI16/2053, PI16/0044]; Intramural Research Program of the National Human Genome Research Institute; FEDER funds FX This research was supported by grants from the Spanish Health Research Fund FIS PI11/1591 and FIS PI16/2053 to LA, PI16/0044 to LG-G and by the Intramural Research Program of the National Human Genome Research Institute (VG and LE). The project has been co-financed with FEDER funds. NR 9 TC 0 Z9 0 U1 0 U2 0 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PD OCT 27 PY 2016 VL 7 AR 443 DI 10.3389/fimmu.2016.00443 PG 7 WC Immunology SC Immunology GA EA1YI UT WOS:000386387700001 PM 27833609 ER PT J AU Aitken, CE Beznoskova, P Vlckova, V Chiu, WL Zhou, FJ Valasek, LS Hinnebusch, AG Lorsch, JR AF Aitken, Colin Echeverria Beznoskova, Petra Vlckova, Vladislava Chiu, Wen-Ling Zhou, Fujun Valasek, Leos Shivaya Hinnebusch, Alan G. Lorsch, Jon R. TI Eukaryotic translation initiation factor 3 plays distinct roles at the mRNA entry and exit channels of the ribosomal preinitiation complex SO ELIFE LA English DT Article ID START-CODON RECOGNITION; SACCHAROMYCES-CEREVISIAE; IN-VIVO; AUG RECOGNITION; MULTIFACTOR COMPLEX; PROTEIN-SYNTHESIS; TERMINAL DOMAIN; 40S SUBUNITS; FACTOR EIF3; PCI DOMAIN AB Eukaryotic translation initiation factor 3 (eIF3) is a central player in recruitment of the pre-initiation complex (PIC) to mRNA. We probed the effects on mRNA recruitment of a library of S. cerevisiae eIF3 functional variants spanning its 5 essential subunits using an in vitro-reconstituted system. Mutations throughout eIF3 disrupt its interaction with the PIC and diminish its ability to accelerate recruitment to a native yeast mRNA. Alterations to the eIF3a CTD and eIF3b/i/g significantly slow mRNA recruitment, and mutations within eIF3b/i/g destabilize eIF2.GTP.Met-tRNA(i) binding to the PIC. Using model mRNAs lacking contacts with the 40S entry or exit channels, we uncovered a critical role for eIF3 requiring the eIF3a NTD, in stabilizing mRNA interactions at the exit channel, and an ancillary role at the entry channel requiring residues of the eIF3a CTD. These functions are redundant: defects at each channel can be rescued by filling the other channel with mRNA C1 [Aitken, Colin Echeverria; Zhou, Fujun; Lorsch, Jon R.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Mech & Regulat Prot Synth, NIH, Bethesda, MD USA. [Beznoskova, Petra; Vlckova, Vladislava; Valasek, Leos Shivaya] Inst Microbiol ASCR, Lab Regulat Gene Express, Prague, Czech Republic. [Chiu, Wen-Ling; Hinnebusch, Alan G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Gene Regulat & Dev, NIH, Bethesda, MD USA. RP Lorsch, JR (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Mech & Regulat Prot Synth, NIH, Bethesda, MD USA.; Valasek, LS (reprint author), Inst Microbiol ASCR, Lab Regulat Gene Express, Prague, Czech Republic.; Hinnebusch, AG (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Gene Regulat & Dev, NIH, Bethesda, MD USA. EM valasekl@biomed.cas.cz; ahinnebusch@nih.gov; jon.lorsch@nih.gov FU National Institutes of Health [Intramural Research Program, GM62128]; Leukemia and Lymphoma Society [5199-12]; Wellcome Trust [090812/13/09/Z]; Centrum of Excellence of the Czech Science Foundation [P305/12/G034] FX National Institutes of Health Intramural Research Program Colin Echeverria Aitken Wen-Ling Chiu Fujun Zhou Alan G Hinnebusch Jon R Lorsch; Leukemia and Lymphoma Society 5199-12 Colin Echeverria Aitken; Wellcome Trust 090812/13/09/Z Leos Shivaya Valasek; Centrum of Excellence of the Czech Science Foundation P305/12/G034 Leos Shivaya Valasek; National Institutes of Health GM62128 Jon R Lorsch NR 68 TC 2 Z9 2 U1 4 U2 4 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD OCT 26 PY 2016 VL 5 AR e20934 DI 10.7554/eLife.20934 PG 37 WC Biology SC Life Sciences & Biomedicine - Other Topics GA EG1PQ UT WOS:000390805100001 ER PT J AU Pommier, Y O'Connor, MJ de Bono, J AF Pommier, Yves O'Connor, Mark J. de Bono, Johann TI Laying a trap to kill cancer cells: PARP inhibitors and their mechanisms of action SO Science Translational Medicine LA English DT Article ID DNA TOPOISOMERASE-I; RIBOSE POLYMERASE INHIBITORS; PROTEIN ADP-RIBOSYLATION; NEGATIVE BREAST-CANCER; DOUBLE-STRAND BREAK; POLY(ADP-RIBOSE) POLYMERASE; HOMOLOGOUS-RECOMBINATION; SYNTHETIC LETHALITY; CATALYTIC INHIBITION; DAMAGE RESPONSE AB Poly(ADP-ribose) polymerase (PARP) inhibitors are the first DNA damage response targeted agents approved for cancer therapy. Here, we focus on their molecular mechanism of action by PARP "trapping" and what this means for both clinical monotherapy and combination with chemotherapeutic agents. C1 [Pommier, Yves] NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. [Pommier, Yves] NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [O'Connor, Mark J.] AstraZeneca, Oncol IMED, DNA Damage Response Biol, Hodgkin Bldg,B900 Chesterford Res Pk, Cambridge CB10 1XL, England. [de Bono, Johann] Inst Canc Res, Drug Dev Unit, London SM2 5PT, England. [de Bono, Johann] Royal Marsden Natl Hlth Serv Fdn Trust, London SM2 5PT, England. RP Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA.; Pommier, Y (reprint author), NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM pommier@nih.gov FU Institute of Cancer Research/Royal Marsden Drug Development Unit through an Experimental Cancer Medical Centre (ECMC) grant from Cancer Research U.K.; Department of Health [C51/A7401]; NHS FX J.d.B. acknowledges support from the Institute of Cancer Research/Royal Marsden Drug Development Unit through an Experimental Cancer Medical Centre (ECMC) grant from Cancer Research U.K. and the Department of Health (C51/A7401) and NHS funding to the National Institute for Health Research Biomedical Research Centre to the Royal Marsden. NR 77 TC 1 Z9 1 U1 10 U2 10 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD OCT 26 PY 2016 VL 8 IS 362 AR 362ps17 DI 10.1126/scitranslmed.aaf9246 PG 7 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA EE2VJ UT WOS:000389442900001 PM 27797957 ER PT J AU Siriwardena, SU Chen, K Bhagwat, AS AF Siriwardena, Sachini U. Chen, Kang Bhagwat, Ashok S. TI Functions and Malfunctions of Mammalian DNA-Cytosine Deaminases SO CHEMICAL REVIEWS LA English DT Review ID INDUCED CYTIDINE DEAMINASE; B MESSENGER-RNA; CLASS-SWITCH RECOMBINATION; SINGLE-STRANDED-DNA; ACTIVATION-INDUCED DEAMINASE; HUMAN-IMMUNODEFICIENCY-VIRUS; INDUCED DEOXYCYTIDINE DEAMINASE; NF-KAPPA-B; ANTIBODY SOMATIC HYPERMUTATION; HIV-1 REVERSE TRANSCRIPTION AB The AID/APOBEC family enzymes convert cytosines in single-stranded DNA to uracils, causing base substitutions and strand breaks. They are induced by cytokines produced during the body's inflammatory response to infections, and they help combat infections through diverse mechanisms. AID is essential for the maturation of antibodies and causes mutations and deletions in antibody genes through somatic hypermutation (SHM) and class-switch recombination (CSR) processes. One member of the APOBEC family, APOBEC1, edits mRNA for a protein involved in lipid transport. Members of the APOBEC3 subfamily in humans (APOBEC3A, APOBEC3B, APOBEC3C, APOBEC3D, APOBEC3F, APOBEC3G, and APOBEC3H) inhibit infections of viruses such as HIV-1, HBV, and HCV, and retrotransposition of endogenous retroelements through mutagenic and nonmutagenic mechanisms. There is emerging consensus that these enzymes can cause mutations in the cellular genome at replication forks or within transcription bubbles depending on the physiological state of the cell and the phase of the cell cycle during which they are expressed. We describe here the state of knowledge about the structures of these enzymes, regulation of their expression, and both the advantageous and deleterious consequences of their expression, including carcinogenesis. We highlight similarities among them and present a holistic view of their regulation and function. C1 [Siriwardena, Sachini U.; Bhagwat, Ashok S.] Wayne State Univ, Dept Chem, Detroit, MI 48202 USA. [Chen, Kang] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Chen, Kang] NIAID, Mucosal Immunol Studies Team, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Chen, Kang; Bhagwat, Ashok S.] Wayne State Univ, Sch Med, Dept Immunol & Microbiol, Detroit, MI 48201 USA. RP Bhagwat, AS (reprint author), Wayne State Univ, Dept Chem, Detroit, MI 48202 USA.; Bhagwat, AS (reprint author), Wayne State Univ, Sch Med, Dept Immunol & Microbiol, Detroit, MI 48201 USA. EM axb@chem.wayne.edu FU National Institutes of Health [GM 57200, U01AI95776, R21AI122256, P30CA22453]; Wayne State University office of Vice-President for research; Burroughs Wellcome Fund; American Congress of Obstetricians and Gynecologists; Wayne State University Maternal Health Initiative; Wayne State University Perinatal Health Initiative; Wayne State University Child Health Initiative FX Molecular graphics were generated using the UCSF Chimera package. We would like to thank Shanqiao Wei and Jessica Stewart (Wayne State University) for help with a figure and Thomas Holland (Wayne State University) for comments on the manuscript. The research at the Bhagwat laboratory was supported by National Institutes of Health grant, GM 57200, and by funds from the Wayne State University office of Vice-President for research. Research in the Chen laboratory was supported by grants from the National Institutes of Health (U01AI95776 Young Investigator Award, R21AI122256, and Grant P30CA22453), the Burroughs Wellcome Fund, American Congress of Obstetricians and Gynecologists, and Wayne State University Maternal, Perinatal and Child Health Initiative. NR 341 TC 2 Z9 2 U1 10 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0009-2665 EI 1520-6890 J9 CHEM REV JI Chem. Rev. PD OCT 26 PY 2016 VL 116 IS 20 BP 12688 EP 12710 DI 10.1021/acs.chemrev.6b00296 PG 23 WC Chemistry, Multidisciplinary SC Chemistry GA EA3WX UT WOS:000386541100003 PM 27585283 ER PT J AU Hickman, AB Dyda, F AF Hickman, Alison B. Dyda, Fred TI DNA Transposition at Work SO CHEMICAL REVIEWS LA English DT Review ID SLEEPING-BEAUTY TRANSPOSON; PLURIPOTENT STEM-CELLS; ROLLING-CIRCLE TRANSPOSONS; BACTERIAL INSERTION SEQUENCES; SITE-SPECIFIC RECOMBINATION; INVERTED TERMINAL REPEATS; GRAM-NEGATIVE BACTERIA; IN-VITRO TRANSPOSITION; MEDIATED GENE-TRANSFER; P-ELEMENT TRANSPOSASE AB DNA transposons are defined segments of DNA that are able to move from one genomic location to another. Movement is facilitated by one or more proteins, called the transposase, typically encoded by the mobile element itself. Here, we first provide an overview of the classification of such mobile elements in a variety of organisms. From a mechanistic perspective, we have focused on one particular group of DNA transposons that encode a transposase with a DD(E/D) catalytic domain that is topologically similar to RNase H. For these, a number of three-dimensional structures of transpososomes (transposase nucleic acid complexes) are available, and we use these to describe the basics of their mechanisms. The DD(E/D) group, in addition to being the largest and most common among all DNA transposases, is the one whose members have been used for a wide variety of genomic applications. Therefore, a second focus of the article is to provide a nonexhaustive overview of transposon applications. Although several non-transposon-based approaches to site-directed genome modifications have emerged in the past decade, transposon-based applications are highly relevant when integration specificity is not sought. In fact, for many applications, the almost-perfect randomness and high frequency of integration make transposon-based approaches indispensable. C1 [Hickman, Alison B.; Dyda, Fred] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Dyda, F (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM fred.dyda@nih.gov FU Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH FX We apologize to all of those colleagues whose work we have not cited. We thank Drs. Ivana Grabundzija, Susu He, and Shweta Kailasan for helpful comments on the manuscript. This work was supported by the Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH. NR 326 TC 1 Z9 1 U1 15 U2 15 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0009-2665 EI 1520-6890 J9 CHEM REV JI Chem. Rev. PD OCT 26 PY 2016 VL 116 IS 20 BP 12758 EP 12784 DI 10.1021/acs.chemrev.6b00003 PG 27 WC Chemistry, Multidisciplinary SC Chemistry GA EA3WX UT WOS:000386541100006 PM 27187082 ER PT J AU Bowen, LN Tyagi, R Li, WX Alfahad, T Smith, B Wright, M Singer, EJ Nath, A AF Bowen, Lauren N. Tyagi, Richa Li, Wenxue Alfahad, Tariq Smith, Bryan Wright, Mary Singer, Elyse J. Nath, Avindra TI HIV-associated motor neuron disease HERV-K activation and response to antiretroviral therapy SO NEUROLOGY LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; HUMAN ENDOGENOUS RETROVIRUSES; CENTRAL-NERVOUS-SYSTEM; REVERSE-TRANSCRIPTASE; PENETRATION-EFFECTIVENESS; VACUOLAR MYELOPATHY; ALS; INFECTION; TAT; IMPAIRMENT AB Objective: To determine whether there is activation of human endogenous retrovirus K (HERV-K) in amyotrophic lateral sclerosis in HIV infection and whether it might respond to treatment with antiretroviral drugs. Methods: In this case series, we present 5 patients with HIV infection who subsequently developed motor neuron disease involving both upper and lower motor neurons. We monitored HERV-K levels in plasma of 4 of these patients. Results: Three patients who received antiretroviral therapy had reversal of symptoms within 6 months of onset of neurologic symptoms and the other 2 had slow neurologic progression over several years. Three patients in whom the levels were measured at onset of neurologic symptoms showed elevated HERV-K levels that responded to optimization of antiretroviral therapy for CNS penetration. Conclusions: Thus, motor neuron disease in individuals with HIV infection may a treatable entity, but early treatment with CNS-penetrating antiretroviral therapy may be necessary. Monitoring of HERV-K levels may help guide treatment. C1 [Bowen, Lauren N.; Tyagi, Richa; Li, Wenxue; Alfahad, Tariq; Smith, Bryan; Nath, Avindra] NINDS, Sect Infect Nervous Syst, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Wright, Mary] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Singer, Elyse J.] Univ Calif Los Angeles, Natl Neurol AIDS Bank, Los Angeles, CA USA. [Singer, Elyse J.] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA. RP Nath, A (reprint author), NINDS, Sect Infect Nervous Syst, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM natha@ninds.nih.gov FU NIH FX Supported by NIH Intramural Funds. NR 32 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD OCT 25 PY 2016 VL 87 IS 17 BP 1756 EP 1762 DI 10.1212/WNL.0000000000003258 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA EI1IZ UT WOS:000392231800012 PM 27664983 ER PT J AU Hampras, SS Sucheston-Campbell, LE Cannioto, R Chang-Claude, J Modugno, F Dork, T Hillemanns, P Preus, L Knutson, KL Wallace, PK Hong, CC Friel, G Davis, W Nesline, M Pearce, CL Kelemen, LE Goodman, MT Bandera, EV Terry, KL Schoof, N Eng, KH Clay, A Singh, PK Joseph, JM Aben, KKH Anton-Culver, H Antonenkova, N Baker, H Bean, Y Beckmann, MW Bisogna, M Bjorge, L Bogdanova, N Brinton, LA Brooks-Wilson, A Bruinsma, F Butzow, R Campbell, IG Carty, K Cook, LS Cramer, DW Cybulski, C Dansonka-Mieszkowska, A Dennis, J Despierre, E Dicks, E Doherty, JA du Bois, A Durst, M Easton, D Eccles, D Edwards, RP Ekici, AB Fasching, PA Fridley, BL Gao, YT Gentry-Maharaj, A Giles, GG Glasspool, R Gronwald, J Harrington, P Harter, P Hasmad, HN Hein, A Heitz, F Hildebrandt, MAT Hogdall, C Hogdall, E Hosono, S Iversen, ES Jakubowska, A Jensen, A Ji, BT Karlan, BY Kellar, M Kelley, JL Kiemeney, LA Klapdor, R Kolomeyevskaya, N Krakstad, C Kjaer, SK Kruszka, B Kupryjanczyk, J Lambrechts, D Lambrechts, S Le, ND Lee, AW Lele, S Leminen, A Lester, J Levine, DA Liang, D Lissowska, J Liu, S Lu, KR Lubinski, J Lundvall, L Massuger, LFAG Matsuo, K McGuire, V McLaughlin, JR McNeish, I Menon, U Moes-Sosnowska, J Narod, SA Nedergaard, L Nevanlinna, H Nickels, S Olson, SH Orlow, I Weber, RP Paul, J Pejovic, T Pelttari, LM Perkins, B Permuth-Wey, J Pike, MC Plisiecka-Halasa, J Poole, EM Risch, HA Rossing, MA Rothstein, JH Rudolph, A Runnebaum, IB Rzepecka, IK Salvesen, HB Schernhammer, E Schmitt, K Schwaab, I Shu, XO Shvetsov, YB Siddiqui, N Sieh, W Song, HL Southey, MC Tangen, IL Teo, SH Thompson, PJ Timorek, A Tsai, YY Tworoger, SS Tyrer, J van Altena, AM Vergote, I Vierkant, RA Walsh, C Wang-Gohrke, S Wentzensen, N Whittemore, AS Wicklund, KG Wilkens, LR Wu, AH Wu, XF Woo, YL Yang, H Zheng, W Ziogas, A Gayther, SA Ramus, SJ Sellers, TA Schildkraut, JM Phelan, CM Berchuck, A Chenevix-Trench, G Cunningham, JM Pharoah, PP Ness, RB Odunsi, K Goode, EL Moysich, KB AF Hampras, Shalaka S. Sucheston-Campbell, Lara E. Cannioto, Rikki Chang-Claude, Jenny Modugno, Francesmary Doerk, Thilo Hillemanns, Peter Preus, Leah Knutson, Keith L. Wallace, Paul K. Hong, Chi-Chen Friel, Grace Davis, Warren Nesline, Mary Pearce, Celeste L. Kelemen, Linda E. Goodman, Marc T. Bandera, Elisa V. Terry, Kathryn L. Schoof, Nils Eng, Kevin H. Clay, Alyssa Singh, Prashant K. Joseph, Janine M. Aben, Katja K. H. Anton-Culver, Hoda Antonenkova, Natalia Baker, Helen Bean, Yukie Beckmann, Matthias W. Bisogna, Maria Bjorge, Line Bogdanova, Natalia Brinton, Louise A. Brooks-Wilson, Angela Bruinsma, Fiona Butzow, Ralf Campbell, Ian G. Carty, Karen Cook, Linda S. Cramer, Daniel W. Cybulski, Cezary Dansonka-Mieszkowska, Agnieszka Dennis, Joe Despierre, Evelyn Dicks, Ed Doherty, Jennifer A. du Bois, Andreas Duerst, Matthias Easton, Doug Eccles, Diana Edwards, Robert P. Ekici, Arif B. Fasching, Peter A. Fridley, Brooke L. Gao, Yu-Tang Gentry-Maharaj, Aleksandra Giles, Graham G. Glasspool, Rosalind Gronwald, Jacek Harrington, Patricia Harter, Philipp Hasmad, Hanis Nazihah Hein, Alexander Heitz, Florian Hildebrandt, Michelle A. T. Hogdall, Claus Hogdall, Estrid Hosono, Satoyo Iversen, Edwin S. Jakubowska, Anna Jensen, Allan Ji, Bu-Tian Karlan, Beth Y. Kellar, Melissa Kelley, Joseph L. Kiemeney, Lambertus A. Klapdor, Ruediger Kolomeyevskaya, Nonna Krakstad, Camilla Kjaer, Susanne K. Kruszka, Bridget Kupryjanczyk, Jolanta Lambrechts, Diether Lambrechts, Sandrina Le, Nhu D. Lee, Alice W. Lele, Shashikant Leminen, Arto Lester, Jenny Levine, Douglas A. Liang, Dong Lissowska, Jolanta Liu, Song Lu, Karen Lubinski, Jan Lundvall, Lene Massuger, Leon F. A. G. Matsuo, Keitaro McGuire, Valeria McLaughlin, John R. McNeish, Ian Menon, Usha Moes-Sosnowska, Joanna Narod, Steven A. Nedergaard, Lotte Nevanlinna, Heli Nickels, Stefan Olson, Sara H. Orlow, Irene Weber, Rachel Palmieri Paul, James Pejovic, Tanja Pelttari, Liisa M. Perkins, Barbara Permuth-Wey, Jenny Pike, Malcolm C. Plisiecka-Halasa, Joanna Poole, Elizabeth M. Risch, Harvey A. Rossing, Mary Anne Rothstein, Joseph H. Rudolph, Anja Runnebaum, Ingo B. Rzepecka, Iwona K. Salvesen, Helga B. Schernhammer, Eva Schmitt, Kristina Schwaab, Ira Shu, Xiao-Ou Shvetsov, Yurii B. Siddiqui, Nadeem Sieh, Weiva Song, Honglin Southey, Melissa C. Tangen, Ingvild L. Teo, Soo-Hwang Thompson, Pamela J. Timorek, Agnieszka Tsai, Ya-Yu Tworoger, Shelley S. Tyrer, Jonathan van Altena, Anna M. Vergote, Ignace Vierkant, Robert A. Walsh, Christine Wang-Gohrke, Shan Wentzensen, Nicolas Whittemore, Alice S. Wicklund, Kristine G. Wilkens, Lynne R. Wu, Anna H. Wu, Xifeng Woo, Yin-Ling Yang, Hannah Zheng, Wei Ziogas, Argyrios Gayther, Simon A. Ramus, Susan J. Sellers, Thomas A. Schildkraut, Joellen M. Phelan, Catherine M. Berchuck, Andrew Chenevix-Trench, Georgia Cunningham, Julie M. Pharoah, Paul P. Ness, Roberta B. Odunsi, Kunle Goode, Ellen L. Moysich, Kirsten B. CA Australian Ovarian Canc Study Grp TI Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer SO ONCOTARGET LA English DT Article DE ovarian cancer; immunosuppression; biomarkers; genetic variation; TGFBR2 ID REGULATORY T-CELLS; FC-GAMMA-RIIB; PERIPHERAL-BLOOD; BREAST-CANCER; DENDRITIC CELLS; LUNG-CANCER; RECEPTOR; STAGE; EXPRESSION; CARCINOMA AB Background: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer. Methods: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients. Results: The most significant global associations for all genes in the pathway were seen in endometrioid (p = 0.082) and clear cell (p = 0.083), with the most significant gene level association seen with TGFBR2 (p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 (p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA (p = 0.035, endometrioid and mucinous), LGALS1 (p = 0.03, mucinous), STAT5B (p = 0.022, clear cell), TGFBR1 (p = 0.021 endometrioid) and TGFBR2 (p = 0.017 and p = 0.025, endometrioid and mucinous, respectively). Conclusions: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients. C1 [Hampras, Shalaka S.; Permuth-Wey, Jenny; Tsai, Ya-Yu; Sellers, Thomas A.; Phelan, Catherine M.] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL 33612 USA. [Sucheston-Campbell, Lara E.] Ohio State Univ, Coll Pharm, 500 W 12th Ave, Columbus, OH 43210 USA. [Sucheston-Campbell, Lara E.] Ohio State Univ, Coll Vet Med, Dept Vet Biosci, Columbus, OH 43210 USA. [Cannioto, Rikki; Preus, Leah; Hong, Chi-Chen; Friel, Grace; Davis, Warren; Clay, Alyssa; Singh, Prashant K.; Joseph, Janine M.; Kruszka, Bridget; Schmitt, Kristina; Moysich, Kirsten B.] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Chang-Claude, Jenny; Nickels, Stefan; Rudolph, Anja; Wang-Gohrke, Shan] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Modugno, Francesmary] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Modugno, Francesmary] Univ Pittsburgh, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA 15261 USA. [Modugno, Francesmary] Magee Womens Res Inst, Womens Canc Res Program, Pittsburgh, PA USA. [Modugno, Francesmary] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Doerk, Thilo; Bogdanova, Natalia; Klapdor, Ruediger] Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany. [Hillemanns, Peter] Hannover Med Sch, Clin Obstet & Gynaecol, Hannover, Germany. [Knutson, Keith L.] Mayo Clin, Dept Immunol, Rochester, MN USA. [Wallace, Paul K.] Roswell Pk Canc Inst, Dept Flow & Image Cytometry, Buffalo, NY 14263 USA. [Nesline, Mary] Roswell Pk Canc Inst, Ctr Personalized Med, Buffalo, NY 14263 USA. [Pearce, Celeste L.; Lee, Alice W.; Pike, Malcolm C.; Wu, Anna H.; Gayther, Simon A.; Ramus, Susan J.] Univ Southern Calif, Norris Comprehens Canc Ctr, Dept Prevent Med, Keck Sch Med, Los Angeles, CA USA. [Kelemen, Linda E.] Alberta Hlth Serv Canc Care, Dept Populat Hlth Res, Calgary, AB, Canada. [Goodman, Marc T.; Thompson, Pamela J.] Cedars Sinai Med Ctr, Canc Prevent & Control, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 USA. [Bandera, Elisa V.] Rutgers Canc Inst New Jersey, Canc Prevent & Control, New Brunswick, NJ USA. [Terry, Kathryn L.; Cramer, Daniel W.] Brigham & Womens Hosp, Obstet & Gynecol Ctr, 75 Francis St, Boston, MA 02115 USA. [Terry, Kathryn L.; Cramer, Daniel W.; Poole, Elizabeth M.; Tworoger, Shelley S.] Harvard Med Sch, Boston, MA USA. [Schoof, Nils] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Eng, Kevin H.; Liu, Song] Roswell Pk Canc Inst, Dept Biostat & Bioinformat, Buffalo, NY 14263 USA. [Aben, Katja K. H.; Kiemeney, Lambertus A.] Radboud Univ Nijmegen, Med Ctr, Dept Hlth Evidence, Nijmegen, Netherlands. [Anton-Culver, Hoda; Ziogas, Argyrios] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA. [Anton-Culver, Hoda; Ziogas, Argyrios] Univ Calif Irvine, Sch Med, Irvine, CA USA. [Antonenkova, Natalia] Byelorussian Inst Oncol & Med Radiol Aleksandrov, Minsk, Byelarus. [Baker, Helen; Dennis, Joe; Dicks, Ed; Harrington, Patricia; Pejovic, Tanja; Perkins, Barbara; Song, Honglin; Tyrer, Jonathan] Univ Cambridge, Strangeways Res Lab, Dept Oncol, Cambridge, England. [Bean, Yukie; Kellar, Melissa] Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Portland, OR 97201 USA. [Bean, Yukie; Kellar, Melissa] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. [Beckmann, Matthias W.; Hein, Alexander] Friedrich Alexander Univ Erlangen Nuremberg, Univ Hosp Erlangen, Dept Gynecol & Obstet, Erlangen, Germany. [Bisogna, Maria; Levine, Douglas A.] Mem Sloan Kettering Canc Ctr, Dept Surg, Gynecol Serv, New York, NY 10021 USA. [Bjorge, Line; Krakstad, Camilla; Salvesen, Helga B.; Tangen, Ingvild L.] Haukeland Hosp, Dept Gynecol & Obstet, Bergen, Norway. [Brinton, Louise A.; Ji, Bu-Tian; Wentzensen, Nicolas; Yang, Hannah] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Brooks-Wilson, Angela] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC, Canada. [Bruinsma, Fiona; Giles, Graham G.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Butzow, Ralf; Leminen, Arto; Nevanlinna, Heli; Pelttari, Liisa M.] Univ Helsinki, Dept Obstet & Gynecol, Helsinki, Finland. [Butzow, Ralf; Leminen, Arto; Nevanlinna, Heli; Pelttari, Liisa M.] Univ Helsinki, Cent Hosp, Helsinki, Finland. [Campbell, Ian G.] Peter MacCallum Canc Ctr, Div Res, Canc Genet Lab, St Andrews Pl, East Melbourne, Australia. [Carty, Karen; Glasspool, Rosalind; Paul, James] Univ Glasgow, Canc Res UK Clin Trials Unit, Beatson West Scotland Canc Ctr, Glasgow, Lanark, Scotland. [Cook, Linda S.] Univ New Mexico, Div Epidemiol & Biostat, Dept Internal Med, Albuquerque, NM 87131 USA. [Cybulski, Cezary] Pomeranian Med Univ, Int Hereditary Canc Ctr, Dept Genet & Pathol, Clin Opthalmol, Szczecin, Poland. [Dansonka-Mieszkowska, Agnieszka; Kupryjanczyk, Jolanta; Moes-Sosnowska, Joanna; Plisiecka-Halasa, Joanna; Rzepecka, Iwona K.] Maria Sklodowska Curie Mem Canc Ctr & Inst Oncol, Dept Pathol & Labolatory Diagnost, Warsaw, Poland. [Despierre, Evelyn; Lambrechts, Diether; Vergote, Ignace] Univ Hosp Leuven, Div Gynecol Oncol, Dept Oncol, Leuven, Belgium. [Doherty, Jennifer A.] Geisel Sch Med Dartmouth, Epidemiol & Biostat Sect, Dept Community & Family Med, Hanover, NH USA. [du Bois, Andreas; Harter, Philipp; Heitz, Florian] Knappschaft GmbH, Evang Huyssens Stiftung, Kliniken Essen Mitte, Dept Gynecol & Gynecol Oncol, Essen, Germany. [Duerst, Matthias; Runnebaum, Ingo B.] Friedrich Schiller Univ, Jena Univ Hosp, Dept Gynecol, Jena, Germany. [Easton, Doug; Pharoah, Paul P.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Eccles, Diana] Princess Anne Hosp, Wessex Clin Genet Serv, Southampton, Hants, England. [Edwards, Robert P.] Univ Pittsburgh, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA. [Edwards, Robert P.] Univ Pittsburgh, Ovarian Canc Ctr Excellence, Pittsburgh, PA USA. [Ekici, Arif B.] Friedrich Alexander Univ Erlangen Nuremberg, Univ Hosp Erlangen, Inst Human Genet, Erlangen, Germany. [Fasching, Peter A.] Univ Calif Los Angeles, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90024 USA. [Fridley, Brooke L.] Univ Kansas, Med Ctr, Dept Biostat, Kansas City, KS 66103 USA. [Gao, Yu-Tang] Shanghai Canc Inst, Shanghai, Peoples R China. [Gentry-Maharaj, Aleksandra] UCL, Inst Womens Hlth, Populat Hlth Sci, London, England. [Giles, Graham G.; Lubinski, Jan] Univ Melbourne, Ctr Epidemiol & Biostat, Melbourne Sch Populat & Global Hlth, Melbourne, Vic 3010, Australia. [Gronwald, Jacek; Jakubowska, Anna] Pomeranian Med Univ, Dept Genet & Pathol, Int Hereditary Canc Ctr, Szczecin, Poland. [Hasmad, Hanis Nazihah; Teo, Soo-Hwang] Canc Res Initiat Fdn, Sime Darby Med Ctr, Subang Jaya, Malaysia. [Hildebrandt, Michelle A. T.; Wu, Xifeng] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Hogdall, Claus; Kjaer, Susanne K.; Lundvall, Lene] Univ Copenhagen, Dept Gynaecol, Rigshosp, Copenhagen, Denmark. [Hogdall, Estrid] Danish Canc Soc, Inst Canc Epidemiol, Copenhagen, Denmark. [Hosono, Satoyo; Matsuo, Keitaro] Aichi Canc Ctr, Res Inst, Div Epidemiol & Prevent, Nagoya, Aichi, Japan. [Iversen, Edwin S.] Duke Univ, Dept Stat Sci, Durham, NC USA. [Jensen, Allan; Kjaer, Susanne K.] Danish Canc Soc, Res Ctr, Dept Virus Lifestyle & Genes, Copenhagen, Denmark. [Karlan, Beth Y.; Lester, Jenny; Walsh, Christine] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Los Angeles, CA 90048 USA. [Kelley, Joseph L.] Univ Pittsburgh, Dept Obstet Gynecol & Reprod Sci, Sch Med, Pittsburgh, PA USA. [Kolomeyevskaya, Nonna; Lele, Shashikant; Odunsi, Kunle] Roswell Pk Canc Inst, Div Gynecol Oncol, Buffalo, NY 14263 USA. [Lambrechts, Diether] VIB, Vesalius Res Ctr, Leuven, Belgium. [Lambrechts, Diether] Univ Leuven, Dept Oncol, Lab Translat Genet, Leuven, Belgium. [Le, Nhu D.] BC Canc Agcy, Canc Control Res, Vancouver, BC, Canada. [Liang, Dong] Texas Southern Univ, Coll Pharm & Hlth Sci, Houston, TX USA. [Lissowska, Jolanta; Lu, Karen] M Sklodowska Curie Mem Canc Ctr & Inst Oncol, Dept Canc Epidemiol & Prevent, Warsaw, Poland. Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA. [Massuger, Leon F. A. G.; van Altena, Anna M.] Radboud Univ Nijmegen, Med Ctr, Dept Gynaecol, Nijmegen, Netherlands. [McGuire, Valeria; Rothstein, Joseph H.; Sieh, Weiva; Whittemore, Alice S.] Stanford Univ, Sch Med, Dept Hlth Res & Policy Epidemiol, Stanford, CA USA. [McLaughlin, John R.] Mt Sinai Hosp, Prosserman Ctr Hlth Res, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada. [McNeish, Ian] Univ Glasgow, Inst Canc Sci, Glasgow, Lanark, Scotland. [Menon, Usha] UCL EGA Inst Womens Hlth, Womens Canc, London, England. [Narod, Steven A.] Womens Coll Res Inst, Toronto, ON, Canada. [Nedergaard, Lotte] Univ Copenhagen, Rigshosp, Dept Pathol, DK-1168 Copenhagen, Denmark. [Olson, Sara H.; Orlow, Irene; Pike, Malcolm C.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, 1275 York Ave, New York, NY 10021 USA. [Weber, Rachel Palmieri; Schernhammer, Eva; Schildkraut, Joellen M.] Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC 27710 USA. [Poole, Elizabeth M.; Tworoger, Shelley S.] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Risch, Harvey A.] Yale Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT USA. [Rossing, Mary Anne; Wicklund, Kristine G.] Fred Hutchinson Canc Res Ctr, Program Epidemiol, Seattle, WA 98104 USA. [Schwaab, Ira] Inst Humangenet Wiesbaden, Wiesbaden, Germany. [Shu, Xiao-Ou; Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, Nashville, TN 37212 USA. [Shvetsov, Yurii B.; Wilkens, Lynne R.] Univ Hawaii, Ctr Canc, Canc Epidemiol Program, Honolulu, HI 96822 USA. [Siddiqui, Nadeem] Glasgow Royal Infirm, Dept Gynaecol Oncol, Glasgow, Lanark, Scotland. [Southey, Melissa C.] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia. [Timorek, Agnieszka] Med Univ Warsaw, Dept Obstet Gynecol & Oncol, Warsaw, Poland. [Timorek, Agnieszka] Brodnowski Hosp, Warsaw, Poland. [Vierkant, Robert A.] Mayo Clin, Dept Hlth Sci Res, Div Biomed Stat & Informat, Rochester, MN USA. [Woo, Yin-Ling] Univ Malaya, UM Canc Res Inst, Dept Obstet & Gynaecol, Fac Med, Kuala Lumpur, Malaysia. [Berchuck, Andrew] Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC 27710 USA. [Chenevix-Trench, Georgia] QIMR Berghofer Med Res Inst, Canc Div, Brisbane, Qld, Australia. [Cunningham, Julie M.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Ness, Roberta B.] Univ Texas Houston, Sch Publ Hlth, Houston, TX USA. [Goode, Ellen L.] Mayo Clin, Div Epidemiol, Dept Hlth Sci Res, Rochester, MN USA. RP Moysich, KB (reprint author), Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. EM Kirsten.moysich@roswellpark.org RI Hein, Alexander/F-6999-2010; Gronwald, Jacek/A-4576-2017; Bjorge, Line/C-1307-2017; salvesen, Helga/C-1187-2017; Brooks-Wilson, Angela/E-9399-2012; Dork, Thilo/J-8620-2012; OI Hein, Alexander/0000-0003-2601-3398; Gronwald, Jacek/0000-0002-3643-2871; Bjorge, Line/0000-0002-0240-2770; salvesen, Helga/0000-0002-4438-8831; Brooks-Wilson, Angela/0000-0003-1009-6408; Krakstad, Camilla/0000-0002-0174-8139 FU Ovarian Cancer Research Fund [PPD/RPCI.07]; Genetic Associations and Mechanisms in Oncology (GAME-ON): a NCI Cancer Post-GWAS Initiative [U19-CA148112, U19-CA148537]; European Community [223175 (HEALTH-F2-2009-223175)]; Canadian Institutes for Health Research (CIHR) [MOP-86727]; CIHR Team in Familial Risks of Breast Cancer; American Cancer Society [CRTG-00-196-01-CCE]; California Cancer Research Program [00-01389V-20170, N01-CN25403, 2II0200]; Cancer Council Victoria; Cancer Council Queensland; Cancer Council New South Wales; Cancer Council South Australia; Cancer Council Tasmania; Cancer Foundation of Western Australia; Cancer Institute of New Jersey; Cancer Research UK [C490/A6187, C490/A10119, C490/A10124, C536/A13086, C536/A6689, C1287/A10118, C1287/A 10710, C12292/A11174, C5047/A8384, C5047/A15007, C5047/A10692]; Celma Mastry Ovarian Cancer Foundation; Danish Cancer Society [94-222-52]; ELAN Program of the University of Erlangen-Nuremberg; Eve Appeal; Helsinki University Central Hospital Research Fund; Helse Vest; Imperial Experimental Cancer Research Centre [C1312/A15589]; Norwegian Cancer Society; Norwegian Research Council; Ovarian Cancer Research Fund; Nationaal Kankerplan of Belgium; L. & S. Milken Foundation; Polish Ministry of Science and Higher Education; US National Institutes of Health/National Center for Research Resources/General Clinical Research Center grant [MO1-RR000056]; US National Cancer Institute (RPCI-UPCI Ovarian Cancer) [R01-CA058598, R01-CA058860, R01-CA061107, R01-CA061132, R01-CA063682, R01-CA064277, R01-CA067262, R01-CA071766, R01-CA074850, R01-CA076016, R01-CA080742, R01-CA080978, R01-CA128978, R01-CA083918, R01-CA087538, R01-CA092044]; US National Cancer Institute (Intramural research funds); National Institute of Environmental Health Sciences [T32ES013678]; US Department of Defense Ovarian Cancer Research Program [W81XWH-07-0449]; US Army Medical Research and Material Command [DAMD17-98-1-8659, DAMD17-01-1-0729, DAMD17-02-1-0666, DAMD17-02-1-0669, W81XWH-10-1-0280, W81XWH-10-1-0341]; National Health and Medical Research Council of Australia [199600, 400413, 400281]; German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research [01 GB 9401]; state of Baden-Wurttemberg through Medical Faculty of the University of Ulm [P.685]; Minnesota Ovarian Cancer Alliance; Mayo Foundation; Fred C. and Katherine B. Andersen Foundation; Lon V. Smith Foundation [LVS-39420]; Polish Committee for Scientific Research [4P05C 028 14, 2P05A 068 27]; Oak Foundation; OHSU Foundation; Mermaid I project; Rudolf-Bartling Foundation; UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; Imperial College London; University College Hospital "Womens Health Theme"; Royal Marsden Hospital; WorkSafeBC; Komen Foundation for the Cure; Breast Cancer Research Foundation; Lon V Smith Foundation grant [LVS-39420]; Australian National Health and Medical Research Council; American Cancer Society Early Detection Professorship [SIOP-06-258-01-COUN]; Barbara Thomason Ovarian Cancer Research Professorship from the American Cancer Society [SIOP-06-090-06]; NCI Cancer Center Support Grant [5P30 CA016056]; [R01-CA114343]; [R01-CA126841]; [R01-CA136924]; [R01-CA149429]; [R03-CA113148]; [R03-CA115195]; [R21-GM86689]; [R37-CA070867]; [R37-CA70867]; [U01-CA069417]; [U01-CA071966]; [CA58860]; [CA92044]; [PSA042205]; [UM1-CA186107]; [P01-CA87969]; [R01-CA49449]; [UM1-CA176726]; [R01-CA67262]; [SPORE P50CA159981-01A1]; [K07-CA095666]; [K07-K07-CA80668]; [CA143047]; [K22-CA138563]; [N01-CN55424]; [N01-PC067010]; [N01-PC035137]; [P01-CA017054]; [P01-CA087696]; [P20-GM103418]; [P30-CA072720]; [P30-CA15083]; [P30-CA168524]; [P30-CA008748]; [P50-CA105009]; [P50-CA136393]; [R01-CA014089]; [R01-CA016056]; [R01-CA017054]; [R01-CA049449]; [R01-CA050385]; [R01-CA054419]; [R01-095023]; [R01-CA106414]; [R01-CA122443]; [R01-CA61107]; [R01-CA112523] FX This study was supported by funding from several sources including the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07); the Genetic Associations and Mechanisms in Oncology (GAME-ON): a NCI Cancer Post-GWAS Initiative (U19-CA148112 and U19-CA148537); the European Community's Seventh Framework Programme under grant agreement no 223175 (HEALTH-F2-2009-223175); the Canadian Institutes for Health Research (CIHR) MOP-86727 and the CIHR Team in Familial Risks of Breast Cancer; the American Cancer Society (CRTG-00-196-01-CCE); the California Cancer Research Program (00-01389V-20170, N01-CN25403, 2II0200); Cancer Council Victoria; Cancer Council Queensland; Cancer Council New South Wales; Cancer Council South Australia; Cancer Council Tasmania; Cancer Foundation of Western Australia; the Cancer Institute of New Jersey; Cancer Research UK (C490/A6187, C490/A10119, C490/A10124, C536/A13086, C536/A6689, C1287/A10118, C1287/A 10710, C12292/A11174, C5047/A8384, C5047/A15007, C5047/A10692); the Celma Mastry Ovarian Cancer Foundation; the Danish Cancer Society (94-222-52); the ELAN Program of the University of Erlangen-Nuremberg; the Eve Appeal; the Helsinki University Central Hospital Research Fund; Helse Vest; Imperial Experimental Cancer Research Centre (C1312/A15589); the Norwegian Cancer Society; the Norwegian Research Council; the Ovarian Cancer Research Fund; Nationaal Kankerplan of Belgium; the L. & S. Milken Foundation; the Polish Ministry of Science and Higher Education; the US National Institutes of Health/National Center for Research Resources/General Clinical Research Center grant MO1-RR000056; the US National Cancer Institute (RPCI-UPCI Ovarian Cancer SPORE P50CA159981-01A1, K07-CA095666, K07-K07-CA80668, CA143047, K22-CA138563, N01-CN55424, N01-PC067010, N01-PC035137, P01-CA017054, P01-CA087696, P20-GM103418, P30-CA072720, P30-CA15083, P30-CA168524, P30-CA008748, P50-CA105009, P50-CA136393, R01-CA014089, R01-CA016056, R01-CA017054, R01-CA049449, R01-CA050385, R01-CA054419, R01-CA058598, R01-CA058860, R01-CA061107, R01-CA061132, R01-CA063682, R01-CA064277, R01-CA067262, R01-CA071766, R01-CA074850, R01-CA076016, R01-CA080742, R01-CA080978, R01-CA128978, R01-CA083918, R01-CA087538, R01-CA092044, R01-095023, R01-CA106414, R01-CA122443, R01-CA61107, R01-CA112523, R01-CA114343, R01-CA126841, R01-CA136924, R01-CA149429, R03-CA113148, R03-CA115195, R21-GM86689, R37-CA070867, R37-CA70867, U01-CA069417, U01-CA071966, CA58860, CA92044, PSA042205, UM1-CA186107, P01-CA87969, R01-CA49449, UM1-CA176726, R01-CA67262 and Intramural research funds); National Institute of Environmental Health Sciences (T32ES013678); the US Department of Defense Ovarian Cancer Research Program (W81XWH-07-0449); the US Army Medical Research and Material Command (DAMD17-98-1-8659, DAMD17-01-1-0729, DAMD17-02-1-0666, DAMD17-02-1-0669, W81XWH-10-1-0280, W81XWH-10-1-0341); the National Health and Medical Research Council of Australia (199600, 400413, and 400281); the German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research (01 GB 9401); the state of Baden-Wurttemberg through Medical Faculty of the University of Ulm (P.685); the Minnesota Ovarian Cancer Alliance; the Mayo Foundation; the Fred C. and Katherine B. Andersen Foundation; the Lon V.; Smith Foundation (LVS-39420); the Polish Committee for Scientific Research (4P05C 028 14 and 2P05A 068 27); the Oak Foundation; the OHSU Foundation; the Mermaid I project; the Rudolf-Bartling Foundation; the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; Imperial College London; University College Hospital "Womens Health Theme" and the Royal Marsden Hospital; WorkSafeBC; Komen Foundation for the Cure; and the Breast Cancer Research Foundation; the Lon V Smith Foundation grant LVS-39420.; G. Chenevix-Trench and P.M. Webb are supported by the Australian National Health and Medical Research Council; B. Karlan holds an American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN); and A. Berchuck holds the Barbara Thomason Ovarian Cancer Research Professorship from the American Cancer Society (SIOP-06-090-06). Cytometry services were provided by the Flow and Image Cytometry Core facility at the Roswell Park Cancer Institute which is supported in part by the NCI Cancer Center Support Grant 5P30 CA016056. NR 44 TC 1 Z9 1 U1 1 U2 1 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD OCT 25 PY 2016 VL 7 IS 43 BP 69097 EP 69110 DI 10.18632/oncotarget.10215 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EB5VI UT WOS:000387448300001 PM 27533245 ER PT J AU Bahr, JC Robey, RW Luchenko, V Basseville, A Chakraborty, AR Kozlowski, H Pauly, GT Patel, P Schneider, JP Gottesman, MM Bates, SE AF Bahr, Julian C. Robey, Robert W. Luchenko, Victoria Basseville, Agnes Chakraborty, Arup R. Kozlowski, Hanna Pauly, Gary T. Patel, Paresma Schneider, Joel P. Gottesman, Michael M. Bates, Susan E. TI Blocking downstream signaling pathways in the context of HDAC inhibition promotes apoptosis preferentially in cells harboring mutant Ras SO ONCOTARGET LA English DT Article DE romidepsin; Ras mutation; apoptosis; MEK inhibitor; AKT inhibitor ID HISTONE DEACETYLASE INHIBITOR; PANCREATIC-CANCER CELLS; ADVANCED SOLID TUMORS; BUPARLISIB BKM120; COLORECTAL-CANCER; INDUCE APOPTOSIS; DOSE-ESCALATION; MEK INHIBITORS; WHOLE-EXOME; MOUSE MODEL AB We previously demonstrated activation of the mitogen-activated protein kinase (MAPK) pathway in a series of romidepsin-selected T-cell lymphoma cell lines as a mechanism of resistance to the histone deacetylase inhibitor (HDI), romidepsin. As Ras mutation leads to activation of both the MAPK and the phosphoinositide 3-kinase (PI3K) pathway, we examined whether combining romidepsin with small molecule pathway inhibitors would lead to increased apoptosis in cancers harboring Ras mutations. We treated 18 Ras mutant or wild-type cell lines with romidepsin in the presence of a MEK inhibitor (PD-0325901) and/or an AKT inhibitor (MK-2206) and examined apoptosis by flow cytometry. A short-term treatment schedule of romidepsin (25 ng/ml for 6 h) was used to more closely model clinical administration. Romidepsin in combination with a MEK and an AKT inhibitor induced apoptosis preferentially in cells harboring mutant versus wild-type Ras (69.1% vs. 21.1%, p < 0.0001). Similar results were found in a subset of cell lines when belinostat was combined with the MEK and AKT inhibitors and when romidepsin was combined with the dual extracellular signaling-related kinase (ERK)/PI3K inhibitor, D-87503, which inhibited both the MAPK and PI3K pathways at 5-10 mu M. The observed apoptosis was caspase-dependent and required Bak and Bax expression. Cells with wild-type or mutant Ras treated with romidepsin alone or in combination with the MEK inhibitor displayed increased expression of proapoptotic Bim. We thus conclude that cancers bearing Ras mutations, such as pancreatic cancer, can be targeted by the combination of an HDI and a dual inhibitor of the MAPK and PI3K pathways. C1 [Bahr, Julian C.; Robey, Robert W.; Luchenko, Victoria; Basseville, Agnes; Chakraborty, Arup R.; Bates, Susan E.] NCI, Dev Therapeut Branch, NIH, Bethesda, MD 20892 USA. [Robey, Robert W.; Kozlowski, Hanna; Gottesman, Michael M.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Pauly, Gary T.; Patel, Paresma; Schneider, Joel P.] NCI, Chem Biol Lab, Frederick Canc Res Ctr, Frederick, MD 21702 USA. [Bates, Susan E.] Columbia Univ, Med Ctr, Div Hematol Oncol, New York, NY 10032 USA. RP Bates, SE (reprint author), NCI, Dev Therapeut Branch, NIH, Bethesda, MD 20892 USA.; Bates, SE (reprint author), Columbia Univ, Med Ctr, Div Hematol Oncol, New York, NY 10032 USA. EM seb2227@cumc.columbia.edu FU Intramural Research Program of the NIH, National Cancer Institute; National Cancer Institute; Celgene Corporation FX This research was supported, in part, by the Intramural Research Program of the NIH, National Cancer Institute. It was also supported in part by a cooperative research and development agreement between the National Cancer Institute and the Celgene Corporation. NR 45 TC 0 Z9 0 U1 1 U2 1 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD OCT 25 PY 2016 VL 7 IS 43 BP 69804 EP 69815 DI 10.18632/oncotarget.12001 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EB5VI UT WOS:000387448300055 PM 27634878 ER PT J AU Kumar, NB Pow-Sang, J Spiess, PE Park, J Salup, R Williams, CR Parnes, H Schell, MJ AF Kumar, Nagi B. Pow-Sang, Julio Spiess, Philippe E. Park, Jong Salup, Raoul Williams, Christopher R. Parnes, Howard Schell, Michael J. TI Randomized, placebo-controlled trial evaluating the safety of one-year administration of green tea catechins SO ONCOTARGET LA English DT Article DE green tea; catechins; safety; prostate cancer ID PROSTATE-CANCER PATIENTS; POLYPHENON-E; EPIGALLOCATECHIN GALLATE; CAMELLIA-SINENSIS; TRAMP MICE; HEALTHY-INDIVIDUALS; PROTEASOME ACTIVITY; ACUTE HEPATITIS; IN-VITRO; CHEMOPREVENTION AB Purpose: Although preclinical, epidemiological and prior clinical trial data suggest that green tea catechins (GTCs) may reduce prostate cancer (PCa) risk, several preclinical studies and case reports have reported liver toxicities and acute gastrointestinal bleeding. Based on these observations, regulatory bodies have required stringent inclusion criteria with frequent, excessive toxicity monitoring and early stopping rules in clinical trials. These requirements have impeded recruitment and retention of subjects in chemoprevention trials and subsequent progress in agent development efforts. Experimental Design: We conducted a placebo-controlled, randomized clinical trial of Polyphenon E (R) (PolyE (R)), a proprietary mixture of decaffeinated GTCs, containing 400 mg (-)-epigallocatechin-3-gallate (EGCG) per day, in 97 men with high-grade prostatic intraepithelial neoplasia (HGPIN) and/or atypical small acinar proliferation (ASAP). PolyE (R) containing 200 mg EGCG was administered with food, BID. A secondary study endpoint in this trial was a comparison of the overall one-year treatment related adverse events and grade 3 or higher adverse event on the two study arms. Monthly assessments of toxicity (CTCAE 4.0), concomitant medications and organ function, including hepatic panel, PT/PTT and LDH, were performed. Results: Daily intake of a standardized, decaffeinated, catechin mixture containing 200 mg EGCG BID taken with food for 1 year accumulated in plasma and was well tolerated and did not produce treatment related adverse effects in men with baseline HGPIN or ASAP. Conclusion: The current data provides evidence of safety of decaffeinated, catechin mixture containing 200 mg EGCG BID to be further tested for prostate cancer prevention or other indications. C1 [Kumar, Nagi B.; Park, Jong] H Lee Moffitt Canc Ctr & Res Inst Inc, Canc Epidemiol, MRC CANCONT, 12902 Magnolia Dr, Tampa, FL 33612 USA. [Kumar, Nagi B.; Pow-Sang, Julio; Spiess, Philippe E.] H Lee Moffitt Canc Ctr & Res Inst Inc, Genitourinary Oncol, WCB GU PROG, 12902 Magnolia Dr, Tampa, FL 33612 USA. [Salup, Raoul] Univ S Florida, Coll Med, Urol, 12901 Bruce B Downs Blvd, Tampa, FL 33612 USA. [Williams, Christopher R.] Univ Florida, UF Hlth Jacksonville, Urol Oncol, Jacksonville, FL 32209 USA. [Parnes, Howard] NCI, Canc Prevent Div, 10 Ctr Dr Bldg 10, Bethesda, MD 20892 USA. [Schell, Michael J.] Moffitt Canc Ctr & Res Inst Inc, Biostat & Bioinformat, MRC BIOS, 12902 Magnolia Dr, Tampa, FL 33612 USA. RP Kumar, NB (reprint author), H Lee Moffitt Canc Ctr & Res Inst Inc, Canc Epidemiol, MRC CANCONT, 12902 Magnolia Dr, Tampa, FL 33612 USA.; Kumar, NB (reprint author), H Lee Moffitt Canc Ctr & Res Inst Inc, Genitourinary Oncol, WCB GU PROG, 12902 Magnolia Dr, Tampa, FL 33612 USA. EM Nagi.Kumar@Moffitt.org FU National Institute of Health - National Cancer Institute [R01 CA12060-01A1] FX The research funding for this work was awarded to Nagi B Kumar by the National Institute of Health - National Cancer Institute R01 CA12060-01A1. NR 45 TC 0 Z9 0 U1 9 U2 9 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD OCT 25 PY 2016 VL 7 IS 43 BP 70794 EP 70802 DI 10.18632/oncotarget.12222 PG 9 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EB5VI UT WOS:000387448300129 PM 28053292 ER PT J AU Xiang, TX Fan, YC Li, CH Li, LL Ying, Y Mu, JH Peng, WY Feng, YX Oberst, M Kelly, K Ren, GS Tao, Q AF Xiang, Tingxiu Fan, Yichao Li, Chunhong Li, Lili Ying, Ying Mu, Junhao Peng, Weiyan Feng, Yixiao Oberst, Michael Kelly, Kathleen Ren, Guosheng Tao, Qian TI DACT2 silencing by promoter CpG methylation disrupts its regulation of epithelial-to-mesenchymal transition and cytoskeleton reorganization in breast cancer cells SO ONCOTARGET LA English DT Article DE DACT2; tumor suppressor; methylation; EMT; breast cancer ID CANDIDATE TUMOR-SUPPRESSOR; BETA-CATENIN; LUNG-CANCER; HEPATOCELLULAR-CARCINOMA; GENE; EXPRESSION; WNT; ANTAGONIST; DAPPER2; MICE AB Wnt signaling plays an important role in breast carcinogenesis. DAPPER2 (DACT2) functions as an inhibitor of canonical Wnt signaling and plays distinct roles in different cell contexts, with its role in breast tumorigenesis unclear. We investigated DACT2 expression in breast cancer cell lines and primary tumors, as well as its functions and molecular mechanisms. Results showed that DACT2 expression was silenced in 9/9 of cell lines. Promoter CpG methylation of DACT2 was detected in 89% (8/9) of cell lines, as well as in 73% (107/147) of primary tumors, but only in 20% (1/5) of surgical margin tissues and in none of normal breast tissues. Demethylation of BT549 and T47D cell lines with 5-aza-2'-deoxycytidine restored DACT2 expression along with promoter demethylation, suggesting that its downregulation in breast cancer is dependent on promoter methylation. Furthermore, ectopic expression of DACT2 induced breast cell apoptosis in vitro, and further inhibited breast tumor cell proliferation, migration and EMT, through antagonizing Wnt/beta-catenin and Akt/GSK-3 signaling. Thus, these results demonstrate that DACT2 functions as a tumor suppressor for breast cancer but was frequently disrupted epigenetically in this cancer. C1 [Xiang, Tingxiu; Mu, Junhao; Peng, Weiyan; Feng, Yixiao; Ren, Guosheng; Tao, Qian] Chongqing Med Univ, Affiliated Hosp 1, Chongqing Key Lab Mol Oncol & Epigenet, Chongqing, Peoples R China. [Fan, Yichao; Li, Lili; Ying, Ying; Tao, Qian] Chinese Univ Hong Kong, Sir YK Pao Ctr Canc, Dept Clin Oncol, Canc Epigenet Lab, Hong Kong, Hong Kong, Peoples R China. [Fan, Yichao; Li, Lili; Ying, Ying; Tao, Qian] Chinese Univ Hong Kong, Li Ka Shing Inst Hlth Sci, Hong Kong, Hong Kong, Peoples R China. [Fan, Yichao; Li, Lili; Ying, Ying; Tao, Qian] CUHK Shenzhen Res Inst, Hong Kong, Hong Kong, Peoples R China. [Li, Chunhong] Suining Sichuan Ctr Hosp, Oncol Dept, Chengdu, Sichuan, Peoples R China. [Oberst, Michael; Kelly, Kathleen] NCI, Signal Transduct Sect, NIH, Bethesda, MD 20892 USA. RP Ren, GS; Tao, Q (reprint author), Chongqing Med Univ, Affiliated Hosp 1, Chongqing Key Lab Mol Oncol & Epigenet, Chongqing, Peoples R China.; Tao, Q (reprint author), Chinese Univ Hong Kong, Sir YK Pao Ctr Canc, Dept Clin Oncol, Canc Epigenet Lab, Hong Kong, Hong Kong, Peoples R China.; Tao, Q (reprint author), Chinese Univ Hong Kong, Li Ka Shing Inst Hlth Sci, Hong Kong, Hong Kong, Peoples R China.; Tao, Q (reprint author), CUHK Shenzhen Res Inst, Hong Kong, Hong Kong, Peoples R China. EM rgs726@163.com; qtao@cuhk.edu.hk FU National Natural Science Foundation of China [31420103915, 81372238, 81572327]; VC special fund from The Chinese University of Hong Kong FX This study was supported by National Natural Science Foundation of China (#31420103915, #81372238, #81572327) and VC special fund from The Chinese University of Hong Kong. NR 36 TC 0 Z9 0 U1 1 U2 1 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD OCT 25 PY 2016 VL 7 IS 43 BP 70924 EP 70935 DI 10.18632/oncotarget.12341 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EB5VI UT WOS:000387448300139 PM 27708215 ER PT J AU Huang, JQ Mondul, AM Weinstein, SJ Koutros, S Derkach, A Karoly, E Sampson, JN Moore, SC Berndt, SI Albanes, D AF Huang, Jiaqi Mondul, Alison M. Weinstein, Stephanie J. Koutros, Stella Derkach, Andriy Karoly, Edward Sampson, Joshua N. Moore, Steven C. Berndt, Sonja I. Albanes, Demetrius TI Serum metabolomic profiling of prostate cancer risk in the prostate, lung, colorectal, and ovarian cancer screening trial SO BRITISH JOURNAL OF CANCER LA English DT Article DE prostate cancer; metabolomic profiling; aggressive; pre-diagnosed serum; pyroglutamine; gamma-glutamyl peptides; N-acetyl amino acids; fatty acids ID TRH-LIKE PEPTIDES; INDOLEAMINE 2,3-DIOXYGENASE; FATTY-ACIDS; GLUTATHIONE METABOLISM; THYROID-HORMONE; GASTRIC-CANCER; BETA-CAROTENE; RAT PROSTATE; T-CELLS; EXPRESSION AB Background: Two recent metabolomic analyses found serum lipid, energy, and other metabolites related to aggressive prostate cancer risk up to 20 years prior to diagnosis. Methods: We conducted a serum metabolomic investigation of prostate cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial that included annual serum total prostate-specific antigen measurement and digital rectal examination. This nested study included 380 cases diagnosed post-screening and 380 controls individually matched to cases on age, race, study centre, and blood-collection date (median time to diagnosis, 10 years (range 4.4-17 years)). Sera were analysed on a highr-resolution accurate mass platform of ultrahigh-performance liquid and gas chromatography/mass spectroscopy that identified 695 known metabolites. Logistic regression conditioned on the matching factors estimated odds ratios (OR) and 95% confidence intervals of risk associated with an 80th percentile increase in the log-metabolite signal. Results: Twenty-seven metabolites were associated with prostate cancer at P<0.05. Pyroglutamine, gamma-glutamylphenylalanine, phenylpyruvate, N-acetylcitrulline, and stearoylcarnitine showed the strongest metabolite-risk signals (ORs = 0.53, 0.51, 0.46, 0.58, and 1.74, respectively; 0.001 <= P <= 0.006). Findings were similar for aggressive disease (peptide chemical class, P = 0.03). None of the P-values were below the threshold of Bonferroni correction, however. Conclusions: A unique metabolomic profile associated with post-screening prostate cancer is identified that differs from that in a previously studied, unscreened population. C1 [Huang, Jiaqi; Weinstein, Stephanie J.; Koutros, Stella; Derkach, Andriy; Sampson, Joshua N.; Moore, Steven C.; Berndt, Sonja I.; Albanes, Demetrius] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Mondul, Alison M.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Karoly, Edward] Metabolon Inc, Morrisville, NC USA. RP Albanes, D (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM daa@nih.gov RI Moore, Steven/D-8760-2016 OI Moore, Steven/0000-0002-8169-1661 FU Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH [Z01-CP010119, ZIA-CP010152-11] FX This work was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH (Z01-CP010119, ZIA-CP010152-11). We thank Drs Christine Berg and Philip Prorok, Division of Cancer Prevention, NCI, the screening centre investigators and staff of the PLCO Cancer Screening Trial, Mr Thomas Riley and staff at Information Management Services, Inc., and Ms Barbara O'Brien and staff at Westat, Inc. for their contributions to the PLCO and the study participants for donating their time and making this study possible. NR 66 TC 0 Z9 0 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD OCT 25 PY 2016 VL 115 IS 9 BP 1087 EP 1095 DI 10.1038/bjc.2016.305 PG 9 WC Oncology SC Oncology GA EA3CS UT WOS:000386477300015 PM 27673363 ER PT J AU Preston, DL Kitahara, CM Freedman, DM Sigurdson, AJ Simon, SL Little, MP Cahoon, EK Rajaraman, P Miller, JS Alexander, BH Doody, MM Linet, MS AF Preston, D. L. Kitahara, C. M. Freedman, D. M. Sigurdson, A. J. Simon, S. L. Little, M. P. Cahoon, E. K. Rajaraman, P. Miller, J. S. Alexander, B. H. Doody, M. M. Linet, M. S. TI Breast cancer risk and protracted low-to-moderate dose occupational radiation exposure in the US Radiologic Technologists Cohort, 1983-2008 SO BRITISH JOURNAL OF CANCER LA English DT Article DE radiation; breast cancer; occupational exposure; cohort study ID ATOMIC-BOMB SURVIVORS; TECHA RIVER COHORT; UNITED-STATES; FLUOROSCOPY COHORT; MORTALITY; TRENDS; REGISTRY; PROPORTION; WORKERS; HEALTH AB Background: Although high-dose ionising radiation is associated with increased breast cancer risks, the association with protracted low-dose-rate exposures remains unclear. The US Radiologic Technologist study provides an opportunity to examine the association between low-to-moderate dose radiation and breast cancer incidence and mortality. Methods: One thousand nine hundred and twenty-two self-reported first primary cancers were diagnosed during 1983-2005 among 66 915 female technologists, and 586 breast cancer deaths occurred during 1983-2008 among 83 538 female cohort members. Occupational breast dose estimates were based on work histories, historical data, and, after the mid-1970s, individual film badge measurements. Excess relative risks were estimated using Poisson regression with birth cohort stratification and adjustment for menopause, reproductive history, and other risk factors. Results: Higher doses were associated with increased breast cancer incidence, with an excess relative risk at 100mGy of 0.07 ( 95% confidence interval (CI): -0.005 to 0.19). Associations were strongest for technologists born before 1930 (excess relative risk at 100mGy = 0.16; 95% CI: 0.03-0.39) with similar patterns for mortality among technologists born before 1930. Conclusions: Occupational radiation to the breast was positively associated with breast cancer risk. The risk was more pronounced for women born before 1930 who began working before 1950 when mean annual doses (37 mGy) were considerably higher than in later years (1.3 mGy). However, because of the uncertainties and possible systematic errors in the occupational dose estimates before 1960, these findings should be treated with caution. C1 [Preston, D. L.] Hirosoft Int, 1335 H, Eureka, CA 95501 USA. [Kitahara, C. M.; Freedman, D. M.; Sigurdson, A. J.; Simon, S. L.; Little, M. P.; Cahoon, E. K.; Rajaraman, P.; Doody, M. M.; Linet, M. S.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr, Rockville, MD 20850 USA. [Miller, J. S.] Informat Management Serv Inc, 6110 Execut Blvd 310, Rockville, MD 20852 USA. [Alexander, B. H.] Univ Minnesota, Sch Publ Hlth, Div Environm Hlth Sci, 426 Church St SE, Minneapolis, MN 55455 USA. RP Preston, DL (reprint author), Hirosoft Int, 1335 H, Eureka, CA 95501 USA. EM preston@hirosoft.net RI Kitahara, Cari/R-8267-2016 FU intramural program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services; Intramural Research Program of the National Institutes of Health; National Cancer Institute FX We thank the radiologic technologists who participated in the study, Jerry Reid of the American Registry of Radiologic Technologists for continued support, and Diane Kampa and Allison Iwan of the University of Minnesota for data management and collection. We are also grateful to Drs. Amy Berrington de Gonzalez and Robert Hoover for helpful suggestions. This research was funded by the intramural program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services.; This work was supported by the Intramural Research Program of the National Institutes of Health and the National Cancer Institute NR 37 TC 0 Z9 0 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD OCT 25 PY 2016 VL 115 IS 9 BP 1105 EP 1112 DI 10.1038/bjc.2016.292 PG 8 WC Oncology SC Oncology GA EA3CS UT WOS:000386477300017 PM 27623235 ER PT J AU Malhotra, J Waterboer, T Pawlita, M Michel, A Cai, QY Zheng, W Gao, YT Lan, Q Rothman, N Langseth, H Grimsrud, TK Yuan, JM Koh, WP Wang, RW Arslan, AA Zeleniuch-Jacquotte, A Boffetta, P AF Malhotra, Jyoti Waterboer, Tim Pawlita, Michael Michel, Angelika Cai, Qiuyin Zheng, Wei Gao, Yu-Tang Lan, Qing Rothman, Nathaniel Langseth, Hilde Grimsrud, Tom K. Yuan, Jian-Min Koh, Woon-Puay Wang, Renwei Arslan, Alan A. Zeleniuch-Jacquotte, Anne Boffetta, Paolo TI Serum biomarkers of polyomavirus infection and risk of lung cancer in never smokers SO BRITISH JOURNAL OF CANCER LA English DT Article DE human polyomaviruses; lung cancer; cancer risk ID MERKEL CELL POLYOMAVIRUS; HUMAN NEUROTROPIC POLYOMAVIRUS; PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; HUMAN-PAPILLOMAVIRUS INFECTIONS; VIRUS-DNA SEQUENCES; JC-VIRUS; T-ANTIGEN; SQUAMOUS-CELL; EPIDEMIOLOGIC EVIDENCE; PLEURAL MESOTHELIOMA AB Background: Lung cancer in never smokers is a significant contributor of cancer mortality worldwide. In this analysis, we explored the role of nine human polyomaviruses, including JC virus (JCV), BK virus (BKV) and Merkel cell virus (MCV), in lung cancer development in never smokers as there are data to support that polyomaviruses are potentially carcinogenic in the human lung. Methods: We used multiplex serology to detect serum antibodies to polyomaviruses in a nested case-control design combining lung cancer cases and controls from four cohort studies - NYU Women's Health Study (NYU-WHS), Janus Serum Bank, Shanghai Women's Health Study and Singapore Chinese Health Study (SCHS). Results: The final analyses included 511 cases and 508 controls. Seroprevalence for each polyomavirus showed significant heterogeneity by study, but overall there were no statistically significant differences between cases and controls. In total, 69.1% of the cases and 68.7% of the controls were seropositive for JCV VP1 antibody. Seropositivity for BKV was higher at 89.0% in cases and 89.8% in controls and lower for MCV at 59.3% in cases and 61.6% in controls. Similar results were obtained after adding an additional retrospective case-control study (Xuanwei study) to the analysis. Conclusions: Our results do not support the hypothesis that seropositivity for polyomaviruses is associated with increased lung cancer risk in never smokers. Future research to evaluate relationship between polyomavirus infection and lung carcinogenesis should focus more on evaluating the presence of virus or viral nucleic acids (DNA or RNA) in lung tumour samples. C1 [Malhotra, Jyoti; Boffetta, Paolo] Icahn Sch Med Mt Sinai, 17 East 102 St,Floor 4 West,Room 110, New York, NY 10029 USA. [Malhotra, Jyoti] Rutgers Canc Inst New Jersey, New Brunswick, NJ USA. [Waterboer, Tim; Pawlita, Michael; Michel, Angelika] German Canc Res Ctr, Heidelberg, Germany. [Cai, Qiuyin; Zheng, Wei] Vanderbilt Univ, Sch Med, 221 Kirkland Hall, Nashville, TN 37235 USA. [Gao, Yu-Tang] Shanghai Canc Inst, Shanghai, Peoples R China. [Lan, Qing; Rothman, Nathaniel] NCI, Rockville, MD USA. [Langseth, Hilde; Grimsrud, Tom K.] Inst Populat Based Canc Res, Canc Registry Norway, Oslo, Norway. [Yuan, Jian-Min; Wang, Renwei] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. [Koh, Woon-Puay] Natl Univ Singapore, Duke NUS Grad Med Sch Singapore, Singapore 117549, Singapore. [Koh, Woon-Puay] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117549, Singapore. [Arslan, Alan A.; Zeleniuch-Jacquotte, Anne] NYU, Sch Med, New York, NY USA. RP Boffetta, P (reprint author), Icahn Sch Med Mt Sinai, 17 East 102 St,Floor 4 West,Room 110, New York, NY 10029 USA. EM paolo.boffetta@mssm.edu RI Waterboer, Tim/G-1252-2010; OI Pawlita, Michael/0000-0002-4720-8306; Zeleniuch-Jacquotte, Anne/0000-0001-9350-1303 FU National Cancer Institute [5UH2CA169111-02]; [R37CA070867]; [UM1CA182910] FX This work was supported by National Cancer Institute (5UH2CA169111-02) and in part by R37CA070867 and UM1CA182910. NR 78 TC 0 Z9 0 U1 6 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD OCT 25 PY 2016 VL 115 IS 9 BP 1131 EP 1139 DI 10.1038/bjc.2016.285 PG 9 WC Oncology SC Oncology GA EA3CS UT WOS:000386477300020 PM 27632373 ER PT J AU Juan, AH Wang, S Ko, KD Zare, H Tsai, PF Feng, XS Vivanco, KO Ascoli, AM Gutierrez-Cruz, G Krebs, J Sidoli, S Knight, AL Pedersen, RA Garcia, BA Casellas, R Zou, JZ Sartorelli, V AF Juan, Aster H. Wang, Stan Ko, Kyung Dae Zare, Hossein Tsai, Pei-Fang Feng, Xuesong Vivanco, Karinna O. Ascoli, Anthony M. Gutierrez-Cruz, Gustavo Krebs, Jordan Sidoli, Simone Knight, Adam L. Pedersen, Roger A. Garcia, Benjamin A. Casellas, Rafael Zou, Jizhong Sartorelli, Vittorio TI Roles of H3K27me2 and H3K27me3 Examined during Fate Specification of Embryonic Stem Cells SO CELL REPORTS LA English DT Article ID H3 LYSINE 27; HISTONE H3; DEVELOPMENTAL REGULATORS; CHROMATIN SIGNATURES; NEURAL INDUCTION; GENE-EXPRESSION; GROUND-STATE; SELF-RENEWAL; ES CELLS; IN-VIVO AB The polycomb repressive complex 2 (PRC2) methylates lysine 27 of histone H3 (H3K27) through its catalytic subunit Ezh2. PRC2-mediated di- and tri-methylation (H3K27me2/H3K27me3) have been interchangeably associated with gene repression. However, it remains unclear whether these two degrees of H3K27 methylation have different functions. In this study, we have generated isogenic mouse embryonic stem cells (ESCs) with a modified H3K27me2/H3K27me3 ratio. Our findings document dynamic developmental control in the genomic distribution of H3K27me2 and H3K27me3 at regulatory regions in ESCs. They also reveal that modifying the ratio of H3K27me2 and H3K27me3 is sufficient for the acquisition and repression of defined cell lineage transcriptional programs and phenotypes and influences induction of the ESC ground state. C1 [Juan, Aster H.; Wang, Stan; Ko, Kyung Dae; Zare, Hossein; Tsai, Pei-Fang; Feng, Xuesong; Vivanco, Karinna O.; Ascoli, Anthony M.; Gutierrez-Cruz, Gustavo; Sartorelli, Vittorio] Natl Inst Arthrit Musculoskeletal & Skin Dis NIAM, Lab Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20892 USA. [Wang, Stan] Wellcome Trust Canc Res UK Gurdon Inst, Tennis Court Rd, Cambridge CB2 1QN, England. [Wang, Stan; Pedersen, Roger A.] Univ Cambridge, Dept Surg, Cambridge CB2 0QQ, England. [Vivanco, Karinna O.] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Krebs, Jordan; Casellas, Rafael] NIAMS, Genom & Immun, NIH, Bethesda, MD 20892 USA. [Sidoli, Simone; Garcia, Benjamin A.] Univ Penn, Perlman Sch Med, Dept Biochem & Biophys, Epigenet Program, Philadelphia, PA 19104 USA. [Knight, Adam L.] NINDS, Synapt Funct Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. [Pedersen, Roger A.] Univ Cambridge, Anne McLaren Lab Regenerat Med, Downing St, Cambridge CB2 3EH, England. [Zou, Jizhong] NHLBI, iPSC Core Facil, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. [Wang, Stan] Columbia Univ Coll Phys & Surg, 630 West 168th St, New York, NY 10032 USA. RP Juan, AH; Sartorelli, V (reprint author), Natl Inst Arthrit Musculoskeletal & Skin Dis NIAM, Lab Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20892 USA. EM juana2@mail.nih.gov; sartorev@mail.nih.gov FU Gates Cambridge Trust; NIH-Cambridge MD/PhD Program; NIH [GM110174]; Intramural Research Program of the NIAMS at the NIH FX We thank Prof. J.B. Gurdon and members of his laboratory in Cambridge, UK for hosting S.W. during the initial part of this work. We also thank the personnel of the NIAMS Sequencing, Light Imaging, and Flow Cytometry Facilities and of the NHLBI Transgenic and Pathology Cores at the National Institutes of Health (NIH). S.W. was supported in part by fellowships from the Gates Cambridge Trust and NIH-Cambridge MD/PhD Program. S.S. and B.A.G. were supported by a grant from the NIH (GM110174). This research was supported in part by the Intramural Research Program of the NIAMS at the NIH. NR 63 TC 2 Z9 2 U1 3 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD OCT 25 PY 2016 VL 17 IS 5 BP 1369 EP 1382 DI 10.1016/j.celrep.2016.09.087 PG 14 WC Cell Biology SC Cell Biology GA EA3TF UT WOS:000386527100015 PM 27783950 ER PT J AU May-Simera, HL Gumerson, JD Gao, C Campos, M Cologna, SM Beyer, T Boldt, K Kaya, KD Patel, N Kretschmer, F Kelley, MW Petralia, RS Davey, MG Li, TS AF May-Simera, Helen L. Gumerson, Jessica D. Gao, Chun Campos, Maria Cologna, Stephanie M. Beyer, Tina Boldt, Karsten Kaya, Koray D. Patel, Nisha Kretschmer, Friedrich Kelley, Matthew W. Petralia, Ronald S. Davey, Megan G. Li, Tiansen TI Loss of MACF1 Abolishes Ciliogenesis and Disrupts Apicobasal Polarity Establishment in the Retina SO CELL REPORTS LA English DT Article ID PLANAR CELL POLARITY; BIEDL SYNDROME PROTEINS; PRIMARY CILIUM; QUAIL OVIDUCT; EPITHELIAL-CELLS; TRANSITION ZONE; CILIARY POCKET; BASAL BODIES; ACTIN; CENTROSOME AB Microtubule actin crosslinking factor 1 (MACF1) plays a role in the coordination of microtubules and actin in multiple cellular processes. Here, we show that MACF1 is also critical for ciliogenesis in multiple cell types. Ablation of Macf1 in the developing retina abolishes ciliogenesis, and basal bodies fail to dock to ciliary vesicles or migrate apically. Photoreceptor polarity is randomized, while inner retinal cells laminate correctly, suggesting that photoreceptor maturation is guided by polarity cues provided by cilia. Deletion of MACF1 in adult photoreceptors causes reversal of basal body docking and loss of outer segments, reflecting a continuous requirement for MACF1 function. MACF1 also interacts with the ciliary proteins MKKS and TALPID3. We propose that a disruption of trafficking across microtubles to actin filaments underlies the ciliogenesis defect in cells lacking MACF1 and that MKKS and TALPID3 are involved in the coordination of microtubule and actin interactions. C1 [May-Simera, Helen L.; Gumerson, Jessica D.; Gao, Chun; Campos, Maria; Kaya, Koray D.; Patel, Nisha; Kretschmer, Friedrich; Li, Tiansen] NEI, Bethesda, MD 20892 USA. [Cologna, Stephanie M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. [Beyer, Tina; Boldt, Karsten] Univ Tubingen, Inst Ophthalm Res, D-72076 Tubingen, Germany. [Kelley, Matthew W.; Petralia, Ronald S.] NIDCD, Bethesda, MD 20892 USA. [Davey, Megan G.] Roslin Inst, Univ Edinburgh, Roslin EH25 9RG, Midlothian, Scotland. [May-Simera, Helen L.] Johannes Gutenberg Univ Mainz, Inst Zool, D-55099 Mainz, Germany. RP May-Simera, HL; Li, TS (reprint author), NEI, Bethesda, MD 20892 USA.; May-Simera, HL (reprint author), Johannes Gutenberg Univ Mainz, Inst Zool, D-55099 Mainz, Germany. EM hmaysime@uni-mainz.de; tiansen.li@nih.gov RI Davey, Megan/C-7723-2013 OI Davey, Megan/0000-0003-0194-9229 FU NEI/NIH [ZIA-EY000490]; NICHD/NIH; NIDCD/NIH (Advanced Imaging Core Facility Code) [ZIC DC000081] FX We thank Dr. Lijin Dong and the NEI Genetic Engineering Core for help with generating MEF cells; Dr. Mones Abu-Asab and the NEI Histology Core for TEM processing; Dr. Robert Fariss (NEI Imaging Core) for help with confocal microscopy; Dr. Haohua Qian (NEI Visual Function Core) for help with ERGs; Dr. Ya-Xian Wang for help with the immunogold labeling; R. Steve Lee, Megan Kopera, and Hideko Takahashi for mouse genotyping and colony management; Linn Geiser for help with RNA-seq; Drs. Tiziana Cogliati and Gail Seabold for critical reading of this manuscript; and Drs. Ronald Liem (Columbia University), Elaine Fuchs (Rockefeller University) and Lotte Pederson (University of Copenhagen) for sharing materials. Research supported by intramural research programs of the NEI/NIH (ZIA-EY000490), NICHD/NIH, and NIDCD/NIH (Advanced Imaging Core Facility Code: ZIC DC000081). NR 57 TC 0 Z9 0 U1 2 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD OCT 25 PY 2016 VL 17 IS 5 BP 1399 EP 1413 DI 10.1016/j.celrep.2016.09.089 PG 15 WC Cell Biology SC Cell Biology GA EA3TF UT WOS:000386527100017 PM 27783952 ER PT J AU Rubel, CA Wu, SP Lin, L Wang, TY Lanz, RB Li, XL Kommagani, R Franco, HL Camper, SA Tong, Q Jeong, JW Lydon, JP DeMayo, FJ AF Rubel, Cory A. Wu, San-Pin Lin, Lin Wang, Tianyuan Lanz, Rainer B. Li, Xilong Kommagani, Ramakrishna Franco, Heather L. Camper, Sally A. Tong, Qiang Jeong, Jae-Wook Lydon, John P. DeMayo, Francesco J. TI A Gata2-Dependent Transcription Network Regulates Uterine Progesterone Responsiveness and Endometrial Function SO CELL REPORTS LA English DT Article ID FEMALE REPRODUCTIVE-TRACT; MOUSE UTERUS; PROSTATE-CANCER; GENE-EXPRESSION; MICE LACKING; FIT INDEXES; RECEPTOR; GATA2; DIETHYLSTILBESTROL; ABNORMALITIES AB Altered progesterone responsiveness leads to female infertility and cancer, but underlying mechanisms remain unclear. Mice with uterine-specific ablation of GATA binding protein 2 (Gata2) are infertile, showing failures in embryo implantation, endometrial decidualization, and uninhibited estrogen signaling. Gata2 deficiency results in reduced progesterone receptor (PGR) expression and attenuated progesterone signaling, as evidenced by genome-wide expression profiling and chromatin immunoprecipitation. GATA2 not only occupies at and promotes expression of the Pgr gene but also regulates downstream progesterone responsive genes in conjunction with the PGR. Additionally, Gata2 knockout uteri exhibit abnormal luminal epithelia with ectopic TRP63 expressing squamous cells and a cancer-related molecular profile in a progesterone-independent manner. Lastly, we found a conserved GATA2-PGR regulatory network in both human and mice based on gene signature and path analyses using gene expression profiles of human endometrial tissues. In conclusion, uterine Gata2 regulates a key regulatory network of gene expression for progesterone signaling at the early pregnancy stage. C1 [Rubel, Cory A.; Lanz, Rainer B.; Li, Xilong; Kommagani, Ramakrishna; Franco, Heather L.; Lydon, John P.; DeMayo, Francesco J.] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. [Wu, San-Pin; DeMayo, Francesco J.] NIEHS, Reprod & Dev Biol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. [Lin, Lin] Univ Calif San Francisco, Dept Family Hlth Care Nursing, San Francisco, CA 94143 USA. [Wang, Tianyuan] NIEHS, Div Intramural Res, POB 12233, Res Triangle Pk, NC 27709 USA. [Camper, Sally A.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Tong, Qiang] Baylor Coll Med, Childrens Nutr Res Ctr, Dept Pediat Med Mol Physiol & Biophys, Houston, TX 77030 USA. [Jeong, Jae-Wook] Michigan State Univ, Dept Obstet & Gynecol & Reprod Biol, Grand Rapids, MI 48824 USA. RP DeMayo, FJ (reprint author), Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA.; DeMayo, FJ (reprint author), NIEHS, Reprod & Dev Biol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. EM francesco.demayo@nih.gov OI Camper, Sally/0000-0001-8556-3379 FU Intramural Research Program of the National Institute of Environmental Health Sciences [Z1AES103311-01]; NIH (University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core) through a cooperative agreement as part of the Specialized Cooperative Centers Program in Reproduction and Infertility Research [R01HD042311, R01HD057873, R01CA77530, U54HD0077495, U54HD055787, U54HD28934] FX We thank Dr. Paul Labhart of Active Motif for performing the ChIP-seq and the Genetically Engineered Mouse and the Microarray Cores at BCM. We also thank Mrs. Janet DeMayo for manuscript editing. This research was supported in part by the Intramural Research Program of the National Institute of Environmental Health Sciences: project Z1AES103311-01 (F.J.D.). This work was supported by NIH grants R01HD042311 (J.P.L.), R01HD057873 (J.W.J.), R01CA77530 (J.P.L.), U54HD0077495 (F.J.D.), U54HD055787 (F.J.D.), and U54HD28934 (University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core) through a cooperative agreement as part of the Specialized Cooperative Centers Program in Reproduction and Infertility Research. NR 47 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD OCT 25 PY 2016 VL 17 IS 5 BP 1414 EP 1425 DI 10.1016/j.celrep.2016.09.093 PG 12 WC Cell Biology SC Cell Biology GA EA3TF UT WOS:000386527100018 PM 27783953 ER PT J AU Earl, J Rico, D Carrillo-De-Santa-Pau, E Rodriguez-Santiago, B Mendez-Pertuz, M Auer, H Gomez, G Grossman, HB Pisano, DG Schulz, WA Perez-Jurado, LA Carrato, A Theodorescu, D Chanock, S Valencia, A Real, FX AF Earl, Julie Rico, Daniel Carrillo-de-Santa-Pau, Enrique Rodriguez-Santiago, Benjamin Mendez-Pertuz, Marinela Auer, Herbert Gomez, Gonzalo Grossman, H. Barton Pisano, David G. Schulz, Wolfgang A. Perez-Jurado, Luis A. Carrato, Alfredo Theodorescu, Dan Chanock, Stephen Valencia, Alfonso Real, Francisco X. TI The UBC-40 Urothelial Bladder Cancer cell line index: a genomic resource for functional studies (vol 16, 1019, 2015) SO BMC GENOMICS LA English DT Correction ID AUTHENTICATION; TUMORS C1 [Earl, Julie; Carrillo-de-Santa-Pau, Enrique; Mendez-Pertuz, Marinela; Real, Francisco X.] CNIO Spanish Natl Canc Res Ctr, Epithelial Carcinogenesis Grp, F BBVA Canc Cell Biol Programme, Madrid, Spain. [Earl, Julie; Carrato, Alfredo] Hosp Ramon & Cajal, Serv Oncol Med, Madrid, Spain. [Rico, Daniel; Valencia, Alfonso] CNIO Spanish Natl Canc Res Ctr, Struct Biol & Biocomp Programme, Struct Computat Biol Grp, Madrid, Spain. [Rodriguez-Santiago, Benjamin] qGenomics, Quantitat Genom Med Lab, Barcelona, Spain. [Rodriguez-Santiago, Benjamin; Perez-Jurado, Luis A.; Real, Francisco X.] Univ Pompeu Fabra, Dept Ciencies Expt Salut, Barcelona, Spain. [Rodriguez-Santiago, Benjamin; Perez-Jurado, Luis A.] Ctr Invest Biomed Red Enfermedades Raras CIBERER, Barcelona, Spain. [Auer, Herbert] Inst Recerca Biomed Barcelona, Parc Cient Barcelona, Barcelona, Spain. [Gomez, Gonzalo; Pisano, David G.] CNIO Spanish Natl Canc Res Ctr, Struct Biol & Biocomp Programme, Bioinformat Unit, Madrid, Spain. [Grossman, H. Barton] Univ Texas MD Anderson Canc Ctr, Dept Urol, Houston, TX 77030 USA. [Schulz, Wolfgang A.] Univ Dusseldorf, Dept Urol, Dusseldorf, Germany. [Theodorescu, Dan] Univ Colorado, Ctr Comprehens Canc, Aurora, CO 80045 USA. [Chanock, Stephen] NCI, Translat Genom Lab, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Real, FX (reprint author), CNIO Spanish Natl Canc Res Ctr, Epithelial Carcinogenesis Grp, F BBVA Canc Cell Biol Programme, Madrid, Spain.; Real, FX (reprint author), Univ Pompeu Fabra, Dept Ciencies Expt Salut, Barcelona, Spain. EM preal@cnio.es NR 8 TC 0 Z9 0 U1 3 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD OCT 25 PY 2016 VL 17 AR 829 DI 10.1186/s12864-016-3179-z PG 2 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA DZ8AZ UT WOS:000386092100002 PM 27782819 ER PT J AU Brettmann, EA Shaik, JS Zangger, H Lye, LF Kuhlmann, FM Akopyants, NS Oschwald, DM Owens, KL Hickerson, SM Ronet, C Fasel, N Beverley, SM AF Brettmann, Erin A. Shaik, Jahangheer S. Zangger, Haroun Lye, Lon-Fye Kuhlmann, F. Matthew Akopyants, Natalia S. Oschwald, Dayna M. Owens, Katherine L. Hickerson, Suzanne M. Ronet, Catherine Fasel, Nicolas Beverley, Stephen M. TI Tilting the balance between RNA interference and replication eradicates Leishmania RNA virus 1 and mitigates the inflammatory response SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE dsRNA virus; protozoan parasite; endosymbiont; trypanosomatid protozoa; microbial pathogenesis ID MUCOCUTANEOUS LEISHMANIASIS; SACCHAROMYCES-CEREVISIAE; VIANNIA BRAZILIENSIS; PARASITE LEISHMANIA; ANTIVIRAL IMMUNITY; IN-VIVO; HOST; INFECTION; CHALLENGE; SEVERITY AB Many Leishmania (Viannia) parasites harbor the double-stranded RNA virus Leishmania RNA virus 1 (LRV1), which has been associated with increased disease severity in animal models and humans and with drug treatment failures in humans. Remarkably, LRV1 survives in the presence of an active RNAi pathway, which in many organisms controls RNA viruses. We found significant levels (0.4 to 2.5%) of small RNAs derived from LRV1 in both Leishmania braziliensis and Leishmania guyanensis, mapping across both strands and with properties consistent with Dicer-mediated cleavage of the dsRNA genome. LRV1 lacks cis-or trans-acting RNAi inhibitory activities, suggesting that virus retention must be maintained by a balance between RNAi activity and LRV1 replication. To tilt this balance toward elimination, we targeted LRV1 using long-hairpin/stem-loop constructs similar to those effective against chromosomal genes. LRV1 was completely eliminated, at high efficiency, accompanied by a massive overproduction of LRV1-specific siRNAs, representing as much as 87% of the total. For both L. braziliensis and L. guyanensis, RNAi-derived LRV1-negative lines were no longer able to induce a Toll-like receptor 3-dependent hyperinflammatory cytokine response in infected macrophages. We demonstrate in vitro a role for LRV1 in virulence of L. braziliensis, the Leishmania species responsible for the vast majority of mucocutaneous leishmaniasis cases. These findings establish a targeted method for elimination of LRV1, and potentially of other Leishmania viruses, which will facilitate mechanistic dissection of the role of LRV1-mediated virulence. Moreover, our data establish a third paradigm for RNAi-viral relationships in evolution: one of balance rather than elimination. C1 [Brettmann, Erin A.; Shaik, Jahangheer S.; Lye, Lon-Fye; Akopyants, Natalia S.; Owens, Katherine L.; Hickerson, Suzanne M.; Beverley, Stephen M.] Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA. [Zangger, Haroun; Ronet, Catherine; Fasel, Nicolas] Univ Lausanne, Dept Biochem, CH-1066 Epalinges, Switzerland. [Kuhlmann, F. Matthew] Washington Univ, Dept Med, Sch Med, Div Infect Dis, St Louis, MO 63110 USA. [Oschwald, Dayna M.] Washington Univ, Genome Technol Access Ctr, Sch Med, St Louis, MO 63110 USA. [Shaik, Jahangheer S.] NIH, Parasit Dis Lab, Bethesda, MD 20892 USA. [Oschwald, Dayna M.] New York Genome Ctr, New York, NY 10013 USA. RP Beverley, SM (reprint author), Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA. EM stephen.beverley@wustl.edu OI Beverley, Stephen/0000-0001-5319-0811 FU NIGMS Cell and Molecular Biology Training Grant [GM: 007067]; Monsanto Excellence Fund for Graduate Fellowships; NIH [RO1AI029646, R56AI099364, FNRS 3100A0-116665/1, IZ70Z0-131421]; Division of Infectious Diseases; NCI Cancer Center Support Grant [P30 CA91842]; NCRR ICTS/CTSA Grant [UL1 TR000448] FX We thank D. E. Dobson for comments on this manuscript, Florence Prevel for excellent technical support, Jean Patterson (Southwest Foundation for Biomedical Research) for providing Lgy M4147 and anti-capsid antisera, P. Bastien (University of Montpellier) for Lbr strains, and S. P. Calderon-Copete for use of a draft Lgy genome. This work was supported in part by NIGMS Cell and Molecular Biology Training Grant GM: 007067 and the Monsanto Excellence Fund for Graduate Fellowships (to E.A.B.), NIH Grants RO1AI029646 and R56AI099364 (to S.M.B.), Grants FNRS 3100A0-116665/1 and IZ70Z0-131421 (to N.F.), and the Division of Infectious Diseases (F.M.K.). Next-generation sequencing was performed at the Washington University School of Medicine, Department of Genetics Genome Technology Access Center (partially supported by NCI Cancer Center Support Grant P30 CA91842 and NCRR ICTS/CTSA Grant UL1 TR000448). S.M.B. would like to dedicate this paper to the late Elisabetta Ullu, a pioneer of trypanosomatid molecular biology, and a very special colleague and friend. NR 65 TC 2 Z9 2 U1 3 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 25 PY 2016 VL 113 IS 43 BP 11998 EP 12005 DI 10.1073/pnas.1615085113 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ7ZI UT WOS:000386087100031 PM 27790981 ER PT J AU Ash, JA Lu, HB Taxier, LR Long, JM Yang, YH Stein, EA Rapp, PR AF Ash, Jessica A. Lu, Hanbing Taxier, Lisa R. Long, Jeffrey M. Yang, Yihong Stein, Elliot A. Rapp, Peter R. TI Functional connectivity with the retrosplenial cortex predicts cognitive aging in rats SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE resting-state fMRI; default mode network; functional connectivity; neurocognitive aging; rat model ID DEFAULT-MODE NETWORK; INDEPENDENT COMPONENT ANALYSIS; STATE BRAIN ACTIVITY; ALZHEIMERS-DISEASE; INTRINSIC CONNECTIVITY; NEURONAL DYSFUNCTION; MEMORY PERFORMANCE; AMYLOID BURDEN; CORTICAL HUBS; AGED RATS AB Changes in the functional connectivity (FC) of large-scale brain networks are a prominent feature of brain aging, but defining their relationship to variability along the continuum of normal and pathological cognitive outcomes has proved challenging. Here we took advantage of a well-characterized rat model that displays substantial individual differences in hippocampal memory during aging, uncontaminated by slowly progressive, spontaneous neurodegenerative disease. By this approach, we aimed to interrogate the underlying neural network substrates that mediate aging as a uniquely permissive condition and the primary risk for neurodegeneration. Using resting state (rs) blood oxygenation level-dependent fMRI and a restrosplenial/posterior cingulate cortex seed, aged rats demonstrated a large-scale network that had a spatial distribution similar to the default mode network (DMN) in humans, consistent with earlier findings in younger animals. Between-group whole brain contrasts revealed that aged subjects with documented deficits in memory (aged impaired) displayed widespread reductions in cortical FC, prominently including many areas outside the DMN, relative to both young adults (Y) and aged rats with preserved memory (aged unimpaired, AU). Whereas functional connectivity was relatively preserved in AU rats, they exhibited a qualitatively distinct network signature, comprising the loss of an anticorrelated network observed in Y adults. Together the findings demonstrate that changes in rs-FC are specifically coupled to variability in the cognitive outcome of aging, and that successful neurocognitive aging is associated with adaptive remodeling, not simply the persistence of youthful network dynamics. C1 [Ash, Jessica A.; Taxier, Lisa R.; Long, Jeffrey M.; Rapp, Peter R.] NIA, Lab Behav Neurosci, Biomed Res Ctr, NIH, Baltimore, MD 21224 USA. [Lu, Hanbing; Yang, Yihong; Stein, Elliot A.] NIA, Neuroimaging Res Branch, Biomed Res Ctr, NIH, Baltimore, MD 21224 USA. [Ash, Jessica A.] SomaLogic Inc, 2945 Wilderness Pl, Boulder, CO 80301 USA. RP Rapp, PR (reprint author), NIA, Lab Behav Neurosci, Biomed Res Ctr, NIH, Baltimore, MD 21224 USA. EM rappp@mail.nih.gov NR 65 TC 0 Z9 0 U1 5 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 25 PY 2016 VL 113 IS 43 BP 12286 EP 12291 DI 10.1073/pnas.1525309113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ7ZI UT WOS:000386087100080 PM 27791017 ER PT J AU Jung, G Alexander, CJ Wu, XFS Piszczek, G Chen, BC Betzig, E Hammer, JA AF Jung, Goeh Alexander, Christopher J. Wu, Xufeng S. Piszczek, Grzegorz Chen, Bi-Chang Betzig, Eric Hammer, John A. TI V-1 regulates capping protein activity in vivo SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE actin; capping protein; V-1; myotrophin; CARMIL ID FILAMENT BARBED END; INDUCED CARDIAC-HYPERTROPHY; CAPPED ACTIN-FILAMENTS; HOMOLOGY DOMAIN 3; ARP2/3 COMPLEX; DICTYOSTELIUM-DISCOIDEUM; STRUCTURAL BASIS; HEART-FAILURE; CELL MOTILITY; CARMIL AB Capping Protein (CP) plays a central role in the creation of the Arp2/3-generated branched actin networks comprising lamellipodia and pseudopodia by virtue of its ability to cap the actin filament barbed end, which promotes Arp2/3-dependent filament nucleation and optimal branching. The highly conserved protein V-1/Myotrophin binds CP tightly in vitro to render it incapable of binding the barbed end. Here we addressed the physiological significance of this CP antagonist in Dictyostelium, which expresses a V-1 homolog that we show is very similar biochemically to mouse V-1. Consistent with previous studies of CP knockdown, overexpression of V-1 in Dictyostelium reduced the size of pseudopodia and the cortical content of Arp2/3 and induced the formation of filopodia. Importantly, these effects scaled positively with the degree of V-1 overexpression and were not seen with a V-1 mutant that cannot bind CP. V-1 is present in molar excess over CP, suggesting that it suppresses CP activity in the cytoplasm at steady state. Consistently, cells devoid of V-1, like cells overexpressing CP described previously, exhibited a significant decrease in cellular F-actin content. Moreover, V-1-null cells exhibited pronounced defects in macropinocytosis and chemotactic aggregation that were rescued by V-1, but not by the V-1 mutant. Together, these observations demonstrate that V-1 exerts significant influence in vivo on major actin-based processes via its ability to sequester CP. Finally, we present evidence that V-1's ability to sequester CP is regulated by phosphorylation, suggesting that cells may manipulate the level of active CP to tune their "actin phenotype." C1 [Jung, Goeh; Alexander, Christopher J.; Hammer, John A.] NHLBI, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. [Wu, Xufeng S.] NHLBI, Light Microscopy Core, NIH, Bldg 10, Bethesda, MD 20892 USA. [Piszczek, Grzegorz] NHLBI, Biophys Core, NIH, Bldg 10, Bethesda, MD 20892 USA. [Chen, Bi-Chang; Betzig, Eric] Howard Hughes Med Inst, Janelia Res Campus, Ashburn, VA 20147 USA. RP Hammer, JA (reprint author), NHLBI, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM hammerj@nhlbi.nih.gov RI Chen , Bi-Chang /F-3480-2014 NR 55 TC 0 Z9 0 U1 3 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 25 PY 2016 VL 113 IS 43 BP E6610 EP E6619 DI 10.1073/pnas.1605350113 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ7ZI UT WOS:000386087100011 PM 27791032 ER PT J AU Liu, CF Brandt, GS Hoang, QYQ Naumova, N Lazarevic, V Hwang, ES Dekker, J Glimcher, LH Ringe, D Petsko, GA AF Liu, Ce Feng Brandt, Gabriel S. Hoang, Quyen Q. Naumova, Natalia Lazarevic, Vanja Hwang, Eun Sook Dekker, Job Glimcher, Laurie H. Ringe, Dagmar Petsko, Gregory A. TI Crystal structure of the DNA binding domain of the transcription factor T-bet suggests simultaneous recognition of distant genome sites SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE T-bet; transcriptional regulation; DNA looping; crystal structure; master regulator ID IFNG GENE-EXPRESSION; INTERFERON-GAMMA; CELL-DIFFERENTIATION; LINEAGE COMMITMENT; DENDRITIC CELLS; BOX DOMAIN; ENHANCER; LOCUS; CTCF; ELEMENTS AB The transcription factor T-bet (Tbox protein expressed in T cells) is one of the master regulators of both the innate and adaptive immune responses. It plays a central role in T-cell lineage commitment, where it controls the T(H)1 response, and in gene regulation in plasma B-cells and dendritic cells. T-bet is a member of the Tbox family of transcription factors; however, T-bet coordinately regulates the expression of many more genes than other Tbox proteins. A central unresolved question is how T-bet is able to simultaneously recognize distant Tbox binding sites, which may be located thousands of base pairs away. We have determined the crystal structure of the Tbox DNA binding domain (DBD) of T-bet in complex with a palindromic DNA. The structure shows a quaternary structure in which the T-bet dimer has its DNA binding regions splayed far apart, making it impossible for a single dimer to bind both sites of the DNA palindrome. In contrast to most other Tbox proteins, a single T-bet DBD dimer binds simultaneously to identical half-sites on two independent DNA. A fluorescence-based assay confirms that T-bet dimers are able to bring two independent DNA molecules into close juxtaposition. Furthermore, chromosome conformation capture assays confirm that T-bet functions in the direct formation of chromatin loops in vitro and in vivo. The data are consistent with a looping/synapsing model for transcriptional regulation by T-bet in which a single dimer of the transcription factor can recognize and coalesce distinct genetic elements, either a promoter plus a distant regulatory element, or promoters on two different genes. C1 [Liu, Ce Feng; Petsko, Gregory A.] Weill Cornell Med Coll, Appel Alzheimers Dis Res Inst, Brain & Mind Res Inst, New York, NY 10021 USA. [Liu, Ce Feng; Brandt, Gabriel S.; Hoang, Quyen Q.; Ringe, Dagmar; Petsko, Gregory A.] Brandeis Univ, Rosenstiel Basic Med Sci Res Ctr, Waltham, MA 02454 USA. [Brandt, Gabriel S.] Franklin & Marshall Coll, Dept Chem, Lancaster, PA 17604 USA. [Hoang, Quyen Q.] Indiana Univ Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA. [Naumova, Natalia; Dekker, Job] Univ Massachusetts, Sch Med, Program Syst Biol, Dept Biochem & Mol Pharmacol, Worcester, MA 01605 USA. [Lazarevic, Vanja; Hwang, Eun Sook; Glimcher, Laurie H.] Harvard Med Sch, Harvard Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Hwang, Eun Sook] Ewha Womans Univ, Coll Pharm, Div Life & Pharmaceut Sci, Seoul 120750, South Korea. [Glimcher, Laurie H.] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Div Rheumatol Allergy & Immunol, Boston, MA 02115 USA. [Glimcher, Laurie H.] Massachusetts Gen Hosp, MIT, Ragon Inst, Charlestown, MA 02129 USA. [Glimcher, Laurie H.] Harvard Univ, Charlestown, MA 02129 USA. [Naumova, Natalia] Epinomics, Menlo Pk, CA 94030 USA. [Lazarevic, Vanja] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Glimcher, Laurie H.] Dana Farber Canc Inst, Off President, Boston, MA 02215 USA. RP Liu, CF; Petsko, GA (reprint author), Weill Cornell Med Coll, Appel Alzheimers Dis Res Inst, Brain & Mind Res Inst, New York, NY 10021 USA.; Liu, CF; Petsko, GA (reprint author), Brandeis Univ, Rosenstiel Basic Med Sci Res Ctr, Waltham, MA 02454 USA. EM cel2010@med.cornell.edu; gpetsko@med.cornell.edu FU NIH [P01-AI056296]; National Research Service Award Individual Training Grant Fellowship [5F32GM069057]; National Cancer Institute [ACB-12002]; National Institute of General Medical Sciences [AGM-12006]; Argonne National Laboratory [DE-AC02-06CH11357] FX This work was supported by NIH Grant P01-AI056296 (to L.H.G. and G.A.P.). G.S.B. was supported in part by National Research Service Award Individual Training Grant Fellowship 5F32GM069057. This work is based on research conducted at the GM/CA CAT (GM/CA@APS) and the Structural Biology Center of the Advanced Photon Source. GM/CA@APS has been funded in whole or in part with Federal funds from the National Cancer Institute (ACB-12002) and the National Institute of General Medical Sciences (AGM-12006). This research used resources of the Advanced Photon Source, a US Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract DE-AC02-06CH11357. NR 63 TC 0 Z9 0 U1 4 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 25 PY 2016 VL 113 IS 43 BP E6572 EP E6581 DI 10.1073/pnas.1613914113 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ7ZI UT WOS:000386087100007 PM 27791029 ER PT J AU Serr, I Furst, RW Ott, VB Scherm, MG Nikolaev, A Gokmen, F Kalin, S Zillmer, S Bunk, M Weigmann, B Kunschke, N Loretz, B Lehr, CM Kirchner, B Haase, B Pfaffl, M Waisman, A Willis, RA Ziegler, AG Daniel, C AF Serr, Isabelle Fuerst, Rainer W. Ott, Verena B. Scherm, Martin G. Nikolaev, Alexei Goekmen, Fuesun Kaelin, Stefanie Zillmer, Stephanie Bunk, Melanie Weigmann, Benno Kunschke, Nicole Loretz, Brigitta Lehr, Claus-Michael Kirchner, Benedikt Haase, Bettina Pfaffl, Michael Waisman, Ari Willis, Richard A. Ziegler, Anette-G. Daniel, Carolin TI miRNA92a targets KLF2 and the phosphatase PTEN signaling to promote human T follicular helper precursors in T1D islet autoimmunity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE miRNA92a; KLF2; PTEN-PI3K signaling; T follicular helper cells; type 1 diabetes ID KRUPPEL-LIKE FACTOR-2; MEMORY TFH CELLS; CHEMOKINE RECEPTOR; PHOSPHOINOSITIDE 3-KINASE; ANTIBODY-RESPONSES; L-SELECTIN; B-CELLS; DIFFERENTIATION; MICRORNAS; EXPRESSION AB Aberrant immune activation mediated by T effector cell populations is pivotal in the onset of autoimmunity in type 1 diabetes (T1D). T follicular helper (TFH) cells are essential in the induction of high-affinity antibodies, and their precursor memory compartment circulates in the blood. The role of TFH precursors in the onset of islet autoimmunity and signaling pathways regulating their differentiation is incompletely understood. Here, we provide direct evidence that during onset of islet autoimmunity, the insulin-specific target T-cell population is enriched with a C-X-C chemokine receptor type 5 (CXCR5)(+) CD4(+) TFH precursor phenotype. During onset of islet autoimmunity, the frequency of TFH precursors was controlled by high expression of microRNA92a (miRNA92a). miRNA92a-mediated TFH precursor induction was regulated by phosphatase and tension homolog (PTEN) -phosphoinositol-3-kinase (PI3K) signaling involving PTEN and forkhead box protein O1 (Foxo1), supporting autoantibody generation and triggering the onset of islet autoimmunity. Moreover, we identify Krueppel-like factor 2 (KLF2) as a target of miRNA92a in regulating human TFH precursor induction. Importantly, a miRNA92a antagomir completely blocked induction of human TFH precursors in vitro. More importantly, in vivo application of a miRNA92a antagomir to nonobese diabetic (NOD) mice with ongoing islet autoimmunity resulted in a significant reduction of TFH precursors in peripheral blood and pancreatic lymph nodes. Moreover, miRNA92a antagomir application reduced immune infiltration and activation in pancreata of NOD mice as well as humanized NOD Scid IL2 receptor gamma chain knockout (NSG) human leucocyte antigen (HLA)-DQ8 transgenic animals. We therefore propose that miRNA92a and the PTE-NPI3K-KLF2 signaling network could function as targets for innovative precision medicines to reduce T1D islet autoimmunity. C1 [Serr, Isabelle; Scherm, Martin G.; Goekmen, Fuesun; Daniel, Carolin] Helmholtz Zentrum Munchen, Inst Diabet Res, Independent Young Investigator Grp Immune Toleran, Helmholtz Diabet Ctr, D-80939 Munich, Germany. [Serr, Isabelle; Fuerst, Rainer W.; Ott, Verena B.; Scherm, Martin G.; Goekmen, Fuesun; Kaelin, Stefanie; Zillmer, Stephanie; Bunk, Melanie; Ziegler, Anette-G.; Daniel, Carolin] Deutsch Zentrum Diabet Forsch, D-85764 Munich, Germany. [Fuerst, Rainer W.; Zillmer, Stephanie; Bunk, Melanie; Ziegler, Anette-G.] Helmholtz Zentrum Munchen, Helmholtz Diabet Ctr, Inst Diabet Res, D-80939 Munich, Germany. [Fuerst, Rainer W.; Zillmer, Stephanie; Bunk, Melanie; Ziegler, Anette-G.] Tech Univ Munich, Klinikum Rechts Isar, D-80939 Munich, Germany. [Ott, Verena B.; Kaelin, Stefanie] Helmholtz Zentrum Munchen, Helmholtz Diabet Ctr, Inst Diabet & Obes, D-80939 Munich, Germany. [Ott, Verena B.; Kaelin, Stefanie] Tech Univ Munich, Div Metab Dis, D-85748 Munich, Germany. [Nikolaev, Alexei; Waisman, Ari] Johannes Gutenberg Univ Mainz, Inst Mol Med, Univ Med, D-55131 Mainz, Germany. [Weigmann, Benno] Univ Erlangen Nurnberg, Dept Med 1, Kussmaul Campus Med Res, D-91052 Erlangen, Germany. [Kunschke, Nicole; Loretz, Brigitta; Lehr, Claus-Michael] Helmholtz Ctr Infect Res, Helmholtz Inst Pharmaceut Res Saarland, Dept Drug Delivery, D-66123 Saarbrucken, Germany. [Lehr, Claus-Michael] Univ Saarland, Dept Pharm, D-66123 Saarbrucken, Germany. [Kirchner, Benedikt; Pfaffl, Michael] Tech Univ Munich, Physiol Weihenstephan, D-85354 Freising Weihenstephan, Germany. [Haase, Bettina] European Mol Biol Lab, Genom Core Facil, D-69117 Heidelberg, Germany. [Willis, Richard A.] NIH, Emory Vaccine Ctr, Tetramer Core Facil, Atlanta, GA 30322 USA. RP Daniel, C (reprint author), Helmholtz Zentrum Munchen, Inst Diabet Res, Independent Young Investigator Grp Immune Toleran, Helmholtz Diabet Ctr, D-80939 Munich, Germany.; Daniel, C (reprint author), Deutsch Zentrum Diabet Forsch, D-85764 Munich, Germany. EM carolin.daniel@helmholtz-muenchen.de RI Waisman, Ari/C-7383-2015 OI Waisman, Ari/0000-0003-4304-8234 FU Deutsche Forschungsgemeinschaft (DFG) [CRC1811, WE 4656/2]; Young Investigator Group (Helmholtz Zentrum Munchen); DFG [CRC1054]; Juvenile Diabetes Research Foundation [JDRF 2-SRA-2014-161-Q-R, JDRF 17-2012-16, JDRF 6-2012-20]; Kompetenznetz Diabetes Mellitus (Competence Network for Diabetes Mellitus) - Federal Ministry of Education and Research Grants [FKZ 01GI0805-07, FKZ 01GI0805]; German Center for Diabetes Research FX We thank Ruth Chmiel and Susanne Hummel for blood sample collection and patient follow-up; Melanie Spornraft and the European Molecular Biology Laboratory Genecore facility, especially Vladimir Benes, for providing reagents and analysis tools; Peter Achenbach and Claudia Matzke for supporting IAAmeasurements in NOD mice; and M. H. Tschop for critical reading of the manuscript. B. W. is supported by Grant WE 4656/2 and Deutsche Forschungsgemeinschaft (DFG) CRC1811 (B02). C.D. is supported by the Young Investigator Group (Helmholtz Zentrum Munchen) and received support through an associated membership in the CRC1054 of the DFG. The work was supported by grants from the Juvenile Diabetes Research Foundation (JDRF 2-SRA-2014-161-Q-R to C.D. and A.-G.Z.), JDRF 17-2012-16 (to A.G.Z.), and JDRF 6-2012-20 (to A.G.Z.); the Kompetenznetz Diabetes Mellitus (Competence Network for Diabetes Mellitus), funded by the Federal Ministry of Education and Research Grants (FKZ 01GI0805-07 and FKZ 01GI0805); and the German Center for Diabetes Research. A.-G. Z. is Principal Investigator of human birth cohort studies. NR 65 TC 0 Z9 0 U1 3 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 25 PY 2016 VL 113 IS 43 BP E6659 EP E6668 DI 10.1073/pnas.1606646113 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ7ZI UT WOS:000386087100016 PM 27791035 ER PT J AU Dluzen, DF Hooten, NN Zhang, YQ Kim, Y Glover, FE Tajuddin, SM Jacob, KD Zonderman, AB Evans, MK AF Dluzen, Douglas F. Hooten, Nicole Noren Zhang, Yongqing Kim, Yoonseo Glover, Frank E. Tajuddin, Salman M. Jacob, Kimberly D. Zonderman, Alan B. Evans, Michele K. TI Racial differences in microRNA and gene expression in hypertensive women SO SCIENTIFIC REPORTS LA English DT Article ID SMOOTH-MUSCLE-CELLS; AFRICAN-AMERICANS; ENDOTHELIAL-CELLS; DIFFERENTIALLY INTERACTS; UNTRANSLATED REGION; CARDIAC-HYPERTROPHY; POLYMORPHIC TARGET; PHOSPHOLIPASE-D; BLOOD-PRESSURE; ATHEROSCLEROSIS AB Systemic arterial hypertension is an important cause of cardiovascular disease morbidity and mortality. African Americans are disproportionately affected by hypertension, in fact the incidence, prevalence, and severity of hypertension is highest among African American (AA) women. Previous data suggests that differential gene expression influences individual susceptibility to selected diseases and we hypothesized that this phenomena may affect health disparities in hypertension. Transcriptional profiling of peripheral blood mononuclear cells from AA or white, normotensive or hypertensive females identified thousands of mRNAs differentially-expressed by race and/or hypertension. Predominant gene expression differences were observed in AA hypertensive females compared to AA normotensives or white hypertensives. Since microRNAs play important roles in regulating gene expression, we profiled global microRNA expression and observed differentially-expressed microRNAs by race and/or hypertension. We identified novel mRNA-microRNA pairs potentially involved in hypertensionrelated pathways and differently-expressed, including MCL1/miR-20a-5p, APOL3/miR-4763-5p, PLD1/miR-4717-3p, and PLD1/miR-4709-3p. We validated gene expression levels via RT-qPCR and microRNA target validation was performed in primary endothelial cells. Altogether, we identified significant gene expression differences between AA and white female hypertensives and pinpointed novel mRNA-microRNA pairs differentially-expressed by hypertension and race. These differences may contribute to the known disparities in hypertension and may be potential targets for intervention. C1 [Dluzen, Douglas F.; Hooten, Nicole Noren; Kim, Yoonseo; Glover, Frank E.; Tajuddin, Salman M.; Jacob, Kimberly D.; Zonderman, Alan B.; Evans, Michele K.] NIA, Lab Epidemiol & Populat Sci, NIH, Baltimore, MD 21224 USA. [Zhang, Yongqing] NIA, Lab Genet & Genom, NIH, Baltimore, MD 21224 USA. [Jacob, Kimberly D.] Franklin & Marshall Coll, Dept Biol, Lancaster, PA 17604 USA. RP Evans, MK (reprint author), NIA, Lab Epidemiol & Populat Sci, NIH, Baltimore, MD 21224 USA. EM me42v@nih.gov OI Tajuddin, Salman M./0000-0002-7919-8528; Dluzen, Douglas/0000-0002-9426-5071; Zonderman, Alan B/0000-0002-6523-4778 FU NIA IRP, NIH FX We wish to thank Dr. Kevin Becker for helpful input and assistance and William Wood III, Dr. Elfin Lehrmann, and Althaf Lohani for technical assistance. We thank Dr. Ngozi Ejiogu and the HANDLS staff for their careful evaluation and management of HANDLS participants. This study was supported and funded by the NIA IRP, NIH. NR 55 TC 0 Z9 0 U1 4 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD OCT 25 PY 2016 VL 6 AR 35815 DI 10.1038/srep35815 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ6WL UT WOS:000386003200001 PM 27779208 ER PT J AU Hyman, SE Landis, SC Leshner, AI AF Hyman, Steven E. Landis, Story C. Leshner, Alan I. TI Research Into Brain Disorders as an Example of Targeted Science SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID UNITED-STATES C1 [Hyman, Steven E.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Landis, Story C.] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Leshner, Alan I.] Amer Assoc Advancement Sci, 12118 Little Creek Dr, Potomac, MD 20854 USA. RP Leshner, AI (reprint author), Amer Assoc Advancement Sci, 12118 Little Creek Dr, Potomac, MD 20854 USA. EM alan.i.leshner@gmail.com NR 5 TC 2 Z9 2 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD OCT 25 PY 2016 VL 316 IS 16 BP 1673 EP 1674 DI 10.1001/jama.2016.12412 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DZ8GB UT WOS:000386107800029 PM 27668392 ER PT J AU Pinsky, PF Doroudi, M AF Pinsky, Paul F. Doroudi, Maryam TI Colorectal Cancer Screening SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Pinsky, Paul F.; Doroudi, Maryam] NCI, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. RP Pinsky, PF (reprint author), NCI, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM pinskyp@mail.nih.gov NR 4 TC 0 Z9 0 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD OCT 25 PY 2016 VL 316 IS 16 BP 1715 EP 1715 DI 10.1001/jama.2016.13849 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA DZ8GB UT WOS:000386107800043 PM 27784086 ER PT J AU Ulland, TK Jain, N Hornick, EE Elliott, EI Clay, GM Sadler, JJ Mills, KAM Janowski, AM Volk, APD Wang, K Legge, KL Gakhar, L Bourdi, M Ferguson, PJ Wilson, ME Cassel, SL Sutterwala, FS AF Ulland, Tyler K. Jain, Nidhi Hornick, Emma E. Elliott, Eric I. Clay, Gwendolyn M. Sadler, Jeffrey J. Mills, Kathleen A. M. Janowski, Ann M. Volk, A. Paige Davis Wang, Kai Legge, Kevin L. Gakhar, Lokesh Bourdi, Mohammed Ferguson, Polly J. Wilson, Mary E. Cassel, Suzanne L. Sutterwala, Fayyaz S. TI Nlrp12 mutation causes C57BL/6J strain-specific defect in neutrophil recruitment SO NATURE COMMUNICATIONS LA English DT Article ID NF-KAPPA-B; FRANCISELLA-TULARENSIS; COLON INFLAMMATION; ADAPTIVE IMMUNITY; DENDRITIC CELLS; CUTTING EDGE; ACTIVATION; MIGRATION; PROTEIN; TUMORIGENESIS AB The inbred mouse strain C57BL/6J is widely used in models of immunological and infectious diseases. Here we show that C57BL/6J mice have a defect in neutrophil recruitment to a range of inflammatory stimuli compared with the related C57BL/6N substrain. This immune perturbation is associated with a missense mutation in Nlrp12 in C57BL/6J mice. Both C57BL/6J and NLRP12-deficient mice have increased susceptibility to bacterial infection that correlates with defective neutrophil migration. C57BL/6J and NLRP12-deficient macrophages have impaired CXCL1 production and the neutrophil defect observed in C57BL/6J and NLRP12-deficient mice is rescued by restoration of macrophage NLRP12. These results demonstrate that C57BL/6J mice have a functional defect in NLRP12 and that macrophages require NLRP12 expression for effective recruitment of neutrophils to inflammatory sites. C1 [Ulland, Tyler K.; Jain, Nidhi; Hornick, Emma E.; Elliott, Eric I.; Sadler, Jeffrey J.; Mills, Kathleen A. M.; Janowski, Ann M.; Volk, A. Paige Davis; Cassel, Suzanne L.; Sutterwala, Fayyaz S.] Univ Iowa, Carver Coll Med, Inflammat Program, Iowa City, IA 52242 USA. [Ulland, Tyler K.; Elliott, Eric I.; Clay, Gwendolyn M.; Wilson, Mary E.; Sutterwala, Fayyaz S.] Univ Iowa, Carver Coll Med, Interdisciplinary Program Mol & Cellular Biol, Iowa City, IA 52242 USA. [Jain, Nidhi; Elliott, Eric I.; Cassel, Suzanne L.; Sutterwala, Fayyaz S.] Cedars Sinai Med Ctr, Dept Med, Los Angeles, CA 90048 USA. [Hornick, Emma E.; Janowski, Ann M.; Legge, Kevin L.; Wilson, Mary E.; Sutterwala, Fayyaz S.] Univ Iowa, Carver Coll Med, Interdisciplinary Program Immunol, Iowa City, IA 52242 USA. [Elliott, Eric I.; Clay, Gwendolyn M.; Legge, Kevin L.; Wilson, Mary E.; Sutterwala, Fayyaz S.] Univ Iowa, Carver Coll Med, Med Scientist Training Program, Iowa City, IA 52242 USA. [Volk, A. Paige Davis] Univ Iowa, Dept Pediat, Carver Coll Med, Iowa City, IA 52242 USA. [Wang, Kai] Univ Iowa, Dept Biostat, Coll Publ Hlth, Iowa City, IA 52242 USA. [Legge, Kevin L.] Univ Iowa, Dept Pathol, Carver Coll Med, Iowa City, IA 52242 USA. [Gakhar, Lokesh] Univ Iowa, Dept Biochem, Carver Coll Med, Iowa City, IA 52242 USA. [Gakhar, Lokesh] Univ Iowa, Prot Crystallog Facil, Carver Coll Med, Iowa City, IA 52242 USA. [Bourdi, Mohammed] NHLBI, Mol & Cellular Toxicol Sect, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Wilson, Mary E.; Cassel, Suzanne L.; Sutterwala, Fayyaz S.] Univ Iowa, Dept Internal Med, Carver Coll Med, Iowa City, IA 52242 USA. [Wilson, Mary E.; Sutterwala, Fayyaz S.] Vet Affairs Med Ctr, Iowa City, IA 52246 USA. [Wilson, Mary E.] Univ Iowa, Dept Microbiol, Carver Coll Med, Iowa City, IA 52242 USA. RP Sutterwala, FS (reprint author), Univ Iowa, Carver Coll Med, Inflammat Program, Iowa City, IA 52242 USA.; Sutterwala, FS (reprint author), Univ Iowa, Carver Coll Med, Interdisciplinary Program Mol & Cellular Biol, Iowa City, IA 52242 USA.; Sutterwala, FS (reprint author), Cedars Sinai Med Ctr, Dept Med, Los Angeles, CA 90048 USA.; Sutterwala, FS (reprint author), Univ Iowa, Carver Coll Med, Interdisciplinary Program Immunol, Iowa City, IA 52242 USA.; Sutterwala, FS (reprint author), Univ Iowa, Carver Coll Med, Med Scientist Training Program, Iowa City, IA 52242 USA.; Sutterwala, FS (reprint author), Univ Iowa, Dept Internal Med, Carver Coll Med, Iowa City, IA 52242 USA.; Sutterwala, FS (reprint author), Vet Affairs Med Ctr, Iowa City, IA 52246 USA. EM fayyaz.sutterwala@cshs.org OI Ulland, Tyler/0000-0002-6507-4989; Legge, Kevin/0000-0001-9800-6854 FU NIH [R01 AI118719, P01 AI44642]; Midwest Regional Center of Excellence [U54 AI057160, R01 AI104706, R01 AR059703, T32 AI007485]; Asthma and Allergy Foundation of America fellowship FX We thank Richard Flavell and Millennium Pharmaceuticals for providing knockout mice, William Nauseef for helpful discussion and Vickie Knepper-Adrian for technical assistance. NIH grants R01 AI118719 (F.S.S.), P01 AI44642 (F.S.S.), the Midwest Regional Center of Excellence project grant U54 AI057160 (F.S.S.), R01 AI104706 (S.L.C.), R01 AR059703 (P.J.F.), T32 AI007485 (A.M.J.) and an Asthma and Allergy Foundation of America fellowship (S.L.C.) supported this work. NR 35 TC 0 Z9 0 U1 12 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD OCT 25 PY 2016 VL 7 AR 13180 DI 10.1038/ncomms13180 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ6VB UT WOS:000385999600001 PM 27779193 ER PT J AU Grist, EPM Flegg, JA Humphreys, G Mas, IS Anderson, TJC Ashley, EA Day, NPJ Dhorda, M Dondorp, AM Abul Faiz, M Gething, PW Hien, TT Hlaing, TM Imwong, M Kindermans, JM Maude, RJ Mayxay, M McDew-White, M Menard, D Nair, S Nosten, F Newton, PN Price, RN Pukrittayakamee, S Takala-Harrison, S Smithuis, F Nguyen, NT Tun, KM White, NJ Witkowski, B Woodrow, CJ Fairhurst, RM Sibley, CH Guerin, PJ AF Grist, Eric P. M. Flegg, Jennifer A. Humphreys, Georgina Mas, Ignacio Suay Anderson, Tim J. C. Ashley, Elizabeth A. Day, Nicholas P. J. Dhorda, Mehul Dondorp, Arjen M. Abul Faiz, M. Gething, Peter W. Hien, Tran T. Hlaing, Tin M. Imwong, Mallika Kindermans, Jean-Marie Maude, Richard J. Mayxay, Mayfong McDew-White, Marina Menard, Didier Nair, Shalini Nosten, Francois Newton, Paul N. Price, Ric N. Pukrittayakamee, Sasithon Takala-Harrison, Shannon Smithuis, Frank Nguyen, Nhien T. Tun, Kyaw M. White, Nicholas J. Witkowski, Benoit Woodrow, Charles J. Fairhurst, Rick M. Sibley, Carol Hopkins Guerin, Philippe J. TI Optimal health and disease management using spatial uncertainty: a geographic characterization of emergent artemisinin-resistant Plasmodium falciparum distributions in Southeast Asia SO INTERNATIONAL JOURNAL OF HEALTH GEOGRAPHICS LA English DT Article DE Surveillance; Drug resistance; Malaria; Artemisinin; Greater Mekong Subregion ID MALARIA; CAMBODIA AB Background: Artemisinin-resistant Plasmodium falciparum malaria parasites are now present across much of mainland Southeast Asia, where ongoing surveys are measuring and mapping their spatial distribution. These efforts require substantial resources. Here we propose a generic 'smart surveillance' methodology to identify optimal candidate sites for future sampling and thus map the distribution of artemisinin resistance most efficiently. Methods: The approach uses the 'uncertainty' map generated iteratively by a geostatistical model to determine optimal locations for subsequent sampling. Results: The methodology is illustrated using recent data on the prevalence of the K13-propeller polymorphism (a genetic marker of artemisinin resistance) in the Greater Mekong Subregion. Conclusion: This methodology, which has broader application to geostatistical mapping in general, could improve the quality and efficiency of drug resistance mapping and thereby guide practical operations to eliminate malaria in affected areas. C1 [Grist, Eric P. M.; Flegg, Jennifer A.; Humphreys, Georgina; Mas, Ignacio Suay; Dhorda, Mehul; Newton, Paul N.; Price, Ric N.; Witkowski, Benoit; Sibley, Carol Hopkins; Guerin, Philippe J.] WorldWide Antimalarial Resistance Network WWARN, Oxford, England. [Grist, Eric P. M.; Flegg, Jennifer A.; Humphreys, Georgina; Mas, Ignacio Suay; Ashley, Elizabeth A.; Dhorda, Mehul; Dondorp, Arjen M.; Hien, Tran T.; Maude, Richard J.; Mayxay, Mayfong; Nosten, Francois; Newton, Paul N.; Price, Ric N.; Smithuis, Frank; White, Nicholas J.; Woodrow, Charles J.; Guerin, Philippe J.] Univ Oxford, Ctr Trop Med & Global Hlth, Nuffield Dept Med, S Parks Rd, Oxford OX3 7LJ, England. [Flegg, Jennifer A.] Monash Univ, Sch Math Sci, Melbourne, Vic, Australia. [Anderson, Tim J. C.; McDew-White, Marina; Nair, Shalini] Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA. [Ashley, Elizabeth A.; Day, Nicholas P. J.; Dondorp, Arjen M.; Abul Faiz, M.; Maude, Richard J.; White, Nicholas J.; Woodrow, Charles J.] Mahidol Univ, Mahidol Oxford Trop Med Res Unit, Bangkok, Thailand. [Fairhurst, Rick M.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Abul Faiz, M.] Dev Care Fdn, Dhaka, Bangladesh. [Abul Faiz, M.] Malaria Res Grp, Dhaka, Bangladesh. [Gething, Peter W.] Univ Oxford, Dept Zool, Spatial Epidemiol & Ecol Grp, Oxford, England. [Hien, Tran T.; Nguyen, Nhien T.] Univ Oxford, Hosp Trop Dis, Clin Res Unit, Ho Chi Minh City, Vietnam. [Hlaing, Tin M.; Tun, Kyaw M.] Def Serv Med Res Ctr, Naypyitaw, Myanmar. [Kindermans, Jean-Marie] Med Sans Frontieres, Brussels, Belgium. [Imwong, Mallika] Mahidol Univ, Fac Trop Med, Dept Mol Trop Med & Genet, Bangkok, Thailand. [Menard, Didier; Witkowski, Benoit] Inst Pasteur Cambodia, Malaria Mol Epidemiol Unit, Phnom Penh, Cambodia. [Nosten, Francois] Mahidol Univ, Shoklo Malaria Res Unit, Mahidol Oxford Trop Med Res Unit, Fac Trop Med, Mae Sot, Thailand. [Mayxay, Mayfong; Newton, Paul N.] Mahosot Hosp, Lao Oxford Mahosot Hosp Wellcome Trust Res Unit L, Microbiol Lab, Viangchan, Laos. [Takala-Harrison, Shannon] Univ Maryland, Sch Med, Inst Global Hlth, Baltimore, MD 21201 USA. [Price, Ric N.] Charles Darwin Univ, Menzies Sch Hlth Res, Darwin, NT, Australia. [Pukrittayakamee, Sasithon] Mahidol Univ, Fac Trop Med, Bangkok, Thailand. [Smithuis, Frank; Tun, Kyaw M.] Myanmar Oxford Clin Res Unit, Yangon, Myanmar. [Sibley, Carol Hopkins] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Maude, Richard J.] Harvard Univ, Harvard TH Chan Sch Publ Hlth, Boston, MA 02115 USA. RP Grist, EPM (reprint author), WorldWide Antimalarial Resistance Network WWARN, Oxford, England.; Grist, EPM (reprint author), Univ Oxford, Ctr Trop Med & Global Hlth, Nuffield Dept Med, S Parks Rd, Oxford OX3 7LJ, England. EM epmgrist@gmail.com OI Gething, Peter/0000-0001-6759-5449 FU UK Department for International Development; Worldwide Antimalarial Resistance Network; Intramural Research Program of the National Institute of Allergy and Infectious Diseases of the National Institutes of Health; Bill and Melinda Gates Foundation; Wellcome Trust of Great Britain; Li Ka Shing Foundation Scholarship; Mahidol University; ExxonMobile Foundation; National Institutes of Health (NIH) [R37AI048071]; Research Facilities Improvement Program from the National Center for Research Resources of the NIH [C06 RR013556, RR017515] FX This study was supported by the UK Department for International Development, the Worldwide Antimalarial Resistance Network, the Intramural Research Program of the National Institute of Allergy and Infectious Diseases of the National Institutes of Health, and the Bill and Melinda Gates Foundation. The Mahidol-University Oxford Tropical Medicine Research Programme is funded by the Wellcome Trust of Great Britain. KMT was supported by a Li Ka Shing Foundation Scholarship. MI was supported by Mahidol University. EPMG was supported by the ExxonMobile Foundation. Work at Texas Biomedical Research Institute was supported by a National Institutes of Health (NIH) Grant (No. R37AI048071) to TJCA and was done in facilities constructed with support from Research Facilities Improvement Program (Grants C06 RR013556 and RR017515) from the National Center for Research Resources of the NIH. NR 31 TC 1 Z9 1 U1 5 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-072X J9 INT J HEALTH GEOGR JI Int. J. Health Geogr. PD OCT 24 PY 2016 VL 15 AR 37 DI 10.1186/s12942-016-0064-6 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EA0EN UT WOS:000386258600001 PM 27776514 ER PT J AU Gill, AL Green, SA Abdullah, S Le Saout, C Pittaluga, S Chen, H Turnier, R Lifson, J Godin, S Qin, J Sneller, MC Cuillerot, JM Sabzevari, H Lane, HC Catalfamo, M AF Gill, Amanda L. Green, Samantha A. Abdullah, Shahed Le Saout, Cecile Pittaluga, Stefania Chen, Hui Turnier, Refika Lifson, Jeffrey Godin, Steven Qin, Jing Sneller, Michael C. Cuillerot, Jean-Marie Sabzevari, Helen Lane, H. Clifford Catalfamo, Marta TI Programed death-1/programed death-ligand 1 expression in lymph nodes of HIV infected patients: results of a pilot safety study in rhesus macaques using anti-programed death-ligand 1 (Avelumab) SO AIDS LA English DT Article DE anti-programed death-ligand 1 immunotherapy; HIV; HIV immunotherapy; programed death-1; programed death-ligand 1 ID T-CELL EXHAUSTION; DISEASE PROGRESSION; PD-1 BLOCKADE; RESPONSES; VIRUS; B7-H1; IMMUNITY; REPLICATION; ACTIVATION; POPULATION AB Objective:The programed death-1 (PD1)/programed death-ligand 1 (PD-L1) pathway plays a critical role in balancing immunity and host immunopathology. During chronic HIV/SIV infection, there is persistent immune activation accompanied by accumulation of virus-specific cells with terminally differentiated phenotypes and expression of regulatory receptors such as PD1. These observations led us to hypothesize that the PD1/PD-L1 pathway contributes to the functional dysregulation and ineffective viral control, and its blockade may be a potential immunotherapeutic target.Methods:Lymph node biopsies from HIV-infected patients (n=23) were studied for expression of PD1 and PD-L1. In addition, we assessed the safety and biological activity of a human anti-PD-L1 antibody (Avelumab) in chronically SIV-infected rhesus macaques.Results:PD-L1 expression was observed in cells with myloid/macrophage morphology in HIV-infected lymph nodes. Administration of anti-PD-L1 was well tolerated, and no changes in body weights, hematologic, or chemistry parameters were observed during the study. Blockade of PD-L1 led to a trend of transient viral control after discontinuation of treatment.Conclusion:Administration of anti-PD-L1 in chronic SIV-infected rhesus macaques was well tolerated. Overall, these data warrant further investigation to assess the efficacy of anti-PD-L1 treatment on viral control in chronic SIV infection as a prelude to such therapy in humans. C1 [Gill, Amanda L.; Green, Samantha A.; Le Saout, Cecile; Chen, Hui; Sneller, Michael C.; Lane, H. Clifford; Catalfamo, Marta] NIAID, CMRS, Immunoregulat Lab, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Abdullah, Shahed; Pittaluga, Stefania] NCI, Pathol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Turnier, Refika] Leidos Biomed Res Inc, Clin Support Lab, Frederick, MD USA. [Lifson, Jeffrey] Frederick Natl Lab, Retroviral Pathogenesis Sect, AIDS & Canc Virus Program, Leidos Biomed Res, Frederick, MD USA. [Godin, Steven] Smithers Avanza Toxicol Serv, Gaithersburg, MD USA. [Qin, Jing] NIAID, Biostat Res Branch, DCR, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Cuillerot, Jean-Marie] EMD Serono Inc, Rockland, MA USA. [Sabzevari, Helen] Compass Therapeut, Cambridge, MA USA. RP Catalfamo, M (reprint author), NIAID, CMRS, Immunoregulat Lab, NIH, Bldg 10 Room 11B16,9000 Rockville Pike, Bethesda, MD 20892 USA. EM catalfam@niaid.nih.gov; catalfam@niaid.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH; National Cancer Institute, NIH [HHSN261200800001E] FX We thank the patients of the National Institute of Allergy and Infectious Diseases HIV Clinic for their participation. The SIVmac239 Gag Peptide Pool was obtained through the NIH-AIDS Reagent Program, Division of AIDS, National Institute of Allergy and Infectious Diseases, NIH. Some mAbs were provided by the NIH-Nonhuman Primate Reagent Resource. This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH. Leidos Biomedical Research, Inc. has been funded in whole or in part with federal funds from the National Cancer Institute, NIH, under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 44 TC 1 Z9 1 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD OCT 23 PY 2016 VL 30 IS 16 BP 2487 EP 2493 DI 10.1097/QAD.0000000000001217 PG 7 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA DZ0KV UT WOS:000385528600010 PM 27490642 ER PT J AU Beydoun, MA Beydoun, HA Mode, N Dore, GA Canas, JA Eid, SM Zonderman, AB AF Beydoun, M. A. Beydoun, H. A. Mode, N. Dore, G. A. Canas, J. A. Eid, S. M. Zonderman, A. B. TI Racial disparities in adult all-cause and cause-specific mortality among us adults: mediating and moderating factors SO BMC PUBLIC HEALTH LA English DT Article DE Race/ethnicity; Socio-economic status; Adult mortality; Cancer; Cardiovascular disease ID CARDIOVASCULAR-DISEASE MORTALITY; FULLY CONDITIONAL SPECIFICATION; BREAST-CANCER MORTALITY; HEART-STUDY EVIDENCE; NON-HISPANIC WHITES; SOCIOECONOMIC-STATUS; HEALTH BEHAVIORS; MULTIPLE IMPUTATION; MEXICAN-AMERICANS; AFRICAN-AMERICAN AB Background: Studies uncovering factors beyond socio-economic status (SES) that would explain racial and ethnic disparities in mortality are scarce. Methods: Using prospective cohort data from the Third National Health and Nutrition Examination Survey (NHANES III), we examined all-cause and cause-specific mortality disparities by race, mediation through key factors and moderation by age (20-49 vs. 50+), sex and poverty status. Cox proportional hazards, discrete-time hazards and competing risk regression models were conducted (N = 16,573 participants, n = 4207 deaths, Median time = 170 months (1-217 months)). Results: Age, sex and poverty income ratio-adjusted hazard rates were higher among Non-Hispanic Blacks (NHBs) vs. Non-Hispanic Whites (NHW). Within the above-poverty young men stratum where this association was the strongest, the socio-demographic-adjusted HR = 2.59, p < 0.001 was only partially attenuated by SES and other factors (full model HR = 2.08, p = 0.003). Income, education, diet quality, allostatic load and self-rated health, were among key mediators explaining NHB vs. NHW disparity in mortality. The Hispanic paradox was observed consistently among women above poverty (young and old). NHBs had higher CVD-related mortality risk compared to NHW which was explained by factors beyond SES. Those factors did not explain excess risk among NHB for neoplasm-related death (fully adjusted HR = 1.41, 95 % CI: 1.02-2.75, p = 0.044). Moreover, those factors explained the lower risk of neoplasm-related death among MA compared to NHW, while CVD-related mortality risk became lower among MA compared to NHW upon multivariate adjustment. Conclusions: In sum, racial/ethnic disparities in all-cause and cause-specific mortality (particularly cardiovascular and neoplasms) were partly explained by socio-demographic, SES, health-related and dietary factors, and differentially by age, sex and poverty strata. C1 [Beydoun, M. A.; Mode, N.; Dore, G. A.; Zonderman, A. B.] NIA, NIH, Biomed Res Ctr, IRP, 251 Bayview Blvd,Suite 100 Room 04B118, Baltimore, MD 21224 USA. [Beydoun, H. A.; Eid, S. M.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Canas, J. A.] Nemours Childrens Clin, Pediat Endocrinol Diabet & Metab, Jacksonville, FL USA. RP Beydoun, MA (reprint author), NIA, NIH, Biomed Res Ctr, IRP, 251 Bayview Blvd,Suite 100 Room 04B118, Baltimore, MD 21224 USA. EM baydounm@mail.nih.gov OI Zonderman, Alan B/0000-0002-6523-4778 FU Intramural Research Program of the NIH; National Institute on Aging FX This work was fully supported by the Intramural Research Program of the NIH, National Institute on Aging. NR 46 TC 0 Z9 0 U1 11 U2 11 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2458 J9 BMC PUBLIC HEALTH JI BMC Public Health PD OCT 22 PY 2016 VL 16 AR 1113 DI 10.1186/s12889-016-3744-z PG 13 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DZ6IL UT WOS:000385965600003 PM 27770781 ER PT J AU Schneider, M van de Water, T Araya, R Bonini, BB Pilowsky, DJ Pratt, C Price, L Rojas, G Seedat, S Sharma, M Susser, E AF Schneider, M. van de Water, T. Araya, R. Bonini, B. B. Pilowsky, D. J. Pratt, C. Price, L. Rojas, G. Seedat, S. Sharma, M. Susser, E. TI Monitoring and evaluating capacity building activities in low and middle income countries: challenges and opportunities SO GLOBAL MENTAL HEALTH LA English DT Article DE Capacity building; low and middle income countries; mental health; monitoring and evaluation; research; teaching and learning ID MENTAL-HEALTH RESEARCH; DISORDERS; GAP; SETTINGS; AFRICA AB Background Lower and middle income countries (LMICs) are home to > 80% of the global population, but mental health researchers and LMIC investigator led publications are concentrated in 10% of LMICs. Increasing research and research outputs, such as in the form of peer reviewed publications, require increased capacity building (CB) opportunities in LMICs. The National Institute of Mental Health (NIMH) initiative, Collaborative Hubs for International Research on Mental Health reaches across five regional 'hubs' established in LMICs, to provide training and support for emerging researchers through hub-specific CB activities. This paper describes the range of CB activities, the process of monitoring, and the early outcomes of CB activities conducted by the five research hubs. Methods The indicators used to describe the nature, the monitoring, and the early outcomes of CB activities were developed collectively by the members of an inter-hub CB workgroup representing all five hubs. These indicators included but were not limited to courses, publications, and grants. Results Results for all indicators demonstrate a wide range of feasible CB activities. The five hubs were successful in providing at least one and the majority several courses; 13 CB recipient-led articles were accepted for publication; and nine grant applications were successful. Conclusions The hubs were successful in providing CB recipients with a wide range of CB activities. The challenge remains to ensure ongoing CB of mental health researchers in LMICs, and in particular, to sustain the CB efforts of the five hubs after the termination of NIMH funding. C1 [Schneider, M.] Univ Cape Town, Cape Town, South Africa. [van de Water, T.; Seedat, S.] Univ Stellenbosch, ZA-7600 Stellenbosch, South Africa. [Araya, R.] London Sch Hyg & Trop Med, London, England. [Bonini, B. B.] Univ Sao Paulo, Sao Paulo, Brazil. [Pilowsky, D. J.; Pratt, C.; Susser, E.] Columbia Univ, New York, NY USA. [Price, L.] NIMH, NIH, Bethesda, MD 20892 USA. [Rojas, G.] Univ Chile, Santiago, Chile. [Sharma, M.] Publ Hlth Fdn India, Delhi, India. RP Schneider, M (reprint author), Univ Cape Town, Fac Hlth Sci, Dept Psychiat & Mental Hlth, POB 241, ZA-8000 Cape Town, South Africa. EM marguerite.schneider@uct.ac.za NR 21 TC 1 Z9 1 U1 3 U2 3 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 2054-4251 J9 GLOB MENT HEALTH JI Glob. Ment. Health PD OCT 21 PY 2016 VL 3 AR e29 DI 10.1017/gmh.2016.24 PG 15 WC Psychiatry SC Psychiatry GA EC2UV UT WOS:000387980600001 ER PT J AU Bai, RL Benjamini, D Cheng, J Basser, PJ AF Bai, Ruiliang Benjamini, Dan Cheng, Jian Basser, Peter J. TI Fast, accurate 2D-MR relaxation exchange spectroscopy (REXSY): Beyond compressed sensing SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID OPTIMAL SAMPLING STRATEGIES; 2D MRI RELAXOMETRY; WATER-EXCHANGE; MAGNETIC-RESONANCE; MYELIN WATER; IN-VIVO; MULTIDIMENSIONAL NMR; PERIPHERAL-NERVE; T-2 DISTRIBUTION; POROUS-MEDIA AB Previously, we showed that compressive or compressed sensing (CS) can be used to reduce significantly the data required to obtain 2D-NMR relaxation and diffusion spectra when they are sparse or well localized. In some cases, an order of magnitude fewer uniformly sampled data were required to reconstruct 2D-MR spectra of comparable quality. Nonetheless, this acceleration may still not be sufficient to make 2D-MR spectroscopy practicable for many important applications, such as studying time-varying exchange processes in swelling gels or drying paints, in living tissue in response to various biological or biochemical challenges, and particularly for in vivo MRI applications. A recently introduced framework, marginal distributions constrained optimization (MADCO), tremendously accelerates such 2D acquisitions by using a priori obtained 1D marginal distribution as powerful constraints when 2D spectra are reconstructed. Here we exploit one important intrinsic property of the 2D-MR relaxation exchange spectra: the fact that the 1D marginal distributions of each 2D-MR relaxation exchange spectrum in both dimensions are equal and can be rapidly estimated from a single Carr-Purcell-Meiboom-Gill (CPMG) or inversion recovery prepared CPMG measurement. We extend the MADCO framework by further proposing to use the 1D marginal distributions to inform the subsequent 2D data-sampling scheme, concentrating measurements where spectral peaks are present and reducing them where they are not. In this way we achieve compression or acceleration that is an order of magnitude greater than that in our previous CS method while providing data in reconstructed 2D-MR spectral maps of comparable quality, demonstrated using several simulated and real 2D T-2-T-2 experimental data. This method, which can be called "informed compressed sensing," is extendable to other 2D- and even ND-MR exchange spectroscopy. C1 [Bai, Ruiliang; Benjamini, Dan; Cheng, Jian; Basser, Peter J.] NICHD, Sect Quantitat Imaging & Tissue Sci, DIBGI, NIH, Bethesda, MD 20892 USA. RP Bai, RL (reprint author), NICHD, Sect Quantitat Imaging & Tissue Sci, DIBGI, NIH, Bethesda, MD 20892 USA. FU Intramural Research Program (IRP) of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH FX This work was supported by the Intramural Research Program (IRP) of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH. We thank our colleague, Dr. Alexandru Avram, for helpful discussions. We are also grateful to our colleagues Dr. Michal Komlosh and Dr. Elizabeth Hutchinson for assistance with NMR experiments. NR 49 TC 0 Z9 0 U1 4 U2 4 PU AMER INST PHYSICS PI MELVILLE PA 1305 WALT WHITMAN RD, STE 300, MELVILLE, NY 11747-4501 USA SN 0021-9606 EI 1089-7690 J9 J CHEM PHYS JI J. Chem. Phys. PD OCT 21 PY 2016 VL 145 IS 15 AR 154202 DI 10.1063/1.4964144 PG 14 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA EA8VD UT WOS:000386916500019 PM 27782473 ER PT J AU Frey, AG Palenchar, DJ Wildemann, JD Philpott, CC AF Frey, Avery G. Palenchar, Daniel J. Wildemann, Justin D. Philpott, Caroline C. TI A Glutaredoxin center dot BolA Complex Serves as an Iron-Sulfur Cluster Chaperone for the Cytosolic Cluster Assembly Machinery SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE biotin; iron; iron-sulfur protein; metal homeostasis; metal ion-protein interaction; metalloprotein; BolA2; Ciapin1; Glrx3; Ndor1 ID SACCHAROMYCES-CEREVISIAE; MONOTHIOL GLUTAREDOXIN; PROTEIN BIOGENESIS; REGULATORY PROTEINS; PHP4 FUNCTION; 3 PICOT; ANAMORSIN; GRX4; HOMEOSTASIS; MATURATION AB Cells contain hundreds of proteins that require iron cofactors for activity. Iron cofactors are synthesized in the cell, but the pathways involved in distributing heme, iron-sulfur clusters, and ferrous/ferric ions to apoproteins remain incompletely defined. In particular, cytosolic monothiol glutaredoxins and BolA-like proteins have been identified as [2Fe-2S]-coordinating complexes in vitro and iron-regulatory proteins in fungi, but it is not clear how these proteins function in mammalian systems or how this complex might affect Fe-S proteins or the cytosolic Fe-S assembly machinery. To explore these questions, we use quantitative immunoprecipitation and live cell proximity-dependent biotinylation to monitor interactions between Glrx3, BolA2, and components of the cytosolic iron-sulfur cluster assembly system. We characterize cytosolic Glrx3BolA2 as a [2Fe-2S] chaperone complex in human cells. Unlike complexes formed by fungal orthologs, human Glrx3-BolA2 interaction required the coordination of Fe-S clusters, whereas Glrx3 homodimer formation did not. Cellular Glrx3BolA2 complexes increased 6-8-fold in response to increasing iron, forming a rapidly expandable pool of Fe-S clusters. Fe-S coordination by Glrx3BolA2 did not depend on Ciapin1 or Ciao1, proteins that bind Glrx3 and are involved in cytosolic Fe-S cluster assembly and distribution. Instead, Glrx3 and BolA2 bound and facilitated Fe-S incorporation into Ciapin1, a [2Fe-2S] protein functioning early in the cytosolic Fe-S assembly pathway. Thus, Glrx3BolA is a [2Fe-2S] chaperone complex capable of transferring [2Fe-2S] clusters to apoproteins in human cells. C1 [Frey, Avery G.; Philpott, Caroline C.] NIDDK, Genet & Metab Sect, Liver Dis Branch, NIH, Bldg 10,Rm 9B-16,10 Ctr Dr,MSC 1800, Bethesda, MD 20892 USA. [Wildemann, Justin D.] Ohio State Univ, Coll Med, Columbus, OH 43210 USA. RP Philpott, CC (reprint author), NIDDK, Genet & Metab Sect, Liver Dis Branch, NIH, Bldg 10,Rm 9B-16,10 Ctr Dr,MSC 1800, Bethesda, MD 20892 USA. EM Carolinep@mail.nih.gov FU National Institutes of Health intramural research program of the NIDDK; Office of Dietary Supplements, Office of the Director, National Institutes of Health FX This work was supported by the National Institutes of Health intramural research program of the NIDDK and the Office of Dietary Supplements, Office of the Director, National Institutes of Health. This work was authored, in whole or in part, by National Institutes of Health staff. The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 56 TC 1 Z9 1 U1 6 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 21 PY 2016 VL 291 IS 43 BP 22344 EP 22356 DI 10.1074/jbc.M116.744946 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EA6SZ UT WOS:000386760600001 ER PT J AU Resto, M Kim, BH Fernandez, AG Abraham, BJ Zhao, KJ Lewis, BA AF Resto, Melissa Kim, Bong-Hyun Fernandez, Alfonso G. Abraham, Brian J. Zhao, Keji Lewis, Brian A. TI O-GlcNAcase Is an RNA Polymerase II Elongation Factor Coupled to Pausing Factors SPT5 and TIF1 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE metabolism; O-GlcNAcylation; RNA polymerase II; transcription; transcription elongation factor ID TRANSCRIPTION IN-VITRO; 7SK SNRNP COMPLEX; P-TEFB; DROSOPHILA-MELANOGASTER; FUNCTIONAL-ANALYSIS; CHRONIC DISEASE; PROMOTER; GENES; RELEASE; PHOSPHORYLATION AB We describe here the identification and functional characterization of the enzyme O-GlcNAcase (OGA) as an RNA polymerase II elongation factor. Using in vitro transcription elongation assays, we show that OGA activity is required for elongation in a crude nuclear extract system, whereas in a purified system devoid of OGA the addition of rOGA inhibited elongation. Furthermore, OGA is physically associated with the known RNA polymerase II (pol II) pausing/elongation factors SPT5 and TRIM28-KAP1-TIF1, and a purified OGA-SPT5-TIF1 complex has elongation properties. Lastly, ChIP-seq experiments show that OGA maps to the transcriptional start site/5 ends of genes, showing considerable overlap with RNA pol II, SPT5, TRIM28-KAP1-TIF1, and O-GlcNAc itself. These data all point to OGA as a component of the RNA pol II elongation machinery regulating elongation genome-wide. Our results add a novel and unexpected dimension to the regulation of elongation by the insertion of O-GlcNAc cycling into the pol II elongation regulatory dynamics. C1 [Resto, Melissa; Fernandez, Alfonso G.; Lewis, Brian A.] NCI, Transcript Regulat & Biochem Unit, Metab Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Kim, Bong-Hyun] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Abraham, Brian J.] Boston Univ, Bioinformat Program, Boston, MA 02215 USA. [Abraham, Brian J.; Zhao, Keji] NHLBI, Lab Epigenome Biol, NIH, Bldg 10, Bethesda, MD 20892 USA. [Fernandez, Alfonso G.] St Jude Childrens Res Hosp, 332 N Lauderdale St, Memphis, TN 38105 USA. [Abraham, Brian J.] Whitehead Inst Biomed Res, 9 Cambridge Ctr, Cambridge, MA 02142 USA. RP Lewis, BA (reprint author), NCI, Transcript Regulat & Biochem Unit, Metab Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM phdbiochemist@gmail.com FU NCI Intramural Program; NHLBI Intramural Program; National Institutes of Health FX This work was supported by the NCI Intramural Program (to B. A. L.) and the NHLBI Intramural Program (to K. Z.), National Institutes of Health. The authors declare they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 75 TC 1 Z9 1 U1 3 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 21 PY 2016 VL 291 IS 43 BP 22703 EP 22713 DI 10.1074/jbc.M116.751420 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EA6SZ UT WOS:000386760600029 PM 27601472 ER PT J AU Raval, MH Quintero, OA Weck, ML Unrath, WC Gallagher, JW Cui, RJ Kachar, B Tyska, MJ Yengo, CM AF Raval, Manmeet H. Quintero, Omar A. Weck, Meredith L. Unrath, William C. Gallagher, James W. Cui, Runjia Kachar, Bechara Tyska, Matthew J. Yengo, Christopher M. TI Impact of the Motor and Tail Domains of Class III Myosins on Regulating the Formation and Elongation of Actin Protrusions SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE actin; cytoskeleton; hair cell; molecular motor; myosin ID DROSOPHILA-NINAC KINASE; HAIR-CELL STEREOCILIA; MOLECULAR TREADMILL; FILOPODIA FORMATION; DENDRITIC NETWORK; HEARING-LOSS; BUNDLES; LOCALIZATION; PROTEINS; BINDING AB Class III myosins (MYO3A and MYO3B) are proposed to function as transporters as well as length and ultrastructure regulators within stable actin-based protrusions such as stereocilia and calycal processes. MYO3A differs from MYO3B in that it contains an extended tail domain with an additional actin-binding motif. We examined how the properties of the motor and tail domains of human class III myosins impact their ability to enhance the formation and elongation of actin protrusions. Direct examination of the motor and enzymatic properties of human MYO3A and MYO3B revealed that MYO3A is a 2-fold faster motor with enhanced ATPase activity and actin affinity. A chimera in which the MYO3A tail was fused to the MYO3B motor demonstrated that motor activity correlates with formation and elongation of actin protrusions. We demonstrate that removal of individual exons (30-34) in the MYO3A tail does not prevent filopodia tip localization but abolishes the ability to enhance actin protrusion formation and elongation in COS7 cells. Interestingly, our results demonstrate that MYO3A slows filopodia dynamics and enhances filopodia lifetime in COS7 cells. We also demonstrate that MYO3A is more efficient than MYO3B at increasing formation and elongation of stable microvilli on the surface of cultured epithelial cells. We propose that the unique features of MYO3A, enhanced motor activity, and an extended tail with tail actin-binding motif, allow it to play an important role in stable actin protrusion length and ultrastructure maintenance. C1 [Raval, Manmeet H.; Unrath, William C.; Yengo, Christopher M.] Penn State Univ, Coll Med, Dept Cellular & Mol Physiol, Hershey, PA 17033 USA. [Quintero, Omar A.] Univ Richmond, Dept Biol, Richmond, VA 23173 USA. [Weck, Meredith L.; Tyska, Matthew J.] Vanderbilt Univ, Med Ctr, Dept Cell & Dev Biol, Nashville, TN 37232 USA. [Gallagher, James W.] Lincoln Univ, Dept Biol, Philadelphia, PA 19104 USA. [Cui, Runjia; Kachar, Bechara] NIDCD, Lab Cell Struct & Dynam, NIH, Bethesda, MD 20892 USA. RP Yengo, CM (reprint author), Penn State Univ, Coll Med, Dept Cellular & Mol Physiol, Hershey, PA 17033 USA. EM cmy11@psu.edu FU National Institutes of Health [EYE018141, DK075555, R01-DK095811, CA160667, DK095811]; Pennsylvania Lions Hearing Research Foundation; National Institutes of Health Vanderbilt University Medical Center Developmental Biology Training Grant [T32-HD007502] FX This work was supported in part by National Institutes of Health Grant EYE018141, Pennsylvania Lions Hearing Research Foundation (to C. M. Y.), and National Institutes of Health Grants DK075555 and R01-DK095811 (to M. J. T.). This work was authored, in whole or in part, by National Institutes of Health staff. The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.; Supported by National Institutes of Health Grant CA160667.; Supported by National Institutes of Health Vanderbilt University Medical Center Developmental Biology Training Grant T32-HD007502.; Supported by National Institutes of Health Grants DK075555 and DK095811.; Supported by National Institutes of Health Grant EYE018141 and the Pennsylvania Lions Hearing Research Foundation. NR 66 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 21 PY 2016 VL 291 IS 43 BP 22781 EP 22792 DI 10.1074/jbc.M116.733741 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EA6SZ UT WOS:000386760600035 PM 27582493 ER PT J AU Gu, DN Mao, YR Tang, ZZ Montaner, J Shen, ZY Zhu, QY Detels, R Jin, X Xiong, R Xu, J Ling, W Erinoff, L Lindblad, R Liu, D Van Veldhuisen, P Hasson, A Wu, ZY AF Gu, Diane Mao, Yurong Tang, Zhenzhu Montaner, Julio Shen, Zhiyong Zhu, Qiuying Detels, Roger Jin, Xia Xiong, Ran Xu, Juan Ling, Walter Erinoff, Lynda Lindblad, Robert Liu, David Van Veldhuisen, Paul Hasson, Albert Wu, Zunyou TI Loss to Follow-Up from HIV Screening to ART Initiation in Rural China SO PLOS ONE LA English DT Article ID SUB-SAHARAN AFRICA; ANTIRETROVIRAL THERAPY; INFECTION; CARE; RETENTION; DIAGNOSIS; COUNTRIES; PROGRAM AB Background Patients who are newly screened HIV positive by EIA are lost to follow-up due to complicated HIV testing procedures. Because this is the first step in care, it affects the entire continuum of care. This is a particular concern in rural China. Objective(s) To assess the routine HIV testing completeness and treatment initiation rates at 18 county-level general hospitals in rural Guangxi. Methods We reviewed original hospital HIV screening records. Investigators also engaged with hospital leaders and key personnel involved in HIV prevention activities to characterize in detail the routine care practices in place at each county. Results 699 newly screened HIV-positive patients between January 1 and June 30, 2013 across the 18 hospitals were included in the study. The proportion of confirmatory testing across the 18 hospitals ranged from 14% to 87% (mean of 43%), and the proportion of newly diagnosed individuals successfully initiated antiretroviral treatment across the hospitals ranged from 3% to 67% (mean of 23%). The average interval within hospitals for individuals to receive the Western Blot (WB) and CD4 test results from HIV positive screening (i.e. achieving testing completion) ranged from 14-116 days (mean of 41.7 days) across the hospitals. The shortest interval from receiving a positive EIA screening test result to receiving WB and CD4 testing and counseling was 0 day and the longest was 260 days. Conclusion The proportion of patients newly screened HIV positive that completed the necessary testing procedures for HIV confirmation and received ART was very low. Interventions are urgently needed to remove barriers so that HIV patients can have timely access to HIV/AIDS treatment and care in rural China. C1 [Gu, Diane; Mao, Yurong; Jin, Xia; Xiong, Ran; Xu, Juan; Wu, Zunyou] Chinese Ctr Dis Control & Prevent, Natl Ctr AIDS STD Control & Prevent, Beijing 102206, Peoples R China. [Tang, Zhenzhu; Shen, Zhiyong; Zhu, Qiuying] Guangxi Ctr Dis Control & Prevent, Nanning, Guangxi, Peoples R China. [Montaner, Julio] Univ British Columbia, BC Ctr Excellence HIV AIDS, Vancouver, BC, Canada. [Detels, Roger] Univ Calif Los Angeles, Dept Epidemiol, Fielding Sch Publ Hlth, Los Angeles, CA USA. [Ling, Walter; Hasson, Albert] Univ Calif Los Angeles, David Geffen Sch Med, Integrated Subst Abuse Programs, Los Angeles, CA 90095 USA. [Erinoff, Lynda; Liu, David] NIDA, NIH, Bethesda, MD 20892 USA. [Lindblad, Robert; Van Veldhuisen, Paul] EMMES Corp, Rockville, MD USA. RP Wu, ZY (reprint author), Chinese Ctr Dis Control & Prevent, Natl Ctr AIDS STD Control & Prevent, Beijing 102206, Peoples R China. EM wuzy@263.net FU National Institute on Drug Abuse (NIDA) of National Institutes of Health (NIH), USA; National Health and Family Planning Commission of the People's Republic of China FX The funders, National Institute on Drug Abuse (NIDA) of National Institutes of Health (NIH), USA, and the National Health and Family Planning Commission of the People's Republic of China, provided support in the form of salaries for authors: DG, YM, ZT, ZS, QZ, XJ, RX, JX, WL, RL, PV, AH and ZW, and supported study activities, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the 'author contributions' section. The EMMES Corporation, USA (https://secure.emmes.com/emmesweb/about) provided support in the data collection and interpretation to authors RL and PV. The funder had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 26 TC 1 Z9 1 U1 3 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 21 PY 2016 VL 11 IS 10 AR e0164346 DI 10.1371/journal.pone.0164346 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ9OE UT WOS:000386205400010 PM 27768710 ER PT J AU Henrich, CJ AF Henrich, Curtis J. TI A Microplate-Based Nonradioactive Protein Synthesis Assay: Application to TRAIL Sensitization by Protein Synthesis Inhibitors SO PLOS ONE LA English DT Article ID CANCER CELLS; TRANSLATION INHIBITORS; NUCLEAR TRANSLATION; INDUCED APOPTOSIS; DOWN-REGULATION; QUANTIFICATION; QUASSINOIDS; VERRUCARIN; ACTIVATION; ANISOMYCIN AB Non-radioactive assays based on incorporation of puromycin into newly synthesized proteins and subsequent detection using anti-puromycin antibodies have been previously reported and well-validated. To develop a moderate-to high-throughput assay, an adaptation is here described wherein cells are puromycin-labeled followed by simultaneously probing puromycin-labeled proteins and a reference protein in situ. Detection using a pair of near IR-labeled secondary antibodies (InCell western, ICW format) allows quantitative analysis of protein synthesis in 384-well plates. After optimization, ICW results were compared to western blot analysis using cycloheximide as a model protein synthesis inhibitor and showed comparable results. The method was then applied to several protein synthesis inhibitors and revealed good correlation between potency as protein synthesis inhibitors to their ability to sensitize TRAIL-resistant renal carcinoma cells to TRAIL-induced apoptosis. C1 [Henrich, Curtis J.] NCI, Mol Targets Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Henrich, Curtis J.] Leidos Biomed Res Inc, Basic Sci Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Henrich, CJ (reprint author), NCI, Mol Targets Lab, Ctr Canc Res, Frederick, MD 21702 USA.; Henrich, CJ (reprint author), Leidos Biomed Res Inc, Basic Sci Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. EM henrichcj@mail.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E] FX This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. This project was funded in part with Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 37 TC 0 Z9 0 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 21 PY 2016 VL 11 IS 10 AR e0165192 DI 10.1371/journal.pone.0165192 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ9OE UT WOS:000386205400063 PM 27768779 ER PT J AU Agyemang, C Meeks, K Beune, E Owusu-Dabo, E Mockenhaupt, FP Addo, J Aikins, ADG Bahendeka, S Danquah, I Schulze, MB Spranger, J Burr, T Agyei-Baffour, P Amoah, SK Galbete, C Henneman, P Klipstein-Grobusch, K Nicolaou, M Adeyemo, A van Straalen, J Smeeth, L Stronks, K AF Agyemang, Charles Meeks, Karlijn Beune, Erik Owusu-Dabo, Ellis Mockenhaupt, Frank P. Addo, Juliet Aikins, Ama de Graft Bahendeka, Silver Danquah, Ina Schulze, Matthias B. Spranger, Joachim Burr, Tom Agyei-Baffour, Peter Amoah, Stephen K. Galbete, Cecilia Henneman, Peter Klipstein-Grobusch, Kerstin Nicolaou, Mary Adeyemo, Adebowale van Straalen, Jan Smeeth, Liam Stronks, Karien TI Obesity and type 2 diabetes in sub-Saharan Africans - Is the burden in today's Africa similar to African migrants in Europe? The RODAM study SO BMC MEDICINE LA English DT Article DE Obesity; Type 2 diabetes; Migrants; Ethnic minority groups; Europe; Sub-Saharan Africa ID UNITED-STATES; RISK-FACTORS; PREVALENCE; POPULATIONS; HEALTH; INEQUALITIES; METAANALYSIS; NETHERLANDS; OVERWEIGHT; DIASPORA AB Background: Rising rates of obesity and type 2 diabetes (T2D) are impending major threats to the health of African populations, but the extent to which they differ between rural and urban settings in Africa and upon migration to Europe is unknown. We assessed the burden of obesity and T2D among Ghanaians living in rural and urban Ghana and Ghanaian migrants living in different European countries. Methods: A multi-centre cross-sectional study was conducted among Ghanaian adults (n = 5659) aged 25-70 years residing in rural and urban Ghana and three European cities (Amsterdam, London and Berlin). Comparisons between groups were made using prevalence ratios (PRs) with adjustments for age and education. Results: In rural Ghana, the prevalence of obesity was 1.3 % in men and 8.3 % in women. The prevalence was considerably higher in urban Ghana (men, 6.9 %; PR: 5.26, 95 % CI, 2.04-13.57; women, 33.9 %; PR: 4.11, 3.13-5.40) and even more so in Europe, especially in London (men, 21.4 %; PR: 15.04, 5.98-37.84; women, 54.2 %; PR: 6.63, 5.04-8.72). The prevalence of T2D was low at 3.6 % and 5.5 % in rural Ghanaian men and women, and increased in urban Ghanaians (men, 10.3 %; PR: 3.06; 1.73-5.40; women, 9.2 %; PR: 1.81, 1.25-2.64) and highest in Berlin (men, 15.3 %; PR: 4.47; 2.50-7.98; women, 10.2 %; PR: 2.21, 1.30-3.75). Impaired fasting glycaemia prevalence was comparatively higher only in Amsterdam, and in London, men compared with rural Ghana. Conclusion: Our study shows high risks of obesity and T2D among sub-Saharan African populations living in Europe. In Ghana, similarly high prevalence rates were seen in an urban environment, whereas in rural areas, the prevalence of obesity among women is already remarkable. Similar processes underlying the high burden of obesity and T2D following migration may also be at play in sub-Saharan Africa as a consequence of urbanisation. C1 [Agyemang, Charles; Meeks, Karlijn; Beune, Erik; Nicolaou, Mary; Stronks, Karien] Univ Amsterdam, Acad Med Ctr, Dept Publ Hlth, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. [Owusu-Dabo, Ellis; Agyei-Baffour, Peter] Kwame Nkrumah Univ Sci & Technol, Sch Publ Hlth, Kumasi, Ghana. [Mockenhaupt, Frank P.; Amoah, Stephen K.] Charite, Inst Trop Med & Int Hlth, Augustenburger Pl 1, D-13353 Berlin, Germany. [Addo, Juliet; Smeeth, Liam] London Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, London, England. [Aikins, Ama de Graft] Univ Ghana, Reg Inst Populat Studies, POB LG 96, Legon, Ghana. [Bahendeka, Silver] MKPGMS Uganda Martyrs Univ, Kampala, Uganda. [Danquah, Ina; Schulze, Matthias B.; Galbete, Cecilia] German Inst Human Nutr Potsdam Rehbrucke, Dept Mol Epidemiol, Arthur Scheunert Allee 114-116, D-14558 Nuthetal, Germany. [Spranger, Joachim] Charite, Dept Endocrinol & Metab, Berlin, Germany. [Spranger, Joachim] Charite, DZHK German Ctr Cardiovasc Res, Partner Site Berlin, Berlin, Germany. [Spranger, Joachim] Charite, CCR, Berlin, Germany. [Burr, Tom] Source BioSci, Nottingham, England. [Amoah, Stephen K.] ResearchGate, Invalidenstr 115, D-10115 Berlin, Germany. [Henneman, Peter] Acad Med Ctr, Dept Clin Genet, Amsterdam, Netherlands. [Klipstein-Grobusch, Kerstin] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Julius Global Hlth, Utrecht, Netherlands. [Klipstein-Grobusch, Kerstin] Univ Witwatersrand, Sch Publ Hlth, Div Epidemiol & Biostat, Fac Hlth Sci, Johannesburg, South Africa. [Adeyemo, Adebowale] NHGRI, Ctr Res Genom & Global Hlth, NIH, 12 South Dr,MSC 5635, Bethesda, MD 20892 USA. [van Straalen, Jan] Acad Med Ctr, Dept Clin Chem, Amsterdam, Netherlands. RP Agyemang, C (reprint author), Univ Amsterdam, Acad Med Ctr, Dept Publ Hlth, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. EM c.o.agyemang@amc.uva.nl OI Schulze, Matthias B./0000-0002-0830-5277 FU European Commission [278901]; Wellcome Trust [WT082178]; DZHK (German Center for cardiovascular research); Berlin Institute of Health (BIH) FX This work was supported by the European Commission under the Framework Programme (Grant Number: 278901). Professor Smeeth's contribution was supported by the Wellcome Trust, grant number WT082178. Professor Joachim Spranger was supported by the DZHK (German Center for cardiovascular research) and the Berlin Institute of Health (BIH). NR 37 TC 0 Z9 0 U1 8 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7015 J9 BMC MED JI BMC Med. PD OCT 21 PY 2016 VL 14 AR 166 DI 10.1186/s12916-016-0709-0 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA DZ6NY UT WOS:000385980400001 PM 27769239 ER PT J AU Shi, YY Pierce, JP White, M Vijayaraghavan, M Compton, W Conway, K Hartman, AM Messer, K AF Shi, Yuyan Pierce, John P. White, Martha Vijayaraghavan, Maya Compton, Wilson Conway, Kevin Hartman, Anne M. Messer, Karen TI E-cigarette use and smoking reduction or cessation in the 2010/2011 TUS-CPS longitudinal cohort SO BMC PUBLIC HEALTH LA English DT Article DE Electronic cigarettes; Smoking cessation; Smoking reduction ID ELECTRONIC CIGARETTES; UNITED-STATES; ADULT SMOKERS; FREE HOMES; ASSOCIATION; AWARENESS; TOBACCO; POLICY; QUIT AB Background: Electronic cigarettes (e-cigarettes) are heavily marketed and widely perceived as helpful for quitting or reducing smoking intensity. We test whether ever-use of e-cigarettes among early adopters was associated with: 1) increased cigarette smoking cessation; and 2) reduced cigarette consumption. Methods: A representative cohort of U.S. smokers (N = 2454) from the 2010 Tobacco Use Supplement to the Current Population Survey (TUS-CPS) was re-interviewed 1 year later. Outcomes were smoking cessation for 30+ days and change in cigarette consumption at follow-up. E-cigarettes use was categorized as for cessation purposes or for another reason. Multivariate regression was used to adjust for demographics and baseline cigarette dependence level. Results: In 2011, an estimated 12 % of adult U.S. smokers had ever used e-cigarettes, and 41 % of these reported use to help quit smoking. Smokers who had used e-cigarettes for cessation were less likely to be quit for 30+ days at follow-up, compared to never-users who tried to quit (11.1 % vs 21.6 %; ORadj = 0.44, 95 % CI = 0.2-0.8). Among heavier smokers at baseline (15+ cigarettes per day (CPD)), ever-use of e-cigarettes was not associated with change in smoking consumption. Lighter smokers (<15 CPD) who had ever used e-cigarettes for quitting had stable consumption, while increased consumption was observed among all other lighter smokers, although this difference was not statistically significant. Conclusions: Among early adopters, ever-use of first generation e-cigarettes to aid quitting cigarette smoking was not associated with improved cessation or with reduced consumption, even among heavier smokers. C1 [Shi, Yuyan; Pierce, John P.; Messer, Karen] Moores UC San Diego Canc Ctr, Canc Prevent & Control Program, 3855 Hlth Sci Dr 0901, La Jolla, CA 92093 USA. [Shi, Yuyan; Pierce, John P.; White, Martha; Messer, Karen] Univ Calif San Diego, Dept Family Med & Publ Hlth, 9500 Gilman Dr 0628, La Jolla, CA 92093 USA. [Vijayaraghavan, Maya] Univ Calif San Francisco, San Francisco Gen Hosp, Div Gen Internal Med, 1545 Divisadero St, San Francisco, CA 94115 USA. [Compton, Wilson; Conway, Kevin] NIDA, NIH, 6001 Execut Blvd, Bethesda, MD 20892 USA. [Hartman, Anne M.] NCI, Tobacco Control Res Branch, Behav Res Program, Div Canc Control & Populat Sci,NIH, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. RP Messer, K (reprint author), Moores UC San Diego Canc Ctr, Canc Prevent & Control Program, 3855 Hlth Sci Dr 0901, La Jolla, CA 92093 USA.; Messer, K (reprint author), Univ Calif San Diego, Dept Family Med & Publ Hlth, 9500 Gilman Dr 0628, La Jolla, CA 92093 USA. EM kmesser@ucsd.edu FU Federal funds National Institute on Drug Abuse at the National Institutes of Health; Food and Drug Administration; Department of Health and Human Services [HHSN271201100027C]; National Cancer Institute at the National Institutes of Health; UC Tobacco-Related Disease Research Program [21RT-0135]; National Cancer Institute [1R01CA172058-02]; Tobacco Use Supplement (TUS) FX This project has been funded with Federal funds from the National Institute on Drug Abuse at the National Institutes of Health, and the Food and Drug Administration, Department of Health and Human Services, (Contract No. HHSN271201100027C). Funding for the Tobacco Use Supplement (TUS) and its follow-up were sponsored by the National Cancer Institute at the National Institutes of Health and conducted by the Census Bureau in conjunction with the Bureau of Labor Statistics' and Census Bureau's Current Population Survey (CPS). In addition, Drs. Shi, Messer and Pierce were partially supported by the UC Tobacco-Related Disease Research Program (grant number 21RT-0135 to YS, KM and JPP), and the National Cancer Institute (grant number 1R01CA172058-02 to YS, KM and JPP). The role of Drs. Conway, Compton, and Ms. Hartman on this paper were through their involvement on Contract No. HHSN271201100027C. They had no involvement in the cited grants. NR 36 TC 0 Z9 0 U1 6 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2458 J9 BMC PUBLIC HEALTH JI BMC Public Health PD OCT 21 PY 2016 VL 16 AR 1105 DI 10.1186/s12889-016-3770-x PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DZ6IJ UT WOS:000385965400004 PM 27769302 ER PT J AU Larsen, E Menashe, I Ziats, MN Pereanu, W Packer, A Banerjee-Basu, S AF Larsen, Eric Menashe, Idan Ziats, Mark N. Pereanu, Wayne Packer, Alan Banerjee-Basu, Sharmila TI A systematic variant annotation approach for ranking genes associated with autism spectrum disorders SO MOLECULAR AUTISM LA English DT Article DE Autistic disorder; Genetic variation; Common variants; Rare variants; Autosomal recessive ID DE-NOVO MUTATIONS; RISK; GENETICS; KNOWLEDGEBASE; EXPRESSION; SHANK3 AB Background: The search for genetic factors underlying autism spectrum disorders (ASD) has led to the identification of hundreds of genes containing thousands of variants that differ in mode of inheritance, effect size, frequency, and function. A major challenge involves assessing the collective evidence in an unbiased, systematic manner for their functional relevance. Methods: Here, we describe a scoring algorithm for prioritization of candidate genes based on the cumulative strength of evidence for each ASD-associated variant cataloged in AutDB (also known as SFARI Gene). We retrieved data from 889 publications to generate a dataset of 2187 rare and 711 common variants distributed across 461 genes implicated in ASD. Each individual variant was manually annotated with multiple attributes extracted from the original report, followed by score assignment using a set of standardized parameters yielding a single score for each gene. Results: There was a wide variation in scores; SHANK3, CHD8, and ADNP had distinctly higher scores than all other genes in the dataset. Our gene scores were significantly correlated with other recently published rankings of ASD genes (RSpearman = 0.40-0.63; p<0.0001), providing support for our scoring algorithm. Conclusions: This new resource, which is freely available, for the first time aggregates on one-platform variants identified from various study types (simplex, multiplex, multigenerational, and consanguineous families), from both common and rare variants, and also incorporates their putative functional consequences to arrive at a genetically and biologically driven ranking scheme. This work represents a major step in moving from simply cataloging autism variants to using data-driven approaches to gain insight into their significance. C1 [Larsen, Eric; Pereanu, Wayne; Banerjee-Basu, Sharmila] MindSpec Inc, 8280 Greensboro Dr,Suite 150, Mclean, VA 22102 USA. [Menashe, Idan] Ben Gurion Univ Negev, Dept Publ Hlth, Fac Hlth Sci, Beer Sheva, Israel. [Ziats, Mark N.] NICHHD, NIH, Bldg 49,Room 2c08, Bethesda, MD 20814 USA. [Packer, Alan] Simons Fdn Autism Res Initiat, New York, NY USA. RP Banerjee-Basu, S (reprint author), MindSpec Inc, 8280 Greensboro Dr,Suite 150, Mclean, VA 22102 USA. EM sharmila@mindspec.org FU Simons Foundation FX This research was funded by the Simons Foundation. NR 32 TC 1 Z9 1 U1 6 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2040-2392 J9 MOL AUTISM JI Mol. Autism PD OCT 21 PY 2016 VL 7 AR 44 DI 10.1186/s13229-016-0103-y PG 8 WC Genetics & Heredity; Neurosciences SC Genetics & Heredity; Neurosciences & Neurology GA DZ6QP UT WOS:000385987300001 PM 27790361 ER PT J AU Sylvetsky, AC Brown, RJ Blau, JE Walter, M Rother, KI AF Sylvetsky, Allison C. Brown, Rebecca J. Blau, Jenny E. Walter, Mary Rother, Kristina I. TI Hormonal responses to non-nutritive sweeteners in water and diet soda SO NUTRITION & METABOLISM LA English DT Article DE Sucralose; Acesulfame-potassium; Diet soda; Non-nutritive sweetener; Gut peptides ID TASTE RECEPTORS; GLUCOSE-HOMEOSTASIS; BODY-WEIGHT; CONSUMPTION; BEVERAGES; PERCEPTION; ABSORPTION; INCREASES; SECRETION; GUSTDUCIN AB Background: Non-nutritive sweeteners (NNS), especially in form of diet soda, have been linked to metabolic derangements (e.g. obesity and diabetes) in epidemiologic studies. We aimed to test acute metabolic effects of NNS in isolation (water or seltzer) and in diet sodas. Methods: We conducted a four-period, cross-over study at the National Institutes of Health Clinical Center (Bethesda, Maryland). Thirty healthy adults consumed 355 mL water with 0 mg, 68 mg, 170 mg, and 250 mg sucralose, and 31 individuals consumed 355 mL caffeine-free Diet Rite Cola T, Diet Mountain Dew T (18 mg sucralose, 18 mg acesulfame-potassium, 57 mg aspartame), and seltzer water with NNS (68 mg sucralose and 41 mg acesulfame-potassium, equivalent to Diet Rite Cola T) in randomized order, prior to oral glucose tolerance tests. Blood samples were collected serially for 130 min. Measures included GLP-1, GIP, glucose, insulin, C-peptide, glucose absorption, gastric emptying, and subjective hunger and satiety ratings. Results: Diet sodas augmented active GLP-1 (Diet Rite Cola T vs. seltzer water, AUC, p = 0.039; Diet Mountain Dew T vs. seltzer water, AUC, p = 0.07), but gastric emptying and satiety were unaffected. Insulin concentrations were nominally higher following all NNS conditions without altering glycemia. Sucralose alone (at any concentration) did not affect metabolic outcomes. Conclusions: Diet sodas but not NNS in water augmented GLP-1 responses to oral glucose. Whether the trends toward higher insulin concentrations after NNS are of clinical importance remains to be determined. Our findings emphasize the need to test metabolic effects of NNS after chronic consumption. C1 [Sylvetsky, Allison C.; Brown, Rebecca J.; Blau, Jenny E.; Rother, Kristina I.] NIDDK, Sect Pediat Diabet & Metab DEOB, NIH, 9000 Rockville Pike,Bldg 10,Room 8C432A, Bethesda, MD 20892 USA. [Sylvetsky, Allison C.] George Washington Univ, Sch Publ Hlth, Milken Inst, Dept Exercise & Nutr Sci, Washington, DC USA. [Sylvetsky, Allison C.] George Washington Univ, Sch Publ Hlth, Milken Inst, Sumner M Redstone Global Ctr Prevent & Wellness, Washington, DC USA. [Walter, Mary] NIDDK, Off Director, NIH, Bethesda, MD 20892 USA. RP Rother, KI (reprint author), NIDDK, Sect Pediat Diabet & Metab DEOB, NIH, 9000 Rockville Pike,Bldg 10,Room 8C432A, Bethesda, MD 20892 USA. EM kristina.rother@nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases [10-DK-0163] FX This work was supported by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases, Protocol 10-DK-0163. NR 35 TC 1 Z9 1 U1 24 U2 24 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1743-7075 J9 NUTR METAB JI Nutr. Metab. PD OCT 21 PY 2016 VL 13 AR 71 DI 10.1186/s12986-016-0129-3 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DZ5GT UT WOS:000385890700001 PM 27777606 ER PT J AU Fu, TM Li, Y Lu, A Li, ZL Vajjhala, PR Cruz, AC Srivastava, DB DiMaio, F Penczek, PA Siegel, RM Stacey, KJ Egelman, EH Wu, H AF Fu, Tian-Min Li, Yang Lu, Alvin Li, Zongli Vajjhala, Parimala R. Cruz, Anthony C. Srivastava, Devendra B. DiMaio, Frank Penczek, Pawel A. Siegel, Richard M. Stacey, Katryn J. Egelman, Edward H. Wu, Hao TI Cryo-EM Structure of Caspase-8 Tandem DED Filament Reveals Assembly and Regulation Mechanisms of the Death-Inducing Signaling Complex SO MOLECULAR CELL LA English DT Article ID CRYSTAL-STRUCTURE; EFFECTOR DOMAIN; IMMUNE-SYSTEM; UNIFIED MODEL; CELL-DEATH; RECEPTOR; DISC; ACTIVATION; INHIBITION; APOPTOSIS AB Caspase-8 activation can be triggered by death receptor-mediated formation of the death-inducing signaling complex (DISC) and by the inflammasome adaptor ASC. Caspase-8 assembles with FADD at the DISC and with ASC at the inflammasome through its tandem death effector domain (tDED), which is regulated by the tDED-containing cellular inhibitor cFLIP and the viral inhibitor MC159. Here we present the caspase-8 tDED filament structure determined by cryoelectron microscopy. Extensive assembly interfaces not predicted by the previously proposed linear DED chain model were uncovered, and were further confirmed by structure-based mutagenesis in filament formation in vitro and Fas-induced apoptosis and ASC-mediated caspase-8 recruitment in cells. Structurally, the two DEDs in caspase-8 use quasi-equivalent contacts to enable assembly. Using the tDED filament structure as a template, structural analyses reveal the interaction surfaces between FADD and caspase-8 and the distinct mechanisms of regulation by cFLIP and MC159 through comingling and capping, respectively. C1 [Fu, Tian-Min; Li, Yang; Lu, Alvin; Li, Zongli; Srivastava, Devendra B.; Wu, Hao] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Fu, Tian-Min; Li, Yang; Lu, Alvin; Srivastava, Devendra B.; Wu, Hao] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Li, Zongli] Harvard Med Sch, Howard Hughes Med Inst, Boston, MA 02115 USA. [Vajjhala, Parimala R.; Stacey, Katryn J.] Univ Queensland, Sch Chem & Mol Biosci, Brisbane, Qld 4072, Australia. [Cruz, Anthony C.; Siegel, Richard M.] NIAMSD, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. [DiMaio, Frank] Univ Washington, Dept Biochem, Seattle, WA 98195 USA. [Penczek, Pawel A.] Univ Texas Houston, Sch Med, Dept Biochem & Mol Biol, Houston, TX 77030 USA. [Stacey, Katryn J.] Univ Queensland, Inst Mol Biosci, Brisbane, Qld 4072, Australia. [Egelman, Edward H.] Univ Virginia, Dept Biochem & Mol Genet, Charlottesville, VA 22908 USA. RP Wu, H (reprint author), Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA.; Wu, H (reprint author), Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. EM wu@crystal.harvard.edu FU NIH [DP1-HD087988, R37-AI050872, R01-AI045937, R01-EB001567, R01-GM60635]; National Health and Medical Research Council of Australia [1050651, 1109738, 1059729] FX We thank Drs. Narayanasami Sukumar, Kay Perry, Ryan Ferrao, Gunes Bozkurt, and Li Wang for their assistance in X-ray diffraction data collection at the Advanced Photon Source. The work was supported by funding from the NIH (DP1-HD087988, R37-AI050872, and R01-AI045937 to H.W.; R01-EB001567 to E.H.E.; and R01-GM60635 to P.A.P.) and the National Health and Medical Research Council of Australia (1050651, 1109738, and 1059729 to K.J.S.). NR 47 TC 1 Z9 1 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 EI 1097-4164 J9 MOL CELL JI Mol. Cell PD OCT 20 PY 2016 VL 64 IS 2 BP 236 EP 250 DI 10.1016/j.molcel.2016.09.009 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EE3RP UT WOS:000389515000005 ER PT J AU Ferre-D'Amare, AR AF Ferre-D'Amare, Adrian R. TI RNA Binding: Getting Specific about Specificity SO CELL CHEMICAL BIOLOGY LA English DT Editorial Material ID TRANSLATIONAL INITIATION SITES; ESCHERICHIA-COLI; LANDSCAPES; PROTEIN AB Sequence-specific nucleic acid binding proteins do not recognize one sequence out of all possibilities; rather, they bind to many sequences with a range of affinities. In this issue of Cell Chemical Biology, Lin et al. (2016), describe the entire landscape of affinities between different RNA molecules and an RNA-binding protein, thus providing a comprehensive description of the factors affecting specificity. C1 [Ferre-D'Amare, Adrian R.] NHLBI, 50 South Dr,MSC 8012, Bethesda, MD 20892 USA. RP Ferre-D'Amare, AR (reprint author), NHLBI, 50 South Dr,MSC 8012, Bethesda, MD 20892 USA. EM adrian.ferre@nih.gov FU Intramural NIH HHS [Z99 HL999999] NR 8 TC 1 Z9 1 U1 1 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2451-9448 J9 CELL CHEM BIOL JI Cell Chem. Biol. PD OCT 20 PY 2016 VL 23 IS 10 BP 1177 EP 1178 DI 10.1016/j.chembiol.2016.10.001 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EC8EG UT WOS:000388372600003 PM 27768867 ER PT J AU Martin, AJ Clark, M Gojanovich, G Manzoor, F Miller, K Kline, DE Morillon, YM Wang, B Tisch, R AF Martin, Aaron J. Clark, Matthew Gojanovich, Gregory Manzoor, Fatima Miller, Keith Kline, Douglas E. Morillon, Y. Maurice Wang, Bo Tisch, Roland TI Anti-coreceptor therapy drives selective T cell egress by suppressing inflammation-dependent chemotactic cues SO JCI INSIGHT LA English DT Article ID TYPE-1 DIABETES-MELLITUS; NOD MICE; NONDEPLETING ANTI-CD4; BETA-CELLS; IFN-GAMMA; MONOCLONAL-ANTIBODIES; PANCREATIC-ISLETS; CROSS-LINKING; MOUSE; CD4 AB There continues to be a need for immunotherapies to treat type 1 diabetes in the clinic. We previously reported that nondepleting anti-CD4 and -CD8 Ab treatment effectively reverses diabetes in new-onset NOD mice. A key feature of the induction of remission is the egress of the majority of islet-resident T cells. How this occurs is undefined. Herein, the effects of coreceptor therapy on islet T cell retention were investigated. Bivalent Ab binding to CD4 and CD8 blocked TCR signaling and T cell cytokine production, while indirectly downregulating islet chemokine expression. These processes were required for T cell retention, as ectopic IFN-gamma or CXCL10 inhibited Ab-mediated T cell purging. Importantly, treatment of humanized mice with nondepleting anti-human CD4 and CD8 Ab similarly reduced tissue-infiltrating human CD4(+) and CD8(+) T cells. These findings demonstrate that Ab binding of CD4 and CD8 interrupts a feed-forward circuit by suppressing T cell-produced cytokines needed for expression of chemotactic cues, leading to rapid T cell egress from the islets. Coreceptor therapy therefore offers a robust approach to suppress T cell-mediated pathology by purging T cells in an inflammation-dependent manner. C1 [Martin, Aaron J.; Clark, Matthew; Gojanovich, Gregory; Manzoor, Fatima; Miller, Keith; Kline, Douglas E.; Morillon, Y. Maurice; Wang, Bo; Tisch, Roland] Univ N Carolina, Sch Med, Dept Microbiol & Immunol, 6th Floor Marsico Hall Room 6111,Campus Box 7290, Chapel Hill, NC 27599 USA. [Martin, Aaron J.] Precis BioSci, Durham, NC USA. [Miller, Keith] Univ Mt Union, Dept Chem & Biochem, Alliance, OH USA. [Kline, Douglas E.] Univ Chicago, Comm Immunol, Chicago, IL 60637 USA. [Kline, Douglas E.] Univ Chicago, Dept Med, Hematol Oncol Sect, Chicago, IL 60637 USA. [Morillon, Y. Maurice] NCI, Lab Tumor Immunol & Biol, Bethesda, MD 20892 USA. [Tisch, Roland] Univ N Carolina, Lineberger Comprehens Canc Ctr, Sch Med, Chapel Hill, NC USA. RP Tisch, R (reprint author), Univ N Carolina, Dept Microbiol & Immunol, 6th Floor Marsico Hall Room 6111,Campus Box 7290, Chapel Hill, NC 27599 USA. EM rmtisch@med.unc.edu FU NCI NIH HHS [P30 CA016086]; NIAID NIH HHS [R21 AI115752]; NIDDK NIH HHS [R01 DK100256] NR 56 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 2379-3708 J9 JCI INSIGHT JI JCI Insight PD OCT 20 PY 2016 VL 1 IS 17 AR e87636 DI 10.1172/jci.insight.87636 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EB1PF UT WOS:000387125100002 PM 27777971 ER PT J AU Rieber, N Gazendam, RP Freeman, AF Hsu, AP Collar, AL Sugui, JA Drummond, RA Rongkavilit, C Hoffman, K Henderson, C Clark, L Mezger, M Swamydas, M Engeholm, M Schule, R Neumayer, B Ebel, F Mikelis, CM Pittaluga, S Prasad, VK Singh, A Milner, JD Williams, KW Lim, JK Kwon-Chung, KJ Holland, SM Hartl, D Kuijpers, TW Lionakis, MS AF Rieber, Nikolaus Gazendam, Roel P. Freeman, Alexandra F. Hsu, Amy P. Collar, Amanda L. Sugui, Janyce A. Drummond, Rebecca A. Rongkavilit, Chokechai Hoffman, Kevin Henderson, Carolyn Clark, Lily Mezger, Markus Swamydas, Muthulekha Engeholm, Maik Schuele, Rebecca Neumayer, Bettina Ebel, Frank Mikelis, Constantinos M. Pittaluga, Stefania Prasad, Vinod K. Singh, Anurag Milner, Joshua D. Williams, Kelli W. Lim, Jean K. Kwon-Chung, Kyung J. Holland, Steven M. Hartl, Dominik Kuijpers, Taco W. Lionakis, Michail S. TI Extrapulmonary Aspergillus infection in patients with CARD9 deficiency SO JCI INSIGHT LA English DT Article ID INVASIVE FUNGAL-INFECTIONS; CONIDIAL MORPHOLOGY; HUMAN NEUTROPHILS; CANDIDA-ALBICANS; INNATE IMMUNITY; FUMIGATUS; PATHOGENESIS; MUTATIONS; VIRULENCE; GENE AB Invasive pulmonary aspergillosis is a life-threatening mycosis that only affects patients with immunosuppression, chemotherapy-induced neutropenia, transplantation, or congenital immunodeficiency. We studied the clinical, genetic, histological, and immunological features of 2 unrelated patients without known immunodeficiency who developed extrapulmonary invasive aspergillosis at the ages of 8 and 18. One patient died at age 12 with progressive intra-abdominal aspergillosis. The other patient had presented with intra-abdominal candidiasis at age 9, and developed central nervous system aspergillosis at age 18 and intra-abdominal aspergillosis at age 25. Neither patient developed Aspergillus infection of the lungs. One patient had homozygous M1I CARD9 (caspase recruitment domain family member 9) mutation, while the other had homozygous Q295X CARD9 mutation; both patients lacked CARD9 protein expression. The patients had normal monocyte and Th17 cell numbers in peripheral blood, but their mononuclear cells exhibited impaired production of proinflammatory cytokines upon fungus-specific stimulation. Neutrophil phagocytosis, killing, and oxidative burst against Aspergillus fumigatus were intact, but neither patient accumulated neutrophils in infected tissue despite normal neutrophil numbers in peripheral blood. The neutrophil tissue accumulation defect was not caused by defective neutrophil-intrinsic chemotaxis, indicating that production of neutrophil chemoattractants in extrapulmonary tissue is impaired in CARD9 deficiency. Taken together, our results show that CARD9 deficiency is the first known inherited or acquired condition that predisposes to extrapulmonary Aspergillus infection with sparing of the lungs, associated with impaired neutrophil recruitment to the site of infection. C1 [Rieber, Nikolaus; Mezger, Markus; Singh, Anurag; Hartl, Dominik] Univ Tubingen, Dept Pediat 1, Infect Dis & Immunol, Ebene C4 Raum 305,Hoppe Seyler Str 1 Bldg, D-72076 Tubingen, Germany. [Rieber, Nikolaus] Tech Univ Munich, Munich Schwabing Hosp, Dept Pediat, Munich, Germany. [Gazendam, Roel P.; Kuijpers, Taco W.] Univ Amsterdam, Sanquin Res, Amsterdam, Netherlands. [Gazendam, Roel P.; Kuijpers, Taco W.] Univ Amsterdam, Acad Med Ctr, Landsteiner Lab, Amsterdam, Netherlands. [Freeman, Alexandra F.; Hsu, Amy P.; Collar, Amanda L.; Sugui, Janyce A.; Drummond, Rebecca A.; Henderson, Carolyn; Clark, Lily; Swamydas, Muthulekha; Williams, Kelli W.; Kwon-Chung, Kyung J.; Holland, Steven M.; Lionakis, Michail S.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Rongkavilit, Chokechai; Lim, Jean K.] Wayne State Univ, Detroit, MI USA. [Rongkavilit, Chokechai; Lim, Jean K.] Childrens Hosp Michigan, Detroit, MI 48201 USA. [Hoffman, Kevin] Icahn Sch Med Mt Sinai, Dept Microbiol, New York, NY 10029 USA. [Engeholm, Maik; Schuele, Rebecca] Hertie Inst Clin Brain Res, Dept Neurodegenerat Dis, Tubingen, Germany. [Engeholm, Maik; Schuele, Rebecca] Ctr Neurol, Tubingen, Germany. [Neumayer, Bettina] Univ Tubingen, Inst Pathol, Tubingen, Germany. [Ebel, Frank] Ludwig Maximilians Univ Munchen, Max von Pettenkofer Inst, Munich, Germany. [Mikelis, Constantinos M.] Texas Tech Univ, Hlth Sci Ctr, Sch Pharm, Dept Biomed Sci, Amarillo, TX USA. [Pittaluga, Stefania] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Prasad, Vinod K.] Duke Univ, Med Ctr, Pediat Blood & Marrow Transplantat, Durham, NC USA. [Milner, Joshua D.] NIAID, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Hartl, D (reprint author), Univ Tubingen, Dept Pediat 1, Infect Dis & Immunol, Ebene C4 Raum 305,Hoppe Seyler Str 1 Bldg, D-72076 Tubingen, Germany.; Lionakis, MS (reprint author), 9000 Rockville Pike,Bldg 10 Room 11C102, Bethesda, MD 20892 USA.; Kuijpers, TW (reprint author), Emma Childrens Hosp, Acad Med Ctr, Immunol & Infect Dis, Locat H7-230,Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. EM Dominik.Hartl@med.uni-tuebingen.de; t.w.kuijpers@amc.uva.nl; lionakism@mail.nih.gov FU NIAID NIH HHS [T32 AI007647] NR 39 TC 0 Z9 0 U1 3 U2 3 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 2379-3708 J9 JCI INSIGHT JI JCI Insight PD OCT 20 PY 2016 VL 1 IS 17 AR e89890 DI 10.1172/jci.insight.89890 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EB1PF UT WOS:000387125100013 PM 27777981 ER PT J AU Saito, R Rocanin-Arjo, A You, YH Darshi, M Van Espen, B Miyamoto, S Pham, J Pu, MY Romoli, S Natarajan, L Ju, WJ Kretzler, M Nelson, R Ono, K Thomasova, D Mulay, SR Ideker, T D'Agati, V Beyret, E Belmonte, JCI Anders, HJ Sharma, K AF Saito, Rintaro Rocanin-Arjo, Anais You, Young-Hyun Darshi, Manjula Van Espen, Benjamin Miyamoto, Satoshi Pham, Jessica Pu, Minya Romoli, Simone Natarajan, Loki Ju, Wenjun Kretzler, Matthias Nelson, Robert Ono, Keiichiro Thomasova, Dana Mulay, Shrikant R. Ideker, Trey D'Agati, Vivette Beyret, Ergin Belmonte, Juan Carlos Izpisua Anders, Hans Joachim Sharma, Kumar TI Systems biology analysis reveals role of MDM2 in diabetic nephropathy SO JCI INSIGHT LA English DT Article ID KIDNEY-DISEASE; METABOLOMICS REVEALS; P53 PATHWAY; NETWORKS; ANTAGONISTS; CYTOSCAPE; DYSFUNCTION; DEFICIENCY; ACTIVATION; MECHANISMS AB To derive new insights in diabetic complications, we integrated publicly available human protein-protein interaction (PPI) networks with global metabolic networks using metabolomic data from patients with diabetic nephropathy. We focused on the participating proteins in the network that were computationally predicted to connect the urine metabolites. MDM2 had the highest significant number of PPI connections. As validation, significant downregulation of MDM2 gene expression was found in both glomerular and tubulointerstitial compartments of kidney biopsy tissue from 2 independent cohorts of patients with diabetic nephropathy. In diabetic mice, chemical inhibition of MDM2 with Nutlin-3a led to reduction in the number of podocytes, increased blood urea nitrogen, and increased mortality. Addition of Nutlin-3a decreased WT1(+) cells in embryonic kidneys. Both podocyte-and tubule-specific MDM2-knockout mice exhibited severe glomerular and tubular dysfunction, respectively. Interestingly, the only 2 metabolites that were reduced in both podocyte and tubule-specific MDM2-knockout mice were 3-methylcrotonylglycine and uracil, both of which were also reduced in human diabetic kidney disease. Thus, our bioinformatics tool combined with multi-omics studies identified an important functional role for MDM2 in glomeruli and tubules of the diabetic nephropathic kidney and links MDM2 to a reduction in 2 key metabolite biomarkers. C1 Univ Calif San Diego, Inst Metabol Med, San Diego, CA USA. [Saito, Rintaro; You, Young-Hyun; Miyamoto, Satoshi; Pham, Jessica; Sharma, Kumar] Univ Calif San Diego, Ctr Renal Translat Med, Div Nephrol Hypertens, San Diego, CA USA. [Saito, Rintaro; You, Young-Hyun; Darshi, Manjula; Van Espen, Benjamin; Miyamoto, Satoshi; Pham, Jessica; Ono, Keiichiro; Ideker, Trey; Sharma, Kumar] Univ Calif San Diego, Dept Med, Div Med Genet, San Diego, CA USA. [Rocanin-Arjo, Anais; Romoli, Simone; Thomasova, Dana; Mulay, Shrikant R.; Anders, Hans Joachim] Klinikum Univ Munchen, LMU Munich, Med Klin & Poliklin 4, Munich, Germany. [Pu, Minya; Natarajan, Loki] Univ Calif San Diego, Dept Family Med & Epidemiol, San Diego, CA USA. [Ju, Wenjun; Kretzler, Matthias] Univ Michigan, Dept Internal Med, Nephrol, Ann Arbor, MI 48109 USA. [Ju, Wenjun; Kretzler, Matthias] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Nelson, Robert] Natl Inst Diabet & Digest & Kidney Dis, Phoenix, AZ USA. [D'Agati, Vivette] Columbia Univ, Coll Phys & Surg, Dept Pathol, Renal Pathol Lab, New York, NY USA. [Beyret, Ergin; Belmonte, Juan Carlos Izpisua] Salk Inst Biol Studies, San Diego, CA USA. [Sharma, Kumar] Vet Affairs Hlth Syst, San Diego, CA USA. RP Sharma, K (reprint author), Univ Calif San Diego, Med, 9500 Gilman Dr, La Jolla, CA 92093 USA.; Sharma, K (reprint author), Univ Calif San Diego, Ctr Renal Translat Med, 9500 Gilman Dr, La Jolla, CA 92093 USA.; Sharma, K (reprint author), Univ Calif San Diego, Inst Metabol Med, 9500 Gilman Dr, La Jolla, CA 92093 USA. EM kumarsharma@ucsd.edu FU BLRD VA [I01 BX000277]; NIDDK NIH HHS [DP3 DK094352, P30 DK081943]; NIGMS NIH HHS [P50 GM085764, P41 GM103504] NR 48 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 2379-3708 J9 JCI INSIGHT JI JCI Insight PD OCT 20 PY 2016 VL 1 IS 17 AR e87877 DI 10.1172/jci.insight.87877 PG 17 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EB1PF UT WOS:000387125100004 PM 27777973 ER PT J AU Burgess, S AF Burgess, Shawn TI GENOMICS A matched set of frog sequences SO NATURE LA English DT Editorial Material AB A whole-genome duplication that occurred around 34 million years ago in the frog Xenopus laevis made generating a genome sequence for this valuable model organism a challenge. This obstacle has finally been overcome. See Article p.336 C1 [Burgess, Shawn] NHGRI, Translat & Funct Genom Branch, NIH, Bethesda, MD 20892 USA. RP Burgess, S (reprint author), NHGRI, Translat & Funct Genom Branch, NIH, Bethesda, MD 20892 USA. EM burgess@mail.nih.gov NR 4 TC 1 Z9 1 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD OCT 20 PY 2016 VL 538 IS 7625 BP 320 EP 321 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EA5PJ UT WOS:000386673100023 PM 27762363 ER PT J AU Psaila, B AF Psaila, Bethan TI Tense your megas! Structural rigidity is key SO BLOOD LA English DT Editorial Material ID BONE-MARROW; MEGAKARYOCYTES; NICHE C1 [Psaila, Bethan] Univ Oxford, Oxford OX1 2JD, England. [Psaila, Bethan] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Psaila, B (reprint author), Univ Oxford, Oxford OX1 2JD, England.; Psaila, B (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. OI Psaila, Beth/0000-0001-8198-9663 NR 10 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD OCT 20 PY 2016 VL 128 IS 16 BP 1997 EP 1999 DI 10.1182/blood-2016-09-734509 PG 3 WC Hematology SC Hematology GA DZ3IL UT WOS:000385739900001 PM 28157674 ER PT J AU Fowler, DH Amarnath, S AF Fowler, Daniel H. Amarnath, Shoba TI IL-27: a new target for GVHD prevention SO BLOOD LA English DT Editorial Material ID T-CELLS; INTERLEUKIN-27; INFLAMMATION C1 [Fowler, Daniel H.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Amarnath, Shoba] Newcastle Univ, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. RP Fowler, DH (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 10 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD OCT 20 PY 2016 VL 128 IS 16 BP 2003 EP 2004 DI 10.1182/blood-2016-08-732974 PG 2 WC Hematology SC Hematology GA DZ3IL UT WOS:000385739900004 PM 28157677 ER PT J AU Abdulhay, N Fiorini, C Kumanovics, A Sun, AA Hansen-Rejali, J Voelkerding, KV Rosenzweig, SD Hill, HR Sankaran, VG AF Abdulhay, Nour Fiorini, Claudia Kumanovics, Attila Sun, Ashleigh A. Hansen-Rejali, Jeannette Voelkerding, Karl V. Rosenzweig, Sergio D. Hill, Harry R. Sankaran, Vijay G. TI Normal hematologic parameters and fetal hemoglobin silencing with heterozygous IKZF1 mutations SO BLOOD LA English DT Letter ID IKAROS; BCL11A; EXPRESSION; DIFFERENTIATION; ANEMIA C1 [Abdulhay, Nour; Fiorini, Claudia; Sankaran, Vijay G.] Boston Childrens Hosp, Div Hematol Oncol, 3 Blackfan Cir,CLS 03001, Boston, MA 02115 USA. [Abdulhay, Nour; Fiorini, Claudia; Sankaran, Vijay G.] Harvard Med Sch, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA USA. [Abdulhay, Nour; Fiorini, Claudia; Sankaran, Vijay G.] Broad Inst Massachusetts Inst Technol & Harvard, Cambridge, MA USA. [Kumanovics, Attila; Hansen-Rejali, Jeannette; Voelkerding, Karl V.; Hill, Harry R.] ARUP Inst Clin & Expt Pathol, ARUP Labs, Salt Lake City, UT USA. [Kumanovics, Attila; Hansen-Rejali, Jeannette; Voelkerding, Karl V.; Hill, Harry R.] Univ Utah, Dept Pathol, Salt Lake City, UT USA. [Sun, Ashleigh A.; Rosenzweig, Sergio D.] NIAID, Serv Immunol, Dept Lab Med, Ctr Clin,NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Sun, Ashleigh A.; Rosenzweig, Sergio D.] NIAID, Primary Immune Deficiency Clin, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Hansen-Rejali, Jeannette; Hill, Harry R.] Univ Utah, Dept Pediat, Salt Lake City, UT USA. [Hansen-Rejali, Jeannette; Hill, Harry R.] Univ Utah, Dept Med, Salt Lake City, UT 84112 USA. RP Sankaran, VG (reprint author), Boston Childrens Hosp, Div Hematol Oncol, 3 Blackfan Cir,CLS 03001, Boston, MA 02115 USA. EM sankaran@broadinstitute.org NR 25 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD OCT 20 PY 2016 VL 128 IS 16 BP 2100 EP 2103 DI 10.1182/blood-2016-08-731943 PG 4 WC Hematology SC Hematology GA DZ3IL UT WOS:000385739900018 PM 27581358 ER PT J AU Langhorne, J Duffy, P AF Langhorne, Jean Duffy, Patrick TI Eradicating Malaria: Discoveries, Challenges, and Questions SO CELL LA English DT Editorial Material C1 [Langhorne, Jean] Francis Crick Inst, London, England. [Duffy, Patrick] NIAID, LMIV, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Langhorne, J (reprint author), Francis Crick Inst, London, England. NR 0 TC 0 Z9 0 U1 4 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD OCT 20 PY 2016 VL 167 IS 3 BP 595 EP 597 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EA1HW UT WOS:000386344100004 ER PT J AU Pierson, TC Graham, BS AF Pierson, Theodore C. Graham, Barney S. TI Zika Virus: Immunity and Vaccine Development SO CELL LA English DT Review ID WEST-NILE-VIRUS; BORNE ENCEPHALITIS-VIRUS; ANTIBODY-DEPENDENT ENHANCEMENT; CD8(+) T-CELLS; DENGUE VIRUS; ENVELOPE PROTEIN; STRUCTURAL BASIS; NEUTRALIZING ANTIBODY; CROSS-REACTIVITY; SURFACE-PROTEINS AB The emergence of Zika virus in the Americas and Caribbean created an urgent need for vaccines to reduce transmission and prevent disease, particularly the devastating neurodevelopmental defects that occur in utero. Rapid advances in Zika immunity and the development of vaccine candidates provide cautious optimism that preventive measures are possible. C1 [Pierson, Theodore C.] NIAID, Viral Pathogenesis Sect, Viral Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Graham, Barney S.] NIAID, Viral Pathogenesis Lab, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Pierson, TC (reprint author), NIAID, Viral Pathogenesis Sect, Viral Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM piersontc@mail.nih.gov FU intramural research program of the Division of Intramural Research, NIAID, NIH; intramural research program of the Vaccine Research Center, NIAID, NIH FX This work was supported by the intramural research programs of the Division of Intramural Research and the Vaccine Research Center, NIAID, NIH. We thank Michael Diamond and Steve Whitehead for their comments on the manuscript. We apologize for the many instances in which the important work of others is not cited due to formatting constraints. Dr. Pierson and Dr. Graham are inventors on patents for ZIKV vaccine candidates. NR 83 TC 8 Z9 9 U1 100 U2 100 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD OCT 20 PY 2016 VL 167 IS 3 BP 625 EP 631 DI 10.1016/j.cell.2016.09.020 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EA1HW UT WOS:000386344100011 PM 27693357 ER PT J AU Gilchuk, I Gilchuk, P Sapparapu, G Lampley, R Singh, V Kose, N Blum, DL Hughes, LJ Satheshkumar, PS Townsend, MB Kondas, AV Reed, Z Weiner, Z Olson, VA Hammarlund, E Raue, HP Slifka, MK Slaughter, JC Graham, BS Edwards, KM Eisenberg, RJ Cohen, GH Joyce, S Crowe, JE AF Gilchuk, Iuliia Gilchuk, Pavlo Sapparapu, Gopal Lampley, Rebecca Singh, Vidisha Kose, Nurgun Blum, David L. Hughes, Laura J. Satheshkumar, Panayampalli S. Townsend, Michael B. Kondas, Ashley V. Reed, Zachary Weiner, Zachary Olson, Victoria A. Hammarlund, Erika Raue, Hans-Peter Slifka, Mark K. Slaughter, James C. Graham, Barney S. Edwards, Kathryn M. Eisenberg, Roselyn J. Cohen, Gary H. Joyce, Sebastian Crowe, James E., Jr. TI Cross-Neutralizing and Protective Human Antibody Specificities to Poxvirus Infections SO CELL LA English DT Article ID ATTENUATED SMALLPOX VACCINE; MONOCLONAL-ANTIBODIES; VIRUS-INFECTION; ENVELOPE PROTEIN; IMMUNE-RESPONSE; B-CELLS; MONKEYPOX; MICE; CHALLENGE; ANTIGEN AB Monkeypox (MPXV) and cowpox (CPXV) areemerging agents that cause severe human infections on an inter-mittentbasis, and variola virus (VARV) has potential for use as an agent of bioterror. Vaccinia immune globulin (VIG) has been used therapeutically to treat severe orthopoxvirus infections but is in short supply. We generated a large panel of orthopoxvirus-specific human monoclonal antibodies (Abs) from immune subjects to investigate the molecular basis of broadly neutralizing antibody responses for diverse orthopox-viruses. Detailed analysis revealed the principal neutralizing antibody specificities that are cross-reactive for VACV, CPXV, MPXV, and VARV and that are determinants of protection in murine challenge models. Optimal protection following respiratory or systemic infection required a mixture of Abs that targeted several membrane proteins, including proteins on enveloped and mature virion forms of virus. This work reveals orthopoxvirus targets for human Abs that mediate cross-protective immunity and identifies new candidate Ab therapeutic mixtures to replace VIG. C1 [Gilchuk, Iuliia; Sapparapu, Gopal; Lampley, Rebecca; Singh, Vidisha; Kose, Nurgun; Blum, David L.; Crowe, James E., Jr.] Vanderbilt Univ, Vanderbilt Vaccine Ctr, Med Ctr, Nashville, TN 37232 USA. [Gilchuk, Pavlo; Joyce, Sebastian; Crowe, James E., Jr.] Vanderbilt Univ, Dept Pathol Microbiol & Immunol, Med Ctr, Nashville, TN 37232 USA. [Gilchuk, Pavlo; Joyce, Sebastian] Vet Adm Tennessee Valley Healthcare Syst, Nashville, TN 37332 USA. [Sapparapu, Gopal; Edwards, Kathryn M.; Crowe, James E., Jr.] Vanderbilt Univ, Dept Pediat, Med Ctr, Nashville, TN 37232 USA. [Hughes, Laura J.; Satheshkumar, Panayampalli S.; Townsend, Michael B.; Kondas, Ashley V.; Reed, Zachary; Olson, Victoria A.] Ctr Dis Control & Prevent, Poxvirus & Rabies Branch, Atlanta, GA 30329 USA. [Reed, Zachary; Weiner, Zachary] Ctr Dis Control & Prevent, Lab Leadership Serv, Atlanta, GA 30329 USA. [Hammarlund, Erika; Raue, Hans-Peter; Slifka, Mark K.] Oregon Natl Primate Res Ctr, Div Neurosci, Beaverton, OR 97006 USA. [Slaughter, James C.] Vanderbilt Univ, Med Ctr, Dept Biostat, Nashville, TN 37232 USA. [Graham, Barney S.] NIAID, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Eisenberg, Roselyn J.] Univ Penn, Sch Vet Med, Dept Pathobiol, Philadelphia, PA 19104 USA. [Cohen, Gary H.] Univ Penn, Sch Dent Med, Dept Microbiol, Philadelphia, PA 19104 USA. RP Crowe, JE (reprint author), Vanderbilt Univ, Vanderbilt Vaccine Ctr, Med Ctr, Nashville, TN 37232 USA.; Crowe, JE (reprint author), Vanderbilt Univ, Dept Pathol Microbiol & Immunol, Med Ctr, Nashville, TN 37232 USA.; Crowe, JE (reprint author), Vanderbilt Univ, Dept Pediat, Med Ctr, Nashville, TN 37232 USA. EM james.crowe@vanderbilt.edu OI Sapparapu, Gopal/0000-0001-9670-1757 FU U.S. NIH [U01 AI48512, HHSN272200900047C, U19 AI109948, 8P51 OD 011092-53]; NCRR [UL1 RR024975-01]; National Center for Advancing Translational Sciences [2 UL1 TR000445-06, BX001444]; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH; NIH [P30 CA68485, DK058404] FX This project received support from the U.S. NIH (grants U01 AI48512 and contract HHSN272200900047C to J.E.C., and U19 AI109948 and 8P51 OD 011092-53 to M.K.S.). The project was supported by NCRR grant UL1 RR024975-01, and is now at the National Center for Advancing Translational Sciences, Grant 2 UL1 TR000445-06, and VA Merit Award BX001444 (to S.J.). This work was supported by intramural funding from the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH. Flow cytometry experiments were performed in the Vanderbilt University Medical Center Flow Cytometry Shared Resource, supported by NIH P30 CA68485 and DK058404. We thank Jill Janssen and the Vanderbilt Clinical Trials Center for regulatory support, and Yingchun Yu, Patricia McGraw, Natalie Thornburg, Shane Crotty, Chwan Hong Foo, J. Charles Whitbeck, and Stuart Isaacs for technical contributions and advice. We thank Y. Xiang and Dirk Zajonc for providing recombinant D8 protein and Shane Crotty for providing H3 protein. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the Centers for Disease Control and Prevention. I.G. and J.E.C. are named as co-inventors on a patent applied for that is associated with some of the antibodies described in this manuscript. NR 41 TC 0 Z9 0 U1 5 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD OCT 20 PY 2016 VL 167 IS 3 BP 684 EP + DI 10.1016/j.cell.2016.09.049 PG 20 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EA1HW UT WOS:000386344100016 PM 27768891 ER PT J AU Mayaphi, SH Martin, DJ Quinn, TC Laeyendecker, O Olorunju, SAS Tintinger, GR Stoltz, AC AF Mayaphi, Simnikiwe H. Martin, Desmond J. Quinn, Thomas C. Laeyendecker, Oliver Olorunju, Steve A. S. Tintinger, Gregory R. Stoltz, Anton C. TI Detection of Acute and Early HIV-1 Infections in an HIV Hyper-Endemic Area with Limited Resources SO PLOS ONE LA English DT Article ID CIRCULATING IMMUNE-COMPLEXES; MOTHER-TO-CHILD; SOUTH-AFRICA; VIRAL-LOAD; TRANSMISSION; ASSAY; CARE; SENSITIVITY; DIAGNOSIS; SETTINGS AB Background Two thirds of the world's new HIV infections are in sub-Saharan Africa. Acute HIV infection (AHI) is the time of virus acquisition until the appearance of HIV antibodies. Early HIV infection, which includes AHI, is the interval between virus acquisition and establishment of viral load set-point. This study aimed to detect acute and early HIV infections in a hyper-endemic setting. Methods This was a cross-sectional diagnostic study that enrolled individuals who had negative rapid HIV results in five clinics in South Africa. Pooled nucleic acid amplification testing (NAAT) was performed, followed by individual sample testing in positive pools. NAAT-positive participants were recalled to the clinics for confirmatory testing and appropriate management. HIV antibody, p24 antigen, Western Blot and avidity tests were performed for characterization of NAAT-positive samples. Results The study enrolled 6910 individuals with negative rapid HIV results. Median age was 27 years (interquartile range {IQR}: 23-31). NAAT was positive in 55 samples, resulting in 0.8% newly diagnosed HIV-infected individuals (95% confidence interval {CI}: 0.6-1.0). The negative predictive value for rapid HIV testing was 99.2% (95% CI: 99.0-99.4). Characterization of NAAT-positive samples revealed that 0.04% (95% CI: 0.000-0.001) had AHI, 0.3% (95% CI: 0.1-0.4) had early HIV infection, and 0.5% (95% CI: 0.5-0.7) had chronic HIV infection. Forty-seven (86%) of NAAT-positive participants returned for follow-up at a median of 4 weeks (IQR: 2-8). Follow-up rapid tests were positive in 96% of these participants. Conclusions NAAT demonstrated that a substantial number of HIV-infected individuals are misdiagnosed at South African points-of-care. Follow-up rapid tests done within a 4 week interval detected early and chronic HIV infections initially missed by rapid HIV testing. This may be a practical and affordable strategy for earlier detection of these infections in resource-constrained settings. Newer molecular tests that can be used at the points-of-care should be evaluated for routine diagnosis of HIV in hyper-endemic settings. C1 [Mayaphi, Simnikiwe H.; Martin, Desmond J.] Univ Pretoria, Dept Med Virol, City Of Tshwane, South Africa. [Mayaphi, Simnikiwe H.] Natl Hlth Lab Serv, Tshwane Acad Div NHLS TAD, City Of Tshwane, South Africa. [Martin, Desmond J.] Toga Labs, Johannesburg, South Africa. [Quinn, Thomas C.; Laeyendecker, Oliver] NIAID, Div Intramural Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Quinn, Thomas C.; Laeyendecker, Oliver] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Olorunju, Steve A. S.] MRC, Biostat Unit, City Of Tshwane, South Africa. [Tintinger, Gregory R.; Stoltz, Anton C.] Univ Pretoria, Dept Internal Med, City Of Tshwane, South Africa. RP Mayaphi, SH (reprint author), Univ Pretoria, Dept Med Virol, City Of Tshwane, South Africa.; Mayaphi, SH (reprint author), Natl Hlth Lab Serv, Tshwane Acad Div NHLS TAD, City Of Tshwane, South Africa. EM sim.mayaphi@up.ac.za FU National Health Laboratory Service Research Trust (NHLS-RT); Federation of Infectious Diseases Societies of Southern Africa and GlaxoSmithKline (FIDSSA-GSK); University of Pretoria research; South African Medical Research Council Self Initiated Research (MRC-SIR); Toga Laboratories; GlaxoSmithKline; National Institute for Communicable Diseases (NICD) HIV Sero-Molecular Laboratory FX 1. National Health Laboratory Service Research Trust (NHLS-RT) grant (www.nhls.ac.za), SHM and DJM. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 2. Federation of Infectious Diseases Societies of Southern Africa and GlaxoSmithKline (FIDSSA-GSK) grant (www.fidssa.co.za), SHM. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 3. University of Pretoria research assistant grant (www.up.ac.za), SHM. The funders had no role instudy design, data collection and analysis, decision to publish, or preparation of the manuscript. 4. South African Medical Research Council Self Initiated Research (MRC-SIR) grant (www.mrc.ac.za), SHM. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 5. Discovery Foundation (www.tshikululu.org.za), SHM. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 6. Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (www.nih.gov), TCQ and OL; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. DJM is an employee of a commercial company, Toga Laboratories. The Toga Laboratories provided support in the form of salaries for [DJM], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. SHM received are search grant from a commercial funder, GlaxoSmithKline. GlaxoSmithKline did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.; We thank all the funders for supporting this study, all study participants, National Institute for Communicable Diseases (NICD) HIV Sero-Molecular Laboratory staff for assisting with 3rd generation HIV ELISA and limiting antigen avidity testing, and special thanks to our research assistants for recruiting and enrolling study participants. NR 46 TC 0 Z9 0 U1 3 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 20 PY 2016 VL 11 IS 10 AR e0164943 DI 10.1371/journal.pone.0164943 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ9NZ UT WOS:000386204500082 PM 27764165 ER PT J AU Speake, C Pichugin, A Sahu, T Malkov, V Morrison, R Pei, Y Juompan, L Milman, N Zarling, S Anderson, C MacDonald, NJ Wong-Madden, S Wendler, J Ishizuka, A MacMillen, ZW Garcia, V Kappe, SH Krzych, U Duffy, PE AF Speake, C. Pichugin, A. Sahu, T. Malkov, V. Morrison, R. Pei, Y. Juompan, L. Milman, N. Zarling, S. Anderson, C. MacDonald, N. J. Wong-Madden, S. Wendler, J. Ishizuka, A. MacMillen, Z. W. Garcia, V. Kappe, S. H. Krzych, U. Duffy, P. E. TI Identification of Novel Pre-Erythrocytic Malaria Antigen Candidates for Combination Vaccines with Circumsporozoite Protein (vol 11, e0159449, 2016) SO PLOS ONE LA English DT Correction C1 [MacDonald, N. J.] NIAID, Lab Malaria Immunol & Vaccinol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 20 PY 2016 VL 11 IS 10 AR e0165489 DI 10.1371/journal.pone.0165489 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ9NZ UT WOS:000386204500154 PM 27764243 ER PT J AU Torres, AR Sweeten, TL Johnson, RC Odell, D Westover, JB Bray-Ward, P Ward, DC Davies, CJ Thomas, AJ Croen, LA Benson, M AF Torres, Anthony R. Sweeten, Thayne L. Johnson, Randall C. Odell, Dennis Westover, Jonna B. Bray-Ward, Patricia Ward, David C. Davies, Christopher J. Thomas, Aaron J. Croen, Lisa A. Benson, Michael TI Common Genetic Variants Found in HLA and KIR Immune Genes in Autism Spectrum Disorder SO FRONTIERS IN NEUROSCIENCE LA English DT Review DE autism; HLA; KIR; haplotype; common genetic variant ID ARTHRITIS SHARED EPITOPE; NECROSIS-FACTOR-ALPHA; RHEUMATOID-ARTHRITIS; FAMILY-HISTORY; NITRIC-OXIDE; NULL ALLELE; ASSOCIATION; DISEASE; BRAIN; RISK AB The "common variant common disease" hypothesis was proposed to explain diseases with strong inheritance. This model suggests that a genetic disease is the result of the combination of several common genetic variants. Common genetic variants are described as a 5% frequency differential between diseased vs. matched control populations. This theory was recently supported by an epidemiology paper stating that about 50% of genetic risk for autism resides in common variants. However, rare variants, rather than common variants, have been found in numerous genome wide genetic studies and many have concluded that the-common variant common disease" hypothesis is incorrect. One interpretation is that rare variants are major contributors to genetic diseases and autism involves the interaction of many rare variants, especially in the brain. It is obvious there is much yet to be learned about autism genetics. Evidence has been mounting over the years indicating immune involvement in autism, particularly the HLA genes on chromosome 6 and KIR genes on chromosome 19. These two large multigene complexes have important immune functions and have been shown to interact to eliminate unwanted virally infected and malignant cells. HLA proteins have important functions in antigen presentation in adaptive immunity and specific epitopes on HLA class I proteins act as cognate ligands for KIR receptors in innate immunity. Data suggests that HLA alleles and KIR activating genes/haplotypes are common variants in different autism populations. For example, class I allele (HLA-A2 and HLA-G 14 bp-indel) frequencies are significantly increased by more than 5% over control populations (Table 2). The HLA-DR4 Class II and shared epitope frequencies are significantly above the control populations (Table 2). Three activating KIR genes: 3DS1, 2DS1, and 2DS2 have increased frequencies of 15, 22, and 14% in autism populations, respectively. There is a 6% increase in total activating KIR genes in autism over control subjects. And, more importantly there is a 12% increase in activating KIR genes and their cognate HLA alleles over control populations (Torres et al., 2012a). These data suggest the interaction of HLA ligand/KIR receptor pairs encoded on two different chromosomes is more significant as a ligand/receptor complex than separately in autism. C1 [Torres, Anthony R.; Odell, Dennis; Westover, Jonna B.; Bray-Ward, Patricia; Ward, David C.; Benson, Michael] Utah State Univ, Ctr Persons Disabil, Logan, UT 84322 USA. [Sweeten, Thayne L.] Utah State Univ, Dept Biol, Brigham City, UT USA. [Johnson, Randall C.] SAIC Frederick Inc, BSP CCR Genet Core, Frederick Natl Lab Canc Res, Frederick, MD USA. [Davies, Christopher J.; Croen, Lisa A.] Utah State Univ, Ctr Integrated BioSyst, Logan, UT 84322 USA. [Thomas, Aaron J.] Kaiser Permanente Northern Calif, Div Res, Oakland, CA USA. RP Torres, AR (reprint author), Utah State Univ, Ctr Persons Disabil, Logan, UT 84322 USA. EM anthony.torres@usu.edu FU Center for Persons with Disabilities, Utah State University; Utah Autism Foundation; National Institutes of Environmental Health Sciences [5RO1 ESO16669]; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Intramural Research Program of NIH, National Cancer Institute, Center for Cancer Research FX We wish to acknowledge funding from the Center for Persons with Disabilities, Utah State University, the Utah Autism Foundation, the National Institutes of Environmental Health Sciences grant (5RO1 ESO16669). We also wish to honor Dr. Reed P. Warren who died in 1998 for encouraging several of us (ART, TS, DO, JW) to pursue the study of immune genes in autism. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This research was supported [in part] by the Intramural Research Program of NIH, National Cancer Institute, Center for Cancer Research. NR 83 TC 1 Z9 1 U1 8 U2 8 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-453X J9 FRONT NEUROSCI-SWITZ JI Front. Neurosci. PD OCT 20 PY 2016 VL 10 AR 463 DI 10.3389/fnins.2016.00463 PG 13 WC Neurosciences SC Neurosciences & Neurology GA DZ2PJ UT WOS:000385683400001 PM 27812316 ER PT J AU Samuel, N Wilson, G Lemire, M Id Said, B Lou, Y Li, W Merino, D Novokmet, A Tran, J Nichols, KE Finlay, JL Choufani, S Remke, M Ramaswamy, V Cavalli, FMG Elser, C Meister, L Taylor, MD Tabori, U Irwin, M Weksberg, R Wasserman, JD Paterson, AD Hansford, JR Achatz, MIW Hudson, TJ Malkin, D AF Samuel, Nardin Wilson, Gavin Lemire, Mathieu Id Said, Badr Lou, Youliang Li, Weili Merino, Diana Novokmet, Ana Tran, James Nichols, Kim E. Finlay, Jonathan L. Choufani, Sanaa Remke, Marc Ramaswamy, Vijay Cavalli, Florence M. G. Elser, Christine Meister, Lynn Taylor, Michael D. Tabori, Uri Irwin, Meredith Weksberg, Rosanna Wasserman, Jonathan D. Paterson, Andrew D. Hansford, Jordan R. Achatz, Maria Isabel W. Hudson, Thomas J. Malkin, David TI Genome-Wide DNA Methylation Analysis Reveals Epigenetic Dysregulation of MicroRNA-34A in TP53-Associated Cancer Susceptibility SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID LI-FRAUMENI; P53 NETWORK; MIR-34A; APOPTOSIS; FAMILIES; MIMICS; TUMORS; CELLS; MICE AB Purpose Although the link between mutant TP53 and human cancer is unequivocal, a significant knowledge gap exists in clinically actionable molecular targets in Li-Fraumeni syndrome (LFS), a highly penetrant cancer predisposition syndrome associated with germline mutations in TP53. This study surveyed the epigenome to identify functionally and clinically relevant novel genes implicated in LFS. Patients and Methods We performed genome-wide methylation analyses of peripheral blood leukocyte DNA in germline TP53 mutation carriers (n = 72) and individuals with TP53 wild type in whom histologically comparable malignancies developed (n = 111). Targeted bisulfite pyrosequencing was performed on a validation cohort of 30 TP53 mutation carriers and 46 patients with TP53 wild type, and candidate sites were evaluated in primary tumors from patients with LFS across multiple histologic tumor types. Results In 183 patients, distinct DNA methylation signatures were associated with deleterious TP53 mutations in peripheral blood leukocytes. TP53-associated DNA methylation marks occurred in genomic regions that harbored p53 binding sites and in genes encoding p53 pathway proteins. Moreover, loss-of-function TP53 mutations were significantly associated with differential methylation at the locus encoding microRNA miR-34A, a key component of the p53 regulatory network (adjusted P < .001), and validated in an independent patient cohort (n = 76, P < .001). Targeted bisulfite pyrosequencing demonstrated that miR-34A was inactivated by hypermethylation across many histologic types of primary tumors from patients with LFS. Moreover, miR-34A tumor hypermethylation was associated with decreased overall survival in a cohort of 29 patients with choroid plexus carcinomas, a characteristic LFS tumor (P < .05). Conclusion Epigenetic dysregulation of miR-34A may comprise an important path in TP53-associated cancer predisposition and represents a therapeutically actionable target with potential clinical relevance. (C) 2016 by American Society of Clinical Oncology C1 [Samuel, Nardin; Wilson, Gavin; Tran, James; Irwin, Meredith; Weksberg, Rosanna; Hudson, Thomas J.; Malkin, David] Univ Toronto, Toronto, ON M5S 1A1, Canada. [Samuel, Nardin; Id Said, Badr; Lou, Youliang; Li, Weili; Novokmet, Ana; Tran, James; Choufani, Sanaa; Remke, Marc; Ramaswamy, Vijay; Cavalli, Florence M. G.; Taylor, Michael D.; Tabori, Uri; Irwin, Meredith; Weksberg, Rosanna; Wasserman, Jonathan D.; Paterson, Andrew D.; Malkin, David] Hosp Sick Children, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. [Samuel, Nardin; Wilson, Gavin; Lemire, Mathieu; Hudson, Thomas J.] Ontario Inst Canc Res, Toronto, ON, Canada. [Elser, Christine] Princess Margaret Canc Ctr, Toronto, ON, Canada. [Merino, Diana] NIH, Bldg 10, Bethesda, MD 20892 USA. [Nichols, Kim E.] St Jude Childrens Res Hosp, 332 N Lauderdale St, Memphis, TN 38105 USA. [Finlay, Jonathan L.] Nationwide Childrens Hosp, Columbus, OH USA. [Meister, Lynn] Joe DiMaggio Childrens Hosp, Hollywood, FL USA. [Hansford, Jordan R.] Royal Childrens Hosp, Childrens Canc Ctr, Melbourne, Vic, Australia. [Achatz, Maria Isabel W.] Hosp AC Camargo Fund Antonio Prudente, Sao Paulo, Brazil. RP Malkin, D (reprint author), Hosp Sick Children, Dept Pediat, Div Hematol Oncol, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. EM david.malkin@sickkids.ca RI Paterson, Andrew/A-4088-2011 OI Paterson, Andrew/0000-0002-9169-118X FU Canadian Institutes for Health Research; Terry Fox Research Institute; SickKids Foundation; Ontario Institute for Cancer Research; Ontario Ministry of Research and Innovation; Cancer in Kids; Leukaemia Auxiliary; Murdoch Childrens Research Institute; Royal Children's Hospital Foundation FX Supported in part through grants from the Canadian Institutes for Health Research, Terry Fox Research Institute, and SickKids Foundation. T.J.H. is supported by a Senior Investigator Award of the Ontario Institute for Cancer Research, with funds provided by the Ontario Ministry of Research and Innovation. Establishment and running of the Children's Cancer Centre Tissue Bank at the Royal Children's Hospital Melbourne is made possible through generous support by Cancer in Kids, Leukaemia Auxiliary, the Murdoch Childrens Research Institute, and the Royal Children's Hospital Foundation. NR 22 TC 1 Z9 1 U1 5 U2 5 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD OCT 20 PY 2016 VL 34 IS 30 BP 3697 EP + DI 10.1200/JCO.2016.67.6940 PG 14 WC Oncology SC Oncology GA DZ6KZ UT WOS:000385972600017 ER PT J AU Park, J Wysocki, RW Amoozgar, Z Maiorino, L Fein, MR Jorns, J Schott, AF Kinugasa-Katayama, Y Lee, Y Won, NH Nakasone, ES Hearn, SA Kuttner, V Qiu, J Almeida, AS Perurena, N Kessenbrock, K Goldberg, MS Egeblad, M AF Park, Juwon Wysocki, Robert W. Amoozgar, Zohreh Maiorino, Laura Fein, Miriam R. Jorns, Julie Schott, Anne F. Kinugasa-Katayama, Yumi Lee, Youngseok Nam Hee Won Nakasone, Elizabeth S. Hearn, Stephen A. Kuettner, Victoria Qiu, Jing Almeida, Ana S. Perurena, Naiara Kessenbrock, Kai Goldberg, Michael S. Egeblad, Mikala TI Cancer cells induce metastasis-supporting neutrophil extracellular DNA traps SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID BREAST-CANCER; MOLECULAR-MECHANISMS; MAMMARY-TUMOR; NET FORMATION; MICE; LUNG; INFLAMMATION; PROMOTE; DISEASE; DEOXYRIBONUCLEASE AB Neutrophils, the most abundant type of leukocytes in blood, can form neutrophil extracellular traps (NETs). These are pathogen-trapping structures generated by expulsion of the neutrophil's DNA with associated proteolytic enzymes. NETs produced by infection can promote cancer metastasis. We show that metastatic breast cancer cells can induce neutrophils to form metastasis-supporting NETs in the absence of infection. Using intravital imaging, we observed NET-like structures around metastatic 4T1 cancer cells that had reached the lungs of mice. We also found NETs in clinical samples of triple-negative human breast cancer. The formation of NETs stimulated the invasion and migration of breast cancer cells in vitro. Inhibiting NET formation or digesting NETs with deoxyribonuclease I (DNase I) blocked these processes. Treatment with NET-digesting, DNase I-coated nanoparticles markedly reduced lung metastases in mice. Our data suggest that induction of NETs by cancer cells is a previously unidentified metastasispromoting tumor-host interaction and a potential therapeutic target. C1 [Park, Juwon; Wysocki, Robert W.; Maiorino, Laura; Fein, Miriam R.; Kinugasa-Katayama, Yumi; Nakasone, Elizabeth S.; Kuettner, Victoria; Qiu, Jing; Almeida, Ana S.; Perurena, Naiara; Egeblad, Mikala] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. [Wysocki, Robert W.] SUNY Stony Brook, Sch Med, Med Scientist Training Program, Stony Brook, NY 11794 USA. [Wysocki, Robert W.; Fein, Miriam R.] SUNY Stony Brook, Grad Program Genet, Stony Brook, NY 11794 USA. [Amoozgar, Zohreh; Goldberg, Michael S.] Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02215 USA. [Maiorino, Laura; Nakasone, Elizabeth S.] Watson Sch Biol Sci, Cold Spring Harbor, NY 11724 USA. [Jorns, Julie; Schott, Anne F.] Univ Michigan, Ann Arbor, MI 48109 USA. [Lee, Youngseok; Nam Hee Won] Korea Univ, Anam Hosp, Dept Pathol, Seoul, South Korea. [Hearn, Stephen A.] NCI, Shared Resources & St Giles Fdn Adv Microscopy Ct, Cold Spring Harbor Lab Canc Ctr, Cold Spring Harbor, NY 11724 USA. [Kessenbrock, Kai] Univ Calif Irvine, Irvine, CA 92697 USA. [Goldberg, Michael S.] Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. [Park, Juwon] Univ Hawaii, John Burns Sch Med, Ctr Cardiovasc Res, Honolulu, HI 96813 USA. [Amoozgar, Zohreh] Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Labs, Boston, MA 02114 USA. [Amoozgar, Zohreh; Perurena, Naiara] Harvard Med Sch, Boston, MA 02115 USA. [Perurena, Naiara] Brigham & Womens Hosp, Div Genet, Dept Med, Boston, MA 02115 USA. RP Egeblad, M (reprint author), Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. EM egeblad@cshl.edu FU CSHL Cancer Center Support Grant [5P30CA045508]; U.S. Department of Defense [W81XWH-14-1-0078]; Long Island 2-Day Walk to Fight Breast Cancer; Joni Gladowsky Breast Cancer Foundation; NIH [5U01CA180944-02]; Hope Foundation; Cancer Research Institute CLIP (Clinic and Laboratory Integration Program) Grant; National Institute of General Medical Sciences Medical Scientist Training Program Training Award [T32-GM008444]; Aid for Cancer Research; Boehringer Ingelheim Fonds; Formacion de Profesorado Universitario fellowship [AP2010-2197]; National Cancer Institute [K99 CA181490]; Deutsche Forschungsgemeinschaft research fellowship [KU 3264/1-1] FX This work was supported by the CSHL Cancer Center Support Grant 5P30CA045508, funds to M.E. from the U.S. Department of Defense (W81XWH-14-1-0078), the Long Island 2-Day Walk to Fight Breast Cancer, and the Joni Gladowsky Breast Cancer Foundation. M.E., J.J., and A.F.S. were supported by funds from NIH (5U01CA180944-02) and the Hope Foundation. M.S.G. was supported by the Cancer Research Institute CLIP (Clinic and Laboratory Integration Program) Grant; R.W.W. was supported by the National Institute of General Medical Sciences Medical Scientist Training Program Training Award (T32-GM008444); Z.A. was supported by Aid for Cancer Research; L.M. is a George A. and Marjorie H. Anderson fellow and is supported by a fellowship from the Boehringer Ingelheim Fonds; N.P. was supported by a Formacion de Profesorado Universitario fellowship (AP2010-2197); K.K. was supported by the National Cancer Institute (K99 CA181490); and V.K. was supported by the Deutsche Forschungsgemeinschaft research fellowship (KU 3264/1-1). NR 48 TC 1 Z9 1 U1 9 U2 9 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD OCT 19 PY 2016 VL 8 IS 361 AR 361ra138 DI 10.1126/scitranslmed.aag1711 PG 12 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA EE2VE UT WOS:000389442300003 PM 27798263 ER PT J AU Seo, DO Funderburk, SC Bhatti, DL Motard, LE Newbold, D Girven, KS McCall, JG Krashes, M Sparta, DR Bruchas, MR AF Seo, Dong-oh Funderburk, Samuel C. Bhatti, Dionnet L. Motard, Laura E. Newbold, Dillan Girven, Kasey S. McCall, Jordan G. Krashes, Michael Sparta, Dennis R. Bruchas, Michael R. TI A GABAergic Projection from the Centromedial Nuclei of the Amygdala to Ventromedial Prefrontal Cortex Modulates Reward Behavior SO JOURNAL OF NEUROSCIENCE LA English DT Article DE amygdala; CEA; MEA; reward; vGat; vmPFC ID INFRALIMBIC CORTEX; FEAR EXTINCTION; MOTIVATED BEHAVIORS; CONDITIONED FEAR; COCAINE-SEEKING; NEURAL CIRCUITS; ACCUMBENS SHELL; NEURONS; MEMORY; ANXIETY AB The neural circuitry underlying mammalian reward behaviors involves several distinct nuclei throughout the brain. It is widely accepted that the midbrain dopamine (DA) neurons are critical for the reward-related behaviors. Recent studies have shown that the centromedial nucleus of the amygdala (CeMA) has a distinct role in regulating reward-related behaviors. However, the CeMA and ventromedial PFC (vmPFC) interaction in reward regulation remains poorly understood. Here, we identify and dissect a GABAergic projection that originates in the CeMA and terminates in the vmPFC (VGat-CreCeMA-vmPFC) using viral-vector-mediated, cell-type-specific optogenetic techniques in mice. Pathway-specific optogenetic activation of the VGat-CreCeMA-vmPFC circuit in awake, behaving animals produced a positive, reward-like phenotype in real-time place preference and increased locomotor activity in open-field testing. In sucrose operant conditioning, the photoactivation of these terminals increased nose-poking effort with no effect on licking behavior and robustly facilitated the extinction of operant behavior. However, photoactivation of these terminals did not induce self-stimulation in the absence of an external reward. The results described here suggest that the VGat-CreCeMA-vmPFC projection acts to modulate existing reward-related behaviors. C1 [Seo, Dong-oh; Funderburk, Samuel C.; Bhatti, Dionnet L.; Motard, Laura E.; Newbold, Dillan; McCall, Jordan G.; Bruchas, Michael R.] Washington Univ, Sch Med, Dept Anesthesiol, Basic Res Div, St Louis, MO 63110 USA. [Bruchas, Michael R.] Washington Univ, Sch Med, Dept Neurosci, St Louis, MO 63110 USA. [Bruchas, Michael R.] Washington Univ, Sch Med, Pain Ctr, St Louis, MO 63110 USA. [Funderburk, Samuel C.; Krashes, Michael] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Girven, Kasey S.; Sparta, Dennis R.] Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. RP Bruchas, MR (reprint author), Washington Univ, Dept Anesthesiol, Sch Med, 660 South Euclid Ave,Box 8054, St Louis, MO 63110 USA. EM bruchasm@wustl.edu OI Bhatti, Dionnet/0000-0003-3031-2067 FU National Institute on Drug Abuse-National Institutes of Health [R01033396]; National Institute on Alcohol Abuse and Alcoholism-National Institutes of Health [R00021417]; AMGEN Biomedical Scholars Program; Howard Hughes Medical Institute Summer Undergraduate Research Fellowship Program (SURF) program; National Institutes of Health [F31 MH101956] FX This work was supported by the National Institute on Drug Abuse-National Institutes of Health (Grant R01033396 to M.R.B.) and the National Institute on Alcohol Abuse and Alcoholism-National Institutes of Health (Grant R00021417 to D.R.S.). S.C.F. was supported by the AMGEN Biomedical Scholars Program and the Howard Hughes Medical Institute Summer Undergraduate Research Fellowship Program (SURF) program. L.E.M. was supported by the AMGEN Biomedical Scholars Program. J.G.M. was supported by the National Institutes of Health (Grant F31 MH101956). We thank Lamley Lawson and Brooke Ealey for technical assistance; Kyle Parker, Adrian Gomez, and tephanie Nygard for coordinating the experimental setup and discussions; and Joseph Dougherty, Durga Mohapatra, and Andrew Shepherd for reagents and discussions. NR 57 TC 1 Z9 1 U1 6 U2 6 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD OCT 19 PY 2016 VL 36 IS 42 BP 10831 EP 10842 DI 10.1523/JNEUROSCI.1164-16.2016 PG 12 WC Neurosciences SC Neurosciences & Neurology GA EE1BK UT WOS:000389315300014 PM 27798138 ER PT J AU Urano, E Miyauchi, K Kojima, Y Hamatake, M Ablan, SD Fudo, S Freed, EO Hoshino, T Komano, J AF Urano, Emiko Miyauchi, Kosuke Kojima, Yoko Hamatake, Makiko Ablan, Sherimay D. Fudo, Satoshi Freed, Eric O. Hoshino, Tyuji Komano, Jun TI A Triazinone Derivative Inhibits HIV-1 Replication by Interfering with Reverse Transcriptase Activity SO CHEMMEDCHEM LA English DT Article DE antiviral agents; drug resistance; HIV-1; NNRTI; reverse transcriptase; triazinones ID IMMUNODEFICIENCY-VIRUS TYPE-1; IN-VITRO RESISTANCE; ANTIRETROVIRAL THERAPY; SUBSTITUTION; MECHANISMS; INFECTION; MOLECULE; DELETION; GENE AB A novel HIV-1 inhibitor, 6-(tert-butyl)-4-phenyl-4-(trifluoromethyl)-1H, 3H-1,3,5-triazin-2-one (compound 1), was identified from a compound library screened for the ability to inhibit HIV-1 replication. EC50 values of compound 1 were found to range from 107.9 to 145.4 nm against primary HIV-1 clinical isolates. In in vitro assays, HIV-1 reverse transcriptase (RT) activity was inhibited by compound 1 with an EC50 of 4.3 mu m. An assay for resistance to compound 1 selected a variant of HIV-1 with a RT mutation (RTL100I); this frequently identified mutation confers mild resistance to non-nucleoside RT inhibitors (NNRTIs). A recombinant HIV-1 bearing RTL100I exhibited a 41-fold greater resistance to compound 1 than the wild-type virus. Compound 1 was also effective against HIV-1 with RTK103N, one of the major mutations that confers substantial resistance to NNRTIs. Computer-assisted docking simulations indicated that compound 1 binds to the RT NNRTI binding pocket in a manner similar to that of efavirenz; however, the putative compound 1 binding site is located further from RTK103 than that of efavirenz. Compound 1 is a novel NNRTI with a unique drug-resistance profile. C1 [Urano, Emiko; Miyauchi, Kosuke; Hamatake, Makiko; Komano, Jun] Natl Inst Infect Dis, AIDS Res Ctr, Shinjuku Ku, 1-23-1 Toyama, Tokyo 1628640, Japan. [Urano, Emiko; Ablan, Sherimay D.; Freed, Eric O.] NCI, Virus Cell Interact Sect, HIV Dynam & Replicat Program, Frederick, MD 21701 USA. [Miyauchi, Kosuke] RIKEN Yokohama Inst, RIKEN Ctr Integrat Med Sci, 1-7-22 Suehiro Cho, Yokohama, Kanagawa 2300045, Japan. [Kojima, Yoko; Komano, Jun] Osaka Prefectural Inst Publ Hlth, Dept Infect Dis, Higashinari Ku, 3-69 Nakamachi,1 Chome, Osaka 5370025, Japan. [Fudo, Satoshi; Hoshino, Tyuji] Chiba Univ, Grad Sch Pharmaceut Sci, Inage Ku, 1-33 Yayoi Cho, Chiba 2638522, Japan. [Komano, Jun] Nagoya Med Ctr, Dept Clin Lab, Naka Ku, 4-1-1 Sannomaru, Nagoya, Aichi 4600001, Japan. RP Komano, J (reprint author), Natl Inst Infect Dis, AIDS Res Ctr, Shinjuku Ku, 1-23-1 Toyama, Tokyo 1628640, Japan.; Komano, J (reprint author), Osaka Prefectural Inst Publ Hlth, Dept Infect Dis, Higashinari Ku, 3-69 Nakamachi,1 Chome, Osaka 5370025, Japan.; Komano, J (reprint author), Nagoya Med Ctr, Dept Clin Lab, Naka Ku, 4-1-1 Sannomaru, Nagoya, Aichi 4600001, Japan. EM komano@nnh.hops.go.jp FU Japanese Ministry of Health, Labor, and Welfare [H18-AIDS-Wakate-003] FX This work was supported in part by the Japanese Ministry of Health, Labor, and Welfare (H18-AIDS-Wakate-003 to J.K.). The authors declare no conflicts of interest. NR 29 TC 0 Z9 0 U1 2 U2 2 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1860-7179 EI 1860-7187 J9 CHEMMEDCHEM JI ChemMedChem PD OCT 19 PY 2016 VL 11 IS 20 BP 2320 EP 2326 DI 10.1002/cmdc.201600375 PG 7 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EB5DE UT WOS:000387392800008 PM 27634404 ER PT J AU Mandal, S Godfrey, KM McDonald, D Treuren, WV Bjornholt, JV Midtvedt, T Moen, B Rudi, K Knight, R Brantsaeter, AL Peddada, SD Eggesbo, M AF Mandal, Siddhartha Godfrey, Keith M. McDonald, Daniel Treuren, Will V. Bjornholt, Jorgen V. Midtvedt, Tore Moen, Birgitte Rudi, Knut Knight, Rob Brantsaeter, Anne Lise Peddada, Shyamal D. Eggesbo, Merete TI Fat and vitamin intakes during pregnancy have stronger relations with a pro-inflammatory maternal microbiota than does carbohydrate intake SO MICROBIOME LA English DT Article DE Compositional shifts; Vitamin D; Mono-unsaturated fat; Proteobacteria ID HUMAN GUT MICROBIOME; INTESTINAL MICROBIOTA; REDUCED DIVERSITY; IMMUNE-SYSTEM; DISEASE; WOMEN; OBESE; COMMUNITY; BACTERIA; ALLOWS AB Background: Although diet is known to have a major modulatory influence on gut microbiota, knowledge of the specific roles of particular vitamins, minerals, and other nutrients is limited. Modulation of the composition of the microbiota in pregnant women is especially important as maternal microbes are transferred during delivery and initiate the colonization process in the infant. We studied the associations between intake of specific dietary nutrients during pregnancy and gut microbiota composition. Methods: Utilizing the Norwegian NoMIC cohort, we examined the relations between intakes of 28 dietary macro-and micronutrients during pregnancy, derived from food frequency questionnaires administered to 60 women in the second trimester, and observed taxonomic differences in their gut microbiota four days after delivery (assessed through Illumina 16S rRNA amplicon analysis). Results: Higher dietary intakes of fat-soluble vitamins, especially vitamin D, were associated with reduced microbial alpha diversity (p value <0.001). Furthermore, using recently developed statistical methodology, we discovered that the variations in fat-soluble vitamins, saturated and mono-unsaturated fat, and cholesterol intake, were associated with changes in phyla composition. Specifically, vitamin D, mono-unsaturated fat, cholesterol, and retinol were associated with relative increases in Proteobacteria, which is a phylum known to encompass multiple pathogens and to have pro-inflammatory properties. In contrast, saturated fat, vitamin E, and protein were associated with relative decreases in Proteobacteria. Conclusions: The results in this article indicate that fats and fat-soluble vitamins are among the most potent dietary modulators of gut microbiota in mothers. The shifts in microbiota due to diet need to be further studied alongside gut microbiota changes during pregnancy to better understand the impact on infant gut microbiota. C1 [Mandal, Siddhartha; Bjornholt, Jorgen V.; Brantsaeter, Anne Lise; Eggesbo, Merete] Norwegian Inst Publ Hlth, Dept Environm Exposure & Epidemiol, Oslo, Norway. [Mandal, Siddhartha] Publ Hlth Fdn India, Gurgaon, India. [Godfrey, Keith M.] Univ Southampton, MRC Lifecourse Epidemiol Unit, Southampton, Hants, England. [Godfrey, Keith M.] Univ Southampton, NIHR Southampton Biomed Res Ctr, Southampton, Hants, England. [Godfrey, Keith M.] Univ Hosp Southampton NHS Fdn Trust, Southampton, Hants, England. [McDonald, Daniel; Knight, Rob] Univ Calif San Diego, Dept Pediat, San Diego, CA 92103 USA. [Treuren, Will V.] Stanford Univ, Dept Microbiol & Immunol, Stanford, CA 94305 USA. [Bjornholt, Jorgen V.] Oslo Univ Hosp, Dept Microbiol, Oslo, Norway. [Bjornholt, Jorgen V.] Univ Oslo, Inst Clin Med, Oslo, Norway. [Midtvedt, Tore] Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, Stockholm, Sweden. [Moen, Birgitte] Norwegian Inst Food Fisheries & Aquaculture, As, Norway. [Rudi, Knut] Norwegian Inst Life Sci, Dept Chem Biotechnol & Food Sci, As, Norway. [Knight, Rob] Univ Calif San Diego, Dept Comp Sci, San Diego, CA USA. [Peddada, Shyamal D.] NIEHS, Biostat & Computat Biol Branch, Durham, NC USA. RP Eggesbo, M (reprint author), Norwegian Inst Publ Hlth, Dept Environm Exposure & Epidemiol, Oslo, Norway. EM merete.eggesbo@fhi.no FU FRIMEDBIO program at the Norwegian Research Council [214324/F20]; project "Early Nutrition" under European Union's Seventh Framework Program (FP7) [289346]; National Institute for Health Research through the NIHR Southampton Biomedical Research Centre; Interdisciplinary Quantitative Biology program (NSF IGERT) [1144807]; Foundation for Research Levy on Agricultural Products; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01 ES101744-04] FX The research leading to these results has received funding from FRIMEDBIO program at the Norwegian Research Council, grant agreement no. 214324/F20 (SM) and the project "Early Nutrition" grant agreement no. 289346 under European Union's Seventh Framework Program (FP7/2007-2013) (ME). KMG is supported by the National Institute for Health Research through the NIHR Southampton Biomedical Research Centre. DM is supported by the Interdisciplinary Quantitative Biology program (NSF IGERT award 1144807). The work of BM is supported by "The Foundation for Research Levy on Agricultural Products". The research of SDP was supported, in part, by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01 ES101744-04]. RK is a Howard Hughes Medical Institute Early Career Scientist. The funders had no role in study design, data collection, and analysis. NR 45 TC 0 Z9 0 U1 16 U2 16 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2049-2618 J9 MICROBIOME JI Microbiome PD OCT 19 PY 2016 VL 4 AR 55 DI 10.1186/s40168-016-0200-3 PG 11 WC Microbiology SC Microbiology GA DZ3ET UT WOS:000385728600001 PM 27756413 ER PT J AU Skolnick, P Volkow, ND AF Skolnick, Phil Volkow, Nora D. TI Re-energizing the Development of Pain Therapeutics in Light of the Opioid Epidemic SO NEURON LA English DT Editorial Material ID PRESCRIPTION; MONOTHERAPY; ABUSE AB Limited options for treating moderate-severe pain led to an overreliance on opioids and the current opioid epidemic. Addressing the factors contributing to a dearth of effective alternatives and re-energizing the development of pain therapeutics is necessary to quell this epidemic. C1 [Skolnick, Phil] NIDA, Div Therapeut & Med Consequences, NIH, Bethesda, MD 20892 USA. [Volkow, Nora D.] NIDA, Off Director, NIH, Bethesda, MD 20892 USA. RP Volkow, ND (reprint author), NIDA, Off Director, NIH, Bethesda, MD 20892 USA. EM nvolkow@nida.nih.gov NR 11 TC 1 Z9 1 U1 4 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD OCT 19 PY 2016 VL 92 IS 2 BP 294 EP 297 DI 10.1016/j.neuron.2016.09.051 PG 4 WC Neurosciences SC Neurosciences & Neurology GA EA6TN UT WOS:000386762000011 PM 27764663 ER PT J AU Tervo, DGR Hwang, BY Viswanathan, S Gaj, T Lavzin, M Ritola, KD Lindo, S Michael, S Kuleshova, E Ojala, D Huang, CC Gerfen, CR Schiller, J Dudman, JT Hantman, AW Looger, LL Schaffer, DV Karpova, AY AF Tervo, D. Gowanlock R. Hwang, Bum-Yeol Viswanathan, Sarada Gaj, Thomas Lavzin, Maria Ritola, Kimberly D. Lindo, Sarah Michael, Susan Kuleshova, Elena Ojala, David Huang, Cheng-Chiu Gerfen, Charles R. Schiller, Jackie Dudman, Joshua T. Hantman, Adam W. Looger, Loren L. Schaffer, David V. Karpova, Alla Y. TI A Designer AAV Variant Permits Efficient Retrograde Access to Projection Neurons SO NEURON LA English DT Article ID ADENOASSOCIATED VIRAL VECTORS; CANINE ADENOVIRUS VECTORS; CENTRAL-NERVOUS-SYSTEM; GENE DELIVERY; RABIES VIRUS; NEURODEGENERATIVE DISEASES; MOUSE-BRAIN; PARKINSONS-DISEASE; DIRECTED EVOLUTION; CRE-RECOMBINASE AB Efficient retrograde access to projection neurons for the delivery of sensors and effectors constitutes an important and enabling capability for neural circuit dissection. Such an approach would also be useful for gene therapy, including the treatment of neurodegenerative disorders characterized by pathological spread through functionally connected and highly distributed networks. Viral vectors, in particular, are powerful gene delivery vehicles for the nervous system, but all available tools suffer from inefficient retrograde transport or limited clinical potential. To address this need, we applied in vivo directed evolution to engineer potent retrograde functionality into the capsid of adeno-associated virus (AAV), a vector that has shown promise in neuroscience research and the clinic. A newly evolved variant, rAAV2-retro, permits robust retrograde access to projection neurons with efficiency comparable to classical synthetic retrograde tracers and enables sufficient sensor/effector expression for functional circuit interrogation and in vivo genome editing in targeted neuronal populations. C1 [Tervo, D. Gowanlock R.; Viswanathan, Sarada; Lavzin, Maria; Ritola, Kimberly D.; Lindo, Sarah; Michael, Susan; Kuleshova, Elena; Huang, Cheng-Chiu; Gerfen, Charles R.; Schiller, Jackie; Dudman, Joshua T.; Hantman, Adam W.; Looger, Loren L.; Karpova, Alla Y.] Howard Hughes Med Inst, Janelia Res Campus, Ashburn, VA 20147 USA. [Hwang, Bum-Yeol; Gaj, Thomas; Ojala, David; Schaffer, David V.] Univ Calif Berkeley, Dept Chem Engn, Berkeley, CA 94720 USA. [Hwang, Bum-Yeol; Gaj, Thomas; Ojala, David; Schaffer, David V.] Univ Calif Berkeley, Helen Wills Neurosci Inst, Berkeley, CA 94720 USA. [Lavzin, Maria; Schiller, Jackie] Technion Med Sch, Dept Physiol, IL-3525433 Haifa, Israel. [Gerfen, Charles R.] NIMH, Lab Syst Neurosci, Bethesda, MD 20892 USA. [Kuleshova, Elena] Russian Acad Sci, Inst Higher Nervous Act & Neurophysiol, Moscow 117485, Russia. [Hwang, Bum-Yeol] 4D Mol Therapeut, Emeryville, CA 94608 USA. [Huang, Cheng-Chiu] TLC Biopharmaceut Inc, San Francisco, CA 94080 USA. RP Karpova, AY (reprint author), Howard Hughes Med Inst, Janelia Res Campus, Ashburn, VA 20147 USA.; Schaffer, DV (reprint author), Univ Calif Berkeley, Dept Chem Engn, Berkeley, CA 94720 USA.; Schaffer, DV (reprint author), Univ Calif Berkeley, Helen Wills Neurosci Inst, Berkeley, CA 94720 USA. EM schaffer@berkeley.edu; alla@janelia.hhmi.org OI Dudman, Joshua/0000-0002-4436-1057 FU NIH [R01EY022975]; Howard Hughes Medical Institute; [F32GM113446] FX We are indebted to K. Svoboda for suggesting the use of Rosa26-STOP-Lox-H2B-EGFP mice. We thank H. Adesnik for providing the Rbp4_KL 100 Cre x tdTomato mouse line, J. Brousseau for invaluable assistance with the pilot experiments, M. Proskurin for help with the rat experiments, and J. Santiago-Ortiz for help with the CRISPR/Cas9 experiments. We are grateful to the members of the J.T.D., A.W.H., Jessell, Ji, A.Y.K., Petreanu, Sabatini, Spruston, Svoboda, and Zuker labs for beta testing rAAV2-retro and contributing their findings to the knowledge base summarized in Table S2. T. Jessell, N. Spruston, and K. Svoboda offered useful discussions and comments on the manuscript. D.V.S. is supported by NIH R01EY022975 and T.G. by F32GM113446. This work was supported by the Howard Hughes Medical Institute. NR 63 TC 5 Z9 5 U1 10 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD OCT 19 PY 2016 VL 92 IS 2 BP 372 EP 382 DI 10.1016/j.neuron.2016.09.021 PG 11 WC Neurosciences SC Neurosciences & Neurology GA EA6TN UT WOS:000386762000020 PM 27720486 ER PT J AU Costa, VD Dal Monte, O Lucas, DR Murray, EA Averbeck, BB AF Costa, Vincent D. Dal Monte, Olga Lucas, Daniel R. Murray, Elisabeth A. Averbeck, Bruno B. TI Amygdala and Ventral Striatum Make Distinct Contributions to Reinforcement Learning SO NEURON LA English DT Article ID PAVLOVIAN-INSTRUMENTAL TRANSFER; NUCLEUS-ACCUMBENS CORE; OUTCOME-SPECIFIC FORMS; PREFRONTAL CORTEX; DOUBLE DISSOCIATION; DECISION-MAKING; ORBITOFRONTAL CORTEX; DOPAMINE NEURONS; PRIMATE AMYGDALA; DORSAL STRIATUM AB Reinforcement learning (RL) theories posit that dopaminergic signals are integrated within the striatum to associate choices with outcomes. Often overlooked is that the amygdala also receives dopaminergic input and is involved in Pavlovian processes that influence choice behavior. To determine the relative contributions of the ventral striatum (VS) and amygdala to appetitive RL, we tested rhesus macaques with VS or amygdala lesions on deterministic and stochastic versions of a two-arm bandit reversal learning task. When learning was characterized with an RL model relative to controls, amygdala lesions caused general decreases in learning from positive feedback and choice consistency. By comparison, VS lesions only affected learning in the stochastic task. Moreover, the VS lesions hastened the monkeys' choice reaction times, which emphasized a speed-accuracy trade-off that accounted for errors in deterministic learning. These results update standard accounts of RL by emphasizing distinct contributions of the amygdala and VS to RL. C1 [Costa, Vincent D.; Dal Monte, Olga; Lucas, Daniel R.; Murray, Elisabeth A.; Averbeck, Bruno B.] NIMH, Neuropsychol Lab, NIH, Bldg 9, Bethesda, MD 20892 USA. RP Costa, VD (reprint author), NIMH, Neuropsychol Lab, NIH, Bldg 9, Bethesda, MD 20892 USA. EM vincent.costa@nih.gov OI Costa, Vincent/0000-0002-5412-8945 FU Intramural Research Program of the National Institute of Mental Health FX This work was supported by the Intramural Research Program of the National Institute of Mental Health. We thank Laura Kennerly, Laura Kakalios, Kati Rothenhoefer, Raquel Vicario-Feliciano, and Pam Noble for assistance with data collection; Stephanie Huard for assistance in constructing the lesion density maps; and Andrew Mitz for technical assistance. NR 61 TC 1 Z9 1 U1 5 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD OCT 19 PY 2016 VL 92 IS 2 BP 505 EP 517 DI 10.1016/j.neuron.2016.09.025 PG 13 WC Neurosciences SC Neurosciences & Neurology GA EA6TN UT WOS:000386762000030 PM 27720488 ER PT J AU Johnson, KA Lovinger, DM AF Johnson, Kari A. Lovinger, David M. TI Presynaptic Plasticity Found in Translation SO NEURON LA English DT Editorial Material ID LONG-TERM DEPRESSION AB In this issue of Neuron, Younts et al. (2016) demonstrate that activation of presynaptic CB1 receptors by retrograde endocannabinoid signaling stimulates protein synthesis in axon terminals to induce long-term depression of hippocampal inhibitory transmission. C1 [Johnson, Kari A.; Lovinger, David M.] NIAAA, Sect Synapt Pharmacol, Lab Integrat Neurosci, NIH, Bethesda, MD 20892 USA. RP Lovinger, DM (reprint author), NIAAA, Sect Synapt Pharmacol, Lab Integrat Neurosci, NIH, Bethesda, MD 20892 USA. EM lovindav@mail.nih.gov NR 11 TC 0 Z9 0 U1 2 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD OCT 19 PY 2016 VL 92 IS 2 DI 10.1016/j.neuron.2016.09.047 PG 4 WC Neurosciences SC Neurosciences & Neurology GA EA6TN UT WOS:000386762000003 PM 27764658 ER PT J AU Song, JB Hu, H Jian, C Wu, KC Chen, XY AF Song, Jibin Hu, Hao Jian, Chao Wu, Kaichun Chen, Xiaoyuan TI New Generation of Gold Nanoshell-Coated Esophageal Stent: Preparation and Biomedical Applications SO ACS APPLIED MATERIALS & INTERFACES LA English DT Article DE gold nanoshell; dopamine; stent; cancer; photothermal therapy; NIR laser ID PHOTOTHERMAL THERAPY; PLASMONIC VESICLES; DRUG-DELIVERY; NANOPARTICLES; CANCER; NANORODS; PACLITAXEL; COATINGS; RELEASE; LIGHT AB Esophageal cancer is one of the six most common cancers in the world, constituting similar to 7% of the gastrointestinal cancers. Esophageal stents can be inserted into the esophagus to open the pathway as a palliative treatment for advanced esophageal cancer. For the treatment of esophageal cancer, a series of anticancer drug-loaded stents such as paclitaxel or 5-fluorouracil/esophageal stent combinations have been prepared by covering a nitinol stent with a polymer or hydrogel shell. For the first time, we developed a gold nanoshell (AuNS)-coated stent with high photothermal efficiency and used in the repetitive photothermal therapy of esophageal cancer. The functionalized stent was prepared by using surface-coated polydopamine as the Au3+ anchor and template. The thickness of the AuNS can be easily adjusted by controlling the reaction time and amount of Au3+. The AuNS-coated stent efficiently increased the temperature of pork and porcine intestines irradiated with a near-infrared (NIR) laser. The deep penetration of the NIR laser and excellent stability of the stent provide opportunity for the clinical applications of the newly functionalized stent. In vitro toxicity experiments showed excellent biocompatibility and safety of this device. Compared with bare metal stent, AuNS-modified stent exhibits great potential to open the duct passageway and suppress tumor growth in future clinical applications. C1 [Song, Jibin; Chen, Xiaoyuan] NIBIB, LOMIN, NIH, Bethesda, MD 20892 USA. [Hu, Hao; Jian, Chao; Wu, Kaichun] Fourth Mil Med Univ, Sate Key Lab Canc Biol, Xian, Peoples R China. [Hu, Hao; Jian, Chao; Wu, Kaichun] Fourth Mil Med Univ, Xijing Hosp Digest Dis, Xian, Peoples R China. RP Chen, XY (reprint author), NIBIB, LOMIN, NIH, Bethesda, MD 20892 USA. EM shawn.chen@nih.gov FU Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH) FX This work was supported by the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH). NR 35 TC 1 Z9 1 U1 39 U2 39 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1944-8244 J9 ACS APPL MATER INTER JI ACS Appl. Mater. Interfaces PD OCT 19 PY 2016 VL 8 IS 41 BP 27523 EP 27529 DI 10.1021/acsami.6b09104 PG 7 WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Science & Technology - Other Topics; Materials Science GA DZ6SO UT WOS:000385992400015 ER PT J AU Robles, AI Olsen, KS Tsui, DWT Georgoulias, V Creaney, J Dobra, K Vyberg, M Minato, N Anders, RA Borresen-Dale, AL Zhou, J Saeetrom, P Nielsen, BS Kirschner, MB Krokan, HE Papadimitrakopoulou, V Tsamardinos, I Roe, OD AF Robles, Ana I. Olsen, Karina Standahl Tsui, Dana W. T. Georgoulias, Vassilis Creaney, Jenette Dobra, Katalin Vyberg, Mogens Minato, Nagahiro Anders, Robert A. Borresen-Dale, Anne-Lise Zhou, Jianwei Saetrom, Pal Nielsen, Boye Schnack Kirschner, Michaela B. Krokan, Hans E. Papadimitrakopoulou, Vassiliki Tsamardinos, Ioannis Roe, Oluf D. TI Excerpts from the 1st international NTNU symposium on current and future clinical biomarkers of cancer: innovation and implementation, June 16th and 17th 2016, Trondheim, Norway SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article DE Bioinformatics; Circulating biomarkers; Circulating tumor cells; DNA repair; Early detection; Early diagnosis ID I LUNG ADENOCARCINOMA; MALIGNANT PLEURAL MESOTHELIOMA; BREAST-CANCER; STAGE-I; PROGNOSTIC CLASSIFIER; GENE-EXPRESSION; GASTRIC-CANCER; POSITIVE CELLS; MESSENGER-RNA; COLON-CANCER AB The goal of biomarker research is to identify clinically valid markers. Despite decades of research there has been disappointingly few molecules or techniques that are in use today. The "1st International NTNU Symposium on Current and Future Clinical Biomarkers of Cancer: Innovation and Implementation", was held June 16th and 17th 2016, at the Knowledge Center of the St. Olavs Hospital in Trondheim, Norway, under the auspices of the Norwegian University of Science and Technology (NTNU) and the HUNT biobank and research center. The Symposium attracted approximately 100 attendees and invited speakers from 12 countries and 4 continents. In this Symposium original research and overviews on diagnostic, predictive and prognostic cancer biomarkers in serum, plasma, urine, pleural fluid and tumor, circulating tumor cells and bioinformatics as well as how to implement biomarkers in clinical trials were presented. Senior researchers and young investigators presented, reviewed and vividly discussed important new developments in the field of clinical biomarkers of cancer, with the goal of accelerating biomarker research and implementation. The excerpts of this symposium aim to give a cutting-edge overview and insight on some highly important aspects of clinical cancer biomarkers to-date to connect molecular innovation with clinical implementation to eventually improve patient care. C1 [Robles, Ana I.] NCI, Human Carcinogenesis Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. [Olsen, Karina Standahl] UiT Artic Univ Norway, Dept Community Med, Tromso, Norway. [Tsui, Dana W. T.] Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA. [Tsui, Dana W. T.] Mem Sloan Kettering Canc Ctr, Ctr Mol Oncol, 1275 York Ave, New York, NY 10021 USA. [Georgoulias, Vassilis] Univ Crete, Sch Med, Dept Med Oncol, Iraklion, Greece. [Creaney, Jenette] Univ Western Australia, Natl Ctr Asbestos Related Dis, Perth, WA, Australia. [Dobra, Katalin] Karolinska Univ Hosp, Karolinska Inst, Dept Lab Med, Div Pathol, Stockholm, Sweden. [Vyberg, Mogens] Aalborg Univ, Aalborg Univ Hosp, Inst Pathol, Dept Clin Med, Aalborg, Denmark. [Minato, Nagahiro] Kyoto Univ, Grad Sch Med, Dept Immunol & Cell Biol, Kyoto, Japan. [Anders, Robert A.] Johns Hopkins Univ, Dept Pathol, Baltimore, MD USA. [Borresen-Dale, Anne-Lise] Norwegian Radium Hosp, Oslo Univ Hosp, Inst Canc Res, Dept Canc Genet, Oslo, Norway. [Zhou, Jianwei] Nanjing Med Univ, Sch Publ Hlth, Ctr Canc, Dept Mol Cell Biol & Toxicol, Nanjing, Jiangsu, Peoples R China. [Saetrom, Pal] NTNU, Dept Comp & Informat Sci, Trondheim, Norway. [Nielsen, Boye Schnack] Mol Histol Bioneer AS, Horsholm, Denmark. [Kirschner, Michaela B.] Univ Zurich Hosp, Div Thorac Surg, Zurich, Switzerland. [Krokan, Hans E.; Roe, Oluf D.] Norwegian Univ Sci & Technol NTNU, Dept Canc Res & Mol Med, Trondheim, Norway. [Papadimitrakopoulou, Vassiliki] MD Anderson, Dept Thorac Head & Neck Med Oncol, Houston, TX USA. [Tsamardinos, Ioannis] Univ Crete, Dept Comp Sci, Iraklion, Greece. [Roe, Oluf D.] Nord Trondelag Hosp Trust, Levanger Hosp, Dept Surg, Canc Clin, Levanger, Norway. [Roe, Oluf D.] Aalborg Univ Hosp, Clin Canc Res Ctr, Dept Clin Med, Aalborg, Denmark. RP Roe, OD (reprint author), Norwegian Univ Sci & Technol NTNU, Dept Canc Res & Mol Med, Trondheim, Norway.; Roe, OD (reprint author), Nord Trondelag Hosp Trust, Levanger Hosp, Dept Surg, Canc Clin, Levanger, Norway.; Roe, OD (reprint author), Aalborg Univ Hosp, Clin Canc Res Ctr, Dept Clin Med, Aalborg, Denmark. EM oluf.roe@ntnu.no OI Tsui, Dana Wai Yi/0000-0002-0595-6664 FU Symposium; NTNU; HUNT Research Center; Boeringer Ingelheim; Bristol Myers Squibb; Norwegian Biochemical Society; Roche; Astra Zeneca; Amgen; PROMEC of NTNU; International Union of Basic and Clinical Pharmacology, Gastrointestinal Section FX We whish to thank all sponsors and supporters of the Symposium, the NTNU, the HUNT Research Center, Boeringer Ingelheim, Bristol Myers Squibb, Norwegian Biochemical Society, Roche, Astra Zeneca, Amgen, the PROMEC of NTNU, International Union of Basic and Clinical Pharmacology, Gastrointestinal Section, the organizing committee and international faculty. NR 62 TC 0 Z9 0 U1 3 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD OCT 19 PY 2016 VL 14 AR 295 DI 10.1186/s12967-016-1059-6 PG 15 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DZ7IV UT WOS:000386039200001 PM 27756323 ER PT J AU Cheng, Y Lu, F Wang, B Li, J Han, JH Ito, D Kong, DH Jiang, LB Wu, J Ha, KS Takashima, E Sattabongkot, J Cao, J Nyunt, MH Kyaw, MP Desai, SA Miller, LH Tsuboi, T Han, ET AF Cheng, Yang Lu, Feng Wang, Bo Li, Jian Han, Jin-Hee Ito, Daisuke Kong, Deok-Hoon Jiang, Lubin Wu, Jian Ha, Kwon-Soo Takashima, Eizo Sattabongkot, Jetsumon Cao, Jun Nyunt, Myat Htut Kyaw, Myat Phone Desai, Sanjay A. Miller, Louis H. Tsuboi, Takafumi Han, Eun-Taek TI Plasmodium vivax GPI-anchored micronemal antigen (PvGAMA) binds human erythrocytes independent of Duffy antigen status SO SCIENTIFIC REPORTS LA English DT Article ID MALARIA PARASITE; VACCINE CANDIDATE; LIGAND DOMAIN; PROTEIN; INVASION; FALCIPARUM; RECEPTOR; IDENTIFICATION; KNOWLESI; MEROZOITES AB Plasmodium vivax, a major agent of malaria in both temperate and tropical climates, has been thought to be unable to infect humans lacking the Duffy (Fy) blood group antigen because this receptor is critical for erythrocyte invasion. Recent surveys in various endemic regions, however, have reported P. vivax infections in Duffy-negative individuals, suggesting that the parasite may utilize alternative receptor-ligand pairs to complete the erythrocyte invasion. Here, we identified and characterized a novel parasite ligand, Plasmodium vivax GPI-anchored micronemal antigen (PvGAMA), that bound human erythrocytes regardless of Duffy antigen status. PvGAMA was localized at the microneme in the mature schizont-stage parasites. The antibodies against PvGAMA fragments inhibited PvGAMA binding to erythrocytes in a dose-dependent manner. The erythrocyte-specific binding activities of PvGAMA were significantly reduced by chymotrypsin treatment. Thus, PvGAMA may be an adhesion molecule for the invasion of Duffy-positive and -negative human erythrocytes. C1 [Cheng, Yang; Lu, Feng; Wang, Bo; Li, Jian; Han, Jin-Hee; Nyunt, Myat Htut; Han, Eun-Taek] Kangwon Natl Univ, Sch Med, Dept Med Environm Biol & Trop Med, Chunchon 200701, Gangwon Do, South Korea. [Cheng, Yang] Jiangnan Univ, Wuxi Med Sch, Dept Parasitol, Wuxi 214122, Jiangsu, Peoples R China. [Cheng, Yang; Ito, Daisuke; Wu, Jian; Desai, Sanjay A.; Miller, Louis H.] NIAID, LMVR, NIH, Rockville, MD USA. [Lu, Feng; Cao, Jun] Jiangsu Inst Parasit Dis, Wuxi, Jiangsu, Peoples R China. [Wang, Bo] Anhui Med Univ, Affiliated Hosp 1, Dept Clin Lab, Hefei, Anhui, Peoples R China. [Li, Jian] Hubei Univ Med, Coll Basic Med, Dept Parasitol, Shiyan, Hubei, Peoples R China. [Ito, Daisuke; Takashima, Eizo; Tsuboi, Takafumi] Ehime Univ, Proteosci Ctr, Div Malaria Res, Matsuyama, Ehime 7908577, Japan. [Kong, Deok-Hoon; Ha, Kwon-Soo] Kangwon Natl Univ, Sch Med, Dept Mol & Cellular Biochem, Chunchon 200701, Gangwon Do, South Korea. [Jiang, Lubin] Inst Pasteur Shanghai, Unit Human Parasite Mol & Cell Biol, Key Lab Mol Virol & Immunol, Shanghai 200031, Peoples R China. [Sattabongkot, Jetsumon] Mahidol Univ, Fac Trop Med, Mahidol Vivax Res Unit, Bangkok 10400, Thailand. [Nyunt, Myat Htut; Kyaw, Myat Phone] Dept Med Res, Yangon, Myanmar. RP Han, ET (reprint author), Kangwon Natl Univ, Sch Med, Dept Med Environm Biol & Trop Med, Chunchon 200701, Gangwon Do, South Korea.; Tsuboi, T (reprint author), Ehime Univ, Proteosci Ctr, Div Malaria Res, Matsuyama, Ehime 7908577, Japan. EM tsuboi.takafumi.mb@ehime-u.ac.jp; etaekhan@gmail.com FU National Research Foundation of Korea (NRF) grant - Korea government (MSIP) [NRF-2014R1A2A1A11052079]; Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Science, ICT & Future Planning [2015R1A4A1038666] FX We are grateful to John H. Adams, University of South Florida, for the pEGFP-HSVgD1_PvDBPII_Sal 1 plasmid DNA; Hye-Yoon Jeon in Prof. KS Ha's laboratory for technical assistance; Jian-bin Mu at NIAID, NIH for critical suggestions on the manuscript; and intramural editor Dera Tompkins for editing assistance. This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (NRF-2014R1A2A1A11052079) and by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (2015R1A4A1038666). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 0 Z9 0 U1 5 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD OCT 19 PY 2016 VL 6 AR 35581 DI 10.1038/srep35581 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ8LM UT WOS:000386121900001 PM 27759110 ER PT J AU Ehmsen, JT Liu, Y Wang, Y Paladugu, N Johnson, AE Rothstein, JD du Lac, S Mattson, MP Hoke, A AF Ehmsen, Jeffrey T. Liu, Yong Wang, Yue Paladugu, Nikhil Johnson, Anna E. Rothstein, Jeffrey D. du Lac, Sascha Mattson, Mark P. Hoke, Ahmet TI The astrocytic transporter SLC7A10 (Asc-1) mediates glycinergic inhibition of spinal cord motor neurons SO SCIENTIFIC REPORTS LA English DT Article ID D-SERINE; STARTLE DISEASE; CLEAVAGE SYSTEM; IN-VITRO; RECEPTOR; HYPEREKPLEXIA; MUTATIONS; BRAIN; CNS; TRANSCRIPTOME AB SLC7A10 (Asc-1) is a sodium-independent amino acid transporter known to facilitate transport of a number of amino acids including glycine, L-serine, L-alanine, and L-cysteine, as well as their D-enantiomers. It has been described as a neuronal transporter with a primary role related to modulation of excitatory glutamatergic neurotransmission. We find that SLC7A10 is substantially enriched in a subset of astrocytes of the caudal brain and spinal cord in a distribution corresponding with high densities of glycinergic inhibitory synapses. Accordingly, we find that spinal cord glycine levels are significantly reduced in Slc7a10-null mice and spontaneous glycinergic postsynaptic currents in motor neurons show substantially diminished amplitudes, demonstrating an essential role for SLC7A10 in glycinergic inhibitory function in the central nervous system. These observations establish the etiology of sustained myoclonus (sudden involuntary muscle movements) and early postnatal lethality characteristic of Slc7a10-null mice, and implicate SLC7A10 as a candidate gene and auto-antibody target in human hyperekplexia and stiff person syndrome, respectively. C1 [Ehmsen, Jeffrey T.; Paladugu, Nikhil; Johnson, Anna E.; Rothstein, Jeffrey D.; Hoke, Ahmet] Johns Hopkins Sch Med, Dept Neurol, 855 N Wolfe St, Baltimore, MD 21205 USA. [Ehmsen, Jeffrey T.; Rothstein, Jeffrey D.; du Lac, Sascha; Mattson, Mark P.; Hoke, Ahmet] Johns Hopkins Sch Med, Solomon H Snyder Dept Neurosci, 725 N Wolfe St, Baltimore, MD 21205 USA. [Ehmsen, Jeffrey T.] Johns Hopkins Sch Med, Med Scientist Training Program, 1830 E Monument St, Baltimore, MD 21205 USA. [Liu, Yong; Wang, Yue; Mattson, Mark P.] Natl Inst Aging Intramural Res Program, Lab Neurosci, 251 Bayview Blvd, Baltimore, MD 21224 USA. [Rothstein, Jeffrey D.] Johns Hopkins Sch Med, Brain Sci Inst, 855 N Wolfe St, Baltimore, MD 21205 USA. RP Hoke, A (reprint author), Johns Hopkins Sch Med, Dept Neurol, 855 N Wolfe St, Baltimore, MD 21205 USA.; Hoke, A (reprint author), Johns Hopkins Sch Med, Solomon H Snyder Dept Neurosci, 725 N Wolfe St, Baltimore, MD 21205 USA. EM ahoke@jhmi.edu FU Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; Michael S. and Karen G. Ansari ALS Center for Cell Therapy and Regeneration Research; National Institute on Aging Intramural Research Program, NIH [NS050275]; Medical Scientist Training Program, NIH [GM007309] FX This work was supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the Michael S. and Karen G. Ansari ALS Center for Cell Therapy and Regeneration Research, the National Institute on Aging Intramural Research Program, NIH grant #NS050275 to the MPI Microscopy Core Facility, and by the Medical Scientist Training Program, NIH grant #GM007309. We thank Dr. Solomon Snyder for providing Slc7a10 heterozygous mice; all members of the Hoke lab and Neuromuscular Division for discussions and sharing of reagents; Dr. Xufeng Wu (NHLBI/NIH) for assistance and use of the Zeiss 880 Airyscan; Lisa Rein for statistical consultation; and Norman Barker for assistance with preliminary figure assembly. NR 46 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD OCT 19 PY 2016 VL 6 AR 35592 DI 10.1038/srep35592 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ8LN UT WOS:000386122000001 PM 27759100 ER PT J AU Lee, JW Huang, BX Kwon, H Rashid, MA Kharebava, G Desai, A Patnaik, S Marugan, J Kim, HY AF Lee, Ji-Won Huang, Bill X. Kwon, HeungSun Rashid, Md Abdur Kharebava, Giorgi Desai, Abhishek Patnaik, Samarjit Marugan, Juan Kim, Hee-Yong TI Orphan GPR110 (ADGRF1) targeted by N-docosahexaenoylethanolamine in development of neurons and cognitive function SO NATURE COMMUNICATIONS LA English DT Article ID PROTEIN-COUPLED RECEPTORS; DOCOSAHEXAENOIC ACID; FATTY-ACIDS; SYNAPTIC PLASTICITY; HIPPOCAMPAL-NEURONS; MASS-SPECTROMETRY; IN-VIVO; MEMORY; BRAIN; MOUSE AB Docosahexaenoic acid (DHA, 22:6n-3) is an omega-3 fatty acid essential for proper brain development. N-docosahexaenoylethanolamine (synaptamide), an endogenous metabolite of DHA, potently promotes neurogenesis, neuritogenesis and synaptogenesis; however, the underlying molecular mechanism is not known. Here, we demonstrate orphan G-protein coupled receptor 110 (GPR110, ADGRF1) as the synaptamide receptor, mediating synaptamide-induced bioactivity in a cAMP-dependent manner. Mass spectrometry-based proteomic characterization and cellular fluorescence tracing with chemical analogues of synaptamide reveal specific binding of GPR110 to synaptamide, which triggers cAMP production with low nM potency. Disruption of this binding or GPR110 gene knockout abolishes while GPR110 overexpression enhances synaptamide-induced bioactivity. GPR110 is highly expressed in fetal brains but rapidly decreases after birth. GPR110 knockout mice show significant deficits in object recognition and spatial memory. GPR110 deorphanized as a functional synaptamide receptor provides a novel target for neurodevelopmental control and new insight into mechanisms by which DHA promotes brain development and function. C1 [Lee, Ji-Won; Huang, Bill X.; Kwon, HeungSun; Rashid, Md Abdur; Kharebava, Giorgi; Desai, Abhishek; Kim, Hee-Yong] NIAAA, Lab Mol Signaling, NIH, 5625 Fishers Lane Room 3N-07, Bethesda, MD 20892 USA. [Patnaik, Samarjit; Marugan, Juan] NIH, Chem Div Preclin Innovat, NCATS, 9800 Med Ctr Dr, Rockville, MD 20892 USA. RP Kim, HY (reprint author), NIAAA, Lab Mol Signaling, NIH, 5625 Fishers Lane Room 3N-07, Bethesda, MD 20892 USA. EM hykim@nih.gov FU Intramural Research Program of NIAAA, NIH FX This research was supported by the Intramural Research Program of NIAAA, NIH. We would like to thank Karl Kevala at LMS, NIAAA for the preparation/analysis of synaptamide, Wyatt Strutz at NanoTemper Technologies, Inc. for the help with the microscale thermophoresis-based binding assay and Arthur Spector, David Lovinger and George Kunos at NIAAA for critical reading of the manuscript. We are also grateful for the support by the Fishers Lane Animal Center staff. NR 57 TC 1 Z9 1 U1 7 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD OCT 19 PY 2016 VL 7 AR 13123 DI 10.1038/ncomms13123 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ1RQ UT WOS:000385617300001 PM 27759003 ER PT J AU Petersen, ME Kedei, N Lewin, NE Blumberg, PM Keck, GE AF Petersen, Mark E. Kedei, Noemi Lewin, Nancy E. Blumberg, Peter M. Keck, Gary E. TI Replacement of the bryostatin A- and B-pyran rings with phenyl rings leads to loss of high affinity binding with PKC SO TETRAHEDRON LETTERS LA English DT Article DE Bryostatin; Analogues; PKC; SAR; Cross coupling; Heck reaction ID PROTEIN-KINASE-C; BIOLOGICAL EVALUATION; ANALOGS; ACTIVATION; ANNULATION; ALDEHYDES; TRIALS AB We describe a convergent synthesis of a bryostatin analogue in which the natural A- and B-ring pyrans have been replaced by phenyl rings. The new analogue exhibited PMA like behavior in cell assays, but failed to maintain high affinity binding for PKC, despite retaining an unaltered C-ring 'binding domain' (C) 2016 Elsevier Ltd. All rights reserved. C1 [Petersen, Mark E.; Keck, Gary E.] Univ Utah, Dept Chem, Salt Lake City, UT 84112 USA. [Kedei, Noemi; Lewin, Nancy E.; Blumberg, Peter M.] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. RP Keck, GE (reprint author), Univ Utah, Dept Chem, Salt Lake City, UT 84112 USA. EM Keck@chem.utah.edu FU NIH [GM28961]; Intramural Research Program, CCR, NCI, NIH [Z1A BC 005270] FX Financial support was provided by the NIH through Grant GM28961 and through the Intramural Research Program, CCR, NCI, NIH (Project Z1A BC 005270). NR 36 TC 0 Z9 0 U1 6 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0040-4039 J9 TETRAHEDRON LETT JI Tetrahedron Lett. PD OCT 19 PY 2016 VL 57 IS 42 BP 4749 EP 4753 DI 10.1016/j.tetlet.2016.09.040 PG 5 WC Chemistry, Organic SC Chemistry GA DZ1KJ UT WOS:000385597000023 PM 27713589 ER PT J AU Migueles, SA Connors, M AF Migueles, Stephen A. Connors, Mark TI Class II-Restricted CD8s: New Lessons Violate Old Paradigms SO IMMUNITY LA English DT Editorial Material ID T-CELLS; COMPLEX C1 [Migueles, Stephen A.; Connors, Mark] NIAID, HIV Specif Immun Sect, Immunoregulat Lab, Div Intramural Res, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Connors, M (reprint author), NIAID, HIV Specif Immun Sect, Immunoregulat Lab, Div Intramural Res, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM mconnors@nih.gov NR 9 TC 1 Z9 1 U1 3 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD OCT 18 PY 2016 VL 45 IS 4 BP 712 EP 714 DI 10.1016/j.immuni.2016.10.004 PG 3 WC Immunology SC Immunology GA EE3FM UT WOS:000389473200004 PM 27760334 ER PT J AU Araya, RE Goldszmid, RS AF Araya, Romina E. Goldszmid, Romina S. TI Two Bugs a NOD Away from Improving Cancer Therapy Efficacy SO IMMUNITY LA English DT Editorial Material ID GUT MICROBIOTA; IMMUNOTHERAPY C1 [Araya, Romina E.; Goldszmid, Romina S.] NCI, Inflammatory Cell Dynam Sect, Canc & Inflammat Program, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Goldszmid, RS (reprint author), NCI, Inflammatory Cell Dynam Sect, Canc & Inflammat Program, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM rgoldszmid@mail.nih.gov NR 10 TC 0 Z9 0 U1 3 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD OCT 18 PY 2016 VL 45 IS 4 BP 714 EP 716 DI 10.1016/j.immuni.2016.10.007 PG 4 WC Immunology SC Immunology GA EE3FM UT WOS:000389473200005 PM 27760335 ER PT J AU Wu, YZ Meitzler, JL Antony, S Juhasz, A Lu, JM Jiang, GJ Liu, H Hollingshead, M Haines, DC Butcher, D Panter, MS Roy, K Doroshow, JH AF Wu, Yongzhong Meitzler, Jennifer L. Antony, Smitha Juhasz, Agnes Lu, Jiamo Jiang, Guojian Liu, Han Hollingshead, Melinda Haines, Diana C. Butcher, Donna Panter, Michaela S. Roy, Krishnendu Doroshow, James H. TI Dual Oxidase2 and pancreatic adenocarcinoma: IFN-gamma-mediated dual oxidase2 overexpression results in H2O2-induced, ERKassociated up-regulation of HIF-1 alpha and VEGF-A SO ONCOTARGET LA English DT Article DE dual oxidase; NADPH oxidase; pancreatic cancer; hydrogen peroxide; angiogenesis ID ENDOTHELIAL GROWTH-FACTOR; CANCER CELL-SURVIVAL; REACTIVE OXYGEN; NADPH OXIDASE; GENE-EXPRESSION; CONSTITUTIVE EXPRESSION; TYROSINE PHOSPHATASES; SIGNALING PATHWAYS; OXIDATIVE STRESS; PROSTATE-CANCER AB Several NADPH oxidase family members, including dual oxidase 2 [DUOX2], are expressed in human tumors, particularly gastrointestinal cancers associated with long-standing chronic inflammation. We found previously that exposure of pancreatic ductal adenocarcinoma cells to the pro-inflammatory cytokine IFN-gamma increased DUOX2 expression (but not other NADPH oxidases) leading to long-lived H2O2 production. To elucidate the pathophysiology of DUOX2-mediated H2O2 formation in the pancreas further, we demonstrate here that IFN-gamma-treated BxPC-3 and CFPAC-1 pancreatic cancer cells (known to increase DUOX2 expression) produce significant levels of intracellular oxidants and extracellular H2O2 which correlate with concomitant upregulation of VEGF-A and HIF-1 alpha transcription. These changes are not observed in the PANC-1 line that does not increase DUOX2 expression following IFN-gamma treatment. DUOX2 knockdown with short interfering RNA significantly decreased IFN-gamma-induced VEGF-A or HIF-1 alpha up-regulation, as did treatment of pancreatic cancer cells with the NADPH oxidase inhibitor diphenylene iodonium, the multifunctional reduced thiol N-acetylcysteine, and the polyethylene glycol-modified form of the hydrogen peroxide detoxifying enzyme catalase. Increased DUOX2-related VEGF-A expression appears to result from reactive oxygen-mediated activation of ERK signaling that is responsible for AP-1-related transcriptional effects on the VEGF-A promoter. To clarify the relevance of these observations in vivo, we demonstrate that many human premalignant pancreatic intraepithelial neoplasms and frank pancreatic cancers express substantial levels of DUOX protein compared to histologically normal pancreatic tissues, and that expression of both DUOX2 and VEGF-A mRNAs is significantly increased in surgically-resected pancreatic cancers compared to the adjacent normal pancreas. C1 [Wu, Yongzhong; Meitzler, Jennifer L.; Antony, Smitha; Juhasz, Agnes; Lu, Jiamo; Jiang, Guojian; Doroshow, James H.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Liu, Han; Hollingshead, Melinda; Panter, Michaela S.; Roy, Krishnendu; Doroshow, James H.] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Haines, Diana C.; Butcher, Donna] NCI, Pathol Histotechnol Lab, Leidos Inc, Frederick Natl Lab Canc Res, Frederick, MD 21701 USA. RP Doroshow, JH (reprint author), NCI, Ctr Canc Res, Bethesda, MD 20892 USA.; Doroshow, JH (reprint author), NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. EM doroshoj@mail.nih.gov FU Center for Cancer Research; Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This project has been funded in whole or in part with federal funds from the Center for Cancer Research and the Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health; the work was also conducted, in part, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 63 TC 0 Z9 0 U1 4 U2 4 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD OCT 18 PY 2016 VL 7 IS 42 BP 68412 EP 68433 DI 10.18632/oncotarget.12032 PG 22 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EB5UT UT WOS:000387446800057 PM 27637085 ER PT J AU Heery, CR Madan, RA Stein, MN Stadler, WM DiPaola, RS Rauckhorst, M Steinberg, SM Marte, JL Chen, CC Grenga, I Donahue, RN Jochems, C Dahut, WL Schlom, J Gulley, JL AF Heery, Christopher R. Madan, Ravi A. Stein, Mark N. Stadler, Walter M. DiPaola, Robert S. Rauckhorst, Myrna Steinberg, Seth M. Marte, Jennifer L. Chen, Clara C. Grenga, Italia Donahue, Renee N. Jochems, Caroline Dahut, William L. Schlom, Jeffrey Gulley, James L. TI Samarium-153-EDTMP (Quadramet (R)) with or without vaccine in metastatic castration-resistant prostate cancer: A randomized Phase 2 trial SO ONCOTARGET LA English DT Article DE therapeutic vaccine; radionuclide; prostate cancer; quadramet; cancer immunotherapy ID DOUBLE-BLIND; SM-153 LEXIDRONAM; CLINICAL-TRIAL; CELL-DEATH; PSA; THERAPY; ANTIGEN; SAFETY; IMMUNOTHERAPY; RADIOTHERAPY AB PSA-TRICOM is a therapeutic vaccine in late stage clinical testing in metastatic castration-resistant prostate cancer (mCRPC). Samarium-153-ethylene diamine tetramethylene phosphonate (Sm-153-EDTMP; Quadramet (R)), a radiopharmaceutical, binds osteoblastic bone lesions and emits beta particles causing local tumor cell destruction. Preclinically, Sm-153-EDTMP alters tumor cell phenotype facilitating immune-mediated killing. This phase 2 multi-center trial randomized patients to Sm-153-EDTMP alone or with PSA-TRICOM vaccine. Eligibility required mCRPC, bone metastases, prior docetaxel and no visceral disease. The primary endpoint was the proportion of patients without radiographic disease progression at 4 months. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and immune responses. Forty-four patients enrolled. Eighteen and 21 patients were evaluable for the primary endpoint in Sm-153-EDTMP alone and combination arms, respectively. There was no statistical difference in the primary endpoint, with two of 18 (11.1%) and five of 21 (23.8%) in Sm-153-EDTMP alone and combination arms, respectively, having stable disease at approximately the 4-month evaluation time point (P = 0.27). Median PFS was 1.7 vs. 3.7 months in the Sm-153-EDTMP alone and combination arms (P = 0.041, HR = 0.51, P = 0.046). No patient in the Sm-153-EDTMP alone arm achieved prostate-specific antigen (PSA) decline > 30% compared with four patients (of 21) in the combination arm, including three with PSA decline > 50%. Toxicities were similar between arms and related to number of Sm-153-EDTMP doses administered. These results provide the rationale for clinical evaluation of new radiopharmaceuticals, such as Ra-223, in combination with PSA-TRICOM. C1 [Heery, Christopher R.; Grenga, Italia; Donahue, Renee N.; Jochems, Caroline; Schlom, Jeffrey] NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. [Madan, Ravi A.; Rauckhorst, Myrna; Marte, Jennifer L.; Dahut, William L.; Gulley, James L.] NCI, Genitourinary Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Stein, Mark N.; DiPaola, Robert S.] Rutgers Canc Inst New Jersey, New Brunswick, NJ USA. [Stadler, Walter M.] Univ Chicago Med, Chicago, IL USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. [Chen, Clara C.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD USA. [DiPaola, Robert S.] Univ Kentucky, Coll Med, Lexington, KY USA. RP Gulley, JL (reprint author), NCI, Genitourinary Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM Gulleyj@mail.nih.gov FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health; Cancer Therapy Evaluation Program (CTEP), National Cancer Institute, National Institutes of Health FX Funding for this study was provided through the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health, and the Cancer Therapy Evaluation Program (CTEP), National Cancer Institute, National Institutes of Health. NR 33 TC 1 Z9 1 U1 1 U2 1 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD OCT 18 PY 2016 VL 7 IS 42 BP 69014 EP 69023 DI 10.18632/oncotarget.10883 PG 10 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EB5UT UT WOS:000387446800102 PM 27486817 ER PT J AU Abubakar, M Orr, N Daley, F Coulson, P Ali, HR Blows, F Benitez, J Milne, R Brenner, H Stegmaier, C Mannermaa, A Chang-Claude, J Rudolph, A Sinn, P Couch, FJ Devilee, P Tollenaar, RAEM Seynaeve, C Figueroa, J Sherman, ME Lissowska, J Hewitt, S Eccles, D Hooning, MJ Hollestelle, A Martens, JWM van Deurzen, CHM Bolla, MK Wang, Q Jones, M Schoemaker, M Wesseling, J van Leeuwen, FE Van 't Veer, L Easton, D Swerdlow, AJ Dowsett, M Pharoah, PD Schmidt, MK Garcia-Closas, M AF Abubakar, Mustapha Orr, Nick Daley, Frances Coulson, Penny Ali, H. Raza Blows, Fiona Benitez, Javier Milne, Roger Brenner, Herman Stegmaier, Christa Mannermaa, Arto Chang-Claude, Jenny Rudolph, Anja Sinn, Peter Couch, Fergus J. Devilee, Peter Tollenaar, Rob A. E. M. Seynaeve, Caroline Figueroa, Jonine Sherman, Mark E. Lissowska, Jolanta Hewitt, Stephen Eccles, Diana Hooning, Maartje J. Hollestelle, Antoinette Martens, John W. M. van Deurzen, Carolien H. M. Bolla, Manjeet K. Wang, Qin Jones, Michael Schoemaker, Minouk Wesseling, Jelle van Leeuwen, Flora E. Van 't Veer, Laura Easton, Douglas Swerdlow, Anthony J. Dowsett, Mitch Pharoah, Paul D. Schmidt, Marjanka K. Garcia-Closas, Montserrat CA KConFab Investigators TI Prognostic value of automated KI67 scoring in breast cancer: a centralised evaluation of 8088 patients from 10 study groups SO BREAST CANCER RESEARCH LA English DT Article DE Breast cancer; Automated KI67; Visual KI67; Prognostication ID IMAGE-ANALYSIS; PROLIFERATIVE ACTIVITY; PROGESTERONE-RECEPTOR; INTERNATIONAL KI67; ESTROGEN-RECEPTOR; RECURRENCE SCORE; KI-67; METAANALYSIS; SURVIVAL; MARKER AB Background: The value of KI67 in breast cancer prognostication has been questioned due to concerns on the analytical validity of visual KI67 assessment and methodological limitations of published studies. Here, we investigate the prognostic value of automated KI67 scoring in a large, multicentre study, and compare this with pathologists' visual scores available in a subset of patients. Methods: We utilised 143 tissue microarrays containing 15,313 tumour tissue cores from 8088 breast cancer patients in 10 collaborating studies. A total of 1401 deaths occurred during a median follow-up of 7.5 years. Centralised KI67 assessment was performed using an automated scoring protocol. The relationship of KI67 levels with 10-year breast cancer specific survival (BCSS) was investigated using Kaplan-Meier survival curves and Cox proportional hazard regression models adjusted for known prognostic factors. Results: Patients in the highest quartile of KI67 (> 12 % positive KI67 cells) had a worse 10-year BCSS than patients in the lower three quartiles. This association was statistically significant for ER-positive patients (hazard ratio (HR) (95 % CI) at baseline = 1.96 (1.31-2.93); P = 0.001) but not for ER-negative patients (1.23 (0.86-1.77); P = 0.248) (P-heterogeneity = 0.064). In spite of differences in characteristics of the study populations, the estimates of HR were consistent across all studies (P-heterogeneity = 0.941 for ER-positive and P-heterogeneity = 0.866 for ER-negative). Among ER-positive cancers, KI67 was associated with worse prognosis in both node-negative (2.47 (1.16-5.27)) and node-positive (1.74 (1.05-2.86)) tumours (P-heterogeneity = 0.671). Further classification according to ER, PR and HER2 showed statistically significant associations with prognosis among hormone receptor-positive patients regardless of HER2 status (P-heterogeneity = 0.270) and among triple-negative patients (1.70 (1.02-2.84)). Model fit parameters were similar for visual and automated measures of KI67 in a subset of 2440 patients with information from both sources. Conclusions: Findings from this large-scale multicentre analysis with centrally generated automated KI67 scores show strong evidence in support of a prognostic value for automated KI67 scoring in breast cancer. Given the advantages of automated scoring in terms of its potential for standardisation, reproducibility and throughput, automated methods appear to be promising alternatives to visual scoring for KI67 assessment. C1 [Abubakar, Mustapha; Coulson, Penny; Jones, Michael; Schoemaker, Minouk; Swerdlow, Anthony J.] Inst Canc Res, Div Genet & Epidemiol, 15 Cotswold Rd, Sutton SM2 5NG, Surrey, England. [Orr, Nick; Daley, Frances; Dowsett, Mitch] Inst Canc Res, Div Breast Canc Res, Breast Canc Now Toby Robins Res Ctr, London, England. [Ali, H. Raza] Univ Cambridge, Canc Res UK Cambridge Inst, Cambridge, England. [Blows, Fiona; Easton, Douglas; Pharoah, Paul D.] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England. [Benitez, Javier] Spanish Natl Canc Res Ctr CNIO, Human Genet Grp, Human Canc Genet Program, Madrid, Spain. [Benitez, Javier] Ctr Invest Red Enfermedades Raras CIBERER, Valencia, Spain. [Milne, Roger] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Milne, Roger] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia. [Brenner, Herman] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Brenner, Herman] German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany. [Brenner, Herman] Natl Ctr Tumor Dis NCT, Heidelberg, Germany. [Brenner, Herman] German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany. [Stegmaier, Christa] Saarland Canc Registry, Saarland, Germany. [Mannermaa, Arto] Univ Eastern Finland, Canc Ctr Eastern Finland, Sch Med, Inst Clin Med Pathol & Forens Med, Kuopio, Finland. [Mannermaa, Arto] Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, Kuopio, Finland. [Chang-Claude, Jenny; Rudolph, Anja] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Chang-Claude, Jenny] Univ Med Ctr Hamburg Eppendorf, Univ Canc Ctr Hamburg, Hamburg, Germany. [Sinn, Peter] Univ Heidelberg Hosp, Inst Pathol, Dept Pathol, Heidelberg, Germany. [Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Devilee, Peter] Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands. [Devilee, Peter] Leiden Univ, Med Ctr, Dept Pathol, Leiden, Netherlands. [Tollenaar, Rob A. E. M.] Leiden Univ, Med Ctr, Dept Surg, Leiden, Netherlands. [Seynaeve, Caroline; Hooning, Maartje J.; Hollestelle, Antoinette; Martens, John W. M.] Erasmus MC Canc Inst, Family Canc Clin, Dept Med Oncol, Rotterdam, Netherlands. [Figueroa, Jonine] Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland. [Sherman, Mark E.; Garcia-Closas, Montserrat] NCI, Div Canc Epidemiol, Rockville, MD USA. [Sherman, Mark E.; Garcia-Closas, Montserrat] NCI, Div Genet, Rockville, MD USA. [Lissowska, Jolanta] M Sklodowska Curie Mem Canc Ctr, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. [Hewitt, Stephen] NCI, Pathol Lab, NIH, Rockville, MD USA. [Eccles, Diana] Southampton Gen Hosp, Fac Med, Acad Unit Canc Sci, Southampton, Hants, England. [van Deurzen, Carolien H. M.] Erasmus MC Canc Inst, Dept Pathol, Rotterdam, Netherlands. [KConFab Investigators] QIMR Berghofer Med Res Inst, Dept Genet, Brisbane, Qld, Australia. [Bolla, Manjeet K.; Wang, Qin; Easton, Douglas; Pharoah, Paul D.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Wesseling, Jelle; Van 't Veer, Laura; Schmidt, Marjanka K.] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Div Mol Pathol, Amsterdam, Netherlands. [van Leeuwen, Flora E.; Schmidt, Marjanka K.] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Div Psychosocial Res & Epidemiol, Amsterdam, Netherlands. [Swerdlow, Anthony J.] Inst Canc Res, Div Breast Canc Res, London, England. [Dowsett, Mitch] Royal Marsden Hosp, Acad Dept Biochem, Fulham Rd, London, England. RP Abubakar, M (reprint author), Inst Canc Res, Div Genet & Epidemiol, 15 Cotswold Rd, Sutton SM2 5NG, Surrey, England. EM Mustapha.Abubakar@icr.ac.uk RI Brenner, Hermann/B-4627-2017 OI Brenner, Hermann/0000-0002-6129-1572 FU Dutch Cancer Society [NKI 2007-3839, 2009 4363, UL1997-1505, DDHK 2004-3124, DDHK 2009-4318]; BBMRI-NL - Dutch government [NWO 184.021.007]; Dutch National Genomics Initiative; Baden Wurttemberg Ministry of Science, Research and Arts; German Cancer Aid (Deutsche Krebshilfe); Kuopio University Hospital grants; Cancer Fund of North Savo; Finnish Cancer Organizations; Academy of Finland; University of Eastern Finland; Deutsche Krebshilfe e.V. [70-2892-BR I, 106332, 108253, 108419]; Hamburg Cancer Society; German Cancer Research Center (DKFZ); Federal Ministry of Education and Research (BMBF) Germany [01KH0402]; NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]; Breast Cancer Research Foundation; Mayo Clinic Breast Cancer Registry; Ting Tsung and Wei Fong Chao Foundation; Biobanking and Biomolecular Resources Research Infrastructure [BBMRI-NL CP16]; Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA; Cancer Research UK [C490/A10124, C490/A16561]; UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge; European Community [223175, HEALTH-F2-2009223175]; Breakthrough Breast Cancer, UK FX The ABCS study was supported by the Dutch Cancer Society (grants NKI 2007-3839; 2009 4363); BBMRI-NL, which is a Research Infrastructure financed by the Dutch government (NWO 184.021.007); and the Dutch National Genomics Initiative.; The ESTHER study was supported by a grant from the Baden Wurttemberg Ministry of Science, Research and Arts. Additional cases were recruited in the context of the VERDI study, which was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe).; The KBCP study was financially supported by the special Government Funding (EVO) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations, the Academy of Finland and by the strategic funding of the University of Eastern Finland.; The MARIE study was supported by the Deutsche Krebshilfe e.V. (70-2892-BR I, 106332, 108253, 108419), the Hamburg Cancer Society, the German Cancer Research Center (DKFZ) and the Federal Ministry of Education and Research (BMBF) Germany (01KH0402).; The MCBCS was supported by an NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), the Breast Cancer Research Foundation, the Mayo Clinic Breast Cancer Registry and a generous gift from the David F. and Margaret T. Grohne Family Foundation and the Ting Tsung and Wei Fong Chao Foundation.; The ORIGO authors thank E. Krol-Warmerdam, and J. Blom; the contributing studies were funded by grants from the Dutch Cancer Society (UL1997-1505) and the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL CP16).; The PBCS study was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The RBCS study was funded by the Dutch Cancer Society (DDHK 2004-3124, DDHK 2009-4318).; The SEARCH study is funded by a programme grant from Cancer Research UK (C490/A10124. C490/A16561) and supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge. Part of this work was supported by the European Community's Seventh Framework Programme under grant agreement number 223175 (grant number HEALTH-F2-2009223175) (COGS). The authors acknowledge funds from Breakthrough Breast Cancer, UK, in support of MG-C at the time this work was carried out and funds from the Cancer Research, UK, in support of MA at the Institute of Cancer Research, London. NR 31 TC 2 Z9 2 U1 11 U2 11 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-542X EI 1465-5411 J9 BREAST CANCER RES JI Breast Cancer Res. PD OCT 18 PY 2016 VL 18 AR 104 DI 10.1186/s13058-016-0765-6 PG 13 WC Oncology SC Oncology GA DZ3QT UT WOS:000385764800001 PM 27756439 ER PT J AU Baraldi, E Giordano, G Stocchero, M Moschino, L Zaramella, P Tran, MR Carraro, S Romero, R Gervasi, MT AF Baraldi, Eugenio Giordano, Giuseppe Stocchero, Matteo Moschino, Laura Zaramella, Patrizia Tran, Maria Rosa Carraro, Silvia Romero, Roberto Gervasi, Maria Teresa TI Untargeted Metabolomic Analysis of Amniotic Fluid in the Prediction of Preterm Delivery and Bronchopulmonary Dysplasia SO PLOS ONE LA English DT Article ID CHRONIC LUNG-DISEASE; SUBSEQUENT DEVELOPMENT; PREMATURE-INFANTS; BIRTH; RISK; IDENTIFICATION; EPIDEMIOLOGY; VALIDATION; BIOMARKERS; DIAGNOSIS AB Objective Bronchopulmonary dysplasia (BPD) is a serious complication associated with preterm birth. A growing body of evidence suggests a role for prenatal factors in its pathogenesis. Metabolomics allows simultaneous characterization of low molecular weight compounds and may provide a picture of such a complex condition. The aim of this study was to evaluate whether an unbiased metabolomic analysis of amniotic fluid (AF) can be used to investigate the risk of spontaneous preterm delivery (PTD) and BPD development in the offspring. Study design We conducted an exploratory study on 32 infants born from mothers who had undergone an amniocentesis between 21 and 28 gestational weeks because of spontaneous preterm labor with intact membranes. The AF samples underwent untargeted metabolomic analysis using mass spectrometry combined with ultra-performance liquid chromatography. The data obtained were analyzed using multivariate and univariate statistical data analysis tools. Results Orthogonally Constrained Projection to Latent Structures-Discriminant Analysis (oCPLS2-DA) excluded effects on data modelling of crucial clinical variables. oCPLS2-DA was able to find unique differences in select metabolites between term (n = 11) and preterm (n = 13) deliveries (negative ionization data set: R-2 = 0.47, mean AUC ROC in prediction = 0.65; positive ionization data set: R-2 = 0.47, mean AUC ROC in prediction = 0.70), and between PTD followed by the development of BPD (n = 10), and PTD without BPD (n = 11) (negative data set: R-2 = 0.48, mean AUC ROC in prediction = 0.73; positive data set: R-2 = 0.55, mean AUC ROC in prediction = 0.71). Conclusions This study suggests that amniotic fluid metabolic profiling may be promising for identifying spontaneous preterm birth and fetuses at risk for developing BPD. These findings support the hypothesis that some prenatal metabolic dysregulations may play a key role in the pathogenesis of PTD and the development of BPD. C1 [Baraldi, Eugenio; Giordano, Giuseppe; Moschino, Laura; Zaramella, Patrizia; Tran, Maria Rosa; Carraro, Silvia; Gervasi, Maria Teresa] Univ Padua, Dept Womens & Childrens Hlth, Padua, Italy. [Baraldi, Eugenio; Giordano, Giuseppe; Moschino, Laura; Carraro, Silvia] Citta Speranza Inst Pediat Res IRP, Padua, Italy. [Stocchero, Matteo] S IN Soluz Informat, Vicenza, Italy. [Romero, Roberto] Wayne State Univ, Perinatol Res Branch, NICHD, NIH,DHHS,Hutzel Womens Hosp, Detroit, MI USA. RP Baraldi, E (reprint author), Univ Padua, Dept Womens & Childrens Hlth, Padua, Italy.; Baraldi, E (reprint author), Citta Speranza Inst Pediat Res IRP, Padua, Italy. EM eugenio.baraldi@unipd.it FU Bando Ricerca Pediatrica Fondazione Cassa di Risparmio di Padova e Rovigo; Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH) FX This study was supported by "Bando Ricerca Pediatrica 2012-2014" Fondazione Cassa di Risparmio di Padova e Rovigo and, in part, by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH). The funding sources had no involvement in the study design, the collection, analysis, and interpretation of data, the writing of the report, and the decision to submit the manuscript for publication. The funding sources and the company S-IN Soluzioni Informatiche (MS) did not provide support in the form of salaries for any of the authors. S-IN Soluzioni Informatiche did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of the authors are articulated in the 'author contributions' section.; This work was supported by "Bando Ricerca Pediatrica 2012-2014" Fondazione Cassa di Risparmio di Padova e Rovigo and, in part, by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH). NR 37 TC 0 Z9 0 U1 7 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 18 PY 2016 VL 11 IS 10 AR e0164211 DI 10.1371/journal.pone.0164211 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ9NV UT WOS:000386203800013 PM 27755564 ER PT J AU Chadwick, RS AF Chadwick, Richard S. TI A Dual Probe and Two Tones Reveal Dual Waves in the Cochlea SO BIOPHYSICAL JOURNAL LA English DT News Item ID MEMBRANE C1 [Chadwick, Richard S.] NIH, Natl Inst Deafness & Other Commun Disorders, Bldg 10, Bethesda, MD 20892 USA. RP Chadwick, RS (reprint author), NIH, Natl Inst Deafness & Other Commun Disorders, Bldg 10, Bethesda, MD 20892 USA. EM chadwick@helix.nih.gov NR 5 TC 0 Z9 0 U1 1 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD OCT 18 PY 2016 VL 111 IS 8 BP 1587 EP 1588 DI 10.1016/j.bpj.2016.09.015 PG 2 WC Biophysics SC Biophysics GA EA0YQ UT WOS:000386315900001 PM 27760344 ER PT J AU Chakrabarty, JK Naik, AG Fessler, MB Munske, GR Chowdhury, SM AF Chakrabarty, Jayanta K. Naik, Aishwarya G. Fessler, Michael B. Munske, Gerhard R. Chowdhury, Saiful M. TI Differential Tandem Mass Spectrometry-Based Cross-Linker: A New Approach for High Confidence in Identifying Protein Cross-Linking SO ANALYTICAL CHEMISTRY LA English DT Article ID MAMMALIAN MITOCHONDRIAL RIBOSOME; ELECTRON-TRANSFER DISSOCIATION; IDENTIFICATION; PEPTIDES; METHODOLOGY; REAGENTS; STRATEGY; BONDS AB Chemical cross-linking and mass spectrometry are now widely used to analyze large-scale protein-protein interactions. The major challenge in cross-linking approaches is the complexity of the mass spectrometric data. New approaches are required that can identify cross-linked peptides with high-confidence and establish a user-friendly analysis protocol for the biomedical scientific community. Here, we introduce a novel cross-linker that can be selectively cleaved in the gas phase using two differential tandem mass-spectrometric fragmentation methods, such as collision-induced or electron transfer dissociation (CID and ETD). This technique produces two signature mass spectra of the same cross-linked peptide, thereby producing high confidence in identifying the sites of interaction. Further-tandem mass spectrometry can also give additional confidence on the peptide sequences. We demonstrate a proof-of-concept for This method using standard peptides and proteins. Peptides and proteins were cross-linked and their fragmentation characteristics were analyzed using CID and ETD tandem mass spectrometry. Two sequential cleavages unambiguously identified cross-linked peptides. In addition, the labeling efficiency of the new cross-linker was evaluated in macrophage immune cells after stimulation with the microbial ligand lipopolysaccharide and subsequent pulldown experiments with biotin-avidin affinity chromatography. We believe this strategy will help advance insights into the structural biology and systems biology of cell signaling. C1 [Chakrabarty, Jayanta K.; Chowdhury, Saiful M.] Univ Texas Arlington, Dept Chem & Biochem, 700 Planetarium Pl, Arlington, TX 76019 USA. [Fessler, Michael B.] NIEHS, Immun Inflammat & Dis Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Munske, Gerhard R.] Washington State Univ, Lab Bioanal, Pullman, WA 98195 USA. RP Chowdhury, SM (reprint author), Univ Texas Arlington, Dept Chem & Biochem, 700 Planetarium Pl, Arlington, TX 76019 USA. EM schowd@uta.edu FU NIGMS, NIH [1UA5GM113216-01]; UT Proteomics Core Facility Network; Intramural Research Program of the National Institute of Environmental Health Sciences, NIH [Z01 ES102005] FX We acknowledge funding from 1UA5GM113216-01, NIGMS, NIH, and also funding from the UT Proteomics Core Facility Network for a mass spectrometer. The authors also acknowledge the Shimadzu Center for Advance Analytical Chemistry (SCAAC) at the University of Texas at Arlington. M.B.F. is funded by the Intramural Research Program of the National Institute of Environmental Health Sciences, NIH (Z01 ES102005). We also thank Dr. Lalith Perera at NIEHS, NIH for molecular modeling support. NR 27 TC 0 Z9 0 U1 18 U2 18 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 EI 1520-6882 J9 ANAL CHEM JI Anal. Chem. PD OCT 18 PY 2016 VL 88 IS 20 BP 10215 EP 10222 DI 10.1021/acs.analchem.6b02886 PG 8 WC Chemistry, Analytical SC Chemistry GA DZ5MY UT WOS:000385907400047 PM 27649375 ER PT J AU Danis, M Carson, SS Hanson, LC AF Danis, Marion Carson, Shannon S. Hanson, Laura C. TI Palliative Care-Led Meetings for Families of ICU Patients Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID INTENSIVE-CARE; INTERVENTIONS C1 [Danis, Marion] NIH, Bldg 10, Bethesda, MD 20892 USA. [Carson, Shannon S.; Hanson, Laura C.] Univ N Carolina, Sch Med, Chapel Hill, NC USA. RP Carson, SS (reprint author), Univ N Carolina, Sch Med, Div Pulm & Crit Care Med, Cecil B Sheps Ctr Hlth Serv Res,Marsico Lung Inst, 4125 Bioinformat Bldg, Chapel Hill, NC 27599 USA. EM scarson@med.unc.edu NR 2 TC 0 Z9 0 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD OCT 18 PY 2016 VL 316 IS 15 BP 1598 EP 1599 DI 10.1001/jama.2016.14322 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DZ0KM UT WOS:000385527600027 PM 27755632 ER PT J AU Wang, CC Lee, JE Lai, BB Macfarlan, TS Xu, SLY Zhuang, LN Liu, CY Peng, WQ Ge, K AF Wang, Chaochen LeE, Ji-Eun Lai, Binbin Macfarlan, Todd S. Xu, Shiliyang Zhuang, Lenan Liu, Chengyu Peng, Weiqun Ge, Kai TI Enhancer priming by H3K4 methyltransferase MLL4 controls cell fate transition SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE enhancer; MLL4/KMT2D; H3K4 methyltransferase; cell fate transition; p300 ID EMBRYONIC STEM-CELLS; GENE-EXPRESSION; SUPER-ENHANCERS; IDENTITY GENES; DIFFERENTIATION; TRANSCRIPTION; DISEASE; GENOME AB Transcriptional enhancers control cell-type-specific gene expression. Primed enhancers are marked by histone H3 lysine 4 (H3K4) mono/di-methylation (H3K4me1/2). Active enhancers are further marked by H3K27 acetylation (H3K27ac). Mixed-lineage leukemia 4 (MLL4/KMT2D) is a major enhancer H3K4me1/2 methyltransferase with functional redundancy with MLL3 (KMT2C). However, its role in cell fate maintenance and transition is poorly understood. Here, we show in mouse embryonic stem cells (ESCs) that MLL4 associates with, but is surprisingly dispensable for the maintenance of, active enhancers of cell-identity genes. As a result, MLL4 is dispensable for cell-identity gene expression and self-renewal in ESCs. In contrast, MLL4 is required for enhancer-binding of H3K27 acetyltransferase p300, enhancer activation, and induction of cell-identity genes during ESC differentiation. MLL4 protein, rather than MLL4-mediated H3K4 methylation, controls p300 recruitment to enhancers. We also show that, in somatic cells, MLL4 is dispensable for maintaining cell identity but essential for reprogramming into induced pluripotent stem cells. These results indicate that, although enhancer priming by MLL4 is dispensable for cell-identity maintenance, it controls cell fate transition by orchestrating p300-mediated enhancer activation. C1 [Wang, Chaochen; LeE, Ji-Eun; Lai, Binbin; Xu, Shiliyang; Zhuang, Lenan; Ge, Kai] NIDDK, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20892 USA. [Macfarlan, Todd S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Dev Biol, NIH, Bethesda, MD 20892 USA. [Liu, Chengyu] NHLBI, Transgen Core, Ctr Mol Med, NIH, Bldg 10, Bethesda, MD 20892 USA. [Peng, Weiqun] George Washington Univ, Dept Phys, Washington, DC 20052 USA. [Peng, Weiqun] George Washington Univ, Dept Anat & Regenerat Biol, Washington, DC 20052 USA. RP Ge, K (reprint author), NIDDK, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20892 USA. EM kai.ge@nih.gov OI Ge, Kai/0000-0002-7442-5138; Macfarlan, Todd/0000-0003-2495-9809 FU Intramural Research Program of the NIDDK of the NIH FX We thank National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Genomics Core for sequencing. This work was supported by the Intramural Research Program of the NIDDK of the NIH (K.G.). NR 25 TC 0 Z9 0 U1 5 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 18 PY 2016 VL 113 IS 42 BP 11871 EP 11876 DI 10.1073/pnas.1606857113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ1PN UT WOS:000385610400072 PM 27698142 ER PT J AU Khoutorsky, A Sorge, RE Prager-Khoutorsky, M Pawlowski, SA Longo, G Jafarnejad, SM Tahmasebi, S Martin, LJ Pitcher, MH Gkogkas, CG Sharif-Naeini, R Ribeiro-Da-Silva, A Bourque, CW Cervero, F Mogil, JS Sonenberg, N AF Khoutorsky, Arkady Sorge, Robert E. Prager-Khoutorsky, Masha Pawlowski, Sophie Anne Longo, Geraldine Jafarnejad, Seyed Mehdi Tahmasebi, Soroush Martin, Loren J. Pitcher, Mark H. Gkogkas, Christos G. Sharif-Naeini, Reza Ribeiro-da-Silva, Alfredo Bourque, Charles W. Cervero, Fernando Mogil, Jeffrey S. Sonenberg, Nahum TI eIF2 alpha phosphorylation controls thermal nociception SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE pain; eIF2 alpha; cellular stress response pathway; TRPV1 ID ENDOPLASMIC-RETICULUM STRESS; EUKARYOTIC INITIATION FACTOR-2-ALPHA; UNFOLDED PROTEIN RESPONSE; LASTING SYNAPTIC PLASTICITY; NECROSIS-FACTOR-ALPHA; LONG-TERM DEPRESSION; TRANSLATIONAL CONTROL; TNF-ALPHA; ALZHEIMERS-DISEASE; NEUROPATHIC PAIN AB A response to environmental stress is critical to alleviate cellular injury and maintain cellular homeostasis. Eukaryotic initiation factor 2 (eIF2) is a key integrator of cellular stress responses and an important regulator of mRNA translation. Diverse stress signals lead to the phosphorylation of the a subunit of eIF2 (Ser51), resulting in inhibition of global protein synthesis while promoting expression of proteins that mediate cell adaptation to stress. Here we report that eIF2 alpha is instrumental in the control of noxious heat sensation. Mice with decreased eIF2 alpha phosphorylation (eIF2 alpha(+/S51A)) exhibit reduced responses to noxious heat. Pharmacological attenuation of eIF2 alpha phosphorylation decreases thermal, but not mechanical, pain sensitivity, whereas increasing eIF2 alpha phosphorylation has the opposite effect on thermal nociception. The impact of eIF2 alpha phosphorylation (p-eIF2 alpha) on thermal thresholds is dependent on the transient receptor potential vanilloid 1. Moreover, we show that induction of eIF2 alpha phosphorylation in primary sensory neurons in a chronic inflammation pain model contributes to thermal hypersensitivity. Our results demonstrate that the cellular stress response pathway, mediated via p-eIF2 alpha, represents a mechanism that could be used to alleviate pathological heat sensation. C1 [Khoutorsky, Arkady; Jafarnejad, Seyed Mehdi; Tahmasebi, Soroush; Sonenberg, Nahum] McGill Univ, Dept Biochem, Montreal, PQ H3A 1A3, Canada. [Khoutorsky, Arkady; Jafarnejad, Seyed Mehdi; Tahmasebi, Soroush; Sonenberg, Nahum] McGill Univ, Rosalind & Morris Goodman Canc Res Ctr, Montreal, PQ H3A 1A3, Canada. [Khoutorsky, Arkady; Cervero, Fernando] McGill Univ, Dept Anesthesia, Montreal, PQ H3G 1Y6, Canada. [Khoutorsky, Arkady; Sorge, Robert E.; Pawlowski, Sophie Anne; Longo, Geraldine; Martin, Loren J.; Sharif-Naeini, Reza; Ribeiro-da-Silva, Alfredo; Cervero, Fernando; Mogil, Jeffrey S.] McGill Univ, Alan Edwards Ctr Res Pain, Montreal, PQ H3G 1Y6, Canada. [Sorge, Robert E.; Martin, Loren J.; Mogil, Jeffrey S.] McGill Univ, Dept Psychol, 1205 Dr Penfield Ave, Montreal, PQ H3A 1B1, Canada. [Prager-Khoutorsky, Masha] McGill Univ, Montreal Gen Hosp, Ctr Res Neurosci, Montreal, PQ H3G 1A4, Canada. [Pawlowski, Sophie Anne; Longo, Geraldine; Ribeiro-da-Silva, Alfredo] McGill Univ, Dept Pharmacol & Therapeut, Montreal, PQ H3G 1Y6, Canada. [Pitcher, Mark H.] NIH, Natl Ctr Complementary & Alternat Med, Porter Neurosci Res Ctr, Bldg 10, Bethesda, MD 20892 USA. [Gkogkas, Christos G.] Univ Edinburgh, Patrick Wild Ctr, Edinburgh EH8 9XD, Midlothian, Scotland. [Gkogkas, Christos G.] Univ Edinburgh, Ctr Integrat Physiol, Edinburgh EH8 9XD, Midlothian, Scotland. [Sharif-Naeini, Reza] McGill Univ, Dept Physiol, Montreal, PQ H3G 1Y6, Canada. RP Sonenberg, N (reprint author), McGill Univ, Dept Biochem, Montreal, PQ H3A 1A3, Canada.; Sonenberg, N (reprint author), McGill Univ, Rosalind & Morris Goodman Canc Res Ctr, Montreal, PQ H3A 1A3, Canada.; Mogil, JS (reprint author), McGill Univ, Alan Edwards Ctr Res Pain, Montreal, PQ H3G 1Y6, Canada.; Mogil, JS (reprint author), McGill Univ, Dept Psychol, 1205 Dr Penfield Ave, Montreal, PQ H3A 1B1, Canada. EM jeffrey.mogil@mcgill.ca; nahum.sonenberg@mcgill.ca FU Canadian Institutes of Health Research (CIHR) [MOP-114994]; CIHR [FDN-143337]; James McGill Chair Program FX We thank A. Sylvestre, S. Perreault, C. Lister, and I. Harvey for technical assistance and I. Daou for technical advice. This work was supported by Canadian Institutes of Health Research (CIHR) Operating Grant MOP-114994 (to N.S.), an unrestricted gift from the Louise and Alan Edwards Foundation (to J.S.M.), CIHR Grant FDN-143337 (to C.W.B.), and the James McGill Chair Program (C.W.B.). NR 56 TC 0 Z9 0 U1 4 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 18 PY 2016 VL 113 IS 42 BP 11949 EP 11954 DI 10.1073/pnas.1614047113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ1PN UT WOS:000385610400085 PM 27698114 ER PT J AU Burdin, DV Kolobov, AA Brocker, C Soshnev, AA Samusik, N Demyanov, AV Brilloff, S Jarzebska, N Martens-Lobenhoffer, J Mieth, M Maas, R Bornstein, SR Bode-Boger, SM Gonzalez, F Weiss, N Rodionov, RN AF Burdin, Dmitry V. Kolobov, Alexey A. Brocker, Chad Soshnev, Alexey A. Samusik, Nikolay Demyanov, Anton V. Brilloff, Silke Jarzebska, Natalia Martens-Lobenhoffer, Jens Mieth, Maren Maas, Renke Bornstein, Stefan R. Bode-Boeger, Stefanie M. Gonzalez, Frank Weiss, Norbert Rodionov, Roman N. TI Diabetes-linked transcription factor HNF4 alpha regulates metabolism of endogenous methylarginines and beta-aminoisobutyric acid by controlling expression of alanine-glyoxylate aminotransferase 2 SO SCIENTIFIC REPORTS LA English DT Article ID GENOME-WIDE ASSOCIATION; NUCLEAR FACTOR 4-ALPHA; HEMOPHILIA-B LEYDEN; ASYMMETRIC DIMETHYLARGININE; L-ARGININE; SYMMETRIC DIMETHYLARGININE; FACTOR-4-ALPHA GENE; BINDING-SITE; DISEASE; POPULATION AB Elevated levels of circulating asymmetric and symmetric dimethylarginines (ADMA and SDMA) predict and potentially contribute to end organ damage in cardiovascular diseases. Alanine-glyoxylate aminotransferase 2 (AGXT2) regulates systemic levels of ADMA and SDMA, and also of beta-aminoisobutyric acid (BAIB)-a modulator of lipid metabolism. We identified a putative binding site for hepatic nuclear factor 4 alpha (HNF4 alpha in AGXT2 promoter sequence. In a luciferase reporter assay we found a 75% decrease in activity of Agxt2 core promoter after disruption of the HNF4 alpha binding site. Direct binding of HNF4 alpha to Agxt2 promoter was confirmed by chromatin immunoprecipitation assay. siRNA-mediated knockdown of Hnf4a led to an almost 50% reduction in Agxt2 mRNA levels in Hepa 1-6 cells. Liver-specific Hnf4a knockout mice exhibited a 90% decrease in liver Agxt2 expression and activity, and elevated plasma levels of ADMA, SDMA and BAIB, compared to wild-type littermates. Thus we identified HNF4 alpha as a major regulator of Agxt2 expression. Considering a strong association between human HNF4A polymorphisms and increased risk of type 2 diabetes our current findings suggest that downregulation of AGXT2 and subsequent impairment in metabolism of dimethylarginines and BAIB caused by HNF4 alpha deficiency might contribute to development of cardiovascular complications in diabetic patients. C1 [Burdin, Dmitry V.] St Petersburg State Univ, Dept Physiol, St Petersburg 199034, Russia. [Kolobov, Alexey A.] St Petersburg State Univ, Dept Biochem, St Petersburg 199034, Russia. [Brocker, Chad; Gonzalez, Frank] NCI, NIH, Bethesda, MD 20892 USA. [Soshnev, Alexey A.] Rockefeller Univ, New York, NY 10065 USA. [Samusik, Nikolay] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Demyanov, Anton V.] Inst Highly Pure Biopreparat, St Petersburg 197110, Russia. [Brilloff, Silke; Jarzebska, Natalia; Weiss, Norbert; Rodionov, Roman N.] Tech Univ Dresden, Univ Ctr Vasc Med, D-01307 Dresden, Germany. [Martens-Lobenhoffer, Jens] Univ Magdeburg, Inst Clin Pharmacol, D-39120 Magdeburg, Germany. [Mieth, Maren; Maas, Renke] Friedrich Alexander Univ Erlangen Nurnberg FAU, Inst Expt & Clin Pharmacol & Toxicol, D-91054 Erlangen, Germany. [Bornstein, Stefan R.] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Dept Internal Med 3, D-01307 Dresden, Germany. RP Rodionov, RN (reprint author), Tech Univ Dresden, Univ Ctr Vasc Med, D-01307 Dresden, Germany. EM Roman.Rodionov@uniklinikum-dresden.de FU Else Kroner-Fresenius-Stiftung [2011_A168]; Erasmus Mundus Action 2 MULTIC scholarship [11-664]; DAAD scholarship [50024759] FX We thank Carmen Friebel, Isabell Wenzel and Annette Rexin for their help with cell culture and Western blot experiments. We thank Theresa Reetz for her help with the luciferase experiments and the expression analysis in the in vitro part of the project. We thank Max Plank Institute Dresden and personally Martin Stoeter and Marc Bickle for help with set-up and optimization of siRNA experiments. We thank Vladimir Todorov for his help with the luciferase experiments set-up. This work was supported by the grant from Else Kroner-Fresenius-Stiftung 2011_A168 to R.N.R., by the Erasmus Mundus Action 2 MULTIC scholarship (award 11-664) to A.K. and by the DAAD scholarship (award 50024759) to D.V.B.; A.A.S. is HHMI Fellow of the Damon Runyon Cancer Research Foundation (DRG-2185-14). NR 68 TC 0 Z9 0 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD OCT 18 PY 2016 VL 6 AR 35503 DI 10.1038/srep35503 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ1CX UT WOS:000385577600001 PM 27752141 ER PT J AU McHugh, CI Lawhorn-Crews, JM Modi, D Douglas, KA Jones, SK Mangner, TJ Collins, JM Shields, AF AF McHugh, Christopher I. Lawhorn-Crews, Jawana M. Modi, Dipenkumar Douglas, Kirk A. Jones, Steven K. Mangner, Thomas J. Collins, Jerry M. Shields, Anthony F. TI Effects of capecitabine treatment on the uptake of thymidine analogs using exploratory PET imaging agents: F-18-FAU, F-18-FMAU, and F-18-FLT SO CANCER IMAGING LA English DT Article DE PET; Oncology; Capecitabine; FLT; FMAU; FAU ID POSITRON-EMISSION-TOMOGRAPHY; THYMIDYLATE SYNTHASE EXPRESSION; FLUOROPYRIMIDINE-BASED CHEMOTHERAPY; METASTATIC COLORECTAL-CANCER; CELL LUNG-CANCER; MITOCHONDRIAL PROLIFERATION; IN-VIVO; PHARMACOKINETICS; TUMORS; FMAU AB Background: A principal goal for the use of positron emission tomography (PET) in oncology is for real-time evaluation of tumor response to chemotherapy. Given that many contemporary anti-neoplastic agents function by impairing cellular proliferation, it is of interest to develop imaging modalities to monitor these pathways. Here we examined the effect of capecitabine on the uptake of thymidine analogs used with PET: 3'-deoxy-3'-[F-18]fluorothymidine (F-18-FLT), 1-(2'-deoxy-2'-[F-18] fluoro-beta-D-arabinofuranosyl) thymidine (F-18-FMAU), and 1-(2'-deoxy-2'-[F-18] fluoro-beta-D- arabinofuranosyl) uracil (F-18-FAU) in patients with advanced cancer. Methods: Fifteen patients were imaged, five with each imaging agent. Patients had been previously diagnosed with breast, colorectal, gastric, and esophageal cancers and had not received therapy for at least 4 weeks prior to the first scan, and had not been treated with any prior fluoropyrimidines. Subjects were imaged within a week before the start of capecitabine and on the second day of treatment, after the third dose of capecitabine. Tracer uptake was quantified by mean standard uptake value (SUVmean) and using kinetic analysis. Results: Patients imaged with F-18-FLT showed variable changes in retention and two patients exhibited an increase in SUVmean of 172.3 and 89.9 %, while the other patients had changes ranging from +19.4 to -25.4 %. The average change in F-18-FMAU retention was 0.2 % (range -24.4 to 23.1) and F-18-FAU was -10.2 % (range -40.3 to 19.2). Observed changes correlated strongly with SUVmax but not kinetic measurements. Conclusions: This pilot study demonstrates that patients treated with capecitabine can produce a marked increase in F-18-FLT retention in some patients, which will require further study to determine if this flare is predictive of therapeutic response. F-18-FAU and F-18-FMAU showed little change, on average, after treatment. C1 [McHugh, Christopher I.; Jones, Steven K.] Wayne State Univ, Canc Biol Grad Program, Detroit, MI 48201 USA. [Lawhorn-Crews, Jawana M.; Modi, Dipenkumar; Douglas, Kirk A.; Shields, Anthony F.] Wayne State Univ, Karmanos Canc Inst & Oncol, 4100 John R,HW04HO, Detroit, MI 48201 USA. [Mangner, Thomas J.] Wayne State Univ, Radiol, Detroit, MI 48201 USA. [Collins, Jerry M.] NCI, Bethesda, MD 20892 USA. RP Shields, AF (reprint author), Wayne State Univ, Karmanos Canc Inst & Oncol, 4100 John R,HW04HO, Detroit, MI 48201 USA. EM shieldsa@karmanos.org FU National Cancer Institute [26XS295] FX The work was funded in part by contract 26XS295 from the National Cancer Institute. NR 51 TC 0 Z9 0 U1 3 U2 3 PU E-MED PI LONDON PA PO BOX 29761, LONDON, NW3 7ZS, ENGLAND SN 1470-7330 EI 1740-5025 J9 CANCER IMAGING JI Cancer Imaging PD OCT 17 PY 2016 VL 16 AR 34 DI 10.1186/s40644-016-0092-2 PG 9 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA EK1RZ UT WOS:000393704700001 PM 27751167 ER PT J AU Talaat, KR Ellis, RD Hurd, J Hentrich, A Gabriel, E Hynes, NA Rausch, KM Zhu, DM Muratova, O Herrera, R Anderson, C Jones, D Aebig, J Brockley, S MacDonald, NJ Wang, XW Fay, MP Healy, SA Durbin, AP Narum, DL Wu, YM Duffy, PE AF Talaat, Kawsar R. Ellis, Ruth D. Hurd, Janet Hentrich, Autumn Gabriel, Erin Hynes, Noreen A. Rausch, Kelly M. Zhu, Daming Muratova, Olga Herrera, Raul Anderson, Charles Jones, David Aebig, Joan Brockley, Sarah MacDonald, Nicholas J. Wang, Xiaowei Fay, Michael P. Healy, Sara A. Durbin, Anna P. Narum, David L. Wu, Yimin Duffy, Patrick E. TI Safety and Immunogenicityof Pfs25-EPA/Alhydrogel (R) , a Transmission Blocking Vaccine against Plasmodium falciparum: An Open Label Study in Malaria Naive Adults SO PLOS ONE LA English DT Article ID AERUGINOSA EXOPROTEIN-A; MEMBRANE-FEEDING ASSAY; CHILDREN; EFFICACY; CANDIDATES; MOSQUITOS; PFS25; VI AB Transmission-blocking vaccines (TBVs) that target sexual stage parasite development could be an integral part of measures for malaria elimination. Pfs25 is a leading TBV candidate, and previous studies conducted in animals demonstrated an improvement of its functional immunogenicity after conjugation to EPA, a recombinant, detoxified ExoProtein A from Pseudomonas aeruginosa. In this report, we describe results of an open-label, dose escalating Phase 1 trial to assess the safety and immunogenicity of Pfs25-EPA conjugates formulated with Alhydrogel (R). Thirty malaria-naIve healthy adults received up to four doses of the conjugate vaccine, with 8, 16, or 47 mu g of conjugated Pfs25 mass, at 0, 2, 4, and 10 months. Vaccinations were generally well tolerated. The majority of solicited adverse events were mild in severity with pain at the injection site the most common complaint. Anemia was the most common laboratory abnormality, but was considered possibly related to the study in only a minority of cases. No vaccine-related serious adverse events occurred. The peak geometric mean anti-Pfs25 antibody level in the highest dose group was 88 (95% CI 53, 147) mu g/mL two weeks after the 4th vaccination, and declined to near baseline one year later. Antibody avidity increased over successive vaccinations. Transmission blocking activity demonstrated in a standard membrane feeding assay (SMFA) also increased from the second to the third dose, and correlated with antibody titer and, after the final dose, with antibody avidity. These results support the further evaluation of Pfs25-EPA/Alhydrogel (R) in a malaria-endemic population. C1 [Talaat, Kawsar R.; Hurd, Janet; Hentrich, Autumn; Hynes, Noreen A.; Durbin, Anna P.] Johns Hopkins Bloomberg Sch Publ Hlth, Ctr Immunizat Res, Baltimore, MD USA. [Ellis, Ruth D.; Rausch, Kelly M.; Zhu, Daming; Muratova, Olga; Herrera, Raul; Anderson, Charles; Jones, David; Aebig, Joan; Brockley, Sarah; MacDonald, Nicholas J.; Wang, Xiaowei; Healy, Sara A.; Narum, David L.; Wu, Yimin; Duffy, Patrick E.] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD USA. [Gabriel, Erin; Fay, Michael P.] NIAID, Biostat Res Branch, Div Clin Res, NIH, Rockville, MD USA. [Hynes, Noreen A.] Johns Hopkins Univ, Div Infect Dis, Dept Med, Sch Med, Baltimore, MD USA. [Ellis, Ruth D.] Biol Consulting Grp, Alexandria, VA USA. [Wu, Yimin] PATH Malaria Vaccine Initiat, Washington, DC 20001 USA. RP Wu, YM (reprint author), NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD USA.; Wu, YM (reprint author), PATH Malaria Vaccine Initiat, Washington, DC 20001 USA. EM ywu@path.org FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases; NIH [HHSN266200400077C]; PATH Malaria Vaccine Initiative [GAT.0888-11-05311-CTA] FX This research was funded in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH (Contract HHSN266200400077C) and by PATH Malaria Vaccine Initiative (Contract GAT.0888-11-05311-CTA). Employees of NIAID were integral in the study design, data collection and analysis and manuscript preparation. NR 34 TC 2 Z9 2 U1 3 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 17 PY 2016 VL 11 IS 10 AR e0163144 DI 10.1371/journal.pone.0163144 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ9NL UT WOS:000386202300003 PM 27749907 ER PT J AU Clement, M Pearson, JA Gras, S van den Berg, HA Lissina, A Llewellyn-Lacey, S Willis, MD Dockree, T McLaren, JE Ekeruche-Makinde, J Gostick, E Robertson, NP Rossjohn, J Burrows, SR Price, DA Wong, FS Peakman, M Skowera, A Wooldridge, L AF Clement, Mathew Pearson, James A. Gras, Stephanie van den Berg, Hugo A. Lissina, Anya Llewellyn-Lacey, Sian Willis, Mark D. Dockree, Tamsin McLaren, James E. Ekeruche-Makinde, Julia Gostick, Emma Robertson, Neil P. Rossjohn, Jamie Burrows, Scott R. Price, David A. Wong, F. Susan Peakman, Mark Skowera, Ania Wooldridge, Linda TI Targeted suppression of autoreactive CD8(+) T-cell activation using blocking anti-CD8 antibodies SO SCIENTIFIC REPORTS LA English DT Article ID MHC CLASS-I; COMPLEX CLASS-I; LONG-TERM REMISSION; KILL BETA-CELLS; MULTIPLE-SCLEROSIS; RECEPTOR RECOGNITION; CORECEPTOR FUNCTION; CROSS-REACTIVITY; STRUCTURAL BASIS; CD8+T CELLS AB CD8(+) T-cells play a role in the pathogenesis of autoimmune diseases such as multiple sclerosis and type 1 diabetes. However, drugs that target the entire CD8(+) T-cell population are not desirable because the associated lack of specificity can lead to unwanted consequences, most notably an enhanced susceptibility to infection. Here, we show that autoreactive CD8(+) T-cells are highly dependent on CD8 for ligand-induced activation via the T-cell receptor (TCR). In contrast, pathogen-specific CD8(+) T-cells are relatively CD8-independent. These generic differences relate to an intrinsic dichotomy that segregates self-derived and exogenous antigen-specific TCRs according to the monomeric interaction affinity with cognate peptide-major histocompatibility complex class I (pMHCI). As a consequence, "blocking" anti-CD8 antibodies can suppress autoreactive CD8(+) T-cell activation in a relatively selective manner. These findings provide a rational basis for the development and in vivo assessment of novel therapeutic strategies that preferentially target disease-relevant autoimmune responses within the CD8(+) T-cell compartment. C1 [Clement, Mathew; Pearson, James A.; Llewellyn-Lacey, Sian; Dockree, Tamsin; McLaren, James E.; Gostick, Emma; Rossjohn, Jamie; Price, David A.; Wong, F. Susan] Cardiff Univ, Div Infect & Immun, Cardiff CF14 4XN, S Glam, Wales. [Gras, Stephanie; Rossjohn, Jamie] Monash Univ, Infect & Immun Program, Clayton, Vic 3800, Australia. [Gras, Stephanie; Rossjohn, Jamie] Monash Univ, Dept Biochem & Mol Biol, Biomed Discovery Inst, Clayton, Vic 3800, Australia. [Gras, Stephanie; Rossjohn, Jamie] Monash Univ, Australian Res Council, Ctr Excellence Adv Mol Imaging, Clayton, Vic 3800, Australia. [van den Berg, Hugo A.] Univ Warwick, Inst Math, Coventry CV4 7AL, W Midlands, England. [Lissina, Anya; Wooldridge, Linda] Univ Bristol, Fac Hlth Sci, Bristol BS8 1TD, Avon, England. [Willis, Mark D.; Robertson, Neil P.] Cardiff Univ, Div Psychol Med & Clin Neurosci, Cardiff CF14 4XN, S Glam, Wales. [Ekeruche-Makinde, Julia] Imperial Coll London, Dept Med, Mucosal Infect & Immun Grp, London SW7 2AZ, England. [Burrows, Scott R.] QIMR Berghofer Med Res Inst, Brisbane, Qld 4029, Australia. [Price, David A.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Peakman, Mark; Skowera, Ania] Kings Coll London, Dept Immunobiol, London SE1 9RT, England. RP Clement, M (reprint author), Cardiff Univ, Div Infect & Immun, Cardiff CF14 4XN, S Glam, Wales. EM clementm@cardiff.ac.uk RI Price, David/C-7876-2013; OI Price, David/0000-0001-9416-2737; Rossjohn, Jamie/0000-0002-2020-7522 FU Wellcome Trust Institutional Strategic Support Fund; National Multiple Sclerosis Society Pilot Project [5997425]; Diabetes UK PhD Studentship; National Institute for Health Research Biomedical Research Centre; St Thomas' National Health Service Foundation Trust and King's College London; Wellcome Trust Intermediate Clinical Fellowship [WT079848MA] FX We thank Dr. Ann Ager for helpful discussions and critical review of the manuscript, Prof Andrew Sewell for generous funding support, and Dr. Katherine Attfield and Prof Lars Fugger for providing BW58 cells expressing human CD8 alpha beta and the 2D1 TCR. The 4C6 clone was kindly provided by D Kronenberg-Versteeg. This work was supported by a Wellcome Trust Institutional Strategic Support Fund Award and a National Multiple Sclerosis Society Pilot Project Award (5997425). J.A.P. was funded by a Diabetes UK PhD Studentship. A.S. and M.P. were supported by the National Institute for Health Research Biomedical Research Centre at Guy's and St Thomas' National Health Service Foundation Trust and King's College London. S.G. is an Australian Research Council Future Fellow (FT120100416), J.R. is a National Health and Medical Research Council Australia Fellow (FT50) and D.A.P. is Wellcome Trust Senior Investigator (100326/Z/12/Z). L.W. was supported by a Wellcome Trust Intermediate Clinical Fellowship (WT079848MA). NR 73 TC 0 Z9 0 U1 4 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD OCT 17 PY 2016 VL 6 AR 35332 DI 10.1038/srep35332 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DY8CO UT WOS:000385356300001 PM 27748447 ER PT J AU Feldman, MJ Sizdahkhani, S Edwards, NA Merrill, MJ Ray-Chaudhury, A Zhuang, ZP Lonser, RR Oldfield, EH Chittiboina, P AF Feldman, Michael J. Sizdahkhani, Saman Edwards, Nancy A. Merrill, Marsha J. Ray-Chaudhury, Abhik Zhuang, Zhengping Lonser, Russell R. Oldfield, Edward H. Chittiboina, Prashant TI Loss of Quiescence in von Hippel-Lindau Hemangioblastomas is Associated with Erythropoietin Signaling SO SCIENTIFIC REPORTS LA English DT Article ID NATURAL-HISTORY; DISEASE; RECEPTOR; CELL; VHL AB von Hippel-Lindau (VHL) patients develop multiple central nervous system hemangioblastomas (HB). Some HBs become symptomatic with exponential growth or cyst formation following long periods of quiescence. Understanding the factors underlying growth in hemangioblastoma may lead to better strategies to arrest or prevent tumor growth. In 5 VHL patients, we resected quiescent hemangioblastomas (Q-HB) that were en-route during surgical access to symptomatic hemangioblastomas (S-HB), for matched tumor analysis. Quantitative reverse transcriptase analysis demonstrated a 2-fold increase in EPO expression in all S-HB, while 4/5 showed either Hypoxia Inducible Factor-1 alpha or 2 alpha upregulation. Additionally, all S-HB had increased phosphorylated erythropoietin (EPO) receptor and phosphorylated STAT-5 relative to matched Q-HB, with increased phosphorylated JAK-2 largely confined to the stromal cells in clusters within the tumors. These findings suggest that Q-HB to S-HB conversion may be associated with an erythropoietin-signaling loop. Furthermore, we found that EPO is detectable in cyst fluid from S-HB (n = 14), while absent in CSF (n = 1). Additionally, S-HB presentation or S-HB resection does not result in discernible change in serum EPO or hemoglobin (n = 60). These observations suggest that the altered erythropoietin signaling is focal and suggests that studying modulation of erythropoietin receptor pathway may lead to strategies in preventing HB growth. C1 [Feldman, Michael J.; Sizdahkhani, Saman; Edwards, Nancy A.; Merrill, Marsha J.; Ray-Chaudhury, Abhik; Zhuang, Zhengping; Lonser, Russell R.; Oldfield, Edward H.; Chittiboina, Prashant] NINDS, Surg Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Oldfield, Edward H.] Ohio State Univ, Wexner Med Ctr, Dept Neurol Surg, Columbus, OH USA. [Oldfield, Edward H.] Univ Virginia, Hlth Sci Ctr, Dept Neurosurg, Charlottesville, VA 22908 USA. RP Chittiboina, P (reprint author), NINDS, Surg Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM prashant.chittiboina@nih.gov FU Intramural Research Program of the National Institute of Neurological Diseases and Stroke; NIH Medical Research Scholars Program; Doris Duke Charitable Foundation; Alexandria Real Estate Equities, Inc.; Howard Hughes Medical Institute; Pfizer, Inc.; NIH FX This work was funded by the Intramural Research Program of the National Institute of Neurological Diseases and Stroke. The study was also supported by the NIH Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from Pfizer, Inc., The Doris Duke Charitable Foundation, The Alexandria Real Estate Equities, Inc. and Mr. and Mrs. Joel S. Marcus and the Howard Hughes Medical Institute, as well as other private donors. For a complete list, please visit the Foundation at: http://fnih.org/work/education-training-0/medical-research-scholarsprogr am. NR 18 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD OCT 17 PY 2016 VL 6 AR 35486 DI 10.1038/srep35486 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DY9NB UT WOS:000385459600001 PM 27748427 ER PT J AU Fu, LZ Wen, L Luu, N Shi, YB AF Fu, Liezhen Wen, Luan Luu, Nga Shi, Yun-Bo TI A simple and efficient method to visualize and quantify the efficiency of chromosomal mutations from genome editing SO SCIENTIFIC REPORTS LA English DT Article ID XENOPUS-TROPICALIS; GENE DISRUPTION; THYROID-HORMONE; TALEN; ENDONUCLEASE; CRISPR/CAS9; INTEGRATION; NUCLEASES; CELL; DNA AB Genome editing with designer nucleases such as TALEN and CRISPR/Cas enzymes has broad applications. Delivery of these designer nucleases into organisms induces various genetic mutations including deletions, insertions and nucleotide substitutions. Characterizing those mutations is critical for evaluating the efficacy and specificity of targeted genome editing. While a number of methods have been developed to identify the mutations, none other than sequencing allows the identification of the most desired mutations, i.e., out-of-frame insertions/deletions that disrupt genes. Here we report a simple and efficient method to visualize and quantify the efficiency of genomic mutations induced by genome-editing. Our approach is based on the expression of a two-color fusion protein in a vector that allows the insertion of the edited region in the genome in between the two color moieties. We show that our approach not only easily identifies developing animals with desired mutations but also efficiently quantifies the mutation rate in vivo. Furthermore, by using LacZ alpha and GFP as the color moieties, our approach can even eliminate the need for a fluorescent microscope, allowing the analysis with simple bright field visualization. Such an approach will greatly simplify the screen for effective genome-editing enzymes and identify the desired mutant cells/animals. C1 [Fu, Liezhen; Wen, Luan; Luu, Nga; Shi, Yun-Bo] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Morphogenesis, NIH, 18 Lib Dr, Bethesda, MD 20892 USA. RP Shi, YB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Morphogenesis, NIH, 18 Lib Dr, Bethesda, MD 20892 USA. EM Shi@helix.nih.gov FU Intramural Research Program of NICHD, NIH FX This work was supported by the Intramural Research Program of NICHD, NIH. NR 17 TC 0 Z9 0 U1 12 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD OCT 17 PY 2016 VL 6 AR 35488 DI 10.1038/srep35488 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DY9NB UT WOS:000385459600003 PM 27748423 ER PT J AU Ren, JS Murphy, G Fan, JH Dawsey, SM Taylor, PR Selhub, J Qiao, YL Abnet, CC AF Ren, Jiansong Murphy, Gwen Fan, Jinhu Dawsey, Sanford M. Taylor, Philip R. Selhub, Jacob Qiao, Youlin Abnet, Christian C. TI Prospective study of serum B vitamins levels and oesophageal and gastric cancers in China SO SCIENTIFIC REPORTS LA English DT Article ID NUTRITION INTERVENTION; GENERAL-POPULATION; DIETARY-FOLATE; HUMAN-PLASMA; RISK; RIBOFLAVIN; COHORT; SUPPLEMENTATION; TRIAL; HOMOCYSTEINE AB B vitamins play an essential role in DNA synthesis and methylation, and may protect against oesophageal and gastric cancers. In this case-cohort study, subjects were enrolled from the General Population Nutrition Intervention Trial in Linxian, China. Subjects included 498 oesophageal squamous cell carcinomas (OSCCs), 255 gastric cardia adenocarcinomas (GCAs), and an age-and sex-matched sub-cohort of 947 individuals. Baseline serum riboflavin, pyridoxal phosphate (PLP), folate, vitamin B12, and flavin mononucleotide (FMN) were measured for all subjects. We estimated the associations with Cox proportional hazard models, with adjustment for potential confounders. Compared to those in the lowest quartile of serum riboflavin, those in the highest had a 44% lower risk of OSCC (HR: 0.56, 95% CI: 0.41 to 0.75). Serum vitamin B12 as a continuous variable was observed to be significantly inversely associated with OSCC (HR: 0.95, 95% CI: 0.89 to 1.01, P for score test = 0.041). Higher serum FMN levels were significantly associated with increased risk of OSCC (HR: 1.08, 95% CI: 1.01 to 1.16) and GCA (HR: 1.09, 95% CI: 1.00 to 1.20). Our study prompted that B vitamins have the potential role as chemopreventive agents for upper gastrointestinal cancers. C1 [Ren, Jiansong] Chinese Acad Med Sci, Natl Canc Ctr, Canc Hosp, Program Off Canc Screening Urban China, Beijing, Peoples R China. [Ren, Jiansong; Fan, Jinhu; Qiao, Youlin] Peking Union Med Coll, Beijing, Peoples R China. [Ren, Jiansong; Murphy, Gwen; Dawsey, Sanford M.; Taylor, Philip R.; Abnet, Christian C.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Fan, Jinhu; Qiao, Youlin] Chinese Acad Med Sci, Canc Hosp, Natl Canc Ctr, Dept Epidemiol, Beijing, Peoples R China. [Selhub, Jacob] Tufts Univ, Jean Mayer US Dept Agr, Human Nutr Res Ctr Aging, Boston, MA 02111 USA. RP Qiao, YL (reprint author), Peking Union Med Coll, Beijing, Peoples R China.; Abnet, CC (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA.; Qiao, YL (reprint author), Chinese Acad Med Sci, Canc Hosp, Natl Canc Ctr, Dept Epidemiol, Beijing, Peoples R China. EM qiaoy@cicams.ac.cn; abnetc@mail.nih.gov RI Abnet, Christian/C-4111-2015 OI Abnet, Christian/0000-0002-3008-7843 FU Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute, NIH; NIH [N01-SC-91030, HHSN261200477001C]; National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences FX This work was supported in part by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute, NIH, and in part by NIH contracts N01-SC-91030 and HHSN261200477001C with the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences. NR 27 TC 0 Z9 0 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD OCT 17 PY 2016 VL 6 AR 35281 DI 10.1038/srep35281 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DY8CI UT WOS:000385355700002 PM 27748414 ER PT J AU Liu, C Rodriguez, K Yao, HHC AF Liu, Chang Rodriguez, Karina Yao, Humphrey H. -C. TI Mapping lineage progression of somatic progenitor cells in the mouse fetal testis SO DEVELOPMENT LA English DT Article DE Testis; Lineage specification; Sertoli cells; Leydig cells; Notch; Hedgehog ID ADULT LEYDIG-CELLS; SUPPRESSOR PROTEIN WT1; MALE SEX DETERMINATION; WILMS-TUMOR GENE; SERTOLI-CELLS; RAT TESTIS; COUP-TFII; TESTOSTERONE PRODUCTION; POSTNATAL-DEVELOPMENT; GONAD DEVELOPMENT AB Testis morphogenesis is a highly orchestrated process involving lineage determination of male germ cells and somatic cell types. Although the origin and differentiation of germ cells are known, the developmental course specific for each somatic cell lineage has not been clearly defined. Here, we construct a comprehensive map of somatic cell lineage progression in the mouse testis. Both supporting and interstitial cell lineages arise from WT1(+) somatic progenitor pools in the gonadal primordium. A subpopulation of WT1(+) progenitor cells acquire SOX9 expression and become Sertoli cells that form testis cords, whereas the remaining WT1(+) cells contribute to progenitor cells in the testis interstitium. Interstitial progenitor cells diversify through the acquisition of HES1, an indication of Notch activation, at the onset of sex determination. HES1(+) interstitial progenitors, through the action of Sertoli cell-derived Hedgehog signals, become positive for GLI1. The GLI1(+) interstitial cells eventually develop into two cell lineages: steroid-producing fetal Leydig cells and non-steroidogenic cells. The fetal Leydig cell population is restricted by Notch2 signaling from the neighboring somatic cells. The non-steroidogenic progenitor cells retain their undifferentiated state during fetal stage and become adult Leydig cells in post-pubertal testis. These results provide the first lineage progression map that illustrates the sequential establishment of somatic cell populations during testis morphogenesis. C1 [Liu, Chang; Rodriguez, Karina; Yao, Humphrey H. -C.] NIEHS, Reprod & Dev Biol Grp, Durham, NC 27709 USA. [Liu, Chang] NHLBI, Genet & Dev Biol Ctr, Bethesda, MD 20892 USA. RP Yao, HHC (reprint author), NIEHS, Reprod & Dev Biol Grp, Durham, NC 27709 USA. EM humphrey.yao@nih.gov RI Yao, Humphrey Hung-Chang/B-4795-2010; OI Yao, Humphrey Hung-Chang/0000-0003-2944-8469; Liu, Chang/0000-0002-8723-7363 FU National Institutes of Health (NIH) National Institute of Environmental Health Sciences [ES102965]; NIH Graduate Partnerships Program FX This work was supported by the Intramural Research Program (ES102965) of the National Institutes of Health (NIH) National Institute of Environmental Health Sciences and NIH Graduate Partnerships Program. Deposited in PMC for release after 12 months. NR 86 TC 2 Z9 2 U1 1 U2 1 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 EI 1477-9129 J9 DEVELOPMENT JI Development PD OCT 15 PY 2016 VL 143 IS 20 BP 3700 EP 3710 DI 10.1242/dev.135756 PG 11 WC Developmental Biology SC Developmental Biology GA EJ8CQ UT WOS:000393452500006 PM 27621062 ER PT J AU Breman, JG Heymann, DL Lloyd, G McCormick, JB Miatudila, M Murphy, FA Muyembe-Tamfun, JJ Piot, P Ruppol, JF Sureau, P van der Groen, G Johnson, KM AF Breman, Joel G. Heymann, David L. Lloyd, Graham McCormick, Joseph B. Miatudila, Malonga Murphy, Frederick A. Muyembe-Tamfun, Jean-Jacques Piot, Peter Ruppol, Jean-Francois Sureau, Pierre van der Groen, Guido Johnson, Karl M. TI Discovery and Description of Ebola Zaire Virus in 1976 and Relevance to the West African Epidemic During 2013-2016 SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Discovery of Ebola Zaire virus; Ebola virus disease; Ebola in 1976 and 2013-2016 ID HEMORRHAGIC-FEVER; SIERRA-LEONE; DISEASE; ANIMALS; GUINEA; CONGO AB Background. In 1976, the first cases of Ebola virus disease in northern Democratic Republic of the Congo (then referred to as Zaire) were reported. This article addresses who was responsible for recognizing the disease; recovering, identifying, and naming the virus; and describing the epidemic. Key scientific approaches used in 1976 and their relevance to the 3-country (Guinea, Sierra Leone, and Liberia) West African epidemic during 2013-2016 are presented. Methods.aEuro integral Field and laboratory investigations started soon after notification, in mid-September 1976, and included virus cell culture, electron microscopy (EM), immunofluorescence antibody (IFA) testing of sera, case tracing, containment, and epidemiological surveys. In 2013-2016, medical care and public health work were delayed for months until the Ebola virus disease epidemic was officially declared an emergency by World Health Organization, but research in pathogenesis, clinical presentation, including sequelae, treatment, and prevention, has increased more recently. Results.aEuro integral Filoviruses were cultured and observed by EM in Antwerp, Belgium (Institute of Tropical Medicine); Porton Down, United Kingdom (Microbiological Research Establishment); and Atlanta, Georgia (Centers for Disease Control and Prevention). In Atlanta, serological testing identified a new virus. The 1976 outbreak (280 deaths among 318 cases) stopped in < 11 weeks, and basic clinical and epidemiological features were defined. The recent massive epidemic during 2013-2016 (11 310 deaths among 28 616 cases) has virtually stopped after > 2 years. Transmission indices (R-0) are higher in all 3 countries than in 1976. Conclusions.aEuro integral An international commission working harmoniously in laboratories and with local communities was essential for rapid success in 1976. Control and understanding of the recent West African outbreak were delayed because of late recognition and because authorities were overwhelmed by many patients and poor community involvement. Despite obstacles, research was a priority in 1976 and recently. C1 [Breman, Joel G.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [McCormick, Joseph B.] Univ Texas Sch Publ Hlth, Brownsville Campus, Houston, TX USA. [Murphy, Frederick A.] Univ Texas, Dept Pathol, Galveston, TX USA. [Miatudila, Malonga] World Bank, Hlth Populat & Nutr, 1818 H St NW, Washington, DC 20433 USA. [Johnson, Karl M.] Ctr Dis Control & Prevent, Special Pathogens Branch, Atlanta, GA USA. [Heymann, David L.] Chatham House Ctr Global Hlth Secur, Porton Down, England. [Heymann, David L.; Piot, Peter] London Sch Hyg & Trop Med, Porton Down, England. [Lloyd, Graham] Med Res Estab, Off Director, Porton Down, England. [Muyembe-Tamfun, Jean-Jacques] Inst Natl Rech Med, Kinshasa, DEM REP CONGO. [Ruppol, Jean-Francois] Fonds Med Trop, Kinshasa, DEM REP CONGO. [Sureau, Pierre] Inst Pasteur, Paris, France. [van der Groen, Guido] Inst Trop Med, Dept Microbiol, Antwerp, Belgium. RP Breman, JG (reprint author), NIH, Fogarty Int Ctr, Fogarty Ctr, Bldg 16,Rm 214,16 Ctr Dr,MSC 6705, Bethesda, MD 20892 USA. EM bremanj@nih.gov FU Fogarty International Center at the National Institutes of Health FX This work was supported by the Fogarty International Center at the National Institutes of Health. NR 40 TC 0 Z9 0 U1 2 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 15 PY 2016 VL 214 SU 3 BP S93 EP S101 DI 10.1093/infdis/jiw207 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DZ8VA UT WOS:000386148800001 PM 27357339 ER PT J AU Chiramel, AI Banadyga, L Dougherty, JD Falzarano, D Martellaro, C Brees, D Taylor, RT Ebihara, H Best, SM AF Chiramel, Abhilash I. Banadyga, Logan Dougherty, Jonathan D. Falzarano, Darryl Martellaro, Cynthia Brees, Dominique Taylor, R. Travis Ebihara, Hideki Best, Sonja M. TI Alisporivir Has Limited Antiviral Effects Against Ebola Virus Strains Makona and Mayinga SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE alisporivir; Ebola virus; cyclophilin A; antivirals; flavivirus ID CYCLOSPORINE; REPLICATION; CYCLOPHILINS; COMBINATION; INFECTION AB Antiviral therapeutics with existing clinical safety profiles would be highly desirable in an outbreak situation, such as the 2013-2016 emergence of Ebola virus (EBOV) in West Africa. Although, the World Health Organization declared the end of the outbreak early 2016, sporadic cases of EBOV infection have since been reported. Alisporivir is the most clinically advanced broad-spectrum antiviral that functions by targeting a host protein, cyclophilin A (CypA). A modest antiviral effect of alisporivir against contemporary (Makona) but not historical (Mayinga) EBOV strains was observed in tissue culture. However, this effect was not comparable to observations for an alisporivir-susceptible virus, the flavivirus tick-borne encephalitis virus. Thus, EBOV does not depend on (CypA) for replication, in contrast to many other viruses pathogenic to humans. C1 [Chiramel, Abhilash I.; Banadyga, Logan; Dougherty, Jonathan D.; Falzarano, Darryl; Martellaro, Cynthia; Taylor, R. Travis; Ebihara, Hideki; Best, Sonja M.] NIAID, Lab Virol, NIH, Rocky Mt Labs, Hamilton, MT USA. [Taylor, R. Travis] Univ Toledo, Coll Med, Dept Med Microbiol & Immunol, Hlth Sci Campus, Toledo, OH 43606 USA. [Falzarano, Darryl] Univ Saskatchewan, Vaccine & Infect Dis Org, Int Vaccine Ctr, Saskatoon, SK, Canada. [Brees, Dominique] Novartis Pharmaceut, Basel, Switzerland. RP Chiramel, AI (reprint author), Rocky Mt Labs, 903 S 4th St, Hamilton, MT 59840 USA. EM abhilash.chiramel@nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 17 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 15 PY 2016 VL 214 SU 3 BP S355 EP S359 DI 10.1093/infdis/jiw241 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DZ8VA UT WOS:000386148800036 PM 27511894 ER PT J AU Chiramel, AI Dougherty, JD Nair, V Robertson, SJ Best, SM AF Chiramel, Abhilash I. Dougherty, Jonathan D. Nair, Vinod Robertson, Shelly J. Best, Sonja M. TI FAM134B, the Selective Autophagy Receptor for Endoplasmic Reticulum Turnover, Inhibits Replication of Ebola Virus Strains Makona and Mayinga SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Ebolavirus; selective autophagy; ER-phagy; reticulon; FAM134B; mouse models; virus replication ID MATRIX PROTEIN VP40; HEMORRHAGIC-FEVER; INFECTION; SYSTEM; GLYCOPROTEIN; MACAQUES; MARBURG; BODIES; ZAIRE AB Selective autophagy of the endoplasmic reticulum (termed ER-phagy) is controlled by members of the FAM134 reticulon protein family. Here we used mouse embryonic fibroblasts from mice deficient in FAM134B to examine the role of the ER in replication of historic (Mayinga) or contemporary (Makona GCO7) strains of Ebola virus (EBOV). Loss of FAM134B resulted in 1-2 log(10) higher production of infectious EBOV, which was associated with increased production of viral proteins GP and VP40 and greater accumulation of nucleocaspid lattices. In addition, only 10% of wild-type cells contained detectable nucleoprotein, whereas knockout of FAM134B resulted in 80% of cells positive for nucleoprotein. Together, these data suggest that FAM134B-dependent ER-phagy is an important limiting event in EBOV replication in mouse cells and may have implications for further development of antiviral therapeutics and murine models of infection. C1 [Chiramel, Abhilash I.; Dougherty, Jonathan D.; Robertson, Shelly J.; Best, Sonja M.] NIAID, Lab Virol, NIH, Rocky Mt Labs, Hamilton, MT USA. [Nair, Vinod] NIAID, Res Technol Branch, NIH, Rocky Mt Labs, Hamilton, MT USA. RP Chiramel, AI (reprint author), NIAID, Virol Lab, NIH, 903 S,Fourth St, Hamilton, MT 59840 USA. EM abhilash.chiramel@nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 26 TC 2 Z9 2 U1 2 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 15 PY 2016 VL 214 SU 3 BP S319 EP S325 DI 10.1093/infdis/jiw270 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DZ8VA UT WOS:000386148800032 PM 27511895 ER PT J AU Cnops, L Van den Eede, P Pettitt, J Heyndrickx, L De Smet, B Coppens, S Andries, I Pattery, T Van Hove, L Meersseman, G Van den Herrewegen, S Vergauwe, N Thijs, R Jahrling, PB Nauwelaers, D Arien, KK AF Cnops, Lieselotte Van den Eede, Peter Pettitt, James Heyndrickx, Leo De Smet, Birgit Coppens, Sandra Andries, Ilse Pattery, Theresa Van Hove, Luc Meersseman, Geert Van den Herrewegen, Sari Vergauwe, Nicolas Thijs, Rein Jahrling, Peter B. Nauwelaers, David Arien, Kevin K. TI Development, Evaluation, and Integration of a Quantitative Reverse-Transcription Polymerase Chain Reaction Diagnostic Test for Ebola Virus on a Molecular Diagnostics Platform SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Ebolavirus; diagnosis; EBOV; SUDV; RT-PCR; outbreak ID POINT-OF-CARE; VIRAL LOAD; HEMORRHAGIC-FEVER; REACTION ASSAYS; UNITED-STATES; SIERRA-LEONE; DISEASE; OUTBREAK; PCR; TIME AB Background. The 2013-2016 Ebola epidemic in West Africa resulted in accelerated development of rapid diagnostic tests for emergency outbreak preparedness. We describe the development and evaluation of the Idylla T prototype Ebola virus test, a fully automated sample-to-result molecular diagnostic test for rapid detection of Zaire ebolavirus (EBOV) and Sudan ebolavirus (SUDV). Methods.aEuro integral The Idylla (TM) prototype Ebola virus test can simultaneously detect EBOV and SUDV in 200 A mu L of whole blood. The sample is directly added to a disposable cartridge containing all reagents for sample preparation, RNA extraction, and amplification by reverse-transcription polymerase chain reaction analysis. The performance was evaluated with a variety of sample types, including synthetic constructs and whole blood samples from healthy volunteers spiked with viral RNA, inactivated virus, and infectious virus. Results.aEuro integral The 95% limits of detection for EBOV and SUDV were 465 plaque-forming units (PFU)/mL (1010 copies/mL) and 324 PFU/mL (8204 copies/mL), respectively. In silico and in vitro analyses demonstrated 100% correct reactivity for EBOV and SUDV and no cross-reactivity with relevant pathogens. The diagnostic sensitivity was 97.4% (for EBOV) and 91.7% (for SUDV), the specificity was 100%, and the diagnostic accuracy was 95.9%. Conclusions.aEuro integral The Idylla (TM) prototype Ebola virus test is a fast, safe, easy-to-use, and near-patient test that meets the performance criteria to detect EBOV in patients with suspected Ebola. C1 [Cnops, Lieselotte; De Smet, Birgit] Inst Trop Med, Dept Clin Sci, Antwerp, Belgium. [Heyndrickx, Leo; Coppens, Sandra; Arien, Kevin K.] Inst Trop Med, Dept Biomed Sci, Antwerp, Belgium. [Van den Eede, Peter; Andries, Ilse; Pattery, Theresa] Janssen Pharmaceut, Janssen Diagnost, Beerse, Belgium. [Van den Eede, Peter; Van Hove, Luc; Meersseman, Geert; Van den Herrewegen, Sari; Vergauwe, Nicolas; Thijs, Rein; Nauwelaers, David] Biocartis, Mechelen, Belgium. [Pettitt, James; Jahrling, Peter B.] NIAID, Integrated Res Facil, NIH, Frederick, MD USA. RP Arien, KK (reprint author), Inst Trop Med, Natl Str 155, B-2000 Antwerp, Belgium. EM karien@itg.be FU Agency for Innovation by Science and Technology, Flemish Government; Janssen Diagnostics, Janssen Pharmaceutica; Biocartis FX This work was supported in part by the Agency for Innovation by Science and Technology, Flemish Government (to L. C. and K. K. A.); Janssen Diagnostics, Janssen Pharmaceutica; and Biocartis. NR 31 TC 1 Z9 1 U1 3 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 15 PY 2016 VL 214 SU 3 BP S192 EP S202 DI 10.1093/infdis/jiw150 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DZ8VA UT WOS:000386148800013 PM 27247341 ER PT J AU de Wit, E Rosenke, K Fischer, RJ Marzi, A Prescott, J Bushmaker, T van Doremalen, N Emery, SL Falzarano, D Feldmann, F Groseth, A Hoenen, T Juma, B McNally, KL Ochieng, M Omballa, V Onyango, CO Owuor, C Rowe, T Safronetz, D Self, J Williamson, BN Zemtsova, G Grolla, A Kobinger, G Rayfield, M Stroher, U Strong, JE Best, SM Ebihara, H Zoon, KC Nichol, ST Nyenswah, TG Bolay, FK Massaquoi, M Feldmann, H Fields, B AF de Wit, Emmie Rosenke, Kyle Fischer, Robert J. Marzi, Andrea Prescott, Joseph Bushmaker, Trenton van Doremalen, Neeltje Emery, Shannon L. Falzarano, Darryl Feldmann, Friederike Groseth, Allison Hoenen, Thomas Juma, Bonventure McNally, Kristin L. Ochieng, Melvin Omballa, Victor Onyango, Clayton O. Owuor, Collins Rowe, Thomas Safronetz, David Self, Joshua Williamson, Brandi N. Zemtsova, Galina Grolla, Allen Kobinger, Gary Rayfield, Mark Stroher, Ute Strong, James E. Best, Sonja M. Ebihara, Hideki Zoon, Kathryn C. Nichol, Stuart T. Nyenswah, Tolbert G. Bolay, Fatorma K. Massaquoi, Moses Feldmann, Heinz Fields, Barry TI Ebola Laboratory Response at the Eternal Love Winning Africa Campus, Monrovia, Liberia, 2014-2015 SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Ebola virus; West Africa; epidemic; mobile laboratory; diagnostics ID SEXUAL TRANSMISSION; SIERRA-LEONE; WEST-AFRICA; VIRUS; OUTBREAK; MANAGEMENT; DISEASE AB West Africa experienced the first epidemic of Ebola virus infection, with by far the greatest number of cases in Guinea, Sierra Leone, and Liberia. The unprecedented epidemic triggered an unparalleled response, including the deployment of multiple Ebola treatment units and mobile/field diagnostic laboratories. The National Institute of Allergy and Infectious Diseases and the Centers for Disease Control and Prevention deployed a joint laboratory to Monrovia, Liberia, in August 2014 to support the newly founded Ebola treatment unit at the Eternal Love Winning Africa (ELWA) campus. The laboratory operated initially out of a tent structure but quickly moved into a fixed-wall building owing to severe weather conditions, the need for increased security, and the high sample volume. Until May 2015, when the laboratory closed, the site handled close to 6000 clinical specimens for Ebola virus diagnosis and supported the medical staff in case patient management. Laboratory operation and safety, as well as Ebola virus diagnostic assays, are described and discussed; in addition, lessons learned for future deployments are reviewed. C1 [de Wit, Emmie; Rosenke, Kyle; Fischer, Robert J.; Marzi, Andrea; Prescott, Joseph; Bushmaker, Trenton; van Doremalen, Neeltje; Falzarano, Darryl; Groseth, Allison; Hoenen, Thomas; McNally, Kristin L.; Safronetz, David; Williamson, Brandi N.; Best, Sonja M.; Ebihara, Hideki; Feldmann, Heinz] NIAID, Virol Lab, NIH, Hamilton, MT USA. [Feldmann, Friederike] NIAID, Rocky Mt Vet Branch, Div Intramural Res, NIH, Hamilton, MT USA. [Emery, Shannon L.; Rowe, Thomas; Self, Joshua; Zemtsova, Galina; Rayfield, Mark; Stroher, Ute; Nichol, Stuart T.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Zoon, Kathryn C.] NIAID, Cytokine Biol Sect, Div Intramural Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Juma, Bonventure; Onyango, Clayton O.; Fields, Barry] Ctr Dis Control & Prevent, Ctr Global Hlth, Div Global Hlth Protect, Nairobi, Kenya. [Ochieng, Melvin; Omballa, Victor; Owuor, Collins] Kenya Govt Med Res Ctr, Ctr Global Hlth Res, Nairobi, Kenya. [Grolla, Allen; Kobinger, Gary; Strong, James E.] Publ Hlth Agcy Canada, Special Pathogens Program, Winnipeg, MB, Canada. [Nyenswah, Tolbert G.; Massaquoi, Moses] Minist Hlth & Social Welf, Monrovia, Liberia. [Bolay, Fatorma K.] Liberian Inst Biomed Res, Charlesville, Liberia. [Falzarano, Darryl] Univ Saskatchewan, Int Vaccine Ctr, Vaccine & Infect Dis Org, Saskatoon, SK, Canada. [Safronetz, David] Publ Hlth Agcy Canada, Winnipeg, MB, Canada. [Groseth, Allison; Hoenen, Thomas] Friedrich Loffler Inst, Greifswald, Germany. RP Feldmann, H (reprint author), NIAID, Virol Lab, DIR, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM feldmannh@niaid.nih.gov OI de Wit, Emmie/0000-0002-9763-7758 FU Intramural Research Program of the NIAID, NIH; CDC FX This work was supported by the Intramural Research Program of the NIAID, NIH, and by the CDC. NR 27 TC 3 Z9 3 U1 2 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 15 PY 2016 VL 214 SU 3 BP S169 EP S176 DI 10.1093/infdis/jiw216 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DZ8VA UT WOS:000386148800010 PM 27333914 ER PT J AU de Wit, E Kramer, S Prescott, J Rosenke, K Falzarano, D Marzi, A Fischer, RJ Safronetz, D Hoenen, T Groseth, A van Doremalen, N Bushmaker, T McNally, KL Feldmann, F Williamson, BN Best, SM Ebihara, H Damiani, IAC Adamson, B Zoon, KC Nyenswah, TG Bolay, FK Massaquoi, M Sprecher, A Feldmann, H Munster, VJ AF de Wit, Emmie Kramer, Shelby Prescott, Joseph Rosenke, Kyle Falzarano, Darryl Marzi, Andrea Fischer, Robert J. Safronetz, David Hoenen, Thomas Groseth, Allison van Doremalen, Neeltje Bushmaker, Trenton McNally, Kristin L. Feldmann, Friederike Williamson, Brandi N. Best, Sonja M. Ebihara, Hideki Damiani, Igor A. C. Adamson, Brett Zoon, Kathryn C. Nyenswah, Tolbert G. Bolay, Fatorma K. Massaquoi, Moses Sprecher, Armand Feldmann, Heinz Munster, Vincent J. TI Clinical Chemistry of Patients With Ebola in Monrovia, Liberia SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Ebola virus; clinical chemistry; West Africa ID OUTCOMES; VIRUS AB The development of point-of-care clinical chemistry analyzers has enabled the implementation of these ancillary tests in field laboratories in resource-limited outbreak areas. The Eternal Love Winning Africa (ELWA) outbreak diagnostic laboratory, established in Monrovia, Liberia, to provide Ebola virus and Plasmodium spp. diagnostics during the Ebola epidemic, implemented clinical chemistry analyzers in December 2014. Clinical chemistry testing was performed for 68 patients in triage, including 12 patients infected with Ebola virus and 18 infected with Plasmodium spp. The main distinguishing feature in clinical chemistry of Ebola virus-infected patients was the elevation in alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and gamma-glutamyltransferase levels and the decrease in calcium. The implementation of clinical chemistry is probably most helpful when the medical supportive care implemented at the Ebola treatment unit allows for correction of biochemistry derangements and on-site clinical chemistry analyzers can be used to monitor electrolyte balance. C1 [de Wit, Emmie; Kramer, Shelby; Prescott, Joseph; Rosenke, Kyle; Falzarano, Darryl; Marzi, Andrea; Fischer, Robert J.; Safronetz, David; Hoenen, Thomas; Groseth, Allison; van Doremalen, Neeltje; Bushmaker, Trenton; McNally, Kristin L.; Feldmann, Friederike; Williamson, Brandi N.; Best, Sonja M.; Ebihara, Hideki; Feldmann, Heinz; Munster, Vincent J.] NIAID, Lab Virol, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. [Zoon, Kathryn C.] NIAID, Cytokine Biol Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Damiani, Igor A. C.; Adamson, Brett; Sprecher, Armand] Med Sans Frontieres, Operat Ctr Brussels, Ixelles, Belgium. [Nyenswah, Tolbert G.; Massaquoi, Moses] Minist Hlth & Social Welf IMS, Greater Monrovia, Liberia. [Bolay, Fatorma K.] Liberian Inst Biomed Res, Charlesville, Liberia. [Falzarano, Darryl] Univ Saskatchewan, Vaccine & Infect Dis Org, Int Vaccine Ctr, Saskatoon, SK, Canada. [Safronetz, David] Publ Hlth Agcy Canada, Winnipeg, MB, Canada. [Hoenen, Thomas; Groseth, Allison] Friedrich Loeffler Inst, Greifswald, Germany. RP Munster, VJ (reprint author), NIAID, Rocky Mt Labs, NIH, 903 S,4th St, Hamilton, MT 59840 USA. EM vincent.munster@nih.gov OI de Wit, Emmie/0000-0002-9763-7758 FU Intramural Research Program of the NIAID, NIH FX The work was supported by the Intramural Research Program of the NIAID, NIH. NR 9 TC 1 Z9 1 U1 2 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 15 PY 2016 VL 214 SU 3 BP S303 EP S307 DI 10.1093/infdis/jiw187 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DZ8VA UT WOS:000386148800030 PM 27471319 ER PT J AU Diarra, B Safronetz, D Sarro, YDS Kone, A Sanogo, M Tounkara, S Togo, ACG Daou, F Maiga, AI Dao, S Rosenke, K Falzarano, D Doumbia, S Zoon, KC Polis, M Siddiqui, S Sow, S Schwan, TG Feldmann, H Diallo, S Koita, OA AF Diarra, Bassirou Safronetz, David Sarro, Yeya Dit Sadio Kone, Amadou Sanogo, Moumine Tounkara, Sady Togo, Antieme C. G. Daou, Fatoumata Maiga, Almoustapha I. Dao, Sounkalo Rosenke, Kyle Falzarano, Darryl Doumbia, Seydou Zoon, Kathryn C. Polis, Michael Siddiqui, Sophia Sow, Samba Schwan, Tom G. Feldmann, Heinz Diallo, Souleyman Koita, Ousmane A. TI Laboratory Response to 2014 Ebola Virus Outbreak in Mali SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Ebola virus; West Africa; epidemic; Mali; diagnostics ID PATIENT-MANAGEMENT; SURVEILLANCE; SUPPORT; UNIT AB Aware of the rapid spread of Ebola virus (EBOV) during the current West African epidemic, Mali took several proactive steps to rapidly identify cases within its borders. Under the Mali International Center for Excellence in Research program, a collaboration between the National Institute of Allergy and Infectious Diseases and the Malian Ministry of Higher Education and Scientific Research established a national EBOV diagnostic site at the University of Sciences, Techniques and Technologies of Bamako in the SEREFO Laboratory. Two separate introductions of EBOV occurred in Mali from neighboring Guinea, but both chains of transmission were quickly halted, and Mali was declared "Ebola free" on 18 January 2015 and has remained so since. The SEREFO Laboratory was instrumental in the success of Mali's Ebola response by providing timely and accurate diagnostics. As of today, the SEREFO Laboratory has tested 103 samples from 88 suspected cases, 10 of which were EBOV positive, since the Ebola diagnostics unit started in April 2014. The establishment of Ebola diagnostics in the SEREFO Laboratory, safety precautions, and diagnostics are described. C1 [Diarra, Bassirou; Sarro, Yeya Dit Sadio; Kone, Amadou; Sanogo, Moumine; Tounkara, Sady; Togo, Antieme C. G.; Daou, Fatoumata; Maiga, Almoustapha I.; Dao, Sounkalo; Doumbia, Seydou; Diallo, Souleyman; Koita, Ousmane A.] Univ Sci Tech & Technol Bamako, Fac Sci & Technol, Univ Clin Res Ctr, SEREFO Lab, Bamako, Mali. [Safronetz, David; Rosenke, Kyle; Falzarano, Darryl; Feldmann, Heinz] NIAID, Virol Lab, NIH, Hamilton, MT USA. [Schwan, Tom G.] NIAID, Lab Zoonot Pathogens, Div Intramural Res, NIH, Hamilton, MT USA. [Zoon, Kathryn C.] NIAID, Cytokine Biol Sect, Div Intramural Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Polis, Michael; Siddiqui, Sophia] NIAID, Div Clin Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Sow, Samba] Minist Hlth, Malian Ctr Dis Control, Ctr Natl Appui Lutte Malad, Ctr Operat Urgence,Malian Ctr Emergency Operat, Bamako, Mali. [Safronetz, David] Publ Hlth Agcy Canada, Natl Microbiol Lab, Winnipeg, MB, Canada. [Falzarano, Darryl] Univ Saskatchewan, Vaccine & Infect Dis Org, Int Vaccine Ctr, Saskatoon, SK, Canada. RP Safronetz, D (reprint author), Natl Microbiol Lab, 1015 Arlington St, Winnipeg, MB R3E 3R2, Canada. EM david.safronetz@phac-aspc.gc.ca FU Intramural Research Program of the NIAID, NIH, through the Mali International Center of Excellence in Research Program FX The work was supported by the Intramural Research Program of the NIAID, NIH, through the Mali International Center of Excellence in Research Program. NR 11 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 15 PY 2016 VL 214 SU 3 BP S164 EP S168 DI 10.1093/infdis/jiw200 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DZ8VA UT WOS:000386148800009 PM 27707892 ER PT J AU Fischer, RJ Bushmaker, T Judson, S Munster, VJ AF Fischer, Robert J. Bushmaker, Trenton Judson, Seth Munster, Vincent J. TI Comparison of the Aerosol Stability of 2 Strains of Zaire ebolavirus From the 1976 and 2013 Outbreaks SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Ebola virus; West Africa; aerosol; stability; Goldberg drum ID CYNOMOLGUS MACAQUES; RHESUS MACAQUES; VIRUS; TRANSMISSION; DISEASE; INFECTION; MONKEYS AB The largest outbreak of Ebola virus disease began in Gu,ck,dou, Guinea, West Africa, in December 2013 and rapidly spread to major population centers in 3 West African countries. Early reports in some scientific and public media speculated that the virus had evolved to more effectively transmit between humans. One route of transmission postulated was aerosol transmission, although there was little epidemiological evidence to support this claim. This study investigates the viability of 2 Zaire ebolavirus strains within aerosols at 22A degrees C and 80% relative humidity over time. The results presented here indicate that there is no difference in virus stability between the 2 strains and that viable virus can be recovered from an aerosol 180 minutes after it is generated. C1 [Fischer, Robert J.; Bushmaker, Trenton; Munster, Vincent J.] NIAID, Lab Virol, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. [Judson, Seth] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90024 USA. RP Munster, VJ (reprint author), NIAID, Virus Ecol Sect, Virol Lab, NIH, 903 S Fourth S, Hamilton, MT 59840 USA. EM munstervj@niaid.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 23 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 15 PY 2016 VL 214 SU 3 BP S290 EP S293 DI 10.1093/infdis/jiw193 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DZ8VA UT WOS:000386148800027 PM 27503365 ER PT J AU Johnson, RF Kurup, D Hagen, KR Fisher, C Keshwara, R Papaneri, A Perry, DL Cooper, K Jahrling, PB Wang, JT ter Meulen, J Wirblich, C Schnell, MJ AF Johnson, Reed F. Kurup, Drishya Hagen, Katie R. Fisher, Christine Keshwara, Rohan Papaneri, Amy Perry, Donna L. Cooper, Kurt Jahrling, Peter B. Wang, Jonathan T. ter Meulen, Jan Wirblich, Christoph Schnell, Matthias J. TI An Inactivated Rabies Virus-Based Ebola Vaccine, FILORAB1, Adjuvanted With Glucopyranosyl Lipid A in Stable Emulsion Confers Complete Protection in Nonhuman Primate Challenge Models SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Ebola; vaccine; rabies; nonhuman primate; GLA-SE; protection; challenge model ID RESPIRATORY-TRACT; VECTORED VACCINE; GLYCOPROTEIN; INFECTION; IMMUNOGENICITY; IMMUNITY; DISEASE; GLA; TRANSMISSION; IMMUNIZATION AB The 2013-2016 West African Ebola virus (EBOV) disease outbreak was the largest filovirus outbreak to date. Over 28 000 suspected, probable, or confirmed cases have been reported, with a 53% case-fatality rate. The magnitude and international impact of this EBOV outbreak has highlighted the urgent need for a safe and efficient EBOV vaccine. To this end, we demonstrate the immunogenicity and protective efficacy of FILORAB1, a recombinant, bivalent, inactivated rabies virus-based EBOV vaccine, in rhesus and cynomolgus monkeys. Our results demonstrate that the use of the synthetic Toll-like receptor 4 agonist glucopyranosyl lipid A in stable emulsion (GLA-SE) as an adjuvant increased the efficacy of FILORAB1 to 100% protection against lethal EBOV challenge, with no to mild clinical signs of disease. Furthermore, all vaccinated subjects developed protective anti-rabies virus antibody titers. Taken together, these results support further development of FILORAB1/GLA-SE as an effective preexposure EBOV vaccine. C1 [Johnson, Reed F.; Papaneri, Amy; Jahrling, Peter B.] NIAID, Emerging Viral Pathogens Sect, NIH, Ft Detrick, MD USA. [Hagen, Katie R.; Perry, Donna L.; Cooper, Kurt; Jahrling, Peter B.] NIAID, Integrated Res Facil, NIH, Ft Detrick, MD USA. [Kurup, Drishya; Fisher, Christine; Keshwara, Rohan; Wirblich, Christoph; Schnell, Matthias J.] Thomas Jefferson Univ, Sidney Kimmel Med Coll, Dept Microbiol & Immunol, Philadelphia, PA 19107 USA. [Schnell, Matthias J.] Thomas Jefferson Univ, Jefferson Vaccine Ctr, Philadelphia, PA 19107 USA. [Wang, Jonathan T.] Thermo Fisher Sci, Genet Sci, San Francisco, CA USA. [ter Meulen, Jan] Immune Design, San Francisco, CA USA. [ter Meulen, Jan] Immune Design, Seattle, WA USA. RP Schnell, MJ (reprint author), Thomas Jefferson Univ, 233 S 10th St,BLSB,Ste 531, Philadelphia, PA 19107 USA. EM matthias.schnell@jefferson.edu FU National Institute of Allergy and Infectious Diseases (NIAID) [R01AI105204]; Jefferson Vaccine Center; NIAID Division of Intramural Research; NIAID Division of Clinical Research; Battelle Memorial Institute; NIAID [HHSN272200700016I] FX This work was supported by the National Institute of Allergy and Infectious Diseases (NIAID; grant R01AI105204 to M. J. S.), the Jefferson Vaccine Center, the NIAID Division of Intramural Research, the NIAID Division of Clinical Research, and through Battelle Memorial Institute's prime contract with the NIAID (contract HHSN272200700016I). NR 49 TC 1 Z9 1 U1 2 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 15 PY 2016 VL 214 SU 3 BP S342 EP S354 DI 10.1093/infdis/jiw231 PG 13 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DZ8VA UT WOS:000386148800035 PM 27456709 ER PT J AU Marzi, A Hanley, PW Haddock, E Martellaro, C Kobinger, G Feldmann, H AF Marzi, Andrea Hanley, Patrick W. Haddock, Elaine Martellaro, Cynthia Kobinger, Gary Feldmann, Heinz TI Efficacy of Vesicular Stomatitis Virus-Ebola Virus Postexposure Treatment in Rhesus Macaques Infected With Ebola Virus Makona SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Ebola virus; VSV-EBOV; postexposure treatment; rhesus macaque ID NONHUMAN-PRIMATES; CYNOMOLGUS MACAQUES; VACCINE; PROGRESSION; PROTECTION; ANTIBODIES; CHALLENGE; OUTBREAK; DISEASE; STRAIN AB The Ebola virus (EBOV) epidemic in West Africa increased the focus on vaccine development against this hemorrhagic fever-causing pathogen, and as a consequence human clinical trials for a few selected platforms were accelerated. One of these vaccines is vesicular stomatitis virus (VSV)-EBOV, also known as rVSV-ZEBOV, a fast-acting vaccine against EBOV and so far the only vaccine with reported efficacy against EBOV infections in humans in phase III clinical trials. In this study, we analyzed the potential of VSV-EBOV for postexposure treatment of rhesus macaques infected with EBOV-Makona. We treated groups of animals with 1 dose of VSV-EBOV either in a single injection at 1 or 24 hours after EBOV exposure or with 2 injections, half the dose at each time point; 1 control group received the same dose of the VSV-based Marburg virus vaccine at both time points; another group remained untreated. Although all untreated animals succumbed to EBOV infection, 33%-67% of the animals in each treatment group survived the infection, including the group treated with the VSV-based Marburg virus vaccine. This result suggests that protection from postexposure vaccination may be antigen unspecific and due rather to an early activation of the innate immune system. In conclusion, VSV-EBOV remains a potent and fast-acting prophylactic vaccine but demonstrates only limited efficacy in postexposure treatment. C1 [Marzi, Andrea; Haddock, Elaine; Martellaro, Cynthia; Feldmann, Heinz] NIAID, Lab Virol, Rocky Mt Labs, NIH, Hamilton, MT USA. [Hanley, Patrick W.] NIAID, Rocky Mt Vet Branch, Rocky Mt Labs, NIH, Hamilton, MT USA. [Kobinger, Gary] Publ Hlth Agcy Canada, Natl Microbiol Lab, Special Pathogens Program, Winnipeg, MB, Canada. RP Marzi, A (reprint author), Rocky Mt Labs, Virol Lab, 903 S Fourth St, Hamilton, MT 59840 USA. EM marzia@niaid.nih.gov FU Division of Intramural Research, NIAID, NIH; Public Health Agency of Canada FX This work was supported by the Division of Intramural Research, NIAID, NIH, and the Public Health Agency of Canada. NR 33 TC 2 Z9 2 U1 8 U2 8 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 15 PY 2016 VL 214 SU 3 BP S360 EP S366 DI 10.1093/infdis/jiw218 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DZ8VA UT WOS:000386148800037 PM 27496978 ER PT J AU Miller, MR McMinn, RJ Misra, V Schountz, T Muller, MA Kurth, A Munster, VJ AF Miller, Megan R. McMinn, Rebekah J. Misra, Vikram Schountz, Tony Mueller, Marcel A. Kurth, Andreas Munster, Vincent J. TI Broad and Temperature Independent Replication Potential of Filoviruses on Cells Derived From Old and New World Bat Species SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE filovirus; bats; replication; temperature; Ebola virus; Marburg virus ID EBOLA-VIRUS; ROUSETTUS-AEGYPTIACUS; FRUIT BATS; MARBURG VIRUS; EXPERIMENTAL INOCULATION; RESERVOIR HOSTS; FLIGHT; INFECTION; FEVER AB Filoviruses are strongly associated with several species of bats as their natural reservoirs. In this study, we determined the replication potential of all filovirus species: Marburg marburgvirus, Ta < Forest ebolavirus, Reston ebolavirus, Sudan ebolavirus, Zaire ebolavirus, and Bundibugyo ebolavirus. Filovirus replication was supported by all cell lines derived from 6 Old and New World bat species: the hammer-headed fruit bat, Buettikofer's epauletted fruit bat, the Egyptian fruit bat, the Jamaican fruit bat, the Mexican free-tailed bat and the big brown bat. In addition, we showed that Marburg virus Angola and Ebola virus Makona-WPGC07 efficiently replicated at 37A degrees C, 37A degrees-41A degrees C, or 41A degrees C, contrary to the hypothesis that temporal elevation in temperature due to flight affects filovirus replication in bats. C1 [Miller, Megan R.; McMinn, Rebekah J.; Munster, Vincent J.] NIAID, Lab Virol, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. [Schountz, Tony] Colorado State Univ, Dept Microbiol Immunol & Pathol, Arthropod Borne & Infect Dis Lab, Ft Collins, CO 80523 USA. [Misra, Vikram] Univ Saskatchewan, Western Coll Vet Med, Dept Microbiol, Saskatoon, SK, Canada. [Mueller, Marcel A.] Univ Bonn, Med Ctr, Inst Virol, Bonn, Germany. [Kurth, Andreas] Robert Koch Inst, Ctr Biol Threats & Special Pathogens, Biosafety Level Lab 4, Berlin, Germany. RP Munster, VJ (reprint author), Rocky Mt Labs, 903 S 4th St, Hamilton, MT 59840 USA. EM vincent.munster@nih.gov OI Mueller, Marcel/0000-0003-2242-5117 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health; Intramural NIAID Research Opportunities program; EU-FP7 ANTIGONE [278976] FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health. Megan Miller is supported by the Intramural NIAID Research Opportunities program. Bat cells (EpoNi/22.1/22.1, HypNi/1.1/1.1) were generated within the framework of EU-FP7 ANTIGONE (no. 278976) and the German Research Council (DR 772/10-1, MU 3564/1-1). NR 32 TC 0 Z9 0 U1 4 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 15 PY 2016 VL 214 SU 3 BP S297 EP S302 DI 10.1093/infdis/jiw199 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DZ8VA UT WOS:000386148800029 PM 27354372 ER PT J AU Phan, JC Pettitt, J George, JS Fakoli, LS Taweh, FM Bateman, SL Bennett, RS Norris, SL Spinnler, DA Pimentel, G Sahr, PK Bolay, FK Schoepp, RJ AF Phan, Jill C. Pettitt, James George, Josiah S. Fakoli, Lawrence S., III Taweh, Fahn M. Bateman, Stacey L. Bennett, Richard S. Norris, Sarah L. Spinnler, David A. Pimentel, Guillermo Sahr, Phillip K. Bolay, Fatorma K. Schoepp, Randal J. TI Lateral Flow Immunoassays for Ebola Virus Disease Detection in Liberia SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Ebola; EBOV; Ebola virus disease; EVD; diagnostics; lateral flow; immunoassay; LFI; antibodies; Liberia; West Africa ID HEMORRHAGIC-FEVER; OUTBREAK AB Background. Lateral flow immunoassays (LFIs) are point-of-care diagnostic assays that are designed for single use outside a formal laboratory, with in-home pregnancy tests the best-known example of these tests. Although the LFI has some limitations over more-complex immunoassay procedures, such as reduced sensitivity and the potential for false-positive results when using complex sample matrices, the assay has the benefits of a rapid time to result and ease of use. These benefits make it an attractive option for obtaining rapid results in an austere environment. In an outbreak of any magnitude, a field-based rapid diagnostic assay would allow proper patient transport and for safe burials to be conducted without the delay caused by transport of samples between remote villages and testing facilities. Use of such point-of-care instruments in the ongoing Ebola virus disease (EVD) outbreak in West Africa would have distinct advantages in control and prevention of local outbreaks, but proper understanding of the technology and interpretation of results are important. Methods.aEuro integral In this study, a LFI, originally developed by the Naval Medical Research Center for Ebola virus environmental testing, was evaluated for its ability to detect the virus in clinical samples in Liberia. Clinical blood and plasma samples and post mortem oral swabs submitted to the Liberian Institute for Biomedical Research, the National Public Health Reference Laboratory for EVD testing, were tested and compared to results of real-time reverse transcription-polymerase chain reaction (rRT-PCR), using assays targeting Ebola virus glycoprotein and nucleoprotein. Results.aEuro integral The LFI findings correlated well with those of the real-time RT-PCR assays used as benchmarks. Conclusions.aEuro integral Rapid antigen-detection tests such as LFIs are attractive alternatives to traditional immunoassays but have reduced sensitivity and specificity, resulting in increases in false-positive and false-negative results. An understanding of the strengths, weaknesses, and limitations of a particular assay lets the diagnostician choose the correct situation to use the correct assay and properly interpret the results. C1 [Phan, Jill C.; Spinnler, David A.; Pimentel, Guillermo] Naval Med Res Ctr, Biol Def Res Directorate, Ft Detrick, MD USA. [Pettitt, James; Bennett, Richard S.] NIH, Integrated Res Facil, Ft Detrick, MD USA. [Bateman, Stacey L.; Norris, Sarah L.; Schoepp, Randal J.] US Army Med Res Inst Infect Dis, 1425 Porter St, Ft Detrick, MD 21702 USA. [George, Josiah S.; Fakoli, Lawrence S., III; Taweh, Fahn M.; Sahr, Phillip K.; Bolay, Fatorma K.] Liberian Inst Biomed Res, Charlesville, Liberia. RP Schoepp, RJ (reprint author), US Army Med Res Inst Infect Dis, 1425 Porter St, Ft Detrick, MD 21702 USA. EM randal.j.schoepp.civ@mail.mil OI Bennett, Richard/0000-0002-7227-4831 FU Department of Defense Medical Countermeasure Systems-Critical Reagents Program; Defense Threat Reduction Agency-Cooperative Biological Engagement Program; Division of Global Emerging Infections Surveillance and Response System (GEIS) Operations at the Armed Forces Health Surveillance Center; Liberian Ministry of Health and Social Welfare; National Institute of Allergy and Infectious Diseases Integrated Research Facility; Battelle Memorial Institute FX This work was supported by the Department of Defense Medical Countermeasure Systems-Critical Reagents Program (to J. C. P., D. A. S., G. P., and R. J. S.), the Defense Threat Reduction Agency-Cooperative Biological Engagement Program (to J. C. P., S. L. B., S. L. N., D. A. S., G. P., and R. J. S.), the Division of Global Emerging Infections Surveillance and Response System (GEIS) Operations at the Armed Forces Health Surveillance Center (to R. J. S.), the Liberian Ministry of Health and Social Welfare (to J. S. G., L. S. F., F. M. T., P. K. S., and F. K. B.), the National Institute of Allergy and Infectious Diseases Integrated Research Facility, and Battelle Memorial Institute (to J. P. and R. S. B.). NR 15 TC 0 Z9 0 U1 4 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 15 PY 2016 VL 214 SU 3 BP S222 EP S228 DI 10.1093/infdis/jiw251 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DZ8VA UT WOS:000386148800017 PM 27443616 ER PT J AU Spengler, JR Lavender, KJ Martellaro, C Carmody, A Kurth, A Keck, JG Saturday, G Scott, DP Nichol, ST Hasenkrug, KJ Spiropoulou, CF Feldmann, H Prescott, J AF Spengler, Jessica R. Lavender, Kerry J. Martellaro, Cynthia Carmody, Aaron Kurth, Andreas Keck, James G. Saturday, Greg Scott, Dana P. Nichol, Stuart T. Hasenkrug, Kim J. Spiropoulou, Christina F. Feldmann, Heinz Prescott, Joseph TI Ebola Virus Replication and Disease Without Immunopathology in Mice Expressing Transgenes to Support Human Myeloid and Lymphoid Cell Engraftment SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Ebola; virus; hemorrhagic fever; humanized NSG-SGM3 mice; myeloid cell; immune response; immunopathology; flow cytometry ID HEMATOPOIETIC STEM-CELLS; DENDRITIC CELLS; HEMORRHAGIC-FEVER; MOUSE MODEL; IMMUNE-RESPONSES; MARBURG VIRUSES; INFECTION; PATHOGENESIS; PATHOLOGY; MONKEYS AB The study of Ebola virus (EBOV) pathogenesis in vivo has been limited to nonhuman primate models or use of an adapted virus to cause disease in rodent models. Herein we describe wild-type EBOV (Makona variant) infection of mice engrafted with human hematopoietic CD34(+) stem cells (Hu-NSG (TM)-SGM3 mice; hereafter referred to as SGM3 HuMice). SGM3 HuMice support increased development of myeloid immune cells, which are primary EBOV targets. In SGM3 HuMice, EBOV replicated to high levels, and disease was observed following either intraperitoneal or intramuscular inoculation. Despite the high levels of viral antigen and inflammatory cell infiltration in the liver, the characteristic histopathology of Ebola virus disease was not observed, and this absence of severe immunopathology may have contributed to the recovery and survival of some of the animals. Future investigations into the underlying mechanisms of the atypical disease presentation in SGM3 HuMice will provide additional insights into the immunopathogenesis of severe EBOV disease. C1 [Spengler, Jessica R.; Nichol, Stuart T.; Spiropoulou, Christina F.] Ctr Dis Control & Prevent, Viral Special Pathogens Branch, Div High Consequence Pathogens & Pathol, Atlanta, GA USA. [Lavender, Kerry J.; Hasenkrug, Kim J.] NIAID, Lab Persistent Viral Dis, NIH, Rocky Mt Labs, Hamilton, MT USA. [Martellaro, Cynthia; Feldmann, Heinz; Prescott, Joseph] NIAID, Lab Virol, NIH, Rocky Mt Labs, Hamilton, MT USA. [Carmody, Aaron] NIAID, Res Technol Branch, NIH, Rocky Mt Labs, Hamilton, MT USA. [Saturday, Greg; Scott, Dana P.] NIAID, Rocky Mt Vet Branch, NIH, Rocky Mt Labs, Hamilton, MT USA. [Keck, James G.] In Vivo Serv, Jackson Lab, Sacramento, CA USA. [Kurth, Andreas] Robert Koch Inst, Ctr Biol Threats & Special Pathogens, Berlin, Germany. RP Prescott, J (reprint author), Rocky Mt Labs, 903 S 4th St, Hamilton, MT 59840 USA. EM prescottjb@niaid.nih.gov OI Spengler, Jessica R./0000-0002-5383-0513 FU Centers for Disease Control and Prevention (CDC); CDC Research Participation Program; National Institutes of Health (NIH) Loan Repayment Program; Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH FX This work was supported by the Centers for Disease Control and Prevention (CDC; emerging infectious disease research core funds); the CDC Research Participation Program (to J. R. S., administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the CDC); the National Institutes of Health (NIH) Loan Repayment Program (award to J. R. S.); and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH. NR 35 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 15 PY 2016 VL 214 SU 3 BP S308 EP S318 DI 10.1093/infdis/jiw248 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DZ8VA UT WOS:000386148800031 PM 27601621 ER PT J AU Yoshida, R Muramatsu, S Akita, H Saito, Y Kuwahara, M Kato, D Changula, K Miyamoto, H Kajihara, M Manzoor, R Furuyama, W Marzi, A Feldmann, H Mweene, A Masumu, J Kapeteshi, J Muyembe-Tamfum, JJ Takada, A AF Yoshida, Reiko Muramatsu, Shino Akita, Hiroshi Saito, Yuji Kuwahara, Miwa Kato, Daisuke Changula, Katendi Miyamoto, Hiroko Kajihara, Masahiro Manzoor, Rashid Furuyama, Wakako Marzi, Andrea Feldmann, Heinz Mweene, Aaron Masumu, Justin Kapeteshi, Jimmy Muyembe-Tamfum, Jean-Jacques Takada, Ayato TI Development of an Immunochromatography Assay (QuickNavi-Ebola) to Detect Multiple Species of Ebolaviruses SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Ebola virus; ebolavirus; EVD; filovirus; nucleoprotein; monoclonal antibody; immunochromatography assay; diagnosis ID VIRUS DISEASE; NUCLEOPROTEIN; ANTIBODIES; BUNDIBUGYO; DIAGNOSIS; MACAQUES; AFRICA; STRAIN AB The latest outbreak of Ebola virus disease (EVD) in West Africa has highlighted the urgent need for the development of rapid and reliable diagnostic assays. We used monoclonal antibodies specific to the ebolavirus nucleoprotein to develop an immunochromatography (IC) assay (QuickNavi-Ebola) for rapid diagnosis of EVD. The IC assay was first evaluated with tissue culture supernatants of infected Vero E6 cells and found to be capable of detecting 10(3)-10(4) focus-forming units/mL of ebolaviruses. Using serum samples from experimentally infected nonhuman primates, we confirmed that the assay could detect the viral antigen shortly after disease onset. It was also noted that multiple species of ebolaviruses could be detected by the IC assay. Owing to the simplicity of the assay procedure and absence of requirements for special equipment and training, QuickNavi-Ebola is expected to be a useful tool for rapid diagnosis of EVD. C1 [Yoshida, Reiko; Miyamoto, Hiroko; Kajihara, Masahiro; Manzoor, Rashid; Furuyama, Wakako; Takada, Ayato] Hokkaido Univ, Res Ctr Zoonosis Control, Div Global Epidemiol, Sapporo, Hokkaido, Japan. [Takada, Ayato] Hokkaido Univ, Global Stn Zoonosis Control, Global Inst Collaborat Res & Educ, Sapporo, Hokkaido, Japan. [Muramatsu, Shino; Akita, Hiroshi; Saito, Yuji; Kuwahara, Miwa; Kato, Daisuke] Denka Seiken, Niigata, Japan. [Changula, Katendi; Mweene, Aaron; Takada, Ayato] Univ Zambia, Sch Vet Med, Lusaka, Zambia. [Marzi, Andrea; Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. [Masumu, Justin; Kapeteshi, Jimmy; Muyembe-Tamfum, Jean-Jacques] Inst Natl Rech Biomed, Kinshasa, DEM REP CONGO. [Masumu, Justin] Univ Pedag Natl, Fac Med Vet, Kinshasa, DEM REP CONGO. RP Takada, A (reprint author), Hokkaido Univ, Div Global Epidemiol, Res Ctr Zoonosis Control, Kita Ku, Kita 20,Nishi 10, Sapporo, Hokkaido 0010020, Japan. EM atakada@czc.hokudai.ac.jp FU Agency for Medical Research and Development; Japan International Cooperation Agency; Health Sciences Division, Minister's Secretariat, Ministry of Health, Labor, and Welfare, Japan (Health and Labor Sciences Research Grant); Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Agency for Medical Research and Development and the Japan International Cooperation Agency within the framework of the Science and Technology Research Partnership for Sustainable Development; the Health Sciences Division, Minister's Secretariat, Ministry of Health, Labor, and Welfare, Japan (Health and Labor Sciences Research Grant); and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 21 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 15 PY 2016 VL 214 SU 3 BP S185 EP S191 DI 10.1093/infdis/jiw252 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DZ8VA UT WOS:000386148800012 PM 27462094 ER PT J AU Tweedie, D Rachmany, L Kim, DS Rubovitch, V Lehrmann, E Zhang, YQ Becker, KG Perez, E Pick, CG Greig, NH AF Tweedie, David Rachmany, Lital Kim, Dong Seok Rubovitch, Vardit Lehrmann, Elin Zhang, Yongqing Becker, Kevin G. Perez, Evelyn Pick, Chaim G. Greig, Nigel H. TI Mild traumatic brain injury-induced hippocampal gene expressions: The identification of target cellular processes for drug development SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE Mild traumatic brain injury (mTBI); Gene expression; Gene ontology; Molecular pathway; Inflammation; Neurological; Neurodegeneration; Dementia ID GLUCAGON-LIKE PEPTIDE-1; REVERSES BEHAVIORAL IMPAIRMENTS; ALZHEIMERS-DISEASE; RECEPTOR AGONIST; HEAD-INJURY; MICE; EXENDIN-4; DONEPEZIL; RATS; NEURONS AB Background: Neurological dysfunction after traumatic brain injury (TBI) poses short-term or long-lasting health issues for family members and health care providers. Presently there are no approved medicines to treat TBI. Epidemiological evidence suggests that TBI may cause neurodegenerative disease later in life. In an effort to illuminate target cellular processes for drug development, we examined the effects of a mild TBI on hippocampal gene expression in mouse. Methods: mTBI was induced in a closed head, weight drop-system in mice (ICR). Animals were anesthetized and subjected to mTBI (30 g). Fourteen days after injury the ipsilateral hippocampus was utilized for cDNA gene array studies. mTBI animals were compared with sham-operated animals. Genes regulated by TBI were identified to define TBI-induced physiological/pathological processes. mTBI regulated genes were divided into functional groupings to provide gene ontologies. Genes were further divided to identify molecular/cellular pathways regulated by mTBI. Results: Numerous genes were regulated after a single mTBI event that mapped to many ontologies and molecular pathways related to inflammation and neurological physiology/pathology, including neurodegenerative disease. Conclusions: These data illustrate diverse transcriptional changes in hippocampal tissues triggered by a single mild injury. The systematic analysis of individual genes that lead to the identification of functional categories, such as gene ontologies and then molecular pathways, illustrate target processes of relevance to TBI pathology. These processes may be further dissected to identify key factors that can be evaluated at the protein level to highlight possible treatments for TBI in human disease and potential biomarkers of neurodegenerative processes. Published by Elsevier B.V. C1 [Tweedie, David; Kim, Dong Seok; Greig, Nigel H.] NIA, Translat Gerontol Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Rachmany, Lital; Rubovitch, Vardit; Pick, Chaim G.] Tel Aviv Univ, Sackler Sch Med, Dept Anat & Anthropol, IL-69978 Tel Aviv, Israel. [Pick, Chaim G.] Tel Aviv Univ, Sagol Sch Neurosci, IL-69978 Tel Aviv, Israel. [Kim, Dong Seok] Peptron Inc, 37-24 Yuseong Daero,1628 Beon Gil, Daejeon 305811, South Korea. [Lehrmann, Elin; Zhang, Yongqing; Becker, Kevin G.] NIA, Genet Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Perez, Evelyn] NIA, Lab Behav Neurosci, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Tweedie, D (reprint author), NIA, Translat Gerontol Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM tweedieda@grc.nia.nih.gov FU Intramural Research Program of the National Institute on Aging, National Institutes of Health; Sackler School of Medicine, Tel-Aviv University; Ari and Regine Aprijaskis Fund at Tel-Aviv University; Israel Science Foundation [108/09]; Joseph Sagol fellowships; National Science Council of Taiwan FX This research was supported in part by (i) the Intramural Research Program of the National Institute on Aging, National Institutes of Health, (ii) the Sackler School of Medicine, Tel-Aviv University, (iii) the Ari and Regine Aprijaskis Fund at Tel-Aviv University, (iv) a grant from the Israel Science Foundation, grant number 108/09, (v) and the Joseph Sagol fellowships and (vi) the National Science Council of Taiwan. This work was performed in partial fulfillment of the requirements for a Ph.D. degree of Lital Rachmany, Sackler Faculty of Medicine, Tel Aviv University, Israel. None of the authors have competing interests in the manuscript. NR 76 TC 1 Z9 1 U1 3 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 EI 1872-678X J9 J NEUROSCI METH JI J. Neurosci. Methods PD OCT 15 PY 2016 VL 272 SI SI BP 4 EP 18 DI 10.1016/j.jneumeth.2016.02.003 PG 15 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA EA6LF UT WOS:000386740000002 PM 26868732 ER PT J AU Roux, A Muller, L Jackson, SN Post, J Baldwin, K Hoffer, B Balaban, CD Barbacci, D Schultz, A Gouty, S Cox, BM Woods, AS AF Roux, Aurelie Muller, Ludovic Jackson, Shelley N. Post, Jeremy Baldwin, Katherine Hoffer, Barry Balaban, Carey D. Barbacci, Damon Schultz, Albert Gouty, Shawn Cox, Brian M. Woods, Amina S. TI Mass spectrometry imaging of rat brain lipid profile changes over time following traumatic brain injury SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE Traumatic brain injury; Controlled cortical impact; Mass spectrometry imaging; Silver nanoparticles implantation; Lipids ID POSTTRAUMATIC EPILEPSY; CHOLESTEROL-METABOLISM; SILVER NANOPARTICLES; PHOSPHOLIPASE-C; CERAMIDE; DISEASE; MECHANISMS; SPHINGOMYELIN; APOPTOSIS; SECTIONS AB Background: Mild traumatic brain injury (TBI) is a common public health issue that may contribute to chronic degenerative disorders. Membrane lipids play a key role in tissue responses to injury, both as cell signals and as components of membrane structure and cell signaling. This study demonstrates the ability of high resolution mass spectrometry imaging (MSI) to assess sequences of responses of lipid species in a rat controlled cortical impact model for concussion. New method: A matrix of implanted silver nanoparticles was implanted superficially in brain sections for matrix-assisted laser desorption (MALDI) imaging of 50 mu m diameter microdomains across unfixed cryostat sections of rat brain. Ion-mobility time-of-flight MS was used to analyze and map changes over time in brain lipid composition in a rats after Controlled Cortical Impact (CCI) TBI. Results: Brain MS images showed changes in sphingolipids near the CCI site, including increased ceramides and decreased sphingomyelins, accompanied by changes in glycerophospholipids and cholesterol derivatives. The kinetics differed for each lipid class; for example ceramides increased as early as 1 day after the injury whereas other lipids changes occurred between 3 and 7 days post injury. Comparison with existing method(s): Silver nanoparticles MALDI matrix is a sensitive new tool for revealing previously undetectable cellular injury response and remodeling in neural, glial and vascular structure of the brain. Conclusions: Lipid biochemical and structural changes after TBI could help highlighting molecules that can be used to determine the severity of such injuries as well as to evaluate the efficacy of potential treatments. (C) 2016 Published by Elsevier B.V. C1 [Roux, Aurelie; Muller, Ludovic; Jackson, Shelley N.; Post, Jeremy; Baldwin, Katherine; Woods, Amina S.] NIDA, Struct Biol Unit, Integrat Neurosci Branch, NIH,IRP, Baltimore, MD 21224 USA. [Gouty, Shawn; Cox, Brian M.] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Dept Pharmacol, Bethesda, MD 20814 USA. [Barbacci, Damon; Schultz, Albert] Ionwerks Inc, Houston, TX 77002 USA. [Balaban, Carey D.] Univ Pittsburgh, Dept Otolaryngol, Pittsburgh, PA 15213 USA. [Balaban, Carey D.] Univ Pittsburgh, Dept Neurobiol, Pittsburgh, PA 15213 USA. [Balaban, Carey D.] Univ Pittsburgh, Dept Commun Sci & Disorders, Pittsburgh, PA 15213 USA. [Balaban, Carey D.] Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA 15213 USA. [Hoffer, Barry] Univ Hosp Cleveland, Cleveland, OH 44106 USA. RP Woods, AS (reprint author), NIDA, Struct Biol Unit, Integrat Neurosci Branch, NIH,IRP, Baltimore, MD 21224 USA. EM awoods@intra.nida.nih.gov FU U.S. Department of Defense; Center for Neuroscience and Regenerative Medicine (CNRM), Rockville, MD; Intramural Research Program of the National Institute on Drug Abuse, NIH; NIH SBIR Phase II [R44DA030853-03 5R44DA036263-03] FX The authors declare no competing financial interests. This work was supported in part by a grant from the U.S. Department of Defense and the Center for Neuroscience and Regenerative Medicine (CNRM), Rockville, MD and by the Intramural Research Program of the National Institute on Drug Abuse, NIH. Ionwerks gratefully acknowledges support of this work through NIH SBIR Phase II grants R44DA030853-03 5R44DA036263-03". The authors acknowledge Dr. Mari Prieto and Glen Gregory of the Thermo Fisher Corporation for technical and instrumentation advice. The authors also thank Gregory Bull for his technical support. The opinions and assertions contained herein are the personal opinions of the authors and are not to be construed as official or reflecting the views of the Uniformed Services University, the Department of Defense, NIDA or the NIH. NR 55 TC 4 Z9 4 U1 13 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 EI 1872-678X J9 J NEUROSCI METH JI J. Neurosci. Methods PD OCT 15 PY 2016 VL 272 SI SI BP 19 EP 32 DI 10.1016/j.jneumeth.2016.02.004 PG 14 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA EA6LF UT WOS:000386740000003 PM 26872743 ER PT J AU Chiu, CC Liao, YE Yang, LY Wang, JY Tweedie, D Karnati, HK Greig, NH Wang, JY AF Chiu, Chong-Chi Liao, Yi-En Yang, Ling-Yu Wang, Jing-Ya Tweedie, David Karnati, Hanuma K. Greig, Nigel H. Wang, Jia-Yi TI Neuroinflammation in animal models of traumatic brain injury SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE Traumatic brain injury (TBI); Neuroinflammation; Glia cells; Astrocytes; Microglia; Controlled cortical impact; Weight-drop impact; Lateralfluid percussion; Measurements evaluating neuroinflammation ID NECROSIS-FACTOR-ALPHA; CONTROLLED CORTICAL IMPACT; PEPTIDE-1 RECEPTOR AGONIST; FLUID PERCUSSION INJURY; CLOSED-HEAD INJURY; SPINAL-CORD-INJURY; SIGNALING PATHWAY; OXIDATIVE STRESS; GENE-EXPRESSION; CEREBRAL-CORTEX AB Traumatic brain injury (TBI) is a leading cause of mortality and morbidity worldwide. Neuroinflammation is prominent in the short and long-term consequences of neuronal injuries that occur after TBI. Neuroinflammation involves the activation of glia, including microglia and astrocytes, to release inflammatory mediators within the brain, and the subsequent recruitment of peripheral immune cells. Various animal models of TBI have been developed that have proved valuable to elucidate the pathophysiology of the disorder and to assess the safety and efficacy of novel therapies prior to clinical trials. These models provide an excellent platform to delineate key injury mechanisms that associate with types of injury (concussion, contusion, and penetration injuries) that occur clinically for the investigation of mild, moderate, and severe forms of TBI. Additionally, TBI modeling in genetically engineered mice, in particular, has aided the identification of key molecules and pathways for putative injury mechanisms, as targets for development of novel therapies for human TBI. This Review details the evidence showing that neuroinflammation, characterized by the activation of microglia and astrocytes and elevated production of inflammatory mediators, is a critical process occurring in various TBI animal models, provides a broad overview of commonly used animal models of TBI, and overviews representative techniques to quantify markers of the brain inflammatory process. A better understanding of neuroinflammation could open therapeutic avenues for abrogation of secondary cell death and behavioral symptoms that may mediate the progression of TBI. (C) 2016 Elsevier B.V. All rights reserved. C1 [Chiu, Chong-Chi] Chi Mei Med Ctr, Dept Gen Surg, Tainan, Taiwan. [Chiu, Chong-Chi] Chi Mei Med Ctr, Dept Gen Surg, Liouying, Taiwan. [Liao, Yi-En] Taipei Med Univ, Sch Pharm, Coll Pharm, Taipei, Taiwan. [Yang, Ling-Yu; Wang, Jing-Ya; Wang, Jia-Yi] Taipei Med Univ, Grad Inst Med Sci, Coll Med, 250 Wu Xing St, Taipei 110, Taiwan. [Tweedie, David; Karnati, Hanuma K.; Greig, Nigel H.] NIA, Drug Design & Dev Sect, Translat Gerontol Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Wang, Jia-Yi] Taipei Med Univ, Sch Med, Dept Physiol, Coll Med, Taipei, Taiwan. RP Wang, JY (reprint author), Taipei Med Univ, Grad Inst Med Sci, Coll Med, 250 Wu Xing St, Taipei 110, Taiwan. EM jywang2010@tmu.edu.tw FU Ministry of Science and Technology, Taiwan [MOST104-2923-B-038-001-MY3]; Chi Mei Medical Center, Tainan and Liouying, Taiwan [100CM-TMU-05]; Intramural Research Program of the National Institute on Aging, NIH, Baltimore, MD, USA FX This study was supported in part by (i) a grant (MOST104-2923-B-038-001-MY3) from the Ministry of Science and Technology, Taiwan; (ii) a grant (100CM-TMU-05) from Chi Mei Medical Center, Tainan and Liouying, Taiwan; and (iii) the Intramural Research Program of the National Institute on Aging, NIH, Baltimore, MD, USA. NR 145 TC 4 Z9 4 U1 5 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 EI 1872-678X J9 J NEUROSCI METH JI J. Neurosci. Methods PD OCT 15 PY 2016 VL 272 SI SI BP 38 EP 49 DI 10.1016/j.jneumeth.2016.06.018 PG 12 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA EA6LF UT WOS:000386740000005 PM 27382003 ER PT J AU Deselms, H Maggio, N Rubovitch, V Chapman, J Schreiber, S Tweedie, D Kim, DS Greig, NH Pick, CG AF Deselms, Hanna Maggio, Nicola Rubovitch, Vardit Chapman, Joab Schreiber, Shaul Tweedie, David Kim, Dong Seok Greig, Nigel H. Pick, Chaim G. TI Novel pharmaceutical treatments for minimal traumatic brain injury and evaluation of animal models and methodologies supporting their development SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE Traumatic brain injury; Animal models of TBI; Exendin-4; N-Acetyl-L-cycteine; Salubrinal; Thrombin ID GLUCAGON-LIKE PEPTIDE-1; PROTEASE-ACTIVATED RECEPTOR-1; ALPHA SYNTHESIS INHIBITOR; REVERSES BEHAVIORAL IMPAIRMENTS; AMYLOID-BETA-PEPTIDE; CLOSED-HEAD INJURY; TNF-ALPHA; COGNITIVE DEFICITS; NEURODEGENERATIVE DISEASES; SYNAPTIC PLASTICITY AB Background: The need for effective pharmaceuticals within animal models of traumatic brain injury (TBI) continues to be paramount, as TBI remains the major cause of brain damage for children and young adults. While preventative measures may act to reduce the incidence of initial blunt trauma, well-tolerated drugs are needed to target the neurologically damaging internal cascade of molecular mechanisms that follow. Such processes, known collectively as the secondary injury phase, include inflammation, excitotoxicity, and apoptosis among other changes still subject to research. In this article positive treatment findings to mitigate this secondary injury in rodent TBI models will be overviewed, and include recent studies on Exendin-4, N-Acetyl-L-cycteine, Salubrinal and Thrombin. Conclusions: These studies provide representative examples of methodologies that can be combined with widely available in vivo rodent models to evaluate therapeutic approaches of translational relevance, as well as drug targets and biochemical cascades that may slow or accelerate the degenerative processes induced by TBI. They employ well-characterized tests such as the novel object recognition task for assessing cognitive deficits. The application of such methodologies provides both decision points and a gateway for implementation of further translational studies to establish the feasibility of clinical efficacy of potential therapeutic interventions. (C) 2016 Elsevier B.V. All rights reserved. C1 [Deselms, Hanna; Rubovitch, Vardit; Pick, Chaim G.] Tel Aviv Univ, Dept Anat & Anthropol, Sackler Sch Med, Tel Aviv, Israel. [Maggio, Nicola; Chapman, Joab] Chaim Sheba Med Ctr, Dept Neurol, J Sagol Neurosci Ctr, Ramat Gan, Israel. [Maggio, Nicola] Chaim Sheba Med Ctr, Talpiot Med Leadership Program, Ramat Gan, Israel. [Maggio, Nicola; Chapman, Joab] Tel Aviv Univ, Sackler Sch Med, Dept Neurol, Tel Aviv, Israel. [Schreiber, Shaul] Tel Aviv Univ, Dept Psychiat, Tel Aviv Sourasky Med Ctr, Tel Aviv, Israel. [Schreiber, Shaul] Tel Aviv Univ, Sackler Fac Med, Tel Aviv, Israel. [Tweedie, David; Kim, Dong Seok; Greig, Nigel H.] NIA, Drug Design & Dev Sect, Translat Gerontol Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. RP Pick, CG (reprint author), Tel Aviv Univ, Dept Anat & Anthropol, Sackler Sch Med, Tel Aviv, Israel. EM pickc@post.tau.ac.il FU Intramural Research Program of the National Institute on Aging, National Institutes of Health; Ari and Regine Aprijaskis Fund at Tel-Aviv University; Israel Science Foundation [108/09] FX This research was supported in part by (i) the Intramural Research Program of the National Institute on Aging, National Institutes of Health, (ii) the Ari and Regine Aprijaskis Fund at Tel-Aviv University, and (iii) a grant from the Israel Science Foundation, grant number 108/09. NR 114 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 EI 1872-678X J9 J NEUROSCI METH JI J. Neurosci. Methods PD OCT 15 PY 2016 VL 272 SI SI BP 69 EP 76 DI 10.1016/j.jneumeth.2016.02.002 PG 8 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA EA6LF UT WOS:000386740000008 PM 26868733 ER PT J AU Clyde, MA Weber, RP Iversen, ES Poole, EM Doherty, JA Goodman, MT Ness, RB Risch, HA Rossing, MA Terry, KL Wentzensen, N Whittemore, AS Anton-Culver, H Bandera, EV Berchuck, A Carney, ME Cramer, DW Cunningham, JM Cushing-Haugen, KL Edwards, RP Fridley, BL Goode, EL Lurie, G McGuire, V Modugno, F Moysich, KB Olson, SH Pearce, CL Pike, MC Rothstein, JH Sellers, TA Sieh, W Stram, D Thompson, PJ Vierkant, RA Wicklund, KG Wu, AH Ziogas, A Tworoger, SS Schildkraut, JM AF Clyde, Merlise A. Weber, Rachel Palmieri Iversen, Edwin S. Poole, Elizabeth M. Doherty, Jennifer A. Goodman, Marc T. Ness, Roberta B. Risch, Harvey A. Rossing, Mary Anne Terry, Kathryn L. Wentzensen, Nicolas Whittemore, Alice S. Anton-Culver, Hoda Bandera, Elisa V. Berchuck, Andrew Carney, Michael E. Cramer, Daniel W. Cunningham, Julie M. Cushing-Haugen, Kara L. Edwards, Robert P. Fridley, Brooke L. Goode, Ellen L. Lurie, Galina McGuire, Valerie Modugno, Francesmary Moysich, Kirsten B. Olson, Sara H. Pearce, Celeste Leigh Pike, Malcolm C. Rothstein, Joseph H. Sellers, Thomas A. Sieh, Weiva Stram, Daniel Thompson, Pamela J. Vierkant, Robert A. Wicklund, Kristine G. Wu, Anna H. Ziogas, Argyrios Tworoger, Shelley S. Schildkraut, Joellen M. CA Ovarian Canc Assoc Consortium TI Risk Prediction for Epithelial Ovarian Cancer in 11 United States-Based Case-Control Studies: Incorporation of Epidemiologic Risk Factors and 17 Confirmed Genetic Loci SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE genetic risk polymorphisms; model evaluation; ovarian cancer; risk model ID SINGLE-NUCLEOTIDE POLYMORPHISMS; MENOPAUSAL HORMONE-THERAPY; BREAST-CANCER; SUSCEPTIBILITY LOCUS; REPLACEMENT THERAPY; TUBAL-LIGATION; METAANALYSIS; MODELS; WOMEN; VARIANTS AB Previously developed models for predicting absolute risk of invasive epithelial ovarian cancer have included a limited number of risk factors and have had low discriminatory power (area under the receiver operating characteristic curve (AUC) < 0.60). Because of this, we developed and internally validated a relative risk prediction model that incorporates 17 established epidemiologic risk factors and 17 genome-wide significant single nucleotide polymorphisms (SNPs) using data from 11 case-control studies in the United States (5,793 cases; 9,512 controls) from the Ovarian Cancer Association Consortium (data accrued from 1992 to 2010). We developed a hierarchical logistic regression model for predicting case-control status that included imputation of missing data. We randomly divided the data into an 80% training sample and used the remaining 20% for model evaluation. The AUC for the full model was 0.664. A reduced model without SNPs performed similarly (AUC = 0.649). Both models performed better than a baseline model that included age and study site only (AUC = 0.563). The best predictive power was obtained in the full model among women younger than 50 years of age (AUC = 0.714); however, the addition of SNPs increased the AUC the most for women older than 50 years of age (AUC = 0.638 vs. 0.616). Adapting this improved model to estimate absolute risk and evaluating it in prospective data sets is warranted. C1 [Clyde, Merlise A.; Iversen, Edwin S.] Duke Univ, Dept Stat Sci, Durham, NC USA. [Weber, Rachel Palmieri] Duke Univ, Sch Med, Dept Community & Family Med, Durham, NC USA. [Poole, Elizabeth M.; Tworoger, Shelley S.] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Poole, Elizabeth M.; Terry, Kathryn L.; Cramer, Daniel W.; Tworoger, Shelley S.] Harvard Med Sch, Boston, MA USA. [Doherty, Jennifer A.] Dartmouth Coll, Geisel Sch Med, Sect Biostat & Epidemiol, Dept Community & Family Med, Hanover, NH 03755 USA. [Goodman, Marc T.] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Canc Prevent & Control, Los Angeles, CA 90048 USA. [Goodman, Marc T.; Thompson, Pamela J.] Cedars Sinai Med Ctr, Dept Biomed Sci, Community & Populat Hlth Res Inst, Los Angeles, CA 90048 USA. [Ness, Roberta B.] Univ Texas Houston, Sch Publ Hlth, Houston, TX USA. [Risch, Harvey A.] Yale Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT USA. [Rossing, Mary Anne; Cushing-Haugen, Kara L.; Wicklund, Kristine G.] Fred Hutchinson Canc Res Ctr, Program Epidemiol, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Rossing, Mary Anne] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Terry, Kathryn L.; Cramer, Daniel W.; Tworoger, Shelley S.] Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Terry, Kathryn L.; Cramer, Daniel W.] Brigham & Womens Hosp, Obstet & Gynecol Epidemiol Ctr, 75 Francis St, Boston, MA 02115 USA. [Wentzensen, Nicolas] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Whittemore, Alice S.; McGuire, Valerie; Rothstein, Joseph H.] Stanford Univ, Sch Med, Dept Hlth Res & Policy Epidemiol, Stanford, CA 94305 USA. [Anton-Culver, Hoda; Ziogas, Argyrios] Univ Calif Irvine, Sch Med, Dept Epidemiol, Irvine, CA 92717 USA. [Bandera, Elisa V.] Rutgers Canc Inst New Jersey, Canc Prevent & Control Program, New Brunswick, NJ USA. [Berchuck, Andrew] Duke Univ, Sch Med, Dept Obstet & Gynecol, Durham, NC USA. [Carney, Michael E.] Univ Hawaii, John A Burns Sch Med, Dept Obstet & Gynecol, Honolulu, HI 96822 USA. [Cunningham, Julie M.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Edwards, Robert P.; Modugno, Francesmary] Univ Pittsburgh, Sch Med, Dept Obstet & Gynecol & Reprod Sci, Div Gynecol Oncol, Pittsburgh, PA USA. [Edwards, Robert P.; Modugno, Francesmary] Univ Pittsburgh, Ovarian Canc Ctr Excellence, Womens Canc Program, Magee Womens Res Inst,Canc Inst, Pittsburgh, PA USA. [Fridley, Brooke L.] Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. [Goode, Ellen L.] Mayo Clin, Dept Hlth Sci Res, Div Epidemiol, Rochester, MN USA. [Lurie, Galina] Univ Hawaii, Ctr Canc, Canc Epidemiol Program, Honolulu, HI 96822 USA. [Modugno, Francesmary] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Moysich, Kirsten B.] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Olson, Sara H.; Pike, Malcolm C.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Pearce, Celeste Leigh; Stram, Daniel; Wu, Anna H.] Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Pearce, Celeste Leigh] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Sellers, Thomas A.] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL USA. [Sieh, Weiva] Icahn Sch Med Mt Sinai, Dept Genet & Genome Sci, New York, NY 10029 USA. [Vierkant, Robert A.] Mayo Clin, Div Biomed Stat & Informat, Dept Hlth Sci Res, Rochester, MN USA. [Schildkraut, Joellen M.] Univ Virginia, Dept Publ Hlth Sci, POB 800765,560 Ray C Hunt Dr, Charlottesville, VA 22903 USA. RP Schildkraut, JM (reprint author), Univ Virginia, Dept Publ Hlth Sci, POB 800765,560 Ray C Hunt Dr, Charlottesville, VA 22903 USA. EM jms2yf@virginia.edu FU Genetic Associations and Mechanisms in Oncology (GAME-ON): a National Cancer Institute Cancer Post-Genome-Wide Association Study Initiative [U19-CA148112]; European Commission [223175-HEALTH-F2-2009-223175]; Ovarian Cancer Research Fund [PPD/RPCI.07]; Department of Defense Award [W81XWH-12-1-0561]; National Institutes of Health [1R21-ES020796-01, K07-CA080668, K07-CA095666, K07-CA143047, K22-CA138563]; National Science Foundation [DMS-1106891]; California Cancer Research Program [00-01389V-20170, 2II0200]; Cancer Prevention Institute of California; Department of Defense [DAMD17-02-1-0666, DAMD17-02-1-0669, W81XWH-10-1-02802]; Fred C. and Katherine B. Andersen Foundation; Lon V Smith Foundation [LVS-39420]; Mayo Foundation; Minnesota Ovarian Cancer Alliance; National Center for Research Resources/General Clinical Research Center [M01-RR000056, N01-CN025403, N01-CN55424, N01-PC67001, N01-PC67010, P01-CA17054, P30-CA14089, P30-CA15083, P30-CA072720, P50-CA105009, P50-CA136393, P50-CA159981, R01-CA058860, R01-CA074850, R01-CA080742]; Rutgers Cancer Institute of New Jersey; US Public Health Service [PSA-042205]; The National Center for Research Resources/General Clinical Research Center [R01-CA092044, R01-CA112523, R01-CA122443, R01-CA126841, R01-CA16056, R01-CA54419, R01-CA58598, R01-CA61132, R01-CA76016, R01-CA83918, R01-CA87538, R01-CA95023, R03-CA113148, R03-CA115195, U01-CA69417, U01-CA71966] FX The scientific development of and funding for this project were supported the Genetic Associations and Mechanisms in Oncology (GAME-ON): a National Cancer Institute Cancer Post-Genome-Wide Association Study Initiative (grant U19-CA148112). The Collaborative Oncological Gene-Environment Study is funded through a European Commission's Seventh Framework Programme grant (agreement number 223175-HEALTH-F2-2009-223175). The Ovarian Cancer Association Consortium is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (grant PPD/RPCI.07) and a Department of Defense Award (W81XWH-12-1-0561). M.A.C. and E.S.I. were supported by the National Institutes of Health (grant 1R21-ES020796-01); M.A.C. was additionally supported by the National Science Foundation (grant DMS-1106891). F.M. was supported by the National Institutes of Health (grant K07-CA080668); S.S.T. and E.M.P. were supported in part by a Department of Defense Award (W81XWH-12-1-0561). Funding of the constituent studies was provided by: the California Cancer Research Program (grants 00-01389V-20170 and 2II0200); the Cancer Prevention Institute of California; the Department of Defense (grants DAMD17-02-1-0666, DAMD17-02-1-0669, and W81XWH-10-1-02802); the Fred C. and Katherine B. Andersen Foundation; the Lon V Smith Foundation (grant LVS-39420); the Mayo Foundation; the Minnesota Ovarian Cancer Alliance; the National Institutes of Health (grants K07-CA095666, K07-CA143047, and K22-CA138563); the National Center for Research Resources/General Clinical Research Center (grant M01-RR000056, N01-CN025403, N01-CN55424, N01-PC67001, N01-PC67010, P01-CA17054, P30-CA14089, P30-CA15083, P30-CA072720, P50-CA105009, P50-CA136393, P50-CA159981, R01-CA058860, R01-CA074850, R01-CA080742, R01-CA092044, R01-CA112523, R01-CA122443, R01-CA126841, R01-CA16056, R01-CA54419, R01-CA58598, R01-CA61132, R01-CA76016, R01-CA83918, R01-CA87538, R01-CA95023, R03-CA113148, R03-CA115195, U01-CA69417, and U01-CA71966); the Rutgers Cancer Institute of New Jersey; and the US Public Health Service (grant PSA-042205). NR 66 TC 0 Z9 0 U1 4 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD OCT 15 PY 2016 VL 184 IS 8 BP 555 EP 569 DI 10.1093/aje/kww091 PG 15 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EA4BH UT WOS:000386552900001 ER PT J AU Xing, CH McCarthy, JM Dupuis, J Cupples, LA Meigs, JB Lin, XH Allen, AS AF Xing, Chuanhua McCarthy, Janice M. Dupuis, Josee Cupples, L. Adrienne Meigs, James B. Lin, Xihong Allen, Andrew S. TI Robust analysis of secondary phenotypes in case-control genetic association studies SO STATISTICS IN MEDICINE LA English DT Article DE case-control; estimating equation; inverse-probability-weighted; secondary phenotype; genetic association study ID BODY-MASS INDEX; FASTING BLOOD-GLUCOSE; ADULT HUMAN HEIGHT; COMMON VARIANT; LOCI; INITIATION; CHILDHOOD; OBESITY; DISEASE; RISK AB The case-control study is a common design for assessing the association between genetic exposures and a disease phenotype. Though association with a given (case-control) phenotype is always of primary interest, there is often considerable interest in assessing relationships between genetic exposures and other (secondary) phenotypes. However, the case-control sample represents a biased sample from the general population. As a result, if this sampling framework is not correctly taken into account, analyses estimating the effect of exposures on secondary phenotypes can be biased leading to incorrect inference. In this paper, we address this problem and propose a general approach for estimating and testing the population effect of a genetic variant on a secondary phenotype. Our approach is based on inverse probability weighted estimating equations, where the weights depend on genotype and the secondary phenotype. We show that, though slightly less efficient than a full likelihood-based analysis when the likelihood is correctly specified, it is substantially more robust to model misspecification, and can out-perform likelihood-based analysis, both in terms of validity and power, when the model is misspecified. We illustrate our approach with an application to a case-control study extracted from the Framingham Heart Study. Copyright (c) 2016 John Wiley & Sons, Ltd. C1 [Xing, Chuanhua; Dupuis, Josee; Cupples, L. Adrienne] Boston Univ, Dept Biostat, Sch Publ Hlth, Boston, MA 02118 USA. [McCarthy, Janice M.; Allen, Andrew S.] Duke Univ, Dept Biostat & Bioinformat, Durham, NC 27710 USA. [Dupuis, Josee; Cupples, L. Adrienne] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Meigs, James B.] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. [Lin, Xihong] Harvard Univ, Dept Biostat, Cambridge, MA 01238 USA. [Allen, Andrew S.] Duke Univ, Ctr Human Genome Variat, Durham, NC 27710 USA. RP Allen, AS (reprint author), Duke Univ, Dept Biostat & Bioinformat, Durham, NC 27710 USA. EM andrew.s.allen@duke.edu OI Dupuis, Josee/0000-0003-2871-3603 FU NIH [R01 DK078616, R01 MH084680] FX JBM and JD acknowledge funding through NIH grant R01 DK078616. ASA and CX acknowledge funding through NIH grant R01 MH084680. NR 20 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD OCT 15 PY 2016 VL 35 IS 23 BP 4226 EP 4237 DI 10.1002/sim.6976 PG 12 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA DW5YC UT WOS:000383722600010 PM 27241694 ER PT J AU Parikh, KS Coles, A Schulte, PJ Kraus, WE Fleg, JL Keteyian, SJ Pina, IL Fiuzat, M Whellan, DJ O'Connor, CM Mentz, RJ AF Parikh, Kishan S. Coles, Adrian Schulte, Phillip J. Kraus, William E. Fleg, Jerome L. Keteyian, Steven J. Pina, Ileana L. Fiuzat, Mona Whellan, David J. O'Connor, Christopher M. Mentz, Robert J. TI Relation of Angina Pectoris to Outcomes, Quality of Life, and Response to Exercise Training in Patients With Chronic Heart Failure (from HF-ACTION) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID DUKE DATA-BANK; STABLE ANGINA; ISCHEMIC CARDIOMYOPATHY; CARDIOVASCULAR-DISEASE; SYSTOLIC DYSFUNCTION; STOCKHOLM APSIS; POPULATION; PROGNOSIS; SYMPTOMS AB Angina pectoris (AP) is associated with worse outcomes in heart failure (HF). We investigated the association of AP with health-related quality of life (HRQoL), exercise capacity, and clinical outcomes and its interaction with exercise training in an HF population. We grouped 2,331 patients with HF with reduced ejection fraction in the Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) trial of usual care +/- exercise training according to whether they had self-reported AP by Canadian classification score. HRQoL and clinical outcomes were assessed by AP status. In HF-ACTION, 406 patients (17%) had AP at baseline (44% with Canadian classification score >= II) with HF severity similar to those without AP. Patients with AP had similar baseline exercise capacity but worse depressive symptoms and HRQoL. AP was associated with 22% greater adjusted risk for all-cause mortality/hospitalizations, driven by. hospitalizations. There was significant interaction between baseline AP and exercise training peak VO2 change (p = 0.019) but not other end points. Exercise training was associated with greater peak VO2 improvement after 3 months in patients with AP (treatment effect = 1.25 ml/kg/min, 95% CI 0.6 to 1.9). In conclusion, AP was associated with worse HRQoL and depressive symptoms. Despite greater peak VO2 improvement with exercise training, patients with AP experienced more adverse outcomes. (C) 2016 Elsevier Inc. All rights reserved. C1 [Parikh, Kishan S.; Coles, Adrian; Fiuzat, Mona; O'Connor, Christopher M.; Mentz, Robert J.] Duke Clin Res Inst, Durham, NC USA. [Parikh, Kishan S.; Kraus, William E.; Mentz, Robert J.] Duke Univ, Med Ctr, Dept Med, Div Cardiol, Durham, NC 27710 USA. [Schulte, Phillip J.] Mayo Clin, Div Cardiovasc Dis, Dept Med, Rochester, MN USA. [Fleg, Jerome L.] NHLBI, Div Cardiovasc Sci, Bldg 10, Bethesda, MD 20892 USA. [Keteyian, Steven J.] Henry Ford Hosp, Dept Med, Div Cardiovasc Med, Detroit, MI 48202 USA. [Pina, Ileana L.] Albert Einstein Coll Med, Dept Med, Div Cardiol, Bronx, NY 10467 USA. [Whellan, David J.] Jefferson Med Coll, Dept Med, Philadelphia, PA USA. [O'Connor, Christopher M.] Inova Heart & Vasc Inst, Div Cardiol, Dept Med, Falls Church, VA USA. RP Parikh, KS (reprint author), Duke Clin Res Inst, Durham, NC USA.; Parikh, KS (reprint author), Duke Univ, Med Ctr, Dept Med, Div Cardiol, Durham, NC 27710 USA. EM Kishati.parikh@dm.duke.edu FU Gilead Sciences; NIH (Bethesda, MD) [U10HL110312, 5T32GM086330-05]; National Heart, Lung, and Blood Institute (Bethesda, MD) [HL063747, HL093374] FX Funding was provided by Gilead Sciences. Work for the analysis was supported by grants U10HL110312 (Dr. Mentz) and 5T32GM086330-05 (Dr. Parikh) from NIH (Bethesda, MD). The HF-ACTION trial was funded by grants HL063747 and HL093374 from the National Heart, Lung, and Blood Institute (Bethesda, MD). NR 22 TC 0 Z9 0 U1 6 U2 6 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 EI 1879-1913 J9 AM J CARDIOL JI Am. J. Cardiol. PD OCT 15 PY 2016 VL 118 IS 8 BP 1211 EP 1216 DI 10.1016/j.amjcard.2016.07.040 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EA0ZX UT WOS:000386319200018 PM 27561194 ER PT J AU Demiral, SB Gambi, C Nieuwland, MS Pickering, MJ AF Demiral, Sukru Baris Gambi, Chiara Nieuwland, Mante S. Pickering, Martin J. TI Neural correlates of verbal joint action: ERPs reveal common perception and action systems in a shared-Stroop task SO BRAIN RESEARCH LA English DT Article DE Joint action; ERP; Language; Shared representations; Stroop ID GO/NOGO TASK; INHIBITION; POTENTIALS; FRAMEWORK; REFLECTS; P3B; N2 AB Recent social-cognitive research suggests that the anticipation of co-actors' actions influences people's mental representations. However, the precise nature of such representations is still unclear. In this study we investigated verbal joint representations in a delayed Stroop paradigm, where each participant responded to one color after a short delay. Participants either performed the task as a single actor (single-action, Experiment 1), or they performed it together (joint-action, Experiment 2). We investigated effects of co-actors' actions on the ERP components associated with perceptual conflict (Go N2) and response selection (P3b). Compared to single-action, joint-action reduced the N2 amplitude congruency effect when participants had to respond (Go trials), indicating that representing a co-actor's utterance helped to dissociate action codes and attenuated perceptual conflict for the responding participant. Yet, on NoGo trials the centro-parietal P3 (P3b) component amplitude increased for joint-action, suggesting that participants mapped the stimuli onto the co-actor's upcoming response as if it were their own response. We conclude that people represent others' utterances similarly to the way they represent their own utterances, and that shared perception-action codes for self and others can sometimes reduce, rather than enhance, perceptual conflict. (C) 2016 Elsevier B.V. All rights reserved. C1 [Demiral, Sukru Baris] NIAAA, Lab Neuroimaging, NIH, 10 Ctr Dr,Bldg 10,B2L124, Bethesda, MD 20892 USA. [Demiral, Sukru Baris; Gambi, Chiara; Nieuwland, Mante S.; Pickering, Martin J.] Univ Edinburgh, Dept Psychol, 7 George Sq, Edinburgh EH8 9JZ, Midlothian, Scotland. RP Demiral, SB (reprint author), NIAAA, Lab Neuroimaging, NIH, 10 Ctr Dr,Bldg 10,B2L124, Bethesda, MD 20892 USA. EM sukru.demiral@nih.gov FU Department of Psychology, The University of Edinburgh; School of Philosophy, Psychology, and Language Sciences, University of Edinburgh FX This work was supported by funding provided by the Department of Psychology, The University of Edinburgh. Chiara Gambi was supported by a Studentship from the School of Philosophy, Psychology, and Language Sciences, University of Edinburgh. NR 37 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 EI 1872-6240 J9 BRAIN RES JI Brain Res. PD OCT 15 PY 2016 VL 1649 BP 79 EP 89 DI 10.1016/j.brainres.2016.08.025 PN A PG 11 WC Neurosciences SC Neurosciences & Neurology GA EA2FT UT WOS:000386408900009 ER PT J AU Rosenke, K Adjemian, J Munster, VJ Marzi, A Falzarano, D Onyango, CO Ochieng, M Juma, B Fischer, RJ Prescott, JB Safronetz, D Omballa, V Owuor, C Hoenen, T Groseth, A Martellaro, C van Doremalen, N Zemtsova, G Self, J Bushmaker, T McNally, K Rowe, T Emery, SL Feldmann, F Williamson, BN Best, SM Nyenswah, TG Grolla, A Strong, JE Kobinger, G Bolay, FK Zoon, KC Stassijns, J Giuliani, R de Smet, M Nichol, ST Fields, B Sprecher, A Massaquoi, M Feldmann, H de Wit, E AF Rosenke, Kyle Adjemian, Jennifer Munster, Vincent J. Marzi, Andrea Falzarano, Darryl Onyango, Clayton O. Ochieng, Melvin Juma, Bonventure Fischer, Robert J. Prescott, Joseph B. Safronetz, David Omballa, Victor Owuor, Collins Hoenen, Thomas Groseth, Allison Martellaro, Cynthia van Doremalen, Neeltje Zemtsova, Galina Self, Joshua Bushmaker, Trenton McNally, Kristin Rowe, Thomas Emery, Shannon L. Feldmann, Friederike Williamson, Brandi N. Best, Sonja M. Nyenswah, Tolbert G. Grolla, Allen Strong, James E. Kobinger, Gary Bolay, Fatorma K. Zoon, Kathryn C. Stassijns, Jorgen Giuliani, Ruggero de Smet, Martin Nichol, Stuart T. Fields, Barry Sprecher, Armand Massaquoi, Moses Feldmann, Heinz de Wit, Emmie TI Plasmodium Parasitemia Associated With Increased Survival in Ebola Virus-Infected Patients SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE coinfection; ebolavirus; plasmodium; survival ID HEMORRHAGIC-FEVER; VIRAL LOAD; ARTEMISININ DERIVATIVES; CASE-MANAGEMENT; SIERRA-LEONE; MOUSE MODEL; MALARIA; DIAGNOSIS; MORTALITY; DISEASE AB Background. The ongoing Ebola outbreak in West Africa has resulted in 28 646 suspected, probable, and confirmed Ebola virus infections. Nevertheless, malaria remains a large public health burden in the region affected by the outbreak. A joint Centers for Disease Control and Prevention/National Institutes of Health diagnostic laboratory was established in Monrovia, Liberia, in August 2014, to provide laboratory diagnostics for Ebola virus. Methods. All blood samples from suspected Ebola virus-infected patients admitted to the Medecins Sans Frontieres ELWA3 Ebola treatment unit in Monrovia were tested by quantitative real-time polymerase chain reaction for the presence of Ebola virus and Plasmodium species RNA. Clinical outcome in laboratory-confirmed Ebola virus-infected patients was analyzed as a function of age, sex, Ebola viremia, and Plasmodium species parasitemia. Results. The case fatality rate of 1182 patients with laboratory-confirmed Ebola virus infections was 52%. The probability of surviving decreased with increasing age and decreased with increasing Ebola viral load. Ebola virus-infected patients were 20% more likely to survive when Plasmodium species parasitemia was detected, even after controlling for Ebola viral load and age; those with the highest levels of parasitemia had a survival rate of 83%. This effect was independent of treatment with antimalarials, as this was provided to all patients. Moreover, treatment with antimalarials did not affect survival in the Ebola virus mouse model. Conclusions. Plasmodium species parasitemia is associated with an increase in the probability of surviving Ebola virus infection. More research is needed to understand the molecular mechanism underlying this remarkable phenomenon and translate it into treatment options for Ebola virus infection. C1 [Rosenke, Kyle; Munster, Vincent J.; Marzi, Andrea; Falzarano, Darryl; Fischer, Robert J.; Prescott, Joseph B.; Safronetz, David; Hoenen, Thomas; Groseth, Allison; Martellaro, Cynthia; van Doremalen, Neeltje; Bushmaker, Trenton; McNally, Kristin; Williamson, Brandi N.; Best, Sonja M.; Feldmann, Heinz; de Wit, Emmie] NIAID, Virol Lab, Div Intramural Res, Rocky Mt Labs,NIH, 903 S 4th St, Hamilton, MT 59840 USA. [Adjemian, Jennifer] NIAID, Epidemiol Unit, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Adjemian, Jennifer] US PHS, Commissioned Corps, Rockville, MD USA. [Onyango, Clayton O.; Juma, Bonventure; Fields, Barry] Ctr Dis Control & Prevent, Ctr Global Hlth, Div Global Hlth Protect, Atlanta, GA USA. [Ochieng, Melvin; Omballa, Victor; Owuor, Collins] Kenya Govt Med Res Ctr, Ctr Global Hlth Res, Nairobi, Kenya. [Zemtsova, Galina; Self, Joshua; Rowe, Thomas; Emery, Shannon L.; Nichol, Stuart T.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Feldmann, Friederike] NIAID, Rocky Mt Vet Branch, Div Intramural Res, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. [Nyenswah, Tolbert G.; Massaquoi, Moses] Minist Hlth & Social Welf Incident Management Sys, Monrovia, Liberia. [Grolla, Allen; Strong, James E.; Kobinger, Gary] Publ Hlth Agcy Canada, Special Pathogens Program, Winnipeg, MB, Canada. [Bolay, Fatorma K.] Liberian Inst Biomed Res, Charlesville, NS, Canada. [Zoon, Kathryn C.] NIAID, Cytokine Biol Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Stassijns, Jorgen; Giuliani, Ruggero; de Smet, Martin; Sprecher, Armand] Med Sans Frontieres, Operat Ctr, Brussels, Belgium. [Falzarano, Darryl] Univ Saskatchewan, Vaccine & Infect Dis Org, Int Vaccine Ctr, Saskatoon, SK, Canada. [Safronetz, David] Publ Hlth Agcy Canada, Winnipeg, MB, Canada. [Hoenen, Thomas; Groseth, Allison] Friedrich Loeffler Inst, Greifswald, Germany. RP de Wit, E (reprint author), NIAID, Virol Lab, Div Intramural Res, Rocky Mt Labs,NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM emmie.dewit@nih.gov OI de Wit, Emmie/0000-0002-9763-7758; Munster, Vincent/0000-0002-2288-3196 FU NIAID/NIH FX This work was partially funded by the Intramural Research Program of the NIAID/NIH. NR 28 TC 8 Z9 8 U1 5 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD OCT 15 PY 2016 VL 63 IS 8 BP 1026 EP 1033 DI 10.1093/cid/ciw452 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DZ7KN UT WOS:000386044400008 PM 27531847 ER PT J AU Pinto, LA Kemp, TJ Torres, BN Isaacs-Soriano, K Ingles, D Abrahamsen, M Pan, YJ Lazcano-Ponce, E Salmeron, J Giuliano, AR AF Pinto, Ligia A. Kemp, Troy J. Torres, B. Nelson Isaacs-Soriano, Kimberly Ingles, Donna Abrahamsen, Martha Pan, Yuanji Lazcano-Ponce, Eduardo Salmeron, Jorge Giuliano, Anna R. TI Quadrivalent Human Papillomavirus (HPV) Vaccine Induces HPV-Specific Antibodies in the Oral Cavity: Results From the Mid-Adult Male Vaccine Trial SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE HPV vaccine; males; serum; mouthwash; saliva ID IMMUNE-RESPONSE; CERVICAL-CANCER; INFECTION; MEN; IMMUNOGENICITY; INFLUENZA; SPECIMENS; EFFICACY; WOMEN; ELISA AB Background. Human papillomavirus virus type 16 (HPV-16) and HPV-18 cause a large proportion of oropharyngeal cancers, which are increasing in incidence among males, and vaccine efficacy against oral HPV infections in men has not been previously evaluated. Methods. Sera and saliva collected in mouthwash and Merocel sponges at day 1 and month 7 were obtained from 150 men aged 27-45 years from Tampa, Florida, and Cuernavaca, Mexico, who received Gardasil at day 1 and months 2 and 6. Specimens were tested for anti-HPV-16 and anti-HPV-18 immunoglobulin G (IgG) levels by an L1 virus-like particle-based enzyme-linked immunosorbent assay. Results. All participants developed detectable serum anti-HPV-16 and anti-HPV-18 antibodies, and most had detectable antibodies in both oral specimen types at month 7 (HPV-16 was detected in 93.2% of mouthwash specimens and 95.7% of sponge specimens; HPV-18 was detected in 72.1% and 65.5%, respectively). Antibody concentrations in saliva were approximately 3 logs lower than in serum. HPV-16- and HPV-18-specific antibody levels, normalized to total IgG levels, in both oral specimen types at month 7 were significantly correlated with serum levels (for HPV-16,. was 0.90 for mouthwash specimens and 0.92 for sponge specimens; for HPV-18,. was 0.89 and 0.86, respectively). Conclusions. This is the first study demonstrating that vaccination of males with Gardasil induces HPV antibody levels at the oral cavity that correlate with circulating levels. C1 [Pinto, Ligia A.; Kemp, Troy J.; Pan, Yuanji] Leidos Biomed Res Inc, HPV Immunol Lab, Frederick Natl Lab Canc Res, Frederick, MD USA. [Torres, B. Nelson; Isaacs-Soriano, Kimberly; Ingles, Donna; Abrahamsen, Martha; Giuliano, Anna R.] H Lee Moffitt Canc Ctr & Res Inst, Ctr Infect Res Canc, Tampa, FL USA. [Lazcano-Ponce, Eduardo; Salmeron, Jorge] Natl Inst Publ Hlth, Cuernavaca, Morelos, Mexico. RP Pinto, LA (reprint author), Leidos Biomed Res, HPV Immunol Lab, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. EM pintol@mail.nih.gov FU Merck Sharp and Dohme; Miles for Moffitt program, Moffitt Cancer Center; National Cancer Institute; National Institutes of Health [HHSN261200800001E]; Moffitt Cancer Center FX This work was supported by the Investigator Initiated Studies Program of Merck Sharp and Dohme (research grant to A. R. G.]; the Miles for Moffitt program, Moffitt Cancer Center; the National Cancer Institute, National Institutes of Health (contract HHSN261200800001E); and the Moffitt Cancer Center. NR 23 TC 0 Z9 0 U1 7 U2 7 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 15 PY 2016 VL 214 IS 8 BP 1276 EP 1283 DI 10.1093/infdis/jiw359 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DZ8UL UT WOS:000386147200026 PM 27511896 ER PT J AU Pickard, FC Konig, G Simmonett, AC Shao, YH Brooks, BR AF Pickard, Frank C. Koenig, Gerhard Simmonett, Andrew C. Shao, Yihan Brooks, Bernard R. TI An efficient protocol for obtaining accurate hydration free energies using quantum chemistry and reweighting from molecular dynamics simulations SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Hydration free energy calculations; Non-Boltzmann Bennett; Implicit solvent ID SOLVATION FREE-ENERGIES; ACCEPTANCE RATIO METHOD; CONSISTENT BASIS-SETS; GENERAL FORCE-FIELD; PARTICLE MESH EWALD; DENSITY FUNCTIONALS; BLIND PREDICTION; MECHANICAL CALCULATIONS; BINDING AFFINITIES; ATOMIC CHARGES AB The non-Boltzmann Bennett (NBB) free energy estimator method is applied to 21 molecules from the blind subset of the SAMPL4 challenge. When NBB is applied with the SMD implicit solvent model, and the OLYP/DZP level of quantum chemistry, highly accurate hydration free energy calculations are obtained with respect to experiment (RMSD = 0.89 kcal.mol(-1)). Other quantum chemical methods are also tested, and the effects of solvent model, density functional, basis set are explored in this benchmarking study, providing a framework for improvements in calculating hydration free energies. We provide a practical guide for using the best QM-NBB protocols that are consistently more accurate than either pure QM or pure MM alone. In situations where high accuracy hydration free energy predictions are needed, the QM-NBB method with SMD implicit solvent should be the first choice of quantum chemists. Published by Elsevier Ltd. C1 [Pickard, Frank C.; Koenig, Gerhard; Simmonett, Andrew C.; Brooks, Bernard R.] NHLBI, NIH, Lab Computat Biol, 5635 Fishers Lane,T-900 Suite, Rockville, MD 20852 USA. [Shao, Yihan] Univ Oklahoma, Dept Chem & Biochem, Norman, OK 73019 USA. [Koenig, Gerhard] Max Planck Inst Kohlenforsch, Kaiser Wilhelm Pl 1, D-45470 Mulheim, NRW, Germany. RP Pickard, FC (reprint author), NHLBI, NIH, Lab Computat Biol, 5635 Fishers Lane,T-900 Suite, Rockville, MD 20852 USA. FU National Heart, Lung and Blood Institute of the National Institutes of Health FX The authors would like to thank Tim Miller, Richard Venable and John Legato for technical assistance with the parallelization of the QM/MM calculations. This work was supported by the intramural research program of the National Heart, Lung and Blood Institute of the National Institutes of Health and utilized the high-performance computational capabilities of the LoBoS (http://www.lobos.nih.gov) and Biowuif (http://hpc.nih.gov) Linux clusters at the National Institutes of Health. NR 98 TC 0 Z9 0 U1 8 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 EI 1464-3391 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD OCT 15 PY 2016 VL 24 IS 20 BP 4988 EP 4997 DI 10.1016/j.bmc.2016.08.031 PG 10 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA DZ5MI UT WOS:000385905800024 PM 27667551 ER PT J AU Zhao, XZ Hymel, D Burke, TR AF Zhao, Xue Zhi Hymel, David Burke, Terrence R., Jr. TI Application of oxime-diversification to optimize ligand interactions within a cryptic pocket of the polo-like kinase 1 polo-box domain SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Plk1 polo-box domain; Ligand optimization; Oxime ligation; Cryptic binding pocket ID PLK1; PEPTIDES; POSITION; ALKYLATION; INHIBITORS; AFFINITY; THERAPY; SURFACE AB By a process involving initial screening of a set of 87 aldehydes using an oxime ligation-based strategy, we were able to achieve a several-fold affinity enhancement over one of the most potent previously known polo-like kinase 1 (Plk1) polo-box domain (PBD) binding inhibitors. This improved binding may result by accessing a newly identified auxiliary region proximal to a key hydrophobic cryptic pocket on the surface of the protein. Our findings could have general applicability to the design of PBD-binding antagonists. Published by Elsevier Ltd. C1 [Zhao, Xue Zhi; Hymel, David; Burke, Terrence R., Jr.] NCI, Biol Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. RP Burke, TR (reprint author), NCI, Biol Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. EM burkete@helix.nih.gov FU NIH Intramural Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health FX Work was supported by the NIH Intramural Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 19 TC 0 Z9 0 U1 4 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X EI 1464-3405 J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD OCT 15 PY 2016 VL 26 IS 20 BP 5009 EP 5012 DI 10.1016/j.bmcl.2016.08.098 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA DZ0AI UT WOS:000385498500031 PM 27624074 ER PT J AU Wells, SA AF Wells, Samuel A., Jr. TI Progress in Endocrine Neoplasia SO CLINICAL CANCER RESEARCH LA English DT Article ID PANCREATIC NEUROENDOCRINE TUMORS; METASTATIC ADRENOCORTICAL CARCINOMA; DIFFERENTIATED THYROID-CANCER; ISLET-CELL-CARCINOMA; GERM-LINE MUTATIONS; PITUITARY-ADENOMAS; ADJUVANT MITOTANE; BRAF MUTATIONS; DOUBLE-BLIND; GENE AB Most endocrine tumors are benign, and afflicted patients usually seek medical advice because of symptoms caused by too much, or too little, native hormone secretion or the impingement of their tumor on a vital structure. Malignant endocrine tumors represent a more serious problem, and patient cure often depends on early diagnosis and treatment. The recent development of novel molecular therapeutics holds great promise for the treatment of patients with locally advanced or metastatic endocrine cancer. In this CCR Focus, expert clinical investigators describe the molecular characteristics of various endocrine tumors and discuss the current status of diagnosis and treatment. (C) 2016 AACR. C1 [Wells, Samuel A., Jr.] NCI, Genet Branch, NIH, Bldg 37,Room 6138,37 Convent Dr, Bethesda, MD 20814 USA. RP Wells, SA (reprint author), NCI, Genet Branch, NIH, Bldg 37,Room 6138,37 Convent Dr, Bethesda, MD 20814 USA. EM wellss@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 93 TC 0 Z9 0 U1 3 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD OCT 15 PY 2016 VL 22 IS 20 BP 4981 EP 4988 DI 10.1158/1078-0432.CCR-16-0384 PG 8 WC Oncology SC Oncology GA DZ1WP UT WOS:000385632700006 PM 27742784 ER PT J AU Payabyab, EC Balasubramaniam, S Edgerly, M Velarde, M Merino, MJ Venkatesan, AM Leuva, H Litman, T Bates, SE Fojo, T AF Payabyab, Eden C. Balasubramaniam, Sanjeeve Edgerly, Maureen Velarde, Margarita Merino, Maria J. Venkatesan, Aradhana M. Leuva, Harshraj Litman, Thomas Bates, Susan E. Fojo, Tito TI Adrenocortical Cancer: A Molecularly Complex Disease Where Surgery Matters SO CLINICAL CANCER RESEARCH LA English DT Article ID ADRENAL-CORTICAL CARCINOMA; LONG-TERM SURVIVAL; LAPAROSCOPIC ADRENALECTOMY; GENOMIC CHARACTERIZATION; ONCOLOGIC OUTCOMES; ADJUVANT MITOTANE; PHASE-II; STAGE-I; THERAPY; TUMORS AB The development of new therapies has lagged behind for rare cancers without defined therapeutic targets. Adrenocortical cancer is no exception. Mitotane, an older agent considered "adrenolytic," is used both to control symptoms in advanced disease and as adjuvant therapy after surgical resection. Molecular characterization of adrenocortical cancer has deepened our understanding of this genetically complex disease while identifying subgroups whose importance remains to be determined. Unfortunately, such studies have yet to demonstrate a therapeutic target for drug development, and to date, no targeted therapy has achieved meaningful outcomes. Consequently, first-line therapy for metastatic disease remains a combination regimen of etoposide, doxorubicin, and cisplatinum established in a randomized clinical trial. In addition to evaluating recent studies in adrenocortical cancer, we raise one critical clinical issue-the risk of peritoneal dissemination following laparoscopic resection of adrenocortical cancer. In a retrospective case series of 267 patients referred to the NCI for the treatment of recurrent or advanced adrenocortical cancer, we found extensive peritoneal dissemination in 25 of the 45 patients (55.6%) who had undergone laparoscopic resection, compared with only 7 of the 222 patients (3%) who had undergone an open resection (P < 0.0001). Although this has been debated in the literature, our data argue for an end to laparoscopic resection of adrenocortical cancers to avoid peritoneal dissemination, a complication of laparoscopy that is uniformly fatal. (C) 2016 AACR. C1 [Payabyab, Eden C.] NCI, Surg Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Payabyab, Eden C.] NCI, Thorac & GI Oncol Branch, NIH, Bethesda, MD 20892 USA. [Balasubramaniam, Sanjeeve] USDA, Div Oncol Prod 1, OHOP, CDER, Silver Spring, MD USA. [Edgerly, Maureen; Velarde, Margarita] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Merino, Maria J.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. [Venkatesan, Aradhana M.] Univ Texas MD Anderson Canc Ctr, Dept Diagnost Radiol, Div Diagnost Imaging, Houston, TX 77030 USA. [Leuva, Harshraj; Bates, Susan E.; Fojo, Tito] James J Peters Vet Adm Med Ctr, Bronx, NY USA. [Litman, Thomas] Univ Copenhagen, Med Biostat, Copenhagen, Denmark. [Bates, Susan E.; Fojo, Tito] Columbia Univ, Dept Med, Med Ctr, Div Med Oncol, New York, NY 10032 USA. RP Fojo, T (reprint author), Columbia Univ, Dept Med, Med Ctr, Div Med Oncol, New York, NY 10032 USA.; Fojo, T (reprint author), James J Peters VA Med Ctr, Bronx, NY 10468 USA. EM atf2116@cumc.columbia.edu OI Balasubramaniam, Sanjeeve/0000-0002-0643-2117 NR 57 TC 2 Z9 2 U1 2 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD OCT 15 PY 2016 VL 22 IS 20 BP 4989 EP 5000 DI 10.1158/1078-0432.CCR-16-1570 PG 12 WC Oncology SC Oncology GA DZ1WP UT WOS:000385632700007 PM 27742785 ER PT J AU Jochmanova, I Pacak, K AF Jochmanova, Ivana Pacak, Karel TI Pheochromocytoma: The First Metabolic Endocrine Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID HYPOXIA-INDUCIBLE FACTORS; ATP-CITRATE LYASE; CELL-METABOLISM; TCA CYCLE; MITOCHONDRIAL METABOLISM; GERMLINE MUTATIONS; TUMOR PROGRESSION; SDH MUTATIONS; COMPLEX-II; PARAGANGLIOMA AB Dysregulated metabolism is one of the key characteristics of cancer cells. The most prominent alterations are present during regulation of cell respiration, which leads to a switch from oxidative phosphorylation to aerobic glycolysis. This metabolic shift results in activation of numerous signaling and metabolic pathways supporting cell proliferation and survival. Recent progress in genetics and metabolomics has allowed us to take a closer look at the metabolic changes present in pheochromocytomas (PHEO) and paragangliomas (PGL). These neuroendocrine tumors often exhibit dysregulation of mitochondrial metabolism, which is driven by mutations in genes encoding Krebs cycle enzymes or by activation of hypoxia signaling. Present metabolic changes are involved in processes associated with tumorigenesis, invasiveness, metastasis, and resistance to various cancer therapies. In this review, we discuss the metabolic nature of PHEOs/PGLs and how unveiling the metabolic disturbances present in tumors could lead to identification of new biomarkers and personalized cancer therapies. (C) 2016 AACR. C1 [Jochmanova, Ivana; Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Med Neuroendocrinol, NIH, Bethesda, MD USA. [Jochmanova, Ivana] Safarik Univ, Fac Med, Dept Internal Med 1, Kosice, Slovakia. RP Pacak, K (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, CRC, Bldg 10,1E-3140,10 Ctr Dr,MSC 1109, Bethesda, MD 20892 USA. EM karel@mail.nih.gov FU Intramural Research Program of the NIH, NICHD FX This research was supported, in part, by the Intramural Research Program of the NIH, NICHD. NR 100 TC 3 Z9 3 U1 2 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD OCT 15 PY 2016 VL 22 IS 20 BP 5001 EP 5011 DI 10.1158/1078-0432.CCR-16-0606 PG 11 WC Oncology SC Oncology GA DZ1WP UT WOS:000385632700008 PM 27742786 ER PT J AU Yingchoncharoen, T Jellis, C Popovic, ZB Wang, L Gai, N Levy, WC Tang, WHW Flamm, S Kwon, DH AF Yingchoncharoen, Teerapat Jellis, Christine Popovic, Zoran B. Wang, Lu Gai, Neville Levy, Wayne C. Tang, W. H. Wilson Flamm, Scott Kwon, Deborah H. TI Focal fibrosis and diffuse fibrosis are predictors of reversed left ventricular remodeling in patients with non-ischemic cardiomyopathy SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE Non-ischemic idiopathic dilated cardiomyopathy; Cardiac magnetic resonance; Left ventricular reversed remodeling; Delayed hyperenhancement; Diffuse fibrosis; T1 mapping ID CARDIOVASCULAR MAGNETIC-RESONANCE; MYOCARDIAL FIBROSIS; DILATED CARDIOMYOPATHY; HEART-FAILURE; POPULATION; DISEASE AB Background: Prognostic value of myocardial fibrosis in patients with non-ischemic idiopathic dilated cardiomyopathy (DCM) is not well-defined. We sought to assess the association of focal and diffuse myocardial fibrosis with left ventricular reversed remodeling (LVRR). Methods: Patients with DCM who underwent cardiac MRI with baseline and subsequent follow-up echocardiography were included in the study. Post-contrast T1 times were corrected for renal function, body size, gadolinium dose and time after Gadolinium injection. Patients were followed over a median time of 29 months to evaluate changes of left ventricular end-systolic volume (LVESV). A Linear Mixed Model was used to assess the relationship between the LVESV during follow-up, corrected post-T1 value delayed hyperenhancement (DHE), and modified Seattle Heart Failure Score (SHFS). Results: A total of 103 patients (mean age 51 +/- 15 years, 61% male) were evaluated. The mean LVEF was 33 +/- 11%, LVESVi 62 +/- 39 ml/m(2), and T1 time 416 +/- 98. DHE was identified in 45 patients (44%). Patients with focal DHE (n = 45) had higher LVESVi at baseline and during follow-up (p = 0.024). Post T1 value >450 was an independent predictor of LVRR at the follow-up (Delta= 24.6ml/m(2) SE 14.6 ml/2, p= 0.0480) in patients despite the presence of DHE, even after adjusting for their SHFS. Conclusion: While DCM patients with focal DHE demonstrated greater adverse LV remodeling than those without focal fibrosis, diffuse fibrosis independently predicts LVRR in DCM patients in patients despite the presence of focal fibrosis. (C) 2016 Published by Elsevier Ireland Ltd. C1 [Jellis, Christine; Popovic, Zoran B.; Wang, Lu; Levy, Wayne C.; Tang, W. H. Wilson; Flamm, Scott; Kwon, Deborah H.] Cleveland Clin, Cleveland, OH 44106 USA. [Yingchoncharoen, Teerapat] Mahidol Univ, Ramathibodi Hosp, Bangkok, Thailand. [Gai, Neville] NIH, Ctr Clin, Radiol & Imaging Sci, Bethesda, MD 20892 USA. RP Kwon, DH (reprint author), Cleveland Clin, Cardiovasc Med J1 5, 9500 Euclid Ave, Cleveland, OH 44195 USA. EM kwond@ccf.org NR 26 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD OCT 15 PY 2016 VL 221 BP 498 EP 504 DI 10.1016/j.ijcard.2016.06.095 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DX9DA UT WOS:000384692600096 PM 27414729 ER PT J AU Mao, CY Wu, P Zhang, SY Yang, J Liu, YT Zuo, CT Zhuang, ZP Shi, CH Xu, YM AF Mao, Cheng-yuan Wu, Ping Zhang, Shu-yu Yang, Jing Liu, Yu-tao Zuo, Chuan-tao Zhuang, Zheng-ping Shi, Chang-he Xu, Yu-ming TI Brain glucose metabolism changes in Parkinson's disease patients with CHCHD2 mutation based on F-18-FDG PET imaging SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Letter DE Parkinson's disease; CHCHD2 mutation; F-18-FDG PET imaging ID NETWORK C1 [Mao, Cheng-yuan; Zhang, Shu-yu; Yang, Jing; Liu, Yu-tao; Shi, Chang-he; Xu, Yu-ming] Zhengzhou Univ, Affiliated Hosp 1, Dept Neurol, 1 Jian She East Rd, Zhengzhou 450000, Henan, Peoples R China. [Mao, Cheng-yuan; Zhang, Shu-yu; Shi, Chang-he; Xu, Yu-ming] Zhengzhou Univ, Affiliated Hosp 1, Inst Clin Med, Zhengzhou 450000, Henan, Peoples R China. [Wu, Ping; Zuo, Chuan-tao] Fudan Univ, Huashan Hosp, Shanghai Med Coll, PET Ctr,Dept Nucl Med, Shanghai, Peoples R China. [Zhuang, Zheng-ping] NINDS, Surg Neurol Branch, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Shi, CH; Xu, YM (reprint author), Zhengzhou Univ, Affiliated Hosp 1, Dept Neurol, 1 Jian She East Rd, Zhengzhou 450000, Henan, Peoples R China. EM shichanghe@gmail.com; xuyuming@zzu.edu.cn NR 5 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-510X EI 1878-5883 J9 J NEUROL SCI JI J. Neurol. Sci. PD OCT 15 PY 2016 VL 369 BP 303 EP 305 DI 10.1016/j.jns.2016.08.042 PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DY1NF UT WOS:000384861000059 PM 27653913 ER PT J AU Presutti, R Harris, SA Kachuri, L Spinelli, JJ Pahwa, M Blair, A Zahm, SH Cantor, KP Weisenburger, DD Pahwa, P McLaughlin, JR Dosman, JA Freeman, LB AF Presutti, Roseanna Harris, Shelley A. Kachuri, Linda Spinelli, John J. Pahwa, Manisha Blair, Aaron Zahm, Shelia Hoar Cantor, Kenneth P. Weisenburger, Dennis D. Pahwa, Punam McLaughlin, John R. Dosman, James A. Freeman, Laura Beane TI Pesticide exposures and the risk of multiple myeloma in men: An analysis of the North American Pooled Project SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE multiple myeloma; pesticides; pooled case-control study; carbamates; insecticides ID NON-HODGKINS-LYMPHOMA; SOFT-TISSUE SARCOMA; AGRICULTURAL HEALTH; NONDIFFERENTIAL MISCLASSIFICATION; UNDETERMINED SIGNIFICANCE; MONOCLONAL GAMMOPATHY; CANCER INCIDENCE; CARCINOGENICITY; APPLICATORS; CHEMICALS AB Multiple myeloma (MM) has been consistently linked with agricultural activities, including farming and pesticide exposures. Three case-control studies in the United States and Canada were pooled to create the North American Pooled Project (NAPP) to investigate associations between pesticide use and haematological cancer risk. This analysis used data from 547 MM cases and 2700 controls. Pesticide use was evaluated as follows: ever/never use; duration of use (years); and cumulative lifetime-days (LD) (days/year handled 3 years of use). Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression adjusted for age, province/state of residence, use of proxy respondents and selected medical conditions. Increased MM risk was observed for ever use of carbaryl (OR52.02, 95% CI51.28-3.21), captan (OR51.98, 95% CI=1.04-3.77) and DDT (OR51.44, 95% CI51.05-1.97). Using the Canadian subset of NAPP data, we observed a more than threefold increase in MM risk (OR53.18, 95% CI51.40-7.23) for <= 10 cumulative LD of carbaryl use. The association was attenuated but remained significant for >10 LD of carbaryl use (OR52.44; 95% CI51.05-5.64; p(trend) = 0.01). For captan, <= 17.5 LD of exposure was also associated with a more than threefold increase in risk (OR53.52, 95% CI51.32-9.34), but this association was attenuated in the highest exposure category of >17.5 LD (OR52.29, 95% CI50.81-6.43; p(trend) = 0.01). An increasing trend (p(trend) = 0.04) was observed for LD of DDT use (LD >22; OR51.92, 95% CI50.95-3.88). In this large North American study of MM and pesticide use, we observed significant increases in MM risk for use of carbaryl, captan and DDT. C1 [Presutti, Roseanna; Harris, Shelley A.; Kachuri, Linda; Pahwa, Manisha] Canc Care Ontario, Occupat Canc Res Ctr, Toronto, ON, Canada. [Presutti, Roseanna; Harris, Shelley A.; Kachuri, Linda; Pahwa, Manisha] Canc Care Ontario, Prevent & Canc Control, 620 Univ Ave, Toronto, ON M5G 2L7, Canada. [Harris, Shelley A.; Kachuri, Linda; McLaughlin, John R.] Univ Toronto, Dalla Lana Sch Publ Hlth, Dept Epidemiol, Toronto, ON, Canada. [Harris, Shelley A.] Univ Toronto, Dalla Lana Sch Publ Hlth, Dept Occupat & Environm Hlth, Toronto, ON, Canada. [Kachuri, Linda; McLaughlin, John R.] Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada. [Spinelli, John J.] British Columbia Canc Agcy Res Ctr, Vancouver, BC, Canada. [Spinelli, John J.] Univ British Columbia, Vancouver, BC, Canada. [Blair, Aaron; Zahm, Shelia Hoar; Cantor, Kenneth P.; Freeman, Laura Beane] US Natl Canc Inst, Div Canc Epidemiol & Genet, Bethesda, MD USA. [Weisenburger, Dennis D.] City Hope Med Ctr, Dept Pathol, Duarte, CA USA. [Pahwa, Punam] Canadian Ctr Hlth & Safety Agr, Hamilton, ON, Canada. [Pahwa, Punam; Dosman, James A.] Univ Saskatchewan, Dept Community Hlth & Epidemiol, Saskatoon, SK, Canada. [McLaughlin, John R.] Publ Hlth Ontario, Toronto, ON, Canada. RP Harris, SA (reprint author), Canc Care Ontario, Prevent & Canc Control, 620 Univ Ave, Toronto, ON M5G 2L7, Canada. EM Shelley.Harris@cancercare.on.Ca RI Beane Freeman, Laura/C-4468-2015; OI Beane Freeman, Laura/0000-0003-1294-4124; harris, shelley/0000-0003-2306-7921 FU Canadian Cancer Society Research Institute [703055]; National Cancer Institute (U.S. National Institutes of Health Intramural Research Program) FX Grant sponsor: Canadian Cancer Society Research Institute; Grant number: 703055; Grant sponsor: National Cancer Institute (U.S. National Institutes of Health Intramural Research Program) NR 42 TC 0 Z9 0 U1 7 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD OCT 15 PY 2016 VL 139 IS 8 BP 1703 EP 1714 DI 10.1002/ijc.30218 PG 12 WC Oncology SC Oncology GA DV9TH UT WOS:000383284500003 PM 27261772 ER PT J AU Byrareddy, SN Arthos, J Cicala, C Villinger, F Ortiz, KT Little, D Sidell, N Kane, MA Yu, JS Jones, JW Santangelo, PJ Zurla, C McKinnon, LR Arnold, KB Woody, CE Walter, L Roos, C Noll, A Van Ryk, D Jelicic, K Cimbro, R Gumber, S Reid, MD Adsay, V Amancha, PK Mayne, AE Parslow, TG Fauci, AS Ansari, AA AF Byrareddy, Siddappa N. Arthos, James Cicala, Claudia Villinger, Francois Ortiz, Kristina T. Little, Dawn Sidell, Neil Kane, Maureen A. Yu, Jianshi Jones, Jace W. Santangelo, Philip J. Zurla, Chiara McKinnon, Lyle R. Arnold, Kelly B. Woody, Caroline E. Walter, Lutz Roos, Christian Noll, Angela Van Ryk, Donald Jelicic, Katija Cimbro, Raffaello Gumber, Sanjeev Reid, Michelle D. Adsay, Volkan Amancha, Praveen K. Mayne, Ann E. Parslow, Tristram G. Fauci, Anthony S. Ansari, Aftab A. TI Sustained virologic control in SIV+ macaques after antiretroviral and alpha(4)beta(7) antibody therapy SO SCIENCE LA English DT Article ID SIMIAN IMMUNODEFICIENCY VIRUS; T-CELL DEPLETION; RETINOIC ACID; LYMPHOID-TISSUE; SIVMAC251 ACQUISITION; TYPE-1 INFECTION; HIV; REPLICATION; EXPRESSION; SIGNATURES AB Antiretroviral drug therapy (ART) effectively suppresses replication of both the immunodeficiency viruses, human (HIV) and simian (SIV); however, virus rebounds soon after ART is withdrawn. SIV-infected monkeys were treated with a 90-day course of ART initiated at 5 weeks post infection followed at 9 weeks post infection by infusions of a primatized monoclonal antibody against the alpha(4)beta(7) integrin administered every 3 weeks until week 32. These animals subsequently maintained low to undetectable viral loads and normal CD4(+) T cell counts in plasma and gastrointestinal tissues for more than 9 months, even after all treatment was withdrawn. This combination therapy allows macaques to effectively control viremia and reconstitute their immune systems without a need for further therapy. C1 [Byrareddy, Siddappa N.; Villinger, Francois; Ortiz, Kristina T.; Little, Dawn; Reid, Michelle D.; Adsay, Volkan; Mayne, Ann E.; Parslow, Tristram G.; Ansari, Aftab A.] Emory Univ, Sch Med, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. [Arthos, James; Cicala, Claudia; Van Ryk, Donald; Jelicic, Katija] NIAID, Immunoregulat Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Villinger, Francois; Amancha, Praveen K.] Emory Univ, Div Pathol, Yerkes Natl Primate Ctr, Atlanta, GA 30329 USA. [Sidell, Neil] Emory Univ, Sch Med, Dept Obstet & Gynecol, Atlanta, GA 30322 USA. [Kane, Maureen A.; Yu, Jianshi; Jones, Jace W.] Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. [Santangelo, Philip J.; Zurla, Chiara] Georgia Inst Technol, Wallace H Coulter Dept Biomed Engn, Atlanta, GA 30680 USA. [Santangelo, Philip J.; Zurla, Chiara] Emory Univ, Atlanta, GA 30680 USA. [McKinnon, Lyle R.] Ctr AIDS Program Res South Africa CAPRISA, Durban, South Africa. [Arnold, Kelly B.; Woody, Caroline E.] Univ Michigan, Dept Biomed Engn, Ann Arbor, MI 48109 USA. [Walter, Lutz; Roos, Christian; Noll, Angela] German Primate Ctr, Leibniz Inst Primate Res, Primate Genet Lab, Gottingen, Germany. [Cimbro, Raffaello] Johns Hopkins Sch Med, Div Rheumatol, Baltimore, MD 21201 USA. [Byrareddy, Siddappa N.] Univ Nebraska Med Ctr, Dept Pharmacol & Expt Neurosci, Omaha, NE 68198 USA. [Villinger, Francois] Univ Louisiana Lafayette, Off Director, New Iberia Res Ctr, New Iberia, LA 70560 USA. [McKinnon, Lyle R.] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB, Canada. RP Ansari, AA (reprint author), Emory Univ, Sch Med, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. EM pathaaa@emory.edu FU NIAID-NIH [R01 AI098628, R01 AI111907, R01 HD077260]; U.S. Food and Drug Administration [U01FD005266]; Intramural Program of the NIAID, NIH, Bethesda, MD; University of Maryland School of Pharmacy Mass Spectrometry Center [SOP1841-1QB2014]; [NIH-ORIP-OD-51OD-11132] FX The authors are deeply grateful to the veterinary staff of the Yerkes National Primate Center, particularly S. Ehnert, C. Souder, and the staff of the Research Services. We thank K. Reimann for making the primatized mAbs for our studies. We also thank M. Rao and K. Peachman for the SIV reagents used for the antibody characterization studies, K. Rogers for FcRg and TRIM5 alpha sequencing, R. Gelezunias and D. Hazuda for providing the antiretroviral drugs, and A. Weddle and J. Weddle for preparation of all graphics. The data presented in this manuscript are tabulated in the main paper and in the supplementary materials. J.A., C.C., and A.S.F. are inventors on patent no. 20160075786 held by the National Institute of Allergy and Infectious Diseases (NIAID), NIH, that covers the use of antagonists of the interaction between HIV gp120 and alpha4beta7 integrin. The work performed herein was supported by NIAID-NIH R01 AI098628, R01 AI111907, R01 HD077260, U.S. Food and Drug Administration U01FD005266, the Intramural Program of the NIAID, NIH, Bethesda, MD, and the base grant to the Yerkes National Primate Research Center of Emory University NIH-ORIP-OD-51OD-11132. Additional support was provided by the University of Maryland School of Pharmacy Mass Spectrometry Center (SOP1841-1QB2014). J.A., C.C., and A.S.F. are investors in the patent and patent application 20160075786 submitted by the NIAID. The authors declare no competing financial interest. NR 34 TC 7 Z9 7 U1 3 U2 3 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD OCT 14 PY 2016 VL 354 IS 6309 BP 197 EP 202 DI 10.1126/science.aag1276 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EC0UN UT WOS:000387816500037 PM 27738167 ER PT J AU Dowd, KA Ko, SY Morabito, KM Yang, ES Pelc, RS DeMaso, CR Castilho, LR Abbink, P Boyd, M Nityanandam, R Gordon, DN Gallagher, JR Chen, XJ Todd, JP Tsybovsky, Y Harris, A Huang, YJS Higgs, S Vanlandingham, DL Andersen, H Lewis, MG De La Barrera, R Eckels, KH Jarman, RG Nason, MC Barouch, DH Roederer, M Kong, WP Mascola, JR Pierson, TC Graham, BS AF Dowd, Kimberly A. Ko, Sung-Youl Morabito, Kaitlyn M. Yang, Eun Sung Pelc, Rebecca S. DeMaso, Christina R. Castilho, Leda R. Abbink, Peter Boyd, Michael Nityanandam, Ramya Gordon, David N. Gallagher, John Robert Chen, Xuejun Todd, John-Paul Tsybovsky, Yaroslav Harris, Audray Huang, Yan-Jang S. Higgs, Stephen Vanlandingham, Dana L. Andersen, Hanne Lewis, Mark G. De La Barrera, Rafael Eckels, Kenneth H. Jarman, Richard G. Nason, Martha C. Barouch, Dan H. Roederer, Mario Kong, Wing-Pui Mascola, John R. Pierson, Theodore C. Graham, Barney S. TI Rapid development of a DNA vaccine for Zika virus SO SCIENCE LA English DT Article ID JAPANESE ENCEPHALITIS-VIRUS; TICK-BORNE ENCEPHALITIS; DENGUE VIRUS; CANDIDATE VACCINE; HEALTHY-ADULTS; ANTIBODY; NEUTRALIZATION; PREMEMBRANE; PROTECTION; CHALLENGE AB Zika virus (ZIKV) was identified as a cause of congenital disease during the explosive outbreak in the Americas and Caribbean that began in 2015. Because of the ongoing fetal risk from endemic disease and travel-related exposures, a vaccine to prevent viremia in women of childbearing age and their partners is imperative. We found that vaccination with DNA expressing the premembrane and envelope proteins of ZIKV was immunogenic in mice and nonhuman primates, and protection against viremia after ZIKV challenge correlated with serum neutralizing activity. These data not only indicate that DNA vaccination could be a successful approach to protect against ZIKV infection, but also suggest a protective threshold of vaccine induced neutralizing activity that prevents viremia after acute infection. C1 [Dowd, Kimberly A.; Pelc, Rebecca S.; DeMaso, Christina R.; Gordon, David N.; Pierson, Theodore C.] NIAID, Viral Pathogenesis Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Ko, Sung-Youl; Morabito, Kaitlyn M.; Yang, Eun Sung; Castilho, Leda R.; Chen, Xuejun; Todd, John-Paul; Roederer, Mario; Kong, Wing-Pui; Mascola, John R.; Graham, Barney S.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Castilho, Leda R.] Univ Fed Rio de Janeiro, COPPE, Chem Engn Program, Inst Alberto Luiz Coimbra Posgrad & Pesquisa Engn, Rio De Janeiro, Brazil. [Abbink, Peter; Boyd, Michael; Nityanandam, Ramya; Barouch, Dan H.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Ctr Virol & Vaccine Res, Boston, MA 02215 USA. [Gallagher, John Robert; Harris, Audray] NIAID, Struct Informat Unit, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Tsybovsky, Yaroslav] Frederick Natl Lab Canc Res, Electron Microscopy Lab, Canc Res Technol Program, Frederick, MD 21702 USA. [Huang, Yan-Jang S.; Higgs, Stephen; Vanlandingham, Dana L.] Kansas State Univ, Coll Vet Med, Dept Diagnost Med Pathobiol, Manhattan, KS 66506 USA. [Andersen, Hanne; Lewis, Mark G.] Bioqual, Rockville, MD 20852 USA. [De La Barrera, Rafael; Eckels, Kenneth H.] Walter Reed Army Inst Res, Translat Med Branch, Silver Spring, MD 20910 USA. [Jarman, Richard G.] Walter Reed Army Inst Res, Viral Dis Branch, Silver Spring, MD 20910 USA. [Nason, Martha C.] NIAID, Biostat Res Branch, Div Clin Res, NIH, Bethesda, MD 20852 USA. RP Pierson, TC (reprint author), NIAID, Viral Pathogenesis Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.; Graham, BS (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM piersontc@niaid.nih.gov; bgraham@mail.nih.gov FU NIH [VRC5283, VRC5288, VRC8400, VRC8111, VRC4974]; National Institute of Allergy and Infectious Diseases; Department of Diagnostic Medicine and Pathobiology, College of Veterinary Medicine, Kansas State University; Frederick National Laboratory for Cancer Research, NIH [HHSN261200800001E]; Leidos Biomedical Research FX We thank A. Fauci, H. Marston, J. Ledgerwood, S. Whitehead, N. Michael, and M. Crank for scientific advice and comments; J. Stein and M. Young for coordinating collaborations; A. Cook and A. Dodson for the macaque work; K. Leung, L. Wang, W. Shi, K. Foulds, M. Donaldson, B. Fisher, A. Creanga, D. Scorpio, and B. Dekosky for laboratory and animal study support; M. Diamond for ZIKV-specific antibodies provided before publication; N. Bourne and A. Barrett for scientific advice and murine experiments; E. Moseley for serological assays; T. Pato for scientific discussion on the purification of SVPs; B. Hartman for help with figure optimization; R. Larocca and A. Badamchi-Zadeh for murine experiments; and N. Mercado for shipping and coordination. The data are tabulated in the main paper and in the supplementary materials. The opinions or assertions contained herein are the private views of the authors and are not to be construed as reflecting the official views of the U.S. Army or Department of Defense. VRC5283, VRC5288, VRC8400, VRC8111, and VRC4974 are available from NIH under a material transfer agreement. ZIKV strain PRVABC59 challenge stock is available from Kansas State University under a material transfer agreement. A patent application describing candidate ZIKV vaccines has been filed with the following authors listed as inventors: B.S.G., T.C.P., W.-P. K., S.-Y.K., K. A. D., E.S.Y., R.S.P., C.R.D., L.R.C., and J. R. M. This work was supported by intramural funding from the National Institute of Allergy and Infectious Diseases; startup funding from the Department of Diagnostic Medicine and Pathobiology, College of Veterinary Medicine, Kansas State University (to D.L.V.); and federal funds from the Frederick National Laboratory for Cancer Research, NIH, under contract HHSN261200800001E with Leidos Biomedical Research (Y.T.). NR 24 TC 11 Z9 13 U1 27 U2 27 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD OCT 14 PY 2016 VL 354 IS 6309 BP 237 EP 240 DI 10.1126/science.aai9137 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EC0UN UT WOS:000387816500047 PM 27708058 ER PT J AU Burroughs, AM Aravind, L AF Burroughs, A. Maxwell Aravind, L. TI RNA damage in biological conflicts and the diversity of responding RNA repair systems SO NUCLEIC ACIDS RESEARCH LA English DT Article ID EUKARYOTE TRYPANOSOMA-BRUCEI; 23S RIBOSOMAL-RNA; NONCODING Y RNAS; SEQUENTIAL 2',3'-CYCLIC PHOSPHODIESTERASE; BACTERIAL POLYNUCLEOTIDE KINASE; STREPTOMYCES-COELICOLOR A3(2); PRRC-ANTICODON NUCLEASE; LIGATED TRANSFER-RNA; CRISPR-CAS SYSTEMS; SARCIN-RICIN LOOP AB RNA is targeted in biological conflicts by enzymatic toxins or effectors. A vast diversity of systems which repair or 'heal' this damage has only recently become apparent. Here, we summarize the known effectors, their modes of action, and RNA targets before surveying the diverse systems which counter this damage from a comparative genomics viewpoint. RNA-repair systems show a modular organization with extensive shuffling and displacement of the constituent domains; however, a general 'syntax' is strongly maintained whereby systems typically contain: a RNA ligase (either ATP-grasp or RtcB superfamilies), nucleotidyltransferases, enzymes modifying RNA-termini for ligation (phosphatases and kinases) or protection (methylases), and scaffold or cofactor proteins. We highlight poorly-understood or previously-uncharacterized repair systems and components, e.g. potential scaffolding cofactors (Rot/TROVE and SPFH/Band-7 modules) with their respective cognate non-coding RNAs (YRNAs and a novel tRNA-like molecule) and a novel nucleotidyltransferase associating with diverse ligases. These systems have been extensively disseminated by lateral transfer between distant prokaryotic and microbial eukaryotic lineages consistent with intense inter-organismal conflict. Components have also often been 'institutionalized' for non-conflict roles, e.g. in RNA-splicing and in RNAi systems (e.g. in kinetoplastids) which combine a distinct family of RNA-acting prim-pol domains with DICER-like proteins. C1 [Burroughs, A. Maxwell; Aravind, L.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Aravind, L (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM aravind@ncbi.nlm.nih.gov FU Intramural Research Program of the National Institutes of Health (NIH); National Library of Medicine; Oxford University Press - NAR FX Intramural Research Program of the National Institutes of Health (NIH); National Library of Medicine. The open access publication charge for this paper has been waived by Oxford University Press - NAR. NR 307 TC 0 Z9 0 U1 10 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD OCT 14 PY 2016 VL 44 IS 18 BP 8525 EP 8555 DI 10.1093/nar/gkw722 PG 31 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EA9ET UT WOS:000386945000007 PM 27536007 ER PT J AU Zhang, FR Hammack, C Ogden, SC Cheng, YC Lee, EM Wen, ZX Qian, XY Nguyen, HN Li, YJ Yao, B Xu, M Xu, TL Chen, L Wang, ZQ Feng, H Huang, WK Yoon, KJ Shan, C Huang, LX Qin, ZH Christian, KM Shi, PY Xu, MJ Xia, MH Zheng, W Wu, H Song, HJ Tang, HL Ming, GL Jin, P AF Zhang, Feiran Hammack, Christy Ogden, Sarah C. Cheng, Yichen Lee, Emily M. Wen, Zhexing Qian, Xuyu Ha Nam Nguyen Li, Yujing Yao, Bing Xu, Miao Xu, Tianlei Chen, Li Wang, Zhiqin Feng, Hao Huang, Wei-Kai Yoon, Ki-jun Shan, Chao Huang, Luoxiu Qin, Zhaohui Christian, Kimberly M. Shi, Pei-Yong Xu, Mingjiang Xia, Menghang Zheng, Wei Wu, Hao Song, Hongjun Tang, Hengli Ming, Guo-Li Jin, Peng TI Molecular signatures associated with ZIKV exposure in human cortical neural progenitors SO NUCLEIC ACIDS RESEARCH LA English DT Article ID VIRUS CAPSID PROTEIN; INDUCED HEMORRHAGE; MOUSE MODEL; GENE; EXPRESSION; CELLS; P53; INHIBITOR; ORGANOIDS; APOPTOSIS AB Zika virus (ZIKV) infection causes microcephaly and has been linked to other brain abnormalities. How ZIKV impairs brain development and function is unclear. Here we systematically profiled transcriptomes of human neural progenitor cells exposed to Asian ZIKV(C), African ZIKV(M), and dengue virus (DENV). In contrast to the robust global transcriptome changes induced by DENV, ZIKV has a more selective and larger impact on expression of genes involved in DNA replication and repair. While overall expression profiles are similar, ZIKV(C), but not ZIKV(M), induces upregulation of viral response genes and TP53. P53 inhibitors can block the apoptosis induced by both ZIKV(C) and ZIKV(M) in hNPCs, with higher potency against ZIKV(C)-induced apoptosis. Our analyses reveal virus- and strain-specific molecular signatures associated with ZIKV infection. These datasets will help to investigate ZIKV-host interactions and identify neurovirulence determinants of ZIKV. C1 [Zhang, Feiran; Li, Yujing; Yao, Bing; Wang, Zhiqin; Huang, Luoxiu; Jin, Peng] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA 30322 USA. [Hammack, Christy; Ogden, Sarah C.; Cheng, Yichen; Lee, Emily M.; Tang, Hengli] Florida State Univ, Dept Biol Sci, B-157, Tallahassee, FL 32306 USA. [Wen, Zhexing; Qian, Xuyu; Ha Nam Nguyen; Huang, Wei-Kai; Yoon, Ki-jun; Christian, Kimberly M.; Song, Hongjun; Ming, Guo-Li] Johns Hopkins Univ, Sch Med, Inst Cell Engn, Baltimore, MD 21205 USA. [Wen, Zhexing; Ha Nam Nguyen; Yoon, Ki-jun; Christian, Kimberly M.; Song, Hongjun; Ming, Guo-Li] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Wen, Zhexing] Emory Univ, Sch Med, Dept Psychiat & Behav Sci, Atlanta, GA 30322 USA. [Wen, Zhexing] Emory Univ, Sch Med, Dept Cell Biol, Atlanta, GA 30322 USA. [Wen, Zhexing] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA. [Qian, Xuyu] Johns Hopkins Univ, Sch Med, Biomed Engn Grad Program, Baltimore, MD 21205 USA. [Xu, Miao; Xia, Menghang; Zheng, Wei] NIH, Natl Ctr Adv Translat Sci, 9800 Med Ctr Dr, Bethesda, MD 20892 USA. [Xu, Tianlei; Chen, Li; Feng, Hao; Qin, Zhaohui; Wu, Hao] Emory Univ, Dept Biostat & Bioinformat, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Huang, Wei-Kai] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Shan, Chao; Shi, Pei-Yong] Univ Texas Med Branch, Sealy Ctr Struct Biol & Mol Biophys, Dept Pharmacol & Toxicol, Dept Biochem & Mol Biol, Galveston, TX 77555 USA. [Xu, Mingjiang] Univ Miami, Miller Sch Med, Dept Biochem & Mol Biol, Sylvester Comprehens Canc Ctr, Miami, FL 33136 USA. [Song, Hongjun; Ming, Guo-Li] Johns Hopkins Univ, Sch Med, Solomon Snyder Dept Neurosci, Baltimore, MD 21205 USA. [Ming, Guo-Li] Johns Hopkins Univ, Dept Psychiat & Behav Sci, Sch Med, Baltimore, MD 21205 USA. RP Jin, P (reprint author), Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA 30322 USA.; Tang, HL (reprint author), Florida State Univ, Dept Biol Sci, B-157, Tallahassee, FL 32306 USA.; Song, HJ; Ming, GL (reprint author), Johns Hopkins Univ, Sch Med, Inst Cell Engn, Baltimore, MD 21205 USA.; Song, HJ; Ming, GL (reprint author), Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA.; Song, HJ; Ming, GL (reprint author), Johns Hopkins Univ, Sch Med, Solomon Snyder Dept Neurosci, Baltimore, MD 21205 USA.; Ming, GL (reprint author), Johns Hopkins Univ, Dept Psychiat & Behav Sci, Sch Med, Baltimore, MD 21205 USA. EM shongju1@jhmi.edu; tang@bio.fsu.edu; gming1@jhmi.edu; peng.jin@emory.edu RI Zheng, Wei/J-8889-2014; OI Zheng, Wei/0000-0003-1034-0757; Qian, Xuyu/0000-0001-5944-3816 FU National Institutes of Health (NIH) [AI119530, AI111250, NS048271, NS095348, NS047344, MH087874, NS079625]; Maryland Stem Cell Research Fund; start-up fund; College of Arts and Sciences and Department of Biological Science at Florida State University seed fund; Emory Genetics Discovery Fund; Emory Integrated Genomics Core (EIGC); Emory University School of Medicine; National Center for Advancing Translational Sciences of the National Institutes of Health [UL1TR000454]; NIH FX National Institutes of Health (NIH) [AI119530 and AI111250 to H.T., NS048271 and NS095348 to G-L.M., NS047344 and MH087874 to H.S., NS079625 to P.J.]; Maryland Stem Cell Research Fund (to H.S. and Z.W.); start-up fund (to H.S. and G-L.M.); College of Arts and Sciences and Department of Biological Science at Florida State University seed fund (to H.T.); Emory Genetics Discovery Fund (to P.J.). This study was supported in part by the Emory Integrated Genomics Core (EIGC), which is subsidized by the Emory University School of Medicine and is one of the Emory Integrated Core Facilities. Additional support was provided by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR000454. The content is solely the responsibility of the authors and does not necessarily reflect the official views of the National Institutes of Health. Funding for open access charge: NIH. NR 51 TC 6 Z9 6 U1 10 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD OCT 14 PY 2016 VL 44 IS 18 BP 8610 EP 8620 DI 10.1093/nar/gkw765 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EA9ET UT WOS:000386945000012 PM 27580721 ER PT J AU Peng, ZM Liao, ZP Matsumoto, Y Yang, A Tomkinson, AE AF Peng, Zhimin Liao, Zhongping Matsumoto, Yoshihiro Yang, Austin Tomkinson, Alan E. TI Human DNA Ligase I Interacts with and Is Targeted for Degradation by the DCAF7 Specificity Factor of the Cul4-DDB1 Ubiquitin Ligase Complex SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE cell cycle; DNA replication; proliferating cell nuclear antigen (PCNA); proteasome; protein turnover; proteolysis; ubiquitin; ubiquitin ligase; DNA ligase I; ubiquitylation ID CELL NUCLEAR ANTIGEN; DOUBLE-STRAND BREAKS; MOLECULAR-CLONING; REPLICATION FORK; GENE-EXPRESSION; AMINO-ACIDS; S-PHASE; REPAIR; DAMAGE; PHOSPHORYLATION AB The synthesis, processing, and joining of Okazaki fragments during DNA replication is complex, requiring the sequential action of a large number of proteins. Proliferating cell nuclear antigen, a DNA sliding clamp, interacts with and coordinates the activity of several DNA replication proteins, including the enzymes flap endonuclease 1 (FEN-1) and DNA ligase I that complete the processing and joining of Okazaki fragments, respectively. Although it is evident that maintaining the appropriate relative stoichiometry of FEN-1 and DNA ligase I, which compete for binding to proliferating cell nuclear antigen, is critical to prevent genomic instability, little is known about how the steady state levels of DNA replication proteins are regulated, in particular the proteolytic mechanisms involved in their turnover. Because DNA ligase I has been reported to be ubiquitylated, we used a proteomic approach to map ubiquitylation sites and screen for DNA ligase I-associated E3 ubiquitin ligases. We identified three ubiquitylated lysine residues and showed that DNA ligase I interacts with and is targeted for ubiquitylation by DCAF7, a specificity factor for the Cul4-DDB1 complex. Notably, knockdown of DCAF7 reduced the degradation of DNA ligase I in response to inhibition of proliferation and replacement of ubiquitylated lysine residues reduced the in vitro ubiquitylation of DNA ligase I by Cul4-DDB1 and DCAF7. In contrast, a different E3 ubiquitin ligase regulates FEN-1 turnover. Thus, although the expression of many of the genes encoding DNA replication proteins is coordinately regulated, our studies reveal that different mechanisms are involved in the turnover of these proteins. C1 [Peng, Zhimin; Matsumoto, Yoshihiro; Tomkinson, Alan E.] Univ New Mexico, Dept Internal Med, Albuquerque, NM 87131 USA. [Peng, Zhimin; Matsumoto, Yoshihiro; Tomkinson, Alan E.] Univ New Mexico, Dept Mol Genet & Microbiol, Albuquerque, NM 87131 USA. [Peng, Zhimin; Matsumoto, Yoshihiro; Tomkinson, Alan E.] Univ New Mexico, Ctr Canc, Albuquerque, NM 87131 USA. [Liao, Zhongping; Yang, Austin] Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. [Liao, Zhongping; Yang, Austin] Univ Maryland, Sch Med, Marlene & Stewart Greenebaum Canc Ctr, Baltimore, MD 21201 USA. [Liao, Zhongping] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Yang, Austin] NIA, NIH, Bethesda, MD 20892 USA. RP Tomkinson, AE (reprint author), Canc Res Facil, 915 Camino Salud,1 Univ New Mexico, Albuquerque, NM 87131 USA. EM atomkinson@salud.unm.edu FU University of New Mexico Comprehensive Cancer Center [P30 CA118100]; National Institute of Health [R01 GM057479] FX This work was supported by the University of New Mexico Comprehensive Cancer Center (Grant P30 CA118100) and National Institute of Health Grant R01 GM057479 (to A. E. T.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 58 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 14 PY 2016 VL 291 IS 42 BP 21893 EP 21902 DI 10.1074/jbc.M116.746198 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EA1DL UT WOS:000386332600006 PM 27573245 ER PT J AU Chen, KH Liu, SH Leysath, CE Miller-Randolph, S Zhang, Y Fattah, R Bugge, TH Leppla, SH AF Chen, Kuang-Hua Liu, Shihui Leysath, Clinton E. Miller-Randolph, Sharmina Zhang, Yi Fattah, Rasem Bugge, Thomas H. Leppla, Stephen H. TI Anthrax Toxin Protective Antigen Variants That Selectively Utilize either the CMG2 or TEM8 Receptors for Cellular Uptake and Tumor Targeting SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE anthrax toxin; mutagenesis in vitro; phage display; receptor; tumor therapy; CMG2; TEM8; protective antigen ID CAPILLARY MORPHOGENESIS PROTEIN-2; CRYSTAL-STRUCTURE; LETHAL FACTOR; CELLS; INTERNALIZATION; PATHOGENESIS; PROTEASE; BINDING; FURIN; HOST AB The protective antigen (PA) moiety of anthrax toxin binds to cellular receptors and mediates the translocation of the two enzymatic moieties of the toxin to the cytosol. Two PA receptors are known, with capillary morphogenesis protein 2 (CMG2) being the more important for pathogenesis and tumor endothelial marker 8 (TEM8) playing a minor role. The C-terminal PA domain 4 (PAD4) has extensive interactions with the receptors and is required for binding. Our previous study identified PAD4 variants having enhanced TEM8 binding specificity. To obtain PA variants that selectively bind to CMG2, here we performed phage display selections using magnetic beads having bound CMG2. We found that PA residue isoleucine 656 plays a critical role in PA binding to TEM8 but has a much lesser effect on PA binding to CMG2. We further characterized the role of residue 656 in distinguishing PA binding to CMG2 versus TEM8 by substituting it with the other 19 amino acids. Of the resulting variants, PA I656Q and PA I656V had significantly reduced activity on TEM8-expressing CHO cells but maintained their activity on CMG2-expressing CHO cells. The preference of these PA mutants for CMG2 over TEM8 was further demonstrated using mouse embryonic fibroblast cells and mice deficient in the CMG2 and/or the TEM8 receptors. The structural basis of the alterations in the receptor binding activities of these mutants is also discussed. C1 [Chen, Kuang-Hua; Liu, Shihui; Leysath, Clinton E.; Miller-Randolph, Sharmina; Zhang, Yi; Fattah, Rasem; Leppla, Stephen H.] NIAID, Parasit Dis Lab, NIH, Bldg 33,Rm 1W20B, Bethesda, MD 20892 USA. [Liu, Shihui; Bugge, Thomas H.] NIDCR, Proteases & Tissue Remodeling Sect, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. [Leysath, Clinton E.] Texas A&M Hlth Sci Ctr, Ctr Innovat Adv Dev & Mfg, Off Publ Hlth Preparedness & Response, 8441 State Hwy 47,Suite 3200, Bryan, TX 77807 USA. RP Leppla, SH (reprint author), NIAID, Parasit Dis Lab, NIH, Bldg 33,Rm 1W20B, Bethesda, MD 20892 USA. EM sleppla@niaid.nih.gov FU NIAID, National Institutes of Health; NIDCR, National Institutes of Health FX This work was supported by the intramural research programs of the NIAID and the NIDCR, National Institutes of Health. K. H. C., S. L., C. E. L., T. H. B., and S. H. L. are inventors on patents of targeted toxins that have all been assigned to the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 30 TC 0 Z9 0 U1 5 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 14 PY 2016 VL 291 IS 42 BP 22021 EP 22029 DI 10.1074/jbc.M116.753301 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EA1DL UT WOS:000386332600017 PM 27555325 ER PT J AU Kravitz, AV O'Neal, TJ Friend, DM AF Kravitz, Alexxai V. O'Neal, Timothy J. Friend, Danielle M. TI Do Dopaminergic Impairments Underlie Physical Inactivity in People with Obesity? SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Review DE obesity; dopamine; exercise; physical activity; physical activity promotion; Parkinson's disease; movement disorders ID DIET-INDUCED OBESITY; HIGH-FAT DIET; D-2/3 RECEPTOR AVAILABILITY; CHRONIC-SCHIZOPHRENIA INPATIENTS; INDUCED MOVEMENT-DISORDERS; GASTRIC BYPASS-SURGERY; LOW-ENERGY INTAKE; BODY-MASS INDEX; BASAL GANGLIA; WEIGHT-LOSS AB Obesity is associated with physical inactivity, which exacerbates the negative health consequences of obesity. Despite a wide consensus that people with obesity should exercise more, there are few effective methods for increasing physical activity in people with obesity. This lack is reflected in our limited understanding of the cellular and molecular causes of physical inactivity in obesity. We hypothesize that impairments in dopamine signaling contribute to physical inactivity in people with obesity, as in classic movement disorders such as Parkinson's disease. Here, we review two lines of evidence supporting this hypothesis: (1) chronic exposure to obesogenic diets has been linked to impairments in dopamine synthesis, release, and receptor function, particularly in the striatum, and (2) striatal dopamine is necessary for the proper control of movement. Identifying the biological determinants of physical inactivity may lead to more effective strategies for increasing physical activity in people with obesity, as well as improve our understanding of why it is difficult for people with obesity to alter their levels of physical activity. C1 [Kravitz, Alexxai V.; O'Neal, Timothy J.; Friend, Danielle M.] Natl Inst Diabet & Digest & Kidney Dis, NIH, Bethesda, MD 20892 USA. [Kravitz, Alexxai V.] NIDA, NIH, Baltimore, MD 21224 USA. RP Kravitz, AV (reprint author), Natl Inst Diabet & Digest & Kidney Dis, NIH, Bethesda, MD 20892 USA.; Kravitz, AV (reprint author), NIDA, NIH, Baltimore, MD 21224 USA. EM lex.kravitz@nih.gov FU NIH Intramural research program FX This work was funded by the NIH Intramural research program. We thank Kavya Devarakonda for comments on this manuscript. NR 120 TC 1 Z9 1 U1 12 U2 12 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD OCT 14 PY 2016 VL 10 AR 514 DI 10.3389/fnhum.2016.00514 PG 8 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA DZ5HL UT WOS:000385892500001 PM 27790107 ER PT J AU Wachter, C Eiden, LE Naumann, N Depboylu, C Weihe, E AF Waechter, Christian Eiden, Lee E. Naumann, Nedye Depboylu, Candan Weihe, Eberhard TI Loss of cerebellar neurons in the progression of lentiviral disease: effects of CNS-permeant antiretroviral therapy SO JOURNAL OF NEUROINFLAMMATION LA English DT Article DE Human immunodeficiency virus (HIV); Neuro-AIDS; Dementia; Neurodegeneration; Antiretroviral therapy ID SIMIAN IMMUNODEFICIENCY VIRUS; BLOOD-BRAIN-BARRIER; CENTRAL-NERVOUS-SYSTEM; AIDS DEMENTIA COMPLEX; PURKINJE-CELL LOSS; HIV-INFECTION; NEUROCOGNITIVE DISORDERS; RHESUS-MONKEYS; SPINOCEREBELLAR ATAXIA; COGNITIVE IMPAIRMENT AB Background: The majority of investigations on HIV-associated neurocognitive disorders (HAND) neglect the cerebellum in spite of emerging evidence for its role in higher cognitive functions and dysfunctions in common neurodegenerative diseases. Methods: We systematically investigated the molecular and cellular responses of the cerebellum as contributors to lentiviral infection-induced neurodegeneration, in the simian immunodeficiency virus (SIV)-infected rhesus macaque model for HIV infection and HAND. Four cohorts of animals were studied: non-infected controls, SIV-infected asymptomatic animals, and SIV-infected AIDS-diseased animals with and without brain-permeant antiretroviral treatment. The antiretroviral utilized was 6-chloro-2', 3'-dideoxyguanosine (6-Cl-ddG), a CNS-permeable nucleoside reverse transcriptase inhibitor. Quantitation of granule cells and Purkinje cells, of an established biomarker of SIV infection (gp41), of microglial/monocyte/macrophage markers (IBA-1, CD68, CD163), and of the astroglial marker (GFAP) were used to reveal cell-specific cerebellar responses to lentiviral infection and antiretroviral therapy (ART). The macromolecular integrity of the blood brain barrier was tested by albumin immunohistochemistry. Results: Productive CNS infection was observed in the symptomatic stage of disease, and correlated with extensive microglial/macrophage and astrocyte activation, and widespread macromolecular blood brain barrier defects. Signs of productive infection, and inflammation, were reversed upon treatment with 6-Cl-ddG, except for a residual low-grade activation of microglial cells and astrocytes. There was an extensive loss of granule cells in the SIV-infected asymptomatic cohort, which was further increased in the symptomatic stage of the disease and persisted after 6-Cl-ddG (administered after the onset of symptoms of AIDS). In the symptomatic stage, Purkinje cell density was reduced. Purkinje cell loss was likewise unaffected by 6-Cl-ddG treatment at this time. Conclusions: Our findings suggest that neurodegenerative mechanisms are triggered by SIV infection early in the disease process, i.e., preceding large-scale cerebellar productive infection and marked neuroinflammation. These affect primarily granule cells early in disease, with later involvement of Purkinje cells, indicating differential vulnerability of the two neuronal populations. The results presented here indicate a role for the cerebellum in neuro-AIDS. They also support the conclusion that, in order to attenuate the development of motor and cognitive dysfunctions in HIV-positive individuals, CNS-permeant antiretroviral therapy combined with anti-inflammatory and neuroprotective treatment is indicated even before overt signs of CNS inflammation occur. C1 [Waechter, Christian; Naumann, Nedye; Depboylu, Candan; Weihe, Eberhard] Univ Marburg, Inst Anat & Cell Biol, Mol Neurosci, Robert Koch Str 8, D-35032 Marburg, Germany. [Eiden, Lee E.] NIMH, Sect Mol Neurosci, Lab Cellular & Mol Regulat, NIH, Bethesda, MD 20892 USA. [Depboylu, Candan] Univ Marburg, Dept Neurol, Expt Neurol, Marburg, Germany. RP Weihe, E (reprint author), Univ Marburg, Inst Anat & Cell Biol, Mol Neurosci, Robert Koch Str 8, D-35032 Marburg, Germany. EM weihe@staff.uni-marburg.de FU Volkswagen Foundation [I-75184] FX This study was supported by a grant of the Volkswagen Foundation (I-75184) to LE and EW. NR 75 TC 0 Z9 0 U1 3 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-2094 J9 J NEUROINFLAMM JI J. Neuroinflamm. PD OCT 14 PY 2016 VL 13 DI 10.1186/s12974-016-0726-0 PG 13 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA DY7MQ UT WOS:000385313800001 ER PT J AU Cha, SA Yun, JS Lim, TS Min, K Song, KH Yoo, KD Park, YM Ahn, YB Ko, SH AF Cha, Seon-Ah Yun, Jae-Seung Lim, Tae-Seok Min, Kyoungil Song, Ki-Ho Yoo, Ki-Dong Park, Yong-Moon Ahn, Yu-Bae Ko, Seung-Hyun TI Diabetic Cardiovascular Autonomic Neuropathy Predicts Recurrent Cardiovascular Diseases in Patients with Type 2 Diabetes SO PLOS ONE LA English DT Article ID SILENT-MYOCARDIAL-ISCHEMIA; MELLITUS; RISK; ASSOCIATION; MORTALITY; STROKE; EPIDEMIOLOGY; INFARCTION; STATEMENT; INDIVIDUALS AB Cardiovascular autonomic neuropathy (CAN) is a risk factor for cardiovascular disease (CVD) and mortality in patients with type 2 diabetes. This study evaluated the relationship between CAN and recurrent CVD in type 2 diabetes. A total of 206 patients with type 2 diabetes who had a history of CVD within 3 years of enrollment were consecutively recruited from January 2001 to December 2009 and followed-up until December 2015. Cardiovascular autonomic function tests were performed using the following heart rate variability parameters: expiration-to-inspiration ratio, response to Valsalva maneuver and standing. We estimated the recurrence of CVD events during the follow-up period. A total of 159 (77.2%) of the 206 patients enrolled completed the follow up, and 78 (49.1%) patients had recurrent episodes of CVD, with an incidence rate of 75.6 per 1,000 patient-years. The mean age and diabetes duration were 62.5 +/- 8.7 and 9.2 +/- 6.9 years, respectively. Patients who developed recurrent CVD also exhibited hypertension (P = 0.004), diabetic nephropathy (P = 0.012), higher mean systolic blood pressure (P = 0.006), urinary albumin excretion (P = 0.015), and mean triglyceride level (P = 0.035) than did patients without recurrent CVD. Multivariable Cox hazard regression analysis revealed that definite CAN was significantly associated with an increased risk of recurrent CVD (hazard ratio [HR] 3.03; 95% confidence interval [CI] 1.39-6.60; P = 0.005). Definite CAN was an independent predictor for recurrent CVD in patients with type 2 diabetes who had a known prior CVD event. C1 [Cha, Seon-Ah; Yun, Jae-Seung; Lim, Tae-Seok; Min, Kyoungil; Song, Ki-Ho; Ahn, Yu-Bae; Ko, Seung-Hyun] Catholic Univ Korea, Div Endocrinol & Metab, Dept Internal Med, Coll Med, Seoul, South Korea. [Yoo, Ki-Dong] Catholic Univ Korea, Div Cardiol, Dept Internal Med, Coll Med, Seoul, South Korea. [Park, Yong-Moon] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. RP Ko, SH (reprint author), Catholic Univ Korea, Div Endocrinol & Metab, Dept Internal Med, Coll Med, Seoul, South Korea. EM kosh@catholic.ac.kr OI Ko, Seung-Hyun/0000-0003-3703-1479; PARK, YONG-MOON/0000-0002-5879-6879 NR 42 TC 0 Z9 0 U1 2 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 14 PY 2016 VL 11 IS 10 AR e0164807 DI 10.1371/journal.pone.0164807 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ0DG UT WOS:000385507000068 PM 27741306 ER PT J AU Baughman, BM Wang, HC An, Y Kireev, D Stashko, MA Jessen, HJ Pearce, KH Frye, SV Shears, SB AF Baughman, Brandi M. Wang, Huanchen An, Yi Kireev, Dmitri Stashko, Michael A. Jessen, Henning J. Pearce, Kenneth H. Frye, Stephen V. Shears, Stephen B. TI A High-Throughput Screening-Compatible Strategy for the Identification of Inositol Pyrophosphate Kinase Inhibitors SO PLOS ONE LA English DT Article ID ISOTHERMAL TITRATION CALORIMETRY; DRUG DISCOVERY; BINDING; HEXAKISPHOSPHATE; ASSAY; METABOLISM; LIBRARIES; STRESS; DESIGN; FAMILY AB Pharmacological tools-'chemical probes'-that intervene in cell signaling cascades are important for complementing genetically-based experimental approaches. Probe development frequently begins with a high-throughput screen (HTS) of a chemical library. Herein, we describe the design, validation, and implementation of the first HTS-compatible strategy against any inositol phosphate kinase. Our target enzyme, PPIP5K, synthesizes 'highenergy' inositol pyrophosphates (PP-InsPs), which regulate cell function at the interface between cellular energy metabolism and signal transduction. We optimized a time-resolved, fluorescence resonance energy transfer ADP-assay to record PPIP5K-catalyzed, ATP-driven phosphorylation of 5-InsP7 to 1,5-InsP8 in 384-well format (Z' = 0.82 +/- 0.06). We screened a library of 4745 compounds, all anticipated to be membrane-permeant, which are known-or conjectured based on their structures-to target the nucleotide binding site of protein kinases. At a screening concentration of 13 mu M, fifteen compounds inhibited PPIP5K > 50%. The potency of nine of these hits was confirmed by dose-response analyses. Three of these molecules were selected from different structural clusters for analysis of binding to PPIP5K, using isothermal calorimetry. Acceptable thermograms were obtained for two compounds, UNC10112646 (Kd = 7.30 +/- 0.03 mu M) and UNC10225498 (Kd = 1.37 +/- 0.03 mu M). These Kd values lie within the 1 +/- 10 mu M range generally recognized as suitable for further probe development. In silico docking data rationalizes the difference in affinities. HPLC analysis confirmed that UNC10225498 and UNC10112646 directly inhibit PPIP5K-catalyzed phosphorylation of 5-InsP7 to 1,5-InsP8; kinetic experiments showed inhibition to be competitive with ATP. No other biological activity has previously been ascribed to either UNC10225498 or UNC10112646; moreover, at 10 mu M, neither compound inhibits IP6K2, a structurally-unrelated PP-InsP kinase. Our screening strategy may be generally applicable to inhibitor discovery campaigns for other inositol phosphate kinases. C1 [Baughman, Brandi M.; Wang, Huanchen; Shears, Stephen B.] NIEHS, Signal Transduct Lab, Res Triangle Pk, NC 27709 USA. [Baughman, Brandi M.; An, Yi; Kireev, Dmitri; Stashko, Michael A.; Pearce, Kenneth H.; Frye, Stephen V.] Univ Nortth Carolina, Ctr Integrat Chem Biol & Drug Discovery, Chapel Hill, NC USA. [Jessen, Henning J.] Univ Freiburg, Inst Organ Chem, D-79104 Freiburg, Germany. RP Shears, SB (reprint author), NIEHS, Signal Transduct Lab, POB 12233, Res Triangle Pk, NC 27709 USA. EM brandi.baughman@nih.gov RI Jessen, Henning/F-5108-2014 OI Jessen, Henning/0000-0002-1025-9484 FU Intramural Research Program of the NIH/National Institute of Environmental Health Sciences; Swiss National Science Foundation [PP00P2_157607]; National Institutes of Health [R01DK101645] FX This work was supported by the Intramural Research Program of the NIH/National Institute of Environmental Health Sciences. HJJ acknowledges support from the Swiss National Science Foundation (grant number PP00P2_157607). KHP and SVF acknowledge the support of the National Institutes of Health under Award Number R01DK101645. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 48 TC 0 Z9 0 U1 4 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 13 PY 2016 VL 11 IS 10 AR e0164378 DI 10.1371/journal.pone.0164378 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ0CV UT WOS:000385505800061 PM 27736936 ER PT J AU Franceschini, N Carty, CL Lu, YC Tao, R Sung, YJ Manichaikul, A Haessler, J Fornage, M Schwander, K Zubair, N Bien, S Hindorff, LA Guo, XQ Bielinski, SJ Ehret, G Kaufman, JD Rich, SS Carlson, CS Bottinger, EP North, KE Rao, DC Chakravarti, A Barrett, PQ Loos, RJF Buyske, S Kooperberg, C AF Franceschini, Nora Carty, Cara L. Lu, Yingchang Tao, Ran Sung, Yun Ju Manichaikul, Ani Haessler, Jeff Fornage, Myriam Schwander, Karen Zubair, Niha Bien, Stephanie Hindorff, Lucia A. Guo, Xiuqing Bielinski, Suzette J. Ehret, Georg Kaufman, Joel D. Rich, Stephen S. Carlson, Christopher S. Bottinger, Erwin P. North, Kari E. Rao, D. C. Chakravarti, Aravinda Barrett, Paula Q. Loos, Ruth J. F. Buyske, Steven Kooperberg, Charles TI Variant Discovery and Fine Mapping of Genetic Loci Associated with Blood Pressure Traits in Hispanics and African Americans SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; LINKAGE DISEQUILIBRIUM; POTASSIUM CHANNELS; HYPERTENSION; METAANALYSIS; POPULATIONS; PREVALENCE; AWARENESS; INDIVIDUALS; LATINOS AB Despite the substantial burden of hypertension in US minority populations, few genetic studies of blood pressure have been conducted in Hispanics and African Americans, and it is unclear whether many of the established loci identified in European-descent populations contribute to blood pressure variation in non-European descent populations. Using the Metabochip array, we sought to characterize the genetic architecture of previously identified blood pressure loci, and identify novel cardiometabolic variants related to systolic and diastolic blood pressure in a multi-ethnic US population including Hispanics (n = 19,706) and African Americans (n = 18,744). Several known blood pressure loci replicated in African Americans and Hispanics. Fourteen variants in three loci (KCNK3, FGF5, ATXN2-SH2B3) were significantly associated with blood pressure in Hispanics. The most significant diastolic blood pressure variant identified in our analysis, rs2586886/KCNK3 (P = 5.2 x 10(-9)), also replicated in independent Hispanic and European-descent samples. African American and trans-ethnic meta-analysis data identified novel variants in the FGF5, ULK4 and HOXA-EVX1 loci, which have not been previously associated with blood pressure traits. Our identification and independent replication of variants in KCNK3, a gene implicated in primary hyperaldosteronism, as well as a variant in HOTTIP (HOXA-EVX1) suggest that further work to clarify the roles of these genes may be warranted. Overall, our findings suggest that loci identified in European descent populations also contribute to blood pressure variation in diverse populations including Hispanics and African Americans D populations that are understudied for hypertension genetic risk factors. C1 [Franceschini, Nora; North, Kari E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Carty, Cara L.] George Washington Univ, Ctr Translat Sci, Washington, DC USA. [Carty, Cara L.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Lu, Yingchang; Bottinger, Erwin P.] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA. [Tao, Ran] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Sung, Yun Ju; Schwander, Karen; Rao, D. C.] Washington Univ, Div Biostat, St Louis, MO USA. [Manichaikul, Ani; Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA 22908 USA. [Haessler, Jeff; Zubair, Niha; Bien, Stephanie; Carlson, Christopher S.; Kooperberg, Charles] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Brown Fdn Inst Mol Med, Houston, TX 77030 USA. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Hindorff, Lucia A.] NHGRI, Div Genom Med, NIH, Bethesda, MD 20892 USA. [Guo, Xiuqing] Univ Calif Los Angeles, Med Ctr, LABiomed Harbor, Inst Translat Genom & Populat Sci, Torrance, CA USA. [Guo, Xiuqing] Univ Calif Los Angeles, Med Ctr, LABiomed Harbor, Dept Pediat, Torrance, CA USA. [Bielinski, Suzette J.] Mayo Clin, Div Epidemiol, Dept Hlth Sci Res, Rochester, MN USA. [Ehret, Georg; Chakravarti, Aravinda] Johns Hopkins Univ, Sch Med, Ctr Complex Dis Genom, Baltimore, MD USA. [Ehret, Georg] Univ Hosp Geneva, Dept Specialties Internal Med, Geneva, Switzerland. [Kaufman, Joel D.] Univ Washington, Dept Environm & Occupat Hlth Sci Epidemiol & Med, Seattle, WA 98195 USA. [Barrett, Paula Q.] Univ Virginia, Dept Pharmacol, Charlottesville, VA 22908 USA. [Buyske, Steven] Rutgers State Univ, Dept Stat & Biostat, Piscataway, NJ USA. RP Franceschini, N (reprint author), Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. EM noraf@unc.edu FU Population Architecture Using Genomics and Epidemiology (PAGE) program - National Human Genome Research Institute (NHGRI) [U01HG004803, U01HG004798, U01HG004802, U01HG004790, U01HG004801]; Epidemiology of putative genetic variants: The Women's Health Initiative through the NHGRI PAGE program [U01HG004790]; National Heart, Lung, and Blood Institute (NHLBI) [R01HL089717, N02-HL-64278]; National Institutes of Health (NIH); U.S. Department of Health and Human Services [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C]; Genetic Epidemiology of Causal Variants Across the Life Course (CALiCo) program [U01HG004803]; National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, R01HL59367, R01HL086694]; NHGRI [U01HG004402, R01 HG006124]; NIH [HHSN268200625226C]; PAGE Coordinating Center [UL1RR025005]; NIH National Center for Advancing Translational Sciences [UL1TR000075]; MESA [N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-001079, UL1-TR-000040]; National Center for Research Resources [UL1RR033176]; National Center for Advancing Translational Sciences [UL1TR000124]; STAR research assistance agreement [RD831697]; National Center for Advancing Translational Sciences, CTSI [UL1TR000124]; National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) [DK063491]; Andrea and Charles Bronfman Philanthropies; [R21HL123677]; [5 R01 HL086694]; [R01HL071051]; [R01HL071205]; [R01HL071250]; [R01HL071251]; [R01HL071258]; [R01HL071259]; [R01HL98077]; [HL071205]; [P50ES015915] FX This work was supported by the Population Architecture Using Genomics and Epidemiology (PAGE) program which is funded by the National Human Genome Research Institute (NHGRI) [U01HG004803 (to the Genetic Epidemiology of Causal Variants Across the Life Course (CALiCo) program, U01HG004798 (to the Epidemiologic Architecture of Genes Linked to Environment (EAGLE)), U01HG004802 (to the Multi-Ethnic Cohort (MEC)), U01HG004790 (to the Women's Health Initiative (WHI)), and U01HG004801 (to the PAGE Coordinating Center), and the irrespective NHGRI ARRA supplements. The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. The complete list of PAGE members can be found at http://www.pagestudy.org. The data and materials included in this report result from a collaboration between the following studies. Funding support for the "Epidemiology of putative genetic variants: The Women's Health Initiative" study is provided through the NHGRI PAGE program (U01HG004790 and its NHGRI ARRA supplement). The WHI program is funded by the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. Funding support for the Genetic Epidemiology of Causal Variants Across the Life Course (CALiCo) program is provided through the NHGRI PAGE program [U01HG004803 and its NHGRI ARRA supplement]. The following CALiCo studies contributed to this manuscript and are funded by the following agencies: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; NHGRI contract U01HG004402; and NIH contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the NIH and NIH Roadmap for Medical Research. Assistance with phenotype harmonization, SNP selection and annotation, data cleaning, data management, integration and dissemination, and general study coordination was provided by the PAGE Coordinating Center [U01HG004801-01 and its NHGRI ARRA supplement]. The National Institutes of Mental Health also contributes to the support for the PAGE Coordinating Center. Additional support for this work was provided by the NHGRI through [R01 HG006124]. CLC received support from UL1TR000075 from the NIH National Center for Advancing Translational Sciences. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Center for Advancing Translational Sciences or the NIH. NF receives support from R21HL123677. PQB receives support from NHLBI grant R01HL089717. Metabochip genotyping for the HyperGen and GenNet studies was supported by 5 R01 HL086694. MESA was conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-001079, and UL1-TR-000040. MESA Family is conducted and supported by the NHLBI in collaboration with MESA investigators.; Support is provided by grants and contracts R01HL071051, R01HL071205, R01HL071250, R01HL071251, R01HL071258, R01HL071259, by the National Center for Research Resources, Grant UL1RR033176, and the National Center for Advancing Translational Sciences, Grant UL1TR000124. This publication was developed under a STAR research assistance agreement, No. RD831697 (MESA Air), awarded by the U.S Environmental protection Agency (EPA). It has not been formally reviewed by the EPA. The views expressed in this document are solely those of the authors and the EPA does not endorse any products or commercial services mentioned in this publication. Metabochip genotyping data was supported in part by grants and contracts R01HL98077, N02-HL-64278, HL071205, UL1TR000124, DK063491, RD831697, and P50ES015915. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, California, USA) and the Broad Institute of Harvard and MIT (Boston, Massachusetts, USA) using the Affymetrix Genome-Wide Human SNP Array 6.0. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The Mount Sinai BioMe Biobank is supported by The Andrea and Charles Bronfman Philanthropies. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 38 TC 1 Z9 1 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 13 PY 2016 VL 11 IS 10 AR e0164132 DI 10.1371/journal.pone.0164132 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ0CV UT WOS:000385505800042 PM 27736895 ER PT J AU Holmes, EC Dudas, G Rambaut, A Andersen, KG AF Holmes, Edward C. Dudas, Gytis Rambaut, Andrew Andersen, Kristian G. TI The evolution of Ebola virus: Insights from the 2013-2016 epidemic SO NATURE LA English DT Review ID NIEMANN-PICK C1; SIERRA-LEONE; WEST-AFRICA; SEXUAL TRANSMISSION; MAXIMUM-LIKELIHOOD; RNA VIRUSES; FRUIT BATS; REAL-TIME; OUTBREAK; INFLUENZA AB The 2013-2016 epidemic of Ebola virus disease in West Africa was of unprecedented magnitude and changed our perspective on this lethal but sporadically emerging virus. This outbreak also marked the beginning of large-scale real-time molecular epidemiology. Here, we show how evolutionary analyses of Ebola virus genome sequences provided key insights into virus origins, evolution and spread during the epidemic. We provide basic scientists, epidemiologists, medical practitioners and other outbreak responders with an enhanced understanding of the utility and limitations of pathogen genomic sequencing. This will be crucially important in our attempts to track and control future infectious disease outbreaks. C1 [Holmes, Edward C.] Univ Sydney, Charles Perkins Ctr, Sch Life & Environm Sci, Marie Bashir Inst Infect Dis & Biosecur, Sydney, NSW 2006, Australia. [Holmes, Edward C.] Univ Sydney, Charles Perkins Ctr, Sydney Med Sch, Sydney, NSW 2006, Australia. [Dudas, Gytis] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. [Dudas, Gytis; Rambaut, Andrew] Univ Edinburgh, Ashworth Labs, Inst Evolutionary Biol, Edinburgh EH9 3FL, Midlothian, Scotland. [Rambaut, Andrew] Univ Edinburgh, Ctr Immunol Infect & Evolut, Ashworth Labs, Edinburgh EH9 3FL, Midlothian, Scotland. [Rambaut, Andrew] NIH, Fogarty Int Ctr, MSC 2220, Bethesda, MD 20892 USA. [Andersen, Kristian G.] Scripps Res Inst, Dept Immunol & Microbial Sci, San Diego, CA 92037 USA. [Andersen, Kristian G.] Scripps Res Inst, Dept Integrat Struct & Computat Biol, San Diego, CA 92037 USA. [Andersen, Kristian G.] Scripps Translat Sci Inst, San Diego, CA 92037 USA. RP Holmes, EC (reprint author), Univ Sydney, Charles Perkins Ctr, Sch Life & Environm Sci, Marie Bashir Inst Infect Dis & Biosecur, Sydney, NSW 2006, Australia.; Holmes, EC (reprint author), Univ Sydney, Charles Perkins Ctr, Sydney Med Sch, Sydney, NSW 2006, Australia.; Andersen, KG (reprint author), Scripps Res Inst, Dept Immunol & Microbial Sci, San Diego, CA 92037 USA.; Andersen, KG (reprint author), Scripps Res Inst, Dept Integrat Struct & Computat Biol, San Diego, CA 92037 USA.; Andersen, KG (reprint author), Scripps Translat Sci Inst, San Diego, CA 92037 USA. EM edward.holmes@sydney.edu.au; kristian@andersen-lab.com OI Dudas, Gytis/0000-0002-0227-4158; Holmes, Edward/0000-0001-9596-3552 FU NHMRC [AF30]; EU [278433-PREDEMICS, 643476-COMPARE]; Mahan Postdoctoral Fellowship from the Computational Biology Program at Fred Hutchinson Cancer Research Center; Wellcome Trust Strategic Award (VIZIONS) [093724]; NIH National Center for Advancing Translational Studies Clinical and Translational Science Award [UL1TR001114]; NIAID [HHSN272201400048C] FX We thank all the African doctors, nurses, scientists, and outbreak responders who worked to control the 2013-2016 EVD epidemic, some of whom tragically died in the process. We also thank the EBOV genome sequence data producers for making their data publicly available, S. Schaffner for suggestions and reading of the manuscript, and L. M. Carvalho for donating evolutionary rate data. E.C.H. is funded by an NHMRC Australia Fellowship (AF30). G.D. is supported by EU (FP7/2007-2013) Grant Agreement no. 278433-PREDEMICS and the Mahan Postdoctoral Fellowship from the Computational Biology Program at Fred Hutchinson Cancer Research Center. A.R. is supported by EU (FP7/2007-2013) Grant Agreement no. 278433-PREDEMICS, H2020 Grant Agreement no. 643476-COMPARE, and a Wellcome Trust Strategic Award (VIZIONS; 093724). K.G.A. is a PEW Biomedical Scholar, and his work is supported by an NIH National Center for Advancing Translational Studies Clinical and Translational Science Award UL1TR001114, and NIAID contract HHSN272201400048C. NR 97 TC 3 Z9 3 U1 30 U2 30 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD OCT 13 PY 2016 VL 538 IS 7624 BP 193 EP 200 DI 10.1038/nature19790 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EA5OS UT WOS:000386671000036 PM 27734858 ER PT J AU Mallick, S Li, H Lipson, M Mathieson, I Gymrek, M Racimo, F Zhao, MY Chennagiri, N Nordenfelt, S Tandon, A Skoglund, P Lazaridis, I Sankararaman, S Fu, QM Rohland, N Renaud, G Erlich, Y Willems, T Gallo, C Spence, JP Song, YS Poletti, G Balloux, F van Driem, G de Knijff, P Romero, IG Jha, AR Behar, DM Bravi, CM Capelli, C Hervig, T Moreno-Estrada, A Posukh, OL Balanovska, E Balanovsky, O Karachanak-Yankova, S Sahakyan, H Toncheva, D Yepiskoposyan, L Tyler-Smith, C Xue, Y Abdullah, MS Ruiz-Linares, A Beall, CM Di Rienzo, A Jeong, C Starikovskaya, EB Metspalu, E Parik, J Villems, R Henn, BM Hodoglugil, U Mahley, R Sajantila, A Stamatoyannopoulos, G Wee, JTS Khusainova, R Khusnutdinova, E Litvinov, S Ayodo, G Comas, D Hammer, MF Kivisild, T Klitz, W Winkler, CA Labuda, D Bamshad, M Jorde, LB Tishkoff, SA Watkins, WS Metspalu, M Dryomov, S Sukernik, R Singh, L Thangaraj, K Paabo, S Kelso, J Patterson, N Reich, D AF Mallick, Swapan Li, Heng Lipson, Mark Mathieson, Iain Gymrek, Melissa Racimo, Fernando Zhao, Mengyao Chennagiri, Niru Nordenfelt, Susanne Tandon, Arti Skoglund, Pontus Lazaridis, Iosif Sankararaman, Sriram Fu, Qiaomei Rohland, Nadin Renaud, Gabriel Erlich, Yaniv Willems, Thomas Gallo, Carla Spence, Jeffrey P. Song, Yun S. Poletti, Giovanni Balloux, Francois van Driem, George de Knijff, Peter Romero, Irene Gallego Jha, Aashish R. Behar, Doron M. Bravi, Claudio M. Capelli, Cristian Hervig, Tor Moreno-Estrada, Andres Posukh, Olga L. Balanovska, Elena Balanovsky, Oleg Karachanak-Yankova, Sena Sahakyan, Hovhannes Toncheva, Draga Yepiskoposyan, Levon Tyler-Smith, Chris Xue, Yali Abdullah, M. Syafiq Ruiz-Linares, Andres Beall, Cynthia M. Di Rienzo, Anna Jeong, Choongwon Starikovskaya, Elena B. Metspalu, Ene Parik, Juri Villems, Richard Henn, Brenna M. Hodoglugil, Ugur Mahley, Robert Sajantila, Antti Stamatoyannopoulos, George Wee, Joseph T. S. Khusainova, Rita Khusnutdinova, Elza Litvinov, Sergey Ayodo, George Comas, David Hammer, Michael F. Kivisild, Toomas Klitz, William Winkler, Cheryl A. Labuda, Damian Bamshad, Michael Jorde, Lynn B. Tishkoff, Sarah A. Watkins, W. Scott Metspalu, Mait Dryomov, Stanislav Sukernik, Rem Singh, Lalji Thangaraj, Kumarasamy Paeaebo, Svante Kelso, Janet Patterson, Nick Reich, David TI The Simons Genome Diversity Project: 300 genomes from 142 diverse populations SO NATURE LA English DT Article ID MODERN HUMANS; MUTATION-RATE; HISTORY; NEANDERTHAL; ANCESTRY; SEQUENCE; AFRICA; DISPERSAL; ADMIXTURE; INFERENCE AB Here we report the Simons Genome Diversity Project data set: high quality genomes from 300 individuals from 142 diverse populations. These genomes include at least 5.8 million base pairs that are not present in the human reference genome. Our analysis reveals key features of the landscape of human genome variation, including that the rate of accumulation of mutations has accelerated by about 5% in non-Africans compared to Africans since divergence. We show that the ancestors of some pairs of present-day human populations were substantially separated by 100,000 years ago, well before the archaeologically attested onset of behavioural modernity. We also demonstrate that indigenous Australians, New Guineans and Andamanese do not derive substantial ancestry from an early dispersal of modern humans; instead, their modern human ancestry is consistent with coming from the same source as that of other non-Africans. C1 [Mallick, Swapan; Lipson, Mark; Mathieson, Iain; Zhao, Mengyao; Chennagiri, Niru; Nordenfelt, Susanne; Tandon, Arti; Skoglund, Pontus; Lazaridis, Iosif; Sankararaman, Sriram; Fu, Qiaomei; Rohland, Nadin; Reich, David] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. [Mallick, Swapan; Li, Heng; Gymrek, Melissa; Zhao, Mengyao; Chennagiri, Niru; Nordenfelt, Susanne; Tandon, Arti; Skoglund, Pontus; Lazaridis, Iosif; Sankararaman, Sriram; Fu, Qiaomei; Rohland, Nadin; Patterson, Nick; Reich, David] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. [Mallick, Swapan; Zhao, Mengyao; Chennagiri, Niru; Nordenfelt, Susanne; Reich, David] Harvard Med Sch, Howard Hughes Med Inst, Boston, MA 02115 USA. [Gymrek, Melissa] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Gymrek, Melissa] MIT, Harvard MIT Div Hlth Sci & Technol, Cambridge, MA USA. [Gymrek, Melissa; Erlich, Yaniv; Willems, Thomas; Klitz, William] New York Genome Ctr, New York, NY 10013 USA. [Racimo, Fernando] Univ Calif Berkeley, Dept Integrat Biol, Berkeley, CA 94720 USA. [Fu, Qiaomei] Chinese Acad Sci, Key Lab Vertebrate Evolut & Human Origins Chinese, IVPP, Beijing 100044, Peoples R China. [Renaud, Gabriel; Paeaebo, Svante; Kelso, Janet] Max Planck Inst Evolutionary Anthropol, Dept Evolutionary Genet, D-04103 Leipzig, Germany. [Erlich, Yaniv] Columbia Univ, Dept Comp Sci, New York, NY 10027 USA. [Erlich, Yaniv] Columbia Univ, Ctr Computat Biol & Bioinformat, New York, NY 10032 USA. [Willems, Thomas] MIT, Computat & Syst Biol Program, Cambridge, MA 02139 USA. [Gallo, Carla; Poletti, Giovanni] Univ Peruana Cayetano Heredia, Fac Ciencias & Filosofia, Labs Invest & Desarrollo, Lima 15102, Peru. [Spence, Jeffrey P.] Univ Calif Berkeley, Computat Biol Grad Grp, Berkeley, CA 94720 USA. [Song, Yun S.] Univ Calif Berkeley, Div Comp Sci, Berkeley, CA 94720 USA. [Song, Yun S.] Univ Penn, Dept Stat, Philadelphia, PA 19104 USA. [Song, Yun S.] Univ Penn, Dept Math, Philadelphia, PA 19104 USA. [Song, Yun S.] Univ Penn, Dept Biol, Philadelphia, PA 19104 USA. [Balloux, Francois] UCL, Genet Inst, Gower St, London WC1E 6BT, England. Univ Bern, Inst Linguist, CH-3012 Bern, Switzerland. [de Knijff, Peter] Leiden Univ, Med Ctr, Dept Human & Clin Genet, Postzone S5-P, NL-2333 ZA Leiden, Netherlands. [Romero, Irene Gallego] Nanyang Technol Univ, Sch Biol Sci, Singapore 637551, Singapore. [Romero, Irene Gallego] Nanyang Technol Univ, Lee Kong Chian Sch Med, Singapore 636921, Singapore. [Jha, Aashish R.; Di Rienzo, Anna; Jeong, Choongwon] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Behar, Doron M.; Sahakyan, Hovhannes; Metspalu, Ene; Parik, Juri; Villems, Richard; Litvinov, Sergey; Kivisild, Toomas; Metspalu, Mait] Estonian Bioctr, Evolutionary Biol Grp, EE-51010 Tartu, Estonia. [Bravi, Claudio M.] Univ Nacl La Plata, Inst Multidisciplinario Biol Celular IMBICE, Lab Genet Mol Poblac, CCT CONICET La Plata,CIC Buenos Aires, B1906APO, La Plata, Buenos Aires, Argentina. [Capelli, Cristian] Univ Oxford, Dept Zool, Oxford OX1 3PS, England. [Hervig, Tor] Univ Bergen, Dept Clin Sci, N-5021 Bergen, Norway. [Moreno-Estrada, Andres] CINVESTAV, Natl Lab Genom Biodivers LANGEBIO, Guanajuato 36821, Mexico. [Posukh, Olga L.] Siberian Branch Russian Acad Sci, Inst Cytol & Genet, Novosibirsk 630090, Russia. [Posukh, Olga L.] Novosibirsk State Univ, Novosibirsk 630090, Russia. [Balanovska, Elena; Balanovsky, Oleg] Med Genet Res Ctr, Moscow 115478, Russia. [Balanovsky, Oleg] Vavilov Inst Gen Genet, Moscow 119991, Russia. [Balanovsky, Oleg] Moscow Inst Phys & Technol, Dolgopruclniy 141700, Russia. [Karachanak-Yankova, Sena; Toncheva, Draga] Med Univ Sofia, Dept Med Genet, Natl Human Genome Ctr, Sofia 1431, Bulgaria. [Sahakyan, Hovhannes; Yepiskoposyan, Levon] Natl Acad Sci Armenia, Inst Mol Biol, Lab Ethnogen, Yerevan 0014, Armenia. [Tyler-Smith, Chris; Xue, Yali] Wellcome Trust Sanger Inst, Wellcome Genome Campus, Hinxton CB1O 1SA, Cambs, England. [Abdullah, M. Syafiq] RIPAS Hosp, Bandar Seri Begawan, Brunei. [Ruiz-Linares, Andres] UCL, Dept Genet Evolut & Environm, London WC1E 6BT, England. [Beall, Cynthia M.] Case Western Reserve Univ, Dept Anthropol, Cleveland, OH 44106 USA. [Starikovskaya, Elena B.; Dryomov, Stanislav; Sukernik, Rem] Russian Acad Sci, Siberian Branch, Inst Mol & Cellular Biol, Lab Human Mol Genet, Novosibirsk 630090, Russia. [Metspalu, Ene; Villems, Richard] Univ Tartu, Dept Evolutionary Biol, EE-51010 Tartu, Estonia. [Villems, Richard] Estonian Acad Sci, EE-10130 Tallinn, Estonia. [Henn, Brenna M.] SUNY Stony Brook, Dept Ecol & Evolut, Stony Brook, NY 11794 USA. [Hodoglugil, Ugur] NextBio, Santa Clara, CA 95050 USA. [Mahley, Robert] Gladstone Inst, San Francisco, CA 94158 USA. [Sajantila, Antti] Univ Helsinki, Dept Forens Med, FIN-00014 Helsinki, Finland. [Stamatoyannopoulos, George] Univ Washington, Div Med Genet, Dept Med, Seattle, WA 98195 USA. [Wee, Joseph T. S.] Natl Canc Ctr Singapore, Singapore 169610, Singapore. [Khusainova, Rita; Khusnutdinova, Elza; Litvinov, Sergey] Russian Acad Sci, Inst Biochem & Genet, Ufa Res Ctr, Ufa 450054, Russia. [Khusainova, Rita; Khusnutdinova, Elza; Litvinov, Sergey] Bashkir State Univ, Dept Genet & Fundamental Med, Ufa 450074, Russia. [Ayodo, George] Jaramogi Oginga Odinga Univ Sci & Technol, Banda 40601, Kenya. [Comas, David] Univ Pompeu Fabra, Dept Ciencies Expt St, Inst Biol Evolut CSIC UPF, Barcelona 08003, Spain. [Hammer, Michael F.] Univ Arizona, ARL Div Biotechnol, Tucson, AZ 85721 USA. [Kivisild, Toomas] Univ Cambridge, Div Biol Anthropol, Fitzwilliam St, Cambridge CB2 1QH, England. [Winkler, Cheryl A.] Leiclos Biomed Res Inc, NCI, Ctr Canc Res, Frederick Natl Lab,Basie Res Lab, Frederick, MD 21702 USA. [Labuda, Damian] Univ Montreal, CHU St Justine, Dept Pediat, Montreal, PQ H3T 1C5, Canada. [Bamshad, Michael] Univ Washington, Dept Pediat, Seattle, WA 98119 USA. [Jorde, Lynn B.] Univ Utah, Dept Human Genet, Sch Med, Salt Lake City, UT 34112 USA. [Tishkoff, Sarah A.] Univ Penn, Dept Genet & Biol, Philadelphia, PA 19104 USA. [Watkins, W. Scott] Univ Utah, Eccles Inst Human Genet, Dept Human Genet, Salt Lake City, UT 84112 USA. [Dryomov, Stanislav] Russian Acad Sci, Siberian Branch, Inst Archaeol & Ethnog, Dept Paleolith Archaeol, Novosibirsk 630090, Russia. [Sukernik, Rem] Altai State Univ, Barnaul 656000, Russia. [Singh, Lalji; Thangaraj, Kumarasamy] CSIR Ctr Cellular & Mol Biol, Hyderabad 500007, Andhra Pradesh, India. [Sankararaman, Sriram] Univ Calif Los Angeles, Dept Comp Sci, Los Angeles, CA 90095 USA. [Sankararaman, Sriram] Univ Calif Los Angeles, Dept Human Genet Sci, Los Angeles, CA 90095 USA. [Singh, Lalji] Genome Fdn, Hyderabad 500076, Andhra Pradesh, India. RP Mallick, S (reprint author), Harvard Med Sch, Dept Genet, Boston, MA 02115 USA.; Mallick, S (reprint author), Broad Inst Harvard & MIT, Cambridge, MA 02142 USA.; Mallick, S (reprint author), Harvard Med Sch, Howard Hughes Med Inst, Boston, MA 02115 USA. EM shop@genetics.med.harvard.edu; reich@genetics.med.harvard.edu RI Khusnutdinova, Elza/A-4810-2013; Litvinov, Sergey/L-1738-2013; OI Thangaraj, Kumarasamy/0000-0002-0075-0106 FU Simons Foundation [SFARI 280376]; US National Science Foundation [BCS-1032255]; Human Frontier Science program [LT001095/2014]; Wenner-Gren foundation; Swedish Research Council (VR) [2014-453]; NIJ [2014-DN-BX-K089]; Career Award at the Scientific Interface from the Burroughs Wellcome Fund; Natural Sciences and Engineering Research Council of Canada; ERC [FP7- 261213]; Russian Foundation for Basic Research [15-04-02543, 16-34-00599, 11-04-00725-a, 16-06-00303, 16-04-00890]; Russian Scientific Fund [14-04-00827]; Estonian Research Council; European Regional Development Fund (European Union) through the Centre of Excellence in Genomics to Estonian Biocentre; University of Tartu; Spanish MINECO [CGL-44351-P]; NIH [GM59290, 5DPIES022577 05, 1R01DK104339-01, 1R01GM113657-01, R01-GM094402, GM100233]; Wellcome Trust [093051]; NSF [0924726, 1153911]; CSIR Network Project grant [GENESIS: BSC0121]; Packard Fellowship for Science and Engineering; Max Planck Society FX We thank the volunteers who donated samples. We thank H. Blanche, N. Boivin, H. Cann (deceased), E. Eichler, H. Greely, M. Petraglia, K. Prufer, A. Rogers, M. Steinrucken, U. Stenzel and P Sudmant for comments, critiques, discussions, or advice on assembling samples. We thank S. Fan for uploading 21 genomes to the European Genome-phenome archive. The sequencing was funded by the Simons Foundation (SFARI 280376) and the US National Science Foundation (BCS-1032255). I.M. was supported by a Long Term Fellowship grant LT001095/2014 from the Human Frontier Science program. P.S. was supported by the Wenner-Gren foundation and the Swedish Research Council (VR grant 2014-453). T.W. and M.G. were supported by an NIJ grant 2014-DN-BX-K089. Y.E. was supported by a Career Award at the Scientific Interface from the Burroughs Wellcome Fund and by NIJ grant 2014-DN-BX-K089. D.L. was supported by the Natural Sciences and Engineering Research Council of Canada. T.K. was supported by ERC Starting Investigator grant FP7- 261213. R.S. received support from Russian Foundation for Basic Research (#15-04-02543). S.D. received support from the Russian Foundation for Basic Research (#16-34-00599). R.K., E.K. and S.L. were supported by the Russian Foundation for Basic Research (11-04-00725-a). E.B. was supported by the Russian Foundation for Basic Research (16-06-00303). G.B. was supported by the Russian Scientific Fund (14-04-00827) and by the Russian Foundation for Basic Research (16-04-00890). D.M.B., H.S., E.M., R.V. and M.M. were supported by Institutional Research Funding from the Estonian Research Council IUT24-1 and by the European Regional Development Fund (European Union) through the Centre of Excellence in Genomics to Estonian Biocentre and University of Tartu. D.C. was supported by the Spanish MINECO grant CGL-44351-P L.B.J. and W.S.W. were supported by NIH grant GM59290. S.A.T. was supported by NIH grants 5DPIES022577 05, 1R01DK104339-01, and 1R01GM113657-01. C.T.-S. and Y.X. were supported by The Wellcome Trust grant 093051. C.M.B. was supported by NSF grants 0924726 and 1153911. K.T. was supported by CSIR Network Project grant (GENESIS: BSC0121). J.P.S. and Y.S.S. were supported in part by an NIH grant R01-GM094402, and a Packard Fellowship for Science and Engineering. G.R.. J.K and S.P. were funded by the Max Planck Society. N.P. and D.R. were supported by NIH grant GM100233 and D.R. is a Howard Hughes Medical Institute investigator. NR 45 TC 10 Z9 10 U1 35 U2 35 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD OCT 13 PY 2016 VL 538 IS 7624 BP 201 EP + DI 10.1038/nature18964 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EA5OS UT WOS:000386671000037 PM 27654912 ER PT J AU Ahn, IE Jerussi, T Farooqui, M Tian, X Wiestner, A Gea-Banacloche, J AF Ahn, Inhye E. Jerussi, Theresa Farooqui, Mohammed Tian, Xin Wiestner, Adrian Gea-Banacloche, Juan TI Atypical Pneumocystis jirovecii pneumonia in previously untreated patients with CLL on single-agent ibrutinib SO BLOOD LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; NON-HIV; OPEN-LABEL; RITUXIMAB; TRIAL; FLUDARABINE; CYCLOPHOSPHAMIDE; BENDAMUSTINE; THERAPY; PHASE-3 AB Ibrutinib is not known to confer risk for Pneumocystis jirovecii pneumonia (PCP). We observed 5 cases of PCP in 96 patients receiving single-agent ibrutinib, including 4 previously untreated. Clinical presentations included asymptomatic pulmonary infiltrates, chronic cough, and shortness of breath. The diagnosis was often delayed. Median time from starting ibrutinib to occurrence of PCP was 6 months (range, 2-24). The estimated incidence of PCP was 2.05 cases per 100 patient-years (95% confidence interval, 0.67-4.79). At the time of PCP, all patients had CD4 T-cell count >500/mu L (median, 966/mu L) and immunoglobulin G (IgG) >500 mg/dL (median, 727 mg/dL). All patients underwent bronchoalveolar lavage. P jirovecii was identified by polymerase chain reaction in all 5 cases; direct fluorescence antibody staining was positive in 1. All events were grade <= 2 and resolved with oral therapy. Secondary prophylaxis was not given to 3 patients; after 61 patient-months of follow up, no recurrence occurred. Lack of correlation with CD4 count and IgG level suggests that susceptibility to PCP may be linked to Bruton tyrosine kinase (BTK) inhibition. If confirmed, this association could result in significant changes in surveillance and/or prophylaxis, possibly extending to other BTK inhibitors. This trial was registered at www.clinicaltrials.gov as #NCT01500733 and #NCT02514083. C1 [Ahn, Inhye E.] NCI, Med Oncol Serv, NIH, Bethesda, MD 20892 USA. [Jerussi, Theresa] NIH, Off Patient Safety & Clin Qual, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Farooqui, Mohammed; Wiestner, Adrian] NHLBI, Lymphoid Malignancy Sect, Hematol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Tian, Xin] NHLBI, Off Biostat Res, NIH, Bldg 10, Bethesda, MD 20892 USA. [Gea-Banacloche, Juan] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Gea-Banacloche, J (reprint author), NCI, NIH, 10 Ctr Dr,Room 13E-3-3330, Bethesda, MD 20892 USA.; Wiestner, A (reprint author), NHLBI, Hematol Branch, NIH, 10 Ctr Dr,Bldg 10,CRC 3-5140, Bethesda, MD 20892 USA. EM wiestnea@nhlbi.nih.gov; banacloj@mail.nih.gov FU National Institutes of Health National Heart, Lung, and Blood Institute; National Cancer Institute FX This work was funded by the Intramural Research Program of the National Institutes of Health National Heart, Lung, and Blood Institute and the National Cancer Institute. NR 19 TC 2 Z9 2 U1 5 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD OCT 13 PY 2016 VL 128 IS 15 BP 1940 EP 1943 DI 10.1182/blood-2016-06-722991 PG 4 WC Hematology SC Hematology GA DZ3IA UT WOS:000385738500007 PM 27503501 ER PT J AU Casanova, R Wang, XH Reyes, J Akita, Y Serre, ML Vizuete, W Chui, HC Driscoll, I Resnick, SM Espeland, MA Chen, JC AF Casanova, Ramon Wang, Xinhui Reyes, Jeanette Akita, Yasuyuki Serre, Marc L. Vizuete, William Chui, Helena C. Driscoll, Ira Resnick, Susan M. Espeland, Mark A. Chen, Jiu-Chiuan CA WHIMS-MRI Study Grp TI A Voxel-Based Morphometry Study Reveals Local Brain Structural Alterations Associated with Ambient Fine Particles in Older Women SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE air pollution; brain; MRI; PM2.5; VBM ID HEALTH INITIATIVE MEMORY; POSTMENOPAUSAL HORMONE-THERAPY; AIR-POLLUTION; PARTICULATE MATTER; WHIMS-MRI; COGNITIVE FUNCTION; WHITE-MATTER; RESIDENTIAL PROXIMITY; INTRACRANIAL VOLUME; BASAL GANGLIA AB Objective: Exposure to ambient fine particulate matter (PM2.5: PM with aerodynamic diameters <2.5 mu m) has been linked with cognitive deficits in older adults. Using fine-grained voxel-wise analyses, we examined whether PM2.5 exposure also affects brain structure. Methods: Brain MRI data were obtained from 1365 women (aged 71-89) in the Women's Health Initiative Memory Study and local brain volumes were estimated using RAVENS (regional analysis of volumes in normalized space). Based on geocoded residential locations and air monitoring data from the U.S. Environmental Protection Agency, we employed a spatiotemporal model to estimate long-term (3-year average) exposure to ambient PM2.5 preceding MRI scans. Voxel-wise linear regression models were fit separately to gray matter (GM) and white matter (WM) maps to analyze associations between brain structure and PM2.5 exposure, with adjustment for potential confounders. Results: Increased PM2.5 exposure was associated with smaller volumes in both cortical GM and subcortical WM areas. For GM, associations were clustered in the bilateral superior, middle, and medial frontal gyri. For WM, the largest clusters were in the frontal lobe, with smaller clusters in the temporal, parietal, and occipital lobes. No statistically significant associations were observed between PM2.5 exposure and hippocampal volumes. Conclusions: Long-term PM2.5 exposures may accelerate loss of both GM and WM in older women. While our previous work linked smaller WM volumes to PM2.5, this is the first neuroimaging study reporting associations between air pollution exposure and smaller volumes of cortical GM. Our data support the hypothesized synaptic neurotoxicity of airborne particles. C1 [Casanova, Ramon; Espeland, Mark A.] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC 27101 USA. [Wang, Xinhui; Chen, Jiu-Chiuan] Univ Southern Calif, Dept Prevent Med, Los Angeles, CA USA. [Reyes, Jeanette; Akita, Yasuyuki; Serre, Marc L.; Vizuete, William] Univ N Carolina, Chapel Hill, NC USA. [Chui, Helena C.] Univ Southern Calif, Dept Neurol, Los Angeles, CA USA. [Driscoll, Ira] Univ Wisconsin, Dept Psychol, Milwaukee, WI 53201 USA. [Resnick, Susan M.] NIA, Lab Behav Neurosci, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Casanova, R (reprint author), Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC 27101 USA. EM casanova@wakehealth.edu OI vizuete, william/0000-0002-1399-2948 FU National Heart, Lung, and Blood Institute; Wyeth Pharmaceuticals, Inc., St. Davids, PA; Intramural Research Program, NIA, NIH; [R21AG051113-01]; [R01AG033078]; [P50-AG05142] FX The Women's Health Initiative is funded by the National Heart, Lung, and Blood Institute. The Women's Health Initiative Memory Study was funded in part by Wyeth Pharmaceuticals, Inc., St. Davids, PA. The research work was supported by R21AG051113-01 (PIs: RC and JC) R01AG033078 (PI: JC). HC is supported by P50-AG05142. SR is supported by the Intramural Research Program, NIA, NIH. NR 57 TC 2 Z9 2 U1 18 U2 18 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD OCT 13 PY 2016 VL 10 AR 495 DI 10.3389/fnhum.2016.00495 PG 9 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA DZ5GS UT WOS:000385890600001 PM 27790103 ER PT J AU Liu, YT Luo, JN Nassel, DR AF Liu, Yiting Luo, Jiangnan Nassel, Dick R. TI The Drosophila Transcription Factor Dimmed Affects Neuronal Growth and Differentiation in Multiple Ways Depending on Neuron Type and Developmental Stage SO FRONTIERS IN MOLECULAR NEUROSCIENCE LA English DT Article DE bHLH transcription factor; insulin-like peptide; insulin receptor; apoptosis; neuroendocrine cells; neuropeptide ID PROGRAMMED CELL-DEATH; CENTRAL-NERVOUS-SYSTEM; BLOOD-BRAIN-BARRIER; PEPTIDERGIC NEURONS; IMMUNOREACTIVE NEURONS; LEUCOKINERGIC NEURONS; ENTEROENDOCRINE CELLS; NEUROENDOCRINE CELLS; ECLOSION HORMONE; ECDYSIS BEHAVIOR AB Growth of postmitotic neurons occurs during different stages of development, including metamorphosis, and may also be part of neuronal plasticity and regeneration. Recently we showed that growth of post-mitotic neuroendocrine cells expressing the basic helix loop helix (bHLH) transcription factor Dimmed (Dimm) in Drosophila could be regulated by insulin/IGF signaling and the insulin receptor (dlnR). Dimm is also known to confer a secretory phenotype to neuroendocrine cells and can be part of a combinatorial code specifying terminal differentiation in peptidergic neurons. To further understand the mechanisms of Down function we ectopically expressed Dimm or Dimm together with dlnR in a wide range of Dimm positive and Dimm negative peptidergic neurons, sensory neurons, interneurons, motor neurons, and gut endocrine cells. We provide further evidence that dlnR mediated cell growth occurs in a Dimm dependent manner and that one source of insulin-like peptide (DILP) for dlnR mediated cell growth in the OHS is DILP6 from glial cells. Expressing both Dimm and dlnR in Dimm negative neurons induced growth of cell bodies, whereas dlnR alone did not. We also found that Dimm alone can regulate cell growth depending on specific cell type. This may be explained by the finding that the dlnR is a direct target of Dimm. Conditional gene targeting experiments showed that Dimm alone could affect cell growth in certain neuron types during metamorphosis or in the adult stage. Another important finding was that ectopic Dimm inhibits apoptosis of several types of neurons normally destined for programmed cell death (PCD). Taken together our results suggest that Dimm plays multiple transcriptional roles at different developmental stages in a cell type-specific manner. In some cell types ectopic Dimm may act together with resident combinatorial code transcription factors and affect terminal differentiation, as well as act in transcriptional networks that participate in long term maintenance of neurons which might lead to blocked apoptosis. C1 [Liu, Yiting; Luo, Jiangnan; Nassel, Dick R.] Stockholm Univ, Dept Zool, Stockholm, Sweden. [Luo, Jiangnan] NICHHD, Sect Neuronal Connect, NIH, Bethesda, MD 20892 USA. RP Nassel, DR (reprint author), Stockholm Univ, Dept Zool, Stockholm, Sweden. EM dnassel@zoologi.su.se FU National Institute of Child Health & Human Development (NICHD); Swedish Research Council (VR) [621-2010-5742] FX We are grateful to Drs. P. Herrero, C. Wegener, D. Park, H. Stocker, P. Leopold, O. Alekseyenko, R. Baines, K. Rewitz, E. A. Kravitz, C. Korge, J. Ewer, J. H. Park, H. Dircksen, P. Taghert, and I. Miguel-Aliaga for providing flies and reagents. Also the following organizations are thanked for flies and reagents: The Bloomington Drosophila Stock Center, Bloomington, IN, The Vienna Drosophila Resource Center, Vienna, Austria, and Developmental Studies Hybridoma Bank, developed under the auspices of the National Institute of Child Health & Human Development (NICHD) and maintained by The University of Iowa, Department of Biological Sciences, Iowa City, IA 52242, Stina Hoglund and the Imaging Facility at Stockholm University (IFSU) are acknowledged for maintenance of the confocal microscopes. This study was supported by the Swedish Research Council (VR; 621-2010-5742) to DN. NR 80 TC 0 Z9 0 U1 3 U2 3 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5099 J9 FRONT MOL NEUROSCI JI Front. Molec. Neurosci. PD OCT 13 PY 2016 VL 9 AR 97 DI 10.3389/fnmol.2016.00097 PG 21 WC Neurosciences SC Neurosciences & Neurology GA DY9GS UT WOS:000385442500002 PM 27790090 ER PT J AU Tang, HX Jiang, XQ Wang, XF Wang, S Sofia, H Fox, D Lauter, K Malin, B Telenti, A Xiong, L Ohno-Machado, L AF Tang, Haixu Jiang, Xiaoqian Wang, Xiaofeng Wang, Shuang Sofia, Heidi Fox, Dov Lauter, Kristin Malin, Bradley Telenti, Amalio Xiong, Li Ohno-Machado, Lucila TI Protecting genomic data analytics in the cloud: state of the art and opportunities SO BMC MEDICAL GENOMICS LA English DT Article ID FULLY-HOMOMORPHIC ENCRYPTION; PRIVACY AB The outsourcing of genomic data into public cloud computing settings raises concerns over privacy and security. Significant advancements in secure computation methods have emerged over the past several years, but such techniques need to be rigorously evaluated for their ability to support the analysis of human genomic data in an efficient and cost-effective manner. With respect to public cloud environments, there are concerns about the inadvertent exposure of human genomic data to unauthorized users. In analyses involving multiple institutions, there is additional concern about data being used beyond agreed research scope and being prcoessed in untrused computational environments, which may not satisfy institutional policies. To systematically investigate these issues, the NIH-funded National Center for Biomedical Computing iDASH (integrating Data for Analysis, 'anonymization' and SHaring) hosted the second Critical Assessment of Data Privacy and Protection competition to assess the capacity of cryptographic technologies for protecting computation over human genomes in the cloud and promoting cross-institutional collaboration. Data scientists were challenged to design and engineer practical algorithms for secure outsourcing of genome computation tasks in working software, whereby analyses are performed only on encrypted data. They were also challenged to develop approaches to enable secure collaboration on data from genomic studies generated by multiple organizations (e.g., medical centers) to jointly compute aggregate statistics without sharing individual-level records. The results of the competition indicated that secure computation techniques can enable comparative analysis of human genomes, but greater efficiency (in terms of compute time and memory utilization) are needed before they are sufficiently practical for real world environments. C1 [Tang, Haixu; Wang, Xiaofeng] Indiana Univ, Sch Informat & Comp, Bloomington, IN 47405 USA. [Jiang, Xiaoqian; Wang, Shuang; Ohno-Machado, Lucila] Univ Calif San Diego, Dept Biomed Informat, La Jolla, CA 92093 USA. [Sofia, Heidi] NHGRI, Rockville, MD USA. [Fox, Dov] Univ San Diego, Sch Law, San Diego, CA 92110 USA. [Lauter, Kristin] Microsoft Res, Redmond, WA USA. [Malin, Bradley] Vanderbilt Univ, Sch Med, Dept Biomed Informat, Nashville, TN 37212 USA. [Telenti, Amalio] J Craig Venter Inst, La Jolla, CA USA. [Xiong, Li] Emory Univ, Dept Math & Comp Sci, Atlanta, GA 30322 USA. RP Tang, HX (reprint author), Indiana Univ, Sch Informat & Comp, Bloomington, IN 47405 USA. EM hatang@indiana.edu FU NHGRI [R01HG007078, R00HG008175]; NLM [R00LM011392, R21LM012060]; NHLBI iDASH [U54HL108460]; NSF [CNS-1408874, CNS-1223495] FX We thank Yongan Zhao, Yuchen Zhang, Yong Li, and Wenrui Dai for their help in organizing this competition. This work was funded in part by the NHGRI (R01HG007078, R00HG008175), NLM (R00LM011392, R21LM012060), NHLBI iDASH (U54HL108460), and NSF (CNS-1408874, CNS-1223495). NR 44 TC 0 Z9 0 U1 5 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1755-8794 J9 BMC MED GENOMICS JI BMC Med. Genomics PD OCT 13 PY 2016 VL 9 AR 63 DI 10.1186/s12920-016-0224-3 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA DY4DX UT WOS:000385050300001 PM 27733153 ER PT J AU Welch, HG Prorok, PC O'Malley, AJ Kramer, BS AF Welch, H. Gilbert Prorok, Philip C. O'Malley, A. James Kramer, Barnett S. TI Breast-Cancer Tumor Size, Overdiagnosis, and Mammography Screening Effectiveness SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID PROSTATE-CANCER; SEER PROGRAM; MORTALITY; NORWAY AB BACKGROUND The goal of screening mammography is to detect small malignant tumors before they grow large enough to cause symptoms. Effective screening should therefore lead to the detection of a greater number of small tumors, followed by fewer large tumors over time. METHODS We used data from the Surveillance, Epidemiology, and End Results (SEER) program, 1975 through 2012, to calculate the tumor-size distribution and size-specific incidence of breast cancer among women 40 years of age or older. We then calculated the size-specific cancer case fatality rate for two time periods: a baseline period before the implementation of widespread screening mammography (1975 through 1979) and a period encompassing the most recent years for which 10 years of follow-up data were available (2000 through 2002). RESULTS After the advent of screening mammography, the proportion of detected breast tumors that were small (invasive tumors measuring <2 cm or in situ carcinomas) increased from 36% to 68%; the proportion of detected tumors that were large (invasive tumors measuring >= 2 cm) decreased from 64% to 32%. However, this trend was less the result of a substantial decrease in the incidence of large tumors (with 30 fewer cases of cancer observed per 100,000 women in the period after the advent of screening than in the period before screening) and more the result of a substantial increase in the detection of small tumors (with 162 more cases of cancer observed per 100,000 women). Assuming that the underlying disease burden was stable, only 30 of the 162 additional small tumors per 100,000 women that were diagnosed were expected to progress to become large, which implied that the remaining 132 cases of cancer per 100,000 women were overdiagnosed (i.e., cases of cancer were detected on screening that never would have led to clinical symptoms). The potential of screening to lower breast cancer mortality is reflected in the declining incidence of larger tumors. However, with respect to only these large tumors, the decline in the size-specific case fatality rate suggests that improved treatment was responsible for at least two thirds of the reduction in breast cancer mortality. CONCLUSIONS Although the rate of detection of large tumors fell after the introduction of screening mammography, the more favorable size distribution was primarily the result of the additional detection of small tumors. Women were more likely to have breast cancer that was overdiagnosed than to have earlier detection of a tumor that was destined to become large. The reduction in breast cancer mortality after the implementation of screening mammography was predominantly the result of improved systemic therapy. C1 [Welch, H. Gilbert; O'Malley, A. James] Dartmouth Inst Hlth Policy & Clin Practice, 35 Centerra Pkwy,HB 7251, Lebanon, NH 03766 USA. [Welch, H. Gilbert] Geisel Sch Med, Dept Med, Hanover, NH USA. [O'Malley, A. James] Geisel Sch Med, Biomed Data Sci, Hanover, NH USA. [Prorok, Philip C.; Kramer, Barnett S.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Welch, HG (reprint author), Dartmouth Inst Hlth Policy & Clin Practice, 35 Centerra Pkwy,HB 7251, Lebanon, NH 03766 USA. EM h.gilbert.welch@dartmouth.edu NR 29 TC 9 Z9 9 U1 12 U2 12 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 13 PY 2016 VL 375 IS 15 BP 1438 EP 1447 DI 10.1056/NEJMoa1600249 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA DY5IH UT WOS:000385132400007 PM 27732805 ER PT J AU Davey, RT Dodd, L Proschan, MA Neaton, J Nordwall, JN Koopmeiners, JS Beigel, J Tierney, J Lane, HC Fauci, AS Massaquoi, MBF Sahr, F Malvy, D AF Davey, Richard T., Jr. Dodd, Lori Proschan, Michael A. Neaton, James Nordwall, Jacquie Neuhaus Koopmeiners, Joseph S. Beigel, John Tierney, John Lane, H. Clifford Fauci, Anthony S. Massaquoi, Moses B. F. Sahr, Foday Malvy, Denis CA Prevail II Writing Grp Multi-Natl Prevail II Study Team TI A Randomized, Controlled Trial of ZMapp for Ebola Virus Infection SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID WEST-AFRICA; VIRAL LOAD; DISEASE; MORTALITY; OUTBREAK; SURVIVAL; EPIDEMIC AB BACKGROUND Data from studies in nonhuman primates suggest that the triple monoclonal antibody cocktail ZMapp is a promising immune-based treatment for Ebola virus disease (EVD). METHODS Beginning in March 2015, we conducted a randomized, controlled trial of ZMapp plus the current standard of care as compared with the current standard of care alone in patients with EVD that was diagnosed in West Africa by polymerase-chain-reaction (PCR) assay. Eligible patients of any age were randomly assigned in a 1:1 ratio to receive either the current standard of care or the current standard of care plus three intravenous infusions of ZMapp (50 mg per kilogram of body weight, administered every third day). Patients were stratified according to baseline PCR cycle-threshold value for the virus (<= 22 vs. >22) and country of enrollment. Oral favipiravir was part of the current standard of care in Guinea. The primary end point was mortality at 28 days. RESULTS A total of 72 patients were enrolled at sites in Liberia, Sierra Leone, Guinea, and the United States. Of the 71 patients who could be evaluated, 21 died, representing an overall case fatality rate of 30%. Death occurred in 13 of 35 patients (37%) who received the current standard of care alone and in 8 of 36 patients (22%) who received the current standard of care plus ZMapp. The observed posterior probability that ZMapp plus the current standard of care was superior to the current standard of care alone was 91.2%, falling short of the prespecified threshold of 97.5%. Frequentist analyses yielded similar results (absolute difference in mortality with ZMapp, -15 percentage points; 95% confidence interval, -36 to 7). Baseline viral load was strongly predictive of both mortality and duration of hospitalization in all age groups. CONCLUSIONS In this randomized, controlled trial of a putative therapeutic agent for EVD, although the estimated effect of ZMapp appeared to be beneficial, the result did not meet the prespecified statistical threshold for efficacy. (Funded by the National Institute of Allergy and Infectious Diseases and others; PREVAIL II ClinicalTrials.gov number, NCT02363322.) C1 [Davey, Richard T., Jr.; Dodd, Lori; Proschan, Michael A.; Tierney, John; Lane, H. Clifford; Fauci, Anthony S.] NIAID, Bldg 10,CRC 4-1479,10 Ctr Dr MSC 1460, Bethesda, MD 20892 USA. [Beigel, John] Leidos Biomed Res, Frederick, MD USA. [Neaton, James; Nordwall, Jacquie Neuhaus; Koopmeiners, Joseph S.] Univ Minnesota, Minneapolis, MN USA. [Massaquoi, Moses B. F.] Liberian Minist Hlth, Monrovia, CA USA. [Sahr, Foday] Republ Sierra Leone Armed Forces, Freetown, Sierra Leone. [Malvy, Denis] Univ Bordeaux, INSERM, Bordeaux, France. RP Davey, RT (reprint author), NIAID, Bldg 10,CRC 4-1479,10 Ctr Dr MSC 1460, Bethesda, MD 20892 USA. EM rdavey@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases (NIAID); INSERM; Republic of Sierra Leone Armed Forces; Ministries of Health; U.S. Embassy staff in the country of Liberia; U.S. Embassy staff in the country of Sierra Leone; U.S. Embassy staff in the country of Guinea; Centers for Disease Control and Prevention (CDC); CDC Foundation; Biomedical Advanced Research and Development Authority; Defense Threat Reduction Agency FX Financial or logistic support for the trial was provided by the National Institute of Allergy and Infectious Diseases (NIAID), INSERM, the Republic of Sierra Leone Armed Forces, the Ministries of Health and the U.S. Embassy staff in the countries of Liberia, Sierra Leone, and Guinea, the Centers for Disease Control and Prevention (CDC) and the CDC Foundation, the Biomedical Advanced Research and Development Authority, and the Defense Threat Reduction Agency. NR 27 TC 3 Z9 3 U1 11 U2 11 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 13 PY 2016 VL 375 IS 15 BP 1448 EP 1456 DI 10.1056/NEJMoa1604330 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA DY5IH UT WOS:000385132400008 ER PT J AU Pinsky, P Prorok, P AF Pinsky, Paul Prorok, Philip TI More on Reevaluating PSA Testing Rates in the PLCO Trial SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID CANCER SCREENING TRIAL; PROSTATE C1 [Pinsky, Paul; Prorok, Philip] NCI, Bethesda, MD 20892 USA. RP Pinsky, P (reprint author), NCI, Bethesda, MD 20892 USA. EM pinskyp@mail.nih.gov NR 3 TC 2 Z9 2 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 13 PY 2016 VL 375 IS 15 BP 1500 EP 1500 DI 10.1056/NEJMc1607379 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA DY5IH UT WOS:000385132400023 PM 27732807 ER PT J AU Wang, DV Ikemoto, S AF Wang, Dong V. Ikemoto, Satoshi TI Coordinated Interaction between Hippocampal Sharp-Wave Ripples and Anterior Cingulate Unit Activity SO JOURNAL OF NEUROSCIENCE LA English DT Article DE anterior cingulate cortex; CA1; hippocampus; memory consolidation; sharp-wave ripple; unit activity ID MEMORY CONSOLIDATION; SPATIAL MEMORY; PREFRONTAL CORTEX; SLOW OSCILLATIONS; AWAKE STATE; SLEEP; REPLAY; SEQUENCES; REORGANIZATION; EXPERIENCE AB Hippocampal-cortical interaction during sleep promotes transformation of memory for long-term storage in the cortex. In particular, hippocampal sharp-wave ripple-associated neural activation is important for this transformation during slow-wave sleep. The anterior cingulate cortex (ACC) has been shown to be crucial for expression and likely storage of long-term memory. However, little is known about how ACC activity is influenced by hippocampal ripple activity during sleep. We report here about coordinated interactions between hippocampal ripple activity and ACC neural firings. By recording from the ACC and hippocampal CA1 simultaneously in mice, we found that almost all ACC neurons showed increased activity before hippocampal ripple activity; moreover, a subpopulation ( 17%) displayed a further activation immediately after ripple activity. This postripple activation of ACC neurons correlated positively with ripple amplitude, and the same neurons were excited upon electrical stimulation of the CA1. Interestingly, the preripple activation of ACC neurons was present during the sleep state, but not during the awake state. These results suggest intimate interactions between hippocampal sharp-wave ripples and ACC neurons in a state-dependent manner. Importantly, sharp-wave ripples and associated activation appear to regulate activity of a small population of ACC neurons, a process that may play a critical role in memory consolidation. C1 [Wang, Dong V.; Ikemoto, Satoshi] NIDA, Behav Neurosci Branch, NIH, Baltimore, MD 21224 USA. RP Wang, DV; Ikemoto, S (reprint author), NIDA, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM dong.wang2@nih.gov; Satoshi.Ikemoto@nih.gov FU Intramural Research Program of National Institute on Drug Abuse, National Institutes of Health FX This work was supported by the Intramural Research Program of National Institute on Drug Abuse, National Institutes of Health. We thank Aleksandr Talishinsky, Andrew J. Kesner, and Alan B. Saul for their helpful comments on the manuscript. NR 51 TC 0 Z9 0 U1 3 U2 3 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD OCT 12 PY 2016 VL 36 IS 41 BP 10663 EP 10672 DI 10.1523/JNEUROSCI.1042-16.2016 PG 10 WC Neurosciences SC Neurosciences & Neurology GA EC8BV UT WOS:000388366000017 PM 27733616 ER PT J AU Gill, KE Cardenas, SA Kassem, L Schulze, TG McMahon, FJ AF Gill, Kelly E. Cardenas, Stephanie A. Kassem, Layla Schulze, Thomas G. McMahon, Francis J. TI Symptom profiles and illness course among Anabaptist and Non-Anabaptist adults with major mood disorders SO INTERNATIONAL JOURNAL OF BIPOLAR DISORDERS LA English DT Article DE Depression; Mania; Bipolar disorder; Amish; Mennonite; Alcohol; Head injury; Concussion ID BIPOLAR AFFECTIVE-DISORDER; TRAUMATIC BRAIN-INJURY; OLD ORDER AMISH; DEPRESSION; IMPACT; LOCI AB Background: Anabaptists comprise large and growing Amish and Mennonite populations with a unique genetic heritage and cultural background. Little is known about the symptoms and course of major mood disorders in Anabaptists. Even less is known about the impact of potential moderators on symptom severity and course. Methods: A sample of Amish and Mennonite participants with bipolar, recurrent unipolar, or schizoaffective bipolar disorder (n = 155) were systematically evaluated with a well-validated instrument. Cases were compared with non-Anabaptist participants (n = 155) matched for age, sex, and psychiatric diagnosis and evaluated by the same methods. Results: Despite substantial cultural differences, the profile of manic and depressive symptoms during illness episodes did not significantly differ between the two groups. Alcohol use disorder (AUD) was significantly less frequent among Anabaptists, and was associated with more major depressive episodes and more hospitalizations for major depression in Anabaptist, but not non-Anabaptist participants. Lifetime history of head injury showed a trend toward association with more episodes of major depression in both Anabaptist and non-Anabaptist groups that did not withstand multiple test correction. Conclusions: The presentation of a highly heritable psychiatric illness such as bipolar disorder does not differ in cases drawn from genetically unique Anabaptist populations. However, alcohol comorbidity, head injury, and their effects on illness course suggest some differences that deserve further investigation. C1 [Gill, Kelly E.; Cardenas, Stephanie A.; Kassem, Layla; Schulze, Thomas G.; McMahon, Francis J.] NIMH, Human Genet Branch, Sect Genet Basis Mood & Anxiety Disorders, Intramural Res Program,NIH, New York, NY USA. [Gill, Kelly E.] Catholic Univ Amer, Dept Psychol, 620 Michigan Ave NE, Washington, DC 20064 USA. [Schulze, Thomas G.] Univ Munich, Med Ctr, Inst Psychiat Phen & Genom, Munich, Germany. RP Gill, KE (reprint author), NIMH, Human Genet Branch, Sect Genet Basis Mood & Anxiety Disorders, Intramural Res Program,NIH, New York, NY USA.; Gill, KE (reprint author), Catholic Univ Amer, Dept Psychol, 620 Michigan Ave NE, Washington, DC 20064 USA. EM kegill13@gmail.com FU NIMH NIH HHS [R01 MH059545, R01 MH059533, R01 MH059548, R01 MH059567, R01 MH060068, R01 MH059534, R01 MH059535, Z01 MH002810, R01 MH059556, R01 MH059553] NR 25 TC 0 Z9 0 U1 3 U2 3 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 2194-7511 J9 INT J BIPOLAR DISORD JI INT. J. BIBPOLAR DISORD. PD OCT 12 PY 2016 VL 4 AR 21 DI 10.1186/s40345-016-0062-4 PG 7 WC Psychiatry SC Psychiatry GA EC4XG UT WOS:000388137100002 PM 27734417 ER PT J AU Chung, WJ Goeckeler-Fried, JL Havasi, V Chiang, A Rowe, SM Plyler, ZE Hong, JS Mazur, M Piazza, GA Keeton, AB White, EL Rasmussen, L Weissman, AM Denny, RA Brodsky, JL Sorscher, EJ AF Chung, W. Joon Goeckeler-Fried, Jennifer L. Havasi, Viktoria Chiang, Annette Rowe, Steven M. Plyler, Zackery E. Hong, Jeong S. Mazur, Marina Piazza, Gary A. Keeton, Adam B. White, E. Lucile Rasmussen, Lynn Weissman, Allan M. Denny, R. Aldrin Brodsky, Jeffrey L. Sorscher, Eric J. TI Increasing the Endoplasmic Reticulum Pool of the F508del Allele of the Cystic Fibrosis Transmembrane Conductance Regulator Leads to Greater Folding Correction by Small Molecule Therapeutics SO PLOS ONE LA English DT Article ID DELTA-F508 CFTR; IN-VITRO; MUTANT PROTEIN; PHE508DEL CFTR; MESSENGER-RNA; DEGRADATION; MUTATION; PROTEASOME; IVACAFTOR; RESCUE AB Small molecules that correct the folding defects and enhance surface localization of the F508del mutation in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) comprise an important therapeutic strategy for cystic fibrosis lung disease. However, compounds that rescue the F508del mutant protein to wild type (WT) levels have not been identified. In this report, we consider obstacles to obtaining robust and therapeutically relevant levels of F508del CFTR. For example, markedly diminished steady state amounts of F508del CFTR compared to WT CFTR are present in recombinant bronchial epithelial cell lines, even when much higher levels of mutant transcript are present. In human primary airway cells, the paucity of Band B F508del is even more pronounced, although F508del and WT mRNA concentrations are comparable. Therefore, to augment levels of "repairable" F508del CFTR and identify small molecules that then correct this pool, we developed compound library screening protocols based on automated protein detection. First, cell-based imaging measurements were used to semi-quantitatively estimate distribution of F508del CFTR by high content analysis of two-dimensional images. We evaluated similar to 2,000 known bioactive compounds from the NIH Roadmap Molecular Libraries Small Molecule Repository in a pilot screen and identified agents that increase the F508del protein pool. Second, we analyzed similar to 10,000 compounds representing diverse chemical scaffolds for effects on total CFTR expression using a multi-plate fluorescence protocol and describe compounds that promote F508del maturation. Together, our findings demonstrate proof of principle that agents identified in this fashion can augment the level of endoplasmic reticulum (ER) resident "Band B" F508del CFTR suitable for pharmacologic correction. As further evidence in support of this strategy, PYR-41 D a compound that inhibits the E1 ubiquitin activating enzyme D was shown to synergistically enhance F508del rescue by C18, a small molecule corrector. Our combined results indicate that increasing the levels of ER-localized CFTR available for repair provides a novel route to correct F508del CFTR. C1 [Chung, W. Joon; Havasi, Viktoria; Rowe, Steven M.; Plyler, Zackery E.; Hong, Jeong S.; Mazur, Marina] Univ Alabama Birmingham, Gregory Fleming James Cyst Fibrosis Res Ctr, Birmingham, AL USA. [Chung, W. Joon] Univ Alabama Birmingham, Dept Neurobiol, Birmingham, AL USA. [Goeckeler-Fried, Jennifer L.; Chiang, Annette; Brodsky, Jeffrey L.] Univ Pittsburgh, Dept Biol Sci, Pittsburgh, PA 15260 USA. [Rowe, Steven M.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Rowe, Steven M.; Hong, Jeong S.] Univ Alabama Birmingham, Dept Cellular Dev & Integrat Biol, Birmingham, AL USA. [Piazza, Gary A.; Keeton, Adam B.] Univ S Alabama, USA Mitchell Canc Inst, Oncol Sci, Mobile, AL 36688 USA. [White, E. Lucile; Rasmussen, Lynn] Southern Res Inst, Drug Discovery Div, Birmingham, AL 35255 USA. [Weissman, Allan M.] NIH, Ctr Canc Res, Frederick, MD USA. [Denny, R. Aldrin] Pfizer, Worldwide Med Chem, Cambridge, MA USA. [Sorscher, Eric J.] Emory Univ, Dept Pediat, Atlanta, GA 30322 USA. RP Sorscher, EJ (reprint author), Emory Univ, Dept Pediat, Atlanta, GA 30322 USA. EM esorscher@emory.edu FU Cystic Fibrosis Foundation [SORSCH05XXO, BRODSK13XX0]; National Institutes of Health [P30DK072482, DK79307]; Center for Cancer Research; National Cancer Institute FX This work was supported by the Cystic Fibrosis Foundation grant to EJS, SORSCH05XXO, cff.org; National Institutes of Health grant to EJS, P30DK072482, nih.gov; Center for Cancer Research, National Cancer Institute, National Institutes of Health grant to AMW, ccr.cancer.gov; Cystic Fibrosis Foundation grant to JLB, BRODSK13XX0; and National Institutes of Health grant to JLB, DK79307, nih.gov. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 0 Z9 0 U1 3 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 12 PY 2016 VL 11 IS 10 AR e0163615- DI 10.1371/journal.pone.0163615 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ0CQ UT WOS:000385505300023 PM 27732613 ER PT J AU Zhao, HQ Winogradoff, D Bui, M Dalal, Y Papoian, GA AF Zhao, Haiqing Winogradoff, David Minh Bui Dalal, Yamini Papoian, Garegin A. TI Promiscuous Histone Mis-Assembly Is Actively Prevented by Chaperones SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID CENP-A NUCLEOSOMES; PROTEIN-STRUCTURE PREDICTION; CENTROMERIC NUCLEOSOMES; CRYSTAL-STRUCTURE; BUDDING YEAST; MOLECULAR SIMULATION; IN-VIVO; CHROMATIN; VARIANTS; HJURP AB Histone proteins are essential for the organization, expression, and inheritance of genetic material for eukaryotic cells. A centromere-specific H3 histone variant, centromere protein A (CENP-A), shares about 50% amino acid sequence identity with H3. CENP-A is required for packaging the centromere and for the proper separation of chromosomes during mitosis. Despite their distinct biological functions, previously reported crystal structures of the CENP-A/H4 and H3/H4 dimers reveal a high degree of similarity. In this work, we characterize the structural dynamics of CENP-A/H4 and H3/H4 dimers based on a dual-resolution approach, using both microsecond-scale explicit-solvent all-atom and coarse-grained (CG) molecular dynamics (MD) simulations. Our data show that the H4 histone is significantly more rigid compared with the H3 histone and its variant CENP-A, hence, serving as a reinforcing structural element within the histone core. We report that the CENP-A/H4 dimer is significantly more dynamic than its canonical counterpart H3/H4, and our results provide a physical explanation for this flexibility. Further, we observe that the centromere-specific chaperone Holliday Junction Recognition Protein (HJURP) stabilizes the CENP-A/H4 dimer by forming a specific electrostatic interaction network. Finally, replacing CENP-A S68 with E68 disrupts the binding interface between CENP-A and HJURP in all-atom MD simulation, and consistently, in vivo experiments demonstrate that replacing CENP-A S68 with E68 disrupts CENP-A's localization to the centromere. Based on all our results, we propose that, during the CENP-A/H4 deposition process, the chaperone HJURP protects various substructures of the dimer, serving both as a folding and binding chaperone. C1 [Zhao, Haiqing; Papoian, Garegin A.] Univ Maryland, Biophys Program, College Pk, MD 20742 USA. [Winogradoff, David; Papoian, Garegin A.] Univ Maryland, Chem Phys Program, College Pk, MD 20742 USA. [Papoian, Garegin A.] Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 USA. [Zhao, Haiqing; Minh Bui; Dalal, Yamini] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. RP Papoian, GA (reprint author), Univ Maryland, Biophys Program, College Pk, MD 20742 USA.; Papoian, GA (reprint author), Univ Maryland, Chem Phys Program, College Pk, MD 20742 USA.; Papoian, GA (reprint author), Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 USA.; Dalal, Y (reprint author), NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. EM dalaly@mail.nih.gov; gpapoian@umd.edu FU joint NCI-UMD Cancer Technology Partnership Program; University of Maryland; CCR/NCI; National Science Foundation [NSF CHE-1363081] FX H.Z. is supported by the joint NCI-UMD Cancer Technology Partnership Program. D.W. is supported by the University of Maryland. M.B. and Y.D. are supported by the intramural research program of the CCR/NCI. G.A.P. is supported by the National Science Foundation NSF CHE-1363081. Computational resources are provided by the Deepthought-II supercomputer at the University of Maryland. NR 67 TC 1 Z9 1 U1 8 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD OCT 12 PY 2016 VL 138 IS 40 BP 13207 EP 13218 DI 10.1021/jacs.6b05355 PG 12 WC Chemistry, Multidisciplinary SC Chemistry GA DY9QG UT WOS:000385469600025 PM 27454815 ER PT J AU Ketcham, JM Volchkov, I Chen, TY Blumberg, PM Kedei, N Lewin, NE Krische, MJ AF Ketcham, John M. Volchkov, Ivan Chen, Te-Yu Blumberg, Peter M. Kedei, Noemi Lewin, Nancy E. Krische, Michael J. TI Evaluation of Chromane-Based Bryostatin Analogues Prepared via Hydrogen-Mediated C-C Bond Formation: Potency Does Not Confer Bryostatin-like Biology SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID PROTEIN-KINASE-C; BRYOZOAN BUGULA-NERITINA; DISEASE TRANSGENIC MICE; PHORBOL ESTER RECEPTOR; ALZHEIMERS-DISEASE; A-RING; ASYMMETRIC-SYNTHESIS; LEUKEMIA-CELLS; FORMING HYDROGENATION; ANTITUMOR MACROLIDES AB The synthesis and biological evaluation of chromane-containing bryostatin analogues WN-2 WN-7 and the previously reported salicylate-based analogue WN-8 are described. Analogues WN-2 WN-7 are prepared through convergent assembly of the chromane-containing fragment B-I with the "binding domain" fragment A-I or its C26-des-methyl congener, fragment A-II. The synthesis of fragment B-I features enantioselective double C-H allylation of 1,3-propanediol to form the C-2-symmetric diol 3 and Heck cyclization of bromo-diene 5 to form the chromane core. The synthesis of salicylate WN-8 is accomplished through the union of fragments A-III and B-II. The highest binding affinities for PKC alpha are observed for the C26-des-methyl analogues WN-3 (K-i = 63.9 nM) and WN-7 (K-i = 63.1 nM). All analogues, WN-2 WN-8, inhibited growth of Toledo cells, with the most potent analogue being WN-7. This response, however, does not distinguish between phorbol ester like and bryostatin-like behavior. In contrast, while many of the analogues contain a conserved C-ring in the binding domain and other features common to analogues with bryostatin-like properties, all analogues evaluated in the U937 proliferation and cell attachment assays displayed phorbol ester-like and/or toxic behavior, including WN-8, for which "bryostatin-like PKC modulatory activities" previously was suggested solely on the basis of PKC binding. These results underscore the importance of considering downstream biological effects, as tumor suppression cannot be inferred from potent PKC binding. C1 [Ketcham, John M.; Volchkov, Ivan; Chen, Te-Yu; Krische, Michael J.] Univ Texas Austin, Dept Chem & Biochem, Austin, TX 78712 USA. [Blumberg, Peter M.; Kedei, Noemi; Lewin, Nancy E.] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. RP Krische, MJ (reprint author), Univ Texas Austin, Dept Chem & Biochem, Austin, TX 78712 USA.; Blumberg, PM (reprint author), NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. EM blumberp@dc37a.nci.nih.gov; mkrische@mail.utexas.edu FU Robert A. Welch Foundation [F-0038]; NIH-NIGMS [RO1-GM093905]; Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute [Z1A BC 005270]; Cancer Prevention Research Institute of Texas [RP101501]; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX The Robert A. Welch Foundation (F-0038) and the NIH-NIGMS (RO1-GM093905) are acknowledged for partial support of this research. Partial support was also provided by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute (Z1A BC 005270). The Cancer Prevention Research Institute of Texas (RP101501) is acknowledged for Postdoctoral Fellowship (I.V.). Skilled technical assistance was provided by Kim Wasik. This project was funded in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. NR 102 TC 1 Z9 1 U1 12 U2 12 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD OCT 12 PY 2016 VL 138 IS 40 BP 13415 EP 13423 DI 10.1021/jacs.6b08695 PG 9 WC Chemistry, Multidisciplinary SC Chemistry GA DY9QG UT WOS:000385469600049 PM 27676096 ER PT J AU zu Erbach-Schoenberg, E Alegana, VA Sorichetta, A Linard, C Lourenco, C Ruktanonchai, NW Graupe, B Bird, TJ Pezzulo, C Wesolowski, A Tatem, AJ AF zu Erbach-Schoenberg, Elisabeth Alegana, Victor A. Sorichetta, Alessandro Linard, Catherine Lourenco, Christoper Ruktanonchai, Nick W. Graupe, Bonita Bird, Tomas J. Pezzulo, Carla Wesolowski, Amy Tatem, Andrew J. TI Dynamic denominators: the impact of seasonally varying population numbers on disease incidence estimates SO POPULATION HEALTH METRICS LA English DT Article DE Health metrics; Mobile phones; Malaria; Surveillance; Disease incidence; Seasonality ID MOBILE PHONE DATA; MALARIA ELIMINATION; HUMAN MOVEMENT; TRANSMISSION; TRAVEL; RISK; SURVEILLANCE; ZANZIBAR; AFRICA AB Background: Reliable health metrics are crucial for accurately assessing disease burden and planning interventions. Many health indicators are measured through passive surveillance systems and are reliant on accurate estimates of denominators to transform case counts into incidence measures. These denominator estimates generally come from national censuses and use large area growth rates to estimate annual changes. Typically, they do not account for any seasonal fluctuations and thus assume a static denominator population. Many recent studies have highlighted the dynamic nature of human populations through quantitative analyses of mobile phone call data records and a range of other sources, emphasizing seasonal changes. In this study, we use mobile phone data to capture patterns of short-term human population movement and to map dynamism in population densities. Methods: We show how mobile phone data can be used to measure seasonal changes in health district population numbers, which are used as denominators for calculating district-level disease incidence. Using the example of malaria case reporting in Namibia we use 3.5 years of phone data to investigate the spatial and temporal effects of fluctuations in denominators caused by seasonal mobility on malaria incidence estimates. Results: We show that even in a sparsely populated country with large distances between population centers, such as Namibia, populations are highly dynamic throughout the year. We highlight how seasonal mobility affects malaria incidence estimates, leading to differences of up to 30 % compared to estimates created using static population maps. These differences exhibit clear spatial patterns, with likely overestimation of incidence in the high-prevalence zones in the north of Namibia and underestimation in lower-risk areas when compared to using static populations. Conclusion: The results here highlight how health metrics that rely on static estimates of denominators from censuses may differ substantially once mobility and seasonal variations are taken into account. With respect to the setting of malaria in Namibia, the results indicate that Namibia may actually be closer to malaria elimination than previously thought. More broadly, the results highlight how dynamic populations are. In addition to affecting incidence estimates, these changes in population density will also have an impact on allocation of medical resources. Awareness of seasonal movements has the potential to improve the impact of interventions, such as vaccination campaigns or distributions of commodities like bed nets. C1 [zu Erbach-Schoenberg, Elisabeth; Alegana, Victor A.; Sorichetta, Alessandro; Lourenco, Christoper; Ruktanonchai, Nick W.; Bird, Tomas J.; Pezzulo, Carla; Tatem, Andrew J.] Univ Southampton, WorldPop, Geog & Environm, Univ Rd, Southampton SO17 1BJ, Hants, England. [zu Erbach-Schoenberg, Elisabeth; Alegana, Victor A.; Sorichetta, Alessandro; Ruktanonchai, Nick W.; Bird, Tomas J.; Pezzulo, Carla; Wesolowski, Amy; Tatem, Andrew J.] Flowminder Fdn, Roslagsgatan 17, S-11355 Stockholm, Sweden. [Linard, Catherine] Univ Libre Bruxelles, Spatial Epidemiol Lab SpELL, Ave FD Roosevelt 50, B-1050 Brussels, Belgium. [Linard, Catherine] Univ Namur, Dept Geog, Rue Bruxelles 61, B-5000 Namur, Belgium. [Lourenco, Christoper] Clinton Hlth Access Initiat, Boston, MA USA. [Graupe, Bonita] Mobile Telecommun Ltd, Windhoek, Namibia. [Wesolowski, Amy] Harvard, Ctr Communicable Dis Dynam, Boston, MA USA. [Wesolowski, Amy] Harvard, Dept Epidemiol, Boston, MA USA. [Wesolowski, Amy] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Tatem, Andrew J.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP zu Erbach-Schoenberg, E (reprint author), Univ Southampton, WorldPop, Geog & Environm, Univ Rd, Southampton SO17 1BJ, Hants, England.; zu Erbach-Schoenberg, E (reprint author), Flowminder Fdn, Roslagsgatan 17, S-11355 Stockholm, Sweden. EM elisabeth.zu.es@gmail.com OI Alegana, Victor/0000-0001-5177-9227 FU NIH/NIAID [U19AI089674]; Bill & Melinda Gates Foundation [OPP1106427, 1032350]; RAPIDD program of the Science & Technology Directorate, Department of Homeland Security and the Fogarty International Center, National Institutes of Health; Wellcome Trust Sustaining Health Grant [106866/Z/15/Z]; James S McDonnell Foundation; Models of Infectious Disease Agent Study program [1U54GM088558]; Burroughs Wellcome Fund FX AJT is supported by funding from NIH/NIAID (U19AI089674), the Bill & Melinda Gates Foundation (OPP1106427, 1032350), the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security and the Fogarty International Center, National Institutes of Health, and a Wellcome Trust Sustaining Health Grant (106866/Z/15/Z), which supports EE and AW. AW is supported by a James S McDonnell Foundation fellowship and the Models of Infectious Disease Agent Study program (cooperative agreement 1U54GM088558) and holds a Career Award at the Scientific Interface from the Burroughs Wellcome Fund. AS is supported by funding from the Bill & Melinda Gates Foundation (OPP1106427, 1032350). NR 47 TC 0 Z9 0 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1478-7954 J9 POPUL HEALTH METR JI Popul. Health Metr. PD OCT 12 PY 2016 VL 14 AR 35 DI 10.1186/s12963-016-0106-0 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DZ3GD UT WOS:000385732300001 PM 27905974 ER PT J AU Andriani, GA Almeida, VP Faggioli, F Mauro, M Tsai, WL Santambrogio, L Maslov, A Gadina, M Campisi, J Vijg, J Montagna, C AF Andriani, Grasiella Angelina Almeida, Vinnycius Pereira Faggioli, Francesca Mauro, Maurizio Tsai, Wanxia Li Santambrogio, Laura Maslov, Alexander Gadina, Massimo Campisi, Judith Vijg, Jan Montagna, Cristina TI Whole Chromosome Instability induces senescence and promotes SASP SO SCIENTIFIC REPORTS LA English DT Article ID INFLAMMATORY CYTOKINE SECRETION; DNA-DAMAGE RESPONSE; CELL-CYCLE ARREST; OXIDATIVE STRESS; GENOMIC INSTABILITY; SPINDLE CHECKPOINT; MAMMALIAN-CELLS; MOUSE OOCYTES; P53 PATHWAY; ANEUPLOIDY AB Age-related accumulation of ploidy changes is associated with decreased expression of genes controlling chromosome segregation and cohesin functions. To determine the consequences of whole chromosome instability (W-CIN) we down-regulated the spindle assembly checkpoint component BUB1 and the mitotic cohesin SMC1A, and used four-color-interphase-FISH coupled with BrdU incorporation and analyses of senescence features to reveal the fate of W-CIN cells. We observed significant correlations between levels of not-diploid cells and senescence-associated features (SAFs). W-CIN induced DNA double strand breaks and elevated oxidative stress, but caused low apoptosis. SAFs of W-CIN cells were remarkably similar to those induced by replicative senescence but occurred in only 13 days versus 4 months. Cultures enriched with not-diploid cells acquired a senescence-associated secretory phenotype (SASP) characterized by IL1B, CXCL8, CCL2, TNF, CCL27 and other pro-inflammatory factors including a novel SASP component CLEC11A. These findings suggest that W-CIN triggers premature senescence, presumably to prevent the propagation of cells with an abnormal DNA content. Cells deviating from diploidy have the ability to communicate with their microenvironment by secretion of an array of signaling factors. Our results suggest that aneuploid cells that accumulate during aging in some mammalian tissues potentially contribute to age-related pathologies and inflammation through SASP secretion. C1 [Andriani, Grasiella Angelina; Faggioli, Francesca; Mauro, Maurizio; Maslov, Alexander; Vijg, Jan; Montagna, Cristina] Albert Einstein Coll Med, Dept Genet, Bronx, NY 10461 USA. [Almeida, Vinnycius Pereira] Univ Fed Goias, Inst Trop Pathol & Publ Hlth, Goiania, Go, Brazil. [Tsai, Wanxia Li; Gadina, Massimo] NIAMSD, Translat Immunol Sect, Off Sci & Technol, NIH, Bethesda, MD 20892 USA. [Santambrogio, Laura; Montagna, Cristina] Albert Einstein Coll Med, Dept Pathol, Bronx, NY 10461 USA. [Campisi, Judith] Buck Inst Res Aging, 8001 Redwood Blvd, Novato, CA USA. [Vijg, Jan] Albert Einstein Coll Med, Dept Ophthalmol & Visual Sci, Bronx, NY 10467 USA. [Vijg, Jan] Yeshiva Univ, Albert Einstein Coll Med, Dept Obstet & Gynecol & Womens Hlth, Bronx, NY USA. RP Montagna, C (reprint author), Albert Einstein Coll Med, Dept Genet, Bronx, NY 10461 USA.; Montagna, C (reprint author), Albert Einstein Coll Med, Dept Pathol, Bronx, NY 10461 USA. EM cristina.montagna@einstein.yu.edu OI Pereira Almeida, Vinnycius/0000-0002-3635-7787 FU CAPES Foundation (Ministry of Education of Brazil, Brasilia-DF); Albert Einstein Cancer Center Support Grant of the National Institutes of Health [P30CA013330]; National Institutes of Health [AG017242] FX We would like to thank the Molecular Cytogenetic Core at Albert Einstein College of Medicine and in particular Dr. Jidong Shan and Dr. Yinghui Song for assisting with the FISH studies. We would also like to thank the CAPES Foundation (Ministry of Education of Brazil, Brasilia-DF, Zip code 70.040-020) for sponsoring Vinnycius Pereira Almeida. Research reported in this publication was supported by the Albert Einstein Cancer Center Support Grant of the National Institutes of Health under award number P30CA013330. Part of this work was also supported by a grant from the National Institutes of Health [AG017242 to J.V. and J.C.]. NR 78 TC 0 Z9 0 U1 8 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD OCT 12 PY 2016 VL 6 AR 35218 DI 10.1038/srep35218 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DY3OF UT WOS:000385002800001 PM 27731420 ER PT J AU Manzoni, C Mamais, A Roosen, DA Dihanich, S Soutar, MPM Plun-Favreau, H Bandopadhyay, R Hardy, J Tooze, SA Cookson, MR Lewis, PA AF Manzoni, Claudia Mamais, Adamantios Roosen, Dorien A. Dihanich, Sybille Soutar, Marc P. M. Plun-Favreau, Helene Bandopadhyay, Rina Hardy, John Tooze, Sharon A. Cookson, Mark R. Lewis, Patrick A. TI mTOR independent regulation of macroautophagy by Leucine Rich Repeat Kinase 2 via Beclin-1 SO SCIENTIFIC REPORTS LA English DT Article ID LRRK2 G2019S MUTATION; BCL-X-L; PARKINSONS-DISEASE; AUTOPHAGIC ACTIVITY; MEDIATED AUTOPHAGY; GTPASE ACTIVITY; SH-SY5Y CELLS; PHOSPHORYLATION; INHIBITOR; PATHWAY AB Leucine rich repeat kinase 2 is a complex enzyme with both kinase and GTPase activities, closely linked to the pathogenesis of several human disorders including Parkinson's disease, Crohn's disease, leprosy and cancer. LRRK2 has been implicated in numerous cellular processes; however its physiological function remains unclear. Recent reports suggest that LRRK2 can act to regulate the cellular catabolic process of macroautophagy, although the precise mechanism whereby this occurs has not been identified. To investigate the signalling events through which LRRK2 acts to influence macroautophagy, the mammalian target of rapamycin (mTOR)/Unc-51-like kinase 1 (ULK1) and Beclin-1/phosphatidylinositol 3-kinase (PI3K) pathways were evaluated in astrocytic cell models in the presence and absence of LRRK2 kinase inhibitors. Chemical inhibition of LRRK2 kinase activity resulted in the stimulation of macroautophagy in a non-canonical fashion, independent of mTOR and ULK1, but dependent upon the activation of Beclin 1-containing class III PI3-kinase. C1 [Manzoni, Claudia; Lewis, Patrick A.] Univ Reading, Sch Pharm, Reading RG6 6AP, Berks, England. [Manzoni, Claudia; Roosen, Dorien A.; Dihanich, Sybille; Soutar, Marc P. M.; Plun-Favreau, Helene; Hardy, John; Lewis, Patrick A.] UCL Inst Neurol, Dept Mol Neurosci, Queen Sq, London WC1N 3BG, England. [Mamais, Adamantios; Roosen, Dorien A.; Cookson, Mark R.] NIA, Cell Biol & Gene Express Sect, Neurogenet Lab, NIH, Bldg 35,35 Convent Dr, Bethesda, MD 20892 USA. [Bandopadhyay, Rina] UCL Inst Neurol, Reta Lila Weston Inst Neurol Studies, 1 Wakefield St, London WC1N 1PJ, England. [Tooze, Sharon A.] London Res Inst, Francis Crick Inst, 44 Lincolns Inn Fields, London WC2A 3LY, England. RP Manzoni, C; Lewis, PA (reprint author), Univ Reading, Sch Pharm, Reading RG6 6AP, Berks, England.; Manzoni, C; Lewis, PA (reprint author), UCL Inst Neurol, Dept Mol Neurosci, Queen Sq, London WC1N 3BG, England. EM c.manzoni@reading.ac.uk; p.a.lewis@reading.ac.uk RI Plun-Favreau, Helene/Q-4111-2016; Hardy, John/C-2451-2009; Soutar, Marc/G-3637-2011; OI Plun-Favreau, Helene/0000-0002-1401-9656; Soutar, Marc/0000-0003-0008-9423; Lewis, Patrick/0000-0003-4537-0489 FU Michael J. Fox Foundation; Parkinson's UK; Rosetrees Trust; Parkinson's UK research fellow [F1002]; Wellcome Trust/MRC Joint Call in Neurodegeneration award [WT089698]; MRC New Investigator Research Grant [MR/L010933/1]; MRC programme grant [MR/N026004/1]; Intramural Research Program of the NIH, National Institute on Aging; Cancer Research UK [FC001187]; UK Medical Research Council [FC001187]; Wellcome Trust [FC001187] FX The authors would like to acknowledge generous research support from the Michael J. Fox Foundation, Parkinson's UK and the Rosetrees Trust. PAL is a Parkinson's UK research fellow (grant F1002). This work was supported in part by the Wellcome Trust/MRC Joint Call in Neurodegeneration award (WT089698) to the UK Parkinson's Disease Consortium (UKPDC) whose members are from the UCL Institute of Neurology, the University of Sheffield and the MRC Protein Phosphorylation Unit at the University of Dundee, by a MRC New Investigator Research Grant (MR/L010933/1) to PAL, and by MRC programme grant MR/N026004/1 to JH, HPF and PAL. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. SAT was supported by the Francis Crick Institute which receives its core funding from Cancer Research UK (FC001187), the UK Medical Research Council (FC001187), and the Wellcome Trust (FC001187). We thank Dr. Claudio Galbiati and Dr. Miriam Manzoni at the Universita degli Studi di Bergamo (IT) for the development of the image quantification script for Supplementary Figure S5. We thank the UCL Cancer Institute CAGE Facility, which provided the Open Biosystems GIPZ shRNAmir. The CAGE Facility is supported by the Welton Foundation, BRC and in part by the Cancer Research UK - UCL Centre. NR 61 TC 2 Z9 2 U1 12 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD OCT 12 PY 2016 VL 6 AR 35106 DI 10.1038/srep35106 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DY3KC UT WOS:000384990300001 PM 27731364 ER PT J AU Morita, M Yoshida, S Iwasaki, R Yasui, T Sato, Y Kobayashi, T Watanabe, R Oike, T Miyamoto, K Takami, M Ozato, K Deng, CX Aburatani, H Tanaka, S Yoshimura, A Toyama, Y Matsumoto, M Nakamura, M Kawana, H Nakagawa, T Miyamoto, T AF Morita, Mayu Yoshida, Shigeyuki Iwasaki, Ryotaro Yasui, Tetsuro Sato, Yuiko Kobayashi, Tami Watanabe, Ryuichi Oike, Takatsugu Miyamoto, Kana Takami, Masamichi Ozato, Keiko Deng, Chu-Xia Aburatani, Hiroyuki Tanaka, Sakae Yoshimura, Akihiko Toyama, Yoshiaki Matsumoto, Morio Nakamura, Masaya Kawana, Hiromasa Nakagawa, Taneaki Miyamoto, Takeshi TI Smad4 is required to inhibit osteoclastogenesis and maintain bone mass SO SCIENTIFIC REPORTS LA English DT Article ID GROWTH-FACTOR-BETA; MESENCHYMAL STEM-CELLS; TGF-BETA; DIFFERENTIATION; HOMEOSTASIS; RESORPTION; MICE; AUTOINDUCTION; OSTEOPOROSIS; METABOLISM AB Bone homeostasis is maintained as a delicate balance between bone-resorption and bone-formation, which are coupled to maintain appropriate bone mass. A critical question is how bone-resorption is terminated to allow bone-formation to occur. Here, we show that TGF beta s inhibit osteoclastogenesis and maintain bone-mass through Smad4 activity in osteoclasts. We found that latent-TGF beta 1 was activated by osteoclasts to inhibit osteoclastogenesis. Osteoclast-specific Smad4 conditional knockout mice (Smad4-cKO) exhibited significantly reduced bone-mass and elevated osteoclast formation relative to controls. TGF beta 1-activation induced expression of Irf8 and Bcl6, both of which encode factors inhibiting osteoclastogenesis, by blocking their negative regulator, Prdm1, in osteoclasts in a Smad4-dependent manner. Reduced bone-mass and accelerated osteoclastogenesis seen in Smad4-cKO were abrogated by Prdm1 deletion. Administration of latent-TGF beta 1-Fc to wild-type mice antagonized LPS-induced bone destruction in a model of activated osteoclast-mediated bone destruction. Thus, latent-TGF beta 1-Fc could serve as a promising new therapeutic agent in bone diseases marked by excessive resorption. C1 [Morita, Mayu; Yoshida, Shigeyuki; Iwasaki, Ryotaro; Kawana, Hiromasa; Nakagawa, Taneaki] Keio Univ, Sch Med, Dept Dent & Oral Surg, Div Oral & Maxillofacial Surg,Shinjuku Ku, 35 Shinano Machi, Tokyo 1608582, Japan. [Yasui, Tetsuro; Tanaka, Sakae] Univ Tokyo, Dept Orthoped Surg, Fac Med, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1138859, Japan. [Sato, Yuiko; Kobayashi, Tami; Watanabe, Ryuichi; Oike, Takatsugu; Miyamoto, Kana; Toyama, Yoshiaki; Matsumoto, Morio; Nakamura, Masaya; Miyamoto, Takeshi] Keio Univ, Sch Med, Dept Orthoped Surg, Shinjuku Ku, 35 Shinano Machi, Tokyo 1608582, Japan. [Sato, Yuiko; Kobayashi, Tami] Keio Univ, Sch Med, Dept Musculoskeletal Reconstruct & Regenerat Surg, Shinjuku Ku, 35 Shinano Machi, Tokyo 1608582, Japan. [Sato, Yuiko; Miyamoto, Takeshi] Keio Univ, Sch Med, Dept Adv Therapy Musculoskeletal Disorders, Shinjuku Ku, 35 Shinano Machi, Tokyo 1608582, Japan. [Takami, Masamichi] Showa Univ, Sch Dent, Dept Pharmacol, Sinagawa Ku, 1-5-8 Hatanodai, Tokyo 1420033, Japan. [Ozato, Keiko] NICHD, Lab Mol Growth Regulat, Genom Differentiat Program, NIH, Bethesda, MD USA. [Deng, Chu-Xia] Univ Macau, Fac Hlth Sci, Taipa, Macau, Peoples R China. [Aburatani, Hiroyuki] Univ Tokyo, RCAST, Genome Sci Div, Meguro Ku, 4-6-1 Komaba, Tokyo 1538904, Japan. [Yoshimura, Akihiko] Keio Univ, Sch Med, Dept Microbiol & Immunol, Shinjuku Ku, 35 Shinano Machi, Tokyo 1608582, Japan. RP Miyamoto, T (reprint author), Keio Univ, Sch Med, Dept Orthoped Surg, Shinjuku Ku, 35 Shinano Machi, Tokyo 1608582, Japan.; Miyamoto, T (reprint author), Keio Univ, Sch Med, Dept Adv Therapy Musculoskeletal Disorders, Shinjuku Ku, 35 Shinano Machi, Tokyo 1608582, Japan. EM miyamoto@z5.keio.jp RI Yoshimura, Akihiko/K-5515-2013 FU Japan Agency for Medical Research and Development; Translational Research Network Program FX Prdm1 flox mice were kindly provided by Dr. A. Sakamoto and Dr. T. Tokuhisa. CtskCre/+ mice were provided by Dr. S. Kato. T. Miyamoto was supported by a grant-in-aid for Scientific Research in Japan and a grant from Japan Agency for Medical Research and Development. Y. Sato and K. Miyamoto were supported by a grant-in-aid for Scientific Research in Japan. This study was supported in part by a Grant-in-aid for Scientific Research and a grant from the Translational Research Network Program. NR 55 TC 1 Z9 1 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD OCT 12 PY 2016 VL 6 AR 35221 DI 10.1038/srep35221 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DY3NO UT WOS:000385001100001 PM 27731422 ER PT J AU Sailer, A Scholz, SW Nalls, MA Schulte, C Federoff, M Price, TR Lees, A Ross, OA Dickson, DW Mok, K Mencacci, NE Schottlaender, L Chelban, V Ling, H O'Sullivan, SS Wood, NW Traynor, BJ Ferrucci, L Federoff, HJ Mhyre, TR Morris, HR Deuschl, G Quinn, N Widner, H Albanese, A Infante, J Bhatia, KP Poewe, W Oertel, W Hoglinger, GU Wullner, U Goldwurm, S Pellecchia, MT Ferreira, J Tolosa, E Bloem, BR Rascol, O Meissner, WG Hardy, JA Revesz, T Holton, JL Gasser, T Wenning, GK Singleton, AB Houlden, H AF Sailer, Anna Scholz, Sonja W. Nalls, Michael A. Schulte, Claudia Federoff, Monica Price, T. Ryan Lees, Andrew Ross, Owen A. Dickson, Dennis W. Mok, Kin Mencacci, Niccolo E. Schottlaender, Lucia Chelban, Viorica Ling, Helen O'Sullivan, Sean S. Wood, Nicholas W. Traynor, Bryan J. Ferrucci, Luigi Federoff, Howard J. Mhyre, Timothy R. Morris, Huw R. Deuschl, Gunther Quinn, Niall Widner, Hakan Albanese, Alberto Infante, Jon Bhatia, Kailash P. Poewe, Werner Oertel, Wolfgang Hoglinger, Gunter U. Wullner, Ullrich Goldwurm, Stefano Pellecchia, Maria Teresa Ferreira, Joaquim Tolosa, Eduardo Bloem, Bastiaan R. Rascol, Olivier Meissner, Wassilios G. Hardy, John A. Revesz, Tamas Holton, Janice L. Gasser, Thomas Wenning, Gregor K. Singleton, Andrew B. Houlden, Henry CA European Multiple Syst Atrophy Uk Multiple Syst Atrophy Study Grp TI A genome-wide association study in multiple system atrophy SO NEUROLOGY LA English DT Article ID PARKINSONS-DISEASE; SNCA VARIANTS; COMMON VARIANTS; INCREASED RISK; GENE; MSA; NEURODEGENERATION; IDENTIFICATION; METAANALYSIS; IMPAIRMENT AB Objective: To identify genetic variants that play a role in the pathogenesis of multiple system atrophy (MSA), we undertook a genome-wide association study (GWAS). Methods: We performed a GWAS with >5 million genotyped and imputed single nucleotide polymorphisms (SNPs) in 918 patients with MSA of European ancestry and 3,864 controls. MSA cases were collected from North American and European centers, one third of which were neuropathologically confirmed. Results: We found no significant loci after stringent multiple testing correction. A number of regions emerged as potentially interesting for follow-up at p < 1 x 10(-6), including SNPs in the genes FBXO47, ELOVL7, EDN1, and MAPT. Contrary to previous reports, we found no association of the genes SNCA and COQ2 with MSA. Conclusions: We present a GWAS in MSA. We have identified several potentially interesting gene loci, including the MAPT locus, whose significance will have to be evaluated in a larger sample set. Common genetic variation in SNCA and COQ2 does not seem to be associated with MSA. In the future, additional samples of well-characterized patients with MSA will need to be collected to perform a larger MSA GWAS, but this initial study forms the basis for these next steps. C1 [Sailer, Anna; Lees, Andrew; Mok, Kin; Mencacci, Niccolo E.; Schottlaender, Lucia; Chelban, Viorica; Ling, Helen; O'Sullivan, Sean S.; Wood, Nicholas W.; Hardy, John A.; Revesz, Tamas; Holton, Janice L.; Houlden, Henry] UCL Inst Neurol, Dept Mol Neurosci & Movement Disorders, London, England. [Sailer, Anna; Lees, Andrew; Mok, Kin; Mencacci, Niccolo E.; Schottlaender, Lucia; Chelban, Viorica; Ling, Helen; O'Sullivan, Sean S.; Wood, Nicholas W.; Hardy, John A.; Revesz, Tamas; Holton, Janice L.; Houlden, Henry] UCL Inst Neurol, Reta Lila Weston Inst, London, England. [Morris, Huw R.] UCL Inst Neurol, Dept Clin Neurosci, London, England. [Quinn, Niall; Bhatia, Kailash P.] UCL Inst Neurol, Sobell Dept Motor Neurosci & Movement Disorders, London, England. [Sailer, Anna] Goethe Univ Frankfurt, Univ Klin, Neurol Klin, Frankfurt, Germany. [Scholz, Sonja W.; Nalls, Michael A.; Price, T. Ryan; Traynor, Bryan J.; Singleton, Andrew B.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Scholz, Sonja W.] NINDS, Neurodegenerat Dis Res Unit, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Scholz, Sonja W.; Federoff, Howard J.; Mhyre, Timothy R.] Georgetown Univ, Dept Neurosci, Washington, DC 20057 USA. [Scholz, Sonja W.] Johns Hopkins Univ Hosp, Dept Neurol, Baltimore, MD 21287 USA. [Schulte, Claudia; Gasser, Thomas] Hertie Inst Clin Brain Res, Dept Neurodegenerat Dis, Tubingen, Germany. German Ctr Neurodegenerat Dis DZNE, Tubingen, Germany. [Ross, Owen A.; Dickson, Dennis W.] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA. [Mok, Kin] Hong Kong Univ Sci & Technol, Div Life Sci, Hong Kong, Hong Kong, Peoples R China. [Ferrucci, Luigi] NIA, NIH, Baltimore, MD 21224 USA. [Deuschl, Gunther] Christian Albrechts Univ Kiel, UKSH, Dept Neurol, Kiel Campus, Kiel, Germany. [Widner, Hakan] Univ Lund Hosp, Dept Clin Sci, Div Neurol, Lund, Sweden. [Albanese, Alberto] Univ Cattolica Sacro Cuore, Ist Clin Humanitas, Milan, Italy. [Infante, Jon] Univ Cantabria, Univ Hosp Marques de Valdecilla IDIVAL, Serv Neurol, Santander, Spain. [Poewe, Werner; Wenning, Gregor K.] Med Univ Innsbruck, Inst Neurol, Vienna, Austria. [Oertel, Wolfgang] Philipps Univ Marburg, Ctr Nervous Dis, Marburg, Germany. [Hoglinger, Gunter U.] Tech Univ Munich, Dept Neurol, Munich, Germany. [Hoglinger, Gunter U.] German Ctr Neurodegenerat Dis DZNE, Munich, Germany. [Wullner, Ullrich] Univ Hosp Bonn, Med Ctr, Dept Neurol, Bonn, Germany. [Wullner, Ullrich] Univ Hosp Bonn, Med Ctr, German Ctr Neurodegenerat Dis, Bonn, Germany. [Goldwurm, Stefano] Ist Clin Perfezionamento, Parkinson Inst, Milan, Italy. [Pellecchia, Maria Teresa] Univ Salerno, Neurosci Sect, Dept Med & Surg, Ctr Neurodegenerat Dis, Salerno, Italy. [Ferreira, Joaquim] Univ Lisbon, Fac Med, Inst Med Mol, Clin Pharmacol Unit, Lisbon, Portugal. [Tolosa, Eduardo] Univ Barcelona, Hosp Clin, Barcelona, Spain. [Bloem, Bastiaan R.] Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Dept Neurol, Nijmegen, Netherlands. [Rascol, Olivier] INSERM, Dept Clin Pharmacol, Clin Investigat Ctr CIC1436, Paris, France. [Rascol, Olivier] INSERM, Dept Neurosci, Clin Investigat Ctr CIC1436, Paris, France. Univ Hosp Toulouse, Fac Med, Toulouse, France. [Meissner, Wassilios G.] CHU Bordeaux, Ctr Reference Atrophie Multisystematisee, Pessac, France. [Meissner, Wassilios G.] Univ Bordeaux, Inst Malad Neurodegenerat, UMR 5293, Bordeaux, France. RP Houlden, H (reprint author), UCL Inst Neurol, Dept Mol Neurosci & Movement Disorders, London, England.; Houlden, H (reprint author), UCL Inst Neurol, Reta Lila Weston Inst, London, England.; Scholz, SW (reprint author), NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA.; Scholz, SW (reprint author), NINDS, Neurodegenerat Dis Res Unit, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA.; Scholz, SW (reprint author), Georgetown Univ, Dept Neurosci, Washington, DC 20057 USA.; Scholz, SW (reprint author), Johns Hopkins Univ Hosp, Dept Neurol, Baltimore, MD 21287 USA. EM sonja.scholz@nih.gov; h.houlden@ucl.ac.uk RI Houlden, Henry/C-1532-2008; Hardy, John/C-2451-2009; Wood, Nicholas/C-2505-2009; Revesz, Tamas/A-8732-2010; OI Houlden, Henry/0000-0002-2866-7777; Wood, Nicholas/0000-0002-9500-3348; Revesz, Tamas/0000-0003-2501-0259; Scholz, Sonja/0000-0002-6623-0429 FU TELETHON Italy [GTB12001]; Fondazione Grigioni per il Morbo di Parkinson FX DNA and brain samples: The authors used DNA samples and phenotype data from the NINDS Human Genetics Resource Center DNA and Cell Line Repository at Coriell (Newark, NJ; ccr.coriell.org/ninds), and thank the patients and the submitters who contributed samples to this repository. Human tissue was obtained from the Queen Square Brain Bank (London, UK), the Institute of Psychiatry Brain Bank, King's College (London, UK), the UK Parkinson's disease tissue bank at Imperial College (London, UK), Newcastle Brain Tissue Resource at Newcastle University (Newcastle, UK), the Manchester Brain Bank at the University of Manchester (Manchester, UK), Jacksonville Brain Bank for Alzheimer's, Parkinson's and Related Disorders at the Mayo Clinic (Jacksonville, FL), the NICHD Brain and Tissue Bank for Developmental Disorders at the University of Maryland (Baltimore, MD), the New York Brain Bank of the Taub Institute at Columbia University (New York, NY), the Human Brain and Spinal Fluid Resource Center (Los Angeles, CA), the Miami Brain Bank (Miami, FL), the Center for Neurodegenerative Disease Research at the University of Pennsylvania (Philadelphia, PA), the Harvard Brain Bank (Boston, MA), the Emory University Alzheimer's Disease Research Center Brain Bank (Atlanta, GA), Neurobiobank Munchen at the Ludwig-Maximilians-Universitat (Munich, Germany), Brain Bank Center Wurzburg (Wurzburg, Germany), the Netherlands Brain Bank at the Netherlands Institute for Neuroscience (Amsterdam, Netherlands), and the Neurological Tissue Bank at the University of Barcelona (Barcelona, Spain). The Italian samples were obtained from the Parkinson Institute Biobank (parkinsonbiobank.com), member of the Telethon Network of Genetic Biobank (project n. GTB12001) funded by TELETHON Italy, and supported by "Fondazione Grigioni per il Morbo di Parkinson." NR 40 TC 4 Z9 4 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD OCT 11 PY 2016 VL 87 IS 15 BP 1591 EP 1598 DI 10.1212/WNL.0000000000003221 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA EI1HU UT WOS:000392228600017 PM 27629089 ER PT J AU Moussawi, K Gupta, A Reda, H AF Moussawi, Khaled Gupta, Anoopum Reda, Haatem TI Clinical Reasoning: A 20-year-old man with headache and double vision SO NEUROLOGY LA English DT Editorial Material ID LYME NEUROBORRELIOSIS; PSEUDOTUMOR CEREBRI; DIAGNOSIS; DISEASE C1 [Moussawi, Khaled; Gupta, Anoopum; Reda, Haatem] Harvard Med Sch, Boston, MA 02115 USA. [Moussawi, Khaled; Gupta, Anoopum; Reda, Haatem] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Moussawi, Khaled; Gupta, Anoopum] Brigham & Womens Hosp, Dept Neurol, 75 Francis St, Boston, MA 02115 USA. [Moussawi, Khaled] Natl Inst Drug Abuse, Baltimore, MD 21224 USA. [Moussawi, Khaled] Johns Hopkins Med, Dept Psychiat, Baltimore, MD 21205 USA. RP Moussawi, K (reprint author), Harvard Med Sch, Boston, MA 02115 USA.; Moussawi, K (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA.; Moussawi, K (reprint author), Brigham & Womens Hosp, Dept Neurol, 75 Francis St, Boston, MA 02115 USA.; Moussawi, K (reprint author), Natl Inst Drug Abuse, Baltimore, MD 21224 USA.; Moussawi, K (reprint author), Johns Hopkins Med, Dept Psychiat, Baltimore, MD 21205 USA. EM khaled.moussawi@nih.gov NR 10 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD OCT 11 PY 2016 VL 87 IS 15 BP E162 EP E167 DI 10.1212/WNL.0000000000003208 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA EI1HU UT WOS:000392228600001 PM 27765826 ER PT J AU Abend, R Jalon, I Gurevitch, G Sar-el, R Shechner, T Pine, DS Hendler, T Bar-Haim, Y AF Abend, R. Jalon, I. Gurevitch, G. Sar-el, R. Shechner, T. Pine, D. S. Hendler, T. Bar-Haim, Y. TI Modulation of fear extinction processes using transcranial electrical stimulation SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; NONINVASIVE BRAIN-STIMULATION; ANTERIOR-CINGULATE-CORTEX; PREFRONTAL CORTEX; ANXIETY DISORDERS; AVERSIVE AMPLIFICATION; MAGNETIC STIMULATION; PROLONGED EXPOSURE; NEURAL MECHANISMS; CONDITIONED FEAR AB Research associates processes of fear conditioning and extinction with treatment of anxiety and stress-related disorders. Manipulation of these processes may therefore be beneficial for such treatment. The current study examines the effects of electrical brain stimulation on fear extinction processes in healthy humans in order to assess its potential relevance for treatment enhancement. Forty-five participants underwent a 3-day fear conditioning and extinction paradigm. Electrical stimulation targeting the medial prefrontal cortex was applied during the extinction-learning phase (Day 2). Participants were randomly assigned to three stimulation conditions: direct-current (DC) stimulation, aimed at enhancing extinction-learning; low-frequency alternating-current (AC) stimulation, aimed at interfering with reconsolidation of the activated fear memory; and sham stimulation. The effect of stimulation on these processes was assessed in the subsequent extinction recall phase (Day 3), using skin conductance response and self-reports. Results indicate that AC stimulation potentiated the expression of fear response, whereas DC stimulation led to overgeneralization of fear response to non-reinforced stimuli. The current study demonstrates the capability of electrical stimulation targeting the medial prefrontal cortex to modulate fear extinction processes. However, the stimulation parameters tested here yielded effects opposite to those anticipated and could be clinically detrimental. These results highlight the potential capacity of stimulation to manipulate processes relevant for treatment of anxiety and stress-related disorders, but also emphasize the need for additional research to identify delivery parameters to enable its translation into clinical practice. Clinical trial identifiers: Modulation of Fear Extinction Processes Using Transcranial Electrical Stimulation; https://clinicaltrials.gov/show/NCT02723188; NCT02723188. C1 [Abend, R.; Gurevitch, G.; Hendler, T.; Bar-Haim, Y.] Tel Aviv Univ, Sch Psychol Sci, POB 39040, IL-69978 Tel Aviv, Israel. [Abend, R.; Jalon, I.; Gurevitch, G.; Sar-el, R.; Hendler, T.] Sourasky Med Ctr, Wohl Inst Adv Imaging, Funct Brain Ctr, Tel Aviv, Israel. [Jalon, I.; Hendler, T.; Bar-Haim, Y.] Tel Aviv Univ, Sagol Sch Neurosci, Tel Aviv, Israel. [Shechner, T.] Univ Haifa, Dept Psychol, Haifa, Israel. [Pine, D. S.] NIMH, Sect Dev Affect Neurosci, Bethesda, MD 20892 USA. [Hendler, T.] Tel Aviv Univ, Fac Med, Tel Aviv, Israel. RP Abend, R (reprint author), Tel Aviv Univ, Sch Psychol Sci, POB 39040, IL-69978 Tel Aviv, Israel. EM rany.abend@gmail.com NR 71 TC 1 Z9 1 U1 12 U2 12 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD OCT 11 PY 2016 VL 6 DI 10.1038/tp.2016.197 PG 7 WC Psychiatry SC Psychiatry GA EH9ZM UT WOS:000392130900002 PM 27727241 ER PT J AU Zhang, MF Wang, ZM Obazee, O Jia, JP Childs, EJ Hoskins, J Figlioli, G Mocci, E Collins, I Chung, CC Hautman, C Arslan, AA Beane-Freeman, L Bracci, PM Buring, J Duell, EJ Gallinger, S Giles, GG Goodman, GE Goodman, PJ Kamineni, A Kolonel, LN Kulke, MH Malats, N Olson, SH Sesso, HD Visvanathan, K White, E Zheng, W Abnet, CC Albanes, D Andreotti, G Brais, L Bueno-de-Mesquita, HB Basso, D Berndt, SI Boutron-Ruault, MC Bijlsma, MF Brenner, H Burdette, L Campa, D Caporaso, NE Capurso, G Cavestro, GM Cotterchio, M Costello, E Elena, J Boggi, U Gaziano, JM Gazouli, M Giovannucci, EL Goggins, M Gross, M Haiman, CA Hassan, M Helzlsouer, KJ Hu, N Hunter, DJ Iskierka-Jazdzewska, E Jenab, M Kaaks, R Key, TJ Khaw, KT Klein, EA Kogevinas, M Krogh, V Kupcinskas, J Kurtz, RC Landi, MT Landi, S Le Marchand, L Mambrini, A Mannisto, S Milne, RL Neale, RE Oberg, AL Panico, S Patel, AV Peeters, PHM Peters, U Pezzilli, R Porta, M Purdue, M Quiros, JR Riboli, E Rothman, N Scarpa, A Scelo, G Shu, XO Silverman, DT Soucek, P Strobel, O Sund, M Malecka-Panas, E Taylor, PR Tavano, F Travis, RC Thornquist, M Tjonneland, A Tobias, GS Trichopoulos, D Vashist, Y Vodicka, P Wactawski-Wende, J Wentzensen, N Yu, H Yu, K Zeleniuch-Jacquotte, A Kooperberg, C Risch, HA Jacobs, EJ Li, DH Fuchs, C Hoover, R Hartge, P Chanock, SJ Petersen, GM Stolzenberg-Solomon, RS Wolpin, BM Kraft, P Klein, AP Canzian, F Amundadottir, LT AF Zhang, Mingfeng Wang, Zhaoming Obazee, Ofure Jia, Jinping Childs, Erica J. Hoskins, Jason Figlioli, Gisella Mocci, Evelina Collins, Irene Chung, Charles C. Hautman, Christopher Arslan, Alan A. Beane-Freeman, Laura Bracci, Paige M. Buring, Julie Duell, Eric J. Gallinger, Steven Giles, Graham G. Goodman, Gary E. Goodman, Phyllis J. Kamineni, Aruna Kolonel, Laurence N. Kulke, Matthew H. Malats, Nuria Olson, Sara H. Sesso, Howard D. Visvanathan, Kala White, Emily Zheng, Wei Abnet, Christian C. Albanes, Demetrius Andreotti, Gabriella Brais, Lauren Bueno-de-Mesquita, H. Bas Basso, Daniela Berndt, Sonja I. Boutron-Ruault, Marie-Christine Bijlsma, Maarten F. Brenner, Hermann Burdette, Laurie Campa, Daniele Caporaso, Neil E. Capurso, Gabriele Cavestro, Giulia Martina Cotterchio, Michelle Costello, Eithne Elena, Joanne Boggi, Ugo Gaziano, J. Michael Gazouli, Maria Giovannucci, Edward L. Goggins, Michael Gross, Myron Haiman, Christopher A. Hassan, Manal Helzlsouer, Kathy J. Hu, Nan Hunter, David J. Iskierka-Jazdzewska, Elzbieta Jenab, Mazda Kaaks, Rudolf Key, Timothy J. Khaw, Kay-Tee Klein, Eric A. Kogevinas, Manolis Krogh, Vittorio Kupcinskas, Juozas Kurtz, Robert C. Landi, Maria T. Landi, Stefano Le Marchand, Loic Mambrini, Andrea Mannisto, Satu Milne, Roger L. Neale, Rachel E. Oberg, Ann L. Panico, Salvatore Patel, Alpa V. Peeters, Petra H. M. Peters, Ulrike Pezzilli, Raffaele Porta, Miquel Purdue, Mark Ramon Quiros, J. Riboli, Elio Rothman, Nathaniel Scarpa, Aldo Scelo, Ghislaine Shu, Xiao-Ou Silverman, Debra T. Soucek, Pavel Strobel, Oliver Sund, Malin Malecka-Panas, Ewa Taylor, Philip R. Tavano, Francesca Travis, Ruth C. Thornquist, Mark Tjonneland, Anne Tobias, Geoffrey S. Trichopoulos, Dimitrios Vashist, Yogesh Vodicka, Pavel Wactawski-Wende, Jean Wentzensen, Nicolas Yu, Herbert Yu, Kai Zeleniuch-Jacquotte, Anne Kooperberg, Charles Risch, Harvey A. Jacobs, Eric J. Li, Donghui Fuchs, Charles Hoover, Robert Hartge, Patricia Chanock, Stephen J. Petersen, Gloria M. Stolzenberg-Solomon, Rachael S. Wolpin, Brian M. Kraft, Peter Klein, Alison P. Canzian, Federico Amundadottir, Laufey T. TI Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21 SO ONCOTARGET LA English DT Article DE pancreatic cancer; GWAS; fine-mapping; imputation; NR5A2 ID GENOME-WIDE ASSOCIATION; URINARY-BLADDER CANCER; LONG-RANGE INTERACTION; RISK LOCI; GENOTYPE IMPUTATION; GENETIC SUSCEPTIBILITY; TERT-CLPTM1L LOCUS; COMMON VARIANT; BREAST-CANCER; COLON-CANCER AB Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88x10(-15)), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22x10(-9)) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70x10(-8)). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 (NR5A2), chr8q24.21 (MYC) and chr5p15.33 (CLPTM1L-TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal (n = 10) and tumor (n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7x10(-8)). This finding was validated in a second set of paired (n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5x10(-4)-2.0x10(-3)). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology. C1 [Zhang, Mingfeng; Jia, Jinping; Hoskins, Jason; Collins, Irene; Hautman, Christopher; Amundadottir, Laufey T.] NCI, Lab Translat Gen, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Wang, Zhaoming; Chung, Charles C.; Beane-Freeman, Laura; Abnet, Christian C.; Albanes, Demetrius; Andreotti, Gabriella; Berndt, Sonja I.; Burdette, Laurie; Caporaso, Neil E.; Hu, Nan; Landi, Maria T.; Purdue, Mark; Rothman, Nathaniel; Silverman, Debra T.; Taylor, Philip R.; Tobias, Geoffrey S.; Wentzensen, Nicolas; Yu, Kai; Hoover, Robert; Hartge, Patricia; Chanock, Stephen J.; Stolzenberg-Solomon, Rachael S.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Wang, Zhaoming; Chung, Charles C.; Burdette, Laurie] Leidos Biomed Res Inc, Canc Genom Res Lab, NCI, Div Canc Epidemiol & Genet,Frederick Natl Lab Can, Frederick, MD USA. [Obazee, Ofure; Figlioli, Gisella; Canzian, Federico] German Canc Res Ctr, Genom Epidemiol Grp, Heidelberg, Germany. [Childs, Erica J.; Mocci, Evelina; Klein, Alison P.] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Arslan, Alan A.] NYU, Dept Obstet & Gynecol, Sch Med, New York, NY 10016 USA. [Arslan, Alan A.; Zeleniuch-Jacquotte, Anne] NYU, Dept Environm Med, Sch Med, 550 1St Ave, New York, NY 10016 USA. [Arslan, Alan A.; Zeleniuch-Jacquotte, Anne] NYU, Inst Canc, New York, NY USA. [Bracci, Paige M.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Buring, Julie; Sesso, Howard D.; Gaziano, J. Michael] Brigham & Womens Hosp, Dept Med, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA. [Buring, Julie; Sesso, Howard D.; Gaziano, J. Michael; Giovannucci, Edward L.; Fuchs, Charles] Harvard Med Sch, Boston, MA USA. [Buring, Julie; Sesso, Howard D.; Gaziano, J. Michael] Brigham & Womens Hosp, Dept Med, Div Aging, 75 Francis St, Boston, MA 02115 USA. [Duell, Eric J.] Catalan Inst Oncol ICO, Unit Nutr & Canc, Canc Epidemiol Res Program, Bellvitge Biomed Res Inst IDIBELL, Barcelona, Spain. [Gallinger, Steven] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada. [Giles, Graham G.; Milne, Roger L.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Giles, Graham G.; Milne, Roger L.] Univ Melbourne, Ctr Biostat & Epidemiol, Melbourne Sch Populat & Global Hlth, Melbourne, Vic 3010, Australia. [Giles, Graham G.] Monash Univ, Dept Epidemiol & Prevent Med, Melbourne, Vic, Australia. [Goodman, Gary E.; White, Emily; Peters, Ulrike; Thornquist, Mark; Kooperberg, Charles] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Goodman, Phyllis J.] Fred Hutchinson Canc Res Ctr, Ctr Stat, Southwest Oncol Grp, 1124 Columbia St, Seattle, WA 98104 USA. [Kamineni, Aruna] Grp Hlth Res Inst, Seattle, WA USA. [Kolonel, Laurence N.; Le Marchand, Loic; Yu, Herbert] Univ Hawaii, Canc Epidemiol Program, Ctr Canc, Honolulu, HI 96822 USA. [Kulke, Matthew H.; Brais, Lauren; Fuchs, Charles; Wolpin, Brian M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. 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Bas] Univ Malaya, Dept Social & Prevent Med, Fac Med, Kuala Lumpur, Malaysia. [Basso, Daniela] Univ Hosp Padova, Dept Lab Med, Padua, Italy. [Boutron-Ruault, Marie-Christine] INSERM, Ctr Res Epidemiol & Populat Hlth CESP, Nutr Hormones & Womens Hlth Team, U1018, F-94805 Villejuif, France. [Boutron-Ruault, Marie-Christine] Univ Paris Sud, UMRS 1018, F-94805 Villejuif, France. [Boutron-Ruault, Marie-Christine] IGR, F-94805 Villejuif, France. [Bijlsma, Maarten F.] Univ Amsterdam, Acad Med Ctr, Lab Expt Oncol & Radiobiol, Amsterdam, Netherlands. [Brenner, Hermann] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Brenner, Hermann] German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany. [Brenner, Hermann] Natl Ctr Tumor Dis NCT, Heidelberg, Germany. [Brenner, Hermann] German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany. [Campa, Daniele; Landi, Stefano] Univ Pisa, Dept Biol, Pisa, Italy. [Capurso, Gabriele] Sapienza Univ Rome, Digest & Liver Dis Unit, Rome, Italy. [Cavestro, Giulia Martina] Univ Vita Salute San Raffaele, IRCCS San Raffaele Sci Inst, Gastroenterol & Gastrointestinal Endoscopy Unit, Milan, Italy. [Cotterchio, Michelle] Canc Care Ontario, Prevent & Canc Control, Toronto, ON, Canada. [Cotterchio, Michelle] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [Costello, Eithne] Univ Liverpool, Natl Inst Hlth Res Liverpool Pancreas Biomed Res, Liverpool, Merseyside, England. [Elena, Joanne; Helzlsouer, Kathy J.] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Boggi, Ugo] Univ Hosp Pisa, Dept Surg, Unit Expt Surg Pathol, Pisa, Italy. [Gaziano, J. Michael] Vet Affairs Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr, Geriatr Res Educ & Clin Ctr, Boston, MA USA. [Gazouli, Maria] Univ Athens, Sch Med, Dept Basic Med Sci, Biol Lab, Athens, Greece. [Giovannucci, Edward L.; Fuchs, Charles] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Giovannucci, Edward L.] Harvard Sch Publ Hlth, Dept Nutr, Boston, MA USA. [Goggins, Michael] Sidney Kimmel Canc Ctr, Dept Pathol, Baltimore, MD USA. [Goggins, Michael; Hunter, David J.] Johns Hopkins Univ, Baltimore, MD USA. [Goggins, Michael] Sidney Kimmel Canc Ctr, Dept Med, Baltimore, MD USA. [Goggins, Michael] Sidney Kimmel Canc Ctr, Dept Oncol, Baltimore, MD USA. [Gross, Myron] Univ Minnesota, Lab Med & Pathol, Minneapolis, MN USA. [Haiman, Christopher A.] Univ Southern Calif, Prevent Med, Los Angeles, CA USA. [Hassan, Manal; Li, Donghui] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX 77030 USA. [Hunter, David J.] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Hunter, David J.] Harvard Sch Publ Hlth, Boston, MA USA. [Iskierka-Jazdzewska, Elzbieta] Med Univ Lodz, Dept Hematol, Lodz, Poland. [Jenab, Mazda; Scelo, Ghislaine] Int Agcy Res Canc, Lyon, France. [Kaaks, Rudolf] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Key, Timothy J.; Travis, Ruth C.] Univ Oxford, Canc Epidemiol Unit, Oxford OX1 2JD, England. [Khaw, Kay-Tee] Univ Cambridge, Sch Clin Med, Cambridge, England. [Klein, Eric A.] Cleveland Clin, Glickman Urol & Kidney Inst, Cleveland, OH 44106 USA. [Kogevinas, Manolis] CIBER Epidemiol & Salud Publ CIBERESP, Ctr Recerca Epidemiol Ambiental CREAL, Madrid, Spain. [Kogevinas, Manolis; Porta, Miquel] Hosp del Mar, Inst Med Res IMIM, Barcelona, Spain. [Kogevinas, Manolis] Natl Sch Publ Hlth, Athens, Greece. [Krogh, Vittorio] Fdn IRCCS Ist Nazl Tumori, Epidemiol & Prevent Unit, Milan, Italy. [Kupcinskas, Juozas] Lithuanian Univ Hlth Sci, Dept Gastroenterol, Kaunas, Lithuania. [Kurtz, Robert C.] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA. [Mambrini, Andrea] ASL1 Massa Carrara, Dept Oncol, Massa Carrara, Italy. [Mannisto, Satu] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Neale, Rachel E.] QIMR Berghofer Med Res Inst, Dept Populat Hlth, Brisbane, Qld, Australia. [Oberg, Ann L.] Mayo Clin, Div Biomed Stat & Informat, Dept Hlth Sci Res, Rochester, MN USA. [Panico, Salvatore] Univ Naples Federico II, Dipartimento Med Clin & Chirurgia, Naples, Italy. [Patel, Alpa V.; Jacobs, Eric J.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Peeters, Petra H. M.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Pezzilli, Raffaele] St Orsola Malpighi Hosp, Dept Digest Dis & Internal Med, Pancreas Unit, Bologna, Italy. [Porta, Miquel] Univ Autonoma Barcelona, Sch Med, Barcelona, Spain. [Porta, Miquel] CIBER Epidemiol Salud Publ CIBERESP, Madrid, Spain. [Ramon Quiros, J.] Publ Hlth & Participat Directorate, Asturias, Spain. [Scarpa, Aldo] Univ & Hosp Trust Verona, ARC NET Ctr Appl Res Canc, Verona, Italy. [Soucek, Pavel] Charles Univ Prague, Fac Med Pilsen, Biomed Ctr, Lab Pharmacogen, Plzen, Czech Republic. [Strobel, Oliver] Univ Heidelberg Hosp, Dept Gen Surg, Heidelberg, Germany. [Sund, Malin] Umea Univ, Dept Surg & Peroperat Sci, Umea, Sweden. [Malecka-Panas, Ewa] Med Univ Lodz, Dept Digest Tract Dis, Lodz, Poland. [Tavano, Francesca] IRCCS Sci Inst & Reg Gen Hosp Casa Sollievo Soffe, Div Gastroenterol, San Giovanni Rotondo, Italy. [Tavano, Francesca] IRCCS Sci Inst & Reg Gen Hosp Casa Sollievo Soffe, Res Lab, San Giovanni Rotondo, Italy. [Tjonneland, Anne] Danish Canc Soc, Inst Canc Epidemiol, Copenhagen, Denmark. [Trichopoulos, Dimitrios] Acad Athens, Bur Epidemiol Res, Athens, Greece. [Trichopoulos, Dimitrios] Hellen Hlth Fdn, Athens, Greece. [Vashist, Yogesh] Univ Hamburg Eppendorf, Dept Gen Visceral & Thorac Surg, Hamburg, Germany. [Vodicka, Pavel] Acad Sci Czech Republic, Inst Expt Med, Dept Mol Biol Canc, Prague, Czech Republic. [Wactawski-Wende, Jean] Univ Buffalo, Dept Social & Prevent Med, Buffalo, NY USA. [Risch, Harvey A.] Yale Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT USA. [Petersen, Gloria M.] Mayo Clin, Div Epidemiol, Dept Hlth Sci Res, Rochester, MN USA. [Kraft, Peter] Harvard Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Klein, Alison P.] Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Wang, Zhaoming] St Jude Childrens Res Hosp, Dept Computat Biol, 332 N Lauderdale St, Memphis, TN 38105 USA. RP Amundadottir, LT (reprint author), NCI, Lab Translat Gen, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM amundadottirl@mail.nih.gov RI Abnet, Christian/C-4111-2015; Gallinger, Steven/E-4575-2013; Brenner, Hermann/B-4627-2017; Kogevinas, Manolis/C-3918-2017; Porta, Miquel/B-5787-2008; Beane Freeman, Laura/C-4468-2015; OI Malats, Nuria/0000-0003-2538-3784; Abnet, Christian/0000-0002-3008-7843; Brenner, Hermann/0000-0002-6129-1572; Porta, Miquel/0000-0003-1684-7428; Beane Freeman, Laura/0000-0003-1294-4124; Hoskins, Jason/0000-0001-6944-1996; Zeleniuch-Jacquotte, Anne/0000-0001-9350-1303 FU Intramural Research Program of the US National Institutes of Health (NIH), National Cancer Institute FX The authors acknowledge the contribution of the staff of the Cancer Genomics Research Laboratory (CGR) at the National Cancer Institute, NIH, for their help throughout the project. This work was supported by the Intramural Research Program of the US National Institutes of Health (NIH), National Cancer Institute. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Additional acknowledgements for individual participating studies are listed in the Supplemental Materials. NR 78 TC 0 Z9 0 U1 9 U2 9 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD OCT 11 PY 2016 VL 7 IS 41 BP 66328 EP 66343 DI 10.18632/oncotarget.11041 PG 16 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EB5UO UT WOS:000387446200004 PM 27579533 ER PT J AU Riz, I Hawley, TS Marsal, JW Hawley, RG AF Riz, Irene Hawley, Teresa S. Marsal, Jeffrey W. Hawley, Robert G. TI Noncanonical SQSTM1/p62-Nrf2 pathway activation mediates proteasome inhibitor resistance in multiple myeloma cells via redox, metabolic and translational reprogramming SO ONCOTARGET LA English DT Article DE multiple myeloma; carfilzomib; SQSTM1/p62; NFE2L2/Nrf2; translation initiation ID ENDOPLASMIC-RETICULUM STRESS; UNFOLDED PROTEIN RESPONSE; TRANSCRIPTION FACTOR NRF2; OPEN READING FRAMES; DRUG-RESISTANCE; CANCER-CELLS; ANTIOXIDANT RESPONSE; GENE-EXPRESSION; BORTEZOMIB RESISTANCE; OXIDATIVE STRESS AB Multiple Myeloma (MM) is a B-cell malignancy characterized by the accumulation of clonal plasma cells in the bone marrow, with drug resistance being a major cause of therapeutic failure. We established a carfilzomib-resistant derivative of the LP-1 MM cell line (LP-1/Cfz) and found that the transcription factor NF-E2 p45-related factor 2 (Nrf2; gene symbol NFE2L2) contributes to carfilzomib resistance. The mechanism of Nrf2 activation involved enhanced translation of Nrf2 as well as its positive regulator, the autophagy receptor sequestosome 1 (SQSTM1)/p62. The eukaryotic translation initiation factor gene EIF4E3 was among the Nrf2 target genes upregulated in LP-1/Cfz cells, suggesting existence of a positive feedback loop. In line with this, we found that siRNA knockdown of eIF4E3 decreased Nrf2 protein levels. On the other hand, elevated SQSTM1/p62 levels were due at least in part to activation of the PERKeIF2 alpha pathway. LP-1/Cfz cells had decreased levels of reactive oxygen species as well as elevated levels of fatty acid oxidation and prosurvival autophagy. Genetic and pharmacologic inhibition of the Nrf2-EIF4E3 axis or the PERK-eIF2 alpha pathway, disruption of redox homeostasis or inhibition of fatty acid oxidation or autophagy conferred sensitivity to carfilzomib. Our findings were supported by clinical data where increased EIF4E3 expression was predictive of Nrf2 target gene upregulation in a subgroup of patients with chemoresistant minimal residual disease and relapsed/refractory MM. Thus, our data offer a preclinical rationale for including inhibitors of the SQSTM1/p62-Nrf2 pathway to the treatment regimens for certain advanced stage MM patients. C1 [Riz, Irene; Marsal, Jeffrey W.; Hawley, Robert G.] George Washington Univ, Dept Anat & Regenerat Biol, Washington, DC 20052 USA. [Hawley, Teresa S.] George Washington Univ, Flow Cytometry Core Facil, Washington, DC USA. [Hawley, Teresa S.] NCI, Flow Cytometry Core, NIH, Bethesda, MD 20892 USA. RP Hawley, RG (reprint author), George Washington Univ, Dept Anat & Regenerat Biol, Washington, DC 20052 USA. EM rghawley@gwu.edu FU Dr. Cyrus and Myrtle Katzen Cancer Research Center at The George Washington University; King Fahd Endowment from The George Washington University School of Medicine and Health Sciences FX We thank Leif Bergsagel for providing the LP-1 and KMS-11 cell lines. This work was supported by a Grant from the Dr. Cyrus and Myrtle Katzen Cancer Research Center at The George Washington University, a King Fahd Endowment from The George Washington University School of Medicine and Health Sciences, and a generous donation from Marc Cohen. NR 103 TC 1 Z9 1 U1 3 U2 3 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD OCT 11 PY 2016 VL 7 IS 41 BP 66360 EP 66385 DI 10.18632/oncotarget.11960 PG 26 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EB5UO UT WOS:000387446200006 PM 27626179 ER PT J AU Fang, EF Kassahun, H Croteau, DL Scheibye-Knudsen, M Marosi, K Lu, HM Shamanna, RA Kalyanasundaram, S Bollineni, RC Wilson, MA Iser, WB Wollman, BN Morevati, M Li, J Kerr, JS Lu, QP Waltz, TB Tian, J Sinclair, DA Mattson, MP Nilsen, H Bohr, VA AF Fang, Evandro Fei Kassahun, Henok Croteau, Deborah L. Scheibye-Knudsen, Morten Marosi, Krisztina Lu, Huiming Shamanna, Raghavendra A. Kalyanasundaram, Sumana Bollineni, Ravi Chand Wilson, Mark A. Iser, Wendy B. Wollman, Bradley N. Morevati, Marya Li, Jun Kerr, Jesse S. Lu, Qiping Waltz, Tyler B. Tian, Jane Sinclair, David A. Mattson, Mark P. Nilsen, Hilde Bohr, Vilhelm A. TI NAD(+) Replenishment Improves Lifespan and Healthspan in Ataxia Telangiectasia Models via Mitophagy and DNA Repair SO CELL METABOLISM LA English DT Article ID DEPENDENT PROTEIN-KINASE; STRAND BREAK REPAIR; HIGH-FAT DIET; CAENORHABDITIS-ELEGANS; NICOTINAMIDE RIBOSIDE; CALORIE RESTRICTION; OXIDATIVE STRESS; GENOME STABILITY; ATM ACTIVATION; STEM-CELLS AB Ataxia telangiectasia (A-T) is a rare autosomal recessive disease characterized by progressive neurodegeneration and cerebellar ataxia. A-T is causally linked to defects in ATM, a master regulator of the response to and repair of DNA double-strand breaks. The molecular basis of cerebellar atrophy and neurodegeneration in A-T patients is unclear. Here we report and examine the significance of increased PARylation, low NAD(+), and mitochondrial dysfunction in ATM-deficient neurons, mice, and worms. Treatments that replenish intracellular NAD(+) reduce the severity of A-T neuropathology, normalize neuromuscular function, delay memory loss, and extend lifespan in both animal models. Mechanistically, treatments that increase intracellular NAD(+) also stimulate neuronal DNA repair and improve mitochondrial quality via mitophagy. This work links two major theories on aging, DNA damage accumulation, and mitochondrial dysfunction through nuclear DNA damage-induced nuclear-mitochondrial signaling, and demonstrates that they are important pathophysiological determinants in premature aging of A-T, pointing to therapeutic interventions. C1 [Fang, Evandro Fei; Croteau, Deborah L.; Scheibye-Knudsen, Morten; Lu, Huiming; Shamanna, Raghavendra A.; Wollman, Bradley N.; Morevati, Marya; Kerr, Jesse S.; Lu, Qiping; Waltz, Tyler B.; Tian, Jane; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. [Kassahun, Henok; Kalyanasundaram, Sumana; Nilsen, Hilde] Univ Oslo, Inst Clin Med, N-1478 Lorenskog, Norway. [Kassahun, Henok; Kalyanasundaram, Sumana; Nilsen, Hilde] Akershus Univ Hosp, N-1478 Lorenskog, Norway. [Marosi, Krisztina; Wilson, Mark A.; Iser, Wendy B.; Mattson, Mark P.] NIA, Lab Neurosci, NIH, Baltimore, MD 21224 USA. [Kalyanasundaram, Sumana] Oslo Univ Hosp, Inst Canc Res, Radium Hosp, Dept Core Facil,Bioinformat Core Facil, N-0379 Oslo, Norway. [Scheibye-Knudsen, Morten; Morevati, Marya; Bohr, Vilhelm A.] Univ Oslo, Dept Biosci, N-0316 Oslo, Norway. [Li, Jun; Sinclair, David A.] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. [Sinclair, David A.] Univ New South Wales, Sch Med Sci, Dept Pharmacol, Sydney, NSW 2052, Australia. [Mattson, Mark P.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. EM vbohr@nih.gov FU Intramural Research Program of the NIH; National Institute on Ageing; ChromaDex South East Norway Regional Health Authority [2015029]; Norwegian Cancer Society [4514636]; NIH/NIA [5R37AG028730-09]; Glenn Medical Foundation FX We thank Boris M. Brenerman, Lynn Froetscher, and Dr. Yujun Hou for their help in the experiments. We appreciate Drs. Kevin Becker; Yongqing Zhang; William H. Wood, III; and Elin Lehrmann for their help in performing microarray and data analysis. We acknowledge Drs. Monica Driscoll, Johan Auwerx, David H. Hall, Coleen T. Murphy, Malene Hansen, Ann M. Rose, and Nektarios Tavernarakis for their expertise in the C. elegans studies. We thank Stale Nygard for statistical support and Bernd Thiede for access to the University of Oslo Mass Spectrometry Core facility. We thank Drs. Atsushi Miyawaki and Richard J. Youle for sharing mt-mKeima plasmid and mt-mKeima integrated Hela cells, and Drs. Nuo Sun and Toren Finkel for their expertise on mt-mKeima-related imaging. We thank Drs. Yie Liu and Beverly Baptiste for critical reading of the manuscript. This research was supported by the Intramural Research Program of the NIH (V.A.B.), the National Institute on Ageing, a 2014-2015 NIA intra-laboratory grant (E.F.F. and V.A.B.), ChromaDex (V.A.B.), a grant from the South East Norway Regional Health Authority (no. 2015029) (H.N.), the Norwegian Cancer Society grant no. 4514636 (R.C.B.), NIH/NIA grant 5R37AG028730-09, and support from the Glenn Medical Foundation (D.A.S.). The V.A.B. laboratory has CRADA arrangements with ChromaDex and GlaxoSmithKline. D.A.S. is a consultant for GSK, Ovascience, and Metrobiotech. NR 45 TC 2 Z9 2 U1 8 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 EI 1932-7420 J9 CELL METAB JI Cell Metab. PD OCT 11 PY 2016 VL 24 IS 4 BP 566 EP 581 DI 10.1016/j.cmet.2016.09.004 PG 16 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA EA3RF UT WOS:000386521200009 PM 27732836 ER PT J AU Yang, L Li, P Yang, WJ Ruan, XB Kiesewetter, K Zhu, J Cao, HM AF Yang, Ling Li, Ping Yang, Wenjing Ruan, Xiangbo Kiesewetter, Kurtis Zhu, Jun Cao, Haiming TI Integrative Transcriptome Analyses of Metabolic Responses in Mice Define Pivotal LncRNA Metabolic Regulators SO CELL METABOLISM LA English DT Article ID LONG NONCODING RNA; CHOLESTEROL-METABOLISM; EVOLUTION; OBESITY; EXPRESSION; HOMEOSTASIS; ANNOTATION; MECHANISMS; REVEALS; DISEASE AB To systemically identify long noncoding RNAs (lncRNAs) regulating energy metabolism, we performed transcriptome analyses to simultaneously profile mRNAs and lncRNAs in key metabolic organs in mice under pathophysiologically representative metabolic conditions. Of 4,759 regulated lncRNAs, function-oriented filters yield 359 tissue-specifically regulated and metabolically sensitive lncRNAs that are predicted by lncRNA-mRNA correlation analyses to function in diverse aspects of energy metabolism. Specific regulations of liver metabolically sensitive lncRNAs (lncLMS) by nutrients, metabolic hormones, and key transcription factors were further defined in primary hepatocytes. Combining genome-wide screens, bioinformatics function predictions, and cell-based analyses, we developed an integrative roadmap to identify lncRNA metabolic regulators. An lncLMS was experimentally confirmed in mice to suppress lipogenesis by forming a negative feedback loop in the SREBP1c pathway. Taken together, this study supports that a class of lncRNAs function as important metabolic regulators and establishes a framework for systemically investigating the role of lncRNAs in physiological homeostasis. C1 [Yang, Ling; Li, Ping; Ruan, Xiangbo; Kiesewetter, Kurtis; Cao, Haiming] NHLBI, Ctr Mol Med, NIH, Bldg 10, Bethesda, MD 20892 USA. [Yang, Wenjing; Zhu, Jun] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. RP Cao, HM (reprint author), NHLBI, Ctr Mol Med, NIH, Bldg 10, Bethesda, MD 20892 USA. EM haiming.cao@nih.gov FU Division of Intramural Research of the NHLBI, National Institutes of Health [HL006103, HL006159] FX This work was supported by the Division of Intramural Research of the NHLBI, National Institutes of Health (grants HL006103 and HL006159). We thank Yanqin Yang in NHLBI DNA sequencing core facility and Gangqing Hu in the laboratory of Keji Zhao for advice on bioinformatics and statistical analyses, and we thank Yoshiyuki Wakabayashi and Poching Liu in the NHLBI DNA sequencing core facility for their help with RNA-seq analysis. NR 39 TC 1 Z9 1 U1 11 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 EI 1932-7420 J9 CELL METAB JI Cell Metab. PD OCT 11 PY 2016 VL 24 IS 4 BP 627 EP 639 DI 10.1016/j.cmet.2016.08.019 PG 13 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA EA3RF UT WOS:000386521200014 PM 27667668 ER PT J AU Raphael, CE Cooper, R Parker, KH Collinson, J Vassiliou, V Pennell, DJ de Silva, R Hsu, LY Greve, AM Nijjer, S Broyd, C Ali, A Keegan, J Francis, DP Davies, JE Hughes, AD Arai, A Frenneaux, M Stables, RH Di Mario, C Prasad, SK AF Raphael, Claire E. Cooper, Robert Parker, Kim H. Collinson, Julian Vassiliou, Vassilis Pennell, Dudley J. de Silva, Ranil Hsu, Li Yueh Greve, Anders M. Nijjer, Sukh Broyd, Chris Ali, Aamir Keegan, Jennifer Francis, Darrel P. Davies, Justin E. Hughes, Alun D. Arai, Andrew Frenneaux, Michael Stables, Rod H. Di Mario, Carlo Prasad, Sanjay K. TI Mechanisms of Myocardial Ischemia in Hypertrophic Cardiomyopathy Insights From Wave Intensity Analysis and Magnetic Resonance SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID LEFT-VENTRICULAR HYPERTROPHY; CORONARY FLOW RESERVE; OBSTRUCTIVE CARDIOMYOPATHY; BLOOD-FLOW; PERFUSION; VELOCITY; HUMANS; ABNORMALITIES; DYSFUNCTION; VALIDATION AB BACKGROUND Angina is common in hypertrophic cardiomyopathy (HCM) and is associated with abnormal myocardial perfusion. Wave intensity analysis improves the understanding of the mechanics of myocardial ischemia. OBJECTIVES Wave intensity analysis was used to describe the mechanisms underlying perfusion abnormalities in patients with HCM. METHODS Simultaneous pressure and flow were measured in the proximal left anterior descending artery in 33 patients with HCM and 20 control patients at rest and during hyperemia, allowing calculation of wave intensity. Patients also underwent quantitative first- pass perfusion cardiac magnetic resonance to measure myocardial perfusion reserve. RESULTS Patients with HCM had a lower coronary flow reserve than control subjects (1.9 +/- 0.8 vs. 2.7 +/- 0.9; p = 0.01). Coronary hemodynamics in HCM were characterized by a very large backward compression wave during systole (38 +/- 11% vs. 21 +/- 6%; p < 0.001) and a proportionately smaller backward expansion wave (27% +/- 8% vs. 33 +/- 6%; p = 0.006) compared with control subjects. Patients with severe left ventricular outflow tract obstruction had a bisferiens pressure waveform resulting in an additional proximally originating deceleration wave during systole. The proportion of waves acting to accelerate coronary flow increased with hyperemia, and the magnitude of change was proportional to the myocardial perfusion reserve (rho = 0.53; p < 0.01). CONCLUSIONS Coronary flow in patients with HCM is deranged. Distally, compressive deformation of intramyocardial blood vessels during systole results in an abnormally large backward compression wave, whereas proximally, severe left ventricular outflow tract obstruction is associated with an additional deceleration wave. Perfusion abnormalities in HCM are not simply a consequence of supply/demand mismatch or remodeling of the intramyocardial blood vessels; they represent a dynamic interaction with the mechanics of myocardial ischemia that may be amenable to treatment. (J Am Coll Cardiol 2016; 68: 1651-60) (C) 2016 by the American College of Cardiology Foundation. C1 [Raphael, Claire E.; Collinson, Julian; Vassiliou, Vassilis; Pennell, Dudley J.; de Silva, Ranil; Ali, Aamir; Keegan, Jennifer; Di Mario, Carlo; Prasad, Sanjay K.] Royal Brompton Hosp, NIHR Cardiovasc Biomed Res Unit, Sydney St, London SW3 6NP, England. [Cooper, Robert; Stables, Rod H.] Liverpool Heart & Chest Hosp, Inst Cardiovasc Med & Sci, Liverpool, Merseyside, England. [Parker, Kim H.] Imperial Coll, Dept Bioengn, London, England. [Hsu, Li Yueh; Greve, Anders M.; Arai, Andrew] NIH, Bldg 10, Bethesda, MD 20892 USA. [Nijjer, Sukh; Broyd, Chris; Francis, Darrel P.; Davies, Justin E.] Imperial Coll, Int Ctr Circulatory Hlth, London, England. [Hughes, Alun D.] UCL, London, England. [Frenneaux, Michael] Univ East Anglia, Dept Cardiol, Norwich, Norfolk, England. RP Raphael, CE (reprint author), Royal Brompton Hosp, NIHR Cardiovasc Biomed Res Unit, Sydney St, London SW3 6NP, England. EM claire.raphael@gmail.com OI Pennell, Dudley/0000-0001-5523-1314 FU British Heart Foundation [FS/14/13/30619]; Rosetrees; NIHR Biomedical Research Unit; Wellcome Trust; Volcano-Philips FX From the aNIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, London, United Kingdom; bInstitute of Cardiovascular Medicine and Science, Liverpool Heart and Chest Hospital, Liverpool, United Kingdom; cDepartment of Bioengineering, Imperial College, London, United Kingdom; dNational Institutes of Health, Bethesda, Maryland; eInternational Centre for Circulatory Health, Imperial College, London, United Kingdom; fUniversity College London, London, United Kingdom; and the gDepartment of Cardiology, University of East Anglia, Norwich, United Kingdom. This study was funded by the British Heart Foundation (FS/14/13/30619), Rosetrees, and the NIHR Biomedical Research Unit. Dr. Raphael was funded by the British Heart Foundation (FS/14/13/30619), Rosetrees, and the Wellcome Trust. Dr. Prasad has received honoraria for talks for Bayer-Schering. Dr. Pennell has received consultancy fees from Siemens and Bayer-Schering; and is a director for and stockowner in Cardiovascular Imaging Solutions. Dr. Davies is a consultant to and receives research grants from Volcano-Philips. Dr. Arai has received research agreements with Siemens and Bayer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 32 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT 11 PY 2016 VL 68 IS 15 BP 1651 EP 1660 DI 10.1016/j.jacc.2016.07.751 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DZ5ZD UT WOS:000385940100007 PM 27712778 ER PT J AU Zhang, J McCann, KL Qiu, C Gonzalez, LE Baserga, SJ Hall, TMT AF Zhang, Jun McCann, Kathleen L. Qiu, Chen Gonzalez, Lauren E. Baserga, Susan J. Hall, Traci M. Tanaka TI Nop9 is a PUF-like protein that prevents premature cleavage to correctly process pre-18S rRNA SO NATURE COMMUNICATIONS LA English DT Article ID PUMILIO-HOMOLOGY DOMAIN; SACCHAROMYCES-CEREVISIAE; TRANSLATION INITIATION; WEB SERVER; YEAST; BIOGENESIS; SUBUNITS; SEQUENCE; COMPUTATION; RECOGNITION AB Numerous factors direct eukaryotic ribosome biogenesis, and defects in a single ribosome assembly factor may be lethal or produce tissue-specific human ribosomopathies. Pre-ribosomal RNAs ( pre-rRNAs) must be processed stepwise and at the correct subcellular locations to produce the mature rRNAs. Nop9 is a conserved small ribosomal subunit biogenesis factor, essential in yeast. Here we report a 2.1-angstrom crystal structure of Nop9 and a small-angle X-ray-scattering model of a Nop9: RNA complex that reveals a 'C'-shaped fold formed from 11 Pumilio repeats. We show that Nop9 recognizes sequence and structural features of the 20S pre-rRNA near the cleavage site of the nuclease, Nob1. We further demonstrate that Nop9 inhibits Nob1 cleavage, the final processing step to produce mature small ribosomal subunit 18S rRNA. Together, our results suggest that Nop9 is critical for timely cleavage of the 20S pre-rRNA. Moreover, the Nop9 structure exemplifies a new class of Pumilio repeat proteins. C1 [Zhang, Jun; McCann, Kathleen L.; Qiu, Chen; Gonzalez, Lauren E.; Hall, Traci M. Tanaka] NIEHS, Epigenet & Stem Cell Biol Lab, NIH, POB 12233,MD F3-05, Res Triangle Pk, NC 27709 USA. [McCann, Kathleen L.; Baserga, Susan J.] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06520 USA. [Baserga, Susan J.] Yale Univ, Sch Med, Dept Therapeut Radiol, New Haven, CT 06520 USA. [Baserga, Susan J.] Yale Univ, Sch Med, Dept Mol Biophys & Biochem, New Haven, CT 06520 USA. RP Hall, TMT (reprint author), NIEHS, Epigenet & Stem Cell Biol Lab, NIH, POB 12233,MD F3-05, Res Triangle Pk, NC 27709 USA.; Baserga, SJ (reprint author), Yale Univ, Sch Med, Dept Genet, New Haven, CT 06520 USA.; Baserga, SJ (reprint author), Yale Univ, Sch Med, Dept Therapeut Radiol, New Haven, CT 06520 USA.; Baserga, SJ (reprint author), Yale Univ, Sch Med, Dept Mol Biophys & Biochem, New Haven, CT 06520 USA. EM susan.baserga@yale.edu; hall4@niehs.nih.gov RI Zhang, Jun/R-1502-2016 OI Zhang, Jun/0000-0002-5842-7424 FU Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences; NIH [GM11570]; US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; National Institute of Health [R01GM105404]; DOE Office of Biological and Environmental Research FX We thank L. Pedersen and the staff of the Southeast Regional Collaborative Access Team beamlines for assistance with X-ray data collection and the staff of SIBYLS for assistance with SAXS data collection. We thank J. Williams and the staff of the NIEHS Protein Microcharacterization Core Facility for mass spectrometric analysis and our colleagues, K. Adelman, R. Stanley, H. Wang and R.S. Williams, for stimulating discussion and critical comments. This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences (T.M.T.H.) and NIH GM11570 to S.J.B. The Advanced Photon Source used for this study is supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract no. W-31-109-Eng-38. The SAXS work was conducted at the Advanced Light Source (ALS), a national user facility operated by Lawrence Berkeley National Laboratory on behalf of the Department of Energy, Office of Basic Energy Sciences, through the Integrated Diffraction Analysis Technologies (IDAT) programme, supported by DOE Office of Biological and Environmental Research. Additional support comes from the National Institute of Health project MINOS (R01GM105404). NR 53 TC 0 Z9 0 U1 6 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD OCT 11 PY 2016 VL 7 AR 13085 DI 10.1038/ncomms13085 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ0SB UT WOS:000385548900001 PM 27725644 ER PT J AU Navarathna, DHMLP Pathirana, RU Lionakis, MS Nickerson, KW Roberts, DD AF Navarathna, Dhammika H. M. L. P. Pathirana, Ruvini U. Lionakis, Michail S. Nickerson, Kenneth W. Roberts, David D. TI Candida albicans ISW2 Regulates Chlamydospore Suspensor Cell Formation and Virulence In Vivo in a Mouse Model of Disseminated Candidiasis SO PLOS ONE LA English DT Article ID SCANNING ELECTRON-MICROSCOPY; GENE DISRUPTION; SACCHAROMYCES-CEREVISIAE; CHANGING EPIDEMIOLOGY; SYSTEMIC CANDIDIASIS; GIANT BLASTOCONIDIA; CYTOKINE EXPRESSION; STRESS-RESPONSE; DUBLINIENSIS; INFECTIONS AB Formation of chlamydospores by Candida albicans was an established medical diagnostic test to confirm candidiasis before the molecular era. However, the functional role and pathological relevance of this in vitro morphological transition to pathogenesis in vivo remain unclear. We compared the physical properties of in vitro-induced chlamydospores with those of large C. albicans cells purified by density gradient centrifugation from Candida-infected mouse kidneys. The morphological and physical properties of these cells in kidneys of mice infected intravenously with wild type C. albicans confirmed that chlamydospores can form in infected kidneys. A previously reported chlamydospore-null Delta isw2/Delta isw2 mutant was used to investigate its role in virulence and chlamydospore induction. Virulence of the Delta isw2/Delta isw2 mutant strain was reduced 3.4-fold compared to wild type C. albicans or the ISW2 reconstituted strain. Altered host inflammatory reactions to the null mutant further indicate that ISW2 is a virulence factor in C. albicans. ISW2 deletion abolished chlamydospore formation within infected mouse kidneys, whereas the reconstituted strain restored chlamydospore formation in kidneys. Under chlamydospore inducing conditions in vitro, deletion of ISW2 significantly delayed chlamydospore formation, and those late induced chlamydospores lacked associated suspensor cells while attaching laterally to hyphae via novel spore-hypha septa. Our findings establish the induction of chlamydospores by C. albicans during mouse kidney colonization. Our results indicate that ISW2 is not strictly required for chlamydospores formation but is necessary for suspensor cell formation. The importance of ISW2 in chlamydospore morphogenesis and virulence may lead to additional insights into morphological differentiation and pathogenesis of C. albicans in the host microenvironment. C1 [Navarathna, Dhammika H. M. L. P.; Roberts, David D.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. [Pathirana, Ruvini U.; Nickerson, Kenneth W.] Univ Nebraska, Sch Biol Sci, Lincoln, NE USA. [Lionakis, Michail S.] NIAID, Fungal Pathogenesis Unit, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Navarathna, DHMLP; Roberts, DD (reprint author), NCI, Pathol Lab, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. EM dhammika.h.navarathna.civ@mail.mil; droberts@helix.nih.gov RI Roberts, David/A-9699-2008 OI Roberts, David/0000-0002-2481-2981 FU Intramural Research Program of National Institute of Allergy and Infectious Diseases; Intramural Research Program of National Cancer Institute; Intramural Research Program of National Institutes of Health (NIH) [A1001175-01, ZIA SC 009173]; Farnesol and Candida albicans Research Fund; University of Nebraska Foundation; Blair Paxton Udale Scholarship from UNL School of Biological Sciences FX This study was supported by the Intramural Research Programs of the National Institute of Allergy and Infectious Diseases and the National Cancer Institute, National Institutes of Health (NIH) (M.S.L., A1001175-01; D.D.R., ZIA SC 009173), Ann L. Kelsall and the Farnesol and Candida albicans Research Fund, University of Nebraska Foundation (to K.W.N.), and the Blair Paxton Udale Scholarship for Life Sciences from UNL School of Biological Sciences (to R.U.P.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 80 TC 0 Z9 0 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 11 PY 2016 VL 11 IS 10 AR e0164449 DI 10.1371/journal.pone.0164449 PG 25 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ0CI UT WOS:000385504400032 PM 27727302 ER PT J AU Sela, I Wolf, YI Koonin, EV AF Sela, Itamar Wolf, Yuri I. Koonin, Eugene V. TI Theory of prokaryotic genome evolution SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE evolutionary genomics; prokaryotic genome size; genome streamlining; positive selection; deletion bias ID ESCHERICHIA-COLI; DNA LOSS; SIZE; COMPLEXITY; DATABASE; ORIGINS; PERSPECTIVE; BACTERIAL; DYNAMICS; BIOLOGY AB Bacteria and archaea typically possess small genomes that are tightly packed with protein-coding genes. The compactness of prokaryotic genomes is commonly perceived as evidence of adaptive genome streamlining caused by strong purifying selection in large microbial populations. In such populations, even the small cost incurred by nonfunctional DNA because of extra energy and time expenditure is thought to be sufficient for this extra genetic material to be eliminated by selection. However, contrary to the predictions of this model, there exists a consistent, positive correlation between the strength of selection at the protein sequence level, measured as the ratio of nonsynonymous to synonymous substitution rates, and microbial genome size. Here, by fitting the genome size distributions in multiple groups of prokaryotes to predictions of mathematical models of population evolution, we show that only models in which acquisition of additional genes is, on average, slightly beneficial yield a good fit to genomic data. These results suggest that the number of genes in prokaryotic genomes reflects the equilibrium between the benefit of additional genes that diminishes as the genome grows and deletion bias (i.e., the rate of deletion of genetic material being slightly greater than the rate of acquisition). Thus, new genes acquired by microbial genomes, on average, appear to be adaptive. The tight spacing of protein-coding genes likely results from a combination of the deletion bias and purifying selection that efficiently eliminates nonfunctional, noncoding sequences. C1 [Sela, Itamar; Wolf, Yuri I.; Koonin, Eugene V.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov FU US Department of Health and Human Services FX We thank members of the group of E.V.K. for helpful discussions. The authors' research is supported by intramural funds of the US Department of Health and Human Services (to the National Library of Medicine). NR 36 TC 2 Z9 2 U1 17 U2 17 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 11 PY 2016 VL 113 IS 41 BP 11399 EP 11407 DI 10.1073/pnas.1614083113 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DY1XE UT WOS:000384886900045 PM 27702904 ER PT J AU Santiago-Frangos, A Kavita, K Schu, DJ Gottesman, S Woodson, SA AF Santiago-Frangos, Andrew Kavita, Kumari Schu, Daniel J. Gottesman, Susan Woodson, Sarah A. TI C-terminal domain of the RNA chaperone Hfq drives sRNA competition and release of target RNA SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE small noncoding RNA; RNA chaperone; intrinsically disordered protein; posttranscriptional regulation; ChiX ID ESCHERICHIA-COLI-HFQ; SM-LIKE PROTEIN; SMALL REGULATORY RNA; RYHB SMALL RNA; MESSENGER-RNA; INTERACTION SURFACES; STRAND DISPLACEMENT; SECONDARY STRUCTURE; STRESS-RESPONSE; OUTER-MEMBRANE AB The bacterial Sm protein and RNA chaperone Hfq stabilizes small noncoding RNAs (sRNAs) and facilitates their annealing to mRNA targets involved in stress tolerance and virulence. Although an arginine patch on the Sm core is needed for Hfq's RNA chaperone activity, the function of Hfq's intrinsically disordered C-terminal domain (CTD) has remained unclear. Here, we use stopped flow spectroscopy to show that the CTD of Escherichia coli Hfq is not needed to accelerate RNA base pairing but is required for the release of dsRNA. The Hfq CTD also mediates competition between sRNAs, offering a kinetic advantage to sRNAs that contact both the proximal and distal faces of the Hfq hexamer. The change in sRNA hierarchy caused by deletion of the Hfq CTD in E. coli alters the sRNA accumulation and the kinetics of sRNA regulation in vivo. We propose that the Hfq CTD displaces sRNAs and annealed sRNA.mRNA complexes from the Sm core, enabling Hfq to chaperone sRNA-mRNA interactions and rapidly cycle between competing targets in the cell. C1 [Santiago-Frangos, Andrew] Johns Hopkins Univ, Cell Mol Dev Biol & Biophys Program, Baltimore, MD 21218 USA. [Kavita, Kumari; Schu, Daniel J.; Gottesman, Susan] NCI, Lab Mol Biol, Bethesda, MD 20892 USA. [Woodson, Sarah A.] Johns Hopkins Univ, Thomas C Jenkins Dept Biophys, Baltimore, MD 21218 USA. [Schu, Daniel J.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Gottesman, S (reprint author), NCI, Lab Mol Biol, Bethesda, MD 20892 USA.; Woodson, SA (reprint author), Johns Hopkins Univ, Thomas C Jenkins Dept Biophys, Baltimore, MD 21218 USA. EM gottesms@helix.nih.gov; swoodson@jhu.edu OI Woodson, Sarah/0000-0003-0170-1987; Santiago-Frangos, Andrew/0000-0001-9615-065X FU National Institute of General Medicine [R01GM46686, R01GM120425]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX The authors thank Nadim Majdalani (NIH) for the hfq- E. coli strain NM694 used for the expression of the Hfq variants, Ricardo Francis for construction of RAF1042, and Subrata Panja for the Hfq Cy3-labeling strategy and protocol. This work was supported by National Institute of General Medicine Grants R01GM46686 and R01GM120425 (to S.A.W.) and, in part, by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (S.G.). NR 81 TC 2 Z9 2 U1 7 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 11 PY 2016 VL 113 IS 41 BP E6089 EP E6096 DI 10.1073/pnas.1613053113 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DY1XE UT WOS:000384886900013 PM 27681631 ER PT J AU Kaburu, SSK Paukner, A Simpson, EA Suomi, SJ Ferrari, PF AF Kaburu, Stefano S. K. Paukner, Annika Simpson, Elizabeth A. Suomi, Stephen J. Ferrari, Pier F. TI Neonatal imitation predicts infant rhesus macaque (Macaca mulatta) social and anxiety-related behaviours at one year SO SCIENTIFIC REPORTS LA English DT Article ID TO-FACE INTERACTIONS; SEX-DIFFERENCES; AUTISTIC DISORDER; REARING CONDITION; PLAY; CHILDREN; DEFICITS; MONKEYS; AGGRESSION; SOCIETIES AB The identification of early markers that predict the development of specific social trajectories is critical to understand the developmental and neurobiological underpinnings of healthy social development. We investigated, in infant rhesus macaques (Macaca mulatta), whether newborns' capacity to imitate facial gestures is a valid predictive marker for the emergence of social competencies later in development, at one year of age. Here we first assessed whether infant macaques (N = 126) imitate lipsmacking gestures (a macaque affiliative expression) performed by a human experimenter in their first week of life. We then collected data on infants' social interactions (aggression, grooming, and play) and self-scratching (a proxy indicator of anxiety) at 11-14 months when infants were transferred into a new enclosure with a large social group. Our results show that neonatal imitators exhibit more dominant behaviours, are less anxious, and, for males only, spend more time in play at one year old. These findings suggest that neonatal imitation may be an early predictor of infant sociality and may help identify infants at risk of neurodevelopmental social deficits. C1 [Kaburu, Stefano S. K.] Univ Calif Davis, Dept Populat Hlth & Reprod, Davis, CA 95616 USA. [Paukner, Annika; Suomi, Stephen J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Poolesville, MD USA. [Simpson, Elizabeth A.] Univ Miami, Dept Psychol, POB 248185, Coral Gables, FL 33124 USA. [Ferrari, Pier F.] Univ Parma, Dipartimento Neurosci, Parma, Italy. [Ferrari, Pier F.] Univ Claude Bernard Lyon, CNRS, Inst Sci Cognit Marc Jeannerod, 67 Bd Pinel, F-69675 Bron, France. RP Kaburu, SSK (reprint author), Univ Calif Davis, Dept Populat Hlth & Reprod, Davis, CA 95616 USA. EM sskkaburu@ucdavis.edu FU Division of Intramural Research, NICHD; NICHD [P01HD064653] FX This research was supported by the Division of Intramural Research, NICHD, and NICHD P01HD064653. We thank Valentina Sclafani, Neal Marquez, Amanda Dettmer, Michelle Miller, Kristen Byers and the animal care staff and volunteers in the Laboratory of Comparative Ethology for help with data collection. NR 60 TC 0 Z9 0 U1 5 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD OCT 11 PY 2016 VL 6 AR 34997 DI 10.1038/srep34997 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DY6MJ UT WOS:000385241100001 PM 27725768 ER PT J AU Park, JE Zhang, XF Choi, SH Okahara, J Sasaki, E Silva, AC AF Park, Jung Eun Zhang, Xian Feng Choi, Sang-Ho Okahara, Junko Sasaki, Erika Silva, Afonso C. TI Generation of transgenic marmosets expressing genetically encoded calcium indicators SO SCIENTIFIC REPORTS LA English DT Article ID MONKEY CALLITHRIX-JACCHUS; FLUORESCENT CA2+ INDICATOR; IMAGING NEURAL ACTIVITY; COMMON MARMOSET; IN-VIVO; GERMLINE TRANSMISSION; LENTIVIRAL VECTORS; NONHUMAN-PRIMATES; HEMATOPOIETIC-CELLS; SOCIAL-ORGANIZATION AB Chronic monitoring of neuronal activity in the living brain with optical imaging techniques became feasible owing to the continued development of genetically encoded calcium indicators (GECIs). Here we report for the first time the successful generation of transgenic marmosets (Callithrix jacchus), an important nonhuman primate model in neurophysiological research, which were engineered to express the green fluorescent protein (GFP)-based family of GECIs, GCaMP, under control of either the CMV or the hSyn promoter. High titer lentiviral vectors were produced, and injected into embryos collected from donor females. The infected embryos were then transferred to recipient females. Eight transgenic animals were born and shown to have stable and functional GCaMP expression in several different tissues. Germline transmission of the transgene was confirmed in embryos generated from two of the founder transgenic marmosets that reached sexual maturity. These embryos were implanted into six recipient females, three of which became pregnant and are in advanced stages of gestation. We believe these transgenic marmosets will be invaluable non-human primate models in neuroscience, allowing chronic in vivo monitoring of neural activity with functional confocal and multi-photon optical microscopy imaging of intracellular calcium dynamics. C1 [Park, Jung Eun; Zhang, Xian Feng; Choi, Sang-Ho; Silva, Afonso C.] NINDS, Cerebral Microcirculat Sect, Lab Funct & Mol Imaging, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Okahara, Junko; Sasaki, Erika] Cent Inst Expt Anim, Dept Appl Dev Biol, Tonomachi, Kawasaki, Kanagawa 2100821, Japan. [Sasaki, Erika] Keio Univ, Keio Adv Res Ctr, Shinjuku Ku, Shinanomachi, Tokyo 1608582, Japan. RP Silva, AC (reprint author), NINDS, Cerebral Microcirculat Sect, Lab Funct & Mol Imaging, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM SilvaA@ninds.nih.gov FU Intramural Research Program of the NIH, NINDS FX This research was supported by the Intramural Research Program of the NIH, NINDS (Alan P. Koretsky, Scientific Director). NR 74 TC 3 Z9 3 U1 5 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD OCT 11 PY 2016 VL 6 AR 34931 DI 10.1038/srep34931 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DY6MD UT WOS:000385240500002 PM 27725685 ER PT J AU Sandoval, PC Claxton, JS Lee, JW Saeed, F Hoffert, JD Knepper, MA AF Sandoval, Pablo C. Claxton, J'Neka S. Lee, Jae Wook Saeed, Fahad Hoffert, Jason D. Knepper, Mark A. TI Systems-level analysis reveals selective regulation of Aqp2 gene expression by vasopressin SO SCIENTIFIC REPORTS LA English DT Article ID RENAL COLLECTING DUCT; RNA-POLYMERASE-II; LONG-TERM REGULATION; PROTEIN-KINASE-A; TRANSCRIPTIONAL REGULATION; AQUAPORIN-2 ABUNDANCE; PRINCIPAL CELLS; PLASMA-MEMBRANE; WATER CHANNEL; KIDNEY AB Vasopressin-mediated regulation of renal water excretion is defective in a variety of water balance disorders in humans. It occurs in part through long-term mechanisms that regulate the abundance of the aquaporin-2 water channel in renal collecting duct cells. Here, we use deep DNA sequencing in mouse collecting duct cells to ask whether vasopressin signaling selectively increases Aqp2 gene transcription or whether it triggers a broadly targeted transcriptional network. ChIP-Seq quantification of binding sites for RNA polymerase II was combined with RNA-Seq quantification of transcript abundances to identify genes whose transcription is regulated by vasopressin. (View curated dataset at https://helixweb.nih.gov/ESBL/Database/Vasopressin/). The analysis revealed only 35 vasopressin-regulated genes (of 3659) including Aqp2. Increases in RNA polymerase II binding and mRNA abundances for Aqp2 far outstripped corresponding measurements for all other genes, consistent with the conclusion that vasopressin-mediated transcriptional regulation is highly selective for Aqp2. Despite the overall selectivity of the net transcriptional response, vasopressin treatment was associated with increased RNA polymerase II binding to the promoter proximal region of a majority of expressed genes, suggesting a nearly global positive regulation of transcriptional initiation with transcriptional pausing. Thus, the overall net selectivity appears to be a result of selective control of transcriptional elongation. C1 [Sandoval, Pablo C.; Claxton, J'Neka S.; Lee, Jae Wook; Saeed, Fahad; Hoffert, Jason D.; Knepper, Mark A.] NHLBI, Epithelial Syst Biol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Lee, Jae Wook] Natl Canc Ctr, Goyang, Gyeonggi Do, South Korea. RP Knepper, MA (reprint author), NHLBI, Epithelial Syst Biol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM knepperm@nhlbi.nih.gov FU Division of Intramural Research, National Heart, Lung and Blood Institute [ZO1-HL001285]; Biomedical Research Training Program for Individuals from Underrepresented Groups of the NHLBI FX The work was funded by the Division of Intramural Research, National Heart, Lung and Blood Institute (project ZO1-HL001285, MAK). Next-generation sequencing was done in the NHLBI DNA Sequencing Core Facility (Jun Zhu, Director). Immunofluorescence microscopy was carried out in the NHLBI Light Microscopy Core Facility (Director, Christian Combs). J. Claxton was supported by Biomedical Research Training Program for Individuals from Underrepresented Groups of the NHLBI. NR 51 TC 1 Z9 1 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD OCT 11 PY 2016 VL 6 AR 34863 DI 10.1038/srep34863 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DY6NK UT WOS:000385243800001 PM 27725713 ER PT J AU Schwan, TG Lopez, JE Safronetz, D Anderson, JM Fischer, RJ Maiga, O Sogoba, N AF Schwan, Tom G. Lopez, Job E. Safronetz, David Anderson, Jennifer M. Fischer, Robert J. Maiga, Ousmane Sogoba, Nafomon TI Fleas and trypanosomes of peridomestic small mammals in sub-Saharan Mali SO PARASITES & VECTORS LA English DT Article DE Siphonaptera; Rodents; Shrews; Trypanosomosis; West Africa ID HERPETOSOMA; INFECTION; SIPHONAPTERA; LEWISI; TRANSMISSION; PULICIDAE; AFRICA; INFANT AB Background: Fleas are obligate blood-feeding ectoparasites and vectors of several bacterial zoonotic pathogens as well as trypanosomes that parasitize rodents and other small mammals. During investigations of tick-and rodent-borne diseases in Mali, West Africa, we included fleas and rodent-borne trypanosomes, both of which are poorly known in this country, but are attracting greater public health interest. Methods: Small mammals were captured in 20 Malian villages from December 2007 to October 2011. Fleas were collected and identified to species, and thin blood smears were prepared, stained and examined microscopically for trypanosomes. Results: We captured 744 small mammals, 68 (9.1 %) of which yielded fleas. Two species of fleas, Xenopsylla cheopis and Xenopsylla nubica, were collected from six species of rodents and one species of shrew. Multimammate rats, Mastomys natalensis, were hosts for 58.5 % of all fleas collected. Xenopsylla cheopis was found in the moister southern savannah while X. nubica was mostly restricted to the drier Sahel. Trypanosomes were found in 3 % of 724 blood smears, although 91 % of parasitemic animals originated from two villages where black rats (Rattus rattus) and M. natalensis were the primary hosts and X. cheopis the dominant flea. The trypanosomes were morphologically consistent with the Trypanosoma (Herpetosoma) lewisi group, flea-borne hemoflagellates that parasitize domestic rats. Conclusions: Xenopsylla cheopis and trypanosomes parasitize peridomestic rats that commingle with people in southern Mali. Given the increasing awareness of flea-borne trypanosomes as possible human pathogens, we hope our findings will stimulate future investigators to examine the potential public health significance of flea-borne trypanosomosis in West Africa. C1 [Schwan, Tom G.; Lopez, Job E.; Fischer, Robert J.] NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, Hamilton, MT 59840 USA. [Lopez, Job E.] Baylor Coll Med, Pediat Trop Med, Houston, TX 77030 USA. [Safronetz, David; Fischer, Robert J.] NIAID, Inst Virol, Rocky Mt Labs, Hamilton, MT USA. [Safronetz, David] Publ Hlth Agcy Canada, Zoonot Dis & Special Pathogens, Winnipeg, MB, Canada. [Anderson, Jennifer M.] NIAID, Lab Malaria & Vector Res, Twinbrook, MD USA. [Maiga, Ousmane; Sogoba, Nafomon] Univ Sci Tech & Technol Bamako, Fac Med & Odontostomatol FMOS, Int Ctr Excellence Res ICER Mali, Bamako, Mali. RP Schwan, TG (reprint author), NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, Hamilton, MT 59840 USA. EM tschwan@niaid.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA. NR 41 TC 0 Z9 0 U1 7 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-3305 J9 PARASITE VECTOR JI Parasites Vectors PD OCT 11 PY 2016 VL 9 AR 541 DI 10.1186/s13071-016-1818-5 PG 7 WC Parasitology SC Parasitology GA DY1IE UT WOS:000384847300001 PM 27724960 ER PT J AU Grue, L Siddiqui, S Limmathurotsakul, D Kamaludi, A Karyana, M Lau, CY AF Grue, Louis Siddiqui, Sophia Limmathurotsakul, Direk Kamaludi, Armaji Karyana, Muhammad Lau, Chuen-Yen TI Commentary: data sharing in South East Asia SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Editorial Material ID VIEWS C1 [Grue, Louis] NCI Campus Frederick, Clin Res Directorate, Clin Monitoring Res Program, Leidos Biomed Res, Frederick, MD 21702 USA. [Siddiqui, Sophia; Lau, Chuen-Yen] NIAID, Collaborat Clin Res Branch, Div Clin Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Limmathurotsakul, Direk] Mahidol Univ, Mahidol Oxford Res Unit, Fac Trop Med, Salaya, Thailand. [Kamaludi, Armaji] Minist Hlth, Natl Inst Hlth Res & Dev, SEAICRN Indonesia, Jakarta, Indonesia. [Karyana, Muhammad] Minist Hlth, Natl Inst Hlth Res & Dev, INA RESPOND Indonesia, Jakarta, Indonesia. RP Grue, L (reprint author), NCI Campus Frederick, Clin Res Directorate, Clin Monitoring Res Program, Leidos Biomed Res, Frederick, MD 21702 USA. EM louis.grue@nih.gov NR 10 TC 0 Z9 0 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1756-1833 J9 BMJ-BRIT MED J JI BMJ-British Medical Journal PD OCT 10 PY 2016 VL 355 AR i5363 DI 10.1136/bmj.i5363 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA DZ4ST UT WOS:000385850800002 PM 27758800 ER PT J AU Ricketts, CJ Crooks, DR Linehan, WM AF Ricketts, Christopher J. Crooks, Daniel R. Linehan, W. Marston TI Targeting HIF2 alpha in Clear-Cell Renal Cell Carcinoma SO CANCER CELL LA English DT Editorial Material ID TUMOR-SUPPRESSOR PROTEIN; HIF-ALPHA; HYDROXYLATION; COMPLEX AB In two recent studies, the HIF2 alpha antagonist, PT2399, decreased HIF2 alpha-dependent transcription and tumor growth in selected VHL-deficient clear-cell renal cell carcinoma (ccRCC) models. These studies validate HIF2 alpha as a therapeutic target in ccRCC, reveal variable sensitivity to HIF2 alpha antagonism, and provide the foundation for predictive biomarker-driven clinical trials. C1 [Ricketts, Christopher J.; Crooks, Daniel R.; Linehan, W. Marston] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Linehan, WM (reprint author), NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM wml@nih.gov NR 10 TC 1 Z9 1 U1 5 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 EI 1878-3686 J9 CANCER CELL JI Cancer Cell PD OCT 10 PY 2016 VL 30 IS 4 BP 515 EP 517 DI 10.1016/j.ccell.2016.09.016 PG 3 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DY7SO UT WOS:000385329800006 PM 27728802 ER PT J AU Eggert, T Wolter, K Ji, JL Ma, C Yevsa, T Klotz, S Medina-Echeverz, J Longerich, T Forgues, M Reisinger, F Heikenwalder, M Wang, XW Zender, L Greten, TF AF Eggert, Tobias Wolter, Katharina Ji, Juling Ma, Chi Yevsa, Tetyana Klotz, Sabrina Medina-Echeverz, Jose Longerich, Thomas Forgues, Marshonna Reisinger, Florian Heikenwalder, Mathias Wang, Xin Wei Zender, Lars Greten, Tim F. TI Distinct Functions of Senescence-Associated Immune Responses in Liver Tumor Surveillance and Tumor Progression SO CANCER CELL LA English DT Article ID HEPATOCELLULAR-CARCINOMA PATIENTS; MONOCYTE CHEMOATTRACTANT PROTEIN-1; NATURAL-KILLER-CELLS; SUPPRESSOR-CELLS; NK CELLS; T-CELLS; CANCER; CHEMOTHERAPY; METASTASIS; RECEPTOR AB Oncogene-induced senescence causes hepatocytes to secrete cytokines, which induce their immune-mediated clearance to prevent tumor initiation, a process termed "senescence surveillance." However, senescent hepatocytes give rise to hepatocellular carcinomas (HCCs), if the senescence program is bypassed or if senescent cells are not cleared. Here, we show context-specific roles for CCR2(+) myeloid cells in liver cancer. Senescence surveillance requires the recruitment and maturation of CCR2(+) myeloid cells, and CCR2 ablation caused outgrowth of HCC. In contrast, HCC cells block the maturation of recruited myeloid precursors, which, through NK cell inhibition, promote growth of murine HCC and worsen the prognosis and survival of human HCC patients. Thus, while senescent hepatocyte-secreted chemokines suppress liver cancer initiation, they may accelerate the growth of fully established HCC. C1 [Eggert, Tobias; Ma, Chi; Medina-Echeverz, Jose; Greten, Tim F.] NCI, Gastrointestinal Malignancy Sect, Thorac & Gastrointestinal Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Wolter, Katharina; Yevsa, Tetyana; Klotz, Sabrina; Zender, Lars] Univ Tubingen, Dept Internal Med 1, Div Gastrointestinal Oncol, D-72076 Tubingen, Germany. [Ji, Juling; Forgues, Marshonna; Wang, Xin Wei] NCI, Lab Human Carcinogenesis, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Longerich, Thomas] Univ Hosp RWTH Aachen, Inst Pathol, D-52074 Aachen, Germany. [Reisinger, Florian; Heikenwalder, Mathias] Tech Univ Munich, Inst Virol, D-81675 Munich, Germany. [Reisinger, Florian; Heikenwalder, Mathias] Helmholtz Zentrum Munchen, D-81675 Munich, Germany. [Reisinger, Florian; Heikenwalder, Mathias] German Canc Res Ctr, Div Chron Inflammat & Canc, D-69120 Heidelberg, Germany. [Zender, Lars] German Canc Res Ctr, German Consortium Translat Canc Res DKTK, Translat Gastrointestinal Oncol Grp, D-69120 Heidelberg, Germany. RP Greten, TF (reprint author), NCI, Gastrointestinal Malignancy Sect, Thorac & Gastrointestinal Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA.; Zender, L (reprint author), Univ Tubingen, Dept Internal Med 1, Div Gastrointestinal Oncol, D-72076 Tubingen, Germany.; Zender, L (reprint author), German Canc Res Ctr, German Consortium Translat Canc Res DKTK, Translat Gastrointestinal Oncol Grp, D-69120 Heidelberg, Germany. EM lars.zender@med.uni-tuebingen.de; tim.greten@nih.gov RI Wang, Xin/B-6162-2009 FU German Research Foundation (DFG) [FOR2314, SFB685]; Gottfried Wilhelm Leibniz Program; European Research Council; German Ministry for Education and Research (BMBF); German Universities Excellence Initiative; German Center for Translational Cancer Research (DKTK); German-Israeli Cooperation in Cancer Research (DKFZ-MOST); ERC; Stiftung Experimentelle Biomedizin (Hofschneider Stiftung); Pre-clinical Comprehensive Center (PCCC); Helmholtz foundation; Intramural Research Program of the NIH; NCI FX This work was supported by the German Research Foundation (DFG; grants FOR2314 [L.Z.] and SFB685 [L.Z.]), the Gottfried Wilhelm Leibniz Program (L.Z.), the European Research Council (projects 'CholangioConcept' [L.Z.], 'Heptromic'[L.Z.]), the German Ministry for Education and Research (BMBF) (eMed [Multiscale HCC]) (L.Z.), the German Universities Excellence Initiative (third funding line: 'future concept') (L.Z.), the German Center for Translational Cancer Research (DKTK) (L.Z.), and the German-Israeli Cooperation in Cancer Research (DKFZ-MOST) (L.Z.). M.H. was supported by an ERC starting grant (LiverCancer mechanism), the Stiftung Experimentelle Biomedizin (Hofschneider Stiftung), the Pre-clinical Comprehensive Center (PCCC), and the Helmholtz foundation. T.F.G. and X.W.W. were supported by the Intramural Research Program of the NIH, NCI. We thank Dr. Michael J. Kruhlak (NIH) for technical assistance with scanning of liver section slides and Florian Heinzmann (University Hospital, Tubingen) for the generation of knockdown validated shRNAs. NR 36 TC 3 Z9 3 U1 21 U2 21 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 EI 1878-3686 J9 CANCER CELL JI Cancer Cell PD OCT 10 PY 2016 VL 30 IS 4 BP 533 EP 547 DI 10.1016/j.ccell.2016.09.003 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DY7SO UT WOS:000385329800008 PM 27728804 ER PT J AU Muvarak, NE Chowdhury, K Xia, LM Robert, C Choi, EY Cai, Y Bellani, M Zou, Y Singh, ZN Duong, VH Rutherford, T Nagaria, P Bentzen, SM Seidman, MM Baer, MR Lapidus, RG Baylin, SB Rassoo, FV AF Muvarak, Nidal E. Chowdhury, Khadiza Xia, Limin Robert, Carine Choi, Eun Yong Cai, Yi Bellani, Marina Zou, Ying Singh, Zeba N. Duong, Vu H. Rutherford, Tyler Nagaria, Pratik Bentzen, Soren M. Seidman, Michael M. Baer, Maria R. Lapidus, Rena G. Baylin, Stephen B. Rassoo, Feyruz V. TI Enhancing the Cytotoxic Effects of PARP Inhibitors with DNA Demethylating Agents - A Potential Therapy for Cancer SO CANCER CELL LA English DT Article ID ACUTE MYELOID-LEUKEMIA; BASE EXCISION-REPAIR; DOUBLE-STRAND BREAKS; ADP-RIBOSE POLYMERS; POLY(ADP-RIBOSE) POLYMERASE; MYELODYSPLASTIC SYNDROME; MAMMALIAN-CELLS; METHYLATION; DECITABINE; LETHALITY AB Poly (ADP-ribose) polymerase inhibitors (PARPis) are clinically effective predominantly for BRCA-mutant tumors. We introduce a mechanism-based strategy to enhance PARPi efficacy based on DNA damage-related binding between DNA methyltransferases (DNMTs) and PARP1. In acute myeloid leukemia (AML) and breast cancer cells, DNMT inhibitors (DNMTis) alone covalently bind DNMTs into DNA and increase PARP1 tightly bound into chromatin. Low doses of DNMTis plus PARPis, versus each drug alone, increase PARPi efficacy, increasing amplitude and retention of PARP1 directly at laser-induced DNA damage sites. This correlates with increased DNA damage, synergistic tumor cytotoxicity, blunting of self-renewal, and strong anti-tumor responses, in vivo in unfavorable AML subtypes and BRCA wild-type breast cancer cells. Our combinatorial approach introduces a strategy to enhance efficacy of PARPis in treating cancer. C1 [Muvarak, Nidal E.; Chowdhury, Khadiza; Robert, Carine; Nagaria, Pratik; Bentzen, Soren M.; Rassoo, Feyruz V.] Univ Maryland, Dept Radiat Oncol, Baltimore, MD 21201 USA. [Choi, Eun Yong; Duong, Vu H.; Baer, Maria R.; Lapidus, Rena G.] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Xia, Limin; Cai, Yi; Baylin, Stephen B.] Johns Hopkins Med Inst, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21231 USA. [Zou, Ying; Singh, Zeba N.] Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. [Bellani, Marina; Seidman, Michael M.] NIA, Lab Mol Gerontol, Baltimore, MD 21224 USA. [Muvarak, Nidal E.; Chowdhury, Khadiza; Robert, Carine; Choi, Eun Yong; Duong, Vu H.; Nagaria, Pratik; Baer, Maria R.; Lapidus, Rena G.; Rassoo, Feyruz V.] Univ Maryland, Marlene & Stewart Greenebaum Canc Ctr, Baltimore, MD 21201 USA. [Rutherford, Tyler] Stevenson Univ, Stevenson, MD 21153 USA. [Bentzen, Soren M.] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Baer, Maria R.] Vet Affairs Med Ctr, Baltimore, MD 21201 USA. [Baylin, Stephen B.] Van Andel Res Inst, Grand Rapids, MI 49503 USA. RP Rassoo, FV (reprint author), Univ Maryland, Dept Radiat Oncol, Baltimore, MD 21201 USA.; Rassoo, FV (reprint author), Univ Maryland, Marlene & Stewart Greenebaum Canc Ctr, Baltimore, MD 21201 USA. EM frassool@som.umaryland.edu FU Laura Ziskin award from Entertainment Industry Foundation; Adelson Medical Research Foundation; Maryland Cigarette Restitution funds; Leukemia and Lymphoma Society [6487-16]; Van Andel Research Institute - Stand Up to Cancer Epigenetics Dream Team; NIH, National Institute on Aging [Z01 AG000746-08] FX We thank Nicole Glynn (Greenebaum Cancer Center) for procuring AML patient samples. We also thank Dr. Pratik Nagaria for careful reading of the manuscript and helpful comments. We thank Dr. Lirong Yu, Division of Systems Biology, National Center for Toxicological Research (US food and Drug Administration) for mass spectometry analysis. Our studies have been supported by funding from a Laura Ziskin award (to F.V.R. and S.B.B.) from the Entertainment Industry Foundation, (to C.R., N.E.M., S.B.B., and F.V.R.), the Adelson Medical Research Foundation (to K.C., F.V.R., and S.B.B.), Maryland Cigarette Restitution funds (to N.E.M.), and a Leukemia and Lymphoma Society award 6487-16 (to F.V.R., M.R.B., and N.E.M.). Research funding provided by Van Andel Research Institute - Stand Up to Cancer Epigenetics Dream Team. Stand Up To Cancer is a program of the Entertainment Industry Foundation, administered by the AACR. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging, Z01 AG000746-08 (to M.M.S. and M.B.). C.R., F.V.R., and S.B.B. share co-inventor ship on US Provisional Patent Application Number: 61/929,680 for the concept of the combinatorial therapy. NR 63 TC 2 Z9 2 U1 14 U2 14 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 EI 1878-3686 J9 CANCER CELL JI Cancer Cell PD OCT 10 PY 2016 VL 30 IS 4 BP 637 EP 650 DI 10.1016/j.ccell.2016.09.002 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DY7SO UT WOS:000385329800015 PM 27728808 ER PT J AU Litzelman, K Kent, EE Mollica, M Rowland, JH AF Litzelman, Kristin Kent, Erin E. Mollica, Michelle Rowland, Julia H. TI How Does Caregiver Well-Being Relate to Perceived Quality of Care in Patients With Cancer? Exploring Associations and Pathways SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID OUTCOMES RESEARCH; SURVEILLANCE CONSORTIUM; MULTIPLE IMPUTATION; PROSTATE-CANCER; LUNG-CANCER; SHORT-FORM; SURVIVORS; LIFE; DISTRESS; SERVICES AB PurposePerceived quality of care (QOC) is an increasingly important metric of care quality and can be affected by such factors among patients with cancer as quality of life and physician trust. This study sought to evaluate whether informal caregiver well-being was also associated with perceived QOC among patients with cancer and assessed potential pathways that link these factors.MethodsThis study used data from the Cancer Care Outcomes Research and Surveillance (CanCORS) consortium. Patients with lung and colorectal cancer enrolled in CanCORS (N = 689) nominated an informal caregiver to participate in a caregiving survey. Both groups self-reported sociodemographic, psychosocial, and caregiving characteristics; cancer characteristics were obtained from the CanCORS core data set. Multivariable logistic regression was used to assess the association between caregiver psychosocial factors and subsequent patient-perceived QOC, controlling for earlier patient-perceived QOC and covariates. Secondary analysis examined potential pathways that link these factors.ResultsPatients whose informal caregiver had higher levels of depressive symptoms were significantly more likely to report fair or poor QOC (odds ratio, 1.06; 95% CI, 1.01 to 1.13). When caregivers reported fair or poor self-rated health, patients were more than three times more likely to report fair or poor perceived QOC (odds ratio, 3.76; 95% CI, 1.76 to 9.55). Controlling for patient psychosocial factors and physician communication and coordination of medical care reduced the effect size and/or statistical significance of these relationships.ConclusionInformal caregivers are an important part of the care team and their well-being is associated with patient-perceived QOC. Engaging informal cancer caregivers as part of the care team and conducting ongoing risk stratification screening and intervention to optimize their health may improve patient-reported outcomes and QOC. C1 [Litzelman, Kristin] Univ Wisconsin Madison, 4115 Nancy Nicholas Hall,1300 Linden Dr, Madison, WI 53706 USA. [Litzelman, Kristin] Univ Wisconsin, Madison, WI USA. [Kent, Erin E.; Mollica, Michelle; Rowland, Julia H.] NCI, Bethesda, MD 20892 USA. RP Litzelman, K (reprint author), Univ Wisconsin Madison, 4115 Nancy Nicholas Hall,1300 Linden Dr, Madison, WI 53706 USA. EM litzelman@wisc.edu FU National Cancer Institute [U01-CA93324, U01-CA93326, U01-CA93329, U01-CA93332, U01-CA93339, U01-CA93344, U01-CA93348]; Department of Veterans Affairs [CRS 02-164] FX Supported by National Cancer Institute Grants No. U01-CA93324, U01-CA93326, U01-CA93329, U01-CA93332, U01-CA93339, U01-CA93344, and U01-CA93348, and the Department of Veterans Affairs (Grant No. CRS 02-164; for Cancer Care Outcomes Research and Surveillance data collection). NR 39 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD OCT 10 PY 2016 VL 34 IS 29 BP 3554 EP + DI 10.1200/JCO.2016.67.3434 PG 13 WC Oncology SC Oncology GA DZ4TJ UT WOS:000385852400011 ER PT J AU Shapcott, KA Schmiedt, JT Saunders, RC Maier, A Leopold, DA Schmid, MC AF Shapcott, Katharine A. Schmiedt, Joscha T. Saunders, Richard C. Maier, Alexander Leopold, David A. Schmid, Michael C. TI Correlated activity of cortical neurons survives extensive removal of feedforward sensory input SO SCIENTIFIC REPORTS LA English DT Article ID PRIMARY VISUAL-CORTEX; AREA V4; INTERNEURONAL CORRELATIONS; TEMPORAL SCALES; STRIATE CORTEX; SPIKE TRAINS; MACAQUE; VARIABILITY; STATE; ATTENTION AB A fundamental property of brain function is that the spiking activity of cortical neurons is variable and that some of this variability is correlated between neurons. Correlated activity not due to the stimulus arises from shared input but the neuronal circuit mechanisms that result in these noise correlations are not fully understood. Here we tested in the visual system if correlated variability in mid-level area V4 of visual cortex is altered following extensive lesions of primary visual cortex (V1). To this end we recorded longitudinally the neuronal correlations in area V4 of two behaving macaque monkeys before and after a V1 lesion while the monkeys fixated a grey screen. We found that the correlations of neuronal activity survived the lesions in both monkeys. In one monkey, the correlation of multi-unit spiking signals was strongly increased in the first week post-lesion, while in the second monkey, correlated activity was slightly increased, but not greater than some week-by-week fluctuations observed. The typical dropoff of inter-neuronal correlations with cortical distance was preserved after the lesion. Therefore, as V4 noise correlations remain without feedforward input from V1, these results suggest instead that local and/or feedback input seem to be necessary for correlated activity. C1 [Shapcott, Katharine A.; Schmiedt, Joscha T.; Schmid, Michael C.] Max Planck Gesell, ESI Neurosci Cooperat, D-60528 Frankfurt, Germany. [Saunders, Richard C.; Leopold, David A.] NIMH, Lab Neuropsychol, Bethesda, MD 20892 USA. [Maier, Alexander] Vanderbilt Univ, Dept Psychol, Nashville, TN 37240 USA. [Leopold, David A.] NINDS, NIMH, Neurophysiol Imaging Facil, Bethesda, MD 20892 USA. [Leopold, David A.] NEI, Bethesda, MD 20892 USA. [Schmid, Michael C.] Newcastle Univ, Inst Neurosci, Framlington Pl, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England. RP Schmid, MC (reprint author), Max Planck Gesell, ESI Neurosci Cooperat, D-60528 Frankfurt, Germany.; Schmid, MC (reprint author), Newcastle Univ, Inst Neurosci, Framlington Pl, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England. EM michael.schmid@ncl.ac.uk OI Maier, Alexander/0000-0002-7250-502X FU Intramural Research Program of the National Institute of Mental Health; Deutsche Forschungsgemeinschaft Emmy Noether grant [Schm 2806/1-1]; IMPRS for Neural Circuits; Whitehall Foundation; Alfred P. Sloan Foundation; Knights Templar Eye Foundation FX This work was supported by the Intramural Research Program of the National Institute of Mental Health (D.A.L.), Deutsche Forschungsgemeinschaft Emmy Noether grant Schm 2806/1-1 (M.C.S.) and the IMPRS for Neural Circuits (K.A.S). A.M. is supported by a research grant from the Whitehall Foundation, a fellowship from the Alfred P. Sloan Foundation and a career starter grant from the Knights Templar Eye Foundation. We thank Dr. Andy Mitz for help and advice on the electrode arrays and Katy Smith and Andy Peters for help with the experiments. NR 39 TC 1 Z9 1 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD OCT 10 PY 2016 VL 6 AR 34886 DI 10.1038/srep34886 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DY5NJ UT WOS:000385146200001 PM 27721468 ER PT J AU Zhou, BR Feng, HQ Ghirlando, R Li, SP Schwieters, CD Bai, YW AF Zhou, Bing-Rui Feng, Hanqiao Ghirlando, Rodolfo Li, Shipeng Schwieters, Charles D. Bai, Yawen TI A Small Number of Residues Can Determine if Linker Histones Are Bound On or Off Dyad in the Chromatosome SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE chromatosome; linker histone; nucleosome; chromatin higher-order structure, methyl-TROSY ID C-TERMINAL DOMAIN; NUCLEAR-MAGNETIC-RESONANCE; IN-VIVO; SEDIMENTATION-VELOCITY; CORE PARTICLE; H1 BINDING; NUCLEOSOME; DNA; RESOLUTION; ORGANIZATION AB Linker histones bind to the nucleosome and regulate the structure and function of chromatin. We have previously shown that the globular domains of chicken H5 and Drosophila H1 linker histones bind to the nucleosome with on- or off-dyad modes, respectively. To explore the determinant for the distinct binding modes, we investigated the binding of a mutant globular domain of H5 to the nucleosome. This mutant, termed GH5_pMut, includes substitutions of five globular domain residues of H5 with the corresponding residues in the globular domain of Drosophila H1. The residues at these five positions play important roles in nucleosome binding by either H5 or Drosophila H1. NMR and spin-labeling experiments showed that GH5_pMut bound to the nucleosome off the dyad. We further found that the nucleosome array condensed by either the GH5_pMut or the globular domain of Drosophila H1 displayed a similar sedimentation coefficient, whereas the same nucleosome array condensed by the wild-type globular domain of H5 showed a much larger sedimentation coefficient. Moreover, NMR and spin-labeling results from the study of the nucleosome in complex with the full-length human linker histone H1.0, whose globular domain shares high sequence conservation with the corresponding globular domain of H5, are consistent with an on-dyad binding mode. Taken together, our results suggest that a small number of residues in the globular domain of a linker histone can control its binding location on the nucleosome and higher-order chromatin structure. (C) 2016 Published by Elsevier Ltd. C1 [Zhou, Bing-Rui; Feng, Hanqiao; Li, Shipeng; Bai, Yawen] NCI, Lab Biochem & Mol Biol, NIH, Bethesda, MD 20892 USA. [Ghirlando, Rodolfo] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Schwieters, Charles D.] NIH, Imaging Sci Lab, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Bai, YW (reprint author), NCI, Lab Biochem & Mol Biol, NIH, Bethesda, MD 20892 USA. EM baiyaw@mail.nih.gov FU NIH, the National Cancer Institute; National Institute of Diabetes and Digestive and Kidney Diseases; Center for Information Technology FX The work is supported by the intramural research programs of the NIH, the National Cancer Institute (Y.B.), the National Institute of Diabetes and Digestive and Kidney Diseases (R.G.), and the Center for Information Technology (C.D.S.). NR 58 TC 0 Z9 0 U1 2 U2 2 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 EI 1089-8638 J9 J MOL BIOL JI J. Mol. Biol. PD OCT 9 PY 2016 VL 428 IS 20 BP 3948 EP 3959 DI 10.1016/j.jmb.2016.08.016 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DY7QJ UT WOS:000385324000006 PM 27558112 ER PT J AU Kutty, RK Samuel, W Boyce, K Cherukuri, A Duncan, T Jaworski, C Nagineni, CN Redmond, TM AF Kutty, R. Krishnan Samuel, William Boyce, Kaifa Cherukuri, Aswini Duncan, Todd Jaworski, Cynthia Nagineni, Chandrasekharam N. Redmond, T. Michael TI Proinflammatory cytokines decrease the expression of genes critical for RPE function SO MOLECULAR VISION LA English DT Article ID RETINAL-PIGMENT EPITHELIUM; MACULAR DEGENERATION; MESENCHYMAL TRANSITION; E-CADHERIN; IN-VITRO; OXIDATIVE STRESS; INTERFERON-GAMMA; VISUAL CYCLE; CELL-LINE; ARPE-19 AB Purpose: Proinflammatory cytokines interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), and interleukin-1 beta (IL-1 beta) secreted by infiltrating lymphocytes or macrophages may play a role in triggering RPE dysfunction associated with age-related macular degeneration (AMD). Binding of these proinflammatory cytokines to their specific receptors residing on the RPE cell surface can activate signaling pathways that, in turn, may dysregulate cellular gene expression. The purpose of the present study was to investigate whether IFN-gamma, TNF-alpha, and IL-1 beta have an adverse effect on the expression of genes essential for RPE function, employing the RPE cell line ARPE-19 as a model system. Methods: ARPE-19 cells were cultured for 3-4 months until they exhibited epithelial morphology and expressed mRNAs for visual cycle genes. The differentiated cells were treated with IFN-gamma, TNF-alpha, and/or IL-1 beta, and gene expression was analyzed with real-time PCR analysis. Western immunoblotting was employed for the detection of proteins. Results: Proinflammatory cytokines (IFN-gamma + TNF-alpha + IL-1 beta) greatly increased the expression of chemokines and cytokines in cultured ARPE-19 cells that exhibited RPE characteristics. However, this response was accompanied by markedly decreased expression of genes important for RPE function, such as CDH1, RPE65, RDH5, RDH10, TYR, and MERTK. This was associated with decreased expression of the genes MITF, TRPM1, and TRPM3, as well as microRNAs miR-204 and miR-211, which are known to regulate RPE-specific gene expression. The decreased expression of the epithelial marker gene CDH1 was associated with increased expression of mesenchymal marker genes (CDH2, VIM, and CCND1) and epithelial-mesenchymal transition (EMT) promoting transcription factor genes (ZEB1 and SNAI1). Conclusions: RPE cells exposed to proinflammatory cytokines IFN-gamma, TNF-alpha, and IL-1 beta showed decreased expression of key genes involved in the visual cycle, epithelial morphology, and phagocytosis. This adverse effect of proinflammatory cytokines, which could be secreted by infiltrating lymphocytes or macrophages, on the expression of genes indispensable for RPE function may contribute to the RPE dysfunction implicated in AMD pathology. C1 [Kutty, R. Krishnan; Samuel, William; Boyce, Kaifa; Cherukuri, Aswini; Duncan, Todd; Jaworski, Cynthia; Redmond, T. Michael] NEI, Lab Retinal Cell & Mol Biol, NIH, Bldg 6,Room 112,6 Ctr Dr,MSC 0608, Bethesda, MD 20892 USA. [Nagineni, Chandrasekharam N.] NCI, Radiat Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kutty, RK (reprint author), NEI, Lab Retinal Cell & Mol Biol, NIH, Bldg 6,Room 112,6 Ctr Dr,MSC 0608, Bethesda, MD 20892 USA. EM kuttyk@nei.nih.gov FU Intramural Research Program, NIH, NEI [1ZIAEY000444-09] FX The authors thank Dr. C. Vijayasarathy (National Institute on Deafness and Other Communication Disorders) for his contribution and critical reading of the manuscript. This study was supported by the Intramural Research Program, NIH, NEI (1ZIAEY000444-09). NR 53 TC 0 Z9 0 U1 0 U2 0 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD OCT 8 PY 2016 VL 22 BP 1156 EP 1168 PG 13 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA EK4NQ UT WOS:000393904200001 PM 27733811 ER PT J AU Wang, HD Naghavi, M Allen, C Barber, RM Bhutta, ZA Carter, A Casey, DC Charlson, FJ Chen, AZ Coates, MM Coggeshall, M Dandona, L Dicker, DJ Erskine, HE Ferrari, AJ Fitzmaurice, C Foreman, K Forouzanfar, MH Fraser, MS Pullman, N Gething, PW Goldberg, EM Graetz, N Haagsma, JA Hay, SI Huynh, C Johnson, C Kassebaum, NJ Kinfu, Y Kulikoff, XR Kutz, M Kyu, HH Larson, HJ Leung, J Liang, XF Lim, SS Lind, M Lozano, R Marquez, N Mensah, GA Mikesell, J Mokdad, AH Mooney, MD Nguyen, G Nsoesie, E Pigott, DM Pinho, C Roth, GA Salomon, JA Sandar, L Silpakit, N Sligar, A Sorensen, RJD Stanaway, J Steiner, C Teeple, S Thomas, BA Troeger, C VanderZanden, A Vollset, SE Wanga, V Whiteford, HA Wolock, T Zoeckler, L Abate, KH Abbafati, C Abbas, KM Abd-Allah, F Abera, SF Abreu, DMX Abu-Raddad, LJ Abyu, GY Achoki, T Adelekan, AL Ademi, Z Adou, AK Adsuar, JC Afanvi, KA Afshin, A Agardh, EE Agarwal, A Agrawal, A Kiadaliri, AA Ajala, ON Akanda, AS Akinyemi, RO Akinyemiju, TF Akseer, N Al Lami, FH Alabed, S Al-Aly, Z Alam, K Alam, NKM Alasfoor, D Aldhahri, SF Aldridge, RW Alegretti, MA Aleman, AV Alemu, ZA Alexander, LT Alhabib, S Ali, R Alkerwi, A Alla, F Allebeck, P Al-Raddadi, R Alsharif, U Altirkawi, KA Martin, EA Alvis-Guzman, N Amare, AT Amegah, AK Ameh, EA Amini, H Ammar, W Amrock, SM Andersen, HH Anderson, B Anderson, GM Antonio, CAT Aregay, AF Arnlov, J Arsenijevic, VSA Al Artaman Asayesh, H Asghar, RJ Atique, S Avokpaho, EFGA Awasthi, A Azzopardi, P Bacha, U Badawi, A Bahit, MC Balakrishnan, K Banerjee, A Barac, A Barker-Collo, SL Barnighausen, T Barregard, L Barrero, LH Basu, A Basu, S Bayou, YT Bazargan-Hejazi, S Beardsley, J Bedi, N Beghi, E Belay, HA Bell, B Bell, ML Bello, AK Bennett, DA Bensenor, IM Berhane, A Bernabe, E Betsu, BD Beyene, AS Bhala, N Bhalla, A Biadgilign, S Bikbov, B Bin Abdulhak, AA Biroscak, BJ Biryukov, S Bjertness, E Blore, JD Blosser, CD Bohensky, MA Borschmann, R Bose, D Bourne, RRA Brainin, M Brayne, CEG Brazinova, A Breitborde, NJK Brenner, H Brewer, JD Brown, A Brown, J Brugha, TS Buckle, GC Butt, ZA Calabria, B Campos-Novato, IR Campuzano, JC Carapetis, JR Cardenas, R Carpenter, D Carrero, JJ Castaneda-Oquela, CA Rivas, JC Catala-Lopez, F Cavalleri, F Cercy, K Cerda, J Chen, WQ Chew, A Chiang, PPC Chibalabala, M Chibueze, CE Chimed-Ochir, O Chisumpa, VH Choi, JYJ Chowdhury, R Christensen, H Christopher, DJ Ciobanu, LG Cirillo, M Cohen, AJ Colistro, V Colomar, M Colquhoun, SM Cooper, C Cooper, LT Cortinovis, M Cowie, BC Crump, JA Damsere-Derry, J Danawi, H Dandona, R Daoud, F Darby, SC Dargan, PI das Neves, J Davey, G Davis, AC Davitoiu, DV de Castro, EF de Jager, P De Leo, D Degenhardt, L Dellavalle, RP Deribe, K Deribew, A Dharmaratne, SD Dhillon, PK Diaz-Torne, C Ding, EL dos Santos, KPB Dossou, E Driscoll, TR Duan, LL Dubey, M Bartholow, B Ellenbogen, RG Lycke, C Elyazar, I Endries, AY Ermakov, SP Eshrati, B Esteghamati, A Estep, K Faghmous, IDA Fahimi, S Jose, E Farid, TA Farinha, CSES Faro, A Farvid, MS Farzadfar, F Feigin, VL Fereshtehnejad, SM Fernandes, JG Fernandes, JC Fischer, F Fitchett, JRA Flaxman, A Foigt, N Fowkes, FGR Franca, EB Franklin, RC Friedman, J Frostad, J Hirst, T Futran, ND Gall, SL Gambashidze, K Gamkrelidze, A Ganguly, P Gankpe, FG Gebre, T Gebrehiwot, TT Gebremedhin, AT Gebru, AA Geleijnse, JM Gessner, BD Ghoshal, AG Gibney, KB Gillum, RF Gilmour, S Giref, AZ Giroud, M Gishu, MD Giussani, G Glaser, E Godwin, WW Gomez-Dantes, H Gona, P Goodridge, A Gopalani, SV Gosselin, RA Gotay, CC Goto, A Gouda, HN Greaves, F Gugnani, HC Gupta, R Gupta, R Gupta, V Gutierrez, RA Hafezi-Nejad, N Haile, D Hailu, AD Hailu, GB Halasa, YA Hamadeh, RR Hamidi, S Hancock, J Handal, AJ Hankey, GJ Hao, YT Harb, HL Harikrishnan, S Haro, JM Havmoeller, R Heckbert, SR Heredia-Pi, IB Heydarpour, P Hilderink, HBM Hoek, HW Hogg, RS Horino, M Horita, N Hosgood, HD Hotez, PJ Hoy, DG Hsairi, M Htet, AS Htike, MMT Hu, GQ Huang, C Huang, H Huiart, L Husseini, A Huybrechts, I Huynh, G Iburg, KM Innos, K Inoue, M Iyer, VJ Jacobs, TA Jacobsen, KH Jahanmehr, N Jakovljevic, MB James, P Javanbakht, M Jayaraman, SP Jayatilleke, AU Jeemon, P Jensen, PN Jha, V Jiang, G Jiang, Y Jibat, T Jimenez-Corona, A Jonas, JB Joshi, TK Kabir, Z Karnak, R Kan, HD Kant, S Karch, A Karema, CK Karimkhani, C Karletsos, D Karthikeyan, G Kasaeian, A Katibeh, M Kaul, A Kawakami, N Kayibanda, JF Keiyoro, PN Kemmer, L Kemp, AH Kengne, AP Keren, A Kereselidze, M Kesavachandran, CN Khader, YS Khalil, IA Khan, AR Khan, EA Khang, YH Khera, S Khoja, TAM Kieling, C Kim, D Kim, YJ Kissela, BM Kissoon, N Knibbs, LD Knudsen, AK Kokubo, Y Kolte, D Kopec, JA Kosen, S Koul, PA Koyanagi, A Krog, NH Defo, BK Bicer, BK Kudom, AA Kuipers, EJ Kulkarni, VS Kumar, GA Kwan, GF Lal, A Lal, DK Lalloo, R Lam, H Lam, JO Langan, SM Lansingh, VC Larsson, A Laryea, DO Latif, AA Lawrynowicz, AEB Leigh, J Levi, M Li, Y Lindsay, MP Lipshultz, SE Liu, PY Liu, S Liu, Y Lo, LT Logroscino, G Lotufo, PA Lucas, RM Lunevicius, R Lyons, RA Ma, S Machado, VMP Mackay, MT MacLachlan, JH El Razek, HMA El Razek, MMA Majdan, M Majeed, A Malekzadeh, R Manamo, WAA Mandisarisa, J Mangalam, S Mapoma, CC Marcenes, W Margolis, DJ Martin, GR Martinez-Raga, J Marzan, MB Masiye, F -Jones, AJM Massano, J Matzopoulos, R Mayosi, BM McGarvey, ST McGrath, JJ Mckee, M McMahon, BJ Meaney, PA Mehari, A Mehndiratta, MM Mena-Rodriguez, F Mekonnen, AB Melaku, YA Memiah, P Memish, ZA Mendoza, W Meretoja, A Meretoja, TJ Mhimbira, FA Micha, R Miller, TR Mirarefin, M Misganaw, A Mock, CN Mohammad, KA Mohammadi, A Mohammed, S Mohan, V Mola, GLD Monasta, L Hernandez, JCM Montero, P Montico, M Montine, TJ Moradi-Lakeh, M Morawska, L Morgan, K Mori, R Mozaffarian, D Mueller, U Murthy, GVS Murthy, S Musa, KI Nachega, JB Nagel, G Naidoo, KS Naik, N Naldi, L Nangia, V Nash, D Nejjari, C Neupane, S Newton, CR Newton, JN Ng, M Ngalesoni, FN Ngirabega, JD Le Nguyen, Q Nisar, MI Pete, PMN Nomura, M Norheim, OF Norman, PE Norrving, B Nyakarahuka, L Ogbo, FA Ohkubo, T Ojelabi, FA Olivares, PR Olusanya, BO Olusanya, JO Opio, JN Oren, E Ortiz, A Osman, M Ota, E Ozdemir, R Pa, M Pandian, JD Pant, PR Papachristou, C Park, EK Park, JH Parry, CD Parsaeian, M Caicedo, AJP Patten, SB Patton, GC Paul, VK Pearce, N Pedro, JM Stokic, LP Pereira, DM Perico, N Pesudovs, K Petzold, M Phillips, MR Piel, FB Pillay, JD Plass, D Platts-Mills, JA Polinder, S Pope, CA Popova, S Poulton, RG Pourmalek, F Prabhakaran, D Qorbani, M Quame-Amaglo, J Quistberg, DA Rafay, A Rahimi, K Rahimi-Movaghar, V Rahman, M Rahman, MHU Rahman, SU Rai, RK Rajavi, Z Rajsic, S Raju, M Rakovac, I Rana, SM Ranabhat, CL Rangaswamy, T Rao, P Rao, SR Refaat, AH Rehm, J Reitsma, MB Remuzzi, G Resnikofff, S Ribeiro, AL Ricci, S Blancas, MJR Roberts, B Roca, A Rojas-Rueda, D Ronfani, L Roshandel, G Rothenbacher, D Roy, A Roy, NK Ruhago, GM Sagar, R Saha, S Sahathevan, R Saleh, MM Sanabria, JR Sanchez-Nino, MD Sanchez-Riera, L Santos, IS Sarmiento-Suarez, R Sartorius, B Satpathy, M Savic, M Sawhney, M Schaub, MP Schmidt, MI Schneider, IJC Schottker, B Schutte, AE Schwebel, DC Seedat, S Sepanlou, SG Servan-Mori, EE Shackelford, KA Shaddick, G Shaheen, A Shahraz, S Shaikh, MA Shakh-Nazarova, M Sharma, R She, J Sheikhbahaei, S Shen, JB Shen, ZY Shepard, DS Sheth, KN Shetty, BP Shi, PL Shibuya, K Shin, MJ Shiri, R Shiue, I Shrime, MG Sigfusdottir, ID Silberberg, DH Silva, DAS Silveira, DGA Silverberg, JI Simard, EP Singh, A Singh, GM Singh, JA Singh, OP Singh, PK Singh, V Soneji, S Soreide, K Soriano, JB Sposato, LA Sreeramareddy, CT Stathopoulou, V Stein, DJ Stein, MB Stranges, S Stroumpoulis, K Sunguya, BF Sur, P Swaminathan, S Sykes, BL Szoeke, CEI Tabares-Seisdedos, R Tabb, KM Takahashi, K Takala, JS Talongwa, RT Tandon, N Tavakkoli, M Taye, B Taylor, HR Ao, BJT Tedla, BA Tefera, WM Ten Have, M Terkawi, AS Tesfay, FH Tessema, GA Thomson, AJ Thorne-Lyman, AL Thrift, AG Thurston, GD Tillmann, T Tirschwell, DL Tonelli, M Topor-Madry, R Topouzis, F Nx, JAT Traebert, J Tran, BX Truelsen, T Trujillo, U Tura, AK Tuzcu, EM Uchendu, US Ukwaja, KN Undurraga, EA Uthman, OA Van Dingenen, R Van Donkelaar, A Vasankari, T Vasconcelos, AMN Venketasubramanian, N Vidavalur, R Vijayakumar, L Villalpando, S Violante, FS Vlassov, VV Wagner, JA Wagner, GR Wallin, MT Wang, LH Watkins, DA Weichenthal, S Weiderpass, E Weintraub, RG Werdecker, A Westerman, R White, RA Wijeratne, T Wilkinson, JD Williams, HC Wiysonge, CS Woldeyohannes, SM Wolfe, CDA Won, SH Wong, JQ Woolf, AD Xavier, D Xiao, QY Xu, GL Yakob, B Yalew, AZ Yan, LL Yano, YC Yaseri, M Ye, P Yebyo, HG Yip, P Yirsaw, BD Yonemoto, N Yonga, G Younis, MZ Yu, SC Zaidi, Z Zaki, MES Zannad, F Zavala, DE Zeeb, H Zeleke, BM Zhang, H Zodpey, S Zonies, D Zuhlke, LJ Vos, T Lopez, AD Murray, CJL AF Wang, Haidong Naghavi, Mohsen Allen, Christine Barber, Ryan M. Bhutta, Zulfiqar A. Carter, Austin Casey, Daniel C. Charlson, Fiona J. Chen, Alan Zian Coates, Matthew M. Coggeshall, Megan Dandona, Lalit Dicker, Daniel J. Erskine, Holly E. Ferrari, Alize J. Fitzmaurice, Christina Foreman, Kyle Forouzanfar, Mohammad H. Fraser, Maya S. Pullman, Nancy Gething, Peter W. Goldberg, Ellen M. Graetz, Nicholas Haagsma, Juanita A. Hay, Simon I. Huynh, Chantal Johnson, Catherine Kassebaum, Nicholas J. Kinfu, Yohannes Kulikoff, Xie Rachel Kutz, Michael Kyu, Hmwe H. Larson, Heidi J. Leung, Janni Liang, Xiaofeng Lim, Stephen S. Lind, Margaret Lozano, Rafael Marquez, Neal Mensah, George A. Mikesell, Joe Mokdad, Ali H. Mooney, Meghan D. Nguyen, Grant Nsoesie, Elaine Pigott, David M. Pinho, Christine Roth, Gregory A. Salomon, Joshua A. Sandar, Logan Silpakit, Naris Sligar, Amber Sorensen, Reed J. D. Stanaway, Jeffrey Steiner, Caitlyn Teeple, Stephanie Thomas, Bernadette A. Troeger, Christopher VanderZanden, Amelia Vollset, Stein Emil Wanga, Valentine Whiteford, Harvey A. Wolock, Timothy Zoeckler, Leo Abate, Kalkidan Hassen Abbafati, Cristiana Abbas, Kaja M. Abd-Allah, Foad Abera, Semaw Ferede Abreu, Daisy M. X. Abu-Raddad, Laith J. Abyu, Gebre Yitayih Achoki, Tom Adelekan, Ademola Lukman Ademi, Zanfina Adou, Arsene Kouablan Adsuar, Jose C. Afanvi, Kossivi Agbelenko Afshin, Ashkan Agardh, Emilie Elisabet Agarwal, Arnav Agrawal, Anurag Kiadaliri, Aliasghar Ahmad Ajala, Oluremi N. Akanda, All Shafqat Akinyemi, Rufus Olusola Akinyemiju, Tomi F. Akseer, Nadia Al Lami, Faris Hasan Alabed, Samer Al-Aly, Ziyad Alam, Khurshid Alam, Noore K. M. Alasfoor, Deena Aldhahri, Saleh Fahed Aldridge, Robert William Alegretti, Miguel Angel Aleman, Alicia V. Alemu, Zewdie Aderaw Alexander, Lily T. Alhabib, Samia Ali, Raghib Alkerwi, Ala'a Alla, Francois Allebeck, Peter Al-Raddadi, Rajaa Alsharif, Ubai Altirkawi, Khalid A. Martin, Elena Alvarez Alvis-Guzman, Nelson Amare, Azmeraw T. Amegah, Adeladza Kofi Ameh, Emmanuel A. Amini, Heresh Ammar, Walid Amrock, Stephen Marc Andersen, Hjalte H. Anderson, Benjamin Anderson, Gregory M. Antonio, Carl Abelardo T. Aregay, Atsede Fantahun Arnlov, Johan Arsenijevic, Valentina S. Arsic Al Artaman Asayesh, Hamid Asghar, Rana Jawad Atique, Suleman Arthur Avokpaho, Euripide Frinel G. Awasthi, Ashish Azzopardi, Peter Bacha, Umar Badawi, Alaa Bahit, Maria C. Balakrishnan, Kalpana Banerjee, Amitava Barac, Aleksandra Barker-Collo, Suzanne L. Barnighausen, Till Barregard, Lars Barrero, Lope H. Basu, Arindam Basu, Sanjay Bayou, Yibeltal Tebekaw Bazargan-Hejazi, Shahrzad Beardsley, Justin Bedi, Neeraj Beghi, Ettore Belay, Haileeyesus Adamu Bell, Brent Bell, Michelle L. Bello, Aminu K. Bennett, Derrick A. Bensenor, Isabela M. Berhane, Adugnaw Bernabe, Eduardo Betsu, Balem Demtsu Beyene, Addisu Shunu Bhala, Neeraj Bhalla, Ashish Biadgilign, Sibhatu Bikbov, Boris Bin Abdulhak, Aref A. Biroscak, Brian J. Biryukov, Stan Bjertness, Espen Blore, Jed D. Blosser, Christopher D. Bohensky, Megan A. Borschmann, Rohan Bose, Dipan Bourne, Rupert R. A. Brainin, Michael Brayne, Carol E. G. Brazinova, Alexandra Breitborde, Nicholas J. K. Brenner, Hermann Brewer, Jerry D. Brown, Alexandria Brown, Jonathan Brugha, Traolach S. Buckle, Geoffrey Colin Butt, Zahid A. Calabria, Bianca Campos-Novato, Ismael Ricardo Campuzano, Julio Cesar Carapetis, Jonathan R. Cardenas, Rosario Carpenter, David Carrero, Juan Jesus Castaneda-Oquela, Carlos A. 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Duan, Leilei Dubey, Manisha Bartholow, Bruce Ellenbogen, Richard G. Lycke, Christian Elyazar, Iqbal Endries, Aman Yesuf Ermakov, Sergey Petrovich Eshrati, Babak Esteghamati, Alireza Estep, Kara Faghmous, Imad D. A. Fahimi, Saman Jose, Emerito Farid, Talha A. Sa Farinha, Carla Sofia e Faro, Andre Farvid, Maryam S. Farzadfar, Farshad Feigin, Valery L. Fereshtehnejad, Seyed-Mohammad Fernandes, Jefferson G. Fernandes, Joao C. Fischer, Florian Fitchett, Joseph R. A. Flaxman, Abraham Foigt, Nataliya Fowkes, F. Gerry R. Franca, Elisabeth Barboza Franklin, Richard C. Friedman, Joseph Frostad, Joseph Hirst, Thomas Futran, Neal D. Gall, Seana L. Gambashidze, Ketevan Gamkrelidze, Amiran Ganguly, Parthasarathi Gankpe, Fortune Gbetoho Gebre, Teshome Gebrehiwot, Tsegaye Tsewelde Gebremedhin, Amanuel Tesfay Gebru, Alemseged Aregay Geleijnse, Johanna M. Gessner, Bradford D. Ghoshal, Aloke Gopal Gibney, Katherine B. Gillum, Richard F. Gilmour, Stuart Giref, Ababi Zergaw Giroud, Maurice Gishu, Melkamu Dedefo Giussani, Giorgia Glaser, Elizabeth Godwin, William W. Gomez-Dantes, Hector Gona, Philimon Goodridge, Amador Gopalani, Sameer Vali Gosselin, Richard A. Gotay, Carolyn C. Goto, Atsushi Gouda, Hebe N. Greaves, Felix Gugnani, Harish Chander Gupta, Rahul Gupta, Rajeev Gupta, Vipin Gutierrez, Reyna A. Hafezi-Nejad, Nima Haile, Demewoz Hailu, Alemayehu Desalegne Hailu, Gessessew Bugssa Halasa, Yara A. Hamadeh, Randah Ribhi Hamidi, Samer Hancock, Jamie Handal, Alexis J. Hankey, Graeme J. Hao, Yuantao Harb, Hilda L. Harikrishnan, Sivadasanpillai Haro, Josep Maria Havmoeller, Rasmus Heckbert, Susan R. Heredia-Pi, Ileana Beatriz Heydarpour, Pouria Hilderink, Henk B. M. Hoek, Hans W. Hogg, Robert S. Horino, Masako Horita, Nobuyuki Hosgood, H. Dean Hotez, Peter J. Hoy, Damian G. Hsairi, Mohamed Htet, Aung Soe Than Htike, Maung Maung Hu, Guoqing Huang, Cheng Huang, Hsiang Huiart, Laetitia Husseini, Abdullatif Huybrechts, Inge Huynh, Grace Iburg, Kim Moesgaard Innos, Kaire Inoue, Manami Iyer, Veena J. Jacobs, Troy A. Jacobsen, Kathryn H. Jahanmehr, Nader Jakovljevic, Mihajlo B. James, Peter Javanbakht, Mehdi Jayaraman, Sudha P. Jayatilleke, Achala Upendra Jeemon, Panniyammakal Jensen, Paul N. Jha, Vivekanand Jiang, Guohong Jiang, Ying Jibat, Tariku Jimenez-Corona, Aida Jonas, Jost B. Joshi, Tushar Kant Kabir, Zubair Karnak, Ritul Kan, Haidong Kant, Surya Karch, Andre Karema, Corine Kakizi Karimkhani, Chante Karletsos, Dimitris Karthikeyan, Ganesan Kasaeian, Amir Katibeh, Marzieh Kaul, Anil Kawakami, Norito Kayibanda, Jeanne Francoise Keiyoro, Peter Njenga Kemmer, Laura Kemp, Andrew Haddon Kengne, Andre Pascal Keren, Andre Kereselidze, Maia Kesavachandran, Chandrasekharan Nair Khader, Yousef Saleh Khalil, Ibrahim A. Khan, Abdur Rahman Khan, Ejaz Ahmad Khang, Young-Ho Khera, Sahil Muthafer Khoja, Tawfik Ahmed Kieling, Christian Kim, Daniel Kim, Yun Jin Kissela, Brett M. Kissoon, Niranjan Knibbs, Luke D. Knudsen, Ann Kristin Kokubo, Yoshihiro Kolte, Dhaval Kopec, Jacek A. Kosen, Soewarta Koul, Parvaiz A. Koyanagi, Ai Krog, Norun Hjertager Defo, Barthelemy Kuate Bicer, Burcu Kucuk Kudom, Andreas A. Kuipers, Ernst J. Kulkarni, Veena S. Kumar, G. Anil Kwan, Gene F. Lal, Aparna Lal, Dharmesh Kumar Lalloo, Ratilal Lam, Hilton Lam, Jennifer O. Langan, Sinead M. Lansingh, Van C. Larsson, Anders Laryea, Dennis Odai Latif, Asma Abdul Lawrynowicz, Alicia Elena Beatriz Leigh, James Levi, Miriam Li, Yongmei Lindsay, M. Patrice Lipshultz, Steven E. Liu, Patrick Y. Liu, Shiwei Liu, Yang Lo, Loon-Tzian Logroscino, Giancarlo Lotufo, Paulo A. Lucas, Robyn M. Lunevicius, Raimundas Lyons, Ronan A. Ma, Stefan Pedro Machado, Vasco Manuel Mackay, Mark T. MacLachlan, Jennifer H. Abd El Razek, Hassan Magdy Abd El Razek, Mohammed Magdy Majdan, Marek Majeed, Azeem Malekzadeh, Reza Ayele Manamo, Wondimu Ayele Mandisarisa, John Mangalam, Srikanth Mapoma, Chabila C. Marcenes, Wagner Margolis, David Joel Martin, Gerard Robert Martinez-Raga, Jose Marzan, Melvin Barrientos Masiye, Felix Mason-Jones, Amanda J. Massano, Joao Matzopoulos, Richard Mayosi, Bongani M. McGarvey, Stephen Theodore McGrath, John J. Mckee, Martin McMahon, Brian J. Meaney, Peter A. Mehari, Alem Mehndiratta, Man Mohan Mena-Rodriguez, Fabiola Mekonnen, Alemayehu B. Melaku, Yohannes Adama Memiah, Peter Memish, Ziad A. Mendoza, Walter Meretoja, Atte Meretoja, Tuomo J. Mhimbira, Francis Apolinary Micha, Renata Miller, Ted R. Mirarefin, Mojde Misganaw, Awoke Mock, Charles N. Abdulmuhsin Mohammad, Karzan Mohammadi, Alireza Mohammed, Shafiu Mohan, Viswanathan Mola, Glen Liddell D. Monasta, Lorenzo Montanez Hernandez, Julio Cesar Montero, Pablo Montico, Marcella Montine, Thomas J. Moradi-Lakeh, Maziar Morawska, Lidia Morgan, Katherine Mori, Rintaro Mozaffarian, Dariush Mueller, Ulrich Satyanarayana Murthy, Gudlavalleti Venkata Murthy, Srinivas Musa, Kamarul Imran Nachega, Jean B. Nagel, Gabriele Naidoo, Kovin S. Naik, Nitish Naldi, Luigi Nangia, Vinay Nash, Denis Nejjari, Chakib Neupane, Subas Newton, Charles R. Newton, John N. Ng, Marie Ngalesoni, Frida Namnyak Ngirabega, Jean de Dieu Quyen Le Nguyen Nisar, Muhammad Imran Nkamedjie Pete, Patrick Martial Nomura, Marika Norheim, Ole F. Norman, Paul E. Norrving, Bo Nyakarahuka, Luke Ogbo, Felix Akpojene Ohkubo, Takayoshi Ojelabi, Foluke Adetola Olivares, Pedro R. Olusanya, Bolajoko Olubukunola Olusanya, Jacob Olusegun Opio, John Nelson Oren, Eyal Ortiz, Alberto Osman, Majdi Ota, Erika Ozdemir, Raziye Pa, Mahesh Pandian, Jeyaraj D. Pant, Puspa Raj Papachristou, Christina Park, Eun-Kee Park, Jae-Hyun Parry, Charles D. Parsaeian, Mahboubeh Caicedo, Angel J. Paternina Patten, Scott B. Patton, George C. Paul, Vinod K. 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Ruhago, George Mugambage Sagar, Rajesh Saha, Sukanta Sahathevan, Ramesh Saleh, Muhammad Muhammad Sanabria, Juan R. Sanchez-Nino, Maria Dolores Sanchez-Riera, Lidia Santos, Itamar S. Sarmiento-Suarez, Rodrigo Sartorius, Benn Satpathy, Maheswar Savic, Miloje Sawhney, Monika Schaub, Michael P. Schmidt, Maria Ines Schneider, Ione J. C. Schottker, Ben Schutte, Aletta E. Schwebel, David C. Seedat, Soraya Sepanlou, Sadaf G. Servan-Mori, Edson E. Shackelford, Katya A. Shaddick, Gavin Shaheen, Amira Shahraz, Saeid Shaikh, Masood Ali Shakh-Nazarova, Marina Sharma, Rajesh She, Jun Sheikhbahaei, Sara Shen, Jiabin Shen, Ziyan Shepard, Donald S. Sheth, Kevin N. Shetty, Balakrishna P. Shi, Peilin Shibuya, Kenji Shin, Min-Jeong Shiri, Rahman Shiue, Ivy Shrime, Mark G. Sigfusdottir, Inga Dora Silberberg, Donald H. Silva, Diego Augusto Santos Silveira, Dayane Gabriele Alves Silverberg, Jonathan I. Simard, Edgar P. Singh, Abhishek Singh, Gitanjali M. Singh, Jasvinder A. Singh, Om Prakash Singh, Prashant Kumar Singh, Virendra Soneji, Samir Soreide, Kjetil Soriano, Joan B. Sposato, Luciano A. Sreeramareddy, Chandrashekhar T. Stathopoulou, Vasiliki Stein, Dan J. Stein, Murray B. Stranges, Saverio Stroumpoulis, Konstantinos Sunguya, Bruno F. Sur, Patrick Swaminathan, Soumya Sykes, Bryan L. Szoeke, Cassandra E. I. Tabares-Seisdedos, Rafael Tabb, Karen M. Takahashi, Ken Takala, Jukka S. Talongwa, Roberto Tchio Tandon, Nikhil Tavakkoli, Mohammad Taye, Bineyam Taylor, Hugh R. Ao, Braden J. Te Tedla, Bemnet Amare Tefera, Worku Mekonnen Ten Have, Margreet Terkawi, Abdullah Sulieman Tesfay, Fisaha Haile Tessema, Gizachew Assefa Thomson, Alan J. Thorne-Lyman, Andrew L. Thrift, Amanda G. Thurston, George D. Tillmann, Taavi Tirschwell, David L. Tonelli, Marcello Topor-Madry, Roman Topouzis, Fotis Nx, Jeffrey Allen Towb Traebert, Jefferson Tran, Bach Xuan Truelsen, Thomas Trujillo, Ulises Tura, Abera Kenay Tuzcu, Emin Murat Uchendu, Uche S. Ukwaja, Kingsley N. Undurraga, Eduardo A. Uthman, Olalekan A. Van Dingenen, Rita Van Donkelaar, Aaron Vasankari, Tommi Vasconcelos, Ana Maria Nogales Venketasubramanian, Narayanaswamy Vidavalur, Ramesh Vijayakumar, Lakshmi Villalpando, Salvador Violante, Francesco S. Vlassov, Vasiliy Victorovich Wagner, Joseph A. Wagner, Gregory R. Wallin, Mitchell T. Wang, Linhong Watkins, David A. Weichenthal, Scott Weiderpass, Elisabete Weintraub, Robert G. Werdecker, Andrea Westerman, Ronny White, Richard A. Wijeratne, Tissa Wilkinson, James D. Williams, Hywel C. Wiysonge, Charles Shey Woldeyohannes, Solomon Meseret Wolfe, Charles D. A. Won, Sungho Wong, John Q. Woolf, Anthony D. Xavier, Denis Xiao, Qingyang Xu, Gelin Yakob, Bereket Yalew, Ayalnesh Zemene Yan, Lijing L. Yano, Yuichiro Yaseri, Mehdi Ye, Pengpeng Yebyo, Henock Gebremedhin Yip, Paul Yirsaw, Biruck Desalegn Yonemoto, Naohiro Yonga, Gerald Younis, Mustafa Z. Yu, Shicheng Zaidi, Zoubida Zaki, Maysaa El Sayed Zannad, Faiez Zavala, Diego E. Zeeb, Hajo Zeleke, Berihun M. Zhang, Hao Zodpey, Sanjay Zonies, David Zuhlke, Liesl Joanna Vos, Theo Lopez, Alan D. Murray, Christopher J. L. CA GBD 015 Mortality and Causes Death TI Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015 SO LANCET LA English DT Article ID ROAD TRAFFIC INJURIES; ECONOMIC-DEVELOPMENT; UNITED-STATES; EPIDEMIOLOGIC TRANSITION; DEVELOPMENT ASSISTANCE; INTEGRATED APPROACH; CIVIL REGISTRATION; ALZHEIMERS-DISEASE; VITAL-STATISTICS; VERBAL AUTOPSY AB Background Improving survival and extending the longevity of life for all populations requires timely, robust evidence on local mortality levels and trends. The Global Burden of Disease 2015 Study (GBD 2015) provides a comprehensive assessment of all-cause and cause-specific mortality for 249 causes in 195 countries and territories from 1980 to 2015. These results informed an in-depth investigation of observed and expected mortality patterns based on sociodemographic measures. Methods We estimated all-cause mortality by age, sex, geography, and year using an improved analytical approach originally developed for GBD 2013 and GBD 2010. Improvements included refinements to the estimation of child and adult mortality and corresponding uncertainty, parameter selection for under-5 mortality synthesis by spatiotemporal Gaussian process regression, and sibling history data processing. We also expanded the database of vital registration, survey, and census data to 14 294 geography-year datapoints. For GBD 2015, eight causes, including Ebola virus disease, were added to the previous GBD cause list for mortality. We used six modelling approaches to assess cause-specific mortality, with the Cause of Death Ensemble Model (CODEm) generating estimates for most causes. We used a series of novel analyses to systematically quantify the drivers of trends in mortality across geographies. First, we assessed observed and expected levels and trends of cause-specific mortality as they relate to the Socio-demographic Index (SDI), a summary indicator derived from measures of income per capita, educational attainment, and fertility. Second, we examined factors affecting total mortality patterns through a series of counterfactual scenarios, testing the magnitude by which population growth, population age structures, and epidemiological changes contributed to shifts in mortality. Finally, we attributed changes in life expectancy to changes in cause of death. We documented each step of the GBD 2015 estimation processes, as well as data sources, in accordance with Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER). Findings Globally, life expectancy from birth increased from 61.7 years (95% uncertainty interval 61.4-61.9) in 1980 to 71.8 years (71.5-72.2) in 2015. Several countries in sub-Saharan Africa had very large gains in life expectancy from 2005 to 2015, rebounding from an era of exceedingly high loss of life due to HIV/AIDS. At the same time, many geographies saw life expectancy stagnate or decline, particularly for men and in countries with rising mortality from war or interpersonal violence. From 2005 to 2015, male life expectancy in Syria dropped by 11.3 years (3.7-17.4), to 62.6 years (56.5-70.2). Total deaths increased by 4.1% (2.6-5.6) from 2005 to 2015, rising to 55.8 million (54.9 million to 56.6 million) in 2015, but age-standardised death rates fell by 17.0% (15.8-18.1) during this time, underscoring changes in population growth and shifts in global age structures. The result was similar for non-communicable diseases (NCDs), with total deaths from these causes increasing by 14.1% (12.6-16.0) to 39.8 million (39.2 million to 40.5 million) in 2015, whereas age-standardised rates decreased by 13.1% (11.9-14.3). Globally, this mortality pattern emerged for several NCDs, including several types of cancer, ischaemic heart disease, cirrhosis, and Alzheimer's disease and other dementias. By contrast, both total deaths and age-standardised death rates due to communicable, maternal, neonatal, and nutritional conditions significantly declined from 2005 to 2015, gains largely attributable to decreases in mortality rates due to HIV/AIDS (42.1%, 39.1-44.6), malaria (43.1%, 34.7-51.8), neonatal preterm birth complications (29.8%, 24.8-34.9), and maternal disorders (29.1%, 19.3-37.1). Progress was slower for several causes, such as lower respiratory infections and nutritional deficiencies, whereas deaths increased for others, including dengue and drug use disorders. Age-standardised death rates due to injuries significantly declined from 2005 to 2015, yet interpersonal violence and war claimed increasingly more lives in some regions, particularly in the Middle East. In 2015, rotaviral enteritis (rotavirus) was the leading cause of under-5 deaths due to diarrhoea (146 000 deaths, 118 000-183 000) and pneumococcal pneumonia was the leading cause of under-5 deaths due to lower respiratory infections (393 000 deaths, 228 000-532 000), although pathogen-specific mortality varied by region. Globally, the effects of population growth, ageing, and changes in age-standardised death rates substantially differed by cause. Our analyses on the expected associations between cause-specific mortality and SDI show the regular shifts in cause of death composition and population age structure with rising SDI. Country patterns of premature mortality (measured as years of life lost [YLLs]) and how they differ from the level expected on the basis of SDI alone revealed distinct but highly heterogeneous patterns by region and country or territory. Ischaemic heart disease, stroke, and diabetes were among the leading causes of YLLs in most regions, but in many cases, intraregional results sharply diverged for ratios of observed and expected YLLs based on SDI. Communicable, maternal, neonatal, and nutritional diseases caused the most YLLs throughout sub-Saharan Africa, with observed YLLs far exceeding expected YLLs for countries in which malaria or HIV/AIDS remained the leading causes of early death. Interpretation At the global scale, age-specific mortality has steadily improved over the past 35 years; this pattern of general progress continued in the past decade. Progress has been faster in most countries than expected on the basis of development measured by the SDI. Against this background of progress, some countries have seen falls in life expectancy, and age-standardised death rates for some causes are increasing. Despite progress in reducing age-standardised death rates, population growth and ageing mean that the number of deaths from most non-communicable causes are increasing in most countries, putting increased demands on health systems. Copyright (C) The Author(s). Published by Elsevier Ltd. C1 [Wang, Haidong; Naghavi, Mohsen; Allen, Christine; Barber, Ryan M.; Carter, Austin; Casey, Daniel C.; Charlson, Fiona J.; Chen, Alan Zian; Coates, Matthew M.; Coggeshall, Megan; Dandona, Lalit; Dicker, Daniel J.; Erskine, Holly E.; Ferrari, Alize J.; Fitzmaurice, Christina; Foreman, Kyle; Forouzanfar, Mohammad H.; Fraser, Maya S.; Goldberg, Ellen M.; Graetz, Nicholas; Huynh, Chantal; Johnson, Catherine; Kassebaum, Nicholas J.; Kulikoff, Xie Rachel; Kutz, Michael; Kyu, Hmwe H.; Larson, Heidi J.; Leung, Janni; Lim, Stephen S.; Lind, Margaret; Lozano, Rafael; Marquez, Neal; Mikesell, Joe; Mokdad, Ali H.; Mooney, Meghan D.; Nguyen, Grant; Nsoesie, Elaine; Pigott, David M.; Pinho, Christine; Roth, Gregory A.; Sandar, Logan; Silpakit, Naris; Sligar, Amber; Sorensen, Reed J. D.; Stanaway, Jeffrey; Steiner, Caitlyn; Teeple, Stephanie; Thomas, Bernadette A.; Troeger, Christopher; VanderZanden, Amelia; Vollset, Stein Emil; Wanga, Valentine; Whiteford, Harvey A.; Wolock, Timothy; Zoeckler, Leo; Achoki, Tom; Afshin, Ashkan; Alexander, Lily T.; Anderson, Gregory M.; Biryukov, Stan; Blore, Jed D.; Brown, Alexandria; Brown, Jonathan; Cercy, Kelly; Chew, Adrienne; Cohen, Aaron J.; Daoud, Farah; Dossou, Edem; Estep, Kara; Flaxman, Abraham; Friedman, Joseph; Frostad, Joseph; Futran, Neal D.; Godwin, William W.; Hancock, Jamie; Kasaeian, Amir; Kemmer, Laura; Khalil, Ibrahim A.; Lindsay, M. Patrice; Liu, Patrick Y.; Masiye, Felix; Mirarefin, Mojde; Misganaw, Awoke; Moradi-Lakeh, Maziar; Morgan, Katherine; Ng, Marie; Quame-Amaglo, Justice; Rao, Puja; Reitsma, Marissa B.; Shackelford, Katya A.; Sur, Patrick; Wagner, Joseph A.; Vos, Theo; Lopez, Alan D.; Murray, Christopher J. L.] Inst Hlth Metr & Evaluat, Seattle, WA USA. 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A.; Langan, Sinead M.; Mckee, Martin; Satyanarayana Murthy, Gudlavalleti Venkata; Pearce, Neil; Roberts, Bayard] London Sch Hyg & Trop Med, London, England. [Lozano, Rafael; Campos-Novato, Ismael Ricardo; Campuzano, Julio Cesar; Gomez-Dantes, Hector; Heredia-Pi, Ileana Beatriz; Mena-Rodriguez, Fabiola; Montanez Hernandez, Julio Cesar; Montero, Pablo; Blancas, Maria Jesus Rios; Servan-Mori, Edson E.; Villalpando, Salvador] Natl Inst Publ Hlth, Cuernavaca, Morelos, Mexico. [Duan, Leilei; Liu, Shiwei; Wang, Linhong] Natl Ctr Chron & Noncommunicable Dis Control & Pr, Beijing, Peoples R China. [Liang, Xiaofeng; Yu, Shicheng] Chinese Ctr Dis Control, Beijing, Peoples R China. [Mensah, George A.] NHLBI, NIH, Ctr Translat Res & Implementat Sci, Bethesda, MD USA. [Salomon, Joshua A.] Dept Global Hlth & Populat, Boston, MA USA. [Al-Raddadi, Rajaa; Barnighausen, Till; Campos-Novato, Ismael Ricardo; Ding, Eric L.; Farvid, Maryam S.; Wagner, Gregory R.] Harvard T H Chan Sch Publ Hlth, Boston, MA USA. [James, Peter] Channing Div Network Med, Dept Epidemiol, Boston, MA USA. [James, Peter] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Osman, Majdi; Shrime, Mark G.] Harvard Med Sch, Boston, MA USA. [Fitchett, Joseph R. A.] Harvard Univ, Boston, MA 02115 USA. [Vollset, Stein Emil; Knudsen, Ann Kristin] Ctr Dis Burden, Oslo, Norway. [Krog, Norun Hjertager; Savic, Miloje] Norwegian Inst Publ Hlth, Oslo, Norway. [Vollset, Stein Emil; Knudsen, Ann Kristin] Dept Global Publ Hlth & Primary Care, Jimma, Ethiopia. [Hailu, Alemayehu Desalegne; Norheim, Ole F.] Univ Bergen, Bergen, Norway. [Abate, Kalkidan Hassen; Gebrehiwot, Tsegaye Tsewelde; Gebremedhin, Amanuel Tesfay] Jimma Univ, Jimma, Ethiopia. [Abbafati, Cristiana] Univ Roma La Sapienza, Rome, Italy. [Abbas, Kaja M.] Virginia Tech, Blacksburg, VA USA. [Abd-Allah, Foad] Cairo Univ, Dept Neurol, Cairo, Egypt. [Abera, Semaw Ferede] Sch Publ Hlth, Coll Hlth Sci, Mekelle, Ethiopia. [Melaku, Yohannes Adama] Sch Publ Hlth, Mekelle, Ethiopia. [Tesfay, Fisaha Haile] Coll Hlth Sci, Mekelle, Ethiopia. [Abyu, Gebre Yitayih; Aregay, Atsede Fantahun; Betsu, Balem Demtsu; Gebru, Alemseged Aregay; Hailu, Gessessew Bugssa; Yalew, Ayalnesh Zemene; Yebyo, Henock Gebremedhin] Mekelle Univ, Mekelle, Ethiopia. [Abera, Semaw Ferede] Kilte AwlaeloHealth & Demog Surveillance Site, Mekelle, Ethiopia. [Abera, Semaw Ferede] Univ Hohenheim, Food Secur & Inst Biol Chem & Nutr, Stuttgart, Germany. [Abera, Semaw Ferede; Franca, Elisabeth Barboza] Univ Fed Minas Gerais, Belo Horizonte, MG, Brazil. [Abu-Raddad, Laith J.] Weill Cornell Med Coll Qatar, Infect Dis Epidemiol Grp, Doha, Qatar. [Adelekan, Ademola Lukman] Publ Hlth Promot Alliance, Osogbo, Nigeria. [Adelekan, Ademola Lukman; Akinyemi, Rufus Olusola; Ojelabi, Foluke Adetola] Univ Ibadan, Ibadan, Nigeria. [Ademi, Zanfina] Univ Basel, Basel, Switzerland. [Azzopardi, Peter] Dept Paediat, Melbourne, Vic, Australia. [Cowie, Benjamin C.; Gibney, Katherine B.; MacLachlan, Jennifer H.] Peter Doherty Inst Infect & Immun, Melbourne, Vic, Australia. [Meretoja, Atte] Dept Med, Melbourne, Vic, Australia. [Alam, Khurshid; Azzopardi, Peter; Borschmann, Rohan; Colquhoun, Samantha M.; Patton, George C.; Weintraub, Robert G.] Murdoch Childrens Res Inst, Melbourne, Vic, Australia. [Szoeke, Cassandra E. I.] Inst Hlth & Ageing, Melbourne, Vic, Australia. [Vijayakumar, Lakshmi] Ctr Youth Mental Hlth, Melbourne, Vic, Australia. [Lopez, Alan D.] Melbourne Sch Populat & Global Hlth, Melbourne, Vic, Australia. [Ademi, Zanfina; Alam, Noore K. M.; Bohensky, Megan A.; Borschmann, Rohan; Colquhoun, Samantha M.; Taylor, Hugh R.; Weintraub, Robert G.; Wijeratne, Tissa] Univ Melbourne, Melbourne, Vic, Australia. [Adou, Arsene Kouablan] Assoc Ivoirienne Bienetre Familial, Abidjan, Cote Ivoire. [Adsuar, Jose C.] Univ Extremadura, Caceres, Spain. [Afanvi, Kossivi Agbelenko] Direct Dist Sanitaire Haho, Notse, Togo. [Afanvi, Kossivi Agbelenko] Univ Lome, Fac Sci Sante, Lome, Togo. [Agardh, Emilie Elisabet] Inst Publ Hlth Sci, Stockholm, Sweden. [Akseer, Nadia; Rehm, Jurgen] Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [Badawi, Alaa] Fac Med, Dept Nutrit Sci, Toronto, ON, Canada. [Lindsay, M. Patrice] Inst Hlth Policy Management & Evaluat, Toronto, ON, Canada. [Popova, Svetlana] Ctr Addict & Mental Hlth, Toronto, ON, Canada. [Agarwal, Arnav] Univ Toronto, Toronto, ON, Canada. [Agarwal, Arnav] McMaster Univ, Hamilton, ON, Canada. [Agarwal, Arnav] SIR Inst Genom & Integrat Biol, Delhi, India. [Agarwal, Arnav] Baylor Coll Med, Dept Internal Med, Houston, TX USA. [Hotez, Peter J.] Baylor Coll Med, Houston, TX USA. [Kiadaliri, Aliasghar Ahmad] Lund Univ, Orthoped Clin Epidemiol Unit, Dept Clin Sci Lund, Lund, Sweden. [Norrving, Bo] Lund Univ, Dept Clin Sci Lund, Skane Univ Hosp, Lund, Sweden. [Kiadaliri, Aliasghar Ahmad] Kerman Univ Med Sci, Inst Futures Studies Hlth, Hlth Serv Management Res Ctr, Kerman, Iran. [Ajala, Oluremi N.] Univ Pittsburgh, Med Ctr, McKeesport, PA USA. [Akanda, All Shafqat] Univ Rhode Isl, Kingston, RI USA. [Akinyemi, Rufus Olusola] Newcastle Univ, Newcastle Upon Tyne, Tyne & Wear, England. [Akinyemiju, Tomi F.] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL USA. [Schwebel, David C.; Singh, Jasvinder A.] Univ Alabama Birmingham, Birmingham, AL USA. [Al Lami, Faris Hasan] Baghdad Coll Med, Baghdad, Iraq. [Alabed, Samer] Univ Sheffield, Sheffield, S Yorkshire, England. [Al-Aly, Ziyad] Washington Univ, St Louis, MO USA. [Driscoll, Tim R.] Sydney Sch Publ Hlth, Sydney, NSW, Australia. [Alam, Khurshid; Kemp, Andrew Haddon; Leigh, James; Mekonnen, Alemayehu B.] Univ Sydney, Sydney, NSW, Australia. [Alam, Noore K. M.] Queensland Hlth, Herston, Qld, Australia. [Alasfoor, Deena] Minist Hlth, Al Khuwair, Oman. [Aldhahri, Saleh Fahed; Altirkawi, Khalid A.] King Saud Univ, Riyadh, Saudi Arabia. [Terkawi, Abdullah Sulieman] King Fahad Med City, Dept Anesthesiol, Riyadh, Saudi Arabia. [Aldhahri, Saleh Fahed] King Fahad Med City, Riyadh, Saudi Arabia. [Aldridge, Robert William] UCL, Inst Hlth Informat, Ctr Publ Hlth Data Sci, London, England. [Aldridge, Robert William; Banerjee, Amitava] UCL, Farr Inst Hlth Informat Res, London, England. [Aldridge, Robert William] UCL, Inst Global Hlth, London, England. [Tillmann, Taavi] UCL, Dept Epidemiol & Publ Hlth, London, England. [Alegretti, Miguel Angel] Fac Med, Dept Prevent & Social Med, Montevideo, Uruguay. [Aleman, Alicia V.] Sch Med, Montevideo, Uruguay. [Cavalleri, Fiorella] Fac Med, Montevideo, Uruguay. [Colistro, Valentina] Univ Republ Montevideo, Montevideo, Uruguay. [Alemu, Zewdie Aderaw] Debre Markos Univ, Debre, Markos, Ethiopia. [Alhabib, Samia] King Abdullah Bin Abdulaziz Univ Hosp, Riyadh, Saudi Arabia. [Alkerwi, Ala'a] Luxembourg Inst Hlth, Luxembourg, Luxembourg. [Alla, Francois] Univ Lorraine, Sch Publ Hlth, Nancy, France. [Allebeck, Peter] Dept Publ Hlth Sci, Stockholm, Sweden. [Carrero, Juan Jesus] Dept Clin Sci Intervent & Technol, Stockholm, Sweden. [Fereshtehnejad, Seyed-Mohammad] Dept Neurobiol Care Sci & Soc, Stockholm, Sweden. [Weiderpass, Elisabete] Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Havmoeller, Rasmus] Karolinska Inst, Stockholm, Sweden. [Al-Raddadi, Rajaa] Minist Hlth, Jeddah, Saudi Arabia. [Alsharif, Ubai] Charite, Berlin, Germany. [Martin, Elena Alvarez] Minist Hlth Social Policy & Equal, Spanish Observ Drugs Govt Delegat Natl Plan Drugs, Madrid, Spain. [Alvis-Guzman, Nelson] Univ Cartagena, Cartagena Indias, Colombia. [Amare, Azmeraw T.; Melaku, Yohannes Adama] Sch Med, Adelaide, SA, Australia. [Ciobanu, Liliana G.; Tessema, Gizachew Assefa] Univ Adelaide, Adelaide, SA, Australia. [Amare, Azmeraw T.] Bahir Dar Univ, Coll Med & Hlth Sci, Bahir Dar, Ethiopia. [Amegah, Adeladza Kofi; Kudom, Andreas A.] Univ Cape Coast, Cape Coast, Ghana. [Ameh, Emmanuel A.] Natl Hosp, Abuja, Nigeria. [Amini, Heresh] Kurdistan Univ Med Sci, Environm Hlth Res Ctr, Sanandaj, Iran. [Amini, Heresh] Dept Epidemiol & Publ Hlth, Basel, Switzerland. [Karema, Corine Kakizi] Swiss Trop & Publ Hlth Inst, Basel, Switzerland. [Ammar, Walid; Harb, Hilda L.] Minist Publ Hlth, Beirut, Lebanon. [Amrock, Stephen Marc] Oregon Hlth & Sci Univ, Portland, OR USA. [Andersen, Hjalte H.] Aalborg Univ, Fac Med, Dept Hlth Sci & Technol, Ctr Sensory Motor Interact, Aalborg, Denmark. [Antonio, Carl Abelardo T.] Univ Philippines, Coll Publ Hlth, Dept Hlth Policy & Adm, Manila, Philippines. Univ Philippines, Coll Publ Hlth, Manila, Philippines. [Arnlov, Johan; Larsson, Anders] Uppsala Univ, Dept Med Sci, Uppsala, Sweden. [Arnlov, Johan] Dalarna Univ, Falun, Sweden. [Arsenijevic, Valentina S. Arsic] Univ Belgrade, Inst Microbiol & Immunol, Sch Med, Belgrade, Serbia. [Barac, Aleksandra] Univ Belgrade, Fac Med, Belgrade, Serbia. [Arsenijevic, Valentina S. Arsic] Univ Children Hosp, Belgrade, Serbia. [Al Artaman] Univ Manitoba, Winnipeg, MB, Canada. [Asayesh, Hamid] Qom Univ Med Sci, Sch Paramed, Dept Emergency Med, Qom, Iran. [Asghar, Rana Jawad] South Asian Publ Hlth Forum, Islamabad, Pakistan. [Atique, Suleman] Taipei Med Univ, Grad Inst Biomed Informat, Taipei, Taiwan. [Arthur Avokpaho, Euripide Frinel G.] Inst Rech Clin Benin, Cotonou, Benin. [Arthur Avokpaho, Euripide Frinel G.; Gankpe, Fortune Gbetoho] Lab Etud & Rech Act & Sante, Parakou, Benin. [Awasthi, Ashish] Sanjay Gandhi Postgrad Inst Med Sci, Lucknow, Uttar Pradesh, India. [Azzopardi, Peter] South Australian Hlth & Med Res Inst, Wardliparingga Aboriginal Res Unit, Adelaide, SA, Australia. [Bacha, Umar] Univ Management & Technol, Sch Hlth Sci, Lahore, Pakistan. [Badawi, Alaa] Publ Hlth Agcy Canada, Toronto, ON, Canada. [Bahit, Maria C.] INECO Neurociencias, Rosario, Argentina. [Balakrishnan, Kalpana] Sri Ramachandra Univ, Dept Environm Hlth Engn, Chennai, Tamil Nadu, India. [Barker-Collo, Suzanne L.] Univ Auckland, Sch Psychol, Auckland, New Zealand. [Barnighausen, Till] Africa Hlth Res Inst, Mtubatuba, South Africa. [Barnighausen, Till; Mohammed, Shafiu] Heidelberg Univ, Inst Publ Hlth, Heidelberg, Germany. [Barregard, Lars] Univ Gothenburg, Dept Occupat & Environm Hlth, Gothenburg, Sweden. [Petzold, Max] Univ Gothenburg, Hlth Metr Unit, Gothenburg, Sweden. [Barrero, Lope H.] Pontificia Univ Javeriana, Sch Engn, Dept Ind Engn, Bogota, Colombia. [Basu, Arindam] Univ Canterbury, Sch Hlth Sci, Christchurch, New Zealand. [Basu, Sanjay] Stanford Univ, Stanford, CA USA. [Bayou, Yibeltal Tebekaw] Jhpiego Ethiopia, Addis Ababa, Ethiopia. [Bazargan-Hejazi, Shahrzad] Charles R Drew Univ Med & Sci, Coll Med, Los Angeles, CA USA. [Bazargan-Hejazi, Shahrzad] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Bazargan-Hejazi, Shahrzad] Kermanshah Univ Med Sci, Kermanshah, Iran. [Beardsley, Justin] Univ Oxford, Ho Chi Minh City, Vietnam. [Bedi, Neeraj] Coll Publ Hlth & Trop Med, Jazan, Saudi Arabia. [Beghi, Ettore] IRCCS Ist Ric Farmacol Mario Negri, Milan, Italy. [Deribe, Kebede; Hailu, Alemayehu Desalegne] Univ Addis Ababa, Sch Publ Hlth, Addis Ababa, Ethiopia. [Belay, Haileeyesus Adamu; Giref, Ababi Zergaw; Haile, Demewoz; Jibat, Tariku; Ayele Manamo, Wondimu Ayele; Tefera, Worku Mekonnen; Yirsaw, Biruck Desalegn] Univ Addis Ababa, Addis Ababa, Ethiopia. [Sheth, Kevin N.] Yale Univ, Sch Med, New Haven, CT USA. [Bell, Michelle L.; Biroscak, Brian J.] Yale Univ, New Haven, CT USA. [Bello, Aminu K.] Univ Alberta, Edmonton, AB, Canada. [Santos, Itamar S.] Univ Sao Paulo, Dept Internal Med, Sao Paulo, Brazil. [Bensenor, Isabela M.; Lotufo, Paulo A.] Univ Sao Paulo, Sao Paulo, Brazil. [Berhane, Adugnaw] Debre Berhane Univ, Debre Berhan, Ethiopia. [Wolfe, Charles D. A.] Div Hlth & Social Care Res, London, England. [Bernabe, Eduardo] Kings Coll London, London, England. [Beyene, Addisu Shunu; Gishu, Melkamu Dedefo] Haramaya Univ, Harar, Ethiopia. [Bhala, Neeraj] Queen Elizabeth Hosp Birmingham, Birmingham, W Midlands, England. [Bhala, Neeraj] Univ Otago, Sch Med, Wellington, New Zealand. [Bhalla, Ashish] Postgrad Inst Med Educ & Res, Chandigarh, India. [Biadgilign, Sibhatu] Independent Publ Hlth Consultants, Addis Ababa, Ethiopia. [Bikbov, Boris] Acad V I Shumakov Fed Res, Ctr Transplantol & Artificial Organs, Dept Nephrol Issues Transplanted Kidney, Moscow, Russia. [Bin Abdulhak, Aref A.] Univ Iowa, Hosp & Clin, Iowa City, IA USA. [Biroscak, Brian J.] Univ S Florida, Tampa, FL USA. [Bjertness, Espen] Univ Oslo, Dept Community Med, Oslo, Norway. [Htet, Aung Soe] Univ Oslo, Oslo, Norway. [Bose, Dipan] World Bank, Washington, DC USA. [Bourne, Rupert R. A.] Anglia Ruskin Univ, Vision & Eye Res Unit, Cambridge, England. [Brainin, Michael] Danube Univ Krems, Krems, Austria. [Brayne, Carol E. G.] Cambridge Inst Publ Hlth, Cambridge, England. [Brazinova, Alexandra; Majdan, Marek] Trnava Univ, Dept Publ Hlth, Fac Hlth Sci & Social Work, Trnava, Slovakia. [Brazinova, Alexandra] Int Neurotrama Res Org, Vienna, Austria. [Shen, Jiabin] Ohio State Univ, Coll Med, Columbus, OH 43210 USA. [Breitborde, Nicholas J. K.] Ohio State Univ, Columbus, OH 43210 USA. [Brenner, Hermann; Schottker, Ben] German Canc Res Ctr, Heidelberg, Germany. [Brewer, Jerry D.] Mayo Clin, Rochester, MN USA. [Brugha, Traolach S.] Univ Leicester, Leicester, Leics, England. [Buckle, Geoffrey Colin; Gosselin, Richard A.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Butt, Zahid A.] Shifa Trust Eye Hosp, Rawalpindi, Pakistan. [Calabria, Bianca; Lal, Aparna; Lucas, Robyn M.] Australian Natl Univ, Natl Ctr Epidemiol & Populat Hlth, Canberra, ACT, Australia. [Degenhardt, Louisa] Natl Drug & Alcohol Res Ctr, Sydney, NSW, Australia. [Resnikofff, Serge] Brien Holden Vis Inst, Sydney, NSW, Australia. [Resnikofff, Serge] Sch Optometry & Vis Sci, Sydney, NSW, Australia. [Calabria, Bianca] Univ New South Wales, Sydney, NSW, Australia. [Carapetis, Jonathan R.] Univ Western Australia, Princess Margaret Hosp Children, Telethon Kids Inst, Subiaco, WA, Australia. [Cardenas, Rosario] Metropolitan Autonomous Univ, Mexico City, DF, Mexico. [Carpenter, David] SUNY Albany, Rensselaer, NY 12144 USA. [Castaneda-Oquela, Carlos A.] Colombian Natl Hlth Observ, Inst Nacl Salud, Bogota, Colombia. [Castaneda-Oquela, Carlos A.] Univ Nacl Colombia, Dept Publ Hlth, Epidemiol & Publ Hlth Evaluat Grp, Bogota, Colombia. [Rivas, Jacqueline Castillo] Caja Costarricense Seguro Social, San Jose, Costa Rica. [Rivas, Jacqueline Castillo] Univ Costa Rica, San Pedro, Montes Oca, Costa Rica. [Catala-Lopez, Ferran] Univ Valencia, INCLIVA Hlth Res Inst & CIBERSAM, Dept Med, Valencia, Spain. [Catala-Lopez, Ferran] Ottawa Hosp Res Inst, Clin Epidemiol Program, Ottawa, ON, Canada. [Cerda, Jorge] Albany Med Coll, Albany, NY 12208 USA. [Chen, Wanqing] Chinese Acad Med Sci, Inst Canc, Beijing, Peoples R China. [Chiang, Peggy Pei -Chia] Gold Coast Hlth, Clin Governance Unit, Southport, Qld, Australia. [Chibalabala, Mirriam] Crowd Watch Afr, Lusaka, Zambia. [Chibueze, Chioma Ezinne; Mori, Rintaro] Natl Ctr Child Hlth & Dev, Tokyo, Japan. [Chimed-Ochir, Odgerel] Univ Occupat & Environm Hlth, Dept Environm Epidemiol, Kitakyushu, Fukuoka, Japan. [Jiang, Ying] Univ Occupat & Environm Hlth, Dept Hlth Dev, Inst Ind Ecol Sci, Kitakyushu, Fukuoka, Japan. [Takahashi, Ken] Univ Occupat & Environm Hlth, Inst Ind Ecol Sci, Dept Environm Epidemiol, Kitakyushu, Fukuoka, Japan. [Chisumpa, Vesper Hichilombwe; Mapoma, Chabila C.; Masiye, Felix] Univ Zambia, Lusaka, Zambia. [Chisumpa, Vesper Hichilombwe] Univ Witwatersrand, Johannesburg, South Africa. [Choi, Jee-Young Jasmine] Seoul Natl Univ Med Lib, Seoul, South Korea. [Chowdhury, Rajiv] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Christensen, Hanne] Bispebjerg Hosp, Copenhagen, Denmark. [Christopher, Devasahayam Jesudas] Christian Med Coll & Hosp, Vellore, Tamil Nadu, India. [Cirillo, Massimo] Univ Salerno, Baronissi, Italy. [Cohen, Aaron J.] Hlth Effects Inst, Boston, MA USA. [Colistro, Valentina] Minist Salud Publ, Montevideo, Uruguay. [Colomar, Mercedes] UNICEM, Montevideo, Uruguay. [Cooper, Cyrus] Univ Southampton, MRC Lifecourse Epidemiol Unit, Southampton, Hants, England. [Cooper, Cyrus] Univ Southampton, NIHR Biomed Res Ctr, Southampton, Hants, England. [Cooper, Cyrus] Univ Hosp Southampton NHS Fdn Trust, Southampton, Hants, England. [Cooper, Leslie Trumbull] Mayo Clin, Jacksonville, FL 32224 USA. [Cortinovis, Monica; Giussani, Giorgia] Mario Negri Inst Pharmacol Res, Milan, Italy. [Cowie, Benjamin C.] WHO, Collaborating Ctr Viral Hepatitis, Victorian Infect Dis Reference Lab Melbourne, Melbourne, Vic, Australia. [Crump, John A.] Dunedin Sch Med, Ctr Int Hlth, Dunedin, New Zealand. [Poulton, Richie G.] Univ Otago, Dunedin, New Zealand. [Damsere-Derry, James] Bldg & Rd Res Inst, Kumasi, Ghana. [Danawi, Hadi; Refaat, Amany H.] Walden Univ, Minneapolis, MN USA. [Dargan, Paul I.] Guys & St Thomas NHS Fdn Trust, London, England. [das Neves, Jose] Univ Porto, Inst Invest & Inovacao Saude I3S, Oporto, Portugal. [das Neves, Jose] Univ Porto, INEB, Oporto, Portugal. [Massano, Joao] Univ Porto, Fac Med, Oporto, Portugal. [Pedro, Joao Mario] Univ Porto, EPIUnit, Oporto, Portugal. [Davey, Gail] Wellcome Trust Brighton & Sussex, Ctr Global Hlth Res, Brighton, E Sussex, England. [Davis, Adrian C.; Greaves, Felix; Newton, John N.] Publ Hlth England, London, England. [Davitoiu, Dragos V.] Univ Med Pharm Bucharest, Bucharest, Romania. [de Castro, E. Filipa] Natl Inst Publ Hlth, Mexico City, DF, Mexico. [de Jager, Pieter] Univ Witwatersrand, Sch Publ Hlth, Johannesburg, South Africa. [Petzold, Max] Univ Witwatersrand, Johannesburg, South Africa. [de Jager, Pieter] Natl Inst Occupat Hlth, Natl Hlth Lab Serv, Johannesburg, South Africa. [De Leo, Diego] Griffith Univ, Brisbane, Qld, Australia. [Dellavalle, Robert P.] Univ Colorado, Sch Med, Aurora, CO USA. [Dellavalle, Robert P.] Univ Colorado, Colorado Sch Publ Hlth, Aurora, CO USA. [Deribe, Kebede] Brighton & Sussex Med Sch, Brighton, E Sussex, England. [Deribew, Amare] KEMRI Wellcome Trust Res Programme, Kilifi, Kenya. [Dharmaratne, Samath D.] Univ Peradeniya, Fac Med, Dept Community Med, Peradeniya, Sri Lanka. [Jeemon, Panniyammakal] Ctr Control Chron Condit, Gurgaon, India. [Dhillon, Preet K.; Ganguly, Parthasarathi; Zodpey, Sanjay] Publ Hlth Fdn India, Gurgaon, India. [Diaz-Torne, Cesar] Hosp Santa Creu i Sant Pau, Barcelona, Spain. [dos Santos, Kadine Priscila Bender] Univ Estado Santa Catarina, Florianopolis, SC, Brazil. [Dubey, Manisha; Rahman, Mohammad Hifz Ur; Singh, Abhishek] Int Inst Populat Sci, Mumbai, Maharashtra, India. [Kieling, Christian; Schmidt, Maria Ines] Univ Fed Rio Grande do Sul, Porto Alegre, RS, Brazil. [Bell, Brent] Univ N Carolina, Chapel Hill, NC USA. [Elyazar, Iqbal] Eijkman Oxford Clin Res Unit, Jakarta, Indonesia. [Endries, Aman Yesuf] Arba Minch Univ, Arba Minch, Ethiopia. [Ermakov, Sergey Petrovich] Russian Acad Sci, Inst Social & Econ Studies Populat, Moscow, Russia. [Ermakov, Sergey Petrovich] Russian Federat, Fed Res Inst Hlth Org & Informat, Minist Hlth, Moscow, Russia. [Eshrati, Babak] Minist Hlth & Med Educ, Tehran, Iran. [Eshrati, Babak] Arak Univ Med Sci, Arak, Iran. [Esteghamati, Alireza; Hafezi-Nejad, Nima] Univ Tehran Med Sci, Endocrinol & Metab Res Ctr, Tehran, Iran. [Fahimi, Saman; Malekzadeh, Reza; Roshandel, Gholamreza; Sepanlou, Sadaf G.] Univ Tehran Med Sci, Digest Dis Res Inst, Tehran, Iran. [Farzadfar, Farshad; Kasaeian, Amir; Parsaeian, Mahboubeh] Univ Tehran Med Sci, Non Communicable Dis Res Ctr, Endocrinol & Metab Populat Sci Inst, Tehran, Iran. [Heydarpour, Pouria] Univ Tehran Med Sci, Multiple Sclerosis Res Ctr, Neuroscience Inst, Tehran, Iran. [Kasaeian, Amir] Univ Tehran Med Sci, Hematol Oncol & Stem Cell Transplantat Res Ctr, Tehran, Iran. [Parsaeian, Mahboubeh] Univ Tehran Med Sci, Dept Epidemiol & Biostat, Sch Publ Hlth, Tehran, Iran. [Rahimi-Movaghar, Vafa] Univ Tehran Med Sci, Sina Trauma & Surg Res Ctr, Tehran, Iran. [Sheikhbahaei, Sara] Univ Tehran Med Sci, Endocrinol & Metab Res Ctr, Tehran, Iran. [Kuipers, Ernst J.] Dept Hlth, Manila, Philippines. [Farid, Talha A.; Khan, Abdur Rahman] Univ Louisville, Louisville, KY 40292 USA. [Sa Farinha, Carla Sofia e] DGS Directorate Gen Hlth, Lisbon, Portugal. [Sa Farinha, Carla Sofia e] Univ Aberta, Lisbon, Portugal. [Faro, Andre] Univ Fed Sergipe, Aracaju, Brazil. [Farvid, Maryam S.] Massachusetts Gen Hosp, Harvard MGH Ctr Genom, Mongan Inst Hlth Policy, Vulnerable Populat, Boston, MA 02114 USA. [Feigin, Valery L.] Natl Inst Stroke & Appl Neurosci, Auckland, New Zealand. [Ao, Braden J. Te] Auckland Univ Technol, Auckland, New Zealand. [Fernandes, Jefferson G.] German Hosp Oswaldo Cruz, Inst Sci Educ, Sao Paulo, Brazil. [Fernandes, Joao C.] Queen Mary Univ London, Ctr Expt Med & Rheumatol, William Harvey Res Inst, Barts & London Sch Med & Dent, London, England. [Fischer, Florian] Univ Bielefeld, Bielefeld, Germany. [Foigt, Nataliya] Acad Med Sci, Inst Gerontol, Kiev, Ukraine. [Shiue, Ivy] Alzheimer Scotland Dementia Res Ctr, Edinburgh, Midlothian, Scotland. [Fowkes, F. Gerry R.] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Franklin, Richard C.] James Cook Univ, Townsville, Qld, Australia. [Futran, Neal D.] Imperial Coll London, Dept Infect Dis Epidemiol, London, England. [Piel, Frederic B.] Imperial Coll London, Dept Epidemiol & Biostat, London, England. [Greaves, Felix; Majeed, Azeem] Imperial Coll London, London, England. [Gall, Seana L.] Univ Tasmania, Hobart, Tas, Australia. [Gambashidze, Ketevan; Gamkrelidze, Amiran; Kereselidze, Maia; Shakh-Nazarova, Marina] Natl Ctr Dis Control & Publ Hlth, Tbilisi, Rep of Georgia. [Ganguly, Parthasarathi; Iyer, Veena J.] Indian Inst Publ Hlth Gandhinagar, Ahmadabad, Gujarat, India. [Gankpe, Fortune Gbetoho] CHU Hassan II, Fes, Morocco. [Gebre, Teshome] Task Force Global Hlth, Decatur, GA USA. [Gebremedhin, Amanuel Tesfay] Ludwig Maximilians Univ Munchen, Munich, Germany. [Gebru, Alemseged Aregay; Hailu, Alemayehu Desalegne] Kilte Awlaelo Hlth & Demog Surveillance Syst, Mekelle, Ethiopia. [Geleijnse, Johanna M.] Wageningen Univ, Div Human Nutr, Wageningen, Netherlands. [Jibat, Tariku] Wageningen Univ, Wageningen, Netherlands. [Gessner, Bradford D.] Agence Med Prevent, Paris, France. [Ghoshal, Aloke Gopal] Natl Allergy Asthma Bronchitis Inst, Kolkata, India. [Gibney, Katherine B.] Royal Melbourne Hosp, Melbourne, Vic, Australia. [Gillum, Richard F.; Mehari, Alem] Howard Univ, Coll Med, Washington, DC 20059 USA. [Gilmour, Stuart; Inoue, Manami] Univ Tokyo, Grad Sch Med, Tokyo, Japan. [Kawakami, Norito] Univ Tokyo, Sch Publ Hlth, Tokyo, Japan. [Shibuya, Kenji] Univ Tokyo, Tokyo, Japan. [Giroud, Maurice] Univ Hosp Dijon, Dijon, France. [Gishu, Melkamu Dedefo] Kersa Hlth & Demog Surveillance Syst, Harar, Ethiopia. [Glaser, Elizabeth] Brandeis Univ, Heller Sch Social Policy & Management, Waltham, MA USA. [Halasa, Yara A.; Shepard, Donald S.; Undurraga, Eduardo A.] Brandeis Univ, Waltham, MA USA. [Gona, Philimon] Univ Massachusetts, Boston, MA USA. [Goodridge, Amador] Inst Invest Cient & Serv Alta Tecnol INDICASAT AI, Ciudad Del Saber, Panama. [Gopalani, Sameer Vali] Govt Federated States Micronesia, Dept Hlth & Social Affairs, Palikir, Micronesia. [Gotay, Carolyn C.; Kissoon, Niranjan; Kopec, Jacek A.; Murthy, Srinivas; Pourmalek, Farshad] Univ British Columbia, Vancouver, BC, Canada. [Goto, Atsushi] Ctr Publ Hlth Sci, Div Epidemiol, Tokyo, Japan. [Inoue, Manami] Natl Canc Ctr, Tokyo, Japan. [Gugnani, Harish Chander] Dept St James Sch Med, Dept Microbiol, The Quarter, Anguilla, England. [Gugnani, Harish Chander] Dept St James Sch Med, Dept Epidemiol & Biostat, The Quarter, Anguilla, England. [Gupta, Rajeev] West Virginia Bur Publ Hlth, Charleston, WV USA. [Gupta, Rajeev] Eternal Heart Care Ctr & Res Inst, Jaipur, Rajasthan, India. [Gupta, Vipin] Univ Delhi, Dept Anthropol, Delhi, India. [Gutierrez, Reyna A.] Natl Inst Psychiat Ramon Fuente, Mexico City, DF, Mexico. [Hamadeh, Randah Ribhi] Arabian Gulf Univ, Manama, Bahrain. [Hamidi, Samer] Hamdan Bin Mohammed Smart Univ, Dubai, U Arab Emirates. [Handal, Alexis J.] Univ New Mexico, Albuquerque, NM 87131 USA. [Hankey, Graeme J.] Univ Western Australia, Sch Med & Pharmacol, Fremantle, WA, Australia. [Norman, Paul E.] Univ Western Australia, Fremantle, WA, Australia. [Hankey, Graeme J.] Harry Perkins Inst Med Res, Nedlands, WA, Australia. [Hankey, Graeme J.] Western Australian Neurosci Res Inst, Nedlands, WA, Australia. [Hao, Yuantao] Sun Yat Sen Univ, Sch Publ Hlth, Guangzhou, Guangdong, Peoples R China. [Harikrishnan, Sivadasanpillai] Sree Chitra Tirunal Inst Med Sci & Technol, Trivandrum, Kerala, India. [Haro, Josep Maria] Parc Sanitari Sant Joan Deu CIBERSAM, Barcelona, Spain. [Haro, Josep Maria] Univ Barcelona, Barcelona, Spain. [Hilderink, Henk B. M.] Natl Inst Publ Hlth & Environm RIVM, Bilthoven, Netherlands. [Hoek, Hans W.] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands. [Tura, Abera Kenay] Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands. [Hoek, Hans W.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. [Hogg, Robert S.] Simon Fraser Univ, Burnaby, BC, Canada. [Hogg, Robert S.] BC Ctr Excellence HIV AIDS, Vancouver, BC, Canada. [Horino, Masako] Nevada Div Publ & Behav Hlth, Dept Hlth & Human Serv, Carson City, NV USA. [Horita, Nobuyuki] Yokohama City Univ Grad Sch Med, Dept Pulmonol, Yokohama, Kanagawa, Japan. [Hosgood, H. Dean] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Hoy, Damian G.] Pacific Commun, Publ Hlth Div, Noumea, New Caledonia. [Hsairi, Mohamed] Salah Azaiz Inst, Dept Epidemiol, Tunis, Tunisia. [Htet, Aung Soe] Minist Hlth, Int Relat Div, Nay Pyi Taw, Myanmar. [Than Htike, Maung Maung] Minist Hlth, Nay Pyi Taw, Myanmar. [Hu, Guoqing] Cent S Univ, Dept Epidemiol & Hlth Stat, Sch Publ Hlth, Changsha, Hunan, Peoples R China. [Huang, Cheng] George Washington Univ, Washington, DC USA. [Huang, Hsiang] Cambridge Hlth Alliance, Cambridge, MA USA. [Huiart, Laetitia] CHU Reunion, St Denis, France. [Husseini, Abdullatif] Birzeit Univ, Birzeit, Israel. [Huybrechts, Inge] IARC, Lyon, France. [Huybrechts, Inge] Univ Ghent, Ghent, Belgium. [Huynh, Grace] Inst Dis Modeling, Bellevue, WA USA. [Iburg, Kim Moesgaard] Aarhus Univ, Aarhus, Denmark. [Innos, Kaire] Natl Inst Hlth Dev, Tallinn, Estonia. [Jacobs, Troy A.] USAID Global Hlth Bur, MCH Div, HIDN, Washington, DC USA. [Jacobsen, Kathryn H.] George Mason Univ, Dept Global & Community Hlth, Fairfax, VA USA. [Jahanmehr, Nader] Shahid Beheshti Univ Med Sci, Sch Publ Hlth, Tehran, Iran. [Katibeh, Marzieh] Shahid Beheshti Univ Med Sci, Ophthalm Epidemiol Res Ctr, Tehran, Iran. [Rajavi, Zhale; Yaseri, Mehdi] Shahid Beheshti Univ Med Sci, Ophthalm Res Ctr, Tehran, Iran. [Jakovljevic, Mihajlo B.] Univ Kragujevac, Fac Med Sci, Kragujevac, Serbia. [Javanbakht, Mehdi] Univ Aberdeen, Aberdeen, Scotland. [Jayaraman, Sudha P.] Virginia Commonwealth Univ, Dept Surg, Richmond, VA USA. [Jayatilleke, Achala Upendra] Postgrad Inst Med, Colombo, Sri Lanka. [Jayatilleke, Achala Upendra] Inst Violence & Injury Prevent, Colombo, Sri Lanka. [Jeemon, Panniyammakal; Prabhakaran, Dorairaj] Ctr Chron Dis Control, New Delhi, India. [Jha, Vivekanand] George Inst Global Hlth India, New Delhi, India. [Jiang, Guohong] Tianjin Ctr Dis Control & Prevent, Tianjin, Tianjin, Peoples R China. [Jimenez-Corona, Aida] Inst Ophthalmol Conde Valencia, Dept Ocular Epidemiol & Visual Hlth, Mexico City, DF, Mexico. [Jimenez-Corona, Aida] Gen Directorate Epidemiol, Minist Hlth, Mexico City, DF, Mexico. [Jonas, Jost B.] Heidelberg Univ, Med Fac Mannheim, Dept Ophthalmol, Mannheim, Germany. [Joshi, Tushar Kant] Ctr Occupat & Environm Hlth, New Delhi, India. [Kabir, Zubair] Natl Univ Ireland Univ Coll Cork, Cork, Ireland. [Karnak, Ritul; Kesavachandran, Chandrasekharan Nair] CSIR Indian Inst Toxicol Res, Lucknow, Uttar Pradesh, India. [She, Jun] Zhongshan Hosp, Lucknow, Uttar Pradesh, India. [Shen, Ziyan; Zhang, Hao] Zhongshan Hosp, Dept Nephrol, Lucknow, Uttar Pradesh, India. [Kan, Haidong] Fudan Univ, Shanghai, Peoples R China. [Kant, Surya] King Georges Med Univ, Lucknow, Uttar Pradesh, India. [Karch, Andre] Epidemiol & Stat Methods Res Grp, Helmholtz Ctr Infect Res, Braunschweig, Germany. [Karch, Andre] German Ctr Infect Res, Hannover Braunschweig Site, Braunschweig, Germany. [Karema, Corine Kakizi] Qual & Equity Hlth Care, Kigali, Rwanda. [Karimkhani, Chante] Case Western Univ Hosp, Cleveland, OH USA. [Karletsos, Dimitris] Univ Pompeu Fabra, Ctr Res Hlth & Econ, Barcelona, Spain. [Karthikeyan, Ganesan; Naik, Nitish; Paul, Vinod K.; Roy, Ambuj; Sagar, Rajesh; Satpathy, Maheswar; Tandon, Nikhil] All India Inst Med Sci, New Delhi, India. [Kaul, Anil] Oklahoma State Univ, Tulsa, OK USA. [Kayibanda, Jeanne Francoise] Inst Rech Ihopital Monttfort, Ottawa, ON, Canada. [Keiyoro, Peter Njenga] Inst Trop & Infect Dis, Nairobi, Kenya. [Keiyoro, Peter Njenga] Sch Continuing & Distance Educ, Nairobi, Kenya. [Lyons, Ronan A.] Farr Inst, Swansea, W Glam, Wales. [Kemp, Andrew Haddon] Swansea Univ, Swansea, W Glam, Wales. [Parry, Charles D.] Alcohol Tobacco & Other Drug Res Unit, Cape Town, South Africa. [Kengne, Andre Pascal; Matzopoulos, Richard; Wiysonge, Charles Shey] South African Med Res Council, Cape Town, South Africa. [Matzopoulos, Richard] Univ Cape Town, Sch Publ Hlth & Family Med, Cape Town, South Africa. [Stein, Dan J.] Univ Cape Town, Dept Psychiat, Cape Town, South Africa. [Kengne, Andre Pascal; Mayosi, Bongani M.; Watkins, David A.] Univ Cape Town, Cape Town, South Africa. [Keren, Andre] Assuta Hosp, Assuta Hashalom, Tel Aviv, Israel. [Khader, Yousef Saleh] Jordan Univ Sci & Technol, Irbid, Jordan. [Khan, Ejaz Ahmad] Hlth Serv Acad, Islamabad, Pakistan. 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[Koyanagi, Ai] Parc Sanitari Sant Joan Deu CIBERSAM, Res & Dev Unit, Barcelona, Spain. [Defo, Barthelemy Kuate] Univ Montreal, Dept Demog & Publ Hlth, Res Inst, Montreal, PQ, Canada. [Defo, Barthelemy Kuate] Univ Montreal, Dept Social & Prevent Med, Sch Publ Hlth, Montreal, PQ, Canada. [Bicer, Burcu Kucuk] Hacettepe Univ, Inst Publ Hlth, Ankara, Turkey. [Kuipers, Ernst J.] Univ Med Ctr Rotterdam, Erasmus MC, Rotterdam, Netherlands. [Kulkarni, Veena S.] Arkansas State Univ, State Univ, AR USA. [Kwan, Gene F.] Boston Univ, Sch Med, Boston, MA USA. [Rao, Sowmya R.] Boston Univ, Dept Surg, Sch Med, Boston, MA USA. [Lam, Hilton] Natl Inst Hlth, Inst Hlth Policy & Dev Studies, Manila, Philippines. [Lam, Jennifer O.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Nachega, Jean B.] Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Tran, Bach Xuan] Johns Hopkins Univ, Baltimore, MD USA. [Lansingh, Van C.] Help Me See Inc, New York, NY USA. [Lansingh, Van C.] Inst Mexicano Oftalmol, Queretaro, Mexico. [Laryea, Dennis Odai] Komfo Anokye Teaching Hosp, Kumasi, Ghana. [Latif, Asma Abdul] WomenUniv, Lahore Coll, Dept Zool, Lahore, Pakistan. [Lawrynowicz, Alicia Elena Beatriz] Inst Nacl Epidemiol Dr Juan H Jara, Mar Del Plata, Argentina. [Levi, Miriam] Tuscany Reg Ctr Occupat Injuries & Dis, Florence, Italy. [Liu, Yang] San Francisco VA Med Ctr, San Francisco, CA USA. [Lindsay, M. Patrice] Heart & Stroke Fdn Canada, Ottawa, ON, Canada. [Lipshultz, Steven E.; Wilkinson, James D.] Wayne State Univ, Sch Med, Detroit, MI USA. [Lipshultz, Steven E.] Childrens Hosp Michigan, Detroit, MI USA. [Simard, Edgar P.] Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Liu, Yang; Phillips, Michael Robert; Xiao, Qingyang] Emory Univ, Atlanta, GA 30322 USA. [Lo, Loon-Tzian] UnionHlth Associates LLC, St Louis, MO USA. [Lo, Loon-Tzian] Alton Mental Hlth Ctr, Alton, IL USA. [Logroscino, Giancarlo] Univ Bari, Bari, Italy. [Lunevicius, Raimundas] Aintree Univ Hosp Natl Hlth Serv Fdn Trust, Liverpool, Merseyside, England. [Lunevicius, Raimundas] Univ Liverpool, Sch Med, Liverpool, Merseyside, England. [Ma, Stefan] Minist Hlth Singapore, Singapore, Singapore. [Ma, Stefan] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore. [Pedro Machado, Vasco Manuel] Dept Publ Hlth, No Region Hlth Adm, Oporto, Portugal. [Mackay, Mark T.; Weintraub, Robert G.] Royal Childrens Hosp, Melbourne, Vic, Australia. [Abd El Razek, Hassan Magdy] Mansoura Fac Med, Mansoura, Egypt. [Abd El Razek, Mohammed Magdy] Aswan Univ Hosp, Aswan Fac Med, Aswan, Egypt. [Mandisarisa, John] JSI Res & Training, Harare, Zimbabwe. [Mangalam, Srikanth] Tech Stand & Safety Author, Toronto, ON, Canada. [Marcenes, Wagner] Kings Coll London, Div Populat & Patient Hlth, Inst Dent, London, England. [Meaney, Peter A.] Univ Penn, Perelman Sch Med, Philadelphia, PA USA. [Margolis, David Joel; Silberberg, Donald H.] Univ Penn, Philadelphia, PA USA. [Martin, Gerard Robert] Childrens Natl Hlth Syst, Washington, DC USA. [Martinez-Raga, Jose] Univ Valencia, Univ Hosp Doctor Peset, Valencia, Spain. [Martinez-Raga, Jose] CEU Cardenal Herrera Univ, Valencia, Spain. [Marzan, Melvin Barrientos] Univ E Ramon Magsaysay Mem Med Ctr, Quezon City, Philippines. [Mason-Jones, Amanda J.] Univ York, Dept Hlth Sci, York, N Yorkshire, England. [Massano, Joao] ULS Matosinhos, Hosp Pedro Hispano, Matosinhos, Portugal. [McMahon, Brian J.] Alaska Native Tribal Hlth Consortium, Anchorage, AK USA. [Meaney, Peter A.] Childrens Hosp Philadelphia, Philadelphia, PA USA. [Mehndiratta, Man Mohan] Janakpuri Superspecialty Hosp, New Delhi, India. [Woldeyohannes, Solomon Meseret] Univ Gondar, Dept Epidemiol & Biostat, Inst Publ Hlth, Gondar, Ethiopia. [Mekonnen, Alemayehu B.; Tedla, Bemnet Amare; Zeleke, Berihun M.] Univ Gondar, Gondar, Ethiopia. [Memiah, Peter] Univ Florida, Pensacola, FL USA. [Memish, Ziad A.] Saudi Minist Hlth, Riyadh, Saudi Arabia. [Memish, Ziad A.] Alfaisal Univ, Coll Med, Riyadh, Saudi Arabia. [Mendoza, Walter] United Nations Populat Fund, Lima, Peru. [Meretoja, Atte] Helsinki Univ Hosp, Dept Neurol, Helsinki, Finland. [Meretoja, Tuomo J.] Helsinki Univ Hosp, Breast Surg Unit, Ctr Comprehens Canc, Helsinki, Finland. [Meretoja, Tuomo J.] Univ Helsinki, Helsinki, Finland. [Mhimbira, Francis Apolinary] Ifakara Hlth Inst, Bagamoyo, Tanzania. [Micha, Renata; Mozaffarian, Dariush] Friedman Sch Nutr Sci & Policy, Boston, MA USA. [Shi, Peilin; Singh, Gitanjali M.] Tufts Univ, Boston, MA 02111 USA. [Miller, Ted R.] Pacific Inst Res Evaluat, Calverton, MD USA. [Miller, Ted R.] Curtin Univ, Ctr Populat Hlth, Perth, WA, Australia. [Abdulmuhsin Mohammad, Karzan] Univ Salahaddin, Erbil, Iraq. [Mohammadi, Alireza] Baqiyatallah Univ Med Sci, Neurosci Res Ctr, Tehran, Iran. [Mohammed, Shafiu] Ahmadu Bello Univ, Hlth Syst & Policy Res Unit, Zaria, Nigeria. [Mohan, Viswanathan] Madras Diabet Res Fdn, Chennai, Tamil Nadu, India. [Mohan, Viswanathan] Dr Mohans Diabet Special Ctr, Chennai, Tamil Nadu, India. [Mola, Glen Liddell D.] Univ Papua New Guinea, Boroko, Papua N Guinea. [Monasta, Lorenzo; Montico, Marcella; Ronfani, Luca] IRCCS Burlo Garofolo, Inst Maternal & Child Hlth, Trieste, Italy. [Moradi-Lakeh, Maziar] Iran Univ Med Sci, Prevent Med & Publ Hlth Res Ctr, Gastrointestinal & Liver Dis Res Ctr, Dept Community Med, Brisbane, Qld, Australia. [Morawska, Lidia] Queensland Univ Technol, Int Lab Air Qual & Hlth, Brisbane, Qld, Australia. [Werdecker, Andrea] Competence Ctr Mortal Follow Up German Natl Cohor, Wiesbaden, Germany. [Mueller, Ulrich; Westerman, Ronny] Fed Inst Populat Res, Wiesbaden, Germany. [Satyanarayana Murthy, Gudlavalleti Venkata] Indian Inst Publ Hlth, Gurgaon, India. [Dhillon, Preet K.; Ganguly, Parthasarathi; Lal, Dharmesh Kumar; Zodpey, Sanjay] Publ Hlth Fdn India, Gurgaon, India. [Musa, Kamarul Imran] Univ Sci Malaysia, Sch Med Sci, Kubang Kerian, Malaysia. [Nachega, Jean B.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. [Caicedo, Angel J. Paternina] Univ Pittsburgh, Publ Hlth Dynam Lab, Pittsburgh, PA USA. [Parry, Charles D.] Univ Stellenbosch, Dept Psychiat, Cape Town, South Africa. [Nachega, Jean B.; Seedat, Soraya; Wiysonge, Charles Shey] Univ Stellenbosch, Cape Town, South Africa. [Nagel, Gabriele; Rothenbacher, Dietrich] Univ Ulm, Inst Epidemiol & Med Biometry, Ulm, Germany. [Naidoo, Kovin S.; Sartorius, Benn] Univ KwaZulu Natal, Durban, South Africa. [Naldi, Luigi; Remuzzi, Giuseppe] Azienda Osped Papa Giovanni XXIII, Bergamo, Italy. [Nangia, Vinay] Suraj Eye Inst, Nagpur, Maharashtra, India. [Nash, Denis] CUNY, Inst Implementat Sci Populat Hlth, Sch Publ Hlth, New York, NY USA. [Nejjari, Chakib] Fac Med, Fes, Morocco. [Neupane, Subas] Univ Tampere, Sch Hlth Sci, Tampere, Finland. [Newton, Charles R.] KEMRI Wellcome Trust, Kilifi, Kenya. [Ngalesoni, Frida Namnyak] Minist Hlth & Social Welf, Dar Es Salaam, Tanzania. [Ngirabega, Jean de Dieu] East African Community Hlth Res Commiss, Kigali, Rwanda. [Quyen Le Nguyen] Duy Tan Univ, Inst Global Hlth Innovat, Da Nang, Vietnam. [Nkamedjie Pete, Patrick Martial] Inst Res Socioecon Dev & Commun, Yaounde, Cameroon. [Nomura, Marika] Natl Inst Publ Hlth, Saitama, Japan. [Nyakarahuka, Luke] Makerere Univ, Kampala, Uganda. [Ogbo, Felix Akpojene] Univ Western Sydney, Ctr Hlth Res, Sydney, NSW, Australia. [Ohkubo, Takayoshi] Teikyo Univ, Sch Med, Tokyo, Japan. [Olivares, Pedro R.] Univ Autonoma Chile, Talca, Chile. [Olusanya, Bolajoko Olubukunola; Olusanya, Jacob Olusegun] Ctr Healthy Start Initiat, Lagos, Nigeria. [Opio, John Nelson] Lira Municipal Council, Lira Dist Local Govt, Lira, Uganda. [Oren, Eyal] Univ Arizona, Tucson, AZ USA. [Ortiz, Alberto] IIS Fdn Jimenez Diaz UAM, Madrid, Spain. [Osman, Majdi] YBank, Cambridge, MA USA. [Ota, Erika; Ozdemir, Raziye] St Lukes Int Univ, Tokyo, Japan. [Ozdemir, Raziye] Karabuk Univ, Karabuk, Turkey. [Pa, Mahesh] JSS Univ, JSS Med Coll, Mysore, Karnataka, India. [Pandian, Jeyaraj D.] Christian Med Coll Ludhiana, Ludhiana, Punjab, India. [Pant, Puspa Raj] Univ W England, Bristol, Avon, England. [Papachristou, Christina] Charite Univ Med Berlin, Berlin, Germany. [Park, Eun-Kee] Kosin Univ, Dept Med Human & Social Med, Coll Med, Busan, South Korea. [Park, Jae-Hyun] Sungkyunkwan Univ, Samsung Biomed Res Inst, Sch Med, Dept Social & Prevent Med, Suwon, South Korea. [Caicedo, Angel J. Paternina] Univ Cartagena, Cartagena, Colombia. [Patten, Scott B.] Univ Calgary, Dept Community Hlth Sci, Calgary, AB, Canada. [Tonelli, Marcello] Univ Calgary, Calgary, AB, Canada. [Pedro, Joao Mario] Hlth Res Ctr Angola, Caxito, Angola. [Stokic, Ljiljana Pejin] Inst Econ, Belgrade, Serbia. [Pereira, David M.] Univ Porto, Fac Farm, Dept Quim, Lab Farm,REQUIMTE LAQV, Oporto, Portugal. [Perico, Norberto; Remuzzi, Giuseppe] IRCCS Ist Ric Farmacol Mario Negri, Bergamo, Italy. [Pesudovs, Konrad; Tesfay, Fisaha Haile] Flinders Univ S Australia, Adelaide, SA, Australia. [Phillips, Michael Robert] Shanghai Jiao Tong Univ, Sch Med, Shanghai, Peoples R China. [Pillay, Julian David] Durban Univ Technol, Durban, South Africa. [Plass, Dietrich] German Environm Agcy, Exposure Assessment & Environm Hlth Indicators, Berlin, Germany. [Terkawi, Abdullah Sulieman] Univ Virginia, Dept Anesthesiol, Charlottesville, VA USA. [Platts-Mills, James A.] Univ Virginia, Charlottesville, VA USA. [Polinder, Suzanne] Erasmus MC, Dept Publ Hlth, Rotterdam, Netherlands. [Pope, C. Arden] Brigham Young Univ, Provo, UT USA. [Qorbani, Mostafa] Alborz Univ Med Sci, Sch Med, Dept Community Med, Karaj, Iran. [Rafay, Anwar; Rana, Saleem M.] Sch Publ Hlth, Lahore, Pakistan. [Rahman, Mahfuzar] Res & Evaluat Div, BRAC, Dhaka, Bangladesh. [Rahman, Mahfuzar] Hamad Med Corp, Doha, Qatar. [Rai, Rajesh Kumar] Soc Hlth & Demog Surveillance, Suri, India. [Rajsic, Sasa] UMIT, ERAWEB Program, Hall, Tyrol, Austria. [Raju, Murugesan] Univ Missouri, Columbia, MO USA. [Rakovac, Ivo] WHO Reg Off Europe, Copenhagen, Denmark. [Rana, Saleem M.] Contech Int Hlth Consultants, Lahore, Pakistan. [Ranabhat, Chhabi L.] Yonsei Univ, Wonju Coll Med, Inst Poverty Alleviat & Int Dev, Wonju, South Korea. [Rangaswamy, Thara] Schizophrenia Res Fdn, Chennai, Tamil Nadu, India. [Refaat, Amany H.] Suez Canal Univ, Ismailia, Egypt. [Rehm, Jurgen] Ctr Addict & Mental Hlth, Toronto, ON, Canada. [Remuzzi, Giuseppe] Univ Milan, Dept Biomed & Clin Sci L Sacco, Milan, Italy. [Ribeiro, Antonio L.] Univ Fed Minas Gerais, Hosp Clin, Belo Horizonte, MG, Brazil. [Ricci, Stefano] UO Neurol USL Umbria 1, Castello, Italy. [Roca, Anna] The Gambia, Med Res Council Unit, Fajara, Gambia. [Rojas-Rueda, David] I SGlobal, Barcelona, Spain. Golestan Univ Med Sci, Gorgan, Iran. [Roshandel, Gholamreza] Golestan Univ Med Sci, Golestan Res Ctr Gastroenterol & Hepatol, Gorgan, Iran. [Roy, Nawal K.] Holmusk, Singapore, Singapore. [Roy, Nawal K.] Duke NUS Med Sch, Singapore, Singapore. [Ruhago, George Mugambage; Sunguya, Bruno F.] Muhimbili Univ Hlth & Allied Sci, Dar Es Salaam, Tanzania. [Saha, Sukanta] Queensland Ctr Mental Hlth Res, Pk Ctr Mental Hlth, Brisbane, Qld, Australia. [Sahathevan, Ramesh] Ballarat Hlth Serv, Ballarat, Vic, Australia. [Sahathevan, Ramesh] Univ Kebangsaan Malaysia, Med Ctr, Kuala Lumpur, Malaysia. [Saleh, Muhammad Muhammad] Dev Res & Projects Ctr, Abuja, Nigeria. [Sanabria, Juan R.] Marshall Univ, Edwards Sch Med J, Huntington, WV USA. [Sanabria, Juan R.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Sanchez-Nino, Maria Dolores] IIS Fdn Jimenez Diaz, Madrid, Spain. [Sanchez-Riera, Lidia] LHosp, Inst Invest Biomed Bellvitge IDIBELL, Lhospitalet De Llobregat, Spain. [Sarmiento-Suarez, Rodrigo] Univ Ciencias Aplicadas & Ambient, Bogota, Colombia. [Sawhney, Monika] Marshall Univ, Huntington, WV USA. [Schaub, Michael P.] Swiss Res Inst Publ Hlth & Addict, Zurich, Switzerland. [Yebyo, Henock Gebremedhin] Univ Zurich, Zurich, Switzerland. [Schneider, Ione J. C.; Silva, Diego Augusto Santos] Univ Fed Santa Catarina, Florianopolis, SC, Brazil. [Schottker, Ben] FOM Univ, Inst Hlth Care & Social Sci, Essen, Germany. [Schutte, Aletta E.] Northwest Univ, Hypertens Africa Res Team HART, Potchefstroom, South Africa. [Parry, Charles D.] Alcohol, Tobacco Other Drug Res Unit, Potchefstroom, South Africa. [Schutte, Aletta E.] South African Med Res Council, Potchefstroom, South Africa. [Shaddick, Gavin] Univ Bath, Bath, Avon, England. [Shaheen, Amira] Najah Univ, Dept Publ Hlth, Nablus, Israel. [Shahraz, Saeid] Tufts Med Ctr, Boston, MA USA. [Shaikh, Masood Ali] Independent Consultant, Karachi, Pakistan. [Sharma, Rajesh] Indian Inst Technol Ropar, Rupnagar, India. [Shen, Jiabin] Nationwide Childrens Hosp, Res Inst, Columbus, OH USA. [Shen, Ziyan] Shanghai Kidney & Dialysis Inst, Shanghai, Peoples R China. [Shetty, Balakrishna P.] Sri Siddhartha Univ, Tumkur, India. [Shetty, Balakrishna P.] ISHA Diagnost, Bangalore, Karnataka, India. [Shin, Min-Jeong] Korea Univ, Grad Sch, Dept Publ Hlth Sci, Seoul, South Korea. [Shiri, Rahman] Finnish Inst Occupat Hlth, Work Org, Work Disabil Prevent, Helsinki, Finland. [Shiue, Ivy] Northumbria Univ, Fac Hlth & Life Sci, Newcastle Upon Tyne, Tyne & Wear, England. [Sigfusdottir, Inga Dora] Reykjavik Univ, Reykjavik, Iceland. [Silveira, Dayane Gabriele Alves] Univ Brasilia, Brasilia, DF, Brazil. [Silverberg, Jonathan I.] Feinberg Sch Med, Chicago, IL USA. [Yano, Yuichiro] Northwestern Univ, Dept Prevent Med, Chicago, IL USA. 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EM cjlm@uw.edu RI Salomon, Joshua/D-3898-2009; Monasta, Lorenzo/B-1388-2012; Hankey, Graeme /H-4968-2014; Nagel, Gabriele/C-3635-2012; Patton, George/B-5246-2013; Brenner, Hermann/B-4627-2017; Martinez-Raga, Jose/B-6251-2017; Majdan, Marek/K-5017-2012; Weiderpass, Elisabete/M-4029-2016; Gishu, Melkamu Dedefo/C-3747-2017; Alsharif, Ubai/C-6527-2017; Tonelli, Marcello/B-3028-2009; Ribeiro, Antonio/C-2707-2009; Amini, Heresh/B-3076-2010; Lotufo, Paulo/A-9843-2008; Karch, Andre/D-6973-2017; Patten, Scott/B-4434-2011; Franklin, Richard/H-1731-2012; Giussani, Giorgia/E-8057-2017; Abbas, Kaja/E-6590-2017; Musa, Kamarul Imran/N-3198-2015; Pereira, David/M-9286-2013; OI Salomon, Joshua/0000-0003-3929-5515; Monasta, Lorenzo/0000-0001-7774-548X; Hankey, Graeme /0000-0002-6044-7328; Nagel, Gabriele/0000-0001-6185-8535; Patton, George/0000-0001-5039-8326; Brenner, Hermann/0000-0002-6129-1572; Martinez-Raga, Jose/0000-0002-2856-6562; Majdan, Marek/0000-0001-8037-742X; Weiderpass, Elisabete/0000-0003-2237-0128; Gishu, Melkamu Dedefo/0000-0002-3466-1232; Alsharif, Ubai/0000-0002-4024-3950; Ribeiro, Antonio/0000-0002-2740-0042; Hoek, Hans/0000-0001-6353-5465; Agrawal, Anurag/0000-0002-0340-5252; Kemp, Andrew/0000-0003-1146-3791; Charlson, Fiona/0000-0003-2876-5040; das Neves, Jose/0000-0002-2317-2759; Degenhardt, Louisa/0000-0002-8513-2218; Gouda, Hebe/0000-0002-5709-4509; Awasthi, Ashish/0000-0002-9308-9782; Jacobsen, Kathryn/0000-0002-4198-6246; Biroscak, Brian/0000-0002-1323-9358; Bernabe, Eduardo/0000-0002-1858-3713; Atique, Suleman/0000-0002-5149-0703; Massano, Joao/0000-0002-5791-7149; Piel, Frederic B./0000-0001-8131-7728; Altirkawi, Khalid/0000-0002-7331-4196; Heydarpour, Pouria/0000-0001-5644-7555; Vlassov, Vasiliy/0000-0001-5203-549X; Alkerwi, Ala'a/0000-0002-7448-3936; Ahmad Kiadaliri, Aliasghar/0000-0002-4254-9099; Kieling, Christian/0000-0001-7691-4149; Javanbakht, Mehdi/0000-0002-8661-8439; Gething, Peter/0000-0001-6759-5449; Husseini, Abdullatif/0000-0001-8767-5956; Taylor, Hugh/0000-0002-9437-784X; Amini, Heresh/0000-0002-4825-1322; Lotufo, Paulo/0000-0002-4856-8450; Karch, Andre/0000-0003-3014-8543; Patten, Scott/0000-0001-9871-4041; Franklin, Richard/0000-0003-1864-4552; Abbas, Kaja/0000-0003-0563-1576; Musa, Kamarul Imran/0000-0002-3708-0628; Pereira, David/0000-0003-0384-7592; Sreeramareddy, Chandrashekhar/0000-0002-5693-7631; Miller, Ted/0000-0002-0958-2639; Xu, Gelin/0000-0002-6194-0341; Al-Aly, Ziyad/0000-0002-2600-0434 FU Bill AMP; Melinda Gates Foundation FX Bill & Melinda Gates Foundation. 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Abate, KH Abbafati, C Abbas, KM Abd-Allah, F Abraham, B Abubakar, I Abu-Raddad, LJ Abu-Rmeileh, NME Ackerman, IN Adebiyi, AO Ademi, Z Adou, AK Afanvi, KA Agardh, EE Agarwal, A Kiadaliri, AA Ahmadieh, H Ajala, ON Akinyemi, RO Akseer, N Al-Aly, Z Alam, K Alam, NKM Aldhahri, SF Alegretti, MA Alemu, ZA Alexander, LT Alhabib, S Ali, R Alkerwi, A Alla, F Allebeck, P Al-Raddadi, R Alsharif, U Altirkawi, KA Alvis-Guzman, N Amare, AT Amberbir, A Amini, H Ammar, W Amrock, SM Andersen, HH Anderson, GM Anderson, B Antonio, CAT Aregay, AF Arnlov, J Al Artaman Asayesh, H Assadi, R Atique, S Avokpaho, EFGA Awasthi, A Quintanilla, BPA Azzopardi, P Bacha, U Badawi, A Balakrishnan, K Banerjee, A Barac, A Barker-Collo, SL Barnighausen, T Barregard, L Barrero, LH Basu, A Bazargan-Hejazi, S Bell, B Bell, ML Bennett, DA Bensenor, IM Benzian, H Berhane, A Bernabe, E Betsu, BD Beyene, AS Bhala, N Bhatt, S Biadgilign, S Bienhofff, K Bikbov, B Biryukov, S Bisanzio, D Bjertness, E Blore, J Borschmann, R Boufous, 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Qorbani, Mostafa Rabiee, Rynaz H. S. Radfar, Amir Rafay, Anwar Rahimi, Kazem Rahimi-Movaghar, Vafa Rahman, Mahfuzar Rahman, Mohammad Hifz Ur Rahman, Sajjad Ur Rai, Rajesh Kumar Rajsic, Sasa Ram, Usha Rao, Puja Refaat, Amany H. Reitsma, Marissa B. Remuzzi, Giuseppe Resnikofff, Serge Reynolds, Alex Ribeiro, Antonio L. Rios Blancas, Maria Jesus Rolm, Hirbo Shore Rojas-Rueda, David Ronfani, Luca Roshandel, Gholamreza Roth, Gregory A. Rothenbacher, Dietrich Roy, Ambuj Sagar, Rajesh Sahathevan, Ramesh Sanabria, Juan R. Dolores Sanchez-Nino, Maria Santos, Itamar S. Santos, Joao Vasco Sarmiento-Suarez, Rodrigo Sartorius, Benn Satpathy, Maheswar Savic, Miloje Sawhney, Monika Schaub, Michael P. Schmidt, Maria Ines Schneider, Ione J. C. Schottker, Ben Schwebel, David C. Scott, James G. Seedat, Soraya Sepanlou, Sadaf G. Servan-Mori, Edson E. Shackelford, Katya A. Shaheen, Amira Shaikh, Masood Ali Sharma, Rajesh Sharma, Upasana Shen, Jiabin Shepard, Donald S. Sheth, Kevin N. 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Tobe-Gai, Ruoyan Tonelli, Marcello Topor-Madry, Roman Topouzis, Fotis Tran, Bach Xuan Dimbuene, Zacharie Tsala Tsilimbaris, Miltiadis Tura, Abera Kenay Tuzcu, Emin Murat Tyrovolas, Stefanos Ukwaja, Kingsley N. Undurraga, Eduardo A. Uneke, Chigozie Jesse Uthman, Olalekan A. van Gool, Coen H. Varakin, Yuri Y. Vasankari, Tommi Venketasubramanian, Narayanaswamy Verma, Raj Kumar Violante, Francesco S. Vladimirov, Sergey K. Vlassov, Vasiliy Victorovich Vollset, Stein Emil Wagner, Gregory R. Waller, Stephen G. Wang, Linhong Watkins, David A. Weichenthal, Scott Weiderpass, Elisabete Weintraub, Robert G. Werdecker, Andrea Westerman, Ronny White, Richard A. Williams, Hywel C. Wiysonge, Charles Shey Wolfe, Charles D. A. Won, Sungho Woodbrook, Rachel Wubshet, Mamo Xavier, Denis Xu, Gelin Yadav, Ajit Kumar Yan, Lijing L. Yano, Yuichiro Yaseri, Mehdi Ye, Pengpeng Yebyo, Henock Gebremedhin Yip, Paul Yonemoto, Naohiro Yoon, Seok-Jun Younis, Mustafa Z. Yu, Chuanhua Zaidi, Zoubida Zaki, Maysaa El Sayed Zeeb, Hajo Zhou, Maigeng Zodpey, Sanjay Zuhlke, Liesl Joanna Murray, Christopher J. L. CA GBD 2015 Dis Injury Incidence TI Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015 SO LANCET LA English DT Article ID EBOLA HEMORRHAGIC-FEVER; SELF-RATED HEALTH; ALZHEIMERS-DISEASE; MENTAL-HEALTH; PLASMODIUM-FALCIPARUM; ANCHORING VIGNETTES; UNITED-STATES; VIRUS DISEASE; HIV INCIDENCE; DEMENTIA AB Background Non-fatal outcomes of disease and injury increasingly detract from the ability of the world's population to live in full health, a trend largely attributable to an epidemiological transition in many countries from causes affecting children, to non-communicable diseases (NCDs) more common in adults. For the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015), we estimated the incidence, prevalence, and years lived with disability for diseases and injuries at the global, regional, and national scale over the period of 1990 to 2015. Methods We estimated incidence and prevalence by age, sex, cause, year, and geography with a wide range of updated and standardised analytical procedures. Improvements from GBD 2013 included the addition of new data sources, updates to literature reviews for 85 causes, and the identification and inclusion of additional studies published up to November, 2015, to expand the database used for estimation of non-fatal outcomes to 60 900 unique data sources. Prevalence and incidence by cause and sequelae were determined with DisMod-MR 2.1, an improved version of the DisMod-MR Bayesian meta-regression tool first developed for GBD 2010 and GBD 2013. For some causes, we used alternative modelling strategies where the complexity of the disease was not suited to DisMod-MR 2.1 or where incidence and prevalence needed to be determined from other data. For GBD 2015 we created a summary indicator that combines measures of income per capita, educational attainment, and fertility (the Socio-demographic Index [SDI]) and used it to compare observed patterns of health loss to the expected pattern for countries or locations with similar SDI scores. Findings We generated 9.3 billion estimates from the various combinations of prevalence, incidence, and YLDs for causes, sequelae, and impairments by age, sex, geography, and year. In 2015, two causes had acute incidences in excess of 1 billion: upper respiratory infections (17.2 billion, 95% uncertainty interval [UI] 15.4-19.2 billion) and diarrhoeal diseases (2.39 billion, 2.30-2.50 billion). Eight causes of chronic disease and injury each affected more than 10% of the world's population in 2015: permanent caries, tension-type headache, iron-deficiency anaemia, age-related and other hearing loss, migraine, genital herpes, refraction and accommodation disorders, and ascariasis. The impairment that affected the greatest number of people in 2015 was anaemia, with 2.36 billion (2.35-2.37 billion) individuals affected. The second and third leading impairments by number of individuals affected were hearing loss and vision loss, respectively. Between 2005 and 2015, there was little change in the leading causes of years lived with disability (YLDs) on a global basis. NCDs accounted for 18 of the leading 20 causes of age-standardised YLDs on a global scale. Where rates were decreasing, the rate of decrease for YLDs was slower than that of years of life lost (YLLs) for nearly every cause included in our analysis. For low SDI geographies, Group 1 causes typically accounted for 20-30% of total disability, largely attributable to nutritional deficiencies, malaria, neglected tropical diseases, HIV/AIDS, and tuberculosis. Lower back and neck pain was the leading global cause of disability in 2015 in most countries. The leading cause was sense organ disorders in 22 countries in Asia and Africa and one in central Latin America; diabetes in four countries in Oceania; HIV/AIDS in three southern sub-Saharan African countries; collective violence and legal intervention in two north African and Middle Eastern countries; iron-deficiency anaemia in Somalia and Venezuela; depression in Uganda; onchoceriasis in Liberia; and other neglected tropical diseases in the Democratic Republic of the Congo. Interpretation Ageing of the world's population is increasing the number of people living with sequelae of diseases and injuries. Shifts in the epidemiological profile driven by socioeconomic change also contribute to the continued increase in years lived with disability (YLDs) as well as the rate of increase in YLDs. Despite limitations imposed by gaps in data availability and the variable quality of the data available, the standardised and comprehensive approach of the GBD study provides opportunities to examine broad trends, compare those trends between countries or subnational geographies, benchmark against locations at similar stages of development, and gauge the strength or weakness of the estimates available. Copyright (C) The Author(s). Published by Elsevier Ltd. C1 [Vos, Theo; Allen, Christine; Arora, Megha; Barber, Ryan M.; Brown, Alexandria; Carter, Austin; Casey, Daniel C.; Charlson, Fiona J.; Chen, Alan Z.; Coggeshall, Megan; Cornaby, Leslie; Dandona, Lalit; Dicker, Daniel J.; Dilegge, Tina; Erskine, Holly E.; Ferrari, Alize J.; Fitzmaurice, Christina; Fleming, Tom; Forouzanfar, Mohammad H.; Fullman, Nancy; Goldberg, Ellen M.; Graetz, Nicholas; Haagsma, Juanita A.; Johnson, Catherine O.; Kassebaum, Nicholas J.; Kawashima, Toana; Kemmer, Laura; Khalil, Ibrahim A.; Kyu, Hmwe H.; Leung, Janni; Lim, Stephen S.; Lopez, Alan D.; Marczak, Laurie; Mokdad, Ali H.; Naghavi, Mohsen; Nguyen, Grant; Nsoesie, Elaine; Olsen, Helen; Pigott, David M.; Pinho, Christine; Rankin, Zane; Reinig, Nikolas; Sandar, Logan; Smith, Alison; Stanaway, Jeffrey; Steiner, Caitlyn; Teeple, Stephanie; Thomas, Bernadette A.; Troeger, Christopher; Wagner, Joseph A.; Wang, Haidong; Wanga, Valentine; Whiteford, Harvey A.; Zoeckler, Leo; Alexander, Lily T.; Anderson, Gregory M.; Bienhofff, Kelly; Biryukov, Stan; Blore, Jed; Brown, Jonathan; Coates, Matthew M.; Daoud, Farah; Estep, Kara; Foreman, Kyle; Fox, Jordan; Friedman, Joseph; Frostad, Joseph; Godwin, William W.; Hancock, Jamie; Huynh, Chantal; Iannarone, Marissa; Kim, Cho-il; Kutz, Michael; Masiye, Felix; Mirarefin, Mojde; Mooney, Meghan D.; Moradi-Lakeh, Maziar; Mullany, Erin; Mumford, John Everett; Rao, Puja; Reitsma, Marissa B.; Reynolds, Alex; Roth, Gregory A.; Shackelford, Katya A.; Sivonda, Anna; Sligar, Amber; Sur, Patrick; Vollset, Stein Emil; Woodbrook, Rachel; Zhou, Maigeng; Murray, Christopher J. 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[Badawi, Alaa] Fac Med, Dept Nutr Sci, Toronto, ON, Canada. [Popova, Svetlana] Ctr Addict & Mental Hlth, Toronto, ON, Canada. [Agarwal, Arnav] Univ Toronto, Toronto, ON, Canada. [Agarwal, Arnav] McMaster Univ, Hamilton, ON, Canada. [Kiadaliri, Aliasghar Ahmad] Lund Univ, Dept Clin Sci Lund, Orthoped, Clin Epidemiol Unit, Lund, Sweden. [Norrving, Bo] Lund Univ, Skane Univ Hosp, Dept Clin Sci Lund, Lund, Sweden. [Kiadaliri, Aliasghar Ahmad] Kerman Univ Med Sci, Inst Futures Studies Hlth, Hlth Serv Management Res Ctr, Kerman, Iran. [Ahmadieh, Hamid; Yaseri, Mehdi] Shahid Beheshti Univ Med Sci, Ophthalm Res Ctr, Tehran, Iran. [Jahanmehr, Nader] Shahid Beheshti Univ Med Sci, Sch Publ Hlth, Tehran, Iran. [Ahmadieh, Hamid] Labbafinejad Med Ctr, Dept Ophthalmol, Tehran, Iran. [Ajala, Oluremi N.] Univ Pittsburgh, Med Ctr, Mckeesport, PA USA. [Akinyemi, Rufus Olusola] Newcastle Univ, Newcastle Upon Tyne, Tyne & Wear, England. [Al-Aly, Ziyad] Washington Univ, St Louis, MO USA. 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[Fereshtehnejad, Seyed-Mohammad] Dept Neurobiol Care Sci & Soc NVS, Stockholm, Sweden. [Weiderpass, Elisabete] Dept Med Epidemiol & Biostatist, Stockholm, Sweden. [Havmoeller, Rasmus] Karolinska Inst, Stockholm, Sweden. [Al-Raddadi, Rajaa] Minist Hlth, Jeddah, Saudi Arabia. [Alsharif, Ubai] Charite, Berlin, Germany. [Alvis-Guzman, Nelson] Univ Cartagena, Cartagena Indias, Colombia. [Amare, Azmeraw T.; Melaku, Yohannes Adama] Sch Med, Adelaide, SA, Australia. [Ciobanu, Liliana G.] Univ Adelaide, Adelaide, SA, Australia. [Amare, Azmeraw T.] Bahir Dar Univ, Coll Med & Hlth Sci, Bahir Dar, Ethiopia. [Amberbir, Alemayehu] Dignitas Int, Zomba, Malawi. [Amini, Heresh] Kurdistan Univ Med Sci, Environm Hlth Res Ctr, Sanandaj, Iran. [Amini, Heresh; Furst, Thomas] Dept Epidemiol & Publ Hlth, Basel, Switzerland. [Karema, Corine Kakizi] Swiss Trop & Publ Hlth Inst, Basel, Switzerland. [Ammar, Walid; Harb, Hilda L.] Minist Publ Hlth, Beirut, Lebanon. [Amrock, Stephen Marc] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Andersen, Hjalte H.] Aalborg Univ, Ctr Sensory Motor Interact, Dept Hlth Sci & Technol, Fac Med, Aalborg, Denmark. [Antonio, Carl Abelardo T.] Univ Philippines Manila, Coll Publ Hlth, Dept Hlth Policy & Adm, Manila, Philippines. [Melaku, Yohannes Adama] Sch Publ Hlth, Mekelle, Ethiopia. [Aregay, Atsede Fantahun; Betsu, Balem Demtsu; Hailu, Gessessew Bugssa; Yebyo, Henock Gebremedhin] Mekelle Univ, Mekelle, Ethiopia. [Arnlov, Johan; Larsson, Anders] Uppsala Univ, Dept Med Sci, Uppsala, Sweden. [Arnlov, Johan] Dalarna Univ, Falun, Sweden. [Asayesh, Hamid] Qom Univ Med Sci, Dept Emergency Med, Sch Paramed, Qom, Iran. [Assadi, Reza] Mashhad Univ Med Sci, Mashhad, Iran. [Atique, Suleman] Taipei Med Univ, Grad Inst Biomed Informat, Taipei, Taiwan. [Avokpaho, Euripide Frinel G. Arthur] Inst Rech Clin Benin, Cotonou, Benin. [Avokpaho, Euripide Frinel G. Arthur] Lab Etud & Rech Act Sante LERAS Afrique, Parakou, Benin. [Awasthi, Ashish] Sanjay Gandhi Postgrad Inst Med Sci, Lucknow, Uttar Pradesh, India. [Quintanilla, Beatriz Paulina Ayala] La Trobe Univ, Judith Lumley Ctr Mother Infant & Family Hlth Res, Melbourne, Vic, Australia. [Quintanilla, Beatriz Paulina Ayala] Peruvian Natl Inst Hlth, Lima, Peru. [Azzopardi, Peter] South Australian Hlth & Med Res Inst, Wardliparingga Aboriginal Res Unit, Adelaide, SA, Australia. [Bacha, Umar] Univ Management & Technol, Sch Hlth Sci, Lahore, Pakistan. [Badawi, Alaa] Publ Hlth Agcy Canada, Toronto, ON, Canada. [Balakrishnan, Kalpana] Sri Ramachandra Univ, Dept Environm Hlth Engn, Madras, Tamil Nadu, India. [Barac, Aleksandra] Univ Belgrade, Fac Med, Belgrade, Serbia. [Barker-Collo, Suzanne L.] Univ Auckland, Sch Psychol, Auckland, New Zealand. [Barnighausen, Till] Africa Hlth Res Inst, Mtubatuba, South Africa. [Barnighausen, Till; Mohammed, Shafiu] Heidelberg Univ, Inst Publ Hlth, Heidelberg, Germany. [Barregard, Lars] Univ Gothenburg, Dept Occupat & Environm Hlth, Gothenburg, Sweden. [Petzold, Max] Univ Gothenburg, Hlth Metr Unit, Gothenburg, Sweden. [Barrero, Lope H.] Pontificia Univ Javeriana, Sch Engn, Dept Ind Engn, Bogota, Colombia. [Basu, Arindam] Univ Canterbury, Sch Hlth Sci, Christchurch, New Zealand. [Bazargan-Hejazi, Shahrzad] Charles R Drew Univ Med & Sci, Coll Med, 1621 E 120th St, Los Angeles, CA 90059 USA. [Bazargan-Hejazi, Shahrzad] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Bazargan-Hejazi, Shahrzad] Kermanshah Univ Med Sci, Kermanshah, Iran. [Sheth, Kevin N.] Sch Med, New Haven, CT USA. [Bell, Michelle L.; Huang, John J.] Yale Univ, New Haven, CT USA. [Santos, Itamar S.] Dept Internal Med, Sao Paulo, Brazil. [Bensenor, Isabela M.; Lotufo, Paulo A.] Univ Sao Paulo, Sao Paulo, Brazil. [Benzian, Habib] NYU, Coll Dent, Dept Epidemiol & Hlth Promot, New York, NY USA. [Berhane, Adugnaw] Debre Berhane Univ, Debre Berhan, Ethiopia. [Wolfe, Charles D. A.] Div Hlth & Social Care Res, London, England. [Bernabe, Eduardo; Hay, Roderick J.] Kings Coll London, London, England. Coll Hlth & Med Sci, Harar, Ethiopia. [Beyene, Addisu Shunu] Haramaya Univ, Harar, Ethiopia. [Bhala, Neeraj] Queen Elizabeth Hosp Birmingham, Birmingham, W Midlands, England. [Bhala, Neeraj] Univ Otago, Sch Med, Wellington, New Zealand. [Furst, Thomas] Dept Infect Dis Epidemiol, London, England. [Piel, Frederic B.] Dept Epidemiol & Biostat, London, England. [Steiner, Timothy J.] Div Brain Sci, London, England. [Bhatt, Samir; Greaves, Felix; Majeed, Azeem; Soljak, Michael] Imperial Coll London, London, England. [Bikbov, Boris] Acad VI Shumakov Fed Res Ctr Transplantol & Artif, Dept Nephrol Issues Transplanted Kidney, Moscow, Russia. [Bjertness, Espen] Dept Community Med, Oslo, Norway. [Htet, Aung Soe] Univ Oslo, Oslo, Norway. [Boufous, Soufiane] Transport & Rd Safety TARS Res, Kensington, NSW, Australia. [Degenhardt, Louisa] Natl Drug & Alcohol Res Ctr, Kensington, NSW, Australia. [Resnikofff, Serge] Brien Holden Vision Inst, Kensington, NSW, Australia. [Calabria, Bianca; Mitchell, Philip B.] Univ New South Wales, Kensington, NSW, Australia. [Brainin, Michael] Danube Univ Krems, Krems, Austria. [Brazinova, Alexandra; Majdan, Marek] Trnava Univ, Fac Hlth Sci & Social Work, Dept Publ Hlth, Trnava, Slovakia. [Brazinova, Alexandra] Int Neurotrauma Res Org, Vienna, Austria. [Lo, Warren D.] Dept Pediat, Columbus, OH USA. [Lo, Warren D.] Dept Neurol, Columbus, OH USA. [Shen, Jiabin] Coll Med, Columbus, OH USA. [Breitborde, Nicholas J. K.] Ohio State Univ, Columbus, OH 43210 USA. [Buchbinder, Rachelle] Cabrini Inst, Monash Dept Clin Epidemiol, Melbourne, Vic, Australia. [Buckle, Geoffrey Colin] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Butt, Zahid A.] Al Shifa Trust Eye Hosp, Rawalpindi, Pakistan. [Calabria, Bianca] Australian Natl Univ, Natl Ctr Epidemiol & Populat Hlth, Canberra, ACT, Australia. [Carabin, Helene] Univ Oklahoma, Hlth Sci Ctr, Dept Biostat & Epidemiol, Oklahoma City, OK USA. [Cardenas, Rosario] Metropolitan Autonomous Univ, Mexico City, DF, Mexico. [Carpenter, David O.] SUNY Albany, Rensselaer, NY USA. [Castaneda-Orjuela, Carlos A.] Inst Nacl Salud, Colombian Natl Hlth Observ, Bogota, Colombia. [Castaneda-Orjuela, Carlos A.] Univ Nacl Colombia, Epidemiol & Publ Hlth Evaluat Grp, Dept Publ Hlth, Bogota, Colombia. [Castillo Rivas, Jacqueline] Caja Costarricense Seguro Social, San Jose, Costa Rica. [Castillo Rivas, Jacqueline] Univ Costa Rica, San Pedro, Montes De Oca, Costa Rica. [Catala-Lopez, Ferran] Univ Valencia, Dept Med, INCLIVA Hlth Res Inst, Valencia, Spain. [Catala-Lopez, Ferran] CIBERSAM, Valencia, Spain. [Catala-Lopez, Ferran] Ottawa Hosp, Res Inst, Clin Epidemiol Program, Ottawa, ON, Canada. [Chang, Jung-Chen] Natl Taiwan Univ, Coll Med, Sch Nursing, Taipei, Taiwan. [Chiang, Peggy Pei-Chia] Gold Coast Hlth, Clin Governance Unit, Southport, Qld, Australia. [Chibueze, Chioma Ezinne] Natl Ctr Child Hlth & Dev, Tokyo, Japan. [Chisumpa, Vesper Hichilombwe] Univ Zambia, Lusaka, Zambia. [Chisumpa, Vesper Hichilombwe] Univ Witwatersrand, Johannesburg, South Africa. [Choi, Jee-Young Jasmine] Seoul Natl Univ Med Lib, Seoul, South Korea. [Chowdhury, Rajiv] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Christensen, Hanne] Bispebjerg Hosp, Copenhagen, Denmark. [Christopher, Devasahayam Jesudas] Christian Med Coll & Hosp, Vellore, Tamil Nadu, India. [Cirillo, Massimo] Univ Salerno, Baronissi, Italy. [Cooper, Cyrus] Univ Southampton, MRC Lifecourse Epidemiol Unit, Southampton, Hants, England. [Cooper, Cyrus] Univ Southampton, NIHR Biomed Res Ctr, Southampton, Hants, England. [Cooper, Cyrus] Univ Hosp Southampton NHS Fdn Trust, Southampton, Hants, England. [Cortinovis, Monica; Perico, Norberto; Remuzzi, Giuseppe] IRCCS Ist Ric Farmacol Mario Negri, Bergamo, Italy. [Crump, John A.] Dunedin Sch Med, Ctr Int Hlth, Dunedin, New Zealand. [Derrett, Sarah] Dunedin Sch Med, Injury Prevent Res Unit, Dept Prevent & Social Med, Dunedin, New Zealand. [Grainger, Rebecca; Poulton, Richie G.] Univ Otago, Dunedin, New Zealand. [Damtew, Solomon Abrha] Wolaita Sodo Univ, Wolaita Sodo, Ethiopia. [Deribe, Kebede; Hailu, Alemayehu Desalegne] Sch Publ Hlth, Addis Ababa, Ethiopia. [Damtew, Solomon Abrha; Giref, Ababi Zergaw; Haile, Demewoz; Jibat, Tariku; Taye, Bineyam] Univ Addis Ababa, Addis Ababa, Ethiopia. [Dargan, Paul I.] Guys & St Thomas NHS Fdn Trust, London, England. [Massano, Joao; Santos, Joao Vasco] Univ Porto, Inst Invest Inovacao Sande i3S, Oporto, Portugal. [das Neves, Jose] Univ Porto, INEB Inst Engn Biomed, Oporto, Portugal. [Massano, Joao; Santos, Joao Vasco] Univ Porto, Fac Med, Oporto, Portugal. [Davey, Gail] Wellcome Trust Brighton & Sussex Ctr Global Hlth, Brighton, E Sussex, England. [Davis, Adrian C.; Greaves, Felix; Newton, John N.; Steel, Nicholas] Publ Hlth England, London, England. [De Leo, Diego] Griffith Univ, Brisbane, Qld, Australia. [Del Gobbo, Liana C.] Stanford Univ, Stanford, CA 94305 USA. [Dellavalle, Robert P.] Univ Colorado, Sch Med, Aurora, CO USA. [Dellavalle, Robert P.] Colorado Sch Publ Hlth, Aurora, CO USA. [Deribe, Kebede] Brighton & Sussex Med Sch, Brighton, E Sussex, England. [Deribew, Amare] KEMRI Wellcome Trust Res Programme, Kilifi, Kenya. [Des Jarlais, Don C.] Mt Sinai Beth Israel, New York, NY USA. [Des Jarlais, Don C.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Dharmaratne, Samath D.] Univ Peradeniya, Fac Med, Dept Community Med, Peradeniya, Sri Lanka. [Jeemon, Panniyammakal] Ctr Control Chron Condit, Gurgaon, India. [Dhillon, Preet K.; Ganguly, Parthasarathi; Zodpey, Sanjay] Publ Hlth Fdn India, Gurgaon, India. [Diaz-Torne, Cesar] Hosp Santa Creu & Sant Pau, Barcelona, Spain. [Dubey, Manisha; Rahman, Mohammad Hifz Ur; Ram, Usha; Singh, Abhishek; Verma, Raj Kumar; Yadav, Ajit Kumar] Int Inst Populat Sci, Bombay, Maharashtra, India. [Duncan, Bruce Bartholow; Kieling, Christian; Schmidt, Maria Ines] Univ Fed Rio Grande do Sul, Porto Alegre, RS, Brazil. [Duncan, Bruce Bartholow] Univ N Carolina, Chapel Hill, NC USA. [Ebrahimi, Hedyeh; Farzadfar, Farshad; Kasaeian, Amir; Parsaeian, Mahboubeh; Pishgar, Farhad] Endocrinol & Metab Populat Sci Inst, Noncommunicable Dis Res Ctr, Tehran, Iran. [Ebrahimi, Hedyeh] Shariati Hosp, Digest Dis Res Inst, Liver & Pancreaticobiliary Dis Res Ctr, Tehran, Iran. [Heydarpour, Pouria] Neurosci Inst, Multiple Sclerosis Res Ctr, Tehran, Iran. [Kasaeian, Amir] Hematol Oncol & Stem Cell Transplantat Res Ctr, Tehran, Iran. [Malekzadeh, Reza; Roshandel, Gholamreza; Sepanlou, Sadaf G.] Digest Dis Res Inst, Tehran, Iran. [Parsaeian, Mahboubeh] Sch Publ Hlth, Dept Epidemiol & Biostat, Tehran, Iran. [Pishgar, Farhad] Urooncol Res Ctr, Tehran, Iran. [Rahimi-Movaghar, Vafa] Sina Trauma & Surg Res Ctr, Tehran, Iran. [Yaseri, Mehdi] Univ Tehran Med Sci, Tehran, Iran. [Elyazar, Iqbal] Eijkman Oxford Clin Res Unit, Jakarta, Indonesia. [Endres, Matthias] Charite Univ Med Berlin, Berlin, Germany. [Endries, Aman Yesuf] Arba Minch Univ, Arba Minch, Ethiopia. [Ermakov, Sergey Petrovich] Russian Acad Sci, Inst Social & Econ Studies Populat, Moscow, Russia. [Ermakov, Sergey Petrovich] Minist Hlth Russian Federat, Fed Res Inst Hlth Org & Informat, Moscow, Russia. [Eshrati, Babak] Minist Hlth & Med Educ, Tehran, Iran. [Eshrati, Babak] Arak Univ Med Sci, Arak, Iran. [Farid, Talha A.] Univ Louisville, Louisville, KY 40292 USA. [Sofia e Sa Farinha, Carla] DGS Directorate Gen Hlth, Lisbon, Portugal. [Faro, Andre] Univ Fed Sergipe, Aracaju, Brazil. [Farvid, Maryam S.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Harvard MGH Ctr Genom Vulnerable Populat & Hlth, Boston, MA 02114 USA. [Feigin, Valery L.] Natl Inst Stroke & Appl Neurosci, Auckland, New Zealand. [Te Ao, Braden J.] Auckland Univ Technol, Auckland, New Zealand. [Kwan, Gene F.] Sch Med, Boston, MA USA. [Felson, David T.] Boston Univ, Boston, MA 02215 USA. [Fernandes, Jefferson G.] German Hosp Oswaldo Cruz, Inst Educ & Sci, Sao Paulo, Brazil. [Fernandes, Joao C.] Queen Mary Univ London, Ctr Expt Med & Rheumatol, William Harvey Res Inst, Barts & London Sch Med & Dent, London, England. [Fischer, Florian] Univ Bielefeld, Bielefeld, Germany. [Shiue, Ivy] Alzheimer Scotland Dementia Res Ctr, Edinburgh, Midlothian, Scotland. [Fowkes, Gerry R.] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Furst, Thomas] James Cook Univ, Townsville, Qld, Australia. [Iyer, Veena J.] Indian Inst Publ Hlth Gandhinagar, Ahmadabad, Gujarat, India. [Gankpe, Fortune Gbetoho] Leras Afrique, Cotonou, Benin. [Gankpe, Fortune Gbetoho] CHU Hassan II, Fes, Morocco. [Gebre, Teshome] Task Force Global Hlth, Decatur, GA USA. [Gebremedhin, Amanuel Tesfay] Univ Munich, Munich, Germany. [Geleijnse, Johanna M.] Div Human Nutr, Wageningen, Netherlands. [Jibat, Tariku] Wageningen Univ, Wageningen, Netherlands. [Gessner, Bradford D.] Agence Med Prevent, Paris, France. [Gibney, Katherine B.] Royal Melbourne Hosp, Melbourne, Vic, Australia. [Ginawi, Ibrahim Abdelmageem Mohamed] Univ Hail, Coll Med, Hail, Saudi Arabia. [Giroud, Maurice] Univ Hosp Dijon, Dijon, France. Coll Hlth & Med Sci, Dire Dawa, Ethiopia. [Gishu, Melkamu Dedefo; Tura, Abera Kenay] Haramaya Univ, Dire Dawa, Ethiopia. [Gishu, Melkamu Dedefo] Kersa Hlth & Demog Surveillance Syst, Harar, Ethiopia. [Glaser, Elizabeth] Heller Sch Social Policy & Management, Waltham, MA USA. [Halasa, Yara A.; Shepard, Donald S.; Undurraga, Eduardo A.] Brandeis Univ, Waltham, MA USA. [Gona, Philimon] Univ Massachusetts Boston, Boston, MA USA. [Goodridge, Amador] Inst Invest Cient & Serv Alta Tecnol INDICASAT AI, Ciudad Del Saber, Panama. [Gopalani, Sameer Vali] Govt Federated States Micronesia, Dept Hlth & Social Affairs, Palikir, Micronesia. [Gotay, Carolyn C.; Kissoon, Niranjan; Kopec, Jacek A.; Pourmalek, Farshad] Univ British Columbia, Vancouver, BC, Canada. [Inoue, Manami] Natl Canc Ctr, Tokyo, Japan. West Virginia Bur Publ Hlth, Charleston, WV USA. Eternal Heart Care Ctr & Res Inst, Jaipur, Rajasthan, India. [Gupta, Vipin] Univ Delhi, Dept Anthropol, Delhi, India. [Gutierrez, Reyna A.] Natl Inst Psychiat Ramon Fuente, Mexico City, DF, Mexico. [Knudsen, Ann Kristin] Dept Global Publ Hlth & Primary Care, Bergen, Norway. [Hailu, Alemayehu Desalegne; Norheim, Ole F.] Univ Bergen, Bergen, Norway. [Hailu, Gessessew Bugssa] Kilte Awlaelo Hlth & Demog Surveillance Syst, Mekelle, Ethiopia. [Hamadeh, Randah Ribhi] Arabian Gulf Univ, Manama, Bahrain. [Hamidi, Samer] Hamdan Bin Mohammed Smart Univ, Dubai, U Arab Emirates. [Hammami, Mouhanad] Wayne Cty Dept Hlth & Human Serv, Detroit, MI USA. [Handal, Alexis J.] Univ New Mexico, Albuquerque, NM 87131 USA. [Hankey, Graeme J.] Univ Western Australia, Sch Med & Pharmacol, Perth, WA, Australia. [Hankey, Graeme J.] Harry Perkins Inst Med Res, Nedlands, WA, Australia. [Hankey, Graeme J.] Western Australian Neurosci Res Inst, Nedlands, WA, Australia. [Hao, Yuantao] Sun Yat Sen Univ, Sch Publ Hlth, Guangzhou, Guangdong, Peoples R China. [Harikrishnan, Sivadasanpillai] Sree Chitra Tirunal Inst Med Sci & Technol, Trivandrum, Kerala, India. [Maria Haro, Josep] Parc Sanitari Sant Joan de Deu CIBERSAM, St Boi De Llobregat, Barcelona, Spain. [Maria Haro, Josep] Univ Barcelona, Barcelona, Spain. [Hay, Roderick J.] Int Fdn Dermatol, London, England. [Hoek, Hans W.] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands. [Tura, Abera Kenay] Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands. [Hoek, Hans W.] Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. [Hoek, Hans W.] Columbia Univ, New York, NY USA. [Horino, Masako] Nevada Div Publ & Behav Hlth, Dept Hlth & Human Serv, Carson City, NV USA. [Horita, Nobuyuki] Yokohama City Univ, Grad Sch Med, Dept Pulmonol, Yokohama, Kanagawa, Japan. [Hosgood, H. Dean] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Hoy, Damian G.] Pacific Commun, Publ Hlth Div, Noumea, New Caledonia. [Htet, Aung Soe] Minist Hlth, Int Relat Div, Nay Pyi Taw, Myanmar. [Huang, Hsiang] Cambridge Hlth Alliance, Cambridge, MA USA. [Iburg, Kim Moesgaard] Aarhus Univ, Aarhus, Denmark. [Innos, Kaire] Natl Inst Hlth Dev, Tallinn, Estonia. [Inoue, Manami] Grad Sch Med, Tokyo, Japan. [Kawakami, Norito] Sch Publ Hlth, Tokyo, Japan. [Shibuya, Kenji] Univ Tokyo, Tokyo, Japan. [Jacobsen, Kathryn H.] George Mason Univ, Dept Global & Community Hlth, Fairfax, VA 22030 USA. [Jakovljevic, Mihajlo B.] Univ Kragujevac, Fac Med Sci, Kragujevac, Serbia. [Javanbakht, Mehdi] Univ Aberdeen, Aberdeen, Scotland. [Jayatilleke, Achala Upendra] Postgrad Inst Med, Colombo, Sri Lanka. [Jayatilleke, Achala Upendra] Inst Violence & Injury Prevent, Colombo, Sri Lanka. [Jee, Sun Ha] Yonsei Univ, Grad Sch Publ Hlth, Seoul, South Korea. [Jeemon, Panniyammakal; Prabhakaran, Dorairaj] Ctr Chron Dis Control, New Delhi, India. [Jiang, Ying] Univ Occupat & Environm Hlth, Inst Ind Ecol Sci, Dept Hlth Dev, Kitakyushu, Fukuoka, Japan. [Jimenez-Corona, Aida] Inst Ophthalmol Conde Valencia, Dept Ocular Epidemiol & Visual Hlth, Mexico City, DF, Mexico. [Jimenez-Corona, Aida] Minist Hlth, Gen Directorate Epidemiol, Mexico City, DF, Mexico. [Jonas, Jost B.] Heidelberg Univ, Dept Ophthalmol, Med Fac Mannheim, Mannheim, Germany. [Kabir, Zubair] Univ Coll Cork, Cork, Ireland. [Kalkonde, Yogeshwar] Soc Educ Act & Res Community Hlth, Gadchiroli, India. [Kamal, Ritul; Kesavachandran, Chandrasekharan Nair] CSIR Indian Inst Toxicol Res, Lucknow, Uttar Pradesh, India. [Kan, Haidong] Fudan Univ, Shanghai, Peoples R China. [Karch, Andre] Helmholtz Ctr Infect Res, Epidemiol & Stat Methods Res Grp, Braunschweig, Germany. [Karch, Andre] German Ctr Infect Res, Hannover Braunschweig Site, Braunschweig, Germany. [Karema, Corine Kakizi] Qual & Equ Hlth Care, Kigali, Rwanda. Case Western Univ Hosp, Cleveland, OH USA. [Kaul, Anil] Oklahoma State Univ, Tulsa, OK USA. [Keiyoro, Peter Njenga] Inst Trop & Infect Dis, Nairobi, Kenya. [Keiyoro, Peter Njenga] Sch Continuing & Distance Educ, Nairobi, Kenya. [Lyons, Ronan A.] Farr Inst, Swansea, W Glam, Wales. [Kemp, Andrew Haddon] Swansea Univ, Swansea, W Glam, Wales. [Keren, Andre] Assuta Hosp, Assuta Hashalom, Tel Aviv, Israel. [Khader, Yousef Saleh] Jordan Univ Sci & Technol, Irbid, Jordan. Hlth Serv Acad, Islamabad, Pakistan. [Khang, Young-Ho] Seoul Natl Univ, Coll Med, Seoul, South Korea. [Won, Sungho] Seoul Natl Univ, Grad Sch Publ Hlth, Seoul, South Korea. [Khera, Sahil] New York Med Coll, Valhalla, NY 10595 USA. [Khoja, Tawfik Ahmed Muthafer] Execut Board Hlth Ministers Council Cooperat Coun, Riyadh, Saudi Arabia. [Khubchandani, Jagdish] Ball State Univ, Muncie, IN 47306 USA. [Kieling, Christian] Hosp Clin Porto Alegre, Porto Alegre, RS, Brazil. [Kim, Cho-il] Korea Hlth Ind Dev Inst, Cheongju, South Korea. [Kim, Daniel] Northeastern Univ, Dept Hlth Sci, Boston, MA 02115 USA. [Kim, Yun Jin] Southern Univ Coll, Skudai, Malaysia. [Knudsen, Ann Kristin; Vollset, Stein Emil] Ctr Dis Burden, Oslo, Norway. [Skogen, Jens Christoffer] Dept Hlth Promot, Oslo, Norway. [Savic, Miloje] Norwegian Inst Publ Hlth, Oslo, Norway. [Kokubo, Yoshihiro] Natl Cerebral & Cardiovasc Ctr, Dept Prevent Cardiol, Suita, Osaka, Japan. [Kolte, Dhaval] Div Cardiol, Providence, RI USA. [McGarvey, Stephen Theodore] Brown Univ, Providence, RI 02912 USA. [Kosen, Soewarta] NIHRD, Ctr Community Empowerment Hlth Policy & Humanitie, Jakarta, Indonesia. [Koul, Parvaiz A.] Sherikashmir Inst Med Sci, Srinagar, Jammu & Kashmir, India. [Koyanagi, Ai] Parc Sanitari Sant Joan de Deu CIBERSAM, Res & Dev Unit, Barcelona, Spain. [Kravchenko, Michael; Varakin, Yuri Y.] Res Ctr Neurol, Moscow, Russia. [Defo, Barthelemy Kuate] Univ Montreal, Dept Demog, Montreal, PQ, Canada. [Defo, Barthelemy Kuate] Univ Montreal, Publ Hlth Res Inst, Montreal, PQ, Canada. [Defo, Barthelemy Kuate] Univ Montreal, Dept Social & Prevent Med, Sch Publ Hlth, Montreal, PQ, Canada. [Bicer, Burcu Kucuk] Hacettepe Univ, Inst Publ Hlth, Ankara, Turkey. [Kudom, Andreas A.] Univ Cape Coast, Cape Coast, Ghana. [Polinder, Suzanne] Dept Publ Hlth, Rotterdam, Netherlands. [Kuipers, Ernst J.] Univ Med Ctr Rotterdam, Erasmus MC, Rotterdam, Netherlands. [Lallukka, Tea; Shiri, Rahman] Finnish Inst Occupat Hlth, Work Disabil Prevent, Work Org, Helsinki, Finland. [Lallukka, Tea] Fac Med, Dept Publ Hlth, Helsinki, Finland. [Meretoja, Tuomo J.] Univ Helsinki, Helsinki, Finland. [Lam, Hilton] Natl Inst Hlth, Inst Hlth Policy & Dev Studies, Manila, Philippines. [Lam, Jennifer O.; Nachega, Jean B.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Tran, Bach Xuan] Johns Hopkins Univ, Baltimore, MD USA. [Langan, Sinead M.; McKee, Martin] London Sch Hyg & Trop Med, London, England. [Lavados, Pablo M.] Univ Desarrollo, Serv Neurol, Clin Alemana, Santiago, Chile. [Leasher, Janet L.] Nova Southeastern Univ, Coll Optometry, Ft Lauderdale, FL 33314 USA. [Leung, Ricky] SUNY Albany, Rensselaer, NY USA. [Levi, Miriam] Tuscany Reg Ctr Occupat Injuries & Dis, Florence, Italy. San Francisco VA Med Ctr, San Francisco, CA USA. [Liang, Juan] Sichuan Univ, West China Univ Hosp 2, Natl Off Maternal & Child Hlth Surveillance, Chengdu, Peoples R China. [Liu, Yang; Phillips, Michael Robert] Emory Univ, Atlanta, GA 30322 USA. [Lloyd, Belinda K.] Monash Univ, Eastern Hlth Clin Sch, Fitzroy, Vic, Australia. [Lloyd, Belinda K.] Eastern Hlth, Melbourne, Vic, Australia. [Lo, Warren D.] Nationwide Childrens Hosp, Columbus, OH USA. [Logroscino, Giancarlo] Univ Bari, Bari, Italy. [Looker, Katharine J.] Univ Bristol, Bristol, Avon, England. [Lunevicius, Raimundas] Aintree Univ Hosp NHS Fdn Trust, Natl Hlth Serv Fdn Trust, Liverpool, Merseyside, England. [Lunevicius, Raimundas] Univ Liverpool, Sch Med, Liverpool, Merseyside, England. [Mackay, Mark T.; Weintraub, Robert G.] Royal Childrens Hosp, Melbourne, Vic, Australia. [Abd El Razek, Mohammed Magdy] Aswan Univ Hosp, Aswan Fac Med, Aswan, Egypt. [Mahdavi, Mandi] Social Secur Org, Res Inst, Tehran, Iran. [Mahdavi, Mandi] Erasmus Univ, Inst Hlth Policy & Management, Rotterdam, Netherlands. [Marcenes, Wagner] Kings Coll London, Inst Dent, Div Populat & Patient Hlth, London, England. [Meaney, Peter A.] Perelman Sch Med, Philadelphia, PA USA. 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[Mueller, Ulrich O.; Westerman, Ronny] Fed Inst Populat Res, Wiesbaden, Germany. [Nachega, Jean B.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. [Paternina Caicedo, Angel J.] Univ Pittsburgh, Publ Hlth Dynam Lab, Pittsburgh, PA USA. [Murdoch, Michele E.] West Herts Hosp NHS Trust, Watford, Hereford, England. [Nachega, Jean B.; Seedat, Soraya; Wiysonge, Charles Shey] Univ Stellenbosch, Cape Town, South Africa. [Nagel, Gabriele; Rothenbacher, Dietrich] Univ Ulm, Inst Epidemiol & Med Biometry, Ulm, Germany. [Naheed, Aliya] Int Ctr Diarrhoeal Dis Res Bangladesh Icddr B, Dhaka, Bangladesh. [Naldi, Luigi; Remuzzi, Giuseppe] Azienda Ospedal Papa Giovanni XXIII, Bergamo, Italy. [Nangia, Vinay] Suraj Eye Inst, Nagpur, Maharashtra, India. [Ngalesoni, Frida Namnyak] Minist Hlth & Social Welf, Dar Es Salaam, Tanzania. [Quyen Le Nguyen] Duy Tan Univ, Inst Global Hlth Innovat, Da Nang, Vietnam. [Nkamedjie Pete, Patrick Martial] Inst Res Socioecon Dev & Commun, Yaounde, Cameroon. Hosp Univ Bellvitge, Lhospitalet De Llobregat, Spain. [Nunes, Bruno P.] Univ Fed Pelotas, Pelotas, Brazil. [Ogbo, Felix Akpojene] Univ Western Sydney, Ctr Hlth Res, Sydney, NSW, Australia. [Oh, In-Hwan] Kyung Hee Univ, Sch Med, Dept Prevent Med, Seoul, South Korea. [Ohkubo, Takayoshi] Teikyo Univ, Sch Med, Tokyo, Japan. [Olivares, Pedro R.] Univ Autonoma Chile, Talca, Chile. [Olusanya, Bolajoko Olubukunola; Olusanya, Jacob Olusegun] Ctr Hlth Start Initiat, Lagos, Nigeria. [Ortiz, Alberto] IIS Fdn Jimenez Diaz UAM, Madrid, Spain. [Osman, Majdi] YBank, Cambridge, MA USA. [Ota, Erika] St Lukes Int Univ, Tokyo, Japan. [Mahesh, P. A.] JSS Univ, JSS Med Coll, Mysore, Karnataka, India. [Park, Eun-Kee] Kosin Univ, Coll Med, Dept Med Humanities & Social Med, Busan, South Korea. [de Azeredo Passos, Valeria Maria] Univ Fed Minas Gerais, Belo Horizonte, MG, Brazil. [Paternina Caicedo, Angel J.] Univ Cartagena, Cartagena, Colombia. [Patten, Scott B.] Dept Community Hlth Sci, Calgary, AB, Canada. [Tonelli, Marcello] Univ Calgary, Calgary, AB, Canada. [Pereira, David M.] Univ Porto, Fac Farm, Dept Quim, REQUIMTE LAQV,Lab Farmacognosia, Oporto, Portugal. [Perez-Padilla, Rogelio] Natl Inst Resp Dis, Mexico City, DF, Mexico. [Pesudovs, Konrad] Flinders Univ Adelaide, Adelaide, SA, Australia. [Petzold, Max] Univ Witwatersrand, Johannesburg, South Africa. [Phillips, Michael Robert] Shanghai Jiao Tong Univ, Sch Med, Shanghai, Peoples R China. [Pillay, Julian David] Durban Univ Technol, Durban, South Africa. [Plass, Dietrich] German Environm Agcy, Exposure Assessment & Environm Hlth Indicators, Berlin, Germany. [Terkawi, Abdullah Sulieman] Dept Anesthesiol, Charlottesville, VA USA. [Platts-Mills, James A.] Univ Virginia, Charlottesville, VA USA. [Pond, Constance D.] Univ Newcastle, Callaghan, NSW, Australia. [Prasad, Noela M.] Fred Hollows Fdn, Sydney, NSW, Australia. [Prasad, Noela M.] Ctr Eye Res Australia, Melbourne, Vic, Australia. 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[Schwebel, David C.; Singh, Jasvinder A.] Univ Alabama Birmingham, Birmingham, AL USA. [Shaheen, Amira] An Najah Univ, Dept Publ Hlth, Nablus, Israel. [Sharma, Rajesh] Indian Inst Technol Ropar, Rupnagar, India. [Sharma, Upasana] ICMR Natl Inst Epidemiol, Chennai, Tamil Nadu, India. [Shen, Jiabin] Nationwide Childrens Hosp, Res Inst, Columbus, OH USA. [Shin, Min-Jeong] Korea Univ, Grad Sch, Dept Publ Hlth Sci, Seoul, South Korea. [Yoon, Seok-Jun] Korea Univ, Coll Med, Dept Prevent Med, Seoul, South Korea. [Shiue, Ivy] Northumbria Univ, Fac Hlth & Life Sci, Newcastle Upon Tyne, Tyne & Wear, England. [Sigfusdottir, Inga Dora] Reykjavik Univ, Reykjavik, Iceland. [Alves Silveira, Dayane Gabriele] Univ Brasilia, Brasilia, DF, Brazil. [Singh, Om Prakash] Banaras Hindu Univ, Inst Med Sci, Dept Med, Varanasi, Uttar Pradesh, India. [Singh, Prashant Kumar] Inst Human Dev, New Delhi, India. [Skogen, Jens Christoffer] Alcohol & Drug Res Western Norway, Stavanger, Norway. 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[Stovner, Lars] St Olavs Hosp, Norwegian Advisory Unit Headache, Trondheim, Norway. [Stroumpoulis, Konstantinos] Alexandra Gen Hosp Athens, Athens, Greece. [Stroumpoulis, Konstantinos] Ctr Hosp Publ Cotentin, Cherbourg, France. [Sunguya, Bruno F.] Muhimbili Univ Hlth & Allied Sci, Dar Es Salaam, Tanzania. [Swaminathan, Soumya] Indian Council Med Res, New Delhi, India. [Sykes, Bryan L.] Univ Calif Irvine, Dept Criminol, Irvine, CA USA. [Sykes, Bryan L.] Univ Calif Irvine, Dept Law & Soc, Irvine, CA USA. [Sykes, Bryan L.] Univ Calif Irvine, Dept Sociol, Irvine, CA USA. [Sykes, Bryan L.] Univ Calif Irvine, Dept Publ Hlth, Irvine, CA USA. [Tabares-Seisdedos, Rafael] Univ Valencia, Dept Med, INCLIVA Hlth Res Inst, Valencia, Spain. [Tabares-Seisdedos, Rafael] CIBERSAM, Valencia, Spain. [Takala, Jukka S.] Minist Manpower, WSH Inst, Singapore, Singapore. [Takala, Jukka S.] Tampere Univ Technol, Tampere, Finland. [Tanne, David] Chaim Sheba Med Ctr, Tel Hashomer, Israel. 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EM tvos@uw.edu RI Tonelli, Marcello/B-3028-2009; Amini, Heresh/B-3076-2010; Lotufo, Paulo/A-9843-2008; Karch, Andre/D-6973-2017; Patten, Scott/B-4434-2011; Scott, James/D-5900-2012; Franklin, Richard/H-1731-2012; Giussani, Giorgia/E-8057-2017; Abbas, Kaja/E-6590-2017; Pereira, David/M-9286-2013; Ribeiro, Antonio/C-2707-2009; Gishu, Melkamu Dedefo/C-3747-2017; Alsharif, Ubai/C-6527-2017; Salomon, Joshua/D-3898-2009; Monasta, Lorenzo/B-1388-2012; Hankey, Graeme /H-4968-2014; Kravchenko, Michael/B-2596-2012; Nagel, Gabriele/C-3635-2012; Patton, George/B-5246-2013; Varakin, Yuriy/C-8634-2012; Martinez-Raga, Jose/B-6251-2017; Majdan, Marek/K-5017-2012; Weiderpass, Elisabete/M-4029-2016 OI Xu, Gelin/0000-0002-6194-0341; Al-Aly, Ziyad/0000-0002-2600-0434; assadi, reza/0000-0002-5016-2994; Heydarpour, Pouria/0000-0001-5644-7555; Vlassov, Vasiliy/0000-0001-5203-549X; Alkerwi, Ala'a/0000-0002-7448-3936; Ahmad Kiadaliri, Aliasghar/0000-0002-4254-9099; Leung, Ricky/0000-0002-2852-6771; Kieling, Christian/0000-0001-7691-4149; Javanbakht, Mehdi/0000-0002-8661-8439; Gething, Peter/0000-0001-6759-5449; Amini, Heresh/0000-0002-4825-1322; Lotufo, Paulo/0000-0002-4856-8450; Karch, Andre/0000-0003-3014-8543; Patten, Scott/0000-0001-9871-4041; Scott, James/0000-0002-0744-0688; Franklin, Richard/0000-0003-1864-4552; Abbas, Kaja/0000-0003-0563-1576; Pereira, David/0000-0003-0384-7592; Sreeramareddy, Chandrashekhar/0000-0002-5693-7631; Miller, Ted/0000-0002-0958-2639; Altirkawi, Khalid/0000-0002-7331-4196; Hoek, Hans/0000-0001-6353-5465; NORMAN, ROSANA/0000-0002-9742-1957; Taylor, Hugh/0000-0002-9437-784X; Kemp, Andrew/0000-0003-1146-3791; Charlson, Fiona/0000-0003-2876-5040; das Neves, Jose/0000-0002-2317-2759; Degenhardt, Louisa/0000-0002-8513-2218; Gouda, Hebe/0000-0002-5709-4509; Awasthi, Ashish/0000-0002-9308-9782; Bisanzio, Donal/0000-0002-7832-2291; Jacobsen, Kathryn/0000-0002-4198-6246; Bernabe, Eduardo/0000-0002-1858-3713; Atique, Suleman/0000-0002-5149-0703; Massano, Joao/0000-0002-5791-7149; Piel, Frederic B./0000-0001-8131-7728; Ribeiro, Antonio/0000-0002-2740-0042; Gishu, Melkamu Dedefo/0000-0002-3466-1232; Alsharif, Ubai/0000-0002-4024-3950; Salomon, Joshua/0000-0003-3929-5515; Monasta, Lorenzo/0000-0001-7774-548X; Hankey, Graeme /0000-0002-6044-7328; Kravchenko, Michael/0000-0001-5187-5518; Nagel, Gabriele/0000-0001-6185-8535; Patton, George/0000-0001-5039-8326; Martinez-Raga, Jose/0000-0002-2856-6562; Majdan, Marek/0000-0001-8037-742X; Weiderpass, Elisabete/0000-0003-2237-0128 FU Bill AMP; Melinda Gates Foundation FX Bill & Melinda Gates Foundation. NR 71 TC 12 Z9 12 U1 94 U2 94 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD OCT 8 PY 2016 VL 388 IS 10053 BP 1545 EP 1602 PG 58 WC Medicine, General & Internal SC General & Internal Medicine GA DY7BU UT WOS:000385285000008 ER PT J AU Kassebaum, NJ Arora, M Barber, RM Bhutta, ZA Carter, A Casey, DC Charlson, FJ Coates, MM Coggeshall, M Cornaby, L Dandona, L Dicker, DJ Erskine, HE Ferrari, AJ Fitzmaurice, C Foreman, K Forouzanfar, MH Fullman, N Gething, PW Goldberg, EM Graetz, N Haagsma, JA Johnson, C Kemmer, L Khalil, IA Kinfu, Y Kutz, MJ Kyu, HH Leung, J Liang, XF Lim, SS Lim, SS Lozano, R Mensah, GA Mikesell, J Mokdad, AH Mooney, MD Naghavi, M Nguyen, G Nsoesie, E Pigott, DM Pinho, C Rankin, Z Reinig, N Salomon, JA Sandar, L Smith, A Sorensen, RJD Stanaway, J Steiner, C Teeple, S Thomas, BA Troeger, C VanderZanden, A Wagner, JA Wanga, V Whiteford, HA Zhou, M Zoeckler, L Abajobir, AA Abate, KH Abbafati, C Abbas, KM Abd-Allah, F Abraham, B Abubakar, I Abu-Raddad, LJ Abu-Rmeileh, NME Achoki, T Ackerman, IN Adebiyi, AO Adedeji, IA Adsuar, JC Afanvi, KA Afshin, A Agardh, EE Agarwal, A Kumar, S Ahmed, MB Kiadaliri, AA Ahmadieh, H Akseer, N Al-Aly, Z Alam, K Alam, NKM Aldhahri, SF Alegretti, MA Aleman, AV Alemu, ZA Alexander, LT Raghib, A Alkerwi, A Alla, F Allebeck, P Alsharif, U Altirkawi, KA Martin, EA Alvis-Guzman, N Amare, AT Amberbir, A Amegah, AK Amini, H Ammar, W Amrock, SM Anderson, GM Anderson, BO Antonio, CAT Anwari, P Arnlov, J Arsenijevic, VSA Artaman, A Asayesh, H Asghar, RJ Avokpaho, EFGA Awasthi, A Quintanilla, BPA Azzopardi, P Bacha, U Badawi, A Balakrishnan, K Banerjee, A Barac, A Barker-Collo, SL Barnighausen, T Barregard, L Barrero, LH Basu, S Bayou, TA Beardsley, J Bedi, N Beghi, E Bell, B Bell, ML Benjet, C Bennett, DA Bensenor, IM Berhane, A Bernabe, E Betsu, BD Beyene, AS Bhala, N Bhansali, A Bhatt, S Biadgilign, S Bienhofff, K Bikbov, B Bin Abdulhak, AA Bisanzio, D Bjertness, E Blore, JD Borschmann, R Boufous, S Bourne, RRA Brainin, M Brazinova, A Breitborde, NJK Brugha, TS Buchbinder, R Buckle, GC Butt, ZA Calabria, B Campos-Nonato, IR Campuzano, JC Carabin, H Carapetis, JR Cardenas, R Carrero, JJ Castaneda-Orjuela, CA Rivas, JC Catala-Lopez, F Cavalleri, F Chang, JC Chiang, PPC Chibalabala, M Chibueze, CE Chisumpa, VH Choi, JYJ Choudhury, L Christensen, H Ciobanu, LG Colistro, V Colomar, M Colquhoun, SM Cortinovis, M Crump, JA Damasceno, A Dandona, R Dargan, PI Das Neves, J Davey, G Davis, AC De Leo, D Degenhardt, L Del Gobbo, LC Derrett, S Des Jarlais, DC Deveber, GA Dharmaratne, SD Dhillon, PK Ding, EL Doyle, KE Driscoll, TR Duan, L Dubey, M Duncan, BB Ebrahimi, H Ellenbogen, RG Elyazar, I Endries, AY Ermakov, SP Eshrati, B Esteghamati, A Estep, K Fahimi, S Farid, TA Farinha, CSES Faro, A Farvid, MS Farzadfar, F Feigin, VL Fereshtehnejad, SM Fernandes, JG Fernandes, JC Fischer, F Fitchett, JRA Foigt, N Fowkes, FGR Franklin, RC Friedman, J Frostad, J Furst, T Futran, ND Gabbe, B Gankpe, FG Garcia-Basteiro, AL Gebrehiwot, TT Gebremedhin, AT Geleijnse, JM Gibney, KB Gillum, RF Ginawi, IAM Giref, AZ Giroud, M Gishu, MD Godwin, WW Gomez-Dantes, H Gona, P Goodridge, A Gopalani, SV Gotay, CC Goto, A Gouda, HN Guo, Y Gupta, R Gupta, R Gupta, V Gutierrez, RA Hafezi-Nejad, N Haile, D Hailu, AD Hailu, GB Halasa, YA Ribhi, R Hamadeh Hamidi, S Hammami, M Handal, AJ Hankey, GJ Harb, HL Harikrishnan, S Haro, JM Hassanvand, MS Hassen, TA Havmoeller, R Hay, RJ Hedayati, MT Heredia-Pi, IB Heydarpour, P Hoek, HW Hoffman, DJ Horino, M Horita, N Hosgood, HD Hoy, DG Hsairi, M Huang, H Huang, JJ Iburg, KM Idrisov, BT Innos, K Inoue, M Jacobsen, KH Jauregui, A Jayatilleke, AU Jeemon, P Jha, V Jiang, GH Jiang, Y Jibat, T Jimenez-Corona, A Jin, Y Jonas, JB Kabir, Z Kajungu, DK Kalkonde, Y Kamal, R Kan, HD Kandel, A Karch, A Karema, CK Karimkhani, C Kasaeian, A Katibeh, M Kaul, A Kawakami, N Kazi, DS Keiyoro, PN Kemp, AH Kengne, AP 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Arsic Artaman, Al Asayesh, Hamid Asghar, Rana Jawad Avokpaho, Euripide Frinel G. Arthur Awasthi, Ashish Quintanilla, Beatriz Paulina Ayala Azzopardi, Peter Bacha, Umar Badawi, Alaa Balakrishnan, Kalpana Banerjee, Amitava Barac, Aleksandra Barker-Collo, Suzanne L. Barnighausen, Till Barregard, Lars Barrero, Lope H. Basu, Sanjay Bayou, Tigist Assefa Beardsley, Justin Bedi, Neeraj Beghi, Ettore Bell, Brent Bell, Michelle L. Benjet, Corina Bennett, Derrick A. Bensenor, Isabela M. Berhane, Adugnaw Bernabe, Eduardo Betsu, Balem Demtsu Beyene, Addisu Shunu Bhala, Neeraj Bhansali, Anil Bhatt, Samir Biadgilign, Sibhatu Bienhofff, Kelly Bikbov, Boris Bin Abdulhak, Aref A. Bisanzio, Donal Bjertness, Espen Blore, Jed D. Borschmann, Rohan Boufous, Soufiane Bourne, Rupert R. A. Brainin, Michael Brazinova, Alexandra Breitborde, Nicholas J. K. Brugha, Traolach S. Buchbinder, Rachelle Buckle, Geoffrey Colin Butt, Zahid A. 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Hafezi-Nejad, Nima Haile, Demewoz Hailu, Alemayehu Desalegne Hailu, Gessessew Bugssa Halasa, Yara A. Ribhi, Randah Hamadeh Hamidi, Samer Hammami, Mouhanad Handal, Alexis J. Hankey, Graeme J. Harb, Hilda L. Harikrishnan, Sivadasanpillai Haro, Josep Maria Hassanvand, Mohammad Sadegh Hassen, Tahir Ahmed Havmoeller, Rasmus Hay, Roderick J. Hedayati, Mohammad T. Heredia-Pi, Ileana Beatriz Heydarpour, Pouria Hoek, Hans W. Hoffman, Daniel J. Horino, Masako Horita, Nobuyuki Hosgood, H. Dean Hoy, Damian G. Hsairi, Mohamed Huang, Hsiang Huang, John J. Iburg, Kim Moesgaard Idrisov, Bulat T. Innos, Kaire Inoue, Manami Jacobsen, Kathryn H. Jauregui, Alejandra Jayatilleke, Achala Upendra Jeemon, Panniyammakal Jha, Vivekanand Jiang, Guohong Jiang, Ying Jibat, Tariku Jimenez-Corona, Aida Jin, Ye Jonas, Jost B. Kabir, Zubair Kajungu, Dan K. Kalkonde, Yogeshwar Kamal, Ritul Kan, Haidong Kandel, Amit Karch, Andre Karema, Corine Kakizi Karimkhani, Chante Kasaeian, Amir Katibeh, Marzieh Kaul, Anil Kawakami, Norito Kazi, Dhruv S. Keiyoro, Peter Njenga Kemp, Andrew Haddon Kengne, Andre Pascal Keren, Andre Kesavachandran, Chandrasekharan Nair Khader, Yousef Saleh Khan, Abdur Rahman Khan, Ejaz Ahmad Khang, Young-Ho Khoja, Tawfik Ahmed Muthafer Khubchandani, Jagdish Kieling, Christian Kim, Cho-il Kim, Daniel Kim, Yun Jin Kissoon, Niranjan Kivipelto, Miia Knibbs, Luke D. Knudsen, Ann Kristin Kokubo, Yoshihiro Kolte, Dhaval Kopec, Jacek A. Koul, Parvaiz A. Koyanagi, Ai Defo, Barthelemy Kuate Kuchenbecker, Ricardo S. Bicer, Burcu Kucuk Kuipers, Ernst J. Kumar, G. Anil Kwan, Gene F. Lalloo, Ratilal Lallukka, Tea Larsson, Anders Latif, Asma Abdul Lavados, Pablo M. Lawrynowicz, Alicia Elena Beatriz Leasher, Janet L. Leigh, James Leung, Ricky Li, Yichong Li, Yongmei Lipshultz, Steven E. Liu, Patrick Y. Liu, Yang Lloyd, Belinda K. Logroscino, Giancarlo Looker, Katharine J. Lotufo, Paulo A. Lucas, Robyn M. Lunevicius, Raimundas Lyons, Ronan A. El Razek, Hassan Magdy Abd Mandavi, Mandi Majdan, Marek Majeed, Azeem Malekzadeh, Reza Malta, Deborah Carvalho Marcenes, Wagner Martinez-Raga, Jose Masiye, Felix Mason-Jones, Amanda J. Matzopoulos, Richard Mayosi, Bongani M. McGrath, John J. Mckee, Martin Meaney, Peter A. Mehari, Alem Melaku, Yohannes Adama Memiah, Peter Memish, Ziad A. Mendoza, Walter Meretoja, Atte Meretoja, Tuomo J. Mesfin, Yonatan Moges Mhimbira, Francis Apolinary Miller, Ted R. Mills, Edward J. Mirarefin, Mojde Mirrakhimov, Erkin M. Mitchell, Philip B. Mock, Charles N. Mohammad, Karzan Abdulmuhsin Mohammadi, Alireza Mohammed, Shafiu Monasta, Lorenzo Montanez Hernandez, Julio Cesar Montico, Marcella Moradi-Lakeh, Maziar Mori, Rintaro Mueller, Ulrich O. Mumford, John Everett Murdoch, Michele E. Murthy, Gudlavalleti Venkata Satyanarayana Nachega, Jean B. Naheed, Aliya Naldi, Luigi Nangia, Vinay Newton, John N. Ng, Marie Ngalesoni, Frida Namnyak Le Nguyen, Quyen Nisar, Muhammad Imran Pete, Patrick Martial Nkamedjie Nolla, Joan M. Norheim, Ole F. Norman, Rosana E. Norrving, Bo Obermeyer, Carla Makhlouf Ogbo, Felix Akpojene Oh, In-Hwan Oladimeji, Olanrewaju Olivares, Pedro R. Olusanya, Bolajoko Olubukunola Olusanya, Jacob Olusegun Oren, Eyal Ortiz, Alberto Ota, Erika Oyekale, Abayomi Samuel Pa, Mahesh Park, Eun-Kee Parsaeian, Mahboubeh Patten, Scott B. Patton, George C. Pedro, Joao Mario Pereira, David M. Perico, Norberto Pesudovs, Konrad Petzold, Max Phillips, Michael Robert Piel, Frederic B. Pillay, Julian David Pishgar, Farhad Plass, Dietrich Polinder, Suzanne Popova, Svetlana Poulton, Richie G. Pourmalek, Farshad Prasad, Noela M. Qorbani, Mostafa Rabiee, Rynaz H. S. Radfar, Amir Rafay, Anwar Rahimi, Kazem Rahimi-Movaghar, Vafa Rahman, Mahfuzar Rahman, Mohammad Hifz Ur Rahman, Sajjad Ur Rai, Dheeraj Rai, Rajesh Kumar Rajsic, Sasa Raju, Murugesan Ram, Usha Ranganathan, Kavitha Refaat, Amany H. Reitsma, Marissa B. Remuzzi, Giuseppe Resnikoff, Serge Reynolds, Alex Ribeiro, Antonio L. Ricci, Stefano Roba, Hirbo Shore Rojas-Rueda, David Ronfani, Luca Roshandel, Gholamreza Roth, Gregory A. Roy, Ambuj Sackey, Ben Benasco Sagar, Rajesh Sanabria, Juan R. Dolores Sanchez-Nino, Maria Santos, Itamar S. Santos, Joao Vasco Sarmiento-Suarez, Rodrigo Sartorius, Benn Satpathy, Maheswar Savic, Miloje Sawhney, Monika Schmidt, Maria Ines Schneider, Ione J. C. Schutte, Aletta E. Schwebel, David C. Seedat, Soraya Sepanlou, Sadaf G. Servan-Mori, Edson E. Shahraz, Saeid Shaikh, Masood Ali Sharma, Rajesh She, Jun Sheikhbahaei, Sara Shen, Jiabin Sheth, Kevin N. Shibuya, Kenji Shigematsu, Mika Shin, Min-Jeong Shin, Rahman Sigfusdottir, Inga Dora Santos Silva, Diego Augusto Silverberg, Jonathan I. Simard, Edgar P. Singh, Abhishek Singh, Jasvinder A. Singh, Prashant Kumar Skirbekk, Vegard Skogen, Jens Christoffer Soljak, Michael Soreide, Kjetil Sorensen, Reed J. D. Sreeramareddy, Chandrashekhar T. Stathopoulou, Vasiliki Steel, Nicholas Stein, Dan J. Stein, Murray B. Steiner, Timothy J. Stovner, Lars Jacob Stranges, Saverio Stroumpoulis, Konstantinos Sunguya, Bruno F. Sur, Patrick J. Swaminathan, Soumya Sykes, Bryan L. Szoeke, Cassandra E. I. Tabares-Seisdedos, Rafael Landon, Nikhil Tanne, David Tavakkoli, Mohammad Taye, Bineyam Taylor, Hugh R. Ao, Braden J. Te Tegegne, Teketo Kassaw Tekle, Dejen Yemane Terkawi, Abdullah Sulieman Tessema, Gizachew Assefa Thakur, J. S. Thomson, Alan J. Thorne-Lyman, Andrew L. Thrift, Amanda G. Thurston, George D. Tobe-Gai, Ruoyan Tonelli, Marcello Topor-Madry, Roman Topouzis, Fotis Tran, Bach Xuan Dimbuene, Zacharie Tsala Tsilimbaris, Miltiadis Tura, Abera Kenay Tuzcu, Emin Murat Tyrovolas, Stefanos Ukwaja, Kingsley N. Undurraga, Eduardo A. Uneke, Chigozie Jesse Uthman, Olalekan A. van Gool, Coen H. van Os, Jim Vasankari, Tommi Vasconcelos, Ana Maria Nogales Venketasubramanian, Narayanaswamy Violante, Francesco S. Vlassov, Vasiliy Victorovich Vollset, Stein Emil Wagner, Gregory R. Wallin, Mitchell T. Wang, Linhong Weichenthal, Scott Weiderpass, Elisabete Weintraub, Robert G. Werdecker, Andrea WestermaM, Ronny Wijeratne, Tissa Wilkinson, James D. Williams, Hywel C. Wiysonge, Charles Shey Woldeyohannes, Solomon Meseret Wolfe, Charles D. A. Won, Sungho Xu, Gelin Yadav, Ajit Kumar Yakob, Bereket Yan, Lijing L. Yan, Yuichiro Yaseri, Mehdi Ye, Pengpeng Yip, Paul Yonemoto, Naohiro Yoon, Seok-Jun Younis, Mustafa Z. Yu, Chuanhua Zaidi, Zoubida Zaki, Maysaa El Sayed Zeeb, Hajo Zodpey, Sanjay Zonies, David Zuhlke, Liesl Joanna Zeeb, Hajo Zodpey, Sanjay Zonies, David Zuhlke, Liesl Joanna Vos, Theo Lopez, Alan D. Murray, Christopher J. L. CA GBD 2015 DALY & HALE TI Global, regional, and national disability-adjusted life-years (DALYs) for 315 diseases and injuries and healthy life expectancy (HALE), 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015 SO LANCET LA English DT Article ID SUSTAINABLE DEVELOPMENT GOALS; UNITED-STATES; 187 COUNTRIES; BACK-PAIN; COMPRESSION; TRENDS; RECOMMENDATIONS; PREVALENCE; MORBIDITY; MORTALITY AB Background Healthy life expectancy (HALE) and disability-adjusted life-years (DALYs) provide summary measures of health across geographies and time that can inform assessments of epidemiological patterns and health system performance, help to prioritise investments in research and development, and monitor progress toward the Sustainable Development Goals (SDGs). We aimed to provide updated HALE and DALYs for geographies worldwide and evaluate how disease burden changes with development. Methods We used results from the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015) for all-cause mortality, cause-specific mortality, and non-fatal disease burden to derive HALE and DALYs by sex for 195 countries and territories from 1990 to 2015. We calculated DALYs by summing years of life lost (YLLs) and years of life lived with disability (YLDs) for each geography, age group, sex, and year. We estimated HALE using the Sullivan method, which draws from age-specific death rates and YLDs per capita. We then assessed how observed levels of DALYs and HALE differed from expected trends calculated with the Socio-demographic Index (SDI), a composite indicator constructed from measures of income per capita, average years of schooling, and total fertility rate. Findings Total global DALYs remained largely unchanged from 1990 to 2015, with decreases in communicable, neonatal, maternal, and nutritional (Group 1) disease DALYs off set by increased DALYs due to non-communicable diseases (NCDs). Much of this epidemiological transition was caused by changes in population growth and ageing, but it was accelerated by widespread improvements in SDI that also correlated strongly with the increasing importance of NCDs. Both total DALYs and age-standardised DALY rates due to most Group 1 causes significantly decreased by 2015, and although total burden climbed for the majority of NCDs, age-standardised DALY rates due to NCDs declined. Nonetheless, age-standardised DALY rates due to several high-burden NCDs (including osteoarthritis, drug use disorders, depression, diabetes, congenital birth defects, and skin, oral, and sense organ diseases) either increased or remained unchanged, leading to increases in their relative ranking in many geographies. From 2005 to 2015, HALE at birth increased by an average of 2.9 years (95% uncertainty interval 2.9-3.0) for men and 3.5 years (3.4-3.7) for women, while HALE at age 65 years improved by 0.85 years (0.78-0.92) and 1.2 years (1.1-1.3), respectively. Rising SDI was associated with consistently higher HALE and a somewhat smaller proportion of life spent with functional health loss; however, rising SDI was related to increases in total disability. Many countries and territories in central America and eastern sub-Saharan Africa had increasingly lower rates of disease burden than expected given their SDI. At the same time, a subset of geographies recorded a growing gap between observed and expected levels of DALYs, a trend driven mainly by rising burden due to war, interpersonal violence, and various NCDs. Interpretation Health is improving globally, but this means more populations are spending more time with functional health loss, an absolute expansion of morbidity. The proportion of life spent in ill health decreases somewhat with increasing SDI, a relative compression of morbidity, which supports continued efforts to elevate personal income, improve education, and limit fertility. Our analysis of DALYs and HALE and their relationship to SDI represents a robust framework on which to benchmark geography-specific health performance and SDG progress. Country-specific drivers of disease burden, particularly for causes with higher-than-expected DALYs, should inform financial and research investments, prevention efforts, health policies, and health system improvement initiatives for all countries along the development continuum. Copyright (C) The Author(s). Published by Elsevier Ltd. C1 [Kassebaum, Nicholas J.; Arora, Megha; Barber, Ryan M.; Carter, Austin; Casey, Daniel C.; Charlson, Fiona J.; Coates, Matthew M.; Coggeshall, Megan; Cornaby, Leslie; Dandona, Lalit; Dicker, Daniel J.; Erskine, Holly E.; Ferrari, Alize J.; Fitzmaurice, Christina; Foreman, Kyle; Forouzanfar, Mohammad H.; Fullman, Nancy; Goldberg, Ellen M.; Haagsma, Juanita A.; Johnson, Catherine; Kemmer, Laura; Khalil, Ibrahim A.; Kinfu, Yohannes; Kutz, Michael J.; Kyu, Hmwe H.; Leung, Janni; Lim, Stephen S.; Lozano, Rafael; Mikesell, Joe; Mokdad, Ali H.; Mooney, Meghan D.; Naghavi, Mohsen; Nguyen, Grant; Nsoesie, Elaine; Pigott, David M.; Pinho, Christine; Rankin, Zane; Reinig, Nikolas; Salomon, Joshua A.; Sandar, Logan; Smith, Alison; Sorensen, Reed J. D.; Stanaway, Jeffrey; Steiner, Caitlyn; Teeple, Stephanie; Thomas, Bernadette A.; Troeger, Chris; VanderZanden, Amelia; Wagner, Joseph A.; Wanga, Valentine; Whiteford, Harvey A.; Zhou, Maigeng; Zoeckler, Leo; Achoki, Tom; Afshin, Ashkan; Alexander, Lily T.; Anderson, Gregory M.; Bienhofff, Kelly; Blore, Jed D.; Estep, Kara; Friedman, Joseph; Frostad, Joseph; Godwin, William W.; Hankey, Graeme J.; Liu, Patrick Y.; Masiye, Felix; Mirarefin, Mojde; Moradi-Lakeh, Maziar; Mumford, John Everett; Ng, Marie; Reitsma, Marissa B.; Reynolds, Alex; Roth, Gregory A.; Sur, Patrick J.; Vollset, Stein Emil; Vos, Theo; Lopez, Alan D.; Murray, Christopher J. L.] Inst Hlth Metr & Evaluat, Seattle, WA USA. [Ellenbogen, Richard G.] Harborview UW Med, Seattle, WA USA. [Mock, Charles N.] Harborview Injury Prevent & Res Ctr, Seattle, WA USA. [Anderson, Benjamin O.; Futran, Neal D.] Univ Washington, Seattle, WA 98195 USA. [Bhutta, Zulfigar A.] Ctr Excellence Women & Child Hlth, Karachi, Pakistan. [Nisar, Muhammad Imran] Aga Khan Univ, Karachi, Pakistan. [Bhutta, Zulfigar A.; Akseer, Nadia] Ctr Global Child Hlth, Toronto, ON, Canada. [Deveber, Gabrielle A.] Hosp Sick Children, Toronto, ON, Canada. [Charlson, Fiona J.; Erskine, Holly E.; Ferrari, Alize J.; Leung, Janni; Whiteford, Harvey A.; Abajobir, Amanuel Alemu; Knibbs, Luke D.] Univ Queensland, Sch Publ Hlth, Brisbane, Qld, Australia. [Lalloo, Ratilal] Univ Queensland, Sch Dent, Brisbane, Qld, Australia. [Alam, Noore K. M.; Gouda, Hebe N.; Guo, Yuming; McGrath, John J.] Univ Queensland, Brisbane, Qld, Australia. [Charlson, Fiona J.; Erskine, Holly E.; Ferrari, Alize J.; Leung, Janni; Whiteford, Harvey A.] Queensland Ctr Mental Hlth Res, Brisbane, Qld, Australia. [Jeemon, Panniyammakal] Ctr Control Chron Condit, New Delhi, India. [Dandona, Lalit; Dandona, Rakhi; Kumar, G. Anil] Publ Hlth Fdn India, New Delhi, India. [Gething, Peter W.] Univ Oxford, Dept Zool, Oxford, England. [Bisanzio, Donal] Univ Oxford, Nuffield Dept Med, Oxford, England. [Raghib, Ali; Bennett, Derrick A.; Jha, Vivekanand; Rahimi, Kazem] Univ Oxford, Oxford, England. [Haagsma, Juanita A.] Univ Med Ctr, Dept Publ Hlth, Erasmus MC, Rotterdam, Netherlands. [Kinfu, Yohannes] Univ Canberra, Fac Hlth, Ctr Res Action Publ Hlth, Canberra, ACT, Australia. [Zhou, Maigeng; Duan, Leilei; Jin, Ye; Li, Yichong; Wang, Linhong] Natl Ctr Chron & Noncommunicable Dis Control & Pr, Beijing, Peoples R China. [Liang, Xiaofeng] Chinese Ctr Dis Control & Prevent, Beijing, Peoples R China. [Mensah, George A.] NHLBI, NIH, Ctr Translat Res & Implementat Sci, Bldg 10, Bethesda, MD 20892 USA. [Salomon, Joshua A.] Harvard Univ, Dept Global Hlth & Populat, Boston, MA 02115 USA. [Thorne-Lyman, Andrew L.] Harvard Univ, Dept Nutr, Boston, MA 02115 USA. [Barnighausen, Till; Campos-Nonato, Ismael Ricardo; Ding, Eric L.; Farvid, Maryam S.; Wagner, Gregory R.] Harvard Univ, Harvard T H Chan Sch Publ Hlth, Boston, MA 02115 USA. [Fitchett, Joseph R. A.] Harvard Univ, Boston, MA 02115 USA. [Abate, Kalkidan Hassen; Ahmed, Muktar Beshir; Gebrehiwot, Tsegaye Tewelde; Gebremedhin, Amanuel Tesfay] Jimma Univ, Jimma, Ethiopia. [Abbafati, Cristiana] Univ Roma La Sapienza, Rome, Italy. [Abbas, Kaja M.] Virginia Tech, Blacksburg, VA USA. [Abd-Allah, Foad] Cairo Univ, Dept Neurol, Cairo, Egypt. [Abraham, Biju] NM SM Govt Coll, Kalpetta, Kerala, India. [Abubakar, Ibrahim] Inst Global Hlth, London, England. [Banerjee, Amitava] Farr Inst Hlth Informat Res, London, England. [Abu-Raddad, Laith J.] Weill Cornell Med Coll Qatar, Infect Dis Epidemiol Grp, Doha, Qatar. [Abu-Raddad, Laith J.] Birzeit Univ, Inst Community & Publ Hlth, Ramallah, Israel. [Abu-Rmeileh, Niveen M. E.] Birzeit Univ, Inst Community & Publ Hlth, Ramallah, Israel. [Ackerman, Ilana N.; Buchbinder, Rachelle; Gabbe, Belinda] Monash Univ, Dept Epidemiol & Prevent Med, Sch Publ Hlth & Prevent Med, Melbourne, Vic, Australia. [Thrift, Amanda G.] Monash Univ, Dept Med, Sch Clin Sci Monash Hlth, Melbourne, Vic, Australia. [Lloyd, Belinda K.] Monash Univ, Eastern Hlth Clin Sch, Melbourne, Vic, Australia. [Adebiyi, Akindele Olupelumi] Univ Ibadan, Coll Med, Ibadan, Nigeria. [Adebiyi, Akindele Olupelumi] Univ Coll Hosp, Ibadan, Nigeria. [Adedeji, Isaac Akinkunmi] Olabisi Onabanjo Univ, Ago Iwoye, Nigeria. [Adsuar, Jose C.] Univ Extremadura, Caceres, Spain. [Afanvi, Kossivi Agbelenko] Direct Dist Sanitaire Haho, Notse, Togo. [Afanvi, Kossivi Agbelenko] Univ Lome, Fac Sci Sante, Lome, Togo. [Agardh, Emilie Elisabet] Inst Publ Hlth Sci, Stockholm, Sweden. [Akseer, Nadia] Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [Badawi, Alaa] Fac Med, Dept Nutrit Sci, Toronto, ON, Canada. [Popova, Svetlana] Ctr Addict & Mental Hlth, Toronto, ON, Canada. [Agarwal, Arnav] Univ Toronto, Toronto, ON, Canada. [Agarwal, Arnav] McMaster Univ, Hamilton, ON, Canada. [Roy, Ambuj; Sagar, Rajesh; Satpathy, Maheswar] All India Inst Med Sci, New Delhi, India. [Kiadaliri, Aliasghar Ahmad] Lund Univ, Dept Clin Sci Lund, Orthoped, Clin Epidemiol Unit, Lund, Sweden. [Norrving, Bo] Lund Univ, Skane Univ Hosp, Dept Clin Sci Lund, Lund, Sweden. [Kiadaliri, Aliasghar Ahmad] Kerman Univ Med Sci, Inst Futures Studies Hlth, Hlth Serv Management Res Ctr, Kerman, Iran. [Ahmadieh, Hamid] Shahid Beheshti Univ Med Sci, Ophthalm Res Ctr, Tehran, Iran. [Katibeh, Marzieh] Shahid Beheshti Univ Med Sci, Ophthalm Epidemiol Res Ctr, Tehran, Iran. [Ahmadieh, Hamid] Labbafinejad Med Ctr, Dept Ophthalmol, Tehran, Iran. [Al-Aly, Ziyad] Washington Univ, St Louis, MO USA. [Alam, Khurshid; Azzopardi, Peter; Borschmann, Rohan; Colquhoun, Samantha M.; Patton, George C.; Weintraub, Robert G.] Murdoch Childrens Res Inst, Melbourne, Vic, Australia. [Azzopardi, Peter] Dept Paediat, Melbourne, Vic, Australia. [Meretoja, Atte] Dept Med, Melbourne, Vic, Australia. [Szoeke, Cassandra E. I.] Inst Hlth & Ageing, Melbourne, Vic, Australia. [Lopez, Alan D.] Melbourne Sch Populat & Global Hlth, Melbourne, Vic, Australia. [Alam, Khurshid; Borschmann, Rohan; Taylor, Hugh R.; Wijeratne, Tissa] Univ Melbourne, Melbourne, Vic, Australia. [Driscoll, Tim R.] Sydney Sch Publ Hlth, Sydney, NSW, Australia. [Alam, Khurshid; Kemp, Andrew Haddon; Leigh, James] Univ Sydney, Sydney, NSW, Australia. [Alam, Noore K. M.] Queensland Hlth, Herston, Qld, Australia. [Aldhahri, Saleh Fahed; Altirkawi, Khalid A.] King Saud Univ, Riyadh, Saudi Arabia. [Terkawi, Abdullah Sulieman] Dept Anesthesiol, Riyadh, Saudi Arabia. [Aldhahri, Saleh Fahed] King Fahad Med City, Riyadh, Saudi Arabia. [Alegretti, Miguel Angel] Fac Med, Dept Prevent & Social Med, Montevideo, Uruguay. [Aleman, Alicia V.] Sch Med, Montevideo, Uruguay. [Cavalleri, Fiorella] Fac Med, Montevideo, Uruguay. [Colistro, Valentina] Univ Republica, Montevideo, Uruguay. [Alemu, Zewdie Aderaw; Tegegne, Teketo Kassaw] Debre Markos Univ, Debre Markos, Ethiopia. [Alkerwi, Ala'a; Stranges, Saverio] LIH, Strassen, Luxembourg. [Alla, Francois] Univ Lorraine, Sch Publ Hlth, Nancy, France. [Allebeck, Peter; Rabiee, Rynaz H. S.] Karolinska Inst, Dept Publ Hlth Sci, Stockholm, Sweden. [Carrero, Juan Jesus] Karolinska Inst, Dept Clin Sci Intervent & Technol, Stockholm, Sweden. [Fereshtehnejad, Seyed-Mohammad] Karolinska Inst, Dept Neurobiol Care Sci & Soc NVS, Stockholm, Sweden. [Kivipelto, Miia] Karolinska Inst, Aging Res Ctr, Stockholm, Sweden. [Weiderpass, Elisabete] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Havmoeller, Rasmus] Karolinska Inst, Stockholm, Sweden. [Alsharif, Ubai] Charite, Berlin, Germany. [Martin, Elena Alvarez] Minist Hlth Social Policy & Equal, Spanish Observ Drugs, Govt Delegat Natl Plan Drugs, Madrid, Spain. [Alvis-Guzman, Nelson] Univ Cartagena, Cartagena Indias, Colombia. [Amare, Azmeraw T.; Melaku, Yohannes Adama] Univ Adelaide, Sch Med, Adelaide, SA, Australia. [Ciobanu, Liliana G.; Tessema, Gizachew Assefa] Univ Adelaide, Adelaide, SA, Australia. [Amare, Azmeraw T.] Bahir Dar Univ, Coll Med & Hlth Sci, Bahir Dar, Ethiopia. [Amberbir, Alemayehu] Dignitas Int, Zomba, Malawi. [Amegah, Adeladza Kofi] Univ Cape Coast, Cape Coast, Ghana. [Amegah, Adeladza Kofi] Natl Hosp, Abuja, Nigeria. [Amini, Heresh] Kurdistan Univ Med Sci, Environm Hlth Res Ctr, Sanandaj, Iran. [Amini, Heresh; Furst, Thomas] Swiss Trop & Publ Hlth Inst, Dept Epidemiol & Publ Hlth, Basel, Switzerland. [Karema, Corine Kakizi] Swiss Trop & Publ Hlth Inst, Basel, Switzerland. [Amini, Heresh; Furst, Thomas] Univ Basel, Basel, Switzerland. [Ammar, Walid; Harb, Hilda L.] Minist Publ Hlth, Beirut, Lebanon. [Amrock, Stephen Marc; Zonies, David] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Antonio, Carl Abelardo T.] Univ Philippines, Dept Hlth Policy & Adm, Coll Publ Hlth, Manila, Philippines. Uppsala Univ, Dept Med Sci, Uppsala, Sweden. [Anwari, Palwasha] Self Employed, Kabul, Afghanistan. [Arnlov, Johan; Larsson, Anders] Uppsala Univ, Dept Med Sci, Uppsala, Sweden. [Arnlov, Johan] Dalarna Univ, Falun, Sweden. [Arsenijevic, Valentina S. Arsic] Univ Belgrade, Inst Microbiol & Immunol, Sch Med, Belgrade, Serbia. [Barac, Aleksandra] Univ Belgrade, Fac Med, Belgrade, Serbia. [Arsenijevic, Valentina S. Arsic; Giref, Ababi Zergaw] Univ Children Hosp, Belgrade, Serbia. [Artaman, Al] Univ Manitoba, Winnipeg, MB, Canada. [Asayesh, Hamid] Qom Univ Med Sci, Sch Paramed, Dept Emergency Med, Qom, Iran. [Asghar, Rana Jawad] South Asian Publ Hlth Forum, Islamabad, Pakistan. [Avokpaho, Euripide Frinel G. Arthur] Inst Rech Clin Benin, Cotonou, Benin. [Avokpaho, Euripide Frinel G. Arthur; Gankpe, Fortune Gbetoho] Lab dEtud & Rech Action Sante LERAS Afr, Parakou, Benin. [Awasthi, Ashish] Sanjay Gandhi Postgrad Inst Med Sci, Lucknow, Uttar Pradesh, India. [Quintanilla, Beatriz Paulina Ayala] Trobe Univ, Judith Lumley Ctr Mother, Infant & Family Hlth Res, Melbourne, Vic, Australia. [Quintanilla, Beatriz Paulina Ayala] Peruvian Natl Inst Hlth, Lima, Peru. [Azzopardi, Peter] South Australian Hlth & Med Res Inst, Wardliparingga Aboriginal Res Unit, Adelaide, SA, Australia. [Bacha, Umar] Univ Management & Technol, Sch Hlth Sci, Lahore, Pakistan. [Badawi, Alaa] Publ Hlth Agcy Canada, Toronto, ON, Canada. [Balakrishnan, Kalpana] Sri Ramachandra Univ, Dept Environm Hlth Engn, Chennai, Tamil Nadu, India. [Barker-Collo, Suzanne L.] Univ Auckland, Sch Psychol, Auckland, New Zealand. [Barnighausen, Till] Africa Hlth Res Inst, Mtubatuba, South Africa. [Barnighausen, Till; Mohammed, Shafiu] Heidelberg Univ, Inst Publ Hlth, Heidelberg, Germany. [Barregard, Lars] Univ Gothenburg, Dept Occupat & Environm Hlth, Gothenburg, Sweden. [Petzold, Max] Univ Gothenburg, Hlth Metr Unit, Gothenburg, Sweden. [Barrero, Lope H.] Pontificia Univ Javeriana, Sch Engn, Dept Ind Engn, Bogota, Colombia. [Basu, Sanjay; Del Gobbo, Liana C.] Stanford Univ, Stanford, CA 94305 USA. [Melaku, Yohannes Adama] Mekelle Univ, Sch Publ Hlth, Mekelle, Ethiopia. [Bayou, Tigist Assefa; Betsu, Balem Demtsu; Hailu, Gessessew Bugssa; Tekle, Dejen Yemane] Mekelle Univ, Mekelle, Ethiopia. [Beardsley, Justin] Univ Oxford, Ho Chi Minh City, Oxford, Vietnam. [Bedi, Neeraj] Coll Publ Hlth & Trop Med, Jazan, Saudi Arabia. [Beghi, Ettore; Cortinovis, Monica] IRCCS Ist Ric Farmacol Mario Negri, Milan, Italy. [Sheth, Kevin N.] Yale Univ, Sch Med, New Haven, CT USA. [Bell, Michelle L.; Huang, John J.] Yale Univ, New Haven, CT USA. [Benjet, Corina; Gutierrez, Reyna A.] Natl Inst Psychiat Ramon Fuente, Mexico City, DF, Mexico. [Santos, Itamar S.] Univ Sao Paulo, Dept Internal Med, Sao Paulo, Brazil. [Bensenor, Isabela M.; Lotufo, Paulo A.] Univ Sao Paulo, Sao Paulo, Brazil. [Berhane, Adugnaw] Debre Berhane Univ, Debre Berhan, Ethiopia. [Wolfe, Charles D. A.] Kings Coll London, Div Hlth & Social Care Res, London, England. [Bernabe, Eduardo; Hay, Roderick J.] Kings Coll London, London, England. [Roba, Hirbo Shore] Haramaya Univ, Coll Hlth & Med Sci, Harar, Ethiopia. [Beyene, Addisu Shunu; Hassen, Tahir Ahmed; Mesfin, Yonatan Moges] Haramaya Univ, Harar, Ethiopia. [Bhala, Neeraj] Queen Elizabeth Hosp Birmingham, Birmingham, W Midlands, England. [Bhala, Neeraj] Univ Otago Med Sch, Wellington, New Zealand. [Bhansali, Anil] Postgrad Inst Med Educ & Res, Chandigarh, India. [Furst, Thomas] Imperial Coll London, Dept Infect Dis Epidemiol, London, England. [Piel, Frederic B.] Imperial Coll London, Dept Epidemiol & Biostat, London, England. [Steiner, Timothy J.] Imperial Coll London, Div Brain Sci, London, England. [Bhatt, Samir; Majeed, Azeem; Soljak, Michael] Imperial Coll London, London, England. [Biadgilign, Sibhatu] Independent Publ Hlth Consultants, Addis Ababa, Ethiopia. [Bikbov, Boris] Acad Shumakov Fed Res Ctr Transplantol & Artifici, Dept Nephrol Issues Transplanted Kidney, Moscow, Russia. [Bin Abdulhak, Aref A.] Univ Iowa Hosp & Clin, Iowa City, IA 52242 USA. [Bjertness, Espen] Univ Oslo, Dept Community Med, Oslo, Norway. [Bourne, Rupert R. A.] Anglia Ruskin Univ, Vision Eye Res Unit, Cambridge, England. [Brainin, Michael] Danube Univ Krems, Krems, Austria. [Brazinova, Alexandra; Majdan, Marek] Trnava Univ, Fac Hlth Sci & Social Work, Dept Publ Hlth, Trnava, Slovakia. [Brazinova, Alexandra] Int Neurotrauma Res Org, Vienna, Austria. [Shen, Jiabin] Ohio State Univ, Coll Med, Columbus, OH 43210 USA. [Breitborde, Nicholas J. K.] Ohio State Univ, Columbus, OH 43210 USA. German Canc Res Ctr, Heidelberg, Germany. [Brugha, Traolach S.] Univ Leicester, Leicester, Leics, England. [Buchbinder, Rachelle] Cabrini Inst, Monash Dept Clin Epidemiol, Melbourne, Vic, Australia. [Buckle, Geoffrey Colin] Univ Calif San Francisco, San Francisco, CA USA. [Butt, Zahid A.] Shifa Trust Eye Hosp, Rawalpindi, Pakistan. [Calabria, Bianca; Lucas, Robyn M.] Australian Natl Univ, Natl Ctr Epidemiol & Populat Hlth, Canberra, ACT, Australia. [Boufous, Soufiane] Transport & Rd Safety TARS Res, Kensington, NSW, Australia. [Degenhardt, Louisa] Natl Drug & Alcohol Res Ctr, Kensington, NSW, Australia. [Resnikoff, Serge] Brien Holden Vision Inst, Kensington, NSW, Australia. [Calabria, Bianca; Mitchell, Philip B.] Univ New S Wales, Kensington, NSW, Australia. [Campos-Nonato, Ismael Ricardo; Campuzano, Julio Cesar; Gomez-Dantes, Hector; Heredia-Pi, Ileana Beatriz; Jauregui, Alejandra; Montanez Hernandez, Julio Cesar; Servan-Mori, Edson E.] Natl Inst Publ Hlth, Cuernavaca, Morelos, Mexico. [Carabin, Helene] Univ Oklahoma Hlth Sci Ctr, Dept Biostat & Epidemiol, Oklahoma City, OK USA. [Carapetis, Jonathan R.] Univ Western Australia, Telethon Kids Inst, Princess Margaret Hosp Children, Subiaco, WA, Australia. [Cardenas, Rosario] Metropolitan Autonomous Univ, Mexico City, DF, Mexico. [Castaneda-Orjuela, Carlos A.] Colombian Natl Hlth Observ, Inst Nacl Salud, Bogota, Colombia. [Castaneda-Orjuela, Carlos A.] Univ Nacl Colombia, Epidemiol & Publ Hlth Evaluat Grp, Dept Publ Hlth, Bogota, Colombia. [Rivas, Jacqueline Castillo] Caja Costarricense Seguro Social, San Jose, Costa Rica. [Rivas, Jacqueline Castillo] Univ Costa Rica, San Pedro, Montes De Oca, Costa Rica. [Catala-Lopez, Ferran; Tabares-Seisdedos, Rafael] Univ Valencia, Dept Med, INCLIVA Hlth Res Inst & CIBERSAM, Valencia, Spain. [Catala-Lopez, Ferran] Ottawa Hosp Res Inst, Clin Epidemiol Program, Ottawa, ON, Canada. [Chang, Jung-Chen] Natl Taiwan Univ, Sch Nursing, Coll Med, Taipei, Taiwan. [Chiang, Peggy Pei-Chia] Clin Governance Unit, Gold Coast Hlth, Southport, Qld, Australia. [Chibalabala, Mirriam] Crowd Watch Afr, Lusaka, Zambia. [Chibueze, Chioma Ezinne; Mori, Rintaro] Natl Ctr Child Hlth & Dev, Tokyo, Japan. [Chisumpa, Vesper Hichilombwe; Masiye, Felix] Univ Zambia, Lusaka, Zambia. [Chisumpa, Vesper Hichilombwe] Univ Witwatersrand, Johannesburg, South Africa. [Choi, Jee-Young Jasmine] Seoul Natl Univ Med Lib, Seoul, South Korea. [Choudhury, Lincoln] World Bank, New Delhi, India. [Christensen, Hanne] Bispebjerg Hosp, Copenhagen, Denmark. [Colistro, Valentina] Ministerio Salud Publ, Montevideo, Uruguay. [Colomar, Mercedes] UNICEM, Montevideo, Uruguay. [Crump, John A.] Univ Otago, Ctr Int Hlth, Dunedin Sch Med, Dunedin, New Zealand. [Derrett, Sarah] Univ Otago, Injury Prevent Res Unit, Dept Prevent & Social Med, Dunedin Sch Med, Dunedin, New Zealand. [Poulton, Richie G.] Univ Otago, Dunedin, New Zealand. [Damasceno, Albertino] Eduardo Mondlane Univ, Fac Med, Maputo, Mozambique. [Dargan, Paul I.] Guys & St Thomas NHS Fdn Trust, London, England. [Das Neves, Jose] Univ Porto, Inst Invest Inovacao Sande I3S, Oporto, Portugal. [Das Neves, Jose] Univ Porto, INEB Inst Engn Biomed, Oporto, Portugal. [Pedro, Joao Mario] Univ Porto, EPI Unit Inst Publ Hlth, Oporto, Portugal. [Santos, Joao Vasco] Univ Porto, Oporto, Portugal. [Davey, Gail] Wellcome Trust Brighton Sussex Ctr Global Hlth Re, Brighton, E Sussex, England. [Davis, Adrian C.; Newton, John N.; Steel, Nicholas] Publ Hlth England, London, England. [De Leo, Diego] Griffith Univ, Brisbane, Qld, Australia. [Des Jarlais, Don C.] Mt Sinai Beth Israel, New York, NY USA. [Des Jarlais, Don C.] Icahn Sch Med Mt Sinai, New York, NY USA. [Dharmaratne, Samath D.] Univ Peradeniya, Dept Community Med, Fac Med, Peradeniya, Sri Lanka. [Jeemon, Panniyammakal] Ctr Control Chron Condit, Gurgaon, India. [Dhillon, Preet K.; Zodpey, Sanjay] Publ Hlth Fdn India, Gurgaon, India. [Doyle, Kerrie E.] RMIT Univ, Bundoora, Vic, Australia. [Dubey, Manisha; Rahman, Mahfuzar; Ram, Usha; Singh, Abhishek; Yadav, Ajit Kumar] Int Inst Populat Sci, Mumbai, Maharashtra, India. [Duncan, Bruce Bartholow; Kieling, Christian; Schmidt, Maria Ines] Univ Fed Rio Grande do Sul, Porto Alegre, RS, Brazil. [Duncan, Bruce Bartholow] Univ N Carolina, Chapel Hill, NC USA. [Ebrahimi, Hedyeh; Esteghamati, Alireza; Farzadfar, Farshad; Hafezi-Nejad, Nima; Kasaeian, Amir; Parsaeian, Mahboubeh; Pishgar, Farhad; Sheikhbahaei, Sara] Endocrinol & Metab Populat Sci Inst, Non Communicable Dis Res Ctr, Tehran, Iran. [Ebrahimi, Hedyeh] Shariati Hosp, Digest Dis Res Inst, Liver & Pancreaticobiliary Dis Res Ctr, Tehran, Iran. [Fahimi, Saman; Malekzadeh, Reza; Roshandel, Gholamreza; Sepanlou, Sadaf G.] Digest Dis Res Inst, Tehran, Iran. [Hassanvand, Mohammad Sadegh] Inst Environm Res, Ctr Air Pollut Res, Tehran, Iran. [Heydarpour, Pouria] Multiple Sclerosis Res Ctr Neurosci Inst, Tehran, Iran. [Kasaeian, Amir] Hematol Oncol & Stem Cell Transplantat Res Ctr, Tehran, Iran. [Parsaeian, Mahboubeh] Sch Publ Hlth, Dept Epidemiol & Biostat, Tehran, Iran. [Pishgar, Farhad] Urooncol Res Ctr, Tehran, Iran. [Rahimi-Movaghar, Vafa] Sina Trauma & Surg Res Ctr, Tehran, Iran. [Yaseri, Mehdi] Univ Tehran Med Sci, Tehran, Iran. [Elyazar, Iqbal] Eijkman Oxford Clin Res Unit, Jakarta, Indonesia. [Endries, Aman Yesuf] Arba Minch Univ, Arba Minch, Ethiopia. [Ermakov, Sergey Petrovich] Russian Acad Sci, Inst Social & Econ Studies Populat, Moscow, Russia. [Ermakov, Sergey Petrovich] Russian Federat, Fed Res Inst Hlth Org & Informat, Minist Hlth, Moscow, Russia. [Eshrati, Babak] Minist Hlth & Med Educ, Tehran, Iran. [Eshrati, Babak] Arak Univ Med Sci, Arak, Iran. [Farid, Talha A.; Khan, Abdur Rahman] Univ Louisville, Louisville, KY 40292 USA. [Sa Farinha, Carla Sofia e] DGS Directorate Gen Hlth, Lisbon, Portugal. [Sa Farinha, Carla Sofia e] Univ Aberta, Lisbon, Portugal. [Faro, Andre] Univ Fed Sergipe, Aracaju, Brazil. [Farvid, Maryam S.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Harvard MGH Ctr Genom, Vulnerable Populat & Hlth Disparities, Boston, MA USA. [Feigin, Valery L.] Natl Inst Stroke & Appl Neurosci, Auckland, New Zealand. [Ao, Braden J. Te] Auckland Univ Technol, Auckland, New Zealand. [Fernandes, Jefferson G.] Inst Educ & Sci, German Hosp Oswaldo Cruz, Sao Paulo, Brazil. [Fernandes, Joao C.] Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med Dent, Ctr Expt Med Rheumatol, London, England. [Fischer, Florian] Univ Bielefeld, Bielefeld, Germany. [Foigt, Nataliya] Acad Med Sci, Inst Gerontol, Kiev, Ukraine. [Fowkes, F. Gerry R.] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Franklin, Richard C.] James Cook Univ, Townsville, Qld, Australia. [Gankpe, Fortune Gbetoho] CHU Hassan II, Fes, Morocco. [Garcia-Basteiro, Alberto L.] Manh Hlth Res Ctr, Manhica, Mozambique. [Garcia-Basteiro, Alberto L.] Barcelona Inst Global Hlth, Barcelona, Spain. [Gebremedhin, Amanuel Tesfay] Univ Munich, Munich, Germany. [Geleijnse, Johanna M.] Wageningen Univ, Div Human Nutr, Wageningen, Netherlands. [Jibat, Tariku] Wageningen Univ, Wageningen, Netherlands. [Gibney, Katherine B.] Univ Melbourne, Peter Doherty Inst Infect & Immun, Melbourne, Vic, Australia. [Gibney, Katherine B.] Royal Melbourne Hosp, Melbourne, Vic, Australia. [Gillum, Richard F.; Mehari, Alem] Howard Univ, Coll Med, Washington, DC USA. [Ginawi, Ibrahim Abdelmageem Mohamed] Univ Hail, Coll Med, Hail, Saudi Arabia. [Hailu, Alemayehu Desalegne] Univ Addis Ababa, Sch Publ Hlth, Addis Ababa, Ethiopia. [Giref, Ababi Zergaw; Haile, Demewoz; Jibat, Tariku] Univ Addis Ababa, Addis Ababa, Ethiopia. [Giroud, Maurice] Univ Hosp Dijon, Dijon, France. [Roba, Hirbo Shore] Haramaya Univ, Coll Hlth & Med Sci, Dawa, Ethiopia. [Gishu, Melkamu Dedefo; Tura, Abera Kenay] Haramaya Univ, Dire Dawa, Ethiopia. [Gishu, Melkamu Dedefo] Kersa Hlth & Demog Surveillance Syst, Harar, Ethiopia. [Gona, Philimon] Univ Massachusetts, Boston, MA USA. [Goodridge, Amador] Inst Invest Cient Serv Alta Tecnol, INDICASAT AIP, Ciudad Del Saber, Panama. [Gopalani, Sameer Vali] Govt Federated States Micronesia, Dept Hlth & Social Affairs, Palikir, Micronesia. [Gotay, Carolyn C.; Kissoon, Niranjan; Kopec, Jacek A.; Pourmalek, Farshad] Univ British Columbia, Vancouver, BC, Canada. [Goto, Atsushi] Div Epidemiol, Ctr Publ Hlth Sci, Tokyo, Japan. [Inoue, Manami] Natl Canc Ctr, Tokyo, Japan. [Gupta, Rahul] West Virginia Bur Publ Hlth, Charleston, WV USA. [Gupta, Rajeev] Eternal Heart Care Ctr & Res Inst, Jaipur, Rajasthan, India. [Gupta, Vipin] Univ Delhi, Dept Anthropol, Delhi, India. [Knudsen, Ann Kristin; Vollset, Stein Emil] Univ Bergen, Dept Global Publ Hlth & Primary Care, Bergen, Norway. [Hailu, Alemayehu Desalegne; Norheim, Ole F.] Univ Bergen, Bergen, Norway. [Hailu, Gessessew Bugssa] Kilte Awlaelo Hlth & Demog Surveillance Syst, Mekelle, Ethiopia. [Halasa, Yara A.; Undurraga, Eduardo A.] Brandeis Univ, Waltham, MA USA. [Hamadeh] Arabian Gulf Univ, Manama, Bahrain. [Hamidi, Samer] Hamdan Bin Mohammed Smart Univ, Dubai, U Arab Emirates. [Hammami, Mouhanad] Wayne Cty Dept Hlth & Human Serv, Detroit, MI USA. [Handal, Alexis J.] Univ New Mexico, Albuquerque, NM USA. [Hankey, Graeme J.] Univ Western Australia, Sch Med & Pharmacol, Perth, WA, Australia. [Hankey, Graeme J.] Harry Perkins Inst Med Res, Nedlands, WA, Australia. [Hankey, Graeme J.] Western Australian Neurosci Res Inst, Nedlands, WA, Australia. [Harikrishnan, Sivadasanpillai] Sree Chitra Tirunal Inst Med Sci & Technol, Trivandrum, Kerala, India. [Haro, Josep Maria] Parc Sanitari Sant Joan Deu CIBERSAM, Barcelona, Spain. [Haro, Josep Maria] Univ Barcelona, Barcelona, Spain. [Hay, Roderick J.] Int Fdn Dermatol, London, England. [Hedayati, Mohammad T.] Mazandaran Univ Med Sci, Sch Med, Dept Med Mycol & Parasitol, Sari, Iran. [Hoek, Hans W.] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands. [Tura, Abera Kenay] Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands. [Hoek, Hans W.] Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, New York, NY USA. [Skirbekk, Vegard] Columbia Univ, New York, NY USA. [Hoffman, Daniel J.] Rutgers State Univ, New Brunswick, NJ USA. [Horino, Masako] Nevada Div Publ & Behav Hlth, Dept Hlth & Human Serv, Carson City, NV USA. [Horita, Nobuyuki] Yokohama City Univ, Dept Pulmonol, Grad Sch Med, Yokohama, Kanagawa, Japan. [Hosgood, H. Dean] Albert Einstein Coll Med, Bronx, NY USA. [Hoy, Damian G.] Publ Hlth Div, Pacific Community, Noumea, New Caledonia. [Hsairi, Mohamed] Salah Azaiz Inst, Dept Epidemiol, Tunis, Tunisia. [Huang, Hsiang] Cambridge Hlth Alliance, Cambridge, MA USA. [Iburg, Kim Moesgaard] Aarhus Univ, Aarhus, Denmark. [Idrisov, Bulat T.] Boston Univ, Boston Med Ctr, Boston, MA USA. [Kwan, Gene F.] Boston Univ, Sch Med, Boston, MA USA. [Innos, Kaire] Natl Inst Hlth Dev, Tallinn, Estonia. [Inoue, Manami] Univ Tokyo, Grad Sch Med, Tokyo, Japan. [Kawakami, Norito] Univ Tokyo, Sch Publ Hlth, Tokyo, Japan. [Shibuya, Kenji] Univ Tokyo, Tokyo, Japan. [Jacobsen, Kathryn H.] George Mason Univ, Dept Global & Community Hlth, Fairfax, VA 22030 USA. [Jayatilleke, Achala Upendra] Postgrad Inst Med, Colombo, Sri Lanka. [Jayatilleke, Achala Upendra] Inst Violence & Injury Prevent, Colombo, Sri Lanka. [Jeemon, Panniyammakal] Ctr Chron Dis Control, New Delhi, India. [Jha, Vivekanand] George Inst Global Hlth India, New Delhi, India. [Jiang, Guohong] Tianjin Ctr Dis Control & Prevent, Tianjin, Tianjin, Peoples R China. [Jiang, Ying] Univ Occupat & Environm Hlth, Inst Ind Ecol Sci, Dept Hlth Dev, Kitakyushu, Fukuoka, Japan. [Jimenez-Corona, Aida] Inst Ophthalmol Conde Valencia, Dept Ocular Epidemiol & Visual Hlth, Mexico City, DF, Mexico. [Jimenez-Corona, Aida] Gen Directorate Epidemiol, Minist Hlth, Mexico City, DF, Mexico. [Jonas, Jost B.] Heidelberg Univ, Med Fac Mannheim, Dept Ophthalmol, Mannheim, Germany. [Kabir, Zubair] Univ Coll Cork, Cork, Ireland. [Kajungu, Dan K.] Sante Stat Analyt Res Inst, Kampala, Uganda. [Kajungu, Dan K.] Mildmay Uganda, Kampala, Uganda. [Kalkonde, Yogeshwar] Action & Res Community Hlth, Soc Educ, Gadchiroli, India. [Kamal, Ritul; Kesavachandran, Chandrasekharan Nair] CSIR Indian Inst Toxicol Res, Lucknow, Uttar Pradesh, India. [She, Jun] Zhongshan Hosp, Dept Pulm Med, Shanghai, Peoples R China. [Kan, Haidong] Fudan Univ, Shanghai, Peoples R China. [Kandel, Amit] SUNY Buffalo, Buffalo, NY USA. [Karch, Andre] Helmholtz Ctr Infect Res, Epidemiol & Stat Methods Res Grp, Braunschweig, Germany. [Karch, Andre] German Ctr Infect Res, Hannover Braunschweig Site, Hannover, Germany. [Karema, Corine Kakizi] Qual & Equity Hlth Care, Kigali, Rwanda. [Karimkhani, Chante] Case Western Univ Hosp, Cleveland, OH USA. [Kaul, Anil] Oklahoma State Univ, Tulsa, OK USA. [Kazi, Dhruv S.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Keiyoro, Peter Njenga] Inst Trop & Infect Dis, Nairobi, Kenya. [Keiyoro, Peter Njenga] Sch Continuing & Distance Educ, Nairobi, Kenya. [Lyons, Ronan A.] Farr Inst, Swansea, W Glam, Wales. [Kemp, Andrew Haddon] Swansea Univ, Swansea, W Glam, Wales. [Kengne, Andre Pascal; Matzopoulos, Richard; Wiysonge, Charles Shey] South African Med Res Council, Cape Town, South Africa. [Matzopoulos, Richard] Univ Cape Town, Sch Publ Hlth & Family Med, Cape Town, South Africa. [Stein, Dan J.] Univ Cape Town, Dept Psychiat, Cape Town, South Africa. [Kengne, Andre Pascal; Mayosi, Bongani M.] Univ Cape Town, Cape Town, South Africa. [Keren, Andre] Assuta Hosp, Assuta Hashalom, Tel Aviv, Israel. [Khader, Yousef Saleh] Jordan Univ Sci & Technol, Irbid, Jordan. [Khan, Ejaz Ahmad] Hlth Serv Acad, Islamabad, Pakistan. [Khang, Young-Ho] Seoul Natl Univ, Coll Med, Seoul, South Korea. [Won, Sungho] Seoul Natl Univ, Grad Sch Publ Hlth, Seoul, South Korea. [Khoja, Tawfik Ahmed Muthafer] Execut Board Hlth Minist Council Cooperat Council, Riyadh, Saudi Arabia. [Khubchandani, Jagdish] Ball State Univ, Muncie, IN 47306 USA. [Kieling, Christian] Hosp Clin Porto Alegre, Porto Alegre, RS, Brazil. [Kim, Cho-il] Korea Hlth Ind Dev Inst, Cheongju, South Korea. [Kim, Daniel] Northeastern Univ, Dept Hlth Sci, Boston, MA USA. [Kim, Yun Jin] Southern Univ Coll, Skudai, Malaysia. [Knudsen, Ann Kristin; Vollset, Stein Emil] Ctr Dis Burden, Oslo, Norway. [Skogen, Jens Christoffer] Norwegian Inst Publ Hlth, Dept Hlth Promot, Oslo, Norway. [Savic, Miloje; Skirbekk, Vegard] Norwegian Inst Publ Hlth, Oslo, Norway. [Kokubo, Yoshihiro] Natl Cerebral & Cardiovasc Ctr, Dept Prevent Cardiol, Suita, Osaka, Japan. [Kolte, Dhaval] Brown Univ, Div Cardiol, Providence, RI USA. [Koul, Parvaiz A.] Sherikashmir Inst Med Sci, Srinagar, Jammu & Kashmir, India. [Koyanagi, Ai] Parc Sanitari Sant Joan Deu CIBERSAM, Res Dev Unit, Barcelona, Spain. [Defo, Barthelemy Kuate] Univ Montreal, Dept Demog, Montreal, PQ, Canada. [Defo, Barthelemy Kuate] Univ Montreal, Publ Hlth Res Inst, Montreal, PQ, Canada. [Defo, Barthelemy Kuate] Univ Montreal, Dept Social & Prevent Med, Sch Publ Hlth, Montreal, PQ, Canada. [Kuchenbecker, Ricardo S.] Univ Fed Rio Grande do Sul, Grad Studies Epidemiol, Porto Alegre, RS, Brazil. [Bicer, Burcu Kucuk] Hacettepe Univ, Inst Publ Hlth, Ankara, Turkey. [Kuipers, Ernst J.] Univ Med Ctr Rotterdam, Erasmus MC, Rotterdam, Netherlands. [Lallukka, Tea; Shin, Rahman] Work Org, Work Disabil Prevent, Finnish Inst Occupat Hlth, Helsinki, Finland. [Lallukka, Tea] Univ Helsinki, Dept Publ Hlth, Fac Med, Helsinki, Finland. [Meretoja, Tuomo J.] Univ Helsinki, Helsinki, Finland. [Latif, Asma Abdul] Lahore Coll Women Univ, Dept Zool, Lahore, Pakistan. [Lavados, Pablo M.] Univ Desarrollo, Clin Alemana, Serv Neurol, Santiago, Chile. [Lawrynowicz, Alicia Elena Beatriz] Inst Nacl Epidemiol Dr Juan H Jara, Mar Del Plata, Argentina. [Leasher, Janet L.] Nova SE Univ, Coll Optometry, Ft Lauderdale, Ft Lauderdale, FL USA. [Leung, Ricky] SUNY Albany, Albany, NY USA. [Li, Yichong] San Francisco VA Med Ctr, San Francisco, CA USA. [Lipshultz, Steven E.; Wilkinson, James D.] Wayne State Univ, Sch Med, Detroit, MI USA. [Lipshultz, Steven E.] Childrens Hosp Michigan, Detroit, MI 48201 USA. [Simard, Edgar P.] Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA USA. [Liu, Yang; Phillips, Michael Robert] Emory Univ, Atlanta, GA USA. [Lloyd, Belinda K.] Turning Point, Eastern Hlth, Melbourne, Vic, Australia. [Logroscino, Giancarlo] Univ Bari, Bari, Italy. [Looker, Katharine J.; Rai, Dheeraj] Univ Bristol, Bristol, Avon, England. [Lunevicius, Raimundas] Aintree Univ, Hosp Natl Hlth Serv Fdn Trust, Liverpool, Merseyside, England. [Lunevicius, Raimundas] Univ Liverpool, Sch Med, Liverpool, Merseyside, England. [El Razek, Hassan Magdy Abd] Mansoura Fac Med, Mansoura, Egypt. Social Secur Org Res Inst, Tehran, Iran. [Mckee, Martin] Erasmus Univ, Inst Hlth Policy & Management, Rotterdam, Netherlands. [Malta, Deborah Carvalho] Univ Fed Minas Gerais, Belo Horizonte, MG, Brazil. [Marcenes, Wagner] Kings Coll London, Div Populat & Patient Hlth, Inst Dent, London, England. [Martinez-Raga, Jose] Univ Valencia, Univ Hosp Doctor Peset, Valencia, Spain. [Martinez-Raga, Jose] CEU Cardenal Herrera Univ, Valencia, Spain. [Mason-Jones, Amanda J.] Univ York, Dept Hlth Sci, York, N Yorkshire, England. [Mckee, Martin; Murthy, Gudlavalleti Venkata Satyanarayana] London Sch Hyg Trop Med, London, England. [Meaney, Peter A.] Univ Penn, Perelman Sch Med, Philadelphia, PA USA. [Meaney, Peter A.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Memiah, Peter] Univ Florida, Pensacola, FL USA. [Memish, Ziad A.] Saudi Minist Hlth, Riyadh, Saudi Arabia. [Memish, Ziad A.] Alfaisal Univ, Coll Med, Riyadh, Saudi Arabia. [Mendoza, Walter] United Nations Populat Fund, Lima, Peru. [Meretoja, Atte] Helsinki Univ Hosp, Dept Neurol, Helsinki, Finland. [Meretoja, Tuomo J.] Helsinki Univ Hosp, Breast Surg Unit, Ctr Comprehens Canc, Helsinki, Finland. [Mhimbira, Francis Apolinary] Ifakara Hlth Inst, Bagamoyo, Tanzania. [Miller, Ted R.] Pacific Inst Res Evaluat, Calverton, MD USA. [Miller, Ted R.] Curtin Univ, Ctr Populat Hlth, Perth, WA, Australia. [Mills, Edward J.] Univ Ottawa, Ottawa, ON, Canada. [Mirrakhimov, Erkin M.] Kyrgyz State Med Acad, Bishkek, Kyrgyzstan. [Mirrakhimov, Erkin M.] Natl Ctr Cardiol & Internal Dis, Bishkek, Kyrgyzstan. [Mohammad, Karzan Abdulmuhsin] Univ Salahaddin, Erbil, Iraq. [Mohammadi, Alireza] Baqiyatallah Univ Med Sci, Neurosci Res Ctr, Tehran, Iran. [Mohammed, Shafiu] Ahmadu Bello Univ, Hlth Syst & Policy Res Unit, Zaria, Nigeria. [Monasta, Lorenzo; Montico, Marcella; Ronfani, Luca] IRCCS Burlo Garofolo, Inst Maternal & Child Hlth, Trieste, Italy. [Moradi-Lakeh, Maziar] Iran Univ Med Sci, Dept Community Med, Gastrointestinal & Liver Dis Res Ctr, Prevent Med & Publ Hlth Res Ctr, Tehran, Iran. [Werdecker, Andrea] Competence Ctr Mortal Follow Up German Natl Cohor, Wiesbaden, Germany. [Mueller, Ulrich O.; WestermaM, Ronny] Fed Inst Populat Res, Wiesbaden, Germany. [Murdoch, Michele E.] West Herts Hosp NHS Trust, Watford, England. [Murthy, Gudlavalleti Venkata Satyanarayana] Indian Inst Publ Hlth, Gurgaon, India. [Dhillon, Preet K.; Zodpey, Sanjay] Publ Hlth Fdn India, Gurgaon, India. [Nachega, Jean B.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. [Nachega, Jean B.; Seedat, Soraya; Wiysonge, Charles Shey] Univ Stellenbosch, Cape Town, South Africa. [Nachega, Jean B.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Tran, Bach Xuan] Johns Hopkins Univ, Baltimore, MD USA. [Naheed, Aliya] Int Ctr Diarrhoeal Dis Res, Dhaka, Bangladesh. [Naldi, Luigi; Remuzzi, Giuseppe] Azienda Osped Papa Giovanni XXIII, Bergamo, Italy. [Nangia, Vinay] Suraj Eye Inst, Nagpur, Maharashtra, India. [Ngalesoni, Frida Namnyak] Minist Hlth & Social Welf, Dar Es Salaam, Tanzania. [Le Nguyen, Quyen] Duy Tan Univ, Inst Global Hlth Innovat, Da Nang, Vietnam. [Pete, Patrick Martial Nkamedjie] Inst Res, Socioecon Dev & Commun, Yaounde, Cameroon. [Nolla, Joan M.] Hosp Univ Bellvitge, Lhospitalet De Llobregat, Spain. [Norman, Rosana E.] Queensland Univ Technol, Inst Hlth & Biomed Innovat, Brisbane, Qld, Australia. [Obermeyer, Carla Makhlouf] Amer Univ Beirut, Ctr Res Populat & Hlth, Fac Hlth Sci, Beirut, Lebanon. [Ogbo, Felix Akpojene] Univ Western Sydney, Ctr Hlth Res, Sydney, NSW, Australia. [Oh, In-Hwan] Kyung Hee Univ, Sch Med, Dept Prevent Med, Seoul, South Korea. [Oladimeji, Olanrewaju] Human Sci Res Council, Durban, South Africa. [Oladimeji, Olanrewaju; Sartorius, Benn] Univ KwaZulu Natal, Durban, South Africa. [Olivares, Pedro R.] Univ Autonoma Chile, Talca, Chile. [Olusanya, Bolajoko Olubukunola; Olusanya, Jacob Olusegun] Ctr Healthy Start Initiat, Lagos, Nigeria. [Oren, Eyal] Univ Arizona, Tucson, AZ USA. [Ortiz, Alberto] IIS Fdn Jimenez Diaz UAM, Madrid, Spain. [Ota, Erika] Lukes Int Univ, Tokyo, Japan. [Schutte, Aletta E.] HART, Mafikeng, South Africa. [Oyekale, Abayomi Samuel] Hypertens NorthWest Univ, Mafikeng, South Africa. [Pa, Mahesh] JSS Univ, JSS Med Coll, Mysore, Karnataka, India. [Park, Eun-Kee] Kosin Univ, Dept Med Human & Social Med, Coll Med, Busan, South Korea. [Patten, Scott B.] Univ Calgary, Dept Community Hlth Sci, Calgary, AB, Canada. [Tonelli, Marcello] Univ Calgary, Calgary, AB, Canada. [Pedro, Joao Mario] Hlth Res Ctr Angola, Caxito, Angola. [Pereira, David M.] Univ Porto, REQUIMTE LAQV, Lab Farm, Dept Quim,Fac Farm, Oporto, Portugal. [Perico, Norberto; Remuzzi, Giuseppe] IRCCS Ist Ric Farmacol Mario Negri, Bergamo, Italy. [Pesudovs, Konrad] Flinders Univ S Australia, Adelaide, SA, Australia. [Petzold, Max] Univ Witwatersrand, Johannesburg, South Africa. [Phillips, Michael Robert] Shanghai Jiao Tong Univ, Sch Med, Shanghai, Peoples R China. [Pillay, Julian David] Durban Univ Technol, Durban, South Africa. [Plass, Dietrich] Exposure Assessment & Environm Hlth Indicators, German Environm Agcy, Berlin, Germany. [Polinder, Suzanne] Erasmus MC, Dept Publ Hlth, Rotterdam, Netherlands. [Prasad, Noela M.] Fred Hollows Fdn, Sydney, NSW, Australia. [Prasad, Noela M.] Ctr Eye Res Australia, Melbourne, Vic, Australia. [Qorbani, Mostafa] Alborz Univ Med Sci, Sch Med, Dept Community Med, Karaj, Iran. [Radfar, Amir] AT Still Univ, Kirksville, MO USA. [Rafay, Anwar] Contech Sch Publ Hlth, Lahore, Pakistan. [Rahman, Mahfuzar] Res & Evaluat Div, BRAC, Dhaka, Bangladesh. [Rahman, Sajjad Ur] Hamad Med Corp, Doha, Qatar. [Rai, Rajesh Kumar] Soc Hlth & Demog Surveillance, Suri, India. [Rajsic, Sasa] UMIT, ERAWEB Program, Hall In Tirol, Austria. [Raju, Murugesan] Univ Missouri, Columbia, MO USA. [Ranganathan, Kavitha] Univ Michigan Hlth Syst, Ann Arbor, MI USA. [Refaat, Amany H.] Walden Univ, Minneapolis, MN USA. [Refaat, Amany H.] Suez Canal Univ, Ismailia, Egypt. [Remuzzi, Giuseppe] Univ Milan, Dept Biomed & Clin Sci Sacco L, Milan, Italy. [Ribeiro, Antonio L.] Univ Fed Minas Gerais, Hosp Clin, Belo Horizonte, MG, Brazil. [Ricci, Stefano] UO Neurol USL Umbria 1, Citta Di Castello, Italy. [Rojas-Rueda, David] Inst Salud Global Barcelona, Barcelona, Spain. [Roshandel, Gholamreza] Golestan Univ Med Sci, Golestan Res Ctr Gastroenterol & Hepatol, Gorgan, Iran. [Sackey, Ben Benasco] World Hlth Org, Accra, Ghana. [Sanabria, Juan R.] Marshall Univ, Edwards Sch Med J, Huntington, WV USA. [Sanabria, Juan R.] Case Western Reserve Univ, Cleveland, OH USA. [Dolores Sanchez-Nino, Maria] IIS Fdn Jimenez Diaz, Madrid, Spain. [Sarmiento-Suarez, Rodrigo] Univ Ciencias Aplicadas Ambient, Bogota, Colombia. [Sawhney, Monika] Marshall Univ, Huntington, WV USA. [Schneider, Ione J. C.; Santos Silva, Diego Augusto] Univ Fed Santa Catarina, Florianopolis, SC, Brazil. [Schutte, Aletta E.] South African Med Res Council, Potchefstroom, South Africa. [Schwebel, David C.; Singh, Jasvinder A.] Univ Alabama Birmingham, Birmingham, AL USA. [Shahraz, Saeid] Tufts Med Ctr, Boston, MA USA. [Shaikh, Masood Ali] Independent Consultant, Karachi, Pakistan. [Sharma, Rajesh] Indian Inst Technol Ropar, Rupnagar, India. [Shen, Jiabin] Res Inst, Nationwide Childrens Hosp, Columbus, OH USA. [Shigematsu, Mika] Natl Inst Infect Dis, Tokyo, Japan. [Shigematsu, Mika] Sandia Natl Labs, Albuquerque, NM USA. [Shin, Min-Jeong] Korea Univ, Dept Publ Hlth Sci, Grad Sch, Seoul, South Korea. [Yoon, Seok-Jun] Korea Univ, Dept Prevent Med, Coll Med, Seoul, South Korea. [Sigfusdottir, Inga Dora] Reykjavik Univ, Reykjavik, Iceland. [Silverberg, Jonathan I.] Northwestern Univ, Feinberg Sch Med, Chicago, IL USA. [Yan, Yuichiro] Northwestern Univ, Dept Prevent Med, Chicago, IL USA. [Singh, Prashant Kumar] Inst Human Dev, New Delhi, India. [Skogen, Jens Christoffer] Alcohol & Drug Res Western Norway, Stavanger, Norway. [Soreide, Kjetil] Stavanger Univ Hosp, Stavanger, Norway. [Sreeramareddy, Chandrashekhar T.] Int Med Univ, Dept Community Med, Kuala Lumpur, Malaysia. [Stathopoulou, Vasiliki] Attikon Univ Hosp, Athens, Greece. [Steel, Nicholas] Univ Anglia, Norwich, Norfolk, England. [Stein, Dan J.] S African MRC, Unit Anxiety Stress Dis, Cape Town, South Africa. [Stein, Murray B.] Univ Calif San Diego, San Diego, CA USA. [Steiner, Timothy J.; Stovner, Lars Jacob] Norwegian Univ Sci & Technol, Dept Neurosci, Trondheim, Norway. [Stovner, Lars Jacob] St Olays Hosp, Norwegian Advisory Unit Headache, Trondheim, Norway. [Stroumpoulis, Konstantinos] Alexandra Gen Hosp Athens, Athens, Greece. [Stroumpoulis, Konstantinos] Ctr Hosp Publ Cotentin, Cherbourg, France. [Sunguya, Bruno F.] Muhimbili Univ Hlth & Allied Sci, Dar Es Salaam, Tanzania. [Swaminathan, Soumya] Indian Council Med Res, New Delhi, India. [Sykes, Bryan L.] Univ Calif Irvine, Dept Criminol Law & Soc Sociol & Publ Hlth, Irvine, CA USA. [Tanne, David] Chaim Sheba Med Ctr, Tel Hashomer, Israel. [Tanne, David] Tel Aviv Univ, Tel Aviv, Israel. 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[Topouzis, Fotis] Aristotle Univ Thessaloniki, Thessaloniki, Greece. [Tran, Bach Xuan] Hanoi Med Univ, Hanoi, Vietnam. [Dimbuene, Zacharie Tsala] Univ Kinshasa, Fac Econ & Management, Dept Populat Sci & Dev, Kinshasa, Congo. [Dimbuene, Zacharie Tsala] African Populat & Hlth Res Ctr, Nairobi, Kenya. [Tsilimbaris, Miltiadis] Univ Crete, Dept Med, Iraklion, Greece. [Tyrovolas, Stefanos] Univ Barcelona, Parc Sanitari Sant Joan Deu, Fundacio Sant Joan Deu, CIBERSAM, Barcelona, Spain. [Ukwaja, Kingsley N.] Fed Teaching Hosp, Dept Internal Med, Abakaliki, Nigeria. [Uneke, Chigozie Jesse] Ebonyi State Univ, Abakaliki, Nigeria. [Uthman, Olalekan A.] Univ Warwick, Warwick Med Sch, Coventry, W Midlands, England. [van Gool, Coen H.] Natl Inst Publ Hlth & Environm, Bilthoven, Netherlands. [van Os, Jim] Maastricht Univ Med Ctr, Maastricht, Netherlands. [Vasankari, Tommi] UKK Inst Hlth Promot Res, Tampere, Finland. [Vasconcelos, Ana Maria Nogales] Univ Brasilia, Brasilia, DF, Brazil. 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[Wilkinson, James D.] Childrens Hosp Michigan, Detroit, MI USA. [Williams, Hywel C.] Univ Nottingham, Ctr Evidence based Dermatol, Nottingham, England. [Woldeyohannes, Solomon Meseret] Univ Gondar, Inst Publ Hlth, Dept Epidemiol & Biostat, Gondar, Ethiopia. [Wolfe, Charles D. A.] Guys St Thomas NHS Fdn Trust & Kings Coll London, Natl Inst Hlth Res Comprehens Biomed Res Ctr, London, England. [Xu, Gelin] Nanjing Univ, Jinling Hosp, Dept Neurol, Sch Med, Nanjing, Peoples R China. [Yakob, Bereket] Univ KwaZulu Natal, Sch Nursing & Publ Hlth, Discipline Publ Hlth Med, Durban, South Africa. [Yan, Lijing L.] Duke Kunshan Univ, Global Hlth Res Ctr, Kunshan, Peoples R China. [Yip, Paul] Univ Hong Kong, Social Work & Social Adm Dept, Hong Kong, Peoples R China. [Yip, Paul] Univ Hong Kong, Hong Kong Jockey Club Ctr Suicide Res & Prevent, Hong Kong, Peoples R China. [Yonemoto, Naohiro] Kyoto Univ, Sch Publ Hlth, Dept Biostat, Kyoto, Japan. [Younis, Mustafa Z.] Jackson State Univ, Jackson, MS USA. [Yu, Chuanhua] Wuhan Univ, Dept Epidemiol & Biostat, Sch Publ Hlth, Wuhan, Peoples R China. [Yu, Chuanhua] Wuhan Univ, Global Hlth Inst, Wuhan, Peoples R China. [Zaidi, Zoubida] Univ Hosp, Setif, Algeria. [Zaki, Maysaa El Sayed] Mansoura Univ, Fac Med, Mansoura, Egypt. [Zeeb, Hajo] Leibniz Inst Prevent Res & Epidemiol, Bremen, Germany. [Zuhlke, Liesl Joanna] Red Cross War Mem Childrens Hosp, Cape Town, South Africa. RP Murray, CJL (reprint author), 2301 5th Ave,Suite 600, Seattle, WA 98121 USA. EM cjlm@uw.edu RI Lotufo, Paulo/A-9843-2008; Karch, Andre/D-6973-2017; Patten, Scott/B-4434-2011; Franklin, Richard/H-1731-2012; Giussani, Giorgia/E-8057-2017; Abbas, Kaja/E-6590-2017; Pereira, David/M-9286-2013; Amini, Heresh/B-3076-2010; Ribeiro, Antonio/C-2707-2009; Salomon, Joshua/D-3898-2009; Monasta, Lorenzo/B-1388-2012; Hankey, Graeme /H-4968-2014; Patton, George/B-5246-2013; Malta, Deborah/H-7880-2012; Martinez-Raga, Jose/B-6251-2017; Majdan, Marek/K-5017-2012; Weiderpass, Elisabete/M-4029-2016; Gishu, Melkamu Dedefo/C-3747-2017; Alsharif, Ubai/C-6527-2017; Tonelli, Marcello/B-3028-2009 OI Mirrakhimov, Erkin/0000-0003-2982-6108; Degenhardt, Louisa/0000-0002-8513-2218; Gouda, Hebe/0000-0002-5709-4509; Awasthi, Ashish/0000-0002-9308-9782; Bisanzio, Donal/0000-0002-7832-2291; Jacobsen, Kathryn/0000-0002-4198-6246; Bernabe, Eduardo/0000-0002-1858-3713; Piel, Frederic B./0000-0001-8131-7728; Altirkawi, Khalid/0000-0002-7331-4196; Hoek, Hans/0000-0001-6353-5465; NORMAN, ROSANA/0000-0002-9742-1957; Alkerwi, Ala'a/0000-0002-7448-3936; Ahmad Kiadaliri, Aliasghar/0000-0002-4254-9099; Leung, Ricky/0000-0002-2852-6771; Kieling, Christian/0000-0001-7691-4149; Gething, Peter/0000-0001-6759-5449; Rai, Dheeraj/0000-0002-7239-3523; Taylor, Hugh/0000-0002-9437-784X; Pishgar, Farhad/0000-0003-0703-8442; Kemp, Andrew/0000-0003-1146-3791; Charlson, Fiona/0000-0003-2876-5040; das Neves, Jose/0000-0002-2317-2759; Lotufo, Paulo/0000-0002-4856-8450; Karch, Andre/0000-0003-3014-8543; Patten, Scott/0000-0001-9871-4041; Franklin, Richard/0000-0003-1864-4552; Abbas, Kaja/0000-0003-0563-1576; Pereira, David/0000-0003-0384-7592; Sreeramareddy, Chandrashekhar/0000-0002-5693-7631; Miller, Ted/0000-0002-0958-2639; Xu, Gelin/0000-0002-6194-0341; Al-Aly, Ziyad/0000-0002-2600-0434; Heydarpour, Pouria/0000-0001-5644-7555; Vlassov, Vasiliy/0000-0001-5203-549X; Amini, Heresh/0000-0002-4825-1322; Ribeiro, Antonio/0000-0002-2740-0042; Salomon, Joshua/0000-0003-3929-5515; Monasta, Lorenzo/0000-0001-7774-548X; Hankey, Graeme /0000-0002-6044-7328; Patton, George/0000-0001-5039-8326; Malta, Deborah/0000-0002-8214-5734; Martinez-Raga, Jose/0000-0002-2856-6562; Majdan, Marek/0000-0001-8037-742X; Weiderpass, Elisabete/0000-0003-2237-0128; Gishu, Melkamu Dedefo/0000-0002-3466-1232; Alsharif, Ubai/0000-0002-4024-3950; FU Bill AMP; Melinda Gates Foundation FX Bill & Melinda Gates Foundation. NR 65 TC 13 Z9 13 U1 61 U2 61 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD OCT 8 PY 2016 VL 388 IS 10053 BP 1603 EP 1658 PG 56 WC Medicine, General & Internal SC General & Internal Medicine GA DY7BU UT WOS:000385285000009 ER PT J AU Forouzanfar, MH Afshin, A Alexander, LT Anderson, HR Bhutta, ZA Biryukov, S Brauer, M Burnett, R Cercy, K Charlson, FJ Cohen, AJ Dandona, L Estep, K Ferrari, AJ Frostad, JJ Fullman, N Gething, PW Godwin, WW Griswold, M Kinfu, Y Kyu, HH Larson, HJ Liang, X Lim, SS Liu, PY Lopez, AD Lozano, R Marczak, L Mensah, GA Mokdad, AH Moradi-Lakeh, M Naghavi, M Neal, B Reitsma, MB Roth, GA Salomon, JA Sur, PJ Vos, T Wagner, JA Wang, H Zhao, Y Zhou, M Aasvang, GM Abajobir, AA Abate, KH Abbafati, C Abbas, KM Abd-Allah, F Abdulle, AM Abera, SF Abraham, B Abu-Raddad, LJ Abyu, GY Adebiyi, AO Adedeji, IA Ademi, Z Adou, AK Adsuar, JC Agardh, EE Agarwal, A Agrawal, A Kiadaliri, AA Ajala, ON Akinyemiju, TF Al-Aly, Z Alam, K Alam, NKM Aldhahri, SF Aldridge, RW Alemu, ZA Ali, R Alkerwi, A Alla, F Allebeck, P Alsharif, U Altirkawi, KA Martin, EA Alvis-Guzman, N Amare, AT Amberbir, A Amegah, AK Amini, H Ammar, W Amrock, SM Andersen, HH Anderson, BO Antonio, CAT Anwar, P Arnlov, J Al Artaman Asayesh, H Asghar, RJ Assadi, R Atique, S Avokpaho, EFGA Awasthi, A Quintanilla, BPA Azzopardi, P Bacha, U Badawi, A Bahit, MC Balakrishnan, K Barac, A Barber, RM Barker-Collo, SL Barnighausen, T Barquera, S Barregard, L Barrero, LH Basu, S Bans, C Bazargan-Hejazi, S Beardsley, J Bedi, N Beghi, E Bell, ML Bello, AK Bennett, DA Bensenor, IM Berhane, A Bernabe, E Betsu, BD Beyene, AS Bhala, N Bhansali, A Bhatt, S Biadgilign, S Bikbov, B Bisanzio, D Bjertness, E Blore, JD Borschmann, R Boufous, S Bourne, RRA Brainin, M Brazinova, A Breitborde, NJK Brenner, H Broday, DM Brugha, TS Brunekreef, B Butt, ZA Cahill, LE Calabria, B Campos-Nonato, IR Cardenas, R Carpenter, D Casey, DC Castaneda-Oquela, CA Rivas, JC Castro, RE Catala-Lopez, F Chang, JC Chiang, PPC Chibalabala, M Chimed-Ochir, O Chisumpa, VH Chitheer, AA Choi, JYJ Christensen, H Christopher, DJ Ciobanu, LG Coates, MM Colquhoun, SM Cooper, LT Cooperrider, K Cornaby, L Cortinovis, M Crump, JA Cuevas-Nasu, L Damasceno, A Dandona, R Darby, SC Dargan, PI das Neves, J Davis, AC Davletov, K de Castro, EF De la Cruz-Gongora, V De Leo, D Degenhardt, L Del Gobbo, LC del Pozo-Cruz, B Dellavalle, RP Deribew, A Des Jarlais, DC Dharmaratne, SD Dhillon, PK Diaz-Tome, C Dicker, D Ding, EL Dorsey, ER Doyle, KE Driscoll, TR Duan, L Dubey, M Duncan, BB Elyazar, I Endries, AY Ermakov, SP Erskine, HE Eshrati, B Esteghamati, A Fahimi, S Faraon, EJA Farid, TA Farinha, CSES Faro, A Farvid, MS Farzadfar, F Feigin, VL Fereshtehnejad, SM Fernandes, JG Fischer, F Fitchett, JRA Fleming, T Foigt, N Foreman, K Fowkes, FGR Franklin, RC Furst, T Futran, ND Gakidou, E Garcia-Basteiro, AL Gebrehiwot, TT Gebremedhin, AT Geleijnse, JM 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Agardh, Emilie Elisabet Agarwal, Arnav Agrawal, Anurag Kiadaliri, Aliasghar Ahmad Ajala, Oluremi N. Akinyemiju, Tomi F. Al-Aly, Ziyad Alam, Khurshid Alam, Noore K. M. Aldhahri, Saleh Fahed Aldridge, Robert William Alemu, Zewdie Aderaw Ali, Raghib Alkerwi, Ala'a Alla, Francois Allebeck, Peter Alsharif, Ubai Altirkawi, Khalid A. Alvarez Martin, Elena Alvis-Guzman, Nelson Amare, Azmeraw T. Amberbir, Alemayehu Amegah, Adeladza Kofi Amini, Heresh Ammar, Walid Amrock, Stephen Marc Andersen, Hjalte H. Anderson, Benjamin O. Antonio, Carl Abelardo T. Anwar, Palwasha Arnlov, Johan Al Artaman Asayesh, Hamid Asghar, Rana Jawad Assadi, Reza Atique, Suleman Avokpaho, Euripide Frinel G. Arthur Awasthi, Ashish Quintanilla, Beatriz Paulina Ayala Azzopardi, Peter Bacha, Umar Badawi, Alaa Bahit, Maria C. Balakrishnan, Kalpana Barac, Aleksandra Barber, Ryan M. Barker-Collo, Suzanne L. Baernighausen, Till Barquera, Simon Barregard, Lars Barrero, Lope H. 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Choi, Jee-Young Jasmine Christensen, Hanne Christopher, Devasahayam Jesudas Ciobanu, Liliana G. Coates, Matthew M. Colquhoun, Samantha M. Cooper, Leslie Trumbull Cooperrider, Kimberly Cornaby, Leslie Cortinovis, Monica Crump, John A. Cuevas-Nasu, Lucia Damasceno, Albertino Dandona, Rakhi Darby, Sarah C. Dargan, Paul I. das Neves, Jose Davis, Adrian C. Davletov, Kairat Filipa de Castro, E. De la Cruz-Gongora, Vanessa De Leo, Diego Degenhardt, Louisa Del Gobbo, Liana C. del Pozo-Cruz, Borja Dellavalle, Robert P. Deribew, Amare Des Jarlais, Don C. Dharmaratne, Samath D. Dhillon, Preet K. Diaz-Tome, Cesar Dicker, Daniel Ding, Eric L. Dorsey, E. Ray Doyle, Kerrie E. Driscoll, Tim R. Duan, Leilei Dubey, Manisha Duncan, Bruce Bartholow Elyazar, Iqbal Endries, Aman Yesuf Ermakov, Sergey Petrovich Erskine, Holly E. Eshrati, Babak Esteghamati, Alireza Fahimi, Saman Aquino Faraon, Emerito Jose Farid, Talha A. Sofia E Sa Farinha, Carla Faro, Andre Farvid, Maryam S. Farzadfar, Farshad Feigin, Valery L. Fereshtehnejad, Seyed-Mohammad Fernandes, Jefferson G. Fischer, Florian Fitchett, Joseph R. A. Fleming, Tom Foigt, Nataliya Foreman, Kyle Fowkes, F. Gerry R. Franklin, Richard C. Fuerst, Thomas Futran, Neal D. Gakidou, Emmanuela Garcia-Basteiro, Alberto L. Gebrehiwot, Tsegaye Tewelde Gebremedhin, Amanuel Tesfay Geleijnse, Johanna M. Gessner, Bradford D. Giref, Ababi Zergaw Giroud, Maurice Gishu, Melkamu Dedefo Goenka, Shifalika Carmen Gomez-Cabrera, Mari Gomez-Dantes, Hector Gona, Philimon Goodridge, Amador Gopalani, Sameer Vali Gotay, Carolyn C. Goto, Atsushi Gouda, Hebe N. Gugnani, Harish Chander Guillemin, Francis Guo, Yuming Gupta, Rahul Gupta, Rajeev Gutierrez, Reyna A. Haagsma, Juanita A. Hafezi-Nejad, Nima Haile, Demewoz Hailu, Gessessew Bugssa Halasa, Yara A. Hamadeh, Randah Ribhi Hamidi, Samer Handal, Alexis J. Hankey, Graeme J. Hao, Yuantao Harb, Hilda L. Harikrishnan, Sivadasanpillai Maria Haro, Josep Hassanvand, Mohammad Sadegh Hassen, Tahir Ahmed Havmoeller, Rasmus Beatriz Heredia-Pi, Ileana Francisco Hernandez-Llanes, Norberto Heydarpour, Pouria Hoek, Hans W. Hoffman, Howard J. Horino, Masako Horita, Nobuyuki Hosgood, H. Dean Hoy, Damian G. Hsairi, Mohamed Htet, Aung Soe Hu, Guoqing Huang, John J. Husseini, Abdullatif Hutchings, Sally J. Huybrechts, Inge Iburg, Kim Moesgaard Idrisov, Bulat T. Ileanu, Bogdan Vasile Inoue, Manami Jacobs, Troy A. Jacobsen, Kathryn H. Jahanmehr, Nader Jakovljevic, Mihajlo B. Jansen, Henrica A. F. M. Jassal, Simerjot K. Javanbakht, Mehdi Jayatilleke, Achala Upendra Jee, Sun Ha Jeemon, Panniyammakal Jha, Vivekanand Jiang, Ying Jibat, Tariku Jin, Ye Johnson, Catherine O. Jonas, Jost B. Kabir, Zubair Kalkonde, Yogeshwar Kamal, Ritul Kan, Haidong Karch, Andre Karema, Corine Kakizi Karimkhani, Chante Kasaeian, Amir Kaul, Anil Kawakami, Norito Kazi, Dhruv S. Keiyoro, Peter Njenga Kemp, Andrew Haddon Kengne, Andre Pascal Keren, Andre Kesavachandran, Chandrasekharan Nair Khader, Yousef Saleh Khan, Abdur Rahman Khan, Ejaz Ahmad Khan, Gulfaraz Khang, Young-Ho Khatibzadeh, Shahab Khera, Sahil Khoja, Tawfik Ahmed Muthafer Khubchandani, Jagdish Kieling, Christian Kim, Cho-il Kim, Daniel Kimokoti, Ruth W. Kissoon, Niranjan Kivipelto, Miia Knibbs, Luke D. Kokubo, Yoshihiro Kopec, Jacek A. Koul, Parvaiz A. Koyanagi, Ai Kravchenko, Michael Kromhout, Hans Krueger, Hans Ku, Tiffany Defo, Barthelemy Kuate Kuchenbecker, Ricardo S. Bicer, Burcu Kucuk Kuipers, Ernst J. Kumar, G. Anil Kwan, Gene F. Lal, Dharmesh Kumar Lalloo, Ratilal Lallukka, Tea Lan, Qing Larsson, Anders Latif, Asma Abdul Beatriz Lawrynowicz, Alicia Elena Leasher, Janet L. Leigh, James Leung, Janni Levi, Miriam Li, Xiaohong Li, Yichong Liang, Juan Liu, Shiwei Lloyd, Belinda K. Logroscino, Giancarlo Lotufo, Paulo A. 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Naheed, Aliya Nangia, Vinay Nassiri, Nariman Newton, John N. Ng, Marie Quyen Le Nguyen Nisar, Muhammad Imran Pete, Patrick Martial Nkamedjie Norheim, Ole F. Norman, Rosana E. Norrving, Bo Nyakarahuka, Luke Obermeyer, Carla Makhlouf Ogbo, Felix Akpojene Oh, In-Hwan Oladimeji, Olanrewaju Olivares, Pedro R. Olsen, Helen Olusanya, Bolajoko Olubukunola Olusanya, Jacob Olusegun Opio, John Nelson Oren, Eyal Orozco, Ricardo Ortiz, Alberto Ota, Erika Mahesh, P. A. Pana, Adrian Park, Eun-Kee Parry, Charles D. Parsaeian, Mahboubeh Patel, Tejas Caicedo, Angel J. Paternina Patil, Snehal T. Patten, Scott B. Patton, George C. Pearce, Neil Pereira, David M. Perico, Norberto Pesudovs, Konrad Petzold, Max Phillips, Michael Robert Piel, Frederic B. Pillay, Julian David Plass, Dietrich Polinder, Suzanne Pond, Constance D. Pope, C. Arden Pope, Daniel Popova, Svetlana Poulton, Richie G. Pourmalek, Farshad Prasad, Noela M. Qorbani, Mostafa Rabiee, Rynaz H. S. Radfar, Amir Rafay, Anwar Rahimi-Movaghar, Vafa Rahman, Mahfuzar Rahman, Mohammad Hifz Ur Rahman, Sajjad Ur Rai, Rajesh Kumar Rajsic, Sasa Raju, Murugesan Ram, Usha Rana, Saleem M. Ranganathan, Kavitha Rao, Puja Razo Garcia, Christian Aspacia Refaat, Amany H. Rehm, Colin D. Rehm, Jurgen Reinig, Nikolas Remuzzi, Giuseppe Resnikoff, Serge Ribeiro, Antonio L. Rivera, Juan A. Rolm, Hirbo Shore Rodriguez, Anna Rodriguez-Ramirez, Sonia Rojas-Rueda, David Roman, Yesenia Ronfani, Luca Roshandel, Gholamreza Rothenbacher, Dietrich Roy, Ambuj Saleh, Muhammad Muhammad Sanabria, Juan R. Dolores Sanchez-Nino, Maria Sanchez-Pimienta, Tania G. Sandar, Logan Santomauro, Damian F. Santos, Itamar S. Sarmiento-Suarez, Rodrigo Sartorius, Benn Satpathy, Maheswar Savic, Miloje Sawhney, Monika Schmidhuber, Josef Schmidt, Maria Ines Schneider, Ione J. C. Schoettker, Ben Schutte, Aletta E. Schwebel, David C. Scott, James G. Seedat, Soraya Sepanlou, Sadaf G. Servan-Mori, Edson E. 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Tedla, Bemnet Amare Tefera, Worku Mekonnen Tegegne, Teketo Kassaw Tekle, Dejen Yemane Terkawi, Abdullah Sulieman Thakur, J. S. Thomas, Bernadette A. Thomas, Matthew Lloyd Thomson, Alan J. Thorne-Lyman, Andrew L. Thrift, Amanda G. Thurston, George D. Tillmann, Taavi Tobe-Gai, Ruoyan Tobollik, Myriam Topor-Madry, Roman Topouzis, Fotis Towbin, Jeffrey Allen Bach Xuan Tran Dimbuene, Zacharie Tsala Tsilimparis, Nikolaos Tura, Abera Kenay Tuzcu, Emin Murat Tyrovolas, Stefanos Ukwaja, Kingsley N. Undurraga, Eduardo A. Uneke, Chigozie Jesse Uthman, Olalekan A. van Donkelaar, Aaron van Os, Jim Varakin, Yuri Y. Vasankari, Tommi Veerman, J. Lennert Venketasubramanian, Narayanaswamy Violante, Francesco S. Vollset, Stein Emil Wagner, Gregory R. Waller, Stephen G. Wang, JianLi Wang, Linhong Wang, Yanping Weichenthal, Scott Weiderpass, Elisabete Weintraub, Robert G. Werdecker, Andrea Westerman, Ronny Whiteford, Harvey A. Wijeratne, Tissa Wiysonge, Charles Shey Wolfe, Charles D. A. Won, Sungho Woolf, Anthony D. Wubshet, Mamo Xavier, Denis Xu, Gelin Yadav, Ajit Kumar Yakob, Bereket Yalew, Ayalnesh Zemene Yano, Yuichiro Yaseri, Mehdi Ye, Pengpeng Yip, Paul Yonemoto, Naohiro Yoon, Seok-Jun Younis, Mustafa Z. Yu, Chuanhua Zaidi, Zoubida Zaki, Maysaa El Sayed Zhu, Jun Zipkin, Ben Zodpey, Sanjay Zuhlke, Liesl Joanna Murray, Christopher J. L. CA GBD 2015 Risk Factors TI Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015 SO LANCET LA English DT Article ID ISCHEMIC-HEART-DISEASE; DOSE-RESPONSE METAANALYSIS; BODY-MASS INDEX; ALCOHOL-CONSUMPTION; CARDIOVASCULAR-DISEASE; BLOOD-PRESSURE; NONCOMMUNICABLE DISEASES; ECONOMIC-DEVELOPMENT; COST-EFFECTIVENESS; REDUCED MORTALITY AB Background The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors-the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57.8% (95% CI 56.6-58.8) of global deaths and 41.2% (39.8-42.8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211.8 million [192.7 million to 231.1 million] global DALYs), smoking (148.6 million [134.2 million to 163.1 million]), high fasting plasma glucose (143.1 million [125.1 million to 163.5 million]), high BMI (120.1 million [83.8 million to 158.4 million]), childhood undernutrition (113.3 million [103.9 million to 123.4 million]), ambient particulate matter (103.1 million [90.8 million to 115.1 million]), high total cholesterol (88.7 million [74.6 million to 105.7 million]), household air pollution (85.6 million [66.7 million to 106.1 million]), alcohol use (85.0 million [77.2 million to 93.0 million]), and diets high in sodium (83.0 million [49.3 million to 127.5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Copyright (C) The Author(s). Published by Elsevier Ltd. 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[Htet, Aung Soe] Univ Oslo, Oslo, Norway. [Boufous, Soufiane] Univ New South Wales, Transport & Rd Safety TARS Res, Kensington, NSW, Australia. [Degenhardt, Louisa] Univ New South Wales, Natl Drug & Alcohol Res Ctr, Kensington, NSW, Australia. [Resnikoff, Serge] Univ New South Wales, Brien Holden Vision Inst, Kensington, NSW, Australia. [Calabria, Bianca] Univ New South Wales, Kensington, NSW, Australia. [Bourne, Rupert R. A.] Anglia Ruskin Univ, Vis & Eye Res Unit, Cambridge, England. [Brainin, Michael] Danube Univers Krems, Krems, Austria. [Brazinova, Alexandra; Majdan, Marek] Trnava Univ, Dept Publ Hlth, Fac Hlth Sci & Social Work, Trnava, Slovakia. [Brazinova, Alexandra] Int Neurotrauma Res Org, Vienna, Austria. [Shen, Jiabin] Ohio State Univ, Coll Med, Columbus, OH 43210 USA. [Breitborde, Nicholas J. K.] Ohio State Univ, Columbus, OH 43210 USA. [Brenner, Hermann; Schoettker, Ben] German Canc Res Ctr, Heidelberg, Germany. [Broday, David M.] Technion, Haifa, Israel. [Brugha, Traolach S.] Univ Leicester, Leicester, Leics, England. [Brunekreef, Bert; Kromhout, Hans] Univ Utrecht, Inst Risk Assessment Sci, Utrecht, Netherlands. [Butt, Zahid A.] Al Shifa Trust Eye Hosp, Rawalpindi, Pakistan. [van Donkelaar, Aaron] Dalhousie Univ, Dept Phys & Atmospher Sci, Halifax, NS, Canada. [Cahill, Leah E.; Martin, Randall V.] Dalhousie Univ, Halifax, NS, Canada. [Calabria, Bianca] Australian Natl Univ, Natl Ctr Epidemiol & Populat Hlth, Canberra, ACT, Australia. [Cardenas, Rosario] Metropolitan Autonomous Univ, Mexico City, DF, Mexico. [Carpenter, David] Univ Albany, Rensselaer, NY USA. [Castaneda-Oquela, Carlos A.] Colombian Natl Hlth Observ, Inst Nacl Salud, Bogota, Colombia. [Castaneda-Oquela, Carlos A.] Univ Nacl Colombia, Dept Publ Hlth, Epidemiol & Publ Hlth Evaluat Grp, Bogota, Colombia. [Castillo Rivas, Jacqueline] Caja Costarricense Seguro Social, San Jose, Costa Rica. [Castillo Rivas, Jacqueline] Univ Costa Rica, San Pedro, Montes De Oca, Costa Rica. [Estanislao Castro, Ruben] Univ Diego Portales, Santiago, Chile. [Catala-Lopez, Ferran] Univ Valencia, Dept Med, INCLIVA Hlth Res Inst, Valencia, Spain. [Catala-Lopez, Ferran] CIBERSAM, Valencia, Spain. [Catala-Lopez, Ferran] Ottawa Hosp, Res Inst, Clin Epidemiol Program, Ottawa, ON, Canada. Natl Taiwan Univ, Coll Med, Sch Nursing, Taipei, Taiwan. [Chiang, Peggy Pei-Chia] Gold Coast Hlth, Clin Governance Unit, Southport, Qld, Australia. [Chibalabala, Mirriam] Crowd Watch Africa, Lusaka, Zambia. [Chimed-Ochir, Odgerel] Univ Occupat & Environm Hlth, Dept Environm Epidemiol, Kitakyushu, Fukuoka, Japan. [Jiang, Ying] Univ Occupat & Environm Hlth, Dept Hlth Dev, Inst Ind Ecol Sci, Kitakyushu, Fukuoka, Japan. [Takahashi, Ken] Univ Occupat & Environm Hlth, Inst Ind Ecol Sci, Dept Environm Epidemiol, Kitakyushu, Fukuoka, Japan. [Chisumpa, Vesper Hichilombwe; Mapoma, Chabila C.; Masiye, Felix] Univ Zambia, Lusaka, Zambia. [Chisumpa, Vesper Hichilombwe] Univ Witwatersrand, Johannesburg, South Africa. [Chitheer, Abdulaal A.] Minist Hlth, Baghdad, Iraq. [Choi, Jee-Young Jasmine] Seoul Natl Univ, Med Lib, Seoul, South Korea. [Christensen, Hanne] Bispebjerg Hosp, Copenhagen, Denmark. [Christopher, Devasahayam Jesudas] Christian Med Coll & Hosp, Vellore, Tamil Nadu, India. [Cooper, Leslie Trumbull] Mayo Clin, Jacksonville, FL 32224 USA. Mario Negri Inst Pharmacol Res, Milan, Italy. [Crump, John A.] Univ Otago, Ctr Int Hlth, Dunedin Sch Med, Dunedin, New Zealand. [Poulton, Richie G.] Univ Otago, Dunedin, New Zealand. [Damasceno, Albertino] Eduardo Mondlane Univ, Fac Med, Maputo, Mozambique. [Dargan, Paul I.] Guys & St Thomas NHS Fdn Trust, London, England. [das Neves, Jose] Univ Porto, Inst Invest & Inovacao Saude i3S, Oporto, Portugal. [das Neves, Jose] Univ Porto, INEB Inst Engn Biomed, Oporto, Portugal. [Davis, Adrian C.; Newton, John N.; Steel, Nicholas] Publ Hlth England, London, England. [Davletov, Kairat] Kazakh Natl Med Univ, Sch Publ Hlth, Alma Ata, Kazakhstan. [De Leo, Diego] Griffith Univ, Brisbane, Qld, Australia. [Dellavalle, Robert P.] Univ Colorado, Sch Med, Aurora, CO USA. [Dellavalle, Robert P.] Colorado Sch Publ Hlth, Aurora, CO USA. [Deribew, Amare] KEMRI Wellcome Trust Res Programme, Kilifi, Kenya. [Des Jarlais, Don C.] Mt Sinai Beth Israel, New York, NY USA. [Des Jarlais, Don C.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Dharmaratne, Samath D.] Univ Peradeniya, Fac Med, Dept Community Med, Peradeniya, Sri Lanka. [Jeemon, Panniyammakal] Publ Hlth Fdn India, Ctr Control Chron Condit, Gurgaon, India. [Dhillon, Preet K.; Lal, Dharmesh Kumar; Zodpey, Sanjay] Publ Hlth Fdn India, Gurgaon, India. [Diaz-Tome, Cesar] Hosp Santa Creu & Sant Pau, Barcelona, Spain. [Dorsey, E. Ray] Univ Rochester, Med Ctr, Rochester, NY 14642 USA. [Doyle, Kerrie E.] RMIT Univ, Bundoora, Vic, Australia. [Dubey, Manisha; Rahman, Mohammad Hifz Ur; Ram, Usha; Singh, Abhishek; Yadav, Ajit Kumar] Int Inst Populat Sci, Bombay, Maharashtra, India. [Duncan, Bruce Bartholow; Kieling, Christian; Schmidt, Maria Ines] Univ Fed Rio Grande do Sul, Porto Alegre, RS, Brazil. [Duncan, Bruce Bartholow] Univ Nouth Carolina, Chapel Hill, NC USA. [Elyazar, Iqbal] Eijkman Oxford Clin Res Unit, Jakarta, Indonesia. [Endries, Aman Yesuf] Arba Minch Univ, Arba Minch, Ethiopia. [Ermakov, Sergey Petrovich] Russian Acad Sci, Inst Social & Econ Studies Populat, Moscow, Russia. [Ermakov, Sergey Petrovich] Minist Hlth Russian Federat, Fed Res Inst Hlth Org & Informat, Moscow, Russia. [Eshrati, Babak] Minist Hlth & Med Educ, Tehran, Iran. [Eshrati, Babak] Arak Univ Med Sci, Arak, Iran. [Farzadfar, Farshad; Kasaeian, Amir; Parsaeian, Mahboubeh] Univ Tehran Med Sci, Noncommunicable Dis Res Ctr, Tehran, Iran. [Esteghamati, Alireza; Hafezi-Nejad, Nima; Sheikhbahaei, Sara] Univ Tehran Med Sci, Endocrinol & Metab Populat Sci Inst, Tehran, Iran. [Fahimi, Saman; Malekzadeh, Reza; Roshandel, Gholamreza; Sepanlou, Sadaf G.] Univ Tehran Med Sci, Digest Dis Res Inst, Tehran, Iran. [Hassanvand, Mohammad Sadegh] Univ Tehran Med Sci, Ctr Air Pollut Res, Inst Environm Res, Tehran, Iran. [Heydarpour, Pouria] Univ Tehran Med Sci, Multiple Sclerosis Res Ctr, Neurosci Inst, Tehran, Iran. [Kasaeian, Amir] Univ Tehran Med Sci, Hematol Oncol & Stem Cell Transplantat Res Ctr, Tehran, Iran. [Parsaeian, Mahboubeh] Univ Tehran Med Sci, Dept Epidemiol & Biostat, Sch Publ Hlth, Tehran, Iran. [Rahimi-Movaghar, Vafa] Univ Tehran Med Sci, Sina Trauma & Surg Res Ctr, Tehran, Iran. [Yaseri, Mehdi] Univ Tehran Med Sci, Tehran, Iran. [Aquino Faraon, Emerito Jose] Dept Hlth, Manila, Philippines. [Farid, Talha A.; Khan, Abdur Rahman] Univ Louisville, Louisville, KY USA. [Sofia E Sa Farinha, Carla] DGS Directorate Gen Hlth, Lisbon, Portugal. [Sofia E Sa Farinha, Carla] Univ Aberta, Lisbon, Portugal. [Faro, Andre] Univ Fed Sergipe, Aracaju, Brazil. [Farvid, Maryam S.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Harvard MGH Ctr Genom Vulnerable Populat & Hlth D, Boston, MA 02114 USA. [Feigin, Valery L.] Auckland Univ Technol, Natl Inst Stroke & Appl Neurosci, Auckland, New Zealand. [Fernandes, Jefferson G.] German Hosp Oswaldo Cruz, Inst Educ & Sci, Sao Paulo, Brazil. [Fischer, Florian] Univ Bielefeld, Bielefeld, Germany. [Foigt, Nataliya] Acad Med Sci, Inst Gerontol, Kiev, Ukraine. [Shiue, Ivy] Univ Edinburgh, Alzheimer Scotland Dementia Res Ctr, Edinburgh, Midlothian, Scotland. [Fowkes, F. Gerry R.] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Franklin, Richard C.] James Cook Univ, Townsville, Qld, Australia. [Garcia-Basteiro, Alberto L.] Manhica Hlth Res Ctr, Manhica, Mozambique. [Garcia-Basteiro, Alberto L.] Barcelona Inst Global Hlth, Barcelona, Spain. [Gebremedhin, Amanuel Tesfay] Univ Munich, Munich, Germany. [Geleijnse, Johanna M.] Wageningen Univ, Div Human Nutr, Wageningen, Netherlands. [Jibat, Tariku] Wageningen Univ, Wageningen, Netherlands. [Gessner, Bradford D.] Agence Med Prevent, Paris, France. [Tefera, Worku Mekonnen] Univ Addis Ababa, Coll Hlth Sci, Sch Publ Hlth, Addis Ababa, Ethiopia. [Giref, Ababi Zergaw; Haile, Demewoz; Jibat, Tariku; Manamo, Wondimu Ayele Ayele] Univ Addis Ababa, Addis Ababa, Ethiopia. [Giroud, Maurice] Univ Hosp Dijon, Dijon, France. Haramaya Univ, Coll Hlth & Med Sci, Dire Dawa, Ethiopia. [Gishu, Melkamu Dedefo; Tura, Abera Kenay] Haramaya Univ, Dire Dawa, Ethiopia. [Gishu, Melkamu Dedefo] Kersa Hlth & Demog Surveillance Syst, Harar, Ethiopia. [Martinez-Raga, Jose] Univ Valencia, Univ Hosp Doctor Peset, Valencia, Spain. [Carmen Gomez-Cabrera, Mari] Univ Valencia, Valencia, Spain. [Carmen Gomez-Cabrera, Mari] INCLIVA Biomed Res Inst, Valencia, Spain. [Gona, Philimon] Univ Massachusetts, Boston, MA 02125 USA. [Goodridge, Amador] Inst Invest Cient & Servicios Alta Tecnol INDICAS, Ciudad Del Saber, Panama. [Gopalani, Sameer Vali] Govt Federated States Micronesia, Dept Hlth & Social Affairs, Palikir, Micronesia. [Goto, Atsushi] Natl Canc Ctr, Div Epidemiol, Ctr Publ Hlth Sci, Tokyo, Japan. [Inoue, Manami] Natl Canc Ctr, Tokyo, Japan. [Gugnani, Harish Chander] St James Sch Med, Dept Microbiol, The Quarter, Anguilla, Scotland. [Gugnani, Harish Chander] St James Sch Med, Dept Epidemiol & Biostat, The Quarter, Anguilla, Scotland. West Virginia Bur Publ Hlth, Charleston, WV USA. Eternal Heart Care Ctr & Res Inst, Jaipur, Rajasthan, India. [Gutierrez, Reyna A.; Orozco, Ricardo] Natl Inst Psychiat Ramon Fuente, Mexico City, DF, Mexico. [Haagsma, Juanita A.] Univ Med Ctr, Erasmus MC, Dept Publ Hlth, Rotterdam, Netherlands. [Hailu, Gessessew Bugssa] Kilte Awlaelo Hlth & Demog Surveillance Syst, Mekelle, Ethiopia. [Halasa, Yara A.; Undurraga, Eduardo A.] Brandeis Univ, Waltham, MA USA. [Hamadeh, Randah Ribhi] Arabian Gulf Univ, Manama, Bahrain. [Hamidi, Samer] Hamdan Bin Mohammed Smart Univ, Dubai, U Arab Emirates. [Handal, Alexis J.] Univ New Mexico, Albuquerque, NM 87131 USA. [Hankey, Graeme J.] Univ Western Australia, Sch Med & Pharmacol, Perth, WA, Australia. [Hankey, Graeme J.] Harry Perkins Inst Med Res, Nedlands, WA, Australia. [Hankey, Graeme J.] Western Australian Neurosci Res Inst, Nedlands, WA, Australia. [Hao, Yuantao] Sun Yat Sen Univ, Sch Publ Hlth, Guangzhou, Guangdong, Peoples R China. [Harikrishnan, Sivadasanpillai] Sree Chitra Tirunal Inst Med Sci & Technol, Trivandrum, Kerala, India. [Maria Haro, Josep] Parc Sanitari Sant Joan Deu CIBERSAM, St Boi De Llobregat, Barcelona, Spain. [Maria Haro, Josep] Univ Barcelona, Barcelona, Spain. [Francisco Hernandez-Llanes, Norberto] Comis Nacl Adicc, Mexico City, DF, Mexico. [Hoek, Hans W.] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands. [Tura, Abera Kenay] Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands. [Hoek, Hans W.] Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, New York, NY USA. [Horino, Masako] Dept Hlth & Human Serv, Nevada Div Publ & Behav Hlth, Carson City, NV USA. [Horita, Nobuyuki] Yokohama City Univ, Dept Pulmonol, Grad Sch Med, Yokohama, Kanagawa, Japan. [Hosgood, H. Dean] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Hoy, Damian G.] Pacific Community, Publ Hlth Div, Noumea, New Caledonia. [Hsairi, Mohamed] Salah Azaiz Inst, Dept Epidemiol, Tunis, Tunisia. [Htet, Aung Soe] Minist Hlth, Int Relat Div, Nay Pyi Taw, Myanmar. [Hu, Guoqing] Cent S Univ, Sch Publ Hlth, Dept Epidemiol & Hlth Stat, Changsha, Hunan, Peoples R China. [Husseini, Abdullatif] Birzeit Univ, Birzeit, Israel. [Huybrechts, Inge] Int Agcy Res Canc IARC, Lyon, France. [Huybrechts, Inge] Univ Ghent, Ghent, Belgium. [Iburg, Kim Moesgaard] Aarhus Univ, Aarhus, Denmark. [Idrisov, Bulat T.] Boston Univ, Boston Med Ctr, Boston, MA 02215 USA. [Kwan, Gene F.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Ileanu, Bogdan Vasile; Pana, Adrian] Bucharest Univ Econ Studies, Bucharest, Romania. [Inoue, Manami] Univ Tokyo, Grad Sch Med, Tokyo, Japan. [Kawakami, Norito] Univ Tokyo, Sch Publ Hlth, Tokyo, Japan. [Shibuya, Kenji] Univ Tokyo, Tokyo, Japan. [Jacobs, Troy A.] HIDN, USAID Global Hlth Bur, MCH Div, Washington, DC USA. [Jacobsen, Kathryn H.] George Mason Univ, Dept Global & Community Hlth, Fairfax, VA USA. [Jahanmehr, Nader] Shahid Beheshti Univ Med Sci, Sch Publ Hlth, Tehran, Iran. [Yaseri, Mehdi] Shahid Beheshti Univ Med Sci, Ophthalm Res Ctr, Tehran, Iran. [Jakovljevic, Mihajlo B.] Univ Kragujevac, Fac Med Sci, Kragujevac, Serbia. [Jansen, Henrica A. F. M.] UNFPA Asia & Pacific Reg Off, Bangkok, Thailand. [Jassal, Simerjot K.] Univ Calif San Diego, VA San Diego, San Diego, CA 92103 USA. [Stein, Murray B.] Univ Calif San Diego, San Diego, CA 92103 USA. [Javanbakht, Mehdi] Univ Aberdeen, Aberdeen, Scotland. [Jayatilleke, Achala Upendra] Postgrad Inst Med, Colombo, Sri Lanka. [Jayatilleke, Achala Upendra] Inst Violence & Injury Prevent, Colombo, Sri Lanka. [Jee, Sun Ha] Yonsei Univ, Grad Sch Publ Hlth, Seoul, South Korea. [Jeemon, Panniyammakal] Ctr Chron Dis Control, New Delhi, India. [Jibat, Tariku] Univ Addis Ababa, Debre Zeit, Ethiopia. [Jha, Vivekanand] George Inst Global Hlth India, New Delhi, India. [Jonas, Jost B.] Heidelberg Univ, Med Fac Mannheim, Dept Ophthalmol, Mannheim, Germany. [Kabir, Zubair] Univ Coll Cork, Cork, Ireland. [Kalkonde, Yogeshwar] Soc Educ Act & Res Community Hlth, Gadchiroli, India. [Kamal, Ritul] CSIR Indian Inst Toxicol Res, Lucknow, Uttar Pradesh, India. [She, Jun] Fudan Univ, Dept Pulm Med, Zhongshan Hosp, Shanghai, Peoples R China. [Kan, Haidong] Fudan Univ, Shanghai, Peoples R China. [Karch, Andre] Helmholtz Ctr Infect Res, Epidemiol & Stat Methods Res Grp, Braunschweig, Germany. [Karch, Andre] German Ctr Infect Res, Hannover Braunschweig Site, Braunschweig, Germany. [Karema, Corine Kakizi] Qual & Equity Hlth Care, Kigali, Rwanda. [Karimkhani, Chante] Case Western Univ Hosp, Cleveland, OH USA. [Kaul, Anil] Oklahoma State Univ, Tulsa, OK USA. [Kazi, Dhruv S.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Keiyoro, Peter Njenga] Inst Trop & Infect Dis, Nairobi, Kenya. [Keiyoro, Peter Njenga] Sch Continuing & Distance Educ, Nairobi, Kenya. [Kemp, Andrew Haddon] Swansea Univ, Swansea, W Glam, Wales. [Parry, Charles D.] South African Med Researcil, Alcohol Tobacco & Other Drug Res Unit, Cape Town, South Africa. 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[Khubchandani, Jagdish] Ball State Univ, Muncie, IN 47306 USA. [Kieling, Christian] Hosp Clin Porto Alegre, Porto Alegre, RS, Brazil. Korea Hlth Ind Dev Inst, Cheongju, South Korea. [Kim, Daniel] Northeastern Univ, Dept Hlth Sci, Boston, MA 02115 USA. [Kimokoti, Ruth W.] Simmons Coll, Boston, MA 02115 USA. [Kokubo, Yoshihiro] Natl Cerebral & Cardiovasc Ctr, Dept Prevent Cardiol, Suita, Osaka, Japan. [Koul, Parvaiz A.] Sherikashmir Inst Med Sci, Srinagar, Jammu & Kashmir, India. [Koyanagi, Ai] Parc Sanitari St Joan Deu CIBERSAM, Res & Dev Unit, Barcelona, Spain. [Kravchenko, Michael; Varakin, Yuri Y.] Res Ctr Neurol, Moscow, Russia. [Defo, Barthelemy Kuate] Univ Montreal, Dept Demog, Montreal, PQ, Canada. [Defo, Barthelemy Kuate] Univ Montreal, Publ Hlth Res Inst, Montreal, PQ, Canada. [Defo, Barthelemy Kuate] Univ Montreal, Dept Social & Prevent Med, Sch Publ Hlth, Montreal, PQ, Canada. [Kuchenbecker, Ricardo S.] Univ Fed Rio Grande do Sul, Graduat Studies Epidemiol, Porto Alegre, RS, Brazil. [Bicer, Burcu Kucuk] Hacettepe Univ, Inst Publ Hlth, Ankara, Turkey. [Kuipers, Ernst J.] Univ Med Ctr Rotterdam, Erasmus MC, Rotterdam, Netherlands. [Lallukka, Tea; Shiri, Rahman] Finnish Inst Occupat Hlth, Work Disabil Prevent, Work Org, Helsinki, Finland. [Lallukka, Tea] Univ Helsinki, Dept Publ Hlth, Fac Med, Helsinki, Finland. [Meretoja, Tuomo J.] Univ Helsinki, Helsinki, Finland. [Lan, Qing] NCI, Rockville, MD USA. [Latif, Asma Abdul] Women Univ, Lahore Coll, Dept Zool, Lahore, Pakistan. [Beatriz Lawrynowicz, Alicia Elena] Inst Nacl Epidemiol Dr Juan H Jara, Mar Del Plata, Buenos Aires, Argentina. [Leasher, Janet L.] Nova Southeastern Univ, Coll Optometry, Ft Lauderdale, FL 33314 USA. [Levi, Miriam] Tuscany Reg Ctr Occupat Injuries & Dis, Florence, Italy. [Li, Xiaohong] Natl Ctr Birth Defects Monitoring China, Chengdu, Peoples R China. [Liang, Juan] Sichuan Univ, West China Univ Hosp 2, Natl Off Maternal & Child Hlth Surveillance, Chengdu, Peoples R China. [Lloyd, Belinda K.] Monash Univ, Eastern Hlth Clin Sch, Fitzroy, Vic, Australia. [Lloyd, Belinda K.] Eastern Hlth, Turning Point, Melbourne, Vic, Australia. [Logroscino, Giancarlo] Univ Bari, Bari, Italy. [Lunevicius, Raimundas] Aintree Univ, Hosp Natl Hlth Serv Fdn Trust, Liverpool, Merseyside, England. [Lunevicius, Raimundas] Univ Liverpool, Sch Med, Liverpool, Merseyside, England. [Pope, Daniel] Univ Liverpool, Dept Publ Hlth & Policy, Liverpool, Merseyside, England. [Mahdavi, Mandi] Social Secur Org Res Inst, Tehran, Iran. [Mahdavi, Mandi] Erasmus Univ, Inst Hlth Policy & Management, Rotterdam, Netherlands. [Malta, Deborah Carvalho] Univ Fed Minas Gerais, Belo Horizonte, MG, Brazil. [Marcenes, Wagner] Kings Coll London, Inst Dent, Div Populat & Patient Hlth, London, England. [Martinez-Raga, Jose] CEU Cardenal Herrera Univ, Moncada, Valencia, Spain. [Matsushita, Kunihiro; Nachega, Jean B.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Bach Xuan Tran] Johns Hopkins Univ, Baltimore, MD USA. [Meaney, Peter A.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Meaney, Peter A.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Mehari, Alem] Howard Univ, Coll Med, Washington, DC 20059 USA. [Mekonnen, Alemayehu B.; Tedla, Bemnet Amare] Univ Gondar, Gondar, Ethiopia. [Memish, Ziad A.] Saudi Minist Hlth, Riyadh, Saudi Arabia. [Memish, Ziad A.] Alfaisal Univ, Coll Med, Riyadh, Saudi Arabia. [Mendoza, Walter] United Nations Populat Fund, Lima, Peru. [Mensink, Gert B. M.] Robert Koch Inst, Berlin, Germany. [Meretoja, Atte] Helsinki Univ Hosp, Dept Neurol, Helsinki, Finland. [Meretoja, Tuomo J.] Helsinki Univ Hosp, Ctr Comprehens Canc, Breast Surg Unit, Helsinki, Finland. [Mhimbira, Francis Apolinary] Ifakara Hlth Inst, Bagamoyo, Tanzania. [Miller, Ted R.] Pacific Inst Res & Evaluat, Calverton, MD USA. [Miller, Ted R.] Curtin Univ, Ctr Populat Hlth, Perth, WA, Australia. [Mills, Edward J.] Univ Ottawa, Ottawa, ON, Canada. [Mohammadi, Alireza] Baqiyatallah Univ Med Sci, Neurosci Res Ctr, Tehran, Iran. [Mohammed, Shafiu] Ahmadu Bello Univ, Hlth Syst & Policy Res Unit, Zaria, Nigeria. [Mola, Glen Liddell D.] Univ Papua New Guinea, Boroko, Papua N Guinea. [Monasta, Lorenzo; Montico, Marcella; Ronfani, Luca] IRCCS Burlo Garofolo, Inst Maternal & Child Hlth, Trieste, Italy. [Moradi-Lakeh, Maziar] Iran Univ Med Sci, Dept Community Med, Gastrointestinal & Liver Dis Res Ctr, Prevent Med & Publ Hlth Res Ctr, Tehran, Iran. [Morawska, Lidia] Queensland Univ Technol, Int Lab Air Qual & Hlth, Brisbane, Qld, Australia. [Norman, Rosana E.] Queensland Univ Technol, Inst Hlth & Biomed Innovat, Brisbane, Qld, Australia. [Mori, Rintaro] Natl Ctr Child Hlth & Dev, Tokyo, Japan. [Mozaffarian, Dariush] Tufts Univ, Friedman Sch Nutr Sci & Policy, Boston, MA 02111 USA. 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[Yonemoto, Naohiro] Kyoto Univ, Sch Publ Hlth, Dept Biostat, Kyoto, Japan. [Younis, Mustafa Z.] Jackson State Univ, Jackson, MS USA. [Yu, Chuanhua] Wuhan Univ, Dept Epidemiol & Biostat, Sch Publ Hlth, Wuhan, Peoples R China. [Yu, Chuanhua] Wuhan Univ, Global Hlth Inst, Wuhan, Peoples R China. [Zaidi, Zoubida] Univ Hosp, Setif, Algeria. [Zaki, Maysaa El Sayed] Mansoura Univ, Fac Med, Mansoura, Egypt. [Zhu, Jun] Natl Off MCH Surveillance China, Chengdu, Peoples R China. [Zuhlke, Liesl Joanna] Red Cross War Mem Childrens Hosp, Cape Town, South Africa. RP Murray, CJL (reprint author), Inst Hlth Metr & Evaluat, Seattle, WA 98121 USA. EM cjlm@uw.edu RI Gishu, Melkamu Dedefo/C-3747-2017; Alsharif, Ubai/C-6527-2017; Amini, Heresh/B-3076-2010; Lotufo, Paulo/A-9843-2008; Karch, Andre/D-6973-2017; Patten, Scott/B-4434-2011; Scott, James/D-5900-2012; Giussani, Giorgia/E-8057-2017; Abbas, Kaja/E-6590-2017; Pereira, David/M-9286-2013; Ribeiro, Antonio/C-2707-2009; Salomon, Joshua/D-3898-2009; Monasta, Lorenzo/B-1388-2012; Hankey, Graeme /H-4968-2014; Kravchenko, Michael/B-2596-2012; Patton, George/B-5246-2013; Malta, Deborah/H-7880-2012; Varakin, Yuriy/C-8634-2012; Brenner, Hermann/B-4627-2017; Martinez-Raga, Jose/B-6251-2017; Majdan, Marek/K-5017-2012; Weiderpass, Elisabete/M-4029-2016; Davletov, Kairat/S-1792-2016; OI Gishu, Melkamu Dedefo/0000-0002-3466-1232; Alsharif, Ubai/0000-0002-4024-3950; Amini, Heresh/0000-0002-4825-1322; Lotufo, Paulo/0000-0002-4856-8450; Karch, Andre/0000-0003-3014-8543; Patten, Scott/0000-0001-9871-4041; Scott, James/0000-0002-0744-0688; Abbas, Kaja/0000-0003-0563-1576; Pereira, David/0000-0003-0384-7592; Sreeramareddy, Chandrashekhar/0000-0002-5693-7631; Miller, Ted/0000-0002-0958-2639; Ribeiro, Antonio/0000-0002-2740-0042; Salomon, Joshua/0000-0003-3929-5515; Monasta, Lorenzo/0000-0001-7774-548X; Hankey, Graeme /0000-0002-6044-7328; Kravchenko, Michael/0000-0001-5187-5518; Patton, George/0000-0001-5039-8326; Malta, Deborah/0000-0002-8214-5734; Brenner, Hermann/0000-0002-6129-1572; Martinez-Raga, Jose/0000-0002-2856-6562; Majdan, Marek/0000-0001-8037-742X; Weiderpass, Elisabete/0000-0003-2237-0128; Agrawal, Anurag/0000-0002-0340-5252; Kemp, Andrew/0000-0003-1146-3791; Charlson, Fiona/0000-0003-2876-5040; das Neves, Jose/0000-0002-2317-2759; Degenhardt, Louisa/0000-0002-8513-2218; Awasthi, Ashish/0000-0002-9308-9782; Bisanzio, Donal/0000-0002-7832-2291; Jacobsen, Kathryn/0000-0002-4198-6246; Bernabe, Eduardo/0000-0002-1858-3713; Atique, Suleman/0000-0002-5149-0703; Piel, Frederic B./0000-0001-8131-7728; Altirkawi, Khalid/0000-0002-7331-4196; Hoek, Hans/0000-0001-6353-5465; NORMAN, ROSANA/0000-0002-9742-1957; Xu, Gelin/0000-0002-6194-0341; Al-Aly, Ziyad/0000-0002-2600-0434; assadi, reza/0000-0002-5016-2994; Heydarpour, Pouria/0000-0001-5644-7555; Alkerwi, Ala'a/0000-0002-7448-3936; Ahmad Kiadaliri, Aliasghar/0000-0002-4254-9099; Kieling, Christian/0000-0001-7691-4149; Javanbakht, Mehdi/0000-0002-8661-8439; Gething, Peter/0000-0001-6759-5449; Husseini, Abdullatif/0000-0001-8767-5956; Taylor, Hugh/0000-0002-9437-784X FU Bill AMP; Melinda Gates Foundation FX Bill & Melinda Gates Foundation. NR 139 TC 18 Z9 18 U1 86 U2 86 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD OCT 8 PY 2016 VL 388 IS 10053 BP 1659 EP 1724 PG 66 WC Medicine, General & Internal SC General & Internal Medicine GA DY7BU UT WOS:000385285000010 ER PT J AU Wang, HD Bhutta, ZA Coates, MM Coggeshall, M Dandona, L Diallo, K Franca, EB Fraser, M Fullman, N Gething, PW Hay, SI Kinfu, Y Kita, M Kulikoff, XR Larson, HJ Liang, J Liang, XF Lind, M Lopez, AD Lozano, R Mensah, GA Mikesell, JB Mokdad, AH Mooney, MD Nguyen, G Rakovac, I Salomon, JA Silpakit, N Sligar, A Sorensen, RJD Vos, T Zhu, J Abajobir, AA Abate, KH Abbas, KM Abd-Allah, F Abdulle, AM Abera, SF Aboyans, V Abraham, B Abubakar, I Abu-Raddad, LJ Abu-Rmeileh, NME Abyu, GY Achoki, T Adebiyi, AO Adedeji, IA Adelekan, AL Adou, AK Agarwal, A Ajala, ON Akinyemiju, TF Akseer, N Alam, K Alam, NKM Alasfoor, D Aldridge, RW Alegretti, MA Alemu, ZA Ali, R Alkerwi, A Alla, F Al-Raddadi, R Alsharif, U Altirkawi, KA Martin, EA Alvis-Guzman, N Amare, AT Amberbir, A Amegah, AK Ameh, EA Ammar, W Amrock, SM Andersen, HH Anderson, GM Antonio, CAT Arnlov, J Al Artaman Asayesh, H Asghar, RJ Assadi, R Atique, S Avokpaho, EFGA Awasthi, A Quintanilla, BPA Bacha, U Badawi, A Balakrishnan, K Banerjee, A Banigbe, BF Barac, A Barber, RM Barker-Collo, SL Barnighausen, T Barrero, LH Bayou, TA Bayou, YT Bazargan-Hejazi, S Beardsley, J Bedi, N Bekele, T Bell, ML Bello, AK Bennett, DA Bensenor, IM Berhane, A Bernabe, E Betsu, BD Bhatt, S Biadgilign, S Bikbov, B Birlik, SM Bisanzio, D Bjertness, E Blore, JD Bourne, RRA Brainin, M Brazinova, A Breitborde, NJK Brown, A Buckle, GC Burch, M Butt, ZA Campos-Nonato, IR Campuzano, JC Cardenas, R Carpenter, D Carrero, JJ Carter, A Casey, DC Castaneda-Oquela, CA Rivas, JC Castro, RE Catala-Lopez, F Cercy, K Chang, HY Chang, JC Chibueze, CE Chisumpa, VH Choi, JYJ Chowdhury, R Christopher, DJ Ciobanu, LG Colquhoun, SM Cooper, C Cornaby, L 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C Huang, JJ Huang, H Huiart, L Iburg, KM Idrisov, BT Innos, K Jacobsen, KH Jahanmehr, N Javanbakht, M Jayatilleke, AU Jee, SH Jeemon, P Jha, V Jiang, GH Jiang, Y Jibat, T Jin, Y Jonas, JB Kabir, Z Kalkonde, Y Karnak, R Kan, HD Kang, G Karch, A Karema, CK Kasaeian, A Kaul, A Kawakami, N Kayibanda, JF Kazanjan, K Keiyoro, PN Kemp, AH Kengne, AP Keren, A Kereselidze, M Kesavachandran, CN Khader, YS Khalil, IA Khan, AR Khan, EA Khang, YH Khonelidze, I Khubchandani, J Kim, CI Kim, D Kim, YJ Kissoon, N Kivipelto, M Knibbs, LD Kokubo, Y Kosen, S Koul, PA Koyanagi, A Defo, BK Bicer, BK Kudom, AA Kumar, GA Kyu, HH Lal, DK Lalloo, R Lam, H Lam, JO Lansingh, VC Larsson, A Leigh, J Leung, R Li, YC Li, YM Lindsay, MP Liu, PY Liu, SW Lloyd, BK Lo, WD Logroscino, G Low, N Lunevicius, R Lyons, RA Ma, S Abd El Razek, HM Abd El Razek, MM Mandavi, M Majdan, M Majeed, A Malekzadeh, R Mapoma, CC Marcenes, W -Raga, JM Marzan, MB Masiye, F McGrath, JJ Meaney, PA Mehari, A Mehndiratta, MM Mekonnen, AB Melaku, 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Alasfoor, Deena Aldridge, Robert William Alegretti, Miguel Angel Alemu, Zewdie Aderaw Ali, Raghib Alkerwi, Ala'a Alla, Francois Al-Raddadi, Rajaa Alsharif, Ubai Altirkawi, Khalid A. Martin, Elena Alvarez Alvis-Guzman, Nelson Amare, Azmeraw T. Amberbir, Alemayehu Amegah, Adeladza Kofi Ameh, Emmanuel A. Ammar, Walid Amrock, Stephen Marc Andersen, Hjalte H. Anderson, Gregory M. Antonio, Carl Abelardo T. Arnlov, Johan Al Artaman Asayesh, Hamid Asghar, Rana Jawad Assadi, Reza Atique, Suleman Avokpaho, Euripide Frinel G. Arthur Awasthi, Ashish Quintanilla, Beatriz Paulina Ayala Bacha, Umar Badawi, Alaa Balakrishnan, Kalpana Banerjee, Amitava Banigbe, Bolanle F. Barac, Aleksandra Barber, Ryan M. Barker-Collo, Suzanne L. Barnighausen, Till Barrero, Lope H. Bayou, Tigist Assefa Bayou, Yibeltal Tebekaw Bazargan-Hejazi, Shahrzad Beardsley, Justin Bedi, Neeraj Bekele, Tolesa Bell, Michelle L. Bello, Aminu K. Bennett, Derrick A. Bensenor, Isabela M. Berhane, Adugnaw Bernabe, Eduardo Betsu, Balem Demtsu Bhatt, Samir Biadgilign, Sibhatu Bikbov, Boris Birlik, Sait Mentes Bisanzio, Donal Bjertness, Espen Blore, Jed D. Bourne, Rupert R. A. Brainin, Michael Brazinova, Alexandra Breitborde, Nicholas J. K. Brown, Alexandria Buckle, Geoffrey Colin Burch, Michael Butt, Zahid A. Campos-Nonato, Ismael Ricardo Campuzano, Julio Cesar Cardenas, Rosario Carpenter, David Carrero, Juan Jesus Carter, Austin Casey, Daniel C. Castaneda-Oquela, Carlos A. Rivas, Jacqueline Castillo Castro, Ruben Estanislao Catala-Lopez, Ferran Cercy, Kelly Chang, Hsing-Yi Chang, Jung-Chen Chibueze, Chioma Ezinne Chisumpa, Vesper Hichilombwe Choi, Jee-Young Jasmine Chowdhury, Rajiv Christopher, Devasahayam Jesudas Ciobanu, Liliana G. Colquhoun, Samantha M. Cooper, Cyrus Cornaby, Leslie Damtew, Solomon Abrha Danawi, Hadi Dandona, Rakhi das Neves, Jose Davis, Adrian C. de Jager, Pieter De Leo, Diego Degenhardt, Louisa Deribe, Kebede Deribew, Amare Jarlais, Don C. Des deVeber, Gabrielle A. Dharmaratne, Samath D. Dhillon, Preet K. Ding, Eric L. Doshi, Pratik Pinal Doyle, Kerrie E. Duan, Leilei Dubey, Manisha Ebrahimi, Hedyeh Ellingsen, Christian Lycke Elyazar, Iqbal Endries, Aman Yesuf Ermakov, Sergey Petrovich Eshrati, Babak Esteghamati, Alireza Faraon, Emerito Jose Aquino Farid, Talha A. Farinha, Carla Sofia e Sa Faro, Andre Farvid, Maryam S. Farzadfar, Farshad Fereshtehnejad, Seyed-Mohammad Fernandes, Joao C. Fischer, Florian Fitchett, Joseph R. A. Foigt, Nataliya Franklin, Richard C. Friedman, Joseph Furst, Thomas Gambashidze, Ketevan Gamkrelidze, Amiran Ganguly, Parthasarathi Gebre, Teshome Gebrehiwot, Tsegaye Tewelde Gebremedhin, Amanuel Tesfay Gebru, Alemseged Aregay Gelefinse, Johanna M. Gessner, Bradford D. Ginawi, Ibrahim Abdelmageem Mohamed Giref, Ababi Zergaw Gishu, Melkamu Dedefo Gomez-Dantes, Hector Gona, Philimon Goodridge, Amador Gopalani, Sameer Vali Goto, Atsushi Gouda, Hebe N. Gugnani, Harish Chander Guo, Yuming Gupta, Rahul Gupta, Rajeev Gupta, Vipin Gyawali, Bishal Haagsma, Juanita A. Hafezi-Nejad, Nima Haile, Demewoz Hailu, Alemayehu Desalegne Hailu, Gessessew Bugssa Hamadeh, Randah Ribhi Hancock, Jamie Handal, Alexis J. Hankey, Graeme J. Harb, Hilda L. Harikrishnan, Sivadasanpillai Harun, Kimani M. Havmoeller, Rasmus Hay, Roderick J. Heredia-Pi, Ileana Beatriz Hoek, Hans W. Horino, Masako Horita, Nobuyuki Hosgood, H. Dean Hotez, Peter J. Hoy, Damian G. Hsairi, Mohamed Hu, Guoqing Huang, Cheng Huang, John J. Huang, Hsiang Huiart, Laetitia Iburg, Kim Moesgaard Idrisov, Bulat T. Innos, Kaire Jacobsen, Kathryn H. Jahanmehr, Nader Javanbakht, Mehdi Jayatilleke, Achala Upendra Jee, Sun Ha Jeemon, Panniyammakal Jha, Vivekanand Jiang, Guohong Jiang, Ying Jibat, Tariku Jin, Ye Jonas, Jost B. Kabir, Zubair Kalkonde, Yogeshwar Karnak, Ritul Kan, Haidong Kang, Gagandeep Karch, Andre Karema, Corine Kakizi Kasaeian, Amir Kaul, Anil Kawakami, Norito Kayibanda, Jeanne Francoise Kazanjan, Konstantin Keiyoro, Peter Njenga Kemp, Andrew Haddon Kengne, Andre Pascal Keren, Andre Kereselidze, Maia Kesavachandran, Chandrasekharan Nair Khader, Yousef Saleh Khalil, Ibrahim A. Khan, Abdur Rahman Khan, Ejaz Ahmad Khang, Young -Ho Khonelidze, Irma Khubchandani, Jagdish Kim, Cho-il Kim, Daniel Kim, Yun Jin Kissoon, Niranjan Kivipelto, Miia Knibbs, Luke D. Kokubo, Yoshihiro Kosen, Soewarta Koul, Parvaiz A. Koyanagi, Ai Defo, Barthelemy Kuate Bicer, Burcu Kucuk Kudom, Andreas A. Kumar, G. Anil Kyu, Hmwe H. Lal, Dharmesh Kumar Lalloo, Ratilal Lam, Hilton Lam, Jennifer O. Lansingh, Van C. Larsson, Anders Leigh, James Leung, Ricky Li, Yichong Li, Yongmei Lindsay, M. Patrice Liu, Patrick Y. Liu, Shiwei Lloyd, Belinda K. Lo, Warren D. Logroscino, Giancarlo Low, Nicola Lunevicius, Raimundas Lyons, Ronan A. Ma, Stefan Abd El Razek, Hassan Magdy Abd El Razek, Mohammed Magdy Mandavi, Mandi Majdan, Marek Majeed, Azeem Malekzadeh, Reza Mapoma, Chabila C. Marcenes, Wagner -Raga, Jose Martinez Marzan, Melvin Barrientos Masiye, Felix McGrath, John J. Meaney, Peter A. Mehari, Alem Mehndiratta, Man Mohan Mekonnen, Alemayehu B. Melaku, Yohannes Adama Memiah, Peter Memish, Ziad A. Mendoza, Walter Meretoja, Atte Meretoja, Tuomo J. Mhimbira, Francis Apolinary Miller, Ted R. Mills, Edward J. Mirarefin, Mojde Misganaw, Awoke Mock, Charles N. Mohammad, Karzan Abdulmuhsin Mohammadi, Alireza Mohammed, Shafiu Monasta, Lorenzo Montanez Hernandez, Julio Cesar Montico, Marcella Moore, Ami R. Moradi-Lakeh, Maziar Morawska, Lidia Mori, Rintaro Mueller, Ulrich O. Murphy, Georgina A. V. Murthy, Srinivas Nachega, Jean B. Naheed, Aliya Naidoo, Kovin S. Naldi, Luigi Nand, Devina Nangia, Vinay Neupane, Subas Newton, Charles R. Newton, John N. Ng, Marie Ngalesoni, Frida Namnyak Nguhiu, Peter Quyen Le Nguyen Nisar, Muhammad Imran Pete, Patrick Martial Nkamedjie Norheim, Ole F. Norman, Rosana E. Ogbo, Felix Akpojene Oh, In-Hwan Ojelabi, Foluke Adetola Olivares, Pedro R. Olusanya, Bolajoko Olubukunola Olusanya, Jacob Olusegun Oren, Eyal Ota, Erika Mahesh, P. A. Park, Eun-Kee Park, Hye-Youn Parsaeian, Mahboubeh Caicedo, Angel J. Paternina Patten, Scott B. Pedro, Joao Mario Pereira, David M. Perico, Norberto Pesudovs, Konrad Petzold, Max Phillips, Michael Robert Pillay, Julian David Pishgar, Farhad Polinder, Suzanne Pope, Daniel Popova, Svetlana Pourmalek, Farshad Qorbani, Mostafa Rabiee, Rynaz H. S. Rafay, Anwar Rahimi-Movaghar, Vafa Rahman, Mahfuzar Ur Rahman, Mohammad Hifz Ur Rahman, Sajjad Rai, Rajesh Kumar Raju, Murugesan Ram, Usha Rana, Saleem M. Ranabhat, Chhabi Lal Rao, Puja Refaat, Amany H. Remuzzi, Giuseppe Resnikoff, Serge Reynolds, Alex Rojas-Rueda, David Ronfani, Luca Roshandel, Gholamreza Roth, Gregory A. Roy, Ambuj Ruhago, George Mugambage Sagar, Rajesh Saleh, Muhammad Muhammad Sanabria, Juan R. Sanchez-Nino, Maria Dolores Santos, Itamar S. Santos, Joao Vasco Sarmiento-Suarez, Rodrigo Sartorius, Benn Satpathy, Maheswar Savic, Miloje Sawhney, Monika Schneider, Ione J. C. Schottker, Ben Schwebel, David C. Seedat, Soraya Sepanlou, Sadaf G. Servan-Mori, Edson E. Setegn, Tesfaye Shahraz, Saeid Shaikh, Masood Ali Shakh-Nazarova, Marina Sharma, Rajesh She, Jun Sheikhbahaei, Sara Shen, Jiabin Sheth, Kevin N. Shibuya, Kenji Shin, Hwashin Hyun Shin, Min-Jeong Shiri, Rahman Shuie, Ivy Sigfusdottir, Inga Dora Silva, Diego Augusto Santos Silverberg, Jonathan Simard, Edgar P. Sindi, Shireen Singh, Abhishek Singh, Jasvinder A. Singh, Om Prakash Singh, Prashant Kumar Singh, Virendra Soriano, Joan B. Soshnikov, Sergey Sposato, Luciano A. Sreeramareddy, Chandrashekhar T. Stathopoulou, Vasiliki Steel, Nicholas Stroumpoulis, Konstantinos Sturua, Lela Sunguya, Bruno F. Swaminathan, Soumya Sykes, Bryan L. Szoeke, Cassandra E. I. Tabares-Seisdedos, Rafael Tavakkoli, Mohammad Taye, Bineyam Tedla, Bemnet Amare Tefera, Worku Mekonnen Tekle, Tesfaye Shifa, Girma Temam Terkawi, Abdullah Sulieman Tesfay, Fisaha Haile Tessema, Gizachew Assefa Thapa, Kiran Thomson, Alan J. -Lyman, Andrew L. Thorne Tobe-Gai, Ruoyan Tonelli, Marcello Topor-Madry, Roman Topouzis, Fotis Tran, Bach Xuan Troeger, Christopher Truelsen, Thomas Dimbuene, Zacharie Tsala Tura, Abera Kenay Tyrovolas, Stefanos Ukwaja, Kingsley N. Uneke, Chigozie Jesse Uthman, Olalekan A. Vaezghasemi, Masoud Vasankari, Tommi Vasconcelos, Ana Maria Nogales Venketasubramanian, Narayanaswamy Verma, Raj Kumar Violante, Francesco S. Vladimirov, Sergey K. Vlassov, Vasiliy Victorovich Vollset, Stein Emil Wang, Linhong Wang, Yanping Weichenthal, Scott Weiderpass, Elisabete Weintraub, Robert G. Weiss, Daniel J. Werdecker, Andrea Westerman, Ronny Widdowson, Marc -Alain Wijeratne, Tissa Williams, Thomas Neil Wiysonge, Charles Shey Wolfe, Charles D. A. Wolfe, Ingrid Won, Sungho Wubshet, Mamo Xiao, Qingyang Xu, Gelin Yadav, Ajit Kumar Yakob, Bereket Yano, Yuichiro Yaseri, Mehdi Ye, Pengpeng Yebyo, Henock Gebremedhin Yip, Paul Yonemoto, Naohiro Yoon, Seok-Jun Younis, Mustafa Z. Yu, Chuanhua Zaidi, Zoubida Zaki, Maysaa El Sayed Zeeb, Hajo Zhang, Hao Zhao, Yong Zheng, Yingfeng Zhou, Maigeng Zodpey, Sanjay Murray, Christopher J. L. CA GBD 2015 Child Mortality TI Global, regional, national, and selected subnational levels of stillbirths, neonatal, infant, and under-5 mortality, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015 SO LANCET LA English DT Article ID DEVELOPMENT GOAL 4; CHILD-MORTALITY; DEVELOPING-COUNTRIES; INTEGRATED APPROACH; LIFE EXPECTANCY; NEWBORN BABIES; HEALTH; INTERVENTIONS; DEATH; SURVIVAL AB Background Established in 2000, Millennium Development Goal 4 (MDG4) catalysed extraordinary political, financial, and social commitments to reduce under-5 mortality by two-thirds between 1990 and 2015. At the country level, the pace of progress in improving child survival has varied markedly, highlighting a crucial need to further examine potential drivers of accelerated or slowed decreases in child mortality. The Global Burden of Disease 2015 Study (GBD 2015) provides an analytical framework to comprehensively assess these trends for under-5 mortality, age-specific and cause-specific mortality among children under 5 years, and stillbirths by geography over time. Methods Drawing from analytical approaches developed and refined in previous iterations of the GBD study, we generated updated estimates of child mortality by age group (neonatal, post-neonatal, ages 1-4 years, and under 5) for 195 countries and territories and selected subnational geographies, from 1980-2015. We also estimated numbers and rates of stillbirths for these geographies and years. Gaussian process regression with data source adjustments for sampling and non-sampling bias was applied to synthesise input data for under-5 mortality for each geography. Age-specific mortality estimates were generated through a two-stage age-sex splitting process, and stillbirth estimates were produced with a mixed-effects model, which accounted for variable stillbirth definitions and data source-specific biases. For GBD 2015, we did a series of novel analyses to systematically quantify the drivers of trends in child mortality across geographies. First, we assessed observed and expected levels and annualised rates of decrease for under-5 mortality and stillbirths as they related to the Soci-demographic Index (SDI). Second, we examined the ratio of recorded and expected levels of child mortality, on the basis of SDI, across geographies, as well as differences in recorded and expected annualised rates of change for under-5 mortality. Third, we analysed levels and cause compositions of under-5 mortality, across time and geographies, as they related to rising SDI. Finally, we decomposed the changes in under-5 mortality to changes in SDI at the global level, as well as changes in leading causes of under-5 deaths for countries and territories. We documented each step of the GBD 2015 child mortality estimation process, as well as data sources, in accordance with the Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER). Findings Globally, 5.8 million (95% uncertainty interval [UI] 5.7-6.0) children younger than 5 years died in 2015, representing a 52.0% (95% UI 50.7-53.3) decrease in the number of under-5 deaths since 1990. Neonatal deaths and stillbirths fell at a slower pace since 1990, decreasing by 42.4% (41.3-43.6) to 2.6 million (2.6-2.7) neonatal deaths and 47.0% (35.1-57.0) to 2.1 million (1.8-2.5) stillbirths in 2015. Between 1990 and 2015, global under-5 mortality decreased at an annualised rate of decrease of 3.0% (2.6-3.3), falling short of the 4.4% annualised rate of decrease required to achieve MDG4. During this time, 58 countries met or exceeded the pace of progress required to meet MDG4. Between 2000, the year MDG4 was formally enacted, and 2015, 28 additional countries that did not achieve the 4.4% rate of decrease from 1990 met the MDG4 pace of decrease. However, absolute levels of under-5 mortality remained high in many countries, with 11 countries still recording rates exceeding 100 per 1000 livebirths in 2015. Marked decreases in under-5 deaths due to a number of communicable diseases, including lower respiratory infections, diarrhoeal diseases, measles, and malaria, accounted for much of the progress in lowering overall under-5 mortality in low-income countries. Compared with gains achieved for infectious diseases and nutritional deficiencies, the persisting toll of neonatal conditions and congenital anomalies on child survival became evident, especially in low-income and low-middle-income countries. We found sizeable heterogeneities in comparing observed and expected rates of under-5 mortality, as well as differences in observed and expected rates of change for under-5 mortality. At the global level, we recorded a divergence in observed and expected levels of under-5 mortality starting in 2000, with the observed trend falling much faster than what was expected based on SDI through 2015. Between 2000 and 2015, the world recorded 10.3 million fewer under-5 deaths than expected on the basis of improving SDI alone. Interpretation Gains in child survival have been large, widespread, and in many places in the world, faster than what was anticipated based on improving levels of development. Yet some countries, particularly in sub-Saharan Africa, still had high rates of under-5 mortality in 2015. Unless these countries are able to accelerate reductions in child deaths at an extraordinary pace, their achievement of proposed SDG targets is unlikely. Improving the evidence base on drivers that might hasten the pace of progress for child survival, ranging from cost-effective intervention packages to innovative financing mechanisms, is vital to charting the pathways for ultimately ending preventable child deaths by 2030. C1 [Wang, Haidong; Coates, Matthew M.; Coggeshall, Megan; Dandona, Lalit; Fraser, Maya; Fullman, Nancy; Hay, Simon I.; Kulikoff, Xie Rachel; Larson, Heidi J.; Lind, Margaret; Lopez, Alan D.; Mikesell, Joseph B.; Mokdad, Ali H.; Mooney, Meghan D.; Nguyen, Grant; Silpakit, Naris; Sligar, Amber; Sorensen, Reed J. 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[Gouda, Hebe N.; Guo, Yuming; McGrath, John J.] Univ Queensland, Brisbane, Qld, Australia. [Abate, Kalkidan Hassen; Gebrehiwot, Tsegaye Tewelde; Gebremedhin, Amanuel Tesfay] Jimma Univ, Jimma, Ethiopia. [Abbas, Kaja M.] Virginia Tech, Blacksburg, VA USA. [Abd-Allah, Foad] Cairo Univ, Dept Neurol, Cairo, Egypt. [Abdulle, Abdishakur M.] New York Univ Abu Dhabi, Abu Dhabi, U Arab Emirates. [Melaku, Yohannes Adama] Mekelle Univ, Sch Publ Hlth, Mekelle, Ethiopia. [Abera, Semaw Ferede; Tesfay, Fisaha Haile] Mekelle Univ, Coll Hlth Sci, Mekelle, Ethiopia. [Abyu, Gebre Yitayih; Bayou, Tigist Assefa; Betsu, Balem Demtsu; Gebru, Alemseged Aregay; Hailu, Gessessew Bugssa; Tekle, Tesfaye; Yebyo, Henock Gebremedhin] Mekelle Univ, Mekelle, Ethiopia. [Abera, Semaw Ferede] Kilte AwlaeloHealth & Demog Surveillance Site, Mekelle, Ethiopia. [Abera, Semaw Ferede] Univ Hohenheim, Food Secur, Stuttgart, Germany. [Abera, Semaw Ferede] Univ Hohenheim, Inst Biol Chem & Nutr, Stuttgart, Germany. [Aboyans, Victor] Dupuytren Univ Hosp, Limoges, France. [Abraham, Biju] NMSM Govt Coll Kalpetta, Kalpetta, Kerala, India. [Abubakar, Ibrahim] UCL, Inst Global Hlth, London, England. [Aldridge, Robert William] UCL, Ctr Publ Hlth Data Sci, Inst Hlth Informat, London, England. [Banerjee, Amitava] UCL, Farr Inst Hlth Informat Res, London, England. [Abu-Raddad, Laith J.] Weill Cornell Med Coll Qatar, Infect Dis Epidemiol Grp, Doha, Qatar. [Abu-Rmeileh, Niveen M. E.] Birzeit Univ, Inst Community & Publ Hlth, Ramallah, Israel. [Adebiyi, Akindele Olupelumi] Univ Ibadan, Coll Med, Ibadan, Nigeria. [Adelekan, Ademola Lukman; Ojelabi, Foluke Adetola] Univ Ibadan, Ibadan, Nigeria. [Adebiyi, Akindele Olupelumi] Univ Coll Hosp, Ibadan, Nigeria. [Adedeji, Isaac Akinkunmi] Olabisi Onabanjo Univ, Ago Iwoye, Nigeria. [Adelekan, Ademola Lukman] Publ Hlth Promot Alliance, Osogbo, Nigeria. [Adou, Arsene Kouablan] Assoc Ivoirienne Bien Etre Familial, Abidjan, Cote Ivoire. [Akseer, Nadia] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [Badawi, Alaa] Univ Toronto, Dept Nutr Sci, Fac Med, Toronto, ON, Canada. [Lindsay, M. Patrice] Univ Toronto, Inst Hlth Policy Management & Evaluat, Toronto, ON, Canada. [Popova, Svetlana] Univ Toronto, Ctr Addict & Mental Hlth, Toronto, ON, Canada. [Agarwal, Arnav] Univ Toronto, Toronto, ON, Canada. [Agarwal, Arnav] McMaster Univ, Hamilton, ON, Canada. [Ajala, Oluremi N.] Univ Pittsburgh, Med Ctr, Mckeesport, PA USA. [Akinyemiju, Tomi F.] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL USA. [Schwebel, David C.; Singh, Jasvinder A.] Univ Alabama Birmingham, Birmingham, AL USA. [Alam, Khurshid; Leigh, James; Mekonnen, Alemayehu B.] Univ Sydney, Sydney, NSW, Australia. [Alam, Noore K. M.] Queensland Hlth, Herston, Qld, Australia. [Abajobir, Amanuel Alemu; Knibbs, Luke D.] Univ Queensland, Sch Publ Hlth, Herston, Qld, Australia. [Lalloo, Ratilal] Univ Queensland, Sch Dent, Herston, Qld, Australia. [Alam, Noore K. M.] Univ Queensland, Herston, Qld, Australia. [Alasfoor, Deena] Minist Hlth, Al Khuwair, Oman. [Alegretti, Miguel Angel] Univ Republica, Fac Med, Dept Prevent & Social Med, Montevideo, Uruguay. [Alemu, Zewdie Aderaw] Debre Markos Univ, Debre Markos, Ethiopia. [Alkerwi, Ala'a] Luxembourg Inst Hlth, Strassen, Luxembourg. [Alla, Francois] Univ Lorraine, Sch Publ Hlth, Nancy, France. [Al-Raddadi, Rajaa] Minist Hlth, Jeddah, Saudi Arabia. [Alsharif, Ubai] Charite, Berlin, Germany. [Altirkawi, Khalid A.] King Saud Univ, Riyadh, Saudi Arabia. [Martin, Elena Alvarez] Minist Hlth Social Policy & Equal, Spanish Observ Drugs, Govt Delegat Natl Plan Drugs, Madrid, Spain. [Alvis-Guzman, Nelson] Univ Cartagena, Cartagena De Indias, Colombia. [Amare, Azmeraw T.; Melaku, Yohannes Adama] Univ Adelaide, Sch Med, Adelaide, SA, Australia. [Ciobanu, Liliana G.; Tessema, Gizachew Assefa] Univ Adelaide, Adelaide, SA, Australia. [Amare, Azmeraw T.] Bahir Dar Univ, Coll Med & Hlth Sci, Bahir Dar, Ethiopia. [Setegn, Tesfaye] Bahir Dar Univ, Bahir Dar, Ethiopia. [Amberbir, Alemayehu] Dignitas Int, Zomba, Malawi. [Amegah, Adeladza Kofi; Kudom, Andreas A.] Univ Cape Coast, Cape Coast, Ghana. [Ameh, Emmanuel A.] Natl Hosp, Abuja, Nigeria. [Ammar, Walid; Harb, Hilda L.] Minist Publ Hlth, Beirut, Lebanon. [Amrock, Stephen Marc] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Anderson, Gregory M.] Aalborg Univ, Fac Med, Dept Hlth Sci & Technol, Ctr Sensory Motor Interact, Aalborg, Denmark. [Antonio, Carl Abelardo T.] Univ Philippines, Coll Publ Hlth, Dept Hlth Policy & Adm, Manila, Philippines. [Faraon, Emerito Jose Aquino] Univ Philippines, Coll Publ Hlth, Manila, Philippines. [Arnlov, Johan; Larsson, Anders] Uppsala Univ, Dept Med Sci, Uppsala, Sweden. [Arnlov, Johan] Dalarna Univ, Falun, Sweden. [Al Artaman] Univ Manitoba, Winnipeg, MB, Canada. [Asayesh, Hamid] Qom Univ Med Sci, Sch Paramed, Dept Emergency Med, Qom, Iran. [Asghar, Rana Jawad] South Asian Publ Hlth Forum, Islamabad, Pakistan. RP Wang, HD (reprint author), Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98121 USA. EM haidong@uw.edu RI Pereira, David/M-9286-2013; Abbas, Kaja/E-6590-2017; Salomon, Joshua/D-3898-2009; Monasta, Lorenzo/B-1388-2012; Hankey, Graeme /H-4968-2014; Martinez-Raga, Jose/B-6251-2017; Majdan, Marek/K-5017-2012; Weiderpass, Elisabete/M-4029-2016; Gishu, Melkamu Dedefo/C-3747-2017; Alsharif, Ubai/C-6527-2017; Tonelli, Marcello/B-3028-2009; Karch, Andre/D-6973-2017; Patten, Scott/B-4434-2011; Franklin, Richard/H-1731-2012 OI Kemp, Andrew/0000-0003-1146-3791; das Neves, Jose/0000-0002-2317-2759; Degenhardt, Louisa/0000-0002-8513-2218; Gouda, Hebe/0000-0002-5709-4509; Bisanzio, Donal/0000-0002-7832-2291; Jacobsen, Kathryn/0000-0002-4198-6246; Bernabe, Eduardo/0000-0002-1858-3713; Atique, Suleman/0000-0002-5149-0703; Hoek, Hans/0000-0001-6353-5465; NORMAN, ROSANA/0000-0002-9742-1957; Altirkawi, Khalid/0000-0002-7331-4196; Awasthi, Ashish/0000-0002-9308-9782; Pereira, David/0000-0003-0384-7592; Sreeramareddy, Chandrashekhar/0000-0002-5693-7631; Miller, Ted/0000-0002-0958-2639; Xu, Gelin/0000-0002-6194-0341; Soshnikov, Sergey/0000-0002-6983-7066; assadi, reza/0000-0002-5016-2994; Vlassov, Vasiliy/0000-0001-5203-549X; Birlik, Sait Mentes/0000-0002-9889-8837; Alkerwi, Ala'a/0000-0002-7448-3936; Leung, Ricky/0000-0002-2852-6771; Javanbakht, Mehdi/0000-0002-8661-8439; Gething, Peter/0000-0001-6759-5449; Abbas, Kaja/0000-0003-0563-1576; Salomon, Joshua/0000-0003-3929-5515; Monasta, Lorenzo/0000-0001-7774-548X; Hankey, Graeme /0000-0002-6044-7328; Martinez-Raga, Jose/0000-0002-2856-6562; Majdan, Marek/0000-0001-8037-742X; Weiderpass, Elisabete/0000-0003-2237-0128; Gishu, Melkamu Dedefo/0000-0002-3466-1232; Alsharif, Ubai/0000-0002-4024-3950; Karch, Andre/0000-0003-3014-8543; Patten, Scott/0000-0001-9871-4041; Franklin, Richard/0000-0003-1864-4552 FU Bill & Melinda Gates Foundation FX Bill & Melinda Gates Foundation. NR 76 TC 8 Z9 8 U1 27 U2 27 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD OCT 8 PY 2016 VL 388 IS 10053 BP 1725 EP 1774 PG 50 WC Medicine, General & Internal SC General & Internal Medicine GA DY7BU UT WOS:000385285000011 ER PT J AU Luo, RB Chen, PW Wagenbach, M Jian, XY Jenkins, L Wordeman, L Randazzo, PA AF Luo, Ruibai Chen, Pei-Wen Wagenbach, Michael Jian, Xiaoying Jenkins, Lisa Wordeman, Linda Randazzo, Paul A. TI Direct Functional Interaction of the Kinesin-13 Family Membrane Kinesin-like Protein 2A (Kif2A) and Arf GAP with GTP-binding Protein-like, Ankyrin Repeats and PH Domains1 (AGAP1) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE ADP ribosylation factor (ARF); cell biology; enzyme; GTPase activating protein (GAP); kinesin; protein complex; small GTPase; AGAP1; Kif2A; kinesin-13; Arf GTPase-activating protein; PH domain ID ADP-RIBOSYLATION FACTOR; FOCAL ADHESION KINASE; ACTIVATING PROTEIN; ACTIN CYTOSKELETON; MCAK; NOMENCLATURE; HYDROLYSIS; REGULATORS; TRANSPORT; DYNAMICS AB The molecular basis for control of the cytoskeleton by the Arf GTPase-activating protein AGAP1 has not been characterized. AGAP1 is composed of G-protein-like (GLD), pleckstrin homology (PH), Arf GAP, and ankyrin repeat domains. Kif2A was identified in screens for proteins that bind to AGAP1. The GLD and PH domains of AGAP1 bound the motor domain of Kif2A. Kif2A increased GAP activity of AGAP1, and a protein composed of the GLD and PH domains of AGAP1 increased ATPase activity of Kif2A. Knockdown (KD) of Kif2A or AGAP1 slowed cell migration and accelerated cell spreading. The effect of Kif2A KD on spreading could be rescued by expression of Kif2A-GFP or FLAG-AGAP1, but not by Kif2C-GFP. The effect of AGAP1 KD could be rescued by FLAG-AGAP1, but not by an AGAP1 mutant that did not bind Kif2A efficiently, ArfGAP1-HA or Kif2A-GFP. Taken together, the results support the hypothesis that the Kif2AAGAP1 complex contributes to control of cytoskeleton remodeling involved in cell movement. C1 [Luo, Ruibai; Chen, Pei-Wen; Jian, Xiaoying; Randazzo, Paul A.] NCI, Lab Cellular & Mol Biol, NIH, Bethesda, MD 20892 USA. [Jenkins, Lisa] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Chen, Pei-Wen] Grinnell Coll, Dept Biol, Grinnell, IA 50112 USA. [Wagenbach, Michael; Wordeman, Linda] Univ Washington, Dept Physiol & Biophys, Sch Med, Seattle, WA 98195 USA. [Chen, Pei-Wen] Williams Coll, Williamstown, MA 01267 USA. RP Randazzo, PA (reprint author), NCI, Lab Cellular & Mol Biol, NIH, Bethesda, MD 20892 USA. EM randazzp@mail.nih.gov FU intramural program of the National Cancer Institute [BC007365]; National Institute of General Medical Sciences [GM069429] FX This work was supported by the intramural program of the National Cancer Institute (Project BC007365) and by the National Institute of General Medical Sciences (Grant GM069429) (to L. W.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 43 TC 1 Z9 1 U1 1 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 7 PY 2016 VL 291 IS 41 BP 21350 EP 21362 DI 10.1074/jbc.M116.732479 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DZ6UX UT WOS:000385999200002 ER PT J AU Vrentas, CE Moayeri, M Keefer, AB Greaney, AJ Tremblay, J O'Mard, D Leppla, SH Shoemaker, CB AF Vrentas, Catherine E. Moayeri, Mahtab Keefer, Andrea B. Greaney, Allison J. Tremblay, Jacqueline O'Mard, Danielle Leppla, Stephen H. Shoemaker, Charles B. TI A Diverse Set of Single-domain Antibodies (VHHs) against the Anthrax Toxin Lethal and Edema Factors Provides a Basis for Construction of a Bispecific Agent That Protects against Anthrax Infection SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE anthrax toxin; antibody; epitope mapping; microbial pathogenesis; phage display; toxin; EF; LF; VHH; VNA ID MONOCLONAL-ANTIBODIES; NEUTRALIZING AGENT; VARIABLE DOMAINS; RICIN TOXIN; CHALLENGE; MICE; INHIBITORS; NANOBODIES AB Infection with Bacillus anthracis, the causative agent of anthrax, can lead to persistence of lethal secreted toxins in the bloodstream, even after antibiotic treatment. VHH single-domain antibodies have been demonstrated to neutralize diverse bacterial toxins both in vitro and in vivo, with protein properties such as small size and high stability that make them attractive therapeutic candidates. Recently, we reported on VHHs with in vivo activity against the protective antigen component of the anthrax toxins. Here, we characterized a new set of 15 VHHs against the anthrax toxins that act by binding to the edema factor (EF) and/or lethal factor (LF) components. Six of these VHHs are cross-reactive against both EF and LF and recognize the N-terminal domain (LFN, EFN) of their target(s) with subnanomolar affinity. The cross-reactive VHHs block binding of EF/LF to the protective antigen C-terminal binding interface, preventing toxin entry into the cell. Another VHH appears to recognize the LF C-terminal domain and exhibits a kinetic effect on substrate cleavage by LF. A subset of the VHHs neutralized against EF and/or LF in murine macrophage assays, and the neutralizing VHHs that were tested improved survival of mice in a spore model of anthrax infection. Finally, a bispecific VNA (VHH-based neutralizing agent) consisting of two linked toxin-neutralizing VHHs, JMN-D10 and JMO-G1, was fully protective against lethal anthrax spore infection in mice as a single dose. This set of VHHs should facilitate development of new therapeutic VNAs and/or diagnostic agents for anthrax. C1 [Vrentas, Catherine E.] Frostburg State Univ, Dept Biol, Frostburg, MD 21532 USA. [Vrentas, Catherine E.; Moayeri, Mahtab; Keefer, Andrea B.; Greaney, Allison J.; O'Mard, Danielle; Leppla, Stephen H.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Tremblay, Jacqueline; Shoemaker, Charles B.] Tufts Univ, Cummings Sch Vet Med, Dept Infect Dis & Global Hlth, North Grafton, MA 01536 USA. RP Shoemaker, CB (reprint author), Tufts Univ, Cummings Sch Vet Med, Dept Infect Dis & Global Hlth, 200 Westboro Rd, North Grafton, MA 01536 USA. EM charles.shoemaker@tufts.edu FU National Institute of Allergy and Infectious Diseases (NIAID); National Institutes of Health [U54 AI057159] FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID) and by National Institutes of Health Grant U54 AI057159 (to C.B.S). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 29 TC 0 Z9 0 U1 3 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 7 PY 2016 VL 291 IS 41 BP 21596 EP 21606 DI 10.1074/jbc.M116.749184 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DZ6UX UT WOS:000385999200026 PM 27539858 ER PT J AU Bohlin, J Haberg, SE Magnus, P Reese, SE Gjessing, HK Magnus, MC Parr, CL Page, CM London, SJ Nystad, W AF Bohlin, J. Haberg, S. E. Magnus, P. Reese, S. E. Gjessing, H. K. Magnus, M. C. Parr, C. L. Page, C. M. London, S. J. Nystad, W. TI Prediction of gestational age based on genome-wide differentially methylated regions SO GENOME BIOLOGY LA English DT Article ID DNA METHYLATION; NORWEGIAN MOTHER; BIRTH-WEIGHT; CHILD COHORT; FETAL-GROWTH; METAANALYSIS; ASSOCIATION; PREGNANCY; SELECTION; PATTERNS AB Background: We explored the association between gestational age and cord blood DNA methylation at birth and whether DNA methylation could be effective in predicting gestational age due to limitations with the presently used methods. We used data from the Norwegian Mother and Child Birth Cohort study (MoBa) with Illumina HumanMethylation450 data measured for 1753 newborns in two batches: MoBa 1, n = 1068; and MoBa 2, n = 685. Gestational age was computed using both ultrasound and the last menstrual period. We evaluated associations between DNA methylation and gestational age and developed a statistical model for predicting gestational age using MoBa 1 for training and MoBa 2 for predictions. The prediction model was additionally used to compare ultrasound and last menstrual period-based gestational age predictions. Furthermore, both CpGs and associated genes detected in the training models were compared to those detected in a published prediction model for chronological age. Results: There were 5474 CpGs associated with ultrasound gestational age after adjustment for a set of covariates, including estimated cell type proportions, and Bonferroni-correction for multiple testing. Our model predicted ultrasound gestational age more accurately than it predicted last menstrual period gestational age. Conclusions: DNA methylation at birth appears to be a good predictor of gestational age. Ultrasound gestational age is more strongly associated with methylation than last menstrual period gestational age. The CpGs linked with our gestational age prediction model, and their associated genes, differed substantially from the corresponding CpGs and genes associated with a chronological age prediction model. C1 [Bohlin, J.; Haberg, S. E.; Magnus, P.; Gjessing, H. K.; Magnus, M. C.; Parr, C. L.; Page, C. M.; Nystad, W.] Norwegian Inst Publ Hlth, POB 44040456, Oslo, Norway. [Reese, S. E.; London, S. J.] NIEHS, NIH, US Dept HHS, POB 12233MD A3-05, Durham, NC 27709 USA. RP Bohlin, J (reprint author), Norwegian Inst Publ Hlth, POB 44040456, Oslo, Norway. EM jon.bohlin@fhi.no OI London, Stephanie/0000-0003-4911-5290; Bohlin, Jon/0000-0002-0992-1311 FU NIH (NIH/NIEHS) [N01-ES-75558]; Norwegian Research Council/FUGE [151918/S10]; Norwegian Research Council/Human Biobanks and Health [221097]; Intramural Research Program of the NIH, NIEHS [ZIA ES049019]; Norwegian Extra-Foundation for Health and Rehabilitation [2011.2.0218]; NIH (NIH/NINDS) [1 UO1 NS 047537-01, 2 UO1 NS 047537-06A1] FX The Norwegian Mother and Child Cohort Study is supported by NIH (NIH/NIEHS contract number N01-ES-75558, NIH/NINDS grant number 1 UO1 NS 047537-01 and grant number 2 UO1 NS 047537-06A1) and the Norwegian Research Council/FUGE (grant number 151918/S10). The work is also supported by the Norwegian Research Council/Human Biobanks and Health (grant number 221097 to W.N.) and in part by the Intramural Research Program of the NIH, NIEHS (ZIA ES049019) as well as the Norwegian Extra-Foundation for Health and Rehabilitation (grant number 2011.2.0218). NR 32 TC 2 Z9 2 U1 5 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1474-760X J9 GENOME BIOL JI Genome Biol. PD OCT 7 PY 2016 VL 17 AR 207 DI 10.1186/s13059-016-1063-4 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA DY9PG UT WOS:000385465700002 PM 27717397 ER PT J AU Huang, BL Trofka, A Furusawa, A Norrie, JL Rabinowitz, AH Vokes, SA Taketo, MM Zakany, J Mackem, S AF Huang, Bau-Lin Trofka, Anna Furusawa, Aki Norrie, Jacqueline L. Rabinowitz, Adam H. Vokes, Steven A. Taketo, M. Mark Zakany, Jozsef Mackem, Susan TI An interdigit signalling centre instructs coordinate phalanx-joint formation governed by 5 ' Hoxd-Gli3 antagonism SO NATURE COMMUNICATIONS LA English DT Article ID APICAL ECTODERMAL RIDGE; LIMB DEVELOPMENT; ARTICULAR-CARTILAGE; SYNOVIAL JOINT; BETA-CATENIN; HOX GENES; DIGIT NUMBER; MOUSE LIMB; GLI3; BONE AB The number of phalanges and joints are key features of digit 'identity' and are central to limb functionality and evolutionary adaptation. Prior chick work indicated that digit phalanges and their associated joints arise in a different manner than the more sparsely jointed long bones, and their identity is regulated by differential signalling from adjacent interdigits. Currently, there is no genetic evidence for this model, and the molecular mechanisms governing digit joint specification remain poorly understood. Using genetic approaches in mouse, here we show that functional 5'Hoxd-Gli3 antagonism acts indirectly, through Bmp signalling from the interdigital mesenchyme, to regulate specification of joint progenitors, which arise in conjunction with phalangeal precursors at the digit tip. Phalanx number, although co-regulated, can be uncoupled from joint specification. We propose that 5'Hoxd genes and Gli3 are part of an interdigital signalling centre that sets net Bmp signalling levels from different interdigits to coordinately regulate phalanx and joint formation. C1 [Huang, Bau-Lin; Trofka, Anna; Furusawa, Aki; Mackem, Susan] NCI, Canc & Dev Biol Lab, CCR, Frederick, MD 21702 USA. [Norrie, Jacqueline L.; Rabinowitz, Adam H.; Vokes, Steven A.] Univ Texas Austin, Dept Mol Biosci, Austin, TX 78712 USA. [Norrie, Jacqueline L.; Rabinowitz, Adam H.; Vokes, Steven A.] Univ Texas Austin, Inst Cellular & Mol Biol, Austin, TX 78712 USA. [Taketo, M. Mark] Kyoto Univ, Grad Sch Med, Dept Pharmacol, Sakyo Ku, Yoshida Konoe Cho, Kyoto 6068501, Japan. [Zakany, Jozsef] Univ Geneva, Dept Genet & Evolut, CH-41211 Geneva, Switzerland. [Furusawa, Aki] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. RP Huang, BL (reprint author), NCI, Canc & Dev Biol Lab, CCR, Frederick, MD 21702 USA. EM huangbl@mail.nih.gov; mackems@mail.nih.gov FU Center for Cancer Research, National Cancer Institute, NIH; [NIH R01HD073151] FX We thank Scott Stadler for generously providing Hoxd13 antibody; Denis Duboule both for providing mouse lines and for financial research support to J.Z.; Alex Joyner and David Kingsley and Maurizio Pacifici for providing mouse lines; Richard Behringer, Alex Joyner, David Kingsley, Richard Maas and Rolf Zeller for probes; Lino Tessarollo for assistance in generating RosaHoxd13 knock-in mice; and Cliff Tabin for stimulating discussions. This research was supported by the Center for Cancer Research, National Cancer Institute, NIH (SM, intramural Research Program) and a grant to S.A.V. (NIH R01HD073151). NR 65 TC 0 Z9 0 U1 4 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD OCT 7 PY 2016 VL 7 AR 12903 DI 10.1038/ncomms12903 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ1FE UT WOS:000385583500001 PM 27713395 ER PT J AU Yeom, YS Wang, ZJ Nguyen, TT Kim, HS Choi, C Han, MC Kim, CH Lee, JK Chung, BS Zankl, M Petoussi-Henss, N Bolch, WE Lee, C AF Yeom, Yeon Soo Wang, Zhao Jun Thang Tat Nguyen Kim, Han Sung Choi, Chansoo Han, Min Cheol Kim, Chan Hyeong Lee, Jai Ki Chung, Beom Sun Zankl, Maria Petoussi-Henss, Nina Bolch, Wesley E. Lee, Choonsik TI Development of skeletal system for mesh-type ICRP reference adult phantoms SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE ICRP reference phantom; skeleton; voxel phantom; mesh phantom; Monte Carlo; dose coefficient ID SIMULATION; GEANT4; MODELS; BODY AB The reference adult computational phantoms of the international commission on radiological protection (ICRP) described in Publication 110 are voxel-type computational phantoms based on whole-body computed tomography (CT) images of adult male and female patients. The voxel resolutions of these phantoms are in the order of a few millimeters and smaller tissues such as the eye lens, the skin, and the walls of some organs cannot be properly defined in the phantoms, resulting in limitations in dose coefficient calculations for weakly penetrating radiations. In order to address the limitations of the ICRP-110 phantoms, an ICRP Task Group has been recently formulated and the voxel phantoms are now being converted to a high-quality mesh format. As a part of the conversion project, in the present study, the skeleton models, one of the most important and complex organs of the body, were constructed. The constructed skeleton models were then tested by calculating red bone marrow (RBM) and endosteum dose coefficients (DCs) for broad parallel beams of photons and electrons and comparing the calculated values with those of the original ICRP-110 phantoms. The results show that for the photon exposures, there is a generally good agreement in the DCs between the mesh-type phantoms and the original voxel-type ICRP-110 phantoms; that is, the dose discrepancies were less than 7% in all cases except for the 0.03 MeV cases, for which the maximum difference was 14%. On the other hand, for the electron exposures (<= 4 MeV), the DCs of the mesh-type phantoms deviate from those of the ICRP-110 phantoms by up to similar to 1600 times at 0.03 MeV, which is indeed due to the improvement of the skeletal anatomy of the developed skeleton mesh models. C1 [Yeom, Yeon Soo; Wang, Zhao Jun; Thang Tat Nguyen; Kim, Han Sung; Choi, Chansoo; Han, Min Cheol; Kim, Chan Hyeong; Lee, Jai Ki] Hanyang Univ, Dept Nucl Engn, 222 Wangsimni Ro, Seoul 04763, South Korea. [Chung, Beom Sun] Ajou Univ, Sch Med, Dept Anat, 164 Worldcup Ro, Suwon 16499, South Korea. [Zankl, Maria; Petoussi-Henss, Nina] Deutsch Forschungszentrum Gesundheit & Umwelt Gmb, Helmholtz Zentrum Munchen, Res Unit Med Radiat Phys & Diagnost, Ingolstadter Landstr 1, D-85764 Neuherberg, Germany. [Bolch, Wesley E.] Univ Florida, J Crayton Pruitt Family Dept Biomed Engn, POB 116131, Gainesville, FL 32611 USA. [Lee, Choonsik] NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. RP Kim, CH (reprint author), Hanyang Univ, Dept Nucl Engn, 222 Wangsimni Ro, Seoul 04763, South Korea. EM chkim@hanyang.ac.kr FU Nuclear Safety and Security Commission (NSSC) through Korea Foundation of Nuclear Safety (KOFONS); Ministry of Science, ICT and Future Planning through the National Research Foundation of Korea [1403012, 2015M2A2A6A01045241] FX This project was supported by Nuclear Safety and Security Commission (NSSC) through Korea Foundation of Nuclear Safety (KOFONS) and also by Ministry of Science, ICT and Future Planning through the National Research Foundation of Korea (Project No.: 1403012, 2015M2A2A6A01045241). NR 23 TC 1 Z9 1 U1 1 U2 1 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 EI 1361-6560 J9 PHYS MED BIOL JI Phys. Med. Biol. PD OCT 7 PY 2016 VL 61 IS 19 BP 7054 EP 7073 DI 10.1088/0031-9155/61/19/7054 PG 20 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA DY8QX UT WOS:000385396100010 PM 27648514 ER PT J AU Yuan, H Liu, HL Liu, ZS Owzar, K Han, YH Su, L Wei, YY Hung, RJ McLaughlin, J Brhane, Y Brennan, P Bickeboeller, H Rosenberger, A Houlston, RS Caporaso, N Landi, MT Heinrich, J Risch, A Christiani, DC Gumus, ZH Klein, RJ Amos, CI Wei, QY AF Yuan, Hua Liu, Hongliang Liu, Zhensheng Owzar, Kouros Han, Younghun Su, Li Wei, Yongyue Hung, Rayjean J. McLaughlin, John Brhane, Yonathan Brennan, Paul Bickeboeller, Heike Rosenberger, Albert Houlston, Richard S. Caporaso, Neil Landi, Maria Teresa Heinrich, Joachim Risch, Angela Christiani, David C. Gumus, Zeynep H. Klein, Robert J. Amos, Christopher I. Wei, Qingyi TI A Novel Genetic Variant in Long Non-coding RNA Gene NEXN-AS1 is Associated with Risk of Lung Cancer SO SCIENTIFIC REPORTS LA English DT Article ID GENOME-WIDE ASSOCIATION; SINGLE-NUCLEOTIDE POLYMORPHISMS; SUSCEPTIBILITY LOCUS; POOLED ANALYSIS; DISEASE; EXPRESSION; 5P15.33; ARCHITECTURE; METAANALYSIS; REPLICATION AB Lung cancer etiology is multifactorial, and growing evidence has indicated that long non-coding RNAs (lncRNAs) are important players in lung carcinogenesis. We performed a large-scale meta-analysis of 690,564 SNPs in 15,531 autosomal lncRNAs by using datasets from six previously published genome-wide association studies (GWASs) from the Transdisciplinary Research in Cancer of the Lung (TRICL) consortium in populations of European ancestry. Previously unreported significant SNPs (P value < 1 x 10(-7)) were further validated in two additional independent lung cancer GWAS datasets from Harvard University and deCODE. In the final meta-analysis of all eight GWAS datasets with 17,153 cases and 239,337 controls, a novel risk SNP rs114020893 in the lncRNA NEXN-AS1 region at 1p31.1 remained statistically significant (odds ratio = 1.17; 95% confidence interval = 1.11-1.24; P = 8.31 x 10(-9)). In further in silico analysis, rs114020893 was predicted to change the secondary structure of the lncRNA. Our finding indicates that SNP rs114020893 of NEXN-AS1 at 1p31.1 may contribute to lung cancer susceptibility. C1 [Yuan, Hua] Nanjing Med Univ, Collaborat Innovat Ctr Canc Personalized Med, Nanjing, Jiangsu, Peoples R China. [Yuan, Hua] Nanjing Med Univ, Affiliated Hosp Stomatol, Dept Oral & Maxillofacial Surg, Nanjing, Jiangsu, Peoples R China. [Yuan, Hua; Liu, Hongliang; Liu, Zhensheng; Wei, Qingyi] Duke Univ, Sch Med, Dept Med, Durham, NC 27706 USA. [Yuan, Hua; Liu, Hongliang; Liu, Zhensheng; Owzar, Kouros; Wei, Qingyi] Duke Univ, Med Ctr, Duke Canc Inst, Durham, NC USA. [Owzar, Kouros] Duke Univ, Med Ctr, Dept Biostat & Bioinformat, Durham, NC USA. [Han, Younghun; Amos, Christopher I.] Dartmouth Coll, Geisel Sch Med, Community & Family Med, Hanover, NC USA. [Su, Li; Wei, Yongyue; Christiani, David C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Su, Li; Wei, Yongyue; Christiani, David C.] Harvard Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA. [Hung, Rayjean J.; Brhane, Yonathan] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada. [McLaughlin, John] Publ Hlth Ontario, Toronto, ON, Canada. [Brennan, Paul] Int Agcy Res Canc, Genet Epidemiol Grp, Lyon, France. [Bickeboeller, Heike; Rosenberger, Albert] Univ Gottingen, Univ Med Ctr, Dept Genet Epidemiol, Gottingen, Germany. [Houlston, Richard S.] Inst Canc Res, Div Genet & Epidemiol, London, England. [Caporaso, Neil; Landi, Maria Teresa] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Heinrich, Joachim] Inst Epidemiol 1, German Res Ctr Environm Hlth, Helmholtz Ctr Munich, Neuherberg, Germany. [Heinrich, Joachim] Univ Munich, Univ Hosp Munich, Inst & Outpatient Clin Occupat Social & Environm, Munich, Germany. [Risch, Angela] Salzburg Univ, Dept Mol Biol, Salzburg, Austria. [Risch, Angela] DKFZ German Canc Res Ctr, Dept Epigenom & Canc Risk Factors, Heidelberg, Germany. [Risch, Angela] German Ctr Lung Res DZL, TLRC H, Heidelberg, Germany. [Gumus, Zeynep H.; Klein, Robert J.] Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, New York, NY 10029 USA. RP Wei, QY (reprint author), Duke Univ, Sch Med, Dept Med, Durham, NC 27706 USA.; Wei, QY (reprint author), Duke Univ, Med Ctr, Duke Canc Inst, Durham, NC USA. EM qingyi.wei@duke.edu RI Hung, Rayjean/A-7439-2013; Risch, Angela/H-2669-2013 OI Risch, Angela/0000-0002-8026-5505 FU Transdisciplinary Research in Cancer of the Lung (TRICL) Study on behalf of the Genetic Associations and Mechanisms in Oncology (GAME-ON) Network [U19-CA148127]; Canadian Cancer Society Research Institute [020214]; Ontario Institute of Cancer; Cancer Care Ontario Chair Award; Cancer Research UK [C1298/A8780, C1298/A8362]; NCRN; HEAL; Sanofi-Aventis; NIH [5R01CA055769, 5R01CA127219, 5R01CA133996, 5R01CA121197, U19CA148127, P50 CA70907, R01CA121197, R01CA127219, U19 CA148127, R01 CA55769, K07CA160753, HHSN268200782096C]; Roy Castle Lung Cancer Foundation, UK; Deutsche Krebshilfe [70-2919]; Helmholtz-DAAD fellowship [A/07/97379]; GSF - German Federal Ministry of Education, Science, Research and Technology; State of Bavaria; National Genome Research Network (NGFN); DFG [BI576/2-1, BI 576/2-2]; Helmholtzgemeinschaft (HGF); Federal office for Radiation Protection [BfS: STSch4454]; Institut National du Cancer, France; European Community [LSHG-CT-2005-512113]; Norwegian Cancer Association; Functional Genomics Programme of Research Council of Norway; European Regional Development Fund; State Budget of the Czech Republic (RECAMO) [CZ.1.05/2.1.00/03.0101]; US National Cancer Institute, NIH [R01 CA111703, UO1 CA63673]; Fred Hutchinson Cancer Research Center; US National Cancer Institute [R01 CA092039]; FP7 grant [REGPOT245536]; Estonian Government [SF0180142s08]; EU RDF in the frame of Centre of Excellence in Genomics; Estoinian Research Infrastructure's Roadmap; University of Tartu [SP1GVARENG]; IARC; Intramural Research Program of NIH, NCI, Division of Cancer Epidemiology and Genetics; US Public Health Service from the NCI [N01-CN-45165, N01-RC-45035, N01-RC-37004]; NCI [NO1-CN-25514, NO1-CN-25522, NO1-CN-25515, NO1-CN-25512, NO1-CN-25513, NO1-CN-25516, NO1-CN-25511, NO1-CN-25524, NO1-CN-25518, NO1-CN-75022, NO1-CN-25476, NO1-CN-25404]; American Cancer Society; NIH Genes, Environment and Health Initiative (GEI) [HG-06-033-NCI-01, RO1HL091172-01, U01HG004438, NIH HHSN268200782096C, U01 HG004446]; CPRIT grant [RP100443]; NIH (National Cancer Institute) [CA092824, CA090578, CA074386]; GENADDICT [LSHMCT-2004-005166]; National Institutes of Health [R01-DA017932]; Duke Cancer Institute as part of the P30 Cancer Center Support Grant [NIH CA014236]; Duke Cancer Institute; Duke Cancer Institute, Duke University Medical Center; Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University; LUNGevity Foundation; [U01 HG007033] FX TRICL: This work was supported by the Transdisciplinary Research in Cancer of the Lung (TRICL) Study, U19-CA148127 on behalf of the Genetic Associations and Mechanisms in Oncology (GAME-ON) Network. The Toronto study was supported by Canadian Cancer Society Research Institute(020214), Ontario Institute of Cancer and Cancer Care Ontario Chair Award to RH The ICR study was supported by Cancer Research UK (C1298/A8780 andC1298/A8362-Bobby Moore Fund for Cancer Research UK) and NCRN, HEAL and Sanofi-Aventis. Additional funding was obtained from NIH grants (5R01CA055769, 5R01CA127219, 5R01CA133996, and 5R01CA121197). The Liverpool Lung Project (LLP) was supported by The Roy Castle Lung Cancer Foundation, UK. The ICR and LLP studies made use of genotyping data from the Wellcome Trust Case Control Consortium 2 (WTCCC2); a full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Sample collection for the Heidelberg lung cancer study was in part supported by a grant (70-2919) from the Deutsche Krebshilfe. The work was additionally supported by a Helmholtz-DAAD fellowship (A/07/97379 to MNT) and by the NIH (U19CA148127). The KORA Surveys were financed by the GSF, which is funded by the German Federal Ministry of Education, Science, Research and Technology and the State of Bavaria. The Lung Cancer in the Young study (LUCY) was funded in part by the National Genome Research Network (NGFN), the DFG (BI576/2-1; BI 576/2-2), the Helmholtzgemeinschaft (HGF) and the Federal office for Radiation Protection (BfS: STSch4454). Genotyping was performed in the Genome Analysis Center (GAC) of the Helmholtz Zentrum Muenchen. Support for the Central Europe, HUNT2/Tromso and CARET genome-wide studies was provided by Institut National du Cancer, France. Support for the HUNT2/Tromso genome-wide study was also provided by the European Community (Integrated Project DNA repair, LSHG-CT-2005-512113), the Norwegian Cancer Association and the Functional Genomics Programme of Research Council of Norway. Support for the Central Europe study, Czech Republic, was also provided by the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101). Support for the CARET genome-wide study was also provided by grants from the US National Cancer Institute, NIH (R01 CA111703 and UO1 CA63673), and by funds from the Fred Hutchinson Cancer Research Center. Additional funding for study coordination, genotyping of replication studies and statistical analysis was provided by the US National Cancer Institute (R01 CA092039). The lung cancer GWAS from Estonia was partly supported by a FP7 grant (REGPOT245536), by the Estonian Government (SF0180142s08), by EU RDF in the frame of Centre of Excellence in Genomics and Estoinian Research Infrastructure's Roadmap and by University of Tartu (SP1GVARENG). The work reported in this paper was partly undertaken during the tenure of a Postdoctoral Fellowship from the IARC (for MNT). The Environment and Genetics in Lung Cancer Etiology (EAGLE), the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC), and the Prostate, Lung, Colon, Ovary Screening Trial (PLCO) studies and the genotyping of ATBC, the Cancer Prevention Study II Nutrition Cohort (CPS-II) and part of PLCO were supported by the Intramural Research Program of NIH, NCI, Division of Cancer Epidemiology and Genetics. ATBC was also supported by US Public Health Service contracts (N01-CN-45165, N01-RC-45035 and N01-RC-37004) from the NCI.; PLCO was also supported by individual contracts from the NCI to the University of Colorado Denver (NO1-CN-25514), Georgetown University (NO1-CN-25522), Pacific Health Research Institute (NO1-CN-25515), Henry Ford Health System (NO1-CN-25512), University of Minnesota(NO1-CN-25513), Washington University(NO1-CN-25516), University of Pittsburgh (NO1-CN-25511), University of Utah (NO1-CN-25524), Marshfield Clinic Research Foundation (NO1-CN-25518), University of Alabama at Birmingham (NO1-CN-75022, Westat, Inc. NO1-CN-25476), University of California, Los Angeles (NO1-CN-25404). The Cancer Prevention Study II Nutrition Cohort was supported by the American Cancer Society. The NIH Genes, Environment and Health Initiative (GEI) partly funded DNA extraction and statistical analyses (HG-06-033-NCI-01 andRO1HL091172-01), genotyping at the Johns Hopkins University Center for Inherited Disease Research (U01HG004438 and NIH HHSN268200782096C) and study coordination at the GENEVA Coordination Center (U01 HG004446) for EAGLE and part of PLCO studies. Funding for the MD Anderson Cancer Study was provided by NIH grants (P50 CA70907, R01CA121197, R01CA127219, U19 CA148127, R01 CA55769, K07CA160753) and CPRIT grant (RP100443). Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is funded through a federal contract from the NIH to The Johns Hopkins University (HHSN268200782096C). The Harvard Lung Cancer Study was supported by the NIH (National Cancer Institute) grants CA092824, CA090578, and CA074386. deCODE: The project was funded in part by GENADDICT: LSHMCT-2004-005166), the National Institutes of Health (R01-DA017932). As Duke Cancer Institute members, Q.W. and K.O. acknowledge support from the Duke Cancer Institute as part of the P30 Cancer Center Support Grant (Grant ID: NIH CA014236). Q.W. was also supported by a start-up fund from Duke Cancer Institute, Duke University Medical Center. Hua Yuan was sponsored by Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University. We also acknowledge support from U01 HG007033 (to R.J.K.) and LUNGevity Foundation (to Z.H.G.). NR 38 TC 1 Z9 1 U1 15 U2 15 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD OCT 7 PY 2016 VL 6 AR 34234 DI 10.1038/srep34234 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DY1CS UT WOS:000384833100001 PM 27713484 ER PT J AU Berger, VW AF Berger, Vance W. TI Risk of selection bias in randomized trials: further insight SO TRIALS LA English DT Editorial Material DE Allocation concealment; Berger-Exner test; Conditional unrestricted randomization; Maximal procedure ID ALLOCATION CONCEALMENT; DESIGNS AB The quality of randomization is an under-appreciated facet of trial design. The present piece represents an advance in our collective understanding of how allocation concealment and randomization relate to risk of selection bias in randomized trials, and other measures are also considered. Though the overwhelming majority of the advice given is timely and correct, it is more instructive to focus on the relatively narrow sliver of advice that is incorrect (namely, that trials should not stratify by site, and that unrestricted randomization is a solution to the problem of selection bias), so it is in this context that the comments here must be understood. In no way is this intended to be a rebuttal of the excellent work we have before us. Rather, it is a refinement. C1 [Berger, Vance W.] Natl Canc Inst, 9609 Med Ctr Dr, Rockville, MD 20850 USA. [Berger, Vance W.] Univ Maryland Baltimore Cty, Biometry Res Grp, Natl Canc Inst, 9609 Med Ctr Dr, Rockville, MD 20850 USA. RP Berger, VW (reprint author), Natl Canc Inst, 9609 Med Ctr Dr, Rockville, MD 20850 USA.; Berger, VW (reprint author), Univ Maryland Baltimore Cty, Biometry Res Grp, Natl Canc Inst, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM vb78c@nih.gov NR 15 TC 0 Z9 0 U1 2 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6215 J9 TRIALS JI Trials PD OCT 7 PY 2016 VL 17 AR 485 DI 10.1186/s13063-016-1597-5 PG 5 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DY1IO UT WOS:000384848300001 PM 27717392 ER PT J AU Li, ZW Araoka, T Wu, J Liao, HK Li, M Lazo, M Zhou, B Sui, YH Wu, MZ Tamura, I Xia, Y Beyret, E Matsusaka, T Pastan, I Esteban, CR Guillen, I Guillen, P Campistol, JM Belmonte, JCI AF Li, Zhongwei Araoka, Toshikazu Wu, Jun Liao, Hsin-Kai Li, Mo Lazo, Marta Zhou, Bing Sui, Yinghui Wu, Min-Zu Tamura, Isao Xia, Yun Beyret, Ergin Matsusaka, Taiji Pastan, Ira Esteban, Concepcion Rodriguez Guillen, Isabel Guillen, Pedro Campistol, Josep M. Belmonte, Juan Carlos Izpisua TI 3D Culture Supports Long-Term Expansion of Mouse and Human Nephrogenic Progenitors SO CELL STEM CELL LA English DT Article ID PLURIPOTENT STEM-CELLS; KIDNEY DEVELOPMENT; METANEPHRIC MESENCHYME; INTERMEDIATE MESODERM; RENAL PROGENITORS; INJURY; MODEL; DIFFERENTIATION; INDUCTION; ORGANOIDS AB Transit-amplifying nephron progenitor cells (NPCs) generate all of the nephrons of the mammalian kidney during development. Their limited numbers, poor in vitro expansion, and difficult accessibility in humans have slowed basic and translational research into renal development and diseases. Here, we show that with appropriate 3D culture conditions, it is possible to support long-term expansion of primary mouse and human fetal NPCs as well as NPCs derived from human induced pluripotent stem cells (iPSCs). Expanded NPCs maintain genomic stability, molecular homogeneity, and nephrogenic potential in vitro, ex vivo, and in vivo. Cultured NPCs are amenable to gene targeting and can form nephron organoids that engraft in vivo, functionally couple to the host's circulatory system, and produce urine-like metabolites via filtration. Together, these findings provide a technological platform for studying human nephrogenesis, modeling and diagnosing renal diseases, and drug discovery. C1 [Li, Zhongwei; Araoka, Toshikazu; Wu, Jun; Liao, Hsin-Kai; Li, Mo; Wu, Min-Zu; Tamura, Isao; Xia, Yun; Beyret, Ergin; Esteban, Concepcion Rodriguez; Belmonte, Juan Carlos Izpisua] Salk Inst Biol Studies, Gene Express Lab, 10010 North Torrey Pines Rd, La Jolla, CA 92037 USA. [Araoka, Toshikazu; Wu, Jun; Liao, Hsin-Kai] Univ Catolica San Antonio Murcia UCAM, Campus Jeronimos,135 Guadalupe, Murcia 30107, Spain. [Lazo, Marta; Campistol, Josep M.] Univ Barcelona, Hosp Clin, IDIBAPS, E-08036 Barcelona, Spain. [Zhou, Bing] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA. [Sui, Yinghui] Univ Calif San Diego, Dept Pediat & Cellular & Mol Med, La Jolla, CA 92093 USA. [Matsusaka, Taiji] Tokai Univ, Sch Med, Dept Mol Life Sci, Isehara, Kanagawa 2591193, Japan. [Matsusaka, Taiji] Tokai Univ, Sch Med, Inst Med Sci, Isehara, Kanagawa 2591193, Japan. [Pastan, Ira] NCI, Lab Mol Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Guillen, Isabel; Guillen, Pedro] Fdn Dr Pedro Guillen, Invest Biomed Clin CEMTRO, Ave Ventisquero Condesa 42, Madrid 28035, Spain. RP Belmonte, JCI (reprint author), Salk Inst Biol Studies, Gene Express Lab, 10010 North Torrey Pines Rd, La Jolla, CA 92037 USA. EM belmonte@salk.edu FU Kyoto University Foundation; Nagai Foundation Tokyo; Kidney Foundation, Japan [JKFB15-4]; UCAM; California Institute for Regenerative Medicine (CIRM); Universidad Catolica San Antonio de Murcia (UCAM); Catharina Foundation; Fundacion Dr. Pedro Guillen; G. Harold and Leila Y. Mathers Charitable Foundation; Leona M. and Harry B. Helmsley Charitable Trust [2012-PG-MED002]; Moxie Foundation FX We would like to thank M. Ku and M. Chang of the H.A. and Mary K. Chapman Charitable Foundations Genomic Sequencing Core for performing RNA-seq, J.O. of Human Embryonic Stem Cell Core Facility of Sanford Consortium for Regenerative Medicine for FACS, and M. Schwarz and P. Schwarz for administrative help. T.A. was supported by The Kyoto University Foundation, The Nagai Foundation Tokyo, The Kidney Foundation, Japan (grant JKFB15-4), and the UCAM. M.L and Y.X. were supported by a California Institute for Regenerative Medicine (CIRM) Training Grant fellowship. H.K. Liao was supported by Universidad Catolica San Antonio de Murcia (UCAM). E.B. was supported by a Catharina Foundation fellowship. Work in the laboratory of J.C.I.B. was supported by UCAM (mouse work), Fundacion Dr. Pedro Guillen, The G. Harold and Leila Y. Mathers Charitable Foundation, The Leona M. and Harry B. Helmsley Charitable Trust (2012-PG-MED002), and The Moxie Foundation. NR 31 TC 2 Z9 2 U1 1 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 EI 1875-9777 J9 CELL STEM CELL JI Cell Stem Cell PD OCT 6 PY 2016 VL 19 IS 4 BP 516 EP 529 DI 10.1016/j.stem.2016.07.016 PG 14 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA EE3FS UT WOS:000389473800014 PM 27570066 ER PT J AU Osterburg, AR Nelson, RL Yaniv, BZ Foot, R Donica, WRF Nashu, MA Liu, H Wikenheiser-Brokamp, KA Moss, J Gupta, N McCormack, FX Borchers, MT AF Osterburg, Andrew R. Nelson, Rebecca L. Yaniv, Benyamin Z. Foot, Rachel Donica, Walter R. F. Nashu, Madison A. Liu, Huan Wikenheiser-Brokamp, Kathryn A. Moss, Joel Gupta, Nishant McCormack, Francis X. Borchers, Michael T. TI NK cell activating receptor ligand expression in lymphangioleiomyomatosis is associated with lung function decline SO JCI INSIGHT LA English DT Article ID I-RELATED MOLECULES; NKG2D RECEPTOR; PULMONARY LYMPHANGIOLEIOMYOMATOSIS; GLYCOPROTEIN UL16; ADAPTIVE IMMUNITY; TUMOR-CELLS; GENE TSC2; T-CELLS; INFECTION; INNATE AB Lymphangioleiomyomatosis (LAM) is a rare lung disease of women that leads to progressive cyst formation and accelerated loss of pulmonary function. Neoplastic smooth muscle cells from an unknown source metastasize to the lung and drive destructive remodeling. Given the role of NK cells in immune surveillance, we postulated that NK cell activating receptors and their cognate ligands are involved in LAM pathogenesis. We found that ligands for the NKG2D activating receptor UL-16 binding protein 2 (ULBP2) and ULBP3 are localized in cystic LAM lesions and pulmonary nodules. We found elevated soluble serum ULBP2 (mean = 575 pg/ml +/- 142) in 50 of 100 subjects and ULBP3 in 30 of 100 (mean = 8,300 pg/ml +/- 1,515) subjects. LAM patients had fewer circulating NKG2D(+) NK cells and decreased NKG2D surface expression. Lung function decline was associated with soluble NKG2D ligand (sNKG2DL) detection. The greatest rate of decline forced expiratory volume in 1 second (FEV1, -124 +/- 30 ml/year) in the 48 months after enrollment (NHLBI LAM Registry) occurred in patients expressing both ULBP2 and ULBP3, whereas patients with undetectable sNKG2DL levels had the lowest rate of FEV1 decline (-32.7 +/- 10 ml/year). These data suggest a role for NK cells, sNKG2DL, and the innate immune system in LAM pathogenesis. C1 [Osterburg, Andrew R.; Nelson, Rebecca L.; Yaniv, Benyamin Z.; Foot, Rachel; Donica, Walter R. F.; Nashu, Madison A.; Liu, Huan; Gupta, Nishant; McCormack, Francis X.; Borchers, Michael T.] Univ Cincinnati, Coll Med, Dept Internal Med, Div Pulm Crit Care & Sleep Med, POB 45267-0564, Cincinnati, OH 45267 USA. [Wikenheiser-Brokamp, Kathryn A.] Univ Cincinnati, Dept Pathol & Lab Med, Cincinnati, OH USA. [Wikenheiser-Brokamp, Kathryn A.] Cincinnati Childrens Hosp Med Ctr, Div Pathol & Lab Med, Cincinnati, OH 45229 USA. [Wikenheiser-Brokamp, Kathryn A.] Cincinnati Childrens Hosp Med Ctr, Perinatal Inst, Div Pulm Biol, Cincinnati, OH 45229 USA. [Moss, Joel] NHLBI, Cardiovasc & Pulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Borchers, MT (reprint author), Univ Cincinnati, Coll Med, Dept Internal Med, Div Pulm Crit Care & Sleep Med, POB 45267-0564, Cincinnati, OH 45267 USA. EM BORCHEMT@ucmail.uc.edu FU BLRD VA [I01 BX002347]; NCATS NIH HHS [UL1 TR001425]; NHLBI NIH HHS [R01 HL119538] NR 60 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 2379-3708 J9 JCI INSIGHT JI JCI Insight PD OCT 6 PY 2016 VL 1 IS 16 AR e87270 DI 10.1172/jci.insight.87270 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EB1PC UT WOS:000387124700004 PM 27734028 ER PT J AU Klebanoff, CA Restifo, NP AF Klebanoff, Christopher A. Restifo, Nicholas P. TI Customizing Functionality and Payload Delivery for Receptor-Engineered T Cells SO CELL LA English DT Editorial Material ID CANCERS AB Adoptive immunotherapy using receptor engineering to achieve specific tumor targeting by T cells holds much promise for advancing cancer therapy. Here, two studies by Boice et al. and Roybal et al. provide distinct and potentially complimentary approaches to improve the efficacy and curb potential toxicities of this approach. C1 [Klebanoff, Christopher A.] Mem Sloan Kettering Canc Ctr, Ctr Cell Engn, New York, NY 10065 USA. [Klebanoff, Christopher A.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA. [Restifo, Nicholas P.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Restifo, Nicholas P.] NCI, Ctr Cell Based Therapy, NIH, Bethesda, MD 20892 USA. RP Klebanoff, CA (reprint author), Mem Sloan Kettering Canc Ctr, Ctr Cell Engn, New York, NY 10065 USA.; Klebanoff, CA (reprint author), Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA.; Restifo, NP (reprint author), NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA.; Restifo, NP (reprint author), NCI, Ctr Cell Based Therapy, NIH, Bethesda, MD 20892 USA. EM caklebanoff@gmail.com; restifo@nih.gov NR 10 TC 1 Z9 1 U1 5 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD OCT 6 PY 2016 VL 167 IS 2 BP 302 EP 304 DI 10.1016/j.cell.2016.09.033 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EA1HM UT WOS:000386343100006 PM 27716501 ER PT J AU Chudnovskiy, A Mortha, A Kana, V Kennard, A Ramirez, JD Rahman, A Remark, R Mogno, I Ng, R Gnjatic, S Amir, ED Solovyov, A Greenbaum, B Clemente, J Faith, J Belkaid, Y Grigg, ME Merad, M AF Chudnovskiy, Aleksey Mortha, Arthur Kana, Veronika Kennard, Andrea Ramirez, Juan David Rahman, Adeeb Remark, Romain Mogno, Ilaria Ng, Ruby Gnjatic, Sasha Amir, El-ad David Solovyov, Alexander Greenbaum, Benjamin Clemente, Jose Faith, Jeremiah Belkaid, Yasmine Grigg, Michael E. Merad, Miriam TI Host-Protozoan Interactions Protect from Mucosal Infections through Activation of the Inflammasome SO CELL LA English DT Article ID CONVENTIONAL DENDRITIC CELLS; INNATE LYMPHOID-CELLS; EXPRESSION; RESPONSES; COLITIS; MICE; IMMUNITY; MODEL; GUT; CARCINOGENESIS AB While conventional pathogenic protists have been extensively studied, there is an underappreciated constitutive protist microbiota that is an integral part of the vertebrate microbiome. The impact of these species on the host and their potential contributions to mucosal immune homeostasis remain poorly studied. Here, we show that the protozoan Tritrichomonas musculis activates the host epithelial inflammasome to induce IL-18 release. Epithelialderived IL-18 promotes dendritic cell-driven Th1 and Th17 immunity and confers dramatic protection from mucosal bacterial infections. Along with its role as a "protistic'' antibiotic, colonization with T. musculis exacerbates the development of T-cell-driven colitis and sporadic colorectal tumors. Our findings demonstrate a novel mutualistic host-protozoan interaction that increases mucosal host defenses at the cost of an increased risk of inflammatory disease. C1 [Chudnovskiy, Aleksey; Mortha, Arthur; Kana, Veronika; Remark, Romain; Amir, El-ad David; Merad, Miriam] Icahn Sch Med Mt Sinai, Dept Oncol Sci, 1475 Madison Ave, New York, NY 10028 USA. [Chudnovskiy, Aleksey; Mortha, Arthur; Kana, Veronika; Remark, Romain; Gnjatic, Sasha; Amir, El-ad David; Solovyov, Alexander; Greenbaum, Benjamin; Merad, Miriam] Icahn Sch Med Mt Sinai, Tisch Canc Inst, 1475 Madison Ave, New York, NY 10028 USA. [Chudnovskiy, Aleksey; Mortha, Arthur; Kana, Veronika; Rahman, Adeeb; Remark, Romain; Ng, Ruby; Gnjatic, Sasha; Amir, El-ad David; Clemente, Jose; Faith, Jeremiah; Merad, Miriam] Icahn Sch Med Mt Sinai, Inst Immunol, 1475 Madison Ave, New York, NY 10028 USA. [Rahman, Adeeb; Mogno, Ilaria; Clemente, Jose; Faith, Jeremiah] Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, 1475 Madison Ave, New York, NY 10028 USA. [Ramirez, Juan David] Univ Rosario, GIMUR, Bogota, Colombia. [Kennard, Andrea; Ramirez, Juan David; Grigg, Michael E.] NIAID, Mol Parasitol Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Belkaid, Yasmine] NIAID, Mucosal Immunol Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Belkaid, Yasmine] NIAID, Microbiome Program, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Mortha, Arthur] Univ Toronto, Dept Immunol, 1 Kings Coll Circle, Toronto, ON M5S 1A8, Canada. RP Merad, M (reprint author), Icahn Sch Med Mt Sinai, Dept Oncol Sci, 1475 Madison Ave, New York, NY 10028 USA.; Merad, M (reprint author), Icahn Sch Med Mt Sinai, Tisch Canc Inst, 1475 Madison Ave, New York, NY 10028 USA.; Merad, M (reprint author), Icahn Sch Med Mt Sinai, Inst Immunol, 1475 Madison Ave, New York, NY 10028 USA. EM miriam.merad@mssm.edu FU NIH [R01 CA154947A, R01 CA173861, U01 AI095611]; National Institute of Allergy and Infectious Diseases, NIH FX We thank the M.M. laboratory for helpful discussions and input. We would like to thank Fiona Desland for critical review of the manuscript. We would like to thank Jordi Ochando and the Flow Cytometry facility for their excellent technical support and assistance with cell sorting. We would like to thank Steve Porcella (Genomics Unit, RTB, Rocky Mountain Labs, NIAID), Mariam Quinones (Bioinformatics and Computational Biology Branch, NIAID), and Jacquice Davis (NIAID Microbiome Program) for their assistance with metagenomic and analysis. This study used the Nephele platform from the NIAID Office of Cyber Infrastructure and Computational Biology (OCICB) in Bethesda, MD. M.M. is funded by NIH grants R01 CA154947A, R01 CA173861, and U01 AI095611. This work was supported in part by the National Institute of Allergy and Infectious Diseases, NIH (Y.B. and M.E.G.). M.E.G. Is a Scholar of the Canadian Institute for Advanced Research (CIFAR) Integrated Microbial Biodiversity Program. NR 51 TC 7 Z9 7 U1 8 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD OCT 6 PY 2016 VL 167 IS 2 BP 444 EP + DI 10.1016/j.cell.2016.08.076 PG 27 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EA1HM UT WOS:000386343100020 PM 27716507 ER PT J AU Liu, W Li, H Hong, SH Piszczek, GP Chen, W Rodgers, GP AF Liu, W. Li, H. Hong, S-H Piszczek, G. P. Chen, W. Rodgers, G. P. TI Olfactomedin 4 deletion induces colon adenocarcinoma in ApcMin/+ mice SO ONCOGENE LA English DT Article ID NF-KAPPA-B; INTESTINAL EPITHELIAL-CELLS; BETA-CATENIN EXPRESSION; COLORECTAL-CANCER; STAPHYLOCOCCUS-AUREUS; TRANSCRIPTION FACTOR; CROHNS-DISEASE; STEM-CELLS; HGC-1; PROGRESSION AB Colon carcinogenesis is a multiple-step process involving the accumulation of a series of genetic and epigenetic alterations. The most commonly initiating event of intestinal carcinogenesis is mutation of the adenomatous polyposis coli (APC) gene, which leads to activation of the Wnt/beta-catenin pathway. Olfactomedin 4 (OLFM4) has emerged as an intestinal stem-cell marker, but its biological function in the intestine remains to be determined. Here we show that Olfm4 deletion induced colon adenocarcinoma in the distal colon of Apc(Min/+) mice. Mechanistically, we found that OLFM4 is a target gene of the Wnt/beta-catenin pathway and can downregulate beta-catenin signaling by competing with Wnt ligands for binding to Frizzled receptors, as well as by inhibition of the Akt-GSK-3 beta (Akt-glycogen synthase kinase-3 beta) pathway. We have shown that both Wnt and nuclear factor-kappa B (NF-kappa B) signaling were boosted in tumor tissues of Apc Olfm4 double-mutant mice. These data establish OLFM4 as a critical negative regulator of the Wnt/beta-catenin and NF-kappa B pathways that inhibits colon-cancer development initiated by APC mutation. In addition, Olfm4 deletion significantly enhanced intestinal-crypt proliferation and inflammation induced by azoxymethane/dextran sodium sulfate. Thus, OLFM4 has an important role in the regulation of intestinal inflammation and tumorigenesis, and could be a potential therapeutic target for intestinal malignant tumors. Unlike the human colonic epithelium, the mouse colonic epithelium does not express OLFM4, but nevertheless, systemic OLFM4 deletion promotes colon tumorigenesis and that loss from mucosal neutrophils may have a role to play. C1 [Liu, W.; Li, H.; Hong, S-H; Rodgers, G. P.] NHLBI, Mol & Clin Hematol Branch, NIH, Bldg 10,Room 9N119,9000 Rockville Pike, Bethesda, MD 20892 USA. [Hong, S-H] Natl Canc Ctr, Canc Genom Branch, Goyang Si, Gyeonggi Do, South Korea. [Piszczek, G. P.] NHLBI, Biochem & Biophys Ctr, Bldg 10, Bethesda, MD 20892 USA. [Chen, W.] NIDDK, Genom Core Lab, Bethesda, MD 20892 USA. RP Rodgers, GP (reprint author), NHLBI, Mol & Clin Hematol Branch, NIH, Bldg 10,Room 9N119,9000 Rockville Pike, Bethesda, MD 20892 USA. EM gr5n@nih.gov FU intramural research fund of the National Institutes of Health FX We thank Dr Michael A Eckhaus, National Institutes of Health, for the pathology assistance and Dr Ivan Ding, National Institutes of Health, for helpful suggestions and review of our manuscript. This study was supported by the intramural research fund of the National Institutes of Health. NR 42 TC 1 Z9 1 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD OCT 6 PY 2016 VL 35 IS 40 BP 5237 EP 5247 DI 10.1038/onc.2016.58 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA DZ7NO UT WOS:000386053000003 PM 26973250 ER PT J AU Karl, S White, MT Milne, GJ Gurarie, D Hay, SI Barry, AE Felger, I Mueller, I AF Karl, Stephan White, Michael T. Milne, George J. Gurarie, David Hay, Simon I. Barry, Alyssa E. Felger, Ingrid Mueller, Ivo TI Spatial Effects on the Multiplicity of Plasmodium falciparum Infections SO PLOS ONE LA English DT Article ID PAPUA-NEW-GUINEA; MARK-RELEASE-RECAPTURE; ANOPHELES-GAMBIAE; MALARIA TRANSMISSION; POPULATION-DYNAMICS; VECTOR CONTROL; HOST-SEEKING; KENYAN COAST; P. VIVAX; MOSQUITOS AB As malaria is being pushed back on many frontiers and global case numbers are declining, accurate measurement and prediction of transmission becomes increasingly difficult. Low transmission settings are characterised by high levels of spatial heterogeneity, which stands in stark contrast to the widely used assumption of spatially homogeneous transmission used in mathematical transmission models for malaria. In the present study an individual-based mathematical malaria transmission model that incorporates multiple parasite clones, variable human exposure and duration of infection, limited mosquito flight distance and most importantly geographically heterogeneous human and mosquito population densities was used to illustrate the differences between homogeneous and heterogeneous transmission assumptions when aiming to predict surrogate indicators of transmission intensity such as population parasite prevalence or multiplicity of infection (MOI). In traditionally highly malaria endemic regions where most of the population harbours malaria parasites, humans are often infected with multiple parasite clones. However, studies have shown also in areas with low overall parasite prevalence, infection with multiple parasite clones is a common occurrence. Mathematical models assuming homogeneous transmission between humans and mosquitoes cannot explain these observations. Heterogeneity of transmission can arise from many factors including acquired immunity, body size and occupational exposure. In this study, we show that spatial heterogeneity has a profound effect on predictions of MOI and parasite prevalence. We illustrate, that models assuming homogeneous transmission underestimate average MOI in low transmission settings when compared to field data and that spatially heterogeneous models predict stable transmission at much lower overall parasite prevalence. Therefore it is very important that models used to guide malaria surveillance and control strategies in low transmission and elimination settings take into account the spatial features of the specific target area, including human and mosquito vector distribution. C1 [Karl, Stephan; White, Michael T.; Barry, Alyssa E.; Mueller, Ivo] Walter & Eliza Hall Inst Med Res, Populat Based Biol Div, Parkville, Vic, Australia. [Karl, Stephan; Barry, Alyssa E.; Mueller, Ivo] Univ Melbourne, Dept Med Biol, Parkville, Vic, Australia. [Karl, Stephan] Papua New Guinea Insititute Med Res, Vectorborne Dis Unit, Madang, Madang Province, Papua N Guinea. [White, Michael T.] Imperial Coll, Dept Infect Dis Epidemiol, MRC Ctr Outbreak Anal & Modelling, London, England. [Milne, George J.] Univ Western Australia, Sch Comp Sci & Software Engn, Perth, WA, Australia. [Gurarie, David] Case Western Reserve Univ, Dept Math Appl Math & Stat, Cleveland, OH 44106 USA. [Hay, Simon I.] Inst Hlth Metr & Evaluat, Seattle, WA USA. [Hay, Simon I.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Felger, Ingrid] Swiss Trop & Publ Hlth Inst, Dept Med Parasitol & Infect Biol, Basel, Switzerland. [Felger, Ingrid] Univ Basel, Basel, Switzerland. [Mueller, Ivo] Inst Pasteur, Dept Parasites & Insect Vectors, Malaria Parasites & Hosts Unit, Paris, France. RP Karl, S (reprint author), Walter & Eliza Hall Inst Med Res, Populat Based Biol Div, Parkville, Vic, Australia.; Karl, S (reprint author), Univ Melbourne, Dept Med Biol, Parkville, Vic, Australia.; Karl, S (reprint author), Papua New Guinea Insititute Med Res, Vectorborne Dis Unit, Madang, Madang Province, Papua N Guinea. EM karl@wehi.edu.au RI Hay, Simon/F-8967-2015; OI Hay, Simon/0000-0002-0611-7272; Gurarie, David/0000-0002-5314-7888; Felger, Ingrid/0000-0003-1255-2606 FU Victorian State Government Operational Infrastructure Support; NHMRC (Australia) [GNT 1052760]; MRC (UK); Australian Government NHMRC IRIISS FX SK, AB and IM acknowledge support from the Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS. SK was supported by an NHMRC (Australia) Early Career Fellowship (GNT 1052760). MTW was supported by an MRC (UK) Research Fellowship. The authors thank all researchers and study participants involved in the PNG studies. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 80 TC 0 Z9 0 U1 4 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 6 PY 2016 VL 11 IS 10 AR e0164054 DI 10.1371/journal.pone.0164054 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ2UR UT WOS:000385697600070 PM 27711149 ER PT J AU Nygaard, TK Kobayashi, SD Freedman, B Porter, AR Voyich, JM Otto, M Schneewind, O DeLeo, FR AF Nygaard, Tyler K. Kobayashi, Scott D. Freedman, Brett Porter, Adeline R. Voyich, Jovanka M. Otto, Michael Schneewind, Olaf DeLeo, Frank R. TI Interaction of Staphylococci with Human B cells SO PLOS ONE LA English DT Article ID COMPLEMENT RECEPTOR 2; IMMUNE EVASION; HUMAN NEUTROPHILS; BINDING PROTEIN; INNATE IMMUNITY; IN-VIVO; AUREUS; C3D; ANTIGEN; BLOOD AB Staphylococcus aureus is a leading cause of human infections worldwide. The pathogen produces numerous molecules that can interfere with recognition and binding by host innate immune cells, an initial step required for the ingestion and subsequent destruction of microbes by phagocytes. To better understand the interaction of this pathogen with human immune cells, we compared the association of S. aureus and S. epidermidis with leukocytes in human blood. We found that a significantly greater proportion of B cells associated with S. epidermidis relative to S. aureus. Complement components and complement receptors were important for the binding of B cells with S. epidermidis. Experiments using staphylococci inactivated by ultraviolet radiation and S. aureus isogenic deletion mutants indicated that S. aureus secretes molecules regulated by the SaeR/S two-component system that interfere with the ability of human B cells to bind this bacterium. We hypothesize that the relative inability of B cells to bind S. aureus contributes to the microbe's success as a human pathogen. C1 [Nygaard, Tyler K.; Kobayashi, Scott D.; Freedman, Brett; Porter, Adeline R.; DeLeo, Frank R.] NIAID, Bacteriol Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. [Voyich, Jovanka M.] Montana State Univ, Dept Microbiol & Immunol, Bozeman, MT 59717 USA. [Otto, Michael] NIAID, Bacteriol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Schneewind, Olaf] Univ Chicago, Dept Microbiol, Chicago, IL 60637 USA. RP DeLeo, FR (reprint author), NIAID, Bacteriol Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. EM fdeleo@niaid.nih.gov OI DeLeo, Frank/0000-0003-3150-2516 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health; National Institutes of Health [NIH-R01A1090046] FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health and a grant from the National Institutes of Health (NIH-R01A1090046 to JMV). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 0 Z9 0 U1 2 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 6 PY 2016 VL 11 IS 10 AR e0164410 DI 10.1371/journal.pone.0164410 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ2UR UT WOS:000385697600124 PM 27711145 ER PT J AU Risso, DS Kozlitina, J Sainz, E Gutierrez, J Wooding, S Getachew, B Luiselli, D Berg, CJ Drayna, D AF Risso, Davide S. Kozlitina, Julia Sainz, Eduardo Gutierrez, Joanne Wooding, Stephen Getachew, Betelihem Luiselli, Donata Berg, Carla J. Drayna, Dennis TI Genetic Variation in the TAS2R38 Bitter Taste Receptor and Smoking Behaviors SO PLOS ONE LA English DT Article ID PHENYLTHIOCARBAMIDE; SENSITIVITY; EVOLUTION; NICOTINE; POLYMORPHISMS; ASSOCIATION; PERCEPTION; DEPENDENCE; PTC AB Common TAS2R38 taste receptor gene variants specify the ability to taste phenylthiocarbamide (PTC), 6-n-propylthiouracil (PROP) and structurally related compounds. Tobacco smoke contains a complex mixture of chemical substances of varying structure and functionality, some of which activate different taste receptors. Accordingly, it has been suggested that non-taster individuals may be more likely to smoke because of their inability to taste bitter compounds present in tobacco smoke, but results to date have been conflicting. We studied three cohorts: 237 European-Americans from the state of Georgia, 1,353 European-Americans and 2,363 African-Americans from the Dallas Heart Study (DHS), and 4,973 African-Americans from the Dallas Biobank. Tobacco use data was collected and TAS2R38 polymorphisms were genotyped for all participants, and PTC taste sensitivity was assessed in the Georgia population. In the Georgia group, PTC tasters were less common among those who smoke: 71.5% of smokers were PTC tasters while 82.5% of nonsmokers were PTC tasters (P = 0.03). The frequency of the TAS2R38 PAV taster haplotype showed a trend toward being lower in smokers (38.4%) than in non-smokers (43.1%), although this was not statistically significant (P = 0.31). In the DHS European-Americans, the taster haplotype was less common in smokers (37.0% vs. 44.0% in non-smokers, P = 0.003), and conversely the frequency of the non-taster haplotype was more common in smokers (58.7% vs. 51.5% in non-smokers, P = 0.002). No difference in the frequency of these haplotypes was observed in African Americans in either the Dallas Heart Study or the Dallas Biobank. We conclude that TAS2R38 haplotypes are associated with smoking status in European-Americans but not in African-American populations. PTC taster status may play a role in protecting individuals from cigarette smoking in specific populations. C1 [Risso, Davide S.; Sainz, Eduardo; Gutierrez, Joanne; Drayna, Dennis] NIDCD, Lab Commun Disorders, NIH, Bethesda, MD 20892 USA. [Risso, Davide S.; Luiselli, Donata] Univ Bologna, Lab Mol Anthropol, Bologna, Italy. [Risso, Davide S.; Luiselli, Donata] Univ Bologna, Ctr Genome Biol, Dept Biol Geol & Environm Sci, Bologna, Italy. [Kozlitina, Julia] Univ Texas Southwestern Med Ctr Dallas, McDermott Ctr Human Growth & Dev, Dallas, TX 75390 USA. [Wooding, Stephen] Univ Calif Merced, Hlth Sci Res Inst, Merced, CA USA. [Getachew, Betelihem; Berg, Carla J.] Emory Univ, Dept Behav Sci & Hlth Educ, Woodruff Hlth Sci Ctr, Atlanta, GA 30322 USA. RP Drayna, D (reprint author), NIDCD, Lab Commun Disorders, NIH, Bethesda, MD 20892 USA. EM drayna@nidcd.nih..gov OI Drayna, Dennis/0000-0002-1730-4532 FU National Institute on Deafness and Other Communication Disorders Intramural grant [Z1A-000046-16]; National Institutes of Health [HHSN263201300011C-03]; National Cancer Institute [1R01CA179422-01]; Georgia Cancer Coalition grant; National Center for Advancing Translational Sciences [UL1TR001105]; National Institutes of Health; NIH intramural research program; FDA FX This research was supported by the National Institute on Deafness and Other Communication Disorders Intramural grant number Z1A-000046-16 to DD, by the National Institutes of Health grant (HHSN263201300011C-03; OLAO) to JK, and by National Cancer Institute grant number 1R01CA179422-01 to CB, as well as a Georgia Cancer Coalition grant to CB. The Dallas Heart Study is supported by the National Center for Advancing Translational Sciences award number UL1TR001105, and the Dallas Biobank was funded by the National Institutes of Health. Research reported in this publication was supported by the NIH intramural research program and the FDA through funds obtained under the Family Smoking Prevention and Tobacco Control Act. The content was not reviewed by the Food and Drug Administration, but underwent the standard manuscript clearance process for scientific papers published from the NIH intramural research program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 0 Z9 0 U1 28 U2 28 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 6 PY 2016 VL 11 IS 10 AR e0164157 DI 10.1371/journal.pone.0164157 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ2UR UT WOS:000385697600089 PM 27711175 ER PT J AU Thompson, M Heath, SL Sweeton, B Williams, K Cunningham, P Keele, BF Sen, S Palmer, BE Chomont, N Xu, YX Basu, R Hellerstein, MS Kwa, S Robinson, HL AF Thompson, Melanie Heath, Sonya L. Sweeton, Bentley Williams, Kathy Cunningham, Pamela Keele, Brandon F. Sen, Sharon Palmer, Brent E. Chomont, Nicolas Xu, Yongxian Basu, Rahul Hellerstein, Michael S. Kwa, Suefen Robinson, Harriet L. TI DNA/MVA Vaccination of HIV-1 Infected Participants with Viral Suppression on Antiretroviral Therapy, followed by Treatment Interruption: Elicitation of Immune Responses without Control of Re-Emergent Virus SO PLOS ONE LA English DT Article ID T-CELL EXHAUSTION; PLACEBO-CONTROLLED TRIAL; HIV TYPE-1; INFLUENZA VACCINATION; DISEASE PROGRESSION; INFECTION; REPLICATION; EXPRESSION; IMMUNOGENICITY; VACCINES AB GV-TH-01, a Phase 1 open-label trial of a DNA prime D Modified Vaccinia Ankara (MVA) boost vaccine (GOVX-B11), was undertaken in HIV infected participants on antiretroviral treatment (ART) to evaluate safety and vaccine-elicited T cell responses, and explore the ability of elicited CD8+ T cells to control viral rebound during analytical treatment interruption (TI). Nine men who began antiretroviral therapy (ART) within 18 months of seroconversion and had sustained plasma HIV-1 RNA <50 copies/mL for at least 6 months were enrolled. Median age was 38 years, median pre-ART HIV-1 RNA was 140,000 copies/ml and mean baseline CD4 count was 755/mu l. Two DNA, followed by 2 MVA, inoculations were given 8 weeks apart. Eight subjects completed all vaccinations and TI. Clinical and laboratory adverse events were generally mild, with no serious or grade 4 events. Only reactogenicity events were considered related to study drug. No treatment emergent viral resistance was seen. The vaccinations did not reduce viral reservoirs and virus re-emerged in all participants during TI, with a median time to re-emergence of 4 weeks. Eight of 9 participants had CD8+ T cells that could be stimulated by vaccine-matched Gag peptides prior to vaccination. Vaccinations boosted these responses as well as eliciting previously undetected CD8+ responses. Elicited T cells did not display signs of exhaustion. During TI, temporal patterns of viral re-emergence and Gag-specific CD8+ T cell expansion suggested that vaccine-specific CD8+ T cells had been stimulated by re-emergent virus in only 2 of 8 participants. In these 2, transient decreases in viremia were associated with Gag selection in known CD8+ T cell epitopes. We hypothesize that escape mutations, already archived in the viral reservoir, plus a poor ability of CD8+ T cells to traffic to and control virus at sites of re-emergence, limited the therapeutic efficacy of the DNA/MVA vaccine. C1 [Thompson, Melanie; Sweeton, Bentley; Williams, Kathy] AIDS Res Consortium Atlanta, Atlanta, GA 30312 USA. [Heath, Sonya L.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Cunningham, Pamela] Univ Alabama Birmingham, Alabama Vaccine Res Clin, Birmingham, AL USA. [Keele, Brandon F.] Frederick Natl Lab Canc Res, AIDS & Canc Virus Program, Leidos Biomed Res Inc, Frederick, MD USA. [Sen, Sharon; Palmer, Brent E.] Univ Colorado, Anschutz Med Campus, Aurora, CO USA. [Chomont, Nicolas] CHUM, Ctr Rech, Montreal, PQ, Canada. [Chomont, Nicolas] Univ Montreal, Dept Microbiol Infectiol & Immunol, Montreal, PQ, Canada. [Xu, Yongxian] Emory Univ, Sch Med, Dept Med, Hope Clin,Emory Vaccine Ctr,Div Infect Dis, Atlanta, GA USA. [Basu, Rahul; Hellerstein, Michael S.; Kwa, Suefen; Robinson, Harriet L.] GeoVax Inc, Atlanta, GA USA. [Kwa, Suefen] ViiV Healthcare, Res Triangle Pk, NC USA. RP Thompson, M (reprint author), AIDS Res Consortium Atlanta, Atlanta, GA 30312 USA. EM drmt@mindspring.com FU GeoVax, Inc.; National Cancer Institute [HHSN261200800001E] FX GeoVax, Inc. provided support in the form of employee salaries for YX, RB, MSH, SK, and HLR. Funding for BFK was provided by the National Cancer Institute: HHSN261200800001E. Funding for MT and SLH was provided by GeoVax, Inc. NR 60 TC 0 Z9 0 U1 2 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 6 PY 2016 VL 11 IS 10 AR e0163164 DI 10.1371/journal.pone.0163164 PG 25 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ2UR UT WOS:000385697600015 PM 27711228 ER PT J AU Ioannidis, NM Rothstein, JH Pejaver, V Middha, S McDonnell, SK Baheti, S Musolf, A Li, Q Holzinger, E Karyadi, D Cannon-Albright, LA Teerlink, CC Stanford, JL Isaacs, WB Xu, JF Cooney, KA Lange, EM Schleutker, J Carpten, JD Powell, IJ Cussenot, O Cancel-Tassin, G Giles, GG MacInnis, RJ Maier, C Hsieh, CL Wiklund, F Catalona, WJ Foulkes, WD Mandal, D Eeles, RA Kote-Jarai, Z Bustamante, CD Schaid, DJ Hastie, T Ostrander, EA Bailey-Wilson, JE Radivojac, P Thibodeau, SN Whittemore, AS Sieh, W AF Ioannidis, Nilah M. Rothstein, Joseph H. Pejaver, Vikas Middha, Sumit McDonnell, Shannon K. Baheti, Saurabh Musolf, Anthony Li, Qing Holzinger, Emily Karyadi, Danielle Cannon-Albright, Lisa A. Teerlink, Craig C. Stanford, Janet L. Isaacs, William B. Xu, Jianfeng Cooney, Kathleen A. Lange, Ethan M. Schleutker, Johanna Carpten, John D. Powell, Isaac J. Cussenot, Olivier Cancel-Tassin, Geraldine Giles, Graham G. MacInnis, Robert J. Maier, Christiane Hsieh, Chih-Lin Wiklund, Fredrik Catalona, William J. Foulkes, William D. Mandal, Diptasri Eeles, Rosalind A. Kote-Jarai, Zsofia Bustamante, Carlos D. Schaid, Daniel J. Hastie, Trevor Ostrander, Elaine A. Bailey-Wilson, Joan E. Radivojac, Predrag Thibodeau, Stephen N. Whittemore, Alice S. Sieh, Weiva TI REVEL: An Ensemble Method for Predicting the Pathogenicity of Rare Missense Variants SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID AMINO-ACID SUBSTITUTIONS; NON-SYNONYMOUS VARIANTS; CLINVAR PUBLIC ARCHIVE; GENETIC-VARIANTS; NONSYNONYMOUS SNVS; FUNCTIONAL IMPACT; SEQUENCE VARIANTS; DISEASE; CONSENSUS; MUTATIONS AB The vast majority of coding variants are rare, and assessment of the contribution of rare variants to complex traits is hampered by low statistical power and limited functional data. Improved methods for predicting the pathogenicity of rare coding variants are needed to facilitate the discovery of disease variants from exome sequencing studies. We developed REVEL (rare exome variant ensemble learner), an ensemble method for predicting the pathogenicity of missense variants on the basis of individual tools: MutPred, FATHMM, VEST, PolyPhen, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP, SiPhy, phyloP, and phastCons. REVEL was trained with recently discovered pathogenic and rare neutral missense variants, excluding those previously used to train its constituent tools. When applied to two independent test sets, REVEL had the best overall performance (p < 10(-12)) as compared to any individual tool and seven ensemble methods: MetaSVM, MetaLR, KGGSeq, Condel, CADD, DANN, and Eigen. Importantly, REVEL also had the best performance for distinguishing pathogenic from rare neutral variants with allele frequencies <0.5%. The area under the receiver operating characteristic curve (AUC) for REVEL was 0.046-0.182 higher in an independent test set of 935 recent SwissVar disease variants and 123,935 putatively neutral exome sequencing variants and 0.027-0.143 higher in an independent test set of 1,953 pathogenic and 2,406 benign variants recently reported in ClinVar than the AUCs for other ensemble methods. We provide pre-computed REVEL scores for all possible human missense variants to facilitate the identification of pathogenic variants in the sea of rare variants discovered as sequencing studies expand in scale. C1 [Ioannidis, Nilah M.; Bustamante, Carlos D.] Stanford Univ, Dept Genet, Stanford, CA 94305 USA. [Ioannidis, Nilah M.; Rothstein, Joseph H.; Whittemore, Alice S.; Sieh, Weiva] Stanford Univ, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Rothstein, Joseph H.; Sieh, Weiva] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Rothstein, Joseph H.; Sieh, Weiva] Icahn Sch Med Mt Sinai, Dept Populat Hlth Sci & Policy, New York, NY 10029 USA. [Pejaver, Vikas; Radivojac, Predrag] Indiana Univ, Dept Comp Sci & Informat, Bloomington, IN 47405 USA. [Middha, Sumit] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA. [McDonnell, Shannon K.; Baheti, Saurabh; Schaid, Daniel J.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA. [Musolf, Anthony; Li, Qing; Holzinger, Emily; Bailey-Wilson, Joan E.] NHGRI, Computat & Stat Genom Branch, Baltimore, MD 21224 USA. [Karyadi, Danielle; Ostrander, Elaine A.] NHGRI, Canc Genet & Comparat Genom Branch, Bethesda, MD 20892 USA. [Cannon-Albright, Lisa A.; Teerlink, Craig C.; Cooney, Kathleen A.] Univ Utah, Sch Med, Dept Internal Med, Salt Lake City, UT 84108 USA. [Stanford, Janet L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Isaacs, William B.] Johns Hopkins Univ, Sch Med, Brady Urol Inst, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21287 USA. [Xu, Jianfeng] NorthShore Univ HealthSyst Res Inst, Evanston, IL 60201 USA. [Cooney, Kathleen A.] Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI 48109 USA. [Cooney, Kathleen A.] Univ Michigan, Sch Med, Dept Urol, Ann Arbor, MI 48109 USA. [Lange, Ethan M.] Univ North Carolina Chapel Hill, Dept Genet, Chapel Hill, NC 27599 USA. [Schleutker, Johanna] Univ Turku, Dept Med Biochem & Genet, Turku 20014, Finland. [Schleutker, Johanna] Turku Univ Hosp, Dept Med Genet Tyks Microbiol & Genet, FIN-20520 Turku, Finland. [Carpten, John D.] Translat Genom Res Inst, Integrated Canc Genom Div, Phoenix, AZ 85004 USA. [Powell, Isaac J.] Wayne State Univ, Dept Urol, Detroit, MI 48201 USA. [Cussenot, Olivier; Cancel-Tassin, Geraldine] Univ Paris, Ctr Rech Pathol Prostat & Urol, F-75013 Paris, France. [Giles, Graham G.; MacInnis, Robert J.] Canc Council Victoria, Cancer Epidemiol Ctr, Melbourne, Vic 3004, Australia. [Giles, Graham G.; MacInnis, Robert J.] Univ Melbourne, Ctr Epidemiol & Biostat, Melbourne, Vic 3010, Australia. [Maier, Christiane] Univ Hosp Ulm, Inst Human Genet, D-89075 Ulm, Germany. [Maier, Christiane] Univ Hosp Ulm, Dept Urol, D-89075 Ulm, Germany. [Hsieh, Chih-Lin] Univ Southern Calif, Dept Urol, Los Angeles, CA 90033 USA. [Wiklund, Fredrik] Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden. [Catalona, William J.] Northwestern Univ, Dept Urol, Feinberg Sch Med, Chicago, IL 60611 USA. [Foulkes, William D.] Montreal Gen Hosp, Dept Oncol, Montreal, PQ H3G 1A4, Canada. [Foulkes, William D.] Montreal Gen Hosp, Dept Human Genet, Montreal, PQ H3G 1A4, Canada. [Mandal, Diptasri] Louisiana State Univ, Hlth Sci Ctr, Dept Genet, New Orleans, LA 70112 USA. [Eeles, Rosalind A.; Kote-Jarai, Zsofia] Inst Canc Res, Div Genet & Epidemiol, Sutton SM2 5NG, Surrey, England. [Bustamante, Carlos D.; Hastie, Trevor; Whittemore, Alice S.] Stanford Univ, Dept Biomed Data Sci, Stanford, CA 94305 USA. [Hastie, Trevor] Stanford Univ, Dept Stat, Stanford, CA 94305 USA. [Thibodeau, Stephen N.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA. RP Sieh, W (reprint author), Stanford Univ, Dept Hlth Res & Policy, Stanford, CA 94305 USA.; Sieh, W (reprint author), Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA.; Sieh, W (reprint author), Icahn Sch Med Mt Sinai, Dept Populat Hlth Sci & Policy, New York, NY 10029 USA. EM weiva.sieh@mssm.edu OI Ioannidis, Nilah/0000-0001-9628-8229; Ostrander, Elaine/0000-0001-6075-9738; Cancel-Tassin, Geraldine/0000-0002-9583-6382 FU NIH [U01CA089600, R01CA094069, R01LM009722, R01MH105524, K07CA143047, F32HG008330]; Intramural Research Program of the National Human Genome Research Institute, NIH FX This research was funded by NIH grants U01CA089600, R01CA094069, R01LM009722, R01MH105524, K07CA143047, and F32HG008330 and by the Intramural Research Program of the National Human Genome Research Institute, NIH. NR 54 TC 2 Z9 2 U1 7 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD OCT 6 PY 2016 VL 99 IS 4 BP 877 EP 885 DI 10.1016/j.ajhg.2016.08.016 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA DY7UB UT WOS:000385333700007 PM 27666373 ER PT J AU Ghoussaini, M French, JD Michailidou, K Nord, S Beesley, J Canisus, S Hillman, KM Kaufmann, S Sivakumaran, H Marjaneh, MM Lee, JS Dennis, J Bolla, MK Wang, Q Dicks, E Milne, RL Hopper, JL Southey, MC Schmidt, MK Broeks, A Muir, K Lophatananon, A Fasching, PA Beckmann, MW Fletcher, O Johnson, N Sawyer, EJ Tomlinson, I Burwinkel, B Marme, F Guenel, P Truong, T Bojesen, SE Flyger, H Benitez, J Gonzalez-Neira, A Alonso, R Pita, G Neuhausen, SL Anton-Culver, H Brenner, H Arndt, V Meindl, A Schmutzler, RK Brauch, H Hamann, U Tessier, DC Vincent, D Nevanlinna, H Khan, S Matsuo, K Ito, H Dork, T Bogdanova, NV Lindblom, A Margolin, S Mannermaa, A Kosma, VM Wu, AH Van den Berg, D Lambrechts, D Floris, G Chang-Claude, J Rudolph, A Radice, P Barile, M Couch, FJ Hallberg, E Giles, GG Haiman, CA Le Marchand, L Goldberg, MS Teo, SH Yip, CH Borresen-Dale, AL Zheng, W Cai, QY Winqvist, R Pylkas, K Andrulis, IL Devilee, P Tollenaar, RAEM Garcia-Closas, M Figueroa, J Hall, P Czene, K Brand, JS Darabi, H Eriksson, M Hooning, MJ Koppert, LB Li, JM Shu, XO Zheng, Y Cox, A Cross, SS Shah, M Rhenius, V Choi, JY Kang, D Hartman, M Chia, KS Kabisch, M Torres, D Luccarini, C Conroy, DM Jakubowska, A Lubinski, J Sangrajrang, S Brennan, P Olswold, C Slager, S Shen, CY Hou, MF Swerdlow, A Schoemaker, MJ Simard, J Pharoah, PDP Kristensen, V Chenevix-Trench, G Easton, DF Dunning, AM Edwards, SL AF Ghoussaini, Maya French, Juliet D. Michailidou, Kyriaki Nord, Silje Beesley, Jonathan Canisus, Sander Hillman, Kristine M. Kaufmann, Susanne Sivakumaran, Haran Marjaneh, Mandi Moradi Lee, Jason S. Dennis, Joe Bolla, Manjeet K. Wang, Qin Dicks, Ed Milne, Roger L. Hopper, John L. Southey, Melissa C. Schmidt, Marjanka K. Broeks, Annegien Muir, Kenneth Lophatananon, Artitaya Fasching, Peter A. Beckmann, Matthias W. Fletcher, Olivia Johnson, Nichola Sawyer, Elinor J. Tomlinson, Ian Burwinkel, Barbara Marme, Frederik Guenel, Pascal Truong, Therese Bojesen, Stig E. Flyger, Henrik Benitez, Javier Gonzalez-Neira, Anna Alonso, Rosario Pita, Guillermo Neuhausen, Susan L. Anton-Culver, Hoda Brenner, Hermann Arndt, Volker Meindl, Alfons Schmutzler, Rita K. Brauch, Hiltrud Hamann, Ute Tessier, Daniel C. Vincent, Daniel Nevanlinna, Heli Khan, Sofia Matsuo, Keitaro Ito, Hidemi Dork, Thilo Bogdanova, Natalia V. Lindblom, Annika Margolin, Sara Mannermaa, Arto Kosma, Veli-Matti Wu, Anna H. Van den Berg, David Lambrechts, Diether Floris, Giuseppe Chang-Claude, Jenny Rudolph, Anja Radice, Paolo Barile, Monica Couch, Fergus J. Hallberg, Emily Giles, Graham G. Haiman, Christopher A. Le Marchand, Loic Goldberg, Mark S. Teo, Soo H. Yip, Cheng Har Borresen-Dale, Anne-Lise Zheng, Wei Cai, Qiuyin Winqvist, Robert Pylkas, Katri Andrulis, Irene L. Devilee, Peter Tollenaar, Rob A. E. M. Garcia-Closas, Montserrat Figueroa, Jonine Hall, Per Czene, Kamila Brand, Judith S. Darabi, Hatef Eriksson, Mikael Hooning, Maartje J. Koppert, Linetta B. Li, Jingmei Shu, Xiao-Ou Zheng, Ying Cox, Angela Cross, Simon S. Shah, Mitul Rhenius, Valerie Choi, Ji-Yeob Kang, Daehee Hartman, Mikael Chia, Kee Seng Kabisch, Maria Torres, Diana Luccarini, Craig Conroy, Don M. Jakubowska, Anna Lubinski, Jan Sangrajrang, Suleeporn Brennan, Paul Olswold, Curtis Slager, Susan Shen, Chen-Yang Hou, Ming-Feng Swerdlow, Anthony Schoemaker, Minouk J. Simard, Jacques Pharoah, Paul D. P. Kristensen, Vessela Chenevix-Trench, Georgia Easton, Douglas F. Dunning, Alison M. Edwards, Stacey L. CA kConFab AOCS NBCS Collaborators TI Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen-Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; COMMON VARIANTS; RISK VARIANTS; LOCUS; TUMORS; FOXA1; 2Q35 AB Genome-wide association studies (GWASs) have revealed increased breast cancer risk associated with multiple genetic variants at 5p12. Here, we report the fine mapping of this locus using data from 104,660 subjects from 50 case-control studies in the Breast Cancer Association Consortium (BCAC). With data for 3,365 genotyped and imputed SNPs across a 1 Mb region (positions 44,394,49545,364,167; NCBI build 37), we found evidence for at least three independent signals: the strongest signal, consisting of a single SNP rs10941679, was associated with risk of estrogen-receptor-positive (ER+) breast cancer (per-g allele ER+ = 1.15; 95% CI 1.13-1.18; p = 8.35 x 10(-3)). After adjustment for rs10941679, we detected signal 2, consisting of 38 SNPs more strongly associated with ER-negative (ER-) breast cancer (lead SNP rs6864776: per-a allele OR ER- = 1.10; 95% CI 1.05-1.14; p conditional = 1.44 x 10(-12)), and a single signal 3 SNP (rs200229088: per-t allele OR ER+ = 1.12; 95% CI 1.09-1.15; p conditional = 1.12 x 10(-05)). Expression quantitative trait locus analysis in normal breast tissues and breast tumors showed that the g (risk) allele of rs10941679 was associated with increased expression of FGF10 and MRPS30. Functional assays demonstrated that SNP rs10941679 maps to an enhancer element that physically interacts with the FGF10 and MRPS30 promoter regions in breast cancer cell lines. FGF10 is an oncogene that binds to FGFR2 and is overexpressed in similar to 10% of human breast cancers, whereas MRPS30 plays a key role in apoptosis. These data suggest that the strongest signal of association at 5p12 is mediated through coordinated activation of FGF10 and MRPS30, two candidate genes for breast cancer pathogenesis. C1 [Ghoussaini, Maya; Dicks, Ed; Shah, Mitul; Rhenius, Valerie; Luccarini, Craig; Conroy, Don M.; Pharoah, Paul D. P.; Easton, Douglas F.; Dunning, Alison M.] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England. [French, Juliet D.; Beesley, Jonathan; Hillman, Kristine M.; Kaufmann, Susanne; Sivakumaran, Haran; Marjaneh, Mandi Moradi; Lee, Jason S.; Chenevix-Trench, Georgia; Edwards, Stacey L.] QIMR Berghofer Med Res Inst, Canc Div, Brisbane, Qld 4006, Australia. [Michailidou, Kyriaki; Dennis, Joe; Bolla, Manjeet K.; Wang, Qin; Pharoah, Paul D. P.; Easton, Douglas F.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England. [Michailidou, Kyriaki] Cyprus Inst Neurol & Genet, Dept Electron Microscopy Mol Pathol, CY-1683 Nicosia, Cyprus. [Nord, Silje; Borresen-Dale, Anne-Lise; Kristensen, Vessela] Radiumhospitalet, Inst Canc Res, Dept Canc Genet, Oslo Univ Hosp, N-0310 Oslo, Norway. [Canisus, Sander; Schmidt, Marjanka K.; Broeks, Annegien] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, NL-1066 CX Amsterdam, Netherlands. [Milne, Roger L.; Giles, Graham G.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic 3004, Australia. [Milne, Roger L.; Hopper, John L.; Giles, Graham G.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic 3010, Australia. [Southey, Melissa C.] Univ Melbourne, Dept Pathol, Melbourne, Vic 3010, Australia. [Muir, Kenneth; Lophatananon, Artitaya] Univ Manchester, Inst Populat Hlth, Manchester M13 9PL, Lancs, England. [Muir, Kenneth; Lophatananon, Artitaya] Univ Warwick, Warwick Med Sch, Div Hlth Sci, Coventry CV4 7AL, W Midlands, England. [Fasching, Peter A.; Beckmann, Matthias W.] Univ Erlangen Nurnberg, Dept Gynaecol & Obstet, Univ Hosp Erlangen, Comprehens Canc Ctr Erlangen EMN, D-91054 Erlangen, Germany. [Fasching, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. [Fletcher, Olivia; Johnson, Nichola] Inst Canc Res, Toby Robins Breast Canc Now Res Ctr, London SW3 6JB, England. [Fletcher, Olivia; Johnson, Nichola; Swerdlow, Anthony] Inst Canc Res, Div Breast Canc Res, London SW7 3RP, England. [Sawyer, Elinor J.] Kings Coll London, Guys Hosp, Res Oncol, London SE1 9RT, England. [Tomlinson, Ian] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Tomlinson, Ian] Univ Oxford, Oxford NIHR Biomed Res Ctr, Oxford OX3 7BN, England. [Burwinkel, Barbara; Marme, Frederik] Heidelberg Univ, Dept Obstet & Gynecol, D-69120 Heidelberg, Germany. [Burwinkel, Barbara] German Canc Res Ctr, Mol Epidemiol Grp, D-69120 Heidelberg, Germany. [Marme, Frederik] Heidelberg Univ, Natl Ctr Tumor Dis, D-69120 Heidelberg, Germany. [Guenel, Pascal; Truong, Therese] Univ Paris Saclay, Univ Paris 11, INSERM, Canc & Environm Grp,Ctr Res Epidemiol & Populat H, F-94807 Villejuif, France. [Bojesen, Stig E.] Copenhagen Univ Hosp, Copenhagen Gen Populat Study, Herlev & Gentofte Hosp, DK-2730 Herlev, Denmark. 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[Andrulis, Irene L.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada. [Andrulis, Irene L.] Univ Toronto, Dept Med Genet, Toronto, ON M5S 1A8, Canada. [Devilee, Peter] Leiden Univ, Med Ctr, Dept Pathol, NL-2300 RC Leiden, Netherlands. [Devilee, Peter] Leiden Univ, Med Ctr, Dept Human Genet, NL-2300 RC Leiden, Netherlands. [Tollenaar, Rob A. E. M.] Leiden Univ, Med Ctr, Dept Surg, NL-2300 RC Leiden, Netherlands. [Garcia-Closas, Montserrat; Figueroa, Jonine] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA. [Figueroa, Jonine] Univ Edinburgh, Sch Med, Usher Inst Populat Hlth Sci & Informat, Edinburgh EH8 9AG, Midlothian, Scotland. [Hall, Per; Czene, Kamila; Brand, Judith S.; Darabi, Hatef; Eriksson, Mikael; Li, Jingmei] Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden. [Hooning, Maartje J.] Erasmus MC Canc Inst, Family Canc Clin, Dept Med Oncol, NL-3008 AE Rotterdam, Netherlands. [Koppert, Linetta B.] Erasmus MC Canc Inst, Family Canc Clin, Dept Surg Oncol, NL-3008 AE Rotterdam, Netherlands. [Zheng, Ying] Shanghai Municipal Ctr Dis Control & Prevent, Shanghai 200336, Peoples R China. [Cox, Angela] Univ Sheffield, Dept Oncol & Metab, Sheffield Canc Res, Sheffield S10 2RX, S Yorkshire, England. [Cross, Simon S.] Univ Sheffield, Dept Neurosci, Acad Unit Pathol, Sheffield S10 2HQ, S Yorkshire, England. [Choi, Ji-Yeob; Kang, Daehee] Seoul Natl Univ, Coll Med, Dept Biomed Sci, Seoul 110799, South Korea. [Choi, Ji-Yeob; Kang, Daehee] Seoul Natl Univ, Canc Res Inst, Seoul 110799, South Korea. [Kang, Daehee] Seoul Natl Univ, Dept Prevent Med, Coll Med, Seoul 110799, South Korea. [Hartman, Mikael; Chia, Kee Seng] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117597, Singapore. [Hartman, Mikael] Natl Univ Hlth Syst, Dept Surg, Singapore 117597, Singapore. [Torres, Diana] Pontificia Univ Javeriana, Inst Human Genet, Bogota 11001000, DC, Colombia. [Jakubowska, Anna; Lubinski, Jan] Pomeranian Med Univ, Dept Genet & Pathol, PL-70115 Szczecin, Poland. [Sangrajrang, Suleeporn] Natl Canc Inst, Bangkok 10400, Thailand. [Brennan, Paul] Int Agcy Res Canc, Lyon 08, France. [Shen, Chen-Yang] China Med Univ, Sch Publ Hlth, Taichung 40402, Taiwan. [Shen, Chen-Yang] Acad Sinica, Inst Biomed Sci, Taiwan Biobank, Taipei 115, Taiwan. [Hou, Ming-Feng] Kaohsiung Municipal Hsiaokang Hosp, Dept Surg, Kaohsiung 812, Taiwan. [Swerdlow, Anthony; Schoemaker, Minouk J.] Inst Canc Res, Div Genet & Epidemiol, London SM2 5NG, England. [Simard, Jacques] Univ Laval, Genom Ctr, Ctr Hosp Univ Quebec, Res Ctr, Quebec City, PQ G1V 4G2, Canada. [Kristensen, Vessela] Univ Oslo, Oslo Univ Hosp, Dept Clin Mol Biol, N-0450 Oslo, Norway. RP Dunning, AM (reprint author), Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England.; Edwards, SL (reprint author), QIMR Berghofer Med Res Inst, Canc Div, Brisbane, Qld 4006, Australia. RI Dork, Thilo/J-8620-2012; Nord, Silje/R-5212-2016; Li, Jingmei/I-2904-2012; Brenner, Hermann/B-4627-2017; Yip, Cheng-Har/B-1909-2010; OI Arndt, Volker/0000-0001-9320-8684; Nord, Silje/0000-0002-3271-5356; Li, Jingmei/0000-0001-8587-7511; Brenner, Hermann/0000-0002-6129-1572; Khan, Sofia/0000-0003-4185-8882; Sivakumaran, Haran/0000-0002-4691-4989; Matsuo, Keitaro/0000-0003-1761-6314; Dunning, Alison Margaret/0000-0001-6651-7166 FU Cancer Research UK [10119, 10124]; NCI NIH HHS [R01 CA176785] NR 25 TC 1 Z9 1 U1 7 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD OCT 6 PY 2016 VL 99 IS 4 BP 903 EP 911 DI 10.1016/j.ajhg.2016.07.017 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA DY7UB UT WOS:000385333700010 PM 27640304 ER PT J AU Weiss, K Terhal, PA Cohen, L Bruccoleri, M Irving, M Martinez, AF Rosenfeld, JA Machol, K Yang, YP Liu, PF Walkiewicz, M Beuten, J Gomez-Ospina, N Haude, K Fong, CT Enns, GM Bernstein, JA Fan, J Gotway, G Ghorbani, M van Gassen, K Monroe, GR van Haaften, G Basel-Vanagaite, L Yang, XJ Campeau, PM Muenke, M AF Weiss, Karin Terhal, Paulien A. Cohen, Lior Bruccoleri, Michael Irving, Melita Martinez, Ariel F. Rosenfeld, Jill A. Machol, Keren Yang, Yaping Liu, Pengfei Walkiewicz, Magdalena Beuten, Joke Gomez-Ospina, Natalia Haude, Katrina Fong, Chin-To Enns, Gregory M. Bernstein, Jonathan A. Fan, Judith Gotway, Garrett Ghorbani, Mohammad van Gassen, Koen Monroe, Glen R. van Haaften, Gijs Basel-Vanagaite, Lina Yang, Xiang-Jiao Campeau, Philippe M. Muenke, Maximilian CA DDD Study TI De Novo Mutations in CHD4, an ATP-Dependent Chromatin Remodeler Gene, Cause an Intellectual Disability Syndrome with Distinctive Dysmorphisms SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID NICOLAIDES-BARAITSER SYNDROME; COFFIN-SIRIS SYNDROME; HISTONE DEACETYLASE; DEVELOPMENTAL DISORDERS; SWI/SNF COMPLEX; CHARGE-SYNDROME; DNA-DAMAGE; FAMILY; NURD; PROTEINS AB Chromodomain helicase DNA-binding protein 4 (CHD4) is an ATP-dependent chromatin remodeler involved in epigenetic regulation of gene transcription, DNA repair, and cell cycle progression. Also known as Mi2 beta., CHD4 is an integral subunit of a well-characterized histone deacetylase complex. Here we report five individuals with de novo missense substitutions in CHD4 identified through whole-exome sequencing and web-based gene matching. These individuals have overlapping phenotypes including developmental delay, intellectual disability, hearing loss, macrocephaly, distinct facial dysmorphisms, palatal abnormalities, ventriculomegaly, and hypogonadism as well as additional findings such as bone fusions. The variants, c.3380G>A (p.Arg1127Gln), c.3443G>T (p.Trp1148Leu), c.3518G>T (p.Arg1173Leu), and c.3008G>A, (p.Gly1003Asp) (GenBank: NM_001273.3), affect evolutionarily highly conserved residues and are predicted to be deleterious. Previous studies in yeast showed the equivalent Arg1127 and Trp1148 residues to be crucial for SNF2 function. Furthermore, mutations in the same positions were reported in malignant tumors, and a de novo missense substitution in an equivalent arginine residue in the C-terminal helicase domain of SMARCA4 is associated with Coffin Sins syndrome. Cell-based studies of the p.Arg1127Gln and p.Arg1173Leu mutants demonstrate normal localization to the nucleus and HDAC1 interaction. Based on these findings, the mutations potentially alter the complex activity but not its formation. This report provides evidence for the role of CHD4 in human development and expands an increasingly recognized group of Mendelian disorders involving chromatin remodeling and modification. C1 [Weiss, Karin; Martinez, Ariel F.; Muenke, Maximilian] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Terhal, Paulien A.; van Gassen, Koen; Monroe, Glen R.; van Haaften, Gijs] Univ Utrecht, Med Ctr, Dept Genet, NL-3584 CX Utrecht, Netherlands. [Cohen, Lior; Basel-Vanagaite, Lina] Schneider Children Med Ctr Israel, Pediat Genet, IL-49202 Petah Tiqwa, Israel. [Cohen, Lior; Basel-Vanagaite, Lina] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. [Bruccoleri, Michael; Ghorbani, Mohammad; Yang, Xiang-Jiao] McGill Univ, Rosalind & Morris Goodman Canc Res Ctr, Montreal, PQ H3G 2M1, Canada. [Bruccoleri, Michael; Ghorbani, Mohammad; Yang, Xiang-Jiao] McGill Univ, Ctr Hlth, Dept Med, Montreal, PQ H3G 2M1, Canada. [Irving, Melita] Guys Hosp, Dept Clin Genet, London SE1 9RT, England. [Rosenfeld, Jill A.; Machol, Keren; Yang, Yaping; Liu, Pengfei; Walkiewicz, Magdalena; Beuten, Joke] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Gomez-Ospina, Natalia; Enns, Gregory M.; Bernstein, Jonathan A.] Stanford Univ, Dept Pediat, Div Med Genet, Stanford, CA 94305 USA. [Haude, Katrina; Fong, Chin-To] Univ Rochester, Med Ctr, Dept Pediat Genet, Rochester, NY 14642 USA. [Fan, Judith; Gotway, Garrett] Univ Texas Southwestern Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA. [Monroe, Glen R.; van Haaften, Gijs] Univ Utrecht, Med Ctr, Ctr Mol Med, NL-3584 CX Utrecht, Netherlands. [Basel-Vanagaite, Lina] Rabin Med Ctr, Raphael Recanati Genet Inst, Beilinson Campus, IL-49100 Petah Tiqwa, Israel. [Basel-Vanagaite, Lina] Rabin Med Ctr, Felsenstein Med Res Ctr, IL-49100 Petah Tiqwa, Israel. [Campeau, Philippe M.] Univ Montreal, St Justine Hosp, Dept Pediat, Montreal, PQ H3T 1C4, Canada. RP Muenke, M (reprint author), NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA.; Campeau, PM (reprint author), Univ Montreal, St Justine Hosp, Dept Pediat, Montreal, PQ H3T 1C4, Canada. EM p.campeau@umontreal.ca; mmuenke@nhgri.nih.gov OI Campeau, Philippe/0000-0001-9713-7107 FU Health Innovation Challenge Fund [HICF-1009-003]; Wellcome Trust Sanger Institute [WT098051]; National Institute for Health Research, through the Comprehensive Clinical Research Network; Canadian Institutes of Health Research [RN315908, RN324373]; Fonds de Recherche du Quebec Sante [30647]; National Human Genome Research Institute, NIH FX We are grateful to the patients and their families for consenting to participate in this publication. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of the Wellcome Trust or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12, granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network. P.M.C. is funded by the Canadian Institutes of Health Research Grants RN315908 and RN324373 and the Fonds de Recherche du Quebec Sante grant 30647. We are thankful to the NIH Intramural Sequencing Center (NISC) for supporting sequencing in this project. This work was supported by the intramural program of the National Human Genome Research Institute, NIH. NR 50 TC 1 Z9 1 U1 3 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD OCT 6 PY 2016 VL 99 IS 4 BP 934 EP 941 DI 10.1016/j.ajhg.2016.08.001 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA DY7UB UT WOS:000385333700014 PM 27616479 ER PT J AU Shashi, V Pena, LDM Kim, K Burton, B Hempel, M Schoch, K Walkiewicz, M McLaughlin, HM Cho, M Stong, N Hickey, SE Shuss, CM Freemark, MS Bellet, JS Keels, MA Bonner, MJ El-Dairi, M Butler, M Kranz, PG Stumpel, CTRM Klinkenberg, S Oberndorff, K Alawi, M Santer, R Petrovski, S Kuismin, O Korpi-Heikkila, S Pietilainen, O Aarno, P Kurki, MI Hoischen, A Need, AC Goldstein, DB Kortum, F AF Shashi, Vandana Pena, Loren D. M. Kim, Katherine Burton, Barbara Hempel, Maja Schoch, Kelly Walkiewicz, Magdalena McLaughlin, Heather M. Cho, Megan Stong, Nicholas Hickey, Scott E. Shuss, Christine M. Freemark, Michael S. Bellet, Jane S. Keels, Martha Ann Bonner, Melanie J. El-Dairi, Maysantoine Butler, Megan Kranz, Peter G. Stumpel, Constance T. R. M. Klinkenberg, Sylvia Oberndorff, Karin Alawi, Malik Santer, Rene Petrovski, Slave Kuismin, Outi Korpi-Heikkila, Satu Pietilainen, Olli Aarno, Palotie Kurki, Mitja I. Hoischen, Alexander Need, Anna C. Goldstein, David B. Kortuem, Fanny CA Undiagnosed Dis Network TI De Novo Truncating Variants in ASXL2 Are Associated with a Unique and Recognizable Clinical Phenotype SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID BOHRING-OPITZ SYNDROME; INTELLECTUAL DISABILITY; RECIPROCAL REGULATION; MUTATIONS; GENES; GENOMICS; HOMOLOG; FAMILY AB The ASXL genes (ASXL1, ASXL2, and ASXL3) participate in body patterning during embryogenesis and encode proteins involved in epigenetic regulation and assembly of transcription factors to specific genomic loci. Germline de novo truncating variants in ASXL1 and ASXL3 have been respectively implicated in causing Bohring-Opitz and Bainbridge-Ropers syndromes, which result in overlapping features of severe intellectual disability and dysmorphic features. ASXL2 has not yet been associated with a human Mendelian disorder. In this study, we performed whole-exome sequencing in six unrelated probands with developmental delay, macrocephaly, and dysmorphic features. All six had de novo truncating variants in ASXL2. A careful review enabled the recognition of a specific phenotype consisting of macrocephaly, prominent eyes, arched eyebrows, hypertelorism, a glabellar nevus flammeus, neonatal feeding difficulties, hypotonia, and developmental disabilities. Although overlapping features with Bohring-Opitz and Bainbridge-Ropers syndromes exist, features that distinguish the ASXL2-associated condition from ASXL1- and ASXL3-related disorders are macrocephaly, absence of growth retardation, and more variability in the degree of intellectual disabilities. We were also able to demonstrate with mRNA studies that these variants are likely to exert a dominant-negative effect, given that both alleles are expressed in blood and the mutated ASXL2 transcripts escape nonsense-mediated decay. In conclusion, de novo truncating variants in ASXL2 underlie a neurodevelopmental syndrome with a clinically recognizable phenotype. This report expands the germline disorders that are linked to the ASXL genes. C1 [Shashi, Vandana; Pena, Loren D. M.; Schoch, Kelly] Duke Hlth, Dept Pediat, Div Med Genet, Durham, NC 27710 USA. [Kim, Katherine; Burton, Barbara] Ann & Robert H Lurie Childrens Hosp Chicago, Dept Pediat, Chicago, IL 60611 USA. [Hempel, Maja; Kortuem, Fanny] Univ Med Ctr Hamburg Eppendorf, Inst Human Genet, D-20246 Hamburg, Germany. [Walkiewicz, Magdalena] Baylor Coll Med, Houston, TX 77030 USA. [McLaughlin, Heather M.; Cho, Megan] GeneDx, Gaithersburg, MD 20877 USA. [Stong, Nicholas; Petrovski, Slave; Goldstein, David B.] Columbia Univ, Inst Genom Med, New York, NY 10032 USA. [Hickey, Scott E.; Shuss, Christine M.] Nationwide Childrens Hosp, Div Mol & Human Genet, Columbus, OH 43082 USA. [Undiagnosed Dis Network] NIH, Common Fund, Bldg 10, Bethesda, MD 20892 USA. [Freemark, Michael S.] Duke Hlth, Dept Pediat, Div Endocrinol & Diabet, Durham, NC 27710 USA. [Bellet, Jane S.; Keels, Martha Ann] Duke Hlth, Dept Pediat, Durham, NC 27710 USA. [Bellet, Jane S.] Duke Hlth, Dept Dermatol, Durham, NC 27710 USA. [Keels, Martha Ann] Duke Hlth, Dept Surg, Durham, NC 27710 USA. [Bonner, Melanie J.] Duke Hlth, Psychiat & Behav Sci, Durham, NC 27710 USA. [El-Dairi, Maysantoine] Duke Hlth, Duke Eye Ctr, Durham, NC 27710 USA. [Butler, Megan] Duke Hlth, Dept Pediat, Div Gastroenterol Hepatol & Nutr, Durham, NC 27710 USA. [Kranz, Peter G.] Duke Hlth, Dept Radiol, Div Neuroradiol, Durham, NC 27710 USA. [Stumpel, Constance T. R. M.] Maastricht Univ, Med Ctr, Dept Clin Genet, NL-6202 AZ Maastricht, Netherlands. [Stumpel, Constance T. R. M.] Maastricht Univ, Med Ctr, Sch Oncol & Dev Biol, NL-6202 AZ Maastricht, Netherlands. [Klinkenberg, Sylvia] Maastricht Univ, Med Ctr, Dept Neurol, NL-6202 AZ Maastricht, Netherlands. [Oberndorff, Karin] Zuyderland Med Ctr, Dept Pediat, NL-6162 BG Sittard, Netherlands. [Alawi, Malik] Univ Med Ctr Hamburg Eppendorf, Bioinformat Serv Facil, D-20246 Hamburg, Germany. [Alawi, Malik] Univ Hamburg, Ctr Bioinformat, D-20246 Hamburg, Germany. [Alawi, Malik] Leibniz Inst Expt Virol, Heinrich Pette Inst, Virus Genom, D-20246 Hamburg, Germany. [Santer, Rene] Univ Med Ctr Hamburg Eppendorf, Dept Paediat, D-20246 Hamburg, Germany. [Petrovski, Slave] Univ Melbourne, Dept Med, Austin Hlth, Melbourne, Vic 3050, Australia. [Petrovski, Slave] Univ Melbourne, Royal Melbourne Hosp, Melbourne, Vic 3050, Australia. [Kuismin, Outi] Oulu Univ Hosp, Med Res Ctr Oulu, PEDEGO Res Unit, Oulu 90014, Finland. [Kuismin, Outi] Univ Oulu, Oulu 90014, Finland. [Kuismin, Outi] Oulu Univ Hosp, Dept Clin Genet, Oulu 90029, Finland. [Kuismin, Outi; Aarno, Palotie] Univ Helsinki, Inst Mol Med Finland, FIN-00290 Helsinki, Finland. [Korpi-Heikkila, Satu] Ctr Intellectual Disabil Care, Northern Ostrobothnia Hosp Dist, Oulu 90220, Finland. [Pietilainen, Olli; Aarno, Palotie] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA. [Pietilainen, Olli] Harvard Univ, Dept Stem Cell & Regenerat Biol, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Aarno, Palotie] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Aarno, Palotie; Kurki, Mitja I.] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Aarno, Palotie; Kurki, Mitja I.] Massachusetts Gen Hosp, Dept Psychiat, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Aarno, Palotie] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Kurki, Mitja I.] Broad Inst MIT & Harvard, Genet Anal Platform, Cambridge, MA 02142 USA. [Hoischen, Alexander] Radboud Univ Nijmegen, Med Ctr, Donders Ctr Neurosci, Dept Human Genet, NL-6500 HB Nijmegen, Netherlands. [Need, Anna C.] Imperial Coll London, Dept Med, Div Brain Sci, London W12 0NN, England. RP Shashi, V (reprint author), Duke Hlth, Dept Pediat, Div Med Genet, Durham, NC 27710 USA. EM vandana.shashi@duke.edu RI Hoischen, Alexander/D-1282-2013; OI Hoischen, Alexander/0000-0002-8072-4476; Wangler, Michael/0000-0001-5245-5910; Graham, Brett/0000-0001-8451-8154 FU Undiagnosed Diseases Network [1U01HG007672-01]; Deutsche Forschungsgemeinschaft [KO 4576/1-1]; Pairnomix LLC; Sanofi- Genzyme; Shire; Biomarin; Ultragenyx; Alexion; Armagen; ReGenX Bio FX We are grateful to the inidividuals and their families who contributed to this study and allowed us to publish their information and pictures. We thank I. Jantke for skillful technical assistance. This work was supported by the Undiagnosed Diseases Network (1U01HG007672-01 to V.S.) and the Deutsche Forschungsgemeinschaft (KO 4576/1-1 to F.K.). The authors disclose the following: the Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from molecular testing offered at the Baylor Genetics Laboratories (M.W.); D.B.G. has received consultancy fees and has equity ownership in Pairnomix LLC; H.M.M. and M.C. are employees of GeneDx; B.B. has received honoraria, consulting fees, or funding for clinical trials from Sanofi- Genzyme, Shire, Biomarin, Ultragenyx, Alexion, Armagen, and ReGenX Bio; and E.A.A. from the Undiagnosed Diseases Network is a co-founder of Personalis Inc. NR 33 TC 2 Z9 2 U1 1 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD OCT 6 PY 2016 VL 99 IS 4 BP 991 EP 999 DI 10.1016/j.ajhg.2016.08.017 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA DY7UB UT WOS:000385333700020 PM 27693232 ER PT J AU Cheng, Y Li, ZJ Kardami, E Loh, YP AF Cheng, Yong Li, Zhaojin Kardami, Elissavet Loh, Y. Peng TI Neuroprotective effects of LMW and HMW FGF2 against amyloid beta toxicity in primary cultured hippocampal neurons SO NEUROSCIENCE LETTERS LA English DT Article DE Hippocampal neuron; HMW FGF2; LMW FGF2; Amyloid beta; AKT ID FIBROBLAST GROWTH FACTOR-2; HIGH-MOLECULAR-WEIGHT; PROTEIN-KINASE-C; INDUCED NEUROTOXICITY; IN-VITRO; ALZHEIMERS-DISEASE; CELL-MIGRATION; ISCHEMIC-HEART; SCHWANN-CELLS; ISOFORMS AB Basic Fibroblast growth factor (FGF2) is important in development and maintenance of central nervous system function. Studies have demonstrated that low molecular weight (LMW) FGF2 is a neuroprotective factor against various insults in vivo and in vitro. In the present study we investigated the neuroprotective effects of high molecular weight (HMW) and LMW FGF2 against amyloid beta-induced neurotoxicity. The results showed that both LMW and HMW FGF2 attenuated the amyloid beta toxicity in the primary cultured hippocampal neurons as measured by WST and LDH release assay. Moreover, the analysis suggested that HMW FGF2 had stronger neuroprotective effect than LMW FGF2. We then demonstrated that LMW and HMW FGF2 activated the ERK and AKT signaling pathways in a similar way. Furthermore, using the ERK inhibitor and ART inhibitor, we found that the AKT signaling but not ERK signaling pathway was required for the neuroprotective effects of FGF2. Taken together, these results showed the neuroprotective effects of different forms of FGF2 in an AD model and the mechanism underlying the neuroprotection. Published by Elsevier Ireland Ltd. C1 [Cheng, Yong; Li, Zhaojin; Loh, Y. Peng] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cellular Neurobiol Sect, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. [Kardami, Elissavet] Univ Manitoba, Inst Cardiovasc Sci, St Boniface Hosp, Albrechtsen Res Ctr, Winnipeg, MB, Canada. RP Loh, YP (reprint author), NIH, Bldg 49,Rm 6A-10,49 Convent Dr, Bethesda, MD 20892 USA. EM lohp@mail.nih.gov FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Health and Human Development, National Institutes of Health, USA; Canadian Institutes for Health Research FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Health and Human Development, National Institutes of Health, USA; and the Canadian Institutes for Health Research (E.K.). Expert technical contribution of Dr. Barbara E. Nickel (St. Boniface Research Centre) is greatfully acknowledged. NR 36 TC 0 Z9 0 U1 4 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 EI 1872-7972 J9 NEUROSCI LETT JI Neurosci. Lett. PD OCT 6 PY 2016 VL 632 BP 109 EP 113 DI 10.1016/j.neulet.2016.08.031 PG 5 WC Neurosciences SC Neurosciences & Neurology GA DY7PF UT WOS:000385320900017 PM 27546824 ER PT J AU de Sancho, D Best, RB AF de Sancho, David Best, Robert B. TI Reconciling Intermediates in Mechanical Unfolding Experiments with Two-State Protein Folding in Bulk SO JOURNAL OF PHYSICAL CHEMISTRY LETTERS LA English DT Article ID MOLECULAR-DYNAMICS SIMULATIONS; ATOMIC-FORCE MICROSCOPY; COLD-SHOCK PROTEIN; TITIN IG DOMAIN; SINGLE-MOLECULE; SPECTROSCOPY; AFM; LANDSCAPES; TOPOLOGY; PATHWAY AB Most experimentally well-characterized single domain proteins of less than 100 residues have been found to be two-state folders. That is, only two distinct populations can explain both equilibrium and kinetic measurements. Results from single molecule force spectroscopy, where a protein is unfolded by applying a mechanical pulling force to its ends, have largely confirmed this description for proteins found to be two-state in ensemble experiments. Recently, however, stable intermediates have been reported in mechanical unfolding experiments on a cold-shock protein previously found to be a prototypical two-state folder. Here, we tackle this discrepancy using free energy landscapes and Markov state models derived from coarse-grained molecular simulations. We show that protein folding intermediates can be selectively stabilized by the pulling force and that the populations of these intermediates vary in a force-dependent manner. Our model qualitatively captures the experimental results and suggests a possible origin of the apparent discrepancy. C1 [de Sancho, David] CIC nanoGUNE, Donostia San Sebastian 20018, Spain. [Best, Robert B.] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [de Sancho, David] Ikerbasque, Basque Fdn Sci, Maria Diaz de Haro 3, Bilbao 48013, Spain. RP de Sancho, D (reprint author), CIC nanoGUNE, Donostia San Sebastian 20018, Spain.; Best, RB (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA.; de Sancho, D (reprint author), Ikerbasque, Basque Fdn Sci, Maria Diaz de Haro 3, Bilbao 48013, Spain. EM d.desancho@nanogune.eu; robertbe@helix.nih.gov RI De Sancho, David/C-4995-2009; nanoGUNE, CIC/A-2623-2015 OI De Sancho, David/0000-0002-8985-2685; FU Spanish Ministry of Economy and Competitiveness (MINECO) [CTQ2015-65320-R]; Ikerbasque Research Fellowship; Intramural Research Program of the National Institute of Diabetes and Digestive; Kidney Diseases of the National Institutes of Health FX D.D.S. acknowledges support from the Spanish Ministry of Economy and Competitiveness (MINECO, grant CTQ2015-65320-R) and an Ikerbasque Research Fellowship. R.B.B. was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. D.D.S. acknowledges Jorg Schonfelder, Raul Perez-Jimenez, Victor Munoz, and Frank Noe for helpful discussions. NR 42 TC 0 Z9 0 U1 7 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-7185 J9 J PHYS CHEM LETT JI J. Phys. Chem. Lett. PD OCT 6 PY 2016 VL 7 IS 19 BP 3798 EP 3803 DI 10.1021/acs.jpclett.6b01722 PG 6 WC Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Atomic, Molecular & Chemical SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA DY3BT UT WOS:000384966500015 PM 27626458 ER PT J AU Chesler, AT Szczot, M Bharucha-Goebel, D Ceko, M Donkervoort, S Laubacher, C Hayes, LH Alter, K Zampieri, C Stanley, C Innes, AM Mah, JK Grosmann, CM Bradley, N Nguyen, D Foley, AR Le Pichon, CE Bonnemann, CG AF Chesler, Alexander T. Szczot, Marcin Bharucha-Goebel, Diana Ceko, Marta Donkervoort, Sandra Laubacher, Claire Hayes, Leslie H. Alter, Katharine Zampieri, Cristiane Stanley, Christopher Innes, A. Micheil Mah, Jean K. Grosmann, Carla M. Bradley, Nathaniel Nguyen, David Foley, A. Reghan Le Pichon, Claire E. Bonnemann, Carsten G. TI The Role of PIEZO2 in Human Mechanosensation SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID DISTAL ARTHROGRYPOSIS; INSULAR CORTEX; MERKEL CELLS; TOUCH; CHANNEL; MECHANOTRANSDUCTION; PAIN; MUTATIONS AB BACKGROUND The senses of touch and proprioception evoke a range of perceptions and rely on the ability to detect and transduce mechanical force. The molecular and neural mechanisms underlying these sensory functions remain poorly defined. The stretch-gated ion channel PIEZO2 has been shown to be essential for aspects of mechanosensation in model organisms. METHODS We performed whole-exome sequencing analysis in two patients who had unique neuromuscular and skeletal symptoms, including progressive scoliosis, that did not conform to standard diagnostic classification. In vitro and messenger RNA assays, functional brain imaging, and psychophysical and kinematic tests were used to establish the effect of the genetic variants on protein function and somatosensation. RESULTS Each patient carried compound-inactivating variants in PIEZO2, and each had a selective loss of discriminative touch perception but nevertheless responded to specific types of gentle mechanical stimulation on hairy skin. The patients had profoundly decreased proprioception leading to ataxia and dysmetria that were markedly worse in the absence of visual cues. However, they had the ability to perform a range of tasks, such as walking, talking, and writing, that are considered to rely heavily on proprioception. CONCLUSIONS Our results show that PIEZO2 is a determinant of mechanosensation in humans. C1 [Chesler, Alexander T.; Szczot, Marcin; Ceko, Marta; Laubacher, Claire] NIH, Natl Ctr Complementary & Integrat Hlth, Bldg 10, Bethesda, MD 20892 USA. [Bharucha-Goebel, Diana; Donkervoort, Sandra; Hayes, Leslie H.; Bradley, Nathaniel; Nguyen, David; Foley, A. Reghan; Le Pichon, Claire E.; Bonnemann, Carsten G.] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. [Alter, Katharine; Zampieri, Cristiane; Stanley, Christopher] NIH, Funct & Appl Biomech Sect, Dept Rehabil Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Bharucha-Goebel, Diana] Childrens Natl Hlth Syst, Div Neurol, Washington, DC USA. [Innes, A. Micheil] Univ Calgary, Dept Med Genet, Cumming Sch Med, Calgary, AB, Canada. [Innes, A. Micheil] Univ Calgary, Alberta Childrens Hosp, Res Inst, Cumming Sch Med, Calgary, AB, Canada. [Mah, Jean K.] Univ Calgary, Dept Clin Neurosci, Alberta Childrens Hosp, Res Inst, Calgary, AB, Canada. [Mah, Jean K.] Univ Calgary, Dept Pediat, Alberta Childrens Hosp, Res Inst, Calgary, AB, Canada. [Grosmann, Carla M.] Univ Calif San Diego, Sch Med, Rady Childrens Hosp, Dept Neurosci, San Diego, CA 92103 USA. [Grosmann, Carla M.] Univ Calif San Diego, Sch Med, Rady Childrens Hosp, Dept Pediat, San Diego, CA 92103 USA. RP Chesler, AT (reprint author), Natl Ctr Complementary & Integrat Hlth, 35 Convent Dr,Bldg 35A,Rm 1D822, Bethesda, MD 20892 USA.; Bonnemann, CG (reprint author), Natl Inst Neurol Disorders & Stroke, 35 Convent Dr,Bldg 35B,Rm 2A116, Bethesda, MD 20892 USA. EM alexander.chesler@nih.gov; carsten.bonnemann@nih.gov RI innes, allan micheil/A-9955-2017 FU National Institutes of Health Intramural Research Program; National Institutes of Health Intramural Research Program from the National Center for Complementary and Integrative Health; National Institutes of Health Intramural Research Program from the National Institute of Neurological Disorders and Stroke FX Funded by the National Institutes of Health Intramural Research Program.; Supported by National Institutes of Health Intramural Research Program funding from the National Center for Complementary and Integrative Health (to Dr. Chesler) and from the National Institute of Neurological Disorders and Stroke (to Dr. Bonnemann). NR 28 TC 3 Z9 3 U1 9 U2 9 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 6 PY 2016 VL 375 IS 14 BP 1355 EP 1364 DI 10.1056/NEJMoa1602812 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA DY3EZ UT WOS:000384974900008 PM 27653382 ER PT J AU Zhou, YF Kumari, D Sciascia, N Usdin, K AF Zhou, Yifan Kumari, Daman Sciascia, Nicholas Usdin, Karen TI CGG-repeat dynamics and FMR1 gene silencing in fragile X syndrome stem cells and stem cell-derived neurons SO MOLECULAR AUTISM LA English DT Article DE Fragile X syndrome; Repeat expansion mutation; Repeat-mediated gene silencing; Repeat contractions; Stem cells ID CHEMICALLY-DEFINED CULTURE; HIGH-FUNCTIONING MALE; FULL-MUTATION; MOUSE MODEL; TREMOR/ATAXIA SYNDROME; MESSENGER-RNA; CHROMOSOME FRAGILITY; PROTEIN EXPRESSION; SOMATIC EXPANSION; AGG INTERRUPTIONS AB Background: Fragile X syndrome (FXS), a common cause of intellectual disability and autism, results from the expansion of a CGG-repeat tract in the 5' untranslated region of the FMR1 gene to >200 repeats. Such expanded alleles, known as full mutation (FM) alleles, are epigenetically silenced in differentiated cells thus resulting in the loss of FMRP, a protein important for learning and memory. The timing of repeat expansion and FMR1 gene silencing is controversial. Methods: We monitored the repeat size and methylation status of FMR1 alleles with expanded CGG repeats in patient-derived induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) that were grown for extended period of time either as stem cells or differentiated into neurons. We used a PCR assay optimized for the amplification of large CGG repeats for sizing, and a quantitative methylation-specific PCR for the analysis of FMR1 promoter methylation. The FMR1 mRNA levels were analyzed by qRT-PCR. FMRP levels were determined by western blotting and immunofluorescence. Chromatin immunoprecipitation was used to study the association of repressive histone marks with the FMR1 gene in FXS ESCs. Results: We show here that while FMR1 gene silencing can be seen in FXS embryonic stem cells (ESCs), some silenced alleles contract and when the repeat number drops below similar to 400, DNA methylation erodes, even when the repeat number remains >200. The resultant active alleles do not show the large step-wise expansions seen in stem cells from other repeat expansion diseases. Furthermore, there may be selection against large active alleles and these alleles do not expand further or become silenced on neuronal differentiation. Conclusions: Our data support the hypotheses that (i) large expansions occur prezygotically or in the very early embryo, (ii) large unmethylated alleles may be deleterious in stem cells, (iii) methylation can occur on alleles with >400 repeats very early in embryogenesis, and (iv) expansion and contraction may occur by different mechanisms. Our data also suggest that the threshold for stable methylation of FM alleles may be higher than previously thought. A higher threshold might explain why some carriers of FM alleles escape methylation. It may also provide a simple explanation for why silencing has not been observed in mouse models with >200 repeats. C1 [Zhou, Yifan; Kumari, Daman; Sciascia, Nicholas; Usdin, Karen] NIDDK, Sect Gene Struct & Dis, Lab Mol & Cellular Biol, NIH, Bethesda, MD USA. [Sciascia, Nicholas] NCI, Lab Genome Integr, Bethesda, MD 20892 USA. RP Kumari, D; Usdin, K (reprint author), NIDDK, Sect Gene Struct & Dis, Lab Mol & Cellular Biol, NIH, Bethesda, MD USA. EM damank@helix.nih.gov; ku@helix.nih.gov FU National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health [DK05760218]; National Institutes of Health Center for Regenerative Medicine FX This work was supported by the intramural funds of National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health (DK05760218 to K.U.) and a grant from the National Institutes of Health Center for Regenerative Medicine (K.U.). NR 64 TC 0 Z9 0 U1 10 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2040-2392 J9 MOL AUTISM JI Mol. Autism PD OCT 6 PY 2016 VL 7 AR 42 DI 10.1186/s13229-016-0105-9 PG 13 WC Genetics & Heredity; Neurosciences SC Genetics & Heredity; Neurosciences & Neurology GA DX9EU UT WOS:000384697200001 PM 27713816 ER PT J AU Breman, J AF Breman, Joel TI Donald Ainslie Henderson (1928-2016) OBITUARY SO NATURE LA English DT Biographical-Item C1 [Breman, Joel] US Natl Inst Hlth, Bethesda, MD 20892 USA. RP Breman, J (reprint author), US Natl Inst Hlth, Bethesda, MD 20892 USA. EM bremanj@mail.nih.gov NR 0 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD OCT 6 PY 2016 VL 538 IS 7623 BP 42 EP 42 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DX8LD UT WOS:000384638900026 PM 27708300 ER PT J AU Celia, H Noinaj, N Zakharov, SD Bordignon, E Botos, I Santamaria, M Barnard, TJ Cramer, WA Lloubes, R Buchanan, SK AF Celia, Herve Noinaj, Nicholas Zakharov, Stanislav D. Bordignon, Enrica Botos, Istvan Santamaria, Monica Barnard, Travis J. Cramer, William A. Lloubes, Roland Buchanan, Susan K. TI Structural insight into the role of the Ton complex in energy transduction SO NATURE LA English DT Article ID OUTER-MEMBRANE INTEGRITY; ESCHERICHIA-COLI; PERIPLASMIC DOMAIN; FLAGELLAR MOTOR; PSEUDOMONAS-AERUGINOSA; CONFORMATIONAL-CHANGES; PROTONMOTIVE FORCE; CRYSTAL-STRUCTURE; DIFFRACTION DATA; TERMINAL DOMAIN AB In Gram-negative bacteria, outer membrane transporters import nutrients by coupling to an inner membrane protein complex called the Ton complex. The Ton complex consists of TonB, ExbB, and ExbD, and uses the proton motive force at the inner membrane to transduce energy to the outer membrane via TonB. Here, we structurally characterize the Ton complex from Escherichia coli using X-ray crystallography, electron microscopy, double electron-electron resonance (DEER) spectroscopy, and crosslinking. Our results reveal a stoichiometry consisting of a pentamer of ExbB, a dimer of ExbD, and at least one TonB. Electrophysiology studies show that the Ton subcomplex forms pH-sensitive cation-selective channels and provide insight into the mechanism by which it may harness the proton motive force to produce energy. C1 [Celia, Herve; Lloubes, Roland] Aix Marseille Univ, CNRS, UMR7255, Inst Microbiol Mediterranee,Lab Ingn Syst Macromo, F-13402 Marseille 20, France. [Celia, Herve; Botos, Istvan; Barnard, Travis J.; Buchanan, Susan K.] Natl Inst Diabet & Digest & Kidney Dis, NIH, Bethesda, MD 20892 USA. [Noinaj, Nicholas; Zakharov, Stanislav D.; Cramer, William A.] Purdue Univ, Markey Ctr Struct Biol, Dept Biol Sci, W Lafayette, IN 47907 USA. [Noinaj, Nicholas; Zakharov, Stanislav D.; Cramer, William A.] Purdue Univ, Purdue Inst Inflammat Immunol & Infect Dis, W Lafayette, IN 47907 USA. [Bordignon, Enrica] Free Univ Berlin, Fachbereich Phys, D-14195 Berlin, Germany. [Bordignon, Enrica] Ruhr Univ Bochum, Fac Chem & Biochem, D-45810 Bochum, Germany. [Santamaria, Monica] Hosp La Paz IdiPAZ, Inst Invest, Dept Cirugia Expt, Paseo Castellana 261, Madrid 28046, Spain. RP Lloubes, R (reprint author), Aix Marseille Univ, CNRS, UMR7255, Inst Microbiol Mediterranee,Lab Ingn Syst Macromo, F-13402 Marseille 20, France.; Buchanan, SK (reprint author), Natl Inst Diabet & Digest & Kidney Dis, NIH, Bethesda, MD 20892 USA.; Noinaj, N (reprint author), Purdue Univ, Markey Ctr Struct Biol, Dept Biol Sci, W Lafayette, IN 47907 USA.; Noinaj, N (reprint author), Purdue Univ, Purdue Inst Inflammat Immunol & Infect Dis, W Lafayette, IN 47907 USA. EM nnoinaj@purdue.edu; lloubes@imm.cnrs.fr; skbuchan@helix.nih.gov FU US DOE, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; US DOE, Basic Energy Sciences, Office of Science [DE-AC02-06CH11357]; Office of Science, Office of Basic Energy Sciences, of the US DOE [DE-AC02-05CH11231]; Deutsche Forschungsgemeinschaft [INST 130/972-1 FUGG]; Department of Biological Sciences, Purdue University; National Institute of Allergy and Infectious Diseases [1K22AI113078-01]; Cluster of Excellence RESOLV - Deutsche Forschungsgemeinschaft [EXC 1069]; NIH [NIH GM 038323]; Henry Koffler Professorship at Purdue University; Centre National de la Recherche Scientifique; Aix-Marseille Universite; Agence National de la Recherche (BACMOLMOT) [ANR-14-CE09-0023]; Projets internationaux de cooperation scientifique [PICS05853]; NIH, NIDDK FX We thank the staff at the SER-CAT and GM/CA-CAT beamlines at the Advanced Photon Source (APS), Argonne National Laboratory (use of the APS is supported by the US DOE, Office of Science, Office of Basic Energy Sciences, under Contract No. W-31-109-Eng-38, and by the US DOE, Basic Energy Sciences, Office of Science, under contract No. DE-AC02-06CH11357); the staff at beamlines 5.0.1 and 8.2.1, Advance Light Source at Lawrence Berkeley National Laboratory for their assistance during crystal screening (the Advanced Light Source is supported by the Director, Office of Science, Office of Basic Energy Sciences, of the US DOE under Contract No. DE-AC02-05CH11231); G. Jeschke (ETH Zurich) for providing the Q-band resonator; T. Assafa for the reproducibility measurements; the Deutsche Forschungsgemeinschaft for funding the AWG E580 Q-band spectrometer (INST 130/972-1 FUGG); Y. Li at the NINDS/NIH Protein/Peptide Sequencing Facility for performing mass spectrometry analysis; and members of the Lloubes team, E. Cascales, J. Sturgis and J. P. Duneau for discussions. N.N. is supported by the Department of Biological Sciences, Purdue University and by the National Institute of Allergy and Infectious Diseases (1K22AI113078-01). E.B. is supported by the Cluster of Excellence RESOLV (EXC 1069) funded by the Deutsche Forschungsgemeinschaft. W.A.C. is supported by the NIH (NIH GM 038323) and the Henry Koffler Professorship at Purdue University. H.C. and R.L. are funded by the Centre National de la Recherche Scientifique, the Aix-Marseille Universite and grants from the Agence National de la Recherche (BACMOLMOT [ANR-14-CE09-0023]) and from Projets internationaux de cooperation scientifique (PICS05853). H.C., T.J.B., I.B. and S.K.B. are supported by the Intramural Research Program of the NIH, NIDDK. NR 56 TC 1 Z9 1 U1 30 U2 30 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD OCT 6 PY 2016 VL 538 IS 7623 BP 60 EP + DI 10.1038/nature19757 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DX8LD UT WOS:000384638900033 PM 27654919 ER PT J AU Singh, SR Zeng, XK Zhao, JS Liu, Y Hou, G Liu, HH Hou, SX AF Singh, Shree Ram Zeng, Xiankun Zhao, Jiangsha Liu, Ying Hou, Gerald Liu, Hanhan Hou, Steven X. TI The lipolysis pathway sustains normal and transformed stem cells in adult Drosophila SO NATURE LA English DT Article ID MALPIGHIAN TUBULES; BETA-OXIDATION; ENGULFMENT; GOLGI; HOMEOSTASIS; ACTIVATION; INHIBITION; RECEPTOR; MIDGUT; DYSFUNCTION AB Cancer stem cells (CSCs) may be responsible for tumour dormancy, relapse and the eventual death of most cancer patients(1). In addition, these cells are usually resistant to cytotoxic conditions. However, very little is known about the biology behind this resistance to therapeutics. Here we investigated stem-cell death in the digestive system of adult Drosophila melanogaster. We found that knockdown of the coat protein complex I (COPI)-Arf79F (also known as Arf1) complex selectively killed normal and transformed stem cells through necrosis, by attenuating the lipolysis pathway, but spared differentiated cells. The dying stem cells were engulfed by neighbouring differentiated cells through a draper-myoblast city-Rac1-basket (also known as JNK)-dependent autophagy pathway. Furthermore, Arf1 inhibitors reduced CSCs in human cancer cell lines. Thus, normal or cancer stem cells may rely primarily on lipid reserves for energy, in such a way that blocking lipolysis starves them to death. This finding may lead to new therapies that could help to eliminate CSCs in human cancers. C1 [Singh, Shree Ram; Zeng, Xiankun; Zhao, Jiangsha; Liu, Ying; Hou, Gerald; Liu, Hanhan; Hou, Steven X.] Natl Canc Inst Frederick, Basic Res Lab, NIH, Frederick, MD 21702 USA. RP Hou, SX (reprint author), Natl Canc Inst Frederick, Basic Res Lab, NIH, Frederick, MD 21702 USA. EM hous@mail.nih.gov RI Singh, Shree Ram/B-7614-2008; Liu, Ying /K-8883-2016 OI Singh, Shree Ram/0000-0001-6545-583X; FU Intramural Research Program of the National Institutes of Health, National Cancer Institute FX We thank S. Hayashi, J.-P. Vincent, M. Fortini, C. Thummel, E. Baehrecke, R. P. Kuhnlein, M. Freeman, F. Schweisguth, M. Mlodzik, T. Lecuit, DGRC, VDRC, and the Bloomington Stock Centers for fly stocks; A. Chavanieu and L. Frigerio for Arf1 inhibitors; X. Yang and the Developmental Studies Hybridoma Bank for antibodies; and S. Lockett for help with the confocal microscope. This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 56 TC 1 Z9 1 U1 33 U2 33 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD OCT 6 PY 2016 VL 538 IS 7623 BP 109 EP + DI 10.1038/nature19788 PG 23 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DX8LD UT WOS:000384638900044 PM 27680705 ER PT J AU Wang, XF Barbier, E Chiu, YT He, Y Zhan, J Bi, GH Zhang, HY Feng, B Liu-Chen, LY Wang, JB Xi, ZX AF Wang, Xiao-Fei Barbier, Elisabeth Chiu, Yi-Ting He, Yi Zhan, Jia Bi, Guo-Hua Zhang, Hai-Ying Feng, Bo Liu-Chen, Lee-Yuan Wang, Jia Bei Xi, Zheng-Xiong TI T394A Mutation at the mu Opioid Receptor Blocks Opioid Tolerance and Increases Vulnerability to Heroin Self-Administration in Mice SO JOURNAL OF NEUROSCIENCE LA English DT Article DE addiction; heroin; mu opioid receptor; mutation; self-administration; T394A ID MORPHINE-INDUCED ANALGESIA; OPRM1 A118G POLYMORPHISM; MOLECULAR-MECHANISMS; OPIATE ADDICTION; THREONINE 394; MOUSE MODEL; PHOSPHORYLATION; DESENSITIZATION; DEPENDENCE; INTERNALIZATION AB The etiology and pathophysiology underlying opioid tolerance and dependence are still unknown. Because mu opioid receptor (MOR) plays an essential role in opioid action, many vulnerability-related studies have focused on single nucleotide polymorphisms of MOR, particularly on A118G. In this study, we found that a single-point mutation at the MOR T394 phosphorylation site could be another important susceptive factor in the development of opioid tolerance and dependence in mice. T394A mutation, in which a threonine at 394 was replaced by an alanine, did not alter agonist binding to MOR and opioid analgesia, but resulted in loss of etorphine-induced MOR internalization in spinal dorsal horn neurons and opioid analgesic tolerance induced by either morphine or etorphine. In addition, this mutation also caused an increase in intravenous heroin self-administration and in nucleus accumbens dopamine response to heroin. These findings suggest that T394 phosphorylation following MOR activation causes MOR internalization and desensitization, which subsequently contributes to the development of tolerance in both opioid analgesia and opioid reward. Accordingly, T394A mutation blocks opioid tolerance and leads to an increase in brain dopamine response to opioids and in opioid-taking behavior. Thus, the T394may serve as a new drug target for modulating opioid tolerance and the development of opioid abuse and addiction. C1 [Wang, Xiao-Fei; He, Yi; Zhan, Jia; Bi, Guo-Hua; Zhang, Hai-Ying; Xi, Zheng-Xiong] NIDA, Mol Targets & Medicat Discovery Branch, Intramural Res Program, Baltimore, MD 21224 USA. [Barbier, Elisabeth; Feng, Bo; Wang, Jia Bei] Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. [Chiu, Yi-Ting; Liu-Chen, Lee-Yuan] Temple Univ, Sch Med, Dept Pharmacol, Philadelphia, PA 19140 USA. [Wang, Xiao-Fei] Beijing Inst Pharmacol & Toxicol, Beijing 100850, Peoples R China. RP Wang, JB (reprint author), Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 21201 USA.; Xi, ZX (reprint author), NIDA, Intramural Res Program, Baltimore, MD 21224 USA. EM jwang@rx.umaryland.edu; zxi@mail.nih.gov FU National Institute on Drug Abuse [DA11925, DA018722] FX This work was supported by the Intramural Research Program of the National Institute on Drug Abuse and National Institute on Drug Abuse Grants DA11925 and DA018722 to J.B.W. NR 42 TC 2 Z9 2 U1 6 U2 6 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD OCT 5 PY 2016 VL 36 IS 40 BP 10392 EP 10403 DI 10.1523/JNEUROSCI.0603-16.2016 PG 12 WC Neurosciences SC Neurosciences & Neurology GA EC8BM UT WOS:000388365000015 PM 27707973 ER PT J AU Schmidt, T Ghirlando, R Baber, J Clore, GM AF Schmidt, Thomas Ghirlando, Rodolfo Baber, James Clore, G. Marius TI Quantitative Resolution of Monomer-Dimer Populations by Inversion Modulated DEER EPR Spectroscopy SO CHEMPHYSCHEM LA English DT Article DE double electron-electron resonance (deer); electron paramagnetic resonance (epr) spectroscopy; HIV-1 reverse transcriptase; population distributions; proteins ID ELECTRON-ELECTRON RESONANCE; HIV-1 REVERSE-TRANSCRIPTASE; SPIN-ECHO; PULSED ELECTRON; DISTANCE MEASUREMENTS; MEMBRANE-PROTEINS; ESCHERICHIA-COLI; DOMAIN; TIME; CONFORMATIONS AB A simple method, based on inversion modulated double electron-electron resonance electron paramagnetic resonance (DEER EPR) spectroscopy, is presented for determining populations of monomer and dimer in proteins (as well as any other biological macromolecules). The method is based on analysis of modulation depth versus electron double resonance (ELDOR) pulse flip angle. High accuracy is achieved by complete deuteration, extensive sampling of a large number of ELDOR pulse flip angle values, and combined analysis of differently labeled spin samples. We demonstrate the method using two different proteins: an obligate monomer exemplified by the small immunoglobulin binding B domain of protein A, and the p66 subunit of HIV-1 reverse transcriptase which exists as an equilibrium mixture of monomer and dimer species whose relative populations are affected by glycerol content. This information is crucial for quantitative analysis of distance distributions involving proteins that may exist as mixtures of monomer, dimer and high order multimers under the conditions of the DEER EPR experiment. C1 [Schmidt, Thomas; Ghirlando, Rodolfo; Baber, James; Clore, G. Marius] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM mariusc@mail.nih.gov OI Clore, G. Marius/0000-0003-3809-1027 FU National Institute of Diabetes and Digestive and Kidney Diseases, NIH; Office of the Director of the NIH FX We thank Drs. R. Tycko and D. Murray for useful discussions; Drs. L. Tian and W. Yang for the plasmid of the p66 subunit of HIV reverse transcriptase; and Dr. J. Louis for MTSL-labeled protein A. This work was supported by funds from the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH, and from the Intramural AIDS Targeted Antiviral Program of the Office of the Director of the NIH (to G.M.C.). NR 31 TC 0 Z9 0 U1 7 U2 7 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1439-4235 EI 1439-7641 J9 CHEMPHYSCHEM JI ChemPhysChem PD OCT 5 PY 2016 VL 17 IS 19 BP 2987 EP 2991 DI 10.1002/cphc.201600726 PG 5 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA EA7DW UT WOS:000386790100007 PM 27442455 ER PT J AU Burnett, CJ Li, C Webber, E Tsaousidou, E Xue, SY Bruning, JC Krashes, MJ AF Burnett, C. Joseph Li, Chia Webber, Emily Tsaousidou, Eva Xue, Stephen Y. Bruening, Jens C. Krashes, Michael J. TI Hunger-Driven Motivational State Competition SO NEURON LA English DT Article ID FEEDING-BEHAVIOR; NEURAL CIRCUITS; NEUROPEPTIDE-Y; CONSUMMATORY BEHAVIORS; LATERAL HYPOTHALAMUS; DOPAMINE NEURONS; MICE; NUCLEUS; AGRP; ACTIVATION AB Behavioral choice is ubiquitous in the animal kingdom and is central to goal-oriented behavior. Hypothalamic Agouti-related peptide (AgRP) neurons are critical regulators of appetite. Hungry animals, bombarded by multiple sensory stimuli, are known to modify their behavior during times of caloric need, rapidly adapting to a consistently changing environment. Utilizing ARC AgRP neurons as an entry point, we analyzed the hierarchical position of hunger related to rival drive states. Employing a battery of behavioral assays, we found that hunger significantly increases its capacity to suppress competing motivational systems, such as thirst, anxiety-related behavior, innate fear, and social interactions, often only when food is accessible. Furthermore, real-time monitoring of ARC AgRP activity revealed time-locked responses to conspecific investigation in addition to food presentation, further establishing that, even at the level of ARC AgRP neurons, choices are remarkably flexible computations, integrating internal state, external factors, and anticipated yield. C1 [Burnett, C. Joseph; Li, Chia; Webber, Emily; Xue, Stephen Y.; Krashes, Michael J.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Burnett, C. Joseph; Li, Chia; Webber, Emily; Xue, Stephen Y.; Krashes, Michael J.] NIDA, NIH, Baltimore, MD 21224 USA. [Burnett, C. Joseph] Brown Univ, Grad Partnerships Program, Providence, RI 02912 USA. [Tsaousidou, Eva; Bruening, Jens C.] Max Plank Inst Metab Res, Dept Neuronal Control Metab, Gleueler Str 50, D-50931 Cologne, Germany. [Tsaousidou, Eva; Bruening, Jens C.] Univ Hosp Cologne, Ctr Endocrinol Diabet & Prevent Med CEDP, Kerpener Str 26, D-50924 Cologne, Germany. [Tsaousidou, Eva; Bruening, Jens C.] Univ Cologne, Excellence Cluster Cellular Stress Responses Agin, Joseph Stelzmann Str 26, D-50931 Cologne, Germany. [Tsaousidou, Eva; Bruening, Jens C.] Univ Cologne, CMMC, Joseph Stelzmann Str 26, D-50931 Cologne, Germany. [Tsaousidou, Eva; Bruening, Jens C.] Natl Ctr Diabet Res DZD, Ingolstadter Land Str 1, D-85764 Neuherberg, Germany. RP Krashes, MJ (reprint author), NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA.; Krashes, MJ (reprint author), NIDA, NIH, Baltimore, MD 21224 USA. EM michael.krashes@nih.gov FU Intramural Research Program of the NIH, National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK) [DK075087, DK075089] FX We thank Brad B. Lowell for providing Agrp-ires-Cre mice used in this study. We thank Alex Chesler, Lex Kravitz, and Nima Ghitani for photometry assistance and Alastair Garfield for comments on the manuscript. We thank the GENIE project for the development of GCaMP6. This work was supported by the Intramural Research Program of the NIH, The National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK), DK075087 (M.J.K.), DK075089 (M.J.K.). NR 53 TC 1 Z9 1 U1 9 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD OCT 5 PY 2016 VL 92 IS 1 BP 187 EP 201 DI 10.1016/j.neuron.2016.08.032 PG 15 WC Neurosciences SC Neurosciences & Neurology GA EA6TA UT WOS:000386760700020 PM 27693254 ER PT J AU Barbera, G Liang, B Zhang, LF Gerfen, CR Culurciello, E Chen, R Li, Y Lin, DT AF Barbera, Giovanni Liang, Bo Zhang, Lifeng Gerfen, Charles R. Culurciello, Eugenio Chen, Rong Li, Yun Lin, Da-Ting TI Spatially Compact Neural Clusters in the Dorsal Striatum Encode Locomotion Relevant Information SO NEURON LA English DT Article ID BASAL GANGLIA CIRCUITS; INDIRECT PATHWAYS; CRE-RECOMBINASE; CELL ASSEMBLIES; NEURONS; NETWORK; MOVEMENTS; REWARD; DISORDERS; ENSEMBLES AB An influential striatal model postulates that neural activities in the striatal direct and indirect pathways promote and inhibit movement, respectively. Normal behavior requires coordinated activity in the direct pathway to facilitate intended locomotion and indirect pathway to inhibit unwanted locomotion. In this striatal model, neuronal population activity is assumed to encode locomotion relevant information. Here, we propose a novel encoding mechanism for the dorsal striatum. We identified spatially compact neural clusters in both the direct and indirect pathways. Detailed characterization revealed similar cluster organization between the direct and indirect pathways, and cluster activities from both pathways were correlated with mouse locomotion velocities. Using machine-learning algorithms, cluster activities could be used to decode locomotion relevant behavioral states and locomotion velocity. We propose that neural clusters in the dorsal striatum encode locomotion relevant information and that coordinated activities of direct and indirect pathway neural clusters are required for normal striatal controlled behavior. C1 [Barbera, Giovanni; Liang, Bo; Zhang, Lifeng; Li, Yun; Lin, Da-Ting] NIDA, Intramural Res Program, NIH, 333 Cassell Dr, Baltimore, MD 21224 USA. [Barbera, Giovanni; Culurciello, Eugenio] Purdue Univ, Weldon Sch Biomed Engn, 206 S Martin Jischke Dr, W Lafayette, IN 47907 USA. [Gerfen, Charles R.] NIMH, Intramural Res Program, NIH, Bldg 49,Room 5A60, Bethesda, MD 20814 USA. [Chen, Rong] Univ Maryland, Sch Med, Dept Diagnost Radiol & Nucl Med, 100 N Greene St, Baltimore, MD 21201 USA. [Lin, Da-Ting] Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, 725 N Wolfe St, Baltimore, MD 21205 USA. RP Li, Y; Lin, DT (reprint author), NIDA, Intramural Res Program, NIH, 333 Cassell Dr, Baltimore, MD 21224 USA.; Chen, R (reprint author), Univ Maryland, Sch Med, Dept Diagnost Radiol & Nucl Med, 100 N Greene St, Baltimore, MD 21201 USA.; Lin, DT (reprint author), Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, 725 N Wolfe St, Baltimore, MD 21205 USA. EM rchen@umm.edu; yunlijax@gmail.com; lind3@mail.nih.gov FU NIH/NIDA/IRP FX Research was supported by NIH/NIDA/IRP. We would like to thank the Genetically-Encoded Neuronal Indicator and Effector (GENIE) Project and the Janelia Research Campus of the Howard Hughes Medical Institute for generously allowing the use of GCaMP6 in our research. We would like to thank Dr. Yavin Shaham of NIDA IRP for providing intellectual input on the data analysis and the write-up of the manuscript. E.C. is a co-founder of TeraDeep Inc. Financial Conflicts of Interest are managed by Purdue University's Conflict of Interest Committee. All other authors declare no competing financial interests. NR 39 TC 4 Z9 4 U1 10 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD OCT 5 PY 2016 VL 92 IS 1 BP 202 EP 213 DI 10.1016/j.neuron.2016.08.037 PG 12 WC Neurosciences SC Neurosciences & Neurology GA EA6TA UT WOS:000386760700021 PM 27667003 ER PT J AU Bharti, N Djibo, A Tatem, AJ Grenfell, BT Ferrari, MJ AF Bharti, Nita Djibo, Ali Tatem, Andrew J. Grenfell, Bryan T. Ferrari, Matthew J. TI Measuring populations to improve vaccination coverage SO SCIENTIFIC REPORTS LA English DT Article ID NIGHTTIME SATELLITE IMAGERY; MEASLES EPIDEMIC; UNITED-STATES; BURKINA-FASO; NIGER; NIAMEY; RISK; TRANSMISSION; MORTALITY; OUTBREAK AB In low-income settings, vaccination campaigns supplement routine immunization but often fail to achieve coverage goals due to uncertainty about target population size and distribution. Accurate, updated estimates of target populations are rare but critical; short-term fluctuations can greatly impact population size and susceptibility. We use satellite imagery to quantify population fluctuations and the coverage achieved by a measles outbreak response vaccination campaign in urban Niger and compare campaign estimates to measurements from a post-campaign survey. Vaccine coverage was overestimated because the campaign underestimated resident numbers and seasonal migration further increased the target population. We combine satellite-derived measurements of fluctuations in population distribution with high-resolution measles case reports to develop a dynamic model that illustrates the potential improvement in vaccination campaign coverage if planners account for predictable population fluctuations. Satellite imagery can improve retrospective estimates of vaccination campaign impact and future campaign planning by synchronizing interventions with predictable population fluxes. C1 [Bharti, Nita; Ferrari, Matthew J.] Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Bharti, Nita] Stanford Univ, Woods Inst Environm, Stanford, CA 94305 USA. [Djibo, Ali] Univ Niamey, Niamey, Niger. [Tatem, Andrew J.; Grenfell, Bryan T.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Tatem, Andrew J.] Univ Southampton, Dept Geog, WorldPop, Southampton, Hants, England. [Tatem, Andrew J.] Flowminder Fdn, Stockholm, Sweden. [Grenfell, Bryan T.] Princeton Univ, Dept Ecol & Evolutionary Biol, Woodrow Wilson Sch Publ & Int Affairs, Princeton, NJ 08544 USA. [Ferrari, Matthew J.] Penn State Univ, Dept Stat, University Pk, PA 16802 USA. RP Bharti, N (reprint author), Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA.; Bharti, N (reprint author), Stanford Univ, Woods Inst Environm, Stanford, CA 94305 USA. EM nita@psu.edu FU Branco Weiss-The Society in Science; Bill and Melinda Gates Foundation [OPP1106427, 1032350, OPP1134076]; Huck Institute of Life Science at Penn State University; RAPIDD program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; NIH/NIAID [U19AI089674]; Wellcome Trust [106866/Z/15/Z]; Science and Technology Directorate, Department of Homeland Security [HSHQDC-12-C-00058] FX N.B. acknowledges funding support from Branco Weiss-The Society in Science, the Bill and Melinda Gates Foundation, and the Huck Institute of Life Science at Penn State University. M.J.F. acknowledges support from the Bill and Melinda Gates Foundation. A.J.T. acknowledges funding support from the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health, and is also supported by grants from NIH/NIAID (U19AI089674), the Wellcome Trust (106866/Z/15/Z), and the Bill and Melinda Gates Foundation (OPP1106427, 1032350, OPP1134076). B.T.G. acknowledges funding support from the Bill and Melinda Gates Foundation, the Science and Technology Directorate, Department of Homeland Security (contract HSHQDC-12-C-00058), the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security and the Fogarty International Center, National Institutes of Health. This work forms part of the output of the RAPIDD workshop on Environmental drivers of behavior and disease. NR 48 TC 0 Z9 0 U1 8 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD OCT 5 PY 2016 VL 6 AR 34541 DI 10.1038/srep34541 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DX8TM UT WOS:000384662400001 ER PT J AU Mehta, M Basalingappa, K Griffith, JN Andrade, D Babu, A Amreddy, N Muralidharan, R Gorospe, M Herman, T Ding, WQ Ramesh, R Munshi, A AF Mehta, Meghna Basalingappa, Kanthesh Griffith, James N. Andrade, Daniel Babu, Anish Amreddy, Narsireddy Muralidharan, Ranganayaki Gorospe, Myriam Herman, Terence Ding, Wei-Qun Ramesh, Rajagopal Munshi, Anupama TI HuR silencing elicits oxidative stress and DNA damage and sensitizes human triple-negative breast cancer cells to radiotherapy SO ONCOTARGET LA English DT Article DE HuR; breast cancer; oxidative stress; DNA repair; radiation; siRNA ID DOUBLE-STRAND BREAKS; THIOREDOXIN REDUCTASE INHIBITORS; RNA-BINDING-PROTEINS; ELAV-LIKE PROTEIN; MESSENGER-RNA; IONIZING-RADIATION; PROGESTERONE-RECEPTOR; ESTROGEN-RECEPTOR; DOWN-REGULATION; REPAIR ACTIVITY AB HuR is an mRNA-binding protein whose overexpression in cancer cells has been associated with poor prognosis and resistance to therapy. While reports on HuR overexpression contributing to chemoresistance exist, limited information is available on HuR and radioresistance especially in triple-negative breast cancer (TNBC). In this study we investigated the role of HuR in radiation resistance in three TNBC (MDA-MB-231, MDA-MB-468 and Hs578t) cell lines. Endogenous HuR expression was higher in TNBC cells compared to normal cells. siRNA mediated knockdown of HuR (siHuR) markedly reduced HuR mRNA and protein levels compared to scrambled siRNA (siScr) treatment. Further, siHuR treatment sensitized TNBC cells to ionizing radiation at 2 Gy compared to siScr treatment as evidenced by the significant reduction in clonogenic cell survival from 59%, 49%, and 65% in siScr-treated cells to 40%, 33%, and 46% in siHuR-treated MDA-MB-231, MDA-MB-468 and Hs578t cells, respectively. Molecular studies showed increased ROS production and inhibition of thioredoxin reductase (TrxR) in HuR knockdown cells contributed to radiosensitization. Associated with increased ROS production was evidence of increased DNA damage, demonstrated by a significant increase (p < 0.05) in gamma-H2AX foci that persisted for up to 24 h in siHuR plus radiation treated cells compared to control cells. Further, comet assay revealed that HuR-silenced cells had larger and longer-lasting tails than control cells, indicating higher levels of DNA damage. In conclusion, our studies demonstrate that HuR knockdown in TNBC cells elicits oxidative stress and DNA damage resulting in radiosensitization. C1 [Mehta, Meghna; Basalingappa, Kanthesh; Griffith, James N.; Andrade, Daniel; Herman, Terence; Munshi, Anupama] Univ Oklahoma, Hlth Sci Ctr, Dept Radiat Oncol, Oklahoma City, OK 73106 USA. [Babu, Anish; Amreddy, Narsireddy; Muralidharan, Ranganayaki; Ding, Wei-Qun; Ramesh, Rajagopal] Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK USA. [Babu, Anish; Amreddy, Narsireddy; Muralidharan, Ranganayaki; Ramesh, Rajagopal; Munshi, Anupama] Univ Oklahoma, Hlth Sci Ctr, Stephenson Canc Ctr, Oklahoma City, OK 73106 USA. [Gorospe, Myriam] NIA, NIH, Baltimore, MD 21224 USA. [Ramesh, Rajagopal] Univ Oklahoma, Hlth Sci Ctr, Grad Program Biomed Sci, Oklahoma City, OK USA. RP Munshi, A (reprint author), Univ Oklahoma, Hlth Sci Ctr, Dept Radiat Oncol, Oklahoma City, OK 73106 USA.; Munshi, A (reprint author), Univ Oklahoma, Hlth Sci Ctr, Stephenson Canc Ctr, Oklahoma City, OK 73106 USA. EM amunshi@ouhsc.edu FU National Institutes of General Medical Sciences (NIGMS) of the National Institutes of Health (NIH) [P20GM103639]; National Cancer Institute (NCI) [R01 CA167516]; Stephenson Cancer Center Seed Grant; Presbyterian Health Foundation; Jim and Christy Everest Endowed Chair in Cancer Developmental Therapeutics; NIA-IRP, NIH FX Research reported in this publication was supported by the National Institutes of General Medical Sciences (NIGMS) of the National Institutes of Health (NIH) under Award Number P20GM103639 (AM); by the National Cancer Institute (NCI) grant R01 CA167516 (RR), by funds received from the Stephenson Cancer Center Seed Grant, Presbyterian Health Foundation Seed Grant, and by the Jim and Christy Everest Endowed Chair in Cancer Developmental Therapeutics (RR). MG was supported by the NIA-IRP, NIH. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH. We thank the Stephenson Cancer Center at the University of Oklahoma Health Sciences Center, Oklahoma City, OK for the use of the Functional Genomics Core which provided molecular analysis services. RR is an Oklahoma TSET Research Scholar and holds the Jim and Christy, Everest Endowed Chair in Cancer Developmental Therapeutics. NR 72 TC 1 Z9 1 U1 2 U2 2 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD OCT 4 PY 2016 VL 7 IS 40 BP 64820 EP 64835 DI 10.18632/oncotarget.11706 PG 16 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EB3QQ UT WOS:000387281000023 PM 27588488 ER PT J AU Heske, CM Mendoza, A Edessa, LD Baumgart, JT Lee, SM Trepel, J Proia, DA Neckers, L Helman, LJ AF Heske, Christine M. Mendoza, Arnulfo Edessa, Leah D. Baumgart, Joshua T. Lee, Sunmin Trepel, Jane Proia, David A. Neckers, Len Helman, Lee J. TI STA-8666, a novel HSP90 inhibitor/SN-38 drug conjugate, causes complete tumor regression in preclinical mouse models of pediatric sarcoma SO ONCOTARGET LA English DT Article DE sarcoma; SN-38; drug conjugate; topoisomerase 1 inhibitor; pediatric ID REFRACTORY SOLID TUMORS; PROTRACTED IRINOTECAN SCHEDULE; TOPOISOMERASE-I INHIBITOR; CHILDRENS ONCOLOGY GROUP; PHASE-I; EWING SARCOMA; SIGNALING PATHWAY; SN38 CONJUGATE; BREAST-CANCER; PHARMACOKINETICS AB Long-term survival in patients with metastatic, relapsed, or recurrent Ewing sarcoma and rhabdomyosarcoma is dismal. Irinotecan, a topoisomerase 1 inhibitor, has activity in these sarcomas, but due to poor bioavailability of its active metabolite (SN-38) has had limited clinical efficacy. In this study we have evaluated the efficacy and toxicity of STA-8666, a novel drug conjugate which uses an HSP90 inhibitor to facilitate intracellular, tumor-targeted delivery of the topoisomerase 1 inhibitor SN-38, thus preferentially delivering and concentrating SN-38 within tumor tissue. We present in vivo evidence from mouse xenograft models that STA-8666 results in more persistent inhibition of topoisomerase 1 and prolonged DNA damage compared to irinotecan. This translates into superior antitumor efficacy and survival in multiple aggressive models of both diseases in mouse xenografts, as well as in an irinotecan-resistant model of pediatric osteosarcoma, demonstrated by dramatic tumor shrinkage, durable remission and prolonged complete regressions following short-term treatment, compared to conventional irinotecan. Gene expression analysis performed on xenograft tumors treated with either irinotecan or STA-8666 showed that STA-8666 affected expression of DNA damage and repair genes more robustly than irinotecan. These results suggest that STA-8666 may be a promising new agent for patients with pediatric-type sarcoma. C1 [Heske, Christine M.; Mendoza, Arnulfo; Edessa, Leah D.; Baumgart, Joshua T.; Helman, Lee J.] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Lee, Sunmin; Trepel, Jane] NCI, Dev Therapeut Branch, NIH, Bethesda, MD 20892 USA. [Proia, David A.] Synta Pharmaceut, Lexington, MA USA. [Neckers, Len] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Heske, CM (reprint author), NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. EM christine.heske@nih.gov FU Intramural Research Program of NIH; National Cancer Institute; Center for Cancer Research FX This work was supported by grants from the Intramural Research Program of NIH, the National Cancer Institute, and the Center for Cancer Research. NR 52 TC 0 Z9 0 U1 4 U2 4 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD OCT 4 PY 2016 VL 7 IS 40 BP 65540 EP 65552 DI 10.18632/oncotarget.11869 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EB3QQ UT WOS:000387281000077 PM 27608846 ER PT J AU Kavarthapu, R Dufau, ML AF Kavarthapu, Raghuveer Dufau, Maria L. TI Role of EGF/ERBB1 in the transcriptional regulation of the prolactin receptor independent of estrogen and prolactin in breast cancer cells SO ONCOTARGET LA English DT Article DE prolactin receptor; EGFR/ERBB1; EGF; ER; STAT5b ID INHIBITORY-ACTION; GENERIC PROMOTER; SHORT FORMS; CROSS-TALK; LONG-FORM; ACTIVATION; EXPRESSION; VARIANTS; KINASES; ALPHA AB Prolactin receptor (PRLR) and epidermal growth factor receptor (EGFR/ERBB1) have important roles in the physiology of the human breast and in the etiology and progression of breast cancer. Our present studies in MCF-7 cells revealed that EGF induces up-regulation of PRLR via activation of EGFR signalling pathways leading to activation of estrogen receptor alpha (ER alpha). EGF treatment of MCF-7 cells cultured in absence of estradiol induced expression of PRLR that was consistent with the activation of PRLR generic promoter (hPIII). These were abolished by ER alpha antagonist and siRNA, indicating involvement of ER alpha in EGF-induced hPIII promoter activity. MEK/MAPK and PI3K/AKT pathways participate in the phosphorylation of ER alpha induced by EGF/EGFR. PI3K and MEK inhibitors abolished EGF-induced PRLR promoter activity. Increased recruitment of non-DNA bound unliganded ER alpha to Sp1 and C/EBP beta bound to their sites at hPIII induced by EGF was abrogated by ER alpha siRNA demonstrating the requisite role of phospho-ER alpha in PRLR upregulation. EGF/EGFR, independent of endogenous prolactin induced phosphorylation of STAT5b with participation of c-SRC and recruitment of STAT5b: STAT5b to a GAS site at hPIII. STAT5b interaction with ER alpha was essential for stable phospho-ER alpha recruitment to the SP1/CEBP beta complex. These studies indicate a role for paracrine EGF via EGFR independent of estrogen and prolactin in the transcriptional activation of PRLR gene expression and its contribution to high levels of PRLRs in breast cancer. These by maximizing the actions of endogenous prolactin could have a role in cancer progression and resistance to endocrine therapy. C1 [Kavarthapu, Raghuveer; Dufau, Maria L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Endocrinol, NIH, Bethesda, MD 20892 USA. RP Dufau, ML (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Endocrinol, NIH, Bethesda, MD 20892 USA. EM dufaum@mail.nih.gov FU NIH Intramural Research Program through the Eunice Kennedy Shriver National Institute for Child Health and Human Development FX This work was supported by the NIH Intramural Research Program through the Eunice Kennedy Shriver National Institute for Child Health and Human Development. NR 30 TC 0 Z9 0 U1 0 U2 0 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD OCT 4 PY 2016 VL 7 IS 40 BP 65602 EP 65613 DI 10.18632/oncotarget.11579 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EB3QQ UT WOS:000387281000082 PM 27564112 ER PT J AU Soliman, SE Kovac, P AF Soliman, Sameh E. Kovac, Pavol TI Total Synthesis of the Complete Protective Antigen of Vibrio cholerae O139 SO ANGEWANDTE CHEMIE-INTERNATIONAL EDITION LA English DT Article DE glycosylation; oligosaccharides; O-specific antigens; pathogenic bacteria; stereoselectivity ID STRUCTURAL-ANALYSIS; CONJUGATION-READY; O-PS; LIPOPOLYSACCHARIDE; OLIGOSACCHARIDES; FRAGMENTS; IMMUNITY AB The first chemical synthesis of the complete protective O-antigen of a human-disease-causing pathogenic bacterium is described. The synthesis involved a protecting-group strategy that facilitated the regioselectivity of the key transformations, stereoselective glycosylation reactions, and enabled the one-step global deprotection of the completely assembled, fully protected, phosphorylated hexasaccharide by hydrogenation/hydrogenolysis. The final amino-group-functionalized, linker-equipped antigen was obtained in a form ready for conjugation to suitable carriers, for example, proteins, to yield immunogens. C1 [Soliman, Sameh E.; Kovac, Pavol] NIDDK, LBC, Sect Carbohydrates, NIH, Bethesda, MD 20892 USA. [Soliman, Sameh E.] Univ Alexandria, Dept Chem, Fac Sci, Alexandria 21321, Egypt. RP Kovac, P (reprint author), NIDDK, LBC, Sect Carbohydrates, NIH, Bethesda, MD 20892 USA. EM kpn@helix.nih.gov FU Intramural Research Program of the National Institutes of Health (NIH); National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIH) and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). NR 23 TC 0 Z9 0 U1 9 U2 9 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1433-7851 EI 1521-3773 J9 ANGEW CHEM INT EDIT JI Angew. Chem.-Int. Edit. PD OCT 4 PY 2016 VL 55 IS 41 BP 12850 EP 12853 DI 10.1002/anie.201606116 PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA DZ2ZU UT WOS:000385713200050 PM 27623688 ER PT J AU Brisson, M Drolet, M Benard, E Kreimer, AR AF Brisson, Marc Drolet, Melanie Benard, Elodie Kreimer, Aimee R. TI Effect of HPV on cervical cancer screening in SO CANADIAN MEDICAL ASSOCIATION JOURNAL LA English DT Letter ID HUMAN-PAPILLOMAVIRUS VACCINATION; EFFICACY; FEWER C1 [Brisson, Marc] Univ Laval, Dept Med Sociale & Prevent, Quebec City, PQ, Canada. [Drolet, Melanie; Benard, Elodie] Univ Laval, CHU Quebec, Ctr Rech, Axe Sante Populat & Prat Optimales Sante, Quebec City, PQ, Canada. [Kreimer, Aimee R.] NCI, Infect & Immunoepidemiol, Rockville, MD USA. RP Brisson, M (reprint author), Univ Laval, Dept Med Sociale & Prevent, Quebec City, PQ, Canada. NR 7 TC 0 Z9 0 U1 1 U2 1 PU CMA-CANADIAN MEDICAL ASSOC PI OTTAWA PA 1867 ALTA VISTA DR, OTTAWA, ONTARIO K1G 5W8, CANADA SN 0820-3946 EI 1488-2329 J9 CAN MED ASSOC J JI Can. Med. Assoc. J. PD OCT 4 PY 2016 VL 188 IS 14 BP 1035 EP 1035 DI 10.1503/cmaj.1150121 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA DZ2DL UT WOS:000385652400022 PM 27698024 ER PT J AU Kim, SYH Lemmens, T AF Kim, Scott Y. H. Lemmens, Trudo TI Should assisted dying for psychiatric disorders be legalized in Canada? SO CANADIAN MEDICAL ASSOCIATION JOURNAL LA English DT Editorial Material ID NETHERLANDS; EUTHANASIA; CAPACITY; CARE C1 [Kim, Scott Y. H.] NIH, Dept Bioeth, Bldg 10, Bethesda, MD 20892 USA. [Lemmens, Trudo] Univ Toronto, Fac Law, Toronto, ON, Canada. [Lemmens, Trudo] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. RP Kim, SYH (reprint author), NIH, Dept Bioeth, Bldg 10, Bethesda, MD 20892 USA. EM scott.kim@nih.gov NR 9 TC 2 Z9 2 U1 6 U2 6 PU CMA-CANADIAN MEDICAL ASSOC PI OTTAWA PA 1867 ALTA VISTA DR, OTTAWA, ONTARIO K1G 5W8, CANADA SN 0820-3946 EI 1488-2329 J9 CAN MED ASSOC J JI Can. Med. Assoc. J. PD OCT 4 PY 2016 VL 188 IS 14 BP E337 EP E339 DI 10.1503/cmaj.160365 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA DZ2DL UT WOS:000385652400005 PM 27328688 ER PT J AU Vermeire, J Roesch, F Sauter, D Rua, R Hotter, D Van Nuffel, A Vanderstraeten, H Naessens, E Iannucci, V Landi, A Witkowski, W Baeyens, A Kirchhoff, F Verhasselt, B AF Vermeire, Jolien Roesch, Ferdinand Sauter, Daniel Rua, Rejane Hotter, Dominik Van Nuffel, Anouk Vanderstraeten, Hanne Naessens, Evelien Iannucci, Veronica Landi, Alessia Witkowski, Wojciech Baeyens, Ann Kirchhoff, Frank Verhasselt, Bruno TI HIV Triggers a cGAS-Dependent, Vpu- and Vpr-Regulated Type I Interferon Response in CD4(+) T Cells SO CELL REPORTS LA English DT Article ID NF-KAPPA-B; IMMUNODEFICIENCY-VIRUS TYPE-1; INNATE IMMUNE-RESPONSE; DENDRITIC CELLS; DISEASE PROGRESSION; PROTEIN-R; INFECTION; SENSOR; REPLICATION; EXPRESSION AB Several pattern-recognition receptors sense HIV-1 replication products and induce type I interferon (IFN-I) production under specific experimental conditions. However, it is thought that viral sensing and IFN induction are virtually absent in the main target cells of HIV-1 in vivo. Here, we show that activated CD4(+) T cells sense HIV-1 infection through the cytosolic DNA sensor cGAS and mount a bioactive IFN-I response. Efficient induction of IFN-I by HIV-1 infection requires proviral integration and is regulated by newly expressed viral accessory proteins: Vpr potentiates, while Vpu suppresses cGAS-dependent IFN-I induction. Furthermore, Vpr also amplifies innate sensing of HIV-1 infection in Vpx-treated dendritic cells. Our results identify cGAS as mediator of an IFN-I response to HIV-1 infection in CD4(+) T cells and demonstrate that this response is modulated by the viral accessory proteins Vpr and Vpu. Thus, viral innate immune evasion is incomplete in the main target cells of HIV-1. C1 [Vermeire, Jolien; Van Nuffel, Anouk; Vanderstraeten, Hanne; Naessens, Evelien; Iannucci, Veronica; Landi, Alessia; Witkowski, Wojciech; Baeyens, Ann; Verhasselt, Bruno] Univ Ghent, Dept Clin Chem Microbiol & Immunol, B-9000 Ghent, Belgium. [Roesch, Ferdinand; Rua, Rejane] Inst Pasteur, Unite Virus & Immunite, Dept Virol, F-75015 Paris, France. [Sauter, Daniel; Hotter, Dominik; Kirchhoff, Frank] Univ Ulm, Inst Mol Virol, Med Ctr, D-89081 Ulm, Germany. [Vermeire, Jolien; Roesch, Ferdinand] Fred Hutchinson Canc Res Ctr, Div Human Biol, Seattle, WA 98109 USA. [Rua, Rejane] NINDS, NIH, Bethesda, MD 20892 USA. RP Verhasselt, B (reprint author), Univ Ghent, Dept Clin Chem Microbiol & Immunol, B-9000 Ghent, Belgium. EM bruno.verhasselt@ugent.be FU SBO CellCoVir grant from the agency for Innovation by Science and Technology (IWT) (Flanders, Belgium); HIV-STOP Interuniversity Attraction Poles program of Belgian Science Policy; European Union [FP7 Health-2007-2.3.2-1]; Ghent University [BOF11/GOA/013]; HIVERA IRIFCURE; Research Foundation Flanders (FWO); BOF program Ghent University; ANRS; SIDACTION; AREVA Foundation; FP7 program "HIT HIDDEN HIV" [Health-F3-2012-305762]; Vaccine Research Institute [ANR-10-LABX-77]; Institut Pasteur; International Graduate School in Molecular Medicine, Ulm; Deutsche Forschungsgemeinschaft; FP7 "HIT HIDDEN HIV"; ERC FX This work was supported by an SBO CellCoVir grant from the agency for Innovation by Science and Technology (IWT) (Flanders, Belgium); the HIV-STOP Interuniversity Attraction Poles program of Belgian Science Policy; the European Union FP7 Health-2007-2.3.2-1 Collaborative Project iNEF; Ghent University grant BOF11/GOA/013; HIVERA IRIFCURE; and grants from the Research Foundation Flanders (FWO) to B.V. J.V., A.L., and W.W. are PhD fellows, and B.V. is a Senior Clinical Investigator of the FWO. V.I. was supported by the BOF program Ghent University. F.R. and R.R. are PhD fellows of Universite Denis Diderot and were supported by grants from ANRS, SIDACTION, AREVA Foundation, FP7 program "HIT HIDDEN HIV" (Health-F3-2012-305762), the Vaccine Research Institute (ANR-10-LABX-77), and Institut Pasteur. D.S. and D.H. were supported by the International Graduate School in Molecular Medicine, Ulm. F.K. was supported by the Deutsche Forschungsgemeinschaft, FP7 "HIT HIDDEN HIV," and an ERC advanced grant (Anti-Virome). The funders had no role in study design, data collection and analysis, the decision to publish, or preparation of the manuscript. NR 57 TC 1 Z9 1 U1 2 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD OCT 4 PY 2016 VL 17 IS 2 BP 413 EP 424 DI 10.1016/j.celrep.2016.09.023 PG 12 WC Cell Biology SC Cell Biology GA DZ4SS UT WOS:000385850700010 PM 27705790 ER PT J AU Shintaku, J Peterson, JM Talbert, EE Gu, JM Ladner, KJ Williams, DR Mousavi, K Wang, RN Sartorelli, V Guttridge, DC AF Shintaku, Jonathan Peterson, Jennifer M. Talbert, Erin E. Gu, Jin-Mo Ladner, Katherine J. Williams, Dustin R. Mousavi, Kambiz Wang, Ruoning Sartorelli, Vittorio Guttridge, Denis C. TI MyoD Regulates Skeletal Muscle Oxidative Metabolism Cooperatively with Alternative NF-kappa B SO CELL REPORTS LA English DT Article ID PGC-1 COACTIVATORS; GENE-EXPRESSION; MYOGENIC CELLS; MESSENGER-RNA; DIFFERENTIATION; BINDING; RHABDOMYOSARCOMAS; ACTIVATION; DISEASE; FIBERS AB MyoD is a key regulator of skeletal myogenesis that directs contractile protein synthesis, but whether this transcription factor also regulates skeletal muscle metabolism has not been explored. In a genome-wide ChIP-seq analysis of skeletal muscle cells, we unexpectedly observed that MyoD directly binds to numerous metabolic genes, including those associated with mitochondrial biogenesis, fatty acid oxidation, and the electron transport chain. Results in cultured cells and adult skeletal muscle confirmed that MyoD regulates oxidative metabolism through multiple transcriptional targets, including PGC-1 beta, a master regulator of mitochondrial biogenesis. We find that PGC-1 beta expression is cooperatively regulated by MyoD and the alternative NF-kappa B signaling pathway. Bioinformatics evidence suggests that this cooperativity between MyoD and NF-kappa B extends to other metabolic genes as well. Together, these data identify MyoD as a regulator of the metabolic capacity of mature skeletal muscle to ensure that sufficient energy is available to support muscle contraction. C1 [Shintaku, Jonathan; Peterson, Jennifer M.; Talbert, Erin E.; Gu, Jin-Mo; Ladner, Katherine J.; Williams, Dustin R.; Guttridge, Denis C.] Ohio State Univ, Dept Canc Biol & Genet, Columbus, OH 43210 USA. [Shintaku, Jonathan; Peterson, Jennifer M.; Talbert, Erin E.; Gu, Jin-Mo; Ladner, Katherine J.; Williams, Dustin R.; Guttridge, Denis C.] Ohio State Univ, Ctr Muscle Hlth & Neuromuscular Disorders, Columbus, OH 43210 USA. [Shintaku, Jonathan; Gu, Jin-Mo] Ohio State Univ, Mol Cellular & Dev Biol Grad Program, Columbus, OH 43210 USA. [Mousavi, Kambiz; Sartorelli, Vittorio] NIAMSD, Lab Muscle Stem Cells & Gene Regulat, Bethesda, MD 20892 USA. [Wang, Ruoning] Nationwide Childrens Hosp, Res Inst, Ctr Childhood Canc & Blood Dis, Columbus, OH 43205 USA. RP Guttridge, DC (reprint author), Ohio State Univ, Dept Canc Biol & Genet, Columbus, OH 43210 USA.; Guttridge, DC (reprint author), Ohio State Univ, Ctr Muscle Hlth & Neuromuscular Disorders, Columbus, OH 43210 USA. EM denis.guttridge@osumc.edu FU Intramural Research Program of NIAMS at the NIH; NIH [R01 AR052787] FX We are grateful to N. Weisleder and J. Alloush for sharing their expertise on muscle electroporation, S. Sharma for his contributions to our bioinformatics analyses, and T. Vojt for generating our graphic illustrations. We would also like to thank members of the D.C.G. laboratory who provided support and critical discussions throughout this study. This work was supported in part by the Intramural Research Program of NIAMS at the NIH to V.S. as well as by NIH grant R01 AR052787 to D.C.G. NR 41 TC 0 Z9 0 U1 6 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD OCT 4 PY 2016 VL 17 IS 2 BP 514 EP 526 DI 10.1016/j.celrep.2016.09.010 PG 13 WC Cell Biology SC Cell Biology GA DZ4SS UT WOS:000385850700018 PM 27705798 ER PT J AU Lee, JJ Pedley, A Hoffmann, U Massaro, JM Fox, CS AF Lee, Jane J. Pedley, Alison Hoffmann, Udo Massaro, Joseph M. Fox, Caroline S. TI Association of Changes in Abdominal Fat Quantity and Quality With Incident Cardiovascular Disease Risk Factors SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE cardiovascular disease; computed tomography; epidemiology; fat attenuation; subcutaneous adipose tissue; visceral adipose tissue ID SUBCUTANEOUS ADIPOSE-TISSUE; INTRAABDOMINAL VISCERAL FAT; CARDIOMETABOLIC RISK; BLOOD-PRESSURE; LONGITUDINAL CHANGES; INSULIN SENSITIVITY; JAPANESE-AMERICANS; METABOLIC SYNDROME; HITACHI HEALTH; OBESITY AB BACKGROUND Subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) are associated with adverse cardiometabolic risk profiles. OBJECTIVES This study explored the degree to which changes in abdominal fat quantity and quality are associated with changes in cardiovascular disease (CVD) risk factors. METHODS Study participants (n = 1,106; 44.1% women; mean baseline age 45.1 years) were drawn from the Framingham Heart Study Third Generation cohort who participated in the computed tomography (CT) substudy Exams 1 and 2. Participants were followed for 6.1 years on average. Abdominal adipose tissue volume in cm(3) and attenuation in Hounsfield units (HU) were determined by CT-acquired abdominal scans. RESULTS The mean fat volume change was an increase of 602 cm(3) for SAT and an increase of 703 cm(3) for VAT; the mean fat attenuation change was a decrease of 5.5 HU for SAT and an increase of 0.07 HU for VAT. An increase in fat volume and decrease in fat attenuation were associated with adverse changes in CVD risk factors. An additional 500 cm(3) increase in fat volume was associated with incident hypertension (odds ratio [OR]: 1.21 for SAT; OR: 1.30 for VAT), hypertriglyceridemia (OR: 1.15 for SAT; OR: 1.56 for VAT), and metabolic syndrome (OR: 1.43 for SAT; OR: 1.82 for VAT; all p < 0.05). Similar trends were observed for each additional 5 HU decrease in abdominal adipose tissue attenuation. Most associations remained significant even after further accounting for body mass index change, waist circumference change, or respective abdominal adipose tissue volumes. CONCLUSIONS Increasing accumulation of fat quantity and decreasing fat attenuation are associated with worsening of CVD risk factors beyond the associations with generalized adiposity, central adiposity, or respective adipose tissue volumes. Published by Elsevier on behalf of the American College of Cardiology Foundation. C1 [Lee, Jane J.; Pedley, Alison; Fox, Caroline S.] NHLBI, Div Intramural Res, Framingham Heart Study, Framingham, MA USA. [Lee, Jane J.; Pedley, Alison; Fox, Caroline S.] NHLBI, Populat Studies Branch, Framingham, MA USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Massaro, Joseph M.] Boston Univ, Dept Biostat, Boston, MA 02215 USA. [Fox, Caroline S.] Brigham & Womens Hosp, Dept Endocrinol, 75 Francis St, Boston, MA 02115 USA. [Fox, Caroline S.] Harvard Med Sch, Boston, MA USA. RP Fox, CS (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov FU National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195] FX This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (contract N01-HC-25195). The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; National Institutes of Health; or the U.S. Department of Health and Human Services. Drs. Pedley and Fox are employees of Merck & Company, Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 45 TC 2 Z9 2 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT 4 PY 2016 VL 68 IS 14 BP 1509 EP 1521 DI 10.1016/j.jacc.2016.06.067 PG 13 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DZ5XC UT WOS:000385934400003 PM 27687192 ER PT J AU Jain, CV Jessmon, P Kilburn, BA Jodar, M Sendler, E Krawetz, SA Armant, DR AF Jain, Chandni V. Jessmon, Philip Kilburn, Brian A. Jodar, Meritxell Sendler, Edward Krawetz, Stephen A. Armant, D. Randall TI Regulation of HBEGF by Micro-RNA for Survival of Developing Human Trophoblast Cells SO PLOS ONE LA English DT Article ID GROWTH-FACTOR; PROTEIN-SYNTHESIS; POSTTRANSCRIPTIONAL REGULATION; MESSENGER-RNA; GENE-EXPRESSION; BINDING; PREECLAMPSIA; PHOSPHORYLATION; TRANSLATION; BIOGENESIS AB Introduction The growth factor HBEGF is upregulated post-transcriptionally in the low O-2 environment of the human placenta during the first 10 weeks of pregnancy. We have examined the possible roles of HBEGF turnover and micro-RNA (miRNA) in its regulation by O-2 in human first trimester trophoblast. Methods HTR-8/SVneo trophoblast cells were cultured at 2% or 20% O-2. The cells were transfected with a dual luciferase reporter construct (psiCHECK-2) containing no insert (control), the HBEGF 3' untranslated region (3' UTR), or sub-regions of the 3' UTR, as well as with siRNA for DGCR8. RNA was extracted from trophoblast cells cultured at 2% O-2 for 0-4 h for next-generation sequencing. HBEGF was quantified by ELISA. HBEGF, DGCR8, and beta-actin were examined by western blotting. Results Protein turnover studies, using 10 mu g/ml cyclohexamide, 1 mu g/ml lactocystin, or 100 mu g/ml MG132, demonstrated faster HBEGF degradation at 20% O-2 than 2% O-2, mediated by the proteasome. However, proteasome inhibition failed to initiate HBEGF accumulation at 20% O-2. Reporter assays, comparing to empty vector, demonstrated that the intact HBEGF 3' UTR inhibited expression (0.26), while fragments containing only its flanking regions increased reporter activity (3.15; 3.43). No differential expression of miRNAs was found in trophoblast cells cultured at 2% and 20% O-2. Nevertheless, HBEGF upregulation at 2% O-2 was blocked when the miRNA-processing protein DGCR8 was silenced, suggesting a role for miRNA. Conclusion Our findings suggest involvement of flanking regions of the 3'UTR in activating HBEGF protein synthesis in response to 2% O-2, possibly through a miRNA-mediated mechanism. C1 [Jain, Chandni V.; Jessmon, Philip] Wayne State Univ, Sch Med, Dept Physiol, Detroit, MI 48201 USA. [Jain, Chandni V.; Kilburn, Brian A.; Jodar, Meritxell; Sendler, Edward; Krawetz, Stephen A.; Armant, D. Randall] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Jessmon, Philip; Armant, D. Randall] Wayne State Univ, Sch Med, Dept Anat & Cell Biol, Detroit, MI 48201 USA. [Jodar, Meritxell; Sendler, Edward; Krawetz, Stephen A.] Wayne State Univ, Sch Med, Dept Ctr Mol Med & Genet, Detroit, MI USA. [Armant, D. Randall] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Armant, DR (reprint author), Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA.; Armant, DR (reprint author), Wayne State Univ, Sch Med, Dept Anat & Cell Biol, Detroit, MI 48201 USA.; Armant, DR (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, US Dept HHS, Bethesda, MD 20892 USA. EM d.armant@wayne.edu NR 70 TC 0 Z9 0 U1 3 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 4 PY 2016 VL 11 IS 10 AR e0163913 DI 10.1371/journal.pone.0163913 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ2UK UT WOS:000385696900031 PM 27701455 ER PT J AU Yi, JC Samelson, LE AF Yi, Jason C. Samelson, Lawrence E. TI Microvilli set the stage for T-cell activation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID RECEPTOR; SYNAPSE; ACTIN; FLOW C1 [Yi, Jason C.; Samelson, Lawrence E.] NCI, Lab Cellular & Mol Biol, Ctr Canc Res, Bethesda, MD 20892 USA. RP Samelson, LE (reprint author), NCI, Lab Cellular & Mol Biol, Ctr Canc Res, Bethesda, MD 20892 USA. EM samelsonl@helix.nih.gov NR 12 TC 0 Z9 0 U1 2 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 4 PY 2016 VL 113 IS 40 BP 11061 EP 11062 DI 10.1073/pnas.1613832113 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DX6XI UT WOS:000384528900029 PM 27663734 ER PT J AU Crittenden, JR Tillberg, PW Riad, MH Shima, Y Gerfen, CR Curry, J Housman, DE Nelson, SB Boyden, ES Graybiel, AM AF Crittenden, Jill R. Tillberg, Paul W. Riad, Michael H. Shima, Yasuyuki Gerfen, Charles R. Curry, Jeffrey Housman, David E. Nelson, Sacha B. Boyden, Edward S. Graybiel, Ann M. TI Striosome-dendron bouquets highlight a unique striatonigral circuit targeting dopamine-containing neurons SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE dopamine; striosome; striatum; expansion microscopy ID SUBSTANTIA-NIGRA; TRANSGENIC MICE; COMPARTMENTAL ORGANIZATION; CHOLINERGIC INTERNEURONS; CRE-RECOMBINASE; BASAL GANGLIA; BRAIN-STEM; IN-VIVO; STRIATUM; RECEPTORS AB The dopamine systems of the brain powerfully influence movement and motivation. We demonstrate that striatonigral fibers originating in striosomes form highly unusual bouquet-like arborizations that target bundles of ventrally extending dopamine-containing dendrites and clusters of their parent nigral cell bodies. Retrograde tracing showed that these clustered cell bodies in turn project to the striatum as part of the classic nigrostriatal pathway. Thus, these striosome-dendron formations, here termed "striosome-dendron bouquets," likely represent subsystems with the nigro-striato-nigral loop that are affected in human disorders including Parkinson's disease. Within the bouquets, expansion microscopy resolved many individual striosomal fibers tightly intertwined with the dopamine-containing dendrites and also with afferents labeled by glutamatergic, GABAergic, and cholinergic markers and markers for astrocytic cells and fibers and connexin 43 puncta. We suggest that the striosome-dendron bouquets form specialized integrative units within the dopamine-containing nigral system. Given evidence that striosomes receive input from cortical regions related to the control of mood and motivation and that they link functionally to reinforcement and decision-making, the striosome-dendron bouquets could be critical to dopamine-related function in health and disease. C1 [Crittenden, Jill R.; Riad, Michael H.; Curry, Jeffrey; Boyden, Edward S.; Graybiel, Ann M.] MIT, McGovern Inst Brain Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Crittenden, Jill R.; Riad, Michael H.; Curry, Jeffrey; Boyden, Edward S.; Graybiel, Ann M.] MIT, Dept Brain & Cognit Sci, E25-618, Cambridge, MA 02139 USA. [Crittenden, Jill R.; Housman, David E.] MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Tillberg, Paul W.; Boyden, Edward S.] MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA. [Tillberg, Paul W.; Boyden, Edward S.] MIT, Media Lab, Cambridge, MA 02139 USA. [Shima, Yasuyuki; Nelson, Sacha B.] Brandeis Univ, Dept Biol, Waltham, MA 02453 USA. [Shima, Yasuyuki; Nelson, Sacha B.] Brandeis Univ, Natl Ctr Behav Genom, Waltham, MA 02453 USA. [Gerfen, Charles R.] NIMH, Lab Syst Neurosci, Bethesda, MD 20814 USA. [Boyden, Edward S.] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. RP Graybiel, AM (reprint author), MIT, McGovern Inst Brain Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Graybiel, AM (reprint author), MIT, Dept Brain & Cognit Sci, E25-618, Cambridge, MA 02139 USA. EM graybiel@mit.edu FU William N. and Bernice E. Bumpus Foundation Grant Rapid Response Discovery Award Pilot [2013.1]; Saks Kavanaugh Foundation; CHDI Foundation [A-5552]; Collaborative Center for X- linked Dystonia Parkinsonism at Massachusetts General Hospital; McGovern Institute for Brain Research; MIT Media Laboratory; Open Philanthropy Project; New York StemCell Foundation-Robertson Investigator Award; Hertz fellowship FX We thank Dr. Mark Harnett for helpful discussions; Dr. Yasuo Kubota for text management; and Dr. Dan Hu and Anne C. Kim for technical assistance. This work was supported by William N. and Bernice E. Bumpus Foundation Grant Rapid Response Discovery Award Pilot: 2013.1 (to A.M.G.), the Saks Kavanaugh Foundation (A.M.G.), CHDI Foundation Grant A-5552 (to A.M.G.), the Collaborative Center for X- linked Dystonia Parkinsonism at Massachusetts General Hospital (J.R.C. and A.M.G.), the McGovern Institute for Brain Research (A.M.G. and E.S.B.), MIT Media Laboratory (E.S.B.), and the Open Philanthropy Project (E.S.B.). E.S.B. is the recipient of a New York StemCell Foundation-Robertson Investigator Award, and P.T. is the recipient of a Hertz fellowship. NR 58 TC 3 Z9 3 U1 11 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 4 PY 2016 VL 113 IS 40 BP 11318 EP 11323 DI 10.1073/pnas.1613337113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DX6XI UT WOS:000384528900076 PM 27647894 ER PT J AU Hudson, KL Lauer, MS Collins, FS AF Hudson, Kathy L. Lauer, Michael S. Collins, Francis S. TI Toward a New Era of Trust and Transparency in Clinical Trials SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Hudson, Kathy L.; Lauer, Michael S.; Collins, Francis S.] NIH, Bldg 1,1 Ctr Dr,Room 103, Bethesda, MD 20814 USA. RP Hudson, KL (reprint author), NIH, Bldg 1,1 Ctr Dr,Room 103, Bethesda, MD 20814 USA. EM Kathy.Hudson@nih.gov NR 7 TC 9 Z9 9 U1 4 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD OCT 4 PY 2016 VL 316 IS 13 BP 1353 EP 1354 DI 10.1001/jama.2016.14668 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DX7TC UT WOS:000384591300010 PM 27636028 ER PT J AU Amundsen, CL Richter, HE Menefee, SA Komesu, YM Arya, LA Gregory, T Myers, DL Zyczynski, HM Vasavada, S Nolen, TL Wallace, D Meikle, SF AF Amundsen, Cindy L. Richter, Holly E. Menefee, Shawn A. Komesu, Yuko M. Arya, Lily A. Gregory, Thomas Myers, Deborah L. Zyczynski, Halina M. Vasavada, Sandip Nolen, Tracy L. Wallace, Dennis Meikle, Susan F. CA Pelvic Floor Disorders Network TI OnabotulinumtoxinA vs Sacral Neuromodulation on Refractory Urgency Urinary Incontinence in Women A Randomized Clinical Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID BOTULINUM-TOXIN-A; IDIOPATHIC DETRUSOR OVERACTIVITY; NERVE-STIMULATION; ADVERSE EVENTS; BLADDER; QUESTIONNAIRE; IMPLANTATION; VALIDATION; INJECTIONS; EFFICACY AB IMPORTANCE Women with refractory urgency urinary incontinence are treated with sacral neuromodulation and onabotulinumtoxinA with limited comparative information. OBJECTIVE To assess whether onabotulinumtoxinA is superior to sacral neuromodulation in controlling refractory episodes of urgency urinary incontinence. DESIGN, SETTING, AND PARTICIPANTS Multicenter open-label randomized trial (February 2012-January 2015) at 9 US medical centers involving 381 women with refractory urgency urinary incontinence. INTERVENTIONS Cystoscopic intradetrusor injection of 200 U of onabotulinumtoxinA (n = 192) or sacral neuromodulation (n = 189). MAIN OUTCOMES AND MEASURES Primary outcome, change from baseline mean number of daily urgency urinary incontinence episodes over 6 months, was measured with monthly 3-day diaries. Secondary outcomes included change from baseline in urinary symptom scores in the Overactive Bladder Questionnaire Short Form (SF); range, 0-100, higher scores indicating worse symptoms; Overactive Bladder Satisfaction questionnaire; range, 0-100; includes 5 subscales, higher scores indicating better satisfaction; and adverse events. RESULTS Of the 364 women (mean [SD] age, 63.0 [11.6] years) in the intention-to-treat population, 190 women in the onabotulinumtoxinA group had a greater reduction in 6-month mean number of episodes of urgency incontinence per day than did the 174 in the sacral neuromodulation group (-3.9 vs -3.3 episodes per day; mean difference, 0.63; 95% CI, 0.13 to 1.14; P =.01). Participants treated with onabotulinumtoxinA showed greater improvement in the Overactive Bladder Questionnaire SF for symptom bother (-46.7 vs -38.6; mean difference, 8.1; 95% CI, 3.0 to 13.3; P =.002); treatment satisfaction (67.7 vs 59.8; mean difference, 7.8; 95% CI, 1.6 to 14.1; P =.01) and treatment endorsement (78.1 vs 67.6; mean difference; 10.4, 95% CI, 4.3 to 16.5; P <.001) than treatment with sacral neuromodulation. There were no differences in convenience (67.6 vs 70.2; mean difference, -2.5; 95% CI, -8.1 to 3.0; P =.36), adverse effects (88.4 vs 85.1; mean difference, 3.3; 95% CI, -1.9 to 8.5; P =.22), and treatment preference (92.% vs 89%; risk difference, -3%; 95% CI, -16% to 10%; P =.49). Urinary tract infections were more frequent in the onabotulinumtoxinA group (35% vs 11%; risk difference, -23%; 95% CI, -33% to -13%; P <.001). The need for self-catheterization was 8% and 2% at 1 and 6 months in the onabotulinumtoxinA group. Neuromodulation device revisions and removals occurred in 3%. CONCLUSIONS AND RELEVANCE Amongwomen with refractory urgency urinary incontinence, treatment with onabotulinumtoxinA compared with sacral neuromodulation resulted in a small daily improvement in episodes that although statistically significant is of uncertain clinical importance. In addition, it resulted in a higher risk of urinary tract infections and need for transient self-catheterizations. C1 [Amundsen, Cindy L.] Duke Univ, Dept Obstet & Gynecol, 5324 McFarland Dr,Ste 310, Durham, NC 27707 USA. [Richter, Holly E.] Univ Alabama Birmingham, Dept Obstet & Gynecol, Birmingham, AL 35294 USA. [Menefee, Shawn A.] Kaiser Permanente San Diego, Dept Obstet & Gynecol, San Diego, CA USA. [Komesu, Yuko M.] Univ New Mexico, Dept Obstet & Gynecol, Albuquerque, NM 87131 USA. [Arya, Lily A.] Univ Penn, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA. [Gregory, Thomas] Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Portland, OR 97201 USA. [Myers, Deborah L.] Brown Univ, Dept Obstet & Gynecol, Providence, RI 02912 USA. [Zyczynski, Halina M.] Univ Pittsburgh, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA. [Vasavada, Sandip] Cleveland Clin, Dept Urol, Cleveland, OH 44106 USA. [Nolen, Tracy L.; Wallace, Dennis] RTI Int, Social Stat & Environm Sci, Res Triangle Pk, NC USA. [Meikle, Susan F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Amundsen, CL (reprint author), Duke Univ, Dept Obstet & Gynecol, 5324 McFarland Dr,Ste 310, Durham, NC 27707 USA. EM cindy.amundsen@duke.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; NIH Office of Research on Women's Health at National Institutes of Health 3316 [U01 HD41249U10, HD41261U10 HD41267, U10 HD54215U10-HD41261-11, U10-HD069013, U10-HD054214-06, U10-HD054215-06, U10-HD041267-12, U10-HD069025-01, U10-HD069010, U10-HD054136, U10-HD054241, U10-HD041250-11] FX This work was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the NIH Office of Research on Women's Health at National Institutes of Health 3316 (U01 HD41249U10, HD41261U10 HD41267, U10 HD54215U10-HD41261-11, U10-HD069013, U10-HD054214-06, U10-HD054215-06, U10-HD041267-12, U10-HD069025-01, U10-HD069010, U10-HD054136, U10-HD054241, and U10-HD041250-11). NR 23 TC 5 Z9 6 U1 3 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD OCT 4 PY 2016 VL 316 IS 13 BP 1366 EP 1374 DI 10.1001/jama.2016.14617 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA DX7TC UT WOS:000384591300017 PM 27701661 ER PT J AU Xu, L Nussinov, R Ma, BY AF Xu, Liang Nussinov, Ruth Ma, Buyong TI Coupling of the non-amyloid-component (NAC) domain and the KTK(E/Q)GV repeats stabilize the alpha-synuclein fibrils SO EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article DE Alpha-synuclein; Parkinson's disease; Fibril structure; Molecular dynamics; Drug design ID SOLID-STATE NMR; ATOMIC-FORCE MICROSCOPY; SIDE-CHAIN LENGTH; PARKINSONS-DISEASE; MOLECULAR-DYNAMICS; BETA-HAIRPIN; SECONDARY STRUCTURE; MUTATION; AGGREGATION; OLIGOMERS AB The aggregates of alpha-synuclein (alpha S) are a major pathological hallmark of Parkinson's disease (PD) making their structure-function relationship important for rational drug design. Yet, the atomic structure of the aS aggregates is unavailable, making it difficult to understand the underlying aggregation mechanism. In this work, based on available experimental data, we examined plausible molecular structures of alpha S(20/30 110) fibrils for the first time by employing computational approaches. The optimized structure was used to investigate possible interactions with aggregation inhibitors. Our structural models characterize the essential properties of the five-layered fold of the alpha S fibril. The distribution of the 3-strands and the topology of the five beta-strands in the relatively stable models are in good agreement with experimental values. In particular, we find that the KTK(E/Q)GV repeat motifs significantly stabilize the aS fibrils. The charged residues within each repeat prefer exposure to the solvent in order to further stabilize the inter layered interactions by salt-bridges. The organization of the repeat K(58)T(59)K(60)E(61)Q(62)V(63) between the beta 2 and beta 3 layers significantly affects the stability of the non-amyloid-component (NAC) domain. The coupling between the NAC domain and the KTKEGV repeats indicates that both regions can be potential binding sites for inhibitor design. The distinct binding modes of chemical agents that alter aS aggregation highlight the potential of our models in inhibitor design. (C) 2016 Elsevier Masson SAS. All rights reserved. C1 [Xu, Liang] Dalian Univ Technol, Sch Chem, Dalian 116024, Peoples R China. [Nussinov, Ruth] Tel Aviv Univ, Sackler Inst Mol Med, Dept Human Genet & Mol Med, Sackler Sch Med, IL-69978 Tel Aviv, Israel. [Nussinov, Ruth; Ma, Buyong] NCI, Basic Sci Program, Leidos Biomed Res Inc, Canc & Inflammat Program, Frederick, MD 21702 USA. RP Ma, BY (reprint author), NCI, Basic Sci Program, Leidos Biomed Res Inc, Canc & Inflammat Program, Frederick, MD 21702 USA. EM mabuyong@mail.nih.gov RI Ma, Buyong/F-9491-2011 OI Ma, Buyong/0000-0002-7383-719X FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; China Scholarship Council [CSC201306065001] FX This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract number HHSN261200800001E. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. L. Xu also thanks financial support from China Scholarship Council (CSC201306065001). MD simulations were performed at the high-performance computational facilities of the Biowulf PC/Linux cluster at the NIH (http://biowulf.nih.gov/). NR 65 TC 1 Z9 1 U1 16 U2 16 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0223-5234 EI 1768-3254 J9 EUR J MED CHEM JI Eur. J. Med. Chem. PD OCT 4 PY 2016 VL 121 BP 841 EP 850 DI 10.1016/j.ejmech.2016.01.044 PG 10 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA DU5RT UT WOS:000382269700069 PM 26873872 ER PT J AU Wang, ZL Cabrera, M Yang, JY Yuan, LL Gupta, B Liang, XY Kemirembe, K Shrestha, S Brashear, A Li, XL Porcella, SF Miao, J Yang, ZQ Su, XZ Cui, LW AF Wang, Zenglei Cabrera, Mynthia Yang, Jingyun Yuan, Lili Gupta, Bhavna Liang, Xiaoying Kemirembe, Karen Shrestha, Sony Brashear, Awtum Li, Xiaolian Porcella, Stephen F. Miao, Jun Yang, Zhaoqing Su, Xin-zhuan Cui, Liwang TI Genome-wide association analysis identifies genetic loci associated with resistance to multiple antimalarials in Plasmodium falciparum from China-Myanmar border SO SCIENTIFIC REPORTS LA English DT Article ID ARTEMISININ RESISTANCE; IN-VITRO; DIHYDROARTEMISININ-PIPERAQUINE; DRUG-RESISTANCE; POSITIVE SELECTION; MALARIA PARASITES; CANDIDATE GENES; K13 PROPELLER; PFMDR1 GENE; CAMBODIA AB Drug resistance has emerged as one of the greatest challenges facing malaria control. The recent emergence of resistance to artemisinin (ART) and its partner drugs in ART-based combination therapies (ACT) is threatening the efficacy of this front-line regimen for treating Plasmodium falciparum parasites. Thus, an understanding of the molecular mechanisms that underlie the resistance to ART and the partner drugs has become a high priority for resistance containment and malaria management. Using genome-wide association studies, we investigated the associations of genome-wide single nucleotide polymorphisms with in vitro sensitivities to 10 commonly used antimalarial drugs in 94 P. falciparum isolates from the China-Myanmar border area, a region with the longest history of ART usage. We identified several loci associated with various drugs, including those containing pfcrt and pfdhfr. Of particular interest is a locus on chromosome 10 containing the autophagy-related protein 18 (ATG18) associated with decreased sensitivities to dihydroartemisinin, artemether and piperaquine - an ACT partner drug in this area. ATG18 is a phosphatidylinositol-3-phosphate binding protein essential for autophagy and recently identified as a potential ART target. Further investigations on the ATG18 and genes at the chromosome 10 locus may provide an important lead for a connection between ART resistance and autophagy. C1 [Wang, Zenglei; Cabrera, Mynthia; Gupta, Bhavna; Liang, Xiaoying; Kemirembe, Karen; Shrestha, Sony; Brashear, Awtum; Li, Xiaolian; Miao, Jun; Cui, Liwang] Penn State Univ, Dept Entomol, University Pk, PA 16802 USA. [Yang, Jingyun] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA. [Yang, Jingyun] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. [Yuan, Lili; Yang, Zhaoqing] Kunming Med Univ, Dept Pathogen Biol & Immunol, Kunming 650500, Yunnan Province, Peoples R China. [Porcella, Stephen F.] NIAID, Genom Unit, Res Technol Sect, Rocky Mt Labs,NIH, 904 South 4th St, Hamilton, MT 59840 USA. [Su, Xin-zhuan] NIAID, Lab Malaria & Vector Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Cui, LW (reprint author), Penn State Univ, Dept Entomol, University Pk, PA 16802 USA. EM luc2@psu.edu OI Su, Xinzhuan/0000-0003-3246-3248 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; National Science Foundation of China [U1202226, 31260508]; [U19 AI089672] FX The authors thank Dr. Aswathy Sebastian (Bioinformatics Consulting Center, Pennsylvania State University), Dr. Timothy R. Brick (Human Development and Family Studies, Pennsylvania State University), Dr. Xiang Zhou (Department of Biostatistics, University of Michigan) and Dr. Teri Manolio (National human genome research institute, NIH) for kind advice in the analysis. We thank Dan Sturdevant and Stacy Ricklefs of the Genomics Unit at RML, for help in processing the SNP array. This work was supported by a grant (U19 AI089672) and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, and The National Science Foundation of China (grant number U1202226 and 31260508 to Z.Y.) NR 59 TC 0 Z9 0 U1 4 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD OCT 3 PY 2016 VL 6 AR 33891 DI 10.1038/srep33891 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DX9ZC UT WOS:000384755100001 PM 27694982 ER PT J AU Muranen, TA Blomqvist, C Dork, T Jakubowska, A Heikkila, P Fagerholm, R Greco, D Aittomaki, K Bojesen, SE Shah, M Dunning, AM Rhenius, V Hall, P Czene, K Brand, JS Darabi, H Chang-Claude, J Rudolph, A Nordestgaard, BG Couch, FJ Hart, SN Figueroa, J Garcia-Closas, M Fasching, PA Beckmann, MW Li, JM Liu, JJ Andrulis, IL Winqvist, R Pylkas, K Mannermaa, A Kataja, V Lindblom, A Margolin, S Lubinski, J Dubrowinskaja, N Bolla, MK Dennis, J Michailidou, K Wang, Q Easton, DF Pharoah, PDP Schmidt, MK Nevanlinna, H AF Muranen, Taru A. Blomqvist, Carl Doerk, Thilo Jakubowska, Anna Heikkila, Paivi Fagerholm, Rainer Greco, Dario Aittomaki, Kristiina Bojesen, Stig E. Shah, Mitul Dunning, Alison M. Rhenius, Valerie Hall, Per Czene, Kamila Brand, Judith S. Darabi, Hatef Chang-Claude, Jenny Rudolph, Anja Nordestgaard, Borge G. Couch, Fergus J. Hart, Steven N. Figueroa, Jonine Garcia-Closas, Montserrat Fasching, Peter A. Beckmann, Matthias W. Li, Jingmei Liu, Jianjun Andrulis, Irene L. Winqvist, Robert Pylkas, Katri Mannermaa, Arto Kataja, Vesa Lindblom, Annika Margolin, Sara Lubinski, Jan Dubrowinskaja, Natalia Bolla, Manjeet K. Dennis, Joe Michailidou, Kyriaki Wang, Qin Easton, Douglas F. Pharoah, Paul D. P. Schmidt, Marjanka K. Nevanlinna, Heli TI Patient survival and tumor characteristics associated with CHEK2:p.I157T-findings from the Breast Cancer Association Consortium SO BREAST CANCER RESEARCH LA English DT Article DE Breast cancer; CHEK2; CHK2; I157T; 1100delC; Survival; Pathology; Gene expression ID MAMMARY-GLAND DEVELOPMENT; GENE-EXPRESSION; DNA-DAMAGE; INTRINSIC SUBTYPES; PROGNOSTIC-SIGNIFICANCE; CHEK2 MUTATIONS; RISK; CHEK2-ASTERISK-1100DELC; SUSCEPTIBILITY; WOMEN AB Background: P.I157T is a CHEK2 missense mutation associated with a modest increase in breast cancer risk. Previously, another CHEK2 mutation, the protein truncating c.1100delC has been associated with poor prognosis of breast cancer patients. Here, we have investigated patient survival and characteristics of breast tumors of germ line p.I157T carriers. Methods: We included in the analyses 26,801 European female breast cancer patients from 15 studies participating in the Breast Cancer Association Consortium. We analyzed the association between p.I157T and the clinico-pathological breast cancer characteristics by comparing the p.I157T carrier tumors to non-carrier and c.1100delC carrier tumors. Similarly, we investigated the p.I157T associated risk of early death, breast cancer-associated death, distant metastasis, locoregional relapse and second breast cancer using Cox proportional hazards models. Additionally, we explored the p.I157T-associated genomic gene expression profile using data from breast tumors of 183 Finnish female breast cancer patients (ten p.I157T carriers) (GEO:GSE24450). Differential gene expression analysis was performed using a moderated t test. Functional enrichment was investigated using the DAVID functional annotation tool and gene set enrichment analysis (GSEA). The tumors were classified into molecular subtypes according to the St Gallen 2013 criteria and the PAM50 gene expression signature. Results: P.I157T was not associated with increased risk of early death, breast cancer-associated death or distant metastasis relapse, and there was a significant difference in prognosis associated with the two CHEK2 mutations, p.I157T and c.1100delC. Furthermore, p.I157T was associated with lobular histological type and clinico-pathological markers of good prognosis, such as ER and PR expression, low TP53 expression and low grade. Gene expression analysis suggested luminal A to be the most common subtype for p.I157T carriers and CDH1 (cadherin 1) target genes to be significantly enriched among genes, whose expression differed between p.I157T and non-carrier tumors. Conclusions: Our analyses suggest that there are fundamental differences in breast tumors of CHEK2: p.I157T and c.1100delC carriers. The poor prognosis associated with c.1100delC cannot be generalized to other CHEK2 mutations. C1 [Muranen, Taru A.; Fagerholm, Rainer; Nevanlinna, Heli] Univ Helsinki, Dept Obstet & Gynecol, HUS, POB 70000029, Helsinki, Finland. [Muranen, Taru A.; Fagerholm, Rainer; Nevanlinna, Heli] Helsinki Univ Hosp, HUS, POB 70000029, Helsinki, Finland. [Blomqvist, Carl] Univ Helsinki, Dept Oncol, Helsinki, Finland. [Blomqvist, Carl; Heikkila, Paivi; Aittomaki, Kristiina] Helsinki Univ Hosp, Helsinki, Finland. [Aittomaki, Kristiina] Univ Helsinki, Dept Clin Genet, Helsinki, Finland. [Heikkila, Paivi] Univ Helsinki, Dept Pathol, Helsinki, Finland. [Doerk, Thilo; Dubrowinskaja, Natalia] Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany. [Jakubowska, Anna; Lubinski, Jan] Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland. [Greco, Dario] Finnish Inst Occupat Hlth, Unit Syst Toxicol, Helsinki, Finland. [Bojesen, Stig E.; Nordestgaard, Borge G.] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark. [Bojesen, Stig E.] Copenhagen Univ Hosp, Herlev Hosp, Copenhagen Gen Populat Study, Herlev, Denmark. [Bojesen, Stig E.; Nordestgaard, Borge G.] Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, Herlev, Denmark. [Shah, Mitul; Dunning, Alison M.; Rhenius, Valerie; Easton, Douglas F.; Pharoah, Paul D. P.] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England. [Bolla, Manjeet K.; Dennis, Joe; Michailidou, Kyriaki; Wang, Qin; Easton, Douglas F.; Pharoah, Paul D. P.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Hall, Per; Czene, Kamila; Brand, Judith S.; Darabi, Hatef; Li, Jingmei; Lindblom, Annika] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Margolin, Sara] Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden. [Chang-Claude, Jenny; Rudolph, Anja] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Chang-Claude, Jenny] Univ Med Ctr Hamburg Eppendorf, Univ Canc Ctr Hamburg, Hamburg, Germany. [Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Hart, Steven N.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Figueroa, Jonine; Garcia-Closas, Montserrat] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Garcia-Closas, Montserrat] Inst Canc Res, Div Genet & Epidemiol, London, England. [Fasching, Peter A.; Beckmann, Matthias W.] Univ Erlangen Nurnberg, Comprehens Canc Ctr Erlangen EMN, Univ Hosp Erlangen, Dept Gynaecol & Obstet, Erlangen, Germany. [Fasching, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. [Liu, Jianjun] Genome Inst Singapore, Human Genet Div, Singapore, Singapore. [Andrulis, Irene L.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada. [Andrulis, Irene L.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Winqvist, Robert; Pylkas, Katri] Northern Finland Lab Ctr NordLab, Lab Canc Genet & Tumor Biol, Oulu, Finland. [Winqvist, Robert; Pylkas, Katri] Univ Oulu, Canc & Translat Med Res Unit, Lab Canc Genet & Tumor Biol, Oulu, Finland. [Winqvist, Robert; Pylkas, Katri] Univ Oulu, Bioctr Oulu, Oulu, Finland. [Mannermaa, Arto; Kataja, Vesa] Kuopio Univ Hosp, Ctr Canc, Kuopio, Finland. [Mannermaa, Arto] Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, Kuopio, Finland. [Mannermaa, Arto] Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Kuopio, Finland. [Kataja, Vesa] Jyvaskyla Cent Hosp, Cent Finland Hosp Dist, Jyvaskyla, Finland. [Michailidou, Kyriaki] Cyprus Inst Neurol & Genet, Dept Electron Microscopy Mol Pathol, Nicosia, Cyprus. [Schmidt, Marjanka K.] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands. RP Nevanlinna, H (reprint author), Univ Helsinki, Dept Obstet & Gynecol, HUS, POB 70000029, Helsinki, Finland.; Nevanlinna, H (reprint author), Helsinki Univ Hosp, HUS, POB 70000029, Helsinki, Finland. EM Heli.Nevanlinna@hus.fi RI Rosczak, Agnieszka/K-2975-2012; Dork, Thilo/J-8620-2012; Li, Jingmei/I-2904-2012; OI Li, Jingmei/0000-0001-8587-7511; Muranen, Taru/0000-0002-5895-1808; Dunning, Alison Margaret/0000-0001-6651-7166 FU Cancer Research UK [C1287/A10118, C1287/A12014, C490/A10124, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565]; European Community's Seventh Framework Programme [223175, HEALTH-F2-2009-223175]; ELAN-Fond of the University Hospital of Erlangen; Helsinki University Central Hospital Research Fund; Academy of Finland [266528, 250083, 122715]; Finnish Cancer Society; Nordic Cancer Union; Sigrid Juselius Foundation; Finnish Cultural Foundation; Orion Research Foundation; Cancer Society of Finland; Ida Montin Foundation; UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge; Marit and Hans Rausings Initiative Against Breast Cancer; Deutsche Krebshilfe e.V. [70-2892-BR I, 106332, 108253, 108419]; Hamburg Cancer Society; German Cancer Research Center (DKFZ); Federal Ministry of Education and Research (BMBF) Germany [01KH0402]; Chief Physician Johan Boserup and Lise Boserup Fund; Danish Medical Research Council and Herlev Hospital; NIH grantsan NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA192393, CA116167, CA176785, CA116201]; Breast Cancer Research Foundation; Intramural Research Funds of the National Cancer Institute; Department of Health and Human Services, USA; Agency for Science, Technology and Research of Singapore (A*STAR); US National Institute of Health (NIH); Susan G. Komen Breast Cancer Foundation; National Cancer Institute (USA) [UM1 CA164920]; Finnish Cancer Foundation; University of Oulu; University of Oulu Support Foundation; special Governmental EVO funds for Oulu University Hospital-based research activities; special Government Funding (EVO) of Kuopio University Hospital grants; Cancer Fund of North Savo; Finnish Cancer Organizations; strategic funding of the University of Eastern Finland; Stockholm County Council; Karolinska Institutet; Swedish Cancer Society; Gustav V Jubilee foundation; Bert von Kantzows foundation; SZBCS [PBZ_KBN_122/P05/2004]; intramural grant from Hannover Medical School; National Institutes of Health [CA128978]; Post-Cancer GWAS initiative [1U19 CA148537, 1U19 CA148065, 1U19 CA148112]; Department of Defence [W81XWH-10-1-0341]; Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer; Komen Foundation for the Cure; Ovarian Cancer Research Fund FX BCAC is funded by Cancer Research UK [C1287/A10118, C1287/A12014] and by the European Community's Seventh Framework Programme under grant agreement number 223175 (grant number HEALTH-F2-2009-223175) (COGS); The work of the BBCC was partly funded by ELAN-Fond of the University Hospital of Erlangen; The HEBCS was financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society, The Nordic Cancer Union and the Sigrid Juselius Foundation, The work of TAM has been supported by Finnish Cultural Foundation, Orion Research Foundation, Cancer Society of Finland and Ida Montin Foundation; SEARCH is funded by a programme grant from Cancer Research UK [C490/A10124] and supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge; The pKARMA study was supported by Marit and Hans Rausings Initiative Against Breast Cancer; The MARIE study was supported by the Deutsche Krebshilfe e.V. [70-2892-BR I, 106332, 108253, 108419], the Hamburg Cancer Society, the German Cancer Research Center (DKFZ) and the Federal Ministry of Education and Research (BMBF) Germany [01KH0402]; The CGPS was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council and Herlev Hospital; The MCBCS was supported by the NIH grants CA192393, CA116167, CA176785 an NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201], and the Breast Cancer Research Foundation; The PBCS was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA; The SASBAC study was supported by funding from the Agency for Science, Technology and Research of Singapore (A*STAR), the US National Institute of Health (NIH) and the Susan G. Komen Breast Cancer Foundation; The Ontario Familial Breast Cancer Registry (OFBCR) was supported by grant UM1 CA164920 from the National Cancer Institute (USA).; The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR; The OBCS was supported by research grants from the Finnish Cancer Foundation, the Academy of Finland (grant number 250083, 122715 and Center of Excellence grant number 251314), the Sigrid Juselius Foundation, the University of Oulu, the University of Oulu Support Foundation and the special Governmental EVO funds for Oulu University Hospital-based research activities; The KBCP was financially supported by the special Government Funding (EVO) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations, and by the strategic funding of the University of Eastern Finland; Financial support for KARBAC was provided through the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet, the Swedish Cancer Society, The Gustav V Jubilee foundation and and Bert von Kantzows foundation; The SZBCS was supported by Grant PBZ_KBN_122/P05/2004; The HABCS study was supported by an intramural grant from Hannover Medical School; Funding for the iCOGS infrastructure came from: the European Community's Seventh Framework Programme under grant agreement no 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. NR 66 TC 1 Z9 1 U1 7 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-542X EI 1465-5411 J9 BREAST CANCER RES JI Breast Cancer Res. PD OCT 3 PY 2016 VL 18 AR 98 DI 10.1186/s13058-016-0758-5 PG 15 WC Oncology SC Oncology GA DX5YW UT WOS:000384459700001 PM 27716369 ER PT J AU Lamas, A Marshburn, J Stober, VP Donaldson, SH Garantziotis, S AF Lamas, Adelaida Marshburn, Jamie Stober, Vandy P. Donaldson, Scott H. Garantziotis, Stavros TI Effects of inhaled high-molecular weight hyaluronan in inflammatory airway disease SO RESPIRATORY RESEARCH LA English DT Letter DE Cystic fibrosis; Hyaluronan; Airway inflammation; Induced sputum ID NEBULIZED HYPERTONIC SALINE; CYSTIC-FIBROSIS; ACID IMPROVES; AIRSPACE ENLARGEMENT; PULMONARY-EMPHYSEMA; TOLERABILITY; ELASTASE; HEPARIN; ASTHMA AB Cystic fibrosis (CF) is a chronic inflammatory disease that is affecting thousands of patients worldwide. Adjuvant anti-inflammatory treatment is an important component of cystic fibrosis treatment, and has shown promise in preserving lung function and prolonging life expectancy. Inhaled high molecular weight hyaluronan (HMW-HA) is reported to improve tolerability of hypertonic saline and thus increase compliance, and has been approved in some European countries for use as an adjunct to hypertonic saline treatment in cystic fibrosis. However, there are theoretical concerns that HMW-HA breakdown products may be pro-inflammatory. In this clinical pilot study we show that sputum cytokines in CF patients receiving HMW-HA are not increased, and therefore HMW-HA does not appear to adversely affect inflammatory status in CF airways. C1 [Lamas, Adelaida] Hosp Univ Ramon y Cajal, Inst Ramon y Cajal Invest Sanitaria, Madrid, Spain. [Marshburn, Jamie; Stober, Vandy P.; Garantziotis, Stavros] NIEHS, Div Intramural Res, Durham, NC 27709 USA. [Donaldson, Scott H.] Univ North Carolina Chapel Hill, Chapel Hill, NC USA. [Garantziotis, Stavros] NIEHS, 111 TW Alexander Dr, Durham, NC 27709 USA. RP Garantziotis, S (reprint author), NIEHS, Div Intramural Res, Durham, NC 27709 USA.; Garantziotis, S (reprint author), NIEHS, 111 TW Alexander Dr, Durham, NC 27709 USA. EM garantziotis@niehs.nih.gov RI Garantziotis, Stavros/A-6903-2009 OI Garantziotis, Stavros/0000-0003-4007-375X NR 20 TC 0 Z9 0 U1 4 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-993X EI 1465-9921 J9 RESP RES JI Respir. Res. PD OCT 3 PY 2016 VL 17 AR 123 DI 10.1186/s12931-016-0442-4 PG 4 WC Respiratory System SC Respiratory System GA DX6IJ UT WOS:000384486900001 PM 27716205 ER PT J AU Scheinert, RB Haeri, MH Lehmann, ML Herkenham, M AF Scheinert, Rachel B. Haeri, Mitra H. Lehmann, Michael L. Herkenham, Miles TI Therapeutic effects of stress-programmed lymphocytes transferred to chronically stressed mice SO PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY LA English DT Article DE Psychological stress; Restraint; Depression; Hippocampal neurogenesis ID T-CELLS; IMMUNE-SYSTEM; PSYCHOLOGICAL STRESS; ADULT NEUROGENESIS; BEHAVIOR; BRAIN; DISORDERS; INFLAMMATION; VACCINATION; DEPRESSION AB Our group has recently provided novel insights into a poorly understood component of intercommunication between the brain and the immune system by showing that psychological stress can modify lymphocytes in a manner that may boost resilience to psychological stress. To demonstrate the influence of the adaptive immune system on mood states, we previously showed that cells from lymph nodes of socially defeated mice, but not from unstressed mice, conferred anxiolytic and antidepressant-like effects and elevated hippocampal cell proliferation when transferred into naive lymphopenic Rag2(-/-) mice. In the present study, we asked whether similar transfer could be anxiolytic and antidepressant when done in animals that had been rendered anxious and depressed by chronic psychological stress. First, we demonstrated that lymphopenic Rag2(-/-) mice and their wild-type C57BL/6 mouse counterparts had similar levels of affect normally. Second, we found that following chronic (14 days) restraint stress, both groups displayed an anxious and depressive-like phenotype and decreased hippocampal cell proliferation. Third, we showed that behavior in the open field test and light/dark box was normalized in the restraint-stressed Rag2(-/-) mice following adoptive transfer of lymph node cells from green fluorescent protein (GFP) expressing donor mice previously exposed to chronic (14 days) of social defeat stress. Cells transferred from unstressed donor mice had no effect on behavior. Immunolabeling of GFP+ cells confirmed that tissue engraftment had occurred at 14 days after transfer. We found GFP+ lymphocytes in the spleen, lymph nodes, blood, choroid plexus, and meninges of the recipient Rag2(-/-) mice. The findings suggest that the adaptive immune system may play a key role in promoting recovery from chronic stress. The data support using lymphocytes as a novel therapeutic target for anxiety states. Published by Elsevier Inc. C1 [Scheinert, Rachel B.; Haeri, Mitra H.; Lehmann, Michael L.; Herkenham, Miles] NIMH, Funct Neuroanat Sect, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Herkenham, M (reprint author), Bldg 35,Rm 1C913, Bethesda, MD 20892 USA. EM herkenh@mail.nih.gov OI Herkenham, Miles/0000-0003-2228-4238; Lehmann, Michael/0000-0003-4476-8268 FU NIMH Intramural Research Program [ZIA MH001090] FX Hannah Crowder, Matt Dean, and Jennifer Lee assisted in the study. The work was supported by the NIMH Intramural Research Program, ZIA MH001090. NR 39 TC 0 Z9 0 U1 7 U2 39 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-5846 EI 1878-4216 J9 PROG NEURO-PSYCHOPH JI Prog. Neuro-Psychopharmacol. Biol. Psychiatry PD OCT 3 PY 2016 VL 70 BP 1 EP 7 DI 10.1016/j.pnpbp.2016.04.010 PG 7 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DP9YO UT WOS:000378854200001 PM 27109071 ER PT J AU Illiano, E Bissa, M Paolini, F Zanotto, C Morghen, CD Franconi, R Radaelli, A Venuti, A AF Illiano, Elena Bissa, Massimiliano Paolini, Francesca Zanotto, Carlo Morghen, Carlo De Giuli Franconi, Rosella Radaelli, Antonia Venuti, Aldo TI Prime-boost therapeutic vaccination in mice with DNA/DNA or DNA/Fowlpox virus recombinants expressing the Human Papilloma Virus type 16 E6 and E7 mutated proteins fused to the coat protein of Potato virus X SO VIRUS RESEARCH LA English DT Article DE HPV therapeutic vaccines; Fowlpox virus recombinants; Prime/boost immunizations; Potato virus X coat protein; E6 and E7 modified oncoproteins ID FOWLPOX VIRUS; DNA VACCINES; PRIME/BOOST STRATEGY; HUMAN KERATINOCYTES; IMMUNE-RESPONSES; CANCERS; GENES; ANKARA; TUMORS; CELLS AB The therapeutic antitumor potency of a prime boost vaccination strategy was explored, based on the mutated, nontransforming forms of the E6 (E6(F47R)) and E7 (E7(GGG)) oncogenes of Human Papilloma Virus type 16 (HPV16), fused to the Potato virus X (PVX) coat protein (CP) sequence. Previous data showed that CP fusion improves the immunogenicity of tumor-associated antigens and may thus increase their efficacy. After verifying the correct expression of E6(F47R)CP and E7(GGG)CP inserted into DNA and Fowlpox virus recombinants by Western blotting and immunofluorescence, their combined use was evaluated for therapy in a pre-clinical mouse model of HPV16-related tumorigenicity. Immunization protocols were applied using homologous (DNA/DNA) or heterologous (DNA/Fowlpox) prime-boost vaccine regimens. The humoral immune responses were determined by ELISA, and the therapeutic efficacy evaluated by the delay in tumor appearance and reduced tumor volume after inoculation of syngeneic TC-1* tumor cells. Homologous DNA/DNA genetic vaccines were able to better delay tumor appearance and inhibit tumor growth when DNAE6(F47R)CP and DNAE7(GGG)CP were administered in combination. However, the heterologous DNA/Fowlpox vaccination strategy was able to delay tumor appearance in a higher number of animals when E6(F47R)CP and in particular E7(GGG)CP were administered alone. (C) 2016 Elsevier B.V. All rights reserved. C1 [Illiano, Elena; Bissa, Massimiliano; Radaelli, Antonia] Univ Milan, Dept Pharmacol & Biomol Sci, Milan, Italy. [Paolini, Francesca; Venuti, Aldo] Regina Elena Inst Canc Res, Lab Virol HPV UNIT, Rome, Italy. [Zanotto, Carlo] Univ Milan, Dept Med Biotechnol & Translat Med, Milan, Italy. [Morghen, Carlo De Giuli; Radaelli, Antonia] Univ Milan, CNR Inst Neurosci, Cellular & Mol Pharmacol Sect, Milan, Italy. [Morghen, Carlo De Giuli] Catholic Univ Our Lady Good Counsel, Tirana, Albania. [Franconi, Rosella] Casaccia Res Ctr, Italian Natl Agcy New Technol Energy & Sustainabl, Dept Sustainabil, Lab Biomed Technol,Div Hlth Protect Technol, Rome, Italy. [Bissa, Massimiliano] NCI, NIH, Bethesda, MD 20892 USA. RP Franconi, R (reprint author), Univ Milan, Dept Med Biotechnol & Translat Med, Lab Mol Virol & Recombinant Vaccine Dev, Via Vanvitelli 32, I-20129 Milan, Italy. EM elena.illiano@unimi.it; massimiliano.bissa@unimi.it; francesca.paolini@ifo.gov.it; carlo.zanotto@unimi.it; carlo.degiulimorghen@unimi.it; rosella.franconi@enea.it; antonia.radaelli@unimi.it; aldo.venuti@ifo.gov.it OI Illiano, Elena/0000-0002-8908-9755 FU AIRC [IG 12916]; Project of Mutual Collaboration of the Planning Department of the National Health Service of the Italian Ministry of Health and 'Regina Elena' National Cancer Institute for Implementation of the HPV-UNIT FX This work was partially supported by AIRC IG 12916 and by the Project of Mutual Collaboration of the Planning Department of the National Health Service of the Italian Ministry of Health and 'Regina Elena' National Cancer Institute for Implementation of the HPV-UNIT. The authors thank Silvio Flamini for maintenance of the tumor cells; Giancarlo Cortese and Sabrina Germoni for animal care and technical assistance, and Dr. Christopher Berrie for editorial assistance with the manuscript. NR 56 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1702 EI 1872-7492 J9 VIRUS RES JI Virus Res. PD OCT 2 PY 2016 VL 225 BP 82 EP 90 DI 10.1016/j.virusres.2016.09.011 PG 9 WC Virology SC Virology GA EA2JH UT WOS:000386418100010 PM 27664839 ER PT J AU Arveson, I Elliott, J Tonkura, E Meilleur, K AF Arveson, I. Elliott, J. Tonkura, E. Meilleur, K. TI Validation of FACIT-F and MFI-20 questionnaires in individuals with RYR1-RM SO NEUROMUSCULAR DISORDERS LA English DT Meeting Abstract CT 21st International Congress of the World-Muscle-Society CY OCT 04-08, 2016 CL Granada, SPAIN SP World Muscle Soc C1 [Arveson, I.; Elliott, J.; Tonkura, E.; Meilleur, K.] NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-8966 EI 1873-2364 J9 NEUROMUSCULAR DISORD JI Neuromusc. Disord. PD OCT PY 2016 VL 26 SU 2 MA P.169 BP S137 EP S138 DI 10.1016/j.nmd.2016.06.189 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DY0ME UT WOS:000384790100179 ER PT J AU Witherspoon, J Drinkard, B Waite, M Arveson, I Stockman, M Jain, M Meilleur, K AF Witherspoon, J. Drinkard, B. Waite, M. Arveson, I. Stockman, M. Jain, M. Meilleur, K. TI Local muscle strength, oxygen extraction capacity, and exercise capacity in adults with RYR1-related myopathies: Exploratory study SO NEUROMUSCULAR DISORDERS LA English DT Meeting Abstract CT 21st International Congress of the World-Muscle-Society CY OCT 04-08, 2016 CL Granada, SPAIN SP World Muscle Soc C1 [Witherspoon, J.; Drinkard, B.; Waite, M.; Arveson, I.; Stockman, M.; Jain, M.; Meilleur, K.] NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-8966 EI 1873-2364 J9 NEUROMUSCULAR DISORD JI Neuromusc. Disord. PD OCT PY 2016 VL 26 SU 2 MA P.161 BP S135 EP S135 DI 10.1016/j.nmd.2016.06.181 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DY0ME UT WOS:000384790100171 ER PT J AU Hosek, S Celum, C Wilson, CM Kapogiannis, B Delany-Moretlwe, S Bekker, LG AF Hosek, Sybil Celum, Connie Wilson, Craig M. Kapogiannis, Bill Delany-Moretlwe, Sinead Bekker, Linda-Gail TI Preventing HIV among adolescents with oral PrEP: observations and challenges in the United States and South Africa SO JOURNAL OF THE INTERNATIONAL AIDS SOCIETY LA English DT Editorial Material DE PrEP; adolescents; HIV/AIDS; implementation ID PREEXPOSURE PROPHYLAXIS; RISK-TAKING; WOMEN; SEX; ADHERENCE; ATTITUDES; HIV/AIDS; CONSENT; IMPACT; COHORT AB Introduction: Adolescents and young adults aged B25 are a key population in the HIV epidemic, with very high HIV incidence rates in many geographic settings and a large number who have limited access to prevention services. Thus, any biomedical HIV prevention approach should prepare licensure and implementation strategies for young populations. Oral pre-exposure prophylaxis (PrEP) is the first antiretroviral-based prevention intervention with proven efficacy across many settings and populations, and regulatory and policy approvals at global and national levels are occurring rapidly. We discuss available data from studies in the United States and South Africa on the use of oral PrEP for HIV prevention in adolescent minors, along with some of the implementation challenges. Discussion: Ongoing studies in the United States and South Africa among youth under the age of 18 should provide the safety data needed by the end of 2016 to contribute to licensure of Truvada as daily PrEP in adolescents. The challenges of completing these studies as well as foreseeable broader challenges highlighted by this work are presented. Adherence to daily PrEP is a greater challenge for younger populations, and poor adherence was associated with decreased efficacy in all PrEP trials. Individual-level barriers include limited familiarity with antiretroviral-based prevention, stigma, product storage, and social support. Structural challenges include healthcare financing for PrEP, clinician acceptability and comfort with PrEP delivery, and the limited youth-friendly health services available. These challenges are discussed in the context of the work done to date in the United States and South Africa, but will likely be magnified in the setting of limited resources in many other countries that are heavily impacted by HIV. Conclusions: Adolescent populations are particularly vulnerable to HIV, and oral PrEP in these populations is likely to have an impact on population-level HIV incidence. The challenges of disseminating an HIV biomedical prevention tool requiring daily usage in adolescents are formidable, but addressing these issues and starting dialogues will lay the groundwork for the many other HIV prevention tools now being developed and tested. C1 [Hosek, Sybil] John H Stroger Jr Hosp Cook Cty, Dept Psychiat, Chicago, IL USA. [Celum, Connie] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. [Wilson, Craig M.] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL USA. [Kapogiannis, Bill] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis Branch, Washington, DC USA. [Delany-Moretlwe, Sinead] Univ Witwatersrand, RHI, Johannesburg, South Africa. [Bekker, Linda-Gail] Univ Cape Town, Desmond Tutu HIV Ctr, Cape Town, South Africa. RP Hosek, S (reprint author), 1900 W Polk St,Room 854, Chicago, IL 60302 USA. EM shosek@cookcountyhhs.org NR 43 TC 1 Z9 1 U1 0 U2 0 PU INT AIDS SOCIETY PI GENEVA PA AVENUE DE FRANCE 23, GENEVA, 1202, SWITZERLAND SN 1758-2652 J9 J INT AIDS SOC JI J. Int. AIDS Soc. PD OCT PY 2016 VL 19 SU 6 AR 21107 DI 10.7448/IAS.19.7.21107 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA EM6AH UT WOS:000395394700009 PM 27760684 ER PT J AU Evans, DS Avery, CL Nalls, MA Li, G Barnard, J Smith, EN Tanaka, T Butler, AM Buxbaum, SG Alonso, A Arking, DE Berenson, GS Bis, JC Buyske, S Carty, CL Chen, W Chung, MK Cummings, SR Deo, R Eaton, CB Fox, ER Heckbert, SR Heiss, G Hindorff, LA Hsueh, WC Isaacs, A Jamshidi, Y Kerr, KF Liu, F Liu, YM Lohman, KK Magnani, JW Maher, JF Mehra, R Meng, YA Musani, SK Newton-Cheh, C North, KE Psaty, BM Redline, S Rotter, JI Schnabel, RB Schork, NJ Shohet, RV Singleton, AB Smith, JD Soliman, EZ Srinivasan, SR Taylor, HA Van Wagoner, DR Wilson, JG Young, T Zhang, ZM Zonderman, AB Evans, MK Ferrucci, L Murray, SS Tranah, GJ Whitsel, EA Reiner, AP Sotoodehnia, N AF Evans, Daniel S. Avery, Christy L. Nalls, Mike A. Li, Guo Barnard, John Smith, Erin N. Tanaka, Toshiko Butler, Anne M. Buxbaum, Sarah G. Alonso, Alvaro Arking, Dan E. Berenson, Gerald S. Bis, Joshua C. Buyske, Steven Carty, Cara L. Chen, Wei Chung, Mina K. Cummings, Steven R. Deo, Rajat Eaton, Charles B. Fox, Ervin R. Heckbert, Susan R. Heiss, Gerardo Hindorff, Lucia A. Hsueh, Wen-Chi Isaacs, Aaron Jamshidi, Yalda Kerr, Kathleen F. Liu, Felix Liu, Yongmei Lohman, Kurt K. Magnani, Jared W. Maher, Joseph F. Mehra, Reena Meng, Yan A. Musani, Solomon K. Newton-Cheh, Christopher North, Kari E. Psaty, Bruce M. Redline, Susan Rotter, Jerome I. Schnabel, Renate B. Schork, Nicholas J. Shohet, Ralph V. Singleton, Andrew B. Smith, Jonathan D. Soliman, Elsayed Z. Srinivasan, Sathanur R. Taylor, Herman A., Jr. Van Wagoner, David R. Wilson, James G. Young, Taylor Zhang, Zhu-Ming Zonderman, Alan B. Evans, Michele K. Ferrucci, Luigi Murray, Sarah S. Tranah, Gregory J. Whitsel, Eric A. Reiner, Alex P. Sotoodehnia, Nona CA CHARGE QRS Consortium TI Fine-mapping, novel loci identification, and SNP association transferability in a genome-wide association study of QRS duration in African Americans SO HUMAN MOLECULAR GENETICS LA English DT Article ID RESTING HEART-RATE; COMMON VARIANTS; PR INTERVAL; VENTRICULAR CONDUCTION; CARDIAC CONDUCTION; HUMAN-POPULATIONS; GENETIC-VARIATION; JACKSON HEART; METAANALYSIS; DESIGN AB The electrocardiographic QRS duration, a measure of ventricular depolarization and conduction, is associated with cardiovascular mortality. While single nucleotide polymorphisms (SNPs) associated with QRS duration have been identified at 22 loci in populations of European descent, the genetic architecture of QRS duration in non-European populations is largely unknown. We therefore performed a genome-wide association study (GWAS) meta-analysis of QRS duration in 13,031 African Americans from ten cohorts and a transethnic GWAS meta-analysis with additional results from populations of European descent. In the African American GWAS, a single genome-wide significant SNP association was identified (rs3922844, P = 4 x 10(-14)) in intron 16 of SCN5A, a voltage-gated cardiac sodium channel gene. The QRS-prolonging rs3922844 C allele was also associated with decreased SCN5A RNA expression in human atrial tissue (P = 1.1 x 10(-4)). High density genotyping revealed that the SCN5A association region in African Americans was confined to intron 16. Transethnic GWAS meta-analysis identified novel SNP associations on chromosome 18 in MYL12A (rs1662342, P = 4.9 x 10(-8)) and chromosome 1 near CD1E and SPTA1 (rs7547997, P = 7.9 x 10(-9)). The 22 QRS loci previously identified in populations of European descent were enriched for significant SNP associations with QRS duration in African Americans (P = 9.9 x 10(-7)), and index SNP associations in or near SCN5A, SCN10A, CDKN1A, NFIA, HAND1, TBX5 and SETBP1 replicated in African Americans. In summary, rs3922844 was associated with QRS duration and SCN5A expression, two novel QRS loci were identified using transethnic meta-analysis, and a significant proportion of QRS-SNP associations discovered in populations of European descent were transferable to African Americans when adequate power was achieved. C1 [Evans, Daniel S.; Cummings, Steven R.; Tranah, Gregory J.] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. [Avery, Christy L.; Butler, Anne M.; Heiss, Gerardo; North, Kari E.; Whitsel, Eric A.] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Nalls, Mike A.; Singleton, Andrew B.] NIA, Lab Neurogenet, NIH, Bethesda, MD 20892 USA. [Li, Guo; Bis, Joshua C.; Heckbert, Susan R.; Psaty, Bruce M.; Sotoodehnia, Nona] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Barnard, John] Cleveland Clin, Lerner Res Inst, Dept Quantitat Hlth Sci, Cleveland, OH 44106 USA. [Smith, Erin N.] Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA. [Smith, Erin N.] Univ Calif San Diego, Rady Childrens Hosp, La Jolla, CA 92093 USA. [Tanaka, Toshiko; Ferrucci, Luigi] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. [Buxbaum, Sarah G.] Jackson State Univ, Ctr Excellence Minor Hlth & Hlth Dispar, Jackson, MS USA. [Buxbaum, Sarah G.] Jackson State Univ, Sch Publ Hlth Initiative, Dept Epidemiol & Biostat, Jackson, MS USA. [Alonso, Alvaro] Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. [Arking, Dan E.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Berenson, Gerald S.] Tulane Univ, Dept Med & Cardiol, New Orleans, LA 70118 USA. [Buyske, Steven] Rutgers State Univ, Dept Stat & Biostat, Piscataway, NJ USA. [Buyske, Steven] Rutgers State Univ, Dept Genet, Piscataway, NJ USA. [Carty, Cara L.; Reiner, Alex P.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. Tulane Univ, Dept Epidemiol, New Orleans, LA 70118 USA. [Chung, Mina K.; Mehra, Reena] Cleveland Clin, Dept Cardiovasc Med, Inst Heart & Vasc, Cleveland, OH 44106 USA. [Chung, Mina K.; Mehra, Reena; Van Wagoner, David R.] Cleveland Clin, Lerner Res Inst, Dept Mol Cardiol, Cleveland, OH USA. [Chung, Mina K.; Mehra, Reena] Case Western Reserve Univ, Cleveland Clin, Lerner Coll Med, Cleveland, OH 44106 USA. [Deo, Rajat] Univ Penn, Div Cardiovasc Med, Philadelphia, PA 19104 USA. [Eaton, Charles B.] Brown Univ, Alpert Med Sch, Dept Family Med, Providence, RI 02912 USA. [Eaton, Charles B.] Brown Univ, Alpert Med Sch, Dept Epidemiol, Providence, RI 02912 USA. [Fox, Ervin R.] Univ Mississippi, Med Ctr, Dept Med, Div Cardiovasc Dis, Jackson, MS 39216 USA. [Heckbert, Susan R.; Psaty, Bruce M.; Reiner, Alex P.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Heckbert, Susan R.; Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Hindorff, Lucia A.] NHGRI, NIH, Off Populat Genom, Bethesda, MD 20892 USA. [Hsueh, Wen-Chi] NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ USA. [Isaacs, Aaron] Erasmus Univ, Med Ctr, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands. [Isaacs, Aaron] Maastricht Univ, Dept Biochem, Maastricht Ctr Syst Biol MaCSBio, CARIM Sch Cardiovasc Dis, Maastricht, Netherlands. [Jamshidi, Yalda] St Georges Univ London, Inst Cardiovasc & Cell Sci, Cardiogenet Lab, London, England. [Kerr, Kathleen F.] Univ Washington, Dept Biostat, Sch Publ Hlth, Seattle, WA 98195 USA. [Liu, Felix] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Liu, Yongmei; Lohman, Kurt K.] Wake Forest Univ, Div Publ Hlth Sci, Dept Epidemiol & Prevent, Winston Salem, NC 27109 USA. [Magnani, Jared W.] Univ Pittsburgh, Med Ctr, Inst Heart & Vasc, Dept Med,Div Cardiol, Pittsburgh, PA USA. [Maher, Joseph F.; Taylor, Herman A., Jr.] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Meng, Yan A.; Newton-Cheh, Christopher; Young, Taylor] Broad Inst Harvard & Massachusetts Inst Technol, Program Med & Populat Genet, Cambridge, MA USA. [Musani, Solomon K.] Univ Mississippi, Med Ctr, Jackson Heart Study, Jackson, MS 39216 USA. [Newton-Cheh, Christopher] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Newton-Cheh, Christopher] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Newton-Cheh, Christopher] Harvard Med Sch, Boston, MA 02114 USA. [North, Kari E.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Redline, Susan] Harvard Med Sch, Brigham & Womens Hosp, Div Sleep Med, Dept Med, Boston, MA USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Dept Med, Torrance, CA 90509 USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90509 USA. [Schnabel, Renate B.] Univ Heart Ctr Hamburg, Hamburg, Germany. [Schnabel, Renate B.] German Ctr Cardiovasc Res, Hamburg, Germany. [Schork, Nicholas J.] J Craig Venter Inst, San Diego, CA USA. [Shohet, Ralph V.] Univ Hawaii, John A Burns Sch Med, Ctr Cardiovasc Res, Honolulu, HI 96822 USA. [Smith, Jonathan D.] Cleveland Clin, Dept Cellular & Mol Med, Cleveland, OH 44106 USA. [Soliman, Elsayed Z.; Zhang, Zhu-Ming] Wake Forest Sch Med, Div Publ Hlth Sci, Dept Epidemiol & Prevent, Epidemiol Cardiol Res Ctr EPICARE, Winston Salem, NC USA. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Zonderman, Alan B.; Evans, Michele K.] NIA, Lab Epidemiol & Populat Sci, NIH, Baltimore, MD 21224 USA. [Murray, Sarah S.] Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA. [Whitsel, Eric A.] Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC USA. [Sotoodehnia, Nona] Univ Washington, Div Cardiol, Seattle, WA 98195 USA. RP Evans, DS (reprint author), Mission Hall Global Hlth & Clinical Sci Bldg, San Francisco, CA 94158 USA.; Sotoodehnia, N (reprint author), Metropolitan Pk East Tower,1730 Minor Ave, Seattle, WA 98101 USA. EM devans@psg.ucsf.edu; nsotoo@u.washington.edu FU National Institutes of Health [R01 HL088456, R01 HL116747, R01 HL111089, R01 HL091244, K99 HL098458, 5T32CA009330-30, R01 ES017794, HHSN268200625226C, UL1RR025005, P20MD006899, U24AG051129, HHSN268200782096C]; Laughlin Family; German Research Foundation [SCHNA 1149/3-1]; National Heart, Lung, and Blood Institute (NHLBI)sponsored Candidate gene Association Resource (CARe) project; ARIC; JHS; MESA; CFS; Broad Institute of Harvard; MIT [N01-HC-65226]; Atherosclerosis Risk in Communities (ARIC):National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, R01HL59367, R01HL086694]; National Human Genome Research Institute [U01HG004402]; NIH Roadmap for Medical Research; Cleveland Family Study (CFS): Case Western Reserve University [NIH HL 46380, M01RR00080]; Jackson Heart Study (JHS) from the National Heart, Lung, and Blood Institute [HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C]; National Institute on Minority Health and Health Disparities; Multi-Ethnic Study of Atherosclerosis (MESA): University of Washington [N01-HC-95159]; Regents of the University of California [N01-HC-95160]; Columbia University [N01-HC-95161]; Johns Hopkins University [N01-HC-95162, N01-HC-95168]; University of Minnesota [N01-HC95163]; Northwestern University [N01-HC-95164]; Wake Forest University [N01-HC95165]; University of Vermont [N01-HC-95166]; New England Medical Center [N01-HC-95167]; Harbor-UCLA Research and Education Institute [N01-HC-95169]; Cedars-Sinai Medical Center [R01-HL-071205]; University of Virginia [R01-HL-071205]; Health, Aging, and Body Composition Study (Health ABC): NIA [N01AG62101, N01AG62103, N01AG62106, 1R01AG032098-01A1]; Center for Inherited Disease Research (CIDR); Intramural Research Program of the NIH, National Institute on Aging; Healthy Aging in Neighbourhoods of Diversity across the Life Span Study (HANDLS): intramural research program of the National Institute on Aging; National Center for Minority Health and Health Disparities, National Institutes of Health; National Center on Minority Health and Health Disparities [Z01-AG000513, 2009-149]; Women's Health Initiative (WHI): National Heart, Lung, and Blood Institute; U.S. Department of Health and Human Services [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C]; NHLBI [N02-HL-64278]; Cardiovascular Health Study (CHS):NHLBI [HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, HHSN268200960009C, HL080295, HL087652, HL105756, HL103612, HL120393, HL130114, HL085251]; National Institute of Neurological Disorders and Stroke (NINDS); National Institute on Aging (NIA) [AG023629]; National Center for Advancing Translational Sciences; CTSI [UL1TR000124]; National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) [DK063491]; Baltimore Longitudinal Study of Aging (BLSA): Intramural Research Program of the NIH; National Institute on Aging; MedStar Research Institute; Bogalusa Heart Study (BHS): National Institute of Environmental Health Science [R01ES021724]; National Institute on Aging [R01AG016592]; STSI/TSRI [U54 NS056883]; Scripps Genomic Medicine; National Human Genome Research Institute (NHGRI) [U01HG007416, U01HG007417, U01HG007397, U01HG007376, U01HG007419]; PAGE Coordinating Center [U01HG007419]; NIH [5R01HL090620, 5R01HL111314]; Fondation Leducq [CVD-07-03]; European North American Atrial Fibrillation Research Alliance FX This work was supported by the National Institutes of Health [R01 HL088456 to N.S., R01 HL116747 to N.S., R01 HL111089 to N.S., R01 HL091244 to N.S., K99 HL098458 to C.L.A., 5T32CA009330-30 to A.M.B., R01 ES017794 to E.A.W., P20MD006899 to S.G.B.,and U24AG051129 to D.S.E.], the Laughlin Family [to N.S.], and the German Research Foundation [SCHNA 1149/3-1 to R.B.S.].; As part of the National Heart, Lung, and Blood Institute (NHLBI)sponsored Candidate gene Association Resource (CARe) project, the ARIC, JHS, MESA, and CFS studies contributed parent study data, ancillary study data, and DNA samples through the Broad Institute of Harvard and MIT (N01-HC-65226) to create a genotype/phenotype database for wide dissemination to the biomedical research community.; Atherosclerosis Risk in Communities (ARIC): The ARIC study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by GrantNumber UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research.; Cleveland Family Study (CFS): Case Western Reserve University (NIH HL 46380, M01RR00080).; Jackson Heart Study (JHS): The Jackson Heart Study is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C from the National Heart, Lung, and Blood Institute and the National Institute on Minority Health and Health Disparities. Multi-Ethnic Study of Atherosclerosis (MESA): University of Washington (N01-HC-95159), Regents of the University of California (N01-HC-95160), Columbia University (N01-HC-95161), Johns Hopkins University (N01-HC-95162, N01-HC-95168), University of Minnesota (N01-HC95163), Northwestern University (N01-HC-95164), Wake Forest University (N01-HC95165), University of Vermont (N01-HC-95166), New England Medical Center (N01-HC-95167), Harbor-UCLA Research and Education Institute (N01-HC-95169), Cedars-Sinai Medical Center (R01-HL-071205), and University of Virginia (subcontract to R01-HL-071205).; Health, Aging, and Body Composition Study (Health ABC): The Health ABC study was supported by NIA contracts N01AG62101, N01AG62103, and N01AG62106. The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging.; Healthy Aging in Neighbourhoods of Diversity across the Life Span Study (HANDLS): The HANDLS study was in part supported by the intramural research program of the National Institute on Aging and the National Center for Minority Health and Health Disparities, National Institutes of Health. This research was supported by the Intramural Research Program of the NIH, National Institute on Aging and the National Center on Minority Health and Health Disparities (contract # Z01-AG000513 and human subjects protocol # 2009-149). Data analyses for the HANDLS study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, Md. (http://biowulf.nih.gov).; Women's Health Initiative (WHI): The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. This manuscript was prepared in collaboration with investigators of the WHI, and has been reviewed and/or approved by the Women's Health Initiative (WHI). WHI investigators are listed at https://www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20I nvestigator%20Short%20List.pdf. Funding for WHI SHARe genotyping was provided by NHLBI Contract N02-HL-64278.; Cardiovascular Health Study (CHS): This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, HHSN268200960009C; and NHLBI grants HL080295, HL087652, HL105756, HL103612, HL120393, and HL130114, HL085251 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org/. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.; Baltimore Longitudinal Study of Aging (BLSA): The BLSA was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. A portion of that support was through a R&D contract with MedStar Research Institute.; Bogalusa Heart Study (BHS): BHS is supported by grants R01ES021724 from National Institute of Environmental Health Science and R01AG016592 from the National Institute on Aging. Analysis performed at STSI/TSRI was supported by U54 NS056883 and Scripps Genomic Medicine. The Population Architecture Using Genomics and Epidemiology (PAGE) program is funded by the National Human Genome Research Institute (NHGRI), supported by U01HG007416 (CALiCo), U01HG007417 (ISMMS), U01HG007397 (MEC), U01HG007376 (WHI), and U01HG007419 (Coordinating Center). The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. The complete list of PAGE members can be found at http://www.pagestudy.org. Assistance with data management, data integration, data dissemination, genotype imputation, ancestry deconvolution, and general study coordination was provided by the PAGE Coordinating Center (U01HG007419). The PAGE consortium thanks the staff and participants of all PAGE studies for their important contributions. Funding for the atrial tissue eQTL study was provided by NIH 5R01HL090620, NIH 5R01HL111314, Fondation Leducq CVD-07-03, European North American Atrial Fibrillation Research Alliance. NR 80 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD OCT 1 PY 2016 VL 25 IS 19 BP 4350 EP 4368 DI 10.1093/hmg/ddw284 PG 19 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA EN1YZ UT WOS:000395807800017 PM 27577874 ER PT J AU Compton, WM Han, B Jones, CM Blanco, C Hughes, A AF Compton, Wilson M. Han, Beth Jones, Christopher M. Blanco, Carlos Hughes, Arthur TI Marijuana use and use disorders in adults in the USA, 2002-14: analysis of annual cross-sectional surveys SO LANCET PSYCHIATRY LA English DT Article ID SUBSTANCE USE; UNITED-STATES; CANNABIS USE; PREVALENCE; TRENDS AB Background The study of marijuana use disorders is urgently needed because of increasing marijuana legalisation in multiple jurisdictions, the effect of marijuana use on future risk of psychiatric disorders, and deleterious effects of marijuana exposure. Thus, understanding trends of marijuana use and use disorders and examining factors that might drive these trends (eg, perceptions of harms from marijuana use) is essential. Methods We analysed data from US civilians aged 18 years or older who participated in annual, cross-sectional US National Surveys on Drug Use and Health from 2002 to 2014. The sample in each US state was designed to be approximately equally distributed between participants aged 12-17 years, 18-25 years, and 26 years or older. For each survey year, we estimated prevalence of marijuana use and use disorders, initiation of marijuana use, daily or near daily use, perception of great or no risk of harm from smoking marijuana, perception of state legalisation of medical marijuana use, and mean number of days of marijuana use in the previous year. Descriptive analyses, multivariable logistic regressions, and zerotruncated negative binomial regressions were applied. Findings 596 500 adults participated in the 2002-14 surveys. Marijuana use increased from 10.4% (95% CI 9.97-10.82) to 13.3% (12.84-13.70) in adults in the USA from 2002 to 2014 (beta=0.0252, p< 0.0001), and the prevalence of perceiving great risk of harm from smoking marijuana once or twice a week decreased from 50.4% (49.60-51.25) to 33.3% (32.64-33.96; beta=-0.0625, p< 0.0001). Changes in marijuana use and risk perception generally began in 2006-07. After adjusting for all covariates, changes in risk perceptions were associated with changes in prevalence of marijuana use, as seen in the lower prevalence of marijuana use each year during 2006-14 than in 2002 when perceiving risk of harm from smoking marijuana was included in models. However, marijuana use disorders in adults remained stable at about 1.5% between 2002 and 2014(beta=-0.0042, p=0.22). Interpretation Prevalence and frequency of marijuana use increased in adults in the USA starting in approximately 2007 and showing significantly higher results in multivariable models during 2011-14 (compared with 2002). The associations between increases in marijuana use and decreases in perceiving great risk of harm from smoking marijuana suggest the need for education regarding the risk of smoking marijuana and prevention messages. C1 [Compton, Wilson M.; Blanco, Carlos] NIDA, NIH, Bethesda, MD 20892 USA. [Han, Beth; Hughes, Arthur] Subst Abuse & Mental Hlth Serv Adm, Rockville, MD USA. [Jones, Christopher M.] US Dept HHS, Off Assistant Secretary Planning & Evaluat, Washington, DC 20201 USA. RP Compton, WM (reprint author), NIDA, NIH, Bethesda, MD 20892 USA. EM wcompton@nida.nih.gov FU Substance Abuse and Mental Health Services Administration; National Institute on Drug Abuse; Office of the Assistant Secretary for Planning and Evaluation of the US Department of Health and Human Services FX The National Surveys on Drug Use and Health were supported by contracts from the Substance Abuse and Mental Health Services Administration. This study was jointly sponsored by the Substance Abuse and Mental Health Services Administration, the National Institute on Drug Abuse, and the Office of the Assistant Secretary for Planning and Evaluation of the US Department of Health and Human Services. NR 28 TC 3 Z9 3 U1 1 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2215-0374 J9 LANCET PSYCHIAT JI Lancet Psychiatry PD OCT PY 2016 VL 3 IS 10 BP 954 EP 964 DI 10.1016/S2215-0366(16)30208-5 PG 11 WC Psychiatry SC Psychiatry GA EN9UE UT WOS:000396344300023 PM 27592339 ER PT J AU Koroulakis, A Shankavaram, UT Smart, DK Camphausen, KA Krauze, AV AF Koroulakis, A. Shankavaram, U. T. Smart, D. K. Camphausen, K. A. Krauze, A. V. TI Radiation Therapy Management for Malignant Melanoma: A Population Study SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT 58th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) CY SEP 25-28, 2016 CL Boston, MA SP Amer Soc Radiat Oncol C1 [Koroulakis, A.] George Washington Univ, Sch Med, Washington, DC USA. [Shankavaram, U. T.; Smart, D. K.; Camphausen, K. A.; Krauze, A. V.] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD OCT 1 PY 2016 VL 96 IS 2 SU S MA 3759 BP E717 EP E717 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA EB8QL UT WOS:000387655804338 ER PT J AU Gittleman, HR Lim, D Kattan, M Chakravarti, A Gilbert, MR Lassman, AB Lo, SS Machtay, M Sloan, AE Sulman, EP Tian, D Vogelbaum, MA Wang, TJC Penas-Prado, M Youssef, E Blumenthal, DT Zhang, P Mehta, MP Barnholtz-Sloan, J AF Gittleman, H. R. Lim, D. Kattan, M. Chakravarti, A. Gilbert, M. R. Lassman, A. B. Lo, S. S. Machtay, M. Sloan, A. E. Sulman, E. P. Tian, D. Vogelbaum, M. A. Wang, T. J. C. Penas-Prado, M. Youssef, E. Blumenthal, D. T. Zhang, P. Mehta, M. P. Barnholtz-Sloan, J. TI An Independently Validated Nomogram for Individualized Estimation of Survival Among Patients With Newly Diagnosed Glioblastoma: NRG Oncology/RTOG 0525 and 0825 SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT 58th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) CY SEP 25-28, 2016 CL Boston, MA SP Amer Soc Radiat Oncol C1 [Gittleman, H. R.; Lim, D.; Sloan, A. E.; Tian, D.; Barnholtz-Sloan, J.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Kattan, M.; Vogelbaum, M. A.] Cleveland Clin Fdn, 9500 Euclid Ave, Cleveland, OH 44195 USA. [Chakravarti, A.] Ohio State Univ, Columbus, OH 43210 USA. [Gilbert, M. R.] NCI, NIH, Bethesda, MD 20892 USA. [Lassman, A. B.; Wang, T. J. C.] Columbia Univ, New York, NY USA. [Lo, S. S.; Machtay, M.] Case Western Reserve Univ, Sch Med, Cleveland, OH USA. [Sulman, E. P.; Penas-Prado, M.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Youssef, E.] Barrow Neurol Inst, Phoenix, AZ 85013 USA. [Blumenthal, D. T.] Tel Aviv Med Ctr & Sch Med, Tel Aviv, Israel. [Zhang, P.] NRG Oncol Stat & Data Management Ctr, Philadelphia, PA USA. [Mehta, M. P.] Univ Maryland, Baltimore, MD 21201 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD OCT 1 PY 2016 VL 96 IS 2 SU S MA 208 BP S92 EP S92 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA EB8QL UT WOS:000387655804545 ER PT J AU Jones, JC Morales-Kastresana, A Kesarwala, AH Jenkins, L Choyke, P Camphausen, KA Berzofsky, J AF Jones, J. C. Morales-Kastresana, A. Kesarwala, A. H. Jenkins, L. Choyke, P. Camphausen, K. A. Berzofsky, J. TI NanoFACS: Extracellular Vesicle Subset Sorting for Personalized Medicine and Biodosimetry SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT 58th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) CY SEP 25-28, 2016 CL Boston, MA SP Amer Soc Radiat Oncol C1 [Jones, J. C.; Berzofsky, J.] NCI, Vaccine Branch, Bethesda, MD 20892 USA. [Morales-Kastresana, A.; Jenkins, L.] NCI, Bethesda, MD 20892 USA. [Kesarwala, A. H.; Camphausen, K. A.] NCI, NIH, Bethesda, MD 20892 USA. [Choyke, P.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. RI Jones, Jennifer/C-8691-2015 OI Jones, Jennifer/0000-0002-9488-7719 NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD OCT 1 PY 2016 VL 96 IS 2 SU S MA 119 BP S53 EP S54 PG 2 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA EB8QL UT WOS:000387655804456 ER PT J AU Kalapurakal, JA Gopalakrishnan, M Jung, JW Peterson, S Leisenring, W Laurie, F Rigsby, C Lee, C Fitzgerald, T Lee, C AF Kalapurakal, J. A. Gopalakrishnan, M. Jung, J. W. Peterson, S. Leisenring, W. Laurie, F. Rigsby, C. Lee, C. Fitzgerald, T. Lee, C. TI Accuracy of a Computational Human Phantom Model for Retrospective 3-Dimensional Target-Organ Dosimetry for Late Effects Study of Patients on National Wilms Tumor Study Protocols SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT 58th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) CY SEP 25-28, 2016 CL Boston, MA SP Amer Soc Radiat Oncol C1 [Kalapurakal, J. A.] Northwestern Univ, Dept Radiat Oncol, Chicago, IL 60611 USA. [Gopalakrishnan, M.] Northwestern Mem Hosp, Chicago, IL USA. [Jung, J. W.] East Carolina Univ, Greenville, NC USA. [Peterson, S.; Leisenring, W.] Fred Hutchison Canc Ctr, Seattle, WA USA. [Laurie, F.] Qual Assurance Review Ctr, Lincoln, RI USA. [Rigsby, C.] Lurie Childrens Hosp, Chicago, IL USA. [Lee, C.] Univ Michigan, Ann Arbor, MI 48109 USA. [Fitzgerald, T.] UMass Mem Med Ctr, Worcester, MA USA. [Lee, C.] NCI, NIH, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD OCT 1 PY 2016 VL 96 IS 2 SU S MA 1155 BP S229 EP S229 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA EB8QL UT WOS:000387655805158 ER PT J AU Willers, H Liu, Q Efstathiou, JA Gheorghiu, L Drumm, MR Clayman, RH Eidelman, A Wszolek, MF Feldman, AS Wang, M Marcar, L Citrin, DE Wu, CL Benes, C AF Willers, H. Liu, Q. Efstathiou, J. A. Gheorghiu, L. Drumm, M. R. Clayman, R. H. Eidelman, A. Wszolek, M. F. Feldman, A. S. Wang, M. Marcar, L. Citrin, D. E. Wu, C. L. Benes, C. TI PARP1 Inhibition Radiosensitizes A Subset Of Genotype-Defined Bladder Cancers Through Modulation Of Reactive Oxygen Species SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT 58th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) CY SEP 25-28, 2016 CL Boston, MA SP Amer Soc Radiat Oncol C1 [Willers, H.; Liu, Q.; Efstathiou, J. A.; Gheorghiu, L.; Wang, M.; Marcar, L.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Drumm, M. R.; Clayman, R. H.; Eidelman, A.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA USA. [Wszolek, M. F.; Feldman, A. S.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Urol, Boston, MA USA. [Citrin, D. E.] NCI, Radiat Oncol Branch, Bldg 10, Bethesda, MD 20892 USA. [Wu, C. L.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Benes, C.] Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD OCT 1 PY 2016 VL 96 IS 2 SU S MA 1175 BP S237 EP S238 PG 2 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA EB8QL UT WOS:000387655805178 ER PT J AU Chalasani, N Shah, V Sanyal, AJ Liangpunsakul, S Tang, Q Comerford, M Puri, P Radaeva, S Katz, BP Crabb, D AF Chalasani, Naga Shah, Vijay Sanyal, Arun J. Liangpunsakul, Suthat Tang, Qing Comerford, Megan Puri, Puneet Radaeva, Svetlana Katz, Barry P. Crabb, David TI Acute Alcoholic Hepatitis in the United States: Clinical Characteristics, Outcomes and Relationship with PNPLA3 Genotype and Coffee Drinking SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Meeting Abstract CT 81st Annual Scientific Meeting of the American-College-of-Gastroenterology CY OCT 21-26, 2016 CL Las Vegas, NV SP Amer Coll Gastroenterol C1 [Chalasani, Naga; Tang, Qing; Katz, Barry P.; Crabb, David] Indiana Univ, Indianapolis, IN 46204 USA. [Shah, Vijay] Mayo Clin, Rochester, MN USA. [Sanyal, Arun J.; Puri, Puneet] Virginia Commonwealth Univ, Richmond, VA USA. [Liangpunsakul, Suthat; Comerford, Megan] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Radaeva, Svetlana] NIAAA, NIN, DMHE, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 EI 1572-0241 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD OCT PY 2016 VL 111 SU 1 MA 754 BP S339 EP S339 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EN1IV UT WOS:000395764601187 ER PT J AU Pasricha, PJ Yates, K Sarosiek, I McCallum, R Clarke, J Nguyen, L Dhalla, S Stein, E Koch, K Abell, T Hasler, W Snape, W Lee, L Grover, M Miriel, L Van Natta, M Farrugia, G Tonascia, J Hamilton, F Parkman, H AF Pasricha, Pankaj Jay Yates, Katherine Sarosiek, Irene McCallum, Richard Clarke, John Nguyen, Linda Dhalla, Sameer Stein, Ellen Koch, Kenneth Abell, Thomas Hasler, William Snape, William Lee, Linda Grover, Madhusudan Miriel, Laura Van Natta, Mark Farrugia, Gianrico Tonascia, James Hamilton, Frank Parkman, Henry TI Aprepitant for Symptoms of Gastroparesis and Related Disorders: The APRON Randomized Clinical Trial SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Meeting Abstract CT 81st Annual Scientific Meeting of the American-College-of-Gastroenterology CY OCT 21-26, 2016 CL Las Vegas, NV SP Amer Coll Gastroenterol C1 [Pasricha, Pankaj Jay] Johns Hopkins Univ, Sch Med, Balltimore, MD USA. [Yates, Katherine; Miriel, Laura; Van Natta, Mark; Tonascia, James] Johns Hopkins Univ, Baltimore, MD USA. [Sarosiek, Irene; McCallum, Richard] Texas Tech Univ, Hlth Sci Ctr, El Paso, TX USA. [Clarke, John; Dhalla, Sameer; Stein, Ellen; Lee, Linda] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Nguyen, Linda] Stanford Univ, Med Ctr, Stanford, CA 94305 USA. [Koch, Kenneth] Wake Forest Univ, Sch Med, Wake Forest, NC USA. [Abell, Thomas] Univ Louisville, Sch Med, Louisville, KY 40292 USA. [Hasler, William] Univ Michigan, Sch Med, Ann Arbor, MI USA. [Snape, William] Calif Pacific Med Ctr, San Francisco, CA USA. [Grover, Madhusudan; Farrugia, Gianrico] Mayo Clin, Rochester, MN USA. [Hamilton, Frank] NIDDK, NIH, Bethesda, MD 20892 USA. [Parkman, Henry] Temple Univ, Sch Med, Philadelphia, PA 19122 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 EI 1572-0241 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD OCT PY 2016 VL 111 SU 1 MA 1100 BP S480 EP S481 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EN1IV UT WOS:000395764601531 ER PT J AU Tey, KR Singh, N Takyar, V Trowers, E AF Tey, Kai Rou Singh, Nirmal Takyar, Varun Trowers, Eugene TI Role of Proton Pump Inhibitors in Recurrence of Clostridium difficile Infection: Systematic Review and Meta-Analysis SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Meeting Abstract CT 81st Annual Scientific Meeting of the American-College-of-Gastroenterology CY OCT 21-26, 2016 CL Las Vegas, NV SP Amer Coll Gastroenterol C1 [Tey, Kai Rou; Singh, Nirmal; Trowers, Eugene] Univ Arizona, Coll Med, Tucson, AZ USA. [Takyar, Varun] NIDDK, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 EI 1572-0241 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD OCT PY 2016 VL 111 SU 1 MA 1033 BP S449 EP S450 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EN1IV UT WOS:000395764601465 ER PT J AU Meaden, S Metcalf, CJE Koskella, B AF Meaden, S. Metcalf, C. J. E. Koskella, B. TI The effects of host age and spatial location on bacterial community composition in the English Oak tree (Quercus robur) SO ENVIRONMENTAL MICROBIOLOGY REPORTS LA English DT Article ID RHIZOSPHERE MICROBIOME; ROOT MICROBIOME; GUT MICROBIOME; LIFE-HISTORY; PHYLLOSPHERE; DIVERSITY; ECOLOGY; SEQUENCE; PATTERNS; TRAITS AB Drivers of bacterial community assemblages associated with plants are diverse and include biotic factors, such as competitors and host traits, and abiotic factors, including environmental conditions and dispersal mechanisms. We examine the roles of spatial distribution and host size, as an approximation for age, in shaping the microbiome associated with Quercus robur woody tissue using cultureindependent 16S rRNA gene amplicon sequencing. In addition to providing a baseline survey of the Q. robur microbiome, we screened for the pathogen of acute oak decline. Our results suggest that age is a predictor of bacterial community composition, demonstrating a surprising negative correlation between tree age and alpha diversity. We find no signature of dispersal limitation within the Wytham Woods plot sampled. Together, these results provide evidence for niche-based hypotheses of community assembly and the importance of tree age in bacterial community structure, as well as highlighting that caution must be applied when diagnosing dysbiosis in a long-lived plant host. C1 [Meaden, S.] Univ Exeter, Coll Life & Environm Sci, Penryn Campus, Exeter TR109FE, Devon, England. [Metcalf, C. J. E.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Metcalf, C. J. E.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Koskella, B.] Univ Calif Berkeley, Dept Integrat Biol, Berkeley, CA 94720 USA. RP Meaden, S (reprint author), Univ Exeter, Coll Life & Environm Sci, Penryn Campus, Exeter TR109FE, Devon, England. EM s.meaden@exeter.ac.uk FU Royal Society; University of Exeter; NERC [NE/K00879X/1] FX This work was supported by a Royal Society Research Grant (to CJEM and BK). SM was funded by a studentship at the University of Exeter, BK by a NERC independent research fellowship (NE/K00879X/1), and CJEM by a Royal Society Fellowship. The authors thank Dr. Rob Jackson at the University of Reading for providing an isolate of Brenneria, Dr. Keith Kirby for providing data on tree age and size and Dr. Konrad Paskiewicz as well as the faculty and participants of the NERC-funded population genomics workshop for training in bioinformatics analyses. The 18-ha Long-Term Forest Monitoring Plot is a collaborative project between the University of Oxford, the Centre for Ecology and Hydrology, and the Smithsonian Institution CTFS Forest-GEO (HSBC Climate Partnership). NR 77 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1758-2229 J9 ENV MICROBIOL REP JI Environ. Microbiol. Rep. PD OCT PY 2016 VL 8 IS 5 SI SI BP 649 EP 658 DI 10.1111/1758-2229.12418 PG 10 WC Environmental Sciences; Microbiology SC Environmental Sciences & Ecology; Microbiology GA EM0IP UT WOS:000395002300018 ER PT J AU Liu, T Sabato, P Ivaturi, V Wright, JJ Greer, JM Pratz, KW Smith, BD Rudek, MA AF Liu, Tao Sabato, Philip Ivaturi, Vijay Wright, John J. Greer, Jacqueline M. Pratz, Keith W. Smith, B. Douglas Rudek, Michelle A. TI Population Pharmacokinetics and Pharmacodynamics of Sorafenib in Acute Myelogenous/B-Type Leukemia Patients SO JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS LA English DT Meeting Abstract C1 [Liu, Tao; Sabato, Philip; Ivaturi, Vijay] Univ Maryland, Ctr Translat Med, Baltimore, MD 21201 USA. [Wright, John J.] NCI, Invest Drug Branch, Bethesda, MD 20892 USA. [Greer, Jacqueline M.; Pratz, Keith W.; Smith, B. Douglas; Rudek, Michelle A.] Sindey Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1567-567X EI 1573-8744 J9 J PHARMACOKINET PHAR JI J. Pharmacokinet. Pharmacodyn. PD OCT PY 2016 VL 43 SU 1 MA T-68 BP S79 EP S79 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EK4JU UT WOS:000393893700152 ER PT J AU Lommerse, J Clarke, D Chain, A Witjes, H Teppler, H Acosta, EP Capparelli, E Rizk, ML Wenning, L Kerbusch, T Spector, S Smith, B Mirochnick, M AF Lommerse, Jos Clarke, Diana Chain, Anne Witjes, Han Teppler, Hedy Acosta, Edward P. Capparelli, Edmund Rizk, Matthew L. Wenning, Larissa Kerbusch, Thomas Spector, Stephen Smith, Betsy Mirochnick, Mark TI Raltegravir PK in neonates - Modeling rising and declining PK profiles of newborns exposed to raltegravir in-utero SO JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS LA English DT Meeting Abstract C1 [Lommerse, Jos; Witjes, Han; Kerbusch, Thomas] Certara Strateg Consulting, Oss, Netherlands. [Clarke, Diana] Boston Med Ctr, Boston, MA USA. [Chain, Anne; Teppler, Hedy; Rizk, Matthew L.; Wenning, Larissa] Merck Res Labs, Rahway, NJ USA. [Acosta, Edward P.] Univ Alabama Birmingham, Birmingham, AL USA. [Capparelli, Edmund] Univ Calif San Diego, San Diego, CA 92103 USA. [Spector, Stephen] San Diego & Rady Childrens Hosp, San Diego, CA USA. [Smith, Betsy] NIAID, NIH, Div Aids, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Mirochnick, Mark] Boston Univ, Sch Med, MAAIDS, Bethesda, MD USA. [Mirochnick, Mark] Boston Univ, Sch Med, Bethesda, MD USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1567-567X EI 1573-8744 J9 J PHARMACOKINET PHAR JI J. Pharmacokinet. Pharmacodyn. PD OCT PY 2016 VL 43 SU 1 MA T-34 BP S63 EP S63 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EK4JU UT WOS:000393893700118 ER PT J AU Lommerse, J Clarke, D Chain, A Witjes, H Teppler, H Acosta, EP Capparelli, E Rizk, ML Wenning, L Kerbusch, T Spector, S Smith, B Mirochnick, M AF Lommerse, Jos Clarke, Diana Chain, Anne Witjes, Han Teppler, Hedy Acosta, Edward P. Capparelli, Edmund Rizk, Matthew L. Wenning, Larissa Kerbusch, Thomas Spector, Stephen Smith, Betsy Mirochnick, Mark TI Raltegravir PK in neonates - An adaptive trial design to define an appropriate regimen for neonates from birth to 6 weeks of age. SO JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS LA English DT Meeting Abstract C1 [Lommerse, Jos; Witjes, Han; Kerbusch, Thomas] Certara Strateg Consulting, Oss, Netherlands. [Clarke, Diana] Boston Med Ctr, Boston, MA USA. [Chain, Anne; Teppler, Hedy; Rizk, Matthew L.; Wenning, Larissa] Merck Res Labs, Rahway, NJ USA. [Acosta, Edward P.] Univ Alabama Birmingham, Birmingham, AL USA. [Capparelli, Edmund] Univ Calif San Diego, San Diego, CA 92103 USA. [Spector, Stephen] San Diego & Rady Childrens Hosp, San Diego, CA USA. [Smith, Betsy] NIAID, NIH, Div Aids, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Mirochnick, Mark] Boston Univ, Sch Med, Boston, MA 02215 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1567-567X EI 1573-8744 J9 J PHARMACOKINET PHAR JI J. Pharmacokinet. Pharmacodyn. PD OCT PY 2016 VL 43 SU 1 MA T-33 BP S62 EP S62 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EK4JU UT WOS:000393893700117 ER PT J AU Singh, RP Edwards, AY Ruel, T Wiznia, A Acosta, E Hazra, R Buchanan, AM AF Singh, Rajendra P. Edwards, Alena Yin Ruel, Theodore Wiznia, Andrew Acosta, Edward Hazra, Rohan Buchanan, Ann M. TI Population Pharmacokinetics of Dolutegravir in HIV-Infected Pediatric Subjects SO JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS LA English DT Meeting Abstract C1 [Singh, Rajendra P.] GlaxoSmithKline, CPMS, Philadelphia, PA USA. [Edwards, Alena Yin] ICON Plc Ireland, Dublin, Ireland. [Ruel, Theodore] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Wiznia, Andrew] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Acosta, Edward] Univ Alabama Birmingham, Birmingham, AL USA. [Hazra, Rohan] NICHD, NIH, Bethesda, MD USA. [Buchanan, Ann M.] ViiV Healthcare, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1567-567X EI 1573-8744 J9 J PHARMACOKINET PHAR JI J. Pharmacokinet. Pharmacodyn. PD OCT PY 2016 VL 43 SU 1 MA W-64 BP S114 EP S114 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EK4JU UT WOS:000393893700229 ER PT J AU Keutgen, XM Boufraqech, M Gara, SK Agarwal, S Hruban, R Nickolas, P Quezado, M Wheeler, DL Cam, MM Kebebew, E AF Keutgen, Xavier M. Boufraqech, Myriem Gara, Sudheer Kumar Agarwal, Sunita Hruban, Ralph Nickolas, Papadopoulos Quezado, Martha Wheeler, David L. Cam, Maggie M. Kebebew, Electron TI MicroRNA and Gene Expression Profiling in Syndromic and Sporadic Non-Functioning Pancreatic Neuroendocrine Tumors: An Integrated Analysis SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Meeting Abstract CT Clinical Congress and Scientific Forum of the American-College-of-Surgeons CY OCT 15-20, 2016 CL Washington, DC SP Amer Coll Surg C1 NCI, NIH, Baltimore, MD USA. Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 EI 1879-1190 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD OCT PY 2016 VL 223 IS 4 SU 2 BP E13 EP E14 PG 2 WC Surgery SC Surgery GA EN2FL UT WOS:000395825100028 ER PT J AU Juana, SL Sachin, K Zhang, CP Josefina, SL Francisco, GM Jing, F Ashely, W Fatima, M Paul, R Yamileth, R Hartmut, G Leighton, G Daniel, TS Joaquin, SG Antonio, CPJ AF Lopez Juana, Serrano Sachin, Kumar Zhang Cuiping Lopez Josefina, Serrano Mariscal Francisco, Gutierrez Jing, Fang Ashely, Wellendorf Fatima, Mohmoud Paul, Roche Yamileth, Rangel Hartmut, Geiger Leighton, Grimes Starczynowski Daniel, T. Garcia Joaquin, Sanchez Jose Antonio, Cancelas Perez TI DESCRIPTION OF A NEW LYMPHATIC NETWORK IN BONE MARROW AS EMERGENCY EXITS FOR DENDRITIC PROGENITORS IN INFLAMMATION VIA TLR4/TRAF6/IKK/SNAP23 AND ACTIVATION OF CCL19/CCR7 SO HAEMATOLOGICA LA Spanish DT Meeting Abstract CT 58th National Congress of the Spanish-Society-of-Hematology-and-Hemotherapy CY OCT 20-22, 2016 CL Santiago de Compostela, SPAIN SP Spanish Soc Hematol & Hemotherapy C1 [Lopez Juana, Serrano; Lopez Josefina, Serrano; Mariscal Francisco, Gutierrez; Yamileth, Rangel; Garcia Joaquin, Sanchez] Hosp Univ Reina Sofia, IMIBIC, Cordoba, Spain. [Sachin, Kumar; Zhang Cuiping; Jing, Fang; Hartmut, Geiger; Starczynowski Daniel, T.; Jose Antonio, Cancelas Perez] Cincinnati Childrens Res Fdn, Div Expt Hematol, Cincinnati, OH USA. [Ashely, Wellendorf] CCHMC, Cincinnati Childrens Res Fdn, Div Expt Hematol, Cincinnati, OH USA. [Fatima, Mohmoud] Univ Cincinnati, Hoxworth Blood Ctr, Cincinnati, OH 45221 USA. [Paul, Roche] NCI, Bethesda, MD 20892 USA. [Leighton, Grimes] Univ Cincinnati, Dept Canc Biol, Cincinnati, OH 45221 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD OCT PY 2016 VL 101 SU 4 MA PC-367 BP 290 EP 291 PG 2 WC Hematology SC Hematology GA EI5QG UT WOS:000392548800503 ER PT J AU Apolo, AB Mortazavi, A Stein, M Pal, SK Davarpanah, N Parnes, HL Ning, YM Francis, DC Cordes, LM Berniger, M Steinberg, SM Monk, P Lancaster, T Mayer, T Costello, R Bottaro, DP Dahut, WL AF Apolo, A. B. Mortazavi, A. Stein, M. Pal, S. K. Davarpanah, N. Parnes, H. L. Ning, Y. M. Francis, D. C. Cordes, L. M. Berniger, M. Steinberg, S. M. Monk, P. Lancaster, T. Mayer, T. Costello, R. Bottaro, D. P. Dahut, W. L. TI A phase I study of cabozantinib plus nivolumab (CaboNivo) in patients (pts) refractory metastatic urothelial carcinoma (mUC) and other genitourinary (GU) tumors SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 41st Congress of the European-Society-for-Medical-Oncology (ESMO) CY OCT 07-11, 2016 CL Copenhagen, DENMARK SP European Soc Med Oncol C1 [Apolo, A. B.; Davarpanah, N.; Francis, D. C.; Cordes, L. M.; Berniger, M.; Costello, R.; Bottaro, D. P.; Dahut, W. L.] NCI, Genitourinary Malignancies Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Mortazavi, A.; Monk, P.; Lancaster, T.] Ohio State Univ, Med Ctr, Internal Med, Columbus, OH 43210 USA. [Stein, M.] Canc Inst New Jersey, Div Med Oncol, New Brunswick, NJ USA. [Pal, S. K.] City Hope Natl Med Ctr, Med Oncol, Duarte, CA USA. [Parnes, H. L.; Ning, Y. M.; Steinberg, S. M.] NCI, Med Oncol, Bethesda, MD 20892 USA. [Mayer, T.] Canc Inst New Jersey, Med Oncol, New Brunswick, NJ USA. FU NCI FX NCI NR 0 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD OCT 1 PY 2016 VL 27 SU 6 MA 774PD DI 10.1093/annonc/mdw373.2 PG 1 WC Oncology SC Oncology GA EK4QS UT WOS:000393912500770 ER PT J AU Coyne, GO Chen, A Kummar, S Collins, JM Meehan, RS Suto, M Rubinstein, L Kinders, R Moore, N Parchment, R Horneffer, Y Juwara, L Difilippantonio, M Piekarz, R Doroshow, J AF Coyne, G. O'Sullivan Chen, A. Kummar, S. Collins, J. M. Meehan, R. S. Suto, M. Rubinstein, L. Kinders, R. Moore, N. Parchment, R. Horneffer, Y. Juwara, L. Difilippantonio, M. Piekarz, R. Doroshow, J. TI First-in-human trial of 4 '-thio-2 '-deoxycytidine (TdCyd) in patients with advanced solid tumors SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 41st Congress of the European-Society-for-Medical-Oncology (ESMO) CY OCT 07-11, 2016 CL Copenhagen, DENMARK SP European Soc Med Oncol C1 [Coyne, G. O'Sullivan; Chen, A.; Meehan, R. S.; Horneffer, Y.; Piekarz, R.] NCI, Dev Therapeut Clin, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Kummar, S.] Stanford Univ, Div Oncol, Phase Clin Res 1, Palo Alto, CA 94304 USA. [Collins, J. M.; Difilippantonio, M.; Doroshow, J.] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Suto, M.] Southern Res Inst, Drug Discovery Div, Birmingham, AL USA. [Rubinstein, L.] NCI, Biometr Res Program, Bethesda, MD 20892 USA. [Kinders, R.; Parchment, R.] Frederick Natl Lab Canc Res, Appl Dev Res Directorate, Frederick, MD USA. [Moore, N.; Juwara, L.] Leidos Biomed Res, Clin Monitoring Res Program, Bethesda, MD USA. FU National Cancer Institute FX National Cancer Institute NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD OCT 1 PY 2016 VL 27 SU 6 MA 411TiP DI 10.1093/annonc/mdw368.54 PG 1 WC Oncology SC Oncology GA EK4QS UT WOS:000393912500409 ER PT J AU Gutierrez, ME Giaccone, G Liu, SV Rajan, A Guha, U Halfdanarson, TR Curtis, KK Kunz, PL Gabrail, N Hinson, JM Orlemans, EO AF Gutierrez, M. E. Giaccone, G. Liu, S. V. Rajan, A. Guha, U. Halfdanarson, T. R. Curtis, K. K. Kunz, P. L. Gabrail, N. Hinson, J. M. Orlemans, E. O. TI Phase I, open-label, dose-escalation study of SNX-5422 plus everolimus in neuroendocrine tumors (NETs) SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 41st Congress of the European-Society-for-Medical-Oncology (ESMO) CY OCT 07-11, 2016 CL Copenhagen, DENMARK SP European Soc Med Oncol C1 [Gutierrez, M. E.] John Theurer Canc Ctr, Hematol & Oncol, Hackensack, NJ USA. [Giaccone, G.; Liu, S. V.] Georgetown Univ, Lombardi Canc Ctr, Hematol & Oncol, Washington, DC USA. [Rajan, A.; Guha, U.] NCI, Thorac & Gastrointestinal Oncol, Ctr Canc Res, Bethesda, MD 20892 USA. [Halfdanarson, T. R.] Mayo Clin, Med, Rochester, MN USA. [Curtis, K. K.] Mayo Clin, Internal Med, Scottsdale, AZ USA. [Kunz, P. L.] Stanford Univ, Sch Med, Med Oncol, Palo Alto, CA 94304 USA. [Gabrail, N.] Gabrail Canc Ctr, Hematol, Canton, OH USA. [Hinson, J. M.] Unicorn Pharma Consulting, Clin Res, Nashville, TN USA. [Orlemans, E. O.] Esanex Inc, Clin Res, Indianapolis, IN USA. FU Esanex, Inc. FX Esanex, Inc. NR 0 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD OCT 1 PY 2016 VL 27 SU 6 MA 423PD DI 10.1093/annonc/mdw369.8 PG 1 WC Oncology SC Oncology GA EK4QS UT WOS:000393912500421 ER PT J AU Karzai, F Zimmer, A Lipkowitz, S Annunziata, CM Parker, B Houston, N Ekwede, I Kohn, EC Lee, JM AF Karzai, F. Zimmer, A. Lipkowitz, S. Annunziata, C. M. Parker, B. Houston, N. Ekwede, I. Kohn, E. C. Lee, J-M. TI A phase II study of the cell cycle checkpoint kinases 1 and 2 (CHK1/2) inhibitor (LY2606368; prexasertib) in sporadic triple negative breast cancer (TNBC) SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 41st Congress of the European-Society-for-Medical-Oncology (ESMO) CY OCT 07-11, 2016 CL Copenhagen, DENMARK SP European Soc Med Oncol C1 [Karzai, F.] Natl Inst Minior Hlth & Hlth Dispar, NIH, Bethesda, MD USA. [Zimmer, A.; Lipkowitz, S.; Annunziata, C. M.; Parker, B.; Houston, N.; Ekwede, I.; Kohn, E. C.; Lee, J-M.] NCI, Womens Malignancies Branch, Rockville, MD USA. FU Intramural Program of the Center for Cancer Research, NCI, National Institutes of Health, USA FX This work was funded by the Intramural Program of the Center for Cancer Research, NCI, National Institutes of Health, USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD OCT 1 PY 2016 VL 27 SU 6 MA 231PD DI 10.1093/annonc/mdw365.10 PG 1 WC Oncology SC Oncology GA EK4QS UT WOS:000393912500230 ER PT J AU Lee, JM Karzai, FH Zimmer, A Annunziata, CM Lipkowitz, S Parker, B Houston, N Ekwede, I Kohn, EC AF Lee, J-M. Karzai, F. H. Zimmer, A. Annunziata, C. M. Lipkowitz, S. Parker, B. Houston, N. Ekwede, I. Kohn, E. C. TI A phase II study of the cell cycle checkpoint kinases 1 and 2 inhibitor (LY2606368; Prexasertib monomesylate monohydrate) in sporadic high-grade serous ovarian cancer (HGSOC) and germline BRCA mutation-associated ovarian cancer (gBRCAm plus OvCa) SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 41st Congress of the European-Society-for-Medical-Oncology (ESMO) CY OCT 07-11, 2016 CL Copenhagen, DENMARK SP European Soc Med Oncol C1 [Lee, J-M.; Zimmer, A.; Annunziata, C. M.; Lipkowitz, S.; Parker, B.; Houston, N.; Ekwede, I.; Kohn, E. C.] NCI, Womens Malignancies Branch, Rockville, MD USA. [Karzai, F. H.] Natl Inst Minor Hlth & Hlth Dispar, Div Intramural Res, Rockville, MD USA. FU Intramural Program of the Center for Cancer Research, NCI, National Institutes of Health, USA FX This work was funded by the Intramural Program of the Center for Cancer Research, NCI, National Institutes of Health, USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD OCT 1 PY 2016 VL 27 SU 6 MA 855O DI 10.1093/annonc/mdw374.2 PG 1 WC Oncology SC Oncology GA EK4QS UT WOS:000393912500850 ER PT J AU Mackall, C D'Angelo, S Grupp, S Glod, J Druta, M Chow, W Chagin, K Mehler, M Kari, G Trivedi, T Holdich, T Pandite, L Amado, R AF Mackall, C. D'Angelo, S. Grupp, S. Glod, J. Druta, M. Chow, W. Chagin, K. Mehler, M. Kari, G. Trivedi, T. Holdich, T. Pandite, L. Amado, R. TI Open label non-randomized multi-cohort pilot study of genetically engineered NY-ESO-1 specific NY-ESO-1c259 SPEAR T-cells TM in HLA-A*02+patients with synovial sarcoma (NCT01343043) SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract C1 [Mackall, C.] Stanford Univ, Med Ctr, Stanford Canc Inst, Stanford, CA 94305 USA. [D'Angelo, S.] Mem Sloan Kettering Canc Ctr, Med, 1275 York Ave, New York, NY 10021 USA. [Grupp, S.] Childrens Hosp Philadelphia, Pediat, Philadelphia, PA 19104 USA. [Glod, J.] NCI, Ctr Canc Res, Washington, DC USA. [Druta, M.] H Lee Moffitt Canc Ctr & Res Inst, Oncol, Tampa, FL USA. [Chow, W.] City Hope Natl Med Ctr, Med Oncol, Duarte, CA USA. [Chagin, K.; Mehler, M.; Kari, G.; Trivedi, T.; Pandite, L.; Amado, R.] Adaptimmune LLC, Global Clin Dev, Philadelphia, PA USA. [Holdich, T.] Adaptimmune LTD, Global Clin Dev, Oxford, England. FU Adaptimmune LLC FX Adaptimmune LLC NR 0 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD OCT 1 PY 2016 VL 27 SU 6 MA 1075P DI 10.1093/annonc/mdw378.29 PG 1 WC Oncology SC Oncology GA EK4QX UT WOS:000393913000169 ER PT J AU Miller, DP Roberts, M Petkov, VI Shak, S Howlader, N Cronin, K Penberthy, L AF Miller, D. P. Roberts, M. Petkov, V. I. Shak, S. Howlader, N. Cronin, K. Penberthy, L. TI Breast cancer-specific survival in > 4,600 patients with lymph node-positive (LN plus ) hormone receptor-positive (HR plus ) invasive breast cancer (BC) and 21-gene recurrence score (R) (RS) results in the SEER registries SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 41st Congress of the European-Society-for-Medical-Oncology (ESMO) CY OCT 07-11, 2016 CL Copenhagen, DENMARK SP European Soc Med Oncol C1 [Miller, D. P.; Shak, S.] Genom Hlth Inc, Translat Sci, Redwood City, CA USA. [Roberts, M.] NCI, Div Canc Prevent, Rockville, MD USA. [Petkov, V. I.; Howlader, N.; Cronin, K.; Penberthy, L.] NCI, Div Canc Control & Populat Sci, Rockville, MD USA. FU National Cancer Institute FX National Cancer Institute NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD OCT 1 PY 2016 VL 27 SU 6 MA 150PD DI 10.1093/annonc/mdw364.7 PG 1 WC Oncology SC Oncology GA EK4QS UT WOS:000393912500150 ER PT J AU Nadal, R Parnes, HL Francis, DC Cordes, LM Berninger, M Costello, R Folio, L Linderberg, M Machado, L Steinberg, SM Wright, JJ Ning, YM Bottaro, DP Dahut, WL Apolo, AB AF Nadal, R. Parnes, H. L. Francis, D. C. Cordes, L. M. Berninger, M. Costello, R. Folio, L. Linderberg, M. Machado, L. Steinberg, S. M. Wright, J. J. Ning, Y. M. Bottaro, D. P. Dahut, W. L. Apolo, A. B. TI A phase II study of cabozantinib in patients (pts) with relapsed/refractory metastatic urothelial carcinoma (mUC) SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 41st Congress of the European-Society-for-Medical-Oncology (ESMO) CY OCT 07-11, 2016 CL Copenhagen, DENMARK SP European Soc Med Oncol C1 [Nadal, R.; Parnes, H. L.; Francis, D. C.; Cordes, L. M.; Berninger, M.; Costello, R.; Folio, L.; Linderberg, M.; Machado, L.; Steinberg, S. M.; Wright, J. J.; Ning, Y. M.; Bottaro, D. P.] NCI, Med Oncol, Bethesda, MD 20892 USA. [Dahut, W. L.] NCI, Genitourinary Malignancies Branch, Bethesda, MD 20892 USA. [Apolo, A. B.] NIH, Genitourinary Malignancies Branch, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. FU CTEP NIH FX CTEP NIH NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD OCT 1 PY 2016 VL 27 SU 6 MA 787P DI 10.1093/annonc/mdw373.15 PG 1 WC Oncology SC Oncology GA EK4QS UT WOS:000393912500783 ER PT J AU Patel, MR Ellerton, J Agrawal, M Gordon, M Dirix, L Lee, KW Infante, J Schlichting, M Chin, K Apolo, B AF Patel, M. R. Ellerton, J. Agrawal, M. Gordon, M. Dirix, L. Lee, K-W. Infante, J. Schlichting, M. Chin, K. Apolo, B. TI Avelumab (MSB0010718C; anti-PD-L1) in patients with metastatic urothelial carcinoma progressed after platinum-based therapy or platinum ineligible SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 41st Congress of the European-Society-for-Medical-Oncology (ESMO) CY OCT 07-11, 2016 CL Copenhagen, DENMARK SP European Soc Med Oncol C1 [Patel, M. R.] Florida Canc Specialists, Sarah Cannon Res Inst, Sarasota, FL USA. [Ellerton, J.] Nevada Canc Res Fdn, Dept Med Oncol, Las Vegas, NV USA. [Agrawal, M.] Associates Oncol, Dept Med Oncol, Rockville, MD USA. [Gordon, M.] Pinnacle Oncol Hematol, Div Arizona Ctr Canc Care, Scottsdale, AZ USA. [Dirix, L.] Sint Augustinus Hosp, Dept Med Oncol, Ctr Oncol, Antwerp, Belgium. [Lee, K-W.] Seoul Natl Univ, Bundang Hosp, Dept Internal Med, Coll Med, Seongnam, South Korea. [Infante, J.] Tennessee Oncol PLLC, Department Med Oncol, Sarah Cannon Res Inst, Nashville, TN USA. [Schlichting, M.] Merck KGaA, Dept Biostat, Darmstadt, Germany. [Chin, K.] EMD Serono Inc, Immunooncol, Billerica, MA USA. [Apolo, B.] NCI, NIH, Genitourinary Malignancies Branch, Ctr Canc Res, Bethesda, MD 20892 USA. FU EMD Serono, Inc.; Merck KGaA FX EMD Serono, Inc. and Merck KGaA NR 0 TC 2 Z9 2 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD OCT 1 PY 2016 VL 27 SU 6 MA 777PD DI 10.1093/annonc/mdw373.5 PG 1 WC Oncology SC Oncology GA EK4QS UT WOS:000393912500773 ER PT J AU Shak, S Miller, DP Howlader, N Gliner, N Howe, W Schussler, N Cronin, K Baehner, FL Penberthy, L Petkov, VI AF Shak, S. Miller, D. P. Howlader, N. Gliner, N. Howe, W. Schussler, N. Cronin, K. Baehner, F. L. Penberthy, L. Petkov, V. I. TI Outcome disparities by age and 21-gene recurrence score (R) (RS) result in hormone receptor positive (HR plus ) breast cancer (BC) SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 41st Congress of the European-Society-for-Medical-Oncology (ESMO) CY OCT 07-11, 2016 CL Copenhagen, DENMARK SP European Soc Med Oncol C1 [Shak, S.; Miller, D. P.; Gliner, N.; Baehner, F. L.] Genom Hlth Inc, Translat Sci, Redwood City, CA USA. [Howlader, N.; Cronin, K.; Penberthy, L.; Petkov, V. I.] NCI, Div Canc Control & Populat Sci, Rockville, MD USA. [Howe, W.; Schussler, N.] Informat Management Syst Inc, Analyt Serv & Data Management, Calverton, MD USA. FU National Cancer Institute FX National Cancer Institute NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD OCT 1 PY 2016 VL 27 SU 6 MA 146O DI 10.1093/annonc/mdw364.3 PG 1 WC Oncology SC Oncology GA EK4QS UT WOS:000393912500146 ER PT J AU Sweeney, MM Rass, O Johnson, PS Strain, EC Berry, MS Vo, HT Fishman, MJ Munro, CA Rebok, GW Mintzer, MZ Johnson, MW AF Sweeney, Mary M. Rass, Olga Johnson, Patrick S. Strain, Eric C. Berry, Meredith S. Vo, Hoa T. Fishman, Marc J. Munro, Cynthia A. Rebok, George W. Mintzer, Miriam Z. Johnson, Matthew W. TI Initial Feasibility and Validity of a Prospective Memory Training Program in a Substance Use Treatment Population SO EXPERIMENTAL AND CLINICAL PSYCHOPHARMACOLOGY LA English DT Article DE prospective memory; working memory; cognitive training; substance use disorder; addiction ID METHADONE-MAINTENANCE PATIENTS; WORKING-MEMORY; EXECUTIVE FUNCTION; FORMER USERS; OLDER-ADULTS; CANNABIS USE; DEFICITS; IMPAIRMENT; PERFORMANCE; ECSTASY AB Individuals with substance use disorders have shown deficits in the ability to implement future intentions, called prospective memory. Deficits in prospective memory and working memory, a critical underlying component of prospective memory, likely contribute to substance use treatment failures. Thus, improvement of prospective memory and working memory in substance use patients is an innovative target for intervention. We sought to develop a feasible and valid prospective memory training program that incorporates working memory training and may serve as a useful adjunct to substance use disorder treatment. We administered a single session of the novel prospective memory and working memory training program to participants (n = 22; 13 men, 9 women) enrolled in outpatient substance use disorder treatment and correlated performance to existing measures of prospective memory and working memory. Generally accurate prospective memory performance in a single session suggests feasibility in a substance use treatment population. However, training difficulty should be increased to avoid ceiling effects across repeated sessions. Consistent with existing literature, we observed superior performance on event-based relative to time-based prospective memory tasks. Performance on the prospective memory and working memory training components correlated with validated assessments of prospective memory and working memory, respectively. Correlations between novel memory training program performance and established measures suggest that our training engages appropriate cognitive processes. Further, differential event-and time-based prospective memory task performance suggests internal validity of our training. These data support the development of this intervention as an adjunctive therapy for substance use disorders. C1 [Sweeney, Mary M.; Rass, Olga; Johnson, Patrick S.; Strain, Eric C.; Berry, Meredith S.; Fishman, Marc J.; Munro, Cynthia A.; Mintzer, Miriam Z.; Johnson, Matthew W.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Vo, Hoa T.; Fishman, Marc J.] Mt Manor Treatment Ctr, Baltimore, MD USA. [Rebok, George W.] Johns Hopkins Univ, Dept Mental Hlth, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Rass, Olga] US FDA, Ctr Tobacco Prod, Rockville, MD 20857 USA. [Johnson, Patrick S.] Calif State Univ Chico, Chico, CA 95929 USA. [Mintzer, Miriam Z.] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Johnson, MW (reprint author), Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Behav Pharmacol Res Unit, 5510 Nathan Shock Dr, Baltimore, MD 21224 USA. EM marymsweeney@jhmi.edu OI Sweeney, Mary Margaret/0000-0001-6931-4321 FU National Institute on Drug Abuse [R01DA035277, K24DA023186, T32DA07209] FX This research was supported by National Institute on Drug Abuse Grants R01DA035277 and K24DA023186 to Matthew W. Johnson and Eric C. Strain, respectively. Support for Mary M. Sweeney, Olga Rass, Patrick S. Johnson, and Meredith S. Berry was provided by National Institute on Drug Abuse Grant T32DA07209. The funding source had no role other than financial support. We acknowledge Peter Rendell for developing Virtual Week and providing access. We thank Len Onyiah for computer programming. We thank Lisa Mitchell for her assistance in conducting this research. This work was presented in part at the Third Annual Collaborative Perspectives on Addiction Conference of the American Psychological Association and at the 77th Annual Meeting of the College on Problems of Drug Dependence. Initial findings were described in an abstract published in Drug and Alcohol Dependence (i.e., Sweeney, Rass, Johnson, & Johnson, 2015). NR 64 TC 0 Z9 0 U1 0 U2 0 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 1064-1297 EI 1936-2293 J9 EXP CLIN PSYCHOPHARM JI Exp. Clin. Psychopharmacol. PD OCT PY 2016 VL 24 IS 5 BP 390 EP 399 DI 10.1037/pha0000091 PG 10 WC Psychology, Biological; Psychology, Clinical; Pharmacology & Pharmacy; Psychiatry SC Psychology; Pharmacology & Pharmacy; Psychiatry GA EL2ZA UT WOS:000394488200009 PM 27690506 ER PT J AU Abrams, R Tyagi, R Li, WX Bianchet, M Nath, A AF Abrams, Rachel Tyagi, Richa Li, Wenxue Bianchet, Mario Nath, Avindra TI Comparative Modeling of Human Endogenous Retrovirus-K Protease Based on HIV Protease Predicts Efficacy of Protease Inhibitors SO JOURNAL OF NEUROVIROLOGY LA English DT Meeting Abstract CT 14th International Symposium on NeuroVirology CY OCT 25-28, 2016 CL Toronto, CANADA C1 [Abrams, Rachel; Tyagi, Richa; Li, Wenxue; Nath, Avindra] NINDS, NIH, Bethesda, MD 20892 USA. [Bianchet, Mario] Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD USA. EM rachel.abrams@nih.gov NR 0 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-0284 EI 1538-2443 J9 J NEUROVIROL JI J. Neurovirol. PD OCT PY 2016 VL 22 SU 1 MA P1 BP S1 EP S1 PG 1 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA EK7GH UT WOS:000394093700002 ER PT J AU Anderson, M Enose-Akahata, Y Monaco-Kushner, MC Vellucci, A Tanaka, Y Lepene, B Kashanchi, F Jacobson, S AF Anderson, Monique Enose-Akahata, Yoshimi Monaco-Kushner, Maria Chiara Vellucci, Ashley Tanaka, Yuetsu Lepene, Ben Kashanchi, Fatah Jacobson, Steven TI Functional consequences of HTLV-1 viral antigens detected in exosomes from HAM/TSP patients SO JOURNAL OF NEUROVIROLOGY LA English DT Meeting Abstract CT 14th International Symposium on NeuroVirology CY OCT 25-28, 2016 CL Toronto, CANADA C1 [Anderson, Monique; Enose-Akahata, Yoshimi; Monaco-Kushner, Maria Chiara; Vellucci, Ashley; Jacobson, Steven] NIH, Bethesda, MD 20892 USA. [Tanaka, Yuetsu] Univ Ryukyus, Grad Sch Med, Nishihara, Okinawa 90301, Japan. [Lepene, Ben] Ceres Nanosci, Manassas, VA USA. [Kashanchi, Fatah] George Mason Univ, Lab Mol Virol, Fairfax, VA 22030 USA. EM andersonmr2@mail.nih.gov NR 0 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-0284 EI 1538-2443 J9 J NEUROVIROL JI J. Neurovirol. PD OCT PY 2016 VL 22 SU 1 MA P5 BP S3 EP S3 PG 1 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA EK7GH UT WOS:000394093700006 ER PT J AU Dave, RS Nehra, AP Muir, RR Ginwala, R Deleage, C Sagar, D Wigdahl, B Khan, ZK Haddad, E Estes, JD Villinger, F Ansari, A Byrareddy, S Jain, P AF Dave, Rajnish S. Nehra, Artinder P. Muir, Roshell R. Ginwala, Rashida Deleage, Claire Sagar, Divya Wigdahl, Brian Khan, Zafar K. Haddad, Elias Estes, Jacob D. Villinger, Francois Ansari, Aftab Byrareddy, Siddappa Jain, Pooja TI Follicular DCs within deep cerebral lymph nodes are potential reservoir of HIV-CNS infection SO JOURNAL OF NEUROVIROLOGY LA English DT Meeting Abstract CT 14th International Symposium on NeuroVirology CY OCT 25-28, 2016 CL Toronto, CANADA C1 [Dave, Rajnish S.; Nehra, Artinder P.; Ginwala, Rashida; Sagar, Divya; Wigdahl, Brian; Khan, Zafar K.; Jain, Pooja] Drexel Univ, Coll Med, Dept Microbiol & Immunol, Philadelphia, PA 19104 USA. [Dave, Rajnish S.; Nehra, Artinder P.; Ginwala, Rashida; Sagar, Divya; Wigdahl, Brian; Khan, Zafar K.; Jain, Pooja] Drexel Univ, Coll Med, Inst Mol Med & Infect Dis, Philadelphia, PA 19104 USA. [Muir, Roshell R.; Haddad, Elias] Drexel Univ, Coll Med, Dept Med, Div Infect Dis & HIV Med, Philadelphia, PA 19104 USA. [Deleage, Claire; Estes, Jacob D.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, AIDS & Canc Virus Program, Frederick, MD USA. [Villinger, Francois; Ansari, Aftab] Emory Univ, Sch Med, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. [Villinger, Francois; Ansari, Aftab] Emory Univ, Emory Vaccine Ctr, Atlanta, GA 30322 USA. [Byrareddy, Siddappa] Univ Nebraska Med Ctr, Dept Pharmacol & Expt Neurosci, Omaha, NE USA. EM rag78@drexel.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-0284 EI 1538-2443 J9 J NEUROVIROL JI J. Neurovirol. PD OCT PY 2016 VL 22 SU 1 MA P33 BP S16 EP S17 PG 2 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA EK7GH UT WOS:000394093700034 ER PT J AU Doucet-O'Hare, T Johnson, K Wang, TG Medynets, M Ho, W Zhuang, ZP Nath, A AF Doucet-O'Hare, Tara Johnson, Kory Wang, Tongguang Medynets, Marie Ho, Winson Zhuang, Zhengping Nath, Avindra TI Critical Role of Human Endogenous Retroviruses (HERVs) in Neurodevelopment and Neurodevelopmental Tumors SO JOURNAL OF NEUROVIROLOGY LA English DT Meeting Abstract CT 14th International Symposium on NeuroVirology CY OCT 25-28, 2016 CL Toronto, CANADA C1 [Doucet-O'Hare, Tara; Nath, Avindra] NINDS, Sect Infect Nervous Syst, NIH, Bethesda, MD 20892 USA. [Johnson, Kory] NINDS, Bioinformat Sect Informat Technol Program, NIH, Bethesda, MD 20892 USA. [Wang, Tongguang; Medynets, Marie] NINDS, Neural Differentiat Unit, NIH, Bethesda, MD 20892 USA. [Ho, Winson] NINDS, Commun Networks Program, Sect Neurophysiol, NIH, Bethesda, MD 20892 USA. [Zhuang, Zhengping] NCI, NIH, Bethesda, MD 20892 USA. EM doucettt@ninds.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-0284 EI 1538-2443 J9 J NEUROVIROL JI J. Neurovirol. PD OCT PY 2016 VL 22 SU 1 MA P39 BP S19 EP S19 PG 1 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA EK7GH UT WOS:000394093700040 ER PT J AU Geiger, N Li, WX Tyagi, R Bachani, M Malik, N Steiner, J Nath, A AF Geiger, Nicholas Li, Wenxue Tyagi, Richa Bachani, Muzna Malik, Nasir Steiner, Joseph Nath, Avindra TI Development of an inducible cell line screening for therapeutic antagonists to HIV Tat protein SO JOURNAL OF NEUROVIROLOGY LA English DT Meeting Abstract CT 14th International Symposium on NeuroVirology CY OCT 25-28, 2016 CL Toronto, CANADA C1 [Geiger, Nicholas; Li, Wenxue; Tyagi, Richa] NINDS, Sect Infect Nervous Syst, NIH, Bethesda, MD 20892 USA. [Bachani, Muzna; Malik, Nasir; Steiner, Joseph] NINDS, Translat Neurosci Ctr, NIH, Bethesda, MD 20892 USA. [Nath, Avindra] NINDS, SINS & Translat Neurosci Ctr, NIH, Bethesda, MD 20892 USA. EM joe.steiner@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-0284 EI 1538-2443 J9 J NEUROVIROL JI J. Neurovirol. PD OCT PY 2016 VL 22 SU 1 MA P43 BP S21 EP S21 PG 1 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA EK7GH UT WOS:000394093700044 ER PT J AU Gerena, Y Menindez-Delmestre, R Delgado-Nieves, A Gonziclez-Escalante, A Colin-Cruz, L Marshall-Freites, V Rivera-Morales, P Nath, A Wojna, V AF Gerena, Yamil Menindez-Delmestre, Raissa Delgado-Nieves, Andrea Gonziclez-Escalante, Anibal Colin-Cruz, Luis Marshall-Freites, Valerie Rivera-Morales, Paola Nath, Avindra Wojna, Valerie TI HIV-1 Tat Induces Neuronal Insulin Receptor Secretion Through the TNF-Alpha Receptor SO JOURNAL OF NEUROVIROLOGY LA English DT Meeting Abstract CT 14th International Symposium on NeuroVirology CY OCT 25-28, 2016 CL Toronto, CANADA C1 [Gerena, Yamil; Delgado-Nieves, Andrea; Gonziclez-Escalante, Anibal; Colin-Cruz, Luis; Marshall-Freites, Valerie; Rivera-Morales, Paola] Univ Puerto Rico, Dept Pharmacol, Med Sci Campus, San Juan, PR 00936 USA. [Menindez-Delmestre, Raissa] Univ Puerto Rico, NeuroAIDS Res Program, Med Sci Campus, San Juan, PR 00936 USA. [Nath, Avindra] NINDS, NIH, Bethesda, MD 20892 USA. [Wojna, Valerie] Univ Puerto Rico, Dept Internal Med, Div Neurol, Med Sci Campus, San Juan, PR 00936 USA. EM yamil.gerena@upr.edu FU [R01NS099036]; [R21MH095524]; [U54MD007587]; [G12RR003051]; [G12MD007600] FX Supported by R01NS099036, R21MH095524, U54MD007587, G12RR003051, G12MD007600. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-0284 EI 1538-2443 J9 J NEUROVIROL JI J. Neurovirol. PD OCT PY 2016 VL 22 SU 1 MA P45 BP S22 EP S22 PG 1 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA EK7GH UT WOS:000394093700046 ER PT J AU Ginwala, R Charlins, P Akkina, R Caruso, B Loonawat, R Jacobson, S Nambiar, S Chew, GM Ndhlovu, LC Jain, P Khan, ZK AF Ginwala, Rashida Charlins, Paige Akkina, Ramesh Caruso, Breanna Loonawat, Ronak Jacobson, Steven Nambiar, Sreesha Chew, Glen M. Ndhlovu, Lishomwa C. Jain, Pooja Khan, Zafar K. TI HTLV-1 infection and neuropathogenesis in the context of Rag1-/-gamma c-/- (RAG1) mice SO JOURNAL OF NEUROVIROLOGY LA English DT Meeting Abstract CT 14th International Symposium on NeuroVirology CY OCT 25-28, 2016 CL Toronto, CANADA C1 [Ginwala, Rashida; Loonawat, Ronak; Nambiar, Sreesha; Jain, Pooja; Khan, Zafar K.] Drexel Univ, Coll Med, Dept Microbiol & Immunol, Philadelphia, PA 19104 USA. [Ginwala, Rashida; Loonawat, Ronak; Nambiar, Sreesha; Jain, Pooja; Khan, Zafar K.] Drexel Univ, Coll Med, Inst Mol Med & Infect Dis, Philadelphia, PA 19104 USA. [Charlins, Paige; Akkina, Ramesh] Colorado State Univ, Dept Microbiol Immunol & Pathol, Ft Collins, CO 80523 USA. [Caruso, Breanna; Jacobson, Steven] NIH, Viral Immunol Sect, Neuroimmunol Branch, Bldg 10, Bethesda, MD 20892 USA. [Chew, Glen M.; Ndhlovu, Lishomwa C.] Univ Hawaii, Dept Trop Med Med Microbiol & Pharmacol, John A Burns Sch Med, Honolulu, HI 96822 USA. EM zafar.khan@drexelmed.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-0284 EI 1538-2443 J9 J NEUROVIROL JI J. Neurovirol. PD OCT PY 2016 VL 22 SU 1 MA P47 BP S23 EP S23 PG 1 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA EK7GH UT WOS:000394093700048 ER PT J AU Hategan, AP Bianchet, M Karnaukhova, E Steiner, J Dimitriadis, E Nath, A AF Hategan, Alina Popescu Bianchet, Mario Karnaukhova, Elena Steiner, Joseph Dimitriadis, Emilios Nath, Avindra TI HIV-Tat protein: molecular structure, aggregation and interaction with amyloid beta SO JOURNAL OF NEUROVIROLOGY LA English DT Meeting Abstract CT 14th International Symposium on NeuroVirology CY OCT 25-28, 2016 CL Toronto, CANADA C1 [Hategan, Alina Popescu; Steiner, Joseph; Nath, Avindra] NINDS, Sect Infect Nervous Syst, Bethesda, MD 20892 USA. [Bianchet, Mario] Johns Hopkins Sch Med, Dept Neurog, Baltimore, MD USA. [Karnaukhova, Elena] FDA, CBER, Silver Spring, MD USA. [Dimitriadis, Emilios] NIBIB, Scanning Probe Microscopy Unit, Bethesda, MD USA. EM alina.popescu@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-0284 EI 1538-2443 J9 J NEUROVIROL JI J. Neurovirol. PD OCT PY 2016 VL 22 SU 1 MA P127 BP S62 EP S62 PG 1 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA EK7GH UT WOS:000394093700128 ER PT J AU Henderson, L Johnson, T Barclay, R Tyagi, R Bachani, M Sacktor, N Letendre, S Steiner, J Kashanchi, F Nath, A AF Henderson, Lisa Johnson, Tory Barclay, Robert Tyagi, Richa Bachani, Muzna Sacktor, Ned Letendre, Scott Steiner, Joseph Kashanchi, Fatah Nath, Avindra TI Detection of HIV-1 Tat protein and TAR RNA in cerebrospinal fluid from patients on antiretroviral therapy: targeting persistent Tat production using antisense oligonucleotides SO JOURNAL OF NEUROVIROLOGY LA English DT Meeting Abstract CT 14th International Symposium on NeuroVirology CY OCT 25-28, 2016 CL Toronto, CANADA C1 [Henderson, Lisa; Tyagi, Richa; Nath, Avindra] NINDS, Sect Infect Nervous Syst, Bethesda, MD 20892 USA. [Johnson, Tory; Sacktor, Ned] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21218 USA. [Barclay, Robert] George Mason Univ, Sch Syst Biol, Natl Ctr Biodef & Infect Dis, Fairfax, VA 22030 USA. [Bachani, Muzna; Steiner, Joseph] NINDS, Translat Neurosci Ctr, Bethesda, MD 20892 USA. [Letendre, Scott] Univ Calif San Diego, La Jolla, CA 92093 USA. [Kashanchi, Fatah] George Mason Univ, Sch Syst Biol, Mol Virol Lab, Fairfax, VA 22030 USA. EM lisa.henderson@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-0284 EI 1538-2443 J9 J NEUROVIROL JI J. Neurovirol. PD OCT PY 2016 VL 22 SU 1 MA P58 BP S28 EP S29 PG 2 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA EK7GH UT WOS:000394093700059 ER PT J AU Henderson, L Li, WX Tyagi, R Nath, A AF Henderson, Lisa Li, Wenxue Tyagi, Richa Nath, Avindra TI Modulation of HIV replication in lymphocytes, macrophages and astrocytes by association of HIV mRNA with TAR DNA binding protein 43 SO JOURNAL OF NEUROVIROLOGY LA English DT Meeting Abstract CT 14th International Symposium on NeuroVirology CY OCT 25-28, 2016 CL Toronto, CANADA C1 [Henderson, Lisa; Li, Wenxue; Tyagi, Richa; Nath, Avindra] NINDS, Sect Infect Nervous Syst, Bethesda, MD 20892 USA. EM lisa.henderson@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-0284 EI 1538-2443 J9 J NEUROVIROL JI J. Neurovirol. PD OCT PY 2016 VL 22 SU 1 MA P57 BP S28 EP S28 PG 1 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA EK7GH UT WOS:000394093700058 ER PT J AU Iordanskiy, S Sampey, G Van Duyne, R Woodson, C Fry, K Saifuddin, M Romerio, F Kashanchi, F AF Iordanskiy, Sergey Sampey, Gavin Van Duyne, Rachel Woodson, Caitlin Fry, Kelsi Saifuddin, Mohammed Romerio, Fabio Kashanchi, Fatah TI A new approach to "Shock and Kill" for various organs including CNS: Therapeutic doses of irradiation activate viral transcription and induce apoptosis in HIV-1 infected cells SO JOURNAL OF NEUROVIROLOGY LA English DT Meeting Abstract CT 14th International Symposium on NeuroVirology CY OCT 25-28, 2016 CL Toronto, CANADA C1 [Iordanskiy, Sergey; Sampey, Gavin; Woodson, Caitlin; Fry, Kelsi; Saifuddin, Mohammed; Kashanchi, Fatah] George Mason Univ, Natl Ctr Biodef & Infect Dis, Fairfax, VA 22030 USA. [Van Duyne, Rachel] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Romerio, Fabio] Univ Maryland, Sch Med, Dept Med, College Pk, MD 20742 USA. EM fkashanc@gmu.edu NR 0 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-0284 EI 1538-2443 J9 J NEUROVIROL JI J. Neurovirol. PD OCT PY 2016 VL 22 SU 1 MA P61 BP S30 EP S30 PG 1 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA EK7GH UT WOS:000394093700062 ER PT J AU Leibovitch, E Caruso, B Schindler, M Luciano, N Ha, SK Lee, N Billioux, B Guy, J Li, XZ Yen, C Sati, P Silva, A Reich, D Jacobson, S AF Leibovitch, Emily Caruso, Breanna Schindler, Matthew Luciano, Nick Ha, Seung-Kwon Lee, Nathanael Billioux, Bridgette Guy, Joseph Li, Xiaozhen Yen, Cecil Sati, Pascal Silva, Afonso Reich, Daniel Jacobson, Steven TI Herpesvirus trigger accelerates a neuroinflammatory demyelinating disease in a nonhuman primate model of multiple sclerosis SO JOURNAL OF NEUROVIROLOGY LA English DT Meeting Abstract CT 14th International Symposium on NeuroVirology CY OCT 25-28, 2016 CL Toronto, CANADA C1 [Leibovitch, Emily; Caruso, Breanna; Schindler, Matthew; Luciano, Nick; Ha, Seung-Kwon; Lee, Nathanael; Billioux, Bridgette; Guy, Joseph; Li, Xiaozhen; Yen, Cecil; Sati, Pascal; Silva, Afonso; Reich, Daniel; Jacobson, Steven] NINDS, Bethesda, MD 20892 USA. EM emily.leibovitch@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-0284 EI 1538-2443 J9 J NEUROVIROL JI J. Neurovirol. PD OCT PY 2016 VL 22 SU 1 MA P86 BP S42 EP S42 PG 1 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA EK7GH UT WOS:000394093700087 ER PT J AU Li, GH Lee, M Major, E Nath, A AF Li, Guan-Han Lee, MyoungHwa Major, Eugene Nath, Avindra TI HIV infection of astrocytes is detected in vivo by RNAscope and occurs in vitro via a non-classical mechanism SO JOURNAL OF NEUROVIROLOGY LA English DT Meeting Abstract CT 14th International Symposium on NeuroVirology CY OCT 25-28, 2016 CL Toronto, CANADA C1 [Li, Guan-Han; Lee, MyoungHwa; Nath, Avindra] NINDS, Sect Infect Nervous Syst, NIH, Bethesda, MD 20892 USA. [Major, Eugene] NINDS, Lab Mol Med & Neurosci, NIH, Bethesda, MD 20892 USA. EM guanhan.li@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-0284 EI 1538-2443 J9 J NEUROVIROL JI J. Neurovirol. PD OCT PY 2016 VL 22 SU 1 MA P88 BP S43 EP S43 PG 1 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA EK7GH UT WOS:000394093700089 ER PT J AU Li, WX Lee, MH Tyagi, R Bachani, M Steiner, J Nath, A AF Li, Wenxue Lee, Myoung-Hwa Tyagi, Richa Bachani, Muzna Steiner, Joseph Nath, Avindra TI Human Endogenous Retrovirus-K envelope protein induces neurotoxicity by causing p53-dependent nucleolar stress response SO JOURNAL OF NEUROVIROLOGY LA English DT Meeting Abstract CT 14th International Symposium on NeuroVirology CY OCT 25-28, 2016 CL Toronto, CANADA C1 [Li, Wenxue; Lee, Myoung-Hwa; Tyagi, Richa; Nath, Avindra] NINDS, Sect Infect Nervous Syst, NIH, Bethesda, MD 20892 USA. [Bachani, Muzna; Steiner, Joseph] NINDS, Neurotherapeut Unit, NIH, Bethesda, MD 20892 USA. EM liw8@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-0284 EI 1538-2443 J9 J NEUROVIROL JI J. Neurovirol. PD OCT PY 2016 VL 22 SU 1 MA P89 BP S43 EP S43 PG 1 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA EK7GH UT WOS:000394093700090 ER PT J AU Stoff, D AF Stoff, David TI Research Training in Neurovirology: Supporting Pathways to Success SO JOURNAL OF NEUROVIROLOGY LA English DT Meeting Abstract CT 14th International Symposium on NeuroVirology CY OCT 25-28, 2016 CL Toronto, CANADA C1 [Stoff, David] NIMH, Div AIDS Res, Bethesda, MD USA. EM dstoff@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-0284 EI 1538-2443 J9 J NEUROVIROL JI J. Neurovirol. PD OCT PY 2016 VL 22 SU 1 MA P152 BP S74 EP S74 PG 1 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA EK7GH UT WOS:000394093700153 ER PT J AU Wanicek, EL Gray, LR Cheng, WJ Estes, JD Lewin, SR Gorry, PR Churchill, MJ AF Wanicek, Emma L. Gray, Lachlan R. Cheng, Wan-Jung Estes, Jacob D. Lewin, Sharon R. Gorry, Paul R. Churchill, Melissa J. TI Detection of HIV-1 DNA in brain tissue of virally suppressed patients supports the existence of a persistent CNS viral reservoir SO JOURNAL OF NEUROVIROLOGY LA English DT Meeting Abstract CT 14th International Symposium on NeuroVirology CY OCT 25-28, 2016 CL Toronto, CANADA C1 [Wanicek, Emma L.; Gray, Lachlan R.; Cheng, Wan-Jung; Gorry, Paul R.; Churchill, Melissa J.] Burnet Inst, Ctr Biomed Res, Melbourne, Vic, Australia. [Gray, Lachlan R.; Lewin, Sharon R.] Alfred Hosp, Dept Infect Dis, Melbourne, Vic, Australia. [Gray, Lachlan R.; Lewin, Sharon R.] Monash Univ, Melbourne, Vic, Australia. [Estes, Jacob D.] Leidos Biomed Res Inc, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Gray, Lachlan R.] Univ Melbourne, Peter Doherty Inst Infect & Immun, Melbourne, Vic, Australia. [Gray, Lachlan R.] Royal Melbourne Hosp, Melbourne, Vic, Australia. [Estes, Jacob D.] RMIT Univ, Sch Hlth & Biomed Sci, Melbourne, Vic, Australia. [Gray, Lachlan R.] Monash Univ, Dept Med, Melbourne, Vic, Australia. [Estes, Jacob D.] Monash Univ, Dept Microbiol, Clayton, Vic, Australia. EM emma.wanicek@burnet.edu.au NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-0284 EI 1538-2443 J9 J NEUROVIROL JI J. Neurovirol. PD OCT PY 2016 VL 22 SU 1 MA P165 BP S80 EP S80 PG 1 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA EK7GH UT WOS:000394093700166 ER PT J AU Wojna, V Matos, M Rodriguez-Benitez, RJ Menendez-Delmestre, R Nath, A Gerena, Y AF Wojna, Valerie Matos, Miriam Rodriguez-Benitez, Rosa J. Menendez-Delmestre, Raissa Nath, Avindra Gerena, Yamil TI Insulin Receptor Secretion is not associated with abnormal glucose metabolism in HIV-seropositive women SO JOURNAL OF NEUROVIROLOGY LA English DT Meeting Abstract CT 14th International Symposium on NeuroVirology CY OCT 25-28, 2016 CL Toronto, CANADA C1 [Wojna, Valerie] Univ Puerto Rico, Neurol Div, NeuroAIDS Program, Med Sci Campus, San Juan, PR 00936 USA. [Matos, Miriam; Rodriguez-Benitez, Rosa J.; Menendez-Delmestre, Raissa] Univ Puerto Rico, NeuroAIDS Program, Med Sci Campus, San Juan, PR 00936 USA. [Nath, Avindra] NINDS, Sect Infect Nervous Syst, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Gerena, Yamil] Univ Puerto Rico, Dept Pharmacol, NeuroAIDS Program, Med Sci Campus, San Juan, PR 00936 USA. EM valerie.wojna1@upr.edu FU [R21MH095524]; [R01NS099036]; [U54MD007587]; [G12MD007600] FX Supported by R21MH095524, R01NS099036, U54MD007587, G12MD007600 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-0284 EI 1538-2443 J9 J NEUROVIROL JI J. Neurovirol. PD OCT PY 2016 VL 22 SU 1 MA P168 BP S81 EP S82 PG 2 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA EK7GH UT WOS:000394093700169 ER PT J AU Williams, KA Swedo, SE Farmer, CA Grantz, H Grant, PJ D'Souza, P Hommer, R Katsovich, L King, RA Leckman, JF AF Williams, Kyle A. Swedo, Susan E. Farmer, Cristan A. Grantz, Heidi Grant, Paul J. D'Souza, Precilla Hommer, Rebecca Katsovich, Liliya King, Robert A. Leckman, James F. TI Randomized, Controlled Trial of Intravenous Immunoglobulin for Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE PANDAS; obsessive-compulsive disorder; WIG; group A streptococcus pyogenes ID OBSESSIVE-COMPULSIVE DISORDER; TIC-SEVERITY-SCALE; PLASMA-EXCHANGE; BASAL GANGLIA; TOURETTE-SYNDROME; SYDENHAMS CHOREA; CHILDREN; ANTIBODIES; CHILDHOOD; MODEL AB Objective: Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) are hypothesized to occur as a result of cross-reactive antibodies produced in response to group A streptococcal infections. Previous research suggests that immunomodulatory therapies, such as intravenous immunoglobulin (WIG), may lead to rapid and sustained symptom improvement in patients with PANDAS. Method: A total of 35 children meeting criteria for PANDAS and moderate to severe obsessive-compulsive disorder (OCD) were enrolled in a randomized-entry, double-blind, placebo-controlled, 6-week trial of WIG (1 g/kg/day on 2 consecutive days), followed by optional open-label treatment for nonresponders, with follow-up at 12 and 24 weeks. Primary outcome measures were the Children's Yale Brown Obsessive Compulsive Scale (CY-BOCS) and the Clinical Global Impressions Improvement (CGI-I) rating. "Responders" were defined, a priori, by a >= 30% decrease in CY-BOCS total score, and a "much" or "very much" improved rating on CGI-I. Results: During the double-blind phase, the mean decrease in CY-BOCS score was 24% +/- 31% in the WIG group (n = 17) and 12% +/- 27% in the placebo group (n = 18), with six responders in the WIG group (35%) versus four (22%) in the placebo group; these differences were not statistically significant. Twenty-four participants met criteria for nonresponse to double-blind infusion and received open-label IVIG at week 6. Among all participants, the mean CY-BOCS improvement from baseline was 55% +/- 33% at week 12 and 62% +/- 33% at week 24. Conclusion: WIG was safe and well tolerated. Between group differences were smaller than anticipated, and the double-blind comparison failed to demonstrate superiority of WIG over placebo. The observed open-label improvements indicate that future trials would benefit from larger sample sizes designed in part to aid in the identification of biomarkers predictive of a positive response to immunotherapy. Future investigations focused on the natural history of PANDAS are also warranted. C1 [Williams, Kyle A.; Grantz, Heidi; Katsovich, Liliya; King, Robert A.; Leckman, James F.] Yale Univ, Sch Med, Ctr Child Study, New Haven, CT 06510 USA. [Williams, Kyle A.] Massachusetts Gen Hosp, Pediat Neuropsychiat & Immunol Program, Boston, MA 02114 USA. [Swedo, Susan E.; Farmer, Cristan A.; Grant, Paul J.; D'Souza, Precilla; Hommer, Rebecca] NIMH, Pediat & Dev Neurosci Program, Bethesda, MD USA. RP Swedo, SE (reprint author), 10 Ctr Dr,MSC 1255, Bethesda, MD 20892 USA. EM swedos@mail.nih.gov FU Grifols Laboratories; National Institutes of Health (NIH) Bench-to-Bedside Program; National Institute of Mental Health (NIMH) [NCT01281969, protocol 11-M-0058] FX Grifols Laboratories supplied intravenous immunoglobulin for the trial, as well as financial support to the Yale investigators. Additional support was provided by the National Institutes of Health (NIH) Bench-to-Bedside Program, and by the Intramural Research Program of the National Institute of Mental Health (NIMH) (NCT01281969; protocol 11-M-0058). Dr. Williams had full access to all the data in the study and takes responsibility for the integrity of the data analysis. NR 46 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0890-8567 EI 1527-5418 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD OCT PY 2016 VL 55 IS 10 BP 860 EP 867 DI 10.1016/j.jaac.2016.06.017 PG 8 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA EK6YQ UT WOS:000394072600007 PM 27663941 ER PT J AU Heitmann, RJ Batig, AL Levy, G Novotney, J Grubbs, C Batig, TS Gobern, JM Hemman, E Christy, AY Hill, MJ AF Heitmann, Ryan J. Batig, Alison L. Levy, Gary Novotney, Jonathan Grubbs, Calvin, III Batig, Timothy S. Gobern, Joseph M. Hemman, Eileen Christy, Alicia Y. Hill, Micah J. TI Unintended Pregnancy in the Military Health Care System: Who Is Really at Risk? SO MILITARY MEDICINE LA English DT Article ID ACTIVE-DUTY SERVICEWOMEN; UNITED-STATES; UNPLANNED PREGNANCY; CONTRACEPTION; WOMEN; US; COHORT AB Unintended pregnancy is a global issue and one that is reportedly to be higher in the military population. We sought to assess rates of unintended pregnancy among the active duty population in comparison to other military health care beneficiaries. Using a validated six-question survey, patients aged 18 to 42 were surveyed in five different clinics at three major tertiary hospitals from December 2013 to December 2014. Individual survey questions were scored 0, 1, or 2 and a total score was tabulated. A total score of 0 to 3 indicated unintended pregnancy, 4 to 9 indicated ambivalence toward pregnancy, and 10 to 12 indicated intended pregnancy. Subanalysis was performed on two survey questions specifically looking at pregnancy intentions. A total of 1,211 completed surveys were analyzed. Overall, 6.9% of all respondents had an unintended pregnancy compared to 23% of pregnancies in single active duty women. Single, active duty service members were more likely to indicate they did not intend to get pregnant or want a baby before becoming pregnant. Overall, the rate of unintended pregnancy among military health care beneficiaries is low. However, single active duty women are at significantly higher risk for unintended pregnancy and specifically targeted interventions should be implemented for this population. C1 [Heitmann, Ryan J.; Batig, Alison L.; Hemman, Eileen] Madigan Army Med Ctr, Dept Obstet & Gynecol, 9040 Jackson Ave, Tacoma, WA 98431 USA. [Heitmann, Ryan J.; Gobern, Joseph M.; Hill, Micah J.] Walter Reed Natl Mil Med Ctr, Dept Obstet & Gynecol, 8901 Wisconsin Ave, Bethesda, MD 20889 USA. [Levy, Gary] Tripler Army Med Ctr, Dept Obstet & Gynecol, 1 Jarrett White Rd, Honolulu, HI 96859 USA. [Novotney, Jonathan; Grubbs, Calvin, III] Madigan Army Med Ctr, Dept Family Med, 9040 Jackson Ave, Tacoma, WA 98431 USA. [Batig, Timothy S.] Soldier Ctr Med Home, Joint Base Lewis McChord, 17th FAB 555 EN BDE, Tacoma, WA 98431 USA. [Christy, Alicia Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Contracept Discovery Branch, NIH, 31 Ctr Dr, Bethesda, MD 20892 USA. RP Heitmann, RJ (reprint author), Madigan Army Med Ctr, Dept Obstet & Gynecol, 9040 Jackson Ave, Tacoma, WA 98431 USA.; Heitmann, RJ (reprint author), Walter Reed Natl Mil Med Ctr, Dept Obstet & Gynecol, 8901 Wisconsin Ave, Bethesda, MD 20889 USA. NR 18 TC 0 Z9 0 U1 0 U2 0 PU ASSOC MILITARY SURG US PI BETHESDA PA 9320 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0026-4075 EI 1930-613X J9 MIL MED JI Milit. Med. PD OCT PY 2016 VL 181 IS 10 BP 1370 EP 1374 DI 10.7205/MILMED-D-16-00003 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA EL3DB UT WOS:000394498700038 PM 27753577 ER PT J AU Cannon, TD Yu, CH Addington, J Bearden, CE Cadenhead, KS Cornblatt, BA Heinssen, R Jeffries, CD Mathalon, DH McGlashan, TH Perkins, DO Seidman, LJ Tsuang, MT Walker, EF Woods, SW Kattan, MW AF Cannon, Tyrone D. Yu, Changhong Addington, Jean Bearden, Carrie E. Cadenhead, Kristin S. Cornblatt, Barbara A. Heinssen, Robert Jeffries, Clark D. Mathalon, Daniel H. McGlashan, Thomas H. Perkins, Diana O. Seidman, Larry J. Tsuang, Ming T. Walker, Elaine F. Woods, Scott W. Kattan, Michael W. TI An Individualized Risk Calculator for Research in Prodromal Psychosis SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID CLINICAL HIGH-RISK; CONTROLLED-TRIAL; YOUNG-ADULTS; SCHIZOPHRENIA; PREVENTION; PREDICTION; YOUTH; INTERVENTIONS; METAANALYSIS; ADOLESCENTS AB Objective: Approximately 20%-35% of individuals 12-35 years old who meet criteria for a prodromal risk syndrome convert to psychosis within 2 years. However, this estimate ignores the fact that clinical high-risk cases vary considerably in risk. The authors sought to create a risk calculator, based on profiles of risk indicators, that can ascertain the probability of conversion to psychosis in individual patients. Method: The study subjects were 596 clinical high-risk participants from the second phase of the North American Prodrome Longitudinal Study who were followed lip to the time of conversion to psychosis or last contact (up to 2 years). The predictors examined were limited to those that are supported by previous studies and are readily obtainable in general clinical settings. Time-to-event regression was used to build a multivariate model predicting conversion, with internal validation using 1,000 bootstrap resamples. Results: The 2-year probability of conversion to psychosis was 16%. Higher levels of unusual thought content and suspiciousness, greater decline in social functioning, lower verbal learning and memory performance, slower speed of processing, and younger age at baseline each contributed to individual risk for psychosis. Stressful life events, trauma, and family history of schizophrenia were not significant predictors. The multivariate model achieved a concordance index of 0.71 and, as reported in an article by Carrion et al., published concurrently with this one, was validated in an independent external data set. The results are instantiated in a web-based risk prediction tool envisioned to be most useful in research protocols involving the psychosis prodrome. Conclusions: A risk calculator comparable in accuracy to those for cardiovascular disease and cancer is available to predict individualized conversion risks in newly ascertained clinical high-risk cases. Given that the risk calculator can be validly applied only for patients who screen positive on the Structured Clinical Interview for Psychosis Risk Syndromes, which requires training to administer, its most immediate uses will be in research on psychosis risk factors and in research-driven clinical (prevention) trials. C1 [Cannon, Tyrone D.] Yale Univ, Dept Psychol, New Haven, CT 06520 USA. Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. Cleveland Clin, Dept Quantitat Hlth Sci, Cleveland, OH 44106 USA. Univ Calgary, Dept Psychiat, Hotchkiss Brain Inst, Calgary, AB T2N 1N4, Canada. Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA USA. Univ Calif San Diego, Dept Psychiat, San Diego, CA USA. Zucker Hillside Hosp, Dept Psychiat, Glen Oaks, NY USA. NIMH, Bethesda, MD 20892 USA. Univ N Carolina, Renaissance Comp Inst, Chapel Hill, NC USA. UCSF, Dept Psychiat, San Francisco, CA USA. Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. Beth Israel Deaconess Med Ctr, Dept Psychiat, Harvard Med Sch, Boston, MA 02215 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. UCSD, Ctr Behav Genom, Dept Psychiat, La Jolla, CA USA. UCSD, Inst Genom Med, La Jolla, CA USA. Emory Univ, Dept Psychol, Atlanta, GA 30322 USA. Emory Univ, Dept Psychiat, Atlanta, GA 30322 USA. RP Cannon, TD (reprint author), Yale Univ, Dept Psychol, New Haven, CT 06520 USA. FU NIH [U01 MH081902, P50 MH066286, U01 MH081857, U01 MH82022, U01 MH 066134, U01 MH081944, R01 U01MH066069, R01 MH076989, U01 MH081928, U01 MH081988]; Genentech; Pfizer; Auspex; Teva FX Supported by NIH grants U01 MH081902 (to Dr. Cannon), P50 MH066286 (to Dr. Bearden), U01 MH081857 (to Dr. Cornblatt), U01 MH82022 (to Dr. Woods), U01 MH 066134 (to Dr. Addington), U01 MH081944 (to Dr. Cadenhead), R01 U01MH066069 (to Dr. Perkins), R01 MH076989 (to Dr. Mathalon), U01 MH081928 (to Dr Seidman), and U01 MH081988 (to Dr. Walker).; Dr. Cannon has served as a consultant for the Los Angeles County Department of Mental Health and Boehringer-Ingelheim Pharmaceuticals. Dr. Mathalon has served as a consultant for Boehringer-Ingelheim Pharmaceuticals. Dr. Perkins has served as a consultant for Genentech, Lundbeck, Otsuka, and Sunovion, has participated in educational activity for Otsuka, and has received research support from Genentech. Dr. Woods has received investigator-initiated research support from Pfizer and sponsor-initiated research support from Auspex and Teva; he has served as a consultant for Biomedisyn (unpaid), Boehringer-Ingelheim, and Merck and as an unpaid consultant to DSM-5; he has been granted a patent for a method of treating prodromal schizophrenia with glycine agonists and is named as an inventor on a patent pending for a method of predicting psychosis risk using blood biomarker analysis; and he has received royalties from Oxford University Press The other authors report no financial relationships with commercial interests. NR 41 TC 12 Z9 12 U1 4 U2 4 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X EI 1535-7228 J9 AM J PSYCHIAT JI Am. J. Psychiat. PD OCT PY 2016 VL 173 IS 10 BP 980 EP 988 DI 10.1176/appi.ajp.2016.15070890 PG 9 WC Psychiatry SC Psychiatry GA DX1WT UT WOS:000384158400009 PM 27363508 ER PT J AU Zoratti, EM Krouse, RZ Babineau, DC Pongracic, JA O'Connor, GT Wood, RA Hershey, GKK Kercsmar, CM Gruchalla, RS Kattan, M Teach, SJ Sigelman, SM Gergen, PJ Togias, A Visness, CM Busse, WW Liu, AH AF Zoratti, Edward M. Krouse, Rebecca Z. Babineau, Denise C. Pongracic, Jacqueline A. O'Connor, George T. Wood, Robert A. Hershey, Gurjit K. Khurana Kercsmar, Carolyn M. Gruchalla, Rebecca S. Kattan, Meyer Teach, Stephen J. Sigelman, Steven M. Gergen, Peter J. Togias, Alkis Visness, Cynthia M. Busse, William W. Liu, Andrew H. TI Asthma phenotypes in inner-city children SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Allergen sensitization; allergy; airway inflammation; bronchial hyperresponsiveness; asthma phenotypes; asthma severity; IgE; hierarchical cluster; inner-city asthma; rhinitis ID ALLERGIC SENSITIZATION; RESEARCH-PROGRAM; CLUSTER-ANALYSIS; SEVERITY; DISEASE; MORBIDITY; CLASSIFICATION; EXPOSURE; RHINITIS; VIOLENCE AB Background: Children with asthma in low-income urban areas have high morbidity. Phenotypic analysis in these children is lacking, but may identify characteristics to inform successful tailored management approaches. Objective: We sought to identify distinct asthma phenotypes among inner-city children receiving guidelines-based management. Methods: Nine inner-city asthma consortium centers enrolled 717 children aged 6 to 17 years. Data were collected at baseline and prospectively every 2 months for 1 year. Participants' asthma and rhinitis were optimally managed by study physicians on the basis of guidelines. Cluster analysis using 50 baseline and 12 longitudinal variables was performed in 616 participants completing 4 or more follow-up visits. Results: Five clusters (designated A through E) were distinguished by indicators of asthma and rhinitis severity, pulmonary physiology, allergy (sensitization and total serum IgE), and allergic inflammation. In comparison to other clusters, cluster A was distinguished by lower allergy/inflammation, minimally symptomatic asthma and rhinitis, and normal pulmonary physiology. Cluster B had highly symptomatic asthma despite high step-level treatment, lower allergy and inflammation, and mildly altered pulmonary physiology. Cluster C had minimally symptomatic asthma and rhinitis, intermediate allergy and inflammation, and mildly impaired pulmonary physiology. Clusters D and E exhibited progressively higher asthma and rhinitis symptoms and allergy/inflammation. Cluster E had the most symptomatic asthma while receiving high step-level treatment and had the highest total serum IgE level (median, 733 kU/L), blood eosinophil count (median, 400 cells/mm(3)), and allergen sensitizations (15 of 22 tested). Conclusions: Allergy distinguishes asthma phenotypes in urban children. Severe asthma often coclusters with highly allergic children. However, a symptomatic phenotype with little allergy or allergic inflammation was identified. C1 [Zoratti, Edward M.] Henry Ford Hlth Syst, Detroit, MI USA. [Zoratti, Edward M.] Wayne State Univ, Sch Med, Detroit, MI USA. [Krouse, Rebecca Z.; Babineau, Denise C.; Visness, Cynthia M.] Rho Fed Syst Div, Chapel Hill, NC USA. [Pongracic, Jacqueline A.] Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL 60611 USA. [O'Connor, George T.] Boston Univ, Sch Med, Boston, MA 02215 USA. [Wood, Robert A.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Hershey, Gurjit K. Khurana; Kercsmar, Carolyn M.] Cincinnati Childrens Hosp, Cincinnati, OH USA. [Gruchalla, Rebecca S.] Univ Texas Southwestern Med Ctr Dallas, Dallas, TX 75390 USA. [Kattan, Meyer] Columbia Univ, Coll Phys & Surg, New York, NY USA. [Teach, Stephen J.] Childrens Natl Hlth Syst, Washington, DC USA. [Teach, Stephen J.] George Washington Univ, Sch Med & Hlth Sci, Washington, DC 20052 USA. [Sigelman, Steven M.; Gergen, Peter J.; Togias, Alkis] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Busse, William W.] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI USA. [Liu, Andrew H.] Natl Jewish Hlth, Denver, CO USA. [Liu, Andrew H.] Childrens Hosp Colorado, Aurora, CO USA. [Liu, Andrew H.] Univ Colorado, Sch Med, Aurora, CO USA. RP Zoratti, EM (reprint author), Henry Ford Hosp, Dept Internal Med, Div Allergy & Immunol, 4B69 One Ford Pl, Detroit, MI 48202 USA. EM ezoratt1@hfhs.org FU National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Department of Health and Human Services [HHSN272200900052C, HHSN272201000052I, 1UM1AI114271-01]; National Center for Research Resources (NCRR); National Center for Advancing Translational Sciences (NCATS), NIH [NCRR/NIH UL1TR000451, UL1RR025780, UL1TR000075, NCATS/NIH UL1TR000154, UL1TR001082, UL1TR000077 04, UL1TR000040, UL1TR000150, UL1TR001105] FX This project has been funded in whole or in part with federal funds from the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Department of Health and Human Services (under contract nos., HHSN272200900052C and HHSN272201000052I, and 1UM1AI114271-01). Additional support was provided by the National Center for Research Resources (NCRR), and the National Center for Advancing Translational Sciences (NCATS), NIH ( under grant nos. NCRR/NIH UL1TR000451, UL1RR025780, UL1TR000075 and NCATS/NIH UL1TR000154, UL1TR001082, UL1TR000077 04, UL1TR000040, UL1TR000150, and UL1TR001105). GlaxoSmithKline (GSK) provided Ventolin, Flovent, Advair, and Flonase under a clinical trial agreement with NIH-NIAID; GSK did not have a role in the development or approval of the protocol, conduct of the trial, data analysis, decision to submit the manuscript for publication. NR 36 TC 3 Z9 3 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD OCT PY 2016 VL 138 IS 4 BP 1016 EP 1029 DI 10.1016/j.jaci.2016.06.061 PG 14 WC Allergy; Immunology SC Allergy; Immunology GA DZ0AP UT WOS:000385499400007 PM 27720016 ER PT J AU Saunders, EFH Ramsden, CE Sherazy, MS Gelenberg, AJ Davis, JM Rapoport, SI AF Saunders, Erika F. H. Ramsden, Christopher E. Sherazy, Mostafa S. Gelenberg, Alan J. Davis, John M. Rapoport, Stanley I. TI Omega-3 and Omega-6 Polyunsaturated Fatty Acids in Bipolar Disorder: A Review of Biomarker and Treatment Studies SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Review ID PLACEBO-CONTROLLED TRIAL; TASK-FORCE REPORT; EICOSAPENTAENOIC ACID; DOUBLE-BLIND; INTERNATIONAL-SOCIETY; ARACHIDONIC-ACID; OPEN-LABEL; OMEGA-3-FATTY-ACID TREATMENT; I DISORDER; ADD-ON AB Objective: There is growing evidence that inflammation is an important mediator of pathophysiology in bipolar disorder. The omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acid (PUFA) metabolic pathways participate in several inflammatory processes and have been linked through epidemiologic and clinical studies to bipolar disorder and its response to treatment. We review the data on PUFAs as biomarkers in bipolar disorder and n-3 PUFA used as treatment for bipolar disorder. Data Sources: PubMed and CINAHL were searched for articles on PUFA and bipolar disorder published in the English language through November 6, 2013, with an updated search conducted on August 20, 2015. Keywords searched included omega 3 fatty acids and bipolar disorder, omega 3 fatty acids and bipolar mania, omega 3 fatty acids and bipolar depression, omega 3 fatty acids and mania, omega 3 fatty acids and cyclothymia, omega 3 fatty acids and hypomania, fatty acids and bipolar disorder, essential fatty acids and bipolar disorder, polyunsaturated fatty acids and bipolar disorder, DHA and bipolar disorder, and EPA and bipolar disorder. Study Selection: Studies selected measured PUFAs as biomarkers or introduced n-3 PUFA as treatment. Results: We identified 17 relevant human clinical articles that either compared PUFA levels between a bipolar disorder group and a control group or used a PUFA intervention to treat depression or mania in bipolar disorder. Human studies suggest low n-3 red blood cell PUFA concentrations and correlations with clinical severity in studies of plasma concentrations in symptomatic bipolar disorder. Results of published n-3 PUFA dietary supplementation trials for bipolar disorder indicate efficacy in treatment for mania or depression in 5 of 5 open-label trials, efficacy in treatment of depression in 1 of 7 randomized controlled trials, and a signal for treatment of depression in 1 meta-analysis. Conclusions: Biomarker studies of PUFA and treatment studies of n-3 PUFA in bipolar disorder show promise for indicating a way forward in the study of PUFA in bipolar disorder. Investigation of the intake and metabolism of the n-3 and n-6 PUFA when supplementation is provided in treatment trials might offer clues for identification of when and how PUFA may be important for treatment in bipolar disorder. (C) Copyright 2016 Physicians Postgraduate Press, Inc. C1 [Saunders, Erika F. H.; Sherazy, Mostafa S.; Gelenberg, Alan J.] Penn State Coll Med, Dept Psychiat, Hershey, PA USA. [Saunders, Erika F. H.; Sherazy, Mostafa S.; Gelenberg, Alan J.] Penn State Milton S Hershey Med Ctr, Hershey, PA USA. [Saunders, Erika F. H.] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. [Saunders, Erika F. H.] Univ Michigan, Depress Ctr, Ann Arbor, MI 48109 USA. [Ramsden, Christopher E.] NIAAA, Sect Nutr Neurosci, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD USA. [Davis, John M.] Univ Illinois, Dept Psychiat, Chicago, IL 60612 USA. [Rapoport, Stanley I.] NIA, Off Sci Director, NIH, Bethesda, MD 20892 USA. RP Saunders, EFH (reprint author), Penn State Coll Med, Penn State Milton S Hershey Med Ctr, Dept Psychiat, 500 Univ Dr,POB 850,Mail Code HO73, Hershey, PA 17033 USA. EM esaunders@hmc.psu.edu FU National Center for Advancing Translational Sciences, National Institute on Aging, National Institutes of Health (NIH), Bethesda, Maryland [KL2 TR000126]; Intramural Program of the National Institute on Aging, NIH, Bethesda, Maryland; National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland FX The project described was supported by the National Center for Research Resources, grant KL2 RR033180 (Dr Saunders), and is now at the National Center for Advancing Translational Sciences, grant KL2 TR000126, National Institute on Aging, National Institutes of Health (NIH), Bethesda, Maryland. The contribution of Dr Rapoport was supported entirely by the Intramural Program of the National Institute on Aging, NIH, Bethesda, Maryland. The contribution of Dr Ramsden was supported by the National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland. NR 55 TC 1 Z9 1 U1 2 U2 2 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 EI 1555-2101 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD OCT PY 2016 VL 77 IS 10 BP E1301 EP E1308 DI 10.4088/JCP.15r09925 PG 8 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA EJ2DQ UT WOS:000393020500014 PM 27631140 ER PT J AU Mazaki-Tovi, S Tarca, AL Vaisbuch, E Kusanovic, JP Than, NG Chaiworapongsa, T Dong, Z Hassan, SS Romero, R AF Mazaki-Tovi, Shali Tarca, Adi L. Vaisbuch, Edi Pedro Kusanovic, Juan Than, Nandor Gabor Chaiworapongsa, Tinnakorn Dong, Zhong Hassan, Sonia S. Romero, Roberto TI Characterization of visceral and subcutaneous adipose tissue transcriptome in pregnant women with and without spontaneous labor at term: implication of alternative splicing in the metabolic adaptations of adipose tissue to parturition SO JOURNAL OF PERINATAL MEDICINE LA English DT Article DE Adipokines; delivery; fat depots; gestation; high dimensional biology; metabolism; obesity; pregnancy ID GESTATIONAL DIABETES-MELLITUS; ENDOPLASMIC-RETICULUM STRESS; HIGH-MOLECULAR-WEIGHT; MATERNAL SERUM ADIPONECTIN; MESSENGER-RNA EXPRESSION; BINDING-PROTEIN 4; GLUTATHIONE-S-TRANSFERASE; INTEGRIN-LINKED KINASE; FREE FATTY-ACIDS; GLUCOSE-TRANSPORTER EXPRESSION AB Objective: The aim of this study was to determine gene expression and splicing changes associated with parturition and regions (visceral vs. subcutaneous) of the adipose tissue of pregnant women. Study design: The transcriptome of visceral and abdominal subcutaneous adipose tissue from pregnant women at term with (n=15) and without (n=25) spontaneous labor was profiled with the Affymetrix GeneChip Human Exon 1.0 ST array. Overall gene expression changes and the differential exon usage rate were compared between patient groups (unpaired analyses) and adipose tissue regions (paired analyses). Selected genes were tested by quantitative reverse transcription-polymerase chain reaction. Results: Four hundred and eighty-two genes were differentially expressed between visceral and subcutaneous fat of pregnant women with spontaneous labor at term (q-value <0.1; fold change >1.5). Biological processes enriched in this comparison included tissue and vasculature development as well as inflammatory and metabolic pathways. Differential splicing was found for 42 genes [q-value <0.1; differences in Finding Isoforms using Robust Multichip Analysis scores >2] between adipose tissue regions of women not in labor. Differential exon usage associated with parturition was found for three genes (LIMS1, HSPA5, and GSTK1) in subcutaneous tissues. Conclusion: We show for the first time evidence of implication of mRNA splicing and processing machinery in the subcutaneous adipose tissue of women in labor compared to those without labor. C1 [Mazaki-Tovi, Shali] Sheba Med Ctr, Dept Obstet & Gynecol, IL-52621 Tel Hashomer, Israel. [Mazaki-Tovi, Shali] Tel Aviv Univ, Tel Aviv, Israel. [Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS,Hutzel Womens Hosp, Box 4,3990 John R, Detroit, MI 48201 USA. [Romero, Roberto] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Romero, Roberto] Michigan State Univ, Dept Biostat & Epidemiol, E Lansing, MI 48824 USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI 48202 USA. [Tarca, Adi L.; Pedro Kusanovic, Juan; Than, Nandor Gabor; Chaiworapongsa, Tinnakorn; Dong, Zhong; Hassan, Sonia S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, US Dept HHS, Bethesda, MD USA. [Tarca, Adi L.; Pedro Kusanovic, Juan; Than, Nandor Gabor; Chaiworapongsa, Tinnakorn; Dong, Zhong; Hassan, Sonia S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, US Dept HHS, Detroit, MI USA. [Tarca, Adi L.] Wayne State Univ, Dept Comp Sci, Detroit, MI 48202 USA. [Tarca, Adi L.; Chaiworapongsa, Tinnakorn; Hassan, Sonia S.] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Vaisbuch, Edi] Kaplan Med Ctr, Dept Obstet & Gynecol, Rehovot, Israel. [Pedro Kusanovic, Juan] Pontificia Univ Catolica Chile, Sch Med, Dept Obstet & Gynecol, Santiago, Chile. [Pedro Kusanovic, Juan] Hosp Dr Sotero del Rio, Dept Obstet & Gynecol, Ctr Res & Innovat Maternal Fetal Med CIMAF, Santiago, Chile. [Than, Nandor Gabor] Hungarian Acad Sci, Inst Enzymol, Momentum Res Grp, Res Ctr Nat Sci, Budapest, Hungary. [Than, Nandor Gabor] Semmelweis Univ, Dept Pathol & Expt Canc Res 1, Budapest, Hungary. RP Mazaki-Tovi, S (reprint author), Sheba Med Ctr, Dept Obstet & Gynecol, IL-52621 Tel Hashomer, Israel.; Mazaki-Tovi, S (reprint author), Tel Aviv Univ, Tel Aviv, Israel.; Romero, R (reprint author), NICHD, Perinatol Res Branch, NIH, DHHS,Hutzel Womens Hosp, Box 4,3990 John R, Detroit, MI 48201 USA.; Romero, R (reprint author), Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA.; Romero, R (reprint author), Michigan State Univ, Dept Biostat & Epidemiol, E Lansing, MI 48824 USA.; Romero, R (reprint author), Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI 48202 USA. EM shalimazaki@gmail.com; romeror@mail.nih.gov FU Perinatology Research Branch; Program for Perinatal Research and Obstetrics; Division of Intramural Research; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health; U.S. Department of Health and Human Services FX This project was supported, in part, by the Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services. NR 314 TC 1 Z9 1 U1 0 U2 0 PU WALTER DE GRUYTER GMBH PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 0300-5577 EI 1619-3997 J9 J PERINAT MED JI J. Perinat. Med. PD OCT PY 2016 VL 44 IS 7 BP 813 EP 835 DI 10.1515/jpm-2015-0259 PG 23 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA DZ7MF UT WOS:000386049300014 PM 26994472 ER PT J AU Gu, FY Derkach, A Freedman, ND Landi, MT Albanes, D Weinstein, SJ Mondul, AM Matthews, CE Guertin, KA Xiao, Q Zheng, W Shu, XO Sampson, JN Moore, SC Caporaso, NE AF Gu, Fangyi Derkach, Andriy Freedman, Neal D. Landi, Maria Teresa Albanes, Demetrius Weinstein, Stephanie J. Mondul, Alison M. Matthews, Charles E. Guertin, Kristin A. Xiao, Qian Zheng, Wei Shu, Xiao-ou Sampson, Joshua N. Moore, Steven C. Caporaso, Neil E. TI Cigarette smoking behaviour and blood metabolomics SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE Smoking; metabolomics; non-targeted; o-cresol sulphate; bilirubin ID COLORECTAL-CANCER RISK; ALZHEIMERS-DISEASE; SERUM BILIRUBIN; LUNG-CANCER; MASS-SPECTROMETRY; METABOLITES; ASSOCIATION; ANTIOXIDANT; PROFILE; CONSUMPTION AB Background: Identifying circulating metabolites related to cigarette smoking may provide insight into the biological mechanisms of smoking-related diseases and the nature of addiction. However, previous studies are limited, generally small, and have largely targeted a priori metabolites. Methods: We examined associations between cigarette smoking and metabolites using an untargeted metabolomics approach in 892 men and women from four studies including participants from Italy, USA, China and Finland. We examined associations between individual log-transformed metabolites and two key smoking phenotypes (current smoking status and cigarettes per day [cig/day]) using linear regression. Fixed-effect meta-analysis was used to combine results across studies. Strict Bonferroni thresholds were used as our significance criteria. We further examined associated metabolites with other metrics of smoking behaviuor (current versus former, former versus never, smoking duration and years since quitting) in the US study. Results: We identified a total of 25 metabolites associated with smoking behaviours; 24 were associated with current smoking status and eight with cig/day. In addition to three well-established nicotine metabolites (cotinine, hydroxycotinine, cotinine N-oxide), we found an additional 12 xenobiotic metabolites involved in benzoatic (e.g. 3-ethylphenyl-sulphate) or xanthine metabolism (e.g. 1-methylurate), three amino acids (o-cresol sulphate, serotonin, indolepropionate), two lipids (scyllo-inositol, pregnenolone sulphate), four vitamins or cofactors [e.g. bilirubin (Z,Z)], and one carbohydrate (oxalate). Conclusions: We identified associations between cigarette smoking and a diverse range of metabolites. Our findings, with further validation in future studies, have implications regarding aetiology and study design of smoking-related diseases. C1 [Gu, Fangyi; Derkach, Andriy; Freedman, Neal D.; Landi, Maria Teresa; Albanes, Demetrius; Weinstein, Stephanie J.; Matthews, Charles E.; Guertin, Kristin A.; Xiao, Qian; Sampson, Joshua N.; Moore, Steven C.; Caporaso, Neil E.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Mondul, Alison M.] Univ Michigan, Sch Publ Hlth, Ann Arbor, MI 48109 USA. [Zheng, Wei; Shu, Xiao-ou] Vanderbilt Univ, Sch Med, Canc Epidemiol Res Program, Nashville, TN 37212 USA. RP Gu, FY (reprint author), Room 6E426,9609 Med Ctr Dr, Shady Grove, MD 20850 USA. EM fangyigu@gmail.com FU Intramural Research Program of the National Cancer Institute; U.S. Public Health Service [N01-CN-45165, N01-RC-45035, N01-RC-37004, HHSN261201000006C, HHSN261200800001E, HHSN261201500005C]; [UM1 CA173640] FX This work was supported by the Intramural Research Program of the National Cancer Institute. The ATBC Study is additionally supported by U.S. Public Health Service Contract Numbers: N01-CN-45165, N01-RC-45035, N01-RC-37004, HHSN261201000006C, HHSN261200800001E and HHSN261201500005C. The Shanghai Men's Health Study is supported by UM1 CA173640. NR 43 TC 1 Z9 1 U1 2 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 EI 1464-3685 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD OCT PY 2016 VL 45 IS 5 BP 1421 EP 1432 DI 10.1093/ije/dyv330 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EJ4KA UT WOS:000393184400017 PM 26721601 ER PT J AU Xiao, Q Moore, SC Keadle, SK Xiang, YB Zheng, W Peters, TM Leitzmann, MF Ji, BT Sampson, JN Shu, XO Matthews, CE AF Xiao, Qian Moore, Steven C. Keadle, Sarah K. Xiang, Yong-Bing Zheng, Wei Peters, Tricia M. Leitzmann, Michael F. Ji, Bu-Tian Sampson, Joshua N. Shu, Xiao-Ou Matthews, Charles E. TI Objectively measured physical activity and plasma metabolomics in the Shanghai Physical Activity Study SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE sleep timing; chronotype; sleep duration; metabolomics ID GAMMA-GLUTAMYL-TRANSFERASE; CHAIN AMINO-ACIDS; INSULIN SENSITIVITY; PROSPECTIVE COHORT; POTENTIAL ROLE; UNITED-STATES; RISK; METAANALYSIS; ADULTS; ACCELEROMETER AB Background: Physical activity is associated with a variety of health benefits, but the biological mechanisms that explain these associations remain unclear. Metabolomics is a powerful tool to comprehensively evaluate global metabolic signature associated with physical activity and helps to pinpoint the pathways that mediate the health effects of physical activity. There has been limited research on metabolomics and habitual physical activity, and no metabolomics study has examined sedentary behaviour and physical activity of different intensities. Methods: In a group of Chinese adults (N = 277), we used an untargeted approach to examine 328 plasma metabolites in relation to accelerometer-measured physical activity, including overall volume of physical activity (physical activity energy expenditure (PAEE) and duration of physically active time) and sedentary time, and measures related to different intensities of physical activity (moderate-to-vigorous activity (MVPA), light activity, average physical activity intensity). Results: We identified 11 metabolites that were associated with total activity, with a false discovery rate of 0.2 or lower. Notably, we observed generally lower levels of amino acids in the valine, leucine and isoleucine metabolism pathway and of carbohydrates in sugar metabolism among participants with higher activity levels. Moreover, we found that PAEE, time spent in light activity and duration of physically active time were associated with a similar metabolic pattern, whereas the metabolic signature associated with sedentary time mirrored this pattern. In contrast, average activity intensity and time spent in MVPA appeared to be associated with somewhat different metabolic patterns. Conclusions: Overall, the metabolomics patterns support a beneficial role of higher volume of physical activity in cardiometabolic health. Our findings identified candidate pathways and provide insight into the mechanisms underlying the health effects of physical activity. C1 [Xiao, Qian; Moore, Steven C.; Keadle, Sarah K.; Matthews, Charles E.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. [Xiang, Yong-Bing] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Zheng, Wei; Shu, Xiao-Ou] Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, Nashville, TN 37212 USA. [Zheng, Wei; Shu, Xiao-Ou] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37212 USA. [Peters, Tricia M.] McGill Univ, Ctr Hlth, Dept Internal Med, Montreal, PQ, Canada. [Leitzmann, Michael F.] Univ Regensburg, Dept Epidemiol & Prevent Med, Regensburg, Germany. [Ji, Bu-Tian] NCI, Occupat & Environm Epidemiol Branch, Rockville, MD USA. [Sampson, Joshua N.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. RP Xiao, Q (reprint author), 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM xiaoq2@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, National Institutes of Health, Department of Health and Human Services FX The work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, National Institutes of Health, Department of Health and Human Services. NR 50 TC 2 Z9 2 U1 2 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 EI 1464-3685 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD OCT PY 2016 VL 45 IS 5 BP 1433 EP 1444 DI 10.1093/ije/dyw033 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EJ4KA UT WOS:000393184400018 PM 27073263 ER PT J AU Nelson, SM Panagiotou, OA Anic, GM Mondul, AM Mannisto, S Weinstein, SJ Albanes, D AF Nelson, Shakira M. Panagiotou, Orestis A. Anic, Gabriella M. Mondul, Alison M. Mannisto, Satu Weinstein, Stephanie J. Albanes, Demetrius TI Metabolomics analysis of serum 25-hydroxy-vitamin D in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE 25-hydroxy-vitamin D; serum metabolites; metabolomics; fatty acids; amino acids; lipids; CMPF ID VITAMIN-D-RECEPTOR; CIRCULATING 25-HYDROXYVITAMIN D; DRUG-INDUCED OSTEOMALACIA; ISCHEMIC-HEART-DISEASE; PROSTATE-CANCER; MENDELIAN RANDOMIZATION; MYOCARDIAL-INFARCTION; CELL DYSFUNCTION; SUBSEQUENT RISK; RECTAL-CANCER AB Background: Vitamin D has been discussed in the context of cardiovascular disease, cancer, bone health and other outcomes. Epidemiological studies have reported on the importance of vitamin D in cancer prevention and treatment. The discovery of vitamin D-associated metabolites through agnostic metabolomics analyses offers a new approach for elucidating disease aetiology and health-related pathway identification. Methods: Baseline serum 25-hydroxy-vitamin D [25(OH) D] and 940 serum metabolites were measured in 392 men from eight nested cancer case-control studies in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of Finnish male smokers (aged 50-69 years). The metabolomic profiling was conducted using mass spectrometry. We used linear regression to estimate the standardized beta-coefficient as the effect metric for the associations between metabolites and 25(OH) D levels. Results: A majority of the metabolites associated with 25(OH) D were of lipid origin, including 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) [beta-estimate 0.38 per 1 standard deviation (SD) increment], stearoyl-arachidonoyl-glycerophosphoethanolamine (GPPE) (-0.38 per SD) and two essential fatty acids: eicosapentaenoate (EPA; 0.17 per SD) and docosahexaenoate (DHA; 0.13 per SD). Each of these lipid metabolites was associated with 25(OH) D at the principal components corrected P-value of 3.09 x 10(-4). Conclusions: The large number of metabolites, particularly lipid compounds, found to be associated with serum 25(OH) D provide new biological clues relevant to the role of vitamin D status and human health outcomes. The present findings should be re-examined in other metabolomics studies of diverse populations. C1 [Nelson, Shakira M.] NCI, Canc Prevent Fellowship Program, Canc Prevent Div, Bethesda, MD 20892 USA. [Nelson, Shakira M.; Anic, Gabriella M.; Weinstein, Stephanie J.; Albanes, Demetrius] NCI, Metab Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Panagiotou, Orestis A.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Mondul, Alison M.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Mannisto, Satu] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. RP Nelson, SM (reprint author), US Natl Canc Inst, 9609 Med Ctr Dr,6E402, Rockville, MD 20892 USA. EM shakira.nelson@nih.gov FU Intramural Research Program of the National Cancer Institute at the National Institutes of Health; U.S. Public Health Service from the National Cancer Institute, Department of Health and Human Services [HHSN261201500005C] FX This work was supported by the Intramural Research Program of the National Cancer Institute at the National Institutes of Health and by U.S. Public Health Service contract HHSN261201500005C from the National Cancer Institute, Department of Health and Human Services. NR 54 TC 2 Z9 2 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 EI 1464-3685 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD OCT PY 2016 VL 45 IS 5 BP 1458 EP 1468 DI 10.1093/ije/dyw148 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EJ4KA UT WOS:000393184400020 PM 27524818 ER PT J AU Walker, DI Uppal, K Zhang, LP Vermeulen, R Smith, M Hu, W Purdue, MP Tang, XJ Reiss, B Kim, S Li, LY Huang, HL Pennell, KD Jones, DP Rothman, N Lan, Q AF Walker, Douglas I. Uppal, Karan Zhang, Luoping Vermeulen, Roel Smith, Martyn Hu, Wei Purdue, Mark P. Tang, Xiaojiang Reiss, Boris Kim, Sungkyoon Li, Laiyu Huang, Hanlin Pennell, Kurt D. Jones, Dean P. Rothman, Nathaniel Lan, Qing TI High-resolution metabolomics of occupational exposure to trichloroethylene SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE Exposome; Metabolic phenotype; VOC exposure; Bioeffect monitoring; Population screening; High-resolution metabolomics; Trichlororoethylene ID ADENOSINE-DEAMINASE ACTIVITY; MASS-SPECTROMETRY; WIDE ASSOCIATION; FUNCTIONAL IMPLICATIONS; CHLORINATED SOLVENTS; TRICHLOROACETIC-ACID; KIDNEY-DISEASE; RISK-FACTORS; LARGE-SCALE; WORKERS AB Background: Occupational exposure to trichloroethylene (TCE) has been linked to adverse health outcomes including non-Hodgkin's lymphoma and kidney and liver cancer; however, TCE's mode of action for development of these diseases in humans is not well understood. Methods: Non-targeted metabolomics analysis of plasma obtained from 80 TCE-exposed workers [full shift exposure range of 0.4 to 230 parts-per-million of air (ppm(a))] and 95 matched controls were completed by ultra-high resolution mass spectrometry. Biological response to TCE exposure was determined using a metabolome-wide association study (MWAS) framework, with metabolic changes and plasma TCE metabolites evaluated by dose-response and pathway enrichment. Biological perturbations were then linked to immunological, renal and exposure molecular markers measured in the same population. Results: Metabolic features associated with TCE exposure included known TCE metabolites, unidentifiable chlorinated compounds and endogenous metabolites. Exposure resulted in a systemic response in endogenous metabolism, including disruption in purine catabolism and decreases in sulphur amino acid and bile acid biosynthesis pathways. Metabolite associations with TCE exposure included uric acid (beta = 0.13, P-value = 3.6 x 10(-5)), glutamine (beta = 0.08, P-value = 0.0013), cystine (beta = 0.75, P-value = 0.0022), methylthioadenosine (beta = -1.6, P-value = 0.0043), taurine (beta = -2.4, P-value = 0.0011) and chenodeoxycholic acid (beta = -1.3, P-value = 0.0039), which are consistent with known toxic effects of TCE, including immunosuppression, hepatotoxicity and nephrotoxicity. Correlation with additional exposure markers and physiological end-points supported known disease associations. Conclusions: High-resolution metabolomics correlates measured occupational exposure to internal dose and metabolic response, providing insight into molecular mechanisms of exposure-related disease aetiology. C1 [Walker, Douglas I.; Uppal, Karan; Jones, Dean P.] Emory Univ, Pulm Allergy & Crit Med, Atlanta, GA 30322 USA. [Walker, Douglas I.; Pennell, Kurt D.] Tufts Univ, Deptartment Civil & Environm Engn, Medford, MA 02155 USA. [Zhang, Luoping; Smith, Martyn] Univ Calif Berkeley, Environm Hlth Sci, Berkeley, CA 94720 USA. [Vermeulen, Roel] Univ Utrecht, Inst Risk Assessment Sci, Utrecht, Netherlands. [Hu, Wei; Purdue, Mark P.; Rothman, Nathaniel; Lan, Qing] NCI, Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Tang, Xiaojiang; Li, Laiyu; Huang, Hanlin] Guangdong Med Lab Anim Ctr, Guangzhou, Guangdong, Peoples R China. [Reiss, Boris] Univ Washington, Dept Environm & Occupat Hlth Sci, Seattle, WA 98195 USA. [Kim, Sungkyoon] Seoul Natl Univ, Sch Publ Hlth, Seoul, South Korea. RP Walker, DI (reprint author), Emory Univ, Dept Med, Whitehead Res Ctr 205, Div Pulm, Atlanta, GA 30322 USA. EM douglas.walker@emory.edu FU National Institutes of Health and National Cancer Society; National Institute of Environmental Health Science [P30 ES019776, ES023485, RO1 ES009047]; National Heart, Blood and Lung Institute [IHL113451]; Department of Science and Technology of Guangdong Province, China [2007A050100004] FX This work was supported by intramural funds received from the National Institutes of Health and National Cancer Society; National Institute of Environmental Health Science to D.P.J. [award numbers P30 ES019776, ES023485, RO1 ES009047]; National Heart, Blood and Lung Institute [award number IHL113451]; and Department of Science and Technology of Guangdong Province, China [award number 2007A050100004]. NR 76 TC 0 Z9 0 U1 5 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 EI 1464-3685 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD OCT PY 2016 VL 45 IS 5 BP 1517 EP 1527 DI 10.1093/ije/dyw218 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EJ4KA UT WOS:000393184400025 PM 27707868 ER PT J AU Ong, JS Cuellar-Partida, G Lu, Y Fasching, PA Hein, A Burghaus, S Beckmann, MW Lambrechts, D Van Nieuwenhuysen, E Vergote, I Vanderstichele, A Doherty, JA Rossing, MA Chang-Claude, J Eilber, U Rudolph, A Wang-Gohrke, S Goodman, MT Bogdanova, N Dork, T Durst, M Hillemanns, P Runnebaum, IB Antonenkova, N Butzow, R Leminen, A Nevanlinna, H Pelttari, LM Edwards, RP Kelley, JL Modugno, F Moysich, KB Ness, RB Cannioto, R Hogdall, E Hogdall, CK Jensen, A Giles, GG Bruinsma, F Kjaer, SK Hildebrandt, MAT Liang, D Lu, KH Wu, XF Bisogna, M Dao, F Levine, DA Cramer, DW Terry, KL Tworoger, SS Stampfer, M Missmer, S Bjorge, L Salvesen, HB Kopperud, RK Bischof, K Aben, KKH Kiemeney, LA Massuger, LFAG Brooks-Wilson, A Olson, SH McGuire, V Rothstein, JH Sieh, W Whittemore, AS Cook, LS Le, ND Gilks, CB Gronwald, J Jakubowska, A Lubinski, J Kluz, T Song, HL Tyrer, JP Wentzensen, N Brinton, L Trabert, B Lissowska, J McLaughlin, JR Narod, SA Phelan, C Anton-Culver, H Ziogas, A Eccles, D Campbell, I Gayther, SA Gentry-Maharaj, A Menon, U Ramus, SJ Wu, AH Dansonka-Mieszkowska, A Kupryjanczyk, J Timorek, A Szafron, L Cunningham, JM Fridley, BL Winham, SJ Bandera, EV Poole, EM Morgan, TK Risch, HA Goode, EL Schildkraut, JM Pearce, CL Berchuck, A Pharoah, PDP Chenevix-Trench, G Gharahkhani, P Neale, RE Webb, PM MacGregor, S AF Ong, Jue-Sheng Cuellar-Partida, Gabriel Lu, Yi Fasching, Peter A. Hein, Alexander Burghaus, Stefanie Beckmann, Matthias W. Lambrechts, Diether Van Nieuwenhuysen, Els Vergote, Ignace Vanderstichele, Adriaan Doherty, Jennifer Anne Rossing, Mary Anne Chang-Claude, Jenny Eilber, Ursula Rudolph, Anja Wang-Gohrke, Shan Goodman, Marc T. Bogdanova, Natalia Dork, Thilo Durst, Matthias Hillemanns, Peter Runnebaum, Ingo B. Antonenkova, Natalia Butzow, Ralf Leminen, Arto Nevanlinna, Heli Pelttari, Liisa M. Edwards, Robert P. Kelley, Joseph L. Modugno, Francesmary Moysich, Kirsten B. Ness, Roberta B. Cannioto, Rikki Hogdall, Estrid Hogdall, Claus K. Jensen, Allan Giles, Graham G. Bruinsma, Fiona Kjaer, Susanne K. Hildebrandt, Michelle A. T. Liang, Dong Lu, Karen H. Wu, Xifeng Bisogna, Maria Dao, Fanny Levine, Douglas A. Cramer, Daniel W. Terry, Kathryn L. Tworoger, Shelley S. Stampfer, Meir Missmer, Stacey Bjorge, Line Salvesen, Helga B. Kopperud, Reidun K. Bischof, Katharina Aben, Katja K. H. Kiemeney, Lambertus A. Massuger, Leon F. A. G. Brooks-Wilson, Angela Olson, Sara H. McGuire, Valerie Rothstein, Joseph H. Sieh, Weiva Whittemore, Alice S. Cook, Linda S. Le, Nhu D. Gilks, C. Blake Gronwald, Jacek Jakubowska, Anna Lubinski, Jan Kluz, Tomasz Song, Honglin Tyrer, Jonathan P. Wentzensen, Nicolas Brinton, Louise Trabert, Britton Lissowska, Jolanta McLaughlin, John R. Narod, Steven A. Phelan, Catherine Anton-Culver, Hoda Ziogas, Argyrios Eccles, Diana Campbell, Ian Gayther, Simon A. Gentry-Maharaj, Aleksandra Menon, Usha Ramus, Susan J. Wu, Anna H. Dansonka-Mieszkowska, Agnieszka Kupryjanczyk, Jolanta Timorek, Agnieszka Szafron, Lukasz Cunningham, Julie M. Fridley, Brooke L. Winham, Stacey J. Bandera, Elisa V. Poole, Elizabeth M. Morgan, Terry K. Risch, Harvey A. Goode, Ellen L. Schildkraut, Joellen M. Pearce, Celeste L. Berchuck, Andrew Pharoah, Paul D. P. Chenevix-Trench, Georgia Gharahkhani, Puya Neale, Rachel E. Webb, Penelope M. MacGregor, Stuart CA Australian Ovarian Canc Study TI Association of vitamin D levels and risk of ovarian cancer: a Mendelian randomization study SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article ID GENOME-WIDE ASSOCIATION; CIRCULATING 25-HYDROXYVITAMIN D; D-BINDING PROTEIN; MORTALITY; MECHANISMS AB Background: In vitro and observational epidemiological studies suggest that vitamin D may play a role in cancer prevention. However, the relationship between vitamin D and ovarian cancer is uncertain, with observational studies generating conflicting findings. A potential limitation of observational studies is inadequate control of confounding. To overcome this problem, we used Mendelian randomization (MR) to evaluate the association between single nucleotide polymorphisms (SNPs) associated with circulating 25-hydroxyvitamin D [25(OH)D] concentration and risk of ovarian cancer. Methods: We employed SNPs with well-established associations with 25(OH) D concentration as instrumental variables for MR: rs7944926 (DHCR7), rs12794714 (CYP2R1) and rs2282679 (GC). We included 31 719 women of European ancestry (10 065 cases, 21 654 controls) from the Ovarian Cancer Association Consortium, who were genotyped using customized Illumina Infinium iSelect (iCOGS) arrays. A two-sample (summary data) MR approach was used and analyses were performed separately for all ovarian cancer (10 065 cases) and for high-grade serous ovarian cancer (4121 cases). Results: The odds ratio for epithelial ovarian cancer risk (10 065 cases) estimated by combining the individual SNP associations using inverse variance weighting was 1.27 (95% confidence interval: 1.06 to 1.51) per 20 nmol/L decrease in 25(OH) D concentration. The estimated odds ratio for high-grade serous epithelial ovarian cancer (4121 cases) was 1.54 (1.19, 2.01). Conclusions: Genetically lowered 25-hydroxyvitamin D concentrations were associated with higher ovarian cancer susceptibility in Europeans. These findings suggest that increasing plasma vitamin D levels may reduce risk of ovarian cancer. C1 [Ong, Jue-Sheng; Cuellar-Partida, Gabriel; Lu, Yi; Gharahkhani, Puya; MacGregor, Stuart] QIMR Berghofer Med Res Inst, Stat Genet Lab, Herston, Qld 4006, Australia. [Ong, Jue-Sheng; Cuellar-Partida, Gabriel] Univ Queensland, Sch Med, St Lucia, Qld 4072, Australia. [Chenevix-Trench, Georgia] QIMR Berghofer Med Res Inst, Canc Genet Lab, Herston, Qld 4006, Australia. [Neale, Rachel E.; Webb, Penelope M.] QIMR Berghofer Med Res Inst, Gynaecol Canc Lab, Herston, Qld 4006, Australia. [Campbell, Ian; Australian Ovarian Canc Study] Peter MacCallum Canc Ctr, Div Res, East Melbourne, Vic, Australia. [Pharoah, Paul D. P.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Fasching, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. [Fasching, Peter A.; Hein, Alexander; Burghaus, Stefanie; Beckmann, Matthias W.] Friedrich Alexander Univ Erlangen Nuremberg, Comprehens Canc Ctr Erlangen EMN, Dept Gynecol & Obstet, Univ Hosp Erlangen, D-91054 Erlangen, Germany. [Lambrechts, Diether] Univ Leuven, Dept Oncol, Lab Translat Genet, Leuven, Belgium. [Lambrechts, Diether] VIB, Vesalius Res Ctr, Leuven, Belgium. [Van Nieuwenhuysen, Els; Vergote, Ignace; Vanderstichele, Adriaan] Univ Hosp Leuven, Dept Obstet & Gynaecol, Div Gynecol Oncol, Leuven, Belgium. [Van Nieuwenhuysen, Els; Vergote, Ignace; Vanderstichele, Adriaan] Univ Hosp Leuven, Leuven Canc Inst, Leuven, Belgium. [Doherty, Jennifer Anne] Dartmouth Coll, Geisel Sch Med, Dept Community & Family Med, Sect Biostat & Epidemiol, Hanover, NH 03755 USA. [Rossing, Mary Anne] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Rossing, Mary Anne] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Program Epidemiol, 1124 Columbia St, Seattle, WA 98104 USA. [Chang-Claude, Jenny; Eilber, Ursula; Rudolph, Anja] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Wang-Gohrke, Shan] Univ Ulm, Dept Obstet & Gynecol, Ulm, Germany. [Goodman, Marc T.] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Canc Prevent & Control, Los Angeles, CA 90048 USA. [Goodman, Marc T.] Cedars Sinai Med Ctr, Dept Biomed Sci, Community & Populat Hlth Res Inst, Los Angeles, CA 90048 USA. [Bogdanova, Natalia] Hannover Med Sch, Radiat Oncol Res Unit, Hannover, Germany. [Dork, Thilo] Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany. [Durst, Matthias; Runnebaum, Ingo B.] Friedrich Schiller Univ, Jena Univ Hosp, Dept Gynecol, Jena, Germany. [Hillemanns, Peter] Hannover Med Sch, Clin Obstet & Gynaecol, Hannover, Germany. [Antonenkova, Natalia] NN Alexandrov Natl Canc Ctr Belarus, Minsk, Byelarus. [Butzow, Ralf] Univ Helsinki, Dept Pathol, Helsinki, Finland. [Butzow, Ralf; Leminen, Arto; Nevanlinna, Heli; Pelttari, Liisa M.] Helsinki Univ Hosp, Helsinki, Finland. [Leminen, Arto; Nevanlinna, Heli; Pelttari, Liisa M.] Univ Helsinki, Dept Obstet & Gynecol, Helsinki, Finland. [Edwards, Robert P.; Kelley, Joseph L.; Modugno, Francesmary] Univ Pittsburgh, Sch Med, Div Gynecol Oncol, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA. [Edwards, Robert P.; Modugno, Francesmary] Magee Womens Res Inst, Womens Canc Res Program, Pittsburgh, PA USA. [Edwards, Robert P.; Modugno, Francesmary] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Modugno, Francesmary] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Moysich, Kirsten B.; Cannioto, Rikki] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Ness, Roberta B.] Univ Texas Houston, Sch Publ Hlth, Houston, TX USA. [Hogdall, Estrid; Jensen, Allan; Kjaer, Susanne K.] Danish Canc Soc Res Ctr, Dept Virus Lifestyle & Genes, Copenhagen, Denmark. [Hogdall, Estrid] Univ Copenhagen, Herlev Hosp, Dept Pathol, Mol Unit, Copenhagen, Denmark. [Giles, Graham G.] Monash Univ, Dept Epidemiol & Prevent Med, Melbourne, Vic, Australia. [Giles, Graham G.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia. [Giles, Graham G.; Bruinsma, Fiona] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Hogdall, Claus K.; Kjaer, Susanne K.] Univ Copenhagen, Rigshosp, Dept Gynaecol, Copenhagen, Denmark. [Hildebrandt, Michelle A. T.; Wu, Xifeng] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Liang, Dong] Texas Southern Univ, Coll Pharm & Hlth Sci, Houston, TX USA. [Lu, Karen H.] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA. [Bisogna, Maria; Dao, Fanny; Levine, Douglas A.] Mem Sloan Kettering Canc Ctr, Dept Surg, Gynecol Serv, 1275 York Ave, New York, NY 10021 USA. [Cramer, Daniel W.; Terry, Kathryn L.] Brigham & Womens Hosp, Obstet & Gynecol Epidemiol Ctr, 75 Francis St, Boston, MA 02115 USA. [Tworoger, Shelley S.; Stampfer, Meir; Missmer, Stacey; Poole, Elizabeth M.] Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Tworoger, Shelley S.; Stampfer, Meir; Missmer, Stacey; Poole, Elizabeth M.] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Tworoger, Shelley S.; Stampfer, Meir; Missmer, Stacey; Poole, Elizabeth M.] Harvard Med Sch, Boston, MA USA. [Missmer, Stacey] Brigham & Womens Hosp, Dept Obstet & Gynecol, 75 Francis St, Boston, MA 02115 USA. [Bjorge, Line; Salvesen, Helga B.; Kopperud, Reidun K.; Bischof, Katharina] Haukeland Hosp, Dept Gynecol & Obstet, Bergen, Norway. [Bjorge, Line; Salvesen, Helga B.; Kopperud, Reidun K.; Bischof, Katharina] Univ Bergen, Dept Clin Sci, Ctr Canc Biomarkers, Bergen, Norway. [Aben, Katja K. H.; Kiemeney, Lambertus A.] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Nijmegen, Netherlands. [Aben, Katja K. H.] Netherlands Comprehens Canc Org, Utrecht, Netherlands. [Massuger, Leon F. A. G.] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Mol Life Sci, Dept Obstet & Gynaecol, Nijmegen, Netherlands. [Brooks-Wilson, Angela] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC, Canada. [Brooks-Wilson, Angela] Simon Fraser Univ, Dept Biomed Physiol & Kinesiol, Burnaby, BC, Canada. [Olson, Sara H.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [McGuire, Valerie; Rothstein, Joseph H.; Sieh, Weiva; Whittemore, Alice S.] Stanford Univ, Sch Med, Dept Hlth Res & Policy Epidemiol, Stanford, CA 94305 USA. [Cook, Linda S.] Univ New Mexico, Dept Internal Med, Div Epidemiol & Biostat, Albuquerque, NM 87131 USA. [Le, Nhu D.] BC Canc Agcy, Canc Control Res, Vancouver, BC, Canada. [Gilks, C. Blake] Univ British Columbia, Pathol & Lab Med, Vancouver, BC, Canada. [Gronwald, Jacek; Jakubowska, Anna; Lubinski, Jan] Pomeranian Med Univ, Dept Genet & Pathol, Int Hereditary Canc Ctr, Szczecin, Poland. [Kluz, Tomasz] Univ Rzeszow, Fac Med, Frederick Chopin Clin Prov Hosp 1, Inst Midwifery & Emergency Med,Clin Obstet & Gyne, Rzeszow, Poland. [Song, Honglin; Tyrer, Jonathan P.; Pharoah, Paul D. P.] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England. [Wentzensen, Nicolas; Brinton, Louise; Trabert, Britton] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Lissowska, Jolanta] M Sklodowska Curie Mem Canc Ctr, Dept Epidemiol & Prevent, Warsaw, Poland. [McLaughlin, John R.] Publ Hlth Ontario, Toronto, ON, Canada. [Narod, Steven A.] Univ Toronto, Womens Coll Res Inst, Toronto, ON, Canada. [Phelan, Catherine] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL USA. [Anton-Culver, Hoda; Ziogas, Argyrios] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA. [Anton-Culver, Hoda] Univ Calif Irvine, Sch Med, Ctr Canc Genet Res & Prevent, Irvine, CA 92717 USA. [Eccles, Diana] Univ Southampton, Fac Med, Southampton, Hants, England. [Gayther, Simon A.; Ramus, Susan J.; Wu, Anna H.; Pearce, Celeste L.] Univ Southern Calif, Norris Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA. [Gentry-Maharaj, Aleksandra; Menon, Usha] UCL, Inst Womens Hlth, Womens Canc, London, England. [Dansonka-Mieszkowska, Agnieszka; Szafron, Lukasz] Maria Sklodowska Curie Mem Canc Ctr & Inst Oncol, Dept Pathol & Lab Diagnost, Warsaw, Poland. [Kupryjanczyk, Jolanta; Timorek, Agnieszka] Warsaw Med Univ, Fac Med 2, Dept Obstet Gynaecol & Oncol, Warsaw, Poland. [Kupryjanczyk, Jolanta; Timorek, Agnieszka] Brodnowski Hosp, Warsaw, Poland. [Cunningham, Julie M.] Mayo Clin, Div Expt Pathol, Dept Lab Med & Pathol, Rochester, MN USA. [Fridley, Brooke L.] Univ Kansas, Dept Biostat, Kansas City, KS USA. [Winham, Stacey J.] Mayo Clin, Dept Hlth Sci Res, Div Biomed Stat & Informat, Rochester, MN USA. [Bandera, Elisa V.] Rutgers Canc Inst New Jersey, New Brunswick, NJ USA. [Morgan, Terry K.] OHSU, Dept Pathol, Portland, OR USA. [Morgan, Terry K.] OHSU, Dept Obstet & Gynaecol, Portland, OR USA. [Risch, Harvey A.] Yale Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT USA. [Goode, Ellen L.] Mayo Clin, Div Epidemiol, Dept Hlth Sci Res, Rochester, MN USA. [Schildkraut, Joellen M.] Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC USA. [Schildkraut, Joellen M.] Duke Canc Inst, Canc Control & Populat Sci, Durham, NC USA. [Pearce, Celeste L.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Berchuck, Andrew] Duke Univ, Med Ctr, Duke Canc Inst, Durham, NC USA. [Neale, Rachel E.] QIMR Berghofer Med Res Inst, Canc Aetiol & Prevent Lab, Herston, Qld 4006, Australia. RP MacGregor, S (reprint author), QIMR Berghofer Med Res Inst, Stat Genet Lab, Herston, Qld 4006, Australia.; MacGregor, S (reprint author), QIMR Berghofer Med Res Inst, Locked Bag 2000, Herston, Qld 4029, Australia. EM stuart.macgregor@qimrberghofer.edu.au RI Gronwald, Jacek/A-4576-2017; Hein, Alexander/F-6999-2010; salvesen, Helga/C-1187-2017; Brooks-Wilson, Angela/E-9399-2012 OI Gronwald, Jacek/0000-0002-3643-2871; Hein, Alexander/0000-0003-2601-3398; salvesen, Helga/0000-0002-4438-8831; Brooks-Wilson, Angela/0000-0003-1009-6408 FU COGS project; European Commission's Seventh Framework Programme Grant [223175 HEALTH F2 2009-223175]; Genetic Associations and Mechanisms in Oncology (GAME-ON); NCI Cancer Post-GWAS Initiative [U19-CA148112]; Ovarian Cancer Association Consortium; Ovarian Cancer Research Fund; California Cancer Research Program [00-01389V-20170, N01-CN25403, 2II0200]; Canadian Institutes of Health Research [MOP-86727]; Cancer Australia; Cancer Council Victoria; Cancer Council Queensland; Cancer Council New South Wales; Cancer Council South Australia; Cancer Council Tasmania; Cancer Foundation of Western Australia; Cancer Institute of New Jersey; Cancer Research UK [C490/A6187, C490/A10119, C490/A10124]; Danish Cancer Society [94-222-52]; ELAN Program of the University of Erlangen-Nuremberg; Eve Appeal; Helsinki University Central Hospital Research Fund; Helse Vest; Norwegian Cancer Society; Norwegian Research Council; Nationaal Kankerplan of Belgium; L & S Milken Foundation; Polish Ministry of Science and Higher Education [4 PO5C 028 14, 2 PO5A 068 27]; Roswell Park Cancer Institute Alliance Foundation; US National Cancer Institute (Intramural research funds) [K07-CA095666, K07-CA80668, K07-CA143047, K22-CA138563, N01-CN55424, N01-PC67001, N01-PC067010, N01-PC035137, P01-CA017054, P01-CA087696, P30-CA072720, P30-CA15083, P30-CA008748, P50-CA159981, P50-CA105009, P50-CA136393, R01-CA149429, R01-CA014089, R01-CA016056]; NIH/National Center for Research Resources/General Clinical Research Center [MO1-RR000056]; US Army Medical Research and Material Command [DAMD17-01-1-0729, DAMD17-02-1-0666, DAMD17-02-1-0669, W81XWH-07-0449, W81XWH-10-1-02802]; US Public Health Service [PSA-042205]; National Health and Medical Research Council of Australia [199600, 400281]; German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research [01GB 9401]; State of Baden-Wurttemberg through Medical Faculty of the University of Ulm [P.685]; German Cancer Research Center; Minnesota Ovarian Cancer Alliance; Mayo Foundation; Fred C. and Katherine B. Andersen Foundation; Lon V. Smith Foundation [LVS-39420]; Oak Foundation; OHSU Foundation; Mermaid I project; Rudolf-Bartling Foundation; UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; Imperial College London; University College Hospital 'Womens Health Theme'; Royal Marsden Hospital; Work Safe BC 14; University of Queensland; QIMR Berghofer Medical Research Institute; NHMRC Early Career Fellowship; National Health and Medical Research Council; Australian Research Council Future Fellowship; [R01-CA017054]; [R01-CA049449]; [R01-CA050385]; [R01-CA054419]; [R01-CA058598]; [R01-CA058860]; [R01-CA061107]; [R01-CA061132]; [R01-CA063678]; [R01-CA063682]; [R01-CA067262]; [R01-CA071766]; [R01-CA074850]; [R01-CA080978]; [R01-CA083918]; [R01-CA087538]; [R01-CA092044]; [R01-CA095023]; [R01-CA126841]; [R01-CA136924]; [R03-CA113148]; [R03-CA115195]; [U01CA069417]; [U01-CA071966]; [UM1-CA186107]; [UM1-CA176726]; [R01-CA122443]; [R01-CA112523]; [R01-CA114343] FX This work was supported by the COGS project, which is funded through a European Commission's Seventh Framework Programme Grant (agreement number 223175 HEALTH F2 2009-223175); the Genetic Associations and Mechanisms in Oncology (GAME-ON): a NCI Cancer Post-GWAS Initiative (U19-CA148112); the Ovarian Cancer Association Consortium is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). Funding of the constituent studies was provided by the California Cancer Research Program (00-01389V-20170, N01-CN25403, 2II0200); the Canadian Institutes of Health Research (MOP-86727); Cancer Australia; Cancer Council Victoria; Cancer Council Queensland; Cancer Council New South Wales; Cancer Council South Australia; Cancer Council Tasmania; Cancer Foundation of Western Australia; the Cancer Institute of New Jersey; Cancer Research UK (C490/A6187, C490/A10119, C490/A10124); the Danish Cancer Society (94-222-52); the ELAN Program of the University of Erlangen-Nuremberg; the Eve Appeal; the Helsinki University Central Hospital Research Fund; Helse Vest; the Norwegian Cancer Society; the Norwegian Research Council; the Ovarian Cancer Research Fund; Nationaal Kankerplan of Belgium; the L & S Milken Foundation; the Polish Ministry of Science and Higher Education (4 PO5C 028 14, 2 PO5A 068 27); the Roswell Park Cancer Institute Alliance Foundation; the US National Cancer Institute (K07-CA095666, K07-CA80668, K07-CA143047, K22-CA138563, N01-CN55424, N01-PC67001, N01-PC067010, N01-PC035137, P01-CA017054, P01-CA087696, P30-CA072720, P30-CA15083, P30-CA008748, P50-CA159981, P50-CA105009, P50-CA136393, R01-CA149429, R01-CA014089, R01-CA016056, R01-CA017054, R01-CA049449, R01-CA050385, R01-CA054419, R01-CA058598, R01-CA058860, R01-CA061107, R01-CA061132, R01-CA063678, R01-CA063682, R01-CA067262, R01-CA071766, R01-CA074850, R01-CA080978, R01-CA083918, R01-CA087538, R01-CA092044, R01-CA095023, R01-CA122443, R01-CA112523, R01-CA114343, R01-CA126841, R01-CA136924, R03-CA113148, R03-CA115195, U01CA069417, U01-CA071966, UM1-CA186107, UM1-CA176726 and Intramural research funds); the NIH/National Center for Research Resources/General Clinical Research Center (MO1-RR000056); the US Army Medical Research and Material Command (DAMD17-01-1-0729, DAMD17-02-1-0666, DAMD17-02-1-0669, W81XWH-07-0449, W81XWH-10-1-02802); the US Public Health Service (PSA-042205); the National Health and Medical Research Council of Australia (199600 and 400281); the German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research (01GB 9401); the State of Baden-Wurttemberg through Medical Faculty of the University of Ulm (P.685); the German Cancer Research Center; the Minnesota Ovarian Cancer Alliance; the Mayo Foundation; the Fred C. and Katherine B. Andersen Foundation; the Lon V. Smith Foundation (LVS-39420); the Oak Foundation; Eve Appeal; the OHSU Foundation; the Mermaid I project; the Rudolf-Bartling Foundation; the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge, Imperial College London, University College Hospital 'Womens Health Theme' and the Royal Marsden Hospital; and Work Safe BC 14. Investigator-specific funding: JS and GC thank the University of Queensland and QIMR Berghofer Medical Research Institute for scholarship support. YL was supported by the NHMRC Early Career Fellowship. GCT, REN and PMW are supported by the National Health and Medical Research Council.; SM acknowledges funding support from an Australian Research Council Future Fellowship. NR 43 TC 4 Z9 4 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 EI 1464-3685 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD OCT PY 2016 VL 45 IS 5 BP 1619 EP 1630 DI 10.1093/ije/dyw207 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EJ4KA UT WOS:000393184400034 PM 27594614 ER PT J AU Han, B Compton, WM Mojtabai, R Colpe, L Hughes, A AF Han, Beth Compton, Wilson M. Mojtabai, Ramin Colpe, Lisa Hughes, Arthur TI Trends in Receipt of Mental Health Treatments Among Adults in the United States, 2008-2013 SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID PRIMARY-CARE; DEPRESSIVE-DISORDERS; COLLABORATIVE CARE; OLDER-ADULTS; SERVICES; PSYCHIATRISTS; MEDICATION; STRATEGIES; MANAGEMENT; ATTITUDES AB Objective: This study examined trends in the 12-month prevalence of receiving mental health treatments among adults 18 years or older and among different generational cohorts in the United States between 2008 and 2013. Methods: We examined data from 274,900 persons 18 years or older who participated in the 2008-2013 National Surveys on Drug Use and Health (then linked to the 2011-2014 Area Health Resources Files at the county level). Multivariable logistic regressions were applied to assess trends in the model-adjusted prevalence of receiving mental health treatments. Results: Between 2008 and 2013, the 12-month prevalence of mental illness (MI) remained stable in adults 18 years or older in the United States and in each of the examined generational cohorts. Receipt of psychotropic medications without inpatient or outpatient treatment increased in the overall adult population, baby boomers with MI, and Generation X with MI. The increase was 23.8% (6.3% to 7.8%, P < .001) among all adults, 28.4% (20.4% to 26.2%, P = .010) among baby boomers with MI, and 34.7% (14.7% to 19.8%, P = .001) among Generation X with MI. Among the Silent Generation with MI, receipt of mental health treatments remained unchanged. Conclusions: The prevalence of receiving psychotropic medications without inpatient or outpatient treatment increased among the overall adult population, baby boomers with MI, and Generation X with MI between 2008 and 2013. With the ongoing mental health parity and health reform efforts, further studies are warranted to monitor trends in mental health treatment in these populations. (C) Copyright 2016 Physicians Postgraduate Press, Inc. C1 [Han, Beth; Hughes, Arthur] Subst Abuse & Mental Hlth Serv Adm, Rockville, MD USA. [Compton, Wilson M.] NIDA, NIH, Bethesda, MD 20892 USA. [Mojtabai, Ramin] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD USA. [Mojtabai, Ramin] Johns Hopkins Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD USA. [Colpe, Lisa] NIMH, NIH, Bethesda, MD 20892 USA. RP Han, B (reprint author), 5600 Fishers Ln,15E85C, Rockville, MD 20857 USA. EM beth.han@samhsa.hhs.gov NR 37 TC 0 Z9 0 U1 1 U2 1 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 EI 1555-2101 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD OCT PY 2016 VL 77 IS 10 BP 1365 EP 1371 DI 10.4088/JCP.15m09982 PG 7 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA EJ2DQ UT WOS:000393020500026 PM 27486895 ER PT J AU Chou, SP Goldstein, RB Smith, SM Huang, BJ Ruan, WJ Zhang, HT Jung, J Saha, TD Pickering, RP Grant, BF AF Chou, S. Patricia Goldstein, Rise B. Smith, Sharon M. Huang, Boji Ruan, W. June Zhang, Haitao Jung, Jeesun Saha, Tulshi D. Pickering, Roger P. Grant, Bridget F. TI The Epidemiology of DSM-5 Nicotine Use Disorder: Results From the National Epidemiologic Survey on Alcohol and Related Conditions-III SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; GENERAL-POPULATION SAMPLE; SUBSTANCE USE DISORDERS; SERIOUS MENTAL-ILLNESS; UNITED-STATES; CIGARETTE-SMOKING; TOBACCO USE; PSYCHIATRIC-DISORDERS; PROCEDURAL VALIDITY; HEALTH-CARE AB Objective: To present nationally representative information on the prevalence, correlates, psychiatric comorbidity, and treatment of DSM-5 nicotine use disorder (NUD) and the public health burden of US cigarette consumption among adults with NUD and other psychiatric disorders. Methods: Using data from the 2012-2013 National Epidemiologic Survey on Alcohol and Related Conditions-III (N = 36,309), we conducted weighted cross-tabulations and multivariate logistic regression analyses to estimate prevalences and examine comorbidity of NUD. Results: Prevalences of 12-month and lifetime DSM-5 NUD were 20.0% and 27.9%, respectively. Nicotine use disorder was more frequent among men, non-Hispanic whites, younger individuals, the previously married, those with less education and lower incomes, and those residing in rural areas. Adjusting for sociodemographic characteristics and additional psychiatric comorbidity, 12-month NUD and lifetime NUD were significantly associated with other substance use and antisocial personality disorders (odds ratios [ORs] = 1.5-5.1, 12-month; 1.5-5.6, lifetime). Twelve-month severe NUD was generally associated with major depressive, bipolar I, bipolar II, panic, generalized anxiety, posttraumatic stress, and schizotypal, borderline, and antisocial personality disorders (ORs = 1.3-2.5). Individuals with current NUD and at least 1 psychiatric disorder comprised 11.1% of US adults but smoked 53.6% of total cigarettes consumed. Treatment was utilized by 20.3% of respondents with 12-month and 18.8% with lifetime NUD. Conclusions: Findings underscore the need to address nicotine use in clinical settings. Recognition of psychiatrically vulnerable subpopulations may inform etiologic research, prevention, and treatment of NUD. (C) Copyright 2016 Physicians Postgraduate Press, Inc. C1 [Chou, S. Patricia; Goldstein, Rise B.; Smith, Sharon M.; Huang, Boji; Ruan, W. June; Zhang, Haitao; Jung, Jeesun; Saha, Tulshi D.; Pickering, Roger P.; Grant, Bridget F.] NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, 5635 Fishers Ln,Room 3071, Bethesda, MD 20892 USA. RP Chou, SP (reprint author), NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, 5635 Fishers Ln,Room 3071, Bethesda, MD 20892 USA. EM Patricia.Chou@nih.gov OI Goldstein, Rise/0000-0002-9603-9473 FU National Institute on Alcohol Abuse and Alcoholism (NIAAA) FX The National Epidemiologic Survey on Alcohol and Related Conditions-III (NESARC-III) is funded by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) with supplemental support from the National Institute on Drug Abuse, National Institutes of Health, Bethesda, Maryland. NR 50 TC 0 Z9 0 U1 1 U2 1 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 EI 1555-2101 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD OCT PY 2016 VL 77 IS 10 BP 1404 EP 1412 DI 10.4088/JCP.15m10114 PG 9 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA EJ2DQ UT WOS:000393020500031 PM 27135834 ER PT J AU Saunders, EFH Ramsden, CE Sherazy, MS Gelenberg, AJ Davis, JM Rapoport, SI AF Saunders, Erika F. H. Ramsden, Christopher E. Sherazy, Mostafa S. Gelenberg, Alan J. Davis, John M. Rapoport, Stanley I. TI Reconsidering Dietary Polyunsaturated Fatty Acids in Bipolar Disorder: A Translational Picture SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Editorial Material ID CYTOSOLIC PHOSPHOLIPASE A(2); PLACEBO-CONTROLLED TRIAL; RAT FRONTAL-CORTEX; OPEN-LABEL TRIAL; ARACHIDONIC-ACID; DOUBLE-BLIND; DOCOSAHEXAENOIC ACID; BRAIN PHOSPHOLIPIDS; UNANESTHETIZED RAT; OMEGA-3-FATTY-ACID TREATMENT AB Inflammation is an important mediator of pathophysiology in bipolar disorder. The omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acid (PUFA) metabolic pathways participate in several inflammatory processes and have been linked through epidemiologic and clinical studies to bipolar disorder and its response to treatment. We review the proposed role of PUFA metabolism in neuroinflammation, modulation of brain PUFA metabolism by antimanic medications in rodent models, and anti-inflammatory pharmacotherapy in bipolar disorder and in major depressive disorder (MDD). Although the convergence of findings between preclinical and postmortem clinical data is compelling, we investigate why human trials of PUFA as treatment are mixed. We view the biomarker and treatment study findings in light of the evidence for the hypothesis that arachidonic acid hypermetabolism contributes to bipolar disorder pathophysiology and propose that a combined high n-3 plus low n-6 diet should be tested as an adjunct to current medication in future trials. (C) Copyright 2016 Physicians Postgraduate Press, Inc. C1 [Saunders, Erika F. H.; Sherazy, Mostafa S.; Gelenberg, Alan J.] Penn State Coll Med, Dept Psychiat, Hershey, PA USA. [Saunders, Erika F. H.; Sherazy, Mostafa S.; Gelenberg, Alan J.] Penn State Milton S Hershey Med Ctr, Hershey, PA USA. [Saunders, Erika F. H.] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. [Saunders, Erika F. H.] Univ Michigan, Depress Ctr, Ann Arbor, MI 48109 USA. [Ramsden, Christopher E.] NIAAA, Sect Nutr Neurosci, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD USA. [Davis, John M.] Univ Illinois, Dept Psychiat, Chicago, IL 60612 USA. [Rapoport, Stanley I.] NIA, Off Sci Director, NIH, Bethesda, MD 20892 USA. RP Saunders, EFH (reprint author), Penn State Coll Med, Penn State Milton S Hershey Med Ctr, Dept Psychiat, 500 Univ Dr,POB 850,Mail Code HO73, Hershey, PA 17033 USA. EM esaunders@hmc.psu.edu FU National Center for Advancing Translational Sciences, National Institute on Aging, National Institutes of Health (NIH), Bethesda, Maryland [KL2 TR000126]; Intramural Program of the National Institute on Aging, NIH, Bethesda, Maryland; National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland FX The project described was supported by the National Center for Research Resources, grant KL2 RR033180 (Dr Saunders), and is now at the National Center for Advancing Translational Sciences, grant KL2 TR000126, National Institute on Aging, National Institutes of Health (NIH), Bethesda, Maryland. The contribution of Dr Rapoport was supported entirely by the Intramural Program of the National Institute on Aging, NIH, Bethesda, Maryland. The contribution of Dr Ramsden was supported by the National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland. NR 103 TC 0 Z9 0 U1 2 U2 2 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 EI 1555-2101 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD OCT PY 2016 VL 77 IS 10 BP E1342 EP E1347 DI 10.4088/JCP.15com10431 PG 6 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA EJ2DQ UT WOS:000393020500019 PM 27788314 ER PT J AU Flink, BJ Kunz, LM Kooby, DA Gillespie, TW Adsay, V AF Flink, Benjamin J. Kunz, Lauren M. Kooby, David A. Gillespie, Theresa W. Adsay, Volkan TI Confirming the Utility of an Improved and Simplified Pancreatic Adenocarcinoma Staging System Using the National Cancer Data Base SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Meeting Abstract C1 Atlanta Vet Affairs Med Ctr, Decatur, GA USA. Emory Univ, Atlanta, GA 30322 USA. NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 EI 1879-1190 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD OCT PY 2016 VL 223 IS 4 SU 1 BP S139 EP S139 PG 1 WC Surgery SC Surgery GA EJ2YM UT WOS:000393077500261 ER PT J AU Shell, J Zhang, LS Zhang, YQ Shen, M Boufraqech, M Nilubol, N Patel, D Kebebew, E AF Shell, Jasmine Zhang, Lisa Zhang, Yaqin Shen, Min Boufraqech, Myriem Nilubol, Naris Patel, Dhaval Kebebew, Electron TI Combination Therapy with Sorafenib and Vemurafenib Is Effective in Anaplastic Thyroid Cancer SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Meeting Abstract C1 [Shell, Jasmine; Zhang, Lisa; Zhang, Yaqin; Shen, Min; Boufraqech, Myriem; Nilubol, Naris; Patel, Dhaval; Kebebew, Electron] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 EI 1879-1190 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD OCT PY 2016 VL 223 IS 4 SU 1 BP S45 EP S45 PG 1 WC Surgery SC Surgery GA EJ2YM UT WOS:000393077500090 ER PT J AU O'Hara, EG Nuche-Berenguer, B Kirui, NK Cheng, SY Chege, PM Buckwalter, V Laktabai, J Pastakia, SD AF O'Hara, Elizabeth G. Nuche-Berenguer, Bernardo Kirui, Nicholas K. Cheng, Stephanie Y. Chege, Patrick M. Buckwalter, Victor Laktabai, Jeremiah Pastakia, Sonak Dinesh TI Diabetes in rural Africa: what can Kenya show us? SO LANCET DIABETES & ENDOCRINOLOGY LA English DT Editorial Material ID WESTERN KENYA; CARE C1 [O'Hara, Elizabeth G.; Kirui, Nicholas K.; Laktabai, Jeremiah; Pastakia, Sonak Dinesh] Moi Univ, USAID Acad Model Providing Access Healthcare AMPA, Moi Teaching & Referral, Sch Med, Eldoret 30100, Kenya. [O'Hara, Elizabeth G.] Univ Washington, Seattle, WA 98195 USA. [Nuche-Berenguer, Bernardo] NIDDK, NIH, Bethesda, MD 20892 USA. [Cheng, Stephanie Y.; Pastakia, Sonak Dinesh] Purdue Univ, Coll Pharm, Indianapolis, IN 46202 USA. [Chege, Patrick M.; Buckwalter, Victor; Pastakia, Sonak Dinesh] Webuye Dist Hosp, Webuye, Kenya. [Chege, Patrick M.; Laktabai, Jeremiah; Pastakia, Sonak Dinesh] Moi Univ, Sch Med, Eldoret, Kenya. RP Pastakia, SD (reprint author), Moi Univ, USAID Acad Model Providing Access Healthcare AMPA, Moi Teaching & Referral, Sch Med, Eldoret 30100, Kenya.; Pastakia, SD (reprint author), Purdue Univ, Coll Pharm, Indianapolis, IN 46202 USA.; Pastakia, SD (reprint author), Webuye Dist Hosp, Webuye, Kenya.; Pastakia, SD (reprint author), Moi Univ, Sch Med, Eldoret, Kenya. EM spastaki@gmail.com FU Abbott; President's Emergency Plan for AIDS Relief through the US Agency for International Development [AID-623-A-12-0001]; National Institutes of Health [UL1 TR001108]; National Center for Advancing Translational Sciences; Clinical and Translational Sciences Award; Abbott Fund; Afya Bora Consortium Fellowship; Eli Lilly FX SDP reports grants and personal fees from Abbott, unrelated to this work. All other authors declare no competing interests. This research was supported by the President's Emergency Plan for AIDS Relief through the US Agency for International Development under the terms of Cooperative Agreement No. AID-623-A-12-0001. The contents of this Comment are the sole responsibility of Webuye District Hospital and AMPATH and do not necessarily reflect the views of USAID or the US Government. This publication was also made possible by the Indiana Clinical and Translational Sciences Institute, funded in part by grant number UL1 TR001108 from the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award. We thank Abbott for providing glucose testing supplies and the Abbott Fund for providing financial support for this work. We also thank Eli Lilly and Company for donating insulin and providing seed funding to support the authors' overarching work in diabetes. We thank the department of Family Medicine and the Mennonite Central Committee, who provided a grant to the clinic and were an integral part in making these data available, and the Afya Bora Consortium Fellowship. We received research and ethics approval from the local Moi University Institutional Review and Ethics Committee and from the US institutions involved. We only analysed the de-identified data from our database for this Comment and had a waiver of informed consent for this retrospective review. NR 9 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2213-8587 J9 LANCET DIABETES ENDO JI Lancet Diabetes Endocrinol. PD OCT PY 2016 VL 4 IS 10 BP 807 EP 809 DI 10.1016/S2213-8587(16)30086-9 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EJ2FI UT WOS:000393025100008 PM 27344101 ER PT J AU Bennett, PH Magliano, DJ Alberti, KG Zimmet, P AF Bennett, Peter H. Magliano, Dianna J. Alberti, K. George Zimmet, Paul TI Liberating non-communicable disease data SO LANCET DIABETES & ENDOCRINOLOGY LA English DT Letter C1 [Bennett, Peter H.] NIH, Phoenix, AZ 85014 USA. [Magliano, Dianna J.] Baker IDI Heart & Diabet Inst, Melbourne, Vic, Australia. [Alberti, K. George] Imperial Coll, St Marys Campus, London, England. [Zimmet, Paul] Monash Univ, Dept Med, Melbourne, Vic, Australia. RP Bennett, PH (reprint author), NIH, Phoenix, AZ 85014 USA. EM pbennett@nih.gov NR 9 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2213-8587 J9 LANCET DIABETES ENDO JI Lancet Diabetes Endocrinol. PD OCT PY 2016 VL 4 IS 10 BP 815 EP 816 DI 10.1016/S2213-8587(16)30220-0 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EJ2FI UT WOS:000393025100014 PM 27567937 ER PT J AU Willeit, P Kaptoge, S Welsh, P Butterworth, AS Chowdhury, R Spackman, SA Pennells, L Gao, P Burgess, S Freitag, DF Sweeting, M Wood, AM Cook, NR Judd, S Trompet, S Nambi, V Olsen, MH Everett, BM Kee, F Auml;rnlov, J Salomaa, V Levy, D Kauhanen, J Laukkanen, JA Kavousi, M Ninomiya, T Casas, JP Daniels, LB Lind, L Kistorp, CN Rosenberg, J Mueller, T Rubattu, S Panagiotakos, DB Franco, OH de Lemos, JA Luchner, A Kizer, JR Kiechl, S Salonen, JT Wannamethee, SG de Boer, RA Nordestgaard, BG Andersson, J Jorgensen, T Melander, O Ballantyne, CM DeFilippi, C Ridker, PM Cushman, M Rosamond, WD Thompson, SG Gudnason, V Sattar, N Danesh, J Di Angelantonio, E AF Willeit, Peter Kaptoge, Stephen Welsh, Paul Butterworth, Adam S. Chowdhury, Rajiv Spackman, Sarah A. Pennells, Lisa Gao, Pei Burgess, Stephen Freitag, Daniel F. Sweeting, Michael Wood, Angela M. Cook, Nancy R. Judd, Suzanne Trompet, Stella Nambi, Vijay Olsen, Michael Hecht Everett, Brendan M. Kee, Frank Arnlov, Johan Salomaa, Veikko Levy, Daniel Kauhanen, Jussi Laukkanen, Jari A. Kavousi, Maryam Ninomiya, Toshiharu Casas, Juan-Pablo Daniels, Lori B. Lind, Lars Kistorp, Caroline N. Rosenberg, Jens Mueller, Thomas Rubattu, Speranza Panagiotakos, Demosthenes B. Franco, Oscar H. de Lemos, James A. Luchner, Andreas Kizer, Jorge R. Kiechl, Stefan Salonen, Jukka T. Wannamethee, S. Goya de Boer, Rudolf A. Nordestgaard, Borge G. Andersson, Jonas Jorgensen, Torben Melander, Olle Ballantyne, Christie M. DeFilippi, Christopher Ridker, Paul M. Cushman, Mary Rosamond, Wayne D. Thompson, Simon G. Gudnason, Vilmundur Sattar, Naveed Danesh, John Di Angelantonio, Emanuele CA Natriuretic Peptides Studies Coll TI Natriuretic peptides and integrated risk assessment for cardiovascular disease: an individual-participant-data meta-analysis SO LANCET DIABETES & ENDOCRINOLOGY LA English DT Article ID C-REACTIVE PROTEIN; ASSOCIATION TASK-FORCE; CORONARY-HEART-DISEASE; GENERAL-POPULATION; NT-PROBNP; COST-EFFECTIVENESS; TROPONIN-T; PRACTICE GUIDELINES; COLLABORATIVE CARE; ACCF/AHA GUIDELINE AB Background Guidelines for primary prevention of cardiovascular diseases focus on prediction of coronary heart disease and stroke. We assessed whether or not measurement of N-terminal-pro-B-type natriuretic peptide (NT-proBNP) concentration could enable a more integrated approach than at present by predicting heart failure and enhancing coronary heart disease and stroke risk assessment. Methods In this individual-participant-data meta-analysis, we generated and harmonised individual-participant data from relevant prospective studies via both de-novo NT-proBNP concentration measurement of stored samples and collection of data from studies identified through a systematic search of the literature (PubMed, Scientific Citation Index Expanded, and Embase) for articles published up to Sept 4, 2014, using search terms related to natriuretic peptide family members and the primary outcomes, with no language restrictions. We calculated risk ratios and measures of risk discrimination and reclassification across predicted 10 year risk categories (ie, <5%, 5% to <7.5%, and >= 7.5%), adding assessment of NT-proBNP concentration to that of conventional risk factors (ie, age, sex, smoking status, systolic blood pressure, history of diabetes, and total and HDL cholesterol concentrations). Primary outcomes were the combination of coronary heart disease and stroke, and the combination of coronary heart disease, stroke, and heart failure. Findings We recorded 5500 coronary heart disease, 4002 stroke, and 2212 heart failure outcomes among 95617 participants without a history of cardiovascular disease in 40 prospective studies. Risk ratios (for a comparison of the top third vs bottom third of NT-proBNP concentrations, adjusted for conventional risk factors) were 1.76 (95% CI 1.56-1.98) for the combination of coronary heart disease and stroke and 2.00 (1.77-2.26) for the combination of coronary heart disease, stroke, and heart failure. Addition of information about NT-proBNP concentration to a model containing conventional risk factors was associated with a C-index increase of 0.012 (0.010-0.014) and a net reclassification improvement of 0.027 (0.019-0.036) for the combination of coronary heart disease and stroke and a C-index increase of 0.019 (0.016-0.022) and a net reclassification improvement of 0.028 (0.019-0.038) for the combination of coronary heart disease, stroke, and heart failure. Interpretation In people without baseline cardiovascular disease, NT-proBNP concentration assessment strongly predicted first-onset heart failure and augmented coronary heart disease and stroke prediction, suggesting that NT-proBNP concentration assessment could be used to integrate heart failure into cardiovascular disease primary prevention. Copyright (C) 2016 The Author(s). Published by Elsevier Ltd C1 [Willeit, Peter; Kaptoge, Stephen; Butterworth, Adam S.; Chowdhury, Rajiv; Spackman, Sarah A.; Pennells, Lisa; Gao, Pei; Burgess, Stephen; Freitag, Daniel F.; Sweeting, Michael; Wood, Angela M.; Thompson, Simon G.; Danesh, John; Di Angelantonio, Emanuele] Univ Cambridge, Cambridge, England. [Willeit, Peter; Kiechl, Stefan] Med Univ Innsbruck, Innsbruck, Austria. [Welsh, Paul] Univ Glasgow, Glasgow, Lanark, Scotland. [Gao, Pei] Peking Univ, Beijing, Peoples R China. [Cook, Nancy R.; Everett, Brendan M.; Ridker, Paul M.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Cook, Nancy R.; Everett, Brendan M.; Ridker, Paul M.] Harvard Med Sch, Boston, MA 02115 USA. [Judd, Suzanne] Univ Alabama Birmingham, Birmingham, AL 35487 USA. [Trompet, Stella] Leiden Univ, Med Ctr, Leiden, Netherlands. [Nambi, Vijay] Michael E DeBakey Baylor Coll Med, Houston, TX 77030 USA. [Nambi, Vijay; Ballantyne, Christie M.] Houston Methodist DeBakey Heart & Vasc Ctr, Houston, TX 77030 USA. [Olsen, Michael Hecht] Odense Univ Hosp, Odense, Denmark. [Kee, Frank] Queens Univ Belfast, Belfast, Antrim, North Ireland. [Arnlov, Johan; Lind, Lars] Uppsala Univ, Uppsala, Sweden. [Salomaa, Veikko] Natl Inst Hlth & Welf, Helsinki, Finland. [Levy, Daniel] NIH, Bldg 10, Bethesda, MD 20892 USA. [Kauhanen, Jussi; Laukkanen, Jari A.] Univ Eastern Finland, Kuopio, Finland. [Kavousi, Maryam; Franco, Oscar H.] Erasmus MC, Rotterdam, Netherlands. [Ninomiya, Toshiharu] Kyushu Univ, Fukuoka, Japan. [Casas, Juan-Pablo] UCL, Farr Inst Hlth Informat, London, England. [Daniels, Lori B.] Univ Calif San Diego, San Diego, CA 92103 USA. [Kistorp, Caroline N.; Nordestgaard, Borge G.] Univ Copenhagen, Copenhagen, Denmark. [Kistorp, Caroline N.] Herlev Hosp, Copenhagen, Denmark. [Rosenberg, Jens] Copenhagen Univ Hosp, Glostrup, Denmark. [Mueller, Thomas] Konventhosp Barmherzige Bruder, Linz, Austria. [Rubattu, Speranza] Univ Roma La Sapienza, Rome, Italy. [Rubattu, Speranza] Ist Ricovero & Cura Carattere Sci Neuromed, Pozzilli, Italy. [Panagiotakos, Demosthenes B.] Harokopio Univ Athens, Athens, Greece. [de Lemos, James A.] Univ Texas Southwestern Med Sch, Dallas, TX 75390 USA. [Luchner, Andreas] Univ Klinikum Regensburg, Regensburg, Germany. [Luchner, Andreas] Klinikum St Marien, Amberg, Germany. [Kizer, Jorge R.] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Salonen, Jukka T.] Metab Analyt Serv, Helsinki, Finland. [Wannamethee, S. Goya] UCL, London, England. [de Boer, Rudolf A.] Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands. [Andersson, Jonas] Umea Univ, Umea, Sweden. [Jorgensen, Torben] Res Ctr Prevent & Hlth, Glostrup, Denmark. [Melander, Olle] Malmo Univ Hosp, Malmo, Sweden. [Ballantyne, Christie M.] Baylor Coll Med, Houston, TX 77030 USA. [DeFilippi, Christopher] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Cushman, Mary] Univ Vermont, Burlington, VT 05405 USA. [Rosamond, Wayne D.] Univ N Carolina, Chapel Hill, NC 27514 USA. [Gudnason, Vilmundur] Icelandic Heart Assoc, Kopavogur, Iceland. [Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. [Sattar, Naveed] Univ Glasgow, Glasgow, Lanark, Scotland. RP Willeit, P (reprint author), Univ Cambridge, Dept Publ Hlth & Primary Care, Strangeways Res Lab, Cambridge CB1 8RN, England. OI Jorgensen, Torben/0000-0001-9453-2830 FU UK Medical Research Council [G0800270]; British Heart Foundation [SP/09/002]; British Heart Foundation Cambridge Cardiovascular Centre of Excellence; National Institute for Health Research Cambridge Biomedical Research Centre; European Research Council; European Commission Framework Programme 7 [HEALTH-F2-2012-279233]; Evelyn Trust FX The work of the coordinating centre was funded by the UK Medical Research Council (G0800270), British Heart Foundation (SP/09/002), British Heart Foundation Cambridge Cardiovascular Centre of Excellence, National Institute for Health Research Cambridge Biomedical Research Centre, European Research Council, and European Commission Framework Programme 7 (HEALTH-F2-2012-279233). The collaboration's website has compiled a list provided by investigators of some of the funders of the component studies in this analysis. Laboratory measurements were supported by a grant from the Evelyn Trust. Roche donated N-terminal-pro-B-type natriuretic peptide reagents. NR 62 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2213-8587 J9 LANCET DIABETES ENDO JI Lancet Diabetes Endocrinol. PD OCT PY 2016 VL 4 IS 10 BP 840 EP 849 DI 10.1016/S2213-8587(16)30196-6 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EJ2FI UT WOS:000393025100025 ER PT J AU Tahsili-Fahadan, P Simpkins, AN Leigh, R Merino, JG AF Tahsili-Fahadan, Pouya Simpkins, Alexis N. Leigh, Richard Merino, Jose G. TI Stuttering lacunar infarction captured on serial MRIs SO NEUROLOGY-CLINICAL PRACTICE LA English DT Editorial Material ID TRANSIENT ISCHEMIC ATTACK; STROKE; TIA C1 [Tahsili-Fahadan, Pouya; Simpkins, Alexis N.; Leigh, Richard; Merino, Jose G.] NINDS, Stroke Diagnost & Therapeut Sect, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Merino, Jose G.] Johns Hopkins Community Phys, Bethesda, MD USA. RP Tahsili-Fahadan, P (reprint author), NINDS, Stroke Diagnost & Therapeut Sect, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM pfahada1@jhmi.edu FU NIH/NINDS FX Supported by the Intramural Research Program of the NIH/NINDS. NR 7 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 2163-0402 EI 2163-0933 J9 NEUROL-CLIN PRACT JI Neurol.-Clin. Pract. PD OCT PY 2016 VL 6 IS 5 BP E37 EP E39 DI 10.1212/CPJ.0000000000000231 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA EJ3GX UT WOS:000393101700001 PM 27847687 ER PT J AU Boyer, WR Wolff-Hughes, DL Bassett, DR Churilla, JR Fitzhugh, EC AF Boyer, William R. Wolff-Hughes, Dana L. Bassett, David R. Churilla, James R. Fitzhugh, Eugene C. TI Accelerometer-Derived Total Activity Counts, Bouted Minutes of Moderate to Vigorous Activity, and Insulin Resistance: NHANES 2003-2006 SO PREVENTING CHRONIC DISEASE LA English DT Article ID PHYSICAL-ACTIVITY; MODEL ASSESSMENT; US ADULTS; SENSITIVITY; INDIVIDUALS; INTENSITY; GLUCOSE; PERCENTILES; HOMEOSTASIS; VOLUME AB Introduction The objective of this study was to compare the associations of accelerometer- derived total activity counts per day and minutes of bouted moderate to vigorous physical activity (MVPA) with insulin resistance. Methods The sample included 2,394 adults (aged >= 20 y) from the 2003-2006 National Health and Nutrition Examination Survey. Time spent in MVPA, measured by using 2 cutpoints (>= 2,020 counts/min [MVPA(2,020)] and >= 760 counts/min [MVPA(760)]), was calculated for bouts of at least 8 to 10 minutes. Total activity counts per day reflects the total amount of activity across all intensities. Insulin resistance was measured via the homeostatic model assessment of insulin resistance (HOMA-IR) and the quantitative insulin sensitivity check index (QUICKI). Two nested regression models regressed HOMA-IR and QUICKI, respectively, on minutes of bouted MVPA and total activity counts per day. We used an adjusted Wald F statistic to illustrate strength of association. Results After adjustment for covariates, total activity counts per day was more strongly associated with both HOMA-IR (adjusted Wald F = 36.83, P < .001) and QUICKI (adjusted Wald F = 29.44, P < .001) compared with MVPA(2,020) (HOMA-IR, adjusted Wald F = 4.00, P =.06; QUICKI, adjusted Wald F = 1.08, P = .31). Total activity counts per day was more strongly associated with both HOMA-IR (adjusted Wald F = 13.64, P < .001) and QUICKI (adjusted Wald F = 12.10, P < .001) compared with MVPA(760) (HOMA-IR, adjusted Wald F = 1.13, P = .30; QUICKI, adjusted Wald F = 0.97, P = .33). Conclusion Our study indicated that total activity counts per day has stronger associations with insulin resistance compared with minutes of bouted MVPA. The most likely explanation is that total activity counts per day captures data on light physical activity and intermittent MVPA, both of which influence insulin resistance. C1 [Boyer, William R.; Bassett, David R.; Fitzhugh, Eugene C.] Univ Tennessee, Dept Kinesiol Recreat & Sports Studies, 1914 Andy Holt Ave,307 HPER Bldg, Knoxville, TN 37996 USA. [Wolff-Hughes, Dana L.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Churilla, James R.] Univ North Florida, Dept Clin & Appl Movement Sci, Jacksonville, FL USA. RP Boyer, WR (reprint author), Univ Tennessee, Dept Kinesiol Recreat & Sports Studies, 1914 Andy Holt Ave,307 HPER Bldg, Knoxville, TN 37996 USA. EM wboyer1@vols.utk.edu NR 32 TC 1 Z9 1 U1 0 U2 0 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1545-1151 J9 PREV CHRONIC DIS JI Prev. Chronic Dis. PD OCT PY 2016 VL 13 AR E146 DI 10.5888/pcd13.160159 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EJ3JS UT WOS:000393109100007 PM 27763832 ER PT J AU Thornton, AM Shevach, EM AF Thornton, Angela M. Shevach, Ethan M. TI Tregs, Helios and tumor immunity: the sun has not yet risen SO TRANSLATIONAL CANCER RESEARCH LA English DT Editorial Material ID REGULATORY T-CELLS; ANTIBODIES; EFFICACY C1 [Thornton, Angela M.; Shevach, Ethan M.] NIAID, Immunol Lab, NIH, Bldg 10,Rm 11N315, Bethesda, MD 20892 USA. RP Shevach, EM (reprint author), NIAID, Immunol Lab, NIH, Bldg 10,Rm 11N315, Bethesda, MD 20892 USA. EM eshevach@niaid.nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases FX Work in the authors' laboratory is supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 14 TC 0 Z9 0 U1 0 U2 0 PU AME PUBL CO PI SHEUNG WAN PA ROOM 604 6-F HOLLYWOOD CENTER, 77-91, QUEENS ROAD, SHEUNG WAN, HONG KONG 00000, PEOPLES R CHINA SN 2218-676X EI 2219-6803 J9 TRANSL CANCER RES JI Transl. Cancer Res. PD OCT PY 2016 VL 5 SU 4 BP S672 EP S674 DI 10.21037/tcr.2016.10.47 PG 3 WC Oncology SC Oncology GA EJ6JA UT WOS:000393324100013 ER PT J AU Ustun, C Arock, M Kluin-Nelemans, HC Reiter, A Sperr, WR George, T Horny, HP Hartmann, K Sotlar, K Damaj, G Hermine, O Verstovsek, S Metcalfe, DD Gotlib, J Akin, C Valent, P AF Ustun, Celalettin Arock, Michel Kluin-Nelemans, Hanneke C. Reiter, Andreas Sperr, Wolfgang R. George, Tracy Horny, Hans-Peter Hartmann, Karin Sotlar, Karl Damaj, Gandhi Hermine, Olivier Verstovsek, Srdan Metcalfe, Dean D. Gotlib, Jason Akin, Cem Valent, Peter TI Advanced systemic mastocytosis: from molecular and genetic progress to clinical practice SO HAEMATOLOGICA LA English DT Review ID NEOPLASTIC MAST-CELLS; TYROSINE KINASE INHIBITORS; ACUTE MYELOID-LEUKEMIA; D816V-MUTATED ONCOGENIC VARIANT; C-KIT MUTATION; IMATINIB MESYLATE; RESPONSE CRITERIA; PEDIATRIC MASTOCYTOSIS; ACTIVATING MUTATIONS; THERAPEUTIC TARGET AB Systemic mastocytosis is a heterogeneous disease characterized by the accumulation of neoplastic mast cells in the bone marrow and other organ organs/tissues. Mutations in KIT, most frequently KIT D816V, are detected in over 80% of all systemic mastocytosis patients. While most systemic mastocytosis patients suffer from an indolent disease variant, some present with more aggressive variants, collectively called "advanced systemic mastocytosis", which include aggressive systemic mastocytosis, systemic mastocytosis with an associated hematologic, clonal non mast cell-lineage disease, and mast cell leukemia. Whereas patients with indolent systemic mastocytosis have a near normal life expectancy, patients with advanced systemic mastocytosis have a reduced life expectancy. Although cladribine and interferon-alpha are of benefit in a group of patients with advanced systemic mastocytosis, no curative therapy is available for these patients except possible allogeneic hematopoietic stem cell transplantation. Recent studies have also revealed additional somatic defects (apart from mutations in KIT) in a majority of patients with advanced systemic mastocytosis. These include TET2, SRSF2, ASXL1, RUNX1, JAK2, and/or RAS mutations, which may adversely impact prognosis and survival in particular systemic mastocytosis with an associated hematological neoplasm. In addition, several additional signaling molecules involved in the abnormal proliferation of mast cells in systemic mastocytosis have been identified. These advances have led to a better understanding of the biology of advanced systemic mastocytosis and to the development of new targeted treatment concepts. Herein, we review the biology and pathogenesis of advanced systemic mastocytosis, with a special focus on novel molecular findings as well as current and evolving therapeutic options. C1 [Ustun, Celalettin] Univ Minnesota, Dept Med, Div Hematol Oncol & Transplantat, Box 736 UMHC, Minneapolis, MN 55455 USA. [Arock, Michel] Ecole Normale Super, CNRS, UMR8113, Mol & Cellular Oncol,LBPA, Cachan, France. [Arock, Michel] Pierre & Marie Curie Paris VI Univ, Pitie Salpetriere Hosp, Lab Hematol, Paris, France. [Kluin-Nelemans, Hanneke C.] Univ Groningen, Univ Med Ctr Groningen, Dept Hematol, Groningen, Netherlands. [Reiter, Andreas] Univ Med Ctr Mannheim, Dept Hematol & Oncol, Mannheim, Germany. [Sperr, Wolfgang R.; Valent, Peter] Med Univ Vienna, Div Hematol & Hemostaseol, Dept Internal Med 1, Vienna, Austria. [Sperr, Wolfgang R.; Valent, Peter] Med Univ Vienna, Ludwig Boltzmann Cluster Oncol, Vienna, Austria. [George, Tracy] Univ New Mexico, Hematopathol Div, Albuquerque, NM USA. [George, Tracy] TriCore Reference Labs, Albuquerque, NM USA. [Horny, Hans-Peter; Sotlar, Karl] Ludwig Maximilians Univ Munchen, Inst Pathol, Munich, Germany. [Hartmann, Karin] Univ Cologne, Dept Dermatol, Cologne, Germany. [Hartmann, Karin] Univ Lubeck, Dept Dermatol, Lubeck, Germany. [Damaj, Gandhi] Caen Univ Hosp, Dept Clin Hematol, Caen, France. [Hermine, Olivier] Paris Descartes Univ, Fac Med, Clin Hematol Dept, Paris, France. [Hermine, Olivier] Paris Descartes Univ, AP HP Necker Enfants Malades, Paris, France. [Hermine, Olivier] Fac Med, Paris, France. [Hermine, Olivier] Mastocytosis Reference Ctr, AP HP Necker Enfants Malades, Paris, France. [Verstovsek, Srdan] Univ Texas MD Anderson Canc Ctr, Div Canc Med, Dept Leukemia, Houston, TX 77030 USA. [Metcalfe, Dean D.] NIAID, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Gotlib, Jason] Stanford Canc Inst, Div Hematol, Stanford, CA USA. [Akin, Cem] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Boston, MA USA. RP Ustun, C (reprint author), Univ Minnesota, Dept Med, Div Hematol Oncol & Transplantat, Box 736 UMHC, Minneapolis, MN 55455 USA. EM custun@umn.edu OI Akin, Cem/0000-0001-6301-4520 FU Fondation de France; Charles and Ann Johnson Foundation; Agence nationale pour la recherche (ANR); Fondation pour la recherche medicale (FRM); Austrian Science Funds (FWF) [SFB F4611, SFB F4704-B20]; Deutsche Jose Carreras Leukamie-Stiftung e.V. [H 11/03, R 13/05]; Division of Intramural Research, NIAID/NIH FX The authors thank Sabrina Porter for her assistance in the manuscript preparation. M. Arock is supported by Fondation de France. J. Gotlib is supported by the Charles and Ann Johnson Foundation. O. Hermine is supported by Agence nationale pour la recherche (ANR) and by Fondation pour la recherche medicale (FRM). P. Valent is supported by Austrian Science Funds (FWF) Projects SFB F4611 and SFB F4704-B20. A. Reiter is supported by research grants from the 'Deutsche Jose Carreras Leukamie-Stiftung e.V. (H 11/03 and R 13/05) ). D. D. Metcalfe is supported by the Division of Intramural Research, NIAID/NIH. NR 129 TC 0 Z9 0 U1 2 U2 2 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD OCT PY 2016 VL 101 IS 10 BP 1133 EP 1143 DI 10.3324/haematol.2016.146563 PG 11 WC Hematology SC Hematology GA EI5QF UT WOS:000392548700015 PM 27694501 ER PT J AU Greenberg, SJ AF Greenberg, Stephen J. TI Erich Meyerhoff, AHIP, FMLA, 1919-2015: a remembrance OBITUARY SO JOURNAL OF THE MEDICAL LIBRARY ASSOCIATION LA English DT Biographical-Item C1 [Greenberg, Stephen J.] Natl Lib Med, Hist Med Div, Bethesda, MD 20894 USA. RP Greenberg, SJ (reprint author), Natl Lib Med, Hist Med Div, Bethesda, MD 20894 USA. EM greenbes@mail.nih.gov NR 1 TC 0 Z9 0 U1 0 U2 0 PU MEDICAL LIBRARY ASSOC PI CHICAGO PA 65 EAST WACKER PLACE, STE 1900, CHICAGO, IL 60601-7298 USA SN 1536-5050 J9 J MED LIBR ASSOC JI J. Med. Libr. Assoc. PD OCT PY 2016 VL 104 IS 4 BP 263 EP 266 DI 10.3163/1536-5050.104.4.003 PG 4 WC Information Science & Library Science SC Information Science & Library Science GA EJ1AA UT WOS:000392941300003 ER PT J AU Keselman, A Quasem, S Kelly, JE Dutcher, GA AF Keselman, Alla Quasem, Sanjana Kelly, Janice E. Dutcher, Gale A. TI Evaluation of a health sciences internship for Latino and Native American library students SO JOURNAL OF THE MEDICAL LIBRARY ASSOCIATION LA English DT Article DE Internships and Residency; Librarians; Libraries; Medical; Library Science/Education; Program Evaluation AB Purpose: This paper presents a qualitative evaluation of a graduate-level internship for Latino and Native American library science students or students who are interested in serving those populations. Methods: The authors analyzed semi-structured interviews with thirteen internship program graduates or participants. Results: The analysis suggests that the program increased participants' interest in health sciences librarianship and led to improved career opportunities, both in health sciences libraries and other libraries with health information programming. It also highlights specific factors that are likely to contribute to the strength of career pipeline programs aiming to bring Latino and Native American students and students who are interested in serving those communities into health librarianship. Conclusions: Exposing graduate-level interns to a broad range of health sciences librarianship tasks, including outreach to Latino and Native American communities and formal mentorship, is likely to maximize interns' interests in both health sciences librarianship and service to these communities. C1 [Keselman, Alla; Kelly, Janice E.; Dutcher, Gale A.] Natl Lib Med, Div Specialized Informat Serv, 6707 Democracy Blvd,Suite 510, Bethesda, MD 20892 USA. [Quasem, Sanjana] Montgomery Cty Dept Hlth & Human Serv, Asian Amer Hlth Initiat, 1335 Piccard Dr, Rockville, MD 20850 USA. RP Keselman, A (reprint author), Natl Lib Med, Div Specialized Informat Serv, 6707 Democracy Blvd,Suite 510, Bethesda, MD 20892 USA. EM keselmana@mail.nih.gov FU intramural research program of the NLM, NIH FX The authors thank Jeanette Ryan and Gerald J. Perry, AHIP, for their comments on an earlier version of this manuscript. We are also grateful to the participants for their time and thoughts. This work was supported by intramural research program of the NLM, NIH. NR 3 TC 0 Z9 0 U1 3 U2 3 PU MEDICAL LIBRARY ASSOC PI CHICAGO PA 65 EAST WACKER PLACE, STE 1900, CHICAGO, IL 60601-7298 USA SN 1536-5050 J9 J MED LIBR ASSOC JI J. Med. Libr. Assoc. PD OCT PY 2016 VL 104 IS 4 BP 328 EP 332 DI 10.3163/1536-5050.104.4.016 PG 5 WC Information Science & Library Science SC Information Science & Library Science GA EJ1AA UT WOS:000392941300016 PM 27822159 ER PT J AU Banegas, MP Harlan, LC Mann, B Yabroff, KR AF Banegas, Matthew P. Harlan, Linda C. Mann, Bhupinder Yabroff, K. Robin TI Toward greater adoption of minimally invasive and nephron-sparing surgical techniques for renal cell cancer in the United States SO UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS LA English DT Article DE Renal cellcancer; Patterns of care; Partial nephrectomy; Radical nephrectomy; Open radical nephrectomy; Laparoscopic radical nephrectomy; Nephron-sparing surgery ID LAPAROSCOPIC RADICAL NEPHRECTOMY; CHRONIC KIDNEY-DISEASE; DONOR NEPHRECTOMY; EAU GUIDELINES; FOLLOW-UP; CARCINOMA; TRENDS; SURGERY; TUMORS; SURVIVAL AB Purpose: To examine national, population-based utilization trends of nephron-sparing and minimally invasive techniques for the surgical management of patients with adult renal cell cancer (RCC) in the United States. Methods: Linked data from the National Cancer Institutes Patterns of Care studies and the Area Health Resource File were used to evaluate trends of nephron-sparing and minimally invasive techniques in a sample of 1,110 patients newly diagnosed with American Joint Committee on Cancer stages I-II RCC, in 2004 and 2009, who underwent surgery. Descriptive statistics were used to assess patterns of surgery between 2004 and 2009. Multivariable logistic regression analyses were used to evaluate the associations between demographic, clinical, hospital, and area-level health care characteristics with surgery utilization, stratified by the subset of patients who were potentially eligible for partial nephrectomy (PN) vs. radical nephrectomy (RN) and laparoscopic RN (LRN) vs. open RN, respectively. Results: Between 2004 and 2009, PN use among stage I patients with tumors <= 7cm increased from 29% to 41%, respectively (P = 0.22). Among patients with stage I tumors=4cm, use of PN significantly increased from 43% in 2004 to 55% in 2009 (P <= 0.05). Among patients with stage I tumors >4 to 7cm, laparoscopic partial nephrectomy increased from 8% to 15%, whereas LRN increased from 38% to 69%, between 2004 and 2009 (P = 0.07). Significant increases in LRN use were observed for both stage I (from 43% in 2004 to 58% in 2009; P <= 0.05) and stage II patients (from 16% in 2004 to 47% in 2009; P <= 0.01). Patients diagnosed at an older age, with larger tumors, non-clear cell RCC and who did not receive treatment in a hospital with residency training were significantly less likely to receive PN vs. RN; whereas, those diagnosed in 2009 with stage I disease were significantly more likely to receive LRN vs. open RN. Conclusions: This study highlights a significant shift toward increased use of nephron-sparing and minimally invasive surgical techniques to treat patients with RCC in the United States. Our findings are among the first population-based reports in which most eligible patients with RCC received PN over RN. In light of the long-standing evidence on the improved patient outcomes, future investigation is warranted to identify the barriers to increased adoption of these nephron-sparing and minimally invasive approaches. (C) 2016 Elsevier Inc. All rights reserved C1 [Banegas, Matthew P.] Kaiser Permanente Northwest, Ctr Hlth Res, Portland, OR 97210 USA. [Harlan, Linda C.; Yabroff, K. Robin] NCI, Healthcare Assessment Res Branch, Healthcare Delivery Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Mann, Bhupinder] NCI, Clin Invest Branch, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. EM Matthew.P.Banegas@kpchr.org FU National Cancer Institute [HHSN261201000024C, HHSN261201000025C, HHSN261201000032C, HHSN261201000027C, HHSN261201000026C, HHSN261201000140C, HHSN261201000037C, HHSN261201000033C, HHSN261201000034C, HHSN261201000035C, HHSN261201000029C, HHSN261201000031C, HHSN261201000028C, HHSN261201000030C] FX Supported by National Cancer Institute contracts: HHSN261201000024C; HHSN261201000025C; HHSN261201000032C; HHSN261201000027C; HHSN261201000026C; HHSN261201000140C; HHSN261201000037C; HHSN261201000033C; HHSN261201000034C; HHSN261201000035C; HHSN261201000029C; HHSN261201000031C; HHSN261201000028C; HHSN261201000030C. NR 52 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1078-1439 EI 1873-2496 J9 UROL ONCOL-SEMIN ORI JI Urol. Oncol.-Semin. Orig. Investig. PD OCT PY 2016 VL 34 IS 10 DI 10.1016/j.urolonc.2016.05.021 PG 9 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA EI6XJ UT WOS:000392640600014 ER PT J AU Papadakis, GZ Millo, C Bagci, U Patronas, NJ Collins, MT AF Papadakis, G. Z. Millo, C. Bagci, U. Patronas, N. J. Collins, M. T. TI Value of F-18-NaF PET/CT imaging in the assessment of Gorham-Stout disease activity SO EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING LA English DT Meeting Abstract CT Annual Congress of the European-Association-of-Nuclear-Medicine (EANM) CY OCT 15-19, 2016 CL Barcelona, SPAIN SP European Assoc Nucl Med C1 [Papadakis, G. Z.; Patronas, N. J.] NIH, Dept Radiol & Imaging Sci, CC, Bldg 10, Bethesda, MD 20892 USA. [Millo, C.] NIH, Div Nucl Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Bagci, U.] UCF, Elect & Comp Sci Dept, CRCV, Orlando, FL USA. [Collins, M. T.] Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1619-7070 EI 1619-7089 J9 EUR J NUCL MED MOL I JI Eur. J. Nucl. Med. Mol. Imaging PD OCT PY 2016 VL 43 SU 1 MA P171 BP S597 EP S597 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EH5HF UT WOS:000391802500280 ER PT J AU Kelly, MJ Parsons, SK Cohen, JT Castellino, SM Kelly, K Keller, F Henzer, TJ Kumar, A Johnson, P Meyer, RM Morton, LM Radford, J Raemaekers, J Hodgson, DC Evens, AM AF Kelly, M. J. Parsons, S. K. Cohen, J. T. Castellino, S. M. Kelly, K. Keller, F. Henzer, T. J. Kumar, A. Johnson, P. Meyer, R. M. Morton, L. M. Radford, J. Raemaekers, J. Hodgson, D. C. Evens, A. M. TI CONSTRUCTION OF A DECISION MODEL TO AID TREATMENT CHOICES FOR EARLY STAGE HODGKIN LYMPHOMA: BRINGING SURVIVORSHIP FORWARD SO HAEMATOLOGICA LA English DT Meeting Abstract CT 10th International Symposium on Hodgkin Lymphoma CY OCT 22-25, 2016 CL Cologne, GERMANY C1 [Kelly, M. J.] Tufts Med Ctr MC, Floating Hosp Children, Div Pediat Hematol Oncol, Boston, MA USA. [Kelly, M. J.; Parsons, S. K.] Tufts Univ, Sch Med, Dept Pediat, Boston, MA 02111 USA. [Parsons, S. K.; Cohen, J. T.; Henzer, T. J.] Tufts MC, Inst Clin Res & Hlth Policy Studies, Boston, MA USA. [Parsons, S. K.; Kumar, A.; Evens, A. M.] Tufts MC, Div Hematol Oncol, Boston, MA USA. [Cohen, J. T.] Tufts MC, Ctr Evaluat Value & Risk Hlth, Boston, MA USA. [Castellino, S. M.; Keller, F.] Emory Univ, Sch Med, Childrens Hosp Atlanta, Aflca Canc Ctr, Atlanta, GA USA. [Castellino, S. M.; Keller, F.] Emory Univ, Sch Med, Childrens Hosp Atlanta, Blood Disorders Ctr, Atlanta, GA USA. [Kelly, K.] Roswell Pk Canc Inst, Div Pediat Hematol Oncol, Buffalo, NY 14263 USA. [Johnson, P.] Canc Res UK Ctr, Southampton, Hants, England. [Meyer, R. M.] Queens Univ, NCIC Clin Trials Grp, Dept Oncol, Kingston, ON, Canada. [Meyer, R. M.] Queens Univ, NCIC Clin Trials Grp, Dept Med, Kingston, ON, Canada. [Meyer, R. M.] Queens Univ, NCIC Clin Trials Grp, Dept Community Hlth & Epidemiol, Kingston, ON, Canada. [Morton, L. M.] NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Radford, J.] Univ Manchester, Inst Canc Sci, Manchester M13 9PL, Lancs, England. [Raemaekers, J.] Radboud Univ Nijmegen, Med Ctr, Dept Hematol, Nijmegen, Netherlands. [Hodgson, D. C.] Univ Toronto, Princess Margaret Canc Ctr, Radiat Med Programme, Toronto, ON, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD OCT PY 2016 VL 101 SU 5 MA P056 BP 16 EP 17 PG 2 WC Hematology SC Hematology GA EI5QI UT WOS:000392549000041 ER PT J AU Pilichowska, M Pittaluga, S Ferry, JA Hemminger, J Gupta, G Kritharis, A Gascoyne, RD Evens, AM Jaffe, ES AF Pilichowska, M. Pittaluga, S. Ferry, J. A. Hemminger, J. Gupta, G. Kritharis, A. Gascoyne, R. D. Evens, A. M. Jaffe, E. S. TI GRAY ZONE LYMPHOMA WITH FEATURES INTERMEDIATE BETWEEN DIFFUSE LARGE B-CELL LYMPHOMA AND CLASSICAL HODGKIN LYMPHOMA: DIAGNOSTIC EXPERIENCES AND CHALLENGES FROM A MULTICENTER STUDY SO HAEMATOLOGICA LA English DT Meeting Abstract CT 10th International Symposium on Hodgkin Lymphoma CY OCT 22-25, 2016 CL Cologne, GERMANY C1 [Pilichowska, M.; Gupta, G.] Tufts Med Ctr, Dept Pathol, Boston, MA USA. [Pittaluga, S.; Jaffe, E. S.] NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Ferry, J. A.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Hemminger, J.] Ohio State Univ, Dept Pathol, Wexner Med Ctr, Columbus, OH 43210 USA. [Kritharis, A.; Evens, A. M.] Tufts Med Ctr, Div Hematol Oncol, Boston, MA USA. [Gascoyne, R. D.] British Columbia Canc Agcy, Ctr Lymphoid Canc, Vancouver, BC, Canada. NR 0 TC 0 Z9 0 U1 1 U2 1 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD OCT PY 2016 VL 101 SU 5 MA P004 BP 21 EP 22 PG 2 WC Hematology SC Hematology GA EI5QI UT WOS:000392549000050 ER PT J AU Nair, P Aiello, LP Gardner, TW Jampol, LM Ferris, FL AF Nair, Prashant Aiello, Lloyd Paul Gardner, Thomas W. Jampol, Lee M. Ferris, Frederick L., III TI Report From the NEI/FDA Diabetic Retinopathy Clinical Trial Design and Endpoints Workshop SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Editorial Material ID MACULAR EDEMA; INTRAVITREAL TRIAMCINOLONE; EXPLORATORY ANALYSIS; UNITED-STATES; BASE-LINE; PROGRESSION; RANIBIZUMAB; RISK; PREVALENCE; SEVERITY C1 [Aiello, Lloyd Paul] Joslin Diabet Ctr, Boston, MA 02215 USA. [Gardner, Thomas W.] Univ Michigan, Ann Arbor, MI 48109 USA. [Jampol, Lee M.] Northwestern Univ, Chicago, IL 60611 USA. [Ferris, Frederick L., III] NEI, Bethesda, MD 20892 USA. RP Ferris, FL (reprint author), NEI, NIH, Bethesda, MD 20892 USA. EM ferrisf@nei.nih.gov NR 22 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD OCT PY 2016 VL 57 IS 13 BP 5127 EP 5142 DI 10.1167/iovs.16-20356 PG 16 WC Ophthalmology SC Ophthalmology GA EI4ND UT WOS:000392469600005 PM 27699406 ER PT J AU Sifuentes, CJ Kim, JW Swaroop, A Raymond, PA AF Sifuentes, Christopher J. Kim, Jung-Woong Swaroop, Anand Raymond, Pamela A. TI Rapid, Dynamic Activation of Muller Glial Stem Cell Responses in Zebrafish SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article DE retinal regeneration; light damage; zebrafish; RNA-seq; Muller glia ID NF-KAPPA-B; RETINA REGENERATION; ADULT ZEBRAFISH; SIGNALING PATHWAY; GENE-EXPRESSION; IN-VITRO; NEURONAL PROGENITORS; TRANSCRIPTION FACTOR; SONIC HEDGEHOG; PROLIFERATION AB PURPOSE. Zebrafish neurons regenerate from Muller glia following retinal lesions. Genes and signaling pathways important for retinal regeneration in zebrafish have been described, but our understanding of how Muller glial stem cell properties are regulated is incomplete. Mammalian Muller glia possess a latent neurogenic capacity that might be enhanced in regenerative therapies to treat degenerative retinal diseases. METHODS. To identify transcriptional changes associated with stem cell properties in zebrafish Muller glia, we performed a comparative transcriptome analysis from isolated cells at 8 and 16 hours following an acute photic lesion, prior to the asymmetric division that produces retinal progenitors. RESULTS. We report a rapid, dynamic response of zebrafish Muller glia, characterized by activation of pathways related to stress, nuclear factor-kappa B (NF-kappa B) signaling, cytokine signaling, immunity, prostaglandin metabolism, circadian rhythm, and pluripotency, and an initial repression of Wnt signaling. When we compared publicly available transcriptomes of isolated mouse Muller glia from two retinal degeneration models, we found that mouse Muller glia showed evidence of oxidative stress, variable responses associated with immune regulation, and repression of pathways associated with pluripotency, development, and proliferation. CONCLUSIONS. Categories of biological processes/pathways activated following photoreceptor loss in regeneration-competent zebrafish Muller glia, which distinguished them from mouse Muller glia in retinal degeneration models, included cytokine signaling (notably NF-kappa B), prostaglandin E2 synthesis, expression of core clock genes, and pathways/metabolic states associated with pluripotency. These regulatory mechanisms are relatively unexplored as potential mediators of stem cell properties likely to be important in Muller glial cells for successful retinal regeneration. C1 [Sifuentes, Christopher J.; Raymond, Pamela A.] Univ Michigan, Dept Mol Cellular & Dev Biol, Ann Arbor, MI 48109 USA. [Kim, Jung-Woong] Chung Ang Univ, Dept Life Sci, Coll Nat Sci, Seoul, South Korea. [Kim, Jung-Woong; Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. RP Raymond, PA (reprint author), 830 North Univ Ave, Ann Arbor, MI 48109 USA. EM praymond@umich.edu FU National Institutes of Health (NIH) [R01 EY004318]; Intramural Research Program of the National Eye Institute [EY000474, EY000546]; NIH [T32 EY013934, P30 EY007003] FX Supported by National Institutes of Health (NIH) R01 EY004318 (PAR), NIH T32 EY013934 (CJS), NIH P30 EY007003, and Intramural Research Program of the National Eye Institute (EY000474 and EY000546 to AS). NR 87 TC 0 Z9 0 U1 1 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD OCT PY 2016 VL 57 IS 13 BP 5148 EP 5160 DI 10.1167/iovs.16-19973 PG 13 WC Ophthalmology SC Ophthalmology GA EI4ND UT WOS:000392469600007 PM 27699411 ER PT J AU Lissa, D Robles, AI AF Lissa, Delphine Robles, Ana I. TI Methylation analyses in liquid biopsy SO TRANSLATIONAL LUNG CANCER RESEARCH LA English DT Review DE Circulating tumor DNA (ctDNA); biomarker; early detection; prognosis; cancer monitoring; bisulfite-based PCR assays ID CELL LUNG-CANCER; METASTATIC BREAST-CANCER; CIRCULATING TUMOR-CELLS; DNA METHYLATION; PLASMA DNA; TRANSLATIONAL IMPLICATIONS; PROMOTER METHYLATION; PROSTATE-CANCER; BLOOD-PLASMA; DIGITAL PCR AB Lung cancer is the leading cause of cancer-related deaths worldwide. Recent implementation of low-dose computed tomography (LDCT) screening is predicted to lead to diagnosis of lung cancer at an earlier stage, with survival benefit. However, there is still a pressing need for biomarkers that will identify individuals eligible for screening, as well as improve the diagnostic accuracy of LDCT. In addition, biomarkers for prognostic stratification of patients with early stage disease, and those that can be used as surrogates to monitor tumor evolution, will greatly improve clinical management. Molecular alterations found in the DNA of tumor cells, such as mutations, translocations and methylation, are reflected in DNA that is released from the tumor into the bloodstream. Thus, in recent years, circulating tumor DNA (ctDNA) has gained increasing attention as a noninvasive alternative to tissue biopsies and potential surrogate for the entire tumor genome. Activating gene mutations found in ctDNA have been proven effective in predicting response to targeted therapy. Analysis of ctDNA is also a valuable tool for longitudinal follow-up of cancer patients that does not require serial biopsies and may anticipate the acquisition of resistance. DNA methylation has also emerged as a promising marker for early detection, prognosis and real-time followup of tumor dynamics that is independent of the genomic composition of the primary tumor. This review summarizes the various investigational applications of methylated ctDNA in lung cancer reported to date. It also provides a brief overview of the technologies for analysis of DNA methylation in liquid biopsies, and the challenges that befall the implementation of methylated ctDNA into routine clinical practice. C1 [Lissa, Delphine; Robles, Ana I.] NCI, Human Carcinogenesis Lab, NIH, 37 Convent Dr,Rm 3060D,MSC 4258, Bethesda, MD 20892 USA. RP Robles, AI (reprint author), NCI, Human Carcinogenesis Lab, NIH, 37 Convent Dr,Rm 3060D,MSC 4258, Bethesda, MD 20892 USA. EM Ana_Robles@nih.gov FU Intramural Research Program of the National Cancer Institute, NIH [Z99 CA999999] FX The authors are supported by the Intramural Research Program of the National Cancer Institute, NIH (Z99 CA999999). NR 84 TC 1 Z9 1 U1 1 U2 1 PU AME PUBL CO PI SHEUNG WAN PA ROOM 604 6-F HOLLYWOOD CENTER, 77-91, QUEENS ROAD, SHEUNG WAN, HONG KONG 00000, PEOPLES R CHINA SN 2218-6751 EI 2226-4477 J9 TRANSL LUNG CANCER R JI Transl. Lung Cancer Res. PD OCT PY 2016 VL 5 IS 5 BP 492 EP 504 DI 10.21037/tlcr.2016.10.03 PG 13 WC Oncology SC Oncology GA EI5QM UT WOS:000392549400005 PM 27826530 ER PT J AU Perez-Ramirez, C Canadas-Garre, M Robles, AI Molina, MA Faus-Dader, MJ Calleja-Hernandez, MA AF Perez-Ramirez, Cristina Canadas-Garre, Marisa Robles, Ana I. Angel Molina, Miguel Jose Faus-Dader, Maria Angel Calleja-Hernandez, Miguel TI Liquid biopsy in early stage lung cancer SO TRANSLATIONAL LUNG CANCER RESEARCH LA English DT Review DE Non-small cell lung cancer (NSCLC); circulating cell-free DNA (cfDNA); early detection; prognosis; cancer monitoring ID CIRCULATING TUMOR DNA; GROWTH-FACTOR RECEPTOR; SMALL-CELL-LUNG; PLASMA DNA; MUTATIONS; SERUM; EGFR; QUANTIFICATION; ASSOCIATION; NSCLC AB Lung cancer is the leading cause of cancer-associated deaths worldwide. Surgery is the standard treatment for early-stage non-small cell lung cancer (NSCLC). However, 30% to 80% of these patients will die within 5 yearS of diagnosis. Circulating cell-free DNA (cfDNA) harbors pathologic characteristics of the original tumor, such as gene mutations or epigenetic alterations. Analysis of cfDNA has revolutionized the clinical care of advanced lung cancer patients undergoing targeted therapies. However, the low concentration of cfDNA in the blood of early-stage NSCLC patients has hampered its use for management of early disease. Continuing development of more specific and sensitive techniques for detection and analysis of cfDNA will soon enable its leverage in early stage and, perhaps, even screening settings. Therefore, cfDNA analysis may become a tool used for routine NSCLC diagnosis and for monitoring tumor burden, as well as for identifying hidden residual disease. In this review, we will focus on the current evidence of cfDNA in patients with early-stage NSCLC, new and upcoming approaches to identify circulating-tumor biomarkers, their clinical applications and future directions. C1 [Perez-Ramirez, Cristina; Canadas-Garre, Marisa; Angel Calleja-Hernandez, Miguel] Complejo Hosp Univ Granada, Inst Invest Biosanitaria Granada, UGC Prov Farm Granada, Pharmacogenet Unit, Avda Fuerzas Armadas 2, Granada 18014, Spain. [Perez-Ramirez, Cristina; Jose Faus-Dader, Maria] Univ Granada, Fac Pharm, Dept Biochem, Campus Univ Cartuja S-N, Granada 18071, Spain. [Robles, Ana I.] NCI, Human Carcinogenesis Lab, 37 Convent Dr, Bethesda, MD 20892 USA. [Angel Molina, Miguel] Hosp Univ Quiron Dexeus, Pangaea Biotech SL, C Sabino Arana 5-19, Barcelona 08028, Spain. [Angel Calleja-Hernandez, Miguel] Univ Granada, Fac Pharm, Dept Pharmacol, Campus Univ Cartuja S-N, Granada 18071, Spain. RP Canadas-Garre, M (reprint author), Complejo Hosp Univ Granada, Inst Invest Biosanitaria Granada, UGC Prov Farm Granada, Pharmacogenet Unit, Avda Fuerzas Armadas 2, Granada 18014, Spain. EM marisacgarre@gmail.com FU Ministerio de Educacion, Cultura y Deporte [FPU12/04722] FX This work was partly supported by a research grant for Cristina Perez-Ramirez (FPU12/04722), from Ministerio de Educacion, Cultura y Deporte. NR 62 TC 2 Z9 2 U1 2 U2 2 PU AME PUBL CO PI SHEUNG WAN PA ROOM 604 6-F HOLLYWOOD CENTER, 77-91, QUEENS ROAD, SHEUNG WAN, HONG KONG 00000, PEOPLES R CHINA SN 2218-6751 EI 2226-4477 J9 TRANSL LUNG CANCER R JI Transl. Lung Cancer Res. PD OCT PY 2016 VL 5 IS 5 BP 517 EP 524 DI 10.21037/tlcr.2016.10.15 PG 8 WC Oncology SC Oncology GA EI5QM UT WOS:000392549400008 PM 27826533 ER PT J AU Boufraqech, M Klubo-Gwiezdzinska, J Kebebew, E AF Boufraqech, Myriem Klubo-Gwiezdzinska, Joanna Kebebew, Electron TI MicroRNAs in the thyroid SO BEST PRACTICE & RESEARCH CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article DE microRNA; thyroid cancer; diagnosis; prognosis; treatment; circulating microRNA ID EPITHELIAL-MESENCHYMAL TRANSITION; FINE-NEEDLE-ASPIRATION; DUAL-SPECIFICITY PHOSPHATASE; ACTIVATED PROTEIN-KINASE; SQUAMOUS-CELL CARCINOMA; BRAF V600E MUTATION; UP-REGULATION; MIR-146B EXPRESSION; TUMOR-SUPPRESSOR; DOWN-REGULATION AB MicroRNAs (miRNAs) are small non-coding RNA comprising approximately 19-25 nucleotides. miRNAs can act as tumour suppressors or oncogenes, and aberrant expression of miRNAs has been reported in several human cancers and has been associated with cancer initiation and progression. Recent evidence suggests that miRNAs play a major role in thyroid carcinogenesis. In this review, we summarize the role of miRNAs in thyroid cancer and describe the oncogenic or tumour suppressor function of miRNAs as well as their clinical utility as prognostic or diagnostic markers in thyroid cancer. Published by Elsevier Ltd. C1 [Boufraqech, Myriem; Kebebew, Electron] NCI, Endocrine Oncol Branch, NIH, Bethesda, MD 20892 USA. [Klubo-Gwiezdzinska, Joanna] NIDDK, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. RP Kebebew, E (reprint author), NCI, Endocrine Oncol Branch, Bethesda, MD 20892 USA. EM kebebewe@mail.nih.gov FU intramural research program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health [1ZIABC01127506] FX Supported by the intramural research program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health (Grant No: 1ZIABC01127506). NR 147 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1521-690X EI 1532-1908 J9 BEST PRACT RES CL EN JI Best Pract. Res. Clin. Endoc. Metab. PD OCT PY 2016 VL 30 IS 5 BP 603 EP 619 DI 10.1016/j.beem.2016.10.001 PG 17 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EH6TK UT WOS:000391906600006 PM 27923454 ER PT J AU Liu, Z Kiesewetter, D Niu, G Chen, X AF Liu, Z. Kiesewetter, D. Niu, G. Chen, X. TI Differentiating Cancer From Inflammation: Positron Emission Tomography With A Boron-Derived Leucine Mimic SO EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING LA English DT Meeting Abstract CT Annual Congress of the European-Association-of-Nuclear-Medicine (EANM) CY OCT 15-19, 2016 CL Barcelona, SPAIN SP European Assoc Nucl Med C1 [Liu, Z.; Kiesewetter, D.; Niu, G.; Chen, X.] NIH, Chevy Chase, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1619-7070 EI 1619-7089 J9 EUR J NUCL MED MOL I JI Eur. J. Nucl. Med. Mol. Imaging PD OCT PY 2016 VL 43 SU 1 MA OP307 BP S96 EP S96 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EH5GW UT WOS:000391801600228 ER PT J AU Zhang, J Hall, NC Schoder, H Schwartz, LP Wilson, WH Kelloff, G Knopp, MV AF Zhang, J. Hall, N. C. Schoder, H. Schwartz, L. P. Wilson, W. H. Kelloff, G. Knopp, M. V. TI The Oncology Biomarker Qualification Initiative (OBQI): Multi-institutional Demonstration Using FDG-PET in Non-Hodgkin's Lymphoma SO EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING LA English DT Meeting Abstract CT Annual Congress of the European-Association-of-Nuclear-Medicine (EANM) CY OCT 15-19, 2016 CL Barcelona, SPAIN SP European Assoc Nucl Med C1 [Zhang, J.; Knopp, M. V.] Ohio State Univ, Columbus, OH 43210 USA. [Hall, N. C.] Philadelphia VA Med Ctr, Philadelphia, PA USA. [Schoder, H.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Schwartz, L. P.] Columbia Univ, New York, NY USA. [Wilson, W. H.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Kelloff, G.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1619-7070 EI 1619-7089 J9 EUR J NUCL MED MOL I JI Eur. J. Nucl. Med. Mol. Imaging PD OCT PY 2016 VL 43 SU 1 MA OP687 BP S204 EP S204 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EH5GW UT WOS:000391801600505 ER PT J AU Armato, SG Drukker, K Li, F Hadjiiski, L Tourassi, GD Engelmann, RM Giger, ML Redmond, G Farahani, K Kirby, JS Clarke, LP AF Armato, Samuel G., III Drukker, Karen Li, Feng Hadjiiski, Lubomir Tourassi, Georgia D. Engelmann, Roger M. Giger, Maryellen L. Redmond, George Farahani, Keyvan Kirby, Justin S. Clarke, Laurence P. TI LUNGx Challenge for computerized lung nodule classification SO JOURNAL OF MEDICAL IMAGING LA English DT Article DE lung nodule; classification; computer-aided diagnosis; challenge; computed tomography; image analysis ID SOLITARY PULMONARY NODULES; CT SCANS; TOMOGRAPHY IMAGES; AIDED DETECTION; SCREENING CT; SEGMENTATION; PERFORMANCE; PROBABILITY; ALGORITHMS; EXTRACTION AB The purpose of this work is to describe the LUNGx Challenge for the computerized classification of lung nodules on diagnostic computed tomography (CT) scans as benign or malignant and report the performance of participants' computerized methods along with that of six radiologists who participated in an observer study performing the same Challenge task on the same dataset. The Challenge provided sets of calibration and testing scans, established a performance assessment process, and created an infrastructure for case dissemination and result submission. Ten groups applied their own methods to 73 lung nodules (37 benign and 36 malignant) that were selected to achieve approximate size matching between the two cohorts. Area under the receiver operating characteristic curve (AUC) values for these methods ranged from 0.50 to 0.68; only three methods performed statistically better than random guessing. The radiologists' AUC values ranged from 0.70 to 0.85; three radiologists performed statistically better than the best-performing computer method. The LUNGx Challenge compared the performance of computerized methods in the task of differentiating benign from malignant lung nodules on CT scans, placed in the context of the performance of radiologists on the same task. The continued public availability of the Challenge cases will provide a valuable resource for the medical imaging research community. (C) 2016 Society of Photo-Optical Instrumentation Engineers (SPIE) C1 [Armato, Samuel G., III; Drukker, Karen; Li, Feng; Engelmann, Roger M.; Giger, Maryellen L.] Univ Chicago, Dept Radiol, 5841 South Maryland Ave,MC 2026, Chicago, IL 60637 USA. [Hadjiiski, Lubomir] Univ Michigan, Dept Radiol, 1500 East Med Ctr Dr, Ann Arbor, MI 48109 USA. [Tourassi, Georgia D.] Biomed Sci & Engn Ctr, Hlth Data Sci Inst, Oak Ridge Natl Lab, POB 2008 MS6085, Oak Ridge, TN 37831 USA. [Redmond, George; Farahani, Keyvan; Clarke, Laurence P.] NCI, Canc Imaging Program, Div Canc Treatment & Diag, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. [Kirby, Justin S.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Canc Imaging Program, 8560 Progress Dr, Frederick, MD 21702 USA. RP Armato, SG (reprint author), Univ Chicago, Dept Radiol, 5841 South Maryland Ave,MC 2026, Chicago, IL 60637 USA. EM s-armato@uchicago.edu FU SPIE; AAPM; NCI; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; U.S. Department of Energy [DE-AC05-00OR22725] FX This paper is dedicated to the memory of Laurence P. Clarke, PhD, whose vision helped shape not only the LUNGx Challenge but also, more importantly, the broader imaging research landscape of open science, consensus building, and collegiality that provides context for the significance of grand challenges. He worked tirelessly to advance research objectives by helping to surmount obstacles, building bridges across institutions or governmental agencies, and selflessly advocating on behalf of other investigators who shared his devotion to imaging research. Dr. Clarke's career had a dramatic impact on the current state of medical imaging research around the world. His leadership was profound, his scientific contributions substantial, his intentions sincere, his humor infectious, and his personality genuine; he will be greatly missed by all his coauthors, colleagues, and friends. The authors would like to express their appreciation to Angela Keyser and Shayna Knazik from the AAPM and Diane Cline and Sandy Hoelterhoff from the SPIE for their assistance in making this challenge a reality. The LUNGx Challenge was supported by SPIE, AAPM, and NCI. The authors are grateful to the groups that participated in the LUNGx Challenge, including groups led by Yoganand Balagurunathan (H. Lee Moffitt Cancer Center), Wookjin Choi (University of Maryland School of Medicine, now at Memorial Sloan Kettering Cancer Center), Samuel Hawkins (University of South Florida), Xiaojie Huang (GE Global Research), Lyndsey Pickup (Mirada Medical, now at Optellum), Jiangdian Song (Northeastern University, China), Yubing Tong (University of Pennsylvania), and Rafael Wiemker (Philips Research Labs Hamburg). These participating groups deserve recognition for their work to develop their lung nodule classification methods and for their contributions to the success of the Challenge. The authors would like to thank the radiologists who participated in the observer study: Prachi Agarwal, MD, Aamer Chughtai, MD, Jonathan Chung, MD, Heber MacMahon, MD, Steven Montner, MD, and Smita Patel, MD. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This manuscript has been authored in part by UT-Battelle, LLC under Contract No. DE-AC05-00OR22725 with the U.S. Department of Energy. The US Government retains and the publisher, by accepting the article for publication, acknowledges that the US Government retains a nonexclusive, paid-up, irrevocable, worldwide license to publish or reproduce the published form of this manuscript, or allow others to do so, for US Government purposes. The Department of Energy will provide public access to these results of federally sponsored research in accordance with the DOE Public Access Plan (http://energy.gov/downloads/doe-public-access-plan). NR 39 TC 0 Z9 0 U1 3 U2 3 PU SPIE-SOC PHOTO-OPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 2329-4302 EI 2329-4310 J9 J MED IMAGING JI J. Med. Imaging PD OCT PY 2016 VL 3 IS 4 AR UNSP 044506 DI 10.1117/1.JMI.3.4.044506 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EG5ZW UT WOS:000391124500015 PM 28018939 ER PT J AU Hashiguchi, T Arakawa, S Takahashi, S Gonzalez, FJ Sueyoshi, T Negishi, M AF Hashiguchi, Takuyu Arakawa, Shingo Takahashi, Shogo Gonzalez, Frank J. Sueyoshi, Tatsuya Negishi, Masahiko TI Phosphorylation of Farnesoid X Receptor at Serine 154 Links Ligand Activation With Degradation SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID PROTEIN-KINASE-C; VITAMIN-D-RECEPTOR; ANDROGEN RECEPTOR; NUCLEAR RECEPTORS; CROSS-TALK; ALPHA; CAR; EXPRESSION; BINDING; CANCER AB Comparison of 11 human nuclear receptor amino acid sequences revealed a conserved phosphorylation motif within their DNA-binding domains as an intramolecular signal that regulates proteolytic degradation. Nuclear receptors use this signal to either degrade or proscribe degradation through either the proteasome or nonproteasome pathways. A phosphomimetic farnesoid X receptor (FXR) S154D mutant neither bound to nor trans-activated an FXR-response element-driven reporter gene and was rapidly degraded in COS-1 cells. Ectopically expressed FXR had increased Ser154 phosphorylation in COS-1 cells after ligand treatment, and knock-down of the nuclear vaccinia-related kinase 1 (VRK1) greatly reduced this phosphorylation. FXR was phosphorylated at Ser154 in the nucleus of centrilobular hepatocytes only in ligand-treated mice. Thus, FXR Ser154 phosphorylation is a rheostat for activation and subsequent degradation that controls receptor levels and activity. C1 [Hashiguchi, Takuyu; Arakawa, Shingo; Sueyoshi, Tatsuya; Negishi, Masahiko] NIEHS, Pharmacogenet Sect, Reprod & Dev Biol Lab, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. [Takahashi, Shogo; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Negishi, M (reprint author), NIEHS, Pharmacogenet Sect, Reprod & Dev Biol Lab, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM negishi@niehs.nih.gov FU Daiichi Sankyo Co., Ltd., Medicinal Safety Research Laboratories, Japan; Strategic Young Researcher Overseas Visits Program for Accelerating Brain Circulation, Japan Society for the Promotion of Science (JSPS); National Institutes of Health Intramural Research Program [Z01ES1005-01] FX Human FXR/pCMV-ICIS and Nr0b2-#UTR/pGL4-TK were provided by Grace L. Guo (Rutgers University); pCMXhROR alpha 1 was from Jetten Anton (NIEHS); the expression plasmid and antiserum for hSF1/Ad4BP were from Ken-ichirou Morohashi (Kyushu University); and pCW7-Myc-Ub vector was from Andrew Wallace (North Carolina State University). S.A. was on leave with pay from Daiichi Sankyo Co., Ltd., Medicinal Safety Research Laboratories, Japan. T.H. was supported by the Strategic Young Researcher Overseas Visits Program for Accelerating Brain Circulation, Japan Society for the Promotion of Science (JSPS).; This work was supported by the National Institutes of Health Intramural Research Program: Z01ES1005-01. NR 26 TC 0 Z9 0 U1 1 U2 1 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD OCT PY 2016 VL 30 IS 10 BP 1070 EP 1080 DI 10.1210/me.2016-1105 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EG7EH UT WOS:000391208200011 PM 27571290 ER PT J AU Cheezum, MK Redon, CE Burrell, AS Kaviratne, AS Bindeman, J Maeda, D Balmakhtar, H Pezel, A Wisniewski, P Delacruz, P Nguyen, B Bonner, WM Villines, TC AF Cheezum, Michael K. Redon, Christophe E. Burrell, Allison S. Kaviratne, Anthony S. Bindeman, Jody Maeda, Daisuke Balmakhtar, Houria Pezel, Ashly Wisniewski, Piotr Delacruz, Panfilo Binh Nguyen Bonner, William M. Villines, Todd C. TI Effects of Breast Shielding during Heart Imaging on DNA Double-Strand-Break Levels: A Prospective Randomized Controlled Trial SO RADIOLOGY LA English DT Article ID PERIPHERAL-BLOOD LYMPHOCYTES; CARDIAC CT ANGIOGRAPHY; COMPUTED-TOMOGRAPHY; IONIZING-RADIATION; DOSE REDUCTION; GAMMA-H2AX; QUALITY; CANCER; BIOMARKERS; GUIDELINES AB Purpose: To examine the effect of breast shielding on blood lymphocyte deoxyribonucleic acid (DNA) double-strand-break levels resulting from in vivo radiation and ex vivo radiation at breast-tissue level, and the effect of breast shielding on image quality. Materials and Methods: The study was approved by institutional review and commpliant with HIPAA guidelines. Adult women who underwent 64-section coronary computed tomographic (CT) angiography and who provided informed consent were prospectively randomized to the use (n = 50) or absence (n = 51) of bismuth breast shields. Peripheral blood samples were obtained before and 30 minutes after in vivo radiation during CT angiography to compare DNA double-strand-break levels by gamma-H2AX immunofluorescence in blood lymphocytes. To estimate DNA double-strand-break induction at breast-tissue level, a blood sample was taped to the sternum for ex vivo radiation with or without shielding. Data were analyzed by linear regression and independent sample t tests. Results: Breast shielding had no effect on DNA double-strand-break levels from ex vivo radiation of blood samples under shields at breast-tissue level (unadjusted regression: beta = -.08; P = .43 versus no shielding), or in vivo radiation of circulating lymphocytes (beta = 2.07; P = .50). Predictors of increased DNA double-strand-break levels included total radiation dose, increasing tube potential, and tube current (P < .05). With current radiation exposures (median, 3.4 mSv), breast shielding yielded a 33% increase in image noise and 19% decrease in the rate of excellent quality ratings. Conclusion: Among women who underwent coronary CT angiography, breast shielding had no effect on DNA double-strand-break levels in blood lymphocytes exposed to in vivo radiation, or ex vivo radiation at breast-tissue level. At present relatively low radiation exposures, breast shielding contributed to an increase in image noise and a decline in image quality. The findings support efforts to minimize radiation by primarily optimizing CT settings. (C) RSNA, 2016 C1 [Cheezum, Michael K.; Kaviratne, Anthony S.; Bindeman, Jody; Villines, Todd C.] Walter Reed Natl Mil Med Ctr, Dept Med, Cardiol Serv, 8901 Wisconsin Ave, Bethesda, MD 20889 USA. [Binh Nguyen] Walter Reed Natl Mil Med Ctr, Dept Radiol, 8901 Wisconsin Ave, Bethesda, MD 20889 USA. [Redon, Christophe E.; Burrell, Allison S.; Maeda, Daisuke; Balmakhtar, Houria; Bonner, William M.] NCI, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Burrell, Allison S.] George Washington Univ, Inst Biomed Sci, Washington, DC USA. [Balmakhtar, Houria] George Mason Univ, Fairfax, VA 22030 USA. [Pezel, Ashly; Wisniewski, Piotr] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Delacruz, Panfilo] San Antonio Mil Med Ctr, Dept Med, San Antonio, TX USA. RP Cheezum, MK (reprint author), Walter Reed Natl Mil Med Ctr, Dept Med, Cardiol Serv, 8901 Wisconsin Ave, Bethesda, MD 20889 USA. EM mcheezum@gmail.com FU American Medical Association Foundation; Radiation Nuclear Countermeasure Program (National Institute of Allergy and Infectious Diseases); Intramural Research Program of the Center for Cancer Research (National Cancer Institute, National Institutes of Health, Bethesda, Maryland) FX M.K.C. supported by American Medical Association Foundation. W.M.B. supported by Radiation Nuclear Countermeasure Program (National Institute of Allergy and Infectious Diseases). W.M.B. supported by Intramural Research Program of the Center for Cancer Research (National Cancer Institute, National Institutes of Health, Bethesda, Maryland). NR 30 TC 0 Z9 0 U1 1 U2 1 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD OCT PY 2016 VL 281 IS 1 BP 62 EP 71 DI 10.1148/radiol.2016152301 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EG8NJ UT WOS:000391313600008 PM 27082782 ER PT J AU Obolensky, OI Doerr, TP Ogurtsov, AY Yu, YK AF Obolensky, O. I. Doerr, T. P. Ogurtsov, A. Y. Yu, Yi-Kuo TI Can dielectric spheres accurately model atomic-scale interactions? SO EPL LA English DT Article ID NEON DIMER; SPECTROSCOPY; POLARIZABILITIES; SIMULATIONS; PROGRESS; NE-2 AB We calculate the polarization portion of electrostatic interactions at the atomic scale using quantum-mechanical methods such as density functional theories (DFT) and the coupled cluster approach, and using classical methods such as a surface charge method and a polarizable force field. The agreement among various methods is investigated. Using the coupled clusters method CCSD(T) with large basis sets as the reference, we find that for systems comprising two to six atoms and ions in S-states the classical surface charge method performs much better than commonly used DFT methods with moderate basis sets such as B3LYP/6-31G(d, p). The remarkable performance of the classical approach comes as a surprise. The present results indicate that the use of a rigorous formalism of classical electrostatics can be better justified for determining molecular interactions at intermediate distances than some of the widely used methods of quantum chemistry. Copyright (C) EPLA, 2016 C1 [Obolensky, O. I.; Doerr, T. P.; Ogurtsov, A. Y.; Yu, Yi-Kuo] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [Obolensky, O. I.] AF Ioffe Inst, St Petersburg, Russia. RP Yu, YK (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM yyu@ncbi.nlm.nih.gov FU Intramural Research Program of NIH, National Library of Medicine FX This research was supported by the Intramural Research Program of the NIH, National Library of Medicine. We thank the administrative group of the National Institutes of Health Biowulf Clusters, where most of the computational tasks were carried out using the Gaussian 09 software package [35] and TINKER 7.1 [11]. NR 35 TC 0 Z9 0 U1 0 U2 0 PU EPL ASSOCIATION, EUROPEAN PHYSICAL SOCIETY PI MULHOUSE PA 6 RUE DES FRERES LUMIERE, MULHOUSE, 68200, FRANCE SN 0295-5075 EI 1286-4854 J9 EPL-EUROPHYS LETT JI EPL PD OCT PY 2016 VL 116 IS 2 AR 24003 DI 10.1209/0295-5075/116/24003 PG 6 WC Physics, Multidisciplinary SC Physics GA EG3MX UT WOS:000390950300008 ER PT J AU Babic, B Keutgen, X Nockel, P Miettinen, M Millo, C Herscovitch, P Patel, D Nilubol, N Cochran, C Gorden, P Kebebew, E AF Babic, Bruna Keutgen, Xavier Nockel, Pavel Miettinen, Markke Millo, Corina Herscovitch, Peter Patel, Dhaval Nilubol, Naris Cochran, Craig Gorden, Phillip Kebebew, Electron TI Insulinoma Due to Multiple Pancreatic Microadenoma Localized by Multimodal Imaging SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID NEUROENDOCRINE TUMORS; HYPERINSULINEMIC HYPOGLYCEMIA; DIAGNOSIS; PET AB Context: Insulinomas are usually due to a solitary tumor, but they can be challenging to localize. Case Description: A 66-year-old woman presented with a 1-year history of episodic neuroglycopenic hypoglycemia and was suspected of having an insulinoma. On a supervised fast, she was found to be hypoglycemic at 39 mg/dL, with an insulin of 40 mu U/mL 26 hours into the fast and a proinsulin of 35 pmol/L. Contrast-enhanced computed tomography and magnetic resonance imaging did not localize a pancreatic lesion. Intra-arterial calcium stimulation testing showed a step-up of venous insulin levels at injection of the superior mesenteric artery and proximal and mid-splenic artery, and a Ga-68-DOTATATE positron emission tomography/computed tomography showed focal uptake in the neck of the pancreas with a standardized uptake value of 12. Despite negative intraoperative pancreatic palpation and ultrasound, the patient underwent an extended distal pancreatectomy with normalization of biochemical levels and resolution of her symptoms. Pathology showed four subcentimeter neuroendocrine tumors that were positive for insulin, consistent with a diagnosis of multiple microadenomas. Conclusions: Multiple microadenomas are a rare cause of hyperinsulinemic hypoglycemia and localization, and resection of these tumors may be facilitated by multimodal imaging. C1 [Babic, Bruna; Keutgen, Xavier; Nockel, Pavel; Patel, Dhaval; Nilubol, Naris; Kebebew, Electron] NCI, Endocrine Oncol Branch, NIH, Bethesda, MD 20892 USA. [Miettinen, Markke] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Millo, Corina; Herscovitch, Peter] NIH, PET Dept, Ctr Clin, Bethesda, MD 20814 USA. [Cochran, Craig; Gorden, Phillip] NIDDK, NIH, Bethesda, MD 20892 USA. RP Kebebew, E (reprint author), NCI, Endocrine Oncol Branch, CRC Room 4-5952,10 Ctr Dr,MSC 1201, Bethesda, MD 20892 USA. EM kebebewe@mail.nih.gov NR 21 TC 0 Z9 0 U1 0 U2 0 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD OCT PY 2016 VL 101 IS 10 BP 3559 EP 3563 DI 10.1210/jc.2016-2717 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EG2CI UT WOS:000390849800006 PM 27504852 ER PT J AU Nilubol, N Freedman, EM Quezado, MM Patel, D Kebebew, E AF Nilubol, Naris Freedman, Esther M. Quezado, Martha M. Patel, Dhaval Kebebew, Electron TI Pancreatic Neuroendocrine Tumor Secreting Vasoactive Intestinal Peptide and Dopamine With Pulmonary Emboli: A Case Report SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID ISLET-CELL TUMORS; NEOPLASMS; VIPOMAS AB Context: The vasoactive intestinal peptide-secreting neuroendocrine tumor ( VIPoma) is a very rare pancreatic tumor. We report the first case of a patient with VIPoma that co-secreted dopamine and had pulmonary emboli. Case Description: A 67-year-old woman presented with 2 months of watery diarrhea, severe generalized weakness, 6.8 kg of weight loss, a facial rash, and hypokalemia. Colonoscopy did not reveal the cause of the chronic diarrhea. Initial biochemical testing showed markedly elevated serum vasoactive intestinal peptide ( VIP) and pancreatic polypeptide. Computed tomography scan of the abdomen and pelvis revealed a 5.4-cm distal pancreatic mass. Octreoscan showed an intense uptake in the area of the pancreatic mass. Incidental pulmonary emboli were found and treated. Additional biochemical testing revealed a markedly elevated urinary dopamine level. The patient received preoperative alpha-blockade and octreotide. She underwent a successful laparoscopic distal pancreatectomy. Postoperative urinary dopamine and pancreatic polypeptide were within normal limits. Serum VIP decreased by half but remained elevated. Pathology confirmed a grade 1 pancreatic neuroendocrine tumor without lymph node metastasis. The patient's symptoms resolved and no longer required octreotide. Metastatic workup including computed tomography, F18-fluorodeoxglucose positron emission tomography, and Ga68-DOTATATE scans were negative during 4 years of follow-up. Conclusions: VIPoma is a rare subtype of pancreatic neuroendocrine tumor that can secrete dopamine and can be associated with thromboembolism. C1 [Nilubol, Naris; Freedman, Esther M.; Patel, Dhaval; Kebebew, Electron] NCI, Endocrine Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Quezado, Martha M.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Nilubol, N (reprint author), NCI, Endocrine Oncol Branch, NIH, Clin Res Ctr, Bldg 10 CRC,Room 4-5932, Bethesda, MD 20892 USA. EM naris.nilubol@nih.gov FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 14 TC 1 Z9 1 U1 0 U2 0 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD OCT PY 2016 VL 101 IS 10 BP 3564 EP 3567 DI 10.1210/jc.2016-2051 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EG2CI UT WOS:000390849800007 PM 27583474 ER PT J AU El-Maouche, D Sadowski, SM Papadakis, GZ Guthrie, L Cottle-Delisle, C Merkel, R Millo, C Chen, CC Kebebew, E Collins, MT AF El-Maouche, Diala Sadowski, Samira M. Papadakis, Georgios Z. Guthrie, Lori Cottle-Delisle, Candice Merkel, Roxanne Millo, Corina Chen, Clara C. Kebebew, Electron Collins, Michael T. TI Ga-68-DOTATATE for Tumor Localization in Tumor-Induced Osteomalacia SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID GA-68 DOTATATE PET/CT; ONCOGENIC OSTEOMALACIA; DIAGNOSIS; UTILITY AB Context: Phosphaturic mesenchymal tumors (PMTs) are small, typically difficult to localize, and express somatostatin receptors. Recent work suggests imaging studies using (68)Gallium (Ga-68)-conjugated somatostatin peptide analogues, such as 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) TATE, which enables somatostatin receptor imaging with positron emission tomography (PET), may be useful at identifying these tumors. Objective: Our objective was to evaluate the use of Ga-68-DOTATATE PET/computed tomography (CT) for tumor localization in tumor-induced osteomalacia (TIO). Design: This was a single-center prospective study of patients with TIO. Setting: The study was conducted at the National Institutes of Health Clinical Center between February 2014 and February 2015. Subjects: Eleven subjects (six females, five males) with TIO were included. Intervention: Subjects underwent Ga-68-DOTATATE PET/CT in addition to In-111-pentetreotide single-photon emission CT (Octreoscan-SPECT/CT) and fluorodeoxyglucose-PET/CT (F-18 FDG-PET/CT) scan. Main Outcome Measures: Localization of PMTs on the previously described imaging modalities were determined. Results: The tumor was successfully localized in 6/11 (54.5%) subjects (one was metastatic). The tumor was identified by Ga-68-DOTATATE in all six cases. Both Octreoscan-SPECT/ CT and F-18 FDG-PET each identified the tumor in 4/6. In no cases was Ga-68-DOTATATE the only imaging study to identify the tumor. Conclusions: In this first prospective study comparing Ga-68-DOTATATE PET/CT to Octreoscan-SPECT/ CT and F-18 FDG-PET in TIO localization, Ga-68-DOTATATE PET/CT demonstrated the greatest sensitivity and specificity, suggesting that it may be the best single study for localization of PMTs in TIO. C1 [El-Maouche, Diala] Univ Miami, Miller Sch Med, Dept Med, Div Endocrinol Diabet & Metab, Miami, FL 33136 USA. [El-Maouche, Diala; Guthrie, Lori; Collins, Michael T.] Natl Inst Dent & Craniofacial Res, Skeletal Clin Studies Unit, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. [Sadowski, Samira M.] Univ Hosp Geneva, Thorac & Endocrine Surg, Geneva, Switzerland. [Sadowski, Samira M.; Cottle-Delisle, Candice; Merkel, Roxanne; Kebebew, Electron] NCI, Endocrine Oncol Branch, NIH, Bethesda, MD 20892 USA. [Papadakis, Georgios Z.; Millo, Corina] NIH, Positron Emiss Tomog Dept, Warren Grant Magnusson Clin Ctr, Bldg 10, Bethesda, MD 20892 USA. [Chen, Clara C.] NIH, Div Nucl Med, Radiol & Imaging Sci, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. RP Collins, MT (reprint author), 30 Convent Dr,Bldg 30,Room 228,MSC 4320, Bethesda, MD 20892 USA. EM mcollins@dir.nidcr.nih.gov FU Division of Intramural Research; National Cancer Institute; National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD FX This work was supported by the Division of Intramural Research, the National Cancer Institute and National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD. NR 19 TC 0 Z9 0 U1 2 U2 2 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD OCT PY 2016 VL 101 IS 10 BP 3575 EP 3581 DI 10.1210/jc.2016-2052 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EG2CI UT WOS:000390849800010 PM 27533306 ER PT J AU Joffe, H Crawford, SL Freeman, MP White, DP Bianchi, MT Kim, S Economou, N Camuso, J Hall, JE Cohen, LS AF Joffe, Hadine Crawford, Sybil L. Freeman, Marlene P. White, David P. Bianchi, Matt T. Kim, Semmie Economou, Nicole Camuso, Julie Hall, Janet E. Cohen, Lee S. TI Independent Contributions of Nocturnal Hot Flashes and Sleep Disturbance to Depression in Estrogen-Deprived Women SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID MIDDLE-AGED WOMEN; MENOPAUSAL TRANSITION; VASOMOTOR SYMPTOMS; BREAST-CANCER; BAZEDOXIFENE/CONJUGATED ESTROGENS; PERIMENOPAUSAL WOMEN; MASS-SPECTROMETRY; RANDOMIZED-TRIAL; HORMONE AGONIST; MOOD AB Context: Women are at increased risk for mood disturbance during the menopause transition. Hot flashes (HFs), sleep disruption, and fluctuating estradiol levels correlate with menopause-associated depression but co-occur, making cause and effect relationships difficult to disentangle. Objective: Using a GnRH agonist (GnRHa) experimental model, we investigated whether depressive symptoms are associated with HFs and/or are explained by concomitant sleep fragmentation in the absence of estradiol fluctuation. Design and Intervention: Depressive symptoms, objective polysomnographic sleep parameters, subjective sleep quality, serum estradiol, and HFs were assessed before and 4 weeks after openlabel depot GnRHa (leuprolide 3.75-mg) administration. Setting: Academic medical center. Participants: Twenty-nine healthy nondepressed premenopausal volunteers (mean age, 27.3 years). Results: Serum estradiol was rapidly and uniformly suppressed. HFs developed in 69% of the subjects. Onunivariate analysis, worsening ofmoodwaspredicted by increases in time in light sleep (stage N1), number of transitions to wake, non-REM arousals, subjective sleep quality, and reductions in perceived sleep efficiency (all P < .045), as well as the number of nighttime (P = .006), but not daytime (P = .28), HFs reported. In adjusted models, the number of nighttime HFs reported, increases in non-REM arousals, time in stage N1, transitions to wake, and reduced sleep quality remained significant predictors of mood deterioration (P <= .05). Conclusions: Depressive symptoms emerged after estradiol withdrawal in association with objectively and subjectively measured sleep disturbance and the number of nighttime, but not daytime, HFs reported. Results suggest that sleep disruption and perceived nighttime HFs both contribute to vulnerability to menopause-associated depressive symptoms in hypoestrogenic women. C1 [Joffe, Hadine; Kim, Semmie; Camuso, Julie] Harvard Med Sch, Brigham & Womens Hosp, Dept Psychiat, Boston, MA 02115 USA. [Joffe, Hadine] Harvard Med Sch, Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, Boston, MA 02215 USA. [Joffe, Hadine; Freeman, Marlene P.; Economou, Nicole; Cohen, Lee S.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Crawford, Sybil L.] Univ Massachusetts, Sch Med, Dept Med, Div Prevent & Behav Med, Worcester, MA 01655 USA. [White, David P.] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Div Sleep Med, Boston, MA 02115 USA. [Bianchi, Matt T.] Harvard Med Sch, Massachusetts Gen Hosp, Sleep Div, Dept Neurol, Boston, MA 02114 USA. [Hall, Janet E.] Harvard Med Sch, Massachusetts Gen Hosp, Reprod Endocrine Unit, Dept Med, Boston, MA 02114 USA. [Hall, Janet E.] NIEHS, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RP Joffe, H (reprint author), Brigham & Womens Hosp, 75 Francis St,Thorn 1111, Boston, MA 02115 USA. EM hjoffe@partners.org OI Hall, Janet/0000-0003-4644-3061 FU National Institute of Mental Health [5R01MH082922] FX This work was supported by National Institute of Mental Health Grant 5R01MH082922 (to H.J.). NR 43 TC 1 Z9 1 U1 3 U2 3 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD OCT PY 2016 VL 101 IS 10 BP 3847 EP 3855 DI 10.1210/jc.2016-2348 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EG2CI UT WOS:000390849800042 PM 27680875 ER PT J AU Marchand, NE Davaasambuu, G McElrath, TF Davaasambuu, E Baatar, T Troisi, R AF Marchand, Nathalie E. Davaasambuu, Ganmaa McElrath, Thomas F. Davaasambuu, Enkhmaa Baatar, Tsedmaa Troisi, Rebecca TI Prevalence of pregnancy hypertensive disorders in Mongolia SO PREGNANCY HYPERTENSION-AN INTERNATIONAL JOURNAL OF WOMENS CARDIOVASCULAR HEALTH LA English DT Article DE Preeclampsia; Monglia ID BIRTH-WEIGHT; PREECLAMPSIA; METAANALYSIS; OUTCOMES; RISK AB Objective: To estimate the prevalence of preeclampsia in a contemporary population of Mongolian women living in urban and rural areas. We determined the sensitivity and specificity of diagnosis based on established diagnostic criteria and assessed whether local diagnostic criteria were similar to those used in the US. Study design: Cross-sectional study of urban and nomadic pregnant women recruited in Ulaanbaatar (n =136) and rural provinces (n = 85). Main outcome measures: Preeclampsia defined as hypertension new to pregnancy after 20 weeks and proteinuria (or protein creatinine ratio >= 0.3 and dipstick reading > +1) or in the absence of proteinuria, hypertension and onset of: renal insufficiency, impaired liver function, thrombocytopenia, pulmonary edema, cerebral visual symptoms. Prevalence of preeclampsia based on established criteria was compared with prevalence based on local physician's diagnosis. Results: Prevalence of local physician diagnosed preeclampsia was 9.5% (13.2% urban, 3.5% rural). Prevalence based on established diagnostic criteria was 4.1% (4.4% urban, 3.5% rural). Sensitivity of physician's diagnosis was 23.8%, specificity was 98.0%, false negative rate was 2.0% and false positive rate was 76.2%. While prevalence based on local physician's diagnosis was over double that based on diagnostic criteria, overdiagnosis did not result in adverse effects. Women fulfilling diagnostic criteria for preeclampsia had babies with higher birth weights than women who did not (p-value = 0.006). Conclusion: The 4.1% prevalence of preeclampsia in Mongolia was consistent with global estimates of 28%, suggesting the pathophysiology of preeclampsia here may be similar to that found globally. Sensitivity of physician's diagnosis was low, specificity was high. (C) 2016 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved. C1 [Marchand, Nathalie E.; Davaasambuu, Ganmaa] Harvard TH Chan Sch Publ Hlth, Dept Nutr, 677 Huntington Blvd, Boston, MA 02115 USA. [Davaasambuu, Ganmaa] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 181 Longwood Ave, Boston, MA 02115 USA. [McElrath, Thomas F.] Harvard Med Sch, Brigham & Womens Hosp, Div Maternal Fetal Med, Dept Obstet & Gynecol, 75 Francis St, Boston, MA 02115 USA. [Davaasambuu, Enkhmaa; Baatar, Tsedmaa] Natl Ctr Maternal & Child Hlth, Khuvisgalchdin St, Bayangol Dist, Ulaanbaatar, Mongol Peo Rep. [Troisi, Rebecca] NCI, Div Canc Epidemiol, NIH, Dept Hlth & Human Serv, 9609 Med Ctr Dr, Rockville, MD 20850 USA. [Troisi, Rebecca] NCI, Div Genet, NIH, Dept Hlth & Human Serv, 9609 Med Ctr Dr, Rockville, MD 20850 USA. RP Marchand, NE (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Nutr, 677 Huntington Blvd, Boston, MA 02115 USA. EM nmarchand@mail.harvard.edu; gdavaa-sa@hsph.harvard.edu; tmcelrath@partners.org; enkhee.khar@yahoo.com; tsedmaabaatar@gmail.com; troisir@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 15 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2210-7789 J9 PREGNANCY HYPERTENS JI Pregnancy Hypertens. PD OCT PY 2016 VL 6 IS 4 BP 413 EP 417 DI 10.1016/j.preghy.2016.10.001 PG 5 WC Obstetrics & Gynecology; Peripheral Vascular Disease SC Obstetrics & Gynecology; Cardiovascular System & Cardiology GA EG1WT UT WOS:000390825400032 PM 27939492 ER PT J AU Rattanasinganchan, P Sopitthummakhun, K Doi, K Hu, XZ Payne, DM Pisitkun, T Leelahavanichkul, A AF Rattanasinganchan, Panthip Sopitthummakhun, Kittipat Doi, Kent Hu, Xuzhen Payne, D. Michael Pisitkun, Trairak Leelahavanichkul, Asada TI A folic acid-induced rat model of renal injury to identify biomarkers of tubulointerstitial fibrosis from urinary exosomes SO ASIAN BIOMEDICINE LA English DT Article DE Biomarkers; chronic kidney disease; folic acid; interstitial fibrosis; proteomics; urine exosomes ID ACUTE KIDNEY INJURY; DISEASE; MARKER AB Background: Chronic tubulointerstitial (TI) fibrosis is difficult to diagnose. Urinary exosomes contain many potential biomarkers, and may be useful to identify biomarkers of TI fibrosis. However, a suitable animal model to investigate urinary exosome biomarkers for TI fibrosis has not yet been specifically identified. Objective: To test the suitability of a folic-acid induced rat model of renal injury for identifying potential biomarkers of fibrosis from urinary exosomes. Methods: We employed a rat model of renal injury using a single intraperitoneal injection of folic acid. Urinary exosomes were isolated and analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results: We demonstrated severe acute kidney injury after folic acid injection by a 6-fold decrease in creatinine clearance at day 2, severe inflammatory cell infiltration in the TI area at day 7, and renal fibrosis at day 14. We collected 24 h urine samples from folic acid-injected rats and vehicle-injected control rats at days 7 and 14, then isolated urinary exosomes using a differential centrifugation method. We found that levels of exosomal marker proteins ALG-2-interacting protein 1 (ALIX; PDCD6IP) and tumor susceptibility gene 101 (TSG101) were higher in folic acid-injected rats than in control rats. LC-MS/MS analysis of urinary exosomal proteins from the folic acid-injected and control rats identified 372 proteins, including various potential TI fibrosis biomarkers. Conclusion: We demonstrated the feasibility of using a folic acid-induced rat model of TI fibrosis for urinary proteomic analysis. These rats excreted sufficient urinary exosomes permitting the large-scale analysis and discovery of potential biomarkers of renal fibrosis. C1 [Rattanasinganchan, Panthip] Huachiew Chalermprakiet Univ, Fac Med Technol, Samut Prakan 10540, Thailand. [Sopitthummakhun, Kittipat; Payne, D. Michael; Pisitkun, Trairak] Chulalongkorn Univ, Syst Biol Ctr, Res Affairs, Fac Med, Bangkok 10330, Thailand. [Sopitthummakhun, Kittipat] Huachiew Chalermprakiet Univ, Fac Sci & Technol, Samut Prakan 10540, Thailand. [Doi, Kent; Hu, Xuzhen; Leelahavanichkul, Asada] NIDDK, Kidney Dis Branch, Bethesda, MD 20892 USA. [Leelahavanichkul, Asada] Chulalongkorn Univ, Dept Microbiol, Ctr Excellence Immunol & Immune Mediated Dis, Fac Med, Bangkok 10330, Thailand. RP Leelahavanichkul, A (reprint author), Chulalongkorn Univ, Dept Microbiol, Fac Med, Bangkok 10330, Thailand. EM asada.l@chula.ac.th FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; Chulalongkorn Academic Advancement into 2nd Century Project; postdoctoral scholarship, Chulalongkorn University Ratchadaphiseksomphot Fund; Ratchadaphiseksomphot fund FX This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases and the Chulalongkorn Academic Advancement into its 2nd Century Project. KS was supported by a postdoctoral scholarship, Chulalongkorn University Ratchadaphiseksomphot Fund. KS is currently at the Faculty of Science and Technology, Huachiew Chalermprakiet University, and the Systems Biology Center, Research Affairs, Faculty of Medicine, Chulalongkorn University. AL is supported by the Ratchadaphiseksomphot fund and a grant for the new faculty, Faculty of Medicine, Chulalongkorn University. AL also works at the Center of Excellence in Immunology and Immune-mediated Diseases, Department of Microbiology, Faculty of Medicine, Chulalongkorn University. The authors thank Dr. Robert A. Star and Dr. Peter S.T. Yuen for their advice on this study. NR 32 TC 1 Z9 1 U1 0 U2 0 PU CHULALONGKORN UNIV, FAC MED PI BANGKOK PA CHULALONGKORN UNIV, FAC MED, 1873, RAMA 4, BANGKOK, 10330, THAILAND SN 1905-7415 EI 1875-855X J9 ASIAN BIOMED JI Asian Biomed. PD OCT PY 2016 VL 10 IS 5 BP 491 EP 502 DI 10.5372/1905-7415.1005.513 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EF8NN UT WOS:000390585900010 ER PT J AU Gulley, JL Madan, RA AF Gulley, James L. Madan, Ravi A. TI Developing immunotherapy strategies in the treatment of prostate cancer SO ASIAN JOURNAL OF UROLOGY LA English DT Review DE Prostate cancer; Immunotherapy; Combination therapies ID ANDROGEN DEPRIVATION THERAPY; DOSE-ESCALATION TRIAL; SIPULEUCEL-T APC8015; PHASE-III; DOCETAXEL; SURVIVAL; VACCINE; RADIOTHERAPY; COMBINATION; IPILIMUMAB AB The clinical development of immunotherapy has gained significant impetus in recent years across the field of medical oncology. Mounting preclinical and clinical data have demonstrated the potential of immune-based treatments to augment anti-tumor immune responses. With one of the first modern immunotherapies approved in prostate cancer and multiple others in late stage development, immune treatment strategies need to be optimized to ensure the best clinical outcomes. Combination strategies with androgen deprivation therapy, anti-androgen therapy, radiation and chemotherapy have demonstrated the potential maximize immune response in prostate cancer patients. These combinations are currently being evaluated in clinical trials at every stage of prostate cancer from the newly diagnosed to the most advanced stages. Data from these studies will provide guidance for the future clinical implementation of immunotherapy in prostate cancer. (C) 2016 Editorial Office of Asian Journal of Urology. Production and hosting by Elsevier B.V. C1 [Gulley, James L.; Madan, Ravi A.] NCI, Genitourinary Malignancies Branch, NIH, Bethesda, MD 20892 USA. RP Madan, RA (reprint author), NCI, Genitourinary Malignancies Branch, NIH, Bethesda, MD 20892 USA. EM madanr@mail.nih.gov NR 44 TC 2 Z9 2 U1 1 U2 1 PU ELSEVIER SINGAPORE PTE LTD PI SINGAPORE PA 3 KILLINEY ROAD 08-01, WINSLAND HOUSE 1, SINGAPORE, 239519, SINGAPORE SN 2214-3882 EI 2214-3890 J9 ASIAN J UROL JI ASIAN J. UROL. PD OCT PY 2016 VL 3 IS 4 SI SI BP 278 EP 285 DI 10.1016/j.ajur.2016.08.008 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA EG1VB UT WOS:000390819500014 ER PT J AU Hannah-Shmouni, F Trivellin, G Stratakis, CA AF Hannah-Shmouni, Fady Trivellin, Giampaolo Stratakis, Constantine A. TI Genetics of gigantism and acromegaly SO GROWTH HORMONE & IGF RESEARCH LA English DT Review DE Acromegaly; Gigantism; IGF-1; GH; Genetics; X-LAG; Pituitary adenoma ID MULTIPLE ENDOCRINE NEOPLASIA; MCCUNE-ALBRIGHT SYNDROME; X-LINKED ACROGIGANTISM; PITUITARY-ADENOMA PREDISPOSITION; INTERACTING PROTEIN GENE; CARNEY COMPLEX; AIP MUTATIONS; THERAPEUTIC RESPONSES; GERMLINE MUTATIONS; LARGE COHORT AB Gigantism and acromegaly are rare disorders that are caused by excessive GH secretion and/or high levels of its mediator, IGF-1. Gigantism occurs when excess GH or IGF-1 lead to increased linear growth, before the end of puberty and epiphyseal closure. The majority of cases arise from a benign GH-secreting pituitary adenoma, with an incidence of pituitary gigantism and acromegaly of approximately 8 and 11 per million person-years, respectively. Over the past two decades, our increasing understanding of the molecular and genetic etiologies of pituitary gigantism and acromegaly yielded several genetic causes, including multiple endocrine neoplasia type 1 and 4, McCune-Albright syndrome, Camey complex, familial isolated pituitary adenoma, pituitary adenoma association due to defects in familial succinate dehydrogenase genes, and the recently identified X-linked acrogigantism. The early diagnosis of these conditions helps guide early intervention, screening, and genetic counseling of patients and their family members. In this review, we provide a concise and up-to-date discussion on the genetics of gigantism and acromegaly. Published by Elsevier Ltd. C1 [Hannah-Shmouni, Fady; Trivellin, Giampaolo; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet SEGEN, NIH, Bethesda, MD 20892 USA. RP Stratakis, CA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet SEGEN, NIH, Bethesda, MD 20892 USA.; Stratakis, CA (reprint author), NICHD, SEGEN, PDEGEN, NIH,CRC, Bldg 10,Room 1-3330,10 Ctr Dr,MSC1103, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov OI Trivellin, Giampaolo/0000-0003-2384-4153 FU Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH) [HD00920] FX This work was supported by the Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), protocol HD00920. NR 59 TC 2 Z9 2 U1 2 U2 2 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1096-6374 EI 1532-2238 J9 GROWTH HORM IGF RES JI Growth Horm. IGF Res. PD OCT-DEC PY 2016 VL 30-31 BP 37 EP 41 DI 10.1016/j.ghir.2016.08.002 PG 5 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA EG0LN UT WOS:000390724400006 PM 27657986 ER PT J AU George, IC Sati, P Absinta, M Cortese, ICM Sweeney, EM Shea, CD Reich, DS AF George, Ilena C. Sati, Pascal Absinta, Martina Cortese, Irene C. M. Sweeney, Elizabeth M. Shea, Colin D. Reich, Daniel S. TI Clinical 3-tesla FLAIR* MRI improves diagnostic accuracy in multiple sclerosis SO MULTIPLE SCLEROSIS JOURNAL LA English DT Article DE MRI; central veins; multiple sclerosis; diagnosis AB Objective: To evaluate clinical fluid-attenuated inversion recovery (FLAIR)* 3T magnetic resonance imaging (MRI), which is sensitive to perivenular inflammatory demyelinating lesions, in diagnosing multiple sclerosis (MS). Background: Central veins may be a distinguishing feature of MS lesions. FLAIR*, a combined contrast derived from clinical MRI scans, has not been studied as a clinical tool for diagnosing MS. Methods: Two experienced MS neurologists evaluated 87 scan pairs (T-2-FLAIR/FLAIR*), separately and side-by-side, from 68 MS cases, 8 healthy volunteers, and 11 individuals with other neurological diseases. Raters judged cases based on experience, published criteria, and a visual assessment of the "40% rule," whereby MS is favored if >40% of lesions demonstrate a central vein. Diagnostic accuracy was determined with area under the receiver operating characteristic curve (AUC), and inter-rater reliability was assessed with Cohen's kappa (kappa). Results: Diagnostic accuracy was high: rater 1, AUC 0.94 (95% confidence interval: 0.89, 0.97) for T-2-FLAIR, 0.95 (0.92, 0.98) for FLAIR*; rater 2, 0.94 (0.90, 0.98) and 0.90 (0.85, 0.95). AUC improved when images were considered together: rater 1, 0.99 (0.98, 1.00); rater 2, 0.98 (0.96, 0.99). Inter-rater agreement was substantial for T-2-FLAIR (kappa = 0.68) and FLAIR* (kappa = 0.74), despite low agreement on the 40% rule (kappa = 0.47) (p << 0.001 in all cases). Conclusions: Joint clinical evaluation of T-2-FLAIR and FLAIR* images modestly improves diagnostic accuracy for MS and does not require counting lesions with central veins. C1 [Reich, Daniel S.] NINDS, Translat Neuroradiol Unit, Div Neuroimmunol & Neurovirol, NIH, Bldg 10,10 Ctr Dr,MSC 1400,Room 5C103, Bethesda, MD 20892 USA. [George, Ilena C.; Sati, Pascal; Absinta, Martina; Cortese, Irene C. M.; Sweeney, Elizabeth M.; Shea, Colin D.] NINDS, Div Neuroimmunol & Neurovirol, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [George, Ilena C.] Yale Univ, New Haven, CT USA. [Absinta, Martina] Raffaele Sci Inst, Milan, Italy. [Sweeney, Elizabeth M.; Reich, Daniel S.] Johns Hopkins Sch Publ Hlth, Baltimore, MD USA. RP Reich, DS (reprint author), NINDS, Translat Neuroradiol Unit, Div Neuroimmunol & Neurovirol, NIH, Bldg 10,10 Ctr Dr,MSC 1400,Room 5C103, Bethesda, MD 20892 USA. EM reichds@ninds.nih.gov FU Intramural Research Program of NINDS FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported by the Intramural Research Program of NINDS. NR 24 TC 1 Z9 1 U1 1 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD OCT PY 2016 VL 22 IS 12 BP 1578 EP 1586 DI 10.1177/1352458515624975 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EF8JO UT WOS:000390575300017 PM 26769065 ER PT J AU Olson, K Galbraith, J Cain, G Geisler, W AF Olson, Kristin Galbraith, James Cain, Grace Geisler, William TI MISSED OPPORTUNITIES TO SCREEN AND TREAT CHLAMYDIA AND GONORRHEA IN THE EMERGENCY DEPARTMENT SETTING SO SEXUALLY TRANSMITTED DISEASES LA English DT Meeting Abstract CT Sexually Transmitted Diseases (STD) Prevention Conference CY SEP 20-23, 2016 CL Atlanta, GA C1 [Olson, Kristin] Univ Alabama Birmingham, Dept Biostat, NIH Med Scientist Training Program, Birmingham, AL 35294 USA. [Galbraith, James] Univ Alabama Birmingham, Dept Emergency Med, Birmingham, AL USA. [Cain, Grace] Univ Alabama Birmingham, Sch Med, Birmingham, AL USA. [Geisler, William] Univ Alabama Birmingham, Div Infect Dis, Birmingham, AL USA. EM kmolson@uab.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0148-5717 EI 1537-4521 J9 SEX TRANSM DIS JI Sex. Transm. Dis. PD OCT PY 2016 VL 43 SU 2 MA THP 118 BP S224 EP S225 PG 2 WC Infectious Diseases SC Infectious Diseases GA EG0BO UT WOS:000390695900358 ER PT J AU Koncsos, G Varga, ZV Baranyai, T Boengler, K Rohrbach, S Li, L Schluter, KD Schreckenberg, R Radovits, T Olah, A Matyas, C Lux, A Al-Khrasani, M Komlodi, T Bukosza, N Mathe, D Deres, L Bartekova, M Rajtik, T Adameova, A Szigeti, K Hamar, P Helyes, Z Tretter, L Pacher, P Merkely, B Giricz, Z Schulz, R Ferdinandy, P AF Koncsos, Gabor Varga, Zoltan V. Baranyai, Tamas Boengler, Kerstin Rohrbach, Susanne Li, Ling Schlueter, Klaus-Dieter Schreckenberg, Rolf Radovits, Tamas Olah, Attila Matyas, Csaba Lux, Arpad Al-Khrasani, Mahmoud Komlodi, Timea Bukosza, Nora Mathe, Domokos Deres, Laszlo Bartekova, Monika Rajtik, Tomas Adameova, Adriana Szigeti, Krisztian Hamar, Peter Helyes, Zsuzsanna Tretter, Laszlo Pacher, Pal Merkely, Bela Giricz, Zoltan Schulz, Rainer Ferdinandy, Peter TI Diastolic dysfunction in prediabetic male rats: Role of mitochondrial oxidative stress SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE obesity; type 2 diabetes; high-fat diet; reactive oxygen species; diabetic cardiomyopathy ID IMPAIRED FASTING GLUCOSE; HIGH-FAT DIET; LEFT-VENTRICULAR HYPERTROPHY; INDUCED CARDIAC-HYPERTROPHY; MUSCLE-CELL APOPTOSIS; OXIDASE 4 NOX4; DIABETES-MELLITUS; CARDIOVASCULAR-DISEASE; METABOLIC SYNDROME; HEART-FAILURE AB Although incidence and prevalence of prediabetes are increasing, little is known about its cardiac effects. Therefore, our aim was to investigate the effect of prediabetes on cardiac function and to characterize parameters and pathways associated with deteriorated cardiac performance. Long-Evans rats were fed with either control or high-fat chow for 21 wk and treated with a single low dose (20 mg/kg) of streptozotocin at week 4. High-fat and streptozotocin treatment induced prediabetes as characterized by slightly elevated fasting blood glucose, impaired glucose and insulin tolerance, increased visceral adipose tissue and plasma leptin levels, as well as sensory neuropathy. In prediabetic animals, a mild diastolic dysfunction was observed, the number of myocardial lipid droplets increased, and left ventricular mass and wall thickness were elevated; however, no molecular sign of fibrosis or cardiac hypertrophy was shown. In prediabetes, production of reactive oxygen species was elevated in subsarcolemmal mitochondria. Expression of mitofusin-2 was increased, while the phosphorylation of phos-pholamban and expression of Bcl-2/adenovirus E1B 19-kDa protein-interacting protein 3 (BNIP3, a marker of mitophagy) decreased. However, expression of other markers of cardiac auto-and mitophagy, mitochondrial dynamics, inflammation, heat shock proteins, Ca2+/calmodulin-dependent protein kinase II, mammalian target of rapamycin, or apoptotic pathways were unchanged in prediabetes. This is the first comprehensive analysis of cardiac effects of prediabetes indicating that mild diastolic dysfunction and cardiac hypertrophy are multifactorial phenomena that are associated with early changes in mitophagy, cardiac lipid accumulation, and elevated oxidative stress and that prediabetes-induced oxidative stress originates from the subsarcolemmal mitochondria. C1 [Koncsos, Gabor; Varga, Zoltan V.; Baranyai, Tamas; Al-Khrasani, Mahmoud; Pacher, Pal; Giricz, Zoltan; Ferdinandy, Peter] Semmelweis Univ, Fac Med, Dept Pharmacol & Pharmacotherapy, Budapest, Hungary. [Boengler, Kerstin; Rohrbach, Susanne; Li, Ling; Schlueter, Klaus-Dieter; Schreckenberg, Rolf; Schulz, Rainer] Justus Liebig Univ, Fac Med, Inst Physiol, Giessen, Germany. [Radovits, Tamas; Olah, Attila; Matyas, Csaba; Lux, Arpad; Merkely, Bela] Semmelweis Univ, Heart & Vasc Ctr, Budapest, Hungary. [Komlodi, Timea; Tretter, Laszlo] Semmelweis Univ, Fac Med, Dept Med Biochem, Budapest, Hungary. [Bukosza, Nora; Hamar, Peter] Semmelweis Univ, Fac Med, Inst Pathophysiol, Budapest, Hungary. [Mathe, Domokos; Szigeti, Krisztian] Semmelweis Univ, Fac Med, Dept Biophys & Radiat Biol, Budapest, Hungary. [Mathe, Domokos] CROmed Translat Res Ctr, Budapest, Hungary. [Deres, Laszlo] Univ Pecs, Fac Med, Dept Internal Med 1, Pecs, Hungary. [Bartekova, Monika] Comenius Univ, Fac Med, Inst Physiol, Bratislava, Slovakia. [Bartekova, Monika] Slovak Acad Sci, Inst Heart Res, Bratislava, Slovakia. [Rajtik, Tomas; Adameova, Adriana] Comenius Univ, Fac Pharm, Dept Pharmacol & Toxicol, Bratislava, Slovakia. [Helyes, Zsuzsanna] Univ Pecs, Fac Med, Dept Pharmacol & Pharmacotherapy, Pecs, Hungary. [Helyes, Zsuzsanna] Univ Pecs, Szentagothai Res Ctr, Pecs, Hungary. [Helyes, Zsuzsanna] Univ Pecs, MTA PTE NAP Chron Pain Res Grp B, Pecs, Hungary. [Varga, Zoltan V.; Pacher, Pal] NIAAA, Lab Cardiovasc Physiol & Tissue Injury, NIH, Bethesda, MD USA. RP Giricz, Z (reprint author), Nagyvarad Ter 4, H-1089 Budapest, Hungary. EM giricz.zoltan@med.semmelweis-univ.hu RI Matyas, Csaba/K-6053-2016 OI Matyas, Csaba/0000-0001-6095-7611 FU European Foundation for the Study of Diabetes (EFSD) New Horizons Collaborative Research Initiative from the European Association for the Study of Diabetes (EASD); Hungarian Scientific Research Fund [OTKA K 109737, PD100245]; Slovak Scientific Grant Agency [VEGA1/0638/12]; Hungarian Academy of Sciences; Rosztoczy Foundation; European Cooperation in Science and Technology [COST-BM1203-STSM 090515-058721]; German Research Foundation [BO-2955/2-1, SCHU 843/9-1] FX This work was supported by the European Foundation for the Study of Diabetes (EFSD) New Horizons Collaborative Research Initiative from the European Association for the Study of Diabetes (EASD) and Hungarian Scientific Research Fund (OTKA K 109737, PD100245 to T. Radovits) and Slovak Scientific Grant Agency (VEGA1/0638/12). Z. Giricz, T. Radovits, and K. Szigeti hold a "Janos Bolyai Research Scholarship" from the Hungarian Academy of Sciences, and Z. Varga was supported by the Rosztoczy Foundation. P. Ferdinandy is a Szentagothai Fellow of the National Program of Excellence (TAMOP 4.2.4. A/2-11-1-2012-0001). T. Baranyai is supported by the European Cooperation in Science and Technology (COST-BM1203-STSM 090515-058721). K. Boengler and R. Schreckenberg are supported by the German Research Foundation (BO-2955/2-1 and SCHU 843/9-1). NR 86 TC 2 Z9 2 U1 6 U2 6 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 EI 1522-1539 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD OCT PY 2016 VL 311 IS 4 BP H927 EP H943 DI 10.1152/ajpheart.00049.2016 PG 17 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA EF1WP UT WOS:000390116100007 PM 27521417 ER PT J AU Chauhan, G Arnold, C Chu, A Fornage, M Reyahi, A Bis, J Havulinna, A Lehmann, O Launer, L Ikram, M Carlsson, P Chasman, D Childs, S Longstreth, W Seshadri, S Debette, S AF Chauhan, G. Arnold, C. Chu, A. Fornage, M. Reyahi, A. Bis, J. Havulinna, A. Lehmann, O. Launer, L. Ikram, M. Carlsson, P. Chasman, D. Childs, S. Longstreth, W., Jr. Seshadri, S. Debette, S. TI FOXF2, A NOVEL RISK LOCUS FOR STROKE AND SMALL ARTERY DISEASE: A GENOME-WIDE ASSOCIATION STUDY SO INTERNATIONAL JOURNAL OF STROKE LA English DT Meeting Abstract C1 [Chauhan, G.; Debette, S.] INSERM, U1219, Neuroepidemiol, Bordeaux, France. [Arnold, C.; Childs, S.] Univ Calgary, Alberta Childrens Hosp, Res Inst, Calgary, AB, Canada. [Arnold, C.; Childs, S.] Univ Calgary, Dept Biochem & Mol Biol, Calgary, AB, Canada. [Chu, A.; Chasman, D.] Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA. [Fornage, M.] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA. [Fornage, M.] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Reyahi, A.; Carlsson, P.] Univ Gothenburg, Dept Chem & Mol Biol, Gothenburg, Sweden. [Bis, J.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Havulinna, A.] Natl Inst Hlth & Welf, Helsinki, Finland. [Lehmann, O.] Univ Alberta, Dept Ophthalmol, Edmonton, AB T6G 2M7, Canada. [Launer, L.] NIA, IRP, NIH, Bethesda, MD 20892 USA. [Ikram, M.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Longstreth, W., Jr.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Seshadri, S.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1747-4930 EI 1747-4949 J9 INT J STROKE JI Int. J. Stroke PD OCT PY 2016 VL 11 IS SUPP 3 MA 62 BP 28 EP 28 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EA8TP UT WOS:000386912100064 ER PT J AU Srivanitchapoom, P Shamim, EA Diomi, P Hattori, T Pandey, S Vorbach, S Park, JE Wu, TX Auh, S Hallett, M AF Srivanitchapoom, Prachaya Shamim, Ejaz A. Diomi, Pierre Hattori, Takaaki Pandey, Sanjay Vorbach, Sherry Park, Jung E. Wu, Tianxia Auh, Sungyoung Hallett, Mark TI Differences in active range of motion measurements in the upper extremity of patients with writer's cramp compared with healthy controls SO JOURNAL OF HAND THERAPY LA English DT Article DE Focal hand dystonia; Writer's cramp; Biomechanical assessment; Botulinum toxin; Dystonia Disability Scale ID FOCAL HAND DYSTONIA; MUSICIANS; INHIBITION; DISCRIMINATION; PLASTICITY; MUSCLES; REFLEX AB Study Design: Exploratory case-control study. Introduction: Writer's cramp (WC) is a type of focal hand dystonia. The central nervous system plays a role in its pathophysiology, but abnormalities in the affected musculoslceletal components may also be relevant. Purpose of the Study: We compared the active range of motion (ROM) in patients with WC and healthy volunteers (HVs) and correlated the findings with disease duration and severity. Methods: Affected limb joints were measured with goniometers. Patients were assessed at least 3 months after their last botulinum toxin (botulinum neurotoxin) injection, and strength was clinically normal. t tests were used to compare the ROMs of WC with matched HVs. The Spearman correlation coefficient assessed the relationship of active ROMs to the disease duration and handwriting subscore of the Dystonia Disability Scale. Results: ROMs of D1 metacarpophalangeal (MCP) joint extension as well as D2 and D5 MCP flexion were significantly smaller in WC, and distal interphalangeal joint extension in D3 and D5 was significantly greater compared with HVs. There were negative correlations between D2 MCP flexion and disease duration and with Dystonia Disability Scale. Discussion: Abnormalities in ROMs in WC were found. Severity and disease duration correlated with reduced D2 MCP flexion. This may be related to intrinsic biomechanical abnormalities, co-contraction of muscles, or a combination of subclinical weakness and atrophy from repeated botulinum neurotoxin injections. Conclusions: Hand biomechanical properties should not be ignored in the pathophysiology of WC. (C) 2016 Hanley & Belfus, an imprint of Elsevier Inc. All rights reserved. C1 [Srivanitchapoom, Prachaya; Shamim, Ejaz A.; Diomi, Pierre; Hattori, Takaaki; Vorbach, Sherry; Park, Jung E.; Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Srivanitchapoom, Prachaya] Mahidol Univ, Siriraj Hosp, Fac Med, Div Neurol,Dept Med, Bangkok, Thailand. [Shamim, Ejaz A.] Kaiser Permanente, Dept Neurol, Midatlantic Permanente Res Inst, Rockville, MD USA. [Pandey, Sanjay] Govind Ballabh Pant Hosp, Dept Neurol, New Delhi, India. [Wu, Tianxia; Auh, Sungyoung] NINDS, Clin Neurosci Program, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Srivanitchapoom, P (reprint author), Mahidol Univ, Siriraj Hosp, Fac Med, Dept Med, 2 Prannok Rd, Bangkok 10700, Bangkok Noi, Thailand. EM prachaya.srivanitchapoom@nih.gov FU Intramural NIH HHS [Z99 NS999999] NR 28 TC 0 Z9 0 U1 0 U2 0 PU HANLEY & BELFUS-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0894-1130 EI 1545-004X J9 J HAND THER JI J. Hand Ther. PD OCT-DEC PY 2016 VL 29 IS 4 BP 489 EP 495 DI 10.1016/j.jht.2016.02.001 PG 7 WC Orthopedics; Rehabilitation; Surgery SC Orthopedics; Rehabilitation; Surgery GA EF1KG UT WOS:000390083100012 PM 27773588 ER PT J AU Birdwell, L Lodish, M Tirosh, A Chittiboina, P Keil, M Lyssikatos, C Belyavskaya, E Feelders, RA Stratakis, CA AF Birdwell, Leah Lodish, Maya Tirosh, Amit Chittiboina, Prashant Keil, Meg Lyssikatos, Charlampos Belyavskaya, Elena Feelders, Richard A. Stratakis, Constantine A. TI Coagulation Profile Dynamics in Pediatric Patients with Cushing Syndrome: A Prospective, Observational Comparative Study SO JOURNAL OF PEDIATRICS LA English DT Article ID THROMBOEMBOLIC COMPLICATIONS; VENOUS THROMBOEMBOLISM; CHILDREN; DISEASE; FIBRINOLYSIS; INFLAMMATION; THROMBOSIS; OBESITY AB Objective To evaluate the association between Cushing syndrome and hypercoagulability in children. Study design A prospective, observational study was performed of 54 patients with Cushing syndrome, 15.1 +/- 3.9 years, treated at the National Institutes of Health Clinical Center. Coagulation profiles were taken before and 6-12 months after surgery and compared with 18 normocortisolemic children, 13.7 +/- 3.6 years. Results At baseline, patients with Cushing syndrome had greater levels of the procoagulant factor VIII (FVIII) vs controls (145 IU/dL +/- 84 vs 99 +/- 47, P = .04); 6-12 months after surgery, FVIII levels decreased to 111 +/- 47, P = .05. Patients with Cushing syndrome had greater levels of the antifibrinolytic alpha 2-antiplasmin, 96 alpha 17% vs 82 alpha 26%, P = .015. After surgery, antifibrinolytic a2-antiplasmin levels decreased to 82 +/- 24%, P < .001. Anticoagulants were greater in patients with Cushing syndrome vs controls at baseline, including protein C (138 +/- 41% vs 84 +/- 25%, P < .001), protein S (94 +/- 19% vs 74 +/- 19%, P = .001), and antithrombin III (96 +/- 18% vs 77 +/- 13%, P < .0001). The 24-hour urinary free cortisol levels correlated positively with FVIII levels, r = 0.43, P = .004. Conclusion Children with Cushing syndrome had elevated procoagulants, antifibrinolytics, and anticoagulants at baseline compared with controls; normalization of coagulation measures was seen after surgical cure. Despite the increase in anticoagulants, hypercortisolemia is associated with a hypercoagulable state in children, as is the case in adults. This finding has potential implications for prevention of venous thromboembolism in children with Cushing syndrome. C1 [Birdwell, Leah] Univ Maryland, College Pk, MD 20742 USA. [Birdwell, Leah; Lodish, Maya; Tirosh, Amit; Keil, Meg; Lyssikatos, Charlampos; Belyavskaya, Elena; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, NIH, Bethesda, MD USA. [Chittiboina, Prashant] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Feelders, Richard A.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. RP Lodish, M (reprint author), NICHD, NIH, Clin Res Ctr, Bldg 10,Room 1-3330,10 Ctr Dr,MSC 1103, Bethesda, MD 20892 USA. EM lodishma@mail.nih.gov FU Intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development FX Supported by the Intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The authors declare no conflicts of interest. NR 19 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD OCT PY 2016 VL 177 BP 227 EP 231 DI 10.1016/j.jpeds.2016.06.087 PG 5 WC Pediatrics SC Pediatrics GA EF0NO UT WOS:000390022700044 PM 27496264 ER PT J AU Little, MP AF Little, Mark P. TI Radiation and circulatory disease SO MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH LA English DT Review DE Circulatory disease; Radiation; Heart disease; Stroke; Review ID CORONARY-HEART-DISEASE; ATOMIC-BOMB SURVIVORS; CHERNOBYL EMERGENCY WORKERS; BREAST-CANCER RADIOTHERAPY; URANIUM MINERS COHORT; LONG-TERM MORTALITY; LOW-DOSE-RATE; CARDIOVASCULAR-DISEASES; IONIZING-RADIATION; CEREBROVASCULAR DISEASES AB Exposure to therapeutic doses of ionizing radiation is associated with damage to the heart and coronary arteries. However, only recently have studies with high-quality individual dosimetry data allowed this risk to be quantified while also adjusting for concomitant chemotherapy, and medical and lifestyle risk factors. At lower levels of exposure the evidence is less clear. In this article I review radiation-associated risks of circulatory disease in groups treated with radiotherapy for malignant and non-malignant disease, and in occupationally- or environmentally-exposed groups receiving rather lower levels of radiation dose, also for medical diagnostic purposes. Results of a meta-analysis suggest that excess relative risks per unit dose for various types of heart disease do not exhibit statistically significant (p > 0.2) heterogeneity between studies. Although there are no marked discrepancies between risks derived from the high-dose therapeutic and medical diagnostic studies and from the moderate/low dose occupational and environmental studies, at least for ischemic heart disease and stroke there are indications of larger risks per unit dose for lower dose rate and fractionated exposures. Risks for stroke and other types of circulatory disease are significantly more variable (p < 0.0001), possibly resulting from confounding and effect-modification by well known (but unobserved) risk factors. Adjustment for any of mean dose, dose fractionation or age at exposure results in the residual heterogeneity for cerebrovascular disease becoming non-significant. The review provides strong evidence in support of a causal association between both low and high dose radiation exposure and most types of circulatory disease. Published by Elsevier B.V. C1 [Little, Mark P.] NCI, Radiat Epidemiol Branch, Bethesda, MD 20892 USA. RP Little, MP (reprint author), NCI, Room 7E546,9609 Med Ctr Dr,MSC 9778, Rockville, MD 20892 USA. EM mark.little@nih.gov OI Little, Mark/0000-0003-0980-7567 FU Intramural Research Program of the National Institutes of Health, the National Cancer Institute, Division of Cancer Epidemiology and Genetics FX The Intramural Research Program of the National Institutes of Health, the National Cancer Institute, Division of Cancer Epidemiology and Genetics supported this work. NR 109 TC 3 Z9 3 U1 3 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1383-5742 EI 1388-2139 J9 MUTAT RES-REV MUTAT JI Mutat. Res.-Rev. Mutat. Res. PD OCT-DEC PY 2016 VL 770 SI SI BP 299 EP 318 DI 10.1016/j.mrrev.2016.07.008 PN B PG 20 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA EF1HG UT WOS:000390075300007 PM 27919337 ER PT J AU Mahle, WT Nicolson, SC Hollenbeck-Pringle, D Gaies, MG Witte, MK Lee, EK Goldsworthy, M Stark, PC Burns, KM Scheurer, MA Cooper, DS Thiagarajan, R Ben Sivarajan, V Colan, SD Schamberger, MS Shekerdemian, LS AF Mahle, William T. Nicolson, Susan C. Hollenbeck-Pringle, Danielle Gaies, Michael G. Witte, Madolin K. Lee, Eva K. Goldsworthy, Michelle Stark, Paul C. Burns, Kristin M. Scheurer, Mark A. Cooper, David S. Thiagarajan, Ravi Ben Sivarajan, V. Colan, Steven D. Schamberger, Marcus S. Shekerdemian, Lara S. CA Pediat Heart Network Investigators TI Utilizing a Collaborative Learning Model to Promote Early Extubation Following Infant Heart Surgery SO PEDIATRIC CRITICAL CARE MEDICINE LA English DT Article DE mechanical ventilation; outcomes; tetralogy of Fallot ID CARDIAC-SURGERY; OPERATING-ROOM; CHILDREN AB Objective: To determine whether a collaborative learning strategy-derived clinical practice guideline can reduce the duration of endotracheal intubation following infant heart surgery. Design: Prospective and retrospective data collected from the Pediatric Heart Network in the 12 months pre- and post-clinical practice guideline implementation at the four sites participating in the collaborative (active sites) compared with data from five Pediatric Heart Network centers not participating in collaborative learning (control sites). Setting: Ten children's hospitals. Patients: Data were collected for infants following two-index operations: 1) repair of isolated coarctation of the aorta (birth to 365 d) and 2) repair of tetralogy of Fallot (29-365 d). There were 240 subjects eligible for the clinical practice guideline at active sites and 259 subjects at control sites. Interventions: Development and application of early extubation clinical practice guideline. Measurements and Main Results: After clinical practice guideline implementation, the rate of early extubation at active sites increased significantly from 11.7% to 66.9% (p < 0.001) with no increase in reintubation rate. The median duration of postoperative intubation among active sites decreased from 21.2 to 4.5 hours (p < 0.001). No statistically significant change in early extubation rates was found in the control sites 11.7% to 13.7% (p = 0.63). At active sites, clinical practice guideline implementation had no statistically significant impact on median ICU length of stay (71.9 hr pre- vs 69.2 hr post-implementation; p = 0.29) for the entire cohort. There was a trend toward shorter ICU length of stay in the tetralogy of Fallot subgroup (71.6 hr pre- vs 54.2 hr postimplementation, p = 0.068). Conclusions: A collaborative learning strategy designed clinical practice guideline significantly increased the rate of early extubation with no change in the rate of reintubation. The early extubation clinical practice guideline did not significantly change postoperative ICU length of stay. C1 [Mahle, William T.] Emory Univ, Dept Pediat, Atlanta, GA 30322 USA. [Nicolson, Susan C.] Childrens Hosp Philadelphia, Dept Anesthesia, Philadelphia, PA 19104 USA. [Hollenbeck-Pringle, Danielle; Stark, Paul C.] New England Res Inst, 9 Galen St, Watertown, MA 02172 USA. [Gaies, Michael G.] Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA. [Witte, Madolin K.] Univ Utah, Dept Pediat, Salt Lake City, UT USA. [Lee, Eva K.] Georgia Inst Technol, Dept Ind Engn, Atlanta, GA 30332 USA. [Goldsworthy, Michelle; Shekerdemian, Lara S.] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Burns, Kristin M.] NHLBI, Bldg 10, Bethesda, MD 20892 USA. [Scheurer, Mark A.] Med Univ South Carolina, Dept Pediat, Charleston, SC USA. [Cooper, David S.] Cincinnati Childrens Hosp, Dept Pediat, Cincinnati, OH USA. [Thiagarajan, Ravi; Colan, Steven D.] Boston Childrens Hosp, Dept Cardiol, Boston, MA USA. [Ben Sivarajan, V.] Hosp Sick Children, Dept Crit Care Med, Toronto, ON, Canada. [Schamberger, Marcus S.] Riley Childrens Hosp, Dept Pediat, Indianapolis, IN USA. RP Mahle, WT (reprint author), Emory Univ, Dept Pediat, Atlanta, GA 30322 USA. EM wmahle@emory.edu FU National Heart, Lung, and Blood Institute [HL068270, HL109777, HL109816, HL109818, HL109778, HL109743, HL109673, HL109741, HL109737, HL109781]; National Institutes of Health (NIH); NIH; Pediatric Heart Network; National Science Foundation; NHLBI; Bristol Myers Squibb (Events Adjudication Committee); NIH HLBI FX Supported by HL068270, HL109777, HL109816, HL109818, HL109778, HL109743, HL109673, HL109741, HL109737, and HL109781 from the National Heart, Lung, and Blood Institute.; Dr. Mahle received support for article research from the National Institutes of Health (NIH). Dr. Nicolson received support for article research from the NIH. Dr. Hollenbeck-Pringle received support for article research from the NIH. Her institution received funding from the NIH. Dr. Witte received support for article research from the NIH. Her institution received funding from the Pediatric Heart Network. Dr. Lee received support for article research from the NIH. Her institution received funding from the National Science Foundation. Dr. Goldsworthy received support for article research from the NHLBI. Dr. Stark received support for article research from the NIH. His institution received funding from the NIH. Dr. Burns received support for article research from the NIH. Dr. Thiagarajan's institution received funding from Bristol Myers Squibb (Events Adjudication Committee). Dr. Golan received support for article research from the NIH. His institution received funding from NIH HLBI. Dr. Schamberger received support for article research from the NIH. His institution received funding from the Pediatric Heart Network. The remaining authors have disclosed that they do not have any potential conflicts of interest. NR 15 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1529-7535 EI 1947-3893 J9 PEDIATR CRIT CARE ME JI Pediatr. Crit. Care Med. PD OCT PY 2016 VL 17 IS 10 BP 939 EP 947 DI 10.1097/PCC.0000000000000918 PG 9 WC Critical Care Medicine; Pediatrics SC General & Internal Medicine; Pediatrics GA EF2EA UT WOS:000390136300011 PM 27513600 ER PT J AU Dietz, BM Hajirahimkhan, A Dunlap, TL Bolton, JL AF Dietz, Birgit M. Hajirahimkhan, Atieh Dunlap, Tareisha L. Bolton, Judy L. TI Botanicals and Their Bioactive Phytochemicals for Women's Health SO PHARMACOLOGICAL REVIEWS LA English DT Review ID BREAST-CANCER CELLS; VITEX-AGNUS-CASTUS; NF-KAPPA-B; HUMULUS-LUPULUS L.; ESTROGEN-RECEPTOR-BETA; ARYL-HYDROCARBON RECEPTOR; HORMONE-REPLACEMENT THERAPY; RANDOMIZED CONTROLLED-TRIAL; URINARY-TRACT-INFECTIONS; PLACEBO-CONTROLLED TRIAL AB Botanical dietary supplements are increasingly popular for women's health, particularly for older women. The specific botanicals women take vary as a function of age. Younger women will use botanicals for urinary tract infections, especially Vaccinium macrocarpon (cranberry), where there is evidence for efficacy. Botanical dietary supplements for premenstrual syndrome (PMS) are less commonly used, and rigorous clinical trials have not been done. Some examples include Vitex agnus-castus (chasteberry), Angelica sinensis (dong quai), Viburnum opulus/prunifolium (cramp bark and black haw), and Zingiber officinale (ginger). Pregnant women have also used ginger for relief from nausea. Natural galactagogues for lactating women include Trigonella foenum-graecum (fenugreek) and Silybum marianum (milk thistle); however, rigorous safety and efficacy studies are lacking. Older women suffering menopausal symptoms are increasingly likely to use botanicals, especially since the Women's Health Initiative showed an increased risk for breast cancer associated with traditional hormone therapy. Serotonergic mechanisms similar to antidepressants have been proposed for Actaea/Cimicifuga racemosa (black cohosh) and Valeriana officinalis (valerian). Plant extracts with estrogenic activities for menopausal symptom relief include Glycine max (soy), Trifolium pratense (red clover), Pueraria lobata (kudzu), Humulus lupulus (hops), Glycyrrhiza species (licorice), Rheum rhaponticum (rhubarb), Vitex agnus-castus (chasteberry), Linum usitatissimum (flaxseed), Epimedium species (herba Epimedii, horny goat weed), and Medicago sativa (alfalfa). Some of the estrogenic botanicals have also been shown to have protective effects against osteoporosis. Several of these botanicals could have additional breast cancer preventive effects linked to hormonal, chemical, inflammatory, and/or epigenetic pathways. Finally, although botanicals are perceived as natural safe remedies, it is important for women and their healthcare providers to realize that they have not been rigorously tested for potential toxic effects and/or drug/botanical interactions. Understanding the mechanism of action of these supplements used for women's health will ultimately lead to standardized botanical products with higher efficacy, safety, and chemopreventive properties. C1 [Dietz, Birgit M.; Hajirahimkhan, Atieh; Dunlap, Tareisha L.; Bolton, Judy L.] Univ Illinois, Coll Pharm, Dept Med Chem & Pharmacognosy, Ctr Bot Dietary Supplements,NIH, Chicago, IL USA. RP Bolton, JL (reprint author), Univ Illinois, Dept Med Chem & Pharmacognosy, Coll Pharm, 833 South Wood St,M-C 781, Chicago, IL 60612 USA. EM judy.bolton@uic.edu FU National Institutes of Health Office of Dietary Supplements (ODS); National Center for Complementary and Integrated Health (NCCIH) [P50 AT000155, T32 AT007533] FX This work was supported in part by the National Institutes of Health Office of Dietary Supplements (ODS) and National Center for Complementary and Integrated Health (NCCIH) [Grants P50 AT000155 and T32 AT007533]. NR 514 TC 2 Z9 2 U1 18 U2 18 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0031-6997 EI 1521-0081 J9 PHARMACOL REV JI Pharmacol. Rev. PD OCT PY 2016 VL 68 IS 4 BP 1026 EP 1073 DI 10.1124/pr.115.010843 PG 48 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EF2AH UT WOS:000390126100004 PM 27677719 ER PT J AU Kim, MJ Seo, SW Kim, ST Lee, JM Na, DL AF Kim, Min-Jeong Seo, Sang Won Kim, Sung Tae Lee, Jong-Min Na, Duk L. TI Diffusion Tensor Changes According to Age at Onset and Apolipoprotein E Genotype in Alzheimer Disease SO ALZHEIMER DISEASE & ASSOCIATED DISORDERS LA English DT Article DE age of onset; Alzheimer disease; apolipoproteins E; diffusion tensor imaging ID CEREBRAL GLUCOSE-METABOLISM; APOE GENOTYPE; WHITE-MATTER; CORTICAL THICKNESS; EPSILON-4 ALLELE; HUMAN BRAIN; PATTERNS; PRESENILE; DEMENTIA; NEUROGENESIS AB Age at onset is one of the most important factors that affects the clinical course in Alzheimer disease (AD), whereas other factors such as apolipoprotein E (apoE) genotype may also play a major role. In this study, we aimed to investigate the effect of age at onset and apoE genotype on white-matter changes in AD using diffusion tensor imaging. About 213 patients with AD and 66 normal individuals underwent diffusion tensor imaging, and apoE genotype was obtained in all AD patients and in 24 normal individuals. When multiple regression analysis was conducted, a younger age at onset was associated with lower fractional anisotropy in both deep-located long-range limbic and association fibers and superficial-located short-range association fibers in the frontal, the temporal, and the parietal lobes, and with a higher mean diffusivity in deep-located fibers and the bilateral medial thalamus. When analyzed separately in apoE e4 carriers and noncarriers, e4 carriers showed an association between a younger age at onset and lower fractional anisotropy, mainly in deep-located fibers, whereas noncarriers showed this association in both deep-located and superficial-located fibers. There was no difference in the spatial distribution between carriers and noncarriers in the association between the age at onset and mean diffusivity. Our results suggest that the topographical distribution of white-matter changes in AD is significantly affected by the interaction between age at onset and apoE genotype. C1 [Kim, Min-Jeong] Seoul Natl Univ Hosp, Dept Neurol, Seoul, South Korea. [Seo, Sang Won; Na, Duk L.] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Neurol, 81 Irwon Ro, Seoul 06351, South Korea. [Kim, Sung Tae] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Radiol, Seoul, South Korea. [Seo, Sang Won; Na, Duk L.] Sungkyunkwan Univ, Samsung Med Ctr, Neurosci Ctr, Seoul, South Korea. [Seo, Sang Won] Sungkyunkwan Univ, SAIHST, Dept Clin Res Design & Evaluat, Seoul, South Korea. [Seo, Sang Won; Na, Duk L.] Sungkyunkwan Univ, SAIHST, Dept Hlth Sci & Technol, Seoul, South Korea. [Lee, Jong-Min] Hanyang Univ, Dept Biomed Engn, Seoul, South Korea. [Kim, Min-Jeong] NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. RP Na, DL (reprint author), Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Neurol, 81 Irwon Ro, Seoul 06351, South Korea. EM dukna@naver.com FU Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea [A110394, HI14C2746] FX Supported by a grant from the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A110394 & HI14C2746). NR 40 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0893-0341 J9 ALZ DIS ASSOC DIS JI Alzheimer Dis. Assoc. Dis. PD OCT-DEC PY 2016 VL 30 IS 4 BP 297 EP 304 DI 10.1097/WAD.0000000000000155 PG 8 WC Clinical Neurology; Pathology SC Neurosciences & Neurology; Pathology GA EE0IQ UT WOS:000389258200002 PM 27227996 ER PT J AU Clark, SL Romero, R Dildy, GA Callaghan, WM Smiley, RM Bracey, AW Hankins, GD D'Alton, ME Foley, M Pacheco, LD Vadhera, RB Herlihy, JP Berkowitz, RL Belfort, MA AF Clark, Steven L. Romero, Roberto Dildy, Gary A. Callaghan, William M. Smiley, Richard M. Bracey, Arthur W. Hankins, Gary D. D'Alton, Mary E. Foley, Mike Pacheco, Luis D. Vadhera, Rakesh B. Herlihy, J. Patrick Berkowitz, Richard L. Belfort, Michael A. TI 3 Proposed diagnostic criteria for the case definition of amniotic fluid embolism in research studies SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE amniotic fluid embolism; critical care ID MATERNAL PULMONARY CIRCULATION; SEPTIC SHOCK; CELLS; PREGNANCY AB Amniotic fluid embolism is a leading cause of maternal mortality in developed countries. Our understanding of risk factors, diagnosis, treatment, and prognosis is hampered by a lack of uniform clinical case definition; neither histologic nor laboratory findings have been identified unique to this condition. Amniotic fluid embolism is often overdiagnosed in critically ill peripartum women, particularly when an element of coagulopathy is involved. Previously proposed case definitions for amniotic fluid embolism are nonspecific, and when viewed through the eyes of individuals with experience in critical care obstetrics, would include women with a number of medical conditions much more common than amniotic fluid embolism. We convened a working group under the auspices of a committee of the Society for Maternal-Fetal Medicine and the Amniotic Fluid Embolism Foundation whose task was to develop uniform diagnostic criteria for the research reporting of amniotic fluid embolism. These criteria rely on the presence of the classic triad of hemodynamic and respiratory compromise accompanied by strictly defined disseminated intravascular coagulopathy. It is anticipated that limiting research reports involving amniotic fluid embolism to women who meet these criteria will enhance the validity of published data and assist in the identification of risk factors, effective treatments, and possibly useful biomarkers for this condition. A registry has been established in conjunction with the Perinatal Research Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development to collect both clinical information and laboratory specimens of women with suspected amniotic fluid embolism in the hopes of identifying unique biomarkers of this condition. C1 [Clark, Steven L.] Baylor Coll Med, Houston, TX 77030 USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Div Obstet & Maternal Fetal Med, Div Intramural Res,NIH, Detroit, MI USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Div Obstet & Maternal Fetal Med, Div Intramural Res,NIH, Bethesda, MD USA. Columbia Univ, New York, NY USA. Ctr Dis Control & Prevent, Atlanta, GA USA. Banner Hlth, Phoenix, AZ USA. Univ Texas Med Branch, Galveston, TX 77555 USA. RP Clark, SL (reprint author), Baylor Coll Med, Houston, TX 77030 USA. EM slclark@bcm.edu FU Intramural CDC HHS [CC999999] NR 27 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD OCT PY 2016 VL 215 IS 4 BP 408 EP 412 DI 10.1016/j.ajog.2016.06.037 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EE3RJ UT WOS:000389513600004 PM 27372270 ER PT J AU Romero, R AF Romero, Roberto TI A profile of Emanuel A. Friedman, MD, DMedSci SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Biographical-Item C1 [Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Rockville, MD 20847 USA. RP Romero, R (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Rockville, MD 20847 USA. NR 8 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD OCT PY 2016 VL 215 IS 4 BP 413 EP 414 DI 10.1016/j.ajog.2016.07.034 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EE3RJ UT WOS:000389513600005 PM 27496073 ER PT J AU Melamed, N Pittini, A Hiersch, L Yogev, Y Korzeniewski, SS Romero, R Barrett, J AF Melamed, Nir Pittini, Alex Hiersch, Liran Yogev, Yariv Korzeniewski, Steven S. Romero, Roberto Barrett, Jon TI Serial cervical length determination in twin pregnancies reveals 4 distinct patterns with prognostic significance for preterm birth SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE biomarker; cervical ripening; longitudinal study; prediction; pregnancy; prematurity; preterm labor; ultrasound ID RANDOMIZED CONTROLLED-TRIAL; SONOGRAPHIC MEASUREMENT; FETAL FIBRONECTIN; TRANSVAGINAL SONOGRAPHY; PROSPECTIVE MULTICENTER; MULTIPLE PREGNANCIES; ASYMPTOMATIC WOMEN; GESTATIONAL-AGE; LOW-RISK; PREDICTION AB BACKGROUND: Women with a twin gestation are at increased risk for preterm birth (PTB), and sonographic cervical length (CL) is a powerful predictor for spontaneous PTB. Obstetricians frequently monitor CL in multiple gestations; yet, the optimal method to integrate and interpret the results of serial sonographic CL has not been determined. OBJECTIVE: We sought to determine whether there are different patterns of cervical shortening in twin gestations, and whether such patterns are related to the risk of PTB. STUDY DESIGN: We conducted a retrospective study of all women with twins followed up in a single tertiary referral center during 2012 through 2014. All women underwent serial measurements of CL every 2-3 weeks starting from 14-18 weeks and until 28-32 weeks of gestation. Changes in CL were analyzed and classified into distinct patterns that were initially identified by visual inspection of all individual cases. Each pattern was then characterized by several parameters including information about when cervical shortening began, the rate of shortening, and whether a plateau was observed. Locally weighted regression mean profiles were generated to describe each pattern of CL over time. The association of these patterns with spontaneous PTB was determined. The specific characteristics of each pattern that further determined the risk of PTB were identified using multivariable logistic regression analysis. RESULTS: We studied 441 women who had a total of 2826 measurements of CL done. Overall, 4 main patterns of change in CL were identified: pattern I, stable cervix (n = 196); pattern II, early and rapid shortening (n = 18); pattern III, late shortening (n = 109); and pattern IV, early shortening with a plateau (n = 118). The rate of PTB at < 34 weeks was lowest in cases of pattern I (11.7%), followed by pattern IV (14.4%) and pattern III (20.2%), and was highest for women with pattern II (44.4%) (P < .001). In cases with pattern III (late shortening), the most important factors affecting the risk of PTB were the shortening rate, the gestational age at the onset of cervical shortening, and the initial plateau of CL. In the case of pattern IV (early shortening with a plateau), it was only the new plateau at which cervical shortening stopped that was associated with the risk of PTB. CONCLUSION: Changes in sonographic CL over time in twin gestations can be classified into 4 patterns, each associated with a different risk of PTB. C1 [Melamed, Nir; Pittini, Alex; Barrett, Jon] Univ Toronto, Sunnybrook Hlth Sci Ctr, Dept Obstet & Gynecol, Div Maternal Fetal Med, Toronto, ON, Canada. [Hiersch, Liran; Yogev, Yariv] Rabin Med Ctr, Dept Obstet & Gynecol, Petah Tiqwa, Israel. [Hiersch, Liran; Yogev, Yariv] Tel Aviv Univ, Sackler Fac Med, Tel Aviv, Israel. [Korzeniewski, Steven S.; Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Dev, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Bethesda, MD USA. [Korzeniewski, Steven S.; Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Dev, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Bethesda, MD USA. [Korzeniewski, Steven S.] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. [Korzeniewski, Steven S.; Romero, Roberto] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Romero, Roberto] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. RP Melamed, N (reprint author), Univ Toronto, Sunnybrook Hlth Sci Ctr, Dept Obstet & Gynecol, Div Maternal Fetal Med, Toronto, ON, Canada. EM nir.melamed@sunnybrook.ca FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Department of Health and Human Services; NICHD, NIH [HSN27520130000, HSN275201300006C] FX This research was supported, in part, by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Department of Health and Human Services, and, in part, with federal funds from NICHD, NIH under contract nos. HSN27520130000 and HSN275201300006C. NR 72 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD OCT PY 2016 VL 215 IS 4 AR 476.e1 DI 10.1016/j.ajog.2016.05.018 PG 11 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EE3RJ UT WOS:000389513600024 PM 27207277 ER PT J AU Silver, RM Saade, GR Thorsten, V Parker, CB Reddy, UM Drews-Botsch, C Conway, D Coustan, D Dudley, DJ Bukowski, R Hogue, CJR Pinar, H Varner, MW Goldenberg, R Willinger, M AF Silver, Robert M. Saade, George R. Thorsten, Vanessa Parker, Corette B. Reddy, Uma M. Drews-Botsch, Carey Conway, Deborah Coustan, Donald Dudley, Donald J. Bukowski, Radek Hogue, Carol J. Rowland Pinar, Halit Varner, Michael W. Goldenberg, Robert Willinger, Marian TI Factor V Leiden, prothrombin G20210A, and methylene tetrahydrofolate reductase mutations and stillbirth: the Stillbirth Collaborative Research Network SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE placenta; stillbirth; thrombophilia ID PREGNANCY OUTCOMES; NULLIPAROUS WOMEN; FETAL LOSS; COMPLICATIONS; THROMBOPHILIA; POLYMORPHISM; RISK; GENE AB BACKGROUND: An evaluation for heritable thrombophilias is recommended in the evaluation of stillbirth. However, the association between thrombophilias and stillbirth remains uncertain. OBJECTIVE: We sought to assess the association between maternal and fetal/placental heritable thrombophilias and stillbirth in a population-based, case-control study in a geographically, racially, and ethnically diverse population. STUDY DESIGN: We conducted secondary analysis of data from the Stillbirth Collaborative Research Network, a population-based case-control study of stillbirth. Testing for factor V Leiden, prothrombin G20210A, methylene tetrahydrofolate reductase C677T and A1298C, and plasminogen activating inhibitor (PAI)-1 4G/5G mutations was done on maternal and fetal (or placental) DNA from singleton pregnancies. Data analyses were weighted for oversampling and other aspects of the design. Odds ratios (OR) were generated from univariate models regressing stillbirth/live birth status on each thrombophilia marker. RESULTS: Results were available for >= 1 marker in 488 stillbirths and 1342 live birth mothers and 405 stillbirths and 990 live birth fetuses. There was an increased odds of stillbirth for maternal homozygous factor V Leiden mutation (2/488; 0.4% vs 1/1380; 0.0046%; OR, 87.44; 95% confidence interval, 7.88-970.92). However, there were no significant differences in the odds of stillbirth for any other maternal thrombophilia, even after stratified analyses. Fetal 4G/4G PAI-1 (OR, 0.63; 95% confidence interval, 0.43-0.91) was associated with decreased odds of stillbirth. Other fetal thrombophilias were similar among groups. CONCLUSION: Most maternal and fetal thrombophilias were not associated with stillbirth. Maternal factor V Leiden was weakly associated with stillbirth, and the fetal PAI-1 4G/4G polymorphism was associated with live birth. Our data do not support routine testing for heritable thrombophilias as part of an evaluation for possible causes of stillbirth. C1 [Silver, Robert M.; Varner, Michael W.] Univ Utah, Sch Med, Salt Lake City, UT USA. [Saade, George R.; Bukowski, Radek] Univ Texas Med Branch, Galveston, TX 77555 USA. [Conway, Deborah; Dudley, Donald J.] Hlth Sci Ctr San Antonio, San Antonio, TX USA. [Thorsten, Vanessa; Parker, Corette B.] RTI Int, Res Triangle Pk, NC USA. [Reddy, Uma M.; Willinger, Marian] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, NIH, Bethesda, MD USA. [Drews-Botsch, Carey] Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Hogue, Carol J. Rowland] Emory Univ, Sch Med, Atlanta, GA 30322 USA. [Coustan, Donald; Pinar, Halit] Brown Univ, Sch Med, Providence, RI 02912 USA. [Goldenberg, Robert] Columbia Univ, New York, NY USA. RP Silver, RM (reprint author), Univ Utah, Sch Med, Salt Lake City, UT USA. EM bsilver@hsc.utah.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [U10-HD045953, U10-HD045925, U10-HD045952, U10-HDO45955, U10-HD045944, U01-HD045954] FX This work, including the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, and approval of the manuscript, was supported by grant funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development: U10-HD045953 Brown University, Rhode Island; U10-HD045925 Emory University, Georgia; U10-HD045952 University of Texas Medical Branch at Galveston, Texas; U10-HDO45955 University of Texas Health Sciences Center at San Antonio, Texas; U10-HD045944 University of Utah Health Sciences Center, Utah; and U01-HD045954 RTI International, North Carolina. NR 30 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD OCT PY 2016 VL 215 IS 4 AR 468.e1 DI 10.1016/j.ajog.2016.04.026 PG 17 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EE3RJ UT WOS:000389513600021 ER PT J AU Tian, YF Tian, XY Gawlak, G Sarich, N Sacks, DB Birukova, AA Birukov, KG AF Tian, Yufeng Tian, Xinyong Gawlak, Grzegorz Sarich, Nicolene Sacks, David B. Birukova, Anna A. Birukov, Konstantin G. TI Role of IQGAP1 in endothelial barrier enhancement caused by OxPAPC SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Article DE phosphatidylcholine; vascular biology; signal transduction; lung; endothelial cells; IQ domain containing guanosine 5 '-triphosphatase-activating protein; guanosine 5 '-triphosphatase; permeability; cytoskeleton; oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphatidylcholine ID INDUCED LUNG INJURY; CELL-CELL ADHESION; RHO FAMILY GTPASES; OXIDIZED PHOSPHOLIPIDS; PROTECTIVE RESPONSE; OXIDATION-PRODUCTS; BETA-CATENIN; IN-VIVO; RAC; DYSFUNCTION AB Oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphatidylcholine (OxPAPC) attenuates agonist-induced endothelial cell (EC) permeability and increases pulmonary endothelial barrier function via enhancement of both the peripheral actin cytoskeleton and cell junctions mediated by Rac1 and Cdc42 GTPases. This study evaluated the role for the multifunctional Rac1/Cdc42 effector and regulator, IQ domain containing GTPase-activating protein (IQGAP1), as a molecular transducer of the OxPAPC-mediated EC barrier-enhancing signal. IQGAP1 knockdown in endothelial cells by gene-specific small-interfering RNA abolished OxPAPC-induced enlargement of VE-cadherin-positive adherens junctions, suppressed peripheral accumulation of actin polymerization regulators, namely cortactin, neural Wiskott-Aldrich syndrome protein (N-WASP), and actin-related protein 3, and attenuated remodeling of the peripheral actin cytoskeleton. Inhibition of OxPAPC-induced barrier enhancement by IQGAP1 knockdown was due to suppressed Rac1 and Cdc42 activation. Expression of an IQGAP1 truncated mutant showed that the GTPase regulatory domain of IQGAP1 was essential for the OxPAPC-induced membrane localization of cortactin, adherens junction proteins VE-cadherin and p120-catenin, as well as for EC permeability response. IQGAP1 knockdown attenuated the protective effect of OxPAPC against thrombin-induced cell contraction, cell junction disruption, and EC permeability. These results demonstrate for the first time the role of IQGAP1 as a critical transducer of OxPAPC-induced Rac1/Cdc42 signaling to the actin cytoskeleton and adherens junctions, which promotes cortical cytoskeletal remodeling and EC barrier-protective effects of oxidized phospholipids. C1 [Tian, Yufeng; Tian, Xinyong; Gawlak, Grzegorz; Sarich, Nicolene; Birukova, Anna A.; Birukov, Konstantin G.] Univ Chicago, Dept Med, Sect Pulm & Crit Care Med, 5841 S Maryland Ave, Chicago, IL 60637 USA. [Sacks, David B.] NIH, Ctr Clin, Dept Lab Med, Bethesda, MD 20892 USA. RP Birukov, KG (reprint author), Univ Chicago, Lung Injury Ctr, Sect Pulm & Crit Med, Dept Med, 5841 S Maryland Ave,MC-6026, Chicago, IL 60637 USA. EM kbirukov@medicine.bsd.uchicago.edu FU National Institutes of Health [HL-076259, HL-087823, HL-107920, HL-130431, GM-114171] FX This work was supported by National Institutes of Health Grants HL-076259, HL-087823, HL-107920, HL-130431, and GM-114171. NR 59 TC 0 Z9 0 U1 2 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1040-0605 EI 1522-1504 J9 AM J PHYSIOL-LUNG C JI Am. J. Physiol.-Lung Cell. Mol. Physiol. PD OCT 1 PY 2016 VL 311 IS 4 BP L800 EP L809 DI 10.1152/ajplung.00095.2016 PG 10 WC Physiology; Respiratory System SC Physiology; Respiratory System GA EE5IP UT WOS:000389640200013 ER PT J AU Zhao, Y Yang, CR Raghuram, V Parulekar, J Knepper, MA AF Zhao, Yue Yang, Chin-Rang Raghuram, Viswanathan Parulekar, Jaya Knepper, Mark A. TI BIG: a large-scale data integration tool for renal physiology SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE data science; kidney physiology; systems biology; BIG data ID COLLECTING DUCT CELLS; GENE-EXPRESSION; KIDNEY; PHOSPHORYLATION AB Due to recent advances in high-throughput techniques, we and others have generated multiple proteomic and transcriptomic databases to describe and quantify gene expression, protein abundance, or cellular signaling on the scale of the whole genome/proteome in kidney cells. The existence of so much data from diverse sources raises the following question: "How can researchers find information efficiently for a given gene product over all of these data sets without searching each data set individually?" This is the type of problem that has motivated the "Big-Data" revolution in Data Science, which has driven progress in fields such as marketing. Here we present an online Big-Data tool called BIG (Biological Information Gatherer) that allows users to submit a single online query to obtain all relevant information from all indexed databases. BIG is accessible at http://big.nhlbi.nih.gov/. C1 [Zhao, Yue; Yang, Chin-Rang; Raghuram, Viswanathan; Parulekar, Jaya; Knepper, Mark A.] NHLBI, Epithelial Syst Biol Lab, Syst Biol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Knepper, MA (reprint author), NIH, Bldg 10,Rm 6N307,10 Ctr Dr,MSC 1603, Bethesda, MD 20892 USA. EM knepperm@nhlbi.nih.gov FU Division of Intramural Research, National Heart, Lung, and Blood Institute [ZIA-HL001285, ZIA-HL006129] FX This work was supported by the Division of Intramural Research, National Heart, Lung, and Blood Institute (project ZIA-HL001285 and ZIA-HL006129, M. A. Knepper). NR 17 TC 2 Z9 2 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X EI 1522-1466 J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD OCT 1 PY 2016 VL 311 IS 4 BP F787 EP F792 DI 10.1152/ajprenal.00249.2016 PG 6 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA EE5KI UT WOS:000389645300015 PM 27279488 ER PT J AU Manolio, TA AF Manolio, Teri A. TI Implementing genomics and pharmacogenomics in the clinic: The National Human Genome Research Institute's genomic medicine portfolio SO ATHEROSCLEROSIS LA English DT Review DE Genomics; Pharmacogenomics; Clinical care ID CORONARY-HEART-DISEASE; GENETIC RISK SCORE; UNDIAGNOSED DISEASES; ARTERY-DISEASE; CARDIOVASCULAR-DISEASE; MYOCARDIAL-INFARCTION; FAMILY-HISTORY; OF-HEALTH; MI-GENES; VARIANTS AB Increasing knowledge about the influence of genetic variation on human health and growing availability of reliable, cost-effective genetic testing have spurred the implementation of genomic medicine in the clinic. As defined by the National Human Genome Research Institute (NHGRI), genomic medicine uses an individual's genetic information in his or her clinical care, and has begun to be applied effectively in areas such as cancer genomics, pharmacogenomics, and rare and undiagnosed diseases. In 2011 NHGRI published its strategic vision for the future of genomic research, including an ambitious research agenda to facilitate and promote the implementation of genomic medicine. To realize this agenda, NHGRI is consulting and facilitating collaborations with the external research community through a series of "Genomic Medicine Meetings," under the guidance and leadership of the National Advisory Council on Human Genome Research. These meetings have identified and begun to address significant obstacles to implementation, such as lack of evidence of efficacy, limited availability of genomics expertise and testing, lack of standards, and difficulties in integrating genomic results into electronic medical records. The six research and dissemination initiatives comprising NHGRI's genomic research portfolio are designed to speed the evaluation and incorporation, where appropriate, of genomic technologies and findings into routine clinical care. Actual adoption of successful approaches in clinical care will depend upon the willingness, interest, and energy of professional societies, practitioners, patients, and payers to promote their responsible use and share their experiences in doing so. Published by Elsevier Ireland Ltd. C1 [Manolio, Teri A.] NHGRI, Div Genom Med, 5635 Fishers Lane,Room 4113,MSC 9305, Bethesda, MD 20892 USA. RP Manolio, TA (reprint author), NHGRI, Div Genom Med, 5635 Fishers Lane,Room 4113,MSC 9305, Bethesda, MD 20892 USA. EM manolio@nih.gov FU Intramural NIH HHS [Z99 HG999999] NR 81 TC 0 Z9 0 U1 6 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 EI 1879-1484 J9 ATHEROSCLEROSIS JI Atherosclerosis PD OCT PY 2016 VL 253 BP 225 EP 236 DI 10.1016/j.atherosclerosis.2016.08.034 PG 12 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EE2GG UT WOS:000389401200032 PM 27612677 ER PT J AU Yang, B Thrift, AP Figueiredo, JC Jenkins, MA Schumacher, FR Conti, DV Lin, Y Win, AK Limburg, PJ Berndt, SI Brenner, H Chan, AT Chang-Claude, J Hoffmeister, M Hudson, TJ Le Marchand, L Newcomb, PA Slattery, ML White, E Peters, U Casey, G Campbell, PT AF Yang, Baiyu Thrift, Aaron P. Figueiredo, Jane C. Jenkins, Mark A. Schumacher, Fredrick R. Conti, David V. Lin, Yi Win, Aung Ko Limburg, Paul J. Berndt, Sonja I. Brenner, Hermann Chan, Andrew T. Chang-Claude, Jenny Hoffmeister, Michael Hudson, Thomas J. Le Marchand, Loic Newcomb, Polly A. Slattery, Martha L. White, Emily Peters, Ulrike Casey, Graham Campbell, Peter T. TI Common variants in the obesity-associated genes FTO and MC4R are not associated with risk of colorectal cancer SO CANCER EPIDEMIOLOGY LA English DT Article DE Obesity; Genetic variants; Colorectal cancer; Case-control study ID METAANALYSIS; LOCI AB Background: Obesity is a convincing risk factor for colorectal cancer. Genetic variants in or near FTO and MC4R are consistently associated with body mass index and other body size measures, but whether they are also associated with colorectal cancer risk is unclear. Methods: In the discovery stage, we tested associations of 677 FTO and 323 MC4R single nucleotide polymorphisms (SNPs) 100 kb upstream and 300 kb downstream from each respective locus with risk of colorectal cancer in data from the Colon Cancer Family Registry (CCFR: 1960 cases; 1777 controls). Next, all SNPs that were nominally statistically significant (p < 0.05) in the discovery stage were included in replication analyses in data from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO: 9716 cases; 9844 controls). Results: In the discovery stage, 43 FTO variants and 18 MC4R variants were associated with colorectal cancer risk (p < 0.05). No SNPs remained statistically significant in the replication analysis after accounting for multiple comparisons. Conclusion: We found no evidence that individual variants in or near the obesity-related genes FTO and MC4R are associated with risk of colorectal cancer. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Yang, Baiyu; Campbell, Peter T.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Yang, Baiyu] Emory Univ, Dept Epidemiol, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Thrift, Aaron P.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Thrift, Aaron P.] Baylor Coll Med, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. [Figueiredo, Jane C.; Schumacher, Fredrick R.; Conti, David V.; Casey, Graham] Univ Southern Calif, Dept Prevent Med, Keck Sch Med, Los Angeles, CA USA. [Jenkins, Mark A.; Win, Aung Ko] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Melbourne, Vic, Australia. [Lin, Yi; Newcomb, Polly A.; White, Emily] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Limburg, Paul J.] Mayo Clin, Div Gastroenterol & Hepatol, Rochester, MN USA. [Berndt, Sonja I.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Brenner, Hermann; Hoffmeister, Michael] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Brenner, Hermann] German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany. [Brenner, Hermann] German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany. [Brenner, Hermann] German Canc Res Ctr, Natl Ctr Tumor Dis NCT, Heidelberg, Germany. [Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Chan, Andrew T.] Harvard Med Sch, Boston, MA USA. [Chan, Andrew T.] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Chang-Claude, Jenny] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Hudson, Thomas J.] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada. [Hudson, Thomas J.] Ontario Inst Canc Res, Toronto, ON, Canada. [Hudson, Thomas J.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Le Marchand, Loic] Univ Hawaii, Program Epidemiol, Ctr Canc, Honolulu, HI 96822 USA. [Newcomb, Polly A.; White, Emily; Peters, Ulrike] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Slattery, Martha L.] Univ Utah, Dept Internal Med, Hlth Sci Ctr, Salt Lake City, UT 84112 USA. RP Campbell, PT (reprint author), Amer Canc Soc, Natl Home Off, Epidemiol Res Program, 250 Williams St NW, Atlanta, GA 30303 USA. EM Peter.Campbell@cancer.org RI Brenner, Hermann/B-4627-2017; OI Brenner, Hermann/0000-0002-6129-1572; Win, Aung Ko/0000-0002-2794-5261; Hoffmeister, Michael/0000-0002-8307-3197 FU NCI NIH HHS [U24 CA074783, U24 CA074794, U24 CA074799, U01 CA074800, U24 CA074800, U24 CA074806, U24 CA097735, UM1 CA167551] NR 11 TC 1 Z9 1 U1 3 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1877-7821 EI 1877-783X J9 CANCER EPIDEMIOL JI Cancer Epidemiol. PD OCT PY 2016 VL 44 BP 1 EP 4 DI 10.1016/j.canep.2016.07.003 PG 4 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA EE3RU UT WOS:000389515700001 PM 27449576 ER PT J AU Kim, C Zhang, X Chan, AT Sesso, HD Rifai, N Stampfer, MJ Ma, J AF Kim, Chul Zhang, Xuehong Chan, Andrew T. Sesso, Howard D. Rifai, Nader Stampfer, Meir J. Ma, Jing TI Inflammatory biomarkers, aspirin, and risk of colorectal cancer: Findings from the physicians' health study SO CANCER EPIDEMIOLOGY LA English DT Article DE CRP; IL-6; TNFR-2; Colorectal cancer; Aspirin ID C-REACTIVE PROTEIN; INTERLEUKIN-6; METAANALYSIS; MARKERS; DISEASE; COHORT; WOMEN AB Background: Chronic inflammation has been implicated in colorectal carcinogenesis. However, the associations between plasma inflammatory markers and risk of colorectal cancer have been inconsistent. Methods: In a nested case-control study in the Physicians' Health Study, we prospectively investigated the associations of plasma C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor receptor 2 (TNFR-2) with risk of colorectal cancer, and whether aspirin modified these associations among 268 colorectal cancer patients and 446 age-and smoking-matched controls. Results: In multivariate-adjusted models, plasma levels of CRP, IL-6 and TNFR-2 were not significantly associated with risk of colorectal cancer, although a positive trend was observed for TNFR-2 (RRhighestvs. (lowestquartile) = 1.55; 95% CI = 0.95-2.54; P-trend = 0.05). We observed a statistically significant association between elevated TNFR-2 levels and colorectal cancer risk in the placebo arm (RRhighestvs.lowesttertile = 1.77; 95% CI = 1.02-3.06; P-trend = 0.02), but not in the aspirin arm (P-trend = 0.72). However, the interaction between TNFR-2 and aspirin was not statistically significant (P-interaction = 0.34). Conclusion: Plasma inflammatory markers were not significantly associated with colorectal cancer risk among men, though there was a statistically non-significant positive trend between TNFR-2 and colorectal cancer risk. More studies are required to understand the relationship between the role of TNF alpha pathway, aspirin, and colorectal cancer risk. Published by Elsevier Ltd. C1 [Kim, Chul] Univ Minnesota, Sch Med, Dept Med, Minneapolis, MN 55455 USA. [Kim, Chul] NCI, Med Oncol Serv, NIH, Bethesda, MD 20892 USA. [Zhang, Xuehong; Chan, Andrew T.; Stampfer, Meir J.; Ma, Jing] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Zhang, Xuehong; Chan, Andrew T.; Sesso, Howard D.; Stampfer, Meir J.; Ma, Jing] Harvard Med Sch, Boston, MA USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Sesso, Howard D.; Stampfer, Meir J.] Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Sesso, Howard D.] Brigham & Womens Hosp, Dept Med, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA. [Rifai, Nader] Childrens Hosp Med Ctr, Dept Pathol, Boston, MA USA. [Stampfer, Meir J.] Harvard Sch Publ Hlth, Dept Nutr, Boston, MA USA. RP Kim, C (reprint author), Bldg 10,Room B2L312,10 Ctr Dr, Bethesda, MD 20814 USA.; Ma, J (reprint author), Brigham & Womens Hosp, Channing Div Network Med, 181 Longwood Ave, Boston, MA 02115 USA. EM kimc5@mail.nih.gov; jing.ma@channing.harvard.edu FU National Cancer Institute [CA42182, CA097193, CA019894, U54CA155626]; National Heart, Lung, and Blood Institute [HL26490, HL34595]; National Cancer Institute of Canada [019894]; National Institute of Health [R01 CA137178] FX This study was supported by Grant Numbers CA42182, CA097193, CA019894, U54CA155626 from the National Cancer Institute, by Grant Numbers HL26490 and HL34595 from the National Heart, Lung, and Blood Institute, and a grant (019894) from the National Cancer Institute of Canada. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Heart, Lung, and Blood Institute. This work was also supported by National Institute of Health grants R01 CA137178 (to A.T.C.). A.T.C. is a Damon Runyon Cancer Foundation Clinical Investigator. NR 26 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1877-7821 EI 1877-783X J9 CANCER EPIDEMIOL JI Cancer Epidemiol. PD OCT PY 2016 VL 44 BP 65 EP 70 DI 10.1016/j.canep.2016.07.012 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA EE3RU UT WOS:000389515700009 PM 27504605 ER PT J AU Anton-Culver, H Chang, J Bray, F Znaor, A Stevens, L Eser, S Silverman, B Nimri, O Pavlou, P Charalambous, H Demetriou, A Ward, K Ziogas, A AF Anton-Culver, Hoda Chang, Jenny Bray, Freddie Znaor, Ariana Stevens, Lisa Eser, Sultan Silverman, Barbara Nimri, Omar Pavlou, Pavlos Charalambous, Haris Demetriou, Anna Ward, Kevin Ziogas, Argyrios TI Cancer burden in four countries of the Middle East Cancer Consortium (Cyprus; Jordan; Israel; Izmir (Turkey)) with comparison to the United States surveillance; epidemiology and end results program SO CANCER EPIDEMIOLOGY LA English DT Article DE Population-based cancer registries; Middle East; SEER; Cancer burden; Cancer risk ID TOBACCO SMOKING AB It is important that population-based cancer registries provide accurate and reliable data for public health purposes. These data are essential data for planning of cancer control and prevention. In this study, we examined cancer incidence rates (year 2005-2010) in four MECC registries (Cyprus, Jordan, Israel, Izmir (Turkey)) and compared with the rates in the US. The overall age-standardized incidence rates for males were highest in the US followed by Israeli Jews, Izmir (Turkey), Cyprus, Israeli Arabs, and lowest in Jordan. In women the rates of cancer of all sites were also highest in US women followed by Israeli Jews, Cyprus, Israeli Arabs, Izmir (Turkey), and lowest in Jordan. It is of interest that although site-specific cancer rates differ between the countries studied, prostate, lung and colorectal cancers are within the five most common cancers males in all countries studied. In females, breast colorectal and endometrium cancers are three of the five most common cancers in females in all countries studied. The results presented in this paper can have implications for opportunities in cancer control and prevention in these countries. Future studies on individual cancer sites with highest rates in these Countries are currently underway. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Anton-Culver, Hoda; Chang, Jenny; Ziogas, Argyrios] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA. [Bray, Freddie; Znaor, Ariana] Int Agcy Res Canc, Lyon, France. [Stevens, Lisa] NCI, Ctr Global Hlth, Bethesda, MD 20892 USA. [Eser, Sultan] Izmir & Hacettepe Univ, Izmir Canc Registry, Ankara, Turkey. [Silverman, Barbara] Israel Natl Canc Registry, Haifa, Israel. [Pavlou, Pavlos; Charalambous, Haris; Demetriou, Anna] Cyprus Canc Registry, Nicosia, Cyprus. [Ward, Kevin] Emory Univ, Georgia Canc Registry, Atlanta, GA 30322 USA. RP Anton-Culver, H (reprint author), Univ Calif Irvine, Dept Epidemiol, Sch Med, 224 Irvine Hall, Irvine, CA 92697 USA. EM hantoncu@uci.edu NR 14 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1877-7821 EI 1877-783X J9 CANCER EPIDEMIOL JI Cancer Epidemiol. PD OCT PY 2016 VL 44 BP 195 EP 202 DI 10.1016/j.canep.2016.06.004 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA EE3RU UT WOS:000389515700033 PM 27502627 ER PT J AU Newton, R Whitby, D AF Newton, Robert Whitby, Denise TI Beral et al's 1990 paper on Kaposi's sarcoma among persons with AIDS: demonstrating the power of descriptive epidemiology SO CANCER EPIDEMIOLOGY LA English DT Article DE Beral; Kaposi's; Sarcoma ID SEXUALLY-TRANSMITTED INFECTION; RISK-FACTORS; HUMAN-HERPESVIRUS-8 INFECTION; ANTIRETROVIRAL THERAPY; DNA-SEQUENCES; HERPESVIRUS; TRANSMISSION; AFRICA; UGANDA; CANCER AB Here we discuss the impact of Beral et al's 1990 paper "Kaposi's sarcoma among persons with AIDS: a sexually transmitted infection?" Not only did this paper galvanise research into the underlying infectious cause of Kaposi's sarcoma, it also demonstrated the power of observational epidemiology in pointing the way towards major discoveries. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Newton, Robert] MRC UVRI Uganda Res Unit AIDS, POB 49, Entebbe, Uganda. [Newton, Robert] Univ York, Dept Hlth Sci, York, N Yorkshire, England. [Whitby, Denise] Frederick Natl Lab Canc Res, Viral Oncol Sect, AIDS & Canc Virus Program, Frederick, MD USA. RP Newton, R (reprint author), MRC UVRI Res Unit AIDS, POB 49, Entebbe, Uganda. EM Rob.Newton@mrcuganda.org NR 32 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1877-7821 EI 1877-783X J9 CANCER EPIDEMIOL JI Cancer Epidemiol. PD OCT PY 2016 VL 44 BP 222 EP 225 DI 10.1016/j.canep.2016.07.014 PG 4 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA EE3RU UT WOS:000389515700035 PM 27554680 ER PT J AU Aviles-Santa, ML Schneiderman, N Savage, PJ Kaplan, RC Teng, YP Perez, CM Suarez, EL Cai, JW Giachello, AL Talavera, GA Cowie, CC AF Aviles-Santa, M. Larissa Schneiderman, Neil Savage, Peter J. Kaplan, Robert C. Teng, Yanping Perez, Cynthia M. Suarez, Erick L. Cai, Jianwen Giachello, Aida L. Talavera, Gregory A. Cowie, Catherine C. TI IDENTIFYING PROBABLE DIABETES MELLITUS AMONG HISPANICS/LATINOS FROM FOUR US CITIES: FINDINGS FROM THE HISPANIC COMMUNITY HEALTH STUDY/STUDY OF LATINOS SO ENDOCRINE PRACTICE LA English DT Article ID IMPAIRED GLUCOSE-TOLERANCE; FASTING PLASMA-GLUCOSE; UNITED-STATES; DIVERSE BACKGROUNDS; HEMOGLOBIN A(1C); RISK-FACTORS; PREVALENCE; A1C; POPULATION; DIAGNOSIS AB OBJECTIVE: The aim of this study was to compare the ability of American Diabetes Association (ADA) diagnostic criteria to identify U.S. Hispanics/Latinos from diverse heritage groups with probable diabetes mellitus and assess cardiovascular risk factor correlates of those criteria. METHODS: Cross-sectional analysis of data from 15,507 adults from 6 Hispanic/Latino heritage groups, enrolled in the Hispanic Community Health Study/Study of Latinos. The prevalence of probable diabetes mellitus was estimated using individual or combinations of ADA-defined cut points. The sensitivity and specificity of these criteria at identifying diabetes mellitus from ADA-defined prediabetes and normoglycemia were evaluated. Prevalence ratios of hypertension, abnormal lipids, and elevated urinary albumin-creatinine ratio for unrecognized diabetes mellitus-versus prediabetes and normoglycemia-were calculated. RESULTS: Among Hispanics/Latinos (mean age, 43 years) with diabetes mellitus, 39.4% met laboratory test criteria for probable diabetes, and the prevalence varied by heritage group. Using the oral glucose tolerance test as the gold standard, the sensitivity of fasting plasma glucose (FPG) and hemoglobin A1c-alone or in combination-was low (18, 23, and 33%, respectively) at identifying probable diabetes mellitus. Individuals who met any criterion for probable diabetes mellitus had significantly higher (P<.05) prevalence of most cardiovascular risk factors than those with normoglycemia or prediabetes, and this association was not modified by Hispanic/Latino heritage group. CONCLUSION: FPG and hemoglobin A1c are not sensitive (but are highly specific) at detecting probable diabetes mellitus among Hispanics/Latinos, independent of heritage group. Assessing cardiovascular risk factors at diagnosis might prompt multitarget interventions and reduce health complications in this young population. C1 [Aviles-Santa, M. Larissa] NHLBI, 6701 Rockledge Dr,Room 10188, Bethesda, MD 20892 USA. [Schneiderman, Neil] Univ Miami, Coral Gables, FL 33124 USA. [Savage, Peter J.; Cowie, Catherine C.] NIDDKD, Bethesda, MD USA. [Kaplan, Robert C.] Yeshiva Univ, Albert Einstein Coll Med, Bronx, NY USA. [Teng, Yanping; Cai, Jianwen] Univ North Carolina Chapel Hill, Chapel Hill, NC USA. [Perez, Cynthia M.; Suarez, Erick L.] Univ Puerto Rico, Sch Publ Hlth, Dept Biostat & Epidemiol, San Juan, PR 00936 USA. [Giachello, Aida L.] Northwestern Univ, Fienberg Sch Med, Chicago, IL 60611 USA. [Talavera, Gregory A.] San Diego State Univ, Grad Sch Publ Hlth, Inst Behav & Community Hlth, Chula Vista, CA USA. RP Aviles-Santa, ML (reprint author), NHLBI, 6701 Rockledge Dr,Room 10188, Bethesda, MD 20892 USA. EM avilessantal@nhlbi.nih.gov FU National Heart, Lung, and Blood Institute (NIMBI) [N01-HC65233, N01-HC65234, N01-HC65235, N01-HC65236, N01-HC65237] FX The baseline examination of the Hispanic Community Health Study/Study of Latinos was carried out as a collaborative study supported by contracts from the National Heart, Lung, and Blood Institute (NIMBI) to the University of North Carolina (N01-HC65233), University of Miami (N01-HC65234), Albert Einstein College of Medicine (N01-HC65235), Northwestern University (N01-HC65236), and San Diego State University (N01-HC65237). The following MEI Institutes/Offices collaborated and cofunded the first phase of the study: the National Institute on Minority-Health and Health Disparities, the National Institute on Deafness and Other Communication Disorders, the National Institute of Dental and Craniofacial Research, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Neurological Disorders and Stroke, and the NIH Office of Dietary Supplements. NR 40 TC 1 Z9 1 U1 2 U2 2 PU AMER ASSOC CLINICAL ENDOCRINOLOGISTS PI JACKSONVILLE PA 245 RIVERSIDE AVENUE, STE 200, JACKSONVILLE, FL 32202 USA SN 1530-891X EI 1934-2403 J9 ENDOCR PRACT JI Endocr. Pract. PD OCT PY 2016 VL 22 IS 10 BP 1151 EP 1160 DI 10.4158/EP151111.OR PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EE7YZ UT WOS:000389842700002 PM 27295013 ER PT J AU Grosicki, GJ Standley, RA Murach, KA Raue, U Minchev, K Coen, PM Newman, AB Cummings, S Harris, T Kritchevsky, S Goodpaster, BH Trappe, S AF Grosicki, Greg J. Standley, Robert A. Murach, Kevin A. Raue, Ulrika Minchev, Kiril Coen, Paul M. Newman, Anne B. Cummings, Steven Harris, Tamara Kritchevsky, Stephen Goodpaster, Bret H. Trappe, Scott CA Hlth ABC Study TI Improved single muscle fiber quality in the oldest-old SO JOURNAL OF APPLIED PHYSIOLOGY LA English DT Article DE single fiber; oldest-old; muscle quality; aging; contractile function ID HUMAN SKELETAL-MUSCLE; AGE-RELATED-CHANGES; M-VASTUS-LATERALIS; CONTRACTILE PROPERTIES; SHORTENING VELOCITY; AGING MUSCLE; PHYSICAL-ACTIVITY; SARCOMERE LENGTH; BODY-COMPOSITION; ISOMETRIC FORCE AB We examined single muscle fiber contractile function of the oldest-old (3F/2M, 89 +/- 1 yr old) enrolled in The Health, Aging, and Body Composition Study (The Health ABC Study). Vastus lateralis muscle biopsies were obtained and single muscle fiber function was determined (n = 105) prior to myosin heavy chain (MHC) isoform identification with sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Cross-sectional area of MHC I muscle fibers (5,576 +/- 333 mu m(2); n = 58) was 21% larger (P < 0.05) than MHC IIa fibers (4,518 +/- 386 mu m(2); n = 47). Normalized power (an indicator of muscle fiber quality incorporating size, strength, and speed) of MHC I and IIa muscle fibers was 2.3 +/- 0.1 and 17.4 +/- 0.8 W/l, respectively. Compared with previous research from our lab using identical procedures, MHC I normalized power was 28% higher than healthy 20 yr olds and similar to younger octogenarians (similar to 80 yr old). Normalized power of MHC IIa fibers was 63% greater than 20 yr olds and 39% greater than younger octogenarians. These comparative data suggest that power output per unit size (i. e., muscle quality) of remaining muscle fibers improves with age, a phenomenon more pronounced in MHC IIa fibers. Age-related single muscle fiber quality improvements may be a compensatory mechanism to help offset decrements in whole muscle function. C1 [Grosicki, Greg J.; Murach, Kevin A.; Raue, Ulrika; Minchev, Kiril; Trappe, Scott] Ball State Univ, Human Performance Lab, Muncie, IN 47306 USA. [Standley, Robert A.; Coen, Paul M.; Goodpaster, Bret H.] Translat Res Inst Metab & Diabet, Orlando, FL USA. [Newman, Anne B.] Univ Pittsburgh, Ctr Aging & Populat Hlth, Pittsburgh, PA USA. [Cummings, Steven] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. [Harris, Tamara] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. [Kritchevsky, Stephen] Wake Forest Sch Med, Sticht Ctr Aging, Winston Salem, NC USA. RP Trappe, S (reprint author), Ball State Univ, Human Performance Lab, Muncie, IN 47306 USA. EM strappe@bsu.edu OI Coen, Paul/0000-0002-2805-2115 FU National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; NIA [R01-AG-028050, R01-AG038576]; NINR [R01-NR012459] FX This research was supported by National Institute on Aging (NIA) contracts N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106; NIA Grants R01-AG-028050 and R01-AG038576; and NINR Grant R01-NR012459. This study was supported in part by the Intramural Research Program of the NIA. NR 74 TC 0 Z9 0 U1 3 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 8750-7587 EI 1522-1601 J9 J APPL PHYSIOL JI J. Appl. Physiol. PD OCT 1 PY 2016 VL 121 IS 4 BP 878 EP 884 DI 10.1152/japplphysiol.00479.2016 PG 7 WC Physiology; Sport Sciences SC Physiology; Sport Sciences GA EE5LZ UT WOS:000389650600007 PM 27516537 ER PT J AU Dubnikov, T Ben-Gedalya, T Reiner, R Hoepfner, D Cabral, WA Marini, JC Cohen, E AF Dubnikov, Tatyana Ben-Gedalya, Tziona Reiner, Robert Hoepfner, Dominic Cabral, Wayne A. Marini, Joan C. Cohen, Ehud TI PrP-containing aggresomes are cytosolic components of an ER quality control mechanism SO JOURNAL OF CELL SCIENCE LA English DT Article DE Protein aggregation; Aggresome; Prion protein; Endoplasmic reticulum; Neurodegeneration ID PRION PROTEIN; ENDOPLASMIC-RETICULUM; STRAUSSLER-SYNDROME; SCRAPIE ISOFORM; CULTURED-CELLS; DEGRADATION; GLYCOSYLATION; TRANSLOCATION; PROTEOSTASIS; COMPARTMENTS AB Limited detoxification capacity often directs aggregation-prone, potentially hazardous, misfolded proteins to be deposited in designated cytosolic compartments known as 'aggresomes'. The roles of aggresomes as cellular quality control centers, and the cellular origin of the deposits contained within these structures, remain to be characterized. Here, we utilized the observation that the prion protein (PrP, also known as PRNP) accumulates in aggresomes following the inhibition of folding chaperones, members of the cyclophilin family, to address these questions. We found that misfolded PrP molecules must pass through the endoplasmic reticulum (ER) in order to be deposited in aggresomes, that the Golgi plays no role in this process and that cytosolic PrP species are not deposited in pre-existing aggresomes. Prior to their deposition in the aggresome, PrP molecules lose the ER localization signal and have to acquire a GPI anchor. Our discoveries indicate that PrP aggresomes are cytosolic overflow deposition centers for the ER quality control mechanisms and highlight the importance of these structures for the maintenance of protein homeostasis within the ER. C1 [Dubnikov, Tatyana; Ben-Gedalya, Tziona; Reiner, Robert; Cohen, Ehud] Hebrew Univ Jerusalem, Sch Med, IMRIC, Biochem & Mol Biol, IL-91120 Jerusalem, Israel. [Ben-Gedalya, Tziona] Hadassah Univ Hosp, Dept Obstet & Gynecol, IL-91120 Jerusalem, Israel. [Hoepfner, Dominic] Novartis Inst BioMed Res, Novartis Campus, CH-4056 Basel, Switzerland. [Cabral, Wayne A.; Marini, Joan C.] NICHD, Bone & Extracellular Matrix Branch, NIH, Bethesda, MD 20892 USA. RP Cohen, E (reprint author), Hebrew Univ Jerusalem, Sch Med, IMRIC, Biochem & Mol Biol, IL-91120 Jerusalem, Israel. EM ehudc@ekmd.huji.ac.il OI Cohen, Ehud/0000-0001-5552-7086 FU European Research Council (ERC) [E.C. 281010] FX This study was generously supported by the European Research Council (ERC) [grant number E.C. 281010]. NR 51 TC 1 Z9 1 U1 1 U2 1 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 EI 1477-9137 J9 J CELL SCI JI J. Cell Sci. PD OCT 1 PY 2016 VL 129 IS 19 BP 3635 EP 3647 DI 10.1242/jcs.186981 PG 13 WC Cell Biology SC Cell Biology GA EE4SE UT WOS:000389594700012 PM 27550517 ER PT J AU Contopoulos-Ioannidis, D Tseretopoulou, X Ancker, M Walterspiel, JN Panagiotou, OA Maldonado, Y Ioannidis, JPA AF Contopoulos-Ioannidis, Despina Tseretopoulou, Xanthippi Ancker, Megan Walterspiel, Juan N. Panagiotou, Orestis A. Maldonado, Yvonne Ioannidis, John P. A. TI Comparative rates of harms in randomized trials from more developed versus less developed countries may be different SO JOURNAL OF CLINICAL EPIDEMIOLOGY LA English DT Review DE Comparative safety; Comparative harms; More developed countries; Less developed countries; Randomized trials; Meta-analyses ID CLINICAL-TRIALS; SYSTEMATIC REVIEWS; MEDICAL INTERVENTIONS; ADVERSE EVENTS; METAANALYSES; QUALITY; SAFETY; HEALTH; HETEROGENEITY; STATEMENT AB Objectives: We set up to evaluate the relative risk of harms in trials performed in less developed vs. more developed countries. Study Design and Setting: Meta-epidemiologic evaluation using the Cochrane Database of Systematic Reviews. We considered meta analyses with at least one randomized clinical trial (RCT) in a less developed country and one RCT in a more developed country. We targeted severe adverse events (AEs), discontinuations due to AEs, any AE, organ system-specific AEs, individual AEs, and all discontinuations due to any reason. We estimated the relative odds ratio (ROR) of harms between more and less developed countries for each topic and the summary ROR (sROR) across topics under each category of harms. Results: We identified 42 systematic reviews (128 meta-analyses, 521 independent RCTs). Summary sRORs did not differ significantly from 1.00 for any harm category. Nominally significant RORs were found in only 6/128 meta-analyses. However, in 27% (35/128) of meta analyses the ROR point estimates indicated relative differences between country settings > 2-fold. Considering also ROR 95% confidence intervals, in 92% (118/128) of meta-analyses one could not exclude a 2-fold difference in both directions. Conclusions: We identified limited comparative evidence on harms in trials from these two country settings. Substantial differences in the risk point estimates were common; the potential for modest differences could rarely be excluded with confidence. (C) 2016 Elsevier Inc. All rights reserved. C1 [Contopoulos-Ioannidis, Despina; Maldonado, Yvonne] Stanford Univ, Sch Med, Div Infect Dis, Dept Pediat, 300 Pasteur Dr,Room G312, Stanford, CA 94305 USA. [Contopoulos-Ioannidis, Despina] Palo Alto Med Fdn, Res Inst, 795 El Camino Real,Ames Bldg,Room 2A027B, Palo Alto, CA 94301 USA. [Contopoulos-Ioannidis, Despina; Ioannidis, John P. A.] Meta Res Innovat Ctr Stanford METRICS, 1070 Arastradero Rd, Palo Alto, CA 94304 USA. [Tseretopoulou, Xanthippi] NHS Trust, Leeds Teaching Hosp, Great George St, Leeds LS1 3EX, W Yorkshire, England. [Ancker, Megan] Med San Frontieres, 8 Rue St Sabin, F-75011 Paris, France. [Walterspiel, Juan N.] Mendocino Coast Dist Hosp, 700 River Dr, Ft Bragg, CA 95437 USA. [Panagiotou, Orestis A.] NCI, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr,Room 7E136, Bethesda, MD 20892 USA. [Maldonado, Yvonne; Ioannidis, John P. A.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Redwood Bldg TI52,150 Governors Lane, Stanford, CA 94305 USA. [Maldonado, Yvonne] Stanford Univ, Sch Med, Fac Dev & Divers, 291 Campus Dr, Stanford, CA 94305 USA. [Ioannidis, John P. A.] Stanford Univ, Sch Med, Dept Med, Stanford Prevent Res Ctr, Med Sch Off Bldg,1265 Welch Rd, Stanford, CA 94305 USA. [Ioannidis, John P. A.] Stanford Univ, Dept Stat, Sch Humanities & Sci, Sequoia Hall,390 Serra Mall, Stanford, CA 94305 USA. RP Contopoulos-Ioannidis, D (reprint author), Stanford Univ, Sch Med, Div Infect Dis, Dept Pediat, 300 Pasteur Dr,Room G312, Stanford, CA 94305 USA. EM dcontop@stanford.edu NR 36 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0895-4356 EI 1878-5921 J9 J CLIN EPIDEMIOL JI J. Clin. Epidemiol. PD OCT PY 2016 VL 78 BP 10 EP 21 DI 10.1016/j.jclinepi.2016.02.032 PG 12 WC Health Care Sciences & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA EE4ZV UT WOS:000389615400004 PM 27063207 ER PT J AU Miao, HX Chen, L Mirzaeimoghri, M Kasica, R Wen, H AF Miao, Houxun Chen, Lei Mirzaeimoghri, Mona Kasica, Richard Wen, Han TI Cryogenic Etching of High Aspect Ratio 400-nm Pitch Silicon Gratings SO JOURNAL OF MICROELECTROMECHANICAL SYSTEMS LA English DT Article DE Cryogenic silicon etching; deep reactive ion etching; high aspect ratio silicon grating ID X-RAY; TRANSMISSION GRATINGS; DIFFRACTION GRATINGS; THROUGH-SILICON; FABRICATION; TEMPERATURES; MEMS AB The cryogenic process and the Bosch process are two widely used processes for reactive ion etching of high aspect ratio silicon structures. This paper focuses on the cryogenic deep etching of 400-nm pitch silicon gratings with various etching mask materials, including polymer, Cr, SiO2, and Cr-on-polymer. The undercut is found to be the key factor limiting the achievable aspect ratio for the direct hard masks of Cr and SiO2, while the etch selectivity responds to the limitation of the polymer mask. The Cr-on-polymer mask provides the same high selectivity as Cr and reduces the excessive undercut introduced by direct hard masks. By optimizing the etching parameters, we etched a 400-nm pitch grating to approximate to 10.6 mu m depth, corresponding to an aspect ratio of approximate to 53. [2016-0106] C1 [Miao, Houxun; Mirzaeimoghri, Mona; Wen, Han] NIH, Bldg 10, Bethesda, MD 20892 USA. [Chen, Lei; Kasica, Richard] NIST, Gaithersburg, MD 20899 USA. [Mirzaeimoghri, Mona] Univ Maryland, College Pk, MD 20742 USA. RP Miao, HX (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM houxun.miao@nih.gov; lei.chen@nist.gov; mona.mirzaeimoghri@nih.gov; richard.kasica@nist.gov; han.wen@nih.gov OI Liddle, James/0000-0002-2508-7910 FU National Heart, Lung, and Blood Institute; National Institutes of Health FX This work was supported in part by the National Heart, Lung, and Blood Institute through the Intramural Research Program, and in part by the National Institutes of Health. Subject Editor M. Wong. NR 32 TC 0 Z9 0 U1 4 U2 4 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 1057-7157 EI 1941-0158 J9 J MICROELECTROMECH S JI J. Microelectromech. Syst. PD OCT PY 2016 VL 25 IS 5 BP 963 EP 967 DI 10.1109/JMEMS.2016.2593339 PG 5 WC Engineering, Electrical & Electronic; Nanoscience & Nanotechnology; Instruments & Instrumentation; Physics, Applied SC Engineering; Science & Technology - Other Topics; Instruments & Instrumentation; Physics GA EE8TC UT WOS:000389897800019 PM 27799726 ER PT J AU Metwally, T Burke, A Tsai, JY Collins, MT Boyce, AM AF Metwally, Tarek Burke, Andrea Tsai, Jeffrey Y. Collins, Michael T. Boyce, Alison M. TI Fibrous Dysplasia and Medication-Related Osteonecrosis of the Jaw SO JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Article ID BISPHOSPHONATE-RELATED OSTEONECROSIS; MCCUNE-ALBRIGHT SYNDROME; CANCER-PATIENTS; INTRAVENOUS PAMIDRONATE; RISK-FACTORS; ACTIVATING MUTATIONS; BONE; THERAPY; PATHOGENESIS; ASSOCIATION AB Purpose: Osteonecrosis of the jaw (ONJ) is an established side effect of intravenous bisphosphonates and other antiresorptive medications. Although bisphosphonates are frequently prescribed for patients with the skeletal disorder fibrous dysplasia (FD), there are no reports of ONJ in this population. This has led some to conclude that patients with FD are at low risk for the development of bisphosphonate-related ONJ. Patients and Methods: Patients were evaluated as part of a longstanding FD natural history study at the National Institutes of Health. Results: Of 76 patients with FD who were treated with bisphosphonates, 4 developed ONJ (5.4%). Three patients developed ONJ in areas of FD-affected bone and 1 in an area of normal bone. All 4 patients had features known to be associated with ONJ in the general population, including long-term high-dose intravenous bisphosphonate treatment, periodontal and endodontic infections, and dentoalveolar surgical procedures. Conclusions: These cases establish ONJ as a potential complication of bisphosphonate treatment in patients with FD. The presence of established risk factors for ONJ in this group of patients with FD suggests that high-risk patients could be identified before the development of ONJ. Clinicians should use caution in prescribing bisphosphonates to patients with FD and should do so only for established indications. Published by Elsevier Inc on behalf of the American Association of Oral and Maxillofacial Surgeons C1 [Metwally, Tarek; Burke, Andrea; Collins, Michael T.; Boyce, Alison M.] Natl Inst Dent & Craniofacial Res, Sect Skeletal Disorders & Mineral Homeostasis, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. [Metwally, Tarek] Univ Michigan, Sch Dent, Ann Arbor, MI 48109 USA. [Tsai, Jeffrey Y.] SUNY Buffalo, Sch Dent Med, Dept Oral & Maxillofacial Surg, Buffalo, NY USA. [Boyce, Alison M.] Childrens Natl Hlth Syst, Div Endocrinol & Diabet, Washington, DC USA. [Boyce, Alison M.] Childrens Natl Hlth Syst, Bone Hlth Program, Div Orthopaed & Sports Med, Washington, DC USA. RP Boyce, AM (reprint author), NIH, 30 Convent Dr,Room 228,MSC 4320, Bethesda, MD 20892 USA. EM boyceam@mail.nih.gov FU Intramural Research Program of the National Institute of Dental and Craniofacial Research, National Institutes of Health (NIH); NIH Medical Research Scholars Program; NIH; Doris Duke Charitable Foundation; American Association for Dental Research; Howard Hughes Medical Institute; Colgate-Palmolive Company; alumni of student research programs FX This research was supported by the Intramural Research Program of the National Institute of Dental and Craniofacial Research, National Institutes of Health (NIH) and the NIH Medical Research Scholars Program, a public-and-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from the Doris Duke Charitable Foundation, the American Association for Dental Research, the Howard Hughes Medical Institute, the Colgate-Palmolive Company, alumni of student research programs, and other individual supporters. For a complete list, please visit the foundation Web site (http://www.fnih.org). NR 42 TC 0 Z9 0 U1 1 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0278-2391 EI 1531-5053 J9 J ORAL MAXIL SURG JI J. Oral Maxillofac. Surg. PD OCT PY 2016 VL 74 IS 10 BP 1983 EP 1999 DI 10.1016/j.joms.2016.04.001 PG 17 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA EE3QW UT WOS:000389511800015 PM 27137436 ER PT J AU Chowell, G Viboud, C Simonsen, L Moghadas, SM AF Chowell, Gerardo Viboud, Cecile Simonsen, Lone Moghadas, Seyed M. TI Characterizing the reproduction number of epidemics with early subexponential growth dynamics SO JOURNAL OF THE ROYAL SOCIETY INTERFACE LA English DT Article DE effective reproduction number; phenomenological model; generalized-growth model; epidemics; exponential growth; subexponential growth ID EBOLA-VIRUS DISEASE; NONLINEAR INCIDENCE RATES; EPIDEMIOLOGIC MODELS; MOUTH-DISEASE; TRANSMISSION DYNAMICS; INFECTIOUS-DISEASE; BEHAVIOR; INFLUENZA; OUTBREAKS; SMALLPOX AB Early estimates of the transmission potential of emerging and re-emerging infections are increasingly used to inform public health authorities on the level of risk posed by outbreaks. Existing methods to estimate the reproduction number generally assume exponential growth in case incidence in the first few disease generations, before susceptible depletion sets in. In reality, outbreaks can display subexponential (i.e. polynomial) growth in the first few disease generations, owing to clustering in contact patterns, spatial effects, inhomogeneous mixing, reactive behaviour changes or other mechanisms. Here, we introduce the generalized growth model to characterize the early growth profile of outbreaks and estimate the effective reproduction number, with no need for explicit assumptions about the shape of epidemic growth. We demonstrate this phenomenological approach using analytical results and simulations from mechanistic models, and provide validation against a range of empirical disease datasets. Our results suggest that subexponential growth in the early phase of an epidemic is the rule rather the exception. Mechanistic simulations show that slight modifications to the classical susceptible-infectious-removed model result in subexponential growth, and in turn a rapid decline in the reproduction number within three to five disease generations. For empirical outbreaks, the generalized-growth model consistently outperforms the exponential model for a variety of directly and indirectly transmitted diseases datasets (pandemic influenza, measles, smallpox, bubonic plague, cholera, foot-and-mouth disease, HIV/AIDS and Ebola) with model estimates supporting subexponential growth dynamics. The rapid decline in effective reproduction number predicted by analytical results and observed in real and synthetic datasets within three to five disease generations contrasts with the expectation of invariant reproduction number in epidemics obeying exponential growth. The generalized-growth concept also provides us a compelling argument for the unexpected extinction of certain emerging disease outbreaks during the early ascending phase. Overall, our approach promotes a more reliable and data-driven characterization of the early epidemic phase, which is important for accurate estimation of the reproduction number and prediction of disease impact. C1 [Chowell, Gerardo] Georgia State Univ, Sch Publ Hlth, Atlanta, GA 30303 USA. [Chowell, Gerardo; Viboud, Cecile] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Simonsen, Lone] Univ Copenhagen, Dept Publ Hlth, Copenhagen, Denmark. [Simonsen, Lone] George Washington Univ, Dept Global Hlth, Washington, DC USA. [Moghadas, Seyed M.] York Univ, Agent Based Modelling Lab, Toronto, ON, Canada. RP Chowell, G (reprint author), Georgia State Univ, Sch Publ Hlth, Atlanta, GA 30303 USA.; Chowell, G (reprint author), NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. EM gchowell@gsu.edu OI Simonsen, Lone/0000-0003-1535-8526 FU NSF as part of the joint NSF-NIH-USDA Ecology and Evolution of Infectious Diseases programme [1414374]; UK Biotechnology and Biological Sciences Research Council [BB/M008894/1]; NSF-IIS RAPID award [1518939]; NSF [1318788 III]; Division of International Epidemiology and Population Studies, The Fogarty International Center, US National Institutes of Health; RAPIDD Programme of the Science and Technology Directorate; EC Marie Curie Horizon fellowship; Natural Sciences and Engineering Research Council of Canada (NSERC); Mathematics of Information Technology and Complex Systems (Mitacs) FX G.C. acknowledges financial support from the NSF grant no. 1414374 as part of the joint NSF-NIH-USDA Ecology and Evolution of Infectious Diseases programme; UK Biotechnology and Biological Sciences Research Council grant no. BB/M008894/1, NSF-IIS RAPID award no. 1518939 and NSF grant no. 1318788 III: Small: Data Management for Real-Time Data-Driven Epidemic simulation, and the Division of International Epidemiology and Population Studies, The Fogarty International Center, US National Institutes of Health. C.V. and L.S. acknowledges financial support from the RAPIDD Programme of the Science and Technology Directorate and the Division of International Epidemiology and Population Studies, The Fogarty International Center, US National Institutes of Health. L.S. also acknowledges generous support from an EC Marie Curie Horizon 2020 fellowship. S.M. acknowledges the support from the Natural Sciences and Engineering Research Council of Canada (NSERC), and the Mathematics of Information Technology and Complex Systems (Mitacs). NR 71 TC 2 Z9 2 U1 6 U2 6 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 1742-5689 EI 1742-5662 J9 J R SOC INTERFACE JI J. R. Soc. Interface PD OCT 1 PY 2016 VL 13 IS 123 AR 20160659 DI 10.1098/rsif.2016.0659 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE7OW UT WOS:000389813700017 ER PT J AU Schmidt, LS Linehan, WM AF Schmidt, Laura S. Linehan, W. Marston TI Genetic predisposition to kidney cancer SO SEMINARS IN ONCOLOGY LA English DT Review DE Von Hippel-Lindau; Hereditary papillary renal carcinoma; Birt-Hogg-Dube syndrome; Hereditary leiomyomatosis and renal cell carcinoma; Kidney neoplasms; Inherited renal cancer syndromes ID RENAL-CELL CARCINOMA; HOGG-DUBE-SYNDROME; TUMOR-SUPPRESSOR PROTEIN; TYROSINE KINASE DOMAIN; HIPPEL-LINDAU-DISEASE; TUBEROUS SCLEROSIS COMPLEX; HYPOXIA-INDUCIBLE FACTORS; MITF GERMLINE MUTATION; HEREDITARY LEIOMYOMATOSIS; FUMARATE-HYDRATASE AB Kidney cancer is not a single disease but is made up of a number of different types of cancer classified by histology that are disparate in presentation, clinical course, and genetic basis. Studies of families with inherited renal cell carcinoma (RCC) have provided the basis for our understanding of the causative genes and altered metabolic pathways in renal cancer with different histologies. Von Hippel-Lindau disease was the first renal cancer disorder with a defined genetic basis. Over the next two decades, the genes responsible for a number of other inherited renal cancer syndromes including hereditary papillary renal carcinoma, Birt-Hogg-Dube'syndrome, hereditary leiomyomatosis and renal cell carcinoma, and succinate dehydrogenase associated renal cancer were identified. Recently, renal cell carcinoma has been confirmed as part of the clinical phenotype in individuals from families with BAPI-associated tumor predisposition syndrome and MiTF-associated cancer syndrome. Here we summarize the clinical characteristics of and causative genes for these and other inherited RCC syndromes, the pathways that are dysregulated when the inherited genes are mutated, and recommended clinical management of patients with these inherited renal cancer syndromes. Published by Elsevier Inc. C1 [Schmidt, Laura S.; Linehan, W. Marston] NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Schmidt, Laura S.] Leidos Biomed Res Inc, Basic Sci Program, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Linehan, WM (reprint author), NCI, Urol Oncol Branch, CRC, Room 1-5940,10 Ctr Dr,MSC 1107, Bethesda, MD 20892 USA. EM WML@nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; Federal funds from Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E] FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. This project has been funded in part with Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. NR 98 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0093-7754 EI 1532-8708 J9 SEMIN ONCOL JI Semin. Oncol. PD OCT PY 2016 VL 43 IS 5 BP 566 EP 574 DI 10.1053/j.seminoncol.2016.09.001 PG 9 WC Oncology SC Oncology GA EE8HH UT WOS:000389865800008 PM 27899189 ER PT J AU Crawford, ED Rosenberg, MT Partin, AW Cooperberg, MR Maccini, M Loeb, S Pettaway, CA Shore, ND Arangua, P Hoenemeyer, J Leveridge, M Leapman, M Pinto, P Thompson, IM Carroll, P Eastham, J Gomella, L Klein, EA AF Crawford, E. David Rosenberg, Matt T. Partin, Alan W. Cooperberg, Matthew R. Maccini, Michael Loeb, Stacy Pettaway, Curtis A. Shore, Neal D. Arangua, Paul Hoenemeyer, John Leveridge, Mike Leapman, Michael Pinto, Peter Thompson, Ian M., Jr. Carroll, Peter Eastham, James Gomella, Leonard Klein, Eric A. TI An Approach Using PSA Levels of 1.5 ng/mL as the Cutoff for Prostate Cancer Screening in Primary Care SO UROLOGY LA English DT Article ID ANTIGEN; AGE; BENEFITS; TRIAL; HARMS; RISK C1 Univ Colorado, Hlth Sci Ctr, Aurora, CO USA. Midmichigan Hlth Ctr, Jackson, MI USA. Johns Hopkins Med Inst, James Buchanan Brady Urol Inst, Dept Pathol, Baltimore, MD 21205 USA. Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, Dept Urol, San Francisco, CA 94143 USA. NYU, Dept Urol & Populat Hlth, New York, NY USA. Univ Texas MD Anderson Canc Ctr, Dept Urol, Div Surg, Houston, TX 77030 USA. Carolina Urol Res Ctr, Atlantic Urol Clin, Myrtle Beach, SC USA. Queens Univ, Kingston Gen Hosp, Dept Urol, Dept Oncol, Kingston, ON, Canada. Univ Calif San Francisco, Dept Urol, San Francisco, CA USA. NCI, Ctr Canc Res, Bethesda, MD 20892 USA. Univ Texas Hlth Sci Ctr San Antonio, Dept Urol, San Antonio, TX 78229 USA. Mem Sloan Kettering Canc Ctr, Dept Urol, New York, NY USA. Thomas Jefferson Univ, Kimmel Canc Ctr, Philadelphia, PA 19107 USA. Cleveland Clin, Glickman Urol & Kidney Inst, Cleveland, OH 44106 USA. RP Crawford, ED (reprint author), Univ Colorado Denver, Mail Stop F 710,POB 6510, Aurora, CO 80045 USA. EM david.crawford@ucdenver.edu FU NCI NIH HHS [P30 CA008748] NR 25 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 EI 1527-9995 J9 UROLOGY JI Urology PD OCT PY 2016 VL 96 SI SI BP 116 EP 120 DI 10.1016/j.urology.2016.07.001 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA EE4CN UT WOS:000389549700023 PM 27450937 ER PT J AU Le, VTM Tkaczyk, C Chau, S Rao, RL Dip, EC Pereira-Franchi, EP Cheng, L Lee, S Koelkebeck, H Hilliard, JJ Yu, XQ Datta, V Nguyen, V Weiss, W Prokai, L O'Day, T Stover, CK Sellman, BR Diep, BA AF Le, Vien T. M. Tkaczyk, Christine Chau, Sally Rao, Renee L. Dip, Etyene Castro Pereira-Franchi, Eliane P. Cheng, Lily Lee, Sally Koelkebeck, Holly Hilliard, Jamese J. Yu, Xiang Qing Datta, Vivekananda Vien Nguyen Weiss, William Prokai, Laszlo O'Day, Terrence Stover, C. Kendall Sellman, Bret R. Diep, Binh An TI Critical Role of Alpha-Toxin and Protective Effects of Its Neutralization by a Human Antibody in Acute Bacterial Skin and Skin Structure Infections SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID RESISTANT STAPHYLOCOCCUS-AUREUS; PANTON-VALENTINE LEUKOCIDIN; SOFT-TISSUE INFECTIONS; HUMAN C5A RECEPTORS; VIRULENCE DETERMINANTS; MONOCLONAL-ANTIBODY; PRACTICE GUIDELINES; DISEASES SOCIETY; RABBIT MODEL; PNEUMONIA AB Methicillin-resistant Staphylococcus aureus (MRSA) causes large-scale epidemics of acute bacterial skin and skin structure infections (ABSSSI) within communities across the United States. Animal models that reproduce ABSSSI as they occur in humans are urgently needed to test new therapeutic strategies. Alpha-toxin plays a critical role in a variety of staphylococcal infection models in mice, but its role in the pathogenesis of ABSSSI remains to be elucidated in rabbits, which are similar to humans in their susceptibility to S. aureus superantigens and certain bicomponent pore-forming leukocidins. We report here a new rabbit model of ABSSSI and show that those infected with a mutant deficient in expression of alpha-toxin (Delta hla) developed a small dermonecrotic lesion, whereas those infected with isogenic USA300 MRSA wild-type or complemented Delta hla strains developed ABSSSI that mimic the severe infections that occur in humans, including the large central dermonecrotic core surrounded by erythema, induration, and marked subcutaneous hemorrhage. More importantly, immunoprophylaxis with MEDI4893*, an anti-alphatoxin human monoclonal antibody, significantly reduced the severity of disease caused by a USA300 wild-type strain to that caused by the Delta hla mutant, indicating that this toxin could be completely neutralized during infection. Thus, this study illustrates a potential high standard for the development of new immunotherapeutic agents in which a toxin-neutralizing antibody provides protection to the same degree achieved with a toxin gene knockout. When MEDI4893* was administered as adjunctive therapy with a subtherapeutic dose of linezolid, the combination was significantly more efficacious than either agent alone in reducing the severity of ABSSSI. C1 [Le, Vien T. M.; Chau, Sally; Rao, Renee L.; Dip, Etyene Castro; Pereira-Franchi, Eliane P.; Diep, Binh An] Univ Calif San Francisco, Dept Med, Div HIV Infect Dis & Global Med, San Francisco, CA USA. [Tkaczyk, Christine; Hilliard, Jamese J.; Stover, C. Kendall; Sellman, Bret R.] MedImmune LLC, Dept Infect Dis, Gaithersburg, MD 20878 USA. [Cheng, Lily; Lee, Sally; Koelkebeck, Holly] MedImmune LLC, Dept Pathol, Gaithersburg, MD USA. [Yu, Xiang Qing] MedImmune LLC, Translat Sci, Gaithersburg, MD USA. [Datta, Vivekananda] NCI, NIH, Bethesda, MD 20892 USA. [Vien Nguyen; Weiss, William; Prokai, Laszlo] Univ North Texas, Hlth Sci Ctr, Preclin Serv, Ft Worth, TX USA. [O'Day, Terrence] MedImmune LLC, Stat Sci, Gaithersburg, MD USA. RP Diep, BA (reprint author), Univ Calif San Francisco, Dept Med, Div HIV Infect Dis & Global Med, San Francisco, CA USA.; Sellman, BR (reprint author), MedImmune LLC, Dept Infect Dis, Gaithersburg, MD 20878 USA. EM SellmanB@MedImmune.com; binh.diep@ucsf.edu FU HHS \ National Institutes of Health (NIH) [R01 AI087674]; U.S. Public Health Service grant [NIH R01 AI087674]; MedImmune, LLC, grant FX This work, including the efforts of Binh An Diep, was funded by HHS vertical bar National Institutes of Health (NIH) (R01 AI087674).; This work was supported by U.S. Public Health Service grant NIH R01 AI087674 and a MedImmune, LLC, grant. NR 37 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD OCT PY 2016 VL 60 IS 10 BP 5640 EP 5648 DI 10.1128/AAC.00710-16 PG 9 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA ED7PD UT WOS:000389059800003 PM 27401576 ER PT J AU Davis, MI Patrick, SL Blanding, WM Dwivedi, V Suryadi, J Golden, JE Coussens, NP Lee, OW Shen, M Boxer, MB Hall, MD Sharlow, ER Drew, ME Morris, JC AF Davis, Mindy I. Patrick, Stephen L. Blanding, Walker M. Dwivedi, Varun Suryadi, Jimmy Golden, Jennifer E. Coussens, Nathan P. Lee, Olivia W. Shen, Min Boxer, Matthew B. Hall, Matthew D. Sharlow, Elizabeth R. Drew, Mark E. Morris, James C. TI Identification of Novel Plasmodium falciparum Hexokinase Inhibitors with Antiparasitic Activity SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID LACTATE PRODUCTION; MALARIA PARASITES; LIBRARY AB Plasmodium falciparum, the deadliest species of malaria parasites, is dependent on glycolysis for the generation of ATP during the pathogenic red blood cell stage. Hexokinase (HK) catalyzes the first step in glycolysis, transferring the gamma-phosphoryl group of ATP to glucose to yield glucose-6-phosphate. Here, we describe the validation of a high-throughput assay for screening small-molecule collections to identify inhibitors of the P. falciparum HK (PfHK). The assay, which employed an ADP-Glo reporter system in a 1,536-well-plate format, was robust with a signal-to-background ratio of 3.4 +/- 1.2, a coefficient of variation of 6.8% +/- 2.9%, and a Z'-factor of 0.75 +/- 0.08. Using this assay, we screened 57,654 molecules from multiple small-molecule collections. Confirmed hits were resolved into four clusters on the basis of structural relatedness. Multiple singleton hits were also identified. The most potent inhibitors had 50% inhibitory concentrations as low as similar to 1 mu M, and several were found to have low-micromolar 50% effective concentrations against asexual intraerythrocytic-stage P. falciparum parasites. These molecules additionally demonstrated limited toxicity against a panel of mammalian cells. The identification of PfHK inhibitors with antiparasitic activity using this validated screening assay is encouraging, as it justifies additional HTS campaigns with more structurally amenable libraries for the identification of potential leads for future therapeutic development. C1 [Davis, Mindy I.; Coussens, Nathan P.; Lee, Olivia W.; Shen, Min; Boxer, Matthew B.; Hall, Matthew D.] NCATS, NIH, Rockville, MD USA. [Patrick, Stephen L.; Blanding, Walker M.; Suryadi, Jimmy; Morris, James C.] Clemson Univ, Dept Biochem & Genet, Eukaryot Pathogens Innovat Ctr, Clemson, SC 29634 USA. [Dwivedi, Varun; Drew, Mark E.] Ohio State Univ, Dept Microbial Infect & Immun, Columbus, OH 43210 USA. [Dwivedi, Varun; Drew, Mark E.] Ohio State Univ, Dept Med Chem & Pharmacognosy, Columbus, OH 43210 USA. [Golden, Jennifer E.] Univ Wisconsin, Sch Pharm, Dept Pharmaceut Sci, Madison, WI 53706 USA. [Sharlow, Elizabeth R.] Univ Virginia, Dept Pharmacol, Charlottesville, VA 22908 USA. RP Morris, JC (reprint author), Clemson Univ, Dept Biochem & Genet, Eukaryot Pathogens Innovat Ctr, Clemson, SC 29634 USA. EM jmorri2@clemson.edu OI Golden, Jennifer/0000-0002-6813-3710 FU HHS \ National Institutes of Health (NIH) [1R03HD081723]; HHS \ National Institutes of Health (NIH); U.S. National Institutes of Health [1R03HD081723]; Intramural Research Program of the NIH, NCATS; Fiske Drug Discovery Lab at the University of Virginia FX This work, including the efforts of James C. Morris, was funded by HHS vertical bar National Institutes of Health (NIH) (1R03HD081723). This work, including the efforts of Mindy I. Davis, Nathan P. Coussens, Olivia W. Lee, Min Shen, Matthew B. Boxer, and Matthew D. Hall, was funded by HHS vertical bar National Institutes of Health (NIH).; This work was supported in part by U.S. National Institutes of Health grant 1R03HD081723 to J.C.M. and in part by the Intramural Research Program of the NIH, NCATS, and the Fiske Drug Discovery Lab at the University of Virginia. NR 25 TC 0 Z9 0 U1 3 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD OCT PY 2016 VL 60 IS 10 BP 6023 EP 6033 DI 10.1128/AAC.00914-16 PG 11 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA ED7PD UT WOS:000389059800045 PM 27458230 ER PT J AU Prosser, GA Rodenburg, A Khoury, H de Chiara, C Howell, S Snijders, AP de Carvalho, LPS AF Prosser, Gareth A. Rodenburg, Anne Khoury, Hania de Chiara, Cesira Howell, Steve Snijders, Ambrosius P. de Carvalho, Luiz Pedro S. TI Glutamate Racemase Is the Primary Target of beta-Chloro-D-Alanine in Mycobacterium tuberculosis SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID ANTIBIOTIC D-CYCLOSERINE; ACTIVE-SITE PEPTIDE; ESCHERICHIA-COLI; SALMONELLA-TYPHIMURIUM; SUBSTITUTED ALANINES; HELICOBACTER-PYLORI; N-GLYCOLYLATION; DRUG DISCOVERY; PROTEIN FAMILY; DNA GYRASE AB The increasing global prevalence of drug resistance among many leading human pathogens necessitates both the development of antibiotics with novel mechanisms of action and a better understanding of the physiological activities of preexisting clinically effective drugs. Inhibition of peptidoglycan (PG) biosynthesis and cross-linking has traditionally enjoyed immense success as an antibiotic target in multiple bacterial pathogens, except in Mycobacterium tuberculosis, where it has so far been underexploited. D-Cycloserine, a clinically approved antituberculosis therapeutic, inhibits enzymes within the D-alanine subbranch of the PGbiosynthetic pathway and has been a focus in our laboratory for understanding peptidoglycan biosynthesis inhibition and for drug development in studies of M. tuberculosis. During our studies on alternative inhibitors of the D-alanine pathway, we discovered that the canonical alanine racemase (Alr) inhibitor beta-chloro-D-alanine (BCDA) is a very poor inhibitor of recombinant M. tuberculosis Alr, despite having potent antituberculosis activity. Through a combination of enzymology, microbiology, metabolomics, and proteomics, we show here that BCDA does not inhibit the D-alanine pathway in intact cells, consistent with its poor in vitro activity, and that it is instead a mechanism-based inactivator of glutamate racemase (MurI), an upstream enzyme in the same early stage of PG biosynthesis. This is the first report to our knowledge of inhibition of MurI in M. tuberculosis and thus provides a valuable tool for studying this essential and enigmatic enzyme and a starting point for future MurI-targeted antibacterial development. C1 [Prosser, Gareth A.; Rodenburg, Anne; Khoury, Hania; de Chiara, Cesira; de Carvalho, Luiz Pedro S.] Francis Crick Inst, Mycobacterial Metab & Antibiot Res Lab, London, England. [Howell, Steve; Snijders, Ambrosius P.] Francis Crick Inst, Prote Sci Technol Platform, London, England. [Prosser, Gareth A.] NIAID, TB Res Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Prosser, GA; de Carvalho, LPS (reprint author), Francis Crick Inst, Mycobacterial Metab & Antibiot Res Lab, London, England.; Prosser, GA (reprint author), NIAID, TB Res Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM gareth.prosser@nih.gov; Luiz.Carvalho@crick.ac.uk FU Wellcome Trust [104785/Z/14/Z]; Medical Research Council (MRC); Cancer Research UK (CRUK) FX This work, including the efforts of Steve Howell, Luiz Pedro S. de Carvalho, Gareth A. Prosser, Anne Rodenburg, Hania Khoury, Cesira de Chiara, and Ambrosius P. Snijders, was funded by Wellcome Trust. This work, including the efforts of Luiz Pedro S. de Carvalho, was funded by Wellcome Trust (104785/Z/14/Z). This work, including the efforts of Steve Howell, Luiz Pedro S. de Carvalho, Gareth A. Prosser, Anne Rodenburg, Hania Khoury, Cesira de Chiara, and Ambrosius P. Snijders, was funded by Medical Research Council (MRC). This work, including the efforts of Steve Howell, Luiz Pedro S. de Carvalho, Gareth A. Prosser, Anne Rodenburg, Hania Khoury, Cesira de Chiara, and Ambrosius P. Snijders, was funded by Cancer Research UK (CRUK). NR 47 TC 1 Z9 1 U1 11 U2 11 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD OCT PY 2016 VL 60 IS 10 BP 6091 EP 6099 DI 10.1128/AAC.01249-16 PG 9 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA ED7PD UT WOS:000389059800053 PM 27480853 ER PT J AU Lipsky, LM Gee, B Liu, AY Nansel, TR AF Lipsky, Leah M. Gee, Benjamin Liu, Aiyi Nansel, Tonja R. TI Glycemic control and variability in association with body mass index and body composition over 18 months in youth with type 1 diabetes SO DIABETES RESEARCH AND CLINICAL PRACTICE LA English DT Article DE Body mass index; Body composition; Diabetes mellitus, type 1; Adolescent; Hemoglobin A glycosylated; 1,5-Anhydroglucitol ID WEIGHT-GAIN; YOUNG-ADULTS; INSULIN-RESISTANCE; ADOLESCENT GIRLS; BLOOD-PRESSURE; RISK-FACTORS; MELLITUS; 1,5-ANHYDROGLUCITOL; CHILDREN; COMPLICATIONS AB Aims: The impact of adiposity on glycemic control in type 1 diabetes patients has important implications for preventing complications. This study examined associations of glycemic outcomes with body mass index (BMI, kg/m(2)) and body composition in youth with type 1 diabetes. Methods: This is a secondary analysis of an 18-month randomized controlled dietary intervention trial (N = 136, baseline age = 12.3 +/- 2.5 y, HbA1c = 8.1 +/- 1.0% (65 +/- 11 mmol/mol)). Measured height and weight every 3 months were abstracted from medical records. Body composition was assessed by dual energy X-ray absorptiometry (DXA) at baseline, 12 and 18 months. Glycated hemoglobin (HbA1c) and glycemic variability assessed by masked 3-day continuous blood glucose monitoring (CGM) were obtained every 3 months. 1,5-Anhydroglucitol (1,5-AG) was assessed every 6 months. Adjusted random effects models for repeated measures estimated associations of time-varying BMI and body composition with time-varying glycemic outcomes. Results: There was no treatment effect on glycemic outcomes. HbA1c was not associated with BMI or body composition indicators. 1,5-AG was inversely associated with BMI and adiposity indicators (% fat, trunk fat mass and trunk % fat), adjusting for developmental covariates. Adiposity indicators were positively associated with % glucose > 180 mg/dL and > 126 mg/dL when adjusting for developmental covariates, and % glucose > 126 mg/dL when additionally adjusting for diabetes-related covariates. Fewer consistent relationships were observed for 3-day mean glucose and % glucose < 70.2 mg/dL. BMI and body composition variables were not associated with standard deviation of glycemic values or mean amplitude of glycemic excursions. Conclusions: The role of greater BMI and adiposity in diabetes management in youth with type 1 diabetes may relate specifically to increased hyperglycemic excursions. Published by Elsevier Ireland Ltd. C1 [Lipsky, Leah M.; Gee, Benjamin; Nansel, Tonja R.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Hlth Behav Branch, Div Intramural Populat Hlth Res, Bethesda, MD 20892 USA. [Liu, Aiyi] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, Bethesda, MD USA. RP Lipsky, LM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Hlth Behav Branch, Div Intramural Populat Hlth Res, Bethesda, MD 20892 USA. EM lipskylm@mail.nih.gov OI Nansel, Tonja/0000-0002-8298-7595; Liu, Aiyi/0000-0002-6618-5082; Lipsky, Leah/0000-0003-2645-4388 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development Intramural Research Program [HHSN267200703434C, HSN2752008000031/HHSN275002] FX The authors thank the research staff at the clinical site and the participants for their contributions to this study. This research was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Intramural Research Program (contract #HHSN267200703434C and HSN2752008000031/HHSN275002). The funding source had no involvement in the design or conduct of the study or in writing the manuscript or submitting it for publication. NR 30 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0168-8227 EI 1872-8227 J9 DIABETES RES CLIN PR JI Diabetes Res. Clin. Pract. PD OCT PY 2016 VL 120 BP 97 EP 103 DI 10.1016/j.diabres.2016.07.028 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EA6PK UT WOS:000386750900013 PM 27525365 ER PT J AU Ramnitz, MS Gourh, P Goldbach-Mansky, R Wodajo, F Ichikawa, S Econs, MJ White, KE Molinolo, A Chen, MY Heller, T Del Rivero, J Seo-Mayer, P Arabshahi, B Jackson, MB Hatab, S McCarthy, E Guthrie, LC Brillante, BA Gafni, RI Collins, MT AF Ramnitz, Mary Scott Gourh, Pravitt Goldbach-Mansky, Raphaela Wodajo, Felasfa Ichikawa, Shoji Econs, Michael J. White, Kenneth E. Molinolo, Alfredo Chen, Marcus Y. Heller, Theo Del Rivero, Jaydira Seo-Mayer, Patricia Arabshahi, Bita Jackson, Malaka B. Hatab, Sarah McCarthy, Edward Guthrie, Lori C. Brillante, Beth A. Gafni, Rachel I. Collins, Michael T. TI Phenotypic and Genotypic Characterization and Treatment of a Cohort With Familial Tumoral Calcinosis/Hyperostosis-Hyperphosphatemia Syndrome SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE FAMILIAL TUMORAL CALCINOSIS; FIBROBLAST GROWTH FACTOR 23; HYPEROSTOSIS-HYPERPHOSPHATEMIA SYNDROME; HYPERPHOSPHATEMIA ID HOMOZYGOUS MISSENSE MUTATION; PHOSPHATE BINDER; CALCINOSIS; GALNT3; ACETAZOLAMIDE; CHILDREN; FIBROBLAST-GROWTH-FACTOR-23; HYPOPHOSPHATEMIA; MANIFESTATIONS; CALCIFICATION AB Familial tumoral calcinosis ( FTC)/hyperostosis-hyperphosphatemia syndrome ( HHS) is a rare disorder caused by mutations in the genes encoding fibroblast growth factor-23 ( FGF23), N-acetylgalactosaminyltransferase 3 ( GALNT3), or KLOTHO. The result is functional deficiency of, or resistance to, intact FGF23 ( iFGF23), causing hyperphosphatemia, increased renal tubular reabsorption of phosphorus ( TRP), elevated or inappropriately normal 1,25-dihydroxyvitamin D-3 ( 1,25D), ectopic calcifications, and/or diaphyseal hyperostosis. Eight subjects with FTC/HHS were studied and treated. Clinical manifestations varied, even within families, ranging from asymptomatic to large, disabling calcifications. All subjects had hyperphosphatemia, increased TRP, and elevated or inappropriately normal 1,25D. C-terminal FGF23 was markedly elevated whereas iFGF23 was comparatively low, consistent with increased FGF23 cleavage. Radiographs ranged from diaphyseal hyperostosis to massive calcification. Two subjects with severe calcifications also had overwhelming systemic inflammation and elevated C-reactive protein ( CRP). GALNT3 mutations were identified in seven subjects; no causative mutation was found in the eighth. Biopsies from four subjects showed ectopic calcification and chronic inflammation, with areas of heterotopic ossification observed in one subject. Treatment with low phosphate diet, phosphate binders, and phosphaturia-inducing therapies was prescribed with variable response. One subject experienced complete resolution of a calcific mass after 13 months of medical treatment. In the two subjects with systemic inflammation, interleukin-1 ( IL-1) antagonists significantly decreased CRP levels with resolution of calcinosis cutis and perilesional inflammation in one subject and improvement of overall well-being in both subjects. This cohort expands the phenotype and genotype of FTC/HHS and demonstrates the range of clinical manifestations despite similar biochemical profiles and genetic mutations. Overwhelming systemic inflammation has not been described previously in FTC/HHS; the response to IL-1 antagonists suggests that anti-inflammatory drugs may be useful adjuvants. In addition, this is the first description of heterotopic ossification reported in FTC/ HHS, possibly mediated by the adjacent inflammation. (C) 2016 American Society for Bone and Mineral Research. C1 [Ramnitz, Mary Scott; Molinolo, Alfredo; Guthrie, Lori C.; Brillante, Beth A.; Gafni, Rachel I.; Collins, Michael T.] Natl Inst Dent & Craniofacial Res, Skeletal Clin Studies Unit, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. [Gourh, Pravitt; Goldbach-Mansky, Raphaela] NIAMSD, NIH, Bethesda, MD 20892 USA. [Wodajo, Felasfa] Virginia Canc Specialists, Musculoskeletal Tumor Surg, Fairfax, VA USA. [Ichikawa, Shoji; Econs, Michael J.] Indiana Univ Sch Med, Dept Med, Indianapolis, IN 46202 USA. [Econs, Michael J.; White, Kenneth E.] Indiana Univ Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46202 USA. [Chen, Marcus Y.] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Heller, Theo] NIDDK, NIH, Bethesda, MD 20892 USA. [Del Rivero, Jaydira] NCI, NIH, Bethesda, MD 20892 USA. [Seo-Mayer, Patricia] Pediat Specialists Virginia, Div Nephrol & Hypertens, Fairfax, VA USA. [Seo-Mayer, Patricia] Georgetown Univ, Sch Med, Fairfax, VA USA. [Arabshahi, Bita] Pediat Specialists Virginia, Dept Rheumatol, Fairfax, VA USA. [Jackson, Malaka B.] Univ South Carolina, Sch Med, Dept Pediat Endocrinol, Columbia, SC USA. [Hatab, Sarah] Emory Univ, Sch Med, Dept Pediat Endocrinol, Atlanta, GA USA. [McCarthy, Edward] Johns Hopkins Univ Hosp, Dept Pathol, Baltimore, MD 21287 USA. RP Collins, MT (reprint author), NIH, 30 Convent Dr Room 228 MSC 4320, Bethesda, MD 20892 USA. EM mcollins@mail.nih.gov OI Econs, Michael/0000-0003-0940-1911 FU Division of Intramural Research of the NIDCR, NIH, DHHS; NIH [AR42228] FX This research was supported by the Division of Intramural Research of the NIDCR, NIH, DHHS. Work performed in MJE's lab was supported by NIH grant AR42228. We thank Brian Kirmse for patient samples, and Leah R Padgett, Austin M Riley, and Joseph Bondi for assisting with DNA sequencing. NR 38 TC 2 Z9 3 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0884-0431 EI 1523-4681 J9 J BONE MINER RES JI J. Bone Miner. Res. PD OCT PY 2016 VL 31 IS 10 BP 1845 EP 1854 DI 10.1002/jbmr.2870 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA ED5JU UT WOS:000388888700011 PM 27164190 ER PT J AU Rose, JB Vergneau-Grosset, C Steffey, MA Johnson, EG Chen, VS Mohr, FC Harvey, C Guzman, DSM AF Rose, Josephine B. Vergneau-Grosset, Claire Steffey, Michele A. Johnson, Eric G. Chen, Vivian S. Mohr, F. Charles Harvey, Carolynn Guzman, David Sanchez-Migallon TI ADRENALECTOMY AND NEPHRECTOMY IN A RABBIT (ORYCTOLAGUS CUNICULUS) WITH ADRENOCORTICAL CARCINOMA AND RENAL AND URETERAL TRANSITIONAL CELL CARCINOMA SO Journal of Exotic Pet Medicine LA English DT Article DE hypertestosteronism; rabbit; renal transitional cell carcinoma; adrenocortical carcinoma; GnRH agonist; deslorelin ID ZEALAND WHITE-RABBIT; 2 DOGS; POLYCYTHEMIA; DESLORELIN; DISEASE; FERRETS; GNRH; MANAGEMENT; IMPLANTS; FEATURES AB A 9-year-old neutered male rabbit (Oryctolagus cuniculus) previously diagnosed with right nephromegaly was presented with increased sexual behavior associated with hypertestosteronemia. Left adrenomegaly and an obstructive mass in the right renal pelvis and proximal ureter leading to severe hydronephrosis of the right kidney were diagnosed by abdominal ultrasound. A left adrenalectomy and right nephrectomy were performed and samples were submitted for histopathology, confirming the diagnosis of adrenocortical carcinoma and a transitional cell carcinoma of the ureter and renal pelvis. Increased sexual behavior resolved within 2 months following surgical resection of the affected left adrenal gland, but recurred 8 months later. The right adrenal gland had increased in size when compared to earlier ultrasonographic evalution. A 4.7-mg deslorelin implant was placed subcutaneously, which resulted in a decrease of testosteronemia and sexual behaviors for up to 18 months. Copyright 2016 Elsevier Inc. All rights reserved. C1 Univ Calif Davis, Sch Vet Med, Vet Med Teaching Hosp, Davis, CA 95616 USA. [Guzman, David Sanchez-Migallon] Univ Calif Davis, Sch Vet Med, Dept Med, One Shields Ave, Davis, CA 95616 USA. [Guzman, David Sanchez-Migallon] Univ Calif Davis, Sch Vet Med, Dept Epidemiol, One Shields Ave, Davis, CA 95616 USA. Univ Calif Davis, Sch Vet Med, Dept Surg & Radiol Sci, Davis, CA 95616 USA. Univ Calif Davis, Sch Vet Med, Dept Pathol Microbiol & Immunol, Davis, CA 95616 USA. NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. Chabot Vet Hosp, Hayward, CA USA. RP Guzman, DSM (reprint author), Univ Calif Davis, Sch Vet Med, Dept Med, One Shields Ave, Davis, CA 95616 USA.; Guzman, DSM (reprint author), Univ Calif Davis, Sch Vet Med, Dept Epidemiol, One Shields Ave, Davis, CA 95616 USA. EM guzman@ucdavis.edu NR 43 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1557-5063 EI 1931-6283 J9 J EXOT PET MED JI J. Exot. Pet Med. PD OCT PY 2016 VL 25 IS 4 BP 332 EP 341 DI 10.1053/j.jepm.2016.06.010 PG 10 WC Veterinary Sciences SC Veterinary Sciences GA ED9AV UT WOS:000389163300009 ER PT J AU Hoft, DF Lottenbach, K Goll, JB Hill, H Winokur, PL Patel, SM Brady, RC Chen, WH Edwards, K Creech, CB Frey, SE Blevins, TP Salomon, R Belshe, RB AF Hoft, Daniel F. Lottenbach, Kathleen Goll, Johannes B. Hill, Heather Winokur, Patricia L. Patel, Shital M. Brady, Rebecca C. Chen, Wilbur H. Edwards, Kathryn Creech, C. Buddy Frey, Sharon E. Blevins, Tamara P. Salomon, Rachelle Belshe, Robert B. TI Priming Vaccination With Influenza Virus H5 Hemagglutinin Antigen Significantly Increases the Duration of T cell Responses Induced by a Heterologous H5 Booster Vaccination SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE H5N1; influenza; vaccine; prime/boost; human; clade ID A/H5N1 VACCINE; PANDEMIC INFLUENZA; A VIRUS; HETEROSUBTYPIC IMMUNITY; ALUMINUM-HYDROXIDE; IMMUNOGENICITY; PROTECTION; SAFETY; MICE; ADJUVANTS AB Background. Influenza A(H5N1) virus and other avian influenza virus strains represent major pandemic threats. Like all influenza A virus strains, A(H5N1) viruses evolve rapidly. Innovative immunization strategies are needed to induce cross-protective immunity. Methods. Subjects primed with clade 1 H5 antigen, with or without adjuvant, and H5-naive individuals were boosted with clade 2 H5 antigen. The impact of priming on T cells capable of both proliferation and cytokine production after antigen restimulation was assessed. Results. Subjects previously vaccinated with clade 1 H5 antigen developed significantly enhanced clade 2 H5 cross-reactive T cell responses detectable 6 months after vaccination with clade 2 H5 antigen. Priming dose (15 mu g vs 45 or 90 mu g) had no effect on magnitude of heterotypic H5 T cell responses. In contrast, age at priming negatively modulated both the magnitude and duration of heterotypic H5 T cell responses. Elderly subjects developed significantly less heterotypic H5 T cell boosting, predominantly for T cells capable of cytokine production. Adjuvant had a positive albeit weaker effect than age. The magnitude of CD4(+) interferon-gamma producing T cells correlated with H5 antibody responses. Conclusions. H5 heterotypic priming prior to onset of an A(H5N1) pandemic may increase magnitude and duration of immunity against a newly drifted pandemic H5 virus. C1 [Hoft, Daniel F.; Lottenbach, Kathleen; Frey, Sharon E.; Blevins, Tamara P.; Belshe, Robert B.] St Louis Univ, Dept Internal Med, St Louis, MO 63103 USA. [Goll, Johannes B.; Hill, Heather] Emmes Corp, Rockville, MD USA. [Chen, Wilbur H.] Univ Maryland, Sch Med, Ctr Vaccine Dev, Baltimore, MD 21201 USA. [Salomon, Rachelle] NIAID, Div Microbiol & Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Winokur, Patricia L.] Univ Iowa, Dept Internal Med, Iowa City, IA 52242 USA. [Winokur, Patricia L.] Iowa City VA Healthcare Syst, Iowa City, IA USA. [Patel, Shital M.] Baylor Coll Med, Dept Mol Virol & Microbiol, Houston, TX 77030 USA. [Brady, Rebecca C.] Cincinnati Childrens Hosp, Gamble Program Clin Studies, Cincinnati, OH USA. [Edwards, Kathryn; Creech, C. Buddy] Vanderbilt Univ, Dept Pediat, Vanderbilt Vaccine Res Program, Nashville, TN USA. RP Hoft, DF (reprint author), Edward A Doisy Res Ctr, Dept Internal Med, 1100 S Grand Blvd,8th Flr, St Louis, MO 63104 USA.; Hoft, DF (reprint author), Edward A Doisy Res Ctr, Dept Mol Microbiol Immunol, 1100 S Grand Blvd,8th Flr, St Louis, MO 63104 USA. EM hoftdf@slu.edu FU National Institutes of Health Vaccine and Treatment Evaluation Unit Program [HHSN272200800003C, HHSN272200800008C, HHSN272200800002, HHSN272200800006C, HHSN2722 00800001C, HHSN272200800007C] FX This work was supported by the National Institutes of Health Vaccine and Treatment Evaluation Unit Program (grants HHSN272200800003C [Saint Louis University], HHSN272200800008C [University of Iowa], HHSN272200800002 [Baylor College of Medicine], HHSN272200800006C [Cincinnati Children's Hospital], HHSN2722 00800001C [University of Maryland], and HHSN272200800007C [Vanderbilt University]). NR 36 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 1 PY 2016 VL 214 IS 7 BP 1020 EP 1029 DI 10.1093/infdis/jiw310 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DZ8RF UT WOS:000386137800008 PM 27443611 ER PT J AU Hernandez, DG Reed, X Singleton, AB AF Hernandez, Dena G. Reed, Xylena Singleton, Andrew B. TI Genetics in Parkinson disease: Mendelian versus non-Mendelian inheritance SO JOURNAL OF NEUROCHEMISTRY LA English DT Review DE Parkinsons Disease; genetics; mendelian; risk alleles ID EARLY-ONSET PARKINSONISM; ALPHA-SYNUCLEIN GENE; GENOME-WIDE ASSOCIATION; REPEAT KINASE 2; AUTOSOMAL-DOMINANT PARKINSONISM; LRRK2 GLY2385ARG VARIANT; P-TYPE ATPASE; LEWY BODIES; RISK-FACTOR; IN-VIVO AB Parkinson's disease is a common, progressive neurodegenerative disorder, affecting 3% of those older than 75years of age. Clinically, Parkinson's disease (PD) is associated with resting tremor, postural instability, rigidity, bradykinesia, and a good response to levodopa therapy. Over the last 15 years, numerous studies have confirmed that genetic factors contribute to the complex pathogenesis of PD. Highly penetrant mutations producing rare, monogenic forms of the disease have been discovered in singular genes such as SNCA, Parkin, DJ-1, PINK 1, LRRK2, and VPS35. Unique variants with incomplete penetrance in LRRK2 and GBA have been shown to be strong risk factors for PD in certain populations. Additionally, over 20 common variants with small effect sizes are now recognized to modulate the risk for PD. Investigating Mendelian forms of PD has provided precious insight into the pathophysiology that underlies the more common idiopathic form of disease; however, no treatment methodologies have developed. Furthermore, for identified common risk alleles, the functional basis underlying risk principally remains unknown. The challenge over the next decade will be to strengthen the findings delivered through genetic discovery by assessing the direct, biological consequences of risk variants in tandem with additional high-content, integrated datasets. This review discusses monogenic risk factors and mechanisms of Mendelian inheritance of Parkinson disease. Highly penetrant mutations in SNCA, Parkin, DJ-1, PINK 1, LRRK2 and VPS35 produce rare, monogenic forms of the disease, while unique variants within LRRK2 and GBA show incomplete penetrance and are strong risk factors for PD. Additionally, over 20 common variants with small effect sizes modulate disease risk. The challenge over the next decade is to strengthen genetic findings by assessing direct, biological consequences of risk variants in tandem with high-content, integrated datasets. This article is part of a . C1 [Hernandez, Dena G.; Reed, Xylena; Singleton, Andrew B.] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. [Hernandez, Dena G.] German Ctr Neurodegenerat Dis DZNE Tubingen, Tubingen, Germany. RP Singleton, AB (reprint author), NIA, Neurogenet Lab, Bethesda, MD 20892 USA. EM singleta@mail.nih.gov FU Intramural NIH HHS [Z01 AG000949-02]; NIA NIH HHS [Z01 AG000958, Z01 AG000949, Z01 AG000957] NR 204 TC 12 Z9 12 U1 18 U2 18 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD OCT PY 2016 VL 139 SU 1 BP 59 EP 74 DI 10.1111/jnc.13593 PG 16 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA DZ3SV UT WOS:000385770500004 PM 27090875 ER PT J AU Beilina, A Cookson, MR AF Beilina, Alexandra Cookson, Mark R. TI Genes associated with Parkinson's disease: regulation of autophagy and beyond SO JOURNAL OF NEUROCHEMISTRY LA English DT Review DE chaperone-mediated autophagy; genetics; lysosomes; mitophagy; Parkinson's disease; protein complexes ID CHAPERONE-MEDIATED AUTOPHAGY; REPEAT KINASE 2; ALPHA-SYNUCLEIN ACCUMULATION; GENOME-WIDE ASSOCIATION; COMPLEX I ACTIVITY; MITOCHONDRIAL DEPOLARIZATION; DAMAGED MITOCHONDRIA; UBIQUITIN LIGASE; PROTEASE PARL; WASH COMPLEX AB Substantial progress has been made in the genetic basis of Parkinson's disease (PD). In particular, by identifying genes that segregate with inherited PD or show robust association with sporadic disease, and by showing the same genes are found on both lists, we have generated an outline of the cause of this condition. Here, we will discuss what those genes tell us about the underlying biology of PD. We specifically discuss the relationships between protein products of PD genes and show that common links include regulation of the autophagy-lysosome system, an important way by which cells recycle proteins and organelles. We also discuss whether all PD genes should be considered to be in the same pathway and propose that in some cases the relationships are closer, whereas in other cases the interactions are more distant and might be considered separate. Beilina and Cookson review the links between genes for Parkinson's disease (red) and the autophagy-lysosomal system. They propose the hypothesis that many of the known PD genes can be assigned to pathways that affect (I) turnover of mitochondria via mitophagy (II) turnover of several vesicular structures via macroautophagy or chaperone-mediated autophagy or (III) general lysosome function. This article is part of a . C1 [Beilina, Alexandra; Cookson, Mark R.] NIA, Cell Biol & Gene Express Sect, Neurogenet Lab, 35 Convent Dr, Bethesda, MD 20892 USA. RP Cookson, MR (reprint author), NIA, Cell Biol & Gene Express Sect, Neurogenet Lab, 35 Convent Dr, Bethesda, MD 20892 USA. EM cookson@mail.nih.gov NR 181 TC 8 Z9 8 U1 8 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD OCT PY 2016 VL 139 SU 1 BP 91 EP 107 DI 10.1111/jnc.13266 PG 17 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA DZ3SV UT WOS:000385770500007 PM 26223426 ER PT J AU Collins, GT Abbott, M Galindo, K Rush, EL Rice, KC France, CP AF Collins, Gregory T. Abbott, Megan Galindo, Kayla Rush, Elise L. Rice, Kenner C. France, Charles P. TI Discriminative Stimulus Effects of Binary Drug Mixtures: Studies with Cocaine, MDPV, and Caffeine SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID CONSTITUENT 3,4-METHYLENEDIOXYPYROVALERONE MDPV; 2ND-GENERATION LEGAL HIGHS; BRAZILIAN FEDERAL POLICE; LOCOMOTOR-ACTIVITY; BATH SALTS; SYNTHETIC STIMULANTS; RATS; DOPAMINE; CATHINONES; METHAMPHETAMINE AB Illicit drug preparations often include more than one pharmacologically active compound. For example, cocaine and synthetic cathinones [e.g., 3,4-methylenedioxypyrovalerone (MDPV)] are often mixed with caffeine before sale. Caffeine is likely added to these preparations because it is inexpensive and legal; however, caffeine might also mimic or enhance some of the effects of cocaine or MDPV. In these studies, male Sprague-Dawley rats were trained to discriminate 10 mg/kg cocaine from saline, and the discriminative stimulus effects of cocaine, caffeine, and MDPV were evaluated alone and as binary mixtures (cocaine and caffeine, MDPV and caffeine, and cocaine and MDPV) at fixed-dose ratios of 3: 1, 1: 1, and 1: 3 relative to the dose of each drug that produced 50% cocaine-appropriate responding. Dose-addition analyses were used to determine the nature of the drug-drug interactions for each mixture (e.g., additive, supra-additive, or subadditive). Although additive interactions were observed for most mixtures, supra-additive interactions were observed at the 50% effect level for the 1: 1 mixture of cocaine and caffeine and at the 80% effect level for all three mixtures of cocaine and caffeine, as well as for the 3: 1 and 1: 3 mixtures of cocaine and MDPV. These results demonstrate that with respect to cocaine-like discriminative stimulus effects, caffeine can function as a substitute in drug preparations containing either cocaine or MDPV, with enhancements of cocaine-like effects possible under certain conditions. Further research is needed to determine whether similar interactions exist for other abuse-related or toxic effects of drug preparations, including cocaine, synthetic cathinones, and caffeine. C1 [Collins, Gregory T.; Abbott, Megan; Galindo, Kayla; Rush, Elise L.; France, Charles P.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharm, 7703 Floyd Curl Dr, MC 7764, San Antonio, TX 78229 USA. [France, Charles P.] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX USA. [Collins, Gregory T.] Univ Texas Hlth Sci Ctr San Antonio, South Texas Vet Hlth Care Sys, San Antonio, TX USA. [Rice, Kenner C.] Chemical Biol Res Branch, NIAAA, Natl Inst Drug Abuse, Bethesda, MD USA. RP Collins, GT (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Pharm, 7703 Floyd Curl Dr, MC 7764, San Antonio, TX 78229 USA. EM collinsg@uthscsa.edu FU National Institutes of Health (NIH) research grant from the National Institute on Drug Abuse (NIDA) [R01 DA039146]; NIH Intramural Research Programs of NIDA; National Institute of Alcohol Abuse and Alcoholism (NIAAA); Senior Scientist Award from NIDA [K05 DA017918]; Welch Foundation [AQ-0039] FX This work was supported, in part, by a National Institutes of Health (NIH) research grant (R01 DA039146) from the National Institute on Drug Abuse (NIDA), as well as the NIH Intramural Research Programs of NIDA and the National Institute of Alcohol Abuse and Alcoholism (NIAAA). C.P.F. is supported by a Senior Scientist Award [K05 DA017918] from NIDA as well as a grant from the Welch Foundation [Grant AQ-0039]. NR 50 TC 0 Z9 0 U1 4 U2 4 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 EI 1521-0103 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD OCT 1 PY 2016 VL 359 IS 1 BP 1 EP 10 DI 10.1124/jpet.116.234252 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA ED7RR UT WOS:000389067700001 PM 27493274 ER PT J AU Can, A Zanos, P Moaddel, R Kang, HJ Dossou, KSS Wainer, IW Cheer, JF Frost, DO Huang, XP Gould, TD AF Can, Adem Zanos, Panos Moaddel, Ruin Kang, Hye Jin Dossou, Katinia S. S. Wainer, Irving W. Cheer, Joseph F. Frost, Douglas O. Huang, Xi-Ping Gould, Todd D. TI Effects of Ketamine and Ketamine Metabolites on Evoked Striatal Dopamine Release, Dopamine Receptors, and Monoamine Transporters SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID METHYL-D-ASPARTATE; NICOTINIC ACETYLCHOLINE-RECEPTORS; RESISTANT MAJOR DEPRESSION; SCAN CYCLIC VOLTAMMETRY; RAT PREFRONTAL CORTEX; ADD-ON TRIAL; IN-VIVO; ANTIDEPRESSANT EFFICACY; BIPOLAR DEPRESSION; NUCLEUS-ACCUMBENS AB Following administration at subanesthetic doses, (R,S)-ketamine (ketamine) induces rapid and robust relief from symptoms of depression in treatment-refractory depressed patients. Previous studies suggest that ketamine's antidepressant properties involve enhancement of dopamine (DA) neurotransmission. Ketamine is rapidly metabolized to (2S,6S)- and (2R,6R)-hydroxynorketamine (HNK), which have antidepressant actions independent of N-methyl-D-aspartate glutamate receptor inhibition. These antidepressant actions of (2S, 6S; 2R, 6R)- HNK, or other metabolites, as well as ketamine's side effects, including abuse potential, may be related to direct effects on components of the dopaminergic (DAergic) system. Here, brain and blood distribution/clearance and pharmacodynamic analyses at DA receptors (D1-D5) and the DA, norepinephrine, and serotonin transporters were assessed for ketamine and its major metabolites (norketamine, dehydronorketamine, and HNKs). Additionally, we measured electrically evoked mesolimbic DA release and decay using fast-scan cyclic voltammetry following acute administration of subanesthetic doses of ketamine (2, 10, and 50 mg/kg, i.p.). Following ketamine injection, ketamine, norketamine, and multiple hydroxynorketamines were detected in the plasma and brain of mice. Dehydronorketamine was detectable in plasma, but concentrations were below detectable limits in the brain. Ketamine did not alter the magnitude or kinetics of evoked DA release in the nucleus accumbens in anesthetized mice. Neither ketamine's enantiomers nor its metabolites had affinity for DA receptors or the DA, noradrenaline, and serotonin transporters ( up to 10 mu M). These results suggest that neither the side effects nor antidepressant actions of ketamine or ketamine metabolites are associated with direct effects on mesolimbic DAergic neurotransmission. Previously observed in vivo changes in DAergic neurotransmission following ketamine administration are likely indirect. C1 [Can, Adem; Zanos, Panos; Cheer, Joseph F.; Frost, Douglas O.; Gould, Todd D.] Univ Maryland, Sch Med, Dept Psychiat, Room 936 MSTF,685 West Baltimore St, Baltimore, MD 21201 USA. [Frost, Douglas O.; Gould, Todd D.] Univ Maryland, Sch Med, Dept Pharmacol, Baltimore, MD 21201 USA. [Cheer, Joseph F.; Gould, Todd D.] Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. [Can, Adem] Notre Dame Maryland Univ, Dept Psychol, Baltimore, MD USA. [Moaddel, Ruin; Dossou, Katinia S. S.; Wainer, Irving W.] NIA, Biomed Res Ctr, NIH, Baltimore, MD 21224 USA. [Kang, Hye Jin; Huang, Xi-Ping] Univ N Carolina, Sch Med, Natl Inst Mental Hlth, Dept Pharmacol,Psychoact Drug Screening Program, Chapel Hill, NC USA. [Wainer, Irving W.] Mitchell Woods Pharmaceut, Shelton, CT USA. RP Gould, TD (reprint author), Univ Maryland, Sch Med, Dept Psychiat, Room 936 MSTF,685 West Baltimore St, Baltimore, MD 21201 USA. EM gouldlab@me.com FU NIMH Psychoactive Drug Screening Program [HHSN-271-2008-025C] FX The authors thank Craig J. Thomas and Patrick J. Morris from the National Institutes of Health, National Center for Advancing Translational Medicine for providing (2S,6S)- and (2R,6R)-hydroxynorketamine. Receptor binding profiles and Ki determinations were generously provided by the NIMH Psychoactive Drug Screening Program, Contract # HHSN-271-2008-025C, directed by Dr. Bryan Roth (University of North Carolina, Chapel Hill, NC) in conjunction with Jamie Driscoll (NIMH, Bethesda, MD). NR 73 TC 0 Z9 0 U1 3 U2 3 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 EI 1521-0103 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD OCT 1 PY 2016 VL 359 IS 1 BP 159 EP 170 DI 10.1124/jpet.116.235838 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA ED7RR UT WOS:000389067700019 PM 27469513 ER PT J AU Dluzen, DF Sutliff, AK Chen, G Watson, CJW Ishmael, FT Lazarus, P AF Dluzen, Douglas F. Sutliff, Aimee K. Chen, Gang Watson, Christy J. W. Ishmael, Faoud T. Lazarus, Philip TI Regulation of UGT2B Expression and Activity by miR-216b-5p in Liver Cancer Cell Lines SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID HUMAN UDP-GLUCURONOSYLTRANSFERASES; MESSENGER-RNA LEVELS; GENE-EXPRESSION; PROSTATE-CANCER; EPIRUBICIN GLUCURONIDATION; PROTEIN QUANTIFICATION; TARGET RECOGNITION; MICRORNAS; 2B7; POLYMORPHISM AB The UDP-glucuronosyltransferase (UGT) 2B enzymes are important in the detoxification of a variety of endogenous and exogenous compounds, including many hormones, drugs, and carcinogens. Identifying novel mechanisms governing their expression is important in understanding patient-specific response to drugs and cancer risk factors. In silico prediction algorithm programs were used to screen for microRNAs (miRNAs) as potential regulators of UGT2B enzymes, with miR-216b-5p identified as a potential candidate. Luciferase data suggested the presence of a functional miR-216b-5p binding motif within the 3 ' untranslated regions of UGTs 2B7, 2B4, and 2B10. Overexpression of miR-216b-5p mimics significantly repressed UGT2B7 (P < 0.001) and UGT2B10 (P = 0.0018) mRNA levels in HuH-7 cells and UGT2B4 (P < 0.001) and UGT2B10 (P - 0.018) mRNA in Hep3B cells. UGT2B7 protein levels were repressed in both HuH-7 and Hep3B cells in the presence of increasing miR-216b-5p concentrations, corresponding with significant (P < 0.001 and P = 0.011, respectively) decreases in glucuronidation activity against the UGT2B7-specific substrate epirubicin. Inhibition of endogenous miR-216b-5p levels significantly increased UGT2B7 mRNA levels in HuH-7 (P = 0.021) and Hep3B (P = 0.0068) cells, and increased epirubicin glucuronidation by 85% (P = 0.057) and 50% (P = 0.012) for HuH-7 and Hep3B cells, respectively. UGT2B4 activity against codeine and UGT2B10 activity against nicotine were significantly decreased in both HuH-7 and Hep3B cells (P < 0.001 and P = 0.0048, and P = 0.017 and P = 0.043, respectively) after overexpression of miR-216b-5p mimic. This is the first evidence that miRNAs regulate UGT 2B7 2B4 and 2B10 expression, and that miR-216b-5p regulation of UGT2B proteins may be important in regulating the metabolism of UGT2B substrates. C1 [Dluzen, Douglas F.] NIA, NIH, Baltimore, MD 21224 USA. [Ishmael, Faoud T.] Penn State Univ, Coll Med, Dept Pulm Med, Hershey, PA USA. [Sutliff, Aimee K.; Chen, Gang; Watson, Christy J. W.; Lazarus, Philip] Washington State Univ, Coll Pharm, Dept Pharmaceut Sci, POB 1495, Spokane, WA 99210 USA. RP Lazarus, P (reprint author), Washington State Univ, Coll Pharm, Dept Pharmaceut Sci, POB 1495, Spokane, WA 99210 USA. EM phil.lazarus@wsu.edu OI Dluzen, Douglas/0000-0002-9426-5071 FU Washington State University Mass Spectrometry Core Facility FX The authors thank the Washington State University Mass Spectrometry Core Facility for their support and help with analysis of glucuronide detection. The authors acknowledge the assistance and help of Amity Platt for her advice and help in refining molecular techniques. NR 42 TC 0 Z9 0 U1 3 U2 3 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 EI 1521-0103 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD OCT 1 PY 2016 VL 359 IS 1 BP 182 EP 193 DI 10.1124/jpet.116.235044 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA ED7RR UT WOS:000389067700021 PM 27474751 ER PT J AU Haller, ST Yan, YL Drummond, CA Xie, J Tian, J Kennedy, DJ Shilova, VY Xie, ZJ Liu, J Cooper, CJ Malhotra, D Shapiro, JI Fedorova, OV Bagrov, AY AF Haller, Steven T. Yan, Yanling Drummond, Christopher A. Xie, Joe Tian, Jiang Kennedy, David J. Shilova, Victoria Y. Xie, Zijian Liu, Jiang Cooper, Christopher J. Malhotra, Deepak Shapiro, Joseph I. Fedorova, Olga V. Bagrov, Alexei Y. TI Rapamycin Attenuates Cardiac Fibrosis in Experimental Uremic Cardiomyopathy by Reducing Marinobufagenin Levels and Inhibiting Downstream Pro-Fibrotic Signaling SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE cardiac fibrosis; cardiomyopathy; cardiovascular diseases; fibrosis; heart failure ID ENDOGENOUS CARDIOTONIC STEROIDS; NA/K-ATPASE INHIBITION; LOWERS BLOOD-PRESSURE; CHRONIC-RENAL-FAILURE; PROTEIN-KINASE-C; MONOCLONAL-ANTIBODY; DERMAL FIBROBLASTS; MAMMALIAN TARGET; KIDNEY-DISEASE; CYCLOSPORINE-A AB Background-Experimental uremic cardiomyopathy causes cardiac fibrosis and is causally related to the increased circulating levels of the cardiotonic steroid, marinobufagenin (MBG), which signals through Na/K-ATPase. Rapamycin is an inhibitor of the serine/threonine kinase mammalian target of rapamycin (mTOR) implicated in the progression of many different forms of renal disease. Given that Na/K-ATPase signaling is known to stimulate the mTOR system, we speculated that the ameliorative effects of rapamycin might influence this pathway. Methods and Results-Biosynthesis of MBG by cultured human JEG-3 cells is initiated by CYP27A1, which is also a target for rapamycin. It was demonstrated that 1 mu mol/L of rapamycin inhibited production of MBG in human JEG-2 cells. Male Sprague-Dawley rats were subjected to either partial nephrectomy (PNx), infusion of MBG, and/or infusion of rapamycin through osmotic minipumps. PNx animals showed marked increase in plasma MBG levels (1025 +/- 60 vs 377 +/- 53 pmol/L; P<0.01), systolic blood pressure (169 +/- 1 vs 111 +/- 1 mm Hg; P<0.01), and cardiac fibrosis compared to controls. Plasma MBG levels were significantly decreased in PNx-rapamycin animals compared to PNx (373 +/- 46 vs 1025 +/- 60 pmol/L; P<0.01), and cardiac fibrosis was substantially attenuated by rapamycin treatment. Conclusions-Rapamycin treatment in combination with MBG infusion significantly attenuated cardiac fibrosis. Our results suggest that rapamycin may have a dual effect on cardiac fibrosis through (1) mTOR inhibition and (2) inhibiting MBG-mediated profibrotic signaling and provide support for beneficial effect of a novel therapy for uremic cardiomyopathy. C1 [Haller, Steven T.; Drummond, Christopher A.; Xie, Joe; Tian, Jiang; Kennedy, David J.; Cooper, Christopher J.; Malhotra, Deepak] Univ Toledo, Coll Med & Life Sci, 2801 W Bancroft St, Toledo, OH 43606 USA. [Shilova, Victoria Y.; Fedorova, Olga V.; Bagrov, Alexei Y.] NIA, Cardiovasc Sci Lab, Baltimore, MD 21224 USA. [Yan, Yanling; Xie, Zijian; Liu, Jiang; Shapiro, Joseph I.] Marshall Univ, Joan C Edwards Sch Med, Huntington, WV USA. RP Haller, ST (reprint author), Univ Toledo, Div Cardiovasc Med, 3000 Arlington Ave, Toledo, OH 43614 USA. EM steven.haller@utoledo.edu OI Drummond, Christopher/0000-0002-0378-9882 FU American Heart Association (National and Ohio Valley Affilate) [13POST16860035]; National Institutes of Health (NIH) [HL-105649]; American Heart Association Scientist Development Grant [12SDG12050473]; David and Helen Boone Foundation Research Fund; Central Society for Clinical and Translational Research; National Heart, Lung and Blood Institute (NHLBI), NIH [5U01HL071556]; NIH [1R01HL109015-01]; NHLBI, NIH [5U01HL071556]; Intramural Research Program, National Institute on Aging, NIH FX Haller has received support from the American Heart Association (National and Ohio Valley Affilate) (Grant No.: 13POST16860035). Tian is supported by the National Institutes of Health (NIH; Grant No.: HL-105649). Kennedy is supported by an American Heart Association Scientist Development Grant (12SDG12050473), the David and Helen Boone Foundation Research Fund, and an Early Career Development Award from the Central Society for Clinical and Translational Research. Cooper has received support from the National Heart, Lung and Blood Institute (NHLBI), NIH (5U01HL071556). Shapiro has received support from the NIH (1R01HL109015-01) and NHLBI, NIH (5U01HL071556). Zijian Xie has received support from the NIH (1R01HL109015-01). Fedorova and Bagrov are supported by the Intramural Research Program, National Institute on Aging, NIH. NR 46 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD OCT PY 2016 VL 5 IS 10 AR e004106 DI 10.1161/JAHA.116.004106 PG 22 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EA6OM UT WOS:000386748500037 ER PT J AU Murthy, VL Abbasi, SA Siddique, J Colangelo, LA Reis, J Venkatesh, BA Carr, JJ Terry, JG Camhi, SM Jerosch-Herold, M de Ferranti, S Das, S Freedman, J Carnethon, MR Lewis, CE Lima, JAC Shah, RV AF Murthy, Venkatesh L. Abbasi, Siddique A. Siddique, Juned Colangelo, Laura A. Reis, Jared Venkatesh, Bharath A. Carr, J. Jeffrey Terry, James G. Camhi, Sarah M. Jerosch-Herold, Michael de Ferranti, Sarah Das, Saumya Freedman, Jane Carnethon, Mercedes R. Lewis, Cora E. Lima, Joao A. C. Shah, Ravi V. TI Transitions in Metabolic Risk and Long-Term Cardiovascular Health: Coronary Artery Risk Development in Young Adults (CARDIA) Study SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE epidemiology; metabolic syndrome; obesity; risk factor ID CHILDHOOD OBESITY; ABDOMINAL OBESITY; BLOOD-PRESSURE; HEART-FAILURE; ASSOCIATION CONFERENCE; ADIPOSE-TISSUE; MIDDLE-AGE; ECHOCARDIOGRAPHY; ATHEROSCLEROSIS; POPULATION AB Background-Despite evidence suggesting that early metabolic dysfunction impacts cardiovascular disease risk, current guidelines focus on risk assessments later in life, missing early transitions in metabolic risk that may represent opportunities for averting the development of cardiovascular disease. Methods and Results-In 4420 young adults in the Coronary Artery Risk Development in Young Adults (CARDIA) study, we defined a "metabolic" risk score based on components of the Third Report of the Adult Treatment Panel's definition of metabolic syndrome. Using latent class trajectory analysis adjusted for sex, race, and time-dependent body mass index, we identified 6 distinct metabolic trajectories over time, specified by initial and final risk: low-stable, low-worsening, high-stable, intermediate-worsening, intermediate-stable, and high-worsening. Overall, individuals gained weight over time in CARDIA with statistically but not clinically different body mass index trend over time. Dysglycemia and dyslipidemia over time were highest in initially high or worsening trajectory groups. Divergence in metabolic trajectories occurred in early adulthood (before age 40), with 2 of 3 individuals experiencing an increase in metabolic risk over time. Membership in a higher-risk trajectory (defined as initially high or worsening over time) was associated with greater prevalence and extent of coronary artery calcification, left ventricular mass, and decreased left ventricular strain at year 25. Importantly, despite similar rise in body mass index across trajectories over 25 years, coronary artery calcification and left ventricular structure and function more closely tracked risk factor trajectories. Conclusions-Transitions in metabolic risk occur early in life. Obesity-related metabolic dysfunction is related to subclinical cardiovascular phenotypes independent of evolution in body mass index, including coronary artery calcification and myocardial hypertrophy and dysfunction. C1 [Murthy, Venkatesh L.] Univ Michigan, Dept Med, Cardiovasc Med Div, Ann Arbor, MI 48109 USA. [Murthy, Venkatesh L.] Univ Michigan, Dept Radiol, Div Nucl Med, Ann Arbor, MI 48109 USA. [Abbasi, Siddique A.] Brown Univ, Alpert Med Sch, Providence VA Med Ctr, Providence, RI 02912 USA. [Abbasi, Siddique A.] Brown Univ, Alpert Med Sch, Cardiovasc Inst, Providence, RI 02912 USA. [Siddique, Juned; Colangelo, Laura A.] Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Carnethon, Mercedes R.] Northwestern Univ, Dept Preventat Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Reis, Jared] NHLBI, Div Cardiovasc Sci, Bethesda, MD USA. [Venkatesh, Bharath A.; Lima, Joao A. C.] Johns Hopkins Univ, Dept Med, Div Cardiol, Johns Hopkins Med Inst, Baltimore, MD USA. [Carr, J. Jeffrey; Terry, James G.] Vanderbilt Univ, 221 Kirkland Hall, Nashville, TN 37235 USA. [Camhi, Sarah M.] Univ Massachusetts, Exercise & Hlth Sci Depaitment, Coll Nursing & Hlth Sci, Boston, MA 02125 USA. [Jerosch-Herold, Michael] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, Noninvas Cardiovasc Imaging Sect, Boston, MA 02115 USA. [Jerosch-Herold, Michael] Brigham & Womens Hosp, Dept Radiol, 75 Francis St, Boston, MA 02115 USA. [de Ferranti, Sarah] Boston Childrens Hosp, Preventat Cardiol, Boston, MA USA. [Das, Saumya] Beth Israel Deaconess Med Ctr, Dept Med, Div Cardiovasc, Boston, MA 02215 USA. [Freedman, Jane] Univ Massachusetts, Dept Med, Worcester, MA 01605 USA. [Lewis, Cora E.] Univ Alabama Birmingham, Div Preventat Med, Birmingham, AL USA. [Shah, Ravi V.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Shah, RV (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA.; Murthy, VL (reprint author), Univ Michigan, Dept Med Cardiol, Ann Arbor, MI 48109 USA. EM vlmurthy@med.umich.edu; rvshah@partners.org OI Carr, John/0000-0002-4398-8237 FU National Heart, Lung, and Blood Institute (NHLBI) [N01 HC 95159, N01 HC 95160, N01 HC 95161, N01 HC 95162, N01 HC 95163, N01 HC 95164, N01 HC 95165, N01 HC 95166, N01 HC 95168, N01 HC 95169, HL098445-05]; NCRR [UL1-TR-000040, UL1-RR-025005]; American Heart Association; Thrasher Research Foundation; NHLBI, the Intramural Research Program of the National Institute on Aging (NIA) [HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, HHSN268200900041C]; NIA [AG0005]; NHLBI [AG0005] FX This research was supported by contracts N01 HC 95159, N01 HC 95160, N01 HC 95161, N01 HC 95162, N01 HC 95163, N01 HC 95164, N01 HC 95165, N01 HC 95166, N01 HC 95168, N01 HC 95169, and HL098445-05 (to Carr) from the National Heart, Lung, and Blood Institute (NHLBI) and by grants UL1-TR-000040 and UL1-RR-025005 from NCRR. Dr Shah is supported by an American Heart Association Fellow-to-Faculty Award and the Thrasher Research Foundation. The CARDIA study is supported by contracts HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, and HHSN268200900041C from the NHLBI, the Intramural Research Program of the National Institute on Aging (NIA), and an intra-agency agreement between NIA and NHLBI (AG0005). NR 37 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD OCT PY 2016 VL 5 IS 10 AR e003934 DI 10.1161/JAHA.116.003934 PG 14 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EA6OM UT WOS:000386748500028 ER PT J AU Yang, ZH Bando, M Sakurai, T Chen, Y Emma-Okon, B Wilhite, B Fukuda, D Vaisman, B Pryor, M Wakabayashi, Y Sampson, M Yu, ZX Sakurai, A Zarzour, A Miyahara, H Takeo, J Sakaue, H Sata, M Remaley, AT AF Yang, Zhi-Hong Bando, Masahiro Sakurai, Toshihiro Chen, Ye Emma-Okon, Beatrice Wilhite, Bree Fukuda, Daiju Vaisman, Boris Pryor, Milton Wakabayashi, Yoshiyuki Sampson, Maureen Yu, Zu-Xi Sakurai, Akiko Zarzour, Abdalrahman Miyahara, Hiroko Takeo, Jiro Sakaue, Hiroshi Sata, Masataka Remaley, Alan T. TI Long-chain monounsaturated fatty acid-rich fish oil attenuates the development of atherosclerosis in mouse models SO MOLECULAR NUTRITION & FOOD RESEARCH LA English DT Article DE Atherosclerosis; Cholesterol efflux; Inflammation; Long-chain monounsaturated fatty acids; PPAR signaling pathway ID REVERSE CHOLESTEROL TRANSPORT; C57BL/6J MICE; DEFICIENT MICE; PPAR-GAMMA; EXPRESSION; METABOLISM; EFFLUX; ABCA1; DIET; SUPPLEMENTATION AB Scope: Fish oil-derived long-chain monounsaturated fatty acids (LCMUFA) containing chain lengths longer than 18 were previously shown to improve cardiovascular disease risk factors in mice. However, it is not known if LCMUFA also exerts anti-atherogenic effects. The main objective of the present study was to investigate the effect of LCMUFA on the development of atherosclerosis in mouse models. Methods and results: LDLR-KO mice were fed Western diet supplemented with 2% (w/w) of either LCMUFA concentrate, olive oil, or not (control) for 12 wk. LCMUFA, but not olive oil, significantly suppressed the development of atherosclerotic lesions and several plasma inflammatory cytokine levels, although there were no major differences in plasma lipids between the three groups. At higher doses 5% (w/w) LCMUFA supplementation was observed to reduce pro-atherogenic plasma lipoproteins and to also reduce atherosclerosis in ApoE-KO mice fed a Western diet. RNA sequencing and subsequent qPCR analyses revealed that LCMUFA upregulated PPAR signaling pathways in liver. In cell culture studies, apoB-depleted plasma from LDLR-K mice fed LCMUFA showed greater cholesterol efflux from macrophage-like THP-1 cells and ABCA1-overexpressing BHK cells. Conclusion: Our research showed for the first time that LCMUFA consumption protects against diet-induced atherosclerosis, possibly by upregulating the PPAR signaling pathway. C1 [Yang, Zhi-Hong; Sakurai, Toshihiro; Emma-Okon, Beatrice; Vaisman, Boris; Pryor, Milton; Sakurai, Akiko; Zarzour, Abdalrahman; Remaley, Alan T.] NHLBI, Lipoprot Metab Sect, Cardiopulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Bando, Masahiro; Fukuda, Daiju; Sakaue, Hiroshi; Sata, Masataka] Univ Tokushima, Grad Sch, Inst Biomed Sci, Tokushima, Japan. [Chen, Ye] NHLBI, Syst Biol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. [Wilhite, Bree] NIAAA, Sect Nutrit Neurosci, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD USA. [Wakabayashi, Yoshiyuki] NHLBI, DNA Sequencing Core, NIH, Bldg 10, Bethesda, MD 20892 USA. [Sampson, Maureen] NIH, Ctr Clin, Dept Lab Med, Bethesda, MD 20892 USA. [Yu, Zu-Xi] NHLBI, Pathol Core, NIH, Bldg 10, Bethesda, MD 20892 USA. [Miyahara, Hiroko; Takeo, Jiro] Nippon Suisan Kaisha, Cent Res Lab, Tokyo, Japan. RP Yang, ZH (reprint author), NHLBI, Lipoprot Metab Sect, Cardiopulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM zhihong.yang@nih.gov FU Intramural Research Program of the National Heart, Lung and Blood Institute (NHLBI); Office of Dietary Supplements (ODS) Research Scholars Program at National Institutes of Health FX We wish to thank Tadaomi Naka and Yuji Hirouchi for technical assistance and Lita Freeman for her help with the preparation of the manuscript. This research was supported by the Intramural Research Program of the National Heart, Lung and Blood Institute (NHLBI) and the Office of Dietary Supplements (ODS) Research Scholars Program at National Institutes of Health. NR 29 TC 0 Z9 0 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1613-4125 EI 1613-4133 J9 MOL NUTR FOOD RES JI Mol. Nutr. Food Res. PD OCT PY 2016 VL 60 IS 10 BP 2208 EP 2218 DI 10.1002/mnfr.201600142 PG 11 WC Food Science & Technology SC Food Science & Technology GA DZ8ZD UT WOS:000386160900009 PM 27273599 ER PT J AU Franceschini, N Deng, Y Flessner, MF Eckfeldt, JH Kramer, HJ Lash, JP Lee, DJ Melamed, ML Moncrieft, AE Ricardo, AC Rosas, SE Kaplan, RC Raij, L Cai, JW AF Franceschini, Nora Deng, Yu Flessner, Michael F. Eckfeldt, John H. Kramer, Holly J. Lash, James P. Lee, David J. Melamed, Michal L. Moncrieft, Ashley E. Ricardo, Ana C. Rosas, Sylvia E. Kaplan, Robert C. Raij, Leopoldo Cai, Jianwen TI Smoking patterns and chronic kidney disease in US Hispanics: Hispanic Community Health Study/Study of Latinos SO NEPHROLOGY DIALYSIS TRANSPLANTATION LA English DT Article DE chronic kidney disease; Hispanics; Latinos; intermittent smoking ID GLOMERULAR-FILTRATION-RATE; CIGARETTE-SMOKING; RISK-FACTOR; TOBACCO USE; COLLABORATIVE METAANALYSIS; POPULATION COHORTS; HIGHER ALBUMINURIA; SUPEROXIDE ANION; UNITED-STATES; PROGRESSION AB Intermittent smoking is prevalent among Hispanics, but little is known about whether this smoking pattern associates with increased chronic kidney disease (CKD) risk in this population. The objective of the present study is to identify patterns of exposure associated with CKD in US Hispanics. We used cross-sectional data on 15 410 participants of the Hispanics Community Health Study/the Study of Latinos, a population-based study of individuals aged 18-74 years, recruited in 2008 to 2011 from four US field centers (Bronx, NY; Chicago, IL; Miami, FL; San Diego, CA). Smoking exposure was obtained through a questionnaire. CKD was defined by an estimated glomerular filtration rate of < 60 mL/min/1.73 m(2) or a urine albumin-to-creatinine ratio of a parts per thousand yen30 mg/g. Approximately 14% of individuals were daily and 7% were intermittent smokers, and 16% were past smokers. There was a significant interaction between smoking status and pack-years of exposure (P = 0.0003). In adjusted models, there was an increased odds of CKD among daily, intermittent and past smokers by pack-years compared with never smokers. The association of intermittent smokers was significant at 10 pack-years [odds ratio (OR) = 1.38, 95% confidence intervals (CI) 1.06, 1.81], whereas for daily smokers this association was observed at 40 pack-years (OR = 1.43, 95% CI 1.09, 1.89). Our findings of increased risk of CKD among Hispanics who are intermittent smokers support screening and smoking cessation interventions targeted to this population for the prevention of CKD. It also suggests novel mechanistic pathways for kidney toxicity that should be further explored in future studies. C1 [Franceschini, Nora] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27514 USA. [Deng, Yu; Cai, Jianwen] Univ North Carolina Chapel Hill, Dept Biostat, Collaborat Studies Coordinating Ctr, Chapel Hill, NC USA. [Flessner, Michael F.] NIDDK, Bethesda, MD USA. [Eckfeldt, John H.] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. [Kramer, Holly J.] Loyola Univ, Div Nephrol, Maywood, IL 60153 USA. [Lash, James P.; Ricardo, Ana C.] Univ Illinois, Dept Med, Chicago, IL USA. [Lee, David J.; Moncrieft, Ashley E.; Raij, Leopoldo] Univ Miami, Miami, FL USA. [Melamed, Michal L.; Kaplan, Robert C.] Albert Einstein Coll Med, New York, NY USA. [Rosas, Sylvia E.] Harvard Univ, Joslin Diabet Ctr, Boston, MA 02115 USA. RP Franceschini, N (reprint author), Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27514 USA. EM noraf@unc.edu FU National Heart, Lung, and Blood Institute (NHLBI) [N01-HC65233]; University of Miami [N01-HC65234]; Albert Einstein College of Medicine [N01-HC65235]; Northwestern University [N01-HC65236]; San Diego State University [N01-HC65237]; National Institute of Diabetes and Digestive and Kidney Diseases [K23 DK094829, K24 DK092290]; National Institutes of Health [R21HL123677-01] FX The HCHS/SOL was carried out as a collaborative study supported by contracts from the National Heart, Lung, and Blood Institute (NHLBI) to the University of North Carolina (N01-HC65233), University of Miami (N01-HC65234), Albert Einstein College of Medicine (N01-HC65235), Northwestern University (N01-HC65236) and San Diego State University (N01-HC65237). The following institutes, centers or offices contribute to the HCHS/SOL through a transfer of funds to the NHLBI: National Center on Minority Health and Health Disparities, the National Institute on Deafness and Other Communications Disorders, the National Institute of Dental and Craniofacial Research, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Neurological Disorders and Stroke, and the Office of Dietary Supplements. A.C.R. and J.P.L. are funded by the National Institute of Diabetes and Digestive and Kidney Diseases (K23 DK094829, A.C.R.; K24 DK092290, J.P.L.). N.F. and J.C. had full access to the data and take responsibility for the integrity of the data and the accuracy of the data analysis. N.F. is supported by the National Institutes of Health grant R21HL123677-01. NR 45 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0931-0509 EI 1460-2385 J9 NEPHROL DIAL TRANSPL JI Nephrol. Dial. Transplant. PD OCT PY 2016 VL 31 IS 10 BP 1670 EP 1676 DI 10.1093/ndt/gfw210 PG 7 WC Transplantation; Urology & Nephrology SC Transplantation; Urology & Nephrology GA DZ8YT UT WOS:000386159700023 PM 27257272 ER PT J AU Shmulewitz, D Stohl, M Keyes, KM Brown, Q Saha, TD Hasin, D AF Shmulewitz, Dvora Stohl, Malka Keyes, Katherine M. Brown, Qiana Saha, Tulshi D. Hasin, Deborah TI Effects of State-Level Tobacco Environment on Cigarette Smoking are Stronger Among Those With Individual-Level Risk Factors SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID ALCOHOL-USE-DISORDER; ADVERSE CHILDHOOD EXPERIENCES; NATIONAL EPIDEMIOLOGIC SURVEY; GENERAL-POPULATION SAMPLE; PSYCHIATRIC DIAGNOSTIC MODULES; INTERVIEW SCHEDULE AUDADIS; DRUG-USE; FAMILY-HISTORY; UNITED-STATES; REPRESENTATIVE SAMPLE AB To better understand the impact of the state-level tobacco environment (eg, tobacco control policies, attitudes towards smoking) on cigarette smoking, we examined whether the relationship of state tobacco environments to smoking is modified by individual-level vulnerability factors. In a nationally representative sample of US adults (N = 34 638), past-year smoking and heavy smoking were examined. State-level tobacco environment was defined by tobacco-related control policies and attitudes, ranging from permissive to restrictive; individual vulnerability was defined by childhood maltreatment and/or parental substance problems. Additive interaction tested differences in state-level tobacco environment effects on smoking and heavy smoking by individual-level vulnerability. Significant interactions (P values < .01) indicated that the state tobacco environment had the strongest relationship to smoking outcomes among individuals with greatest individual vulnerability. For example, among respondents with childhood maltreatment and parental substance problems, those in states with permissive tobacco environments had 13.3% greater prevalence of smoking than those in restrictive states. Among respondents with neither individual-level risk factor, those in permissive states had 2.8% greater prevalence than those in restrictive states (interaction P value = .0002). Further restricting states' smoking environments could help reduce the prevalence of smoking and heavy smoking, particularly among those at increased individual risk in the general population. This study shows that the protective effect of restrictive state-level tobacco environments on smoking or heavy smoking was stronger among those especially vulnerable due to individual-level risk factors (parental substance problems, childhood maltreatment). Thus, public health campaigns to influence attitudes towards smoking or legislation to strengthen tobacco control could have a broad effect, particularly impacting those with vulnerability to smoking, which may help decrease smoking prevalence and reduce the massive public health burden of tobacco-related morbidity and mortality. C1 [Shmulewitz, Dvora; Hasin, Deborah] Columbia Univ, Med Ctr, Dept Psychiat, 1051 Riverside Dr 123, New York, NY 10032 USA. [Shmulewitz, Dvora; Stohl, Malka; Hasin, Deborah] New York State Psychiat Inst & Hosp, Clin Phenomenol, New York, NY 10032 USA. [Keyes, Katherine M.; Brown, Qiana; Hasin, Deborah] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. [Saha, Tulshi D.] NIAAA, Lab Epidemiol & Biometry, Bethesda, MD USA. RP Hasin, D (reprint author), Columbia Univ, Med Ctr, Dept Psychiat, 1051 Riverside Dr 123, New York, NY 10032 USA. EM deborah.hasin@gmail.com FU National Institutes of Health [U01AA018111, T32DA031099, K01AA021511]; New York State Psychiatric Institute FX This work was supported by grants from the National Institutes of Health (grant number U01AA018111 to [DS, PI: DH], grant number T32DA031099 to [QB, PI: DH], and grant number K01AA021511 to [KMK]) and the New York State Psychiatric Institute [DH]. The funding sources had no further involvement in this research. NR 78 TC 0 Z9 0 U1 4 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-2203 EI 1469-994X J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD OCT PY 2016 VL 18 IS 10 BP 2020 EP 2030 DI 10.1093/ntr/ntw114 PG 11 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA DZ9NC UT WOS:000386201100014 PM 27130948 ER PT J AU Rodriguez, D Chakraborty, S Warnick, E Crane, S Gao, ZG O'Connor, R Jacobson, KA Carlsson, J AF Rodriguez, David Chakraborty, Saibal Warnick, Eugene Crane, Steven Gao, Zhan-Guo O'Connor, Robert Jacobson, Kenneth A. Carlsson, Jens TI Structure-Based Screening of Uncharted Chemical Space for Atypical Adenosine Receptor Agonists SO ACS CHEMICAL BIOLOGY LA English DT Article ID DRUG DISCOVERY; MOLECULAR DOCKING; ANTITUMOR-ACTIVITY; NATURAL-PRODUCTS; A(2A) RECEPTOR; LIGANDS; DATABASE; OPPORTUNITIES; ACTIVATION; COMPLEXITY AB Small molecule screening libraries cover only a small fraction of the astronomical number of possible drug-like compounds, limiting the success of ligand discovery efforts. Computational screening of virtual libraries representing unexplored chemical space could potentially bridge this gap. Drug development for adenosine receptors (ARs) as targets for inflammation and cardiovascular diseases has been hampered by the paucity of agonist scaffolds. To identify novel AR agonists, a virtual library of synthetically tractable nucleosides with alternative bases was generated and structure-based virtual screening guided selection of compounds for synthesis. Pharmacological assays were carried out at three AR subtypes for 13 ribosides. Nine compounds displayed significant activity at the ARs, and several of these represented atypical agonist scaffolds. The discovered ligands also provided insights into receptor activation and revealed unknown interactions of endogenous and clinical compounds with the ARs. The results demonstrate that virtual compound databases provide access to bioactive matter from regions of chemical space that are sparsely populated in commercial libraries, an approach transferrable to numerous drug targets. C1 [Rodriguez, David] Stockholm Univ, Sci Life Lab, Dept Biochem & Biophys, SE-10691 Stockholm, Sweden. [Rodriguez, David] Stockholm Univ, Ctr Biomembrane Res, SE-10691 Stockholm, Sweden. [Chakraborty, Saibal; Warnick, Eugene; Crane, Steven; Gao, Zhan-Guo; O'Connor, Robert; Jacobson, Kenneth A.] NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Carlsson, Jens] Uppsala Univ, Sci Life Lab, Dept Med Chem, BMC, POB 574, SE-75123 Uppsala, Sweden. RP Jacobson, KA (reprint author), NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA.; Carlsson, J (reprint author), Uppsala Univ, Sci Life Lab, Dept Med Chem, BMC, POB 574, SE-75123 Uppsala, Sweden. EM kennethj@helix.nih.gov; jens.carlsson@orgfarm.uu.se FU Swedish Research Council [2013-05708]; Swedish Foundation for Strategic Research [ICA10-0098]; Science for Life Laboratory; NIDDK; Sven och Lily Lawski Foundation [N2014-0049] FX We thank A. Ranganathan and A. Zeifman for their critical reading of the manuscript. This work was supported by grants from the Swedish Research Council (2013-05708), the Swedish Foundation for Strategic Research (ICA10-0098), and the Science for Life Laboratory to J.C. and by funding from the NIDDK Intramural Research Program to K.A.J. D.R. was funded by a postdoctoral fellowship from the Sven och Lily Lawski Foundation (N2014-0049). Computational resources were provided by the Swedish National Infrastructure for Computing. We thank OpenEye Scientific Software for the use of OEChem and of OMEGA at no cost. J.C. and D.R. participate in the European COST Action CM1207 (GLISTEN). NR 51 TC 0 Z9 0 U1 2 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1554-8929 EI 1554-8937 J9 ACS CHEM BIOL JI ACS Chem. Biol. PD OCT PY 2016 VL 11 IS 10 BP 2763 EP 2772 DI 10.1021/acschembio.6b00357 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DZ9IE UT WOS:000386187700012 PM 27439119 ER PT J AU Wiegand, SL Swortwood, MJ Huestis, MA Thorp, J Jones, HE Vora, NL AF Wiegand, Samantha L. Swortwood, Madeleine J. Huestis, Marilyn A. Thorp, John Jones, Hendree E. Vora, Neeta L. TI Naloxone and Metabolites Quantification in Cord Blood of Prenatally Exposed Newborns and Correlations with Maternal Concentrations SO AJP REPORTS LA English DT Article DE buprenorphine; naloxone; opioid use disorder; pregnancy ID NEONATAL ABSTINENCE SYNDROME; BUPRENORPHINE; PREGNANCY AB ObjectiveTo quantify naloxone and metabolite concentrations in newborns prenatally exposed to sublingual buprenorphine/naloxone and to correlate neonatal and maternal metabolite concentrations. MethodsThis is a prospective observational cohort study. Eleven pregnant women treated for opioid use disorder with sublingual buprenorphine/naloxone were enrolled. Maternal and newborn blood was collected and analyzed for naloxone, buprenorphine, and metabolites via liquid chromatography tandem mass spectrometry. Descriptive statistics and correlation coefficients were utilized to analyze data. ResultsMaternal daily naloxone and buprenorphine doses were 1 to 5mg and 4 to 20mg, respectively; the mean (standard deviation) time from medication until delivery was 9.9 (4.3) hours. Naloxone was below the limits of quantification (LOQ) in five infants and six mothers with a range of less than LOQ to 0.3 g/L. There was a strong positive correlation between maternal and newborn naloxone concentrations: Spearman's = 0.89 (p<0.01). There were strong positive correlations between maternal and neonatal assays for the buprenorphine analyte concentrations: buprenorphine = 0.88 (p<0.01), norbuprenorphine = 0.71 (p=0.01), and norbuprenorphine-glucuronide = 0.98 (p<0.01), but not for buprenorphine-glucuronide, = 0.53 (p=0.10). ConclusionNaloxone and buprenorphine are transferred to the fetus during prenatal exposure to maternal sublingual buprenorphine/naloxone. The quantity of naloxone transferred from maternal circulation is minimal and highly correlated with maternal concentrations. C1 [Wiegand, Samantha L.; Thorp, John; Jones, Hendree E.; Vora, Neeta L.] Univ N Carolina, Dept Obstet & Gynecol, Sch Med, Chapel Hill, NC USA. [Swortwood, Madeleine J.; Huestis, Marilyn A.] NIDA, Dept Chem & Drug Metab, Intramural Res Program, NIH, Baltimore, MD USA. RP Wiegand, SL (reprint author), Berry Bldg,One Wyoming St, Dayton, OH 45409 USA. EM samwiegand@gmail.com FU NICHD NIH HHS [K12 HD001441] NR 26 TC 0 Z9 0 U1 1 U2 1 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 2157-6998 EI 2157-7005 J9 AJP REP JI AJP Rep. PD OCT PY 2016 VL 6 IS 4 BP e385 EP e390 DI 10.1055/s-0036-1593993 PG 6 WC Pediatrics SC Pediatrics GA ED6LQ UT WOS:000388967500001 PM 27896019 ER PT J AU Duis, J Dean, S Applegate, C Harper, A Xiao, R He, WM Dollar, JD Sun, LR Waberski, MB Crawford, TO Hamosh, A Stafstrom, CE AF Duis, Jessica Dean, Shannon Applegate, Carolyn Harper, Amy Xiao, Rui He, Weimin Dollar, James D. Sun, Lisa R. Waberski, Marta Biderman Crawford, Thomas O. Hamosh, Ada Stafstrom, Carl E. TI KIF5A Mutations Cause an Infantile Onset Phenotype Including Severe Myoclonus with Evidence of Mitochondrial Dysfunction SO ANNALS OF NEUROLOGY LA English DT Article ID HEREDITARY SPASTIC PARAPLEGIA; HEAVY-CHAIN KIF5A; GABA(A) RECEPTOR; TRANSPORT; VARIANTS; PROTEINS; EPILEPSY AB Missense mutations in kinesin family member 5A (KIF5A) cause spastic paraplegia 10. We report on 2 patients with de novo stop-loss frameshift variants in KIF5A resulting in a novel phenotype that includes severe infantile onset myoclonus, hypotonia, optic nerve abnormalities, dysphagia, apnea, and early developmental arrest. We propose that alteration and elongation of the carboxy-terminus of the protein has a dominant-negative effect, causing mitochondrial dysfunction in the setting of an abnormal kinesin "motor." These results highlight the role of expanded testing and whole-exome sequencing in critically ill infants and emphasize the importance of accurate test interpretation. C1 [Duis, Jessica; Applegate, Carolyn; Hamosh, Ada] Johns Hopkins Univ, Sch Med, Dept Pediat, McKusick Nathans Inst Genet Med, 1800 Orleans St, Baltimore, MD 21287 USA. [Dean, Shannon; Sun, Lisa R.; Crawford, Thomas O.; Stafstrom, Carl E.] Johns Hopkins Univ, Sch Med, Pediat Neurol, Baltimore, MD USA. [Harper, Amy] Carolinas Pediat Neurol Care, Charlotte, NC USA. [Xiao, Rui; He, Weimin] Baylor Coll Med, Dept Mol & Human Genet, Baylor Miraca Genet Labs, Houston, TX 77030 USA. [Dollar, James D.] Carolinas Pathol Grp, Charlotte, NC USA. [Waberski, Marta Biderman] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Duis, J (reprint author), Johns Hopkins Univ, Sch Med, Dept Pediat, McKusick Nathans Inst Genet Med, 1800 Orleans St, Baltimore, MD 21287 USA. EM jduis1@jhmi.edu FU NHGRI NIH HHS [U54 HG006542, UM1 HG006542] NR 17 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0364-5134 EI 1531-8249 J9 ANN NEUROL JI Ann. Neurol. PD OCT PY 2016 VL 80 IS 4 BP 633 EP 637 DI 10.1002/ana.24744 PG 5 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA ED0XZ UT WOS:000388568700016 PM 27463701 ER PT J AU Hotta, VT Bluemke, DA Staszko, KF Pereira, ANRE Rochitte, CE AF Hotta, Viviane Tiemi Bluemke, David A. Staszko, Kamila Fernanda Rodrigues Epitacio Pereira, Ana Neri Rochitte, Carlos Eduardo TI Rare Complication of non-Treated Abdominal Aortic Aneurysm: Extensive Thrombus in Right Cardiac Chambers SO ARQUIVOS BRASILEIROS DE CARDIOLOGIA LA English DT Article DE Aortic Aneurysm, Abdominal / complications; Thrombosis; Heart Atria; Echocardiography AB A 78-year-old patient presented with shortness of breath after falling down. Transthoracic echocardiogram showed an extensive thrombus in the right atrium (RA), extensive thrombosis of the inferior vena cava (IVC), and abdominal aortic aneurysm (AAA). A magnetic resonance confirmed the thrombosis of the RA extending to the IVC, which was apparently fused to the abdominal aortic aneurysm (compression? erosion?). This case illustrates a severe and rare complication of a non-treated AAA. There probably was IVC erosion by the aortic aneurysm, leading to blood stasis and extensive thrombosis of the IVC and right cardiac chambers. C1 [Hotta, Viviane Tiemi; Staszko, Kamila Fernanda; Rodrigues Epitacio Pereira, Ana Neri; Rochitte, Carlos Eduardo] Univ Sao Paulo, Fac Med, Inst Coracao, Sao Paulo, Brazil. [Bluemke, David A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Hotta, VT (reprint author), Univ Sao Paulo, Unidade Clin Miocardiopatias & Doencas Aorta, Fac Med, Inst Coracao, Ave Dr Eneas Carvalho Aguiar,44, BR-05403000 Sao Paulo, SP, Brazil. EM viviane.hotta@gmail.com OI Bluemke, David/0000-0002-8323-8086 NR 4 TC 0 Z9 0 U1 0 U2 0 PU ARQUIVOS BRASILEIROS CARDIOLOGIA PI RIO DE JANEIRO PA AVENIDA MARECHAL CAMARA 160-330 CENTRO, RIO DE JANEIRO, RJ 20 020-907, BRAZIL SN 0066-782X J9 ARQ BRAS CARDIOL JI Arq. Bras. Cardiol. PD OCT PY 2016 VL 107 IS 4 BP 378 EP 380 DI 10.5935/abc.20160143 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA ED1BM UT WOS:000388578700011 PM 27849260 ER PT J AU Kim, S Yeganova, L Wilbur, WJ AF Kim, Sun Yeganova, Lana Wilbur, W. John TI Meshable: searching PubMed abstracts by utilizing MeSH and MeSH-derived topical terms SO BIOINFORMATICS LA English DT Article AB Medical Subject Headings (MeSH (R)) is a controlled vocabulary for indexing and searching biomedical literature. MeSH terms and subheadings are organized in a hierarchical structure and are used to indicate the topics of an article. Biologists can use either MeSH terms as queries or the MeSH interface provided in PubMed (R) for searching PubMed abstracts. However, these are rarely used, and there is no convenient way to link standardized MeSH terms to user queries. Here, we introduce a web interface which allows users to enter queries to find MeSH terms closely related to the queries. Our method relies on co-occurrence of text words and MeSH terms to find keywords that are related to each MeSH term. A query is then matched with the keywords for MeSH terms, and candidate MeSH terms are ranked based on their relatedness to the query. The experimental results show that our method achieves the best performance among several term extraction approaches in terms of topic coherence. Moreover, the interface can be effectively used to find full names of abbreviations and to disambiguate user queries. C1 [Kim, Sun; Yeganova, Lana; Wilbur, W. John] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Kim, S (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM sun.kim@nih.gov FU Intramural Research Program of the NIH, National Library of Medicine FX Intramural Research Program of the NIH, National Library of Medicine. NR 12 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 EI 1460-2059 J9 BIOINFORMATICS JI Bioinformatics PD OCT 1 PY 2016 VL 32 IS 19 BP 3044 EP 3046 DI 10.1093/bioinformatics/btw331 PG 3 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA DZ7BX UT WOS:000386020100027 PM 27288493 ER PT J AU Mohammad, MK Pepper, DJ Kedar, A Bhaijee, F Familoni, B Rashed, H Cutts, T Abell, TL AF Mohammad, Mohammad Khalid Pepper, Dominique J. Kedar, Archana Bhaijee, Feriyl Familoni, Babajide Rashed, Hani Cutts, Teresa Abell, Thomas L. TI Measures of Autonomic Dysfunction in Diabetic and Idiopathic Gastroparesis SO GASTROENTEROLOGY RESEARCH LA English DT Article DE Gastroparesis; Diabetes; Autonomic nervous system; Sympathetic function; Vagal dysfunction ID MANAGEMENT; MELLITUS AB Background: Gastroparesis is a condition classically characterized by delayed gastric emptying and is associated with considerable morbidity. While the etiology of gastroparesis remains elusive, autonomic dysfunction may play an important role, especially as many patients with gastroparesis also have diabetes. The aim of this study was to determine whether measures of autonomic function differ between adults with diabetic gastroparesis (DG) and adults with idiopathic gastroparesis (IG). Methods: Tests of systemic autonomic function were performed among 20 adults with GD (six men and 14 women, mean age: 42 years) and 21 adults with IG (seven men and 14 women, mean age: 37 years). Measures included vagal cholinergics by R-R interval percentage variation (RRI-PV) and sympathetic adrenergics by vasoconstriction to cold (VC) and postural adjustment ratio (PAR). The two groups were compared using Wilcoxon rank sum tests and linear regression analysis (STATA 10.0). Results: In univariate analysis, the following autonomic measures differed significantly between DG and IG: VC (P = 0.004), PAR (P = 0.045), VC + PAR (P = 0.002) and RRI-PV (P < 0.001). In multivariate analysis (P = 0.002, R-2 = 0.55), only RRI-PV (adjusted odds ratio (aOR): 1.02, 95% confidence interval (CI): 1.01 - 1.03) differed significantly between DG and IG patients. Conclusions: Vagal cholinergics are affected to a greater degree in DG compared to IG, suggesting that impaired vagal tone is not a universal mechanism for gastroparesis. C1 [Mohammad, Mohammad Khalid; Kedar, Archana; Abell, Thomas L.] Univ Louisville, Dept Med, Div Gastroenterol Hepatol & Nutr, 550 S Jackson St,ACB3 A3L15, Louisville, KY 40202 USA. [Pepper, Dominique J.] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Pepper, Dominique J.] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. [Bhaijee, Feriyl] AmeriPath Indiana, Indianapolis, IN USA. [Familoni, Babajide] US Army, Res Dev & Engn Command, NVESD, Ft Belvoir, VA USA. [Rashed, Hani] Methodist Univ Hosp, Neurosci Inst & Canc Ctr, Memphis, TN USA. [Cutts, Teresa] Wake Forest Sch Med, Div Publ Hlth, Winston Salem, NC USA. RP Abell, TL (reprint author), Univ Louisville, Dept Med, Div Gastroenterol Hepatol & Nutr, 550 S Jackson St,ACB3 A3L15, Louisville, KY 40202 USA. EM thomas.abell@louisville.edu NR 19 TC 0 Z9 0 U1 0 U2 0 PU ELMER PRESS INC PI QUEBEC PA 9160 BOUL LEDUC, BUREAU 410, BROSSARD, QUEBEC, J4Y 0E3, CANADA SN 1918-2805 EI 1918-2813 J9 GASTROENTEROL RES JI Gasteroenterol. Res. PD OCT PY 2016 VL 9 IS 4-5 BP 65 EP 69 DI 10.14740/gr713w PG 5 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA ED2OZ UT WOS:000388688500001 PM 27785328 ER PT J AU Vargas, AJ Quackenbush, J Glass, K AF Vargas, Ashley J. Quackenbush, John Glass, Kimberly TI Diet-induced weight loss leads to a switch in gene regulatory network control in the rectal mucosa SO GENOMICS LA English DT Article DE Weight loss; Colorectal cancer; Colorectum; Diet; Gene network; Gene regulation; Diet ID OBESITY-RELATED CANCERS; BODY-MASS INDEX; COLORECTAL-CANCER; COLON-CANCER; C-MYC; HEALTH-PROFESSIONALS; RISK; EXPRESSION; TRANSCRIPTION; METAANALYSIS AB Background: Weight loss may decrease risk of colorectal cancer in obese individuals, yet its effect in the colorectum is not well understood. We used integrative network modeling, Passing Attributes between Networks for Data Assimilation, to estimate transcriptional regulatory network models from mRNA expression levels from rectal mucosa biopsies measured pre- and post-weight loss in 10 obese, pre-menopausal women. Results: We identified significantly greater regulatory targeting of glucose transport pathways in the post-weight loss regulatory network, including "regulation of glucose transport" (FDR = 0.02), "hexose transport" (FDR = 0.06), "glucose transport" (FDR = 0.06) and "monosaccharide transport" (FDR = 0.08). These findings were not evident by gene expression analysis alone. Network analysis also suggested a regulatory switch from NFKB1 to MAX control of MYC post-weight loss. Conclusions: These network-based results expand upon standard gene expression analysis by providing evidence for a potential mechanistic alteration caused by weight loss. (C) 2016 The Authors. Published by Elsevier Inc. C1 [Vargas, Ashley J.; Quackenbush, John] Harvard Univ, Harvard Sch Publ Hlth, Boston, MA USA. [Vargas, Ashley J.] NCI, Canc Prevent Fellowship Program, Rockville, MD USA. [Quackenbush, John; Glass, Kimberly] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Glass, Kimberly] Brigham & Womens Hosp, Channing Div Network Med, 181 Longwood Ave,Rm 577, Boston, MA 02115 USA. RP Glass, K (reprint author), Brigham & Womens Hosp, Channing Div Network Med, 181 Longwood Ave,Rm 577, Boston, MA 02115 USA. EM rekrg@channing.harvard.edu FU Cancer Prevention Fellowship Program, National Cancer Institute; National Heart, Lung, and Blood Institute of the US National Institutes of Health [1R01 HL111759] FX AV was supported by the Cancer Prevention Fellowship Program, National Cancer Institute. JQ and KG were supported by a grant from the National Heart, Lung, and Blood Institute of the US National Institutes of Health (1R01 HL111759) NR 49 TC 0 Z9 0 U1 1 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 EI 1089-8646 J9 GENOMICS JI Genomics PD OCT PY 2016 VL 108 IS 3-4 BP 126 EP 133 DI 10.1016/j.ygeno.2016.08.001 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA ED1CD UT WOS:000388580500003 PM 27524493 ER PT J AU Brown, AM Sankineni, S Cieciera, M Mertan, FV Folio, L Merino, MJ Pinto, PA Choyke, P Turkbey, B AF Brown, A. M. Sankineni, S. Cieciera, M. Mertan, F. V. Folio, L. Merino, M. J. Pinto, P. A. Choyke, P. Turkbey, B. TI Semiautomated Prostate Cancer Segmentation on High b-Value Diffusion-Weighted Magnetic Resonance Imaging Predicts Whole Mount Histopathology SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT 58th Annual Meeting of the American-Society-for-Radiation-Oncology CY SEP 25-28, 2016 CL Boston, MA SP Amer Soc Radiat Oncol C1 [Brown, A. M.] Duke Univ, Sch Med, Durham, NC USA. [Brown, A. M.; Sankineni, S.; Cieciera, M.; Mertan, F. V.; Choyke, P.; Turkbey, B.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Cieciera, M.] Univ Heidelberg Hosp, Heidelberg, Germany. [Folio, L.] NIH, Dept Diagnost Radiol, Radiol & Imaging Sci, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Merino, M. J.] NCI, Pathol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Pinto, P. A.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD OCT 1 PY 2016 VL 96 IS 2 SU S MA 2560 BP E229 EP E230 PG 2 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA EB8QL UT WOS:000387655802559 ER PT J AU Greer, MD Valle, L Madan, RA Krauze, AV Kaushal, A Brown, AM Choyke, P Citrin, DE Turkbey, B AF Greer, M. D. Valle, L. Madan, R. A. Krauze, A. V. Kaushal, A. Brown, A. M. Choyke, P. Citrin, D. E. Turkbey, B. TI Magnetic Resonance Imaging Findings Associated With Urinary Symptoms After Intensity Modulated Radiation Therapy for Prostate Cancer SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT 58th Annual Meeting of the American-Society-for-Radiation-Oncology CY SEP 25-28, 2016 CL Boston, MA SP Amer Soc Radiat Oncol C1 [Greer, M. D.] Cleveland Clin, Lerner Coll Med, Cleveland, OH USA. [Greer, M. D.; Choyke, P.; Turkbey, B.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Valle, L.; Citrin, D. E.] NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. [Madan, R. A.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Krauze, A. V.] NCI, NIH, Bethesda, MD 20892 USA. [Brown, A. M.] Duke Univ, Sch Med, Durham, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD OCT 1 PY 2016 VL 96 IS 2 SU S MA 2654 BP E269 EP E269 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA EB8QL UT WOS:000387655802652 ER PT J AU Greer, MD Brown, AM Shih, JH Summers, RM Marko, J Law, YM Pinto, PA Citrin, DE Choyke, P Turkbey, B AF Greer, M. D. Brown, A. M. Shih, J. H. Summers, R. M. Marko, J. Law, Y. M. Pinto, P. A. Citrin, D. E. Choyke, P. Turkbey, B. TI Bridging the Gap: Accuracy and Agreement of PIRADSv2 for Multiple Readers for Magnetic Resonance Imaging Prostate Tumor Detection SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT 58th Annual Meeting of the American-Society-for-Radiation-Oncology CY SEP 25-28, 2016 CL Boston, MA SP Amer Soc Radiat Oncol C1 [Greer, M. D.] Cleveland Clin, Lerner Coll Med, Cleveland, OH 44106 USA. [Greer, M. D.; Brown, A. M.; Choyke, P.; Turkbey, B.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Brown, A. M.] Duke Univ, Sch Med, Durham, NC USA. [Shih, J. H.] NCI, Biometr Res Branch, NIH, Bethesda, MD 20892 USA. [Summers, R. M.] NIH, Ctr Clin, Imaging Biomarkers & Comp Aided Diag Lab, Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Marko, J.] Walter Reed Natl Mil Med Ctr, Bethesda, MD USA. [Law, Y. M.] Singapore Gen Hosp, Singapore, Singapore. [Pinto, P. A.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Citrin, D. E.] NCI, Radiat Oncol Branch, Bldg 10, Bethesda, MD 20892 USA. OI Greer, Matthew/0000-0003-4409-4398 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD OCT 1 PY 2016 VL 96 IS 2 SU S MA 2550 BP E225 EP E225 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA EB8QL UT WOS:000387655802549 ER PT J AU Krauze, AV Cheng, JY Ning, H Hawes, MK Mackey, M Zgela, TC Smart, DK Citrin, DE Rowe, L Camphausen, KA AF Krauze, A. V. Cheng, J. Y. Ning, H. Hawes, M. K. Mackey, M. Zgela, T. Cooley Smart, D. K. Citrin, D. E. Rowe, L. Camphausen, K. A. TI Deformable Registration for Estimation of Cumulative Dose and Normal Tissue Complication Probability in Patients Receiving Reirradiation for Recurrent High-Grade Glioma SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT 58th Annual Meeting of the American-Society-for-Radiation-Oncology CY SEP 25-28, 2016 CL Boston, MA SP Amer Soc Radiat Oncol C1 [Krauze, A. V.; Cheng, J. Y.; Ning, H.; Hawes, M. K.; Mackey, M.; Zgela, T. Cooley; Smart, D. K.; Rowe, L.; Camphausen, K. A.] NCI, NIH, Bethesda, MD 20892 USA. [Rowe, L.] NCI, Radiat Oncol Branch, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD OCT 1 PY 2016 VL 96 IS 2 SU S MA 2304 BP E125 EP E125 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA EB8QL UT WOS:000387655802304 ER PT J AU Reed, A Valle, L Krauze, AV Kaushal, A Choyke, P Turkbey, B Pinto, PA Wood, B Citrin, DE AF Reed, A. Valle, L. Krauze, A. V. Kaushal, A. Choyke, P. Turkbey, B. Pinto, P. A. Wood, B. Citrin, D. E. TI Magnetic Resonance Imaging Guided Fusion Biopsy Commonly Alters Radiation-Based Treatment Recommendations SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT 58th Annual Meeting of the American-Society-for-Radiation-Oncology CY SEP 25-28, 2016 CL Boston, MA SP Amer Soc Radiat Oncol C1 [Reed, A.; Wood, B.] NCI, Bethesda, MD 20892 USA. [Valle, L.; Kaushal, A.; Citrin, D. E.] NCI, Radiat Oncol Branch, Bldg 10, Bethesda, MD 20892 USA. [Krauze, A. V.] NCI, NIH, Bethesda, MD 20892 USA. [Choyke, P.; Turkbey, B.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Pinto, P. A.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD OCT 1 PY 2016 VL 96 IS 2 SU S MA 2638 BP E262 EP E263 PG 2 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA EB8QL UT WOS:000387655802636 ER PT J AU Rowe, L Mackey, M Smart, DK Ning, H Gilbert, MR Camphausen, KA Krauze, AV AF Rowe, L. Mackey, M. Smart, D. K. Ning, H. Gilbert, M. R. Camphausen, K. A. Krauze, A. V. TI Outcomes and Prognostic Features of Glioblastoma Multiforme in the Temozolomide Era SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT 58th Annual Meeting of the American-Society-for-Radiation-Oncology CY SEP 25-28, 2016 CL Boston, MA SP Amer Soc Radiat Oncol C1 [Rowe, L.; Mackey, M.; Smart, D. K.; Ning, H.; Gilbert, M. R.; Camphausen, K. A.; Krauze, A. V.] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD OCT 1 PY 2016 VL 96 IS 2 SU S MA 2244 BP E100 EP E100 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA EB8QL UT WOS:000387655802245 ER PT J AU Valle, L Greer, MD Muthigi, A Krauze, AV Kaushal, A Su, D Pinto, PA Wood, B Merino, MJ Ning, H Arora, B Cooley-Zgela, T Choyke, P Turkbey, B Citrin, DE AF Valle, L. Greer, M. D. Muthigi, A. Krauze, A. V. Kaushal, A. Su, D. Pinto, P. A. Wood, B. Merino, M. J. Ning, H. Arora, B. Cooley-Zgela, T. Choyke, P. Turkbey, B. Citrin, D. E. TI Assessment of Multiparametric Magnetic Resonance Imaging for the Detection of Local Recurrence After Low-Dose-Rate Brachytherapy SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT 58th Annual Meeting of the American-Society-for-Radiation-Oncology CY SEP 25-28, 2016 CL Boston, MA SP Amer Soc Radiat Oncol C1 [Valle, L.; Kaushal, A.; Arora, B.; Cooley-Zgela, T.; Citrin, D. E.] NCI, Radiat Oncol Branch, Bldg 10, Bethesda, MD 20892 USA. [Greer, M. D.; Turkbey, B.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Muthigi, A.; Su, D.] NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. [Krauze, A. V.; Ning, H.] NCI, NIH, Bethesda, MD 20892 USA. [Pinto, P. A.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Wood, B.] NCI, Bethesda, MD 20892 USA. [Merino, M. J.] NCI, Pathol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Choyke, P.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD OCT 1 PY 2016 VL 96 IS 2 SU S MA 2598 BP E245 EP E246 PG 2 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA EB8QL UT WOS:000387655802596 ER PT J AU Arthofer, E Hot, B Petersen, J Strakova, K Jager, S Grundmann, M Kostenis, E Gutkind, JS Schulte, G AF Arthofer, Elisa Hot, Belma Petersen, Julian Strakova, Katerina Jager, Stefan Grundmann, Manuel Kostenis, Evi Gutkind, J. Silvio Schulte, Gunnar TI WNT Stimulation Dissociates a Frizzled 4 Inactive-State Complex with G alpha(12/13) SO MOLECULAR PHARMACOLOGY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; FAMILIAL EXUDATIVE VITREORETINOPATHY; HETEROTRIMERIC G-PROTEINS; LIVING CELLS; TRANSMEMBRANE DOMAINS; SIGNAL-TRANSDUCTION; PLASMA-MEMBRANE; P115 RHOGEF; SELECTIVITY; ACTIVATION AB Frizzleds (FZDs) are unconventional G protein-coupled receptors that belong to the class Frizzled. They are bound and activated by the Wingless/Int-1 lipoglycoprotein (WNT) family of secreted lipoglycoproteins. To date, mechanisms of signal initiation and FZD-G protein coupling remain poorly understood. Previously, we showed that FZD(6) assembles withG alpha(i1)/G alpha(q) (but not withG alpha(s), G alpha(o) and G alpha(12/13)), and that these inactive-state complexes are dissociated by WNTs and regulated by the phosphoprotein Dishevelled (DVL). Here, we investigated the inactive-state assembly of heterotrimeric G proteins with FZD(4), a receptor important in retinal vascular development and frequently mutated in Norrie disease or familial exudative vitreoretinopathy. Live-cell imaging experiments using fluorescence recovery after photobleaching show that human FZD(4) assembles-in a DVL-independent manner-with G alpha(12/13) but not representatives of other heterotrimeric G protein subfamilies, such as G alpha(i1), G alpha(o), G alpha(s), andG alpha(q). The FZD(4)-Gprotein complex dissociates upon stimulation with WNT-3A, WNT-5A, WNT-7A, and WNT-10B. In addition, WNT-induced dynamic mass redistribution changes in untransfected and, even more so, in FZD(4) green fluorescent protein-transfected cells depend on G alpha(12/13). Furthermore, expression of FZD(4) and G alpha(12) or G alpha(13) in human embryonic kidney 293 cells induces WNT-dependent membrane recruitment of p115-RHOGEF (RHO guanine nucleotide exchange factor, molecular weight 115 kDa), a direct target of G alpha(12/13) signaling, underlining the functionality of an FZD(4)-G alpha(12/13)-RHO signaling axis. In summary, G alpha(12/13)-mediatedWNT/FZD(4) signaling through p115-RHOGEF offers an intriguing and previously unappreciated mechanistic link of FZD(4) signaling to cytoskeletal rearrangements and RHO signaling with implications for the regulation of angiogenesis during embryonic and tumor development. C1 [Arthofer, Elisa; Hot, Belma; Petersen, Julian; Strakova, Katerina; Jager, Stefan; Schulte, Gunnar] Karolinska Inst, Dept Physiol & Pharmacol, Sect Receptor Biol & Signaling, Nanna Svartz Vag 2, S-17177 Stockholm, Sweden. [Arthofer, Elisa] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Signal Transduct, NIH, Bethesda, MD USA. [Strakova, Katerina; Schulte, Gunnar] Masaryk Univ, Inst Expt Biol, Fac Sci, Brno, Czech Republic. [Grundmann, Manuel; Kostenis, Evi] Univ Bonn, Inst Pharmaceut Biol, Mol Cellular & Pharmacobiol Sect, Bonn, Germany. [Gutkind, J. Silvio] Univ Calif San Diego, Dept Pharmacol, Moores Canc Ctr, La Jolla, CA 92093 USA. RP Schulte, G (reprint author), Karolinska Inst, Dept Physiol & Pharmacol, Sect Receptor Biol & Signaling, Nanna Svartz Vag 2, S-17177 Stockholm, Sweden. EM gunnar.schulte@ki.se FU Karolinska Institutet; Karolinska Institutet's Eye Disease Research Foundation; Board of Doctoral Education at Karolinska Institutet; Swedish Research Council [2011-2435, 2013-5708, 2015-02899]; Swedish Cancer Society [CAN 2011/690, CAN 2014/659]; Knut and Alice Wallenberg Foundation [KAW2008.0149]; Karolinska Institutet National Institutes of Health Joint PhD Program in Neuroscience; Czech Science Foundation [13-32990S]; Program "KI-MU" [CZ.1.07/2.3.00/20.0180]; European Social Fund; state budget of the Czech Republic; Marie Curie ITN WntsApp [608180]; Intramural Research Program of the National Institutes of Health National Institute of Dental and Craniofacial Research [Z01DE00551]; ERASMUS+ program FX The study was financially supported by grants from Karolinska Institutet; Karolinska Institutet's Eye Disease Research Foundation; the Board of Doctoral Education at Karolinska Institutet (J.P., B.H.); the Swedish Research Council [Grants 2011-2435, 2013-5708, and 2015-02899]; the Swedish Cancer Society [Project Grants CAN 2011/690 and CAN 2014/659]; the Knut and Alice Wallenberg Foundation [Grant KAW2008.0149]; the Karolinska Institutet National Institutes of Health Joint PhD Program in Neuroscience (E.A.); the Czech Science Foundation [Grant 13-32990S]; and the Program "KI-MU" [Grant CZ.1.07/2.3.00/20.0180], cofinanced from European Social Fund and the state budget of the Czech Republic and the Marie Curie ITN WntsApp [608180; www.wntsapp.eu]. This research was supported in part by the Intramural Research Program of the National Institutes of Health National Institute of Dental and Craniofacial Research [Grant Z01DE00551]. S.J. was supported by the ERASMUS+ program. NR 70 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X EI 1521-0111 J9 MOL PHARMACOL JI Mol. Pharmacol. PD OCT 1 PY 2016 VL 90 IS 4 BP 447 EP 459 DI 10.1124/mol.116.104919 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA ED3AR UT WOS:000388722100005 PM 27458145 ER PT J AU Berchiche, YA Sakmar, TP AF Berchiche, Yamina A. Sakmar, Thomas P. TI CXC Chemokine Receptor 3 Alternative Splice Variants Selectively Activate Different Signaling Pathways SO MOLECULAR PHARMACOLOGY LA English DT Article ID RESONANCE ENERGY-TRANSFER; T-LYMPHOCYTES; BETA-ARRESTIN; TYROSINE SULFATION; PROTEIN-1 RECEPTOR; CELL-MIGRATION; TERMINAL TAIL; I-TAC; EXPRESSION; LIGAND AB The G protein-coupled receptor (GPCR) C-X-C chemokine receptor 3 (CXCR3) is a potential drug target that mediates signaling involved in cancer metastasis and inflammatory diseases. The CXCR3 primary transcript has three potential alternative splice variants and cell-type specific expression results in receptor variants that are believed to have different functional characteristics. However, the molecular pharmacology of ligand binding to CXCR3 alternative splice variants and their downstream signaling pathways remain poorly explored. To better understand the role of the functional consequences of alternative splicing of CXCR3, we measured signaling in response to four different chemokine ligands (CXCL4, CXCL9, CXCL10, and CXCL11) with agonist activity at CXCR3. Both CXCL10 and CXCL11 activated splice variant CXCR3A. Whereas CXCL10 displayed full agonistic activity for G alpha(i) activation and extracellular signal regulated kinase ( ERK) 1/2 phosphorylation and partial agonist activity for beta-arrestin recruitment, CXCL9 triggered only modest ERK1/2 phosphorylation. CXCL11 induced CXCR3B-mediated beta-arrestin recruitment and little ERK phosphorylation. CXCR3Alt signaling was limited to modest ligand-induced receptor internalization and ERK1/2 phosphorylation in response to chemokines CXCL11, CXCL10, and CXCL9. These results show that CXCR3 splice variants activate different signaling pathways and that CXCR3 variant function is not redundant, suggesting a mechanism for tissue specific biased agonism. Our data show an additional layer of complexity for chemokine receptor signaling that might be exploited to target specific CXCR3 splice variants. C1 [Berchiche, Yamina A.; Sakmar, Thomas P.] Rockefeller Univ, Lab Chem Biol & Signal Transduct, 1230 York Ave, New York, NY 10021 USA. [Sakmar, Thomas P.] Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Neurogeriatr, Ctr Alzheimer Res, Huddinge, Sweden. [Berchiche, Yamina A.] NIAID, B Cell Mol Immunol Sect, Immunoregulat Lab, US Natl Inst Hlth, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Sakmar, TP (reprint author), Lab Chem Biol & Signal Transduct, Box 187,RRB 510,1230 York Ave, New York, NY 10065 USA. EM sakmar@rockefeller.edu RI Sakmar, Thomas/D-1833-2015 OI Sakmar, Thomas/0000-0002-2836-8953 FU Fonds de la Recherche en Sante du Quebec fellowship, Quebec, Canada FX This work was supported by a Fonds de la Recherche en Sante du Quebec fellowship, Quebec, Canada (Y.A.B.). NR 54 TC 3 Z9 3 U1 4 U2 4 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X EI 1521-0111 J9 MOL PHARMACOL JI Mol. Pharmacol. PD OCT 1 PY 2016 VL 90 IS 4 BP 483 EP 495 DI 10.1124/mol.116.105502 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA ED3AR UT WOS:000388722100008 PM 27512119 ER PT J AU Fink, EL Prince, DK Kaltman, JR Atkins, DL Austin, M Warden, C Hutchison, J Daya, M Goldberg, S Herren, H Tijssen, JA Christenson, J Vaillancourt, C Miller, R Schmicker, RH Callaway, CW AF Fink, Ericka L. Prince, David K. Kaltman, Jonathan R. Atkins, Dianne L. Austin, Michael Warden, Craig Hutchison, Jamie Daya, Mohamud Goldberg, Scott Herren, Heather Tijssen, Janice A. Christenson, James Vaillancourt, Christian Miller, Ronna Schmicker, Robert H. Callaway, Clifton W. CA Resuscitation Outcomes Consortium TI Unchanged pediatric out-of-hospital cardiac arrest incidence and survival rates with regional variation in North America SO RESUSCITATION LA English DT Article DE Pediatric; Cardiac arrest; Resuscitation; Outcomes; Epidemiology ID OUTCOMES CONSORTIUM ROC; CARDIOPULMONARY-RESUSCITATION; CHILDREN; EPIDEMIOLOGY; TERMINATION; YOUNGER; TRENDS; SCENE; TIME AB Aim: Outcomes for pediatric out-of-hospital cardiac arrest (OHCA) are poor. Our objective was to determine temporal trends in incidence and mortality for pediatric OHCA. Methods: Adjusted incidence and hospital mortality rates of pediatric non-traumatic OHCA patients from 2007-2012 were analyzed using the 9 region Resuscitation Outcomes Consortium Epidemiological Registry (ROC-Epistry) database. Children were divided into 4 age groups: perinatal (<3 days), infants (3 days-1 year), children (1-11 years), and adolescents (12-19 years). ROC regions were analyzed post hoc. Results: We studied 1738 children with OHCA. The age- and sex-adjusted incidence rate of OHCA was 8.3 per 100,000 person-years (75.3 for infants vs. 3.7 for children and 6.3 for adolescents, per 100,000 person-years, p < 0.001). Incidence rates differed by year (p < 0.001) without overall linear trend. Annual survival rates ranged from 6.7-10.2%. Survival was highest in the perinatal (25%) and adolescent (17.3%) groups. Stratified by age group, survival rates over time were unchanged (all p > 0.05) but there was a non-significant linear trend (1.3% increase) in infants. In the multivariable logistic regression analysis, infants, unwitnessed event, initial rhythm of asystole, and region were associated with worse survival, all p < 0.001. Survival by region ranged from 2.6-14.7%. Regions with the highest survival had more cases of EMS-witnessed OHCA, bystander CPR, and increased EMS-defibrillation (all p < 0.05). Conclusions: Overall incidence and survival of children with OHCA in ROC regions did not significantly change over a recent 5 year period. Regional variation represents an opportunity for further study to improve outcomes. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Fink, Ericka L.] UPMC, Childrens Hosp Pittsburgh, Div Pediat Crit Care Med, 4401 Penn Ave,Fac Pavilion,2nd Floor, Pittsburgh, PA 15224 USA. [Prince, David K.; Herren, Heather; Schmicker, Robert H.] Univ Washington, Clin Trial Ctr, Dept Biostat, Seattle, WA 98195 USA. [Kaltman, Jonathan R.] NHLBI, Div Cardiovasc Sci, Bldg 10, Bethesda, MD 20892 USA. [Atkins, Dianne L.] Univ Iowa, Carver Coll Med, Stead Dept Pediat, Iowa City, IA USA. [Austin, Michael] Univ Ottawa, Ottawa Hosp, Dept Emergency Med, Ottawa, ON, Canada. [Warden, Craig] Oregon Hlth & Sci Univ, Doernbecher Childrens Hosp, Portland, OR USA. [Hutchison, Jamie] Univ Toronto, Interdept Div Crit Care Med, Toronto, ON, Canada. [Daya, Mohamud] Oregon Hlth & Sci Univ, Dept Emergency Med, Portland, OR 97201 USA. [Goldberg, Scott; Miller, Ronna] Univ Texas Southwestern Med Ctr Dallas, Dept Emergency Med, Dallas, TX USA. [Tijssen, Janice A.] Univ Western Ontario, London Hlth Sci Ctr, Dept Pediat, Div Pediat Crit Care Med, London, ON, Canada. [Christenson, James] Univ British Columbia, Dept Emergency Med, Vancouver, BC, Canada. [Vaillancourt, Christian] Univ Ottawa, Ottawa Hosp, Res Inst, Dept Emergency Med, Ottawa, ON K1N 6N5, Canada. [Callaway, Clifton W.] Univ Pittsburgh, Dept Emergency Med, Pittsburgh, PA USA. RP Fink, EL (reprint author), UPMC, Childrens Hosp Pittsburgh, Div Pediat Crit Care Med, 4401 Penn Ave,Fac Pavilion,2nd Floor, Pittsburgh, PA 15224 USA. EM finkel@ccm.upmc.edu OI Fink, Ericka/0000-0002-3683-4571 FU National Heart, Lung and Blood Institute [5U01 HL077863, HL077866, HL077867, HL077871, HL077872, HL077873, HL077881, HL077885, HL077887, HL077908]; National Institute of Neurological Disorders and Stroke; U.S. Army Medical Research & Material Command; Canadian Institutes of Health Research (CIHR)-Institute of Circulatory and Respiratory Health, Defence Research and Development Canada; Heart, Stroke Foundation of Canada; American Heart Association; Patient Centered Outcomes Research Institute; National Institutes of Health FX The study was supported through research grants from: the ROC is supported by a series of cooperative agreements to nine regional clinical centers and one Data Coordinating Center (5U01 HL077863-University of Washington Data Coordinating Center, HL077866-Medical College of Wisconsin, HL077867-University of Washington, HL077871-University of Pittsburgh, HL077872-St. Michael's Hospital, HL077873-Oregon Health and Science University, HL077881-University of Alabama at Birmingham, HL077885-Ottawa Hospital Research Institute, HL077887-University of Texas SW Medical Ctr/Dallas, HL077908-University of California San Diego) from the National Heart, Lung and Blood Institute in partnership with the National Institute of Neurological Disorders and Stroke, U.S. Army Medical Research & Material Command, The Canadian Institutes of Health Research (CIHR)-Institute of Circulatory and Respiratory Health, Defence Research and Development Canada and the Heart, Stroke Foundation of Canada and the American Heart Association. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung and Blood Institute or the National Institutes of Health.; Dr. Fink reports funding from the Patient Centered Outcomes Research Institute and National Institutes of Health, neither of which had involvement in this research paper. NR 30 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0300-9572 J9 RESUSCITATION JI Resuscitation PD OCT PY 2016 VL 107 BP 121 EP 128 DI 10.1016/j.resuscitation.2016.07.244 PG 8 WC Critical Care Medicine; Emergency Medicine SC General & Internal Medicine; Emergency Medicine GA ED5FP UT WOS:000388877300034 PM 27565862 ER PT J AU Jewell, CM Katen, KS Barber, LM Cannon, C Garantziotis, S Cidlowski, JA AF Jewell, Christine M. Katen, Kevin S. Barber, Lisa M. Cannon, Crystal Garantziotis, Stavros Cidlowski, John A. TI Healthy glucocorticoid receptor N363S carriers dysregulate gene expression associated with metabolic syndrome SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE metabolic syndrome; insulin resistance; type 2 diabetes; cardiovascular disease ID 11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE-1; SUBCUTANEOUS ADIPOSE-TISSUE; CORONARY-ARTERY-DISEASE; INSULIN-RESISTANCE; DIABETES-MELLITUS; CENTRAL OBESITY; I DEFICIENCY; RISK-FACTORS; POLYMORPHISMS; VARIANT AB The glucocorticoid receptor single-nucleotide polymorphism (SNP) N363S has been reported to be associated with metabolic syndrome, type 2 diabetes, and cardiovascular disease. Our aim was to determine how the N363S SNP modifies glucocorticoid receptor signaling in a healthy population of individuals prior to the onset of disease. We examined the function of the N363S SNP in a cohort of subjects from the general population of North Carolina. Eighteen N363S heterozygous carriers and 36 noncarrier, control subjects were examined for clinical and biochemical parameters followed by a low-dose dexa-methasone suppression test to evaluate glucocorticoid responsiveness. Serum insulin measurements revealed that N363S carriers have higher levels of insulin, although not statistically significant, compared with controls. Glucocorticoid receptor protein levels evaluated in peripheral blood mononuclear cells from each clinical subject showed no difference between N363S and control. However, investigation of gene expression profiles in macrophages isolated from controls and N363S carriers using microarray, quantitative RT-PCR, and Nano-String analyses revealed that the N363S SNP had an altered profile compared with control. These changes in gene expression occurred in both the absence and the presence of glucocorticoids. Thus, our observed difference in gene regulation between normal N363S SNP carriers and noncarrier controls may underlie the emergence of metabolic syndrome, type 2 diabetes, and cardiovascular disease associated with the N363S polymorphism. C1 [Jewell, Christine M.; Katen, Kevin S.; Cidlowski, John A.] NIEHS, Signal Transduct Lab, NIH, US Dept HHS, POB 12233, Res Triangle Pk, NC 27709 USA. [Garantziotis, Stavros] NIEHS, Clin Res Unit, NIH, US Dept HHS, POB 12233, Res Triangle Pk, NC 27709 USA. [Barber, Lisa M.; Cannon, Crystal] SRA Int Inc, Durham, NC USA. RP Cidlowski, JA (reprint author), NIEHS, POB 12233,MD F3-07, Res Triangle Pk, NC 27709 USA. EM cidlows1@niehs.nih.gov RI Garantziotis, Stavros/A-6903-2009 OI Garantziotis, Stavros/0000-0003-4007-375X FU Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. NR 48 TC 0 Z9 0 U1 1 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 EI 1522-1555 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD OCT 1 PY 2016 VL 311 IS 4 BP E741 EP E748 DI 10.1152/ajpendo.00105.2016 PG 8 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA EC9IB UT WOS:000388457000008 PM 27600822 ER PT J AU Hanif, A Edin, ML Zeldin, DC Morisseau, C Nayeem, MA AF Hanif, Ahmad Edin, Matthew L. Zeldin, Darryl C. Morisseau, Christophe Nayeem, Mohammed A. TI Deletion of soluble epoxide hydrolase enhances coronary reactive hyperemia in isolated mouse heart: role of oxylipins and PPAR gamma SO AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY LA English DT Article DE coronary reactive hyperemia; epoxyeicosatrienoic acids; dihydroxyeicosatrienoic acids; soluble epoxide hydrolase; oxylipins; isolated perfused heart ID K-ATP CHANNELS; MODULATES VASCULAR-RESPONSE; BLOOD-PRESSURE REGULATION; ADENOSINE A(2A) RECEPTOR; SMOOTH-MUSCLE-CELLS; ENDOTHELIAL-CELLS; EPOXYEICOSATRIENOIC ACIDS; CYP-EPOXYGENASES; LIPOXYGENASE PRODUCTS; MYOCARDIAL-INFARCTION AB The relationship between soluble epoxide hydrolase (sEH) and coronary reactive hyperemia (CRH) response to a brief ischemic insult is not known. Epoxyeicosatrienoic acids (EETs) exert cardioprotective effects in ischemia/reperfusion injury. sEH converts EETs into dihydroxyeicosatrienoic-acids (DHETs). Therefore, we hypothesized that knocking out sEH enhances CRH through modulation of oxylipin profiles, including an increase in EET/DHET ratio. Compared with sEH(+/+), sEH(-/-) mice showed enhanced CRH, including greater repayment volume (RV; 28% higher, P < 0.001) and repayment/debt ratio (32% higher, P < 0.001). Oxylipins from the heart perfusates were analyzed by LC-MS/MS. The 14,15-EET/14,15-DHET ratio was 3.7-fold higher at baseline (P < 0.001) and 5.6-fold higher postischemia (P < 0.001) in sEH(-/-) compared with sEH(-/-) mice. Likewise, the baseline 9,10-and 12,13-EpOME/DiHOME ratios were 3.2-fold (P < 0.01) and 3.7-fold (P < 0.001) higher, respectively in sEH(-/-) compared with sEH(+/+) mice. 13-HODE was also significantly increased at baseline by 71% (P < 0.01) in sEH(-/-) vs. sEH(+/+) mice. Levels of 5-, 11-, 12-, and 15-hydroxyeicosatetraenoic acids were not significantly different between the two strains (P > 0.05), but were decreased postischemia in both groups (P = 0.02, P = 0.04, P = 0.05, P = 0.03, respectively). Modulation of CRH by peroxisome proliferator-activated receptor gamma (PPAR gamma) was demonstrated using a PPAR gamma -antagonist (T0070907), which reduced repayment volume by 25% in sEH(+/+) (P < 0.001) and 33% in sEH(-/-) mice (P < 0.01), and a PPAR gamma-agonist (rosiglitazone), which increased repayment volume by 37% in both sEH(+/+) (P = 0.04) and sEH(-/-) mice (P = 0.04). L-NAME attenuated CRH in both sEH(-/-) and sEH(+/+). These data demonstrate that genetic deletion of sEH resulted in an altered oxylipin profile, which may have led to an enhanced CRH response. C1 [Hanif, Ahmad; Nayeem, Mohammed A.] West Virginia Univ, Ctr Basic & Translat Stroke Res, Sch Pharm, Basic Pharmaceut Sci, Morgantown, WV USA. [Edin, Matthew L.; Zeldin, Darryl C.] NIEHS, Div Intramural Res, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Morisseau, Christophe] Univ Calif Davis, Davis, CA 95616 USA. RP Nayeem, MA (reprint author), West Virginia Univ, Dept Pharmaceut Sci, Sch Pharm, Ctr Basic & Translat Stroke Res, Biomed Res Bldg,2nd Floor,Rm 220, Morgantown, WV 26506 USA. EM mnayeem@hsc.wvu.edu RI Nayeem, Mohammed/A-3949-2017 OI Nayeem, Mohammed/0000-0002-7827-4760 FU National Institutes of Health (NIH) [HL-114559]; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01 ES025034]; National Institute of General Medical Sciences of the NIH [U54GM104942] FX This work was supported by National Institutes of Health (NIH; Grant HL-114559) to M. A. Nayeem and the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01 ES025034 to D. C. Zeldin). The West Virginia Clinical and Translational Science Institute is supported by the National Institute of General Medical Sciences of the NIH under award number U54GM104942. NR 58 TC 0 Z9 0 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6119 EI 1522-1490 J9 AM J PHYSIOL-REG I JI Am. J. Physiol.-Regul. Integr. Comp. Physiol. PD OCT 1 PY 2016 VL 311 IS 4 BP R676 EP R688 DI 10.1152/ajpregu.00237.2016 PG 13 WC Physiology SC Physiology GA EC9HX UT WOS:000388456500007 PM 27488890 ER PT J AU Resnik, DB AF Resnik, David B. TI BIOETHICS AND CLIMATE CHANGE: A RESPONSE TO MACPHERSON AND VALLES SO BIOETHICS LA English DT Editorial Material DE bioethics; climate change; history; policy ID ETHICS AB Two articles published in Bioethics recently have explored the ways that bioethics can contribute to the climate change debate. Cheryl Cox Macpherson argues that bioethicists can play an important role in the climate change debate by helping the public to better understand the values at stake and the trade-offs that must be made in individual and social choices, and Sean Valles claims that bioethicists can contribute to the debate by framing the issues in terms of the public health impacts of climate change.(1) While Macpherson and Valles make valid points concerning a potential role for bioethics in the climate change debate, it is important to recognize that much more than ethical analysis and reflection will be needed to significantly impact public attitudes and government policies. C1 [Resnik, David B.] NIEHS, NIH, 111 Alexander Dr,Box 12233,Mail Drop E1-06, Res Triangle Pk, NC 27709 USA. RP Resnik, DB (reprint author), NIEHS, NIH, 111 Alexander Dr,Box 12233,Mail Drop E1-06, Res Triangle Pk, NC 27709 USA. EM resnikd@niehs.nih.gov FU Intramural NIH HHS [ZIA ES102646-07] NR 21 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-9702 EI 1467-8519 J9 BIOETHICS JI Bioethics PD OCT PY 2016 VL 30 IS 8 BP 649 EP 652 DI 10.1111/bioe.12261 PG 4 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA EC7EP UT WOS:000388299300014 PM 27161019 ER PT J AU Chen, X Walters, KJ AF Chen, Xiang Walters, Kylie J. TI H-1, N-15, C-13 resonance assignments for Saccharomyces cerevisiae Rad23 UBL domain SO BIOMOLECULAR NMR ASSIGNMENTS LA English DT Article DE Ubiquitin-proteasome pathway; UV excision repair protein Rad23; Ubiquitin-like domain; NMR ID UBIQUITIN-LIKE DOMAINS; REPAIR PROTEIN HHR23A; PROTEASOME; S5A; SUBUNIT; BINDING; DNA; RECEPTOR; RPN1; IDENTIFICATION AB Rad23 functions in nucleotide excision repair and proteasome-mediated protein degradation. It has four distinct structural domains that are connected by flexible linker regions, including an N-terminal ubiquitin-like (UBL) domain that binds proteasomes. We report in this NMR study the H-1, N-15 and C-13 resonance assignments for the backbone and side chain atoms of the Rad23 UBL domain (Rad23(UBL)) with BioMagResBank accession number 25825. We find that a Rad23 proline amino acid (P20) located in a loop undergoes isomerization. The secondary structural elements predicted from the NMR data fit well to that of the Rad23(UBL) when complexed with E4 ubiquitin ligase Ufd2, as reported in a crystallographic structure. These complete assignments can be used to study the protein dynamics of the Rad23(UBL) and its interaction of with other ubiquitin receptors or proteasome subunits. C1 [Chen, Xiang; Walters, Kylie J.] NCI, Prot Proc Sect, Struct Biophys Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Walters, KJ (reprint author), NCI, Prot Proc Sect, Struct Biophys Lab, Ctr Canc Res, Frederick, MD 21702 USA. EM kylie.walters@nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This research was funded by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research to K.J.W. We thank Janusz Koscielniak for his technical assistance with the NMR facility. NR 22 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1874-2718 EI 1874-270X J9 BIOMOL NMR ASSIGN JI Biomol. NMR Assign. PD OCT PY 2016 VL 10 IS 2 BP 291 EP 295 DI 10.1007/s12104-016-9686-7 PG 5 WC Biophysics; Spectroscopy SC Biophysics; Spectroscopy GA EC7AI UT WOS:000388287400011 PM 27188292 ER PT J AU Arbyn, M Xu, L Wentzensen, N AF Arbyn, Marc Xu, Lan Wentzensen, Nicolas TI Reply to HPV Test Results Provide Useful Risk Stratification Information in Women with ASC-H Pap Test Findings SO CANCER CYTOPATHOLOGY LA English DT Letter ID TRIAGE; METAANALYSIS C1 [Arbyn, Marc; Xu, Lan] Sci Inst Publ Hlth, Belgian Canc Ctr, Canc Epidemiol Unit, Brussels, Belgium. [Wentzensen, Nicolas] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. RP Arbyn, M (reprint author), Sci Inst Publ Hlth, Belgian Canc Ctr, Canc Epidemiol Unit, Brussels, Belgium. NR 7 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1934-662X EI 1934-6638 J9 CANCER CYTOPATHOL JI Cancer Cytopathol. PD OCT PY 2016 VL 124 IS 10 BP 754 EP 755 DI 10.1002/cncy.21754 PG 3 WC Oncology; Pathology SC Oncology; Pathology GA EC0CK UT WOS:000387765100013 PM 27336222 ER PT J AU Freedman, DM Wu, JC Chen, HL Kuncl, RW Enewold, LR Engels, EA Freedman, ND Pfeiffer, RM AF Freedman, Daryl Michal Wu, Jincao Chen, Honglei Kuncl, Ralph W. Enewold, Lindsey R. Engels, Eric A. Freedman, Neal D. Pfeiffer, Ruth M. TI Associations between cancer and Alzheimer's disease in a US Medicare population SO CANCER MEDICINE LA English DT Article DE Alzheimer's disease; Cancer; case-control; cohort ID RISK-FACTORS; UNITED-STATES; OLDER-ADULTS; DEMENTIA; DIAGNOSIS; METAANALYSIS; EPIDEMIOLOGY; SURVEILLANCE; BREAST; RATES AB Several studies have reported bidirectional inverse associations between cancer and Alzheimer's disease (AD). This study evaluates these relationships in a Medicare population. Using Surveillance, Epidemiology, and End Results (SEER) linked to Medicare data, 1992-2005, we evaluated cancer risks following AD in a case-control study of 836,947 cancer cases and 142,869 controls as well as AD risk after cancer in 742,809 cancer patients and a non-cancer group of 420,518. We applied unconditional logistic regression to estimate odds ratios (ORs) and Cox proportional hazards models to estimate hazards ratios (HRs). We also evaluated cancer in relation to automobile injuries as a negative control to explore potential study biases. In the case-control analysis, cancer cases were less likely to have a prior diagnosis of AD than controls (OR = 0.86; 95% CI = 0.81-0.92). Cancer cases were also less likely than controls to have prior injuries from automobile accidents to the same degree (OR = 0.83; 95% CI = 0.78-0.88). In the prospective cohort, there was a lower risk observed in cancer survivors, HR = 0.87 (95% CI = 0.84-0.90). In contrast, there was no association between cancer diagnosis and subsequent automobile accident injuries (HR = 1.03; 95% CI = 0.98-1.07). That cancer risks were similarly reduced after both AD and automobile injuries suggest biases against detecting cancer in persons with unrelated medical conditions. The modestly lower AD risk in cancer survivors may reflect underdiagnosis of AD in those with a serious illness. This study does not support a relationship between cancer and AD. C1 [Freedman, Daryl Michal; Wu, Jincao; Engels, Eric A.; Freedman, Neal D.; Pfeiffer, Ruth M.] NCI, Dept Hlth & Human Serv, NIH, Div Canc Epidemiol & Genet, Rockville, MD USA. [Chen, Honglei] NIEHS, Aging & Neuroepidemiol Grp, Durham, NC USA. [Kuncl, Ralph W.] Univ Redlands, Dept Biol, Redlands, CA 92373 USA. [Enewold, Lindsey R.] NCI, Dept Hlth & Human Serv, NIH, Div Canc Control & Populat Sci, Rockville, MD USA. RP Freedman, DM (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,7E538, Rockville, MD 20850 USA. EM freedmam@mail.nih.gov OI Chen, Honglei/0000-0003-3446-7779 FU Intramural Research Program of the National Institutes of Health; National Cancer Institute; National Institute of Environmental Health Sciences; U.S. Public Health Service FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, the National Institute of Environmental Health Sciences and the U.S. Public Health Service. NR 41 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2045-7634 J9 CANCER MED-US JI Cancer Med. PD OCT PY 2016 VL 5 IS 10 BP 2965 EP 2976 DI 10.1002/cam4.850 PG 12 WC Oncology SC Oncology GA EC8CS UT WOS:000388368500033 PM 27628596 ER PT J AU Walford, GA Gustafsson, S Rybin, D Stancakova, A Chen, H Liu, CT Hong, JY Jensen, RA Rice, K Morris, AP Magi, R Tonjes, A Prokopenko, I Kleber, ME Delgado, G Silbernagel, G Jackson, AU Appel, EV Grarup, N Lewis, JP Montasser, ME Landenvall, C Staiger, H Luan, J Frayling, TM Weedon, MN Xie, WJ Morcillo, S Martinez-Larrad, MT Biggs, ML Chen, YDI Corbaton-Anchuelo, A Faerch, K Gomez-Zumaquero, JM Goodarzi, MO Kizer, JR Koistinen, HA Leong, A Lind, L Lindgren, C Machicao, F Manning, AK Martin-Nunez, GM Rojo-Martinez, G Rotter, JI Siscovick, DS Zmuda, JM Zhang, ZY Serrano-Rios, M Smith, U Soriguer, F Hansen, T Jorgensen, TJ Linnenberg, A Pedersen, O Walker, M Langenberg, C Scott, RA Wareham, NJ Fritsche, A Haring, HU Stefan, N Groop, L O'Connell, JR Boehnke, M Bergman, RN Collins, FS Mohlke, KL Tuomilehto, J Marz, W Kovacs, P Stumvoll, M Psaty, BM Kuusisto, J Laakso, M Meigs, JB Dupuis, J Ingelsson, E Florez, JC AF Walford, Geoffrey A. Gustafsson, Stefan Rybin, Denis Stancakova, Alena Chen, Han Liu, Ching-Ti Hong, Jaeyoung Jensen, Richard A. Rice, Ken Morris, Andrew P. Magi, Reedik Toenjes, Anke Prokopenko, Inga Kleber, Marcus E. Delgado, Graciela Silbernagel, Guenther Jackson, Anne U. Appel, Emil V. Grarup, Niels Lewis, Joshua P. Montasser, May E. Landenvall, Claes Staiger, Harald Luan, Jian'an Frayling, Timothy M. Weedon, Michael N. Xie, Weijia Morcillo, Sonsoles Teresa Martinez-Larrad, Maria Biggs, Mary L. Chen, Yii-Der Ida Corbaton-Anchuelo, Arturo Faerch, Kristine Miguel Gomez-Zumaquero, Juan Goodarzi, Mark O. Kizer, Jorge R. Koistinen, Heikki A. Leong, Aaron Lind, Lars Lindgren, Cecilia Machicao, Fausto Manning, Alisa K. Maria Martin-Nunez, Gracia Rojo-Martinez, Gemma Rotter, Jerome I. Siscovick, David S. Zmuda, Joseph M. Zhang, Zhongyang Serrano-Rios, Manuel Smith, Ulf Soriguer, Federico Hansen, Torben Jorgensen, Torben J. Linnenberg, Allan Pedersen, Oluf Walker, Mark Langenberg, Claudia Scott, Robert A. Wareham, Nicholas J. Fritsche, Andreas Haering, Hans-Ulrich Stefan, Norbert Groop, Leif O'Connell, Jeff R. Boehnke, Michael Bergman, Richard N. Collins, Francis S. Mohlke, Karen L. Tuomilehto, Jaakko Maerz, Winfried Kovacs, Peter Stumvoll, Michael Psaty, Bruce M. Kuusisto, Johanna Laakso, Markku Meigs, James B. Dupuis, Josee Ingelsson, Erik Florez, Jose C. TI Genome-Wide Association Study of the Modified Stumvoll Insulin Sensitivity Index Identifies BCL2 and FAM19A2 as Novel Insulin Sensitivity Loci SO DIABETES LA English DT Article ID GLUCOSE-TOLERANCE TEST; EUGLYCEMIC CLAMP; GLYCEMIC TRAITS; METAANALYSIS; GENE; PATHOPHYSIOLOGY; HERITABILITY; RESISTANCE; RELEASE; SNP AB Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: rs13422522 (NYAP2; P = 8.87 x 10(-11)), rs12454712 (BCL2; P = 2.7 x 10(-8)), and rs10506418 (FAM19A2; P = 1.9 x 10(-8)). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci. C1 [Walford, Geoffrey A.; Florez, Jose C.] Massachusetts Gen Hosp, Diabet Unit, Diabet Res Ctr, Boston, MA 02114 USA. [Walford, Geoffrey A.; Manning, Alisa K.; Florez, Jose C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Walford, Geoffrey A.; Leong, Aaron; Manning, Alisa K.; Meigs, James B.; Florez, Jose C.] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. [Gustafsson, Stefan; Lind, Lars] Uppsala Univ, Dept Med Sci, Uppsala, Sweden. [Rybin, Denis] Boston Univ, Sch Publ Hlth, Data Coordinating Ctr, Boston, MA USA. [Stancakova, Alena] Univ Eastern Finland, Kuopio, Finland. [Stancakova, Alena; Kuusisto, Johanna; Laakso, Markku] Kuopio Univ Hosp, Kuopio, Finland. [Chen, Han; Liu, Ching-Ti; Hong, Jaeyoung; Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Chen, Han] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Jensen, Richard A.; Biggs, Mary L.; Siscovick, David S.; Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Jensen, Richard A.; Siscovick, David S.; Psaty, Bruce M.] Univ Washington, Dept Med, Seattle, WA USA. [Rice, Ken; Biggs, Mary L.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Morris, Andrew P.] Univ Liverpool, Dept Biostat, Liverpool, Merseyside, England. [Morris, Andrew P.; Prokopenko, Inga; Lindgren, Cecilia] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Magi, Reedik] Univ Tartu, Estonian Genome Ctr, Tartu, Estonia. [Toenjes, Anke; Stumvoll, Michael] Univ Leipzig, Dept Med, Leipzig, Germany. [Prokopenko, Inga] Imperial Coll London, Dept Genom Common Dis, London, England. [Prokopenko, Inga] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England. [Kleber, Marcus E.; Delgado, Graciela; Maerz, Winfried] Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Heidelberg, Germany. [Silbernagel, Guenther] Med Univ Graz, Dept Internal Med, Div Angiol, Graz, Austria. [Jackson, Anne U.; Boehnke, Michael] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Jackson, Anne U.; Boehnke, Michael] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Appel, Emil V.; Grarup, Niels; Hansen, Torben; Pedersen, Oluf] Univ Copenhagen, Fac Hlth & Med Sci, Ctr Basic Metab Res, Novo Nordisk Fdn, Copenhagen, Denmark. [Lewis, Joshua P.; Montasser, May E.; O'Connell, Jeff R.] Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. [Lewis, Joshua P.; Montasser, May E.; O'Connell, Jeff R.] Univ Maryland, Sch Med, Program Personalized & Genom Med, Baltimore, MD 21201 USA. [Landenvall, Claes; Groop, Leif] Lund Univ, Ctr Diabet, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden. [Landenvall, Claes] Uppsala Univ, Sci Life Lab, Dept Immunol Genet & Pathol, Uppsala, Sweden. [Staiger, Harald; Fritsche, Andreas; Haering, Hans-Ulrich; Stefan, Norbert] Univ Tubingen Hosp, Div Endocrinol & Diabetol Angiol Nephrol & Clin C, Dept Internal Med, Tubingen, Germany. [Staiger, Harald; Machicao, Fausto; Fritsche, Andreas; Haering, Hans-Ulrich; Stefan, Norbert] German Ctr Diabet Res DZD, Tubingen, Germany. [Staiger, Harald; Machicao, Fausto; Fritsche, Andreas; Haering, Hans-Ulrich; Stefan, Norbert] Univ Tubingen, Helmholtz Ctr Munich, Inst Diabet Res & Metab Dis, Tubingen, Germany. [Luan, Jian'an; Langenberg, Claudia; Scott, Robert A.; Wareham, Nicholas J.] Univ Cambridge, Sch Clin Med, MRC Epidemiol Unit, Cambridge, England. [Frayling, Timothy M.; Weedon, Michael N.; Xie, Weijia] Univ Exeter, Sch Med, Exeter, Devon, England. [Morcillo, Sonsoles] CIBER Pathophysiol Obes & Nutr, Madrid, Spain. [Morcillo, Sonsoles; Rojo-Martinez, Gemma; Soriguer, Federico] Hosp Reg Univ Malaga, Dept Endocrinol & Nutr, Malaga, Spain. [Teresa Martinez-Larrad, Maria; Corbaton-Anchuelo, Arturo; Serrano-Rios, Manuel] Hosp Clin San Carlos IdISSC, Spanish Biomed Res Ctr Diabet & Associated Metab, Inst Invest Sanitaria, Madrid, Spain. [Chen, Yii-Der Ida; Rotter, Jerome I.] Harbor UCLA Med Ctr, Dept Pediat, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA. [Chen, Yii-Der Ida; Rotter, Jerome I.] Harbor UCLA Med Ctr, Dept Med, LABioMed, Torrance, CA 90509 USA. [Faerch, Kristine] Steno Diabet Ctr, Gentofte, Denmark. [Miguel Gomez-Zumaquero, Juan; Rojo-Martinez, Gemma; Soriguer, Federico] Inst Invest Biomed Malaga IBIMA, Malaga, Spain. [Miguel Gomez-Zumaquero, Juan] Hosp Carlos Haya Malaga, Sequencing & Genotyping Platform, Malaga, Spain. [Goodarzi, Mark O.] Cedars Sinai Med Ctr, Div Endocrinol Diabet & Metab, Los Angeles, CA 90048 USA. [Kizer, Jorge R.] Albert Einstein Coll Med, Dept Med, Bronx, NY 10467 USA. [Kizer, Jorge R.] Montefiore Med Ctr, 111 E 210th St, Bronx, NY 10467 USA. [Kizer, Jorge R.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Koistinen, Heikki A.] Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland. [Koistinen, Heikki A.] Minerva Fdn, Inst Med Res, Biomedicum 2U, Helsinki, Finland. [Koistinen, Heikki A.] Univ Helsinki, Dept Med, Helsinki, Finland. [Koistinen, Heikki A.] Univ Helsinki, Abdominal Ctr Endocrinol, Helsinki, Finland. [Koistinen, Heikki A.] Univ Helsinki, Cent Hosp, Helsinki, Finland. [Leong, Aaron; Meigs, James B.] Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. [Lindgren, Cecilia; Manning, Alisa K.; Meigs, James B.] Broad Inst Massachusetts Inst Technol & Harvard U, Cambridge, MA USA. [Maria Martin-Nunez, Gracia] Hosp Reg Univ & Virgen de la Victoria Malaga, Dept Endocrinol & Nutr, Malaga, Spain. [Rojo-Martinez, Gemma; Soriguer, Federico] CIBER Diabet & Enfermedades Metab Asociadas CIBER, Madrid, Spain. [Siscovick, David S.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Siscovick, David S.] New York Acad Med, New York, NY USA. [Zmuda, Joseph M.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Zhang, Zhongyang] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Zhang, Zhongyang] Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, New York, NY 10029 USA. [Smith, Ulf] Univ Gothenburg, Sahlgrenska Acad, Dept Mol & Clin Med, Lundberg Lab Diabet Res, Gothenburg, Sweden. [Jorgensen, Torben J.] Univ Copenhagen, Fac Hlth & Med Sci, Dept Publ Hlth, Copenhagen, Denmark. [Jorgensen, Torben J.] Aalborg Univ, Fac Med, Aalborg, Denmark. [Jorgensen, Torben J.; Linnenberg, Allan] Res Ctr Prevent & Hlth, Copenhagen, Denmark. [Linnenberg, Allan] Rigshosp, Dept Clin Expt Res, Glostrup, Denmark. [Linnenberg, Allan] Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark. [Walker, Mark] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne, Tyne & Wear, England. [Groop, Leif] Univ Helsinki, Finnish Inst Mol Med, Helsinki, Finland. [Bergman, Richard N.] Cedars Sinai Med Ctr, Diabet & Obes Res Inst, Los Angeles, CA USA. [Collins, Francis S.] NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA. [Mohlke, Karen L.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Tuomilehto, Jaakko] Natl Inst Hlth & Welf, Chron Dis Prevent Unit, Helsinki, Finland. [Tuomilehto, Jaakko] Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria. [Tuomilehto, Jaakko] King Abdulaziz Univ, Diabet Res Grp, Jeddah, Saudi Arabia. [Tuomilehto, Jaakko] Dasman Diabet Inst, Dasman, Kuwait. [Maerz, Winfried] Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, Graz, Austria. [Maerz, Winfried] Synlab Serv GmbH, Synlab Acad, Mannheim, Germany. [Maerz, Winfried] Synlab Serv GmbH, Synlab Acad, Augsburg, Germany. [Kovacs, Peter] Univ Leipzig, Integrated Res & Treatment IFB Ctr AdiposityDis, Leipzig, Germany. [Psaty, Bruce M.] Univ Washington, Epidemiol & Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Res Inst, Seattle, WA USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Seattle, WA USA. [Kuusisto, Johanna; Laakso, Markku] Univ Eastern Finland, Dept Med, Kuopio, Finland. [Dupuis, Josee] NHLBI, Framingham Heart Study, Framingham, MA USA. [Ingelsson, Erik] Uppsala Univ, Dept Med Sci, Mol Epidemiol & Sci Life Lab, Uppsala, Sweden. [Ingelsson, Erik] Stanford Univ, Dept Med, Sch Med, Div Cardiovasc Med, Stanford, CA 94305 USA. RP Walford, GA (reprint author), Massachusetts Gen Hosp, Diabet Unit, Diabet Res Ctr, Boston, MA 02114 USA.; Walford, GA (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.; Walford, GA (reprint author), Harvard Med Sch, Dept Med, Boston, MA 02115 USA. EM gwalford@partners.org RI Grarup, Niels/K-2807-2015; OI Grarup, Niels/0000-0001-5526-1070; Koistinen, Heikki/0000-0001-7870-070X; Staiger, Harald/0000-0002-9507-5333; Chen, Han/0000-0002-9510-4923; Jorgensen, Torben/0000-0001-9453-2830; Stefan, Norbert/0000-0002-2186-9595 FU National Institutes of Health [DK099249]; Academy of Finland [77299, 124243]; German Research Council (DFG) [SFB 1052, SPP 1629 TO 718/2-1]; German Diabetes Association; Diabetes Hilfs-und Forschungsfonds Deutschland (DHFD); Federal Ministry of Education and Research (BMBF), Germany, Federal Ministry of Education and Research (BMBF), Germany, FKZ [01EO1501, AD2-060E]; Boehringer Ingelheim Foundation; National Heart, Lung, and Blood Institute [N02-HL-6-4278, N01-HC-25195, HL084756, HHSN268201500001I, HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, U01HL080295, HL105756, HL120393]; National Institute of Diabetes and Digestive and Kidney Diseases [R01 DK078616, U01-DK085526, 2R01 DK078616, K24 DK080140]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine; Boston Medical Center; American Diabetes Association Research Foundation [7-12-MN-02]; National Institute of Neurological Disorders and Stroke; National Institute on Aging (NIA) [R01AG023629]; Knut and Alice Wallenberg Foundation; European Research Council (ERC Starting Grant); Swedish Diabetes Foundation [2013-024]; Swedish Research Council [2012-1397]; Swedish Heart-Lung Foundation [20120197]; Nordic Center of Excellence in Disease Genetics [WT098017]; 7th Framework Program of the European Union [201668, 305739]; INTERREG-IV-Oberrhein-Program [A28]; European Regional Development Fund (ERDF); Wissenschaftsoffensive; German Federal Ministry of Education and Research as part of the Competence Cluster of Nutrition and Cardiovascular Health (nutriCARD); Danish Research Council; Danish Centre for Health Technology Assessment; Novo Nordisk; Research Foundation of Copenhagen County; Ministry of Internal Affairs and Health of Denmark; Danish Heart Foundation; Danish Pharmaceutical Association; Augustinus Foundation; Ib Henriksen Foundation; Becket Foundation; the Danish Diabetes Association; National Human Genome Research Institute [ZIA-HG000024]; National Institutes of Health from National Institute of General Medical Sciences [K23GM102678]; National Institutes of Health from National Heart, Lung, and Blood Institute [HL084756]; Sigrid Juselius Foundation; Folkhalsan Research Foundation; Nordic Center of Excellence in Disease Genetics; European Union [GA FP6 2004-005272]; Signe and Ane Gyllenberg Foundation; Swedish Cultural Foundation in Finland; Finnish Diabetes Research Foundation; Foundation for Life and Health in Finland; Finnish Medical Society; Paavo Nurmi Foundation; Helsinki University Central Hospital Research Foundation; Perklen Foundation; Ollqvist Foundation; Narpes Health Care Foundation; Ahokas Foundation; Ministry of Education in Finland; Municipal Health Care Center and Hospital in Jakobstad; Health Care Centers in Vasa, Narpes, and Korsholm; German Federal Ministry of Education and Research; Medical Research Council [MC_UU_12015/1, MC_U106179471]; Diabetes UK; Medical Research Council-GlaxoSmithKline pilot program grant [G0701863]; Novo Nordisk Foundation Center for Basic Metabolic Research, an independent research center at the University of Copenhagen - the Novo Nordisk Foundation; Instituto de Salud Carlos III [PI11/00880, PS09/02117]; Fondo Europeo para el Desarrollo Regional, Red de Centros RCMN [C03/08, FEDER 2FD 1997/2309]; Instituto de Salud Carlos III-RETIC, Madrid, Spain [RD06/0015/0012, FIS 03/1618]; CIBER in Diabetes and Associated Metabolic Disorders (Instituto de Salud Carlos III, Ministerio de Ciencia e Innovacion); Madrid Autonomous Community [MOIR S2010/BMD-2423]; Eli Lilly Lab, Spain; Bayer Pharmaceutical Co., Spain; Fundacion Mutua Madrilena, Spain FX This work was supported by National Institutes of Health grant DK099249 (to G.A.W.). Grant support was provided to cohorts. For METSIM, the study was funded by the Academy of Finland (grants 77299 and 124243). For Sorbs, the work was supported by grants from the German Research Council (DFG-SFB 1052, "Obesity mechanisms," A01, C01, B03, and SPP 1629 TO 718/2-1), the German Diabetes Association, and the Diabetes Hilfs-und Forschungsfonds Deutschland (DHFD). This work was further supported by the Federal Ministry of Education and Research (BMBF), Germany, FKZ (01EO1501, AD2-060E to P.K.), and by the Boehringer Ingelheim Foundation. For FHS, the study was supported by the National Heart, Lung, and Blood Institute (contract nos. N02-HL-6-4278 [supporting its contract with Affymetrix, Inc., for genotyping services], N01-HC-25195, HL084756, and HHSN268201500001I) and the National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK078616 to J.D., U01-DK085526 to H.C. and J.D., 2R01 DK078616 and K24 DK080140 to J.M.). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. A.K.M. was supported by American Diabetes Association Research Foundation (grant 7-12-MN-02). For CHS, research was supported by National Heart, Lung, and Blood Institute contract nos. HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086 and grant nos. U01HL080295, HL105756, and HL120393, with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided by R01AG023629 from the National Institute on Aging (NIA). For ULSAM, the project was supported by the Knut and Alice Wallenberg Foundation (Wallenberg Academy Fellow), the European Research Council (ERC Starting Grant), the Swedish Diabetes Foundation (grant 2013-024), the Swedish Research Council (grant 2012-1397), and the Swedish Heart-Lung Foundation (20120197). A.P.M. is a Wellcome Trust Senior Fellow in Basic Biomedical Science (grant WT098017 from the Nordic Center of Excellence in Disease Genetics). For LURIC, the study was supported by the 7th Framework Program (AtheroRemo, grant agreement no. 201668, and RiskyCAD, grant agreement no. 305739) of the European Union and by the INTERREG-IV-Oberrhein-Program (Project A28, Genetic mechanisms of cardiovascular diseases) with support from the European Regional Development Fund (ERDF) and the Wissenschaftsoffensive. M.E.K. and W.M. are supported by the German Federal Ministry of Education and Research as part of the Competence Cluster of Nutrition and Cardiovascular Health (nutriCARD). For Inter99, the study was financially supported by research grants from the Danish Research Council, the Danish Centre for Health Technology Assessment, Novo Nordisk, the Research Foundation of Copenhagen County, Ministry of Internal Affairs and Health of Denmark, the Danish Heart Foundation, the Danish Pharmaceutical Association, the Augustinus Foundation, the Ib Henriksen Foundation, the Becket Foundation, and the Danish Diabetes Association. For FUSION, the study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (DK093757, DK072193, DK062370) and the National Human Genome Research Institute (ZIA-HG000024). H.A.K. has received funding from the Academy of Finland (support for clinical research careers, grant no. 258753).; Work on the Amish Studies was supported by National Institutes of Health awards K23GM102678 (from National Institute of General Medical Sciences) to J.P.L. and HL084756 (from National Heart, Lung, and Blood Institute) to J.R.O. The Botnia study has been financially supported by grants from the Sigrid Juselius Foundation, the Folkhalsan Research Foundation, the Nordic Center of Excellence in Disease Genetics, a European Union grant (EXGENESIS, GA FP6 2004-005272), the Signe and Ane Gyllenberg Foundation, the Swedish Cultural Foundation in Finland, the Finnish Diabetes Research Foundation, the Foundation for Life and Health in Finland, the Finnish Medical Society, the Paavo Nurmi Foundation, the Helsinki University Central Hospital Research Foundation, the Perklen Foundation, the Ollqvist Foundation, the Narpes Health Care Foundation, and the Ahokas Foundation. The DGI study was further supported by a Swedish Research Council Linne grant (2006-237) and by the Ministry of Education in Finland, the Municipal Health Care Center and Hospital in Jakobstad, and the Health Care Centers in Vasa, Narpes, and Korsholm. The Tubingen study was supported in part by a grant from the German Federal Ministry of Education and Research to the German Center for Diabetes Research (DZD e.V.). For the Ely Study, J.L., C. Lang, R.A.S., and N.J.W. acknowledge support from the Medical Research Council (MC_UU_12015/1). The Ely Study was funded by the Medical Research Council (MC_U106179471) and Diabetes UK. Genotyping in the Ely and Fenland studies was supported in part by a Medical Research Council-GlaxoSmithKline pilot program grant (G0701863). For the Birth Cohort 1936 and Inter99 studies, work was support by the Novo Nordisk Foundation Center for Basic Metabolic Research, an independent research center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (www.metabol.ku.dk). Work on the Pizarra study was support by Instituto de Salud Carlos III PI11/00880 and Instituto de Salud Carlos III PS09/02117. For Segovia, this work was supported by the Fondo Europeo para el Desarrollo Regional, Red de Centros RCMN (C03/08) grants FEDER 2FD 1997/2309, the Instituto de Salud Carlos III-RETIC RD06/0015/0012, Madrid, Spain (FIS 03/1618); CIBER in Diabetes and Associated Metabolic Disorders (Instituto de Salud Carlos III, Ministerio de Ciencia e Innovacion); and the Madrid Autonomous Community (MOIR S2010/BMD-2423), and by educational grants from Eli Lilly Lab, Spain; Bayer Pharmaceutical Co., Spain; and the Fundacion Mutua Madrilena 2008, Spain. NR 26 TC 2 Z9 2 U1 8 U2 8 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD OCT PY 2016 VL 65 IS 10 BP 3200 EP 3211 DI 10.2337/db16-0199 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EC8EJ UT WOS:000388372900037 PM 27416945 ER PT J AU Henry, RK Astbury, C Stratakis, CA Hickey, SE AF Henry, Rohan K. Astbury, Caroline Stratakis, Constantine A. Hickey, Scott E. TI 17p13.3 microduplication including CRK leads to overgrowth and elevated growth factors: A case report SO EUROPEAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE 17p13.3 microduplications; CRK gene; Growth factors; Central precocious puberty ID RECEPTOR TYROSINE KINASE; I RECEPTOR; C-CRK; HYPERPLASIA; DELINEATION; PHENOTYPES AB 17p13.3 microduplications classified as class I duplications involving YWHAE but not PAFAH1B1 (formerly LIS1) and class II duplications which extend to involve PAFAH1B1, are associated with diverse phenotypes including intellectual disability and structural brain malformations. We report a girl with an approximately 1.58 Mb apparently terminal gain of 17p13.3, which contains more than 20 genes including the YWHAE and CRK genes (OMIM: 164762). She had increased growth factors accompanied by pathologic tall stature. In addition to these, she developed central precocious puberty at 7 years old. In individuals with class I 17p13.3 microduplications including CRK, we recommend biochemical evaluation of the growth hormone axis. Providers caring for these patients should be aware of their possible risk for the development of central precocious puberty. (C) 2016 Elsevier Masson SAS. All rights reserved. C1 [Henry, Rohan K.] Ohio State Univ, Coll Med, Nationwide Childrens Hosp, Div Endocrinol,Dept Pediat, Columbus, OH 43205 USA. [Astbury, Caroline] Nationwide Childrens Hosp, Dept Pathol & Lab Med, Columbus, OH USA. [Astbury, Caroline] Ohio State Univ, Coll Med, Dept Pathol, Columbus, OH 43210 USA. [Stratakis, Constantine A.] NICHHD, Dev Endocrinol & Genet, NICHD, NIH, Bethesda, MD 20892 USA. [Hickey, Scott E.] Ohio State Univ, Coll Med, Nationwide Childrens Hosp, Div Mol & Human Genet,Dept Pediat, Columbus, OH 43210 USA. RP Henry, RK (reprint author), Nationwide Childrens Hosp, Div Endocrinol, 700 Childrens Dr, Columbus, OH 43205 USA. EM rohan.henry@nationwidechildrens.org FU Intramural Research Program of Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH) [HD008920] FX This research was supported by the Intramural Research Program of Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH) (HD008920). NR 14 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1769-7212 EI 1878-0849 J9 EUR J MED GENET JI Eur. J. Med. Genet. PD OCT PY 2016 VL 59 IS 10 BP 512 EP 516 DI 10.1016/j.ejmg.2016.09.006 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA EC6YS UT WOS:000388283200005 PM 27633569 ER PT J AU Varma, H Faust, PL Iglesias, AD Lagana, SM Wou, K Hirano, M DiMauro, S Mansukani, MM Hoff, KE Nagy, PL Copeland, WC Naini, AB AF Varma, Hemant Faust, Phyllis L. Iglesias, Alejandro D. Lagana, Stephen M. Wou, Karen Hirano, Michio DiMauro, Salvatore Mansukani, Mahesh M. Hoff, Kirsten E. Nagy, Peter L. Copeland, William C. Naini, Ali B. TI Whole exome sequencing identifies a homozygous POLG2 missense variant in an infant with fulminant hepatic failure and mitochondrial DNA depletion SO EUROPEAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE Mitochondrial DNA depletion; POLG2; Hepatic failure; Whole-exome sequencing; POLG ID POLYMERASE GAMMA; ACCESSORY SUBUNIT; DISEASE AB Mitochondrial DNA (mtDNA) depletion syndrome manifests as diverse early-onset diseases that affect skeletal muscle, brain and liver function. Mutations in several nuclear DNA-encoded genes cause mtDNA depletion. We report on a patient, a 3-month-old boy who presented with hepatic failure, and was found to have severe mtDNA depletion in liver and muscle. Whole-exome sequencing identified a homozygous missense variant (c.544C > T, p.R182W) in the accessory subunit of mitochondrial DNA polymerase gamma (POLG2), which is required for mitochondrial DNA replication. This variant is predicted to disrupt a critical region needed for homodimerization of the POLG2 protein and cause loss of processive DNA synthesis. Both parents were phenotypically normal and heterozygous for this variant. Heterozygous mutations in POLG2 were previously associated with progressive external ophthalmoplegia and mtDNA deletions. This is the first report of a patient with a homozygous mutation in POLG2 and with a clinical presentation of severe hepatic failure and mitochondrial depletion. (C) 2016 Elsevier Masson SAS. All rights reserved. C1 [Varma, Hemant; Faust, Phyllis L.; Lagana, Stephen M.; Mansukani, Mahesh M.; Nagy, Peter L.; Naini, Ali B.] Columbia Univ, Dept Pathol & Cell Biol, 630 W,168th St, New York, NY 10032 USA. [Iglesias, Alejandro D.] Columbia Univ, Div Med Genet, New York Presbyterian Hosp, New York, NY 10027 USA. [Wou, Karen] New York Presbyterian Hosp, Div Genet, New York, NY USA. [Hirano, Michio; DiMauro, Salvatore] Columbia Univ, Med Ctr, Dept Neurol, New York, NY 10027 USA. [Mansukani, Mahesh M.; Nagy, Peter L.; Naini, Ali B.] Columbia Univ, Med Ctr, Div Personalized Genom Med, Dept Pathol & Cell Biol, New York, NY 10027 USA. [Hoff, Kirsten E.; Copeland, William C.] NIEHS, Genome Integr & Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Copeland, WC (reprint author), NIEHS, Genome Integr & Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA.; Naini, AB (reprint author), 630 W 168th St,P&S 17-401, New York, NY 10032 USA. EM copelan1@niehs.nih.gov; abn2@cumc.columbia.edu FU National Institutes of Health [5P01 HD080642-02 NIH/NICHD]; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [ES 065078] FX Part of this research was supported by National Institutes of Health grants 5P01 HD080642-02 NIH/NICHD (to ABN) and the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (ES 065078 to WCC). We thank the CUMC Neuromuscular Laboratory for performing the enzyme histochemistry staining of the muscle biopsy. The variant has been submitted to the ClinVar database (Submission number: SUB1740227). NR 21 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1769-7212 EI 1878-0849 J9 EUR J MED GENET JI Eur. J. Med. Genet. PD OCT PY 2016 VL 59 IS 10 BP 540 EP 545 DI 10.1016/j.ejmg.2016.08.012 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA EC6YS UT WOS:000388283200011 PM 27592148 ER PT J AU Li, W Yang, HJ Dimitrov, DS AF Li, Wei Yang, Hongjia Dimitrov, Dimiter S. TI Identification of high-affinity anti-CD16A allotype-independent human antibody domains SO EXPERIMENTAL AND MOLECULAR PATHOLOGY LA English DT Article DE Natural killer (NK) cells; CD16A; ADCC; Antibody domains; BiKE ID NATURAL-KILLER-CELLS; FC-GAMMA-RIIIA; T-CELLS; IGG-FC; RECEPTOR; CD16; PROTEIN; POLYMORPHISM; EXPRESSION; CYTOTOXICITY AB CD16A (Fc gamma RIIIA) is an activating receptor mostly expressed on natural killer (NK) cells and monocytes/macrophages. It can mediate antibody-dependent cell-mediated cytotoxicity (ADCC) through low-affinity interaction with human immunoglobulin G (IgG) Fc. It can also mediate cell lysis if NK cells are guided by bispecific killer cells engagers (BiKEs). BiKEs showed some success in clinical trials of cancer and are promising candidate therapeutics. However, currently reported BiKEs are based on antibody fragments (scFvs) of relatively large size. The CDI 6A-specific antibodies are also typically from animal origin. Decreasing the BiKE size could result in enhanced penetration into solid tumor and normal tissues, and using fully human antibodies could decrease the likelihood of immunogenicity. Here we report the identification and characterization of two antibody domains, D6 and E11, isolated from a very large human VH antibody domain library displayed on phage. D6 and E11 bound CD16A with EC50 of 4 nM and 8 nM, respectively, but not other Fc gamma receptors (Fc gamma Rs) such as CD64 (Fc gamma RI), CD32 (Fc gamma RII) and CD16B (Fc gamma RIIIB). They bound to both CD16A allotypes (158F,V) with equal affinity and competed with each other as well as with human IgG1 and the mouse anti-CD 16A antibody 3G8. These and other results were used to build a molecular docking model predicting that D6 and Ell may bind to the CD16A membrane proximal D2 domain by interacting with its BC, C'E and EF loops. Importantly, cross-linked (bivalent) D6 and Ell induced secretion of IL-2 after binding to CD16A-expressing Jurkat T cells. The small size of these antibody domains combined with their high-affinity, specific, allotype-independent, activating interactions with CDI 6A could allow generation of novel highly effective BiKEs and other candidate protein therapeutics. Published by Elsevier Inc. C1 [Li, Wei; Dimitrov, Dimiter S.] NCI, Prot Interact Sect, Canc & Inflammat Program, Ctr Canc Res,NIH, Frederick, MD 21702 USA. [Yang, Hongjia] Palisades Charter High Sch, 15777 Bowdoin St, Pacific Palisades, CA 90272 USA. RP Li, W; Dimitrov, DS (reprint author), 1050 Boyles Dr,Bldg 567,Room 180,Room 152, Frederick, MD 21702 USA. EM wei.li3@nih.gov; dimitrdi@mail.nih.gov FU Intramural Research Program, National Cancer Institute, National Institutes of Health; Stand Up To Cancer-St. Baldrick's Pediatric Dream Team translational research grant [SU2C-AACR-DT113] FX We thank members of our group for help. This work was supported in part by the Intramural Research Program, National Cancer Institute, National Institutes of Health and by a Stand Up To Cancer-St. Baldrick's Pediatric Dream Team translational research grant (SU2C-AACR-DT113). Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. NR 33 TC 0 Z9 0 U1 3 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4800 EI 1096-0945 J9 EXP MOL PATHOL JI Exp. Mol. Pathol. PD OCT PY 2016 VL 101 IS 2 BP 281 EP 289 DI 10.1016/j.yexmp.2016.10.001 PG 9 WC Pathology SC Pathology GA ED0RA UT WOS:000388548400016 PM 27712994 ER PT J AU Kainerstorfer, J Chowdhry, F Gandjbakhche, A Tromberg, B Gannot, I AF Kainerstorfer, Jana Chowdhry, Fatima Gandjbakhche, Amir Tromberg, Bruce Gannot, Israel TI Optical Diagnostic and Biophotonic Methods from Bench to Bedside SO JOURNAL OF BIOMEDICAL OPTICS LA English DT Editorial Material C1 [Kainerstorfer, Jana] Carnegie Mellon Univ, Dept Biomed Engn, Scott Hall,Room 4N105,5000 Forbes Ave, Pittsburgh, PA 15213 USA. [Chowdhry, Fatima; Gandjbakhche, Amir] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, 9 Mem Dr,B1-E11, Bethesda, MD 20814 USA. [Tromberg, Bruce] Beckman Laser Inst & Med Clin, Laser Microbeam & Med Program, 1002 Hlth Sci Rd, Irvine, CA 92617 USA. [Gannot, Israel] Johns Hopkins Univ, Whiting Sch Engn, Dept Elect & Comp Engn, Baltimore, MD 21218 USA. [Gannot, Israel] Tel Aviv Univ, Fac Engn, Dept Biomed Engn, IL-69978 Tel Aviv, Israel. RP Kainerstorfer, J (reprint author), Carnegie Mellon Univ, Dept Biomed Engn, Scott Hall,Room 4N105,5000 Forbes Ave, Pittsburgh, PA 15213 USA. EM jkainers@andrew.cmu.edu; fatima.chowdhry@nih.gov; gandjbaa@mail.nih.gov; bjtrombe@uci.edu; gannot@eng.tau.ac.il NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPIE-SOC PHOTO-OPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 1083-3668 EI 1560-2281 J9 J BIOMED OPT JI J. Biomed. Opt. PD OCT PY 2016 VL 21 IS 10 AR 101401 DI 10.1117/1.JBO.21.10.101401 PG 2 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA EC5YN UT WOS:000388213300003 ER PT J AU Watts, JM Dumitriu, B Hilden, P Kishtagari, A Rapaport, F Chen, C Ahn, J Devlin, SM Stein, EM Rampal, R Levine, RL Young, N Tallman, MS AF Watts, Justin M. Dumitriu, Bogdan Hilden, Patrick Kishtagari, Ashwin Rapaport, Franck Chen, Christina Ahn, Jihae Devlin, Sean M. Stein, Eytan M. Rampal, Raajit Levine, Ross L. Young, Neal Tallman, Martin S. TI Telomere length and associations with somatic mutations and clinical outcomes in acute myeloid leukemia SO LEUKEMIA RESEARCH LA English DT Article DE Acute myeloid leukemia; Telomere length; Clinical outcomes; Somatic mutations ID STEM-CELLS AB We examined the genetic implications and clinical impact of telomere length (TL) in 67 patients with acute myeloid leukemia (AML). There was a trend toward improved survival at 6 months in patients with longer TL. We found that patients with activating mutations, such as FLT3-ITD, had shorter TL, while those with mutations in epigenetic modifying enzymes, particularly IDH1 and IDH2, had longer TL. These are intriguing findings that warrant further investigation in larger cohorts. Our data show the potential of TL as a predictive biomarker in AML and identify genetic subsets that may be particularly vulnerable to telomere-targeted therapies. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Watts, Justin M.] Univ Miami, Sylvester Comprehens Canc Ctr, Miller Sch Med, Div Hematol Oncol,Dept Med, Miami, FL USA. [Watts, Justin M.; Kishtagari, Ashwin; Rapaport, Franck; Ahn, Jihae; Stein, Eytan M.; Rampal, Raajit; Levine, Ross L.; Tallman, Martin S.] Weill Cornell Med Coll, Mem Sloan Kettering Canc Ctr, Leukemia Serv, Dept Med,Human Oncol & Pathogenesis Program, New York, NY USA. [Dumitriu, Bogdan; Young, Neal] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Hilden, Patrick; Devlin, Sean M.] Weill Cornell Med Coll, Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY USA. [Kishtagari, Ashwin] Mt Sinai St Lukes Roosevelt Hosp, Dept Med, New York, NY USA. RP Watts, JM (reprint author), Clin Res Bldg,1120NW 14th St,Suite 610C, Miami, FL 33145 USA. EM jwatts@med.miami.edu FU American Society of Clinical Oncology (ASCO) Young Investigator Award (YIA); Memorial Sloan Kettering Cancer Center; National Heart, Lung, and Blood Institute FX This research was supported by an American Society of Clinical Oncology (ASCO) Young Investigator Award (YIA) (recipient: Justin Watts, mentor: Martin Tallman). This work was also supported by and completed at Memorial Sloan Kettering Cancer Center and the National Heart, Lung, and Blood Institute in equal collaboration. NR 16 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 EI 1873-5835 J9 LEUKEMIA RES JI Leuk. Res. PD OCT PY 2016 VL 49 BP 62 EP 65 DI 10.1016/j.leukres.2016.07.013 PG 4 WC Oncology; Hematology SC Oncology; Hematology GA EC7JQ UT WOS:000388314100010 PM 27568819 ER PT J AU Norsworthy, KJ Cho, E Arora, J Kowalski, J Tsai, HL Warlick, E Showel, M Pratz, KW Sutherland, LA Gore, SD Ferguson, A Sakoian, S Greer, J Espinoza-Delgado, I Jones, RJ Matsui, WH Smith, BD AF Norsworthy, Kelly J. Cho, Eunpi Arora, Jyoti Kowalski, Jeanne Tsai, Hua-Ling Warlick, Erica Showel, Margaret Pratz, Keith W. Sutherland, Lesley A. Gore, Steven D. Ferguson, Anna Sakoian, Sarah Greer, Jackie Espinoza-Delgado, Igor Jones, Richard J. Matsui, William H. Smith, B. Douglas TI Differentiation therapy in poor risk myeloid malignancies: Results of companion phase II studies SO LEUKEMIA RESEARCH LA English DT Article DE Differentiation; Acute myeloid leukemia; Myelodysplastic syndrome; Bexarotene; Entinostat ID TRANS-RETINOIC ACID; ACUTE PROMYELOCYTIC LEUKEMIA; COLONY-STIMULATING FACTOR; CELL LUNG-CANCER; ARSENIC TRIOXIDE; MYELODYSPLASTIC SYNDROME; INTERFERON-ALPHA; GROWTH-FACTORS; CHEMOTHERAPY; TRIAL AB Pre-clinical data in non-M3 AML supports the use of differentiation therapy, but clinical activity has been limited. Myeloid growth factors can enhance anti-leukemic activity of differentiating agents in vitro. We conducted companion phase II trials investigating sargramostim (GM-CSF) 125 mu g/m(2)/day plus 1) bexarotene (BEX) 300 mg/m(2)/day or 2) entinostat (ENT) 4-8 mg/m(2)/week in patients with MDS or relapsed/refractory AML. Primary endpoints were response after at least two treatment cycles and toxicity. 26 patients enrolled on the BEX trial had a median of 2 prior treatments and 24 enrolled on the ENT trial had a median of 1. Of 13 response-evaluable patients treated with BEX, the best response noted was hematologic improvement in neutrophils (HI-N) seen in 4 (31%) patients; none achieved complete (CR) or partial remission (PR). Of 10 treated with ENT, there was 1 (10%) partial remission (PR) and 2 (20%) with HI-N. The secondary endpoint responses of HI-N with each combination were accompanied by a numerical increase in ANC (BEX: 524 to 931 cells/mm(3), p = 0.096; ENT: 578 to 1 137 cells/mm(3), p = 0.15) without increasing marrow blasts. Shared grade 3-4 non-hematologic toxicities included febrile neutropenia, bone pain, fatigue, and dyspnea. GM-CSF plus either BEX or ENT are well tolerated in resistant and refractory MDS and AML and showed modest clinical and biologic activity, most commonly HI-N. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Norsworthy, Kelly J.; Cho, Eunpi; Tsai, Hua-Ling; Warlick, Erica; Showel, Margaret; Pratz, Keith W.; Sutherland, Lesley A.; Gore, Steven D.; Ferguson, Anna; Sakoian, Sarah; Greer, Jackie; Jones, Richard J.; Matsui, William H.; Smith, B. Douglas] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Arora, Jyoti; Kowalski, Jeanne] Emory Univ, Biostat & Bioinformat Shared Resource, Winship Canc Inst, Atlanta, GA 30322 USA. [Espinoza-Delgado, Igor] NCI, Canc Therapy Evaluat Program, Rockville, MD USA. [Cho, Eunpi] Palo Alto Med Fdn, Sunnyvale, CA USA. [Arora, Jyoti] Med Univ South Carolina, Dept Publ Hlth Sci, Charleston, SC USA. [Warlick, Erica] Univ Minnesota, Div Hematol Oncol & Transplantat, Minneapolis, MN USA. [Sutherland, Lesley A.] Univ Maryland, Sch Med, Dept Dermatol, Baltimore, MD 21201 USA. [Gore, Steven D.] Yale Canc Ctr, New Haven, CT USA. RP Smith, BD (reprint author), Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, CRBI, 1650 Orleans St,Room 246, Baltimore, MD 21218 USA. EM bdsmith@jhmi.edu FU National Institutes of Health [P01 CA015396] FX This work was supported by the National Institutes of Health (P01 CA015396). NR 42 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 EI 1873-5835 J9 LEUKEMIA RES JI Leuk. Res. PD OCT PY 2016 VL 49 BP 90 EP 97 DI 10.1016/j.leukres.2016.09.003 PG 8 WC Oncology; Hematology SC Oncology; Hematology GA EC7JQ UT WOS:000388314100015 PM 27619199 ER PT J AU Hall, KD Kerns, JC Brychta, R Knuth, ND AF Hall, Kevin D. Kerns, Jennifer C. Brychta, Robert Knuth, Nicholas D. TI Response to "Overstated Metabolic Adaptation After 'The Biggest Loser' Intervention" SO OBESITY LA English DT Letter ID MASSIVE WEIGHT-LOSS C1 [Hall, Kevin D.; Brychta, Robert] NIDDK, Lab Biol Modeling, Bethesda, MD 20892 USA. [Kerns, Jennifer C.] Washington DC Vet Affairs Med Ctr, Hosp Sect, Washington, DC USA. [Knuth, Nicholas D.] Towson Univ, Dept Kinesiol, Baltimore, MD USA. RP Hall, KD (reprint author), NIDDK, Lab Biol Modeling, Bethesda, MD 20892 USA. EM kevinh@niddk.nih.gov NR 6 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD OCT PY 2016 VL 24 IS 10 BP 2026 EP 2026 DI 10.1002/oby.21635 PG 1 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA EC6WH UT WOS:000388276900004 PM 27581560 ER PT J AU Dilthey, AT Gourraud, PA Mentzer, AJ Cereb, N Iqbal, Z McVean, G AF Dilthey, Alexander T. Gourraud, Pierre-Antoine Mentzer, Alexander J. Cereb, Nezih Iqbal, Zamin McVean, Gil TI High-Accuracy HLA Type Inference from Whole-Genome Sequencing Data Using Population Reference Graphs SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID HIGH-RESOLUTION HLA; CLASS-I; SUSCEPTIBILITY; DISEASE; MHC AB Genetic variation at the Human Leucocyte Antigen (HLA) genes is associated with many autoimmune and infectious disease phenotypes, is an important element of the immunological distinction between self and non-self, and shapes immune epitope repertoires. Determining the allelic state of the HLA genes (HLA typing) as a by-product of standard whole-genome sequencing data would therefore be highly desirable and enable the immunogenetic characterization of samples in currently ongoing population sequencing projects. Extensive hyperpolymorphism and sequence similarity between the HLA genes, however, pose problems for accurate read mapping and make HLA type inference from whole-genome sequencing data a challenging problem. We describe how to address these challenges in a Population Reference Graph (PRG) framework. First, we construct a PRG for 46 (mostly HLA) genes and pseudogenes, their genomic context and their characterized sequence variants, integrating a database of over 10,000 known allele sequences. Second, we present a sequence-to-PRG paired-end read mapping algorithm that enables accurate read mapping for the HLA genes. Third, we infer the most likely pair of underlying alleles at G group resolution from the IMGT/HLA database at each locus, employing a simple likelihood framework. We show that HLA*PRG, our algorithm, outperforms existing methods by a wide margin. We evaluate HLA*PRG on six classical class I and class II HLA genes (HLA-A, -B, -C, -DQA1, -DQB1, -DRB1) and on a set of 14 samples (3 samples with 2 x 100bp, 11 samples with 2 x 250bp Illumina HiSeq data). Of 158 alleles tested, we correctly infer 157 alleles (99.4%). We also identify and re-type two erroneous alleles in the original validation data. We conclude that HLA*PRG for the first time achieves accuracies comparable to gold-standard reference methods from standard whole-genome sequencing data, though high computational demands (currently similar to 30-250 CPU hours per sample) remain a significant challenge to practical application. C1 [Dilthey, Alexander T.; Mentzer, Alexander J.; Iqbal, Zamin; McVean, Gil] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Dilthey, Alexander T.] NHGRI, NIH, Bethesda, MD 20892 USA. [Gourraud, Pierre-Antoine] UCSF, Dept Neurol, San Francisco, CA USA. [Gourraud, Pierre-Antoine] Univ Nantes, Nantes Univ Hosp, INSERM, Unit ATIP 1064,Avenir Team 6, Nantes, France. [Cereb, Nezih] Histogenetics, Ossining, NY USA. [McVean, Gil] Univ Oxford, Li Ka Shing Ctr Hlth Informat & Discovery, Oxford, England. RP Dilthey, AT (reprint author), Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.; Dilthey, AT (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM dilthey@well.ox.ac.uk OI Mentzer, Alexander/0000-0002-4502-2209; Iqbal, Zamin/0000-0001-8466-7547 FU Wellcome Trust [100956/Z/13/Z, 090532/Z/09/Z, 064693, 079110, 095778, 106289]; Nuffield Department of Medicine Fellowship; Royal Society [102541/Z/13/Z]; European Research Council Advanced Grant [294557]; ATIP-Avenir INSERM program; Region Pays de Loire ConnecTalent FX The study was funded by grant 100956/Z/13/Z from the Wellcome Trust to GM, a Nuffield Department of Medicine Fellowship to ZI, a Sir Henry Dale Fellowship jointly awarded by the Wellcome Trust and the Royal Society to ZI (102541/Z/13/Z), and a Wellcome Trust Core Award to the Wellcome Trust Centre for Human Genetics (090532/Z/09/Z). The Ugandan work was supported by funding from the Wellcome Trust, grant numbers 064693, 079110 and 095778, to Alison M Elliott, a European Research Council Advanced Grant to Adrian Hill (294557) and a Wellcome Trust Clinical Research Training Fellowship to AJM (106289). PAG is supported by ATIP-Avenir INSERM program and the Region Pays de Loire ConnecTalent. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 0 Z9 0 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-734X EI 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD OCT PY 2016 VL 12 IS 10 AR e1005151 DI 10.1371/journal.pcbi.1005151 PG 16 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA EB8SC UT WOS:000387660200031 PM 27792722 ER PT J AU Kaplan, RM Fang, ZY Morgan, G AF Kaplan, Robert M. Fang, Zhengyi Morgan, Glen TI Providers' advice concerning smoking cessation: Evidence from the Medical Expenditures Panel Survey SO PREVENTIVE MEDICINE LA English DT Article DE Smoking; Tobacco; Primary care; Patient counseling; Preventive care; Physician adherence; Survey ID TOBACCO AB Importance and objective. We estimate how often adult smokers are advised to quit using a nationally representative sample of adults in the United States. Design and participants. Data are from the 2012-2013 household component of the United States (US) Medical Expenditures Panel Survey (MEPS). Main outcome measure. Current smoking and advice to quit offered by providers. Results. Smoking was reported by 18.26% (CI 17.13%-19.38%) of 2012 MEPS respondents. Less than half of adult smokers (47.24%, CI 44.30%-50.19%) were advised to quit by their physicians although 17.57% (CI 15.37%-19.76%) had not seen a doctor in the last 12 months. Advice to quit was given significantly less often to respondents classified as: aged 18-44 (40.29%), men (40.20%), less educated (42.26%), lower family income (43.51%), Hispanic (33.82%), never married (39.55%), and living outside the northeast. Smoking status at year 2 for patients who had received advice to quit was similar (85.13%: SE 1.62%) to those who had seen a physician but were not advised to quit (81.95%: SE 2.05%). Advice to quit smoking was less common than the use of common medical screening tests. Conclusions and relevance. Smoking cessation advice is given to less than half of current cigarette smokers and it is least likely to be given to themost vulnerable populations. Efforts to reduce smoking are deployed less often than other preventive practices. The rate of advice to quit has not changed over the last decade. Health care providers are missing an important opportunity to affect health behaviors and outcomes. Published by Elsevier Inc. C1 [Kaplan, Robert M.] Univ Calif Los Angeles, Los Angeles, CA USA. [Fang, Zhengyi] Social & Sci Syst Inc, Silver Spring, MD USA. [Morgan, Glen] NCI, Bethesda, MD 20892 USA. RP Kaplan, RM (reprint author), Univ Calif Los Angeles, Dept Hlth Policy & Management, Fielding Sch Publ Hlth, Los Angeles, CA 90095 USA. EM rmkaplan@ucla.edu NR 15 TC 1 Z9 1 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 EI 1096-0260 J9 PREV MED JI Prev. Med. PD OCT PY 2016 VL 91 BP 32 EP 36 DI 10.1016/j.ypmed.2016.07.012 PG 5 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA EC7ME UT WOS:000388322800005 PM 27475105 ER PT J AU El-Toukhy, SM Choi, K AF El-Toukhy, Sherine M. Choi, Kelvin TI Magazine hyped: Trends in tobacco advertising and readership characteristics, 2010-2014 SO PREVENTIVE MEDICINE LA English DT Article DE Advertising placement; Disparities; Magazine tobacco advertising; National trends; Readership characteristics ID CURRENT CIGARETTE-SMOKING; SMOKELESS TOBACCO; UNITED-STATES; ELECTRONIC CIGARETTES; PRODUCT USE; ADULTS; INDUSTRY; YOUTH; DOCUMENTS; CESSATION AB We tracked magazine advertisements for seven tobacco products in U. S. magazines from 2010 to 2014 and examined magazine readership characteristics that are associated with advertising placement in 2014. Advertising data came from Kantar Media's Intelligence and readership data came from a 2014 Experian's nationally representative survey of 4667 adult tobacco users. At magazine level, we aggregated total and product-specific number of advertisements and expenditures by year and calculated readership demographics. We used linear and poisson regression models to examine trends in number of tobacco advertisements and expenditures and readership characteristics associated with number of tobacco advertisements in 2014. Analyses were conducted in 2015. There were 5317 tobacco advertisements with expenditures of $ 796 million that appeared in 322 magazines during 2010-2014. Cigarette advertisements accounted for 2928 (55%), followed by e-cigarettes (n = 862, 16%), and snus (n = 534, 10%). Advertisements increased by 2.79 ad/ year for cigarettes, 1.94 ad/ year for e-cigarettes, and 0.78 ad/ year for chewing tobacco (p < 0.05). In 2014, number of advertisements was associated with select readership characteristics (p b 0.05). For every 10% increase in 18-39 year-old readers, advertisement rate increased by 1.48 times for cigarettes, 3.44 times for e-cigarettes, and 2.15 times for chewing tobacco. For every 10% increase in readers who earn =$ 24,999, advertisement rate increased by 1.37 times for cigarettes and 1.70 times for e-cigarettes. Magazine tobacco advertising has increased especially for cigarettes and is targeted toward certain demographic subgroups. Regulating tobacco magazine advertising should be integral to tobacco control policies. (C) 2016 Elsevier Inc. All rights reserved. C1 [El-Toukhy, Sherine M.; Choi, Kelvin] Natl Inst Minor Hlth & Hlth Dispar, Div Intramural Res, Bethesda, MD USA. RP El-Toukhy, SM (reprint author), 9000 Rockville Pike,Bldg 3,Rm 5E11, Bethesda, MD 20892 USA. EM sherine.el-toukhy@nih.gov OI El-Toukhy, Sherine/0000-0002-0329-5823 FU Division of Intramural Research of the National Institute on Minority Health and Health Disparities, National Institutes of Health FX The effort of Dr. Sherine El-Toukhy and Dr. Kelvin Choi was supported by the Division of Intramural Research of the National Institute on Minority Health and Health Disparities, National Institutes of Health. NR 39 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 EI 1096-0260 J9 PREV MED JI Prev. Med. PD OCT PY 2016 VL 91 BP 132 EP 137 DI 10.1016/j.ypmed.2016.08.017 PG 6 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA EC7ME UT WOS:000388322800020 PM 27519170 ER PT J AU Sakuma, KLK Felicitas-Perkins, JQ Blanco, L Fagan, P Perez-Stable, EJ Pulvers, K Romero, D Trinidad, DR AF Sakuma, Kari-Lyn K. Felicitas-Perkins, Jamie Quibol Blanco, Lyzette Fagan, Pebbles Perez-Stable, Eliseo J. Pulvers, Kim Romero, Devan Trinidad, Dennis R. TI Tobacco use disparities by racial/ethnic groups: California compared to the United States SO PREVENTIVE MEDICINE LA English DT Article DE Tobacco use; Smoking; Minority health; Tobacco control; Tobacco disparities ID CONTROL PROGRAMS; ASIAN-AMERICANS; ADULT SMOKERS; CIGARETTE CONSUMPTION; INTERMITTENT SMOKING; CANCER RATES; LUNG-CANCER; DECLINE; LIGHT; ASSOCIATION AB Racial/ethnic disparities in cigarette use and cessation persist. This study compared cigarette consumption and former smoking trends in California (CA) with the rest of the United States (US) by racial/ethnic categories of non-Hispanic White, Black, Hispanic/Latino, and Asian/Pacific Islander groups. Data were analyzed from the 1992 to 2011 Tobacco Use Supplement to the Current Population Survey. Consumption levels across decades were examined and adjusted logistic regression models were fit to compare across CA and US. Results indicated steady declines in ever smoking prevalence for all groups with much lower magnitudes of change among US Blacks and Whites compared to their CA counterparts. After controlling for age, gender, and education, CA had significantly fewer heavy smokers (OR = 0.45, 95% CI: 0.38-0.54), more light and intermittent smokers (LITS; OR = 1.68, 95% CI: 1.45-1.93), and a greater proportion of former smokers (OR = 1.35, 95% CI: 1.24-1.48) than the rest of US. Data were stratified by race/ethnicity and the patterns shown were mostly consistent with CA performing statistically better than their US counterparts with the exception of Black LITS and Asian/Pacific Islander former smokers. California's success in reducing tobacco use disparities may serve as a prime example of tobacco control policy for the country. CA and the US will need to continue to address tobacco use and cessation in the context of the growing diversity of the population. (C) 2016 Elsevier Inc. All rights reserved. C1 [Sakuma, Kari-Lyn K.] Oregon State Univ, Coll Publ Hlth & Human Sci, Sch Soda! & Behav Hlth Sci, 412 Waldo Hall, Corvallis, OR 97331 USA. [Felicitas-Perkins, Jamie Quibol; Blanco, Lyzette] Claremont Grad Univ, Sch Community & Global Hlth, Claremont, CA USA. [Fagan, Pebbles] Univ Harwaii, Ctr Canc, Honolulu, HI USA. [Perez-Stable, Eliseo J.] Univ Calif San Francisco, Med Effect Res Ctr Divers Populat, Dept Med, Div Gen Internal Med, San Francisco, CA 94143 USA. [Pulvers, Kim; Romero, Devan] Calif State Univ San Marcos, San Marcos, CA USA. [Trinidad, Dennis R.] Univ Calif San Diego, San Diego, CA 92103 USA. [Perez-Stable, Eliseo J.] Natl Inst Minor Hlth & Hlth Dispar, NIH, Bethesda, MD USA. RP Sakuma, KLK (reprint author), Oregon State Univ, Coll Publ Hlth & Human Sci, Sch Soda! & Behav Hlth Sci, 412 Waldo Hall, Corvallis, OR 97331 USA. EM karilyn.sakuma@oregonstate.edu FU National Cancer Institute [1R03CA150559]; Tobacco-Related Disease Research Program of the University of California Office of the President [23RT-0016]; Oregon State University FX This work was supported by the National Cancer Institute (grant #1R03CA150559, PI: Trinidad), the Tobacco-Related Disease Research Program of the University of California Office of the President (grant #23RT-0016, PI: Trinidad), and Oregon State University. NR 48 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 EI 1096-0260 J9 PREV MED JI Prev. Med. PD OCT PY 2016 VL 91 BP 224 EP 232 DI 10.1016/j.ypmed.2016.08.035 PG 9 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA EC7ME UT WOS:000388322800034 PM 27575315 ER PT J AU Watson, M Geller, AC Tucker, MA Guy, GP Weinstock, MA AF Watson, Meg Geller, Alan C. Tucker, Margaret A. Guy, Gery P. Weinstock, Martin A. TI Melanoma burden and recent trends among non-Hispanic whites aged 15-49 years, United States SO PREVENTIVE MEDICINE LA English DT Article DE Melanoma; Cancer incidence; Cancer mortality; Trends; Adolescent and young adult ID CUTANEOUS MELANOMA; CANCER REGISTRIES; REPORTING DELAY; INCIDENCE RATES; SUN EXPOSURE; SURVIVAL; US; ADULTS; WOMEN; RISK AB Melanoma is among the most common cancers for adolescents and young adults. Updated information on melanoma among adults <50 is needed. The objective of this study was to examine invasive melanoma in the United States among people aged 15-49 years for the group at highest risk, non-Hispanic whites. In 2015, we analyzed population-based cancer registry data from the Centers for Disease Control and Prevention's National Program of Cancer Registries and the National Cancer Institute's Surveillance, Epidemiology, and End Results program to examineme lanoma incidence and death rates and trends among non-Hispanic whites aged 15-49 years by sex and age. We also present incidence trends with regard to thickness and site on the body. Among non-Hispanic whites aged 15-49 years, rates were higher among females. Thin melanomas increased among both sexes during 19922006 and stabilized during 2006-2012. For the period 1992-2012, melanomas thicker than 4 mm increased among males and melanomas 1.01-2.00 mm thick increased among females. Melanomas were most commonly diagnosed on the trunk and lower extremity among females and on the trunk and upper extremity among males. Increases in melanoma incidence among non-Hispanic whites aged 15-49 years across various thicknesses suggest that melanoma trends are not solely related to increased screening but are, in part, related to true increases. Declines in melanoma rates of about 3% a year from the mid-2000s to 2012 in the youngest age groups offer hope that melanoma incidence may decline in future generations. Published by Elsevier Inc. C1 [Watson, Meg; Guy, Gery P.] Ctr Dis Control & Prevent, Epidemiol & Appl Res Branch, Div Canc Prevent & Control, 4770 Buford Hwy NE MS-F76, Atlanta, GA 30341 USA. [Geller, Alan C.] Harvard Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA USA. [Tucker, Margaret A.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Weinstock, Martin A.] Brown Univ, VA Med Ctr, Dept Dermatol, Providence, RI 02912 USA. [Weinstock, Martin A.] Brown Univ, VA Med Ctr, Dept Epidemiol, Providence, RI 02912 USA. RP Watson, M (reprint author), Ctr Dis Control & Prevent, Epidemiol & Appl Res Branch, Div Canc Prevent & Control, 4770 Buford Hwy NE MS-F76, Atlanta, GA 30341 USA. EM Eze5@cdc.gov FU Intramural CDC HHS [CC999999] NR 24 TC 0 Z9 0 U1 2 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 EI 1096-0260 J9 PREV MED JI Prev. Med. PD OCT PY 2016 VL 91 BP 294 EP 298 DI 10.1016/j.ypmed.2016.08.032 PG 5 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA EC7ME UT WOS:000388322800042 PM 27565055 ER PT J AU Daumit, GL McGinty, EE Pronovost, P Dixon, LB Guallar, E Ford, DE Cahoon, EK Boonyasai, RT Thompson, D AF Daumit, Gail L. McGinty, Emma E. Pronovost, Peter Dixon, Lisa B. Guallar, Eliseo Ford, Daniel E. Cahoon, Elizabeth K. Boonyasai, Romsai T. Thompson, David TI Patient Safety Events and Harms During Medical and Surgical Hospitalizations for Persons With Serious Mental Illness SO PSYCHIATRIC SERVICES LA English DT Article ID SICKLE-CELL-DISEASE; ADVERSE EVENTS; CARE; SCHIZOPHRENIA; MORTALITY; PREVALENCE; DISORDERS; SMOKING; COMMUNICATION; INDIVIDUALS AB Objective: This study explored the risk of patient safety events and associated nonfatal physical harms and mortality in a cohort of persons with serious mental illness. This group experiences high rates of medical comorbidity and premature mortality and may be at high risk of adverse patient safety events. Methods: Medical record review was conducted for medical-surgical hospitalizations occurring during 1994-2004 in a community-based cohort of Maryland adults with serious mental illness. Individuals were eligible if they died within 30 days of a medical-surgical hospitalization and if they also had at least one prior medical-surgical hospitalization within five years of death. All admissions took place at Maryland general hospitals. A case-crossover analysis examined the relationships among patient safety events, physical harms, and elevated likelihood of death within 30 days of hospitalization. Results: A total of 790 hospitalizations among 253 adults were reviewed. The mean number of patient safety events per hospitalization was 5.8, and the rate of physical harms was 142 per 100 hospitalizations. The odds of physical harm were elevated in hospitalizations in which 22 of the 34 patient safety events occurred (p < .05), including medical events (odds ratio [OR] = 1.5, 95% confidence interval [CI] = 1.3-1.7) and procedure-related events (OR = 1.6, CI = 1.2-2.0). Adjusted odds of death within 30 days of hospitalization were elevated for individuals with any patient safety event, compared with those with no event (OR = 3.7, CI = 1.4-10.3). Conclusions: Patient safety events were positively associated with physical harm and 30-day mortality in nonpsychiatric hospitalizations for persons with serious mental illness. C1 [Daumit, Gail L.; Ford, Daniel E.; Boonyasai, Romsai T.] Johns Hopkins Univ, Sch Med, Dept Internal Med, Baltimore, MD USA. [Pronovost, Peter; Thompson, David] Johns Hopkins Univ, Sch Med, Dept Anesthesiol, Baltimore, MD USA. [Pronovost, Peter; Thompson, David] Johns Hopkins Univ, Sch Med, Dept Crit Care Med, Baltimore, MD USA. [Daumit, Gail L.; McGinty, Emma E.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD 21205 USA. [Dixon, Lisa B.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Dixon, Lisa B.] Columbia Univ Coll Phys & Surg, Dept Psychiat, 722 W 168th St, New York, NY 10032 USA. [Guallar, Eliseo] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Cahoon, Elizabeth K.] NCI, Radiat Epidemiol Branch, Bethesda, MD 20892 USA. RP McGinty, EE (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD 21205 USA. EM emcginty@jhsph.edu FU National Institute of Mental Health [R01MH074070, K24MH093763]; Ernst and Young FX The authors gratefully acknowledge support from grants R01MH074070 and K24MH093763 from the National Institute of Mental Health.; Dr. Pronovost reports receipt of grant support from Ernst and Young. The other authors report no financial relationships with commercial interests. NR 49 TC 0 Z9 0 U1 8 U2 8 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 1075-2730 EI 1557-9700 J9 PSYCHIAT SERV JI Psychiatr. Serv. PD OCT 1 PY 2016 VL 67 IS 10 BP 1067 EP 1074 DI 10.1176/appi.ps.201500415 PG 8 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA EC6TC UT WOS:000388268600015 ER PT J AU Kuzu, G Keskin, O Nussinov, R Gursoy, A AF Kuzu, Guray Keskin, Ozlem Nussinov, Ruth Gursoy, Attila TI PRISM-EM: template interface-based modelling of multi-protein complexes guided by cryo-electron microscopy density maps SO ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY LA English DT Article DE multimolecular protein complexes; modelling protein assemblies; PRISM-EM; three-dimensional electron microscopy; protein structure prediction ID FITTING ATOMIC MODELS; ELECTRON-MICROSCOPY; MACROMOLECULAR ASSEMBLIES; WEB SERVER; I-TASSER; DOCKING; PREDICTION; SEGMENTATION; SCALE; TOOL AB The structures of protein assemblies are important for elucidating cellular processes at the molecular level. Three-dimensional electron microscopy (3DEM) is a powerful method to identify the structures of assemblies, especially those that are challenging to study by crystallography. Here, a new approach, PRISM-EM, is reported to computationally generate plausible structural models using a procedure that combines crystallographic structures and density maps obtained from 3DEM. The predictions are validated against seven available structurally different crystallographic complexes. The models display mean deviations in the backbone of <5 angstrom. PRISM-EM was further tested on different benchmark sets; the accuracy was evaluated with respect to the structure of the complex, and the correlation with EM density maps and interface predictions were evaluated and compared with those obtained using other methods. PRISM-EM was then used to predict the structure of the ternary complex of the HIV-1 envelope glycoprotein trimer, the ligand CD4 and the neutralizing protein m36. C1 [Kuzu, Guray; Keskin, Ozlem] Koc Univ, Ctr Computat Biol & Bioinformat, TR-34450 Istanbul, Turkey. [Kuzu, Guray; Keskin, Ozlem] Koc Univ, Coll Engn, TR-34450 Istanbul, Turkey. [Keskin, Ozlem] Koc Univ, Coll Engn, Chem & Biol Engn, TR-34450 Istanbul, Turkey. [Nussinov, Ruth] NCI, Canc & Inflammat Program, Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. [Gursoy, Attila] Koc Univ, Comp Engn, TR-34450 Istanbul, Turkey. [Kuzu, Guray] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. RP Keskin, O (reprint author), Koc Univ, Ctr Computat Biol & Bioinformat, TR-34450 Istanbul, Turkey.; Keskin, O (reprint author), Koc Univ, Coll Engn, TR-34450 Istanbul, Turkey.; Keskin, O (reprint author), Koc Univ, Coll Engn, Chem & Biol Engn, TR-34450 Istanbul, Turkey.; Gursoy, A (reprint author), Koc Univ, Comp Engn, TR-34450 Istanbul, Turkey. EM okeskin@ku.edu.tr; agursoy@ku.edu.tr RI Gursoy, Attila/E-9565-2015 OI Gursoy, Attila/0000-0002-2297-2113 FU TUBITAK (The Scientific and Technological Research Council of Turkey) fellowship; TUBITAK Research Grant [114M196]; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX We thank Drs Sriram Subramaniam, Erin E. H. Tran and Lesley A. Earl for guidance relating to the incorporation of the 3DEM information and for critical reading of this manuscript, insight and discussions. GK was supported by a TUBITAK (The Scientific and Technological Research Council of Turkey) fellowship. This work was supported by TUBITAK Research Grant No. 114M196. It was also funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 66 TC 0 Z9 0 U1 2 U2 2 PU INT UNION CRYSTALLOGRAPHY PI CHESTER PA 2 ABBEY SQ, CHESTER, CH1 2HU, ENGLAND SN 2059-7983 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Struct. Biol. PD OCT PY 2016 VL 72 BP 1137 EP 1148 DI 10.1107/S2059798316013541 PN 10 PG 12 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA EB7TE UT WOS:000387592700007 PM 27710935 ER PT J AU Hamilton, DH Roselli, M Ferroni, P Costarelli, L Cavaliere, F Taffuri, M Palena, C Guadagni, F AF Hamilton, Duane H. Roselli, Mario Ferroni, Patrizia Costarelli, Leopoldo Cavaliere, Francesco Taffuri, Mariateresa Palena, Claudia Guadagni, Fiorella TI Brachyury, a vaccine target, is overexpressed in triple-negative breast cancer SO ENDOCRINE-RELATED CANCER LA English DT Article DE brachyury; TNBC; tumor antigen; vaccine target ID EPITHELIAL-MESENCHYMAL TRANSITION; TRANSCRIPTION FACTOR BRACHYURY; HUMAN CARCINOMA-CELLS; TUMOR-CELLS; PHENOTYPE; METASTASIS; EXPRESSION; SUBTYPES; PROGRESSION; RESISTANCE AB Patients diagnosed with triple-negative breast cancer (TNBC) have a high rate of tumor metastasis and a poor prognosis. The treatment option for these patients is currently chemotherapy, which results in very low response rates. Strategies that exploit the immune system for the treatment of cancer have now shown the ability to improve survival in several tumor types. Identifying potential targets for immune therapeutic interventions is an important step in developing novel treatments for TNBC. In this study, in silico analysis of publicly available datasets and immunohistochemical analysis of primary and metastatic tumor biopsies from TNBC patients were conducted to evaluate the expression of the transcription factor brachyury, which is a driver of tumor metastasis and resistance and a target for cancer vaccine approaches. Analysis of breast cancer datasets demonstrated a predominant expression of brachyury mRNA in TNBC and in basal vs luminal or HER2 molecular breast cancer subtypes. At the protein level, variable levels of brachyury expression were detected both in primary and metastatic TNBC lesions. A strong association was observed between nuclear brachyury protein expression and the stage of disease, with nuclear brachyury being more predominant in metastatic vs primary tumors. Survival analysis also demonstrated an association between high levels of brachyury in the primary tumor and poor prognosis. Two brachyury-targeting cancer vaccines are currently undergoing clinical evaluation; the data presented here provide rationale for using brachyury-targeting immunotherapy approaches for the treatment of TNBC. C1 [Hamilton, Duane H.; Palena, Claudia] NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. [Roselli, Mario] Univ Roma Tor Vergata, Tor Vergata Clin Ctr, Dept Syst Med, Med Oncol, Rome, Italy. [Ferroni, Patrizia; Guadagni, Fiorella] San Raffaele Roma Open Univ, Rome, Italy. [Costarelli, Leopoldo; Taffuri, Mariateresa] San Giovanni Hosp Addolorata, Dept Pathol, Rome, Italy. [Cavaliere, Francesco] San Giovanni Hosp Addolorata, Dept Surg, Rome, Italy. [Guadagni, Fiorella] IRCCS San Raffaele Pisana, Interinst Multidisciplinary Biobank BioBIM, Rome, Italy. RP Palena, C (reprint author), NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. EM palenac@mail.nih.gov RI Ferroni, Patrizia/C-2705-2017 OI Ferroni, Patrizia/0000-0002-9877-8712 FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health; European Social Fund, under the Italian Ministry of Education, University and Research [PON03PE_00146_1/10 BIBIOFAR (CUP B88F12000730005)] FX This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health and by research funding from the European Social Fund, under the Italian Ministry of Education, University and Research PON03PE_00146_1/10 BIBIOFAR (CUP B88F12000730005) to F G. NR 46 TC 1 Z9 1 U1 1 U2 1 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 1351-0088 EI 1479-6821 J9 ENDOCR-RELAT CANCER JI Endocr.-Relat. Cancer PD OCT PY 2016 VL 23 IS 10 BP 783 EP 796 DI 10.1530/ERC-16-0037 PG 14 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA EB7WV UT WOS:000387602700013 PM 27580659 ER PT J AU Di Francesco, A Di Germanio, C Panda, AC Huynh, P Peaden, R Navas-Enamorado, I Bastian, P Lehrmann, E Diaz-Ruiz, A Ross, D Siegel, D Martindale, JL Bernier, M Gorospe, M Abdelmohsen, K de Cabo, R AF Di Francesco, Andrea Di Germanio, Clara Panda, Amaresh C. Huynh, Phu Peaden, Robert Navas-Enamorado, Ignacio Bastian, Paul Lehrmann, Elin Diaz-Ruiz, Alberto Ross, David Siegel, David Martindale, Jennifer L. Bernier, Michel Gorospe, Myriam Abdelmohsen, Kotb de Cabo, Rafael TI Novel RNA-binding activity of NQ01 promotes SERPINA1 mRNA translation SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE NQO1; RNA binding protein; SERPINA1; A1AT; Neutrophil elastase; mRNA translation ID NAD(P)H-QUINONE OXIDOREDUCTASE 1; MUTANT ALPHA(1)-ANTITRYPSIN-Z; ENDOPLASMIC-RETICULUM; CANCER-CELLS; ALPHA-1-ANTITRYPSIN; MICE; NQO1; NRF2; EMPHYSEMA; ELASTASE AB NAD(P)H: quinone oxidoreductase (NQO1) is essential for cell defense against reactive oxidative species, cancer, and metabolic stress. Recently, NQO1 was found in ribonucleoprotein (RNP) complexes, but NQO1-interacting mRNAs and the functional impact of such interactions are not known. Here, we used ribonucleoprotein immunoprecipitation (RIP) and microarray analysis to identify comprehensively the subset of NQOI target mRNAs in human hepatoma HepG2 cells. One of its main targets, SERPINAI mRNA, encodes the serine protease inhibitor oc-1-antitrypsin, AlAT, which is associated with disorders including obesity-related metabolic inflammation, chronic obstructive pulmonary disease (COPD), liver cirrhosis and hepatocellular carcinoma. Biotin pulldown analysis indicated that NQO1 can bind the 3' untranslated region (UTR) and the coding region (CR) of SERPINAI mRNA. NQOI did not affect SERPINAI mRNA levels; instead, it enhanced the translation of SERPINAI mRNA, as NQOI silencing decreased the size of polysomes forming on SERPINAI mRNA and lowered the abundance of AlAT. Luciferase reporter analysis further indicated that NQOI regulates SERPINAI mRNA translation through the SERPINAI 3'UTR. Accordingly, NQO1-KO mice had reduced hepatic and serum levels of AlAT and increased activity of neutrophil elastase (NE), one of the main targets of AlAT. We propose that this novel mechanism of action of NQOI as an RNA-binding protein may help to explain its pleiotropic biological effects. Published by Elsevier Inc. C1 [Di Francesco, Andrea; Di Germanio, Clara; Huynh, Phu; Peaden, Robert; Navas-Enamorado, Ignacio; Diaz-Ruiz, Alberto; Bernier, Michel; de Cabo, Rafael] NIA, Expt Gerontol Sect, Translat Gerontol Branch, 251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. [Panda, Amaresh C.; Bastian, Paul; Lehrmann, Elin; Martindale, Jennifer L.; Gorospe, Myriam; Abdelmohsen, Kotb] NIA, RNA Regulat Sect, Lab Genet & Genom, 251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. [Ross, David; Siegel, David] Univ Colorado, Skaggs Sch Pharm & Pharmaceut Sci, Dept Pharmaceut Sci, Anschutz Med Campus,12858 East Montview Blvd, Aurora, CO 80045 USA. RP Abdelmohsen, K (reprint author), NIA, Lab Genet & Genom, Bayview Res Ctr, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA.; de Cabo, R (reprint author), NIA, Translat Gerontol Branch, Bayview Res Ctr, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM abdelmohsenk@grc.nia.nih.gov; deCaboRa@grc.nia.nih.gov FU Intramural Research Program of the National Institute on Aging, NIH, United States of America [AG000362-02] FX We thank Dawn Phillips, Dawn Nines and Justine Lucas for animal care, Lynn Wu for technical assistance, Drs. Kevin Becker and Yongquing Zhang for microarray analysis. We also thank Drs. Frank Gonzalez and Anil K. Jaiswal for providing the NQO1 null mice. This work was supported by the Intramural Research Program of the National Institute on Aging, NIH, United States of America (Grant number AG000362-02). NR 46 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 EI 1873-4596 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD OCT PY 2016 VL 99 BP 225 EP 233 DI 10.1016/j.freeradbiomed.2016.08.005 PG 9 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA EC3AD UT WOS:000387995400022 PM 27515817 ER PT J AU Haass-Koffler, CL Giovenco, DE Lee, MR Zywiak, WH de la Monte, SM Kenna, GA Swift, RM Leggio, L AF Haass-Koffler, Carolina L. Giovenco, Danielle E. Lee, Mary R. Zywiak, William H. de la Monte, Suzanne M. Kenna, George A. Swift, Robert M. Leggio, Lorenzo TI Serum Insulin Levels Are Reduced by Intravenous Ghrelin Administration but Do Not Correlate with Alcohol Craving in Alcohol-Dependent Individuals SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Article DE ghrelin; insulin; incretins; glucagon; leptin; alcohol craving; alcoholism ID METABOLIC SYNDROME; GLUCOSE-TOLERANCE; RAT ISLETS; BETA-CELLS; LEPTIN; SECRETION; DRINKING; HUMANS; SYSTEM; MEN AB Increasing evidence supports a role for appetite-regulating pathways like ghrelin, insulin, and leptin in alcoholism. We previously reported that intravenous (i.v.) exogenous ghrelin increases alcohol craving. We also reported i.v. ghrelin reduces endogenous serum leptin, whose levels, in turn, negatively correlated with alcohol craving. Exogenous ghrelin administration decreases insulin secretion both in vitro and in vivo experiments. This study tested the hypothesis that i.v. ghrelin may also decrease endogenous serum insulin levels in alcoholic individuals. Additionally, we explored possible correlations between serum insulin and alcohol craving, since a correlation between insulin and alcohol craving was previously reported. This was a double-blind, placebo-controlled human laboratory study (n=43). Non-treatment-seeking, alcohol-dependent, heavy drinkers were randomized to receive i.v. ghrelin or placebo, followed by an alcohol cue-reactivity procedure. There was a main effect for i.v. ghrelin, compared to placebo in reducing serum insulin (P <.05). There was also a time effect (P <.001) but not ghrelin x time interaction (P >.05). We did not find a correlation between the reduction of serum insulin and alcohol craving (P >.05). The change in serum insulin was consistent with a parallel reduction in serum connective-peptide in the ghrelin group compared with placebo, although this difference did not reach statistical significance (P=.076). No similar effects were found for other glucose-regulating hormones analyzed i.e. glucagon, glucagon-like peptide-1, and gastric inhibitory peptide (Ps >.05). These findings indicate i.v. ghrelin administration has an effect on reducing serum insulin in alcohol-dependent individuals; however, the reduction of insulin did not correlate with changes in alcohol cue-elicited craving. We speculate that, unlike for leptin, the interactions between ghrelin and insulin relationship are limited at the peripheral level. However, mechanistic studies are needed to investigate this hypothesis. C1 [Haass-Koffler, Carolina L.; Lee, Mary R.; Leggio, Lorenzo] NIAAA, Sect Clin Psychoneuroendocrinol & Neuropsychophar, 10 Ctr Dr,10CRC 15330,MSC 1108,Room 1-5429, Bethesda, MD 20892 USA. [Haass-Koffler, Carolina L.; Lee, Mary R.; Leggio, Lorenzo] NIDA, NIH, Bethesda, MD 20892 USA. [Haass-Koffler, Carolina L.; Giovenco, Danielle E.; Leggio, Lorenzo] Brown Univ, Ctr Alcohol & Addict Studies, Dept Behav & Social Sci, Providence, RI 02912 USA. [Haass-Koffler, Carolina L.; Zywiak, William H.; Kenna, George A.; Swift, Robert M.] Brown Univ, Ctr Alcohol & Addict Studies, Dept Psychiat & Human Behav, Providence, RI 02912 USA. [Swift, Robert M.] Vet Affairs Med Ctr, Providence, RI USA. [de la Monte, Suzanne M.] Rhode Isl Hosp, Dept Pathol, Providence, RI 02902 USA. [de la Monte, Suzanne M.] Rhode Isl Hosp, Dept Neurosurg, Providence, RI USA. [de la Monte, Suzanne M.] Brown Univ, Warren Alpert Med Sch, Providence, RI 02912 USA. RP Haass-Koffler, CL; Leggio, L (reprint author), NIAAA, Sect Clin Psychoneuroendocrinol & Neuropsychophar, 10 Ctr Dr,10CRC 15330,MSC 1108,Room 1-5429, Bethesda, MD 20892 USA.; Leggio, L (reprint author), NIDA, NIH, Bethesda, MD 20892 USA.; Haass-Koffler, CL (reprint author), Brown Univ, Ctr Alcohol & Addict Studies, Dept Psychiat & Human Behav, NIDA,NIH, Box G-S121-5, Providence, RI 02912 USA. EM carolina_haass-koffler@brown.edu; lorenzo.leggio@nih.gov FU National Institutes of Health [ZIA-AA000218]; National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research; National Institute on Drug Abuse Intramural Research Program; National Institute on Alcohol Abuse and Alcoholism [R21-AA019709, K01AA023867] FX This work was supported by the National Institutes of Health intramural funding (grant no. ZIA-AA000218; Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, to L.L.), jointly supported by the National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research; and the National Institute on Drug Abuse Intramural Research Program. The parent study was funded by the National Institute on Alcohol Abuse and Alcoholism (grant no. R21-AA019709 to L.L. while at Brown University). Dr. Haass-Koffler's current work is supported by the National Institute on Alcohol Abuse and Alcoholism (grant no. K01AA023867 to C.L.H.-K.) and previously by the National Institute on Alcohol Abuse and Alcoholism (training grant 5T32AA007459-28 to C.L.H.-K.). NR 42 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1461-1457 EI 1469-5111 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD OCT PY 2016 VL 19 IS 10 DI 10.1093/ijnp/pyw048 PG 7 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA EC3CC UT WOS:000388001200005 ER PT J AU Eke, PI Wei, L Thornton-Evans, GO Borrell, LN Borgnakke, WS Dye, B Genco, RJ AF Eke, Paul I. Wei, Liang Thornton-Evans, Gina O. Borrell, Luisa N. Borgnakke, Wenche S. Dye, Bruce Genco, Robert J. TI Risk Indicators for Periodontitis in US Adults: NHANES 2009 to 2012 SO JOURNAL OF PERIODONTOLOGY LA English DT Article DE Diabetes mellitus; dental health surveys; epidemiology; periodontitis; population surveillance; smoking ID DISEASE SURVEILLANCE PROJECT; CURRENT CIGARETTE-SMOKING; UNITED-STATES; CASE DEFINITIONS; NATIONAL-HEALTH; POPULATION; ASSOCIATION; PREVALENCE; OBESITY; UPDATE AB Background: Through the use of optimal surveillance measures and standard case definitions, it is now possible to more accurately determine population-average risk profiles for severe (SP) and non-severe periodontitis (NSP) in adults (aged 30 years and older) in the United States. Methods: Data from the 2009 to 2012 National Health and Nutrition Examination Survey were used, which, for the first time, used the "gold standard'' full-mouth periodontitis surveillance protocol to classify severity of periodontitis following suggested Centers for Disease Control/American Academy of Periodontology case definitions. Probabilities of periodontitis by: 1) sociodemographics, 2) behavioral factors, and 3) comorbid conditions were assessed using prevalence ratios (PRs) estimated by predicted marginal probability from multivariable generalized logistic regression models. Analyses were further stratified by sex for each classification of periodontitis. Results: Likelihood of total periodontitis (TP) increased with age for overall and NSP relative to non-periodontitis. Compared with non-Hispanic whites, TP was more likely in Hispanics (adjusted [a] PR = 1.38; 95% confidence interval 95% CI: 1.26 to 1.52) and non-Hispanic blacks (aPR = 1.35; 95% CI: 1.22 to 1.50), whereas SP was most likely in non-Hispanic blacks (aPR = 1.82; 95% CI: 1.44 to 2.31). There was at least a 50% greater likelihood of TP in current smokers compared with non-smokers. In males, likelihood of TP in adults aged 65 years and older was greater (aPR = 2.07; 95% CI: 1.76 to 2.43) than adults aged 30 to 44 years. This probability was even greater in women (aPR = 3.15; 95% CI: 2.63 to 3.77). Likelihood of TP was higher in current smokers relative to non-smokers regardless of sex and periodontitis classification. TP was more likely in men with uncontrolled diabetes mellitus (DM) compared with adults without DM. Conclusions: Assessment of risk profiles for periodontitis in adults in the United States based on gold standard periodontal measures show important differences by severity of disease and sex. Cigarette smoking, specifically current smoking, remains an important modifiable risk for all levels of periodontitis severity. Higher likelihood of TP in older adults and in males with uncontrolled DM is noteworthy. These findings could improve identification of target populations for effective public health interventions to improve periodontal health of adults in the United States. C1 [Eke, Paul I.] Ctr Dis Control & Prevent, Div Populat Hlth, Atlanta, GA USA. [Wei, Liang] DB Consulting Grp, Atlanta, GA USA. [Thornton-Evans, Gina O.] Ctr Dis Control & Prevent, Div Oral Hlth, Atlanta, GA USA. [Borrell, Luisa N.] CUNY, Dept Epidemiol & Biostat, Grad Sch Publ Hlth & Hlth Policy, New York, NY 10021 USA. [Borgnakke, Wenche S.] Univ Michigan, Sch Dent, Dept Periodont & Oral Med, Ann Arbor, MI 48109 USA. [Dye, Bruce] Natl Inst Dent & Craniofacial Res, Bethesda, MD USA. [Genco, Robert J.] SUNY Buffalo, UB Microbiome Ctr, Sch Dent Med, Buffalo, NY USA. [Genco, Robert J.] SUNY Buffalo, UB Microbiome Ctr, Sch Med, Buffalo, NY USA. [Genco, Robert J.] SUNY Buffalo, UB Microbiome Ctr, Sch Biomed Sci, Buffalo, NY USA. RP Eke, PI (reprint author), Ctr Dis Control & Prevent, Div Populat Hlth, Natl Ctr Chron Dis & Hlth Promot, Atlanta, GA 30341 USA. EM peke@cdc.gov NR 41 TC 5 Z9 5 U1 6 U2 6 PU AMER ACAD PERIODONTOLOGY PI CHICAGO PA 737 NORTH MICHIGAN AVENUE, SUITE 800, CHICAGO, IL 60611-2690 USA SN 0022-3492 EI 1943-3670 J9 J PERIODONTOL JI J. Periodont. PD OCT PY 2016 VL 87 IS 10 BP 1174 EP 1185 DI 10.1902/jop.2016.160013 PG 12 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA EC3EV UT WOS:000388009400012 PM 27367420 ER PT J AU Weng, DY Chen, JG Taslim, C Hsu, PC Marian, C David, SP Loffredo, CA Shields, PG AF Weng, Daniel Y. Chen, Jinguo Taslim, Cenny Hsu, Ping-Ching Marian, Catalin David, Sean P. Loffredo, Christopher A. Shields, Peter G. TI Persistent Alterations of Gene Expression Profiling of Human Peripheral Blood Mononuclear Cells From Smokers SO MOLECULAR CARCINOGENESIS LA English DT Article DE cigarette smoke; gene expression; peripheral blood mononuclear cells ID ARYL-HYDROCARBON RECEPTOR; TUMOR-SUPPRESSOR GENE; CIGARETTE-SMOKE; LUNG-CANCER; TOBACCO PRODUCTS; BRONCHIAL EPITHELIUM; OXIDATIVE STRESS; DNA METHYLATION; IN-VITRO; AIRWAY AB The number of validated biomarkers of tobacco smoke exposure is limited, and none exist for tobacco-related cancer. Additional biomarkers for smoke, effects on cellular systems in vivo are needed to improve early detection of lung cancer, and to assist the Food and Drug Administration in regulating exposures to tobacco products. We assessed the effects of smoking on the gene expression using human cell cultures and blood from a cross-sectional study. We profiled global transcriptional changes in cultured smokers' peripheral blood mononuclear cells (PBMCs) treated with cigarette smoke condensate (CSC) in vitro (n = 7) and from well-characterized smokers' blood (n = 36). ANOVA with adjustment for covariates and Pearson correlation were used for statistical analysis in this study. CSC in vitro altered the expression of 1 178 genes (177 genes with >1.5-fold-change) at P < 0.05. In vivo, PBMCs of heavy and light smokers differed for 614 genes (29 with > 1.5-fold-change) at P < 0.05 (309 remaining significant after adjustment for age, race, and gender). Forty-one genes were persistently altered both in vitro and in vivo, 22 having the same expression pattern reported for non-small cell lung cancer. Our data provides evidence that persistent alterations of gene expression in vitro and in vivo may relate to carcinogenic effects of cigarette smoke, and the identified genes may serve as potential biomarkers for cancer. The use of an in vitro model to corroborate results from human studies provides a novel way to understand human exposure and effect. (C) 2015 Wiley Periodicals, Inc. C1 [Weng, Daniel Y.; Taslim, Cenny; Hsu, Ping-Ching; Marian, Catalin; Shields, Peter G.] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Chen, Jinguo] NIH, Ctr Human Immunol, Bldg 10, Bethesda, MD 20892 USA. [Marian, Catalin] Univ Med & Pharm, Timisoara, Romania. [David, Sean P.] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA. [Loffredo, Christopher A.] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. RP Shields, PG (reprint author), Ohio State Univ, Wexner Med Ctr, Ctr Comprehens Canc, 460 W 10th Ave,9th Floor,Suite D920, Columbus, OH 43210 USA. OI Marian, Catalin/0000-0002-7749-1384 FU Transdisciplinary Tobacco Use Research Center [P50 CA84718]; National Cancer Institute; National Institute on Drug Abuse [P30 CA051008]; National Cancer Institute, Laboratory Assessment of Tobacco Use Behavior and Exposure to Toxins [N01 PC64402]; National Cancer Institute [K08 DA14276]; National Institute on Drug Abuse FX Grant sponsor: Transdisciplinary Tobacco Use Research Center; Grant number: P50 CA84718; Grant sponsor: National Cancer Institute and the National Institute on Drug Abuse; Grant number: P30 CA051008; Grant sponsor: National Cancer Institute, Laboratory Assessment of Tobacco Use Behavior and Exposure to Toxins; Grant number: N01 PC64402; Grant sponsor: National Cancer Institute; Grant number: K08 DA14276; Grant sponsor: National Institute on Drug Abuse NR 67 TC 2 Z9 2 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0899-1987 EI 1098-2744 J9 MOL CARCINOGEN JI Mol. Carcinog. PD OCT PY 2016 VL 55 IS 10 BP 1424 EP 1437 DI 10.1002/mc.22385 PG 14 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA EC1GG UT WOS:000387852300003 PM 26294040 ER PT J AU Lessler, J Metcalf, CJE Cutts, FT Grenfell, BT AF Lessler, Justin Metcalf, C. Jessica E. Cutts, Felicity T. Grenfell, Bryan T. TI Impact on Epidemic Measles of Vaccination Campaigns Triggered by Disease Outbreaks or Serosurveys: A Modeling Study SO PLOS MEDICINE LA English DT Article ID MASS VACCINATION; RUBELLA CONTROL; UNITED-STATES; CHALLENGES; TIME AB Background Routine vaccination supplemented by planned campaigns occurring at 2-5 y intervals is the core of current measles control and elimination efforts. Yet, large, unexpected outbreaks still occur, even when control measures appear effective. Supplementing these activities with mass vaccination campaigns triggered when low levels of measles immunity are observed in a sample of the population (i.e., serosurveys) or incident measles cases occur may provide a way to limit the size of outbreaks. Methods and Findings Measles incidence was simulated using stochastic age-structured epidemic models in settings conducive to high or low measles incidence, roughly reflecting demographic contexts and measles vaccination coverage of four heterogeneous countries: Nepal, Niger, Yemen, and Zambia. Uncertainty in underlying vaccination rates was modeled. Scenarios with case-or serosurvey-triggered campaigns reaching 20% of the susceptible population were compared to scenarios without triggered campaigns. The best performing of the tested case-triggered campaigns prevent an average of 28,613 (95% CI 25,722-31,505) cases over 15 y in our highest incidence setting and 599 (95% CI 464-735) cases in the lowest incidence setting. Serosurvey-triggered campaigns can prevent 89,173 (95% CI, 86,768-91,577) and 744 (612-876) cases, respectively, but are triggered yearly in high-incidence settings. Triggered campaigns reduce the highest cumulative incidence seen in simulations by up to 80%. While the scenarios considered in this strategic modeling exercise are reflective of real populations, the exact quantitative interpretation of the results is limited by the simplifications in country structure, vaccination policy, and surveillance system performance. Careful investigation into the cost-effectiveness in different contexts would be essential before moving forward with implementation. Conclusions Serologically triggered campaigns could help prevent severe epidemics in the face of epidemiological and vaccination uncertainty. Hence, small-scale serology may serve as the basis for effective adaptive public health strategies, although, in high-incidence settings, case-triggered approaches are likely more efficient. C1 [Lessler, Justin] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Metcalf, C. Jessica E.; Grenfell, Bryan T.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Metcalf, C. Jessica E.] Princeton Univ, Off Populat Res, Princeton, NJ 08544 USA. [Metcalf, C. Jessica E.; Grenfell, Bryan T.] Fogarty Int Ctr, Bethesda, MD USA. [Cutts, Felicity T.] London Sch Hyg & Trop Med, London, England. RP Lessler, J (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. EM justin@jhu.edu OI Lessler, Justin/0000-0002-9741-8109 FU Bill and Melinda Gates Foundation [705580-3]; RAPIDD program of the Science & Technology Directorate, Department of Homeland Security; NIH Fogarty International Center; Science and Technology Directorate, Department of Homeland Security [HSHQDC-12 C-00058]; Science & Technology Directorate of the Department of Homeland Security FX This work was funded by the Bill and Melinda Gates Foundation (Award #705580-3) (JL, CJEM, and BTG); the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security and the NIH Fogarty International Center (JL, CJEM, and BTG), and a grant from the Science and Technology Directorate, Department of Homeland Security (HSHQDC-12 C-00058) (BTG). BTG is a member of the leadership team for the RAPIDD program at the Fogarty International Center. This program is funded by the Science & Technology Directorate of the Department of Homeland Security, which had no role in the design, data collection, analysis, decision to publish or preparation of this manuscript. NR 23 TC 1 Z9 1 U1 3 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1549-1676 J9 PLOS MED JI PLos Med. PD OCT PY 2016 VL 13 IS 10 AR e1002144 DI 10.1371/journal.pmed.1002144 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA EB8QN UT WOS:000387656000008 PM 27727285 ER PT J AU Colonne, PM Winchell, CG Graham, JG Onyilagha, FI MacDonald, LJ Doeppler, HR Storz, P Kurten, RC Beare, PA Heinzen, RA Voth, DE AF Colonne, Punsiri M. Winchell, Caylin G. Graham, Joseph G. Onyilagha, Frances I. MacDonald, Laura J. Doeppler, Heike R. Storz, Peter Kurten, Richard C. Beare, Paul A. Heinzen, Robert A. Voth, Daniel E. TI Vasodilator-Stimulated Phosphoprotein Activity Is Required for Coxiella burnetii Growth in Human Macrophages SO PLOS PATHOGENS LA English DT Article ID PROTEIN-KINASE PHOSPHORYLATION; F-ACTIN BINDING; Q-FEVER; ENA/VASP PROTEINS; FOCAL-ADHESION; DIFFERENTIAL EXPRESSION; LISTERIA-MONOCYTOGENES; CHLAMYDIA-TRACHOMATIS; THP-1 CELLS; HOST-CELLS AB Coxiella burnetii is an intracellular bacterial pathogen that causes human Q fever, an acute flu-like illness that can progress to chronic endocarditis and liver and bone infections. Humans are typically infected by aerosol-mediated transmission, and C. burnetii initially targets alveolar macrophages wherein the pathogen replicates in a phagolysosome-like niche known as the parasitophorous vacuole (PV). C. burnetii manipulates host cAMP-dependent protein kinase (PKA) signaling to promote PV formation, cell survival, and bacterial replication. In this study, we identified the actin regulatory protein vasodilator-stimulated phosphoprotein (VASP) as a PKA substrate that is increasingly phosphorylated at S157 and S239 during C. burnetii infection. Avirulent and virulent C. burnetii triggered increased levels of phosphorylated VASP in macrophage-like THP-1 cells and primary human alveolar macrophages, and this event required the C alpha subunit of PKA. VASP phosphorylation also required bacterial protein synthesis and secretion of effector proteins via a type IV secretion system, indicating the pathogen actively triggers prolonged VASP phosphorylation. Optimal PV formation and intracellular bacterial replication required VASP activity, as siRNA-mediated depletion of VASP reduced PV size and bacterial growth. Interestingly, ectopic expression of a phospho-mimetic VASP (S239E) mutant protein prevented optimal PV formation, whereas VASP (S157E) mutant expression had no effect. VASP (S239E) expression also prevented trafficking of bead-containing phagosomes to the PV, indicating proper VASP activity is critical for heterotypic fusion events that control PV expansion in macrophages. Finally, expression of dominant negative VASP (S157A) in C. burnetii-infected cells impaired PV formation, confirming importance of the protein for proper infection. This study provides the first evidence of VASP manipulation by an intravacuolar bacterial pathogen via activation of PKA in human macrophages. C1 [Colonne, Punsiri M.; Winchell, Caylin G.; Graham, Joseph G.; Onyilagha, Frances I.; MacDonald, Laura J.; Voth, Daniel E.] Univ Arkansas Med Sci, Dept Microbiol & Immunol, Little Rock, AR 72205 USA. [Doeppler, Heike R.; Storz, Peter] Mayo Clin, Dept Canc Biol, Jacksonville, FL 32224 USA. [Kurten, Richard C.] Univ Arkansas Med Sci, Dept Physiol & Biophys, Little Rock, AR 72205 USA. [Kurten, Richard C.] Arkansas Childrens Hosp, Res Inst, 800 Marshall St, Little Rock, AR 72202 USA. [Beare, Paul A.; Heinzen, Robert A.] NIAID, Coxiella Pathogenesis Sect, Bacteriol Lab, Rocky Mt Labs,NIH, Hamilton, MT USA. RP Voth, DE (reprint author), Univ Arkansas Med Sci, Dept Microbiol & Immunol, Little Rock, AR 72205 USA. EM dvoth@uams.edu FU National Institutes of Health/National Institute of Allergy and Infectious Diseases [R01AI087669, R21AI107148]; Arkansas Biosciences Institute; Center for Microbial Pathogenesis and Host Inflammatory Responses (National Institutes of Health/National Institute of General Medical Sciences) [P20GM103625]; Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases; National Institutes of Health/National Center for Research Resources/National Center for Advancing Translational Sciences [UL1TR000039]; National Institutes of Health/National Institute of General Medical Sciences [R01GM086435] FX This work was supported by funding from the National Institutes of Health/National Institute of Allergy and Infectious Diseases (R01AI087669 and R21AI107148), the Arkansas Biosciences Institute, and the Center for Microbial Pathogenesis and Host Inflammatory Responses (National Institutes of Health/National Institute of General Medical Sciences P20GM103625) (DEV). This work was also supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases (RAH and PAB). RCK was supported by the Arkansas Biosciences Institute and the National Institutes of Health/National Center for Research Resources/National Center for Advancing Translational Sciences (UL1TR000039). PS was supported by the National Institutes of Health/National Institute of General Medical Sciences (R01GM086435). JGG was supported by a supplement to R01AI087669 to promote diversity in research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 60 TC 0 Z9 0 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD OCT PY 2016 VL 12 IS 10 AR e1005915 DI 10.1371/journal.ppat.1005915 PG 23 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA EB8UO UT WOS:000387666900024 PM 27711191 ER PT J AU Yao, XY Wu, J Lin, M Sun, WX He, X Gowda, C Bolland, S Long, CA Wang, RF Su, XZ AF Yao, Xiangyu Wu, Jian Lin, Meng Sun, Wenxiang He, Xiao Gowda, Channe Bolland, Silvia Long, Carole A. Wang, Rongfu Su, Xin-zhuan TI Increased CD40 Expression Enhances Early STING-Mediated Type I Interferon Response and Host Survival in a Rodent Malaria Model SO PLOS PATHOGENS LA English DT Article ID NF-KAPPA-B; INNATE IMMUNE-RESPONSES; CYCLIC GMP-AMP; SYSTEMIC AUTOIMMUNE-DISEASES; RECEPTOR SIGNALING PATHWAYS; CYTOTOXIC T-LYMPHOCYTES; PLASMODIUM-FALCIPARUM; PROTECTIVE IMMUNITY; CD40-CD40 LIGAND; GENE-EXPRESSION AB Both type I interferon (IFN-I) and CD40 play a significant role in various infectious diseases, including malaria and autoimmune disorders. CD40 is mostly known to function in adaptive immunity, but previous observations of elevated CD40 levels early after malaria infection of mice led us to investigate its roles in innate IFN-I responses and disease control. Using a Plasmodium yoelii nigeriensis N67 and C57BL/6 mouse model, we showed that infected CD40(-/-) mice had reduced STING and serum IFN-beta levels day-2 post infection, higher day-4 parasitemia, and earlier deaths. CD40 could greatly enhance STING-stimulated luciferase signals driven by the IFN-beta promoter in vitro, which was mediated by increased STING protein levels. The ability of CD40 to influence STING expression was confirmed in CD40(-/-) mice after malaria infection. Substitutions at CD40 TRAF binding domains significantly decreased the IFN-beta signals and STING protein level, which was likely mediated by changes in STING ubiquitination and degradation. Increased levels of CD40, STING, and ISRE driven luciferase signal in RAW Lucia were observed after phagocytosis of N67-infected red blood cells (iRBCs), stimulation with parasite DNA/RNA, or with selected TLR ligands [LPS, poly(I:C), and Pam3CSK4]. The results suggest stimulation of CD40 expression by parasite materials through TLR signaling pathways, which was further confirmed in bone marrow derived dendritic cells/macrophages (BMDCs/BMDMs) and splenic DCs from CD40(-/-), TLR3(-/-)TLR4(-/-), TRIF-/-, and MyD88(-/-) mice after iRBC stimulation or parasite infection. Our data connect several signaling pathways consisting of phagocytosis of iRBCs, recognition of parasite DNA/RNA (possibly GPI) by TLRs, elevated levels of CD40 and STING proteins, increased IFN-I production, and longer host survival time. This study reveals previously unrecognized CD40 function in innate IFN-I responses and protective pathways in infections with malaria strains that induce a strong IFN-I response, which may provide important information for better understanding and management of malaria. C1 [Yao, Xiangyu; Wu, Jian; He, Xiao; Long, Carole A.; Su, Xin-zhuan] NIAID, Lab Malaria & Vector Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Lin, Meng; Wang, Rongfu] Houston Methodist Res Inst, Ctr Inflammat & Epigenet, Houston, TX USA. [Sun, Wenxiang; Bolland, Silvia] NIAID, Immunogenet Lab, NIH, Bethesda, MD 20892 USA. [Gowda, Channe] Penn State Univ, Dept Biochem & Mol Biol, Coll Med, Hershey, PA USA. RP Su, XZ (reprint author), NIAID, Lab Malaria & Vector Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.; Wang, RF (reprint author), Houston Methodist Res Inst, Ctr Inflammat & Epigenet, Houston, TX USA. EM rwang3@tmhs.org; xsu@niaid.nih.gov OI Su, Xinzhuan/0000-0003-3246-3248 FU Division of Intramural Research at the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health; National Cancer Institute, NIH [R01CA090327, R01CA101795] FX This work was supported by the Division of Intramural Research at the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, and in part supported by grants from the National Cancer Institute, NIH (R01CA090327 and R01CA101795) to RW. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 72 TC 0 Z9 0 U1 2 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD OCT PY 2016 VL 12 IS 10 AR e1005930 DI 10.1371/journal.ppat.1005930 PG 29 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA EB8UO UT WOS:000387666900033 PM 27716849 ER PT J AU Van Dyke, AL Kemp, TJ Corbel, AF Zhu, B Gao, YT Wang, BS Rashid, A Shen, MC Hildesheim, A Hsing, AW Pinto, LA Koshiol, J AF Van Dyke, Alison L. Kemp, Troy J. Corbel, Amanda F. Zhu, Bin Gao, Yu-Tang Wang, Bing-Sheng Rashid, Asif Shen, Ming-Chang Hildesheim, Allan Hsing, Ann W. Pinto, Ligia A. Koshiol, Jill TI Lipopolysaccharide-pathway proteins are associated with gallbladder cancer among adults in Shanghai, China with mediation by systemic inflammation SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE Gallbladder cancer; Lipopolysaccharide-pathway; Inflammation; Mediation analysis ID BILIARY-TRACT CANCER; HELICOBACTER-PYLORI INFECTION; CHOLESTEROL GALLSTONES; RISK; POLYMORPHISMS; CARCINOMA; STONES; CD14; METAANALYSIS; SEPSIS AB Purpose: We examined inflammation as a mediator of associations between bacterial infection markers and gallbladder cancer (GBC). Methods: Bacterial response proteins (lipopolysaccharide [LPS], soluble cluster of differentiation 14 [sCD14], and LPS-binding protein [LBP]) were measured in 40 GBC cases and 126 gallstone controls with data on 63 serum inflammation markers. The relationships of LPS, LBP, and sCD14 with GBC were examined by logistic regression, which also was used to evaluate whether these associations are influenced by systemic inflammation as measured by a combinatorial inflammation score. Results: The third versus the first tertiles of sCD14 and of LBP were associated with an increased GBC risk (odds ratio [95% confidence interval]: 5.41 [2.00-16.75] for sCD14, and 6.49 [2.24-23.79] for LBP). sCD14 and LBP were strongly associated with inflammation score (above vs. below the median), which itself was associated with a more than 21-fold increased risk of GBC for the third versus first tertiles. Associations between GBC and sCD14 and LBP were markedly attenuated when the inflammation score was included in the model. While LPS was not associated with GBC or inflammation, only 35% of cases and 22% of controls had detectable levels. Conclusions: These findings suggest that these LPS-pathway proteins are associated with GBC via inflammation-related pathways. Published by Elsevier Inc. C1 [Van Dyke, Alison L.; Corbel, Amanda F.; Hildesheim, Allan; Koshiol, Jill] NCI, DCEG, Infect & Imniunoepidemiol Branch, 9609 Med Ctr Dr,6E210, Bethesda, MD 20892 USA. [Kemp, Troy J.; Pinto, Ligia A.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, HPV Immunol Lab, Frederick, MD USA. [Zhu, Bin] NCI, DCEG, Biostat Branch, Bethesda, MD 20892 USA. [Gao, Yu-Tang; Shen, Ming-Chang] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Wang, Bing-Sheng] Fudan Univ, Zhongshan Hosp, Sch Med, Dept Gen Surg, Shanghai, Peoples R China. [Rashid, Asif] MD Anderson Canc Ctr, Dept Pathol, Houston, TX USA. [Shen, Ming-Chang] Fudan Univ, Canc Hosp, Dept Pathol, Shanghai, Peoples R China. [Hsing, Ann W.] Stanford Univ, Stanford Canc Inst, Ctr Innovat Global Hlth, Stanford, CA 94305 USA. RP Van Dyke, AL (reprint author), NCI, DCEG, Infect & Imniunoepidemiol Branch, 9609 Med Ctr Dr,6E210, Bethesda, MD 20892 USA. EM alison.vandyke@nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics; Office of Research on Women's Health, National Institutes of Health FX The authors thank Ken Matsui, PhD, for discussions and review of the article. Additionally, we honor the contribution of the late Christopher Owen Miller for his assistance with the LPS assay. This work was supported by general funds from the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics and the Office of Research on Women's Health, National Institutes of Health. NR 34 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 EI 1873-2585 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD OCT PY 2016 VL 26 IS 10 BP 704 EP 709 DI 10.1016/j.annepidem.2016.08.009 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EB8HJ UT WOS:000387631800008 PM 27793274 ER PT J AU Deol, A Sengsayadeth, S Ahn, KW Wang, HL Aljurf, M Antin, JH Battiwalla, M Bornhauser, M Cahn, JY Camitta, B Chen, YB Cutler, CS Gale, RP Ganguly, S Hamadani, M Inamoto, Y Jagasia, M Kamble, R Koreth, J Lazarus, HM Liesveld, J Litzow, MR Marks, DI Nishihori, T Olsson, RF Reshef, R Rowe, JM Saad, AA Sabloff, M Schouten, HC Shea, TC Soiffer, RJ Uy, GL Waller, EK Wiernik, PH Wirk, B Woolfrey, AE Bunjes, D Devine, S de Lima, M Sandmaier, BM Weisdorf, D Khoury, HJ Saber, W AF Deol, Abhinav Sengsayadeth, Salyka Ahn, Kwang Woo Wang, Hai-Lin Aljurf, Mahmoud Antin, Joseph Harry Battiwalla, Minoo Bornhauser, Martin Cahn, Jean-Yves Camitta, Bruce Chen, Yi-Bin Cutler, Corey S. Gale, Robert Peter Ganguly, Siddhartha Hamadani, Mehdi Inamoto, Yoshihiro Jagasia, Madan Kamble, Rammurti Koreth, John Lazarus, Hillard M. Liesveld, Jane Litzow, Mark R. Marks, David I. Nishihori, Taiga Olsson, Richard F. Reshef, Ran Rowe, Jacob M. Saad, Ayman A. Sabloff, Mitchell Schouten, Harry C. Shea, Thomas C. Soiffer, Robert J. Uy, Geoffrey L. Waller, Edmond K. Wiernik, Peter H. Wirk, Badeep Woolfrey, Ann E. Bunjes, Donald Devine, Steven de Lima, Marcos Sandmaier, Brenda M. Weisdorf, Dan Khoury, Hanna Jean Saber, Wael TI Does FLT3 Mutation Impact Survival After Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia? A Center for International Blood and Marrow Transplant Research (CIBMTR) Analysis SO CANCER LA English DT Article DE acute myeloid leukemia; allogeneic stem cell transplantation; FMS-like tyrosine kinase 3 (FLT3); 1 more ID MINIMAL RESIDUAL DISEASE; ALLOGENEIC TRANSPLANTATION; TANDEM DUPLICATIONS; COMPLETE REMISSION; 12 TRIALS; AML; PROGNOSIS; GENE; CYTOGENETICS; DISTINCT AB BACKGROUND: Patients with FMS like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML) have a poor prognosis and are referred for early allogeneic hematopoietic stem cell transplantation (HCT). METHODS: Data from the Center for International Blood and Marrow Transplant Research (CIBMTR) were used to evaluate 511 adult patients with de novo AML who underwent HCT during 2008 through 2011 to determine whether FLT3 mutations had an impact on HCT outcomes. RESULTS: In total, 158 patients (31%) had FLT3 mutations. Univariate and multivariate analyses revealed an increased risk of relapse at 3 years in the FLT3 mutated group compared with the wild-type (WT) group (38% [95% confidence interval (CI), 30%-45%] vs 28% [95% CI, 24%-33%]; P = .04; relative risk, 1.60 [95% CI, 1.15-2.22]; P = .0048). However, FLT3 mutation status was not significantly associated with nonrelapse mortality, leukemia-free survival, or overall survival. Although more patients in the FLT3 mutated group died from relapsed primary disease compared with those in the WT group (60% vs 46%), the 3-year overall survival rate was comparable for the 2 groups (mutated group: 49%; 95% CI, 40%-57%; WT group: 55%, 95% CI, 50%-60%; P = .20). CONCLUSIONS: The current data indicate that FLT3 mutation status did not adversely impact overall survival after HCT, and about 50% of patients with this mutation who underwent HCT were long-term survivors. (C) 2016 American Cancer Society. C1 [Deol, Abhinav] Wayne State Univ, Karmanos Canc Inst, Dept Oncol, 4100 John R,4 HWCRC, Detroit, MI 48201 USA. [Sengsayadeth, Salyka; Jagasia, Madan] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Ahn, Kwang Woo; Wang, Hai-Lin; Hamadani, Mehdi; Saber, Wael] Med Coll Wisconsin, Dept Med, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Ahn, Kwang Woo] Med Coll Wisconsin, Inst Hlth & Soc, Div Biostat, Milwaukee, WI 53226 USA. [Aljurf, Mahmoud] King Faisal Specialist Hosp Ctr & Res, Dept Oncol, Riyadh, Saudi Arabia. [Antin, Joseph Harry; Cutler, Corey S.; Koreth, John; Soiffer, Robert J.] Dana Farber Canc Inst, Dept Med Oncol, Ctr Hematol Oncol, Boston, MA 02115 USA. [Battiwalla, Minoo] NHLBI, Hematol Branch, Bethesda, MD 20892 USA. [Bornhauser, Martin] Carl Gustav Carus Univ Hosp, Dresden, Germany. [Cahn, Jean-Yves] Univ Hosp, Dept Hematol, Grenoble, France. [Camitta, Bruce] Med Coll Wisconsin, Midwest Ctr Canc & Blood Disorders, Milwaukee, WI 53226 USA. [Camitta, Bruce] Childrens Hosp Wisconsin, Milwaukee, WI 53201 USA. [Chen, Yi-Bin] Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02114 USA. [Gale, Robert Peter] Imperial Coll London, Dept Med, Div Expt Med, Hematol Res Ctr, London, England. [Ganguly, Siddhartha] Univ Kansas, Med Ctr, Div Hematol & Oncol, Blood & Marrow Transplantat, Kansas City, KS 66103 USA. [Inamoto, Yoshihiro] Natl Canc Ctr, Div Hematopoiet Stem Cell Transplantat, Tokyo, Japan. [Kamble, Rammurti] Baylor Coll Med, Ctr Cell & Gene Therapy, Div Hematol & Oncol, Houston, TX 77030 USA. [Lazarus, Hillard M.] Univ Hosp Case Med Ctr, Seidman Canc Ctr, Cleveland, OH USA. [Liesveld, Jane] Univ Rochester, Med Ctr, Dept Med, Rochester, NY 14642 USA. [Litzow, Mark R.] Mayo Clin, Div Hematol, Rochester, NY USA. [Litzow, Mark R.] Mayo Clin, Transplant Ctr, Rochester, NY USA. [Marks, David I.] Univ Hosp Bristol Natl Hlth Serv Trust, Pediat Bone Marrow Transplant, Bristol, Avon, England. [Nishihori, Taiga] H Lee Moffitt Canc Ctr & Res Inst, Dept Blood & Marrow Transplantat, Tampa, FL USA. [Olsson, Richard F.] Karolinska Inst, Div Therapeut Immunol, Dept Lab Med, Stockholm, Sweden. [Olsson, Richard F.] Uppsala Univ, Ctr Clin Res Sormland, Uppsala, Sweden. [Reshef, Ran] Columbia Univ, Med Ctr, Blood & Marrow Transplantat Program, New York, NY USA. [Reshef, Ran] Columbia Univ, Med Ctr, Columbia Ctr Translat Immunol, New York, NY USA. [Rowe, Jacob M.] Shaare Zedek Med Ctr, Dept Hematol, Jerusalem, Israel. [Saad, Ayman A.] Univ Alabama Birmingham, Dept Med, Div Hematol Oncol, Birmingham, AL 35294 USA. [Sabloff, Mitchell] Univ Ottawa, Dept Med, Div Hematol, Ottawa, ON, Canada. [Sabloff, Mitchell] Ottawa Hosp, Res Inst, Ottawa, ON, Canada. [Schouten, Harry C.] Acad Hosp Maastricht, Dept Hematol, Maastricht, Netherlands. [Shea, Thomas C.] Univ North Carolina Hlth Care, Dept Med, Div Hematol & Oncol, Chapel Hill, NC USA. [Uy, Geoffrey L.] Washington Univ, Sch Med, Div Oncol, St Louis, MO USA. [Waller, Edmond K.; Khoury, Hanna Jean] Emory Univ, Winship Canc Inst, Dept Hematol & Med Oncol, Atlanta, GA 30322 USA. [Wiernik, Peter H.] Our Lady Mercy Med Ctr, Bronx, NY USA. [Wirk, Badeep] Seattle Canc Care Alliance, Div Bone Marrow Transplant, Seattle, WA USA. [Woolfrey, Ann E.] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Bunjes, Donald] Ulm Univ Hosp, Dept Internal Med 3, Ulm, Germany. [Devine, Steven] Ohio State Univ, Dept Internal Med, Comprehens Canc Ctr James, Columbus, OH 43210 USA. [de Lima, Marcos] Univ Hosp Case Med Ctr, Seidman Canc Ctr, Dept Med, Cleveland, OH USA. [Sandmaier, Brenda M.] Univ Washington, Div Med Oncol, Seattle, WA 98195 USA. [Sandmaier, Brenda M.] Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA. [Weisdorf, Dan] Natl Marrow Donor Program Be Match, Ctr Int Blood & Marrow Transplant Res, Minneapolis, MN USA. RP Deol, A (reprint author), Wayne State Univ, Karmanos Canc Inst, Dept Oncol, 4100 John R,4 HWCRC, Detroit, MI 48201 USA. EM deola@karmanos.org OI Saad, Ayman /0000-0003-0003-0130 FU Public Health Service grant from the National Cancer Institute (NCI) [5U24-CA076518]; National Heart, Lung, and Blood Institute (NHLBI); National Institute of Allergy and Infectious Diseases (NIAID); NHLIB; NCI [5U10HL069294]; Health Resources and Services Administration/Department of Health and Human Services from the Office of Naval Research [HHSH250201200016C, N00014-13-1-0039, N00014-14-1-0028]; Alexion; Amgen, Inc; Be the Match Foundation; Bristol-Myers Squibb Oncology; Celgene Corporation; Chimeric, Inc; Fred Hutchinson Cancer Research Center; Gamida Cell Ltd; Genentech, Inc; Genzyme Corporation; Gilead Sciences, Inc; Health Research, Inc; Roswell Park Cancer Institute; HistoGenetics, Inc; Incyte Corporation; Jazz Pharmaceuticals, Inc; Jeff Gordon Children's Foundation; Leukemia and Lymphoma Society; Medical College of Wisconsin; Merck and Company, Inc; Mesoblast; Millennium: The Takeda Oncology Company; Miltenyi Biotec, Inc; National Marrow Donor Program; Neovii Biotech NA, Inc; Novartis Pharmaceuticals Corporation; Onyx Pharmaceuticals; Optum Health Care Solutions, Inc; Otsuka America Pharmaceutical, Inc; Otsuka Pharmaceutical Company, Ltd-Japan; Oxford Immunotec; Perkin Elmer, Inc; Pharmacyclics; Sanofi US; Seattle Genetics; Sigma-Tau Pharmaceuticals; Spectrum Pharmaceuticals, Inc; St Baldrick's Foundation; Sunesis Pharmaceuticals, Inc; Swedish Orphan Biovitrum, Inc; Telomere Diagnostics, Inc; TerumoBCT; Therakos, Inc; University of Minnesota; Wellpoint, Inc FX The Center for International Blood and Marrow Transplant Research (CIBMTR) is supported by a Public Health Service grant (cooperative agreement 5U24-CA076518) from the National Cancer Institute (NCI), the National Heart, Lung, and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases (NIAID); by the NHLIB and the NCI (grant/cooperative agreement 5U10HL069294); by the Health Resources and Services Administration/Department of Health and Human Services (contract HHSH250201200016C; grants N00014-13-1-0039 and N00014-14-1-0028) from the Office of Naval Research; by an anonymous donation to the Medical College of Wisconsin; and by grants from Alexion; Amgen, Inc (a corporate member); Be the Match Foundation; Bristol-Myers Squibb Oncology (a corporate member); Celgene Corporation (a corporate member); Chimeric, Inc (a corporate member); the Fred Hutchinson Cancer Research Center; Gamida Cell Ltd; Genentech, Inc; Genzyme Corporation; Gilead Sciences, Inc (a corporate member); Health Research, Inc; the Roswell Park Cancer Institute; HistoGenetics, Inc; Incyte Corporation; Jazz Pharmaceuticals, Inc (a corporate member); Jeff Gordon Children's Foundation; The Leukemia and Lymphoma Society; The Medical College of Wisconsin; Merck and Company, Inc; Mesoblast; Millennium: The Takeda Oncology Company; Miltenyi Biotec, Inc (a corporate member); the National Marrow Donor Program; Neovii Biotech NA, Inc; Novartis Pharmaceuticals Corporation; Onyx Pharmaceuticals; Optum Health Care Solutions, Inc; Otsuka America Pharmaceutical, Inc; Otsuka Pharmaceutical Company, Ltd-Japan; Oxford Immunotec; Perkin Elmer, Inc; Pharmacyclics; Sanofi US (a corporate member); Seattle Genetics; Sigma-Tau Pharmaceuticals; Spectrum Pharmaceuticals, Inc (a corporate member); St Baldrick's Foundation; Sunesis Pharmaceuticals, Inc (a corporate member); Swedish Orphan Biovitrum, Inc; Telomere Diagnostics, Inc; TerumoBCT; Therakos, Inc; the University of Minnesota; and Wellpoint, Inc (a corporate member). NR 24 TC 1 Z9 2 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD OCT 1 PY 2016 VL 122 IS 19 BP 3005 EP 3014 DI 10.1002/cncr.30140 PG 10 WC Oncology SC Oncology GA EB5KN UT WOS:000387413300013 PM 27315441 ER PT J AU Gahl, RF Dwivedi, P Tjandra, N AF Gahl, Robert F. Dwivedi, Pallavi Tjandra, Nico TI Bcl-2 proteins bid and bax form a network to permeabilize the mitochondria at the onset of apoptosis SO CELL DEATH & DISEASE LA English DT Article ID MEMBRANE CURVATURE; SINGLE CELLS; FAMILY; TARGETS; DEATH; BINDING; CYTOSOL; ARFGAP1; DOMAIN; ACTIN AB The most critical step in the initiation of apoptosis is the activation of the Bcl-2 family of proteins to oligomerize and permeabilize the outer-mitochondrial membrane (OMM). As this step results in the irreversible release of factors that enhance cellular degradation, it is the point of no return in programmed cell death and would be an ideal therapeutic target. However, the arrangement of the Bcl-2 proteins in the OMM during permeabilization still remains unknown. It is also unclear whether the Bcl-2 protein, Bid, directly participates in the formation of the oligomers in live cells, even though it is cleaved and translocates to the OMM at the initiation of apoptosis. Therefore, we utilized confocal microscopy to measure Forster resonance energy transfer (FRET) efficiencies in live cells to determine the conformation(s) and intermolecular contacts of Bid within these Bcl-2 oligomers. We found that Bid adopts an extended conformation, which appears to be critical for its association with the mitochondrial membrane. This conformation is also important for intermolecular contacts within the Bid oligomer. More importantly for the first time, direct intermolecular contacts between Bid and Bax were observed, thereby, confirming Bid as a key component of these oligomers. Furthermore, the observed FRET efficiencies allowed us to propose an oligomeric arrangement of Bid, Bax, and possibly other members of the Bcl-2 family of proteins that form a self-propagating network that permeabilizes the OMM. C1 [Gahl, Robert F.; Dwivedi, Pallavi; Tjandra, Nico] NHLBI, Lab Mol Biophys, Biochem & Biophys Ctr, NIH, 50 South Dr,Bldg 50,Room 3503, Bethesda, MD 20892 USA. RP Tjandra, N (reprint author), NHLBI, Lab Mol Biophys, Biochem & Biophys Ctr, NIH, 50 South Dr,Bldg 50,Room 3503, Bethesda, MD 20892 USA. EM tjandran@nhlbi.nih.gov FU Intramural Research Program of the NIH; NHLBI FX This work was supported by the Intramural Research Program of the NIH, and NHLBI. We thank Duck-Yeon Lee of the NHLBI Biochemical Facility for assistance in mass spectrometry and Xufeng Wu of the NHLBI Light Microscopy Core for assistance in obtaining confocal images. We also would like to thank Richard Youle and Ashley C Barnes for helpful comments and suggestions on the manuscript. NR 52 TC 0 Z9 0 U1 7 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-4889 J9 CELL DEATH DIS JI Cell Death Dis. PD OCT PY 2016 VL 7 AR e2424 DI 10.1038/cddis.2016.320 PG 11 WC Cell Biology SC Cell Biology GA EB4QU UT WOS:000387358800030 PM 27763642 ER PT J AU Bulluck, H Rosmini, S Abdel-Gadir, A White, SK Bhuva, AN Treibel, TA Fontana, M Ramlall, M Hamarneh, A Sirker, A Herrey, AS Manisty, C Yellon, DM Kellman, P Moon, JC Hausenloy, DJ AF Bulluck, Heerajnarain Rosmini, Stefania Abdel-Gadir, Amna White, Steven K. Bhuva, Anish N. Treibel, Thomas A. Fontana, Marianna Ramlall, Manish Hamarneh, Ashraf Sirker, Alex Herrey, Anna S. Manisty, Charlotte Yellon, Derek M. Kellman, Peter Moon, James C. Hausenloy, Derek J. TI Residual Myocardial Iron Following Intramyocardial Hemorrhage During the Convalescent Phase of Reperfused ST-Segment-Elevation Myocardial Infarction and Adverse Left Ventricular Remodeling SO CIRCULATION-CARDIOVASCULAR IMAGING LA English DT Article DE intramyocardial hemorrhage; residual myocardial iron; ST-segment-elevation myocardial infarction; T2 mapping; T2*mapping ID CARDIAC MAGNETIC-RESONANCE; MICROVASCULAR OBSTRUCTION; PROGNOSTIC VALUE; FUNCTIONAL RECOVERY; HEART-FAILURE; ENHANCEMENT; VALIDATION; MORTALITY; STEMI; CORE AB Background The presence of intramyocardial hemorrhage (IMH) in ST-segment-elevation myocardial infarction patients reperfused by primary percutaneous coronary intervention has been associated with residual myocardial iron at follow-up, and its impact on adverse left ventricular (LV) remodeling is incompletely understood and is investigated here. Methods and Results Forty-eight ST-segment-elevation myocardial infarction patients underwent cardiovascular magnetic resonance at 42 days post primary percutaneous coronary intervention, of whom 40 had a follow-up scan at 5 +/- 2 months. Native T1, T2, and T2* maps were acquired. Eight out of 40 (20%) patients developed adverse LV remodeling. A subset of 28 patients had matching T2* maps, of which 15/28 patients (54%) had IMH. Eighteen of 28 (64%) patients had microvascular obstruction on the acute scan, of whom 15/18 (83%) patients had microvascular obstruction with IMH. On the follow-up scan, 13/15 patients (87%) had evidence of residual iron within the infarct zone. Patients with residual iron had higher T2 in the infarct zone surrounding the residual iron when compared with those without. In patients with adverse LV remodeling, T2 in the infarct zone surrounding the residual iron was also higher than in those without (60 [54-64] ms versus 53 [51-56] ms; P=0.025). Acute myocardial infarct size, extent of microvascular obstruction, and IMH correlated with the change in LV end-diastolic volume (Pearson's rho of 0.64, 0.59, and 0.66, respectively; P=0.18 and 0.62, respectively, for correlation coefficient comparison) and performed equally well on receiver operating characteristic curve for predicting adverse LV remodeling (area under the curve: 0.99, 0.94, and 0.95, respectively; P=0.19 for receiver operating characteristic curve comparison). Conclusions The majority of ST-segment-elevation myocardial infarction patients with IMH had residual myocardial iron at follow-up. This was associated with persistently elevated T2 values in the surrounding infarct tissue and adverse LV remodeling. IMH and residual myocardial iron may be potential therapeutic targets for preventing adverse LV remodeling in reperfused ST-segment-elevation myocardial infarction patients. C1 [Bulluck, Heerajnarain; White, Steven K.; Ramlall, Manish; Hamarneh, Ashraf; Yellon, Derek M.; Hausenloy, Derek J.] UCL, Inst Cardiovasc Sci, Hatter Cardiovasc Inst, London WC1E 6BT, England. [Bulluck, Heerajnarain; White, Steven K.; Ramlall, Manish; Hamarneh, Ashraf; Sirker, Alex; Yellon, Derek M.; Moon, James C.; Hausenloy, Derek J.] Univ Coll London Hosp, Biomed Res Ctr, Natl Inst Hlth Res, London, England. [Bulluck, Heerajnarain; Rosmini, Stefania; Abdel-Gadir, Amna; White, Steven K.; Bhuva, Anish N.; Treibel, Thomas A.; Fontana, Marianna; Ramlall, Manish; Hamarneh, Ashraf; Sirker, Alex; Herrey, Anna S.; Manisty, Charlotte; Moon, James C.; Hausenloy, Derek J.] St Bartholomews Hosp, Barts Heart Ctr, London, England. [Kellman, Peter] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Hausenloy, Derek J.] Duke Natl Univ Singapore, Cardiovasc & Metab Disorders Program, Singapore, Singapore. [Hausenloy, Derek J.] Natl Heart Ctr Singapore, Natl Heart Res Inst Singapore, Singapore, Singapore. RP Hausenloy, DJ (reprint author), Duke NUS Grad Med Sch Singapore, Cardiovasc & Metab Dis Program, 8 Coll Rd, Singapore 169857, Singapore. EM derek.hausenloy@duke-nus.edu.sg FU British Heart Foundation [FS/10/039/28270]; Rosetrees Trust; National Institute for Health Research University College London Hospitals Biomedical Research Centre FX This work was supported by the British Heart Foundation (FS/10/039/28270), the Rosetrees Trust, and the National Institute for Health Research University College London Hospitals Biomedical Research Centre. NR 36 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1941-9651 EI 1942-0080 J9 CIRC-CARDIOVASC IMAG JI Circ.-Cardiovasc. Imaging PD OCT PY 2016 VL 9 IS 10 AR e004940 DI 10.1161/CIRCIMAGING.116.004940 PG 10 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA EA8SK UT WOS:000386908700002 ER PT J AU Eaton, CB Pettinger, M Rossouw, J Martin, LW Foraker, R Quddus, A Liu, SM Wampler, NS Wu, WCH Manson, JE Margolis, K Johnson, KC Allison, M Corbie-Smith, G Rosamond, W Breathett, K Klein, L AF Eaton, Charles B. Pettinger, Mary Rossouw, Jacques Martin, Lisa Warsinger Foraker, Randi Quddus, Abdullah Liu, Simin Wampler, Nina S. Wu, Wen-Chih Hank Manson, JoAnn E. Margolis, Karen Johnson, Karen C. Allison, Matthew Corbie-Smith, Giselle Rosamond, Wayne Breathett, Khadijah Klein, Liviu TI Risk Factors for Incident Hospitalized Heart Failure With Preserved Versus Reduced Ejection Fraction in a Multiracial Cohort of Postmenopausal Women SO CIRCULATION-HEART FAILURE LA English DT Article DE heart failure; hospitalization; prevalence; public health; risk factors ID ATHEROSCLEROSIS RISK; SYSTOLIC FUNCTION; COMORBIDITIES; COMMUNITIES; PREVALENCE AB Background Heart failure is an important and growing public health problem in women. Risk factors for incident hospitalized heart failure with preserved ejection fraction (HFpEF) compared with heart failure with reduced ejection fraction (HFrEF) in women and differences by race/ethnicity are not well characterized. Methods and Results We prospectively evaluated the risk factors for incident hospitalized HFpEF and HFrEF in a multiracial cohort of 42170 postmenopausal women followed up for a mean of 13.2 years. Cox regression models with time-dependent covariate adjustment were used to define risk factors for HFpEF and HFrEF. Differences by race/ethnicity about incidence rates, baseline risk factors, and their population-attributable risk percentage were analyzed. Risk factors for both HFpEF and HFrEF were as follows: older age, white race, diabetes mellitus, cigarette smoking, and hypertension. Obesity, history of coronary heart disease (other than myocardial infarction), anemia, atrial fibrillation, and more than one comorbidity were associated with HFpEF but not with HFrEF. History of myocardial infarction was associated with HFrEF but not with HFpEF. Obesity was found to be a more potent risk factor for African American women compared with white women for HFpEF (P for interaction=0.007). For HFpEF, the population-attributable risk percentage was greatest for hypertension (40.9%) followed by obesity (25.8%), with the highest population-attributable risk percentage found in African Americans for these risk factors. Conclusions In this multiracial cohort of postmenopausal women, obesity stands out as a significant risk factor for HFpEF, with the strongest association in African American women. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000611. C1 [Eaton, Charles B.; Quddus, Abdullah] Mem Hosp Rhode Isl, Ctr Primary Care & Prevent, Pawtucket, RI USA. [Eaton, Charles B.; Liu, Simin] Brown Univ, Sch Publ Hlth, Alpert Med Sch, Providence, RI 02912 USA. [Pettinger, Mary] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Rossouw, Jacques] NHLBI, Womens Hlth Initiat Branch, Div Cardiovasc Sci, Bldg 10, Bethesda, MD 20892 USA. [Martin, Lisa Warsinger] George Washington Univ, Sch Med & Hlth Sci, Washington, DC 20052 USA. [Foraker, Randi] Ohio State Univ, Coll Publ Hlth, Div Epidemiol, Columbus, OH 43210 USA. [Wampler, Nina S.] Univ Arizona, Ctr Canc, Phoenix, AZ USA. [Wu, Wen-Chih Hank] Providence VA Med Ctr, Providence, RI USA. [Manson, JoAnn E.] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA USA. [Margolis, Karen] HealthPartners Inst Res & Educ, Minneapolis, MN USA. [Johnson, Karen C.] Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. [Allison, Matthew] Univ Calif San Diego, La Jolla, CA 92093 USA. [Corbie-Smith, Giselle; Rosamond, Wayne] Univ N Carolina, Chapel Hill, NC USA. [Breathett, Khadijah] Ohio State Univ, Wexner Med Ctr, Columbus, OH 43210 USA. [Breathett, Khadijah] Ohio State Univ, Davis Heart & Lung Res Inst, Columbus, OH 43210 USA. [Klein, Liviu] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Eaton, CB (reprint author), Mem Hosp Rhode Isl, 111 Brewster St, Pawtucket, RI 02860 USA. EM charles_eaton@mhri.org OI Allison, Matthew/0000-0003-0777-8272 FU National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services [HHSN268 201100046C, HHSN268201100001C, HHSN268201100002C, HHSN 268201100003C, HHSN268201100004C, HHSN271201100004C] FX The Women's Health Initiative program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services (contracts HHSN268 201100046C, HHSN268201100001C, HHSN268201100002C, HHSN 268201100003C, HHSN268201100004C, and HHSN271201100004C). NR 27 TC 3 Z9 3 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1941-3289 EI 1941-3297 J9 CIRC-HEART FAIL JI Circ.-Heart Fail. PD OCT PY 2016 VL 9 IS 10 AR e002883 DI 10.1161/CIRCHEARTFAILURE.115.002883 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EA8SW UT WOS:000386909900001 ER PT J AU Croston, TL Nayak, AP Lemons, AR Goldsmith, WT Gu, JK Germolec, DR Beezhold, DH Green, BJ AF Croston, T. L. Nayak, A. P. Lemons, A. R. Goldsmith, W. T. Gu, J. K. Germolec, D. R. Beezhold, D. H. Green, B. J. TI Influence of Aspergillus fumigatus conidia viability on murine pulmonary microRNA and mRNA expression following subchronic inhalation exposure SO CLINICAL AND EXPERIMENTAL ALLERGY LA English DT Article DE allergens and epitopes; animal models; genetics ID HELICOBACTER-PYLORI INFECTION; ALLERGIC AIRWAYS DISEASE; BETA-GLUCAN RECEPTOR; CIGARETTE-SMOKE; MOUSE LUNG; CELLULAR MICRORNA; IMMUNE-RESPONSES; GENE-EXPRESSION; DOWN-REGULATION; T-CELLS AB Background Personal exposure to fungal bioaerosols derived from contaminated building materials or agricultural commodities may induce or exacerbate a variety of adverse health effects. The genomic mechanisms that underlie pulmonary immune responses to fungal bioaerosols have remained unclear. Objective The impact of fungal viability on the pulmonary microRNA and messenger RNA profiles that regulate murine immune responses was evaluated following subchronic inhalation exposure to Aspergillus fumigatus conidia. Methods Three groups of naive B6C3F1/N mice were exposed via nose-only inhalation to A. fumigatus viable conidia, heat-inactivated conidia (HIC), or HEPA-filtered air twice a week for 13 weeks. Total RNA was isolated from whole lung 24 and 48 h postfinal exposure and was further processed for gene expression and microRNA array analysis. The molecular network pathways between viable and HIC groups were evaluated. Results Comparison of data sets revealed increased Il4, Il13 and Il33 expression in mice exposed to viable vs. HIC. Of 415 microRNAs detected, approximately 50% were altered in mice exposed to viable vs. HIC 48 h postexposure. Significantly down-regulated (P <= 0.05) miR-29a-3p was predicted to regulate TGF-beta 3 and Clec7a, genes involved in innate responses to viable A. fumigatus. Also significantly down-regulated (P <= 0.05), miR-23b-3p regulates genes involved in pulmonary IL-13 and IL-33 responses and SMAD2, downstream of TGF-b signalling. Using Ingenuity Pathway Analysis, a novel interaction was identified between viable conidia and SMAD2/3. Conclusions and Clinical Relevance Examination of the pulmonary genetic profiles revealed differentially expressed genes and microRNAs following subchronic inhalation exposure to A. fumigatus. MicroRNAs regulating genes involved in the pulmonary immune responses were those with the greatest fold change. Specifically, germinating A. fumigatus conidia were associated with Clec7a and were predicted to interact with Il13 and Il33. Furthermore, altered microRNAs may serve as potential biomarkers to evaluate fungal exposure. C1 [Croston, T. L.; Nayak, A. P.; Lemons, A. R.; Green, B. J.] NIOSH, Allergy & Clin Immunol Branch, Hlth Effects Lab Div, Ctr Dis Control & Prevent, 1095 Willowdale Rd, Morgantown, WV 26505 USA. [Goldsmith, W. T.] NIOSH, Engn & Control Technol Branch, Hlth Effects Lab Div, Ctr Dis Control & Prevent, Morgantown, WV USA. [Gu, J. K.] NIOSH, Biostat & Epidemiol Branch, Hlth Effects Lab Div, Ctr Dis Control & Prevent, Morgantown, WV USA. [Germolec, D. R.] NIEHS, Toxicol Branch, DNTP, POB 12233, Res Triangle Pk, NC 27709 USA. [Beezhold, D. H.] NIOSH, Off Director, Hlth Effects Lab Div, Ctr Dis Control & Prevent, Morgantown, WV USA. RP Croston, TL (reprint author), NIOSH, Allergy & Clin Immunol Branch, Hlth Effects Lab Div, Ctr Dis Control & Prevent, 1095 Willowdale Rd, Morgantown, WV 26505 USA. EM xzu9@cdc.gov OI Lemons, Angela/0000-0003-3057-9888 FU NIOSH [AES12007001-1-0-6]; NIEHS [AES12007001-1-0-6]; Centers for Disease Control and Prevention-NIOSH [927ZLCT] FX The authors acknowledge Dr. Michael Kashon in the Biostatistics and Epidemiology Branch, National Institute for Occupational Safety and Health (NIOSH), for assistance with statistical analysis and representation, as well as Brandon F. Law in the Allergy and Clinical Immunology Branch, NIOSH, for assistance in harvesting and processing samples. The authors would also thank Dr. Paivi Salo from the National Institute of Environmental Health Sciences (NIEHS) and Dr. John Noti, NIOSH for participating in the internal NIEHS and NIOSH review process. This study was supported in part by an interagency agreement between NIOSH and NIEHS (AES12007001-1-0-6) as a collaborative National Toxicology Program research activity. This study was also funded in part by Centers for Disease Control and Prevention-NIOSH intramural funds (927ZLCT). The findings and conclusions in this study are those of the authors and do not necessarily represent the views of National Institute for Occupational Safety and Health. NR 70 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0954-7894 EI 1365-2222 J9 CLIN EXP ALLERGY JI Clin. Exp. Allergy PD OCT PY 2016 VL 46 IS 10 BP 1315 EP 1327 DI 10.1111/cea.12783 PG 13 WC Allergy; Immunology SC Allergy; Immunology GA EA9IR UT WOS:000386956900007 PM 27473664 ER PT J AU Wand, T Fang, M Chen, C Hardy, N McCoy, JP Dumitriu, B Young, NS Biancotto, A AF Wand, Taylor Fang, Mike Chen, Christina Hardy, Nathan McCoy, J. Philip, Jr. Dumitriu, Bogdan Young, Neal S. Biancotto, Angelique TI Telomere content measurement in human hematopoietic cells: Comparative analysis of qPCR and Flow-FISH techniques SO CYTOMETRY PART A LA English DT Article DE telomere; qPCR; Flow-FISH; TRF2 ID IN-SITU HYBRIDIZATION; APLASTIC-ANEMIA; LENGTH MEASUREMENTS; MYELOID-LEUKEMIA; DNA-CONTENT; CYTOMETRY; INSTABILITY; CANCER; MUTATIONS; DYNAMICS AB Abnormal telomere lengths have been linked to cancer and other hematologic disorders. Determination of mean telomere content (MTC) is traditionally performed by Southern blotting and densitometry, giving a mean telomere restriction fragment (TRF) value for the total cell population studied. Here, we compared a quantitative Polymerase Chain Reaction approach (qPCR) and a flow cytometric approach, fluorescence in situ hybridization (Flow-FISH), to evaluate telomere content distribution in total patient peripheral blood mononuclear cells or specific cell populations. Flow-FISH is based on in situ hybridization using a fluorescein-labeled peptide nucleic acid (PNA) (CCCTAA)(3) probe and DNA staining with propidium iodide. We showed that both qPCR and Flow-FISH provide a robust measurement, with Flow-FISH measuring a relative content longer than qPCR at a single cell approach and that TRF2 fluorescence intensity did not correlate with MTC. Both methods showed comparable telomere content reduction with age, and the rate of relative telomere loss was similar. Published 2016 Wiley Periodicals Inc. This article is a US government work and, as such, is in the public domain in the United States of America. C1 [Wand, Taylor; Young, Neal S.; Biancotto, Angelique] Natl Inst Hlth, Ctr Human Immunol Autoimmun & Inflammat, Bethesda, MD 20892 USA. [Fang, Mike; Chen, Christina; Hardy, Nathan; Dumitriu, Bogdan; Young, Neal S.] Natl Heart Lung & Blood Inst Natl Inst Hlth, Hematol Branch, Bethesda, MD 20892 USA. [McCoy, J. Philip, Jr.] Natl Heart Lung & Blood Inst, Natl Inst Hlth, Flow Cytometry Core, Bethesda, MD 20892 USA. RP Biancotto, A (reprint author), Natl Inst Hlth, Ctr Human Immunol Autoimmun & Inflammat, Bethesda, MD 20892 USA.; Biancotto, A (reprint author), Natl Inst Hlth, 10 Ctr Dr,MSC 1357,Bldg 10,Rm 7N110a, Bethesda, MD 20892 USA. EM biancoa@mail.nih.gov OI Hardy, Nathan/0000-0002-3833-6461 FU NIH; NHLBI; CHI intramural research program FX This work supported by the NIH, NHLBI, and CHI intramural research program. NR 41 TC 0 Z9 0 U1 7 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4922 EI 1552-4930 J9 CYTOM PART A JI Cytom. Part A PD OCT PY 2016 VL 89A IS 10 BP 914 EP 921 DI 10.1002/cyto.a.22982 PG 8 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EB2UH UT WOS:000387217600007 PM 27717244 ER PT J AU Gold, AL Shechner, T Farber, MJ Spiro, CN Leibenluft, E Pine, DS Britton, JC AF Gold, Andrea L. Shechner, Tomer Farber, Madeline J. Spiro, Carolyn N. Leibenluft, Ellen Pine, Daniel S. Britton, Jennifer C. TI AMYGDALA-CORTICAL CONNECTIVITY: ASSOCIATIONS WITH ANXIETY, DEVELOPMENT, AND THREAT SO DEPRESSION AND ANXIETY LA English DT Article; Proceedings Paper CT 18th Annual Scientific Research Symposium of the Anxiety-and-Depression-Association-of-America (ADAA) CY 2015 CL Miami, FL SP Anxiety & Depress Assoc Amer DE anxiety/anxiety disorders; child/adolescent; functional MRI; GAD/generalized anxiety disorder; SAD/social anxiety disorder/social phobia ID FUNCTIONAL CONNECTIVITY; PREFRONTAL CORTEX; FEAR EXTINCTION; SOCIAL ANXIETY; CONDITIONED FEAR; NEURAL RESPONSE; EMOTIONAL BRAIN; EARLY-ADULTHOOD; ALTERED FEAR; DISORDER AB Background: Amygdala-prefrontal cortex (PFC) functional connectivity may be influenced by anxiety and development. A prior study on anxiety found age-specific dysfunction in the ventromedial PFC (vmPFC), but not amygdala, associated with threat-safety discrimination during extinction recall (Britton et al.[8]). However, translational research suggests that amygdala-PFC circuitry mediates responses following learned extinction. Anxiety-related perturbations may emerge in functional connectivity within this circuit during extinction recall tasks. The current report uses data from the prior study to examine how anxiety and development relate to task-dependent amygdala-PFC connectivity. Methods: Eighty-two subjects (14 anxious youths, 15 anxious adults, 25 healthy youths, 28 healthy adults) completed an extinction recall task, which directed attention to different aspects of stimuli. Generalized psychophysiological interaction analysis tested whether task-dependent functional connectivity with anatomically defined amygdala seed regions differed across anxiety and age groups. Results: Whole-brain analyses showed significant interactions of anxiety, age, and attention task (i.e., threat appraisal, explicit threat memory, physical discrimination) on left amygdala functional connectivity with the vmPFC and ventral anterior cingulate cortex (Talairach XYZ coordinates: -16, 31, -6 and 1, 36, -4). During threat appraisal and explicit threat memory (vs. physical discrimination), anxious youth showed more negative amygdala-PFC coupling, whereas anxious adults showed more positive coupling. Conclusions: In the context of extinction recall, anxious youths and adults manifested opposite directions of amygdalavm PFC coupling, specifically when appraising and explicitly remembering previously learned threat. Future research on anxiety should consider associations of both development and attention to threat with functional connectivity perturbations. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. C1 [Gold, Andrea L.; Farber, Madeline J.; Leibenluft, Ellen; Pine, Daniel S.] NIMH, Emot & Dev Branch, NIH, Bldg 15K,MSC 2670, Bethesda, MD 20892 USA. [Shechner, Tomer] Univ Haifa, Dept Psychol, Haifa, Israel. [Spiro, Carolyn N.] Rutgers State Univ, Dept Psychol, New Brunswick, NJ USA. [Britton, Jennifer C.] Univ Miami, Dept Psychol, POB 248185, Coral Gables, FL 33124 USA. RP Gold, AL (reprint author), NIMH, Emot & Dev Branch, NIH, Bldg 15K,MSC 2670, Bethesda, MD 20892 USA. EM andrea.gold@nih.gov OI Gold, Andrea/0000-0003-4447-776X FU Intramural Research Program at the National Institute of Mental Health [K99/R00MH091183] FX Contract grant sponsor: Intramural Research Program at the National Institute of Mental Health; Contract grant number: K99/R00MH091183. NR 74 TC 1 Z9 1 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1091-4269 EI 1520-6394 J9 DEPRESS ANXIETY JI Depress. Anxiety PD OCT PY 2016 VL 33 IS 10 BP 917 EP 926 DI 10.1002/da.22470 PG 10 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA EB5FE UT WOS:000387398400005 PM 27699940 ER PT J AU Mansour, SC Pletzer, D de la Fuente-Nunez, C Kim, P Cheung, GYC Joo, HS Otto, M Hancock, REW AF Mansour, Sarah C. Pletzer, Daniel de la Fuente-Nunez, Cesar Kim, Paul Cheung, Gordon Y. C. Joo, Hwang-Soo Otto, Michael Hancock, Robert E. W. TI Bacterial Abscess Formation Is Controlled by the Stringent Stress Response and Can Be Targeted Therapeutically SO EBIOMEDICINE LA English DT Article DE Staphylococcus aureus; Pseudomonas aeruginosa; ppGpp; Cationic peptide; DJK-5 ID RESISTANT STAPHYLOCOCCUS-AUREUS; PHENOL-SOLUBLE MODULINS; EMERGENCY-DEPARTMENT; ESCHERICHIA-COLI; (P)PPGPP; PEPTIDES; INFECTIONS; BIOFILMS; PPGPP; ANTIBIOFILM AB Cutaneous abscess infections are difficult to treat with current therapies and alternatives to conventional antibiotics are needed. Understanding the regulatory mechanisms that govern abscess pathology should reveal therapeutic interventions for these recalcitrant infections. Here we demonstrated that the stringent stress response employed by bacteria to cope and adapt to environmental stressors was essential for the formation of lesions, but not bacterial growth, in a methicillin resistant Staphylococcus aureus (MRSA) cutaneous abscess mouse model. To pharmacologically confirm the role of the stringent response in abscess formation, a cationic peptide that causes rapid degradation of the stringent response mediator, guanosine tetraphosphate (ppGpp), was employed. The therapeutic application of this peptide strongly inhibited lesion formation in mice infected with Gram-positive MRSA and Gram-negative Pseudomonas aeruginosa. Overall, we provide insights into the mechanisms governing abscess formation and a paradigm for treating multidrug resistant cutaneous abscesses. (C) 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). C1 [Mansour, Sarah C.; Pletzer, Daniel; de la Fuente-Nunez, Cesar; Kim, Paul; Hancock, Robert E. W.] Univ British Columbia, Dept Microbiol & Immunol, Ctr Microbial Dis & Immun Res, Vancouver, BC V6T 1Z4, Canada. [Cheung, Gordon Y. C.; Joo, Hwang-Soo; Otto, Michael] NIAID, Bacteriol Lab, Pathogen Mol Genet Sect, NIH, Bethesda, MD 20814 USA. RP Hancock, REW (reprint author), Univ British Columbia, Dept Microbiol & Immunol, Ctr Microbial Dis & Immun Res, Vancouver, BC V6T 1Z4, Canada. EM bob@hancocklab.com RI Pletzer, Daniel/G-5737-2013 OI Pletzer, Daniel/0000-0001-5750-7505 FU NIAID NIH HHS [R33 AI098701] NR 35 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2352-3964 J9 EBIOMEDICINE JI EBioMedicine PD OCT PY 2016 VL 12 BP 219 EP 226 DI 10.1016/j.ebiom.2016.09.015 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA EA8IM UT WOS:000386878500038 PM 27658736 ER PT J AU Billings, M Dye, BA Iafolla, T Baer, AN Grisius, M Alevizos, I AF Billings, Monisha Dye, Bruce A. Iafolla, Timothy Baer, Alan N. Grisius, Margaret Alevizos, Ilias TI Significance and Implications of Patient-reported Xerostomia in Sjogren's Syndrome: Findings From the National Institutes of Health Cohort SO EBIOMEDICINE LA English DT Article DE Sjogren's syndrome; Xerostomia; Hyposalivation; Autoimmune disorders; Salivary gland dysfunction ID SALIVARY-GLAND FUNCTION; CLASSIFICATION CRITERIA; DEHYDROEPIANDROSTERONE; PATHOGENESIS; DYSFUNCTION; FEATURES; MOUTH AB Background: Xerostomia is a chief complaint of patients with Sjogren's syndrome(SS). However, newer proposals for SS classification remove xerostomia and hyposalivation from the criteria list. Given these developments and the importance of patient-centered research outcomes, we sought to evaluate the utility of patient-reported xerostomia with implications for classification criteria, and clinical trials targeting SS treatment modalities. Methods: A nested case-control study was designed within The National Institute of Dental and Craniofacial Research/National Institutes of Health (NIDCR/NIH) SS Cohort -one of the largest SS cohorts in the US. Clinical characteristics of those with and without xerostomia in SS and other salivary gland dysfunctions were compared. Several analytical methods were employed, including multivariable logistic regression modeling. Findings: The NIDCR/NIH Sjogren's Syndrome Clinic has an open cohort with ongoing enrollment since 1984. This open cohort comprised of 2046 participants by August 27, 2015. Baseline data of 701 SS, 355 Sicca, and 247 ISS participants within the source cohort were analyzed. Xerostomia was highest among SS participants (87.4%, 95% CI: 84.8%-89.8%) compared to Sicca (72.4%, 95% CI: 67.4%-77.0%, p < 0.001) and ISS groups (38.1%, 95% CI: 32.0%-44.4%, p < 0.001). Those with xerostomia were more likely to have SS than Sicca/ISS (OR = 4.98, 95% CI: 3.78-6.56). The ability of xerostomia to screen for SS among thosewith salivary gland dysfunction was higher than screening for Sicca/ISS. Screening diagnostics of xerostomia were of greater utility compared to hyposalivation. After adjusting for confounding in multivariable modeling, SS participants with xerostomia were more likely to be White (Black/African Americans (OR: 0.40, 95% CI: 0.23-0.68, p-value= 0.001) and Asians (OR: 0.49, 95% CI: 0.25-0.96, p-value= 0.038) were less likely to have xerostomia compared to Whites), have dry eye symptoms for >3 months (OR: 5.80, 95% CI: 3.62-9.28, p-value <0.001), a lower Van Bijsterveld score (OR: 0.55, 95% CI: 0.34-0.90, p-value = 0.017), a lower stimulated salivary flow rate (OR: 1.67, 95% CI: 1.06-2.65, p-value = 0.028), a focus score of >2 (OR: 1.92, 95% CI: 1.20-3.09, p-value= 0.007), and salivary gland swelling (OR: 49.39, 95% CI: 2.02-1206.30, p-value = 0.017). Age, gender, fatigue, pain, anxiety, and autoantibodies were not significantly associated with xerostomia. Interpretation: Findings from this study indicate that patient-reported xerostomia is highly prevalent among SS patients and is associated with several clinical phenotypes of this complex syndrome, thereby making it an important indicator of SS. The evidence also suggests that xerostomia is not limited to low salivary flow but might be reflective of compositional changes of saliva. Consequently, these findings suggest the need to consider xerostomia in the development of SS classification criteria and in patient-centered outcomes research in SS intervention trials. Published by Elsevier B.V. C1 [Billings, Monisha; Baer, Alan N.; Grisius, Margaret; Alevizos, Ilias] Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. [Dye, Bruce A.; Iafolla, Timothy] Natl Inst Dent & Craniofacial Res, Program Anal & Reporting Branch, NIH, Bethesda, MD USA. [Baer, Alan N.] Johns Hopkins Univ, Sch Med, Div Rheumatol, Baltimore, MD USA. RP Alevizos, I (reprint author), Bldg 10,Room 1N110,MSC-1190, Bethesda, MD 20892 USA. EM alevizosi@mail.nih.gov NR 43 TC 1 Z9 1 U1 2 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2352-3964 J9 EBIOMEDICINE JI EBioMedicine PD OCT PY 2016 VL 12 BP 270 EP 279 DI 10.1016/j.ebiom.2016.09.005 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA EA8IM UT WOS:000386878500044 PM 27639822 ER PT J AU Legros, M Otero, M Aznar, VR Solari, H Gould, F Lloyd, AL AF Legros, Mathieu Otero, Marcelo Romeo Aznar, Victoria Solari, Hernan Gould, Fred Lloyd, Alun L. TI Comparison of two detailed models of Aedes aegypti population dynamics SO ECOSPHERE LA English DT Article DE Aedes aegypti; model comparison; mosquito-borne diseases; population dynamics; spatial model; vector control ID TETRAVALENT DENGUE VACCINE; YELLOW-FEVER MOSQUITO; HEMORRHAGIC-FEVER; DIPTERA; SYSTEMS; CULICIDAE; EFFICACY AB The success of control programs for mosquito-borne diseases can be enhanced by crucial information provided by models of the mosquito populations. Models, however, can differ in their structure, complexity, and biological assumptions, and these differences impact their predictions. Unfortunately, it is typically difficult to determine why two complex models make different predictions because we lack structured side-by-side comparisons of models using comparable parameterization. Here, we present a detailed comparison of two complex, spatially explicit, stochastic models of the population dynamics of Aedes aegypti, the main vector of dengue, yellow fever, chikungunya, and Zika viruses. Both models describe the mosquito's biological and ecological characteristics, but differ in complexity and specific assumptions. We compare the predictions of these models in two selected climatic settings: a tropical and weakly seasonal climate in Iquitos, Peru, and a temperate and strongly seasonal climate in Buenos Aires, Argentina. Both models were calibrated to operate at identical average densities in unperturbed conditions in both settings, by adjusting parameters regulating densities in each model (number of larval development sites and amount of nutritional resources). We show that the models differ in their sensitivity to environmental conditions (temperature and rainfall) and trace differences to specific model assumptions. Temporal dynamics of the Ae. aegypti populations predicted by the two models differ more markedly under strongly seasonal Buenos Aires conditions. We use both models to simulate killing of larvae and/or adults with insecticides in selected areas. We show that predictions of population recovery by the models differ substantially, an effect likely related to model assumptions regarding larval development and (direct or delayed) density dependence. Our methodical comparison provides important guidance for model improvement by identifying key areas of Ae. aegypti ecology that substantially affect model predictions, and revealing the impact of model assumptions on population dynamics predictions in unperturbed and perturbed conditions. C1 [Legros, Mathieu; Gould, Fred] North Carolina State Univ, Dept Entomol, Raleigh, NC 27695 USA. [Legros, Mathieu] Swiss Fed Inst Technol, Inst Integrat Biol, Univ Str 16, CH-8092 Zurich, Switzerland. [Otero, Marcelo; Romeo Aznar, Victoria; Solari, Hernan] Univ Buenos Aires, Fac Ciencias Exactas 7 Nat, Dept Fis, Pabellon 1,Ciudad Univ, RA-1428 Buenos Aires, DF, Argentina. [Otero, Marcelo; Romeo Aznar, Victoria; Solari, Hernan] IFIBA CONICET, Pabellon 1,Ciudad Univ, RA-1428 Buenos Aires, DF, Argentina. [Gould, Fred; Lloyd, Alun L.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Lloyd, Alun L.] North Carolina State Univ, Dept Math & Biomath, Grad Program, Raleigh, NC 27695 USA. RP Lloyd, AL (reprint author), NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA.; Lloyd, AL (reprint author), North Carolina State Univ, Dept Math & Biomath, Grad Program, Raleigh, NC 27695 USA. EM alun_lloyd@ncsu.edu FU Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directory, Department of Homeland Security; Fogarty International Center, National Institutes of Health; Universidad de Buenos Aires [UBACYT 20020100100734, UBACYT 20020110100205, UBACYT 20020130100361BA]; National Institutes for Health [R01-AI54954, R01-AI091980, P01-AI098670]; National Science Foundation [RTG/DMS-1246991] FX We acknowledge the support of the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directory, Department of Homeland Security, and Fogarty International Center, National Institutes of Health. This work was also supported by grants from the Universidad de Buenos Aires (UBACYT 20020100100734, UBACYT 20020110100205, and UBACYT 20020130100361BA; MO, VRA, and HS), the National Institutes for Health (R01-AI54954, R01-AI091980, and P01-AI098670; ML, FG, and ALL) and the National Science Foundation (RTG/DMS-1246991; ALL). NR 39 TC 0 Z9 0 U1 14 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2150-8925 J9 ECOSPHERE JI Ecosphere PD OCT PY 2016 VL 7 IS 10 AR e01515 DI 10.1002/ecs2.1515 PG 19 WC Ecology SC Environmental Sciences & Ecology GA EB2TU UT WOS:000387216300048 ER PT J AU Many, GM Yokosaki, Y Uaesoontrachoon, K Nghiem, PP Bello, L Dadgar, S Yin, Y Damsker, JM Cohen, HB Kornegay, JN Bamman, MM Mosser, DM Nagaraju, K Hoffman, EP AF Many, Gina M. Yokosaki, Yasuyuki Uaesoontrachoon, Kitipong Nghiem, Peter P. Bello, Luca Dadgar, Sherry Yin, Ying Damsker, Jesse M. Cohen, Heather B. Kornegay, Joe N. Bamman, Marcas M. Mosser, David M. Nagaraju, Kanneboyina Hoffman, Eric P. TI OPN-a induces muscle inflammation by increasing recruitment and activation of pro-inflammatory macrophages SO EXPERIMENTAL PHYSIOLOGY LA English DT Article ID DUCHENNE MUSCULAR-DYSTROPHY; SKELETAL-MUSCLE; RECEPTOR 4; THERAPEUTIC TARGET; BONE SIALOPROTEIN; OSTEOPONTIN; REGENERATION; FIBROSIS; INFILTRATION; MYOGENESIS AB Although osteopontin (OPN) is an important mediator of muscle remodelling in health and disease, functional differences in human spliced OPN variants in themuscle microenvironment have not been characterized. We thus sought to define the pro-inflammatory activities of human OPN isoforms (OPN-a, OPN-b and OPN-c) on cells present in regenerating muscle. OPN transcripts were quantified in normal and dystrophic human and dog muscle. Human macrophages and myoblasts were stimulated with recombinant human OPN protein isoforms, and cytokine mRNA and protein induction was assayed. OPN isoforms were greatly increased in dystrophic human (OPN-a > OPN-b > OPN-c) and dog muscle (OPN-a = OPN-c). In healthy human muscle, mechanical loading also upregulated OPN-a expression (eightfold; P < 0.01), but did not significantly upregulate OPN-c expression (twofold; P > 0.05). In vitro, OPN-a displayed the most pronounced pro-inflammatory activity among isoforms, acting on both macrophages and myoblasts. In vitro and in vivo data revealed that OPN-a upregulated tenascin-C (TNC), a known Toll-like receptor 4 (TLR4) agonist. Inhibition of TLR4 signalling attenuated OPN-mediated macrophage cytokine production. In summary, OPN-a is the most abundant and functionally active human spliced isoform in the skeletal muscle microenvironment. Here, OPN-a promotes pro-inflammatory signalling in both macrophages and myoblasts, possibly through induction of TNC-TLR4 signalling. Together, our findings suggest that specific targeting of OPN-a and/or TNC signalling in the damaged muscle microenvironment may be of therapeutic relevance. C1 [Many, Gina M.; Uaesoontrachoon, Kitipong; Nghiem, Peter P.; Bello, Luca; Dadgar, Sherry; Damsker, Jesse M.; Nagaraju, Kanneboyina; Hoffman, Eric P.] Childrens Natl Med Ctr, Res Ctr Genet Med, Washington, DC 20010 USA. [Many, Gina M.; Nghiem, Peter P.; Nagaraju, Kanneboyina; Hoffman, Eric P.] George Washington Univ, Sch Med & Hlth Sci, Dept Integrat Syst Biol, Washington, DC 20052 USA. [Yokosaki, Yasuyuki] Hiroshima Univ, Minami Ku, Hiroshima, Japan. [Nghiem, Peter P.; Kornegay, Joe N.] Texas A&M Univ, Dept Vet Integrat Biosci, College Stn, TX USA. [Yin, Ying] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. [Damsker, Jesse M.] ReveraGen BioPharma, Rockville, MD USA. [Cohen, Heather B.; Mosser, David M.] Univ Maryland, Dept Cell Biol & Mol Genet, College Pk, MD 20742 USA. [Many, Gina M.; Bamman, Marcas M.] Univ Alabama Birmingham, Dept Cell Dev & Integrat Biol, Birmingham, AL USA. RP Hoffman, EP (reprint author), SUNY Binghamton, Sch Pharm & Pharmaceut Sci, Res, POB 6000, Binghamton, NY 13902 USA. EM ehoffman@binghamton.edu OI Bello, Luca/0000-0002-3075-6525 FU NIH [5P50AR060836, 5R01NS029525, 5K26OD011171, 1P50AR060836]; Clark Charitable Foundation, Inc.; [T32HD071866] FX E.P.H.'s work was supported by NIH grants 5P50AR060836 and 5R01NS029525 and by the Clark Charitable Foundation, Inc. G.M.M. was supported by T32HD071866 and the Clark Charitable Foundation, Inc. K.N.'s contribution to this project was provided by the following NIH grants: 5K26OD011171 and 1P50AR060836. NR 44 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0958-0670 EI 1469-445X J9 EXP PHYSIOL JI Exp. Physiol. PD OCT PY 2016 VL 101 IS 10 BP 1285 EP 1300 DI 10.1113/EP085768 PG 16 WC Physiology SC Physiology GA EB1BI UT WOS:000387080900005 PM 27452303 ER PT J AU Seow, WJ Downward, GS Wei, H Rothman, N Reiss, B Xu, J Bassig, BA Li, J He, J Hosgood, HD Wu, G Chapman, RS Tian, L Wei, F Caporaso, NE Vermeulen, R Lan, Q AF Seow, W. J. Downward, G. S. Wei, H. Rothman, N. Reiss, B. Xu, J. Bassig, B. A. Li, J. He, J. Hosgood, H. D. Wu, G. Chapman, R. S. Tian, L. Wei, F. Caporaso, N. E. Vermeulen, R. Lan, Q. TI Indoor concentrations of nitrogen dioxide and sulfur dioxide from burning solid fuels for cooking and heating in Yunnan Province, China SO INDOOR AIR LA English DT Article DE Coal; Household air pollution; Indoor; Nitrogen dioxide; Sulfur dioxide; Ventilation ID OBSTRUCTIVE PULMONARY-DISEASE; HOUSEHOLD AIR-POLLUTION; TIME-ACTIVITY PATTERNS; LUNG-CANCER RISK; RETROSPECTIVE COHORT; FUYUAN COUNTIES; COAL; XUANWEI; EXPOSURE; ADMISSIONS AB The Chinese national pollution census has indicated that the domestic burning of solid fuels is an important contributor to nitrogen dioxide (NO2) and sulfur dioxide (SO2) emissions in China. To characterize indoor NO2 and SO2 air concentrations in relation to solid fuel use and stove ventilation in the rural counties of Xuanwei and Fuyuan, in Yunnan Province, China, which have among the highest lung cancer rates in the nation, a total of 163 participants in 30 selected villages were enrolled. Indoor 24-h NO2 and SO2 samples were collected in each household over two consecutive days. Compared to smoky coal, smokeless coal use was associated with higher NO2 concentrations [geometric mean (GM) = 132 mu g/m(3) for smokeless coal and 111 mu g/m(3) for smoky coal, P = 0.065] and SO2 [limit of detection = 24 mu g/m(3); percentage detected (% Detect) = 86% for smokeless coal and 40% for smoky coal, P < 0.001]. Among smoky coal users, significant variation of NO2 and SO2 air concentrations was observed across different stove designs and smoky coal sources in both counties. Model construction indicated that the measurements of both pollutants were influenced by stove design. This exposure assessment study has identified high levels of NO2 and SO2 as a result of burning solid fuels for cooking and heating. C1 [Seow, W. J.; Wei, H.; Rothman, N.; Bassig, B. A.; Caporaso, N. E.; Lan, Q.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Reiss, B.; Vermeulen, R.] Univ Utrecht, Div Environm Epidemiol, Inst Risk Assessment Sci, Utrecht, Netherlands. [Xu, J.] Univ Hong Kong, Div Epidemiol & Biostat, Sch Publ Hlth, Li Ka Shing Fac Med, Hong Kong, Hong Kong, Peoples R China. [Li, J.; He, J.] Qujing Centers Dis Control & Prevent, Qujing, Peoples R China. [Hosgood, H. D.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Wu, G.; Wei, F.] China Natl Environm Monitoring Ctr, Beijing, Peoples R China. [Chapman, R. S.] Chulalongkorn Univ, Coll Publ Hlth Sci, Bangkok, Thailand. RP Seow, WJ (reprint author), 9609 Med Ctr Dr,Room 6E632, Rockville, MD 20850 USA. EM weijie.seow2@nih.gov RI Vermeulen, Roel/F-8037-2011 OI Vermeulen, Roel/0000-0003-4082-8163 FU National Institutes of Health intramural research program FX This project was supported by the National Institutes of Health intramural research program. NR 27 TC 0 Z9 0 U1 6 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0905-6947 EI 1600-0668 J9 INDOOR AIR JI Indoor Air PD OCT PY 2016 VL 26 IS 5 BP 776 EP 783 DI 10.1111/ina.12251 PG 8 WC Construction & Building Technology; Engineering, Environmental; Public, Environmental & Occupational Health SC Construction & Building Technology; Engineering; Public, Environmental & Occupational Health GA EB4NL UT WOS:000387348500012 PM 26340585 ER PT J AU Downward, GS Hu, W Rothman, N Reiss, B Wu, G Wei, F Xu, J Seow, WJ Brunekreef, B Chapman, RS Qing, L Vermeulen, R AF Downward, G. S. Hu, W. Rothman, N. Reiss, B. Wu, G. Wei, F. Xu, J. Seow, W. J. Brunekreef, B. Chapman, R. S. Qing, L. Vermeulen, R. TI Outdoor, indoor, and personal black carbon exposure from cookstoves burning solid fuels SO INDOOR AIR LA English DT Article DE Black carbon; Coal; China; Solid fuels; Household air pollution; Climate change; PM2.5 absorbance ID HOUSEHOLD STOVE IMPROVEMENT; LUNG-CANCER MORTALITY; AIR-POLLUTION; XUAN-WEI; RETROSPECTIVE COHORT; PARTICULATE MATTER; CURRENT PROGRESS; FUYUAN COUNTIES; CHINA; RISK AB Black carbon (BC) emissions from solid fuel combustion are associated with increased morbidity and mortality and are important drivers of climate change. We studied BC measurements, approximated by particulate matter (PM2.5) absorbance, in rural Yunnan province, China, whose residents use a variety of solid fuels for cooking and heating including bituminous and anthracite coal, and wood. Measurements were taken over two consecutive 24-h periods from 163 households in 30 villages. PM2.5 absorbance (PMabs) was measured using an EEL 043 Smoke Stain Reflectometer. PMabs measurements were higher in wood burning households (16.3 x 10(-5)/m) than bituminous and anthracite coal households (12 and 5.1 x 10(-5)/m, respectively). Among bituminous coal users, measurements varied by a factor of two depending on the coal source. Portable stoves (which are lit outdoors and brought indoors for use) were associated with reduced PMabs levels, but no other impact of stove design was observed. Outdoor measurements were positively correlated with and approximately half the level of indoor measurements (r = 0.49, P < 0.01). Measurements of BC (as approximated by PMabs) in this population are modulated by fuel type and source. This provides valuable insight into potential morbidity, mortality, and climate change contributions of domestic usage of solid fuels. C1 [Downward, G. S.; Reiss, B.; Brunekreef, B.; Vermeulen, R.] Univ Utrecht, Inst Risk Assessment Sci, Div Environm Epidemiol, Utrecht, Netherlands. [Hu, W.; Rothman, N.; Seow, W. J.; Qing, L.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Wu, G.; Wei, F.] China Natl Environm Monitoring Ctr, Beijing, Peoples R China. [Xu, J.] Univ Hong Kong, Hong Kong, Hong Kong, Peoples R China. [Chapman, R. S.] Chulalongkorn Univ, Coll Publ Hlth Sci, Bangkok, Thailand. RP Downward, GS (reprint author), Univ Utrecht, Inst Risk Assessment Sci, Yalelaan 2, NL-3584 CM Utrecht, Netherlands. EM g.s.downward@uu.nl RI Vermeulen, Roel/F-8037-2011 OI Vermeulen, Roel/0000-0003-4082-8163 FU National Institutes of Health [HHSN261201400122P] FX This project was supported by the National Institutes of Health (HHSN261201400122P) intramural research program. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The authors would like to acknowledge Johan Beekhuizen and Meng Wang from the Institute for Risk Assessment Sciences, Utrecht University for their support in the production of Figure 1. NR 40 TC 1 Z9 1 U1 18 U2 18 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0905-6947 EI 1600-0668 J9 INDOOR AIR JI Indoor Air PD OCT PY 2016 VL 26 IS 5 BP 784 EP 795 DI 10.1111/ina.12255 PG 12 WC Construction & Building Technology; Engineering, Environmental; Public, Environmental & Occupational Health SC Construction & Building Technology; Engineering; Public, Environmental & Occupational Health GA EB4NL UT WOS:000387348500013 PM 26452237 ER PT J AU Kim, B Hewitt, S Chung, JY Kim, JH AF Kim, B. Hewitt, S. Chung, J. Y. Kim, J. H. TI Survival significance of BIM in cervical cancer SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER LA English DT Meeting Abstract C1 [Kim, B.] Incheon Int St Marys Hosp, OBGYN, Inchon, South Korea. [Hewitt, S.] NCI, Expt Pathol Lab, Bethesda, MD 20892 USA. [Chung, J. Y.] NCI, Expt Pathol Lab 1, Bethesda, MD 20892 USA. [Kim, J. H.] Yonsei Univ, Coll Med, Dept Obstet & Gynecol, Seoul, South Korea. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1048-891X EI 1525-1438 J9 INT J GYNECOL CANCER JI Int. J. Gynecol. Cancer PD OCT PY 2016 VL 26 SU 3 MA IGCS-0657 BP 361 EP 361 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA EB1KD UT WOS:000387109100303 ER PT J AU Noone, AM Kohn, E Penberthy, L Cronin, K Minasian, L Temkin, S AF Noone, A. M. Kohn, E. Penberthy, L. Cronin, K. Minasian, L. Temkin, S. TI Hysterectomy-corrected trends in uterine cancer among reproductive aged women in the United States: SEER 1992 to 2010 SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER LA English DT Meeting Abstract C1 [Noone, A. M.; Penberthy, L.; Cronin, K.] NCI, Div Canc Control & Populat Sci, Rockville, MD USA. [Kohn, E.] NCI, Div Canc Treatment & Diag, Rockville, MD USA. [Minasian, L.] NCI, Canc Prevent Div, Rockville, MD USA. [Temkin, S.] Johns Hopkins Sch Med, Gynecol Oncol, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1048-891X EI 1525-1438 J9 INT J GYNECOL CANCER JI Int. J. Gynecol. Cancer PD OCT PY 2016 VL 26 SU 3 MA IGCS-0259 BP 1089 EP 1089 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA EB1KD UT WOS:000387109100923 ER PT J AU Moore, SC Matthews, CE Shu, XO Yu, K Gail, MH Xu, X Ji, BT Chow, WH Cai, QY Li, HL Yang, G Ruggieri, D Boyd-Morin, J Rothman, N Hoover, RN Gao, YT Zheng, W Ziegler, RG AF Moore, Steven C. Matthews, Charles E. Shu, Xiao Ou Yu, Kai Gail, Mitchell H. Xu, Xia Ji, Bu-Tian Chow, Wong-Ho Cai, Qiuyin Li, Honglan Yang, Gong Ruggieri, David Boyd-Morin, Jennifer Rothman, Nathaniel Hoover, Robert N. Gao, Yu-Tang Zheng, Wei Ziegler, Regina G. TI Endogenous Estrogens, Estrogen Metabolites, and Breast Cancer Risk in Postmenopausal Chinese Women SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID CHROMATOGRAPHY-MASS SPECTROMETRY; URINARY ESTROGENS; STEROID-HORMONES; AMERICAN WOMEN; UNITED-STATES; SEX-HORMONES; ESTRADIOL; PREMENOPAUSAL; RECEPTOR; JAPANESE AB Background: The role of estrogen metabolismin determining breast cancer risk and differences in breast cancer rates between high-incidence and low-incidence nations is poorly understood. Methods: We measured urinary concentrations of estradiol and estrone (parent estrogens) and 13 estrogen metabolites formed by irreversible hydroxylation at the C-2, C-4, or C-16 positions of the steroid ring in a nested case-control study of 399 postmenopausal invasive breast cancer case participants and 399 matched control participants from the population-based Shanghai Women's Health Study cohort. Odds ratios (ORs) and 95% confidence intervals (CIs) of breast cancer by quartiles of metabolic pathway groups, pathway ratios, and individual estrogens/estrogen metabolites were estimated by multivariable conditional logistic regression. Urinary estrogen/estrogen metabolite measures were compared with those of postmenopausal non-hormone-using Asian Americans, a population with three-fold higher breast cancer incidence rates. All statistical tests were two-sided. Results: Urinary concentrations of parent estrogens were strongly associated with breast cancer risk (ORQ4vsQ1 = 1.94, 95% CI = 1.21 to 3.12, P-trend = .01). Of the pathway ratios, the 2-pathway: total estrogens/estrogen metabolites and 2-pathway: parent estrogens were inversely associated with risk (ORQ4vsQ1 = 0.57, 95% CI = 0.35 to 0.91, P-trend =.03, and ORQ4vsQ1 = 0.61, 95% CI = 0.37 to 0.99, P-trend = .04, respectively). After adjusting for parent estrogens, these associations remained clearly inverse but lost statistical significance (ORQ4vsQ1 = 0.65, 95% CI = 0.39 to 1.06, P-trend = .12 and ORQ4vsQ1 = 0.76, 95% CI = 0.44 to 1.32, P-trend = .28). The urinary concentration of all estrogens/estrogen metabolites combined in Asian American women was triple that in Shanghai women. Conclusions: Lower urinary parent estrogen concentrations and more extensive 2-hydroxylation were each associated with reduced postmenopausal breast cancer risk in a low-risk nation. Markedly higher total estrogen/estrogen metabolite concentrations in postmenopausal United States women (Asian Americans) than in Shanghai women may partly explain higher breast cancer rates in the United States. C1 [Moore, Steven C.; Matthews, Charles E.; Yu, Kai; Gail, Mitchell H.; Ji, Bu-Tian; Rothman, Nathaniel; Hoover, Robert N.; Ziegler, Regina G.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Shu, Xiao Ou; Cai, Qiuyin; Yang, Gong; Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med, Nashville, TN 37212 USA. [Xu, Xia] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Canc Res Technol Program, Frederick, MD USA. [Li, Honglan; Gao, Yu-Tang] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Chow, Wong-Ho] Univ Texas MD Anderson Canc Ctr, Div OVP Canc Prevent & Populat Sci, Dept Epidemiol, Houston, TX 77030 USA. [Ruggieri, David; Boyd-Morin, Jennifer] Informat Management Serv Inc, Rockville, MD USA. RP Moore, SC (reprint author), Div Canc Epidemiol & Genet, Metab Epidemiol Branch, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM moorest@mail.nih.gov RI Moore, Steven/D-8760-2016 OI Moore, Steven/0000-0002-8169-1661 FU Intramural Research Program of the National Cancer Institute, National Institutes of Health (NIH), Department of Health and Human Services; NIH [R37CA70867, UM1CA182910] FX This work was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health (NIH), Department of Health and Human Services. The Shanghai Women's Health Study was supported primarily by NIH grants R37CA70867 and UM1CA182910. NR 52 TC 3 Z9 3 U1 2 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD OCT PY 2016 VL 108 IS 10 AR djw103 DI 10.1093/jnci/djw103 PG 12 WC Oncology SC Oncology GA EA9FN UT WOS:000386947400002 ER PT J AU Polley, E Kunkel, M Evans, D Silvers, T Delosh, R Laudeman, J Ogle, C Reinhart, R Selby, M Connelly, J Harris, E Fer, N Sonkin, D Kaur, G Monks, A Malik, S Morris, J Teicher, BA AF Polley, Eric Kunkel, Mark Evans, David Silvers, Thomas Delosh, Rene Laudeman, Julie Ogle, Chad Reinhart, Russell Selby, Michael Connelly, John Harris, Erik Fer, Nicole Sonkin, Dmitriy Kaur, Gurmeet Monks, Anne Malik, Shakun Morris, Joel Teicher, Beverly A. TI Small Cell Lung Cancer Screen of Oncology Drugs, Investigational Agents, and Gene and microRNA Expression SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID PHASE-II; THERAPEUTIC TARGETS; PATHWAY ACTIVATION; INHIBITOR; BCL-2; GENOME; NEUROENDOCRINE; CARCINOMA; TRIAL; LINES AB Background: Small cell lung carcinoma (SCLC) is an aggressive, recalcitrant cancer, often metastatic at diagnosis and unresponsive to chemotherapy upon recurrence, thus it is challenging to treat. Methods: Sixty-three human SCLC lines and three NSCLC lines were screened for response to 103US Food and Drug Administration-approved oncology agents and 423 investigational agents. The investigational agents library was a diverse set of small molecules that included multiple compounds targeting the same molecular entity. The compounds were screened in triplicate at nine concentrations with a 96-hour exposure time using an ATP Lite endpoint. Gene expression was assessed by exon array, and microRNA expression was derived by direct digital detection. Activity across the SCLC lines was associated with molecular characteristics using pair-wise Pearson correlations. Results: Results are presented for inhibitors of targets: BCL2, PARP1, mTOR, IGF1R, KSP/Eg5, PLK-1, AURK, and FGFR1. A relational map identified compounds with similar patterns of response. Unsupervised microRNA clustering resulted in three distinct SCLC subgroups. Associating drug responsewithmicro-RNA expression indicated that lines most sensitive to etoposide and topotecan expressed highmiR-200c-3p and lowmiR-140-5p andmiR-9-5p. The BCL-2/BCL-XL inhibitors produced similar response patterns. Sensitivity to ABT-737 correlated with higher ASCL1 and BCL2. Several classes of compounds targeting nuclear proteins regulatingmitosis produced a response pattern distinct from the etoposide response pattern. Conclusions: Agents targeting nuclear kinases appear to be effective in SCLC lines. Confirmation of SCLC line findings in xenografts is needed. The drug and compound response, gene expression, and microRNA expression data are publicly available at http://sclccelllines.cancer.gov. C1 [Evans, David; Silvers, Thomas; Delosh, Rene; Laudeman, Julie; Ogle, Chad; Reinhart, Russell; Selby, Michael; Connelly, John; Harris, Erik; Fer, Nicole; Monks, Anne] Leidos Biomed Res Inc, Mol Pharmacol Grp, Frederick Natl Lab Canc Res, Frederick, MD USA. [Kunkel, Mark; Kaur, Gurmeet; Morris, Joel; Teicher, Beverly A.] NCI, Dev Therapeut Program, Div Canc Treatment & Diag, Rockville, MD USA. [Polley, Eric; Sonkin, Dmitriy] NCI, Biometr Res Program, Div Canc Treatment & Diag, Rockville, MD USA. [Malik, Shakun] NCI, Canc Therapy Evaluat Program, Rockville, MD USA. RP Teicher, BA (reprint author), NCI, Mol Pharmacol Branch, RM 4-W602,MSC 9735,9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM beverly.teicher@nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute FX This work was supported in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. This research was supported ( in part) by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute. NR 63 TC 2 Z9 2 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD OCT PY 2016 VL 108 IS 10 AR djw122 DI 10.1093/jnci/djw122 PG 11 WC Oncology SC Oncology GA EA9FN UT WOS:000386947400009 ER PT J AU Sonderman, JS Bethea, TN Kitahara, CM Patel, AV Harvey, C Knutsen, SF Park, Y Park, SY Fraser, GE Teras, LR Purdue, MP Stolzenberg-Solomon, RZ Gillanders, EM Palmer, JR Kolonel, LN Blot, WJ AF Sonderman, Jennifer S. Bethea, Traci N. Kitahara, Cari M. Patel, Alpa V. Harvey, Chinonye Knutsen, Synnove F. Park, Yikyung Park, Song-Yi Fraser, Gary E. Teras, Lauren R. Purdue, Mark P. Stolzenberg-Solomon, Rachael Z. Gillanders, Elizabeth M. Palmer, Julie R. Kolonel, Laurence N. Blot, William J. TI Multiple Myeloma Mortality in Relation to Obesity Among African Americans SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID BODY-MASS INDEX; POOLED ANALYSIS; METAANALYSIS; CANCER; SIZE AB Multiple myeloma (MM) incidence and mortality are higher among African Americans (AAs) than among other population groups. The prevalence of obesity is also elevated among AAs, but few studies have examined risk of this cancer in relation to body size among AAs. We combined data from seven prospective cohorts tracking mortality among 239 597 AA adults and used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for death because of MM according to body mass index (BMI) at cohort entry, adjusted for age (as time-scale) and sex. Relative to those with normal BMIs (18.5-25 kg/m(2)), mortality increased monotonically as BMI increased, with hazard ratios reaching 1.43 (95% CI = 1.03 to 1.97) for BMIs of 35 kg/m(2) or greater. The findings suggest that obesity is a risk factor for MM and a contributor to the elevated rates and rising incidence trends of MM among AAs in the United States. C1 [Sonderman, Jennifer S.; Blot, William J.] Int Epidemiol Inst, Rockville, MD USA. [Bethea, Traci N.; Palmer, Julie R.] Boston Univ, Slone Epidemiol Ctr, Boston, MA 02215 USA. [Kitahara, Cari M.; Park, Yikyung; Purdue, Mark P.; Stolzenberg-Solomon, Rachael Z.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Patel, Alpa V.; Teras, Lauren R.] Amer Canc Soc, Atlanta, GA 30329 USA. [Harvey, Chinonye; Gillanders, Elizabeth M.] NCI, Epidemiol & Genom Res Program, Rockville, MD USA. [Knutsen, Synnove F.; Fraser, Gary E.] Loma Linda Univ, Loma Linda, CA 92350 USA. [Park, Yikyung] Washington Univ, Sch Med, St Louis, MO USA. [Park, Song-Yi] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. [Kolonel, Laurence N.] Univ Hawaii, Off Publ Hlth Studies, Honolulu, HI 96822 USA. [Blot, William J.] Vanderbilt Univ, Med Ctr, 1455 Res Blvd,Suite 550, Nashville, TN 20850 USA. RP Blot, WJ (reprint author), Vanderbilt Univ, Med Ctr, 1455 Res Blvd,Suite 550, Nashville, TN 20850 USA. EM william.j.blot@vanderbilt.edu RI Kitahara, Cari/R-8267-2016 FU National Cancer Institute's Intramural Research Program in the Division of Cancer Epidemiology and Genetics; Epidemiology and Genomics Research Program in the Division of Cancer Control and Populations Sciences; Intramural Research Program of the National Cancer Institute, National Institutes of Health; National Cancer Institute [R01 CA94594, R01 CA058420, UM1 CA164974, R37 CA54281, R01 CA092447]; American Cancer Society; American Recovery and Reinvestment Act [3R01 CA092447-08S1] FX This work was supported by the National Cancer Institute's Intramural Research Program in the Division of Cancer Epidemiology and Genetics and the Epidemiology and Genomics Research Program in the Division of Cancer Control and Populations Sciences. The NIH-AARP study is supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. The Adventist Health Study 2 is funded by grant R01 CA94594 from the National Cancer Institute. The Black Women's Health Study is funded by grants R01 CA058420 and UM1 CA164974 from the National Cancer Institute. The Cancer Prevention Study II Nutrition Cohort is supported by the American Cancer Society. The Multiethnic Cohort Study (MEC) is funded by grant R37 CA54281 from the National Cancer Institute. The PLCO is supported by contracts from the Division of Cancer Prevention, National Cancer Institute, National Institutes of Health. The Southern Community Cohort Study (SCCS) is funded by grant R01 CA092447 from the National Cancer Institute including special allocations from the American Recovery and Reinvestment Act (3R01 CA092447-08S1). NR 19 TC 0 Z9 0 U1 2 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD OCT PY 2016 VL 108 IS 10 AR djw120 DI 10.1093/jnci/djw120 PG 4 WC Oncology SC Oncology GA EA9FN UT WOS:000386947400007 ER PT J AU Cai, ML Huang, Y Yang, RB Craigie, R Clore, GM AF Cai, Mengli Huang, Ying Yang, Renbin Craigie, Robert Clore, G. M. TI A simple and robust protocol for high-yield expression of perdeuterated proteins in Escherichia coli grown in shaker flasks SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE Protein expression; Perdeuterated proteins; NMR; Shaker flask; Modified M9 medium; Cell adaptation ID H-2; NMR AB We present a simple, convenient and robust protocol for expressing perdeuterated proteins in E. coli BL21(DE3) cells in shaker flasks that reduces D2O usage tenfold and d(7)-glucose usage by 30 %. Using a modified M9 medium and optimized growth conditions, we were able to grow cells in linear log phase to an OD600 of up to 10. Inducing the cells with isopropyl beta-d-1-thiogalactopyranoside at an OD600 of 10, instead of less than 1, enabled us to increase the cell mass tenfold per unit volume of cell culture. We show that protein expression levels per cell are the same when induced at an OD600 between 1 and 10 under these growth conditions. Thus, our new protocol can increase protein yield per unit volume of cell culture tenfold. Adaptation of E. coli from H2O-based to D2O-based medium is also key for ensuring high levels of protein expression in D2O. We find that a simple three-step adaptation approach-Luria-Bertani (LB) medium in H2O to LB in D2O to modified-M9 medium in D2O is both simple and reliable. The method increases the yield of perdeuterated proteins by up to tenfold using commonly available air shakers without any requirement for specialized fermentation equipment. C1 [Cai, Mengli; Clore, G. M.] NIDDK, Labs Chem Phys, NIH, Bethesda, MD 20892 USA. [Huang, Ying; Yang, Renbin; Craigie, Robert] NIDDK, Labs Mol Biol, NIH, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDK, Labs Chem Phys, NIH, Bethesda, MD 20892 USA.; Craigie, R (reprint author), NIDDK, Labs Mol Biol, NIH, Bethesda, MD 20892 USA. EM robertc@niddk.nih.gov; mariusc@mail.nih.gov OI Clore, G. Marius/0000-0003-3809-1027 FU Intramural Program of the National Institute of Diabetes and Digestive Diseases of the National Institutes of Health; Intramural AIDS Targeted Antiviral program of the Office of the Director of the NIH FX This work was supported by the Intramural Program of the National Institute of Diabetes and Digestive Diseases of the National Institutes of Health and by the Intramural AIDS Targeted Antiviral program of the Office of the Director of the NIH (to G.M.C. and R.C.). NR 7 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0925-2738 EI 1573-5001 J9 J BIOMOL NMR JI J. Biomol. NMR PD OCT PY 2016 VL 66 IS 2 BP 85 EP 91 DI 10.1007/s10858-016-0052-y PG 7 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA EB6IJ UT WOS:000387485100001 PM 27709314 ER PT J AU Strickland, M Schwieters, CD Gobl, C Opina, ACL Strub, MP Swenson, RE Vasalatiy, O Tjandra, N AF Strickland, Madeleine Schwieters, Charles D. Goebl, Christoph Opina, Ana C. L. Strub, Marie-Paule Swenson, Rolf E. Vasalatiy, Olga Tjandra, Nico TI Characterizing the magnetic susceptibility tensor of lanthanide-containing polymethylated-DOTA complexes SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE Lanthanide; DOTA; Pseudocontact shift; PCS; Magnetic susceptibility tensor ID MRI CONTRAST AGENTS; MOLECULAR-STRUCTURE DETERMINATION; SATURATION-TRANSFER CEST; NMR-SPECTROSCOPY; PARAMAGNETIC NMR; WATER EXCHANGE; XPLOR-NIH; GADOLINIUM COMPLEXES; PSEUDOCONTACT SHIFTS; TETRAAMIDE COMPLEXES AB Lanthanide complexes based on the DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) cage are commonly used as phase contrast agents in magnetic resonance imaging, but can also be utilized in structural NMR applications due to their ability to induce either paramagnetic relaxation enhancement or a pseudocontact shift (PCS) depending on the choice of the lanthanide. The size and sign of the PCS for any given atom is determined by its coordinates relative to the metal center, and the characteristics of the lanthanide's magnetic susceptibility tensor. Using a polymethylated DOTA tag (Ln-M8-SPy) conjugated to ubiquitin, we calculated the position of the metal center and characterized the susceptibility tensor for a number of lanthanides (dysprosium, thulium, and ytterbium) under a range of pH and temperature conditions. We found that there was a difference in temperature sensitivity for each of the complexes studied, which depended on the size of the lanthanide ion as well as the isomeric state of the cage. Using O-17-NMR, we confirmed that the temperature sensitivity of the compounds was enhanced by the presence of an apically bound water molecule. Since amide-containing lanthanide complexes are known to be pH sensitive and can be used as probes of physiological pH, we also investigated the effect of pH on the Ln-M8-SPy susceptibility tensor, but we found that the changes in this pH range (5.0-7.4) were not significant. C1 [Strickland, Madeleine; Strub, Marie-Paule; Tjandra, Nico] NHLBI, Lab Mol Biophys, Biochem & Biophys Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. [Schwieters, Charles D.] NIH, Off Intramural Res, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. [Goebl, Christoph] Tech Univ Munich, Dept Chem, Lichtenbergstr 4, D-85748 Garching, Germany. [Opina, Ana C. L.; Swenson, Rolf E.; Vasalatiy, Olga] NHLBI, Imaging Probe Dev Ctr, NIH, Rockville, MD 20850 USA. RP Tjandra, N (reprint author), NHLBI, Lab Mol Biophys, Biochem & Biophys Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM tjandran@nhlbi.nih.gov RI Goebl, Christoph/G-7578-2016; OI Gobl, Christoph/0000-0001-8614-1434 FU Intramural Research Programs of the National Heart, Lung, and Blood Institute; Center for Information Technology of the NIH FX The project was funded by the Intramural Research Programs of the National Heart, Lung, and Blood Institute and the Center for Information Technology of the NIH. We also thank Dr. Duck-Yeon Lee of the Biochemical Core Facility, National Heart, Lung, and Blood Institute for expertise and advice regarding mass spectrometry-related experiments. We appreciate the assistance of Dr. James Ferretti in acquiring the 17O NMR spectra. NR 61 TC 1 Z9 1 U1 7 U2 7 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0925-2738 EI 1573-5001 J9 J BIOMOL NMR JI J. Biomol. NMR PD OCT PY 2016 VL 66 IS 2 BP 125 EP 139 DI 10.1007/s10858-016-0061-x PG 15 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA EB6IJ UT WOS:000387485100005 PM 27659040 ER PT J AU Gold, AL Sheridan, MA Peverill, M Busso, DS Lambert, HK Alves, S Pine, DS McLaughlin, KA AF Gold, Andrea L. Sheridan, Margaret A. Peverill, Matthew Busso, Daniel S. Lambert, Hilary K. Alves, Sonia Pine, Daniel S. McLaughlin, Katie A. TI Childhood abuse and reduced cortical thickness in brain regions involved in emotional processing SO JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY LA English DT Article DE Abuse; childhood adversity; ventromedial prefrontal cortex; temporal cortex; cortical thickness ID LIMBIC GRAY-MATTER; VENTROMEDIAL PREFRONTAL CORTEX; POSTTRAUMATIC-STRESS-DISORDER; SURFACE-AREA; CONDUCT DISORDER; MALTREATED CHILDREN; FEAR EXTINCTION; 1ST ONSET; ADOLESCENTS; METAANALYSIS AB Background: Alterations in gray matter development represent a potential pathway through which childhood abuse is associated with psychopathology. Several prior studies find reduced volume and thickness of prefrontal (PFC) and temporal cortex regions in abused compared with nonabused adolescents, although most prior research is based on adults and volume-based measures. This study tests the hypothesis that child abuse, independent of parental education, predicts reduced cortical thickness in prefrontal and temporal cortices as well as reduced gray mater volume (GMV) in subcortical regions during adolescence. Methods: Structural MRI scans were obtained from 21 adolescents exposed to physical and/or sexual abuse and 37 nonabused adolescents (ages 13-20). Abuse was operationalized using dichotomous and continuous measures. We examined associations between abuse and brain structure in several a priori-defined regions, controlling for parental education, age, sex, race, and total brain volume for subcortical GMV. Significance was evaluated at p < .05 with a false discovery rate correction. Results: Child abuse exposure and severity were associated with reduced thickness in ventromedial prefrontal cortex (PFC), right lateral orbitofrontal cortex, right inferior frontal gyrus, bilateral parahippocampal gyrus (PHG), left temporal pole, and bilateral inferior, right middle, and right superior temporal gyri. Neither abuse measure predicted cortical surface area or subcortical GMV. Bilateral PHG thickness was inversely related to externalizing symptoms. Conclusions: Child abuse, an experience characterized by a high degree of threat, is associated with reduced cortical thickness in ventromedial and ventrolateral PFC and medial and lateral temporal cortex in adolescence. Reduced PHG thickness may be a mediator linking abuse with externalizing psychopathology, although prospective research is needed to evaluate this possibility. C1 [Gold, Andrea L.; Pine, Daniel S.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Sheridan, Margaret A.] Univ North Carolina Chapel Hill, Chapel Hill, NC USA. [Peverill, Matthew; Lambert, Hilary K.; McLaughlin, Katie A.] Univ Washington, 3939 Univ Way NE, Seattle, WA 98105 USA. [Busso, Daniel S.; Alves, Sonia] Harvard Grad Sch Educ, Cambridge, MA USA. RP McLaughlin, KA (reprint author), Univ Washington, 3939 Univ Way NE, Seattle, WA 98105 USA. EM mclaughk@uw.edu OI Gold, Andrea/0000-0003-4447-776X FU National Institutes of Health [K01-MH092526, K01-MH092555]; Child Health Young Investigator Award from Charles H. Hood Foundation FX This research was supported by grants from the National Institutes of Health (K01-MH092526 and K01-MH092555) and a Child Health Young Investigator Award from the Charles H. Hood Foundation. These funders provided support for all data collection and analysis. In addition, this research was supported, in part, by the Intramural Research Program of the National Institutes of Health. The authors declare that, except for income received from their primary employers, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest. NR 59 TC 0 Z9 0 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9630 EI 1469-7610 J9 J CHILD PSYCHOL PSYC JI J. Child Psychol. Psychiatry PD OCT PY 2016 VL 57 IS 10 BP 1154 EP 1164 DI 10.1111/jcpp.12630 PG 11 WC Psychology, Developmental; Psychiatry; Psychology SC Psychology; Psychiatry GA EB1PE UT WOS:000387125000007 PM 27647051 ER PT J AU Spiegel, S Proia, RL AF Spiegel, Sarah Proia, Richard L. TI In Memoriam: Roscoe Owen Brady (1923-2016) SO JOURNAL OF LIPID RESEARCH LA English DT Biographical-Item C1 [Spiegel, Sarah] Virginia Commonwealth Univ, Sch Med, Dept Biochem & Mol Biol, Richmond, VA 23284 USA. [Spiegel, Sarah] Virginia Commonwealth Univ, Sch Med, Massey Canc Ctr, Richmond, VA 23284 USA. [Proia, Richard L.] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD USA. RP Spiegel, S (reprint author), Virginia Commonwealth Univ, Sch Med, Dept Biochem & Mol Biol, Richmond, VA 23284 USA.; Spiegel, S (reprint author), Virginia Commonwealth Univ, Sch Med, Massey Canc Ctr, Richmond, VA 23284 USA.; Proia, RL (reprint author), NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD USA. EM sarah.spiegel@vcuhealth.org; proia@nih.gov NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 EI 1539-7262 J9 J LIPID RES JI J. Lipid Res. PD OCT PY 2016 VL 57 IS 10 BP 1749 EP 1750 DI 10.1194/jlr.E071548 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EB2ZR UT WOS:000387231600001 ER PT J AU Maddipati, KR Romero, R Chaiworapongsa, T Chaemsaithong, P Zhou, SL Xu, ZH Tarca, AL Kusanovic, JP Gomez, R Docheva, N Honn, KV AF Maddipati, Krishna Rao Romero, Roberto Chaiworapongsa, Tinnakorn Chaemsaithong, Piya Zhou, Sen-Lin Xu, Zhonghui Tarca, Adi L. Kusanovic, Juan Pedro Gomez, Ricardo Docheva, Nikolina Honn, Kenneth V. TI Clinical chorioamnionitis at term: the amniotic fluid fatty acyl lipidome SO JOURNAL OF LIPID RESEARCH LA English DT Article DE lipoxygenase; eicosanoids; inflammation; omega-3 fatty acids; lipidomics; intra-amniotic inflammation; infection; parturition; epoxy fatty acids; epoxygenase ID PLASMA CYTOKINE PROFILE; PRETERM LABOR; INTRAAMNIOTIC INFECTION; MICROBIAL INVASION; CYCLOOXYGENASE-2 COX-2; EICOSAPENTAENOIC ACID; INFLAMMATORY RESPONSE; HUMAN PARTURITION; RESOLUTION; PROSTAGLANDINS AB Clinical chorioamnionitis at term (TCC) is the most common obstetrical infliction diagnosed in labor and delivery units worldwide and is associated with a substantial increase in maternal and neonatal morbidity and mortality. This obstetrical complication is a heterogeneous condition, as only half of patients have detectable microorganisms in the amniotic cavity. Because bioactive lipids play a key role in the initiation and resolution of an inflammatory response, we aimed to characterize the amniotic fluid lipidome in patients with TCC. We studied the amniotic fluid of patients in the following groups: 1) spontaneous labor at term without clinical chorioamnionitis (TLB) and 2) spontaneous labor at term with clinical chorioamnionitis (TCC). The TCC group was subdivided into a) those with microbial invasion of the amniotic cavity (TCC-MIAC) and b) those without microbial invasion of the amniotic cavity (TCC-noMIAC). The amniotic fluid concentration of proinflammatory lipid mediators did not differ between patients in TLB with TCC. In contrast, concentration of lipids with anti-inflammatory/proresolution properties was significantly lower in all patients with TCC than in those with TLB. These results suggest that while proinflammatory lipid mediators are involved in infection-driven intra-amniotic inflammation, a relative deficiency of anti-inflammatory/proresolution lipid mediator biosynthesis is a characteristic of TCC. C1 [Maddipati, Krishna Rao; Zhou, Sen-Lin; Honn, Kenneth V.] Wayne State Univ, Sch Med, Dept Pathol, Bioact Lipids Res Program, Detroit, MI 48201 USA. [Maddipati, Krishna Rao; Zhou, Sen-Lin] Wayne State Univ, Sch Med, Lipid Core Facil, Detroit, MI 48202 USA. [Romero, Roberto; Chaiworapongsa, Tinnakorn; Chaemsaithong, Piya; Xu, Zhonghui; Tarca, Adi L.; Kusanovic, Juan Pedro; Docheva, Nikolina] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH,Dept Hlth & Human Serv, Bethesda, MD USA. [Romero, Roberto; Chaiworapongsa, Tinnakorn; Chaemsaithong, Piya; Xu, Zhonghui; Tarca, Adi L.; Kusanovic, Juan Pedro; Docheva, Nikolina] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH,Dept Hlth & Human Serv, Detroit, MI USA. [Romero, Roberto] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Romero, Roberto] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. [Tarca, Adi L.] Wayne State Univ, Dept Comp Sci, Detroit, MI 48202 USA. [Chaiworapongsa, Tinnakorn; Chaemsaithong, Piya; Tarca, Adi L.; Docheva, Nikolina] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Kusanovic, Juan Pedro] Hosp Dr Sotero del Rio, Ctr Res & Innovat Maternal Fetal Med CIMAF, Dept Obstet & Gynecol, Santiago, Chile. [Kusanovic, Juan Pedro; Gomez, Ricardo] Pontificia Univ Catolica Chile, Div Obstet & Gynecol, Santiago, Chile. [Gomez, Ricardo] Hosp Clin La Florida, Ctr Perinatal Diag CEDIP, Res & Acad Innovat, Santiago, Chile. RP Maddipati, KR (reprint author), Wayne State Univ, Sch Med, Dept Pathol, Bioact Lipids Res Program, Detroit, MI 48201 USA.; Maddipati, KR (reprint author), Wayne State Univ, Sch Med, Lipid Core Facil, Detroit, MI 48202 USA. EM maddipati@wayne.edu OI Maddipati, Krishna Rao/0000-0003-1445-791X FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Department of Health and Human Services; NICHD (Foundation for the National Institutes of Health) [HHSN275201300006C]; National Center for Research Resources (Foundation for the National Institutes of Health) [S10RR027926]; Perinatal Virtual Discovery Grant from Wayne State University FX This work was supported in part by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Department of Health and Human Services; in part with federal funds from NICHD (Foundation for the National Institutes of Health, contract no. HHSN275201300006C); and in part by the National Center for Research Resources (Foundation for the National Institutes of Health, grant S10RR027926) and a Perinatal Virtual Discovery Grant from Wayne State University (K.R.M.). This article is a continuation of our biochemical characterization of clinical chorioamnionitis at term and represents the eighth in the series. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 69 TC 0 Z9 0 U1 3 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 EI 1539-7262 J9 J LIPID RES JI J. Lipid Res. PD OCT PY 2016 VL 57 IS 10 BP 1906 EP 1916 DI 10.1194/jlr.P069096 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EB2ZR UT WOS:000387231600016 PM 27538821 ER PT J AU Schulz, JB Cookson, MR Hausmann, L AF Schulz, Joerg B. Cookson, Mark R. Hausmann, Laura TI The impact of fraudulent and irreproducible data to the translational research crisis - solutions and implementation SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE 60th Anniversary Journal of Neurochemistry; clinical trials; data reproducibility; scholarly publishing; statistics ID AMYOTROPHIC-LATERAL-SCLEROSIS; ISCHEMIC-STROKE; REDUCING WASTE; MMR SCARE; INCREASING VALUE; BIOMEDICAL-RESEARCH; METAANALYSIS; SECRETS; VACCINE; THROMBECTOMY AB One of the aims of basic neuroscience research is ultimately the development of therapeutics to cure diseases. Funders granting money to research institutions increasingly express interest into how their financial resources are used and look for successful translation in clinical practice. Disappointingly, many findings that started out promising in basic research projects and phase I trials did not live up to the promise of therapeutic efficacy in later phase II or III trials. An inordinately high amount of time and money is thus spent on research that does not always have the required human impact. Potential reasons for these problems are numerous. Although research misconduct occurs and contributes to this shortcoming, it is not the only important factor. Frequently, basic science results turn out to be irreproducible. Irreproducibility, outside of malfeasance, is multifactorial and can include poor experimental design, conduct, statistical analysis, reporting standards, and conceptual flaws. Further confounding problems include an insufficient transferability of animal to human physiology, as well as intersubject group variability, for example, sexual dimorphisms. While the causes of poor data reproducibility are therefore numerous, equally there are many groups that can contribute to improvements in how basic science is reported. Here, we will review how the Journal of Neurochemistry can contribute to increasing the value of preclinical and translational research. C1 [Schulz, Joerg B.; Hausmann, Laura] Rhein Westfal TH Aachen, Univ Hosp, Dept Neurol, Pauwelsstr 30, D-52074 Aachen, Germany. [Schulz, Joerg B.] Forschungszentrum Julich, JARA BRAIN Inst Mol Neurosci & Neuroimaging, Aachen, Germany. [Schulz, Joerg B.] Rhein Westfal TH Aachen, Aachen, Germany. [Cookson, Mark R.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Schulz, JB (reprint author), Rhein Westfal TH Aachen, Univ Hosp, Dept Neurol, Pauwelsstr 30, D-52074 Aachen, Germany. EM jschulz@ukaachen.de NR 64 TC 0 Z9 0 U1 8 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD OCT PY 2016 VL 139 SU 2 BP 253 EP 270 DI 10.1111/jnc.13844 PG 18 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA EB0ZD UT WOS:000387074600017 PM 27797406 ER PT J AU Kaufman, HL Russell, J Hamid, O Bhatia, S Terheyden, P D'Angelo, SP Shih, KC Lebbe, C Linette, GP Milella, M Brownell, I Lewis, KD Lorch, JH Chin, K Mahnke, L von Heydebreck, A Cuillerot, JM Nghiem, P AF Kaufman, Howard L. Russell, Jeffery Hamid, Omid Bhatia, Shailender Terheyden, Patrick D'Angelo, Sandra P. Shih, Kent C. Lebbe, Celeste Linette, Gerald P. Milella, Michele Brownell, Isaac Lewis, Karl D. Lorch, Jochen H. Chin, Kevin Mahnke, Lisa von Heydebreck, Anja Cuillerot, Jean-Marie Nghiem, Paul TI Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial SO LANCET ONCOLOGY LA English DT Article ID PD-L1 EXPRESSION; PREDICTIVE BIOMARKER; UNITED-STATES; TUMOR-CELLS; POLYOMAVIRUS; IMMUNOTHERAPY; BLOCKADE; SURVIVAL; CANCER; METAANALYSIS AB Background Merkel cell carcinoma is a rare, aggressive skin cancer with poor prognosis in patients with advanced disease. Current standard care uses various cytotoxic chemotherapy regimens, but responses are seldom durable. Tumour oncogenesis is linked to Merkel cell polyomavirus integration and ultraviolet-radiation-induced mutations, providing rationale for treatment with immunotherapy antibodies that target the PD-L1/PD-1 pathway. We assessed treatment with avelumab, an anti-PD-L1 monoclonal antibody, in patients with stage IV Merkel cell carcinoma that had progressed after cytotoxic chemotherapy. Methods In this multicentre, international, prospective, single-group, open-label, phase 2 trial, patients with stage IV chemotherapy-refractory, histologically confirmed Merkel cell carcinoma (aged >= 18 years) were enrolled from 35 cancer treatment centres and academic hospitals in North America, Europe, Australia, and Asia. Key eligibility criteria were an ECOG performance status of 0 or 1, measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, adequate haematological, hepatic, and renal function, and immune-competent status (patients with HIV, immunosuppression, haematological malignancies, and previous organ transplantation were excluded). Patient selection was not based on PD-L1 expression or Merkel cell polyomavirus status. Collection of biopsy material or use of archival tissue for these assessments was mandatory. Avelumab was given intravenously at a dose of 10 mg/kg every 2 weeks. The primary endpoint was confi rmed objective response (complete response or partial response) assessed according to RECIST version 1.1 by an independent review committee. Safety and clinical activity were assessed in all patients who received at least one dose of study drug (the modified intention-to-treat population). This trial is registered with ClinicalTrials.gov as NCT02155647. Findings Between July 25, 2014, and Sept 3, 2015, 88 patients were enrolled and received at least one dose of avelumab. Patients were followed up for a median of 10.4 months (IQR 8.6-13.1). The proportion of patients who achieved an objective response was 28 (31.8% [95.9% CI 21.9-43.1]) of 88 patients, including eight complete responses and 20 partial responses. Responses were ongoing in 23 (82%) of 28 patients at the time of analysis. Five grade 3 treatment-related adverse events occurred in four (5%) patients: lymphopenia in two patients, blood creatine phosphokinase increase in one patient, aminotransferase increase in one patient, and blood cholesterol increase in one patient; there were no treatment-related grade 4 adverse events or treatment-related deaths. Serious treatment-related adverse events were reported in five patients (6%): enterocolitis, infusion-related reaction, aminotransferases increased, chondrocalcinosis, synovitis, and interstitial nephritis (n=1 each). Interpretation Avelumab was associated with durable responses, most of which are still ongoing, and was well tolerated; hence, avelumab represents a new therapeutic option for advanced Merkel cell carcinoma. C1 [Kaufman, Howard L.] Rutgers State Univ, Rutgers Canc Inst New Jersey, New Brunswick, NJ 08901 USA. [Russell, Jeffery] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Hamid, Omid] Angeles Clin & Res Inst, Los Angeles, CA USA. [Bhatia, Shailender] Univ Washington, Med Ctr South Lake Union, Div Oncol, Seattle, WA 98195 USA. [Nghiem, Paul] Univ Washington, Med Ctr South Lake Union, Div Dermatol, Seattle, WA 98195 USA. [Terheyden, Patrick] Univ Lubeck, Dept Dermatol, Lubeck, Germany. [D'Angelo, Sandra P.] Weill Cornell Med Coll, Mem Sloan Kettering Canc Ctr, New York, NY USA. [Shih, Kent C.] Sarah Cannon Res Inst Tennessee Oncol, Nashville, TN USA. [Lebbe, Celeste] Hop St Louis, AP HP, Fac Paris Diderot, Serv Dermatol,INSERM,U976, Paris, France. [Lebbe, Celeste] Hop St Louis, AP HP, Fac Paris Diderot, CIC,INSERM,U976, Paris, France. [Linette, Gerald P.] Washington Univ, Sch Med, Div Oncol, St Louis, MO USA. [Milella, Michele] Regina Elena Inst Canc Res, Rome, Italy. [Brownell, Isaac] NCI, Bethesda, MD 20892 USA. [Lewis, Karl D.] Univ Colorado Denver, Sch Med, Div Med Oncol, Aurora, CO USA. [Lorch, Jochen H.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Chin, Kevin; Mahnke, Lisa; Cuillerot, Jean-Marie] EMD Serono, Billerica, MA USA. [von Heydebreck, Anja] Merck KGaA, Darmstadt, Germany. RP Kaufman, HL (reprint author), Rutgers State Univ, Rutgers Canc Inst New Jersey, New Brunswick, NJ 08901 USA. EM hk553@cinj.rutgers.edu FU Merck KGaA, Darmstadt, Germany FX Merck KGaA, Darmstadt, Germany NR 42 TC 9 Z9 9 U1 7 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD OCT PY 2016 VL 17 IS 10 BP 1374 EP 1385 DI 10.1016/S1470-2045(16)30364-3 PG 12 WC Oncology SC Oncology GA EB0SM UT WOS:000387055800039 PM 27592805 ER PT J AU Fei, DL Motowski, H Chatrikhi, R Prasad, S Yu, J Gao, SJ Kielkopf, CL Bradley, RK Varmus, H AF Fei, Dennis Liang Motowski, Hayley Chatrikhi, Rakesh Prasad, Sameer Yu, Jovian Gao, Shaojian Kielkopf, Clara L. Bradley, Robert K. Varmus, Harold TI Wild-Type U2AF1 Antagonizes the Splicing Program Characteristic of U2AF1-Mutant Tumors and Is Required for Cell Survival SO PLOS GENETICS LA English DT Article ID SITE RECOGNITION; CANCER GENES; RNA-BINDING; MUTATIONS; SPECIFICITY; PROTEINS; U2AF(35); GENOME; SF3B1; AG AB We have asked how the common S34F mutation in the splicing factor U2AF1 regulates alternative splicing in lung cancer, and why wild-type U2AF1 is retained in cancers with this mutation. A human lung epithelial cell line was genetically modified so that U2AF1S34F is expressed from one of the two endogenous U2AF1 loci. By altering levels of mutant or wildtype U2AF1 in this cell line and by analyzing published data on human lung adenocarcinomas, we show that S34F-associated changes in alternative splicing are proportional to the ratio of S34F: wild-type gene products and not to absolute levels of either the mutant or wild-type factor. Preferential recognition of specific 3' splice sites in S34F-expressing cells is largely explained by differential in vitro RNA-binding affinities of mutant versus wild-type U2AF1 for those same 3' splice sites. Finally, we show that lung adenocarcinoma cell lines bearing U2AF1 mutations do not require the mutant protein for growth in vitro or in vivo. In contrast, wild-type U2AF1 is required for survival, regardless of whether cells carry the U2AF1S34F allele. Our results provide mechanistic explanations of the magnitude of splicing changes observed in U2AF1-mutant cells and why tumors harboring U2AF1 mutations always retain an expressed copy of the wild-type allele. C1 [Fei, Dennis Liang; Motowski, Hayley; Prasad, Sameer; Yu, Jovian; Varmus, Harold] NHGRI, Canc Biol Sect, Canc Genet Branch, Bethesda, MD 20892 USA. [Fei, Dennis Liang; Varmus, Harold] Weill Cornell Med, Meyer Canc Ctr, Dept Med, New York, NY 10065 USA. [Chatrikhi, Rakesh; Kielkopf, Clara L.] Univ Rochester, Med Ctr, Ctr RNA Biol, Dept Biochem & Biophys, Rochester, NY 14627 USA. [Gao, Shaojian] NCI, Genet Branch, Bethesda, MD 20892 USA. [Bradley, Robert K.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Computat Biol Program, 1124 Columbia St, Seattle, WA 98104 USA. [Bradley, Robert K.] Fred Hutchinson Canc Res Ctr, Div Basic Sci, 1124 Columbia St, Seattle, WA 98104 USA. RP Fei, DL; Varmus, H (reprint author), NHGRI, Canc Biol Sect, Canc Genet Branch, Bethesda, MD 20892 USA.; Fei, DL; Varmus, H (reprint author), Weill Cornell Med, Meyer Canc Ctr, Dept Med, New York, NY 10065 USA.; Kielkopf, CL (reprint author), Univ Rochester, Med Ctr, Ctr RNA Biol, Dept Biochem & Biophys, Rochester, NY 14627 USA.; Bradley, RK (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Computat Biol Program, 1124 Columbia St, Seattle, WA 98104 USA.; Bradley, RK (reprint author), Fred Hutchinson Canc Res Ctr, Div Basic Sci, 1124 Columbia St, Seattle, WA 98104 USA. EM dlf2002@med.cornell.edu; clara_kielkopf@urmc.rochester.edu; rbradley@fredhutch.org; varmus@med.cornell.edu OI Yu, Jovian/0000-0001-9214-7576; Bradley, Robert/0000-0002-8046-1063 FU Intramural Program at the National Institutes of Health; Meyer Cancer Center at Weill Cornell Medicine; Edward P. Evans Foundation; Ellison Medical Foundation [AG-NS-1030-13]; National Heart, Lung, and Blood Institute [R01 HL128239]; National Institute of Diabetes and Digestive and Kidney Diseases [R01 DK103854]; National Institute of General Medical Sciences [R01 GM070503] FX HV was supported by the Intramural Program at the National Institutes of Health and is now supported by the Meyer Cancer Center at Weill Cornell Medicine (meyercancer.weill.cornell.edu/). RKB is supported by the Edward P. Evans Foundation (epefoundation.org/), Ellison Medical Foundation (www.ellisonfoundation.org/)(AG-NS-1030-13), National Heart, Lung, and Blood Institute (www.nhlbi.nih.gov/) (R01 HL128239), and National Institute of Diabetes and Digestive and Kidney Diseases (www.niddk.nih.gov/) (R01 DK103854). CLK is supported by the Edward P. Evans Foundation and National Institute of General Medical Sciences (www.nigms.nih.gov) (R01 GM070503). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 2 Z9 2 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD OCT PY 2016 VL 12 IS 10 AR e1006384 DI 10.1371/journal.pgen.1006384 PG 26 WC Genetics & Heredity SC Genetics & Heredity GA EA5SM UT WOS:000386683300045 PM 27776121 ER PT J AU Gong, J Hutter, CM Newcomb, PA Ulrich, CM Bien, SA Campbell, PT Baron, JA Berndt, SI Bezieau, S Brenner, H Casey, G Chan, AT Chang-Claude, J Du, MM Duggan, D Figueiredo, JC Gallinger, S Giovannucci, EL Haile, RW Harrison, TA Hayes, RB Hoffmeister, M Hopper, JL Hudson, TJ Jeon, J Jenkins, MA Kocarnik, J Kury, S Le Marchand, L Lin, Y Lindor, NM Nishihara, R Ogino, S Potter, JD Rudolph, A Schoen, RE Schrotz-King, P Seminara, D Slattery, ML Thibodeau, SN Thornquist, M Toth, R Wallace, R White, E Jiao, S Lemire, M Hsu, L Peters, U AF Gong, Jian Hutter, Carolyn M. Newcomb, Polly A. Ulrich, Cornelia M. Bien, Stephanie A. Campbell, Peter T. Baron, John A. Berndt, Sonja I. Bezieau, Stephane Brenner, Hermann Casey, Graham Chan, Andrew T. Chang-Claude, Jenny Du, Mengmeng Duggan, David Figueiredo, Jane C. Gallinger, Steven Giovannucci, Edward L. Haile, Robert W. Harrison, Tabitha A. Hayes, Richard B. Hoffmeister, Michael Hopper, John L. Hudson, Thomas J. Jeon, Jihyoun Jenkins, Mark A. Kocarnik, Jonathan Kury, Sebastien Le Marchand, Loic Lin, Yi Lindor, Noralane M. Nishihara, Reiko Ogino, Shuji Potter, John D. Rudolph, Anja Schoen, Robert E. Schrotz-King, Petra Seminara, Daniela Slattery, Martha L. Thibodeau, Stephen N. Thornquist, Mark Toth, Reka Wallace, Robert White, Emily Jiao, Shuo Lemire, Mathieu Hsu, Li Peters, Ulrike CA CCFR GECCO TI Genome-Wide Interaction Analyses between Genetic Variants and Alcohol Consumption and Smoking for Risk of Colorectal Cancer SO PLOS GENETICS LA English DT Article ID MOLECULAR PATHOLOGICAL EPIDEMIOLOGY; ENVIRONMENT INTERACTION; SUSCEPTIBILITY LOCI; CIGARETTE-SMOKING; POOLED ANALYSIS; COLON-CANCER; ASSOCIATION; METAANALYSIS; MTOR; POPULATION AB Genome-wide association studies (GWAS) have identified many genetic susceptibility loci for colorectal cancer (CRC). However, variants in these loci explain only a small proportion of familial aggregation, and there are likely additional variants that are associated with CRC susceptibility. Genome-wide studies of gene-environment interactions may identify variants that are not detected in GWAS of marginal gene effects. To study this, we conducted a genome-wide analysis for interaction between genetic variants and alcohol consumption and cigarette smoking using data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Interactions were tested using logistic regression. We identified interaction between CRC risk and alcohol consumption and variants in the 9q22.32/HIATL1 (Pinteraction = 1.76x10(-8); permuted pvalue 3.51x10 -8) region. Compared to non-/occasional drinking light to moderate alcohol consumption was associated with a lower risk of colorectal cancer among individuals with rs9409565 CT genotype (OR, 0.82 [95% CI, 0.74-0.91]; P = 2.1x10(-4)) and TT genotypes (OR, 0.62 [95% CI, 0.51-0.75]; P = 1.3x10(-6)) but not associated among those with the CC genotype (p = 0.059). No genome-wide statistically significant interactions were observed for smoking. If replicated our suggestive finding of a genome-wide significant interaction between genetic variants and alcohol consumption might contribute to understanding colorectal cancer etiology and identifying subpopulations with differential susceptibility to the effect of alcohol on CRC risk. C1 [Gong, Jian; Newcomb, Polly A.; Ulrich, Cornelia M.; Bien, Stephanie A.; Du, Mengmeng; Harrison, Tabitha A.; Jeon, Jihyoun; Kocarnik, Jonathan; Lin, Yi; Potter, John D.; Thornquist, Mark; White, Emily; Jiao, Shuo; Hsu, Li; Peters, Ulrike] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Hutter, Carolyn M.] NHGRI, Div Genom Med, Bethesda, MD 20892 USA. [Ulrich, Cornelia M.] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA. [Campbell, Peter T.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Baron, John A.] Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC USA. [Berndt, Sonja I.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Bezieau, Stephane; Kury, Sebastien] CHU Nantes, Serv Genet Med, Nantes, France. [Brenner, Hermann; Hoffmeister, Michael] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Brenner, Hermann] German Canc Consortium DKTK, Heidelberg, Germany. [Casey, Graham; Figueiredo, Jane C.; Haile, Robert W.] Univ Southern Calif, Keck Sch Med, Los Angeles, CA USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Chan, Andrew T.] Harvard Med Sch, Boston, MA USA. [Chan, Andrew T.] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Chang-Claude, Jenny; Rudolph, Anja] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Duggan, David] Translat Genom Res Inst, Phoenix, AZ USA. [Gallinger, Steven] Univ Hlth Network, Toronto Gen Hosp, Dept Surg, Toronto, ON, Canada. [Giovannucci, Edward L.] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Hayes, Richard B.] NYU, Sch Med, Div Epidemiol, New York, NY USA. [Hopper, John L.; Jenkins, Mark A.] Univ Melbourne, Melbourne Sch Populat Hlth, Melbourne, Vic, Australia. [Hudson, Thomas J.; Lemire, Mathieu] Ontario Inst Canc Res, Toronto, ON, Canada. [Le Marchand, Loic] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96822 USA. [Lindor, Noralane M.] Mayo Clin, Dept Hlth Sci Res, Scottsdale, AZ USA. [Nishihara, Reiko] Harvard Sch Publ Hlth, Dana Farber Canc Inst, Boston, MA USA. [Ogino, Shuji] Harvard Sch Publ Hlth, Dept Epidemiol, Harvard Med Sch, Boston, MA USA. [Potter, John D.] Massey Univ, Ctr Publ Hlth Res, Wellington, New Zealand. [Schoen, Robert E.] Univ Pittsburgh, Med Ctr, Dept Med & Epidemiol, Pittsburgh, PA USA. [Schrotz-King, Petra; Toth, Reka] Natl Ctr Tumor Dis, Div Prevent Oncol, Heidelberg, Germany. [Schrotz-King, Petra; Toth, Reka] German Canc Res Ctr, Heidelberg, Germany. [Seminara, Daniela] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Slattery, Martha L.] Univ Utah, Hlth Sci Ctr, Dept Internal Med, Salt Lake City, UT USA. [Thibodeau, Stephen N.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Thibodeau, Stephen N.] Mayo Clin, Dept Lab Genet, Rochester, MN USA. [Wallace, Robert] Univ Iowa, Dept Epidemiol, Iowa City, IA USA. RP Peters, U (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. EM upeters@fhcrc.org RI Brenner, Hermann/B-4627-2017; OI Brenner, Hermann/0000-0002-6129-1572; Hayes, Richard/0000-0002-0918-661X; Bien, Stephanie/0000-0002-8713-4583; Hoffmeister, Michael/0000-0002-8307-3197 FU National Cancer Institute, National Institutes of Health, U.S. Department of Health, and Human Services [U01 CA137088, R01 CA059045, R01 CA120582]; Hospital Clinical Research Program (PHRC); Regional Council of Pays de la Loire; Groupement des Entreprises Francaises dans la Lutte contre le Cancer (GEFLUC); Association Anne de Bretagne Genetique; Ligue Regionale Contre le Cancer (LRCC); National Institutes of Health [R01 CA60987, UM1 CA167551, R01 CA48998, P01 CA 055075, UM1 CA167552, R01 137178, R01 CA 151993, K07 CA190673, P50 CA 127003, R01 CA137178, P01 CA 087969, UM1 CA186107, R01 CA151993, R35 CA197735]; National Cancer Institute, National Institutes of Health [U01 CA122839, R01 CA143237]; German Research Council (Deutsche Forschungsgemeinschaft) [BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1]; German Federal Ministry of Education and Research [01KH0404, 01ER0814]; Ontario Research Fund; Canadian Institutes of Health Research; Ontario Institute for Cancer Research from the Ontario Ministry of Research and Innovation; Division of Cancer Epidemiology and Genetics; Division of Cancer Prevention, National Cancer Institute, NIH, DHHS; National Institutes of Health (NIH), Genes, Environment and Health Initiative (GEI) [Z01 CP 010200]; NIH [U01 HG004446]; NIH GEI [U01 HG 004438]; National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C]; The National Institutes of Health [K07190673, R01 CA042182, R37 CA54281, P01 CA033619, R01 CA63464, U01 CA074783, R01 CA076366, K05 CA154337] FX GECCO is supported by National Cancer Institute, National Institutes of Health, U.S. Department of Health, and Human Services (U01 CA137088; R01 CA059045; R01 CA120582). ASTERISK is supported by a Hospital Clinical Research Program (PHRC), the Regional Council of Pays de la Loire, the Groupement des Entreprises Francaises dans la Lutte contre le Cancer (GEFLUC), the Association Anne de Bretagne Genetique and the Ligue Regionale Contre le Cancer (LRCC). COLO2&3 is supported by National Institutes of Health (R01 CA60987). CCFR is supported by National Institutes of Health (UM1 CA167551) and through cooperative agreements with members of the Colon Cancer Family Registry and P.I.s. This genome wide scan was supported by the National Cancer Institute, National Institutes of Health by U01 CA122839 and R01 CA143237 to Graham Casey. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the CFRs, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the CFR. The following Colon CFR centers contributed data to this manuscript and were supported by National Institutes of Health: Australasian Colorectal Cancer Family Registry (U01/U24 CA097735), Ontario Registry for Studies of Familial Colorectal Cancer (U01/U24 CA074783), and Seattle Colorectal Cancer Family Registry (U01/U24 CA074794). DACHS is supported by German Research Council (Deutsche Forschungsgemeinschaft, BR 1704/6-1, BR 1704/6-3, BR 1704/6-4 and CH 117/1-1), and the German Federal Ministry of Education and Research (01KH0404 and 01ER0814). DALS is supported by National Institutes of Health (R01 CA48998 to MLS). HPFS is supported by the National Institutes of Health (P01 CA 055075, UM1 CA167552, R01 137178, R01 CA 151993, R35 CA197735, K07 CA190673, and P50 CA 127003), NHS by the National Institutes of Health (R01 CA137178, P01 CA 087969, UM1 CA186107, R01 CA151993, R35 CA197735, K07190673, and P50 CA 127003,) and PHS by the National Institutes of Health (R01 CA042182). MEC is supported by National Institutes of Health (R37 CA54281, P01 CA033619, and R01 CA63464). OFCCR is supported by National Institutes of Health through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783, see CCFR section above). Additional funding toward genetic analyses of OFCCR includes the Ontario Research Fund, the Canadian Institutes of Health Research, and the Ontario Institute for Cancer Research through generous support from the Ontario Ministry of Research and Innovation. PLCO is supported by Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. Additionally, a subset of control samples were genotyped as part of the Cancer Genetic Markers of Susceptibility (CGEMS) Prostate Cancer GWAS (Yeager, M et al. Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nat Genet 2007 May;39(5):645-9), Colon CGEMS pancreatic cancer scan (PanScan) (Amundadottir, L et al. Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer. Nat Genet. 2009 Sep;41(9):986-90, and Petersen, GM et al. A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Nat Genet. 2010 Mar;42(3):224-8), and the Lung Cancer and Smoking study (Landi MT, et al.; A genome-wide association study of lung cancer identifies a region of chromosome 5p15 associated with risk for adenocarcinoma. Am J Hum Genet. 2009 Nov;85(5):679-91). The prostate and PanScan study datasets were accessed with appropriate approval through the dbGaP online resource (http.//cgems.cancer.gov/data/) accession numbers phs000207.v1.p1 and phs000206.v3.p2, respectively, and the lung datasets were accessed from the dbGaP website (http://www.ncbi.nlm.nih.gov/gap) through accession number phs000093.v2.p2. Funding for the Lung Cancer and Smoking study was provided by National Institutes of Health (NIH), Genes, Environment and Health Initiative (GEI) Z01 CP 010200, NIH U01 HG004446, and NIH GEI U01 HG 004438. For the lung study, the GENEVA Coordinating Center provided assistance with genotype cleaning and general study coordination, and the Johns Hopkins University Center for Inherited Disease Research conducted genotyping. PMH is supported by National Institutes of Health (R01 CA076366 to P.A. Newcomb). VITAL is supported byNational Institutes of Health (K05 CA154337). WHI is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 90 TC 0 Z9 0 U1 6 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD OCT PY 2016 VL 12 IS 10 AR e1006296 DI 10.1371/journal.pgen.1006296 PG 21 WC Genetics & Heredity SC Genetics & Heredity GA EA5SM UT WOS:000386683300006 PM 27723779 ER PT J AU Jakobsdottir, J van der Lee, SJ Bis, JC Chouraki, V Li-Kroeger, D Yamamoto, S Grove, ML Naj, A Vronskaya, M Salazar, JL DeStefano, AL Brody, JA Smith, AV Amin, N Sims, R Ibrahim-Verbaas, CA Choi, SH Satizabal, CL Lopez, OL Beiser, A Ikram, MA Garcia, ME Hayward, C Varga, TV Ripatti, S Franks, PW Hallmans, G Rolandsson, O Jansson, JH Porteous, DJ Salomaa, V Eiriksdottir, G Rice, KM Bellen, HJ Levy, D Uitterlinden, AG Emilsson, V Rotter, JI Aspelund, T O'Donnell, CJ Fitzpatrick, AL Launer, LJ Hofman, A Wang, LS Williams, J Schellenberg, GD Boerwinkle, E Psaty, BM Seshadri, S Shulman, JM Gudnason, V Van Duijn, CM AF Jakobsdottir, Johanna van der Lee, Sven J. Bis, Joshua C. Chouraki, Vincent Li-Kroeger, David Yamamoto, Shinya Grove, Megan L. Naj, Adam Vronskaya, Maria Salazar, Jose L. DeStefano, Anita L. Brody, Jennifer A. Smith, Albert V. Amin, Najaf Sims, Rebecca Ibrahim-Verbaas, Carla A. Choi, Seung-Hoan Satizabal, Claudia L. Lopez, Oscar L. Beiser, Alexa Ikram, M. Arfan Garcia, Melissa E. Hayward, Caroline Varga, Tibor V. Ripatti, Samuli Franks, Paul W. Hallmans, Goran Rolandsson, Olov Jansson, Jan-Hakon Porteous, David J. Salomaa, Veikko Eiriksdottir, Gudny Rice, Kenneth M. Bellen, Hugo J. Levy, Daniel Uitterlinden, Andre G. Emilsson, Valur Rotter, Jerome I. Aspelund, Thor O'Donnell, Christopher J. Fitzpatrick, Annette L. Launer, Lenore J. Hofman, Albert Wang, Li-San Williams, Julie Schellenberg, Gerard D. Boerwinkle, Eric Psaty, Bruce M. Seshadri, Sudha Shulman, Joshua M. Gudnason, Vilmundur Van Duijn, Cornelia M. CA Cohorts Heart Aging Res Genomic Ep Genetic Environm Risk Alzheimer's TI Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease SO PLOS GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; DROSOPHILA-MELANOGASTER DEVELOPMENT; HAPLOTYPE RECONSTRUCTION; IDENTIFIES VARIANTS; APOLIPOPROTEIN-E; COMMON VARIANTS; UNITED-STATES; PROTEIN; GENETICS; MUTATION AB We performed an exome-wide association analysis in 1393 late-onset Alzheimer's disease (LOAD) cases and 8141 controls from the CHARGE consortium. We found that a rare variant (P155L) in TM2D3 was enriched in Icelanders (similar to 0.5% versus < 0.05% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES substudy, P155L was associated with increased risk and earlier onset of LOAD [odds ratio (95% CI) = 7.5 (3.5-15.9), p = 6.6x10(-9)]. Mutation in the Drosophila TM2D3 homolog, almondex, causes a phenotype similar to loss of Notch/Presenilin signaling. Human TM2D3 is capable of rescuing these phenotypes, but this activity is abolished by P155L, establishing it as a functionally damaging allele. Our results establish a rare TM2D3 variant in association with LOAD susceptibility, and together with prior work suggests possible links to the beta-amyloid cascade. C1 [Jakobsdottir, Johanna; Smith, Albert V.; Eiriksdottir, Gudny; Emilsson, Valur; Aspelund, Thor; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [van der Lee, Sven J.; Amin, Najaf; Ibrahim-Verbaas, Carla A.; Ikram, M. Arfan; Uitterlinden, Andre G.; Hofman, Albert; Van Duijn, Cornelia M.] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [Bis, Joshua C.; Brody, Jennifer A.; Psaty, Bruce M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Chouraki, Vincent; Satizabal, Claudia L.; Beiser, Alexa; Levy, Daniel; Seshadri, Sudha] Boston Univ, Sch Med, Boston, MA 02118 USA. [Chouraki, Vincent; DeStefano, Anita L.; Choi, Seung-Hoan; Satizabal, Claudia L.; Beiser, Alexa; Levy, Daniel; O'Donnell, Christopher J.; Seshadri, Sudha] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Li-Kroeger, David; Yamamoto, Shinya; Salazar, Jose L.; Bellen, Hugo J.; Shulman, Joshua M.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Li-Kroeger, David; Yamamoto, Shinya; Bellen, Hugo J.; Shulman, Joshua M.] Texas Childrens Hosp, Jan & Dan Duncan Neurol Res Inst, Houston, TX 77030 USA. [Yamamoto, Shinya; Bellen, Hugo J.; Shulman, Joshua M.] Baylor Coll Med, Program Dev Biol, Houston, TX 77030 USA. [Grove, Megan L.; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Sch Publ Hlth, Houston, TX 77030 USA. [Naj, Adam] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Vronskaya, Maria; Sims, Rebecca; Williams, Julie] Cardiff Univ, Med Res Council MRC Ctr Neuropsychiat Genet & Gen, Inst Psychol Med & Clin Neurosci, Cardiff, S Glam, Wales. [DeStefano, Anita L.; Choi, Seung-Hoan; Beiser, Alexa] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Smith, Albert V.; Gudnason, Vilmundur] Univ Iceland, Fac Med, Reykjavik, Iceland. [Ibrahim-Verbaas, Carla A.; Ikram, M. Arfan] Erasmus Univ, Med Ctr, Dept Neurol, Rotterdam, Netherlands. [Lopez, Oscar L.] Univ Pittsburgh, Med Ctr, Dept Neurol, Pittsburgh, PA USA. [Ikram, M. Arfan] Erasmus Univ, Med Ctr, Dept Radiol, Rotterdam, Netherlands. [Garcia, Melissa E.; Launer, Lenore J.] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. [Hayward, Caroline] Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland. [Hayward, Caroline; Porteous, David J.] Univ Edinburgh, Ctr Genom & Expt Med, Generat Scotland, Edinburgh, Midlothian, Scotland. [Varga, Tibor V.; Franks, Paul W.] Lund Univ, Genet & Mol Epidemiol Unit, Dept Clin Sci, Malmo, Sweden. [Ripatti, Samuli] Univ Helsinki, FIMM, Helsinki, Finland. [Ripatti, Samuli] Univ Helsinki, Dept Publ Hlth, Helsinki, Finland. [Franks, Paul W.; Jansson, Jan-Hakon] Umea Univ Hosp, Dept Publ Hlth & Clin Med, Umea, Sweden. [Franks, Paul W.] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA. [Hallmans, Goran] Umea Univ, Dept Biobank Res, Umea, Sweden. [Rolandsson, Olov] Umea Univ, Sect Family Med, Dept Publ Hlth & Clin Med, Umea, Sweden. [Jansson, Jan-Hakon] Skelleftea Hosp, Res Unit, Skelleftea, Sweden. [Porteous, David J.] Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Edinburgh, Midlothian, Scotland. [Salomaa, Veikko] Natl Inst Hlth & Welf, Helsinki, Finland. [Rice, Kenneth M.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Bellen, Hugo J.] Howard Hughes Med Inst, Durham, NC USA. [Levy, Daniel; O'Donnell, Christopher J.] NHLBI, Div Intramural Res, NIH, Bldg 10, Bethesda, MD 20892 USA. [Uitterlinden, Andre G.] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands. [Emilsson, Valur] Univ Iceland, Fac Pharmaceut Sci, Reykjavik, Iceland. [Rotter, Jerome I.] Los Angeles BioMed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Dept Med, Torrance, CA 90509 USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90509 USA. [Aspelund, Thor] Univ Iceland, Ctr Publ Hlth, Reykjavik, Iceland. [Fitzpatrick, Annette L.; Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Fitzpatrick, Annette L.] Collaborat Hlth Studies Coordinating Ctr, Seattle, WA USA. [Wang, Li-San; Schellenberg, Gerard D.] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Boerwinkle, Eric] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. RP Gudnason, V (reprint author), Iceland Heart Assoc, Kopavogur, Iceland.; Van Duijn, CM (reprint author), Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands.; Shulman, JM (reprint author), Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA.; Shulman, JM (reprint author), Texas Childrens Hosp, Jan & Dan Duncan Neurol Res Inst, Houston, TX 77030 USA.; Shulman, JM (reprint author), Baylor Coll Med, Program Dev Biol, Houston, TX 77030 USA.; Gudnason, V (reprint author), Univ Iceland, Fac Med, Reykjavik, Iceland. EM Joshua.Shulman@bcm.edu; villi@hjarta.is; c.vanduijn@erasmusmc.nl OI Salazar, Jose/0000-0002-1727-306X; van der Lee, Sven/0000-0003-1606-8643; Yamamoto, Shinya/0000-0003-2172-8036; Varga, Tibor/0000-0002-2383-699X; Beiser, Alexa/0000-0001-8551-7778 FU National Heart, Lung, and Blood Institute (NHLBI) [HL105756]; NHLBI [HL120393]; NIH [U01-AG049506, U01-AG049505, U54-HG003273, GMR2556929]; National Institute on Aging (NIA) [N01-AG-12100, HHSN271201200022C]; NIH/NIA [R01-AG033193, R01-AG050631, C06-RR029965]; Alzheimer's Association; American Federation for Aging Research; Huffington Foundation; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital; Burroughs Wellcome Fund; Eunice Kennedy Shriver National Institute of Child Health & Human Development [U54HD083092]; Alzheimer's Association [NIRH-15-364099]; Robert and Renee Belfer Family Foundation; Target ALS FX Infrastructure for the CHARGE Consortium is supported in part by the National Heart, Lung, and Blood Institute (NHLBI, http://www.nhlbi.nih.gov) grant HL105756. Funding support for the CHARGE Consortium Exome Chip analyses is provided in part by the NHLBI grant HL120393. Support for centralized calling of the exome chip was provided by Building on GWAS for NHLBI-diseases: the U.S. CHARGE consortium through the National Institutes of Health (NIH, https://www.nih.gov) American Recovery and Reinvestment Act of 2009 (ARRA) (5RC2HL102419). The CHARGE consortium is a founding component of the Alzheimer's Disease Sequencing Project, and receives sequencing and analysis support through the grants from NIH: U01-AG049506, U01-AG049505, and U54-HG003273. AGES study is supported by the National Institute on Aging (NIA, https://www.nia.nih.gov) contracts N01-AG-12100 and HHSN271201200022C with contributions from the National Eye Institute (NEI, https://nei.nih.gov), National Institute on Deafness and Other Communication Disorders (NIDCD, https://www.nidcd.nih.gov), NHLBI, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). JMS was supported by grants from the NIH/NIA (R01-AG033193, R01-AG050631, C06-RR029965), the Alzheimer's Association, the American Federation for Aging Research, Huffington Foundation, Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, and a Career Award for Medical Scientists from the Burroughs Wellcome Fund. The work was additionally supported by U54HD083092 from the Eunice Kennedy Shriver National Institute of Child Health & Human Development. SY was supported by the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital and the Alzheimer's Association (NIRH-15-364099). HJB is a Howard Hughes Medical Institute Investigator and also received support from the Robert and Renee Belfer Family Foundation, the Huffington Foundation, and Target ALS. JS is supported by NIH GMR2556929. Detailed funding information for all studies that contributed to this work are provided in Si Text Funding section. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 59 TC 0 Z9 0 U1 6 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD OCT PY 2016 VL 12 IS 10 AR e1006327 DI 10.1371/journal.pgen.1006327 PG 17 WC Genetics & Heredity SC Genetics & Heredity GA EA5SM UT WOS:000386683300009 PM 27764101 ER PT J AU Peled, A Sarig, O Samuelov, L Bertolini, M Ziv, L Weissglas-Volkov, D Eskin-Schwartz, M Adase, CA Malchin, N Bochner, R Fainberg, G Goldberg, I Sugawara, K Baniel, A Tsuruta, D Luxenburg, C Adir, N Duverger, O Morasso, M Shalev, S Gallo, RL Shomron, N Paus, R Sprecher, E AF Peled, Alon Sarig, Ofer Samuelov, Liat Bertolini, Marta Ziv, Limor Weissglas-Volkov, Daphna Eskin-Schwartz, Marina Adase, Christopher A. Malchin, Natalia Bochner, Ron Fainberg, Gilad Goldberg, Ilan Sugawara, Koji Baniel, Avital Tsuruta, Daisuke Luxenburg, Chen Adir, Noam Duverger, Olivier Morasso, Maria Shalev, Stavit Gallo, Richard L. Shomron, Noam Paus, Ralf Sprecher, Eli TI Mutations in TSPEAR, Encoding a Regulator of Notch Signaling, Affect Tooth and Hair Follicle Morphogenesis SO PLOS GENETICS LA English DT Article ID ECTODERMAL DYSPLASIA; EPIDERMAL HOMEOSTASIS; SEQUENCING DATA; EXPRESSION; PATHWAYS; DISEASES; DOMAIN; PATHOGENESIS; VARIANTS; GROWTH AB Despite recent advances in our understanding of the pathogenesis of ectodermal dysplasias (EDs), the molecular basis of many of these disorders remains unknown. In the present study, we aimed at elucidating the genetic basis of a new form of ED featuring facial dysmorphism, scalp hypotrichosis and hypodontia. Using whole exome sequencing, we identified 2 frameshift and 2 missense mutations in TSPEAR segregating with the disease phenotype in 3 families. TSPEAR encodes the thrombospondin-type laminin G domain and EAR repeats (TSPEAR) protein, whose function is poorly understood. TSPEAR knockdown resulted in altered expression of genes known to be regulated by NOTCH and to be involved in murine hair and tooth development. Pathway analysis confirmed that down-regulation of TSPEAR in keratinocytes is likely to affect Notch signaling. Accordingly, using a luciferase-based reporter assay, we showed that TSPEAR knock-down is associated with decreased Notch signaling. In addition, NOTCH1 protein expression was reduced in patient scalp skin. Moreover, TSPEAR silencing in mouse hair follicle organ cultures was found to induce apoptosis in follicular epithelial cells, resulting in decreased hair bulb diameter. Collectively, these observations indicate that TSPEAR plays a critical, previously unrecognized role in human tooth and hair follicle morphogenesis through regulation of the Notch signaling pathway. C1 [Peled, Alon; Sarig, Ofer; Samuelov, Liat; Eskin-Schwartz, Marina; Malchin, Natalia; Bochner, Ron; Fainberg, Gilad; Goldberg, Ilan; Baniel, Avital; Sprecher, Eli] Tel Aviv Med Ctr & Sch Med, Dept Dermatol, Tel Aviv, Israel. [Peled, Alon; Eskin-Schwartz, Marina; Sprecher, Eli] Tel Aviv Univ, Dept Human Mol Genet & Biochem, Tel Aviv, Israel. [Samuelov, Liat; Adase, Christopher A.; Gallo, Richard L.] Univ Calif San Diego, Div Dermatol, San Diego, CA 92103 USA. [Bertolini, Marta; Paus, Ralf] Univ Munster, Dept Dermatol, Munster, Germany. [Ziv, Limor] Sheba Med Ctr, Ramat Gan, Israel. [Weissglas-Volkov, Daphna; Luxenburg, Chen; Shomron, Noam] Tel Aviv Univ, Dept Cell & Dev Biol, Tel Aviv, Israel. [Sugawara, Koji; Tsuruta, Daisuke] Osaka City Univ, Dept Dermatol, Osaka, Japan. [Adir, Noam] Technion, Fac Chem, Haifa, Israel. [Duverger, Olivier; Morasso, Maria] NIH, Skin Biol Lab, Bldg 10, Bethesda, MD 20892 USA. [Shalev, Stavit] Haemek Med Ctr, Inst Human Genet, Afula, Israel. [Shalev, Stavit] Technion, Rappaport Fac Med, Haifa, Israel. [Paus, Ralf] Univ Manchester, Inst Inflammat & Repair, Ctr Dermatol Res, Manchester, Lancs, England. RP Sprecher, E (reprint author), Tel Aviv Med Ctr & Sch Med, Dept Dermatol, Tel Aviv, Israel.; Sprecher, E (reprint author), Tel Aviv Univ, Dept Human Mol Genet & Biochem, Tel Aviv, Israel. EM elisp@tlvmc.gov.il OI Peled, Alon/0000-0001-6158-1089 NR 44 TC 0 Z9 0 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD OCT PY 2016 VL 12 IS 10 AR e1006369 DI 10.1371/journal.pgen.1006369 PG 17 WC Genetics & Heredity SC Genetics & Heredity GA EA5SM UT WOS:000386683300034 PM 27736875 ER PT J AU Saini, N Roberts, SA Klimczak, LJ Chan, K Grimm, SA Dai, SS Fargo, DC Boyer, JC Kaufmann, WK Taylor, JA Lee, E Cortes-Ciriano, I Park, PJ Schurman, SH Malc, EP Mieczkowski, PA Gordenin, DA AF Saini, Natalie Roberts, Steven A. Klimczak, Leszek J. Chan, Kin Grimm, Sara A. Dai, Shuangshuang Fargo, David C. Boyer, Jayne C. Kaufmann, William K. Taylor, Jack A. Lee, Eunjung Cortes-Ciriano, Isidro Park, Peter J. Schurman, Shepherd H. Malc, Ewa P. Mieczkowski, Piotr A. Gordenin, Dmitry A. TI The Impact of Environmental and Endogenous Damage on Somatic Mutation Load in Human Skin Fibroblasts SO PLOS GENETICS LA English DT Article ID NUCLEOTIDE EXCISION-REPAIR; COPY NUMBER ALTERATION; COMMON FRAGILE SITES; DNA-SEQUENCING DATA; TELOMERE LENGTH; HUMAN CANCERS; POINT MUTATIONS; HUMAN TISSUES; NORMAL-CELLS; HUMAN BRAIN AB Accumulation of somatic changes, due to environmental and endogenous lesions, in the human genome is associated with aging and cancer. Understanding the impacts of these processes on mutagenesis is fundamental to understanding the etiology, and improving the prognosis and prevention of cancers and other genetic diseases. Previous methods relying on either the generation of induced pluripotent stem cells, or sequencing of single-cell genomes were inherently error-prone and did not allow independent validation of the mutations. In the current study we eliminated these potential sources of error by high coverage genome sequencing of single-cell derived clonal fibroblast lineages, obtained after minimal propagation in culture, prepared from skin biopsies of two healthy adult humans. We report here accurate measurement of genome-wide magnitude and spectra of mutations accrued in skin fibroblasts of healthy adult humans. We found that every cell contains at least one chromosomal rearrangement and 600-13,000 base substitutions. The spectra and correlation of base substitutions with epigenomic features resemble many cancers. Moreover, because biopsies were taken from body parts differing by sun exposure, we can delineate the precise contributions of environmental and endogenous factors to the accrual of genetic changes within the same individual. We show here that UV-induced and endogenous DNA damage can have a comparable impact on the somatic mutation loads in skin fibroblasts. C1 [Saini, Natalie; Chan, Kin; Gordenin, Dmitry A.] NIEHS, Genome Integr & Struct Biol Lab, US NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Roberts, Steven A.] Washington State Univ, Sch Mol Biosci, Pullman, WA 99164 USA. [Klimczak, Leszek J.; Grimm, Sara A.; Dai, Shuangshuang; Fargo, David C.] NIEHS, Integrat Bioinformat Support Grp, US NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Boyer, Jayne C.] Univ N Carolina, Dept Environm Sci & Engn, Chapel Hill, NC USA. [Kaufmann, William K.] Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC USA. [Taylor, Jack A.] NIEHS, Epidemiol Branch, US NIH, Res Triangle Pk, NC 27709 USA. [Lee, Eunjung; Cortes-Ciriano, Isidro; Park, Peter J.] Harvard Med Sch, Dept Biomed Informat, Boston, MA USA. [Lee, Eunjung; Park, Peter J.] Brigham & Womens Hosp, Div Genet, 75 Francis St, Boston, MA 02115 USA. [Schurman, Shepherd H.] NIEHS, Clin Res Unit, US NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Malc, Ewa P.; Mieczkowski, Piotr A.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Genet, Chapel Hill, NC USA. RP Gordenin, DA (reprint author), NIEHS, Genome Integr & Struct Biol Lab, US NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM gordenin@niehs.nih.gov OI Schurman, Shepherd/0000-0002-9133-7906; taylor, jack/0000-0001-5303-6398 FU US National Institute of Health Intramural Research Program [Z1AES103266]; NIH from NIEHS [R00E5022633-03]; Breast Cancer Research Program Breakthrough Award from the Department of Defense [BC141727]; Center for Disease Control/ National Institute of Occupational Health and Safety [R21 -OH010550]; NIH [1U01MH106883]; Eleanor and Miles Shore Fellowship; William Randolph Hearst Fund FX This work was supported by the US National Institute of Health Intramural Research Program Project Z1AES103266 to DAG; NIH grant R00E5022633-03 from NIEHS and Breast Cancer Research Program Breakthrough Award BC141727 from the Department of Defense awarded SAR; the Center for Disease Control/ National Institute of Occupational Health and Safety R21 -OH010550 to JCB; NIH grant 1U01MH106883 awarded to PJP; EL is supported in part by the Eleanor and Miles Shore Fellowship and the William Randolph Hearst Fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 79 TC 2 Z9 2 U1 6 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD OCT PY 2016 VL 12 IS 10 AR e1006385 DI 10.1371/journal.pgen.1006385 PG 25 WC Genetics & Heredity SC Genetics & Heredity GA EA5SM UT WOS:000386683300046 PM 27788131 ER PT J AU Dong, XW Sun, YX Ma, BY Nussinov, R Weia, GH AF Dong, Xuewei Sun, Yunxiang Ma, Buyong Nussinov, Ruth Weia, Guanghong TI Lipid interaction and membrane perturbation of different protofibrillar A beta 9-40 trimers: an atomistic simulation study SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 30th Anniversary Symposium of the Protein-Society CY JUL 16-19, 2016 CL Baltimore, MD SP Protein Soc C1 [Dong, Xuewei; Sun, Yunxiang] Fudan Univ, Key Lab Computat Phys Sci MOE, State Key Lab Surface Phys, Shanghai, Peoples R China. [Dong, Xuewei; Sun, Yunxiang] Fudan Univ, Dept Phys, Shanghai, Peoples R China. [Ma, Buyong; Nussinov, Ruth] NCI, Basic Sci Program, Leidos Biomed Res Inc, Canc & Inflammat Program, Bethesda, MD 20892 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. NR 2 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-8368 EI 1469-896X J9 PROTEIN SCI JI Protein Sci. PD OCT PY 2016 VL 25 SU S1 BP 11 EP 11 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EB1YJ UT WOS:000387152400007 ER PT J AU Thanki, N Han, L Lanczycki, CJ He, J Lu, S Chitsaz, F Derbyshire, MK Gonzales, NR Gwadz, M Lu, F Marchler, GH Song, JS Yamashita, RA Zheng, C Bryant, SH Geer, L Marchler-Bauer, A AF Thanki, N. Han, L. Lanczycki, C. J. He, J. Lu, S. Chitsaz, F. Derbyshire, M. K. Gonzales, N. R. Gwadz, M. Lu, F. Marchler, G. H. Song, J. S. Yamashita, R. A. Zheng, C. Bryant, S. H. Geer, L. Marchler-Bauer, A. TI Functional Labeling of Protein Domain Architectures with SPARCLE SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 30th Anniversary Symposium of the Protein-Society CY JUL 16-19, 2016 CL Baltimore, MD SP Protein Soc C1 [Thanki, N.; Han, L.; Lanczycki, C. J.; He, J.; Lu, S.; Chitsaz, F.; Derbyshire, M. K.; Gonzales, N. R.; Gwadz, M.; Lu, F.; Marchler, G. H.; Song, J. S.; Yamashita, R. A.; Zheng, C.; Bryant, S. H.; Geer, L.; Marchler-Bauer, A.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-8368 EI 1469-896X J9 PROTEIN SCI JI Protein Sci. PD OCT PY 2016 VL 25 SU S1 BP 22 EP 22 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EB1YJ UT WOS:000387152400029 ER PT J AU Shrimp, J AF Shrimp, Jonathan TI Next-generation assays to define and manipulate lysine acetyltransferase function SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 30th Anniversary Symposium of the Protein-Society CY JUL 16-19, 2016 CL Baltimore, MD SP Protein Soc C1 [Shrimp, Jonathan] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-8368 EI 1469-896X J9 PROTEIN SCI JI Protein Sci. PD OCT PY 2016 VL 25 SU S1 BP 33 EP 33 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EB1YJ UT WOS:000387152400048 ER PT J AU Roy, A AF Roy, Amitava TI Analysis of Multi-domain Protein Dynamics SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 30th Anniversary Symposium of the Protein-Society CY JUL 16-19, 2016 CL Baltimore, MD SP Protein Soc C1 [Roy, Amitava] NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-8368 EI 1469-896X J9 PROTEIN SCI JI Protein Sci. PD OCT PY 2016 VL 25 SU S1 BP 44 EP 45 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EB1YJ UT WOS:000387152400069 ER PT J AU Hajduczki, A AF Hajduczki, Agnes TI Developing a soluble bifunctional receptor/co-receptor mimetic for structural characterization of the HIV envelope glycoprotein SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 30th Anniversary Symposium of the Protein-Society CY JUL 16-19, 2016 CL Baltimore, MD SP Protein Soc C1 [Hajduczki, Agnes] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-8368 EI 1469-896X J9 PROTEIN SCI JI Protein Sci. PD OCT PY 2016 VL 25 SU S1 BP 57 EP 57 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EB1YJ UT WOS:000387152400087 ER PT J AU Zhao, HY Fu, Y Glasser, C Andrade, E Mayer, ML Patterson, G Schuck, P AF Zhao, Huaying Fu, Yan Glasser, Carla Andrade, Eric Mayer, Mark L. Patterson, George Schuck, Peter TI A New Dimension of Detection in Analytical Ultracentrifugation with Fluorescence Detection System Using Photoswitchable GFPs as Time Domain Probes SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 30th Anniversary Symposium of the Protein-Society CY JUL 16-19, 2016 CL Baltimore, MD SP Protein Soc C1 [Zhao, Huaying; Schuck, Peter] Lab Cellular Imaging & Macromol Biophys, Dynam Macromol Assembly Sect, Bethesda, MD USA. [Fu, Yan; Andrade, Eric; Patterson, George] Natl Inst Biomed Imaging & Bioengn, Sect Biophoton, Bethesda, MD USA. [Glasser, Carla; Mayer, Mark L.] NICHHD, Lab Cellular & Mol Neurophysiol, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-8368 EI 1469-896X J9 PROTEIN SCI JI Protein Sci. PD OCT PY 2016 VL 25 SU S1 BP 140 EP 140 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EB1YJ UT WOS:000387152400242 ER PT J AU Zhao, HY Schuck, P AF Zhao, Huaying Schuck, Peter TI Global Analysis of Data from Multiple Biophysical Methods for Studying Protein Complex Stoichiometry and Affinity SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 30th Anniversary Symposium of the Protein-Society CY JUL 16-19, 2016 CL Baltimore, MD SP Protein Soc C1 [Zhao, Huaying; Schuck, Peter] Natl Inst Biomed Imaging & Bioengn, Dynam Macromol Assembly Sect, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-8368 EI 1469-896X J9 PROTEIN SCI JI Protein Sci. PD OCT PY 2016 VL 25 SU S1 BP 143 EP 144 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EB1YJ UT WOS:000387152400248 ER PT J AU Harwood, KR Hanover, JA AF Harwood, Katryn R. Hanover, John A. TI Epigenetic Regulation and the O-GlcNAcase: OGA as a Reader and Eraser of the Histone Code SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 30th Anniversary Symposium of the Protein-Society CY JUL 16-19, 2016 CL Baltimore, MD SP Protein Soc C1 [Harwood, Katryn R.; Hanover, John A.] NIDDK, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-8368 EI 1469-896X J9 PROTEIN SCI JI Protein Sci. PD OCT PY 2016 VL 25 SU S1 BP 171 EP 171 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EB1YJ UT WOS:000387152400304 ER PT J AU Cao, HP Deterding, LJ Blackshear, PJ AF Cao, Heping Deterding, Leesa J. Blackshear, Perry J. TI Characterization of protein compositions of glanded and glandless cotton seeds SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 30th Anniversary Symposium of the Protein-Society CY JUL 16-19, 2016 CL Baltimore, MD SP Protein Soc C1 [Cao, Heping] ARS, USDA, Southern Reg Res Ctr, 1100 Robert E Lee Blvd, New Orleans, LA 70124 USA. [Deterding, Leesa J.] NIEHS, Lab Struct Biol, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Blackshear, Perry J.] NIEHS, Lab Signal Transduct, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Blackshear, Perry J.] Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA. [Blackshear, Perry J.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-8368 EI 1469-896X J9 PROTEIN SCI JI Protein Sci. PD OCT PY 2016 VL 25 SU S1 BP 174 EP 174 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EB1YJ UT WOS:000387152400309 ER PT J AU Tomoiaga, A Westfall, P Donato, M Draghici, S Hassan, S Romero, R Tellaroli, P AF Tomoiaga, Alin Westfall, Peter Donato, Michele Draghici, Sorin Hassan, Sonia Romero, Roberto Tellaroli, Paola TI Pathway crosstalk effects: shrinkage and disentanglement using a Bayesian hierarchical model SO STATISTICS IN BIOSCIENCES LA English DT Article DE Bayes model; hierarchical modeling; data augmentation; genomic pathway analysis; gene expression ID GENE-SET ANALYSIS; FALSE DISCOVERY RATE; CELLULAR PLASTICITY; ENRICHMENT ANALYSIS; EXPRESSION; IDENTIFICATION; ACTIVATION; REGRESSION; BINARY; CERVIX AB Identifying the biological pathways that are related to various clinical phenotypes is an important concern in biomedical research. Based on estimated expression levels and/or p values, overrepresentation analysis (ORA) methods provide rankings of pathways, but they are tainted because pathways overlap. This crosstalk phenomenon has not been rigorously studied and classical ORA does not take into consideration: (1) that crosstalk effects in cases of overlapping pathways can cause incorrect rankings of pathways, (2) that crosstalk effects can cause both excess type I errors and type II errors, (3) that rankings of small pathways are unreliable, and (4) that type I error rates can be inflated due to multiple comparisons of pathways. We develop a Bayesian hierarchical model that addresses these problems, providing sensible estimates and rankings, and reducing error rates. We show, on both real and simulated data, that the results of our method are more accurate than the results produced by the classical overrepresentation analysis, providing a better understanding of the underlying biological phenomena involved in the phenotypes under study. The R code and the binary datasets for implementing the analyses described in this article are available online at: http://www.eng.wayne.edu/page.php?id=6402. C1 [Tomoiaga, Alin; Westfall, Peter] Texas Tech Univ, Ctr Adv Analyt & Business Intelligence, Lubbock, TX 79409 USA. [Donato, Michele; Draghici, Sorin] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Hassan, Sonia; Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Detroit, MI USA. [Tellaroli, Paola] Univ Padua, Dept Stat Sci, Padua, Italy. RP Tomoiaga, A (reprint author), Texas Tech Univ, Ctr Adv Analyt & Business Intelligence, Lubbock, TX 79409 USA. EM alin.tomoiaga@ttu.edu; peter.westfall@ttu.edu OI Tellaroli, Paola/0000-0002-5112-9256 NR 52 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1867-1764 EI 1867-1772 J9 STAT BIOSCI JI Stat. Biosci. PD OCT PY 2016 VL 8 IS 2 BP 374 EP 394 DI 10.1007/s12561-016-9160-1 PG 21 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA EB3QM UT WOS:000387280600012 ER PT J AU Fleming, BD Ho, M AF Fleming, Bryan D. Ho, Mitchell TI Glypican-3 Targeting Immunotoxins for the Treatment of Liver Cancer SO TOXINS LA English DT Review DE recombinant immunotoxin; glypican-3 (GPC3); hepatocellular carcinoma; liver cancer; monoclonal antibodies; pseudomonas exotoxin ID ADVANCED HEPATOCELLULAR-CARCINOMA; RIBOSOME-INACTIVATING PROTEIN; MONOCLONAL-ANTIBODY THERAPY; NON-HODGKINS-LYMPHOMA; HAIRY-CELL LEUKEMIA; PHASE-I TRIAL; RECOMBINANT IMMUNOTOXIN; PSEUDOMONAS EXOTOXIN; ENDOPLASMIC-RETICULUM; CONTINUOUS-INFUSION AB Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, yet no effective therapeutics exist. This review provides an overview of the recent development of recombinant immunotoxins for the treatment of glypican-3 (GPC3) expressing HCC. GPC3 is a cell surface heparan sulfate proteoglycan that is overexpressed in HCC, but is absent from normal adult human tissues. Treatment of HCC with anti-GPC3 immunotoxins represents a new therapeutic option. Using phage display and hybridoma technologies, three high affinity antibodies (HN3, HS20 and YP7) have been generated against GPC3. Two of these antibodies (HN3 and HS20) have demonstrated the ability to inhibit Wnt/ Yap signaling, leading to a reduction in liver cancer cell proliferation. By combining the HN3 antibody capable of inhibiting Wnt/ Yap signaling with the protein synthesis inhibitory domain of the Pseudomonas exotoxin, a recombinant immunotoxin that exhibits a dual inhibitory mechanism was generated. This immunotoxin was found to be highly effective in the treatment of human HCCs in mouse xenograft models. Engineering of the toxin fragment to reduce the level of immunogenicity is currently being explored. The development of immunotoxins provides opportunities for novel liver cancer therapies. C1 [Fleming, Bryan D.; Ho, Mitchell] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Ho, M (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM Bryan.Fleming@nih.gov; homi@mail.nih.gov FU NIH Intramural Research Program; National Cancer Institute; Center for Cancer Research FX Support for this research was provided by the NIH Intramural Research Program, the National Cancer Institute, and the Center for Cancer Research. The National Cancer Institute (NCI) holds patent rights to the HN3, HS20, and YP7 anti-GPC3 antibodies in many jurisdictions, including the United States (e.g., U.S. Patent 9,206,257, U.S. Patent 9,304,364 and U.S. Patent 9,409,994), China, Japan, South Korea, Singapore, and Europe. Claims cover the antibodies themselves, as well as conjugates that utilize the antibodies, such as recombinant immunotoxins (RITs), antibody drug conjugates (ADCs), bispecific antibodies, and modified T cell receptors (TCRs)/chimeric antigen receptors (CARs). Anyone interested in licensing these antibodies can contact the authors directly for additional information. NR 99 TC 0 Z9 0 U1 2 U2 2 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 2072-6651 J9 TOXINS JI Toxins PD OCT PY 2016 VL 8 IS 10 AR 274 DI 10.3390/toxins8100274 PG 13 WC Toxicology SC Toxicology GA EB4MZ UT WOS:000387347300006 ER PT J AU Wang, XH Liu, HB Wang, HK Meyers, C Chow, L Zheng, ZM AF Wang, Xiaohong Liu, Haibin Wang, Hsu-Kun Meyers, Craig Chow, Louise Zheng, Zhi-Ming TI HPV18 DNA replication inactivates the early promoter P-55 activity and prevents viral E6 expression SO VIROLOGICA SINICA LA English DT Letter ID HUMAN-PAPILLOMAVIRUS TYPE-18; HUMAN KERATINOCYTES; INHIBITION; EPITHELIUM C1 [Wang, Xiaohong; Liu, Haibin; Zheng, Zhi-Ming] NCI, Tumor Virus RNA Biol Sect, RNA Biol Lab, NIH, Frederick, MD 21702 USA. [Wang, Hsu-Kun; Chow, Louise] Univ Alabama Birmingham, Dept Biochem & Mol Genet, Birmingham, AL 35294 USA. [Meyers, Craig] Penn State Univ, Dept Microbiol & Immunol, Coll Med, Hershey, PA 17033 USA. RP Zheng, ZM (reprint author), NCI, Tumor Virus RNA Biol Sect, RNA Biol Lab, NIH, Frederick, MD 21702 USA. EM zhengt@exchange.nih.gov NR 12 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1674-0769 EI 1995-820X J9 VIROL SIN JI Virol. Sin. PD OCT PY 2016 VL 31 IS 5 BP 437 EP 440 DI 10.1007/s12250-016-3887-1 PG 4 WC Virology SC Virology GA EB7ME UT WOS:000387570900007 PM 27822719 ER PT J AU London, RE AF London, Robert E. TI Structural Maturation of HIV-1 Reverse TranscriptaseA Metamorphic Solution to Genomic Instability SO VIRUSES-BASEL LA English DT Review DE HIV-1 reverse transcriptase; reverse transcriptase maturation pathway; metamorphic protein; RNase H domain; subunit-specific RNase H domain unfolding; structural heterodimer ID IMMUNODEFICIENCY-VIRUS TYPE-1; RNASE-H DOMAIN; MUTATION DEVELOPMENT PATHWAYS; POL POLYPROTEIN PRECURSOR; INHIBITOR-BINDING POCKET; TRYPTOPHAN-REPEAT MOTIF; RIBONUCLEASE-H; CRYSTAL-STRUCTURE; ACTIVE-SITE; AMINO-ACIDS AB Human immunodeficiency virus 1 (HIV-1) reverse transcriptase (RT)a critical enzyme of the viral life cycleundergoes a complex maturation process, required so that a pair of p66 precursor proteins can develop conformationally along different pathways, one evolving to form active polymerase and ribonuclease H (RH) domains, while the second forms a non-functional polymerase and a proteolyzed RH domain. These parallel maturation pathways rely on the structural ambiguity of a metamorphic polymerase domain, for which the sequence-structure relationship is not unique. Recent nuclear magnetic resonance (NMR) studies utilizing selective labeling techniques, and structural characterization of the p66 monomer precursor have provided important insights into the details of this maturation pathway, revealing many aspects of the three major steps involved: (1) domain rearrangement; (2) dimerization; and (3) subunit-selective RH domain proteolysis. This review summarizes the major structural changes that occur during the maturation process. We also highlight how mutations, often viewed within the context of the mature RT heterodimer, can exert a major influence on maturation and dimerization. It is further suggested that several steps in the RT maturation pathway may provide attractive targets for drug development. C1 [London, Robert E.] NIEHS, Genome Integr & Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RP London, RE (reprint author), NIEHS, Genome Integr & Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM london@niehs.nih.gov FU Intramural Research Program of the NIH; National Institute of Environmental Health Sciences (NIEHS) [Z01-ES050147] FX The progress toward understanding the structural maturation of HIV-1 reverse transcriptase described in this review was largely the result of the elegant NMR studies performed by Xunhai Zheng. The author is also grateful to Nicolas Sluis-Cremer (University of Pittsburgh), Lars Pedersen (NIEHS) and Geoff Mueller (NIEHS) for critical reading of this manuscript. Finally, the author is grateful for the continued support and encouragement of this project by Thomas Kunkel (NIEHS). Intramural Research Program of the NIH and National Institute of Environmental Health Sciences (NIEHS), Research Project Number Z01-ES050147. NR 144 TC 0 Z9 0 U1 1 U2 1 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD OCT PY 2016 VL 8 IS 10 AR 260 DI 10.3390/v8100260 PG 34 WC Virology SC Virology GA EB6HI UT WOS:000387482200001 ER PT J AU Lusvarghi, S Bewley, CA AF Lusvarghi, Sabrina Bewley, Carole A. TI Griffithsin: An Antiviral Lectin with Outstanding Therapeutic Potential SO VIRUSES-BASEL LA English DT Review DE carbohydrate binding agent; viral envelope glycoproteins; multivalency; resistance; immunogenicity; HIV; HSV; HCV ID ANTI-HIV ACTIVITY; JAPANESE ENCEPHALITIS-VIRUS; ENTRY INHIBITOR GRIFFITHSIN; HEPATITIS-C VIRUS; PROTEIN GRIFFITHSIN; CYANOVIRIN-N; MEMBRANE-FUSION; IN-VITRO; BINDING; GP120 AB Griffithsin (GRFT), an algae-derived lectin, is one of the most potent viral entry inhibitors discovered to date. It is currently being developed as a microbicide with broad-spectrum activity against several enveloped viruses. GRFT can inhibit human immunodeficiency virus (HIV) infection at picomolar concentrations, surpassing the ability of most anti-HIV agents. The potential to inhibit other viruses as well as parasites has also been demonstrated. Griffithsin's antiviral activity stems from its ability to bind terminal mannoses present in high-mannose oligosaccharides and crosslink these glycans on the surface of the viral envelope glycoproteins. Here, we review structural and biochemical studies that established mode of action and facilitated construction of GRFT analogs, mechanisms that may lead to resistance, and in vitro and pre-clinical results that support the therapeutic potential of this lectin. C1 [Lusvarghi, Sabrina; Bewley, Carole A.] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Bewley, CA (reprint author), NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. EM sabrinal@mail.nih.gov; caroleb@mail.nih.gov FU NIH Intramural Research Program (National Institute of Diabetes and Digestive and Kidney Diseases, NIDDK) FX We thank the NIH Intramural Research Program (National Institute of Diabetes and Digestive and Kidney Diseases, NIDDK) for financial support, and Cinque Soto and Peter Kwong, for coordinates for the fully glycosylated (with Man9GlcNAc2) model of gp120. NR 54 TC 0 Z9 0 U1 6 U2 6 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD OCT PY 2016 VL 8 IS 10 AR 296 DI 10.3390/v8100296 PG 18 WC Virology SC Virology GA EB6HI UT WOS:000387482200031 ER PT J AU Calenda, G Levendosky, K Barnable, P Villegas, G Kleinbeck, K Aravantinou, M Keefe, BRO Gettie, A Blanchard, J Derby, N Zydowsky, TM Fernandez-Romero, JA Teleshova, N AF Calenda, Giulia Levendosky, Keith Barnable, Patrick Villegas, Guillermo Kleinbeck, Kyle Aravantinou, Meropi Keefe, Barry R. O. Gettie, Agegnehu Blanchard, James Derby, Nina Zydowsky, Thomas M. Fernandez-Romero, Jose A. Teleshova, Natalia TI Pharmacodynamics of Griffithsin after Vaginal Application of a Gel or Intravaginal Ring in Macaques SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on HIV Research for Prevention (HIV R4P) CY OCT 17-20, 2016 CL Chicago, IL C1 [Calenda, Giulia; Levendosky, Keith; Barnable, Patrick; Villegas, Guillermo; Kleinbeck, Kyle; Aravantinou, Meropi; Derby, Nina; Zydowsky, Thomas M.; Fernandez-Romero, Jose A.; Teleshova, Natalia] Populat Council, 1230 York Ave, New York, NY 10021 USA. [Keefe, Barry R. O.] NCI, Bethesda, MD 20892 USA. [Gettie, Agegnehu] Aaron Diamond AIDS Res Ctr, New York, NY USA. [Blanchard, James] Tulane Natl Primate Res Ctr, Covington, LA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2016 VL 32 SU 1 MA P07.17 BP 216 EP 216 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA EA6YH UT WOS:000386774600394 ER PT J AU Calenda, G Aravantinou, M Villegas, G Levendosky, K Kleinbeck, K Keefe, BRO Gettie, A Blanchard, J Gillevet, P Derby, N Fernandez-Romero, JA Zydowsky, TM Teleshova, N AF Calenda, Giulia Aravantinou, Meropi Villegas, Guillermo Levendosky, Keith Kleinbeck, Kyle Keefe, Barry R. O. Gettie, Agegnehu Blanchard, James Gillevet, Patrick Derby, Nina Fernandez-Romero, Jose A. Zydowsky, Thomas M. Teleshova, Natalia TI Safety of GRFT-containing Vaginal Gels in Rhesus Macaques SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on HIV Research for Prevention (HIV R4P) CY OCT 17-20, 2016 CL Chicago, IL C1 [Calenda, Giulia; Aravantinou, Meropi; Villegas, Guillermo; Levendosky, Keith; Kleinbeck, Kyle; Derby, Nina; Fernandez-Romero, Jose A.; Zydowsky, Thomas M.; Teleshova, Natalia] Populat Council, 1230 York Ave, New York, NY 10021 USA. [Keefe, Barry R. O.] NCI, Bethesda, MD 20892 USA. [Gettie, Agegnehu] Aaron Diamond AIDS Res Ctr, New York, NY USA. [Blanchard, James] Tulane Natl Primate Res Ctr, Covington, LA USA. [Gillevet, Patrick] George Mason Univ, Fairfax, VA 22030 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2016 VL 32 SU 1 MA P07.18 BP 216 EP 216 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA EA6YH UT WOS:000386774600395 ER PT J AU Matteini, AM Tanaka, T Karasik, D Atzmon, G Chou, WC Eicher, JD Johnson, AD Arnold, AM Callisaya, ML Davies, G Evans, DS Holtfreter, B Lohman, K Lunetta, KL Mangino, M Smith, AV Smith, JA Teumer, A Yu, L Arking, DE Buchman, AS Chibinik, LB De Jager, PL Evans, DA Faul, JD Garcia, ME Gillham-Nasenya, I Gudnason, V Hofman, A Hsu, YH Ittermann, T Lahousse, L Liewald, DC Liu, YM Lopez, L Rivadeneira, F Rotter, JI Siggeirsdottir, K Starr, JM Thomson, R Tranah, GJ Uitterlinden, AG Volker, U Volzke, H Weir, DR Yaffe, K Zhao, W Zhuang, WV Zmuda, JM Bennett, DA Cummings, SR Deary, IJ Ferrucci, L Harris, TB Kardia, SLR Kocher, T Kritchevsky, SB Psaty, BM Seshadri, S Spector, TD Srikanth, VK Windham, BG Zillikens, MC Newman, AB Walston, JD Kiel, DP Murabito, JM AF Matteini, Amy M. Tanaka, Toshiko Karasik, David Atzmon, Gil Chou, Wen-Chi Eicher, John D. Johnson, Andrew D. Arnold, Alice M. Callisaya, Michele L. Davies, Gail Evans, Daniel S. Holtfreter, Birte Lohman, Kurt Lunetta, Kathryn L. Mangino, Massimo Smith, Albert V. Smith, Jennifer A. Teumer, Alexander Yu, Lei Arking, Dan E. Buchman, Aron S. Chibinik, Lori B. De Jager, Philip L. Evans, Denis A. Faul, Jessica D. Garcia, Melissa E. Gillham-Nasenya, Irina Gudnason, Vilmundur Hofman, Albert Hsu, Yi-Hsiang Ittermann, Till Lahousse, Lies Liewald, David C. Liu, Yongmei Lopez, Lorna Rivadeneira, Fernando Rotter, Jerome I. Siggeirsdottir, Kristin Starr, John M. Thomson, Russell Tranah, Gregory J. Uitterlinden, Andre G. Voelker, Uwe Voelzke, Henry Weir, David R. Yaffe, Kristine Zhao, Wei Zhuang, Wei Vivian Zmuda, Joseph M. Bennett, David A. Cummings, Steven R. Deary, Ian J. Ferrucci, Luigi Harris, Tamara B. Kardia, Sharon L. R. Kocher, Thomas Kritchevsky, Stephen B. Psaty, Bruce M. Seshadri, Sudha Spector, Timothy D. Srikanth, Velandai K. Windham, B. Gwen Zillikens, M. Carola Newman, Anne B. Walston, Jeremy D. Kiel, Douglas P. Murabito, Joanne M. TI GWAS analysis of handgrip and lower body strength in older adults in the CHARGE consortium SO AGING CELL LA English DT Article DE aging; genomewide association; meta-analysis; muscle strength; older adults; SNP ID MUSCLE STRENGTH; C/EBP-BETA; OXIDATIVE STRESS; SKELETAL-MUSCLE; GENE-EXPRESSION; GRIP STRENGTH; ASSOCIATION; HEALTH; AGE; POLYMORPHISMS AB Decline in muscle strength with aging is an important predictor of health trajectory in the elderly. Several factors, including genetics, are proposed contributors to variability in muscle strength. To identify genetic contributors to muscle strength, a meta-analysis of genomewide association studies of handgrip was conducted. Grip strength was measured using a handheld dynamometer in 27581 individuals of European descent over 65years of age from 14 cohort studies. Genomewide association analysis was conducted on similar to 2.7 million imputed and genotyped variants (SNPs). Replication of the most significant findings was conducted using data from 6393 individuals from three cohorts. GWAS of lower body strength was also characterized in a subset of cohorts. Two genomewide significant (P-value< 5x10(-8)) and 39 suggestive (P-value< 5x10(-5)) associations were observed from meta-analysis of the discovery cohorts. After meta-analysis with replication cohorts, genomewide significant association was observed for rs752045 on chromosome 8 (=0.47, SE=0.08, P-value=5.20x10(-10)). This SNP is mapped to an intergenic region and is located within an accessible chromatin region (DNase hypersensitivity site) in skeletal muscle myotubes differentiated from the human skeletal muscle myoblasts cell line. This locus alters a binding motif of the CCAAT/enhancer-binding protein- (CEBPB) that is implicated in muscle repair mechanisms. GWAS of lower body strength did not yield significant results. A common genetic variant in a chromosomal region that regulates myotube differentiation and muscle repair may contribute to variability in grip strength in the elderly. Further studies are needed to uncover the mechanisms that link this genetic variant with muscle strength. C1 [Matteini, Amy M.; Walston, Jeremy D.] Johns Hopkins Univ, Sch Med, Div Geriatr Med & Gerontol, Baltimore, MD USA. [Tanaka, Toshiko; Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Translat Gerontol Branch, Gerontol Res Ctr, Baltimore, MD 21224 USA. [Karasik, David; Chou, Wen-Chi; Hsu, Yi-Hsiang; Kiel, Douglas P.] Beth Israel Deaconess Med Ctr, Dept Med, Hebrew SeniorLife, Inst Aging Res, Boston, MA 02215 USA. [Karasik, David; Chou, Wen-Chi; Hsu, Yi-Hsiang; Ferrucci, Luigi; Kiel, Douglas P.] Harvard Med Sch, Boston, MA USA. [Karasik, David] Bar Ilan Univ, Fac Med Galilee, IL-13010 Safed, Israel. [Atzmon, Gil] Albert Einstein Coll Med, Inst Aging Res, Dept Med, 1300 Morris Pk Ave, Bronx, NY 10467 USA. [Atzmon, Gil] Albert Einstein Coll Med, Inst Aging Res, Dept Genet, 1300 Morris Pk Ave, Bronx, NY 10467 USA. [Atzmon, Gil] Univ Haifa, Dept Human Biol, Haifa, Israel. [Eicher, John D.; Johnson, Andrew D.] NHLBI, Populat Sci Branch, Bldg 10, Bethesda, MD 20892 USA. [Eicher, John D.; Johnson, Andrew D.; Lunetta, Kathryn L.; Seshadri, Sudha; Murabito, Joanne M.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Arnold, Alice M.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Callisaya, Michele L.; Srikanth, Velandai K.] Monash Univ, Stroke & Ageing Res Grp, Dept Med, Sch Clin Sci, Clayton, Vic, Australia. [Callisaya, Michele L.; Thomson, Russell; Srikanth, Velandai K.] Univ Tasmania, Menzies Inst Med Res, Hobart, Tas, Australia. [Davies, Gail; Liewald, David C.; Deary, Ian J.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemol, Edinburgh, Midlothian, Scotland. [Davies, Gail; Lopez, Lorna] Univ Edinburgh, Dept Psychol, Edinburgh, Midlothian, Scotland. [Evans, Daniel S.; Tranah, Gregory J.; Cummings, Steven R.] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. [Holtfreter, Birte; Kocher, Thomas] Univ Med Greifswald, Dept Restorat Dent Periodontol & Endodointol, Ctr Oral Hlth, Unit Periodontol, Greifswald, Germany. [Lohman, Kurt; Liu, Yongmei] Wake Forest Sch Med, Div Publ Hlth Sci, Ctr Human Genet, Winston Salem, NC USA. [Lunetta, Kathryn L.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Mangino, Massimo; Gillham-Nasenya, Irina; Spector, Timothy D.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England. [Mangino, Massimo] Guys & St Thomas Fdn Trust, NIHR Biomed Res Ctr, London, England. [Smith, Albert V.; Gudnason, Vilmundur; Siggeirsdottir, Kristin] Icelandic Heart Assoc, Kopavogur, Iceland. [Smith, Jennifer A.; Zhao, Wei; Kardia, Sharon L. R.] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Teumer, Alexander; Ittermann, Till; Voelzke, Henry] Univ Med Greifswald, Inst Community Med, Greifswald, Germany. [Yu, Lei; Buchman, Aron S.; Bennett, David A.] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL USA. [Arking, Dan E.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Buchman, Aron S.] Rush Univ, Dept Neurol Sci, Med Ctr, Chicago, IL 60612 USA. [Chibinik, Lori B.; De Jager, Philip L.] Brigham & Womens Hosp, Dept Neurol, Program Translat NeuroPsychiatr Genom, 75 Francis St, Boston, MA 02115 USA. [Chibinik, Lori B.; De Jager, Philip L.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Evans, Denis A.] Rush Univ, Inst Hlth Aging, Med Ctr, Chicago, IL 60612 USA. [Evans, Denis A.] Rush Univ, Dept Internal Med, Med Ctr, Chicago, IL 60612 USA. [Faul, Jessica D.; Weir, David R.] Univ Michigan, Inst Social Res, Survey Res Ctr, Ann Arbor, MI USA. [Garcia, Melissa E.] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. [Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. [Hofman, Albert; Lahousse, Lies; Rivadeneira, Fernando; Uitterlinden, Andre G.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Hsu, Yi-Hsiang] Harvard Sch Publ Hlth, Dept Med Mol & Integrat Physiol Sci, Boston, MA USA. [Lahousse, Lies] Univ Ghent, Dept Resp Med, Ghent, Belgium. [Lahousse, Lies] Ghent Univ Hosp, Ghent, Belgium. [Rivadeneira, Fernando; Uitterlinden, Andre G.; Zillikens, M. Carola] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Rivadeneira, Fernando; Uitterlinden, Andre G.] NCHA, NGI, Rotterdam, Netherlands. [Rotter, Jerome I.] Univ Calif Los Angeles, Dept Pediat, Div Genom Outcome, Los Angeles, CA 90024 USA. [Rotter, Jerome I.] Univ Calif Los Angeles, Dept Med, Inst Translat Genom & Populat Sci, Los Angeles Biomed Res Inst,Harbor UCLA Med Ctr, Los Angeles, CA 90024 USA. [Starr, John M.] Univ Edinburgh, Alzheimer Scotland Dementia Res Ctr, Edinburgh, Midlothian, Scotland. [Voelker, Uwe] Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany. [Voelzke, Henry] German Ctr Cardiovasc Res DZHK, Greifswald, Germany. [Voelzke, Henry] German Ctr Diabet Res DZD, Greifswald, Germany. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Yaffe, Kristine] San Francisco VA Med Ctr, San Francisco, CA USA. [Zhuang, Wei Vivian] Creighton Univ, Sch Med, Ctr Hlth Policy & Eth, Publ Hlth Program, Omaha, NE USA. [Zmuda, Joseph M.; Newman, Anne B.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Deary, Ian J.] Univ Edinburgh, Dept Psychol, Edinburgh, Midlothian, Scotland. [Harris, Tamara B.] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. [Kritchevsky, Stephen B.] Wake Forest Sch Med, Sticht Ctr Aging, Winston Salem, NC USA. [Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Med, Seattle, WA USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Seshadri, Sudha] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Windham, B. Gwen] Univ Mississippi, Med Ctr, Dept Med, Div Geriatr, Jackson, MS 39216 USA. [Murabito, Joanne M.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. RP Matteini, AM (reprint author), Johns Hopkins Ctr Aging & Hlth, 2024 East Monument St,Suite 2-126, Baltimore, MD 21287 USA. EM amatteini@jhmi.edu RI Callisaya, Michele/I-2333-2013; Thomson, Russell/H-5653-2012; OI Callisaya, Michele/0000-0003-2122-1622; Thomson, Russell/0000-0003-4949-4120; Karasik, David/0000-0002-8826-0530; Smith, Jennifer/0000-0002-3575-5468; Lahousse, Lies/0000-0002-3494-4363 FU Johns Hopkins University Claude D. Pepper Older Americans Independence Center (NIA) [P30 AG021334]; Wellcome Trust [FP7/2007-2013]; National Institute for Health Research, National Institute of Diabetes and Digestive and Kidney Diseases [DK063491]; German Federal Ministry of Education and Research [01ZZ0103, 01ZZ0403, 01ZZ9603, 031S2061A, 03ZIK012]; National Institutes of Health [HHSN268200625226C, HHSN268200782096C, N01AG12 100, UL1RR025005]; Biotechnology and Biological Sciences Research Council; National Health and Medical Research Council [NHMRC 100089, NHMRC 1034483, NHMRC 1061457, NHMRC 403000, NHMRC491109, NHMRC606543]; National Institute on Aging [1R01AG032098-01A1, 263 MD 821336, 263 MD 9164, AG016495, AG033193, AG08122, N01AG62101, N01AG 62103, N01AG62106, P30AG10161]; National Institute of Arthritis and Musculoskeletal and Skin Diseases [R01 AR41398, R01-AR051124, RC2ARO58973, U01 AR45580, U01 AR45 583, U01 AR45614, U01 AR45632, U01 AR45647, U01 AR45654]; National Heart, Lung, and Blood Institute [HHSN268200800007C, HHSN268201100005C, HH5N268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HH5N268201100010C, HHSN268201100011C, HHSN268201100012C, HHSN268201200036C]; National Human Genome Research Institute [U01 HG004402]; Medical Research Council, Research Institute for Diseases in the Elderly [014-93-015, RIDE2]; Netherlands Organization for Scientific Research NWO Investments [050-060-810, 175.010.2005.011, 911-03-012]; National Center for Research Resources [UL1 RR024140, N02HL64278, N01-AG-1-2100, HHSN27120 120022C, HL105756, N01HC85083, N01HC85086, RC1 AG035835]; NIA Intramural Research Program; Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); Research Foundation Flanders (FWO); UK Biotechnology and Biological Sciences Research Council; Royal Society; Chief Scientist Office of the Scottish Government, Age UK (The Disconnected Mind project), Lifelong Health and Wellbeing Initiative) [MR/K026992/1]; Medical Research Council; Netherlands Organization of Scientific Research NWO Investments [050-060-810, 175.010.2005.011, 911-03-012]; Research Institute for Diseases in the Elderly [014-93-015]; RIDE2; Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA) [050-060-810]; The National Institute on Aging [R01 AG005394, R01 AG005407, R01 AG0275747, R01 AG027576, R01 AR35582, R01 AR35583, R01AG 023629, R01AG040039, R01AG15819, R01AG17917, R01AG24480, R01AG29451, R01AG30146, R01AR35584, RC2 AG036495, U01 AG 18197, U01-AG027810, U01A0009740]; The National Heart, Lung, and Blood Institute [N01HC25195, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, R01HL086694, R01HL087641, R01HL103612, R01HL120393, R01HL59367, U01 HL080295] FX Johns Hopkins University Claude D. Pepper Older Americans Independence Center (NIA Grant/Award Number P30 AG021334), Wellcome Trust, (Grant/Award Number: 'FP7/2007-2013') National Institute for Health Research, National Institute of Diabetes and Digestive and Kidney Diseases, (Grant/Award Number: 'DK063491') German Federal Ministry of Education and Research, (Grant/Award Number: '01ZZ0103','01ZZ0403','01ZZ9603', '031S2061A','03ZIK012'), National Institutes of Health, (Grant/Award Number: 'HHSN268200625226C','HHSN268200782096C','N01AG12 100','UL1RR025005'), Biotechnology and Biological Sciences Research Council, National Health and Medical Research Council, (Grant/Award Number: 'NHMRC 100089','NHMRC 1034483','NHMRC 1061457','NHMRC 403000','NHMRC491109','NHMRC606543'), National Institute on Aging, (Grant/Award Number: '1R01AG032098-01A1','263 MD 821336'.'263 MD 9164 ','AG016495','AG033193,',AG08122','N01AG62101','N01AG 62103','N01AG62106','P30AG10161','R01 AG005394','R01 AG005407', 'R01 AG0275747','R01 AG027576','R01 AR35582','R01 AR35583','R01AG 023629','R01AG040039','R01AG15819','R01AG17917','R01AG24480', 'R01AG29451','R01AG30146','R01AR35584','RC2 AG036495','U01 AG 18197','U01-AG027810','U01A0009740'), National Institute of Arthritis and Musculoskeletal and Skin Diseases, (Grant/Award Number: 'R01 AR41398','R01-AR051124','RC2ARO58973','U01 AR45580','U01 AR45 583','U01 AR45614','U01 AR45632','U01 AR45647','U01 AR45654') National Heart, Lung, and Blood Institute, (Grant/Award Number: 'HHSN268200800007C','HHSN268201100005C','HH5N268201100006C','HHSN2682011 00007C','HHSN268201100008C','HHSN268201100009C','HH5N268201100010C','HHS N268201100011C','HHSN26820 1100012C','HHSN268201200036C','N01HC25195','N01HC55222','N01HC85079','N0 1HC85080','N01HC85081','N01HC85082','R01HL0866 94','R01HL087641','R01HL103612','R01HL120393','R01HL59367','U01 HL080295'), National Human Genome Research Institute, (Grant/Award Number: 'U01 HG004402') Medical Research Council, Research Institute for Diseases in the Elderly, (Grant/Award Number '014-93-015','RIDE2') Netherlands Organization for Scientific Research NWO Investments, (Grant/Award Number: '050-060-810','175.010.2005.011','911-03-012'), National Center for Research Resources, (Grant/Award Number: 'UL1 RR024140'). "N02HL64278", "N01-AG-1-2100", "HHSN27120 120022C", "HL105756", "N01HC85083", "N01HC85086", "RC1 AG035835", NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), the Althingi (the Icelandic Parliament), Research Foundation Flanders (FWO), UK Biotechnology and Biological Sciences Research Council, The Royal Society, The Chief Scientist Office of the Scottish Government, Age UK (The Disconnected Mind project), Lifelong Health and Wellbeing Initiative: "MR/K026992/1", Medical Research Council, Netherlands Organization of Scientific Research NWO Investments: "nr." 175.010.2005.011", "911-03-012", "050-060-810", Research Institute for Diseases in the Elderly: "014-93-015"; "RIDE2", Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA): "nr. 050-060-810." NR 32 TC 1 Z9 1 U1 6 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1474-9718 EI 1474-9726 J9 AGING CELL JI Aging Cell PD OCT PY 2016 VL 15 IS 5 BP 792 EP 800 DI 10.1111/acel.12468 PG 9 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA DW5VN UT WOS:000383715600001 PM 27325353 ER PT J AU Teumer, A Qi, QB Nethander, M Aschard, H Bandinelli, S Beekman, M Berndt, SI Bidlingmaier, M Broer, L Cappola, A Ceda, GP Chanock, S Chen, MH Chen, TC Chen, YDI Chung, J Miglianico, FD Eriksson, J Ferrucci, L Friedrich, N Gnewuch, C Goodarzi, MO Grarup, N Guo, TW Hammer, E Hayes, RB Hicks, AA Hofman, A Houwing-Duistermaat, JJ Hu, F Hunter, DJ Husemoen, LL Isaacs, A Jacobs, KB Janssen, JAMJL Jansson, JO Jehmlich, N Johnson, S Juul, A Karlsson, M Kilpelainen, TO Kovacs, P Kraft, P Li, C Linneberg, A Liu, YM Loos, RJF Lorentzon, M Lu, YC Maggio, M Magi, R Meigs, J Mellstrom, D Nauck, M Newman, AB Pollak, MN Pramstaller, PP Prokopenko, I Psaty, BM Reincke, M Rimm, EB Rotter, JI Saint Pierre, A Schurmann, C Seshadri, S Sjogren, K Slagboom, PE Strickler, HD Stumvoll, M Suh, YS Sun, Q Zhang, CL Svensson, J Tanaka, T Tare, A Tonjes, A Uh, HW van Duijn, CM van Heemst, D Vandenput, L Vasan, RS Volker, U Willems, SM Ohlsson, C Wallaschofski, H Kaplan, RC AF Teumer, Alexander Qi, Qibin Nethander, Maria Aschard, Hugues Bandinelli, Stefania Beekman, Marian Berndt, Sonja I. Bidlingmaier, Martin Broer, Linda Cappola, Anne Ceda, Gian Paolo Chanock, Stephen Chen, Ming-Huei Chen, Tai C. Chen, Yii-Der Ida Chung, Jonathan Miglianico, Fabiola Del Greco Eriksson, Joel Ferrucci, Luigi Friedrich, Nele Gnewuch, Carsten Goodarzi, Mark O. Grarup, Niels Guo, Tingwei Hammer, Elke Hayes, Richard B. Hicks, Andrew A. Hofman, Albert Houwing-Duistermaat, Jeanine J. Hu, Frank Hunter, David J. Husemoen, Lise L. Isaacs, Aaron Jacobs, Kevin B. Janssen, Joop A. M. J. L. Jansson, John-Olov Jehmlich, Nico Johnson, Simon Juul, Anders Karlsson, Magnus Kilpelainen, Tuomas O. Kovacs, Peter Kraft, Peter Li, Chao Linneberg, Allan Liu, Yongmei Loos, Ruth J. F. Lorentzon, Mattias Lu, Yingchang Maggio, Marcello Magi, Reedik Meigs, James Mellstrom, Dan Nauck, Matthias Newman, Anne B. Pollak, Michael N. Pramstaller, Peter P. Prokopenko, Inga Psaty, Bruce M. Reincke, Martin Rimm, Eric B. Rotter, Jerome I. Saint Pierre, Aude Schurmann, Claudia Seshadri, Sudha Sjogren, Klara Slagboom, P. Eline Strickler, Howard D. Stumvoll, Michael Suh, Yousin Sun, Qi Zhang, Cuilin Svensson, Johan Tanaka, Toshiko Tare, Archana Toenjes, Anke Uh, Hae-Won van Duijn, Cornelia M. van Heemst, Diana Vandenput, Liesbeth Vasan, Ramachandran S. Voelker, Uwe Willems, Sara M. Ohlsson, Claes Wallaschofski, Henri Kaplan, Robert C. CA CHARGE Longevity Working Grp Body Composition Genetics Consorti TI Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits SO AGING CELL LA English DT Article DE aging; genomewide association study; growth hormone axis; IGF-I; IGFBP-3; longevity ID GROWTH-FACTOR-I; FACTOR-BINDING PROTEIN-3; WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; CIRCULATING LEVELS; GENETIC-VARIATION; FACTOR (IGF)-I; CANCER-RISK; INSULIN; DISEASE AB The growth hormone/insulin-like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF-related proteins including IGF-I and IGF-binding protein-3 (IGFBP-3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Through genomewide association study of up to 30884 adults of European ancestry from 21 studies, we confirmed and extended the list of previously identified loci associated with circulating IGF-I and IGFBP-3 concentrations (IGF1, IGFBP3, GCKR, TNS3, GHSR, FOXO3, ASXL2, NUBP2/IGFALS, SORCS2, and CELSR2). Significant sex interactions, which were characterized by different genotype-phenotype associations between men and women, were found only for associations of IGFBP-3 concentrations with SNPs at the loci IGFBP3 and SORCS2. Analyses of SNPs, gene expression, and protein levels suggested that interplay between IGFBP3 and genes within the NUBP2 locus (IGFALS and HAGH) may affect circulating IGF-I and IGFBP-3 concentrations. The IGF-I-decreasing allele of SNP rs934073, which is an eQTL of ASXL2, was associated with lower adiposity and higher likelihood of survival beyond 90years. The known longevity-associated variant rs2153960 (FOXO3) was observed to be a genomewide significant SNP for IGF-I concentrations. Bioinformatics analysis suggested enrichment of putative regulatory elements among these IGF-I- and IGFBP-3-associated loci, particularly of rs646776 at CELSR2. In conclusion, this study identified several loci associated with circulating IGF-I and IGFBP-3 concentrations and provides clues to the potential role of the IGF axis in mediating effects of known (FOXO3) and novel (ASXL2) longevity-associated loci. C1 [Teumer, Alexander] Univ Med Greifswald, Inst Commun Med, D-17475 Greifswald, Germany. [Teumer, Alexander; Chanock, Stephen; Hammer, Elke; Jacobs, Kevin B.; Jehmlich, Nico; Voelker, Uwe] Univ Med Greifswald, Interfac Inst Genet & Funct Genom, D-17475 Greifswald, Germany. [Qi, Qibin; Strickler, Howard D.; Kaplan, Robert C.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10461 USA. [Nethander, Maria] Univ Gothenburg, Salalgrenska Acad, Bioinformat Core Facil, S-40530 Gothenburg, Sweden. [Aschard, Hugues] Harvard Sch Publ Hlth, Dept Epidemiol, Program Genet Epidemiol & Stat Genet, Boston, MA 02115 USA. [Bandinelli, Stefania] Azienda Sanitaria Fimnze ASP, Geriatr Unit, Florence, Italy. [Beekman, Marian; Slagboom, P. Eline] Leiden Univ, Med Ctr, Mol Epidemiol, NL-2300 RC Leiden, Netherlands. [Berndt, Sonja I.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Bidlingmaier, Martin; Reincke, Martin] Klinikum Univ Munchen, Med Klin & Poliklin 4, D-80336 Munich, Germany. [Broer, Linda] Erasmus MC, Dept Epidemiol, Subdiv Genet Epidemiol, Postbus 2040, NL-3000 CA Rotterdam, Netherlands. [Broer, Linda] Erasmus MC, Dept Internal Med, Postbus 2040, NL-3000 CA Rotterdam, Netherlands. [Cappola, Anne] Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Div Endocrinol Diabet & Metab,Dept Med, Philadelphia, PA 19104 USA. [Ceda, Gian Paolo; Maggio, Marcello] Univ Parma, Sect Geriatr, Dept Clin & Expt Med, Parma, Italy. [Ceda, Gian Paolo; Maggio, Marcello] Univ Hosp Parma, Geriatr Rehabil Dept, Parma, Italy. [Chen, Ming-Huei; Seshadri, Sudha] Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA. [Chen, Ming-Huei; Seshadri, Sudha] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Chen, Tai C.] Boston Univ, Sch Med, Sect Endocrinol Diabet & Nutr, Boston, MA 02118 USA. [Chen, Yii-Der Ida; Rotter, Jerome I.] Harbor UCLA Med Ctr, Los Angeles BioMed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90502 USA. [Chung, Jonathan; Guo, Tingwei; Johnson, Simon; Li, Chao; Suh, Yousin; Tare, Archana] Albert Einstein Coll Med, Dept Genet, Bronx, NY 10461 USA. [Miglianico, Fabiola Del Greco; Hicks, Andrew A.; Pramstaller, Peter P.] European Acad Bozen Bolzano EURAC, Ctr Biomed, I-39100 Bolzano, Italy. [Miglianico, Fabiola Del Greco; Pramstaller, Peter P.] Univ Lubeck, Affiliated Inst, D-23562 Lubeck, Germany. [Eriksson, Joel; Lorentzon, Mattias; Mellstrom, Dan; Sjogren, Klara; Svensson, Johan; Vandenput, Liesbeth; Ohlsson, Claes] Univ Gothenburg, Dept Internal Med & Clin Nutr, Inst Med, Sahlgrenska Acad, S-41345 Gothenburg, Sweden. [Ferrucci, Luigi; Tanaka, Toshiko] NIA, Translat Gerontol Branch, Baltimore, MD 21225 USA. [Friedrich, Nele; Wallaschofski, Henri] Univ Med Greifswald, Inst Clin Chem & Lab Med, D-17475 Greifswald, Germany. [Gnewuch, Carsten] Univ Regensburg, Med Ctr, Inst Clin Chem & Lab Med, D-93053 Regensburg, Germany. [Goodarzi, Mark O.] Cedars Sinai Med Ctr, Dept Med, Div Endocrinol Diabet & Metab, Los Angeles, CA 90048 USA. [Grarup, Niels; Kilpelainen, Tuomas O.] Univ Copenhagen, Ctr Basic Metab Res, Sect Metab Genet, Fac Hlth & Med Sci,Novo Nordisk Fdn, DK-2100 Copenhagen, Denmark. [Hayes, Richard B.] NYU, Sch Med, Dept Populat Hlth, Div Epidemiol, New York, NY 10016 USA. [Hofman, Albert] Erasmus Univ, Med Ctr, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands. [Houwing-Duistermaat, Jeanine J.; Isaacs, Aaron; Uh, Hae-Won] Leiden Univ, Med Ctr, Med Stat & Bioinformat, NL-2300 RC Leiden, Netherlands. [Hu, Frank; Hunter, David J.; Nauck, Matthias; Rimm, Eric B.; Sun, Qi] Harvard Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Hu, Frank; Kraft, Peter; Rimm, Eric B.; Sun, Qi] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Hu, Frank; Kraft, Peter; Rimm, Eric B.; Sun, Qi] Harvard Med Sch, Boston, MA 02115 USA. [Hunter, David J.; Kraft, Peter; Nauck, Matthias] Harvard Sch Publ Hlth, Dept Epidemiol & Stat Genet, Boston, MA 02115 USA. [Husemoen, Lise L.; Linneberg, Allan] Capital Reg Denmark, Res Ctr Prevent & Hlth, DK-2600 Copenhagen, Denmark. [Isaacs, Aaron; van Duijn, Cornelia M.; Willems, Sara M.] Erasmus Univ, Med Ctr, Dept Epidemiol, Genet Epidemiol Unit, NL-3000 CA Rotterdam, Netherlands. [Isaacs, Aaron; van Duijn, Cornelia M.] Ctr Med Syst Biol, NL-2300 RC Leiden, Netherlands. [Janssen, Joop A. M. J. L.] Erasmus Univ, Med Ctr, Dept Internal Med, NL-3000 CA Rotterdam, Netherlands. [Jansson, John-Olov] Uiaivers Gothenburg, Inst Neurosci & Physiol, Sahlgrenska Acad, Dept Physiol, S-41345 Gothenburg, Sweden. [Jehmlich, Nico] UFZ, Helmholtz Ctr Environm Res, Dept Prote, D-04318 Leipzig, Germany. [Juul, Anders] Univ Copenhagen, Dept Growth & Reprod, Rigshosp, DK-2100 Copenhagen, Denmark. [Karlsson, Magnus] Lund Univ, Dept Clin Sci, Clin & Mol Osteoporosis Res Unit, S-20502 Malmo, Sweden. [Kovacs, Peter; Stumvoll, Michael] Univ Leipzig, IFB Adipos Dis, D-04103 Leipzig, Germany. [Kraft, Peter] Harvard Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Linneberg, Allan] Glostrup Univ Hosp, Dept Clin Expt Res, DK-2600 Copenhagen, Denmark. [Linneberg, Allan] Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, DK-2200 Copenhagen, Denmark. [Liu, Yongmei] Wake Forest Sch Med, Dept Epidemiol & Prevent, Div Publ Hlth Sci, Winston Salem, NC 27157 USA. [Loos, Ruth J. F.; Lu, Yingchang] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA. [Magi, Reedik] Univ Tartu, Estonian Genome Ctr, Tartu, Estonia. [Magi, Reedik] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Meigs, James] Massachusetts Gen Hosp, Div Gen Med, Dept Med, Boston, MA 02114 USA. [Meigs, James] Harvard Med Sch, Div Gen Med, Boston, MA 02115 USA. [Newman, Anne B.] Univ Pittsburgh, Dept Epidemiol, Sch Publ Hlth, Pittsburgh, PA 15261 USA. [Pollak, Michael N.] McGill Univ, Dept Expt Med, Montreal, PQ H3A 0G4, Canada. [Pollak, Michael N.] McGill Univ, Dept Oncol, Montreal, PQ H3A 0G4, Canada. [Prokopenko, Inga] Imperial Coll London, Sch Publ Hlth, Dept Genom Common Dis, London W12 0NN, England. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98101 USA. [Psaty, Bruce M.] Univ Washington, Dept Med, Seattle, WA 98101 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98101 USA. [Saint Pierre, Aude] INSERM, U1078, Brest, France. [Schurmann, Claudia] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA. [Schurmann, Claudia] Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA. [Suh, Yousin] Albert Einstein Coll Med, Dept Med, Bronx, NY 10461 USA. [Suh, Yousin] Guangdong Med Coll, Inst Aging Res, Dongguan, Peoples R China. [Zhang, Cuilin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH, 6100 Executive Blvd, Rockville, MD 20852 USA. [Toenjes, Anke] Univ Leipzig, Dept Med, D-04103 Leipzig, Germany. [van Heemst, Diana] Leiden Univ, Med Ctr, Gerontol & Geriatr, NL-2300 RC Leiden, Netherlands. [Vasan, Ramachandran S.] Boston Univ, Framingham, MA 01702 USA. [Vasan, Ramachandran S.] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA 01702 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Prevent Med & Epidemiol Sect, Boston, MA 02118 USA. RP Kaplan, RC (reprint author), Albert Einstein Coll Med, 1300 Morris Pk Ave, Bronx, NY 10461 USA. EM robert.kaplan@einstein.yu.edu RI Jehmlich, Nico/B-5403-2009; Slagboom, P. Eline/R-4790-2016; Grarup, Niels/K-2807-2015; Hicks, Andrew/E-9518-2017; OI Slagboom, P. Eline/0000-0002-2875-4723; Grarup, Niels/0000-0001-5526-1070; Hicks, Andrew/0000-0001-6320-0411; Ceda, Gian Paolo/0000-0002-9648-8295; Hayes, Richard/0000-0002-0918-661X; Vandenput, Liesbeth/0000-0002-1712-6131; Linneberg, Allan/0000-0002-0994-0184 FU NCATS NIH HHS [UL1 TR000124, UL1 TR001881]; NHLBI NIH HHS [R01 HL075516, HHSN268200800007C, HHSN268201200036C, N01HC85079, N01HC85081, N01HC85082]; NIA NIH HHS [P01 AG017242, P30 AG024827, R01 AG031890]; NIDDK NIH HHS [K24 DK080140, P30 DK020541, P30 DK063491, R01 DK078616, U01 DK078616] NR 58 TC 3 Z9 3 U1 8 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1474-9718 EI 1474-9726 J9 AGING CELL JI Aging Cell PD OCT PY 2016 VL 15 IS 5 BP 811 EP 824 DI 10.1111/acel.12490 PG 14 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA DW5VN UT WOS:000383715600003 PM 27329260 ER PT J AU Fabbri, E Yang, A Simonsick, EM Chia, CW Zoli, M Haughey, NJ Mielke, MM Ferrucci, L Coen, PM AF Fabbri, Elisa Yang, An Simonsick, Eleanor M. Chia, Chee W. Zoli, Marco Haughey, Norman J. Mielke, Michelle M. Ferrucci, Luigi Coen, Paul M. TI Circulating ceramides are inversely associated with cardiorespiratory fitness in participants aged 54-96years from the Baltimore Longitudinal Study of Aging SO AGING CELL LA English DT Article DE aging; cardiovascular fitness; ceramide; morbidity; plasma sphingolipids ID ALL-CAUSE MORTALITY; INSULIN-RESISTANCE; PHYSICAL-FITNESS; LIPOTOXIC CARDIOMYOPATHY; SPHINGOLIPID METABOLISM; SKELETAL-MUSCLE; HUMAN PLASMA; HEALTHY; MEN; EXERCISE AB Cardiorespiratory fitness (VO2 peak) declines with age and is an independent risk factor for morbidity and mortality in older adults. Identifying biomarkers of low fitness may provide insight for why some individuals experience an accelerated decline of aerobic capacity and may serve as clinically valuable prognostic indicators of cardiovascular health. We investigated the relationship between circulating ceramides and VO2 peak in 443 men and women (mean age of 69) enrolled in the Baltimore Longitudinal Study of Aging (BLSA). Individual species of ceramide were quantified by HPLC-tandem mass spectrometry. VO2 peak was measured by a graded treadmill test. We applied multiple regression models to test the associations between ceramide species and VO2 peak, while adjusting for age, sex, blood pressure, serum LDL, HDL, triglycerides, and other covariates. We found that higher levels of circulating C18:0, C20:0, C24:1 ceramides and C20:0 dihydroceramides were strongly associated with lower aerobic capacity (P<0.001, P<0.001, P=0.018, and P<0.001, respectively). The associations held true for both sexes (with men having a stronger association than women, P value for sex interaction <0.05) and were unchanged after adjusting for confounders and multiple comparison correction. Interestingly, no significant association was found for C16:0, C22:0, C24:0, C26:0, and C22:1 ceramide species, C24:0 dihydroceramide, or total ceramides. Our analysis reveals that specific long-chain ceramides strongly associate with low cardiovascular fitness in older adults and may be implicated in the pathogenesis of low fitness with aging. Longitudinal studies are needed to further validate these associations and investigate the relationship between ceramides and health outcomes. C1 [Fabbri, Elisa; Simonsick, Eleanor M.; Chia, Chee W.; Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. [Fabbri, Elisa; Zoli, Marco] Univ Bologna, Dept Med & Surg Sci, Bologna, Italy. [Yang, An] NIA, Lab Behav Neurosci, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Haughey, Norman J.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21224 USA. [Mielke, Michelle M.] Mayo Clin, Dept Hlth Sci Res & Neurol, Rochester, MN 55905 USA. [Coen, Paul M.] Florida Hosp, Translat Res Inst Metab & Diabet, Orlando, FL 32804 USA. RP Coen, PM (reprint author), Florida Hosp, Translat Res Inst Metab & Diabet, Sanford Burnham Prebys Med Discovery Inst, 301 East Princeton St, Orlando, FL 32804 USA. EM paul.coen@flhosp.org OI Coen, Paul/0000-0002-2805-2115 FU Intramural Research Program of NIH; National Institute on Aging [K01AG044437]; National Institutes of Health/National Institute on Aging [U01 AG37526] FX This research was supported by the Intramural Research Program of NIH, National Institute on Aging, and by a grant from the National Institutes of Health/National Institute on Aging (U01 AG37526) to MMM. Data for these analyses were obtained from the Baltimore Longitudinal Study of Aging, a study performed by the National Institute on Aging. PMC is supported by a career development award from the National Institute on Aging (K01AG044437). NR 45 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1474-9718 EI 1474-9726 J9 AGING CELL JI Aging Cell PD OCT PY 2016 VL 15 IS 5 BP 825 EP 831 DI 10.1111/acel.12491 PG 7 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA DW5VN UT WOS:000383715600004 PM 27135629 ER PT J AU Strong, R Miller, RA Antebi, A Astle, CM Bogue, M Denzel, MS Fernandez, E Flurkey, K Hamilton, KL Lamming, DW Javors, MA de Magalhaes, JP Martinez, PA McCord, JM Miller, BF Muller, M Nelson, JF Ndukum, J Rainger, GE Richardson, A Sabatini, DM Salmon, AB Simpkins, JW Steegenga, WT Nadon, NL Harrison, DE AF Strong, Randy Miller, Richard A. Antebi, Adam Astle, Clinton M. Bogue, Molly Denzel, Martin S. Fernandez, Elizabeth Flurkey, Kevin Hamilton, Karyn L. Lamming, Dudley W. Javors, Martin A. de Magalhaes, Joao Pedro Martinez, Paul Anthony McCord, Joe M. Miller, Benjamin F. Muller, Michael Nelson, James F. Ndukum, Juliet Rainger, G. Ed Richardson, Arlan Sabatini, David M. Salmon, Adam B. Simpkins, James W. Steegenga, Wilma T. Nadon, Nancy L. Harrison, David E. TI Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an -glucosidase inhibitor or a Nrf2-inducer SO AGING CELL LA English DT Article DE acarbose; fish oil; metformin; NDGA; Protandim; rapamycin; UDCA; 17--estradiol ID GENETICALLY HETEROGENEOUS MICE; NORDIHYDROGUAIARETIC ACID; URSODEOXYCHOLIC ACID; DIETARY RESTRICTION; METFORMIN ACTION; FISH-OIL; IN-VIVO; RAPAMYCIN; MECHANISM; EXTENDS AB The National Institute on Aging Interventions Testing Program (ITP) evaluates agents hypothesized to increase healthy lifespan in genetically heterogeneous mice. Each compound is tested in parallel at three sites, and all results are published. We report the effects of lifelong treatment of mice with four agents not previously tested: Protandim, fish oil, ursodeoxycholic acid (UDCA) and metformin - the latter with and without rapamycin, and two drugs previously examined: 17--estradiol and nordihydroguaiaretic acid (NDGA), at doses greater and less than used previously. 17--estradiol at a threefold higher dose robustly extended both median and maximal lifespan, but still only in males. The male-specific extension of median lifespan by NDGA was replicated at the original dose, and using doses threefold lower and higher. The effects of NDGA were dose dependent and male specific but without an effect on maximal lifespan. Protandim, a mixture of botanical extracts that activate Nrf2, extended median lifespan in males only. Metformin alone, at a dose of 0.1% in the diet, did not significantly extend lifespan. Metformin (0.1%) combined with rapamycin (14ppm) robustly extended lifespan, suggestive of an added benefit, based on historical comparison with earlier studies of rapamycin given alone. The -glucosidase inhibitor, acarbose, at a concentration previously tested (1000ppm), significantly increased median longevity in males and 90th percentile lifespan in both sexes, even when treatment was started at 16months. Neither fish oil nor UDCA extended lifespan. These results underscore the reproducibility of ITP longevity studies and illustrate the importance of identifying optimal doses in lifespan studies. C1 [Strong, Randy; Fernandez, Elizabeth; Martinez, Paul Anthony] Univ Texas Hlth Sci Ctr San Antonio, Geriatr Res Educ & Clin Ctr, San Antonio, TX 78229 USA. [Strong, Randy; Fernandez, Elizabeth; Martinez, Paul Anthony] Univ Texas Hlth Sci Ctr San Antonio, Res Serv, South Texas Vet Hlth Care Syst, Dept Pharmacol, San Antonio, TX 78229 USA. [Strong, Randy; Fernandez, Elizabeth; Martinez, Paul Anthony; Nelson, James F.; Salmon, Adam B.] Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst Longev & Aging Studies, 15355 Lambda Dr, San Antonio, TX 78229 USA. [Miller, Richard A.] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. [Miller, Richard A.] Univ Michigan, Geriatr Ctr, Ann Arbor, MI 48109 USA. [Antebi, Adam; Denzel, Martin S.] Max Planck Inst Biol Ageing, D-50931 Cologne, Germany. [Astle, Clinton M.; Bogue, Molly; Flurkey, Kevin; Ndukum, Juliet; Harrison, David E.] Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA. [Hamilton, Karyn L.; Miller, Benjamin F.] Colorado State Univ, Ft Collins, CO 80523 USA. [Lamming, Dudley W.] Univ Wisconsin, Dept Med, Madison, WI 53705 USA. [Javors, Martin A.] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [de Magalhaes, Joao Pedro] Univ Liverpool, Sch Biol Sci, Crown St, Liverpool L69 7ZB, Merseyside, England. [McCord, Joe M.] Univ Colorado, Div Pulm Sci & Crit Care Med, Aurora, CO USA. [Muller, Michael] Univ East Anglia, Norwich Med Sch, Norwich, Norfolk, England. [Nelson, James F.] Univ Texas Hlth Sci Ctr San Antonio, Dept Physiol, San Antonio, TX 78229 USA. [Rainger, G. Ed] Univ Birmingham, Ctr Cardiovasc Sci, Sch Clin & Expt Med, Sch Med, Birmingham, W Midlands, England. [Richardson, Arlan] Univ Oklahoma, Hlth Sci Ctr, Dept Geriatr Med, Oklahoma City, OK 73104 USA. [Richardson, Arlan] VA Med Ctr, Oklahoma City, OK 73104 USA. [Sabatini, David M.] Whitehead Inst Biomed Res, 9 Cambridge Ctr, Cambridge, MA 02142 USA. [Sabatini, David M.] MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Sabatini, David M.] MIT, Howard Hughes Med Inst, Cambridge, MA 02139 USA. [Sabatini, David M.] Broad Inst Harvard & MIT, Seven Cambridge Ctr, Cambridge, MA 02142 USA. [Sabatini, David M.] MIT, David H Koch Inst Integrative Canc Res, Cambridge, MA 02139 USA. [Salmon, Adam B.] Univ Texas Hlth Sci Ctr San Antonio, Dept Mol Med, San Antonio, TX 78229 USA. [Simpkins, James W.] West Virginia Univ, Ctr Basic & Translat Stroke Res, Morgantown, WV 26506 USA. [Steegenga, Wilma T.] Univ Wageningen & Res Ctr, Div Human Nutr, Wageningen, Netherlands. [Nadon, Nancy L.] NIH, Div Aging Biol, Bethesda, MD 20892 USA. [de Magalhaes, Joao Pedro] Univ Liverpool, Inst Ageing & Chron Dis, Integrat Genom Ageing Grp, Liverpool L7 8TX, Merseyside, England. RP Strong, R (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, 15355 Lambda Dr, San Antonio, TX 78245 USA. EM strong@uthscsa.edu RI de Magalhaes, Joao Pedro/B-4741-2010 OI de Magalhaes, Joao Pedro/0000-0002-6363-2465 FU National Institute on Aging [AG013319, AG022303, AG022307, AG022308, AG024824, CA034196] FX National Institute on Aging, (Grant / Award Number: 'AG013319', 'AG022303', 'AG022307', 'AG022308', 'AG024824', 'CA034196'). NR 45 TC 0 Z9 0 U1 11 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1474-9718 EI 1474-9726 J9 AGING CELL JI Aging Cell PD OCT PY 2016 VL 15 IS 5 BP 872 EP 884 DI 10.1111/acel.12496 PG 13 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA DW5VN UT WOS:000383715600009 PM 27312235 ER PT J AU Lee, BP Pilling, LC Emond, F Flurkey, K Harrison, DE Yuan, R Peters, LL Kuchel, GA Ferrucci, L Melzer, D Harries, LW AF Lee, Benjamin P. Pilling, Luke C. Emond, Florence Flurkey, Kevin Harrison, David E. Yuan, Rong Peters, Luanne L. Kuchel, George A. Ferrucci, Luigi Melzer, David Harries, Lorna W. TI Changes in the expression of splicing factor transcripts and variations in alternative splicing are associated with lifespan in mice and humans SO AGING CELL LA English DT Article DE isoforms; lifespan; longevity; mouse; mRNA splicing; splicing factors ID PRE-MESSENGER-RNA; FRONTOTEMPORAL LOBAR DEGENERATION; BINDING PROTEIN; DNA-BINDING; CIRCULATING IGF1; GENE-EXPRESSION; CANCER-CELLS; AGE; TDP-43; MOUSE AB Dysregulation of splicing factor expression and altered alternative splicing are associated with aging in humans and other species, and also with replicative senescence in cultured cells. Here, we assess whether expression changes of key splicing regulator genes and consequent effects on alternative splicing are also associated with strain longevity in old and young mice, across 6 different mouse strains with varying lifespan (A/J, NOD.B10Sn-H2(b)/J, PWD.Phj, 129S1/SvlmJ, C57BL/6J and WSB/EiJ). Splicing factor expression and changes to alternative splicing were associated with strain lifespan in spleen and to a lesser extent in muscle. These changes mainly involved hnRNP splicing inhibitor transcripts with most changes more marked in spleens of young animals from long-lived strains. Changes in spleen isoform expression were suggestive of reduced cellular senescence and retained cellular proliferative capacity in long-lived strains. Changes in muscle isoform expression were consistent with reduced pro-inflammatory signalling in longer-lived strains. Two splicing regulators, HNRNPA1 and HNRNPA2B1, were also associated with parental longevity in humans, in the InCHIANTI aging study. Splicing factors may represent a driver, mediator or early marker of lifespan in mouse, as expression differences were present in the young animals of long-lived strains. Changes to alternative splicing patterns of key senescence genes in spleen and key remodelling genes in muscle suggest that correct regulation of alternative splicing may enhance lifespan in mice. Expression of some splicing factors in humans was also associated with parental longevity, suggesting that splicing regulation may also influence lifespan in humans. C1 [Lee, Benjamin P.; Emond, Florence; Harries, Lorna W.] Univ Exeter, Sch Med, Inst Biomed & Clin Sci, RNA Mediated Mech Dis, Exeter, Devon, England. [Pilling, Luke C.; Melzer, David] Univ Exeter, Sch Med, Inst Biomed & Clin Sci, Egidemiol & Publ Hlth, Exeter, Devon, England. [Flurkey, Kevin; Harrison, David E.; Yuan, Rong; Peters, Luanne L.] Nathan Shock Ctr Excellence Basic Biol Aging, Jackson Lab, Bar Harbor, ME USA. [Kuchel, George A.; Melzer, David] Univ Connecticut, Ctr Hlth, UConn Ctr Aging, Farmington, CT USA. [Ferrucci, Luigi] NIA, Baltimore, MD 21224 USA. [Yuan, Rong] Southern Illinois Univ, Sch Med, Geriatr Res Div, Dept Internal Med, Springfield, IL USA. RP Melzer, D; Harries, LW (reprint author), Univ Exeter, Sch Med, Barrack Rd, Exeter EX2 5DW, Devon, England. EM D.Melzer@exeter.ac.uk; L.W.Harries@exeter.ac.uk OI Lee, Benjamin/0000-0003-4351-9630 FU Wellcome Trust [WT097835MF]; NIH-NIA [AG038070] FX The authors would like to acknowledge the Wellcome Trust (grant number WT097835MF LWH, DM), and NIH-NIA grant number AG038070 to The Jackson Laboratory for providing the funding for this study. We would also like to acknowledge the contributions of Federica Bighi and John Watt for technical assistance. The authors have no conflict of interest to disclose. NR 41 TC 2 Z9 2 U1 8 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1474-9718 EI 1474-9726 J9 AGING CELL JI Aging Cell PD OCT PY 2016 VL 15 IS 5 BP 903 EP 913 DI 10.1111/acel.12499 PG 11 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA DW5VN UT WOS:000383715600012 PM 27363602 ER PT J AU Fauci, A AF Fauci, Anthony TI HIV Prevention Science in 2016: New Weapons in the Arsenal SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on HIV Research for Prevention (HIV R4P) CY OCT 17-20, 2016 CL Chicago, IL C1 [Fauci, Anthony] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2016 VL 32 SU 1 MA PL01.03 BP 14 EP 14 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA EA6YH UT WOS:000386774600005 ER PT J AU Cicala, C AF Cicala, Claudia TI A Central Role for alpha(4)beta(+)(7) CD4(+) T Cells in HIV Transmission and Pathogenesis SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on HIV Research for Prevention (HIV R4P) CY OCT 17-20, 2016 CL Chicago, IL C1 [Cicala, Claudia] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2016 VL 32 SU 1 MA SY02.01 BP 20 EP 20 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA EA6YH UT WOS:000386774600018 ER PT J AU Gonzalez, M AF Gonzalez, Mileidy TI HIV 'Transmission' Signatures are also 'Infectivity' Signatures Universal Across Primate Lenti Viruses SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on HIV Research for Prevention (HIV R4P) CY OCT 17-20, 2016 CL Chicago, IL C1 [Gonzalez, Mileidy] NIH, NCBI, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2016 VL 32 SU 1 MA RT01.04 BP 27 EP 27 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA EA6YH UT WOS:000386774600031 ER PT J AU Doria-Rose, NA Krebs, S Law, W Gift, S Chenine, A Rolland, M Moody, MA Jarosinski, M Georgiev, I Chuang, GY Asokan, M Bailer, RT Cale, EM Louder, M Kwong, PD Polonis, V Haynes, B Tovanabutra, S Robb, M Mascola, JR AF Doria-Rose, Nicole A. Krebs, Shelly Law, Wiliam Gift, Syna Chenine, Agnes Rolland, Morgane Moody, M. Anthony Jarosinski, Marissa Georgiev, Ivelin Chuang, Gwo-Yu Asokan, Mangaiarkarasi Bailer, Robert T. Cale, Evan M. Louder, Mark Kwong, Peter D. Polonis, Victoria Haynes, Barton Tovanabutra, Sodsai Robb, Merlin Mascola, John R. TI HIV-1 MPER-directed Broadly Neutralizing Antibodies from an Acute-infection Cohort RV217 Subject SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on HIV Research for Prevention (HIV R4P) CY OCT 17-20, 2016 CL Chicago, IL C1 [Doria-Rose, Nicole A.; Law, Wiliam; Jarosinski, Marissa; Georgiev, Ivelin; Chuang, Gwo-Yu; Asokan, Mangaiarkarasi; Bailer, Robert T.; Cale, Evan M.; Louder, Mark; Kwong, Peter D.; Mascola, John R.] NIAID, Vaccine Res Ctr, NIH, Rockville, MD USA. [Krebs, Shelly; Gift, Syna; Chenine, Agnes; Rolland, Morgane; Polonis, Victoria; Tovanabutra, Sodsai; Robb, Merlin] Walter Reed Army Inst Res, US Mil HIV Res Program, Silver Spring, MD USA. [Krebs, Shelly; Gift, Syna; Chenine, Agnes; Rolland, Morgane; Polonis, Victoria; Tovanabutra, Sodsai; Robb, Merlin] Henry M Jackson Fdn Adv Mil Med, Bethesda, MD USA. [Moody, M. Anthony; Haynes, Barton] Duke Human Vaccine Inst, Durham, NC USA. [Georgiev, Ivelin] Vanderbilt Univ, Nashville, TN USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2016 VL 32 SU 1 MA OA01.02 BP 36 EP 36 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA EA6YH UT WOS:000386774600051 ER PT J AU Bhiman, JN Wibmer, CK Madzorera, VS Doria-Rose, NA Morris, L Moore, PL AF Bhiman, Jinal N. Wibmer, Constantinos Kurt Madzorera, Vimbai S. Doria-Rose, Nicole A. Morris, Lynn Moore, Penny L. TI Persistence of an HIV Broadly Neutralizing Antibody Lineage Despite Complete Neutralization Escape SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on HIV Research for Prevention (HIV R4P) CY OCT 17-20, 2016 CL Chicago, IL C1 [Bhiman, Jinal N.; Wibmer, Constantinos Kurt; Madzorera, Vimbai S.; Morris, Lynn; Moore, Penny L.] Natl Hlth Lab Serv, Natl Inst Communicable Dis, Johannesburg, South Africa. [Bhiman, Jinal N.; Wibmer, Constantinos Kurt; Morris, Lynn; Moore, Penny L.] Univ Witwatersrand, ZA-2050 Johannesburg, South Africa. [Doria-Rose, Nicole A.] NIAID, NIH, Rockville, MD USA. [Morris, Lynn; Moore, Penny L.] Univ KwaZulu Natal, Durban, South Africa. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2016 VL 32 SU 1 MA OA01.03 BP 37 EP 37 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA EA6YH UT WOS:000386774600052 ER PT J AU Kong, R Xu, K Zhou, TQ Acharya, P Liu, K Ozorowski, G Taft, J Bailer, R Cale, E Chen, L Chuang, GY Doria-Rose, N Joyce, G Louder, M Burton, D Koff, W Connors, M Ward, A Kwong, P Mascola, J AF Kong, Rui Xu, Kai Zhou, Tongqing Acharya, Priyamvada Liu, Kevin Ozorowski, Gabriel Taft, Justin Bailer, Robert Cale, Evan Chen, Lei Chuang, Gwo-Yu Doria-Rose, Nicole Joyce, Gordon Louder, Mark Burton, Dennis Koff, Wayne Connors, Mark Ward, Andrew Kwong, Peter Mascola, John TI Fusion Peptide of HIV-1 as a Site of Vulnerability to Neutralizing Antibody SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on HIV Research for Prevention (HIV R4P) CY OCT 17-20, 2016 CL Chicago, IL C1 [Kong, Rui; Xu, Kai; Zhou, Tongqing; Acharya, Priyamvada; Liu, Kevin; Taft, Justin; Bailer, Robert; Cale, Evan; Chen, Lei; Chuang, Gwo-Yu; Doria-Rose, Nicole; Joyce, Gordon; Louder, Mark; Kwong, Peter; Mascola, John] NIAID, Vaccine Res Ctr, NIH, Rockville, MD USA. [Ozorowski, Gabriel; Burton, Dennis; Ward, Andrew] Scripps Res Inst, La Jolla, CA USA. [Koff, Wayne] Int AIDS Vaccine Initiat, New York, NY USA. [Connors, Mark] NIAID, NIH, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2016 VL 32 SU 1 MA OA01.06 BP 38 EP 38 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA EA6YH UT WOS:000386774600055 ER PT J AU Yolitz, J Wei, DL Van Ryk, D Cicala, C Fauci, AS Arthos, J AF Yolitz, Jason Wei, Danlan Van Ryk, Donald Cicala, Claudia Fauci, Anthony S. Arthos, James TI The Anti-gp120 mAb CH58 Recognizes a Not-fully-processed Form of Surface-expressed Env SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on HIV Research for Prevention (HIV R4P) CY OCT 17-20, 2016 CL Chicago, IL C1 [Yolitz, Jason; Wei, Danlan; Van Ryk, Donald; Cicala, Claudia; Fauci, Anthony S.; Arthos, James] NIAID, NIH, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2016 VL 32 SU 1 MA OA01.05 BP 38 EP 38 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA EA6YH UT WOS:000386774600054 ER PT J AU Santangelo, P Byrareddy, S Cicala, C Ortiz, K Little, D Gumber, S Hong, JJ Zuria, C Villinger, F Ansari, A Fauci, A Arthos, J AF Santangelo, Philip Byrareddy, Siddappa Cicala, Claudia Ortiz, Kristina Little, Dawn Gumber, Sanjeev Hong, J. J. Zuria, Chiara Villinger, Francois Ansari, Aftab Fauci, Anthony Arthos, James TI Immuno-PET/CT Imaging Reveals Differences in Virus and CD4+Cell Localization in SIV Infected Rhesus Macaques Treated with an Anti-alpha 4 beta 7 mAb SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on HIV Research for Prevention (HIV R4P) CY OCT 17-20, 2016 CL Chicago, IL C1 [Santangelo, Philip; Zuria, Chiara] Georgia Inst Technol, Atlanta, GA 30332 USA. [Byrareddy, Siddappa] Univ Nebraska Med Ctr, Omaha, NE USA. [Cicala, Claudia; Fauci, Anthony; Arthos, James] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Ortiz, Kristina; Little, Dawn; Ansari, Aftab] Emory Univ, Atlanta, GA 30322 USA. [Gumber, Sanjeev; Hong, J. J.] Yerkes Natl Primate Res Ctr, Lawrenceville, GA USA. [Villinger, Francois] Univ Louisiana Lafayette, Lafayette, LA 70504 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2016 VL 32 SU 1 MA OA07.02 BP 54 EP 54 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA EA6YH UT WOS:000386774600087 ER PT J AU Sivro, A Yende, N Leask, K Balgobin, A Garrett, N Nawaz, F Cicala, C Arthos, J Ansari, AA Karim, QA Karim, SSA McKinnon, LR AF Sivro, Aida Yende, Nonhlanhla Leask, Kerry Balgobin, Anisha Garrett, Nigel Nawaz, Fatima Cicala, Claudia Arthos, James Ansari, Aftab A. Karim, Quarraisha Abdool Karim, Salim S. Abdool McKinnon, Lyle R. TI The Role of Gut Homing Receptor alpha 4 beta 7 in HIV Pathogenesis and Transmission - a Prospective Cohort Study SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on HIV Research for Prevention (HIV R4P) CY OCT 17-20, 2016 CL Chicago, IL C1 [Sivro, Aida; Yende, Nonhlanhla; Leask, Kerry; Balgobin, Anisha; Garrett, Nigel; Karim, Quarraisha Abdool; Karim, Salim S. Abdool; McKinnon, Lyle R.] Ctr AIDS Programme Res South Africa, Congella, South Africa. [Sivro, Aida; McKinnon, Lyle R.] Univ Manitoba, Winnipeg, MB R3T 2N2, Canada. [Nawaz, Fatima; Cicala, Claudia; Arthos, James] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Ansari, Aftab A.] Emory Univ, Sch Med, Atlanta, GA 30322 USA. [Karim, Quarraisha Abdool; Karim, Salim S. Abdool] Columbia Univ, New York, NY 10027 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2016 VL 32 SU 1 MA OA07.01 BP 54 EP 54 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA EA6YH UT WOS:000386774600086 ER PT J AU Ortiz, A DiNapoli, S Sortino, O Quinones, M Brenchley, J AF Ortiz, Alexandra DiNapoli, Sarah Sortino, Ornella Quinones, Miriam Brenchley, Jason TI Antiretroviral Therapy Contributes to Intestinal Immune Dysfunction in Healthy Macaques SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on HIV Research for Prevention (HIV R4P) CY OCT 17-20, 2016 CL Chicago, IL C1 [Ortiz, Alexandra; DiNapoli, Sarah; Brenchley, Jason] NIAID, LPD, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Sortino, Ornella] NIAID, ICMOB, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Quinones, Miriam] NIAID, BCBB, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2016 VL 32 SU 1 MA OA07.05 BP 56 EP 56 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA EA6YH UT WOS:000386774600090 ER PT J AU Shen, XY Basu, R Kwa, S Labranche, C Beaumont, D Ferrari, G Wyatt, L Moss, B Montefiori, D Tomaras, G Robinson, H AF Shen, Xiaoying Basu, Rahul Kwa, Suefen Labranche, Celia Beaumont, David Ferrari, Guido Wyatt, Linda Moss, Bernard Montefiori, David Tomaras, Georgia Robinson, Harriet TI MVA-expressed gp140 Boosts More Durable V1/V2 and gp120 Antibody Responses than gp120 Protein in Alum SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on HIV Research for Prevention (HIV R4P) CY OCT 17-20, 2016 CL Chicago, IL C1 [Shen, Xiaoying; Beaumont, David; Tomaras, Georgia] Duke Human Vaccine Inst, Durham, NC USA. [Basu, Rahul; Kwa, Suefen; Robinson, Harriet] GeoVax Inc, Smyrna, GA USA. [Labranche, Celia; Ferrari, Guido; Montefiori, David] Duke Univ, Durham, NC 27706 USA. [Wyatt, Linda; Moss, Bernard] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2016 VL 32 SU 1 MA OA08.06 BP 59 EP 59 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA EA6YH UT WOS:000386774600097 ER PT J AU Ditse, Z Karimanzira, O Muenchhoff, M Adland, E Georgiev, I Goulder, P Moore, PL Morris, L AF Ditse, Zanele Karimanzira, Owen Muenchhoff, Maximilian Adland, Emily Georgiev, Ivelin Goulder, Philip Moore, Penny L. Morris, Lynn TI Characterization of Broadly Neutralizing Antibody Responses in HIV-1 Subtype C Infected Children SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on HIV Research for Prevention (HIV R4P) CY OCT 17-20, 2016 CL Chicago, IL C1 [Ditse, Zanele; Karimanzira, Owen; Moore, Penny L.; Morris, Lynn] Natl Hlth Lab Serv, Natl Inst Communicable Dis, Johannesburg, South Africa. [Ditse, Zanele; Moore, Penny L.; Morris, Lynn] Univ Witwatersrand, ZA-2050 Johannesburg, South Africa. [Muenchhoff, Maximilian; Adland, Emily; Goulder, Philip] Univ Oxford, Oxford OX1 2JD, England. [Muenchhoff, Maximilian; Goulder, Philip] Univ KwaZulu Natal, Doris Duke Med Res Inst, HIV Pathogenesis Programme, Durban, South Africa. [Georgiev, Ivelin] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Goulder, Philip] Great Ormond St Hosp Sick Children, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2016 VL 32 SU 1 MA OA09.03 BP 61 EP 61 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA EA6YH UT WOS:000386774600100 ER PT J AU Sheng, ZZ Schramm, C Kwong, PD Shapiro, L AF Sheng, Zizhang Schramm, Chaim Kwong, Peter D. Shapiro, Lawrence TI The Intrinsic Mutability of Antibody Variable Gene Is Critical for Reproducing Similar Mutation Signatures SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on HIV Research for Prevention (HIV R4P) CY OCT 17-20, 2016 CL Chicago, IL C1 [Sheng, Zizhang; Schramm, Chaim; Shapiro, Lawrence] Columbia Univ, Med Ctr, New York, NY 10027 USA. [Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2016 VL 32 SU 1 MA OA09.04 BP 61 EP 61 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA EA6YH UT WOS:000386774600101 ER PT J AU Mitchell, KM Hoots, B Dimitrov, D Farley, J Gelman, M German, D Flynn, C Adeyeye, A Remien, RH Beyrer, C Paz-Bailey, G Boily, MC AF Mitchell, Kate M. Hoots, Brooke Dimitrov, Dobromir Farley, Jason Gelman, Marcy German, Danielle Flynn, Colin Adeyeye, Adeola Remien, Robert H. Beyrer, Chris Paz-Bailey, Gabriela Boily, Marie-Claude TI Potential Impact on HIV Incidence of Increasing Viral Suppression among HIV-positive MSM in Baltimore: Mathematical Modelling for HPTN 078 SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on HIV Research for Prevention (HIV R4P) CY OCT 17-20, 2016 CL Chicago, IL C1 [Mitchell, Kate M.; Boily, Marie-Claude] Imperial Coll London, London, England. [Hoots, Brooke; Paz-Bailey, Gabriela] Ctr Dis Control & Prevent, Atlanta, GA USA. [Dimitrov, Dobromir] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Farley, Jason; German, Danielle; Beyrer, Chris] Johns Hopkins Univ, Baltimore, MD 21218 USA. [Gelman, Marcy] Fenway Inst, Boston, MA USA. [Flynn, Colin] Maryland Dept Hlth & Mental Hyg, Baltimore, MD 21201 USA. [Adeyeye, Adeola] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. [Remien, Robert H.] NY State Psychiat Inst, New York, NY USA. [Remien, Robert H.] Columbia Univ, New York, NY 10027 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2016 VL 32 SU 1 MA OA10.04 BP 64 EP 64 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA EA6YH UT WOS:000386774600107 ER PT J AU Felber, BK Valentin, A Salazar, ER Doueiri, R Rosati, M Hu, XT Alicea, C Bear, J Hirsch, VM Broderick, KE Sardesai, NY Reed, SG Montefiori, DC Shen, XY Tomaras, GD Pavlakis, GN AF Felber, Barbara K. Valentin, Antonio Salazar, Eric Ramirez Doueiri, Rami Rosati, Margherita Hu, Xintao Alicea, Candido Bear, Jenifer Hirsch, Vanessa M. Broderick, Kate E. Sardesai, Niranjan Y. Reed, Steven G. Montefiori, David C. Shen, Xiaoying Tomaras, Georgia D. Pavlakis, George N. TI DNA and Protein Co-delivery Vaccines Using TLR-4-based Adjuvants Induce Potent Immune Responses Able to Delay Heterologous SIV Acquisition SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on HIV Research for Prevention (HIV R4P) CY OCT 17-20, 2016 CL Chicago, IL C1 [Felber, Barbara K.; Valentin, Antonio; Salazar, Eric Ramirez; Doueiri, Rami; Rosati, Margherita; Hu, Xintao; Alicea, Candido; Bear, Jenifer; Pavlakis, George N.] NCI, Frederick, MD 21701 USA. [Hirsch, Vanessa M.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Broderick, Kate E.; Sardesai, Niranjan Y.] Inovio Pharmaceut, Sacramento, CA USA. [Reed, Steven G.] IDRI, Seattle, WA USA. [Montefiori, David C.; Shen, Xiaoying; Tomaras, Georgia D.] Duke Univ, Med Ctr, Durham, NC 27706 USA. RI bebarta, vikhyat/K-3476-2015 NR 0 TC 0 Z9 0 U1 1 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2016 VL 32 SU 1 MA OA11.03 BP 67 EP 67 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA EA6YH UT WOS:000386774600112 ER PT J AU Rouphael, N Morgan, C Li, S Jensen, R Sanchez, B Swann, E Sobieszczyk, M Frank, I Wilson, G Tieu, H Maenza, J Norwood, A Derosa, S David, M Keefer, M AF Rouphael, Nadine Morgan, Cecilia Li, Sue Jensen, Ryan Sanchez, Brittany Swann, Edith Sobieszczyk, Magdalena Frank, Ian Wilson, Greg Tieu, Hong Maenza, Jeanine Norwood, Aliza Derosa, Stephen David, Montefiori Keefer, Michael TI DNA and Protein Co-administration Elicits Higher HIV-specific nAb and Comparable CD4+T-cell Responses as Traditional Prime/Boost Regimens (HVTN 105) SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on HIV Research for Prevention (HIV R4P) CY OCT 17-20, 2016 CL Chicago, IL C1 [Rouphael, Nadine] Emory Univ, Atlanta, GA 30322 USA. [Morgan, Cecilia; Li, Sue; Jensen, Ryan; Sanchez, Brittany; Maenza, Jeanine; Derosa, Stephen] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, 1124 Columbia St, Seattle, WA 98104 USA. [Swann, Edith] NIAID, Div AIDS, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Sobieszczyk, Magdalena] Columbia Univ, New York, NY 10027 USA. [Frank, Ian] Univ Penn, Philadelphia, PA 19104 USA. [Wilson, Greg] Vanderbilt Univ, 221 Kirkland Hall, Nashville, TN 37235 USA. [Tieu, Hong] New York Blood Ctr, New York, NY 10021 USA. [Norwood, Aliza] San Francisco Dept Publ Hlth, San Francisco, CA USA. [David, Montefiori] Duke Univ, Durham, NC 27706 USA. [Keefer, Michael] Univ Rochester, Sch Med & Dent, Rochester, NY 14627 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2016 VL 32 SU 1 MA OA11.04 BP 67 EP 67 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA EA6YH UT WOS:000386774600113 ER PT J AU Dezzutti, C Hu, ML Shetler, C Russo, J Marshall, L Swartz, G Cummins, J Rohan, L AF Dezzutti, Charlene Hu, Minlu Shetler, Cory Russo, Julie Marshall, Leslie Swartz, Glenn Cummins, James Rohan, Lisa TI Evaluation of MK-2048 and Vicriviroc, Formulated as Single or Combination (MK-2048A) Intravaginal Rings, for Development as a Vaginal Microbicide SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on HIV Research for Prevention (HIV R4P) CY OCT 17-20, 2016 CL Chicago, IL C1 [Dezzutti, Charlene; Hu, Minlu; Rohan, Lisa] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Dezzutti, Charlene; Shetler, Cory; Russo, Julie; Rohan, Lisa] Magee Womens Res Inst, Pittsburgh, PA USA. [Marshall, Leslie; Cummins, James] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Swartz, Glenn] Adv BioSci Labs Inc, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2016 VL 32 SU 1 MA OA12.05 BP 71 EP 71 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA EA6YH UT WOS:000386774600120 ER EF