FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Chen, J Bryant, MA Dent, JJ Sun, Y Desierto, MJ Young, NS AF Chen, Jichun Bryant, Mark A. Dent, James J. Sun, Yu Desierto, Marie J. Young, Neal S. TI Hematopoietic lineage skewing and intestinal epithelia degeneration in aged mice with telomerase RNA component deletion SO EXPERIMENTAL GERONTOLOGY LA English DT Article DE Terc(-/-) mice; Aging; Hematopoietic lineage skewing; Intestinal epithelia degeneration; Flow cytometry; Histology ID IDIOPATHIC PULMONARY-FIBROSIS; STEM-CELLS; DYSKERATOSIS-CONGENITA; REVERSE-TRANSCRIPTASE; APLASTIC-ANEMIA; TRIMETHOPRIM-SULFAMETHOXAZOLE; DEFICIENT MICE; T-CELLS; MUTATIONS; DISEASE AB A deletion of a telomerase RNA component (Terc(-/-)) in C57BL/6 (B6) mice resulted in hematopoietic lineage skewing with increased neutrophils and CD11b1 myeloid cells and decreased red blood cells and CD45R B lymphocytes when animals reach ages older than 12 months. There was no decline in bone marrow (BM) c-Kit Sca-1 Lin (KSL) cells in old Terc mice, and the lineage skewing phenomenon was not transferred when BM cells from old Terc(-/-)/donors were transplanted into young B6 recipients. Necropsy and histological examinations found minimal to no change in the lung, spleen and liver but detected severe epithelia degeneration, ulceration and infection in small and large intestines, leading to enteritis, typhlitis and colitis in old TerTerc(-/-)/mice. In a mouse model of dextran-sulfate-sodium-induced typhlitis and colitis, development of intestinal pathology was associated with increases in neutrophils and CD11b(+) myeloid cells and a decrease in CD45R B cells, similar to those observed in old Terc(-/-) mice. Treatment of 11-13 month old Terc(-/-) mice with antibiotic trimethoprim-sulfa water reduced neutrophils and myeloid cells and increased B lymphocytes in the blood, indicating that mitigation of intestinal infection and inflammation could alleviate hematological abnormalities in old Terc(-/-) animals. Published by Elsevier Inc. C1 [Chen, Jichun; Dent, James J.; Sun, Yu; Desierto, Marie J.; Young, Neal S.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Bryant, Mark A.] NIH, Div Vet Resources, Off Res Serv, Bethesda, MD 20892 USA. [Sun, Yu] Soochow Univ, Affiliated Hosp 2, Dept Hematol, Suzhou, Jiangsu, Peoples R China. RP Chen, J (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,Clin Res Ctr Room 3E-5272,10 Ctr Dr, Bethesda, MD 20892 USA. EM chenji@nhlbi.nih.gov FU National Heart, Lung, and Blood Institute, National Institutes of Health Intramural Research Program FX This research was supported by funds from National Heart, Lung, and Blood Institute, National Institutes of Health Intramural Research Program. NR 45 TC 0 Z9 0 U1 1 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0531-5565 EI 1873-6815 J9 EXP GERONTOL JI Exp. Gerontol. PD DEC PY 2015 VL 72 BP 251 EP 260 DI 10.1016/j.exger.2015.10.016 PG 10 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA CW4UD UT WOS:000364989100032 PM 26523501 ER PT J AU Keadle, SK Lyden, K Freedson, PS AF Keadle, Sarah Kozey Lyden, Kate Freedson, Patty S. TI Response to "Breaking-up sedentary time is associated with impairment in activities of daily living" SO EXPERIMENTAL GERONTOLOGY LA English DT Letter DE Letter to editor; Physical activity; Sedentary time ID MONITORS; ADULTS C1 [Keadle, Sarah Kozey] NCI, Div Canc Epidemiol & Genet, Nutr Epidemiol Branch, Bethesda, MD 20892 USA. [Lyden, Kate] Misfit Inc, San Francisco, CA USA. [Freedson, Patty S.] Univ Massachusetts, Dept Kinesiol, Amherst, MA 01003 USA. RP Keadle, SK (reprint author), NCI, 9609 Med Ctr Dr,6E318, Bethesda, MD 20892 USA. EM sarah.keadle@nih.gov OI Keadle, Sarah/0000-0002-9569-9306 NR 10 TC 1 Z9 1 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0531-5565 EI 1873-6815 J9 EXP GERONTOL JI Exp. Gerontol. PD DEC PY 2015 VL 72 BP 279 EP 280 DI 10.1016/j.exger.2015.10.002 PG 2 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA CW4UD UT WOS:000364989100036 ER PT J AU Weber, MM Bauler, LD Lam, J Hackstadt, T AF Weber, Mary M. Bauler, Laura D. Lam, Jennifer Hackstadt, Ted TI Expression and Localization of Predicted Inclusion Membrane Proteins in Chlamydia trachomatis SO INFECTION AND IMMUNITY LA English DT Article ID OBLIGATE INTRACELLULAR PATHOGEN; III SECRETION; DEVELOPMENTAL CYCLE; GENE-EXPRESSION; INC PROTEINS; IDENTIFICATION; GENOME; MECHANISMS; PATHWAY; CELLS AB Chlamydia trachomatis is an obligate intracellular pathogen that replicates in a membrane-bound vacuole termed the inclusion. Early in the infection cycle, the pathogen extensively modifies the inclusion membrane through incorporation of numerous type III secreted effector proteins, called inclusion membrane proteins (Incs). These proteins are characterized by a bilobed hydrophobic domain of 40 amino acids. The presence of this domain has been used to predict up to 59 putative Incs for C. trachomatis; however, localization to the inclusion membrane with specific antibodies has been demonstrated for only about half of them. Here, we employed recently developed genetic tools to verify the localization of predicted Incs that had not been previously localized to the inclusion membrane. Expression of epitope-tagged putative Incs identified 10 that were previously unverified as inclusion membrane localized and thus authentic Incs. One novel Inc and 3 previously described Incs were localized to inclusion membrane microdomains, as evidenced by colocalization with phosphorylated Src (p-Src). Several predicted Incs did not localize to the inclusion membrane but instead remained associated with the bacteria. Using Yersinia as a surrogate host, we demonstrated that many of these are not secreted via type III secretion, further suggesting they may not be true Incs. Collectively, our results highlight the utility of genetic tools for demonstrating secretion from chlamydia. Further mechanistic studies aimed at elucidating effector function will advance our understanding of how the pathogen maintains its unique intracellular niche and mediates interactions with the host. C1 [Weber, Mary M.; Bauler, Laura D.; Lam, Jennifer; Hackstadt, Ted] NIAID, Host Parasite Interact Sect, Bacteriol Lab, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. RP Hackstadt, T (reprint author), NIAID, Host Parasite Interact Sect, Bacteriol Lab, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. EM ted_hackstadt@nih.gov FU 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 60 TC 7 Z9 7 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD DEC PY 2015 VL 83 IS 12 BP 4710 EP 4718 DI 10.1128/IAI.01075-15 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CW4EP UT WOS:000364944400025 PM 26416906 ER PT J AU Fazzino, L Tilly, K Dulebohn, DP Rosa, PA AF Fazzino, Lisa Tilly, Kit Dulebohn, Daniel P. Rosa, Patricia A. TI Long-Term Survival of Borrelia burgdorferi Lacking the Hibernation Promotion Factor Homolog in the Unfed Tick Vector SO INFECTION AND IMMUNITY LA English DT Article ID RPOS REGULATORY PATHWAY; WHITE-FOOTED MICE; LYME-DISEASE; PROTEIN-STRUCTURE; IXODES-SCAPULARIS; ESCHERICHIA-COLI; SWISS-MODEL; STRUCTURE PREDICTION; 100S RIBOSOME; TRANSOVARIAL TRANSMISSION AB Borrelia burgdorferi, a causative agent of Lyme borreliosis, is a zoonotic pathogen that survives in nutrient-limited environments within a tick, prior to transmission to its mammalian host. Survival under these prolonged nutrient-limited conditions is thought to be similar to survival during stationary phase, which is characterized by growth cessation and decreased protein production. Multiple ribosome-associated proteins are implicated in stationary-phase survival of Escherichia coli. These proteins include hibernation-promoting factor (HPF), which dimerizes ribosomes and prevents translation of mRNA. Bioinformatic analyses indicate that B. burgdorferi harbors an hpf homolog, the bb0449 gene. BB0449 protein secondary structure modeling also predicted HPF-like structure and function. However, BB0449 protein was not localized in the ribosome-associated protein fraction of in vitro-grown B. burgdorferi. In wild-type B. burgdorferi, bb0449 transcript and BB0449 protein levels are low during various growth phases. These results are inconsistent with patterns of synthesis of HPF-like proteins in other bacterial species. In addition, two independently derived bb0449 mutants successfully completed the mouse-tick infectious cycle, indicating that bb0449 is not required for prolonged survival in the nutrient-limited environment in the unfed tick or any other stage of infection by B. burgdorferi. We suggest either that BB0449 is associated with ribosomes under specific conditions not yet identified or that BB0449 of B. burgdorferi has a function other than ribosome conformation modulation. C1 [Fazzino, Lisa; Tilly, Kit; Dulebohn, Daniel P.; Rosa, Patricia A.] NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Tilly, K (reprint author), NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM ktilly@niaid.nih.gov; prosa@niaid.nih.gov FU Division of Intramural Research of the NIAID, NIH FX This research was supported by the Division of Intramural Research of the NIAID, NIH. NR 73 TC 1 Z9 1 U1 2 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD DEC PY 2015 VL 83 IS 12 BP 4800 EP 4810 DI 10.1128/IAI.00925-15 PG 11 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CW4EP UT WOS:000364944400034 PM 26438790 ER PT J AU Kusenda, M Vacic, V Malhotra, D Rodgers, L Pavon, K Meth, J Kumar, RA Christian, SL Peeters, H Cho, SS Addington, A Rapoport, JL Sebat, J AF Kusenda, Mary Vacic, Vladimir Malhotra, Dheeraj Rodgers, Linda Pavon, Kevin Meth, Jennifer Kumar, Ravinesh A. Christian, Susan L. Peeters, Hilde Cho, Shawn S. Addington, Anjene Rapoport, Judith L. Sebat, Jonathan TI The Influence of Microdeletions and Microduplications of 16p11.2 on Global Transcription Profiles SO JOURNAL OF CHILD NEUROLOGY LA English DT Article DE autism spectrum disorders (ASD); schizophrenia (SCZ); copy number variation (CNV); gene expression; 16p11; 2 ID LYMPHOBLASTOID CELL-LINES; MENTAL-RETARDATION; GENE DOSAGE; AUTISM; EXPRESSION; REVEALS; SCHIZOPHRENIA; DISORDER; ASSOCIATION; DUPLICATION AB Copy number variants (CNVs) of a 600 kb region on 16p11.2 are associated with neurodevelopmental disorders and changes in brain volume. The authors hypothesize that abnormal brain development associated with this CNV can be attributed to changes in transcriptional regulation. The authors determined the effects of 16p11.2 dosage on gene expression by transcription profiling of lymphoblast cell lines derived from 6 microdeletion carriers, 15 microduplication carriers and 15 controls. Gene dosage had a significant influence on the transcript abundance of a majority (20/34) of genes within the CNV region. In addition, a limited number of genes were dysregulated in trans. Genes most strongly correlated with patient head circumference included SULT1A, KCTD13, and TMEM242. Given the modest effect of 16p11.2 copy number on global transcriptional regulation in lymphocytes, larger studies utilizing neuronal cell types may be needed in order to elucidate the signaling pathways that influence brain development in this genetic disorder. C1 [Kusenda, Mary; Vacic, Vladimir; Malhotra, Dheeraj; Rodgers, Linda; Pavon, Kevin; Meth, Jennifer] Cold Spring Harbor Lab, Stanley Inst Cognit Genom, Cold Spring Harbor, NY 11724 USA. [Kumar, Ravinesh A.; Christian, Susan L.] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Peeters, Hilde] Katholieke Univ Leuven, Fac Med, Dept Human Genet, Lab Genet Human Dev, Leuven, Netherlands. [Cho, Shawn S.; Sebat, Jonathan] Univ Calif San Diego, Beyster Ctr Genom Psychiat Dis, Dept Psychiat, La Jolla, CA 92093 USA. [Cho, Shawn S.; Sebat, Jonathan] Univ Calif San Diego, Beyster Ctr Genom Psychiat Dis, Dept Cellular & Mol Med, La Jolla, CA 92093 USA. [Addington, Anjene; Rapoport, Judith L.] NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. [Kusenda, Mary] Rockville Ctr, Molloy Coll, Dept Biol Chem & Environm Studies, New York, NY 11571 USA. RP Sebat, J (reprint author), Univ Calif San Diego, Beyster Ctr Genom Psychiat Dis, Dept Psychiat, La Jolla, CA 92093 USA. EM jsebat@ucsd.edu OI Sebat, Jonathan/0000-0002-9087-526X; Vacic, Vladimir/0000-0001-6571-2293 FU Simons Foundation [SFARI 178088]; National Institutes of Health [MH076431] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Funding for this study was provided grants to JS from the Simons Foundation (SFARI 178088) and the National Institutes of Health (MH076431). NR 35 TC 0 Z9 0 U1 1 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0883-0738 EI 1708-8283 J9 J CHILD NEUROL JI J. Child Neurol. PD DEC PY 2015 VL 30 IS 14 SI SI BP 1947 EP 1953 DI 10.1177/0883073815602066 PG 7 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA CW3TE UT WOS:000364914000008 PM 26391891 ER PT J AU Pasqua, T Tota, B Penna, C Corti, A Cerra, MC Loh, YP Angelone, T AF Pasqua, T. Tota, B. Penna, C. Corti, A. Cerra, M. C. Loh, Y. P. Angelone, T. TI pGlu-serpinin protects the normotensive and hypertensive heart from ischemic injury SO JOURNAL OF ENDOCRINOLOGY LA English DT Article DE serpinin; Chromogranin A-derived peptides; hypertension; rat heart ID K-ATP CHANNELS; CHROMOGRANIN-A; RAT-HEART; ISCHEMIA/REPERFUSION INJURY; REPERFUSION INJURY; MUSCLE-CELLS; CARDIOPROTECTION; SURVIVAL; INVOLVEMENT; ACTIVATION AB Serpinin peptides derive from proteolytic cleavage of Chromogranin-A at C-terminus. Serpinin and the more potent pyroglutaminated-serpinin (pGlu-Serp) are positive cardiac beta-adrenergic-like modulators, acting through beta 1-AR/AC/cAMP/PKA pathway. Because in some conditions this pathway and/or other pro-survival pathways, activated by other Chromogranin-A fragments, may cross-talk and may be protective, here we explored whether pGlu-Serp cardioprotects against ischemia/reperfusion injury under normotensive and hypertensive conditions. In the latter condition, cardioprotection is often blunted because of the limitations on pro-survival Reperfusion Injury Salvage Kinases (RISK) pathway activation. The effects of pGlu-Serp were evaluated on infarct size (IS) and cardiac function by using the isolated and Langendorff perfused heart of normotensive (Wistar Kyoto, WKY) and spontaneously hypertensive (SHR) rats exposed to ischemic pre-conditioning (PreC) and post-conditioning (PostC). In both WKY and SHR rat, pGlu-Serp induced mild cardioprotection in both PreC and PostC. pGlu-Serp administered at the reperfusion (Serp-PostC) significantly reduced IS, being more protective in SHR than in WKY. Conversely, left ventricular developed pressure (LVDevP) post-ischemic recovery was greater in WKY than in SHR. pGlu-Serp-PostC reduced contracture in both strains. Co-infusion with specific RISK inhibitors (PI3K/Akt, MitoK(ATP) channels and PKC) blocked the pGlu-Serp-PostC protective effects. To show direct effect on cardiomyocytes, we pre-treated H9c2 cells with pGlu-Serp, which were thus protected against hypoxia/reoxygenation. These results suggest pGlu-Serp as a potential modulatory agent implicated in the protective processes that can limit infarct size and overcome the hypertension-induced failure of PostC. C1 [Pasqua, T.; Tota, B.; Cerra, M. C.; Angelone, T.] Univ Calabria, Dept Biol Ecol & ES, Lab Cardiovasc Pathophysiol, I-87036 Arcavacata Di Rende, CS, Italy. [Corti, A.] Ist Sci San Raffaele, Div Mol Oncol, Tumor Biol & Vasc Targeting Unit, I-20132 Milan, Italy. [Loh, Y. P.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. RP Loh, YP (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. EM lohp@mail.nih.gov; tommaso.angelone@unical.it RI Corti, Angelo/F-7046-2012; OI Corti, Angelo/0000-0002-0893-6191; Subba, Rajkrishna/0000-0003-0051-0062 FU MIUR of Italy; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, USA FX This work was supported by the MIUR of Italy (Programma di Ricerca Scientifica di Interesse Nazionale), "Programma ARUE - POR Calabria - FSE 2007/2013 Asse IV" and in part by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, USA. NR 35 TC 1 Z9 1 U1 0 U2 2 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0022-0795 EI 1479-6805 J9 J ENDOCRINOL JI J. Endocrinol. PD DEC PY 2015 VL 227 IS 3 BP 167 EP 178 DI 10.1530/JOE-15-0199 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CW5LA UT WOS:000365035700007 PM 26400960 ER PT J AU Bryson, JL Bhandoola, A AF Bryson, Jerrod L. Bhandoola, Avinash TI Editorial: Ephs, ephrins, and early T cell development SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Editorial Material DE progenitor cells; chemokines; forward signalling ID IN-VITRO; THYMUS; MIGRATION C1 [Bryson, Jerrod L.] Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA USA. [Bhandoola, Avinash] NCI, Lab Genome Integr, T Cell Biol & Dev Unit, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Bhandoola, A (reprint author), NCI, Lab Genome Integr, T Cell Biol & Dev Unit, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM avinash.bhandoola@nih.gov FU NCI NIH HHS [T32 CA009140]; NIGMS NIH HHS [K12 GM081259] NR 11 TC 0 Z9 0 U1 0 U2 2 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 EI 1938-3673 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD DEC PY 2015 VL 98 IS 6 BP 877 EP 879 DI 10.1189/jlb.1CE0315-132R PG 3 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA CW3SL UT WOS:000364912000002 PM 26628637 ER PT J AU Mahfouz, A Ziats, MN Rennert, OM Lelieveldt, BPF Reinders, MJT AF Mahfouz, Ahmed Ziats, Mark N. Rennert, Owen M. Lelieveldt, Boudewijn P. F. Reinders, Marcel J. T. TI Shared Pathways Among Autism Candidate Genes Determined by Co-expression Network Analysis of the Developing Human Brain Transcriptome SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Article DE Autism spectrum disorder; Gene co-expression network; Synaptogenesis; Mitochondrion; Apoptosis ID COPY-NUMBER VARIATION; DE-NOVO MUTATIONS; SPECTRUM DISORDERS; FRONTAL-CORTEX; NEURODEVELOPMENTAL DISORDERS; GENETICS; GENOME; EXPRESSION; REVEALS; CONVERGENCE AB Autism spectrum disorder (ASD) is a neurodevelopmental syndrome known to have a significant but complex genetic etiology. Hundreds of diverse genes have been implicated in ASD; yet understanding how many genes, each with disparate function, can all be linked to a single clinical phenotype remains unclear. We hypothesized that understanding functional relationships between autism candidate genes during normal human brain development may provide convergent mechanistic insight into the genetic heterogeneity of ASD. We analyzed the co-expression relationships of 455 genes previously implicated in autism using the BrainSpan human transcriptome database, across 16 anatomical brain regions spanning prenatal life through adulthood. We discovered modules of ASD candidate genes with biologically relevant temporal co-expression dynamics, which were enriched for functional ontologies related to synaptogenesis, apoptosis, and GABA-ergic neurons. Furthermore, we also constructed co-expression networks from the entire transcriptome and found that ASD candidate genes were enriched in modules related to mitochondrial function, protein translation, and ubiquitination. Hub genes central to these ASD-enriched modules were further identified, and their functions supported these ontological findings. Overall, our multi-dimensional co-expression analysis of ASD candidate genes in the normal developing human brain suggests the heterogeneous set of ASD candidates share transcriptional networks related to synapse formation and elimination, protein turnover, and mitochondrial function. C1 [Mahfouz, Ahmed; Reinders, Marcel J. T.] Delft Univ Technol, Delft Bioinformat Lab, Delft, Netherlands. [Mahfouz, Ahmed; Lelieveldt, Boudewijn P. F.] Leiden Univ, Dept Radiol, Med Ctr, Leiden, Netherlands. [Lelieveldt, Boudewijn P. F.] Delft Univ Technol, Dept Intelligent Syst, Delft, Netherlands. [Ziats, Mark N.; Rennert, Owen M.] NICHHD, NIH, Bethesda, MD 20892 USA. [Ziats, Mark N.] Univ Cambridge, Cambridge, England. [Ziats, Mark N.] Baylor Coll Med, Houston, TX 77030 USA. RP Mahfouz, A (reprint author), Delft Univ Technol, Delft Bioinformat Lab, Delft, Netherlands. EM a.mahfouz@tudelft.nl RI Lelieveldt, Boudewijn/B-6501-2008; OI Lelieveldt, Boudewijn/0000-0001-8269-7603; Mahfouz, Ahmed/0000-0001-8601-2149 FU Dutch Technology Foundation STW, as part of the STW project [12721]; European Union [604102] FX We gratefully acknowledge the Allen Institute for Brain Science. We thank Marc Hulsman for his input on data normalization. We also thank Silvere van der Maarel and Arn M.J.M. van den Maagdenberg for their critical insight on the manuscript. This research has received partial funding from the Dutch Technology Foundation STW, as part of the STW project 12721: "Genes in Space" under the IMAGENE perspective program, and from the European Union Seventh Framework Program (FP7/2007-2013) under grant agreement no. 604102 (Human Brain Project). NR 83 TC 6 Z9 6 U1 3 U2 14 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0895-8696 EI 1559-1166 J9 J MOL NEUROSCI JI J. Mol. Neurosci. PD DEC PY 2015 VL 57 IS 4 BP 580 EP 594 DI 10.1007/s12031-015-0641-3 PG 15 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA CW5HJ UT WOS:000365026000016 PM 26399424 ER PT J AU Goudar, SS Derman, RJ Honnungar, NV Patil, KP Swamy, MK Moore, J Wallace, DD McClure, EM Kodkany, BS Pasha, O Sloan, NL Wright, LL Goldenberg, RL AF Goudar, Shivaprasad S. Derman, Richard J. Honnungar, Narayan V. Patil, Kamal P. Swamy, Mallaiah K. Moore, Janet Wallace, Dennis D. McClure, Elizabeth M. Kodkany, Bhalchandra S. Pasha, Omrana Sloan, Nancy L. Wright, Linda L. Goldenberg, Robert L. TI An Intervention to Enhance Obstetric and Newborn Care in India: A Cluster Randomized-Trial SO MATERNAL AND CHILD HEALTH JOURNAL LA English DT Article DE Emergency obstetric and newborn care; Perinatal mortality; Neonatal mortality; Community mobilization; Quality of care; India ID HEALTH FACILITIES; GLOBAL-NETWORK; MORTALITY; OUTCOMES; STRATEGIES AB This study assessed whether community mobilization and interventions to improve emergency obstetric and newborn care reduced perinatal mortality (PMR) and neonatal mortality rates (NMR) in Belgaum, India. The cluster-randomised controlled trial was conducted in Belgaum District, Karnataka State, India. Twenty geographic clusters were randomized to control or the intervention. The intervention engaged and mobilized community and health authorities to leverage support; strengthened community-based stabilization, referral, and transportation; and aimed to improve quality of care at facilities. 17,754 Intervention births and 15,954 control births weighing a parts per thousand yen1000 g, respectively, were enrolled and analysed. Comparing the baseline period to the last 6 months period, the NMR was lower in the intervention versus control clusters (OR 0.60, 95 % CI 0.34-1.06, p = 0.076) as was the PMR (OR 0.74, 95 % CI 0.46-1.19, p = 0.20) although neither reached statistical significance. Rates of facility birth and caesarean section increased among both groups. There was limited influence on quality of care measures. The intervention had large but not statistically significant effects on neonatal and perinatal mortality. Community mobilization and increased facility care may ultimately improve neonatal and perinatal survival, and are important in the context of the global transition towards institutional delivery. C1 [Goudar, Shivaprasad S.; Honnungar, Narayan V.; Patil, Kamal P.; Swamy, Mallaiah K.; Kodkany, Bhalchandra S.] KLE Univ, Jawaharlal Nehru Med Coll, Womens & Childrens Hlth Res Unit, Belgaum, India. [Derman, Richard J.; Sloan, Nancy L.] Christiana Care Hlth Syst, Dept Obstet & Gynaecol, Newark, DE USA. [Moore, Janet; Wallace, Dennis D.; McClure, Elizabeth M.] Res Triangle Inst, Social Stat & Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. [Pasha, Omrana] Aga Khan Univ, Karachi, Pakistan. [Wright, Linda L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Rockville, MD USA. [Goldenberg, Robert L.] Columbia Univ, Dept Obstet & Gynaecol, New York, NY USA. RP McClure, EM (reprint author), Res Triangle Inst, Social Stat & Environm Hlth Sci, POB 12194, Res Triangle Pk, NC 27709 USA. EM mcclure@rti.org FU Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This study was funded through grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 21 TC 1 Z9 1 U1 0 U2 1 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1092-7875 EI 1573-6628 J9 MATERN CHILD HLTH J JI Matern. Child Health J. PD DEC PY 2015 VL 19 IS 12 BP 2698 EP 2706 DI 10.1007/s10995-015-1792-0 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CW4LW UT WOS:000364964000020 PM 26205277 ER PT J AU Guo, N Zhang, F Zhang, XM Guo, JX Lang, LX Kiesewetter, DO Niu, G Li, QZ Chen, XY AF Guo, Ning Zhang, Fan Zhang, Xiaomeng Guo, Jinxia Lang, Lixin Kiesewetter, Dale O. Niu, Gang Li, Quanzheng Chen, Xiaoyuan TI Quantitative Evaluation of Tumor Early Response to a Vascular-Disrupting Agent with Dynamic PET SO MOLECULAR IMAGING AND BIOLOGY LA English DT Article DE Dynamic PET; Vascular-disrupting agent; Integrin alpha(v)beta(3); [F-18]FPPRGD2 ID ENDOTHELIAL GROWTH-FACTOR; SOLID TUMORS; IN-VIVO; ANGIOGENESIS; CANCER; VEGF(121)/RGEL; GLIOBLASTOMA; INHIBITION AB The purpose of this study is to evaluate the early response of tumors to a vascular-disrupting agent (VDA) VEGF(121)/recombinant toxin gelonin (rGel) using dynamic [F-18]FPPRGD2 positron emission tomography (PET) and kinetic parameter estimation. Two tumor xenograft models: U87MG (highly vascularized) and A549 (moderately vascularized), were selected, and both were randomized into treatment and control groups. Sixty-minute dynamic PET scans with [F-18]FPPRGD2 that targets to integrin alpha(v)beta(3) were performed at days 0 (baseline), 1, and 3 since VEGF(121)/rGel treatment started. Dynamic PET-derived binding potential (BPND) and parametric maps were compared with tumor uptake (%ID/g) and the static PET image at 1 h after the tracer administration. The growth of U87MG tumor was obviously delayed upon VEGF(121)/rGel treatment. A549 tumor was not responsive to the same treatment. BPND of treated U87MG tumors decreased significantly at day 1 (p < 0.05), and the difference was more significant at day 3 (p < 0.01), compared with the control group. However, the tracer uptake (%ID/g) derived from static images at 1-h time point did not show significant difference between the treated and control tumors until day 3. Little difference in tracer uptake (%ID/g) or BPND was found between treated and control A549 tumors. Considering the tracer retention in tumor and the slower clearance due to damaged tumor vasculature after treatment, BPND representing the actual specific binding portion appears to be more sensitive and accurate than the semiquantitative parameters (such as %ID/g) derived from static images to assess the early response of tumor to VDA treatment. Quantitative analysis based on dynamic PET with [F-18]FPPRGD2 shows advantages in distinguishing effective from ineffective treatment during the course of VEGF(121)/rGel therapy at early stage and is therefore more sensitive in assessing therapy response than static PET. C1 [Guo, Ning; Zhang, Xiaomeng; Li, Quanzheng] Harvard Univ, Massachusetts Gen Hosp, Ctr Adv Med Imaging Sci, Dept Radiol,Med Sch, Boston, MA 02114 USA. [Zhang, Fan; Guo, Jinxia] Xiamen Univ, State Key Lab Mol Vaccinol & Mol Diagnost, Sch Publ Hlth, Ctr Mol Imaging & Translat Med, Xiamen 361005, Peoples R China. [Zhang, Fan; Guo, Jinxia; Lang, Lixin; Kiesewetter, Dale O.; Niu, Gang; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. RP Li, QZ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Ctr Adv Med Imaging Sci, Dept Radiol,Med Sch, Boston, MA 02114 USA. EM Li.quanzheng@mgh.harvard.edu; shawn.chen@nih.gov FU National Basic Research Program of China (973 program) [2013CB733803, 2013CB733802]; National Science of Foundation of China (NSFC) [81371596, 81201086]; National Institutes of Health (NIH) [R21CA149587, R01EB013293]; Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), NIH FX This work was supported, in part, by the National Basic Research Program of China (973 program, 2013CB733803, 2013CB733802), the National Science of Foundation of China (NSFC, 81371596, 81201086), the National Institutes of Health (NIH) R21CA149587 and R01EB013293, and the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), NIH. NR 31 TC 0 Z9 0 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1536-1632 EI 1860-2002 J9 MOL IMAGING BIOL JI Mol. Imaging. Biol. PD DEC PY 2015 VL 17 IS 6 BP 865 EP 873 DI 10.1007/s11307-015-0854-4 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CW4DO UT WOS:000364941700016 PM 25896816 ER PT J AU Tejeda, HA Hanks, AN Scott, L Mejias-Aponte, C Hughes, ZA O'Donnell, P AF Tejeda, Hugo A. Hanks, Ashley N. Scott, Liam Mejias-Aponte, Carlos Hughes, Zoe A. O'Donnell, Patricio TI Prefrontal Cortical Kappa Opioid Receptors Attenuate Responses to Amygdala Inputs SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID MESSENGER-RNA; DOPAMINE NEURONS; NUCLEUS-ACCUMBENS; RAT; GLUTAMATE; ANXIETY; CORTEX; MODULATION; ACTIVATION; SYSTEM AB Kappa opioid receptors (KORs) have been implicated in anxiety and stress, conditions that involve activation of projections from the basolateral amygdala (BLA) to the medial prefrontal cortex (mPFC). Although KORs have been studied in several brain regions, their role on mPFC physiology and on BLA projections to the mPFC remains unclear. Here, we explored whether KORs modify synaptic inputs from the BLA to the mPFC using in vivo electrophysiological recordings with electrical and optogenetic stimulation. Systemic administration of the KOR agonist U69,593 inhibited BLA-evoked synaptic responses in the mPFC without altering hippocampus-evoked responses. IntramPFC U69,593 inhibited electrical and optogenetic BLA-evoked synaptic responses, an effect blocked by the KOR antagonist nor-BNI. Bilateral intra-mPFC injection of the KOR antagonist nor-BNI increased center time in the open field test, suggesting an anxiolytic effect. The data demonstrate that mPFC KORs negatively regulate glutamatergic synaptic transmission in the BLA-mPFC pathway and anxiety-like behavior. These findings provide a framework whereby KOR signaling during stress and anxiety can regulate the flow of emotional state information from the BLA to the mPFC. C1 [Tejeda, Hugo A.; O'Donnell, Patricio] Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. [Hanks, Ashley N.; Scott, Liam; Hughes, Zoe A.; O'Donnell, Patricio] Pfizer, Neurosci & Pain Res Unit, Cambridge, MA 02139 USA. [Mejias-Aponte, Carlos] NIDA, Neuronal Networks Sect, Baltimore, MD USA. [O'Donnell, Patricio] Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21201 USA. RP O'Donnell, P (reprint author), Pfizer, Neurosci & Pain Res Unit, 610 Main St, Cambridge, MA 02139 USA. EM patricio.odonnell@pfizer.com RI Hughes, Zoe/E-4808-2011; OI Hughes, Zoe/0000-0001-7174-0944; O'Donnell, Patricio/0000-0001-7788-624X FU NIMH [R01 MH057683]; National Science Foundation Graduate Research Fellowship; Meyerhoff Graduate Fellowship FX We thank Dr Karl Deisseroth for the generous donation of the AAV-CamKII-ChR2 construct for the optogenetics part of the study. The study was supported by NIMH Grant R01 MH057683 (PO'D), a National Science Foundation Graduate Research Fellowship (HAT) and the Meyerhoff Graduate Fellowship (HAT). NR 30 TC 4 Z9 4 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2015 VL 40 IS 13 BP 2856 EP 2864 DI 10.1038/npp.2015.138 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CW2YE UT WOS:000364858200002 PM 25971593 ER PT J AU Passeri, E Wilson, AM Primerano, A Kondo, MA Sengupta, S Srivastava, R Koga, M Obie, C Zandi, PP Goes, FS Valle, D Rapoport, JL Sawa, A Kano, S Ishizuka, K AF Passeri, Eleonora Wilson, Ashley M. Primerano, Amedeo Kondo, Mari A. Sengupta, Srona Srivastava, Rupali Koga, Minori Obie, Cassandra Zandi, Peter P. Goes, Fernando S. Valle, David Rapoport, Judith L. Sawa, Akira Kano, Shin-ichi Ishizuka, Koko TI Enhanced conversion of induced neuronal cells (iN cells) from human fibroblasts: Utility in uncovering cellular deficits in mental illness-associated chromosomal abnormalities SO NEUROSCIENCE RESEARCH LA English DT Article DE iN cells; Fibroblasts; Conversion rate; Process length; Copy number variations (CNVs); Schizophrenia; Childhood-onset schizophrenia; Translational research ID CHILDHOOD-ONSET SCHIZOPHRENIA; IPSC-DERIVED NEURONS; SURROGATE TISSUES; DEFINED FACTORS; STEM-CELLS; UNOPROSTONE; DISORDERS; BRAIN; PHENOTYPES; PROMISE AB The novel technology of induced neuronal cells (iN cells) is promising for translational neuroscience, as it allows the conversion of human fibroblasts into cells with postmitotic neuronal traits. However, a major technical barrier is the low conversion rate. To overcome this problem, we optimized the conversion media. Using our improved formulation, we studied how major mental illness-associated chromosomal abnormalities may impact the characteristics of iN cells. We demonstrated that our new iN cell culture protocol enabled us to obtain more precise measurement of neuronal cellular phenotypes than previous iN cell methods. Thus, this iN cell culture provides a platform to efficiently obtain possible cellular phenotypes caused by genetic differences, which can be more thoroughly studied in research using other human cell models such as induced pluripotent stem cells. (C) 2015 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved. C1 [Passeri, Eleonora; Wilson, Ashley M.; Primerano, Amedeo; Kondo, Mari A.; Sengupta, Srona; Srivastava, Rupali; Koga, Minori; Goes, Fernando S.; Sawa, Akira; Kano, Shin-ichi; Ishizuka, Koko] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21287 USA. [Obie, Cassandra; Valle, David] Johns Hopkins Univ, Sch Med, Inst Med Genet, Baltimore, MD 21287 USA. [Zandi, Peter P.] Johns Hopkins Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD 21287 USA. [Rapoport, Judith L.] NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. RP Sawa, A (reprint author), Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, 600 N Wolfe St, Baltimore, MD 21287 USA. EM asawa1@jhmi.edu; skano2@jhmi.edu; kishizu2@jhmi.edu RI Ishizuka, Koko/L-2071-2014; Kano, Shin-ichi/F-4144-2015; OI Kano, Shin-ichi/0000-0002-5171-3436; Kondo, Mari/0000-0001-7960-2888 FU NIH [P30 CA006973]; USPHS [MH-084018, MH-094268, MH-069853, MH-085226, MH-088753, MH-092443, MH-096208, MH-093458]; Stanley; NARSAD; Maryland Stem Cell Research Fund; Hammerschlag family; Sucampo AG FX We thank Mr. Ravi Tharakan and Dr. Takahiro Kato for technical support. CGH array analyses were conducted at the Sidney Kimmel Cancer Center Microarray Core Facility at JHU, supported by NIH grant P30 CA006973 entitled Regional Oncology Research Center. This work was supported by USPHS grants MH-084018 (A.S.), MH-094268 Silvio O. Conte Center (A.S.), MH-069853 (A.S.), MH-085226 (A.S.), MH-088753 (A.S.), MH-092443 (A.S.), MH-096208 (K.I.) and MH-093458 (S.K.), grants from Stanley (A.S.), NARSAD (A.S., S.K., K.I.) and Maryland Stem Cell Research Fund (A.S., K.I.). S.K. is also supported by the Hammerschlag family. This work was also supported in part by Sucampo AG. NR 24 TC 2 Z9 2 U1 4 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0168-0102 EI 1872-8111 J9 NEUROSCI RES JI Neurosci. Res. PD DEC PY 2015 VL 101 BP 57 EP 61 DI 10.1016/j.neures.2015.07.011 PG 5 WC Neurosciences SC Neurosciences & Neurology GA CW4IL UT WOS:000364954800008 PM 26260244 ER PT J AU Kaewkhaw, R Kaya, KD Brooks, M Homma, K Zou, JZ Chaitankar, V Rao, M Swaroop, A AF Kaewkhaw, Rossukon Kaya, Koray Dogan Brooks, Matthew Homma, Kohei Zou, Jizhong Chaitankar, Vijender Rao, Mahendra Swaroop, Anand TI Transcriptome Dynamics of Developing Photoreceptors in Three-Dimensional Retina Cultures Recapitulates Temporal Sequence of Human Cone and Rod Differentiation Revealing Cell Surface Markers and Gene Networks SO STEM CELLS LA English DT Article DE Human rod and cone photoreceptors; Stem cells; Global gene profiling; Next generation sequencing; Three-dimensional organoid culture; Retina ID PLURIPOTENT STEM-CELLS; LEUCINE-ZIPPER NRL; NEURAL RETINA; HOMEOBOX GENE; EXPRESSION PATTERNS; HORMONE-RECEPTOR; PRECURSOR CELLS; EYE DEVELOPMENT; MOUSE; TRANSPLANTATION AB The derivation of three-dimensional (3D) stratified neural retina from pluripotent stem cells has permitted investigations of human photoreceptors. We have generated a H9 human embryonic stem cell subclone that carries a green fluorescent protein (GFP) reporter under the control of the promoter of cone-rod homeobox (CRX), an established marker of postmitotic photoreceptor precursors. The CRXp-GFP reporter replicates endogenous CRX expression in vitro when the H9 subclone is induced to form self-organizing 3D retina-like tissue. At day 37, CRX1 photoreceptors appear in the basal or middle part of neural retina and migrate to apical side by day 67. Temporal and spatial patterns of retinal cell type markers recapitulate the predicted sequence of development. Cone gene expression is concomitant with CRX, whereas rod differentiation factor neural retina leucine zipper protein (NRL) is first observed at day 67. At day 90, robust expression of NRL and its target nuclear receptor NR2E3 is evident in many CRX1 cells, while minimal S-opsin and no rhodopsin or L/M-opsin is present. The transcriptome profile, by RNA-seq, of developing human photoreceptors is remarkably concordant with mRNA and immunohistochemistry data available for human fetal retina although many targets of CRX, including phototransduction genes, exhibit a significant delay in expression. We report on temporal changes in gene signatures, including expression of cell surface markers and transcription factors; these expression changes should assist in isolation of photoreceptors at distinct stages of differentiation and in delineating coexpression networks. Our studies establish the first global expression database of developing human photoreceptors, providing a reference map for functional studies in retinal cultures. C1 [Kaewkhaw, Rossukon; Kaya, Koray Dogan; Brooks, Matthew; Homma, Kohei; Chaitankar, Vijender; Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. [Kaewkhaw, Rossukon] Mahidol Univ, Fac Med, Ramathibodi Hosp, Res Ctr, Bangkok 10700, Thailand. [Zou, Jizhong; Rao, Mahendra] NIH, Ctr Regenerat Med, Bethesda, MD 20892 USA. [Zou, Jizhong] NHLBI, IPSC Core, Ctr Mol Med, Bethesda, MD 20892 USA. [Homma, Kohei] Nippon Med Sch, Dept Physiol, Tokyo 113, Japan. [Rao, Mahendra] New York Stem Cell Fdn Res Inst, New York, NY 10023 USA. RP Swaroop, A (reprint author), NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bldg 6-338,6 Ctr Dr,MSC 0610, Bethesda, MD 20892 USA. EM swar-oopa@nei.nih.gov OI Swaroop, Anand/0000-0002-1975-1141 FU National Eye Institute, National Institutes of Health [ZO1 EY000450, EY000474]; Japan Society for the Promotion of Science (JSPS); JSPS FX This research was supported by Intramural Research Program (ZO1 EY000450 and EY000474) of the National Eye Institute, National Institutes of Health. K.H. was supported by grant-in-aid for Young Scientists (B) from Japan Society for the Promotion of Science (JSPS) and JSPS Postdoctoral Fellowships for Research Abroad (Kaitoku-NIH). We thank Linn Gieser, Rafael Villasmil, Trevor Cerbini, and Jacklyn Mahgerefteh for technical assistance, Robert Fariss and Chun Gao for assistance with live imaging, and Tiziana Coglaiti for helpful comments and discussion. K.H. is currently affiliated with Department of Physiology, Nippon Medical School, Tokyo, Japan. M.R. is currently affiliated with The New York Stem Cell Foundation Research Institute, New York, NY. NR 71 TC 15 Z9 15 U1 2 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1066-5099 EI 1549-4918 J9 STEM CELLS JI Stem Cells PD DEC PY 2015 VL 33 IS 12 SI SI BP 3504 EP 3518 DI 10.1002/stem.2122 PG 15 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA CW5PR UT WOS:000365049000016 PM 26235913 ER PT J AU Khan, I Arany, P AF Khan, Imran Arany, Praveen TI Biophysical Approaches for Oral Wound Healing: Emphasis on Photobiomodulation SO ADVANCES IN WOUND CARE LA English DT Review ID LEVEL LASER THERAPY; CYTOCHROME-C-OXIDASE; NITRIC-OXIDE; TGF-BETA; IN-VITRO; ELECTROMAGNETIC-FIELDS; LIGHT THERAPY; CELLS; ULTRASOUND; SKIN AB Significance: Oral wounds can lead to significant pain and discomfort as well as affect overall general health due to poor diet and inadequate nutrition. Besides many biological and pharmaceutical methods being investigated, there is growing interest in exploring various biophysical devices that utilize electric, magnetic, ultrasound, pressure, and light energy. Recent Advances: Significant insight into mechanisms of these biophysical devices could provide a clear rationale for their clinical use. Preclinical studies are essential precursors in determining physiological mechanisms and elucidation of causal pathways. This will lead to development of safe and effective therapeutic protocols for clinical wound management. Critical Issues: Identification of precise events initiated by biophysical devices, specifically photobiomodulationthe major focus of this review, offers promising avenues in improving oral wound management. The primary phase responses initiated by the interventions that distinctly contribute to the therapeutic response must be clearly delineated from secondary phase responses. The latter events are a consequence of the wound healing process and must not be confused with causal mechanisms. Future Direction: Clinical adoption of these biophysical devices needs robust and efficacious protocols that can be developed by well-designed preclinical and clinical studies. Elucidation of the precise molecular mechanisms of these biophysical approaches could determine optimization of their applications for predictive oral wound care. C1 [Khan, Imran; Arany, Praveen] Natl Inst Dent & Craniofacial Res, Cell Regulat & Control Unit, NIH, Bethesda, MD 20892 USA. RP Arany, P (reprint author), Natl Inst Dent & Craniofacial Res, Cell Regulat & Control Unit, NIH, 30 Convent Dr,3A-301, Bethesda, MD 20892 USA. EM praveenarany@gmail.com NR 89 TC 5 Z9 5 U1 2 U2 5 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 2162-1918 EI 2162-1934 J9 ADV WOUND CARE JI Adv. Wound Care PD DEC 1 PY 2015 VL 4 IS 12 BP 724 EP 737 DI 10.1089/wound.2014.0623 PG 14 WC Dermatology SC Dermatology GA CV8OF UT WOS:000364546800004 ER PT J AU Kobrin, S Ferrer, R Meissner, H Tiro, J Hall, K Shmueli-Blumberg, D Rothman, A AF Kobrin, Sarah Ferrer, Rebecca Meissner, Helen Tiro, Jasmin Hall, Kara Shmueli-Blumberg, Dikla Rothman, Alex TI Use of Health Behavior Theory in Funded Grant Proposals: Cancer Screening Interventions as a Case Study SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Article DE Behavioral theory; Use of theory; Cancer screening; Grant proposal ID PHYSICAL-ACTIVITY; PUBLIC-HEALTH; IMPLEMENTATION; DETERMINANTS; MODERATORS; MEDIATORS; EDUCATION; MODELS AB Interventions using theory should change behavior and identify both mechanisms of effect and necessary conditions. To date, inconsistent description of "use of theory" has limited understanding of how theory improves intervention impact. The purpose of this study was to describe the use of theory in health behavior intervention development by coding grant proposals. We developed an abstraction tool to characterize investigators, interventions, and theory use and identified seven core elements describing both how and how much theory was used. We used the tool to review and code NCI's funded cancer screening intervention R01 proposals, 1998-2009. Of 116 proposals, 38 met criteria; all but one described a conceptual model unique to the proposed research. Few proposals included plans to identify mechanisms of effect or conditions necessary for intervention effectiveness. Cancer screening intervention grant proposals rarely use theory in ways that advance behavioral or theoretical sciences. Proposed core elements may classify and synthesize the use of theory in behavioral intervention research. C1 [Kobrin, Sarah; Ferrer, Rebecca; Hall, Kara] NCI, Behav Res Program, Bethesda, MD 20892 USA. [Meissner, Helen] NIH, Off Dis Prevent, Bethesda, MD 20892 USA. [Tiro, Jasmin] Univ Texas SW Med Ctr Dallas, Div Behav & Commun Sci, Dallas, TX 75390 USA. [Shmueli-Blumberg, Dikla] Emmes Corp, Rockville, MD USA. [Rothman, Alex] Univ Minnesota, Dept Psychol, Minneapolis, MN 55455 USA. RP Kobrin, S (reprint author), NCI, Behav Res Program, Bethesda, MD 20892 USA. EM kobrins@mail.nih.gov OI Tiro, Jasmin/0000-0001-8300-0441 NR 43 TC 1 Z9 1 U1 1 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD DEC PY 2015 VL 49 IS 6 BP 809 EP 818 DI 10.1007/s12160-015-9714-3 PG 10 WC Psychology, Multidisciplinary SC Psychology GA CV8GL UT WOS:000364519500004 PM 26070290 ER PT J AU Dorner, T Shock, A Goldenberg, DM Lipsky, PE AF Doerner, Thomas Shock, Anthony Goldenberg, David M. Lipsky, Peter E. TI The mechanistic impact of CD22 engagement with epratuzumab on B cell function: Implications for the treatment of systemic lupus erythematosus SO AUTOIMMUNITY REVIEWS LA English DT Review DE Systemic lupus erythematosus; Epratuzumab; B cells; CD22; Biologic therapies ID HUMANIZED ANTI-CD22 ANTIBODY; BCR CROSS-TALK; ANTIGEN RECEPTOR; AUTOIMMUNE-DISEASES; SIGNAL-TRANSDUCTION; TYROSINE-PHOSPHATASE; RHEUMATOID-ARTHRITIS; MONOCLONAL-ANTIBODY; PERIPHERAL-BLOOD; LIPID RAFTS AB Epratuzumab is a B-cell-directed non-depleting monoclonal antibody that targets CD22. It is currently being evaluated in two phase 3 clinical trials in patients with systemic lupus erythematosus (SLE), a disease associated with abnormalities in B-cell function and activation. The mechanism of action of epratuzumab involves perturbation of the B-cell receptor (BCR) signalling complex and intensification of the normal inhibitory role of CD22 on the BCR, leading to reduced signalling and diminished activation of B cells. Such effects may result from down-modulation of CD22 upon binding by epratuzumab, as well as decreased expression of other proteins involved in amplifying BCR signalling capability, notably CD19. The net result is blunting the capacity of antigen engagement to induce B-cell activation. The functional consequences of epratuzumab binding to CD22 include diminished B-cell proliferation, effects on adhesion molecule expression, and B-cell migration, as well as reduced production of pro-inflammatory cytokines, such as IL-6 and TNF. Studies in patients treated with epratuzumab have revealed a number of pharmacodynamic effects that are linked to the mechanism of action (i.e., a loss of the target molecule CD22 from the B-cell surface followed by a modest reduction in peripheral B-cell numbers after prolonged therapy). Together, these data indicate that epratuzumab therapy affords a unique means to modulate BCR complex expression and signalling. (C) 2015 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license. C1 [Doerner, Thomas] Charite, Dept Med Rheumatol & Clin Immunol, D-10117 Berlin, Germany. [Doerner, Thomas] DRFZ Berlin, D-10117 Berlin, Germany. [Shock, Anthony] UCB Pharma, Slough SL1 3WE, West Berkshire, England. [Goldenberg, David M.] Immunomedics Inc, Morris Plains, NJ USA. [Lipsky, Peter E.] NIAMSD, NIH, Bethesda, MD 20892 USA. RP Dorner, T (reprint author), Charite, Dept Med Rheumatol & Clin Immunol, D-10117 Berlin, Germany. EM thomas.doemer@charite.de; tony.shock@ucb.com; dmg.gscancer@att.net; peterlipsky@comcast.net FU UCB Pharma FX The authors acknowledge Jennifer Timoshanko, UCB Pharma, UK for publication coordination and Costello Medical Consulting, UK, for editorial assistance, which was funded by UCB Pharma. NR 136 TC 10 Z9 10 U1 0 U2 16 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-9972 EI 1873-0183 J9 AUTOIMMUN REV JI Autoimmun. Rev. PD DEC PY 2015 VL 14 IS 12 BP 1079 EP 1086 DI 10.1016/j.autrev.2015.07.013 PG 8 WC Immunology SC Immunology GA CV9PH UT WOS:000364618600001 PM 26212727 ER PT J AU Gorelik, M Frischmeyer-Guerrerio, PA AF Gorelik, Mark Frischmeyer-Guerrerio, Pamela A. TI Innate and adaptive dendritic cell responses to immunotherapy SO Current Opinion in Allergy and Clinical Immunology LA English DT Review DE adaptive immunity; allergy; dendritic cells; desensitization; immunotherapy; innate immunity; tolerance ID EPICUTANEOUS IMMUNOTHERAPY; T-CELLS; IMMUNE-RESPONSES; SENSITIZED MICE; PEANUT; INFLAMMATION; ALLERGENS; PROMOTES; SKIN AB Purpose of review In allergic disease, dendritic cells play a critical role in orchestrating immune responses to innate stimuli and promoting the formation of T helper 2 (T(H)2) effector versus T-regulatory cells. Here, we review recent advances in our understanding of how current forms of immunotherapy modulate dendritic cell responses. Recent findings Sublingual immunotherapy (SLIT) and oral immunotherapy (OIT) for peanut allergy alter the expression of costimulatory molecules on dendritic cells, which leads to reduced expression of T(H)2 effector cytokines in an antigen-nonspecific manner. SLIT and OIT also modulate dendritic cell innate immune responses to Toll-like receptor agonists, including enhanced production of interferon and reduced expression of proinflammatory cytokines that may serve to promote the development of tolerance. Dendritic cells isolated from patients post-OIT promoted hypomethylation of the FOXP3 locus in effector T cells. Reduced methylation of the FOXP3 locus has been associated with more persistent clinical desensitization following OIT. Recent studies have additionally highlighted a role for B cells in inducing tolerogenic dendritic cell populations and T-regulatory cells during immunotherapy. Epicutaneous immunotherapy may also elicit immunosuppressive populations of cutaneous dendritic cells, although in some cases, antigen exposure through the skin can lead to sensitization. Finally, efforts have focused on identifying pharmacologic and/or antigen-independent strategies of altering dendritic cell function to enhance the immunosuppressive effects of immunotherapy. Summary Dendritic cells are a critical target of immunotherapy. Alterations in both adaptive and innate immunity likely underlie the immunosuppressive effects of this treatment. C1 [Gorelik, Mark] Johns Hopkins Univ, Sch Med, Dept Pediat, Div Allergy & Immunol, Baltimore, MD 21205 USA. [Frischmeyer-Guerrerio, Pamela A.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Frischmeyer-Guerrerio, PA (reprint author), NIAID, Lab Allerg Dis, 4 Mem Dr,Bldg 4,Room 228B,MSC0430, Bethesda, MD 20892 USA. EM pamela.guerrerio@nih.gov FU Research Training in Pediatric Allergy and Immunology [5T32AI007007]; NIH, NIAID FX M.G. is supported by the Research Training in Pediatric Allergy and Immunology (Grant No. 5T32AI007007) and also has Winkelstein fellowship. P.A.F.-G. is supported by the Intramural Research Program of the NIH, NIAID. NR 32 TC 0 Z9 0 U1 4 U2 15 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1528-4050 EI 1473-6322 J9 CURR OPIN ALLERGY CL JI Curr. Opin. Allergy Clin. Immunol. PD DEC PY 2015 VL 15 IS 6 BP 575 EP 580 DI 10.1097/ACI.0000000000000213 PG 6 WC Allergy; Immunology SC Allergy; Immunology GA CV5DX UT WOS:000364288400009 PM 26509662 ER PT J AU Pillai, R Paglialunga, S Hoang, M Cousteils, K Prentice, KJ Bombardier, E Huang, M Gonzalez, FJ Tupling, AR Wheeler, MB Joseph, JW AF Pillai, Renjitha Paglialunga, Sabina Hoang, Monica Cousteils, Katelyn Prentice, Kacey J. Bombardier, Eric Huang, Mei Gonzalez, Frank J. Tupling, A. Russell Wheeler, Michael B. Joseph, Jamie W. TI Deletion of ARNT/HIF1 beta in pancreatic beta cells does not impair glucose homeostasis in mice, but is associated with defective glucose sensing ex vivo SO DIABETOLOGIA LA English DT Article DE ARNT/HIF1 beta; Insulin release; Metabolism; Pancreatic beta cell ID STIMULATED INSULIN-SECRETION; OXIDATIVE CAPACITY; EXPRESSION; LINES; PYRUVATE; GROWTH AB Aims/hypothesis It has been suggested that the transcription factor ARNT/HIF1 beta is critical for maintaining in vivo glucose homeostasis and pancreatic beta cell glucose-stimulated insulin secretion (GSIS). Our goal was to gain more insights into the metabolic defects seen after the loss of ARNT/HIF1 beta in beta cells. Methods The in vivo and in vitro consequences of the loss of ARNT/HIF1 beta were investigated in beta cell specific Arnt/Hif1 beta knockout mice (beta-Arnt (fl/fl/Cre) mice). Results The only in vivo defects found in beta-Arnt (fl/fl/Cre) mice were significant increases in the respiratory exchange ratio and in vivo carbohydrate oxidation, and a decrease in lipid oxidation. The mitochondrial oxygen consumption rate was unaltered in mouse beta-Arnt (fl/fl/Cre) islets upon glucose stimulation. beta-Arnt (fl/fl/Cre) islets had an impairment in the glucose-stimulated increase in Ca2+ signalling and a reduced insulin secretory response to glucose in the presence of KCl and diazoxide. The glucose-stimulated increase in the NADPH/NADP(+) ratio was reduced in beta-Arnt (fl/fl/Cre) islets. The reduced GSIS and NADPH/NADP(+) levels in beta-Arnt (fl/fl/Cre) islets could be rescued by treatment with membrane-permeable tricarboxylic acid intermediates. Small interfering (si)RNA mediated knockdown of ARNT/HIF1 beta in human islets also inhibited GSIS. These results suggest that the regulation of GSIS by the K-ATP channel-dependent and -independent pathways is affected by the loss of ARNT/HIF1 beta in islets. Conclusions/interpretation This study provides three new insights into the role of ARNT/HIF1 beta in beta cells: (1) ARNT/HIF1 beta deletion in mice impairs GSIS ex vivo; (2) beta-Arnt (fl/fl/Cre) mice have an increased respiratory exchange ratio; and (3) ARNT/HIF1 beta is required for GSIS in human islets. C1 [Pillai, Renjitha; Paglialunga, Sabina; Hoang, Monica; Cousteils, Katelyn; Huang, Mei; Joseph, Jamie W.] Univ Waterloo, Sch Pharm, Kitchener, ON N2G 1C5, Canada. [Prentice, Kacey J.; Wheeler, Michael B.] Univ Toronto, Dept Physiol, Toronto, ON, Canada. [Bombardier, Eric; Tupling, A. Russell] Univ Waterloo, Dept Kinesiol, Waterloo, ON N2L 3G1, Canada. [Gonzalez, Frank J.] NCI, Lab Metab, Bethesda, MD 20892 USA. RP Joseph, JW (reprint author), Univ Waterloo, Sch Pharm, Hlth Sci Campus Bldg A,Room 4008,10A Victoria St, Kitchener, ON N2G 1C5, Canada. EM j3joseph@uwaterloo.ca OI Wheeler, Michael/0000-0002-7480-7267 FU Canadian Institute of Health Research (CIHR) [FRN 86638, MOP-324754]; Natural Sciences and Engineering Research Council of Canada (NSERC); Canadian Diabetes Association; CIHR doctoral research award FX This work was supported by Canadian Institute of Health Research (CIHR) grants to JWJ (FRN 86638) and MBW (MOP-324754), and by a Natural Sciences and Engineering Research Council of Canada (NSERC) and Canadian Diabetes Association doctoral scholarship to RP. KJP is supported by a CIHR doctoral research award. NR 23 TC 2 Z9 2 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD DEC PY 2015 VL 58 IS 12 BP 2832 EP 2842 DI 10.1007/s00125-015-3768-4 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CV4FC UT WOS:000364221200017 PM 26409461 ER PT J AU Griffiths, EC Fairlie-Clarke, K Allen, JE Metcalf, CJE Graham, AL AF Griffiths, Emily C. Fairlie-Clarke, Karen Allen, Judith E. Metcalf, C. Jessica E. Graham, Andrea L. TI Bottom-up regulation of malaria population dynamics in mice co-infected with lung-migratory nematodes SO ECOLOGY LETTERS LA English DT Article DE Co-infection; community ecology; effective propagation; immune profile; parasite ecology; predator community; resource regulation; target cell limitation ID BLOOD-STAGE MALARIA; PLASMODIUM-FALCIPARUM; EFFECTIVE PROPAGATION; HELMINTH COINFECTION; PARASITES; MECHANISMS; RESPONSES; CHABAUDI; TH2; SUSCEPTIBILITY AB When and how populations are regulated by bottom up vs. top down processes, and how those processes are affected by co-occurring species, are poorly characterised across much of ecology. We are especially interested in the community ecology of parasites that must share a host. Here, we quantify how resources and immunity affect parasite propagation in experiments in near-replicate mesocosms'' - i.e. mice infected with malaria (Plasmodium chabaudi) and nematodes (Nippostrongylus brasiliensis). Nematodes suppressed immune responses against malaria, and yet malaria populations were smaller in co-infected hosts. Further analyses of within-host epidemiology revealed that nematode co-infection altered malaria propagation by suppressing target cell availability. This is the first demonstration that bottom-up resource regulation may have earlier and stronger effects than top-down immune mechanisms on within-host community dynamics. Our findings demonstrate the potential power of experimental ecology to disentangle mechanisms of population regulation in complex communities. C1 [Griffiths, Emily C.] N Carolina State Univ, Dept Entomol, Raleigh, NC 27695 USA. [Fairlie-Clarke, Karen] Univ Glasgow, Coll Med & Vet Life Sci, Inst Biodivers Anim Hlth & Comparat Med, Glasgow G61 1QH, Lanark, Scotland. [Allen, Judith E.] Univ Edinburgh, Sch Biol Sci, Inst Immunol & Infect Res, Edinburgh EH8 9YL, Midlothian, Scotland. [Metcalf, C. Jessica E.; Graham, Andrea L.] Princeton Univ, Dept Ecol & Evolut Biol, Princeton, NJ 08544 USA. [Metcalf, C. Jessica E.; Graham, Andrea L.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Graham, AL (reprint author), Princeton Univ, Dept Ecol & Evolut Biol, Princeton, NJ 08544 USA. EM algraham@princeton.edu RI Graham, Andrea/A-8808-2010; Allen, Judith/C-9198-2011 OI Graham, Andrea/0000-0002-6580-2755; Allen, Judith/0000-0002-3829-066X FU U.K. Biotechnology and Biological Sciences Research Council [BB/C508734/1, BB/D01977X/1]; Santander Bank Universities Scheme Research Mobility Award via the University of Sheffield; BES small project grant; BSP international travel award; Princeton University Visiting Student Research Collaborator award FX We acknowledge the invaluable contributions of the animal care staff at the University of Edinburgh, Tina Hansen for microscopy, Kathryn Watt and Sheelagh Duncan for technical assistance, and Rick Maizels and Yvonne Harcus for the nematodes. We thank David Dunne, Jan Bradley, Sarah Reece, Anieke van Leeuwen and Sarah Budischak for comments on previous drafts of this work. We thank Neil Rooney, Owen Petchey, Amy Pedersen and Andy Fenton for discussion and Gustavo Henrique de Carvalho for statistical advice. We are also very grateful to our funders. The empirical work was funded by the U.K. Biotechnology and Biological Sciences Research Council (grant BB/C508734/1 to JEA and fellowship BB/D01977X/1 to ALG) and analyses were supported in part by the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, U.S. Department of Homeland Security, and the Fogarty International Center of the National Institutes of Health. Santander Bank Universities Scheme Research Mobility Award via the University of Sheffield funded ECG's visit to work with Gustavo at Universidade Federal de Sao Carlos, Brazil. ECG's visit to Princeton was funded by a BES small project grant, BSP international travel award, and a Princeton University Visiting Student Research Collaborator award. NR 47 TC 2 Z9 2 U1 4 U2 26 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1461-023X EI 1461-0248 J9 ECOL LETT JI Ecol. Lett. PD DEC PY 2015 VL 18 IS 12 BP 1387 EP 1396 DI 10.1111/ele.12534 PG 10 WC Ecology SC Environmental Sciences & Ecology GA CV8GI UT WOS:000364519000012 PM 26477454 ER PT J AU Sanders, T Liu, YM Tchounwou, PB AF Sanders, Talia Liu, Yi-Ming Tchounwou, Paul B. TI Cytotoxic, genotoxic, and neurotoxic effects of Mg, Pb, and Fe on pheochromocytoma (PC-12) cells SO ENVIRONMENTAL TOXICOLOGY LA English DT Article DE heavy metals; cytotoxicity; genotoxicity; neurotoxicity; PC-12 cells ID VASCULAR SMOOTH-MUSCLE; NERVE GROWTH-FACTOR; LEAD-EXPOSURE; OXIDATIVE STRESS; RAT-BRAIN; PC12 CELLS; IN-VIVO; SYNAPTIC-TRANSMISSION; PARKINSONS-DISEASE; LIPID-PEROXIDATION AB Metals such as lead (Pb), magnesium (Mg), and iron (Fe) are ubiquitous in the environment as a result of natural occurrence and anthropogenic activities. Although Mg, Fe, and others are considered essential elements, high level of exposure has been associated with severe adverse health effects including cardiovascular, hematological, nephrotoxic, hepatotoxic, and neurologic abnormalities in humans. In the present study we hypothesized that Mg, Pb, and Fe are cytotoxic, genotoxic and neurotoxic, and their toxicity is mediated through oxidative stress and alteration in protein expression. To test the hypothesis, we used the pheochromocytoma (PC-12) cell line as a neuro cell model and performed the LDH assay for cell viability, Comet assay for DNA damage, Western blot for oxidative stress, and HPLC-MS to assess the concentration levels of neurological biomarkers such as glutamate, dopamine (DA), and 3-methoxytyramine (3-MT). The results of this study clearly show that Mg, Pb, and Fe, respectively in the form of MgSO4, Pb(NO3)(2), FeCl2, and FeCl3 induce cytotoxicity, oxidative stress, and genotoxicity in PC-12 cells. In addition, exposure to these metallic compounds caused significant changes in the concentration levels of glutamate, dopamine, and 3-MT in PC-12 cells. Taken together the findings suggest that MgSO4, Pb(NO3)(2), FeCl2, and FeCl3 have the potential to induce substantial toxicity to PC-12 cells. (C) 2014 Wiley Periodicals, Inc. C1 [Sanders, Talia; Tchounwou, Paul B.] Jackson State Univ, NIH NIMHD RCMI Ctr Environm Hlth, Cell & Toxicogen Res Lab, Jackson, MS 39217 USA. [Liu, Yi-Ming] Jackson State Univ, NIH NIMHD RCMI Ctr Environm Hlth, Bioanalyt Res Lab, Jackson, MS 39217 USA. RP Tchounwou, PB (reprint author), Jackson State Univ, NIH NIMHD RCMI Ctr Environm Hlth, Cell & Toxicogen Res Lab, 1400 Lynch St,Box18750, Jackson, MS 39217 USA. EM paul.b.tchounwou@jsums.edu FU National Institutes of Health through the RCMI Center for Environmental Health at Jackson State University [G12MD007581] FX National Institutes of Health through the RCMI Center for Environmental Health at Jackson State University.; G12MD007581 NR 92 TC 2 Z9 2 U1 2 U2 20 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1520-4081 EI 1522-7278 J9 ENVIRON TOXICOL JI Environ. Toxicol. PD DEC PY 2015 VL 30 IS 12 BP 1445 EP 1458 DI 10.1002/tox.22014 PG 14 WC Environmental Sciences; Toxicology; Water Resources SC Environmental Sciences & Ecology; Toxicology; Water Resources GA CW1WF UT WOS:000364781900010 PM 24942330 ER PT J AU Ostovaneh, MR Poustchi, H Hemming, K Marjani, H Pourshams, A Nateghi, A Majed, M Navabakhsh, B Khoshnia, M Jaafari, E Mohammadifard, N Malekzadeh, F Merat, S Sadeghi, M Naemi, M Etemadi, A Thomas, GN Sarrafzadegan, N Cheng, KK Marshall, T Malekzadeh, R AF Ostovaneh, Mohammad Reza Poustchi, Hossein Hemming, Karla Marjani, Hajiamin Pourshams, Akram Nateghi, Alireza Majed, Masoud Navabakhsh, Behrouz Khoshnia, Masoud Jaafari, Elham Mohammadifard, Noushin Malekzadeh, Fatemeh Merat, Shahin Sadeghi, Masoumeh Naemi, Mohammad Etemadi, Arash Thomas, G. Neil Sarrafzadegan, Nizal Cheng, K. K. Marshall, Tom Malekzadeh, Reza TI Polypill for the prevention of cardiovascular disease (PolyIran): study design and rationale for a pragmatic cluster randomized controlled trial SO EUROPEAN JOURNAL OF PREVENTIVE CARDIOLOGY LA English DT Article DE Cardiovascular diseases; primary prevention; secondary prevention; polypill ID GOLESTAN COHORT; RISK-FACTORS; DOUBLE-BLIND; IRAN; HEALTH; MORTALITY; STRATEGY; PROGRAM; WORKERS; CARE AB BackgroundThe complexity of treatment regimens, costs and pill burden decrease the medication adherence and contribute to shortfall in cardiovascular preventive drug coverage. The polypill, a fixed dose combination pill of established drugs, is expected to increase adherence and reduce the costs whilst preventing major cardiovascular events (MCVE). Design and methodsThe PolyIran trial is a pragmatic cluster randomized trial nested within the Golestan Cohort Study (GCS). Subjects were randomized to either non-pharmacological preventive interventions alone (minimal care arm) or together with a polypill (polypill arm) comprising hydrochlorothiazide, aspirin, atorvastatin and either enalapril or valsartan. This study benefits from the infrastructure of the primary health care system in Iran and the interventions are delivered by the local auxiliary health workers (Behvarz) to the participants. The primary outcome of the study is the occurrence of first MCVE within five years defined as non-fatal and fatal myocardial infarction, unstable angina, sudden death, heart failure, coronary artery revascularization procedures, and non-fatal and fatal stroke. Trial statusFrom February 2011 to April 2013, 8410 individuals (236 clusters) attended the eligibility assessment. Of those, 3421 in the polypill arm and 3417 in the minimal care arm were eligible. The study is ongoing. ConclusionThe infrastructure of GCS and the primary health care system in Iran enabled the conduct of this pragmatic large-scale trial. If the polypill strategy proves effective, it may be implemented to prevent cardiovascular disease in developing countries. C1 [Ostovaneh, Mohammad Reza; Poustchi, Hossein; Pourshams, Akram; Nateghi, Alireza; Majed, Masoud; Navabakhsh, Behrouz; Jaafari, Elham; Malekzadeh, Fatemeh; Merat, Shahin; Etemadi, Arash; Malekzadeh, Reza] Univ Tehran Med Sci, Shariati Hosp, Digest Dis Res Inst, Tehran 1411713135, Iran. [Ostovaneh, Mohammad Reza] Johns Hopkins Med Inst, Dept Med, Div Gastroenterol & Hepatol, Baltimore, MD 21205 USA. [Hemming, Karla; Thomas, G. Neil; Cheng, K. K.; Marshall, Tom] Univ Birmingham, Sch Hlth & Populat Sci, Birmingham B15 2TT, W Midlands, England. [Marjani, Hajiamin; Khoshnia, Masoud; Naemi, Mohammad] Golestan Univ Med Sci, Golestan Res Ctr Gastroenterol & Herpetol, Gorgan, Iran. [Mohammadifard, Noushin; Sarrafzadegan, Nizal] Isfahan Univ Med Sci, Cardiovasc Res Inst, Isfahan Cardiovasc Res Ctr, Esfahan, Iran. [Sadeghi, Masoumeh] Isfahan Univ Med Sci, Cardiovasc Res Inst, Cardiac Rehabil Res Ctr, Esfahan, Iran. [Etemadi, Arash] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Malekzadeh, R (reprint author), Univ Tehran Med Sci, Shariati Hosp, Digest Dis Res Inst, Tehran 1411713135, Iran. EM malek@tums.ac.ir RI Etemadi, Arash/C-1386-2016; Khoshnia, Masoud/P-5665-2016; OI Etemadi, Arash/0000-0002-3458-1072; Khoshnia, Masoud/0000-0001-7352-8058; Thomas, Graham Neil/0000-0002-2777-1847; Marshall, Tom/0000-0001-9277-5214 FU Digestive Disease Research Institute; Alborz Darou Research Funding Agency; Barekat Research Funding Agency FX The study was supported by the Digestive Disease Research Institute and Alborz Darou and Barekat Research Funding Agencies. NR 24 TC 5 Z9 5 U1 0 U2 3 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 2047-4873 EI 2047-4881 J9 EUR J PREV CARDIOL JI Eur. J. Prev. Cardiol. PD DEC PY 2015 VL 22 IS 12 BP 1609 EP 1617 DI 10.1177/2047487314550803 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CW2LS UT WOS:000364824400011 PM 25230980 ER PT J AU Gillams, A Goldberg, N Ahmed, M Bale, R Breen, D Callstrom, M Chen, MH Choi, BI de Baere, T Dupuy, D Gangi, A Gervais, D Helmberger, T Jung, EM Lee, F Lencioni, R Liang, P Livraghi, T Lu, D Meloni, F Pereira, P Piscaglia, F Rhim, H Salem, R Sofocleous, C Solomon, SB Soulen, M Tanaka, M Vogl, T Wood, B Solbiati, L AF Gillams, Alice Goldberg, Nahum Ahmed, Muneeb Bale, Reto Breen, David Callstrom, Matthew Chen, Min Hua Choi, Byung Ihn de Baere, Thierry Dupuy, Damian Gangi, Afshin Gervais, Debra Helmberger, Thomas Jung, Ernst-Michael Lee, Fred Lencioni, Riccardo Liang, Ping Livraghi, Tito Lu, David Meloni, Franca Pereira, Philippe Piscaglia, Fabio Rhim, Hyunchul Salem, Riad Sofocleous, Constantinos Solomon, Stephen B. Soulen, Michael Tanaka, Masatoshi Vogl, Thomas Wood, Brad Solbiati, Luigi TI Thermal ablation of colorectal liver metastases: a position paper by an international panel of ablation experts, the interventional oncology sans frontiSres meeting 2013 SO EUROPEAN RADIOLOGY LA English DT Article DE Colorectal neoplasms; Liver neoplasms; Ablation techniques; Consensus; Clinical protocols AB Previous attempts at meta-analysis and systematic review have not provided clear recommendations for the clinical application of thermal ablation in metastatic colorectal cancer. Many authors believe that the probability of gathering randomised controlled trial (RCT) data is low. Our aim is to provide a consensus document making recommendations on the appropriate application of thermal ablation in patients with colorectal liver metastases. This consensus paper was discussed by an expert panel at The Interventional Oncology Sans FrontiSres 2013. A literature review was presented. Tumour characteristics, ablation technique and different clinical applications were considered and the level of consensus was documented. Specific recommendations are made with regard to metastasis size, number, and location and ablation technique. Mean 31 % 5-year survival post-ablation in selected patients has resulted in acceptance of this therapy for those with technically inoperable but limited liver disease and those with limited liver reserve or co-morbidities that render them inoperable. In the absence of RCT data, it is our aim that this consensus document will facilitate judicious selection of the patients most likely to benefit from thermal ablation and provide a unified interventional oncological perspective for the use of this technology. aEuro cent Best results require due consideration of tumour size, number, volume and location. aEuro cent Ablation technology, imaging guidance and intra-procedural imaging assessment must be optimised. aEuro cent Accepted applications include inoperable disease due to tumour distribution or inadequate liver reserve. aEuro cent Other current indications include concurrent co-morbidity, patient choice and the test-of-time approach. aEuro cent Future applications may include resectable disease, e.g. for small solitary tumours. C1 [Gillams, Alice] London Clin, Dept Imaging, London W1G 6BW, England. [Goldberg, Nahum; Ahmed, Muneeb] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Bale, Reto] Univ Innsbruck Hosp, A-6020 Innsbruck, Austria. [Breen, David] Southampton Univ Hosp, Southampton, Hants, England. [Callstrom, Matthew] Mayo Clin, Rochester, MN USA. [Chen, Min Hua] Peking Univ Hosp, Beijing, Peoples R China. [Choi, Byung Ihn] Seoul Univ Hosp, Seoul, South Korea. [de Baere, Thierry] Gustave Roussy Canc Campus, Paris, France. [Gangi, Afshin] Univ Strasbourg, Strasbourg, France. [Gervais, Debra] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Helmberger, Thomas] Klinikum Bochenhausen, Munich, Germany. [Jung, Ernst-Michael] Univ Regensburg, D-93053 Regensburg, Germany. [Lee, Fred] Univ Wisconsin, Madison, WI USA. [Lencioni, Riccardo] Univ Pisa, Pisa, Italy. [Liang, Ping] Chinese Peoples Liberat Army Gen Hosp, Beijing, Peoples R China. [Livraghi, Tito] Clin Inst Humanitas, Milan, Italy. [Lu, David] Univ Calif Los Angeles, Los Angeles, CA USA. [Meloni, Franca] Univ Milan, Milan, Italy. [Pereira, Philippe] Heidelberg Univ, Heidelberg, Germany. [Piscaglia, Fabio] Univ Bologna, Bologna, Italy. [Rhim, Hyunchul] Sungkyunkwan Univ, Seoul, South Korea. [Salem, Riad] Northwestern Univ, Chicago, IL 60611 USA. [Sofocleous, Constantinos; Solomon, Stephen B.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Soulen, Michael] Univ Penn, Philadelphia, PA 19104 USA. [Tanaka, Masatoshi] Yokokura Hosp, Miyama, Japan. [Vogl, Thomas] Goethe Univ Frankfurt, D-60054 Frankfurt, Germany. [Wood, Brad] NIH, Bethesda, MD 20892 USA. RP Gillams, A (reprint author), London Clin, Dept Imaging, 20 Devonshire Pl, London W1G 6BW, England. EM alliesorting@gmail.com OI meloni, maria franca/0000-0001-7485-7400 FU NCI NIH HHS [P30 CA060553] NR 0 TC 25 Z9 26 U1 1 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0938-7994 EI 1432-1084 J9 EUR RADIOL JI Eur. Radiol. PD DEC PY 2015 VL 25 IS 12 BP 3438 EP 3454 DI 10.1007/s00330-015-3779-z PG 17 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CV8FS UT WOS:000364517000004 PM 25994193 ER PT J AU Kerr, GD Egbert, SD Al-Nabulsi, I Bailiff, IK Beck, HL Belukha, IG Cockayne, JE Cullings, HM Eckerman, KF Granovskaya, E Grant, EJ Hoshi, M Kaul, DC Kryuchkov, V Mannis, D Ohtaki, M Otani, K Shinkarev, S Simon, SL Spriggs, GD Stepanenko, VF Stricklin, D Weiss, JF Weitz, RL Woda, C Worthington, PR Yamamoto, K Young, RW AF Kerr, George D. Egbert, Stephen D. Al-Nabulsi, Isaf Bailiff, Ian K. Beck, Harold L. Belukha, Irina G. Cockayne, John E. Cullings, Harry M. Eckerman, Keith F. Granovskaya, Evgeniya Grant, Eric J. Hoshi, Masaharu Kaul, Dean C. Kryuchkov, Victor Mannis, Daniel Ohtaki, Megu Otani, Keiko Shinkarev, Sergey Simon, Steven L. Spriggs, Gregory D. Stepanenko, Valeriy F. Stricklin, Daniela Weiss, Joseph F. Weitz, Ronald L. Woda, Clemens Worthington, Patricia R. Yamamoto, Keiko Young, Robert W. TI WORKSHOP REPORT ON ATOMIC BOMB DOSIMETRY-REVIEW OF DOSE RELATED FACTORS FOR THE EVALUATION OF EXPOSURES TO RESIDUAL RADIATION AT HIROSHIMA AND NAGASAKI SO HEALTH PHYSICS LA English DT Article DE atomic bomb; residual radiation; Hiroshima; Nagasaki ID RETROSPECTIVE LUMINESCENCE DOSIMETRY; A-BOMB; EARLY ENTRANTS; GAMMA-RAYS; BLACK RAIN; SURVIVORS; FALLOUT; SOIL; COEFFICIENTS; U-235/U-238 AB Groups of Japanese and American scientists, supported by international collaborators, have worked for many years to ensure the accuracy of the radiation dosimetry used in studies of health effects in the Japanese atomic bomb survivors. Reliable dosimetric models and systems are especially critical to epidemiologic studies of this population because of their importance in the development of worldwide radiation protection standards. While dosimetry systems, such as Dosimetry System 1986 (DS86) and Dosimetry System 2002 (DS02), have improved, the research groups that developed them were unable to propose or confirm an additional contribution by residual radiation to the survivor's total body dose. In recognition of the need for an up-to-date review of residual radiation exposures in Hiroshima and Nagasaki, a half-day technical session was held for reports on newer studies at the 59th Annual HPS Meeting in 2014 in Baltimore, MD. A day-and-a-half workshop was also held to provide time for detailed discussion of the newer studies and to evaluate their potential use in clarifying the residual radiation exposure to atomic bomb survivors at Hiroshima and Nagasaki. The process also involved a re-examination of very early surveys of radioisotope emissions from ground surfaces at Hiroshima and Nagasaki and early reports of health effects. New insights were reported on the potential contribution to residual radiation from neutron-activated radionuclides in the airburst's dust stem and pedestal and in unlofted soil, as well as from fission products and weapon debris from the nuclear cloud. However, disparate views remain concerning the actual residual radiation doses received by the atomic bomb survivors at different distances from the hypocenter. The workshop discussion indicated that measurements made using thermal luminescence and optically stimulated luminescence, like earlier measurements, especially in very thin layers of the samples, could be expanded to detect possible radiation exposures to beta particles and to determine their significance plus the extent of the various residual radiation areas at Hiroshima and Nagasaki. Other suggestions for future residual radiation studies are included in this workshop report. C1 [Kerr, George D.] Kerr Consulting, Knoxville, TN USA. [Egbert, Stephen D.] Leidos Inc, San Diego, CA USA. [Al-Nabulsi, Isaf; Weiss, Joseph F.; Worthington, Patricia R.] US DOE, Washington, DC 20585 USA. [Bailiff, Ian K.] Univ Durham, Durham, England. [Beck, Harold L.] US DOE, New York, NY USA. [Belukha, Irina G.; Stepanenko, Valeriy F.] Med Radiol Res Ctr, Obninsk, Russia. [Cockayne, John E.] Leidos Inc, Alexandria, VA USA. [Cullings, Harry M.; Grant, Eric J.] Radiat Effects Res Fdn, Hiroshima, Japan. [Eckerman, Keith F.] Oak Ridge Natl Lab, Oak Ridge, TN USA. [Granovskaya, Evgeniya; Kryuchkov, Victor; Shinkarev, Sergey] State Res Ctr, Burnasyan Fed Med Biophys Ctr, Moscow, Russia. [Hoshi, Masaharu; Ohtaki, Megu; Otani, Keiko] Hiroshima Univ, Res Inst Radiat Biol & Med, Hiroshima, Japan. [Kaul, Dean C.] Sci Applicat Int Corp, Park City, UT USA. [Mannis, Daniel] Def Threat Reduct Agcy, Ft Belvoir, VA USA. [Simon, Steven L.] NCI, Bethesda, MD 20892 USA. [Spriggs, Gregory D.] Lawrence Livermore Natl Lab, Livermore, CA USA. [Stricklin, Daniela] Appl Res Associates, Arlington, VA USA. [Weitz, Ronald L.] Leidos Inc, Albuquerque, NM USA. [Woda, Clemens] German Ctr Environm Hlth, Helmholtz Zentrum Muenchen, Neuherberg, Germany. [Yamamoto, Keiko] Minist Hlth Labour & Welf, Tokyo, Japan. [Young, Robert W.] Def Nucl Agcy, Winter Pk, FL USA. RP Al-Nabulsi, I (reprint author), US DOE, Off Hlth & Safety, 1000 Independence Ave, Washington, DC 20585 USA. EM isaf.al-nabulsi@hq.doe.gov RI Shinkarev, Sergey /B-3254-2017; Granovskaya, Evgeniya/B-5268-2017; OI Hoshi, Masaharu/0000-0001-6978-0883 FU U.S. Department of Energy (USDOE) FX We wish to thank David Landguth, Oak Ridge National Laboratory, for his organizational expertise that resulted in a highly successful workshop. The help and advice of the Health Physics Society meeting organizers and the staff of Burk and Associates are also greatly appreciated. The participation of Harold L. Beck, Irina G. Belukha, John E. Cockayne, Keith F. Eckerman, Stephen D. Egbert, Evgeniya Granovskaya, Masaharu Hoshi, Dean Kaul, Victor Kryuchkov, Sergey Shinkarev, Gregory D. Spriggs, Valeriy F. Stepanenko, Ronald L. Weitz, and Robert W. Young in the workshop was financially supported by the U.S. Department of Energy (USDOE). The views of the authors do not necessarily reflect those of the USDOE, the U.S. government, or the authors' institutions. NR 58 TC 3 Z9 5 U1 3 U2 17 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD DEC PY 2015 VL 109 IS 6 BP 582 EP 600 DI 10.1097/HP.0000000000000395 PG 19 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA CV5SG UT WOS:000364330800005 PM 26509626 ER PT J AU Jochmanova, I Zhuang, ZP Pacak, K AF Jochmanova, Ivana Zhuang, Zhengping Pacak, Karel TI Pheochromocytoma: Gasping for Air SO Hormones & Cancer LA English DT Review ID ALPHA-TOCOPHERYL SUCCINATE; HYPOXIA-INDUCIBLE FACTOR-1; TUMOR-SUPPRESSOR GENE; MITOCHONDRIAL COMPLEX II; IN-VIVO; CELL-GROWTH; TCA CYCLE; GERMLINE MUTATIONS; RESPIRATORY-CHAIN; PYRUVATE-KINASE AB There has been increasing evidence that pseudohypoxia-a phenomenon that we refer to as "gasping for air"-along with mitochondrial enzyme dysregulation play a crucial role in tumorigenesis, particularly in several hereditary pheochromocytomas (PHEOs) and paragangliomas (PGLs). Alterations in key tricarboxylic acids (TCA) cycle enzymes (SDH, FH, MDH2) have been shown to induce pseudohypoxia via activation of the hypoxia-inducible transcription factor (HIF) signaling pathway that is involved in tumorigenesis, invasiveness, and metastatic spread, including an association with resistance to various cancer therapies and worse prognosis. This review outlines the ongoing story of the pathogenesis of hereditary PHEOs/PGLs, showing the unique and most updated evidence of TCA cycle dysregulation that is tightly linked to hypoxia signaling. C1 [Jochmanova, Ivana; Pacak, Karel] Eunice Kennedy Shriver NICHD, Program Reprod & Adult Endocrinol, NIH, CRC, Bethesda, MD 20892 USA. [Jochmanova, Ivana] Safarik Univ, Fac Med, Dept Internal Med 1, Kosice 04011, Slovakia. [Zhuang, Zhengping] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Pacak, K (reprint author), Eunice Kennedy Shriver NICHD, Program Reprod & Adult Endocrinol, NIH, CRC, Bldg 10,1 East,Room 1E-3140,10 Ctr Dr,MSC 1109, Bethesda, MD 20892 USA. EM karel@mail.nih.gov RI Jochmanova, Ivana/I-9011-2016 OI Jochmanova, Ivana/0000-0003-2346-461X FU Intramural Research Program of the National Institutes of Health, NICHD FX This research was supported, in part, by the Intramural Research Program of the National Institutes of Health, NICHD. NR 209 TC 4 Z9 5 U1 1 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1868-8497 EI 1868-8500 J9 HORM CANCER-US JI Horm. Cancer PD DEC PY 2015 VL 6 IS 5-6 BP 191 EP 205 DI 10.1007/s12672-015-0231-4 PG 15 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA CV6RJ UT WOS:000364397600002 PM 26138106 ER PT J AU Park, DU Friesen, MC Roh, HS Choi, YY Ahn, JJ Lim, HK Kim, SK Koh, DH Jung, HJ Lee, JH Cheong, HK Lim, SY Leem, JH Kim, YH Paek, DM AF Park, D. U. Friesen, M. C. Roh, H. S. Choi, Y. Y. Ahn, J. J. Lim, H. K. Kim, S. K. Koh, D. H. Jung, H. J. Lee, J. H. Cheong, H. K. Lim, S. Y. Leem, J. H. Kim, Y. H. Paek, D. M. TI Estimating retrospective exposure of household humidifier disinfectants SO INDOOR AIR LA English DT Article DE Humidifier disinfectant; PHMG; PGH; Aerosol; Nano-particle; Exposure assessment ID ULTRASONIC HUMIDIFIERS; RISK; CHEMICALS; CHILDREN; DISEASE AB We conducted a comprehensive humidifier disinfectant exposure characterization for 374 subjects with lung disease who presumed their disease was related to humidifier disinfectant use (patient group) and for 303 of their family members (family group) for an ongoing epidemiological study. We visited the homes of the registered patients to investigate disinfectant use characteristics. Probability of exposure to disinfectants was determined from the questionnaire and supporting evidence from photographs demonstrating the use of humidifier disinfectant, disinfectant purchase receipts, any residual disinfectant, and the consistency of their statements. Exposure duration was estimated as cumulative disinfectant use hours from the questionnaire. Airborne disinfectant exposure intensity (g/m(3)) was estimated based on the disinfectant volume (ml) and frequency added to the humidifier per day, disinfectant bulk level (g/ml), the volume of the room (m(3)) with humidifier disinfectant, and the degree of ventilation. Overall, the distribution patterns of the intensity, duration, and cumulative exposure to humidifier disinfectants for the patient group were higher than those of the family group, especially for pregnant women and patients 6years old. Further study is underway to evaluate the association between the disinfectant exposures estimated here with clinically diagnosed lung disease. C1 [Park, D. U.; Jung, H. J.] Korea Natl Open Univ, Dept Environm Hlth, Seoul 110791, South Korea. [Friesen, M. C.] NCI, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, DHHS,NIH, Bethesda, MD 20892 USA. [Roh, H. S.] Tiny Labs, Data Analyt Team, Seoul, South Korea. [Choi, Y. Y.; Ahn, J. J.; Lim, H. K.; Kim, S. K.] Asian Citizens Ctr Environm & Hlth, Seoul, South Korea. [Koh, D. H.] Catholic Kwandong Univ, Int St Marys Hosp, Dept Occupat & Environm Med, Inchon, South Korea. [Lee, J. H.] NeoEnBiz Co, Inst Environm Safety & Protect, Bucheon, South Korea. [Cheong, H. K.] Sungkyunkwan Univ, Sch Med, Dept Social & Prevent Med, Suwon, South Korea. [Lim, S. Y.] Kyung Hee Univ, Coll Med, Dept Occupat & Environm Med, Seoul, South Korea. [Leem, J. H.] Inha Univ Hosp, Dept Occupat & Environm Med, Inchon, South Korea. [Kim, Y. H.] Korea Inst Toxicol, Daejeon, South Korea. [Paek, D. M.] Seoul Natl Univ, Sch Publ Hlth, Seoul, South Korea. RP Park, DU (reprint author), Korea Natl Open Univ, Dept Environm Hlth, Seoul 110791, South Korea. EM pdw545@gmail.com RI Friesen, Melissa/A-5362-2009; OI Cheong, Hae-Kwan/0000-0003-2758-9399 FU Korea Center for Disease Control and Prevention (KCDC) [4851-300-210-13]; Intramural Research Program of the Division of Cancer Epidemiology and Genetics, within the National Cancer Institute of the National Institutes of Health [Z01 CP10122] FX This work was supported by the research funded by Korea Center for Disease Control and Prevention (KCDC) (4851-300-210-13). In particular, the authors would like to thank all of the study subjects who were willing to participate in this study for their cooperation. MCF is supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, within the National Cancer Institute of the National Institutes of Health (Z01 CP10122). NR 24 TC 3 Z9 3 U1 0 U2 7 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 DEC PY 2015 VL 25 IS 6 BP 631 EP 640 DI 10.1111/ina.12180 PG 10 WC Construction & Building Technology; Engineering, Environmental; Public, Environmental & Occupational Health SC Construction & Building Technology; Engineering; Public, Environmental & Occupational Health GA CW0TZ UT WOS:000364703700007 PM 25557769 ER PT J AU Schrack, JA Althoff, KN Jacobson, LP Erlandson, KM Jamieson, BD Koletar, SL Phair, J Ferrucci, L Brown, TT Margolick, JB AF Schrack, Jennifer A. Althoff, Keri N. Jacobson, Lisa P. Erlandson, Kristine M. Jamieson, Beth D. Koletar, Susan L. Phair, John Ferrucci, Luigi Brown, Todd T. Margolick, Joseph B. CA Multictr AIDS Cohort Study TI Accelerated Longitudinal Gait Speed Decline in HIV-Infected Older Men SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE gait speed; HIV-infection; functional decline; disability; aging ID LOWER-EXTREMITY FUNCTION; PHYSICAL PERFORMANCE; SUBSEQUENT DISABILITY; MOBILITY DISABILITY; BODY-COMPOSITION; ENERGETIC COST; LATE-LIFE; AGE; ADULTS; HEALTH AB Background: Gait speed predicts functional decline, disability, and death and is considered a biomarker of biological aging. Changes in gait speed in persons aging with HIV may provide an important method of gauging health and longevity in an under assessed population. The objective of this study was to evaluate and quantify the rate of gait speed decline in HIV-infected (HIV+) men compared with HIV-uninfected (HIV-) men. Methods: The study was nested in the Multicenter AIDS Cohort Study. The primary outcome was usual gait speed in meters per second measured between 2007 and 2013. Differences in the rate of gait speed decline and the incidence of clinically slow gait (<1.0 m/s) were assessed using multivariate linear regression models and Cox proportional hazards models, respectively. Results: A total of 2025 men (973 HIV+ and 1052 HIV-) aged 40 years and older contributed 21,187 person-visits (9955 HIV+ and 11,232 HIV-) to the analysis. Average gait speeds at the age 50 years were 1.24 and 1.19 m/s in HIV- and HIV+ men, respectively (P < 0.001). In fully adjusted models, gait speed decline averaged 0.009 m/s per year after age 50 years (P < 0.001); this decline was 0.025 m/s per year greater in HIV+ men (P < 0.001). Moreover, HIV+ men had a 57% greater risk of developing clinically slow gait (adjusted hazard ratio = 1.57, 95% confidence interval: 1.27 to 1.91). Conclusions: These findings indicate a faster rate of functional decline in HIV-infected men, suggesting greater risks of disability and death with advancing age. C1 [Schrack, Jennifer A.; Althoff, Keri N.; Jacobson, Lisa P.; Margolick, Joseph B.] Johns Hopkins Bloomberg,Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Erlandson, Kristine M.] Univ Colorado, Sch Med, Dept Med, Denver, CO USA. [Jamieson, Beth D.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med Hematol Oncol, Los Angeles, CA 90095 USA. [Koletar, Susan L.] Ohio State Univ, Dept Internal Med, Div Infect Dis, Columbus, OH 43210 USA. [Phair, John] Northwestern Univ, Feinberg Sch Med, Intramural Res Program, Translat Gerontol Branch, Chicago, IL 60611 USA. [Ferrucci, Luigi] NIA, Div Endocrineol & Metab, Internal Med, NIH, Baltimore, MD 21224 USA. [Brown, Todd T.] Johns Hopkins Sch Med, Dept Mol Microbiol & Immunol, Baltimore, MD USA. RP Schrack, JA (reprint author), 615 N Wolfe St,E7144, Baltimore, MD 21205 USA. EM jschrac1@jhu.edu FU National Institute of Allergy and Infectious Diseases (NIAID); National Cancer Institute (NCI); National Heart, Lung, and Blood Institute (NHLBI); National Institute on Deafness and Communication Disorders (NIDCD); NIA [K01AG048765, R03AG040594, K23AG050260]; NIAID [K01AI093197, R01AI093520]; JHU CFAR [1P30AI094189]; [UL1-TR000424] FX The MACS is funded primarily by the National Institute of Allergy and Infectious Diseases (NIAID), with additional co-funding from the National Cancer Institute (NCI). Targeted supplemental funding for specific projects was also provided by the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute on Deafness and Communication Disorders (NIDCD). MACS data collection is also supported by UL1-TR000424 (JHU CTSA). Web site located at http://www.statepi.jhsph.edu/macs/macs.html.; J.A.S. was supported by K01AG048765 from NIA. K.N.A. was supported by K01AI093197 from NIAID. K.M.E. was supported by R03AG040594 and K23AG050260 from NIA. T.T.B. was supported in part by R01AI093520 from the NIAID. L.F. is the Scientific Director of the NIA and a federal employee of the NIH. This work is also supported by the JHU CFAR (1P30AI094189). NR 39 TC 9 Z9 10 U1 2 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD DEC 1 PY 2015 VL 70 IS 4 BP 370 EP 376 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CV5MZ UT WOS:000364316300006 PM 26102450 ER PT J AU Zachariou, V Nikas, CV Safiullah, ZN Behrmann, M Klatzky, R Ungerleider, LG AF Zachariou, Valentinos Nikas, Christine V. Safiullah, Zaid N. Behrmann, Marlene Klatzky, Roberta Ungerleider, Leslie G. TI Common Dorsal Stream Substrates for the Mapping of Surface Texture to Object Parts and Visual Spatial Processing SO JOURNAL OF COGNITIVE NEUROSCIENCE LA English DT Article ID FEATURE-BINDING; PARIETAL CORTEX; NEUROPSYCHOLOGICAL EVIDENCE; ILLUSORY CONJUNCTIONS; FEATURE-INTEGRATION; ATTENTION; RECOGNITION; PATIENT; FORM AB Everyday objects are often composed of multiple parts, each with a unique surface texture. The neural substrates mediating the integration of surface features on different object parts are not fully understood, and potential contributions by both the ventral and dorsal visual pathways are possible. To explore these substrates, we collected fMRI data while human participants performed a difference detection task on two objects with textured parts. The objects could either differ in the assignment of the same texture to different object parts (texture-location) or the types of texture (texture-type). In the ventral stream, comparable BOLD activation levels were observed in response to texture-location and texture-type differences. In contrast, in a priori localized spatial processing regions of the dorsal stream, activation was greater for texture-location than texture-type differences, and the magnitude of the activation correlated with behavioral performance. We confirmed the reliance of surface texture to object part mapping on spatial processing mechanisms in subsequent psychophysical experiments, in which participants detected a difference in the spatial distance of an object relative to a reference line. In this task, distracter objects occasionally appeared, which differed in either texture-location or texture-type. Distracter texture-location differences slowed detection of spatial distance differences, but texture-type differences did not. More importantly, the distracter effects were only observed when texture-location differences were presented within whole shapes and not between separated shape parts at distinct spatial locations. We conclude that both the mapping of texture features to object parts and the representation of object spatial position are mediated by common neural substrates within the dorsal visual pathway. C1 [Zachariou, Valentinos; Nikas, Christine V.; Safiullah, Zaid N.; Ungerleider, Leslie G.] NIMH, NIH, Bethesda, MD 20892 USA. [Behrmann, Marlene; Klatzky, Roberta] Carnegie Mellon Univ, Pittsburgh, PA 15213 USA. RP Zachariou, V (reprint author), NIH, Lab Brain & Cognit, Bethesda, MD 20814 USA. EM zachariouv@mail.nih.gov FU NIMH Intramural Research Program (NIH Clinical Study Protocol) [93-M-0170, NCT00001360]; Center for the Neural Basis of Cognition, University of Pittsburgh [NIH/NIDA R90 DA023420: MNTP]; Carnegie Mellon University; National Science Foundation [BCS 1354350] FX The research reported here was supported by the NIMH Intramural Research Program (NIH Clinical Study Protocol, 93-M-0170, NCT00001360), a fellowship to V. Z. (NIH/NIDA R90 DA023420: MNTP) at the Center for the Neural Basis of Cognition, University of Pittsburgh and Carnegie Mellon University, and a grant from the National Science Foundation to M. B. (BCS 1354350). NR 32 TC 1 Z9 1 U1 3 U2 9 PU MIT PRESS PI CAMBRIDGE PA ONE ROGERS ST, CAMBRIDGE, MA 02142-1209 USA SN 0898-929X EI 1530-8898 J9 J COGNITIVE NEUROSCI JI J. Cogn. Neurosci. PD DEC PY 2015 VL 27 IS 12 BP 2442 EP 2461 DI 10.1162/jocn_a_00871 PG 20 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA CV6QQ UT WOS:000364395500011 PM 26359538 ER PT J AU Nichols, L Pfeifer, K Mammen, AL Shahnoor, N Konersman, CG AF Nichols, Laura Pfeifer, Kurt Mammen, Andrew L. Shahnoor, Nazima Konersman, Chamindra G. TI An Unusual Case of Statin-Induced Myopathy: Anti-HMGCoA Necrotizing Autoimmune Myopathy SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE statin; anti-HMGCR antibody; necrotizing autoimmune myopathy; idiopathic inflammatory myopathy ID PREVENTION; CORONARY; AVERAGE; EVENTS AB Statins are some of the most widely prescribed medications, and though generally well tolerated, can lead to a self-limited myopathy in a minority of patients. Recently, these medications have been associated with a necrotizing autoimmune myopathy (NAM). Statin-associated NAM is characterized by irritable myopathy on electromyography (EMG) and muscle necrosis with minimal inflammation on muscle biopsy. The case presented is a 63-year-old woman who has continued elevation of creatine kinase (CK) after discontinuation of statin therapy. She has irritable myopathy on EMG and NAM is confirmed by muscle biopsy. She subsequently tests positive for an experimental anti-3-hydroxy-3-methylglutaryl-coenzyme A (anti-HMGCoA) antibody that is found to be present in patients with statin-associated NAM. Though statin-associated NAM is a relatively rare entity, it is an important consideration for the general internist in patients who continue to have CK elevation and weakness after discontinuation of statin therapy. Continued research is necessary to better define statin-specific and dose-dependent risk, as well as optimal treatment for this condition. C1 [Nichols, Laura; Pfeifer, Kurt] Med Coll Wisconsin, Dept Internal Med, Milwaukee, WI 53226 USA. [Mammen, Andrew L.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Mammen, Andrew L.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Mammen, Andrew L.] NIAMSD, Muscle Dis Unit, Lab Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20892 USA. [Shahnoor, Nazima; Konersman, Chamindra G.] Med Coll Wisconsin, Dept Neurol, Milwaukee, WI 53226 USA. [Konersman, Chamindra G.] Univ Calif San Diego, San Diego, CA 92103 USA. RP Nichols, L (reprint author), Med Coll Wisconsin, Dept Internal Med, Milwaukee, WI 53226 USA. EM lnichols@mcw.edu NR 18 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD DEC PY 2015 VL 30 IS 12 BP 1879 EP 1883 DI 10.1007/s11606-015-3303-9 PG 5 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA CV8VQ UT WOS:000364566600038 PM 25855481 ER PT J AU Prorok, PC Kramer, BS Miller, AB AF Prorok, Philip C. Kramer, Barnett S. Miller, Anthony B. TI Study designs for determining and comparing sensitivities of disease screening tests SO JOURNAL OF MEDICAL SCREENING LA English DT Article DE overdiagnosis; randomized trial; screening test; sensitivity; study design ID FIELD DIGITAL MAMMOGRAPHY; BREAST-CANCER; FILM MAMMOGRAPHY; TOMOSYNTHESIS; TRIAL; BIOMARKERS; MORTALITY; PROSTATE; PROGRAM; LUNG AB Objective: To investigate the capability of various study designs to determine the sensitivity of a disease screening test. Methods: Quantities that can be calculated from these designs were derived and examined for their relationship to true sensitivity (the ability to detect unrecognized disease that would surface clinically in the absence of screening) and overdiagnosis. Results: To examine the sensitivity of one test, the single cohort design, in which all participants receive the test, is particularly weak, providing only an upper bound on the true sensitivity, and yields no information about overdiagnosis. A randomized design, with one control arm and participants tested in the other, that includes sufficient post-screening follow-up, allows calculation of bounds on, and an approximation to, true sensitivity and also determination of overdiagnosis. Without follow-up, bounds on the true sensitivity can be calculated. To compare two tests, the single cohort paired design in which all participants receive both tests is precarious. The three arm randomized design with post screening follow-up is preferred, yielding an approximation to the true sensitivity, bounds on the true sensitivity, and the extent of overdiagnosis of each test. Without post screening follow-up, bounds on the true sensitivities can be calculated. When an unscreened control arm is not possible, the two-arm randomized design is recommended. Individual test sensitivities cannot be determined, but with sufficient post-screening follow-up, an order relationship can be established, as can the difference in overdiagnosis between the two tests. C1 [Prorok, Philip C.; Kramer, Barnett S.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Miller, Anthony B.] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON M5S 1A1, Canada. RP Prorok, PC (reprint author), NCI, Canc Prevent Div, 9609 Med Ctr Dr,Room 5E608, Bethesda, MD 20892 USA. EM prorokp@mail.nih.gov NR 22 TC 1 Z9 1 U1 0 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0969-1413 EI 1475-5793 J9 J MED SCREEN JI J. Med. Screen. PD DEC PY 2015 VL 22 IS 4 BP 213 EP 220 DI 10.1177/0969141315600003 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CW1EZ UT WOS:000364733700009 PM 26396138 ER PT J AU Shiroma, EJ Kamada, M Smith, C Harris, TB Lee, IM AF Shiroma, Eric J. Kamada, Masamitsu Smith, Colby Harris, Tamara B. Lee, I-Min TI Visual Inspection for Determining Days When Accelerometer Is Worn: Is This Valid? SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE PHYSICAL ACTIVITY; EPIDEMIOLOGY; WEAR TIME; OLDER ADULTS ID PHYSICAL-ACTIVITY; SEDENTARY BEHAVIOR; UNITED-STATES; OLDER-ADULTS; WEAR TIME; PATTERNS AB Purpose Logs have been traditionally used for ascertaining accelerometer wear days in mail study designs, but not all participants complete logs. Visual inspection of accelerometer output may supplement missing logs; however, no data on the validity of this method are available. Methods We compared visual inspection with participant logs in 197 women (mean age, 71.0 yr). Women were mailed an accelerometer to be worn during waking hours for 7 d, marking each wear day on a log before returning the accelerometer by mail. For every participant, we created a series of graphs of accelerometer counts by time of day (one chart for each day with accelerometer output, including mail days). Two raters, masked to log wear status, independently inspected these graphs and scored each day as worn or not worn. Results The median (interquartile range) number of valid wear days using either visual inspection or log was 7 (7-7). For rater 1, the sensitivity and specificity of visual inspection was 99.7% (95% confidence interval, 99.2%-99.9%) and 97.2% (95.2%-98.6%), respectively; for rater 2, the sensitivity and specificity of visual inspection was 99.7% (99.2%-99.9%) and 97.0% (94.9%-98.4%), respectively. Interrater agreement was 99.5%. Conclusions Visual inspection of accelerometer data is a valid alternative to missing participant wear logs when determining wear days in mail study designs. C1 [Shiroma, Eric J.; Kamada, Masamitsu; Smith, Colby; Lee, I-Min] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Prevent Med, Boston, MA USA. [Shiroma, Eric J.; Harris, Tamara B.] NIA, NIH, Bethesda, MD 20892 USA. [Kamada, Masamitsu] Natl Inst Hlth & Nutr, Dept Hlth Promot & Exercise, Shinjuku Ku, Tokyo 162, Japan. RP Shiroma, EJ (reprint author), Suite 3C309,Gateway Bldg,7201 Wisconsin Ave, Bethesda, MD 20814 USA. EM Eric.shiroma@nih.gov RI Kamada, Masamitsu/H-4411-2011 OI Kamada, Masamitsu/0000-0003-1703-076X FU National Institutes of Health [CA154647, CA047988]; National Institutes of Health National Institute on Aging FX This research was supported by research grants CA154647 and CA047988 from the National Institutes of Health. Eric J. Shiroma and Tamara B. Harris were supported in part by the Intramural Research Program of the National Institutes of Health National Institute on Aging. NR 15 TC 3 Z9 3 U1 3 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0195-9131 EI 1530-0315 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD DEC PY 2015 VL 47 IS 12 BP 2558 EP 2562 DI 10.1249/MSS.0000000000000725 PG 5 WC Sport Sciences SC Sport Sciences GA CV8TX UT WOS:000364561800009 PM 26110697 ER PT J AU Patlolla, JMR Kopelovich, L Qian, L Zhang, YT Kumar, G Madka, V Mohammed, A Biddick, L Sadeghi, M Lightfoot, S Rao, CV AF Patlolla, Jagan M. R. Kopelovich, Levy Qian, Li Zhang, Yuting Kumar, Gaurav Madka, Venkateshwar Mohammed, Altaf Biddick, Laura Sadeghi, Michael Lightfoot, Stan Rao, Chinthalapally V. TI Early and delayed intervention with Rapamycin prevents NNK-induced lung adenocarcinoma in A/J mice SO ONCOLOGY REPORTS LA English DT Article DE lung cancer; chemoprevention; rapamycin; early and delayed intervention; A/J mice ID AIRWAY EPITHELIAL-CELLS; BCL-X-L; MAMMALIAN TARGET; INHIBITS APOPTOSIS; SIGNALING PATHWAY; AKT ACTIVATION; CANCER-CELLS; GROWTH; AUTOPHAGY; MTOR AB In tobacco-associated lung cancers, the protein kinase B/mammalian target of rapamycin (Akt/mTOR) pathway frequently is activated by nicotine and its metabolite 4-(methyl nitrosami no)-1-(3-pyridyl)-1-butanone (NNK). The aim of the present study was to examine the effects of early or late intervention with rapamycin in NNK-induced lung adenoma and progression to adenocarcinoma in female A/J mice. At 7 weeks of age, 40 mice/each carcinogen group received one dose of 10 mu mol NNK i.p. Three weeks later, the early intervention groups (25/group) were fed diets containing 0, 8 or 16 ppm rapamycin. The mice were sacrificed after 17 or 34 weeks of drug exposure and tumors were evaluated via histopathology. For late intervention (late adenoma and adenocarcinoma stage), groups of 15 mice were administered diets containing 8 or 16 ppm rapamycin starting 20 weeks after NNK treatment and continuing for 17 weeks before evaluation of tumor progression. Administration of 8 or 16 ppm rapamycin as an early or a late stage intervention significantly suppressed lung adenoma and adenocarcinoma formation (p<0.01-0.0001) after 17 or 34 weeks of exposure. The effect was more pronounced (>50-60% tumor inihibition; p<0.0001) at the early intervention and the size of NNK-induced tumors decreased from >2.10 to = 5 years), ethnicity, and child age were tested. Sixty-nine percent of mothers were overweight or obese, 46% of the children were overweight or obese. For mothers in the U.S. for <5 years, having a low demanding/high responsive style was associated with lower child intake of whole grains in adjusted models vs. a high demanding/high responsive style (p < 0.05). This was not seen for mothers in the U.S. for >= 5 years. Thus, the influence of feeding style on dietary intake may change with length of time in the U.S. These hypotheses-generating findings call for future research to understand how broader socio-cultural factors influence the feeding dynamic among immigrants. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Tovar, Alison] Univ Rhode Isl, Dept Nutr & Food Sci, Kingston, RI 02881 USA. [Choumenkovitch, Silvina F.; Must, Aviva; Vikre, Emily Kuross; Economos, Christina D.] Tufts Univ, Gerald J & Dorothy R Friedman Sch Nutr Sci & Poli, Boston, MA 02111 USA. [Hennessy, Erin] NCI, NIH, Bethesda, MD 20892 USA. [Boulos, Rebecca] Univ New England, Portland, ME 04103 USA. [Must, Aviva] Tufts Univ, Sch Med, Dept Publ Hlth & Community Med, Boston, MA 02111 USA. [Hughes, Sheryl O.] Baylor Coll Med, Childrens Nutr Res Ctr, Houston, TX 77030 USA. [Gute, David M.] Tufts Univ, Sch Engn, Civil & Environm Engn, Medford, MA 02155 USA. RP Tovar, A (reprint author), Univ Rhode Isl, Dept Nutr & Food Sci, 112 Ranger Hall, Kingston, RI 02881 USA. EM alison_tovar@uri.edu; silvina.choumenkovitch@tufts.edu; erin.hennessy@nih.gov; rboulos@une.edu; Aviva.must@tufts.edu; shughes@bcm.edu; david.gute@tufts.edu; Emily.Kuross@tufts.edu; christina.economos@tufts.edu FU Boston Nutrition Obesity Research Center [DK046200]; National Institutes of Health, Bethesda MD [5R01HD057841] FX We would like to thank these members of the Live Well Steering Committee (Nesly Metayer, Franklin Dalembert, Warren Goldstein-Gelb, Maria Landaverde, Melissa McWhinney, Joyce Guilhermino de Padua, Christina Luongo Kamins, Helen Sinzker, Sarah Sliwa, Kerline Tofuri, and Ismael Vasquez). In addition, we thank the Live Well women and children, for their participation in this study. We would also like to acknowledge support from the Boston Nutrition Obesity Research Center (DK046200).; Funding for this research was provided by grant 5R01HD057841 from the National Institutes of Health, Bethesda MD. Postdoctoral research funds for Alison Tovar were provided by a supplement from this grant. NR 69 TC 0 Z9 0 U1 5 U2 17 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0195-6663 EI 1095-8304 J9 APPETITE JI Appetite PD DEC 1 PY 2015 VL 95 BP 211 EP 218 DI 10.1016/j.appet.2015.06.006 PG 8 WC Behavioral Sciences; Nutrition & Dietetics SC Behavioral Sciences; Nutrition & Dietetics GA CT6IT UT WOS:000362917400026 PM 26122753 ER PT J AU Silver, SR Bertke, SJ Hines, CJ Alavanja, MCR Hoppin, JA Lubin, JH Rusiecki, JA Sandler, DP Freeman, LEB AF Silver, Sharon R. Bertke, Steven J. Hines, Cynthia J. Alavanja, Michael C. R. Hoppin, Jane A. Lubin, Jay H. Rusiecki, Jennifer A. Sandler, Dale P. Freeman, Laura E. Beane TI Cancer incidence and metolachlor use in the Agricultural Health Study: An update SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE cancer; epidemiology; pesticide; occupation ID PESTICIDE APPLICATORS; HERBICIDE METOLACHLOR; S-METOLACHLOR; HEPG2 CELLS; ALACHLOR; CYTOTOXICITY; MUTAGENICITY; INFORMATION; METABOLITES; EXPOSURE AB Metolachlor, a widely used herbicide, is classified as a Group C carcinogen by the U.S. Environmental Protection Agency based on increased liver neoplasms in female rats. Epidemiologic studies of the health effects of metolachlor have been limited. The Agricultural Health Study (AHS) is a prospective cohort study including licensed private and commercial pesticide applicators in Iowa and North Carolina enrolled 1993-1997. We evaluated cancer incidence through 2010/2011 (NC/IA) for 49,616 applicators, 53% of whom reported ever using metolachlor. We used Poisson regression to evaluate relations between two metrics of metolachlor use (lifetime days, intensity-weighted lifetime days) and cancer incidence. We saw no association between metolachlor use and incidence of all cancers combined (n = 5,701 with a 5-year lag) or most site-specific cancers. For liver cancer, in analyses restricted to exposed workers, elevations observed at higher categories of use were not statistically significant. However, trends for both lifetime and intensity-weighted lifetime days of metolachor use were positive and statistically significant with an unexposed reference group. A similar pattern was observed for follicular cell lymphoma, but no other lymphoma subtypes. An earlier suggestion of increased lung cancer risk at high levels of metolachlor use in this cohort was not confirmed in this update. This suggestion of an association between metolachlor and liver cancer among pesticide applicators is a novel finding and echoes observation of increased liver neoplasms in some animal studies. However, our findings for both liver cancer and follicular cell lymphoma warrant follow-up to better differentiate effects of metolachlor use from other factors. C1 [Silver, Sharon R.; Bertke, Steven J.; Hines, Cynthia J.] NIOSH, Div Surveillance Hazard Evaluat & Field Studies, Cincinnati, OH 45226 USA. [Alavanja, Michael C. R.; Lubin, Jay H.; Freeman, Laura E. Beane] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Hoppin, Jane A.] N Carolina State Univ, Dept Biol Sci, Raleigh, NC 27695 USA. [Rusiecki, Jennifer A.] Uniformed Serv Univ Hlth Sci, Dept Prevent Med & Biostat, Bethesda, MD 20814 USA. [Sandler, Dale P.] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. RP Silver, SR (reprint author), NIOSH, Div Surveillance Hazard Evaluat & Field Studies, Cincinnati, OH 45226 USA. EM ssilver@cdc.gov RI Beane Freeman, Laura/C-4468-2015; OI Beane Freeman, Laura/0000-0003-1294-4124; Silver, Sharon/0000-0002-7679-5028; Sandler, Dale/0000-0002-6776-0018 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics [Z01CP010119]; Intramural Research Program of the National Institutes of Health, National Institutes of Environmental Health Sciences [Z01ES049030] FX Grant sponsor: Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics; Grant number: Z01CP010119; Grant sponsor: Intramural Research Program of the National Institutes of Health, National Institutes of Environmental Health Sciences; Grant number: Z01ES049030 NR 30 TC 3 Z9 3 U1 1 U2 16 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 DEC 1 PY 2015 VL 137 IS 11 BP 2630 EP 2643 DI 10.1002/ijc.29621 PG 14 WC Oncology SC Oncology GA CT5IU UT WOS:000362843000010 PM 26033014 ER PT J AU Bassig, BA Shu, XO Koh, WP Gao, YT Purdue, MP Butler, LM Adams-Haduch, J Xiang, YB Kemp, TJ Wang, R Pinto, LA Zheng, TZ Ji, BT Hosgood, HD Hu, W Yang, G Zhang, HP Chow, WH Kim, C Seow, WJ Zheng, W Yuan, JM Lan, Q Rothman, N AF Bassig, Bryan A. Shu, Xiao-Ou Koh, Woon-Puay Gao, Yu-Tang Purdue, Mark P. Butler, Lesley M. Adams-Haduch, Jennifer Xiang, Yong-Bing Kemp, Troy J. Wang, Renwei Pinto, Ligia A. Zheng, Tongzhang Ji, Bu-Tian Hosgood, H. Dean Hu, Wei Yang, Gong Zhang, Heping Chow, Wong-Ho Kim, Christopher Seow, Wei Jie Zheng, Wei Yuan, Jian-Min Lan, Qing Rothman, Nathaniel TI Soluble levels of CD27 and CD30 are associated with risk of non-Hodgkin lymphoma in three Chinese prospective cohorts SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE CD27; CD30; immune markers; non-Hodgkin lymphoma; East Asians; prospective study ID B-CELL LYMPHOMA; IMMUNE ACTIVATION; FUTURE RISK; CYTOKINES; MARKERS; BIOMARKERS; DIAGNOSIS; CORRELATE; SHANGHAI; ANTIGEN AB Prospective studies conducted in Western populations have suggested that alterations in soluble CD27 (sCD27) and soluble CD30 (sCD30), two markers indicative of B-cell activation, are associated with risk of non-Hodgkin lymphoma (NHL). Given that the characteristics of NHL in East Asia differ from the West and mechanistic commonalities between these populations with respect to the role of intermediate endpoint biomarkers in lymphomagenesis have not been explored, we conducted a pooled nested case-control study from three prospective studies of Chinese men and women including 218 NHL cases and 218 individually matched controls. Compared with the lowest quartile, ORs (95% CIs) for the second, third and fourth quartiles of sCD27 were 1.60 (0.83-3.09), 1.94 (0.98-3.83) and 4.45 (2.25-8.81), respectively (p(trend)=50.000005). The corresponding ORs for sCD30 were 1.74 (0.85-3.58), 1.86 (0.94-3.67) and 5.15 (2.62-10.12; p(trend)=50.0000002). These associations remained statistically significant in individuals diagnosed with NHL 10 or more years after blood draw. Notably, the magnitude of the associations with NHL risk was very similar to those in Western populations in previous studies. These findings of the similar association between sCD27 or sCD30 and NHL risk across different populations support an important underlying mechanism of B-cell activation in lymphomagenesis. C1 [Bassig, Bryan A.; Ji, Bu-Tian; Hu, Wei; Kim, Christopher; Seow, Wei Jie; Lan, Qing; Rothman, Nathaniel] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Shu, Xiao-Ou; Yang, Gong; Zheng, Wei] Vanderbilt Univ, Sch Med, Div Epidemiol, Vanderbilt Epidemiol Ctr, Nashville, TN 37212 USA. [Koh, Woon-Puay] Duke NUS Grad Med Sch Singapore, Singapore, Singapore. [Gao, Yu-Tang] Shanghai Jiao Tong Univ, Shanghai Canc Inst, Dept Epidemiol, Shanghai 200030, Peoples R China. [Purdue, Mark P.] Ontario Inst Canc Res, Toronto, ON, Canada. [Butler, Lesley M.; Adams-Haduch, Jennifer; Wang, Renwei; Yuan, Jian-Min] Univ Pittsburgh, Div Canc Control & Populat Sci, Inst Canc, Pittsburgh, PA USA. [Butler, Lesley M.; Yuan, Jian-Min] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Xiang, Yong-Bing] Shanghai Jiao Tong Univ, Sch Med, Renji Hosp, Shanghai Canc Inst, Shanghai 200030, Peoples R China. [Kemp, Troy J.; Pinto, Ligia A.] Frederick Natl Lab Canc Res, Leidos Biomed Res Inc, HPV Immunol Lab, Frederick, MD USA. [Zheng, Tongzhang; Zhang, Heping] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Hosgood, H. Dean] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY USA. [Chow, Wong-Ho] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. RP Bassig, BA (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr MSC 9776,Rm 6E618, Bethesda, MD 20892 USA. EM bassigb@mail.nih.gov RI Purdue, Mark/C-9228-2016 OI Yuan, Jian-Min/0000-0002-4620-3108; Purdue, Mark/0000-0003-1177-3108 FU United States National Institutes of Health [R01CA144034, UM1CA182876]; National Institutes of Health [R37 CA70867]; Intramural Research Program of National Institutes of Health, National Cancer Institute FX Grant sponsor: United States National Institutes of Health; Grant numbers: R01CA144034 and UM1CA182876; Grant sponsor: National Institutes of Health; Grant number: R37 CA70867; Grant sponsor: Intramural Research Program of the National Institutes of Health, National Cancer Institute NR 26 TC 3 Z9 3 U1 1 U2 6 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 DEC 1 PY 2015 VL 137 IS 11 BP 2688 EP 2695 DI 10.1002/ijc.29637 PG 8 WC Oncology SC Oncology GA CT5IU UT WOS:000362843000014 PM 26095604 ER PT J AU Resnik, DB Elliott, KC Miller, AK AF Resnik, David B. Elliott, Kevin C. Miller, Aubrey K. TI A framework for addressing ethical issues in citizen science SO ENVIRONMENTAL SCIENCE & POLICY LA English DT Article DE Citizen science; Ethics; Public; Collaboration; Data collection; Community-based research ID PARTICIPATORY RESEARCH; SCIENTIFIC-RESEARCH; ECOLOGICAL RESEARCH; LESSONS; TOOL; AIR; BIODIVERSITY; POLICY; VALUES; UK AB The collaboration between laypeople and professional scientists known as "citizen science" is an important trend in research and data gathering. Citizen science offers important benefits to science and society. For example, citizens can help scientists with data collection and provide advice on research design and implementation. Citizens can also gain a better understanding of scientific concepts and methods. Additionally, citizens can help scientists better understand and address issues of concern to their families and communities. However, citizen science also raises ethical issues that should be addressed when projects begin and throughout the course of scientific investigation. To promote ethical research, scientists should develop guidelines for involvement of citizens in research, communicate effectively with participants and local communities at the outset of their involvement in research projects, carefully oversee their work, develop appropriate publication practices, and provide lay-volunteers with education and training on the responsible conduct of research. Researchers also need to be cognizant of clarifying these roles and responsibilities as well as promoting appropriate and safe citizen participation and transparency of the study methods, data analysis, and communication of results. Published by Elsevier Ltd. C1 [Resnik, David B.; Miller, Aubrey K.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Elliott, Kevin C.] Michigan State Univ, Lyman Briggs Coll, E Lansing, MI 48824 USA. [Elliott, Kevin C.] Michigan State Univ, Dept Fisheries & Wildlife, E Lansing, MI 48824 USA. [Elliott, Kevin C.] Michigan State Univ, Dept Philosophy, E Lansing, MI 48824 USA. RP Resnik, DB (reprint author), NIEHS, NIH, Res Triangle Pk, NC 27709 USA. EM resnikd@niehs.nih.gov FU intramural program of the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH) FX This research is supported, in part, by the intramural program of the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH). It does not represent the views of the NIEHS, NIH, or U.S. government. NR 65 TC 3 Z9 3 U1 7 U2 72 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1462-9011 EI 1873-6416 J9 ENVIRON SCI POLICY JI Environ. Sci. Policy PD DEC PY 2015 VL 54 BP 475 EP 481 DI 10.1016/j.envsci.2015.05.008 PG 7 WC Environmental Sciences SC Environmental Sciences & Ecology GA CT2AC UT WOS:000362603400050 ER PT J AU Walther, S Rusitzka, TV Diesterbeck, US Czerny, CP AF Walther, Stefanie Rusitzka, Tamara V. Diesterbeck, Ulrike S. Czerny, Claus-Peter TI Equine immunoglobulins and organization of immunoglobulin genes SO DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY LA English DT Review DE Horse; Immunoglobulin genes; Immunoglobulin heavy and light chains; Allotype; Diversity; Equine developmental stages ID ANTIBODY REPERTOIRE DEVELOPMENT; EXCEPTIONALLY LONG CDR3H; CHAIN ISOTYPE REGULATION; BETA-LACTOSIDE ANTIBODY; DIFFERENT CATTLE BREEDS; BOVINE IGG2 ALLOTYPES; AMINO-ACID-SEQUENCE; POSTNATAL-DEVELOPMENT; ANTIHAPTEN ANTIBODY; HAEMOPHILUS-SOMNUS AB Our understanding of how equine immunoglobulin genes are organized has increased significantly in recent years. For equine heavy chains, 52 IGHV, 40 IGHD, 8 IGHJ and 11 IGHC are present. Seven of these IGHCs are gamma chain genes. Sequence diversity is increasing between fetal, neonatal, foal and adult age. The kappa light chain contains 60 IGKV, 5 IGKJ and 1 IGKC, whereas there are 144 IGLV, 7 IGLJ, and 7 IGLC for the lambda light chain, which is expressed predominantly in horses. Significant transcriptional differences for IGLV and IGLC are identified in different breeds. Allotypic and allelic variants are observed for IGLC1, IGLC5, and IGLC6/7, and two IGLV pseudogenes are also transcribed. During age development, a decrease in IGLVs is noted, although nucleotide diversity and significant differences in gene usage increased. The following paper suggests a standardization of the existing nomenclature of immunoglobulin genes. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Walther, Stefanie; Rusitzka, Tamara V.; Czerny, Claus-Peter] Univ Gottingen, Inst Vet Med, Dept Anim Sci, Div Microbiol & Anim Hyg,Fac Agr Sci, D-37077 Gottingen, Germany. [Diesterbeck, Ulrike S.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Czerny, CP (reprint author), Univ Gottingen, Inst Vet Med, Dept Anim Sci, Div Microbiol & Anim Hyg,Fac Agr Sci, Burckhardtweg 2, D-37077 Gottingen, Germany. EM swalthe@gwdg.de; trusitz@gwdg.de; ulrike.diesterbeck@nih.gov; cczerny@gwdg.de NR 111 TC 1 Z9 1 U1 7 U2 26 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0145-305X EI 1879-0089 J9 DEV COMP IMMUNOL JI Dev. Comp. Immunol. PD DEC PY 2015 VL 53 IS 2 BP 303 EP 319 DI 10.1016/j.dci.2015.07.017 PG 17 WC Immunology; Zoology SC Immunology; Zoology GA CS5SO UT WOS:000362138500004 PM 26219564 ER PT J AU Messer, K Vijayaraghavan, M White, MM Shi, YY Chang, C Conway, KP Hartman, A Schroeder, MJ Compton, WM Pierce, JP AF Messer, Karen Vijayaraghavan, Maya White, Martha M. Shi, Yuyan Chang, Cindy Conway, Kevin P. Hartman, Anne Schroeder, Megan J. Compton, Wilson M. Pierce, John P. TI Cigarette smoking cessation attempts among current US smokers who also use smokeless tobacco SO ADDICTIVE BEHAVIORS LA English DT Article DE Smokeless tobacco; Smoking cessation; Poly-tobacco use ID HARM REDUCTION; UNITED-STATES; NICOTINE DEPENDENCE; DUAL-USE; PREVALENCE; CALIFORNIA; ADULT; PRODUCTS; SUCCESS; HEALTH AB Introduction: Concurrent use of cigarettes and smokeless tobacco is common, but little is known regarding the association of smokeless tobacco use with cigarette smoking cessation. Dual users may have lower cigarette consumption levels, which may also play a role in smoking cessation. Methods: The 2010-2011 Tobacco Use Supplement to the Current Population Survey included 26,760 current cigarette smokers, of which 675 concurrently used smokeless tobacco. We compared characteristics of the most recent cigarette smoking quit attempt of the past year between dual users and exclusive smokers, using multivariate regression. Results: Dual users (45%) were more likely than exclusive smokers (37%) to have made a cigarette smoking quit attempt during the previous year (p < 0.01), even after adjusting for demographic differences and cigarette dependence levels (OR adj 1.33,95% CI 1.15-1.53). Half (48%) of dual users who made a quit attempt tried to quit "by switching to smokeless tobacco". However, once in a quit attempt, dual users relapsed more quickly than exclusive smokers (Cox regression HRadj 1.13,95% CI 1.02-1.26). There was no difference in 30-day abstinence rates on the most recent quit attempt (ORadj 1.09, 95% CI 0.88-137). For both groups, the best predictor of past 30-day abstinence was cigarette consumption level. Conclusions: Current cigarette smokers who also use smokeless tobacco are more likely to have tried to quit, but relapse more quickly than exclusive smokers, and are not more likely to have attained 30 day smoking cessation. Prospective studies at the population level are needed. (C) 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license. C1 [Messer, Karen; Vijayaraghavan, Maya; White, Martha M.; Shi, Yuyan; Pierce, John P.] Univ Calif San Diego, Moores UCSD Canc Ctr, Canc Prevent & Control Div, La Jolla, CA 92093 USA. [Messer, Karen] Univ Calif San Diego, Div Biostat & Bioinformat, La Jolla, CA 92093 USA. [Messer, Karen; Vijayaraghavan, Maya; Shi, Yuyan; Pierce, John P.] Univ Calif San Diego, Dept Family Med & Publ Hlth, La Jolla, CA 92093 USA. [Chang, Cindy; Schroeder, Megan J.] US FDA, Ctr Tobacco Prod, Silver Spring, MD 20993 USA. [Conway, Kevin P.; Compton, Wilson M.] NIDA, NIH, Bethesda, MD 20892 USA. [Hartman, Anne] NCI, NIH, Div Canc Control & Populat Sci, Rockville, MD 20850 USA. RP Messer, K (reprint author), Univ Calif San Diego, Moores UCSD Canc Ctr, La Jolla, CA 92093 USA. EM kmesser@ucsd.edu OI Conway, Kevin/0000-0002-7638-339X FU National Institute on Drug Abuse, National Institutes of Health; Food and Drug Administration, Department of Health and Human Services [HHSN271201100027C]; UC Tobacco-Related Disease Research Program [21RT-0135]; National Cancer Institute [1R01CA172058-02] FX This project has been funded in whole or in part with federal funds from the National Institute on Drug Abuse, National Institutes of Health, and the Food and Drug Administration, Department of Health and Human Services, under contract no. HHSN271201100027C; and by UC Tobacco-Related Disease Research Program grants 21RT-0135, and National Cancer Institute grant no. 1R01CA172058-02. The funding sources had no involvement in the study design, collection, analysis, or interpretation of data, writing the manuscript and the decision to submit the manuscript for publication. NR 31 TC 5 Z9 5 U1 1 U2 14 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4603 EI 1873-6327 J9 ADDICT BEHAV JI Addict. Behav. PD DEC PY 2015 VL 51 BP 113 EP 119 DI 10.1016/j.addbeh.2015.06.045 PG 7 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA CR8DI UT WOS:000361580900019 PM 26253939 ER PT J AU Wheeler, DC Nolan, BT Flory, AR DellaValle, CT Ward, MH AF Wheeler, David C. Nolan, Bernard T. Flory, Abigail R. DellaValle, Curt T. Ward, Mary H. TI Modeling groundwater nitrate concentrations in private wells in Iowa SO SCIENCE OF THE TOTAL ENVIRONMENT LA English DT Article DE Nitrate; Groundwater contamination; Random forest ID UNITED-STATES; VULNERABILITY; WATER; CONTAMINATION; POLLUTION; DRAINAGE; HEALTH; SPAIN AB Contamination of drinking water by nitrate is a growing problem in many agricultural areas of the country. Ingested nitrate can lead to the endogenous formation of N-nitroso compounds, potent carcinogens. We developed a predictive model for nitrate concentrations in private wells in Iowa. Using 34,084 measurements of nitrate in private wells, we trained and tested random forest models to predict log nitrate levels by systematically assessing the predictive performance of 179 variables in 36 thematic groups (well depth, distance to sinkholes, location, land use, soil characteristics, nitrogen inputs, meteorology, and other factors). The final model contained 66 variables in 17 groups. Some of the most important variables were well depth, slope length within 1 km of the well, year of sample, and distance to nearest animal feeding operation. The correlation between observed and estimated nitrate concentrations was excellent in the training set (r-square = 0.77) and was acceptable in the testing set (r-square = 0.38). The random forest model had substantially better predictive performance than a traditional linear regressionmodel or a regression tree. Our model will be used to investigate the association between nitrate levels in drinking water and cancer risk in the Iowa participants of the Agricultural Health Study cohort. (C) 2015 Elsevier B.V. All rights reserved. C1 [Wheeler, David C.] Virginia Commonwealth Univ, Dept Biostat, Richmond, VA 23298 USA. [Nolan, Bernard T.] US Geol Survey, Reston, VA 22092 USA. [Flory, Abigail R.] Westat Corp, Rockville, MD USA. [DellaValle, Curt T.; Ward, Mary H.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. RP Wheeler, DC (reprint author), Virginia Commonwealth Univ, Dept Biostat, 830 East Main St, Richmond, VA 23298 USA. EM dcwheeler@vcu.edu FU Intramural Research Program of the National Cancer Institute; [HHSN261201300355P] FX We thank Pete Weyer and Jiji Kantamneni for providing nitrate measurement data and Randy Bayless and Les Arihood of the USGS for determining aquifer characteristics at sampled wells. We also thank Mike Giangrande from Westat for performing geocoding of the well locations. This study was supported by the Intramural Research Program of the National Cancer Institute. Any use of trade, firm, or product names is for descriptive purposes only and does not imply endorsement by the U.S. Government. Dr. David Wheeler was supported by contract HHSN261201300355P. Dr. Bernard Nolan was supported through an interagency agreement with the U.S. Geological Survey's National Water Quality Assessment Program. NR 55 TC 7 Z9 7 U1 1 U2 45 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0048-9697 EI 1879-1026 J9 SCI TOTAL ENVIRON JI Sci. Total Environ. PD DEC 1 PY 2015 VL 536 BP 481 EP 488 DI 10.1016/j.scitotenv.2015.07.080 PG 8 WC Environmental Sciences SC Environmental Sciences & Ecology GA CR2VV UT WOS:000361189800052 PM 26232757 ER PT J AU Campbell, JI Kanters, S Bennett, JE Thorlund, K Tsai, AC Mills, EJ Siedner, MJ AF Campbell, Jeffrey I. Kanters, Steve Bennett, John E. Thorlund, Kristian Tsai, Alexander C. Mills, Edward J. Siedner, Mark J. TI Comparative Effectiveness of Induction Therapy for Human Immunodeficiency Virus-Associated Cryptococcal Meningitis: A Network Meta-Analysis SO OPEN FORUM INFECTIOUS DISEASES LA English DT Article DE cryptococcal meningitis; HIV/AIDS; induction therapy; network meta-analysis; therapeutics ID HIGH-DOSE FLUCONAZOLE; RANDOMIZED CONTROLLED-TRIAL; LIPOSOMAL AMPHOTERICIN-B; EARLY FUNGICIDAL ACTIVITY; AIDS PATIENTS; PLUS FLUCYTOSINE; IN-VITRO; ANTIRETROVIRAL THERAPY; COMBINATION THERAPY; ORAL FLUCONAZOLE AB Background. Multiple international treatment guidelines recommend amphotericin-based combination regimens for induction therapy of cryptococcal meningitis. Yet, only 1 trial has reported a mortality benefit for combination amphotericin-flucytosine, and none have reported a mortality benefit for combination amphotericin- fluconazole. Methods. We conducted a Bayesian network meta-analysis to estimate the comparative effectiveness of recommended induction therapies for HIV-associated cryptococcal meningitis. We searched PubMed and Cochrane CENTRAL for clinical reports of induction therapy for HIV-associated cryptococcal meningitis. We extracted or calculated early (two-week) and late (six to 12-week) mortality by treatment arm for the following induction regimens: amphotericin B alone, amphotericin B + flucytosine, amphotericin B + triazoles, amphotericin B + flucytosine + triazoles, triazoles alone, triazoles + flucytosine, liposomal amphotericin B, and amphotericin B + other medicines. Results. In the overall sample (35 studies, n = 2483), we found no evidence of decreased mortality from addition of flucytosine or triazoles to amphotericin B, compared with amphotericin B alone. Although we did find a nonsignificant benefit for addition of flucytosine to amphotericin B in studies including participants with altered levels of consciousness, we did not identify a benefit for combination therapy in restricted analyses in either resource-rich or resource-limited settings, studies conducted before or after 2004, and studies restricted to a high dose of amphotericin B and fluconazole. Conclusions. Given considerations of drug availability and toxicity, there is an important need for additional data to clarify which populations are most likely to benefit from combination therapies for human immunodeficiency virus-associated cryptococcal meningitis. C1 [Campbell, Jeffrey I.; Tsai, Alexander C.; Siedner, Mark J.] Harvard Univ, Sch Med, Boston, MA USA. [Kanters, Steve; Mills, Edward J.] Univ Ottawa, Fac Hlth Sci, Vancouver, BC, Canada. [Kanters, Steve] Univ British Columbia, Sch Populat & Publ Hlth, Vancouver, BC V5Z 1M9, Canada. [Bennett, John E.] NIH, Lab Clin Infect Dis, Bethesda, MD 20892 USA. [Thorlund, Kristian] McMaster Univ, Fac Hlth Sci, Hamilton, ON, Canada. [Tsai, Alexander C.] Massachusetts Gen Hosp, Chester M Pierce MD Div Global Psychiat, Boston, MA 02114 USA. [Tsai, Alexander C.] Mbarara Univ Sci & Technol, Mbarara, Uganda. [Mills, Edward J.] Stanford Univ, Stanford Prevent Res Ctr, Stanford, CA 94305 USA. [Siedner, Mark J.] Massachusetts Gen Hosp, Dept Med, Div Infect Dis, Boston, MA 02114 USA. RP Siedner, MJ (reprint author), MGH Ctr Global Hlth, 100 Cambridge St,15th Flr, Boston, MA 02114 USA. EM msiedner@mgh.harvard.edu NR 70 TC 0 Z9 0 U1 0 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 2328-8957 J9 OPEN FORUM INFECT DI JI Open Forum Infect. Dis. PD WIN PY 2015 VL 2 IS 1 DI 10.1093/ofid/ofv010 PG 11 WC Infectious Diseases SC Infectious Diseases GA CP5KQ UT WOS:000359921100007 ER PT J AU Mgodi, NM Kelly, C Gati, B Greenspan, S Dai, JY Bragg, V Livant, E Piper, JM Nakabiito, C Magure, T Marrazzo, JM Chirenje, ZM Riddler, SA AF Mgodi, Nyaradzo M. Kelly, Cliff Gati, Brenda Greenspan, Susan Dai, James Y. Bragg, Vivian Livant, Edward Piper, Jeanna M. Nakabiito, Clemensia Magure, Tsitsi Marrazzo, Jeanne M. Chirenje, Z. Mike Riddler, Sharon A. CA MTN-003B Protocol Team TI Factors associated with bone mineral density in healthy African women SO ARCHIVES OF OSTEOPOROSIS LA English DT Article DE Bone mineral density; African women; Contraception; DMPA; Body mass index; Lactation; Physical activity ID DEPOT MEDROXYPROGESTERONE ACETATE; LIFE-STYLE; CONTRACEPTION; OSTEOPOROSIS; LACTATION; MASS; PREMENOPAUSAL; IMPLANTS; RECOVERY; WHITE AB There is a paucity of normative bone mineral density (BMD) data in healthy African women. Baseline total hip and lumbar spine BMD was measured in premenopausal women. BMD distribution was comparable to that of a reference population and was impacted by several factors including contraception and duration of lactation. Introduction Normative data on bone mineral density (BMD) and the cumulative impact of lactation, contraceptive use, and other factors on BMD in healthy African women have not been well studied. Objectives The objective of this study was to determine the factors associated with BMD in healthy premenopausal women in Uganda and Zimbabwe. Methods Baseline total hip (TH) and lumbar spine (LS) BMD was measured by dual x-ray absorptiometry in 518 healthy, premenopausal black women enrolling in VOICE, an HIV-1 chemoprevention trial, at sites in Uganda and Zimbabwe. Contraceptive and lactation histories, physical activity assessment, calcium intake, and serum vitamin D levels were assessed. Independent factors associated with BMD were identified using an analysis of covariance model. Results The study enrolled 331 women from Zimbabwe and 187 women from Uganda. Median age was 29 years (IQR 25, 32) and median body mass index (BMI) was 24.8 kg/m(2) (IQR 22.2, 28.6). In univariate analyses, lower TH BMD values were associated with residence in Uganda (p<0.001), lower BMI (p<0.001), and any use of and duration of depot-medroxyprogresterone acetate. Use of oral contraceptives, progestin-only implants, and higher physical activity levels were protective against reduced BMD. Similarly, lower LS BMD values were associated with these same factors but also higher parity and history of breastfeeding. In a multivariable analysis, lower TH and LS BMD values were associated with enrollment in Uganda, lower BMI, and lower physical activity level; contraceptive use was associated with lower spine BMD, and breastfeeding contributed to lower total hip BMD. Conclusions Among healthy premenopausal women, TH and LS BMD was higher in Zimbabwe than Uganda. Additional factors independently associated with BMD included BMI, physical activity level, contraceptive use, and lactation. C1 [Mgodi, Nyaradzo M.; Magure, Tsitsi; Chirenje, Z. Mike] Univ Zimbabwe Univ Calif San Francisco Collaborat, Harare, Zimbabwe. [Kelly, Cliff; Dai, James Y.] Fred Hutchinson Canc Res Ctr, SCHARP, Seattle, WA 98104 USA. [Gati, Brenda; Nakabiito, Clemensia] Makerere Univ Johns Hopkins Univ Res Collaborat, Kampala, Uganda. [Greenspan, Susan; Riddler, Sharon A.] Univ Pittsburgh, Pittsburgh, PA USA. [Bragg, Vivian] FHI360, Durham, NC USA. [Livant, Edward] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Piper, Jeanna M.] NIAID, Div Aids, Bethesda, MD 20892 USA. [Marrazzo, Jeanne M.] Univ Washington, Seattle, WA 98195 USA. RP Mgodi, NM (reprint author), Univ Zimbabwe Univ Calif San Francisco Collaborat, 15 Phillips Ave, Harare, Zimbabwe. EM nmmgodi@uz-ucsf.co.zw OI Kelly, Clifton/0000-0003-0794-3901; Marrazzo, Jeanne/0000-0002-9277-7364 NR 28 TC 0 Z9 0 U1 1 U2 2 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 1862-3522 EI 1862-3514 J9 ARCH OSTEOPOROS JI Arch. Osteoporos. PD DEC PY 2015 VL 10 IS 1 AR 3 DI 10.1007/s11657-015-0206-7 PG 10 WC Endocrinology & Metabolism; Orthopedics SC Endocrinology & Metabolism; Orthopedics GA CN2ZI UT WOS:000358291800003 ER PT J AU Fernandes, BS Molendijk, ML Kohler, CA Soares, JC Leite, CMGS Machado-Vieira, R Ribeiro, TL Silva, JC Sales, PMG Quevedo, J Oertel-Knochel, V Vieta, E Gonzalez-Pinto, A Berk, M Carvalho, AF AF Fernandes, Brisa S. Molendijk, Marc L. Koehler, Cristiano A. Soares, Jair C. Leite, Claudio Manuel G. S. Machado-Vieira, Rodrigo Ribeiro, Thamara L. Silva, Jessica C. Sales, Paulo M. G. Quevedo, Joao Oertel-Knoechel, Viola Vieta, Eduard Gonzalez-Pinto, Ana Berk, Michael Carvalho, Andre F. TI Peripheral brain-derived neurotrophic factor (BDNF) as a biomarker in bipolar disorder: a meta-analysis of 52 studies SO BMC MEDICINE LA English DT Article DE Biomarker; Bipolar disorder; Brain-derived neurotrophic factor; Meta-analysis ID FACTOR SERUM-LEVELS; OPEN-LABEL TRIAL; VS. LATE-STAGE; VAL66MET POLYMORPHISM; DECREASED LEVELS; PLASMA BDNF; ACUTE MANIA; I DISORDER; INTERNATIONAL SOCIETY; SEROTONIN TRANSPORTER AB Background: The neurotrophic hypothesis postulates that mood disorders such as bipolar disorder (BD) are associated with a lower expression of brain-derived neurotrophic factor (BDNF). However, its role in peripheral blood as a biomarker of disease activity and of stage for BD, transcending pathophysiology, is still disputed. In the last few years an increasing number of clinical studies assessing BDNF in serum and plasma have been published. Therefore, it is now possible to analyse the association between BDNF levels and the severity of affective symptoms in BD as well as the effects of acute drug treatment of mood episodes on BDNF levels. Methods: We conducted a systematic review and meta-analysis of all studies on serum and plasma BDNF levels in bipolar disorder. Results: Through a series of meta-analyses including a total of 52 studies with 6,481 participants, we show that, compared to healthy controls, peripheral BDNF levels are reduced to the same extent in manic (Hedges' g = -0.57, P = 0.010) and depressive (Hedges' g = -0.93, P = 0.001) episodes, while BDNF levels are not significantly altered in euthymia. In meta-regression analyses, BDNF levels additionally negatively correlate with the severity of both manic and depressive symptoms. We found no evidence for a significant impact of illness duration on BDNF levels. In addition, in plasma, but not serum, peripheral BDNF levels increase after the successful treatment of an acute mania episode, but not of a depressive one. Conclusions: In summary, our data suggest that peripheral BDNF levels, more clearly in plasma than in serum, is a potential biomarker of disease activity in BD, but not a biomarker of stage. We suggest that peripheral BDNF may, in future, be used as a part of a blood protein composite measure to assess disease activity in BD. C1 [Fernandes, Brisa S.; Berk, Michael] Deakin Univ, IMPACT Strateg Res Ctr, Sch Med, Geelong, Vic 3217, Australia. [Fernandes, Brisa S.] Univ Fed Rio Grande do Sul, Lab Calcium Binding Prot Cent Nervous Syst, Dept Biochem, Porto Alegre, RS, Brazil. [Molendijk, Marc L.] Leiden Univ, Dept Clin Psychol, Inst Psychol, Leiden, Netherlands. [Molendijk, Marc L.] Leiden Univ, Med Ctr, Leiden Inst Brain & Cognit, Leiden, Netherlands. [Koehler, Cristiano A.; Leite, Claudio Manuel G. S.; Ribeiro, Thamara L.; Silva, Jessica C.; Sales, Paulo M. G.; Carvalho, Andre F.] Univ Fed Ceara, Translat Psychiat Res Grp, Fac Med, Fortaleza, Ceara, Brazil. [Koehler, Cristiano A.; Leite, Claudio Manuel G. S.; Ribeiro, Thamara L.; Silva, Jessica C.; Sales, Paulo M. G.; Carvalho, Andre F.] Univ Fed Ceara, Dept Clin Med, Fac Med, Fortaleza, Ceara, Brazil. [Soares, Jair C.; Quevedo, Joao] Texas Hlth & Sci Univ, Dept Psychiat & Behav Sci, Ctr Excellence Mood Disorders, Houston, TX USA. [Machado-Vieira, Rodrigo] Univ Sao Paulo, Lab Neurosci, LIM 27, Inst & Dept Psychiat, Sao Paulo, Brazil. [Machado-Vieira, Rodrigo] Univ Sao Paulo, Ctr Interdisciplinary Res Appl Neurosci NAPNA, Sao Paulo, Brazil. [Machado-Vieira, Rodrigo] NIMH, Expt Therapeut & Pathophysiol Branch, NIH, Bethesda, MD 20892 USA. [Quevedo, Joao] Univ Texas Med Sch Houston, Dept Psychiat & Behav Sci, Ctr Translat Psychiat, Houston, TX USA. [Quevedo, Joao] Univ Texas Hlth Sci Ctr Houston, Neurosci Grad Program, Grad Sch Biomed Sci, Houston, TX 77030 USA. [Quevedo, Joao] Univ Southern Santa Catarina, Grad Program Hlth Sci, Hlth Sci Unit, Lab Neurosci, Criciuma, SC, Brazil. [Oertel-Knoechel, Viola] Goethe Univ Frankfurt, Lab Neuroimaging, Dept Psychiat Psychosomat Med & Psychotherapy, D-60054 Frankfurt, Germany. [Vieta, Eduard] Univ Barcelona, Bipolar Disorders Unit, Inst Neurosci, Hosp Clin,IDIBAPS,CIBERSAM, Barcelona, Catalonia, Spain. [Gonzalez-Pinto, Ana] Univ Basque Country, Dept Neurosci, Biomed Res Ctr Mental Hlth Net CIBERSAM, Leioa, Spain. [Berk, Michael] Orygen, Florey Inst Neurosci & Mental Hlth, Parkville, Vic, Australia. [Berk, Michael] Orygen Youth Hlth Res Ctr, Parkville, Vic, Australia. [Berk, Michael] Univ Melbourne, Dept Psychiat, Parkville, Vic 3052, Australia. RP Fernandes, BS (reprint author), Deakin Univ, IMPACT Strateg Res Ctr, Sch Med, Geelong, Vic 3217, Australia. EM brisasf@gmail.com; andrefc7@terra.com.br RI MACHADO-VIEIRA, RODRIGO/D-8293-2012; Quevedo, Joao/E-5491-2013 OI MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190; Quevedo, Joao/0000-0003-3114-6611 FU CNPq, Brazil [MCTI/CNPQ/Universal 14/2014461833/2014-0]; CAPES, Brazil; NIMH [R01 085667]; Dunn Foundation; CNPq (Brazil, level IA); CNPq (Brazil, level II); NHMRC [1059660]; Pat Rutherford, Jr. Endowed Chair in Psychiatry FX BSF is supported by a postdoctoral scholarship and by a research grant MCTI/CNPQ/Universal 14/2014461833/2014-0, both from CNPq, Brazil. CAK is a recipient of a postdoctoral fellowship from CAPES, Brazil. JCS is supported by NIMH grant R01 085667, the Dunn Foundation and the JQ are supported by research fellowship awards from CNPq (Brazil, level IA). AFC is the recipient of a research fellowship from CNPq (Brazil, level II). MB is supported by a NHMRC Senior Principal Research Fellowship 1059660. None of these agencies had any role in the design and conduct of the study, or decision to submit the manuscript for publication. We thank all authors of the included papers, particularly Drs. Natalie L. Rasgon, Deniz Ceylan, Camilla Langan, Pedro Magalhaes, Antonio L. Teixeira, Yuan-Hwa Chou, Iria Grande, Chenyu Ye, Izabela Barbosa, Menan Rabie, Ru-Band Lu, Ana Gonzales-Pinto, Reiji Yoshimura, Flavio Kapczinski, and Christoph Laske, who kindly provided unpublished data for the paper. NR 108 TC 17 Z9 18 U1 6 U2 17 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 NOV 30 PY 2015 VL 13 AR 289 DI 10.1186/s12916-015-0529-7 PG 22 WC Medicine, General & Internal SC General & Internal Medicine GA CX6BA UT WOS:000365785000001 PM 26621529 ER PT J AU Rajan, A Wakelee, H Giaccone, G AF Rajan, Arun Wakelee, Heather Giaccone, Giuseppe TI Novel Treatments for Thymoma and Thymic Carcinoma SO FRONTIERS IN ONCOLOGY LA English DT Editorial Material DE thymic epithelial tumors; autoimmune paraneoplastic disorders; genomic changes; anti-cytokine antibodies; biological therapies ID ANTI-CYTOKINE AUTOANTIBODIES; EPITHELIAL TUMORS; AUTOIMMUNITY; IMMUNODEFICIENCY; MALIGNANCIES; THYMECTOMY; MANAGEMENT; OUTCOMES C1 [Rajan, Arun] NCI, Thorac & Gastrointestinal Oncol Branch, NIH, Bethesda, MD 20892 USA. [Wakelee, Heather] Stanford Univ, Dept Med, Div Med Oncol, Stanford, CA 94305 USA. [Giaccone, Giuseppe] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA. RP Rajan, A (reprint author), NCI, Thorac & Gastrointestinal Oncol Branch, NIH, Bethesda, MD 20892 USA. EM rajana@mail.nih.gov RI Giaccone, Giuseppe/E-8297-2017 OI Giaccone, Giuseppe/0000-0002-5023-7562 NR 28 TC 0 Z9 0 U1 1 U2 1 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 2234-943X J9 FRONT ONCOL JI Front. Oncol. PD NOV 30 PY 2015 VL 5 AR 267 DI 10.3389/fonc.2015.00267 PG 3 WC Oncology SC Oncology GA CX6LO UT WOS:000365812600001 PM 26649279 ER PT J AU Basar, B Rogers, T Ratnayaka, K Campbell-Washburn, AE Mazal, JR Schenke, WH Sonmez, M Faranesh, AZ Lederman, RJ Kocaturk, O AF Basar, Burcu Rogers, Toby Ratnayaka, Kanishka Campbell-Washburn, Adrienne E. Mazal, Jonathan R. Schenke, William H. Sonmez, Merdim Faranesh, Anthony Z. Lederman, Robert J. Kocaturk, Ozgur TI Segmented nitinol guidewires with stiffness-matched connectors for cardiovascular magnetic resonance catheterization: preserved mechanical performance and freedom from heating SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Article DE Interventional cardiovascular magnetic resonance; Heart catheterization; Image-guided intervention; MR safety; MR heating; Medical devices ID INTERVENTIONAL MRI; RF SAFETY; DEVICES; WIRES; THERMOMETRY; SIGNAL AB Background: Conventional guidewires are not suitable for use during cardiovascular magnetic resonance (CMR) catheterization. They employ metallic shafts for mechanical performance, but which are conductors subject to radiofrequency (RF) induced heating. To date, non-metallic CMR guidewire designs have provided inadequate mechanical support, trackability, and torquability. We propose a metallic guidewire for CMR that is by design intrinsically safe and that retains mechanical performance of commercial guidewires. Methods: The NHLBI passive guidewire is a 0.035" CMR-safe, segmented-core nitinol device constructed using short nitinol rod segments. The electrical length of each segment is less than one-quarter wavelength at 1.5 Tesla, which eliminates standing wave formation, and which therefore eliminates RF heating along the shaft. Each of the electrically insulated segments is connected with nitinol tubes for stiffness matching to assure uniform flexion. Iron oxide markers on the distal shaft impart conspicuity. Mechanical integrity was tested according to International Organization for Standardization (ISO) standards. CMR RF heating safety was tested in vitro in a phantom according to American Society for Testing and Materials (ASTM) F-2182 standard, and in vivo in seven swine. Results were compared with a high-performance commercial nitinol guidewire. Results: The NHLBI passive guidewire exhibited similar mechanical behavior to the commercial comparator. RF heating was reduced from 13 degrees C in the commercial guidewire to 1.2 degrees C in the NHLBI passive guidewire in vitro, using a flip angle of 75 degrees. The maximum temperature increase was 1.1 +/- 0.3 degrees C in vivo, using a flip angle of 45 degrees. The guidewire was conspicuous during left heart catheterization in swine. Conclusions: We describe a simple and intrinsically safe design of a metallic guidewire for CMR cardiovascular catheterization. The guidewire exhibits negligible heating at high flip angles in conformance with regulatory guidelines, yet mechanically resembles a high-performance commercial guidewire. Iron oxide markers along the length of the guidewire impart passive visibility during real-time CMR. Clinical translation is imminent. C1 [Basar, Burcu; Rogers, Toby; Ratnayaka, Kanishka; Campbell-Washburn, Adrienne E.; Mazal, Jonathan R.; Schenke, William H.; Sonmez, Merdim; Faranesh, Anthony Z.; Lederman, Robert J.] NHLBI, NIH, Bethesda, MD 20892 USA. [Basar, Burcu; Kocaturk, Ozgur] Bogazici Univ, Inst Biomed Engn, Istanbul, Turkey. [Ratnayaka, Kanishka] Childrens Natl Med Ctr, Dept Cardiol, Washington, DC 20010 USA. RP Lederman, RJ (reprint author), NHLBI, NIH, Bldg 10,Room 2c713, Bethesda, MD 20892 USA. EM lederman@nih.gov RI Kocaturk, Ozgur/A-1419-2016; OI lederman, robert/0000-0003-1202-6673; Rogers, Toby/0000-0002-6043-3137 FU Division of Intramural Research, National Heart Lung and Blood Institute, National Institutes of Health [Z01-HL006041] FX Supported by the Division of Intramural Research, National Heart Lung and Blood Institute, National Institutes of Health (Z01-HL006041). NR 27 TC 1 Z9 1 U1 1 U2 13 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 NOV 30 PY 2015 VL 17 AR 105 DI 10.1186/s12968-015-0210-5 PG 9 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA CX6EG UT WOS:000365793400001 PM 26620420 ER PT J AU Ascierto, PA Atkins, M Bifulco, C Botti, G Cochran, A Davies, M Demaria, S Dummer, R Ferrone, S Formenti, S Gajewski, TF Garbe, C Khleif, S Kiessling, R Lo, R Lorigan, P Mc Arthur, G Masucci, G Melero, I Mihm, M Palmieri, G Parmiani, G Puzanov, I Romero, P Schilling, B Seliger, B Stroncek, D Taube, J Tomei, S Zarour, HM Testori, A Wang, E Galon, J Ciliberto, G Mozzillo, N Marincola, FM Thurin, M AF Ascierto, Paolo A. Atkins, Michael Bifulco, Carlo Botti, Gerardo Cochran, Alistair Davies, Michael Demaria, Sandra Dummer, Reinhard Ferrone, Soldano Formenti, Silvia Gajewski, Thomas F. Garbe, Claus Khleif, Samir Kiessling, Rolf Lo, Roger Lorigan, Paul Mc Arthur, Grant Masucci, Giuseppe Melero, Ignacio Mihm, Martin Palmieri, Giuseppe Parmiani, Giorgio Puzanov, Igor Romero, Pedro Schilling, Bastian Seliger, Barbara Stroncek, David Taube, Janis Tomei, Sara Zarour, Hassane M. Testori, Alessandro Wang, Ena Galon, Jerome Ciliberto, Gennaro Mozzillo, Nicola Marincola, Francesco M. Thurin, Magdalena TI Future perspectives in melanoma research: meeting report from the "Melanoma Bridge": Napoli, December 3rd-6th 2014 SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article AB The fourth "Melanoma Bridge Meeting" took place in Naples, December 3-6th, 2014. The four topics discussed at this meeting were: Molecular and Immunological Advances, Combination Therapies, News in Immunotherapy, and Tumor Microenvironment and Biomarkers. Until recently systemic therapy for metastatic melanoma patients was ineffective, but recent advances in tumor biology and immunology have led to the development of new targeted and immunotherapeutic agents that prolong progression-free survival (PFS) and overall survival (OS). New therapies, such as mitogen-activated protein kinase (MAPK) pathway inhibitors as well as other signaling pathway inhibitors, are being tested in patients with metastatic melanoma either as monotherapy or in combination, and all have yielded promising results. These include inhibitors of receptor tyrosine kinases (BRAF, MEK, and VEGFR), the phosphatidylinositol 3 kinase (PI3K) pathway [PI3K, AKT, mammalian target of rapamycin (mTOR)], activators of apoptotic pathway, and the cell cycle inhibitors (CDK4/6). Various locoregional interventions including radiotherapy and surgery are still valid approaches in treatment of advanced melanoma that can be integrated with novel therapies. Intrinsic, adaptive and acquired resistance occur with targeted therapy such as BRAF inhibitors, where most responses are short-lived. Given that the reactivation of the MAPK pathway through several distinct mechanisms is responsible for the majority of acquired resistance, it is logical to combine BRAF inhibitors with inhibitors of targets downstream in the MAPK pathway. For example, combination of BRAF/MEK inhibitors (e.g., dabrafenib/trametinib) have been demonstrated to improve survival compared to monotherapy. Application of novel technologies such sequencing have proven useful as a tool for identification of MAPK pathway-alternative resistance mechanism and designing other combinatorial therapies such as those between BRAF and AKT inhibitors. Improved survival rates have also been observed with immune-targeted therapy for patients with metastatic melanoma. Immune-modulating antibodies came to the forefront with anti-CTLA-4, programmed cell death-1 (PD-1) and PD-1 ligand 1 (PD-L1) pathway blocking antibodies that result in durable responses in a subset of melanoma patients. Agents targeting other immune inhibitory (e.g., Tim-3) or immune stimulating (e.g., CD137) receptors and other approaches such as adoptive cell transfer demonstrate clinical benefit in patients with melanoma as well. These agents are being studied in combination with targeted therapies in attempt to produce longer-term responses than those more typically seen with targeted therapy. Other combinations with cytotoxic chemotherapy and inhibitors of angiogenesis are changing the evolving landscape of therapeutic options and are being evaluated to prevent or delay resistance and to further improve survival rates for this patient population. This meeting's specific focus was on advances in combination of targeted therapy and immunotherapy. Both combination targeted therapy approaches and different immunotherapies were discussed. Similarly to the previous meetings, the importance of biomarkers for clinical application as markers for diagnosis, prognosis and prediction of treatment response was an integral part of the meeting. The overall emphasis on biomarkers supports novel concepts toward integrating biomarkers into contemporary clinical management of patients with melanoma across the entire spectrum of disease stage. Translation of the knowledge gained from the biology of tumor microenvironment across different tumors represents a bridge to impact on prognosis and response to therapy in melanoma. C1 [Ascierto, Paolo A.; Botti, Gerardo; Ciliberto, Gennaro; Mozzillo, Nicola] Fdn G Pascale, Ist Nazl Tumori, Naples, Italy. [Atkins, Michael] Georgetown Lombardi Comprehens Canc Ctr, Washington, DC USA. [Bifulco, Carlo] Providence Canc Ctr, Earle A Chiles Res Inst, Translat Mol Pathol, Portland, OR USA. [Cochran, Alistair] Univ Calif Los Angeles, David Geffen Sch Med, John Wayne Canc Inst, Dept Pathol & Lab Med, Santa Monica, CA USA. [Cochran, Alistair] Univ Calif Los Angeles, David Geffen Sch Med, John Wayne Canc Inst, Dept Surg, Santa Monica, CA USA. [Davies, Michael] Univ Texas MD Anderson Canc Ctr, Div Canc Med, Dept Melanoma Med Oncol, Houston, TX 77030 USA. [Demaria, Sandra] Weill Cornell Med Coll, Dept Radiat Oncol, New York, NY USA. [Demaria, Sandra] Weill Cornell Med Coll, Dept Pathol, New York, NY USA. [Dummer, Reinhard] Univ Hosp Zurich, Dept Dermatol, Skin Canc Unit, CH-8091 Zurich, Switzerland. [Ferrone, Soldano] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Formenti, Silvia] Weill Cornell Med Coll, Dept Radiat Oncol, New York, NY USA. [Gajewski, Thomas F.] Univ Chicago Med, Dept Med, Immunol & Canc Program, Chicago, IL USA. [Gajewski, Thomas F.] Univ Chicago Med, Dept Pathol, Immunol & Canc Program, Chicago, IL USA. [Garbe, Claus] Univ Tubingen, Dept Dermatol, Ctr Dermato Oncol, Tubingen, Germany. [Khleif, Samir] Georgia Regents Univ, Georgia Regents Univ Canc Ctr, Augusta, GA USA. [Kiessling, Rolf] Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden. [Lo, Roger] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Lo, Roger] Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA. [Lo, Roger] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90024 USA. [Lorigan, Paul] Univ Manchester, Christie NHS Fdn Trust, Manchester, Lancs, England. [Mc Arthur, Grant] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [Mc Arthur, Grant] Univ Melbourne, Melbourne, Vic 3010, Australia. [Masucci, Giuseppe] Karolinska Hosp, Dept Oncol Pathol, S-10401 Stockholm, Sweden. [Melero, Ignacio] Ctr Invest Med Aplicada, Navarra, Spain. [Melero, Ignacio] Univ Navarra Clin, Navarra, Spain. [Mihm, Martin] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Palmieri, Giuseppe] CNR, Unit Canc Genet, Inst Biomol Chem, Sassari, Italy. [Parmiani, Giorgio] Ist Sci San Raffaele, Div Mol Oncol, Unit Bioimmunotherapy Solid Tumors, I-20132 Milan, Italy. [Puzanov, Igor] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Romero, Pedro] Ludwig Canc Res Ctr, Lausanne, Switzerland. [Romero, Pedro] Univ Lausanne, Lausanne, Switzerland. [Schilling, Bastian] Univ Duisburg Essen, West German Canc Ctr, Univ Hosp,W, Dept Dermatol, Essen, Germany. [Seliger, Barbara] Univ Halle Wittenberg, Inst Med Immunol, D-06108 Halle, Germany. [Stroncek, David] NIH, Cell Proc Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Taube, Janis] Johns Hopkins Univ, Sch Med, Dept Dermatol, Baltimore, MD 21205 USA. [Tomei, Sara] Sidra Med & Res Ctr, Div Translat Med, Doha, Qatar. [Zarour, Hassane M.] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. [Zarour, Hassane M.] Univ Pittsburgh, Dept Immunol, Pittsburgh, PA USA. [Zarour, Hassane M.] Univ Pittsburgh, Dept Dermatol, Pittsburgh, PA 15260 USA. [Testori, Alessandro] Ist Europeo Oncol, Milan, Italy. [Wang, Ena] Sidra Med & Res Ctr, Div Translat Med, Doha, Qatar. [Galon, Jerome] Univ Paris 05, Sorbonne Paris Cite, Ctr Rech Cordeliers, INSERM,UMRS1138,Lab Integrat Canc Immunol, Paris, France. [Marincola, Francesco M.] Sidra Med & Res Ctr, Doha, Qatar. [Thurin, Magdalena] NCI, Canc Diag Program, NIH, Bethesda, MD 20892 USA. [Schilling, Bastian] German Canc Consortium DKTK, Essen, Germany. RP Ascierto, PA (reprint author), Fdn G Pascale, Ist Nazl Tumori, Naples, Italy. EM paolo.ascierto@gmail.com OI Demaria, Sandra/0000-0003-4426-0499; Palmieri, Giuseppe/0000-0002-4350-2276; MELERO BERMEJO, IGNACIO/0000-0002-1360-348X; Lorigan, Paul/0000-0002-8875-2164 FU Fondazione Melanoma Onlus; Society of ImmunoTherapy of Cancer (SITC) FX The meeting was supported by Fondazione Melanoma Onlus and the Society of ImmunoTherapy of Cancer (SITC). A special thanks to 3P Solution of Napoli for their support and cooperation in organizing the meeting and especially to Lucia Politi. NR 0 TC 4 Z9 4 U1 3 U2 9 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 NOV 30 PY 2015 VL 13 AR 374 DI 10.1186/s12967-015-0736-1 PG 20 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CX6ES UT WOS:000365794600002 PM 26619946 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, 403, 2015) SO BMC GENOMICS LA English DT Correction DE Urothelial bladder cancer; Cell line; Genomics; Mutation; Oncogene; Tumor suppressor ID AUTHENTICATION; TUMORS C1 [Earl, Julie; Carrillo-de-Santa-Pau, Enrique; Mendez-Pertuz, Marinela; Real, Francisco X.] CNIO Spanish Natl Canc Res Ctr, F BBVA Canc Cell Biol Programme, Epithelial Carcinogenesis Grp, Madrid 28029, Spain. [Earl, Julie; Carrato, Alfredo] Hosp Ramon & Cajal, Med Oncol Serv, E-28034 Madrid, Spain. [Rico, Daniel; Valencia, Alfonso] CNIO Spanish Natl Canc Res Ctr, Struct Biol & Biocomp Programme, Struct Computat Biol Grp, Madrid 28029, Spain. [Rodriguez-Santiago, Benjamin] qGenomics, Quantitat Genom Med Lab, Barcelona, Spain. [Perez-Jurado, Luis A.] Univ Pompeu Fabra, Dept Ciencies Expt & Salut, Barcelona, Spain. [Rodriguez-Santiago, Benjamin; Perez-Jurado, Luis A.] CIBERER, Barcelona, Spain. [Auer, Herbert] Inst Recerca Biomed Barcelona, Barcelona, Spain. [Gomez, Gonzalo; Pisano, David G.] CNIO Spanish Natl Canc Res Ctr, Struct Biol & Biocomp Programme, Bioinformat Unit, Madrid 28029, 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, F BBVA Canc Cell Biol Programme, Epithelial Carcinogenesis Grp, Melchor Fernandez Almagro 3, Madrid 28029, Spain. EM preal@cnio.es RI Real Arribas, Francisco/H-5275-2015; Valencia, Alfonso/I-3127-2015 OI Real Arribas, Francisco/0000-0001-9501-498X; Valencia, Alfonso/0000-0002-8937-6789 NR 7 TC 1 Z9 1 U1 0 U2 0 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 NOV 30 PY 2015 VL 16 AR 1019 DI 10.1186/s12864-015-2227-4 PG 2 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA CX1UF UT WOS:000365480400002 PM 26621286 ER PT J AU Johnson, JL Kreidler, SM Catellier, DJ Murray, DM Muller, KE Glueck, DH AF Johnson, Jacqueline L. Kreidler, Sarah M. Catellier, Diane J. Murray, David M. Muller, Keith E. Glueck, Deborah H. TI Recommendations for choosing an analysis method that controls Type I error for unbalanced cluster sample designs with Gaussian outcomes SO STATISTICS IN MEDICINE LA English DT Article DE cluster randomized; group randomized; Type I error; unbalanced; Gaussian ID GROUP-RANDOMIZED TRIALS; MAXIMUM-LIKELIHOOD; MODELS; INFERENCE; CANCER AB We used theoretical and simulation-based approaches to study Type I error rates for one-stage and two-stage analytic methods for cluster-randomized designs. The one-stage approach uses the observed data as outcomes and accounts for within-cluster correlation using a general linear mixed model. The two-stage model uses the cluster specific means as the outcomes in a general linear univariatemodel. We demonstrate analytically that both one-stage and two-stage models achieve exact Type I error rates when cluster sizes are equal. With unbalanced data, an exact size.. test does not exist, and Type I error inflation may occur. Via simulation, we compare the Type I error rates for four one-stage and six two-stage hypothesis testing approaches for unbalanced data. With unbalanced data, the two-stage model, weighted by the inverse of the estimated theoretical variance of the cluster means, and with variance constrained to be positive, provided the best Type I error control for studies having at least six clusters per arm. The one-stage model with Kenward-Roger degrees of freedom and unconstrained variance performed well for studies having at least 14 clusters per arm. The popular analytic method of using a one-stage model with denominator degrees of freedom appropriate for balanced data performed poorly for small sample sizes and low intracluster correlation. Because small sample sizes and low intracluster correlation are common features of cluster-randomized trials, the Kenward-Roger method is the preferred one-stage approach. Copyright (C) 2015 John Wiley & Sons, Ltd. C1 [Johnson, Jacqueline L.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Kreidler, Sarah M.] Neptune & Co, Lakewood, CO 80215 USA. [Catellier, Diane J.] RTI Int, Res Triangle Pk, NC USA. [Murray, David M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD USA. [Muller, Keith E.] Univ Florida, Dept Hlth Outcomes & Policy, Gainesville, FL USA. [Glueck, Deborah H.] Univ Colorado Denver, Dept Biostat & Informat, Aurora, CO USA. RP Kreidler, SM (reprint author), Neptune & Co, Garrison St, Lakewood, CO 80215 USA. EM skreidler@neptuneinc.org OI Kreidler, Sarah/0000-0002-2104-5166; Murray, David/0000-0003-0797-9269 FU National Institute of Dental and Craniofacial Research [NIDCR 1 R01DE020832-01A1, 12/09/10-11/30/14] FX Supported by the National Institute of Dental and Craniofacial Research under award NIDCR 1 R01DE020832-01A1, Multilevel and Longitudinal Study Sample Size Tools for Behavioral Scientists (12/09/10-11/30/14), led by Keith Muller and Deborah Glueck NR 26 TC 1 Z9 1 U1 1 U2 3 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 NOV 30 PY 2015 VL 34 IS 27 BP 3531 EP 3545 DI 10.1002/sim.6565 PG 15 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 CV0KU UT WOS:000363940400005 PM 26089186 ER PT J AU Freedman, LS Midthune, D Dodd, KW Carroll, RJ Kipnis, V AF Freedman, Laurence S. Midthune, Douglas Dodd, Kevin W. Carroll, Raymond J. Kipnis, Victor TI A statistical model for measurement error that incorporates variation over time in the target measure, with application to nutritional epidemiology SO STATISTICS IN MEDICINE LA English DT Article DE 24-hour recall; attenuation factor; calibration equations; food frequency questionnaire; recovery biomarker ID WITHIN-PERSON VARIATION; BIOMARKER MEASUREMENTS; RECOVERY BIOMARKERS; 2 VALIDATION; ENERGY; ASSOCIATION; INSTRUMENTS AB Most statistical methods that adjust analyses for measurement error assume that the target exposure T is a fixed quantity for each individual. However, in many applications, the value of T for an individual varies with time. We develop a model that accounts for such variation, describing the model within the framework of a meta-analysis of validation studies of dietary self-report instruments, where the reference instruments are biomarkers. We demonstrate that in this application, the estimates of the attenuation factor and correlation with true intake, key parameters quantifying the accuracy of the self-report instrument, are sometimes substantially modified under the time-varying exposure model compared with estimates obtained under a traditional fixed-exposure model. We conclude that accounting for the time element in measurement error problems is potentially important. Copyright (C) 2015 John Wiley & Sons, Ltd. C1 [Freedman, Laurence S.] Informat Management Serv Inc, Rockville, MD USA. [Freedman, Laurence S.] Gertner Inst, Biostat Unit, Tel Hashomer, Israel. [Midthune, Douglas; Dodd, Kevin W.; Kipnis, Victor] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Carroll, Raymond J.] Texas A&M Univ, Dept Stat, College Stn, TX 77843 USA. RP Freedman, LS (reprint author), Chaim Sheba Med Ctr, Gertner Inst Epidemiol & Hlth Policy Res, Biostat Unit, IL-52621 Tel Hashomer, Israel. EM lsf@actcom.co.il OI Freedman, Laurence/0000-0002-6767-7900 FU National Cancer Institute [U01-CA057030]; National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C] FX We acknowledge the investigators of the Women's Health Initiative WHI for the use of their data. A short list of the investigators appears at http://www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20In vestigator%20Short%20List.pdf. We acknowledge also the use of data from the Validation Studies Pooling Project and the principal investigators of that project Dr. Lenore Arab, Dr. Alanna Moshfegh, Dr. Ross Prentice, Dr. Amy Subar, and Dr. Walter Willett. We acknowledge the advice of Dr. Donna Spiegelman on earlier versions of the manuscript. Carroll's research was supported by a grant from the National Cancer Institute U01-CA057030. The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. NR 15 TC 3 Z9 3 U1 3 U2 8 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 NOV 30 PY 2015 VL 34 IS 27 BP 3590 EP 3605 DI 10.1002/sim.6577 PG 16 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 CV0KU UT WOS:000363940400009 PM 26173857 ER PT J AU Naisbitt, DJ Yang, EL Alhaidari, M Berry, NG Lawrenson, AS Farrell, J Martin, P Strebel, K Owen, A Pye, M French, NS Clarke, SE O'Neill, PM Park, BK AF Naisbitt, Dean J. Yang, Emma L. Alhaidari, Mohammad Berry, Neil G. Lawrenson, Alexandre S. Farrell, John Martin, Philip Strebel, Klaus Owen, Andrew Pye, Matthew French, Neil S. Clarke, Stephen E. O'Neill, Paul M. Park, B. Kevin TI Towards depersonalized abacavir therapy: chemical modification eliminates HLA-B*57:01-restricted CD8(+) T-cell activation SO AIDS LA English DT Article DE abacavir; drug design; drug hypersensitivity; human leukocyte antigen; T-lymphocytes ID STEVENS-JOHNSON-SYNDROME; INDUCED LIVER-INJURY; DRUG HYPERSENSITIVITY; PEPTIDE REPERTOIRE; HLA-B; FLUCLOXACILLIN; ASSOCIATION; REACTIVITY; GENOTYPE; PROVIDES AB Objective:Exposure to abacavir is associated with T-cell-mediated hypersensitivity reactions in individuals carrying human leukocyte antigen (HLA)-B57:01. To activate T cells, abacavir interacts directly with endogenous HLA-B57:01 and HLA-B57:01 expressed on the surface of antigen presenting cells. We have investigated whether chemical modification of abacavir can produce a molecule with antiviral activity that does not bind to HLA-B57:01 and activate T cells.Design:An interdisciplinary laboratory study using samples from human donors expressing HLA-B57:01. Researchers were blinded to the analogue structures and modelling data.Methods:Sixteen 6-amino substituted abacavir analogues were synthesized. Computational docking studies were completed to predict capacity for analogue binding within HLA-B57:01. Abacavir-responsive CD8(+) clones were generated to study the association between HLA-B57:01 analogue binding and T-cell activation. Antiviral activity and the direct inhibitory effect of analogues on proliferation were assessed.Results:Major histocompatibility complex class I-restricted CD8(+) clones proliferated and secreted IFN following abacavir binding to surface and endogenous HLA-B57:01. Several analogues retained antiviral activity and showed no overt inhibitory effect on proliferation, but displayed highly divergent antigen-driven T-cell responses. For example, abacavir and N-propyl abacavir were equally potent at activating clones, whereas the closely related analogues N-isopropyl and N-methyl isopropyl abacavir were devoid of T-cell activity. Docking abacavir analogues to HLA-B57:01 revealed a quantitative relationship between drug-protein binding and the T-cell response.Conclusion:These studies demonstrate that the unwanted T-cell activity of abacavir can be eliminated whilst maintaining the favourable antiviral profile. The in-silico model provides a tool to aid the design of safer antiviral agents that may not require a personalized medicines approach to therapy. Copyright (C) 2015 Wolters Kluwer Health, Inc. All rights reserved. C1 [Naisbitt, Dean J.; Alhaidari, Mohammad; Farrell, John; Martin, Philip; Owen, Andrew; Pye, Matthew; French, Neil S.; Park, B. Kevin] Univ Liverpool, Dept Mol & Clin Pharmacol, MRC, Ctr Drug Safety Sci, Liverpool L69 3GE, Merseyside, England. [Yang, Emma L.; Berry, Neil G.; Lawrenson, Alexandre S.; O'Neill, Paul M.] Univ Liverpool, Dept Chem, Liverpool L69 3GE, Merseyside, England. [Strebel, Klaus] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD USA. [Clarke, Stephen E.] GlaxoSmithKline, Drug Metab & Pharmacokinet, Stevenage, Herts, England. RP Park, BK (reprint author), Univ Liverpool, Liverpool L69 3GE, Merseyside, England. EM bkpark@liv.ac.uk RI Berry, Neil/B-7960-2009; OI Berry, Neil/0000-0003-1928-0738; French, Neil/0000-0002-9376-3482 FU BBSRC GSK; Saudi Arabian Ministry of Higher Education as part of the Centre for Drug Safety Science - Medical Research Council [G0700654]; Medical Research Council [MC_PC_13068] FX This work was funded by BBSRC & GSK (through a studentship to E.L.Y.) and the Saudi Arabian Ministry of Higher Education (through a studentship to M.S.A.) as part of the Centre for Drug Safety Science supported by the Medical Research Council [grant number G0700654]. Funding for this work was in part from a Medical Research Council Confidence in Concepts Award to The University of Liverpool (MC_PC_13068). NR 28 TC 3 Z9 3 U1 1 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 NOV 28 PY 2015 VL 29 IS 18 BP 2385 EP 2395 DI 10.1097/QAD.0000000000000867 PG 11 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA DB4NA UT WOS:000368488500001 PM 26372480 ER PT J AU Murray, CJL Barber, RM Foreman, KJ Ozgoren, AA Abd-Allah, F Abera, SF Aboyans, V Abraham, JP Abubakar, I Abu-Raddad, LJ Abu-Rmeileh, NM Achoki, T Ackerman, IN Ademi, Z Adou, AK Adsuar, JC Afshin, A Agardh, EE Alam, SS Alasfoor, D Albittar, MI Alegretti, MA Alemu, ZA Alfonso-Cristancho, R Alhabib, S Ali, R Alla, F Allebeck, P Almazroa, MA Alsharif, U Alvarez, E Alvis-Guzman, N Amare, AT Ameh, EA Amini, H Ammar, W Anderson, HR Anderson, BO Antonio, CAT Anwari, P Arnlov, J Arsenijevic, VSA Artaman, A Asghar, RJ Assadi, R Atkins, LS Avila, MA Awuah, B Bachman, VF Badawi, A Bahit, MC Balakrishnan, K Banerjee, A Barker-Collo, SL Barquera, S Barregard, L Barrero, LH Basu, A Basu, S Basulaiman, MO Beardsley, J Bedi, N Beghi, E Bekele, T Bell, ML Benjet, C Bennett, DA Bensenor, IM Benzian, H Bernabe, E Bertozzi-Villa, A Beyene, TJ Bhala, N Bhalla, A Bhutta, ZA Bienhoff, K Bikbov, B Biryukov, S Blore, JD Blosser, CD Blyth, FM Bohensky, MA Bolliger, IW Basara, BB Bornstein, NM Bose, D Boufous, S Bourne, RRA Boyers, LN Brainin, M Brayne, CE Brazinova, A Breitborde, NJK Brenner, H Briggs, AD Brooks, PM Brown, JC Brugha, TS Buchbinder, R Buckle, GC Budke, CM Bulchis, A Bulloch, AG Campos-Nonato, IR Carabin, H Carapetis, JR Cardenas, R Carpenter, DO Caso, V Castaneda-Orjuela, CA Castro, RE Catala-Lopez, F Cavalleri, F Cavlin, A Chadha, VK Chang, JC Charlson, FJ Chen, HL Chen, WQ Chiang, PP Chimed-Ochir, O Chowdhury, R Christensen, H Christophi, CA Cirillo, M Coates, MM Coffeng, LE Coggeshall, MS Colistro, V Colquhoun, SM Cooke, GS Cooper, C Cooper, LT Coppola, LM Cortinovis, M Criqui, MH Crump, JA Cuevas-Nasu, L Danawi, H Dandona, L Dandona, R Dansereau, E Dargan, PI Davey, G Davis, A Davitoiu, DV Dayama, A De Leo, D Degenhardt, L Del Pozo-Cruz, B Dellavalle, RP Deribe, K Derrett, S Des Jarlais, DC Dessalegn, M Dharmaratne, SD Dherani, MK Diaz-Torne, C Dicker, D Ding, EL Dokova, K Dorsey, ER Driscoll, TR Duan, L Duber, HC Ebel, BE Edmond, KM Elshrek, YM Endres, M Ermakov, SP Erskine, HE Eshrati, B Esteghamati, A Estep, K Faraon, EJA Farzadfar, F Fay, DF Feigin, VL Felson, DT Fereshtehnejad, SM Fernandes, JG Ferrari, AJ Fitzmaurice, C Flaxman, AD Fleming, TD Foigt, N Forouzanfar, MH Fowkes, FGR Paleo, UF Franklin, RC Furst, T Gabbe, B Gaffikin, L Gankpe, FG Geleijnse, JM Gessner, BD Gething, P Gibney, KB Giroud, M Giussani, G Dantes, HG Gona, P Gonzalez-Medina, D Gosselin, RA Gotay, CC Goto, A Gouda, HN Graetz, N Gugnani, HC Gupta, R Gupta, R Gutierrez, RA Haagsma, J Hafezi-Nejad, N Hagan, H Halasa, YA Hamadeh, RR Hamavid, H Hammami, M Hancock, J Hankey, GJ Hansen, GM Hao, YT Harb, HL Haro, JM Havmoeller, R Hay, SI Hay, RJ Heredia-Pi, IB Heuton, KR Heydarpour, P Higashi, H Hijar, M Hoek, HW Hoffman, HJ Hosgood, HD Hossain, M Hotez, PJ Hoy, DG Hsairi, M Hu, GQ Huang, C Huang, JJ Husseini, A Huynh, C Iannarone, ML Iburg, KM Innos, K Inoue, M Islami, F Jacobsen, KH Jarvis, DL Jassal, SK Jee, SH Jeemon, P Jensen, PN Jha, V Jiang, GH Jiang, Y Jonas, JB Juel, K Kan, HD Karch, A Karema, CK Karimkhani, C Karthikeyan, G Kassebaum, NJ Kaul, A Kawakami, N Kazanjan, K Kemp, AH Kengne, AP Keren, A Khader, YS Khalifa, SEA Khan, EA Khan, G Khang, YH Kieling, C Kim, D Kim, S Kim, Y Kinfu, Y Kinge, JM Kivipelto, M Knibbs, LD Knudsen, AK Kokubo, Y Kosen, S Krishnaswami, S Defo, BK Bicer, BK Kuipers, EJ Kulkarni, C Kulkarni, VS Kumar, GA Kyu, HH Lai, T Lalloo, R Lallukka, T Lam, H Lan, Q Lansingh, VC Larsson, A Lawrynowicz, AEB Leasher, JL Leigh, J Leung, R Levitz, CE Li, B Li, YC Li, YM Lim, SS Lind, M Lipshultz, SE Liu, SW Liu, Y Lloyd, BK Lofgren, KT Logroscino, G Looker, KJ Lortet-Tieulent, J Lotufo, PA Lozano, R Lucas, RM Lunevicius, R Lyons, RA Ma, S Macintyre, MF Mackay, MT Majdan, M Malekzadeh, R Marcenes, W Margolis, DJ Margono, C Marzan, MB Masci, JR Mashal, MT Matzopoulos, R Mayosi, BM Mazorodze, TT Mcgill, NW Mcgrath, JJ Mckee, M McLain, A Meaney, PA Medina, C Mehndiratta, MM Mekonnen, W Melaku, YA Meltzer, M Memish, ZA Mensah, GA Meretoja, A Mhimbira, FA Micha, R Miller, TR Mills, EJ Mitchell, PB Mock, CN Ibrahim, NM Mohammad, KA Mokdad, AH Mola, GLD Monasta, L Hernandez, JCM Montico, M Montine, TJ Mooney, MD Moore, AR Moradi-Lakeh, M Moran, AE Mori, R Moschandreas, J Moturi, WN Moyer, ML Mozaffarian, D Msemburi, WT Mueller, UO Mukaigawara, M Mullany, EC Murdoch, ME Murray, J Murthy, KS Naghavi, M Naheed, A Naidoo, KS Naldi, L Nand, D Nangia, V Narayan, KMV Nejjari, C Neupane, SP Newton, CR Ng, M Ngalesoni, FN Nguyen, G Nisar, MI Nolte, S Norheim, OF Norman, RE Norrving, B Nyakarahuka, L Oh, IH Ohkubo, T Ohno, SL Olusanya, BO Opio, JN Ortblad, K Ortiz, A Pain, AW Pandian, JD Panelo, CIA Papachristou, C Park, EK Park, JH Patten, SB Patton, GC Paul, VK Pavlin, BI Pearce, N Pereira, DM Perez-Padilla, R Perez-Ruiz, F Perico, N Pervaiz, A Pesudovs, K Peterson, CB Petzold, M Phillips, MR Phillips, BK Phillips, DE Piel, FB Plass, D Poenaru, D Polinder, S Pope, D Popova, S Poulton, RG Pourmalek, F Prabhakaran, D Prasad, NM Pullan, RL Qato, DM Quistberg, DA Rafay, A Rahimi, K Rahman, SU Raju, M Rana, SM Razavi, H Reddy, KS Refaat, A Remuzzi, G Resnikoff, S Ribeiro, AL Richardson, L Richardus, JH Roberts, DA Rojas-Rueda, D Ronfani, L Roth, GA Rothenbacher, D Rothstein, DH Rowley, JT Roy, N Ruhago, GM Saeedi, MY Saha, S Sahraian, MA Sampson, UKA Sanabria, JR Sandar, L Santos, IS Satpathy, M Sawhney, M Scarborough, P Schneider, IJ Schottker, B Schumacher, AE Schwebel, DC Scott, JG Seedat, S Sepanlou, SG Serina, PT Servan-Mori, EE Shackelford, KA Shaheen, A Shahraz, S Levy, TS Shangguan, S She, J Sheikhbahaei, S Shi, PL Shibuya, K Shinohara, Y Shiri, R Shishani, K Shiue, I Shrime, MG Sigfusdottir, ID Silberberg, DH Simard, EP Sindi, S Singh, A Singh, JA Singh, L Skirbekk, V Slepak, EL Sliwa, K Soneji, S Soreide, K Soshnikov, S Sposato, LA Sreeramareddy, CT Stanaway, JD Stathopoulou, V Stein, DJ Stein, MB Steiner, C Steiner, TJ Stevens, A Stewart, A Stovner, LJ Stroumpoulis, K Sunguya, BF Swaminathan, S Swaroop, M Sykes, BL Tabb, KM Takahashi, K Tandon, N Tanne, D Tanner, M Tavakkoli, M Taylor, HR Te Ao, BJ Tediosi, F Temesgen, AM Templin, T Ten Have, M Tenkorang, EY Terkawi, AS Thomson, B Thorne-Lyman, AL Thrift, AG Thurston, GD Tillmann, T Tonelli, M Topouzis, F Toyoshima, H Traebert, J Tran, BX Trillini, M Truelsen, T Tsilimbaris, M Tuzcu, EM Uchendu, US Ukwaja, KN Undurraga, EA Uzun, SB Van Brakel, WH Van De Vijver, S van Gool, CH Van Os, J Vasankari, TJ Venketasubramanian, N Violante, FS Vlassov, VV Vollset, SE Wagner, GR Wagner, J Waller, SG Wan, X Wang, HD Wang, JL Wang, LH Warouw, TS Weichenthal, S Weiderpass, E Weintraub, RG Wang, WZ Werdecker, A Westerman, R Whiteford, HA Wilkinson, JD Williams, TN Wolfe, CD Wolock, TM Woolf, AD Wulf, S Wurtz, B Xu, GL Yan, LJL Yano, Y Ye, PP Yentur, GK Yip, P Yonemoto, N Yoon, SJ Younis, MZ Yu, CH Zaki, ME Zhao, Y Zheng, YF Zonies, D Zou, XN Salomon, JA Lopez, AD Vos, T AF Murray, Christopher J. L. Barber, Ryan M. Foreman, Kyle J. Ozgoren, Ayse Abbasoglu Abd-Allah, Foad Abera, Semaw F. Aboyans, Victor Abraham, Jerry P. Abubakar, Ibrahim Abu-Raddad, Laith J. Abu-Rmeileh, Niveen M. Achoki, Tom Ackerman, Ilana N. Ademi, Zanfina Adou, Arsene K. Adsuar, Jose C. Afshin, Ashkan Agardh, Emilie E. Alam, Sayed Saidul Alasfoor, Deena Albittar, Mohammed I. Alegretti, Miguel A. Alemu, Zewdie A. Alfonso-Cristancho, Rafael Alhabib, Samia Ali, Raghib Alla, Francois Allebeck, Peter Almazroa, Mohammad A. Alsharif, Ubai Alvarez, Elena Alvis-Guzman, Nelson Amare, Azmeraw T. Ameh, Emmanuel A. Amini, Heresh Ammar, Walid Anderson, H. Ross Anderson, Benjamin O. Antonio, Carl Abelardo T. Anwari, Palwasha Arnlov, Johan Arsenijevic, Valentina S. Arsic Artaman, Al Asghar, Rana J. Assadi, Reza Atkins, Lydia S. Avila, Marco A. Awuah, Baffour Bachman, Victoria F. Badawi, Alaa Bahit, Maria C. Balakrishnan, Kalpana Banerjee, Amitava Barker-Collo, Suzanne L. Barquera, Simon Barregard, Lars Barrero, Lope H. 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Vos, Theo CA GBD 2013 DALYs Collaborator HALE Collaborator TI Global, regional, and national disability-adjusted life years (DALYs) for 306 diseases and injuries and healthy life expectancy (HALE) for 188 countries, 1990-2013: quantifying the epidemiological transition SO LANCET LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; LOW SOCIOECONOMIC-STATUS; SELF-RATED HEALTH; SYSTEMATIC ANALYSIS; MORTALITY TRENDS; NONCOMMUNICABLE DISEASES; ECONOMIC-DEVELOPMENT; CHANGING RELATION; EUROPEAN-UNION; RISK-FACTORS AB Background The Global Burden of Disease Study 2013 (GBD 2013) aims to bring together all available epidemiological data using a coherent measurement framework, standardised estimation methods, and transparent data sources to enable comparisons of health loss over time and across causes, age-sex groups, and countries. The GBD can be used to generate summary measures such as disability-adjusted life-years (DALYs) and healthy life expectancy (HALE) that make possible comparative assessments of broad epidemiological patterns across countries and time. These summary measures can also be used to quantify the component of variation in epidemiology that is related to sociodemographic development. Methods We used the published GBD 2013 data for age-specific mortality, years of life lost due to premature mortality (YLLs), and years lived with disability (YLDs) to calculate DALYs and HALE for 1990, 1995, 2000, 2005, 2010, and 2013 for 188 countries. We calculated HALE using the Sullivan method; 95% uncertainty intervals (UIs) represent uncertainty in age-specific death rates and YLDs per person for each country, age, sex, and year. We estimated DALYs for 306 causes for each country as the sum of YLLs and YLDs; 95% UIs represent uncertainty in YLL and YLD rates. We quantified patterns of the epidemiological transition with a composite indicator of sociodemographic status, which we constructed from income per person, average years of schooling after age 15 years, and the total fertility rate and mean age of the population. We applied hierarchical regression to DALY rates by cause across countries to decompose variance related to the sociodemographic status variable, country, and time. Findings Worldwide, from 1990 to 2013, life expectancy at birth rose by 6.2 years (95% UI 5.6-6.6), from 65.3 years (65.0-65.6) in 1990 to 71.5 years (71.0-71.9) in 2013, HALE at birth rose by 5.4 years (4.9-5.8), from 56.9 years (54.5-59.1) to 62.3 years (59.7-64.8), total DALYs fell by 3.6% (0.3-7.4), and age-standardised DALY rates per 100 000 people fell by 26.7% (24.6-29.1). For communicable, maternal, neonatal, and nutritional disorders, global DALY numbers, crude rates, and age-standardised rates have all declined between 1990 and 2013, whereas for non-communicable diseases, global DALYs have been increasing, DALY rates have remained nearly constant, and age-standardised DALY rates declined during the same period. From 2005 to 2013, the number of DALYs increased for most specific non-communicable diseases, including cardiovascular diseases and neoplasms, in addition to dengue, food-borne trematodes, and leishmaniasis; DALYs decreased for nearly all other causes. By 2013, the five leading causes of DALYs were ischaemic heart disease, lower respiratory infections, cerebrovascular disease, low back and neck pain, and road injuries. Sociodemographic status explained more than 50% of the variance between countries and over time for diarrhoea, lower respiratory infections, and other common infectious diseases; maternal disorders; neonatal disorders; nutritional deficiencies; other communicable, maternal, neonatal, and nutritional diseases; musculoskeletal disorders; and other non-communicable diseases. However, sociodemographic status explained less than 10% of the variance in DALY rates for cardiovascular diseases; chronic respiratory diseases; cirrhosis; diabetes, urogenital, blood, and endocrine diseases; unintentional injuries; and self-harm and interpersonal violence. Predictably, increased sociodemographic status was associated with a shift in burden from YLLs to YLDs, driven by declines in YLLs and increases in YLDs from musculoskeletal disorders, neurological disorders, and mental and substance use disorders. In most country-specific estimates, the increase in life expectancy was greater than that in HALE. Leading causes of DALYs are highly variable across countries. Interpretation Global health is improving. Population growth and ageing have driven up numbers of DALYs, but crude rates have remained relatively constant, showing that progress in health does not mean fewer demands on health systems. The notion of an epidemiological transition-in which increasing sociodemographic status brings structured change in disease burden-is useful, but there is tremendous variation in burden of disease that is not associated with sociodemographic status. This further underscores the need for country-specific assessments of DALYs and HALE to appropriately inform health policy decisions and attendant actions. C1 [Murray, Christopher J. 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[Del Pozo-Cruz, Borja] Univ Auckland, Auckland 1, New Zealand. [Barregard, Lars] Univ Gothenburg, Dept Occupat & Environm Hlth, Gothenburg, Sweden. [Barrero, Lope H.] Pontificia Univ Javeriana, Dept Ind Engn, Bogota, Colombia. [Basu, Arindam] Univ Canterbury, Sch Hlth Sci, Christchurch 1, New Zealand. [Gaffikin, Lynne] Stanford Univ, Sch Med, Stanford, CA USA. [Basu, Sanjay] Stanford Univ, Stanford, CA 94305 USA. [Beardsley, Justin] Univ Oxford, Ho Chi Minh City, Vietnam. [Bedi, Neeraj] Coll Publ Hlth & Trop Med, Jazan, Saudi Arabia. [Beghi, Ettore; Cortinovis, Monica; Giussani, Giorgia] IRCCS Ist Ric Farmacol Mario Negri, Milan, Italy. [Bekele, Tolesa] Madawalabu Univ, Bale Goba, Ethiopia. [Bell, Michelle L.; Huang, John J.] Yale Univ, New Haven, CT USA. [Benjet, Corina; Gutierrez, Reyna A.] Natl Inst Psychiat Ramon Fuente Muniz, Mexico City, DF, Mexico. [Bensenor, Isabela M.; Kemp, Andrew H.; Lotufo, Paulo A.; Santos, Itamar S.] Univ Sao Paulo, Sao Paulo, Brazil. [Benzian, Habib] NYU, Coll Dent, Dept Epidemiol & Hlth Promot, New York, NY USA. [Thurston, George D.] NYU, Sch Med, Nelson Inst Environm Med, New York, NY USA. [Hagan, Holly] NYU, New York, NY USA. [Bernabe, Eduardo; Hay, Roderick J.; Wolfe, Charles D.] Kings Coll London, London, England. [Deribe, Kebede] Univ Addis Ababa, Sch Publ Hlth, Addis Ababa, Ethiopia. [Beyene, Tariku J.; Mekonnen, Wubegzier] Univ Addis Ababa, Addis Ababa, Ethiopia. [Bhala, Neeraj] Queen Elizabeth Hosp, Birmingham B15 2TH, W Midlands, England. [Bhala, Neeraj] Univ Otago, Sch Med, Dunedin, New Zealand. [Bhalla, Ashish; Jha, Vivekanand] Postgrad Inst Med Educ & Res, Chandigarh 160012, India. [Bhutta, Zulfiqar A.] Aga Khan Univ, Med Ctr, Karachi, Pakistan. [Nisar, Muhammad I.] Aga Khan Univ, Karachi, Pakistan. [Bikbov, Boris] AI Evdokimov Moscow State Univ Med & Dent, Moscow, Russia. [Bikbov, Boris] Acad VI Shumakov Fed Res Ctr Transplantol & Artif, Moscow, Russia. [Driscoll, Tim R.] Univ Sydney, Sydney Sch Publ Hlth, Sydney, NSW 2006, Australia. [Blyth, Fiona M.; Kemp, Andrew H.; Leigh, James] Univ Sydney, Sydney, NSW 2006, Australia. [Basara, Berrak Bora; Yentur, Goekalp K.] Minist Hlth, Gen Directorate Hlth Res, Ankara, Turkey. [Uzun, Selen B.] Minist Hlth, Ankara, Turkey. [Bornstein, Natan M.] Tel Aviv Saurasky Med Ctr, Tel Aviv, Israel. [Bose, Dipan] World Bank, Washington, DC 20433 USA. [Boufous, Soufiane] Univ New S Wales, Transport & Rd Safety TARS Res, Kensington, NSW 2033, Australia. [Resnikoff, Serge] Univ New S Wales, BHVI, Kensington, NSW 2033, Australia. [Degenhardt, Louisa; Mitchell, Philip B.] Univ New S Wales, Kensington, NSW 2033, Australia. [Bourne, Rupert R. A.] Anglia Ruskin Univ, Cambridge, England. [Boyers, Lindsay N.] Georgetown Univ, Washington, DC USA. [Brainin, Michael] Danube Univ Krems, Krems, Austria. [Brayne, Carol E.] Cambridge Inst Publ Hlth, Cambridge, England. [Brazinova, Alexandra] Trnava Univ, Fac Hlth Sci & Social Work, Trnava, Slovakia. [Majdan, Marek] Trnava Univ, Dept Publ Hlth, Trnava, Slovakia. [Breitborde, Nicholas J. K.] Ohio State Univ, Columbus, OH 43210 USA. [Breitborde, Nicholas J. K.] Univ Arizona, Tucson, AZ USA. [Schoettker, Ben] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Brenner, Hermann] 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. [Buchbinder, Rachelle] Monash Univ, Sch Publ Hlth & Prevent Med, Dept Epidemiol & Prevent Med, Melbourne, Vic 3004, Australia. [Lloyd, Belinda K.] Monash Univ, Eastern Hlth Clin Sch, Melbourne, Vic 3004, Australia. [Gabbe, Belinda; Gibney, Katherine B.; Thrift, Amanda G.] Monash Univ, Melbourne, Vic 3004, Australia. [Buckle, Geoffrey C.; Gosselin, Richard A.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Budke, Christine M.] Texas A&M Univ, College Stn, TX USA. [Bulloch, Andrew G.; Patten, Scott B.; Tonelli, Marcello; Wang, Jianli] Univ Calgary, Calgary, AB, Canada. [Carabin, Helene] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. [Carapetis, Jonathan R.] Telethon Inst Child Hlth Res, Subiaco, WA, Australia. [Cardenas, Rosario] Univ Autonoma Metropolitana, Mexico City, DF, Mexico. [Carpenter, David O.] SUNY Albany, Albany, NY 12222 USA. [Caso, Valeria] Univ Perugia, I-06100 Perugia, Italy. [Castaneda-Orjuela, Carlos A.] Colombian Natl Hlth Observ, Bogota, Colombia. [Castaneda-Orjuela, Carlos A.] Univ Nacl Colombia, Dept Publ Hlth, Epidemiol & Publ Hlth Evaluat Grp, Bogota, Colombia. [Castro, Ruben E.] Univ Diego Portales, Santiago, Chile. [Catala-Lopez, Ferran] Spanish Med & Healthcare Prod Agcy AEMPS, Minist Hlth, Div Pharmacoepidemiol & Pharmacovigilance, Madrid, Spain. [Catala-Lopez, Ferran] Univ Valencia, Dept Med, CIBERSAM, Valencia, Spain. [Chadha, Vineet K.] Natl TB Inst, Bengaluru, India. [Chang, Jung-Chen] Natl Taiwan Univ, Coll Med, Taipei, Taiwan. [Hoy, Damian G.] Univ Queensland, Sch Populat Hlth, Brisbane, Qld, Australia. [Knibbs, Luke D.] Univ Queensland, Sch Publ Hlth, Brisbane, Qld, Australia. [Scott, James G.] Univ Queensland, Clin Res Ctr, Brisbane, Qld, Australia. [Charlson, Fiona J.; Erskine, Holly E.; Ferrari, Alize J.; Gouda, Hebe N.; Mcgrath, John J.; Whiteford, Harvey A.] Univ Queensland, Brisbane, Qld, Australia. [Chen, Honglei] NIEHS, Div Intramural Res, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Jiang, Ying] Univ Occupat & Environm Hlth, Dept Hlth Dev, Kitakyushu, Fukuoka 807, Japan. [Jiang, Ying; Takahashi, Ken] Univ Occupat & Environm Hlth, Inst Ind Ecol Sci, Kitakyushu, Fukuoka 807, Japan. [Chimed-Ochir, Odgerel; Jiang, Ying; Takahashi, Ken] Univ Occupat & Environm Hlth, Dept Environm Epidemiol, Kitakyushu, Fukuoka 807, Japan. [Chowdhury, Rajiv; Murray, Joseph] Univ Cambridge, Cambridge, England. [Christensen, Hanne] Bispebjerg Hosp, Copenhagen, Denmark. [Christophi, Costas A.] Cyprus Univ Technol, Limassol, Cyprus. [Cirillo, Massimo] Univ Salerno, I-84081 Baronissi, Italy. [Colistro, Valentina] Univ Republica, Montevideo, Uruguay. [Colistro, Valentina] Minist Salud Publ, Montevideo, Uruguay. [Colquhoun, Samantha M.] Murdoch Childrens Res Inst, Melbourne, Vic, Australia. [Cooper, Cyrus] Univ Southampton, MRC Lifecourse Epidemiol Unit, Southampton, Hants, England. [Criqui, Michael H.; Jassal, Simerjot K.; Stein, Murray B.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Cooper, Leslie T.] Mayo Clin, Rochester, MN USA. [Coppola, Luis M.] Hosp Municipal Ramon Santamarina, Tandil, Argentina. [Crump, John A.] Univ Otago, Dunedin Sch Med, Ctr Int Hlth, Dunedin, New Zealand. [Derrett, Sarah] Univ Otago, Dunedin Sch Med, Dept Prevent & Social Med, Dunedin, New Zealand. [Poulton, Richie G.] Univ Otago, Dunedin, New Zealand. [Derrett, Sarah] Massey Univ, Coll Hlth, Sch Publ Hlth, Palmerston North, New Zealand. [Danawi, Hadi] Walden Univ, Minneapolis, MN USA. [Dandona, Lalit; Dandona, Rakhi; Kumar, G. Anil; Murthy, Kinnari S.; Reddy, K. Srinath] Publ Hlth Fdn India, New Delhi, India. [Dargan, Paul I.] Guys & St Thomas NHS Fdn Trust, London, England. [Davey, Gail] Wellcome Trust Brighton, Brighton, E Sussex, England. [Davey, Gail] Sussex Ctr Global Hlth Res, Brighton, E Sussex, England. [Davis, Adrian; Fay, Derek F.] Publ Hlth England, London, England. [Davitoiu, Dragos V.] Univ Med & Pharm Bucharest, Bucharest, Romania. [Dayama, Anand] Jacobi Med Ctr, Dept Surg, Atlanta, GA USA. [Lalloo, Ratilal] Griffith Univ, Sch Dent & Oral Hlth, Brisbane, Qld 4111, Australia. [De Leo, Diego] Griffith Univ, Brisbane, Qld 4111, Australia. [Dellavalle, Robert P.] Eastern Colorado Healthcare Syst, US Dept Vet Affairs, Denver, CO USA. [Deribe, Kebede] Brighton & Sussex Med Sch, Brighton, E Sussex, England. [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. [Dessalegn, Muluken] Africa Med & Res Fdn Ethiopia, Addis Ababa, Ethiopia. [Dharmaratne, Samath D.] Univ Peradeniya, Peradeniya, Sri Lanka. [Lunevicius, Raimundas] Univ Liverpool, Sch Med, Liverpool L69 3BX, Merseyside, England. [Dherani, Mukesh K.; Pope, Daniel] Univ Liverpool, Liverpool L69 3BX, Merseyside, England. [Diaz-Torne, Cesar] Hosp Santa Creu & Sant Pau, Barcelona, Spain. [Dokova, Klara] Med Univ Varna, Fac Publ Hlth, Dept Social Med, Varna, Bulgaria. [Dorsey, E. Ray] Univ Rochester, Med Ctr, Rochester, NY 14642 USA. [Edmond, Karen M.; Hankey, Graeme J.] Univ Western Australia, Perth, WA 6009, Australia. [Elshrek, Yousef M.] Univ Tripoli, Fac Agr, Dept Food Sci, Tripoli, Libya. [Ermakov, Sergey P.] Russian Acad Sci, Inst Social & Econ Studies Populat, Moscow, Russia. [Ermakov, Sergey P.] Minist Hlth Russian Federat, Fed Res Inst Hlth Org & Informat, Moscow, Russia. [Eshrati, Babak] Arak Univ Med Sci & Hlth Affairs, Arak, Iran. [Esteghamati, Alireza; Farzadfar, Farshad; Hafezi-Nejad, Nima; Sheikhbahaei, Sara] Univ Tehran Med Sci, Communicable Dis Res Ctr, Endocrinol & Metab Res Inst, Tehran, Iran. [Heydarpour, Pouria; Sahraian, Mohammad Ali] Univ Tehran Med Sci, Multiple Sclerosis Res Ctr, Neurosci Inst, Tehran, Iran. [Sepanlou, Sadaf G.] Univ Tehran Med Sci, Digest Dis Res Inst, Tehran, Iran. [Faraon, Emerito Jose A.] UP Coll Publ Hlth, DHPA, Manila, Philippines. [Feigin, Valery L.] Auckland Univ Technol, Natl Inst Stroke & Appl Neurosci, Auckland, New Zealand. [Te Ao, Braden J.] Auckland Univ Technol, Auckland, New Zealand. [Felson, David T.] Boston Univ, Boston, MA 02215 USA. [Fernandes, Jefferson G.] German Hosp Oswaldo Cruz, Inst Educ & Sci, Sao Paulo, Brazil. [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 4811, Australia. [Gankpe, Fortune G.] Leras Afrique, Cotonou, Benin. [Gankpe, Fortune G.] CHU Hassan II, Fes, Morocco. [Geleijnse, Johanna M.] Wageningen Univ, Div Human Nutr, NL-6700 AP Wageningen, Netherlands. [Gessner, Bradford D.] Agence Med Prevent, Paris, France. [Giroud, Maurice] Univ Hosp Dijon, Dijon, France. [Gona, Philimon] Univ Massachusetts, Boston, MA 02125 USA. [Pourmalek, Farshad] Univ British Columbia, Sch Populat & Publ Hlth, Vancouver, BC V5Z 1M9, Canada. [Gotay, Carolyn C.] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Goto, Atsushi] Tokyo Womens Med Univ, Dept Publ Hlth, Tokyo, Japan. [Gugnani, Harish C.] St James Sch Med, Kralendijk, Netherlands. [Gupta, Rahul] West Virginia Bur Publ Hlth, Charleston, WV USA. [Gupta, Rajeev] Fortis Escorts Hosp, Jaipur, Rajasthan, India. [Halasa, Yara A.; Undurraga, Eduardo A.] Brandeis Univ, Waltham, MA USA. [Hamadeh, Randah R.] Arabian Gulf Univ, Manama, Bahrain. [Hammami, Mouhanad] Wayne Cty Dept Hlth & Human Serv, Detroit, MI USA. [Hao, Yuantao] Sun Yae Sen Univ, Sch Publ Hlth, Guangzhou, Guangdong, Peoples R China. [Zheng, Yingfeng] Sun Yae Sen Univ, Zhongshan Ophthalm Ctr, Guangzhou, Guangdong, Peoples R China. [Maria Haro, Josep] Parc Sanitari St Joan Deu CIBERSAM, Barcelona, Spain. [Maria Haro, Josep] Univ Barcelona, Barcelona, Spain. [Hay, Roderick J.] Int Fdn Dermatol, London, England. [Hijar, Martha] Fdn Entornos AC, Cuernavaca, Morelos, Mexico. [Hoek, Hans W.] Columbia Univ, Dept Epidemiol, New York, NY USA. [Moran, Andrew E.] Columbia Univ, New York, NY USA. [Hoffman, Howard J.] Natl Inst Deafness & Other Commun Disorders, Epidemiol & Stat Program, NIH, Bethesda, MD USA. [Mensah, George A.] NHLBI, Ctr Translat Res & Implementat Sci, NIH, Bethesda, MD 20892 USA. [Sampson, Uchechukwu K. A.] NHLBI, NIH, Bethesda, MD 20892 USA. [Hosgood, H. Dean] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Hossain, Mazeda; Mckee, Martin; Pearce, Neil; Pullan, Rachel L.; Tillmann, Taavi] Univ London London Sch Hyg & Trop Med, London WC1E 7HT, England. [Hotez, Peter J.] Baylor Coll Med, Houston, TX 77030 USA. [Hoy, Damian G.] Secretariat Pacific Community, Publ Hlth Div, Noumea, New Caledonia. [Hsairi, Mohamed] Natl Inst Publ Hlth, Tunis, Tunisia. [Hu, Guoqing] Cent S Univ, Sch Publ Hlth, Changsha, Hunan, Peoples R China. [Huang, Cheng] George Washington Univ, Washington, DC USA. [Husseini, Abdullatif] Qatar Univ, Doha, Qatar. [Iburg, Kim M.] Aarhus Univ, Aarhus, Denmark. [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. [Islami, Farhad] Amer Canc Soc, New York, NY USA. [Jacobsen, Kathryn H.] George Mason Univ, Fairfax, VA 22030 USA. [Jee, Sun Ha] Yonsei Univ, Grad Sch Publ Hlth, Seoul 120749, South Korea. [Jeemon, Panniyammakal; Prabhakaran, Dorairaj] Ctr Chron Dis Control, New Delhi, India. [Jiang, Guohong] Tianjin Ctr Dis Control & Prevent, Tianjin, Peoples R China. [Jonas, Jost B.] Heidelberg Univ, Med Fac Mannheim, Dept Ophthalmol, Mannheim, Germany. [Juel, Knud] Natl Inst Publ Hlth, Copenhagen, Denmark. [She, Jun] Fudan Univ, Zhongshan Hosp, Shanghai 200433, Peoples R China. [Kan, Haidong] Fudan Univ, Shanghai 200433, Peoples R China. [Karch, Andre] Helmholtz Ctr Infect Res, Dept Epidemiol, Braunschweig, Germany. [Karch, Andre] German Ctr Infect Res DZIF, Hannover Braunschweig Site, Braunschweig, Germany. [Karema, Corine K.] Minist Hlth, Malaria & Other Parasit Dis Div, Kigali City, Rwanda. [Karimkhani, Chante] Case Western Univ Hosp, Cleveland, OH USA. [Karthikeyan, Ganesan; Paul, Vinod K.; Satpathy, Maheswar; Tandon, Nikhil] All India Inst Med Sci, New Delhi, India. [Kaul, Anil] Oklahoma State Univ, Tulsa, OK USA. [Kazanjan, Konstantin] Natl Ctr Dis Control & Publ Hlth, Tbilisi, Rep of Georgia. [Kengne, Andre P.; Matzopoulos, Richard; Msemburi, William T.; Stein, Dan J.] South African Med Res Council, Cape Town, South Africa. [Sliwa, Karen] Univ Cape Town, Fac Hlth Sci, Hatter Inst Cardiovasc Res Africa, ZA-7925 Cape Town, South Africa. [Matzopoulos, Richard] Univ Cape Town, Sch Publ Hlth & Family Med, ZA-7925 Cape Town, South Africa. [Kengne, Andre P.; Mayosi, Bongani M.; Stein, Dan J.] Univ Cape Town, ZA-7925 Cape Town, South Africa. [Keren, Andre] Hadassah Kerem Univ Hosp, Cardiol, Jerusalem, Israel. [Khader, Yousef S.] Jordan Univ Sci & Technol, Irbid, Jordan. [Khalifa, Shams Eldin A.] Supreme Council Hlth, Doha, Qatar. [Khan, Ejaz A.] Hlth Serv Acad, Islamabad, Pakistan. [Khan, Ejaz A.] Expanded Programme Immunizat, Islamabad, Pakistan. [Khan, Gulfaraz] UAE Univ, Al Ain, U Arab Emirates. [Khang, Young-Ho] Seoul Natl Univ, Coll Med, Seoul, South Korea. [Kieling, Christian] Univ Fed Rio Grande do Sul, Porto Alegre, RS, Brazil. [Kim, Daniel] Northeastern Univ, Boston, MA 02115 USA. [Kim, Sungroul] Soonchunhyang Univ, Seoul, South Korea. [Kim, Yunjin] Southern Univ Coll, Johor Baharu, Malaysia. [Kinfu, Yohannes] Univ Canberra, Canberra, ACT 2601, Australia. [Knudsen, Ann Kristin] Norwegian Inst Publ Hlth, Dept Hlth Registries, Oslo, Norway. [Kinge, Jonas M.; Skirbekk, Vegard; Vollset, Stein Emil] Norwegian Inst Publ Hlth, Oslo, Norway. [Kokubo, Yoshihiro] Natl Cerebral & Cardiovasc Ctr, Suita, Osaka, Japan. [Kosen, Soewarta] NIHRD, Ctr Community Empowerment Hlth Policy & Humanitie, Jakarta, Indonesia. [Krishnaswami, Sanjay; Zonies, David] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Defo, Barthelemy Kuate] Univ Montreal, Montreal, PQ, Canada. [Kuipers, Ernst J.; Polinder, Suzanne; Richardus, Jan Hendrik] Univ Med Ctr Rotterdam, Erasmus MC, Rotterdam, Netherlands. [Kulkarni, Chanda] Rajrajeswari Med Coll & Hosp, Bangalore, Karnataka, India. [Kulkarni, Veena S.] Arkansas State Univ, Jonesboro, AR USA. [Lai, Taavi] Fourth View Consulting, Tallinn, Estonia. [Lalloo, Ratilal] Univ Adelaide, Sch Dent, Australian Res Ctr Populat Oral Hlth, Adelaide, SA, Australia. [Lallukka, Tea] Finnish Inst Occupat Hlth, Disabil Prevent Res Ctr, Helsinki, Finland. [Shiri, Rahman] Finnish Inst Occupat Hlth, Helsinki, Finland. [Lallukka, Tea] Univ Helsinki, Fac Med, Helsinki, Finland. [Lam, Hilton] Natl Inst Hlth, Inst Hlth Policy & Dev Studies, Manila, Philippines. [Lan, Qing] NCI, Rockville, MD USA. [Lansingh, Van C.] Help Me See Inc, New York, NY USA. [Lansingh, Van C.] Inst Mexicano Oftalmol, Queretaro, Mexico. [Larsson, Anders] Uppsala Univ, Uppsala, Sweden. [Lawrynowicz, Alicia E. B.] Inst Nacl Epidemiol Dr Juan H Jara, Mar Del Plata, Buenos Aires, Argentina. [Leasher, Janet L.] Nova SE Univ, Coll Optometry, Ft Lauderdale, FL 33314 USA. [Leung, Ricky] SUNY Albany, Rensselaer, NY USA. [Li, Bin] Jinan Cent Hosp, Jinan, Peoples R China. [Duan, Leilei; Li, Yichong; Liu, Shiwei; Wang, Linhong; Ye, Pengpeng] China CDC, Natl Ctr Chron & Noncommunible Dis Control Preven, Beijing, Peoples R China. [Li, Yichong] Anolinx LLC, Salt Lake City, UT USA. [Lipshultz, Steven E.] Wayne State Univ, Miami, FL USA. [Simard, Edgar P.] Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Liu, Yang; Narayan, K. M. Venkat] Emory Univ, Atlanta, GA 30322 USA. [Lloyd, Belinda K.] Eastern Hlth, Turning Point, Melbourne, Vic, Australia. [Logroscino, Giancarlo] Univ Bari, Bari, Italy. [Looker, Katharine J.] Univ Bristol, Bristol, Avon, England. [Lortet-Tieulent, Joannie] Amer Canc Soc, Atlanta, GA 30329 USA. [Lucas, Robyn M.] Australian Natl Univ, Canberra, ACT, Australia. [Lunevicius, Raimundas] Aintree Univ Hosp NHS Fdn Trust, Liverpool, Merseyside, England. [Lyons, Ronan A.] Swansea Univ, Swansea, W Glam, Wales. [Ma, Stefan] Minist Hlth Singapore, Singapore, Singapore. [Ma, Stefan] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore. [Weintraub, Robert G.] Royal Childrens Hosp, Murdoch Childrens Res Inst, Melbourne, Vic, Australia. [Mackay, Mark T.] Royal Childrens Hosp, Melbourne, Vic, Australia. [Malekzadeh, Reza] Shariati Hosp, Digest Dis Reseach Inst, Tehran, Iran. [Malekzadeh, Reza] Shiraz Univ Med Scinces, Shiraz, Iran. [Marcenes, Wagner] Queen Mary Univ London, London, England. [Meaney, Peter A.] Univ Penn, Pereleman Sch Med, Philadelphia, PA 19104 USA. [Margolis, David J.; Silberberg, Donald H.] Univ Penn, Philadelphia, PA 19104 USA. [Marzan, Melvin B.] Univ East Ramon Magsaysay Mem, Med Ctr, Quezon City, Philippines. [Masci, Joseph R.] Elmhurst Hosp Ctr, Mt Sinai Serv, Elmhurst, NY USA. [Mashal, Mohammad T.] Minist Publ Hlth, Kabul, Afghanistan. [Mazorodze, Tasara T.] AIDC EC, Port Elizabeth, South Africa. [Mcgill, Neil W.] Royal Prince Alfred Hosp, Camperdown, NSW 2050, Australia. [Meaney, Peter A.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Mehndiratta, Man Mohan] Janakpuri Superspecialty Hosp, New Delhi, India. [Melaku, Yohannes A.] Mekelle Univ, Mekelle, Ethiopia. [Meltzer, Michele] Thomas Jefferson Univ, Philadelphia, PA 19107 USA. [Memish, Ziad A.] Saudi Minist Hlth, Riyadh, Saudi Arabia. [Meretoja, Atte] Univ Helsinki, Cent Hosp, Dept Neurol, Helsinki, Finland. [Mhimbira, Francis A.] 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 6845, Australia. [Mills, Edward J.] Univ Ottawa, Ottawa, ON, Canada. [Ibrahim, Norlinah Mohamed] Univ Kebangsaan Malaysia, Med Ctr, Dept Med, Bandar Tun Razak, Malaysia. [Mohammad, Karzan A.] Univ Salahaddin, Erbil, Iraq. [Mola, Glen L. D.] Univ Papua New Guinea, Boroko, Papua N Guinea. [Monasta, Lorenzo; Montico, Marcella; Ronfani, Luca] IRCCS Burlo Garofolo, Inst Maternal & Child Hlth, Trieste, Italy. [Moore, Ami R.] Univ N Texas, Denton, TX 76203 USA. [Moradi-Lakeh, Maziar] Iran Univ Med Sci, Dept Community Med, Tehran, Iran. [Mori, Rintaro] Natl Ctr Child Hlth & Dev, Setagaya Ku, Tokyo, Japan. [Tsilimbaris, Miltiadis] Univ Crete, Dept Med, Iraklion, Greece. [Moschandreas, Joanna] Univ Crete, Iraklion, Greece. [Moturi, Wilkister N.] Egerton Univ, Egerton, Kenya. [Mueller, Ulrich O.] Univ Marburg, Marburg, Germany. [Mukaigawara, Mitsuru] Okinawa Chubu Hosp, Okinawa, Japan. [Murdoch, Michele E.] West Herts Hosp NHS Trust, Watford, England. [Naidoo, Kovin S.] Univ KwaZulu Natal, Durban, South Africa. [Naldi, Luigi] Azienda Osped Papa Giovanni XXIII, Bergamo, Italy. [Nand, Devina] Minist Hlth, Suva, Fiji. [Nangia, Vinay] Suraj Eye Inst, Nagpur, Maharashtra, India. [Nejjari, Chakib] Fac Med, Fes, Morocco. [Neupane, Sudan P.] Univ Oslo, Oslo, Norway. [Ngalesoni, Frida N.] Minist Hlth & Social Welf, Dar Es Salaam, Tanzania. [Nolte, Sandra; Papachristou, Christina] Charite, D-13353 Berlin, Germany. [Nolte, Sandra] Deakin Univ, Melbourne, Vic, Australia. [Vollset, Stein Emil] Univ Bergen, Dept Global Publ Hlth & Primary Care, Bergen, Norway. [Norheim, Ole F.] Univ Bergen, Bergen, Norway. [Norman, Rosana E.] Queensland Univ Technol, Inst Hlth & Biomed Innovat, Brisbane, Qld 4001, Australia. [Norrving, Bo] Lund Univ, Dept Clin Sci, Lund, Sweden. [Nyakarahuka, Luke] Makerere Univ, Kampala, Uganda. [Oh, In-Hwan] Kyung Hee Univ, Seoul, South Korea. [Ohkubo, Takayoshi] Teikyo Univ, Sch Med, Tokyo 173, Japan. [Olusanya, Bolajoko O.] Ctr Hlth Start Initiat, Ikoyi, Nigeria. [Opio, John Nelson] Lira Municipal Council, Lira Dist Local Govt, Lira, Uganda. 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RI Adsuar, Jose C/C-6558-2008; Pereira, David/M-9286-2013; Ribeiro, Antonio/C-2707-2009; Haro, Josep Maria/D-1423-2011; Degenhardt, Louisa/D-4515-2012; Hankey, Graeme /H-4968-2014; Kaul, Anil/B-2075-2016; Carabin, Helene/B-7600-2016; Whiteford, Harvey/A-4840-2009; Charlson, Fiona/F-5290-2011; Patten, Scott/B-4434-2011; Monasta, Lorenzo/B-1388-2012; Rahimi, Kazem/Q-1279-2015; Undurraga, Eduardo/I-3739-2014; Balakrishnan, Kalpana/B-6653-2015; Higashi, Hideki/D-3797-2011; Davis, Adrian/E-6022-2015; Santos, Itamar/K-7055-2012; Patton, George/B-5246-2013; Scott, James/D-5900-2012; Brenner, Hermann/B-4627-2017; Majdan, Marek/K-5017-2012; Alsharif, Ubai/C-6527-2017; Amini, Heresh/B-3076-2010; Lotufo, Paulo/A-9843-2008; Karch, Andre/D-6973-2017; Franklin, Richard/H-1731-2012; Giussani, Giorgia/E-8057-2017; Ermakov, Sergey/G-1709-2016; Sepanlou, Sadaf/H-9343-2016; Bolliger, Ian/C-4207-2016; LOGROSCINO, GIANCARLO/K-5148-2016; Naldi, Luigi/K-6343-2016; Thrift, Amanda/I-6251-2012; Weiderpass, Elisabete/M-4029-2016; Dokova, Klara/N-2448-2016; Jacobsen, Kathryn/B-5857-2008; Nolte, Sandra/B-7498-2008; Tonelli, Marcello/B-3028-2009; Lalloo, Ratilal/O-5624-2014; Tillmann, Taavi/R-6026-2016; Salomon, Joshua/D-3898-2009 OI Adsuar, Jose C/0000-0001-7203-3168; Pereira, David/0000-0003-0384-7592; Ribeiro, Antonio/0000-0002-2740-0042; Haro, Josep Maria/0000-0002-3984-277X; Degenhardt, Louisa/0000-0002-8513-2218; Hankey, Graeme /0000-0002-6044-7328; Whiteford, Harvey/0000-0003-4667-6623; Charlson, Fiona/0000-0003-2876-5040; Patten, Scott/0000-0001-9871-4041; Monasta, Lorenzo/0000-0001-7774-548X; Rahimi, Kazem/0000-0002-4807-4610; Catala-Lopez, Ferran/0000-0002-3833-9312; Bernabe, Eduardo/0000-0002-1858-3713; Piel, Frederic B./0000-0001-8131-7728; Norheim, Ole F./0000-0002-5748-5956; Hoek, Hans/0000-0001-6353-5465; Moradi-Lakeh, Maziar/0000-0001-7381-5305; NORMAN, ROSANA/0000-0002-9742-1957; Castaneda-Orjuela, Carlos/0000-0002-8735-6223; Erskine, Holly/0000-0003-3119-9211; Aboyans, Victor/0000-0002-0322-9818; Gouda, Hebe/0000-0002-5709-4509; Chen, Honglei/0000-0003-3446-7779; Perez-Ruiz, Fernando/0000-0002-5268-1894; Sindi, Shireen/0000-0002-3786-0552; Gething, Peter/0000-0001-6759-5449; Husseini, Abdullatif/0000-0001-8767-5956; Benjet, Corina/0000-0002-4569-6094; Gabbe, Belinda/0000-0001-7096-7688; Prabhakaran, Dorairaj/0000-0002-3172-834X; Neupane, Sudan Prasad/0000-0002-7389-4178; Deribe, Kebede/0000-0002-8526-6996; Taylor, Hugh/0000-0002-9437-784X; Khang, Young-Ho/0000-0002-9585-8266; Ortiz Arduan, Alberto/0000-0002-9805-9523; Kemp, Andrew/0000-0003-1146-3791; Mitchell, Philip/0000-0002-7954-5235; Vlassov, Vasiliy/0000-0001-5203-549X; Soreide, Kjetil/0000-0001-7594-4354; Tediosi, Fabrizio/0000-0001-8671-9400; Miller, Ted/0000-0002-0958-2639; Giussani, Giorgia/0000-0003-2460-3095; Leung, Ricky/0000-0002-2852-6771; Kieling, Christian/0000-0001-7691-4149; Sreeramareddy, Chandrashekhar/0000-0002-5693-7631; Xu, Gelin/0000-0002-6194-0341; Goto, Atsushi/0000-0003-0669-654X; Soshnikov, Sergey/0000-0002-6983-7066; assadi, reza/0000-0002-5016-2994; Heydarpour, Pouria/0000-0001-5644-7555; Stein, Dan/0000-0001-7218-7810; Undurraga, Eduardo/0000-0002-4425-1253; Balakrishnan, Kalpana/0000-0002-5905-1801; Montico, Marcella/0000-0003-0377-8232; Vlassov, Valentin/0000-0003-2845-2992; Mhimbira, Francis/0000-0001-8989-6832; Olusanya, Bolajoko/0000-0002-3826-0583; Higashi, Hideki/0000-0002-5534-0905; Heredia-Pi, Ileana Beatriz/0000-0002-9998-9239; Hay, Simon/0000-0002-0611-7272; Gibney, Katherine/0000-0001-5851-5339; Leasher, Janet/0000-0002-8779-5162; Davis, Adrian/0000-0001-7134-7528; Banerjee, Amitava/0000-0001-8741-3411; Hotez, Peter/0000-0001-8770-1042; Santos, Itamar/0000-0003-3212-8466; Patton, George/0000-0001-5039-8326; Scott, James/0000-0002-0744-0688; Brenner, Hermann/0000-0002-6129-1572; Majdan, Marek/0000-0001-8037-742X; Alsharif, Ubai/0000-0002-4024-3950; Amini, Heresh/0000-0002-4825-1322; Lotufo, Paulo/0000-0002-4856-8450; Karch, Andre/0000-0003-3014-8543; Franklin, Richard/0000-0003-1864-4552; Ermakov, Sergey/0000-0003-1072-1162; Sepanlou, Sadaf/0000-0002-3669-5129; Bolliger, Ian/0000-0001-8055-297X; LOGROSCINO, GIANCARLO/0000-0003-0423-3242; Naldi, Luigi/0000-0002-3160-2835; Thrift, Amanda/0000-0001-8533-4170; Weiderpass, Elisabete/0000-0003-2237-0128; Jacobsen, Kathryn/0000-0002-4198-6246; Nolte, Sandra/0000-0001-6185-9423; Lalloo, Ratilal/0000-0001-5822-1269; Tillmann, Taavi/0000-0002-8428-3719; Salomon, Joshua/0000-0003-3929-5515 FU Bill & Melinda Gates Foundation; Graduate School of Medical Sciences, University Medical Center Groningen (UMCG); National Health and Medical Research Council; National Natural Sciences Foundation of China; German National Cohort Consortium; Brien Holden Vision Institute; National Health and Medical Research Council Public Health (Australian) Early Career Fellowship; Wellcome Trust Fellowship in Public Health and Tropical Medicine [099876]; National Natural Science Foundation for Young Scholars of China [81200051]; Research Fund for the Doctoral Program of Higher Education of China [20110071120060]; Science Foundation for Young Scholars in Zhongshan Hospital [2012ZSQN04]; Scientific Project for Fudan University [20520133474]; Australian National Health and Medical Research Council Senior Principal Research Fellow; Swiss National Science Foundation [PBBSP3-146869, P300P3-154634]; Korean Health Technology R&D Project (Ministry of Health & Welfare, Republic of Korea) [HI13C0729]; CGIAR Research Program on Aquatic Agricultural Systems FX Bill & Melinda Gates Foundation.; On behalf of the GBD 2010 Genitourinary Diseases Expert Group, GR, NoP, and BB would like to acknowledge that their activities within the GBD 2013 have been made on the behalf of the International Society of Nephrology (ISN). ATA received institutional support and grants from the Graduate School of Medical Sciences, University Medical Center Groningen (UMCG). JM has received support from the National Health and Medical Research Council. LLY is also supported by the National Natural Sciences Foundation of China. UOM would like to acknowledge his funding by the German National Cohort Consortium. RB was provided funding support by the Brien Holden Vision Institute. INA would like to acknowledge her funding support from the National Health and Medical Research Council Public Health (Australian) Early Career Fellowship. KD is supported by a Wellcome Trust Fellowship in Public Health and Tropical Medicine (grant number 099876). The funding sources had no role in the writing of the manuscript or the decision to submit it for publication. JS was supported by the National Natural Science Foundation for Young Scholars of China, (number 81200051); Research Fund for the Doctoral Program of Higher Education of China (number 20110071120060); Science Foundation for Young Scholars in Zhongshan Hospital (number 2012ZSQN04); and the Scientific Project for Fudan University (number 20520133474). RB is funded by an Australian National Health and Medical Research Council Senior Principal Research Fellow. TF is grateful to the Swiss National Science Foundation for an Early and an Advanced Postdoc Mobility fellowship (project numbers PBBSP3-146869 and P300P3-154634). SJY and IHO received funding for their work in a grant from the Korean Health Technology R&D Project (Ministry of Health & Welfare, Republic of Korea; grant number HI13C0729). ALT-L was supported by the CGIAR Research Program on Aquatic Agricultural Systems. NR 60 TC 213 Z9 229 U1 82 U2 255 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 NOV 28 PY 2015 VL 386 IS 10009 BP 2145 EP 2191 DI 10.1016/S0140-6736(15)61340-X PG 47 WC Medicine, General & Internal SC General & Internal Medicine GA CX8YW UT WOS:000365992600030 ER PT J AU Hoglinger, D Haberkant, P Aguilera-Romero, A Riezman, H Porter, FD Platt, FM Galione, A Schultz, C AF Hoeglinger, Doris Haberkant, Per Aguilera-Romero, Auxiliadora Riezman, Howard Porter, Forbes D. Platt, Frances M. Galione, Antony Schultz, Carsten TI Intracellular sphingosine releases calcium from lysosomes SO ELIFE LA English DT Article ID TRANSCRIPTION FACTOR EB; MUCOLIPIDOSIS TYPE-IV; PROTEIN-KINASE-C; NIEMANN-PICK C1; 2-PORE CHANNELS; ALKALINE CERAMIDASE; MOBILIZES CALCIUM; NAADP; CA2+; DISEASE AB To elucidate new functions of sphingosine(Sph), we demonstrate that the spontaneous elevation of intracellular Sph levels via caged Sph leads to a significant and transient calcium release from acidic stores that is independent of sphingosine 1-phosphate, extracellular and ER calcium levels. This photo-induced Sph-driven calcium release requires the two-pore channel 1(TPC1) residing on endosomes and lysosomes. Further, uncaging of Sph leads to the translocation of the autophagy-relevant transcription factor EB (TFEB) to the nucleus specifically after lysosomal calcium release. We confirm that Sph accumulates in late endosomes and lysosomes of cells derived from Niemann-Pick disease type C (NPC) patients and demonstrate a greatly reduced calcium release upon Sph uncaging. We conclude that sphingosine is a positive regulator of calcium release from acidic stores and that understanding the interplay between Sph homeostasis, calcium signaling and autophagy will be crucial in developing new therapies for lipid storage disorders such as NPC. C1 [Hoeglinger, Doris; Haberkant, Per; Schultz, Carsten] European Mol Biol Lab, Cell Biol & Biophys Unit, Heidelberg, Germany. [Aguilera-Romero, Auxiliadora; Riezman, Howard] Univ Geneva, Dept Biochem, CH-1211 Geneva, Switzerland. [Porter, Forbes D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Platt, Frances M.; Galione, Antony] Univ Oxford, Dept Pharmacol, S Parks Rd, Oxford OX1 3QT, England. RP Schultz, C (reprint author), European Mol Biol Lab, Cell Biol & Biophys Unit, Heidelberg, Germany. EM schultz@embl.de OI Hoeglinger, Doris/0000-0002-6862-0076; Riezman, Howard/0000-0003-4680-9422 FU Seventh Framework Programme [289278-Sphingonet]; National Center for Competence in Research; European Commission FX Seventh Framework Programme 289278-Sphingonet Doris Hoglinger Howard Riezman Frances M Platt Carsten Schultz; National Center for Competence in Research Chemical Biology Auxiliadora Aguilera-Romero Howard Riezman; European Commission EMBL Interdisciplinary Postdoc Programme Per Haberkant NR 77 TC 9 Z9 9 U1 2 U2 5 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD NOV 27 PY 2015 VL 4 AR e10616 DI 10.7554/eLife.10616 PG 20 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DJ0JY UT WOS:000373889600001 ER PT J AU Cox, NJ Hickling, J Jones, R Rimmelzwaan, GF Lambert, LC Boslego, J Rudenko, L Yeolekar, L Robertson, JS Hombach, J Ortiz, JR AF Cox, Nancy J. Hickling, Julian Jones, Rebecca Rimmelzwaan, Guus F. Lambert, Linda C. Boslego, John Rudenko, Larisa Yeolekar, Leena Robertson, James S. Hombach, Joachim Ortiz, Justin R. TI Report on the second WHO integrated meeting on development and clinical trials of influenza vaccines that induce broadly protective and long-lasting immune responses: Geneva, Switzerland, 5-7 May 2014 SO VACCINE LA English DT Article DE Influenza; Vaccine; Pandemic influenza vaccine; Universal influenza vaccine; H7N9 vaccine; Seasonal influenza vaccine ID DEPENDENT CELLULAR CYTOTOXICITY; A H7N9 VIRUS; PANDEMIC INFLUENZA; SEASONAL INFLUENZA; PRODUCTION CAPACITY; PROTEIN MICROARRAY; HEMAGGLUTININ; VACCINATION; HUMANS; INFECTION AB On 5-7 May 2014, the World Health Organization (WHO) convened the second integrated meeting on "influenza vaccines that induce broadly protective and long-lasting immune responses". Around 100 invited experts from academia, the vaccine industry, research and development funders, and regulatory and public health agencies attended the meeting. Areas covered included mechanisms of protection in natural influenza-virus infection and vaccine-induced immunity, new approaches to influenza-vaccine design and production, and novel routes of vaccine administration. A timely focus was on how this knowledge could be applied to both seasonal influenza and emerging viruses with pandemic potential such as influenza A (H7N9), currently circulating in China. Special attention was given to the development of possible universal influenza vaccines, given that the Global Vaccine Action Plan calls for at least one licensed universal influenza vaccine by 2020. This report highlights some of the topics discussed and provides an update on studies published since the report of the previous meeting. C1 [Cox, Nancy J.] Natl Ctr Infect Dis, Influenza Div, Atlanta, GA 30333 USA. [Hickling, Julian; Jones, Rebecca] Working Tandem Ltd, Cambridge CB1 7AB, England. [Rimmelzwaan, Guus F.] Erasmus MC, Dept Virol, NL-3015 CE Rotterdam, Netherlands. [Lambert, Linda C.] NIAID, Resp Dis Branch, Div Microbiol & Infect Dis, NIH,DHHS, Bethesda, MD 20892 USA. [Boslego, John] PATH, Washington, DC 20001 USA. [Rudenko, Larisa] Russian Acad Med Sci, Inst Expt Med, St Petersburg 197376, Russia. [Yeolekar, Leena] Serum Inst India, Vaccine Prod, Pune, Maharashtra, India. [Hombach, Joachim; Ortiz, Justin R.] WHO, IVB, IVR, Geneva, Switzerland. RP Cox, NJ (reprint author), Natl Ctr Infect Dis, Influenza Div, 1600 Clifton Rd NE, Atlanta, GA 30333 USA. RI Rudenko, Larisa/B-5169-2015 OI Rudenko, Larisa/0000-0002-0107-9959 FU World Health Organization [001] NR 66 TC 2 Z9 2 U1 2 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD NOV 27 PY 2015 VL 33 IS 48 BP 6503 EP 6510 DI 10.1016/j.vaccine.2015.10.014 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA CZ0JN UT WOS:000366791200001 PM 26478203 ER PT J AU Hoffman, SL Vekemans, J Richie, TL Duffy, PE AF Hoffman, Stephen L. Vekemans, Johan Richie, Thomas L. Duffy, Patrick E. TI The march toward malaria vaccines SO VACCINE LA English DT Review DE Malaria; Vaccine; Malaria vaccines; Plasmodium falciparum; Plasmodium falciparum vaccines; Malaria prevention; Malaria elimination ID PLASMODIUM-FALCIPARUM SPOROZOITES; TRANSMISSION-BLOCKING VACCINE; T-CELL IMMUNITY; CIRCUMSPOROZOITE PROTEIN VACCINE; DIRECT VENOUS INOCULATION; IN-ADJUVANT VACCINES; DNA VACCINE; ANTIBODY-RESPONSES; SEQUENTIAL IMMUNIZATION; LISTERIA-MONOCYTOGENES AB In 2013 there were an estimated 584,000 deaths and 198 million clinical illnesses due to malaria, the majority in sub-Saharan Africa. Vaccines would be the ideal addition to the existing armamentarium of anti-malaria tools. However, malaria is caused by parasites, and parasites are much more complex in terms of their biology than the viruses and bacteria for which we have vaccines, passing through multiple stages of development in the human host, each stage expressing hundreds of unique antigens. This complexity makes it more difficult to develop a vaccine for parasites than for viruses and bacteria, since an immune response targeting one stage may not offer protection against a later stage, because different antigens are the targets of protective immunity at different stages. Furthermore, depending on the life cycle stage and whether the parasite is extra- or intra-cellular, antibody and/or cellular immune responses provide protection. It is thus not surprising that there is no vaccine on the market for prevention of malaria, or any human parasitic infection. In fact, no vaccine for any disease with this breadth of targets and immune responses exists. In this limited review, we focus on four approaches to malaria vaccines, (1) a recombinant protein with adjuvant vaccine aimed at Plasmodium falciparum (Pf) pre-erythrocytic stages of the parasite cycle (RTS,S/AS01), (2) whole sporozoite vaccines aimed at Pf pre-erythrocytic stages (PfSPZ Vaccine and PfSPZ-CVac), (3) prime boost vaccines that include recombinant DNA, viruses and bacteria, and protein with adjuvant aimed primarily at Pf pre-erythrocytic, but also asexual erythrocytic stages, and (4) recombinant protein with adjuvant vaccines aimed at Pf and Plasmodium vivax sexual erythrocytic and mosquito stages. We recognize that we are not covering all approaches to malaria vaccine development, or most of the critically important work on development of vaccines against P. vivax, the second most important cause of malaria. Progress during the last few years has been significant, and a first generation malaria candidate vaccine, RTS,S/AS01, is under review by the European Medicines Agency (EMA) for its quality, safety and efficacy under article 58, which allows the EMA to give a scientific opinion about products intended exclusively for markets outside of the European Union. However, much work is in progress to optimize malaria vaccines in regard to magnitude and durability of protective efficacy and the financing and practicality of delivery. Thus, we are hopeful that anti-malaria vaccines will soon be important tools in the battle against malaria. (C) 2015 by American Journal of Preventive Medicine and Elsevier Ltd. All rights reserved. C1 [Hoffman, Stephen L.; Richie, Thomas L.] Sanaria Inc, Rockville, MD 20850 USA. [Vekemans, Johan] GSK Vaccines, Rixensart, Belgium. [Duffy, Patrick E.] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD 20852 USA. RP Hoffman, SL (reprint author), Sanaria Inc, Rockville, MD 20850 USA. EM slhoffman@sanaria.com OI Richie, Thomas/0000-0002-2946-5456 FU Sanaria Inc.; GSK Vaccines; NIAID, NIH FX SLH and TLR are supported by Sanaria Inc., JV by GSK Vaccines, and PED by the Intramural Research Program of NIAID, NIH. NR 110 TC 12 Z9 12 U1 9 U2 28 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD NOV 27 PY 2015 VL 33 SU 4 BP D13 EP D23 DI 10.1016/j.vaccine.2015.07.091 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA CZ0BN UT WOS:000366770200003 PM 26324116 ER PT J AU Lussier, MP Sanz-Clemente, A Roche, KW AF Lussier, Marc P. Sanz-Clemente, Antonio Roche, Katherine W. TI Dynamic Regulation of N-Methyl-d-aspartate (NMDA) and alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors by Posttranslational Modifications SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Review DE alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA receptor AMPAR); glutamate receptor; post-translational modification (PTM); protein palmitoylation; ubiquitin; N-methyl-D-aspartate receptor (NMDA receptor NMDAR) ID LONG-TERM POTENTIATION; DEPENDENT PROTEIN-KINASE; GLUTAMATE RECEPTORS; SYNAPTIC PLASTICITY; SURFACE EXPRESSION; GLUR1 SUBUNIT; TYROSINE PHOSPHORYLATION; DIFFERENTIAL REGULATION; NEURONAL DEVELOPMENT; HIPPOCAMPAL-NEURONS AB Many molecular mechanisms underlie the changes in synaptic glutamate receptor content that are required by neuronal networks to generate cellular correlates of learning and memory. During the last decade, posttranslational modifications have emerged as critical regulators of synaptic transmission and plasticity. Notably, phosphorylation, ubiquitination, and palmitoylation control the stability, trafficking, and synaptic expression of glutamate receptors in the central nervous system. In the current review, we will summarize some of the progress made by the neuroscience community regarding our understanding of phosphorylation, ubiquitination, and palmitoylation of the NMDA and AMPA subtypes of glutamate receptors. C1 [Lussier, Marc P.] Univ Quebec, Dept Chim, Montreal, PQ H3C 3P8, Canada. [Sanz-Clemente, Antonio] Northwestern Univ, Feinberg Sch Med, Dept Pharmacol, Chicago, IL 60611 USA. [Roche, Katherine W.] NINDS, Receptor Biol Sect, NIH, Bethesda, MD 20892 USA. RP Roche, KW (reprint author), NINDS, Bldg 35,Rm 2C-903,9000 Rockville Pike, Bethesda, MD 20892 USA. EM rochek@ninds.nih.gov FU Universite du Quebec a Montreal Start-up Funds; National Institutes of Health NIA Grant [1K99AG041225]; NINDS Intramural Program FX This work was supported by Universite du Quebec a Montreal Start-up Funds (to M.P.L.) and by National Institutes of Health NIA Grant 1K99AG041225 (to A.S.C.) and the NINDS Intramural Program (to K.W.R.). This is the first article in the Thematic Minireview series "Molecular Mechanisms of Synaptic Plasticity." The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the author and does not necessarily represent the official views of the National Institutes of Health. NR 100 TC 9 Z9 9 U1 5 U2 14 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 NOV 27 PY 2015 VL 290 IS 48 BP 28596 EP 28603 DI 10.1074/jbc.R115.652750 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CX5SH UT WOS:000365762300002 PM 26453298 ER PT J AU Luo, XR Nie, J Wang, SW Chen, ZJ Chen, WJ Li, D Hu, H Li, B AF Luo, Xuerui Nie, Jia Wang, Shuaiwei Chen, Zuojia Chen, WanJun Li, Dan Hu, Hui Li, Bin TI Poly(ADP-ribosyl)ation of FOXP3 Protein Mediated by PARP-1 Protein Regulates the Function of Regulatory T Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE ADP-ribosylation; forkhead box P3 (FOXP3); immunosuppression; inhibitor; posttranscriptional regulation; T cell; regulatory T cell ID TRANSCRIPTION FACTOR FOXP3; ADP-RIBOSE POLYMERASE; MODULATION; BINDING AB Poly(ADP-ribose) polymerase 1 (PARP-1) is an ADP-ribosylating enzyme participating in diverse cellular functions. The roles of PARP-1 in the immune system, however, have not been well understood. Here we find that PARP-1 interacts with FOXP3 and induces its poly(ADP-ribosyl)ation. By using PARP-1 inhibitors, we show that reduced poly(ADP-ribosyl)ation of FOXP3 results in not only FOXP3 stabilization and increased FOXP3 downstream genes but also enhanced suppressive function of regulatory T cells. Our results suggest that PARP-1 negatively regulates the suppressive function of Treg cells at the posttranslational level via FOXP3 poly(ADP-ribosyl)ation. This finding has implications for developing PARP-1 inhibitors as potential agents for the prevention and treatment of autoimmune diseases. C1 [Luo, Xuerui; Nie, Jia; Wang, Shuaiwei; Chen, Zuojia; Li, Dan; Li, Bin] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Pasteur Shanghai, Key Lab Mol Virol & Immunol, Shanghai 200031, Peoples R China. [Chen, WanJun] NIDCR, Mucosal Immunol Sect, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. [Hu, Hui] Univ Alabama Birmingham, Sch Med, Dept Microbiol, Birmingham, AL 35294 USA. RP Li, B (reprint author), Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Pasteur Shanghai, Key Lab Mol Virol & Immunol, Shanghai 200031, Peoples R China. EM binli@sibs.ac.cn FU Chinese National Program on Key Basic Research Project [2014CB541800, 2014CB541900]; NSFC [81330072, 31300711, 31370863, 31170825, 31200646, 31200647]; Shanghai Key Grant [14JC1406100]; Shanghai Three-year Plan on Promoting TCM Development Grant [ZY3-LCPT-2-1003] FX This work was supported by Chinese National Program on Key Basic Research Project Grants 2014CB541800, 2014CB541900, NSFC 81330072, 31300711, 31370863, 31170825, 31200646, and 31200647; Shanghai Key Grant 14JC1406100; and Shanghai Three-year Plan on Promoting TCM Development Grant ZY3-LCPT-2-1003. The authors declare that they have no conflicts of interest with the contents of this article. NR 25 TC 5 Z9 5 U1 2 U2 4 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 NOV 27 PY 2015 VL 290 IS 48 BP 28675 EP 28682 DI 10.1074/jbc.M115.661611 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CX5SH UT WOS:000365762300009 PM 26429911 ER PT J AU Sgourakis, NG May, NA Boyd, LF Ying, JF Bax, A Margulies, DH AF Sgourakis, Nikolaos G. May, Nathan A. Boyd, Lisa F. Ying, Jinfa Bax, Ad Margulies, David H. TI A Novel MHC-I Surface Targeted for Binding by the MCMV m06 Immunoevasin Revealed by Solution NMR SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE antigen presentation; herpesvirus; major histocompatibility complex (MHC); nuclear magnetic resonance (NMR); protein-protein interaction; surface plasmon resonance (SPR); MCMV; immunoevasin; m06; gp48 ID MAJOR HISTOCOMPATIBILITY COMPLEX; MOUSE CYTOMEGALOVIRUS GLYCOPROTEIN; RESIDUAL DIPOLAR COUPLINGS; IMMUNE EVASION PROTEINS; MURINE CYTOMEGALOVIRUS; ANTIGEN PRESENTATION; CRYSTAL-STRUCTURE; PERDEUTERATED PROTEINS; HETERONUCLEAR NMR; PEPTIDE BINDING AB As part of its strategy to evade detection by the host immune system, murine cytomegalovirus (MCMV) encodes three proteins that modulate cell surface expression of major histocompatibility complex class I (MHC-I) molecules: the MHC-I homolog m152/gp40 as well as the m02-m16 family members m04/gp34 and m06/gp48. Previous studies of the m04 protein revealed a divergent Ig-like fold that is unique to immunoevasins of the m02-m16 family. Here, we engineer and characterize recombinant m06 and investigate its interactions with full-length and truncated forms of the MHC-I molecule H2-L-d by several techniques. Furthermore, we employ solution NMR to map the interaction footprint of the m06 protein on MHC-I, taking advantage of a truncated H2-L-d, mini-H2-L-d, consisting of only the 12 platform domain. Mini-H2-L-d refolded in vitro with a high affinity peptide yields a molecule that shows outstanding NMR spectral features, permitting complete backbone assignments. These NMR-based studies reveal that m06 binds tightly to a discrete site located under the peptide-binding platform that partially overlaps with the (2)-microglobulin interface on the MHC-I heavy chain, consistent with in vitro binding experiments showing significantly reduced complex formation between m06 and (2)-microglobulin-associated MHC-I. Moreover, we carry out NMR relaxation experiments to characterize the picosecond-nanosecond dynamics of the free mini-H2-L-d MHC-I molecule, revealing that the site of interaction is highly ordered. This study provides insight into the mechanism of the interaction of m06 with MHC-I, suggesting a structural manipulation of the target MHC-I molecule at an early stage of the peptide-loading pathway. C1 [Sgourakis, Nikolaos G.; Ying, Jinfa; Bax, Ad] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [May, Nathan A.; Boyd, Lisa F.; Margulies, David H.] NIAID, Mol Biol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Bax, A (reprint author), NIDDK, Chem Phys Lab, NIH, Bldg 5,Rm 126,5 Mem Dr, Bethesda, MD 20892 USA. EM bax@nih.gov; dhm@nih.gov OI Margulies, David/0000-0001-8530-7375 FU NIDDK; NIAID, National Institutes of Health FX This research was supported by the intramural research programs of the NIDDK and NIAID, National Institutes of Health. The authors declare that they have no conflicts of interest with the contents of this article. NR 66 TC 0 Z9 0 U1 2 U2 8 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 NOV 27 PY 2015 VL 290 IS 48 BP 28857 EP 28868 DI 10.1074/jbc.M115.689661 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CX5SH UT WOS:000365762300027 PM 26463211 ER PT J AU Lu, SY Banerjee, A Jang, H Zhang, J Gaponenko, V Nussinov, R AF Lu, Shaoyong Banerjee, Avik Jang, Hyunbum Zhang, Jian Gaponenko, Vadim Nussinov, Ruth TI GTP Binding and Oncogenic Mutations May Attenuate Hypervariable Region (HVR)-Catalytic Domain Interactions in Small GTPase K-Ras4B, Exposing the Effector Binding Site SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE biophysics; computational biology; nuclear magnetic resonance (NMR); protein conformation; protein dynamic; Ras protein ID ACTIVATED PROTEIN-KINASE; H-RAS PROTEIN; STRUCTURAL BASIS; K-RAS; MEMBRANE-BINDING; CAAX MOTIF; INHIBITORS; DYNAMICS; CANCER; PATHWAY AB K-Ras4B, a frequently mutated oncogene in cancer, plays an essential role in cell growth, differentiation, and survival. Its C-terminal membrane-associated hypervariable region (HVR) is required for full biological activity. In the active GTP-bound state, the HVR interacts with acidic plasma membrane (PM) headgroups, whereas the farnesyl anchors in the membrane; in the inactive GDP-bound state, the HVR may interact with both the PM and the catalytic domain at the effector binding region, obstructing signaling and nucleotide exchange. Here, using molecular dynamics simulations and NMR, we aim to figure out the effects of nucleotides (GTP and GDP) and frequent (G12C, G12D, G12V, G13D, and Q61H) and infrequent (E37K and R164Q) oncogenic mutations on full-length K-Ras4B. The mutations are away from or directly at the HVR switch I/effector binding site. Our results suggest that full-length wild-type GDP-bound K-Ras4B (K-Ras4B(WT)-GDP) is in an intrinsically autoinhibited state via tight HVR-catalytic domain interactions. The looser association in K-Ras4B(WT)-GTP may release the HVR. Some of the oncogenic mutations weaken the HVR-catalytic domain association in the K-Ras4B-GDP/-GTP bound states, which may facilitate the HVR disassociation in a nucleotide-independent manner, thereby up-regulating oncogenic Ras signaling. Thus, our results suggest that mutations can exert their effects in more than one way, abolishing GTP hydrolysis and facilitating effector binding. C1 [Lu, Shaoyong; Zhang, Jian] Shanghai Jiao Tong Univ, Sch Med, Dept Pathophysiol, Key Lab Cell Differentiat & Apoptosis,Chinese Min, Shanghai 200025, Peoples R China. [Lu, Shaoyong; Jang, Hyunbum; Nussinov, Ruth] NCI, Canc & Inflammat Program, Leidos Biomed Res Inc, Frederick, MD 21702 USA. [Banerjee, Avik] Univ Illinois, Dept Chem, Chicago, IL 60607 USA. [Gaponenko, Vadim] Univ Illinois, Dept Mol Genet & Biochem, Chicago, IL 60607 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Sackler Inst Mol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Zhang, J (reprint author), Shanghai Jiao Tong Univ, Sch Med, Dept Pathophysiol, Key Lab Cell Differentiat & Apoptosis,Chinese Min, Shanghai 200025, Peoples R China. EM jian.zhang@sjtu.edu.cn; vadimg@uic.edu; NussinoR@helix.nih.gov RI Regan, Clinton/E-6250-2012 FU National Basic Research Program of China (973 Program) [2015CB910403]; National Natural Science Foundation of China [81322046, 81302689, 81473137]; Shanghai Rising-Star Program Grant [13QA1402300]; Program for New Century Excellent Talents in University [NCET-12-0355]; National Institutes of Health [R01 CA135341]; American Cancer Society [RGS-09-057-01-GMC]; NCI-Frederick, National Institutes of Health [HHSN261200800001E]; NCI-Frederick, National Institutes of Health FX This work was supported by the National Basic Research Program of China (973 Program) Grant 2015CB910403 (to J. Z.), National Natural Science Foundation of China Grants 81322046, 81302689, and 81473137 (to J. Z.), Shanghai Rising-Star Program Grant 13QA1402300) (to J. Z.), Program for New Century Excellent Talents in University (NCET-12-0355) (to J. Z.), National Institutes of Health Grant R01 CA135341 (to V. G.), American Cancer Society Grant RGS-09-057-01-GMC (to V. G.). This work was also supported in whole or in part with Federal funds from the NCI-Frederick, National Institutes of Health under Contract HHSN261200800001E (to R. N.). This work was supported in part by the Intramural Research Program of NCI-Frederick, National Institutes of Health. The authors declare that they have no conflicts of interest with the contents of this article. NR 59 TC 16 Z9 16 U1 0 U2 7 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 NOV 27 PY 2015 VL 290 IS 48 BP 28887 EP 28900 DI 10.1074/jbc.M115.664755 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CX5SH UT WOS:000365762300029 PM 26453300 ER PT J AU Silverstein, N Ewers, D Forrest, LR Fahlke, C Kanner, BI AF Silverstein, Nechama Ewers, David Forrest, Lucy R. Fahlke, Christoph Kanner, Baruch I. TI Molecular Determinants of Substrate Specificity in Sodium-coupled Glutamate Transporters SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE glutamate; membrane transporter reconstitution; neurotransmitter transport; site-directed mutagenesis; sodium transport ID DEPENDENT ASPARTATE TRANSPORTER; RAT-BRAIN; ACID TRANSPORTER; FUNCTIONAL-CHARACTERIZATION; PYROCOCCUS-HORIKOSHII; INDIVIDUAL SUBUNITS; MEMBRANE-VESICLES; CRYSTAL-STRUCTURE; CHLORIDE CHANNEL; BINDING AB Crystal structures of the archaeal homologue Glt(Ph) have provided important insights into the molecular mechanism of transport of the excitatory neurotransmitter glutamate. Whereas mammalian glutamate transporters can translocate both glutamate and aspartate, Glt(Ph) is only one capable of aspartate transport. Most of the amino acid residues that surround the aspartate substrate in the binding pocket of Glt(Ph) are highly conserved. However, in the brain transporters, Thr-352 and Met-362 of the reentrant hairpin loop 2 are replaced by the smaller Ala and Thr, respectively. Therefore, we have studied the effects of T352A and M362T on binding and transport of aspartate and glutamate by Glt(Ph). Substrate-dependent intrinsic fluorescence changes were monitored in transporter constructs containing the L130W mutation. Glt(Ph)-L130W/T352A exhibited an approximate to 15-fold higher apparent affinity for l-glutamate than the wild type transporter, and the M362T mutation resulted in an increased affinity of approximate to 40-fold. An even larger increase of the apparent affinity for l-glutamate, around 130-fold higher than that of wild type, was observed with the T352A/M362T double mutant. Radioactive uptake experiments show that Glt(Ph)-T352A not only transports aspartate but also l-glutamate. Remarkably, Glt(Ph)-M362T exhibited l-aspartate but not l-glutamate transport. The double mutant retained the ability to transport l-glutamate, but its kinetic parameters were very similar to those of Glt(Ph)-T352A alone. The differential impact of mutation on binding and transport of glutamate suggests that hairpin loop 2 not only plays a role in the selection of the substrate but also in its translocation. C1 [Silverstein, Nechama; Kanner, Baruch I.] Hebrew Univ Jerusalem, Fac Med, Inst Med Res Israel Canada, Dept Biochem & Mol Biol, IL-91120 Jerusalem, Israel. [Ewers, David; Fahlke, Christoph] Forschungszentrum Julich, Inst Complex Syst, D-52425 Julich, Germany. [Ewers, David] Hannover Med Sch, Inst Neurophysiol, D-30625 Hannover, Germany. [Forrest, Lucy R.] NINDS, Computat Struct Biol Sect, NIH, Bethesda, MD 20894 USA. RP Kanner, BI (reprint author), Hebrew Univ Jerusalem, Fac Med, Dept Biochem & Mol Biol, POB 12272, IL-91120 Jerusalem, Israel. EM baruch.kanner@mail.huji.ac.il RI Fahlke, Christoph/G-3635-2013 OI Fahlke, Christoph/0000-0001-8602-9952 FU National Institutes of Health from NINDS [NS 16708]; Division of Intramural Research of the National Institutes of Health, NINDS; Deutsche Forschungsgemeinschaft [FA301/9]; United States-Israel Binational Science Foundation [2011268] FX This work was supported by National Institutes of Health Grant NS 16708 from NINDS (to B. I. K.), the Division of Intramural Research of the National Institutes of Health, NINDS (to L. R. F.), Deutsche Forschungsgemeinschaft Grant FA301/9 (to C. F.), and United States-Israel Binational Science Foundation Grant 2011268 (to B. I. K.). The authors declare that they have no conflict 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 41 TC 2 Z9 2 U1 0 U2 4 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 NOV 27 PY 2015 VL 290 IS 48 BP 28988 EP 28996 DI 10.1074/jbc.M115.682666 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CX5SH UT WOS:000365762300037 PM 26475859 ER PT J AU Yang, XB Gao, MM Chen, GB Pierce, BG Lu, JH Weng, NP Mariuzza, RA AF Yang, Xinbo Gao, Mingming Chen, Guobing Pierce, Brian G. Lu, Jinghua Weng, Nan-ping Mariuzza, Roy A. TI Structural Basis for Clonal Diversity of the Public T Cell Response to a Dominant Human Cytomegalovirus Epitope SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE complex; herpesvirus; major histocompatibility complex (MHC); T-cell receptor (TCR); x-ray crystallography ID RECEPTOR RECOGNITION; TCR; REPERTOIRE; SELECTION; PROTEIN; INFECTION; MOLECULE; VIRUSES; USAGE; CTL AB Background: The human public T cell response to a dominant CMV epitope features high clonal diversity. Results: Structures of two public TCRs bound to this CMV epitope and HLA-A2 reveal different recognition strategies. Conclusion: These structures show how the same public complementarity-determining region 3 (CDR3) motif can associate with different variable regions and pair with different CDR3s. Significance: This structural interchangeability generates a clonally diverse public TCR repertoire. Cytomegalovirus (CMV) is a ubiquitous and persistent human pathogen that is kept in check by CD8(+) cytotoxic T lymphocytes. Individuals expressing the major histocompatibility complex (MHC) class I molecule HLA-A2 produce cytotoxic T lymphocytes bearing T cell receptors (TCRs) that recognize the immunodominant CMV epitope NLVPMVATV (NLV). The NLV-specific T cell repertoire is characterized by a high prevalence of TCRs that are frequently observed in multiple unrelated individuals. These public TCRs feature identical, or nearly identical, complementarity-determining region 3 (CDR3) and/or CDR3 sequences. The TCRs may express public CDR3 motifs alone, public CDR3 motifs alone, or dual public CDR3 motifs. In addition, the same public CDR3 motif may pair with different CDR3 motifs (and the reverse), giving rise to highly diverse NLV-specific TCR repertoires. To investigate the structural underpinnings of this clonal diversity, we determined crystal structures of two public TCRs (C7 and C25) in complex with NLVHLA-A2. These TCRs utilize completely different CDR3 and CDR3 motifs that, in addition, can associate with multiple variable and variable regions in NLV-specific T cell repertoires. The C7NLVHLA-A2 and C25NLVHLA-A2 complexes exhibit divergent TCR footprints on peptide-MHC such that C25 is more focused on the central portion of the NLV peptide than is C7. These structures combined with molecular modeling show how the public CDR3 motif of C25 may associate with different variable regions and how the public CDR3 motif of C7 may pair with different CDR3 motifs. This interchangeability of TCR V regions and CDR3 motifs permits multiple structural solutions to binding an identical peptide-MHC ligand and thereby the generation of a clonally diverse public T cell response to CMV. C1 [Yang, Xinbo; Gao, Mingming; Pierce, Brian G.; Mariuzza, Roy A.] Univ Maryland, Inst Biosci & Biotechnol Res, WM Keck Lab Struct Biol, Rockville, MD 20850 USA. [Yang, Xinbo; Gao, Mingming; Mariuzza, Roy A.] Univ Maryland, Dept Cell Biol & Mol Genet, College Pk, MD 20742 USA. [Chen, Guobing; Weng, Nan-ping] NIA, Lymphocyte Differentiat Sect, Lab Mol Biol & Immunol, NIH, Baltimore, MD 21224 USA. [Lu, Jinghua] NIAID, Struct Immunol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Mariuzza, RA (reprint author), Univ Maryland, Inst Biosci & Biotechnol Res, 9600 Gudelsky Dr, Rockville, MD 20850 USA. EM rmariuzz@umd.edu RI Chen, Guobing/D-9572-2012; OI Chen, Guobing/0000-0002-2401-6168; Pierce, Brian/0000-0003-4821-0368 FU United States Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38] FX We thank the National Institute on Aging clinic core for collecting apheresis pack of normal donors. We also thank Peter D. Sun for generous assistance with x-ray data collection. The x-ray SER-CAT beamlines at the Advanced Photon Source were supported by the United States Department of Energy, Basic Energy Sciences, Office of Science, under Contract W-31-109-Eng-38. NR 56 TC 3 Z9 3 U1 0 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 NOV 27 PY 2015 VL 290 IS 48 BP 29106 EP 29119 DI 10.1074/jbc.M115.691311 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CX5SH UT WOS:000365762300048 PM 26429912 ER PT J AU Carafoli, E Klee, CB AF Carafoli, Ernesto Klee, Claude B. TI For love of metals Robert J. P. (Bob) Williams, FRS. February 25, 1926 March 21, 2015. SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Biographical-Item C1 [Carafoli, Ernesto] Univ Padua, Venetian Inst Mol Med, I-35100 Padua, Italy. [Klee, Claude B.] NCI, Bethesda, MD 20892 USA. RP Carafoli, E (reprint author), Univ Padua, Venetian Inst Mol Med, I-35100 Padua, Italy. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD NOV 27 PY 2015 VL 467 IS 4 BP 611 EP 611 DI 10.1016/j.bbrc.2015.09.134 PG 1 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA CW6YV UT WOS:000365145300001 PM 26881282 ER PT J AU Rosenspire, AJ Chen, K AF Rosenspire, Allen J. Chen, Kang TI Anergic B Cells: Precarious On-Call Warriors at the Nexus of Autoimmunity and False-Flagged Pathogens SO FRONTIERS IN IMMUNOLOGY LA English DT Editorial Material DE B cell; anergy; autoimmunity; infection; vaccines; immunotherapy of cancer ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; TOLL-LIKE RECEPTORS; TRANSGENIC MICE; T-CELLS; ANTIBODIES; HIV-1; INDIVIDUALS; INFECTION; VIRUS; IGM C1 [Rosenspire, Allen J.; Chen, Kang] Wayne State Univ, Dept Immunol & Microbiol, Detroit, MI 48202 USA. [Chen, Kang] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. [Chen, Kang] Wayne State Univ, Dept Oncol, Detroit, MI USA. [Chen, Kang] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Detroit, MI USA. [Chen, Kang] Barbara Ann Karmanos Canc Inst, Tumor Biol & Microenvironm Program, Detroit, MI USA. [Chen, Kang] NIAID, Mucosal Immunol Studies Team, NIH, Bethesda, MD 20892 USA. RP Rosenspire, AJ (reprint author), Wayne State Univ, Dept Immunol & Microbiol, Detroit, MI 48202 USA. EM arosenspire@wayne.edu NR 43 TC 1 Z9 1 U1 1 U2 2 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 NOV 26 PY 2015 VL 6 AR UNSP 580 DI 10.3389/fimmu.2015.00580 PG 5 WC Immunology SC Immunology GA CY5WI UT WOS:000366477900001 PM 26635794 ER PT J AU Winuthayanon, W Bernhardt, ML Padilla-Banks, E Myers, PH Edin, ML Lih, FB Hewitt, SC Korach, KS Williams, CJ AF Winuthayanon, Wipawee Bernhardt, Miranda L. Padilla-Banks, Elizabeth Myers, Page H. Edin, Matthew L. Lih, Fred B. Hewitt, Sylvia C. Korach, Kenneth S. Williams, Carmen J. TI Oviductal estrogen receptor alpha signalling prevents protease-mediated embryo death SO ELIFE LA English DT Article ID ZONA-PELLUCIDA; CORTICAL GRANULES; OOCYTE MATURATION; MOUSE EGGS; IN-VITRO; GENE; MICE; KALLIKREIN; EXPRESSION; RESPONSES AB Development of uterine endometrial receptivity for implantation is orchestrated by cyclic steroid hormone-mediated signals. It is unknown if these signals are necessary for oviduct function in supporting fertilization and preimplantation development. Here we show that conditional knockout (cKO) mice lacking estrogen receptor alpha (ER alpha) in oviduct and uterine epithelial cells have impaired fertilization due to a dramatic reduction in sperm migration. In addition, all successfully fertilized eggs die before the 2-cell stage due to persistence of secreted innate immune mediators including proteases. Elevated protease activity in cKO oviducts causes premature degradation of the zona pellucida and embryo lysis, and wild-type embryos transferred into cKO oviducts fail to develop normally unless rescued by concomitant transfer of protease inhibitors. Thus, suppression of oviductal protease activity mediated by estrogen-epithelial ER alpha signaling is required for fertilization and preimplantation embryo development. These findings have implications for human infertility and post-coital contraception. C1 [Winuthayanon, Wipawee; Bernhardt, Miranda L.; Padilla-Banks, Elizabeth; Hewitt, Sylvia C.; Korach, Kenneth S.; Williams, Carmen J.] Natl Inst Environm Hlth Sci, NIH, Reprod & Dev Biol Lab, Res Triangle Pk, NC 27709 USA. [Winuthayanon, Wipawee] Washington State Univ, Coll Vet Med, Sch Mol Biosci, Pullman, WA 99164 USA. [Myers, Page H.] Natl Inst Environm Hlth Sci, NIH, Comparat Med Branch, Res Triangle Pk, NC USA. [Edin, Matthew L.] Natl Inst Environm Hlth Sci, NIH, Immun Inflammat & Dis Lab, Res Triangle Pk, NC USA. [Lih, Fred B.] Natl Inst Environm Hlth Sci, NIH, Epigenet & Stem Cell Biol Lab, Res Triangle Pk, NC USA. RP Winuthayanon, W (reprint author), Natl Inst Environm Hlth Sci, NIH, Reprod & Dev Biol Lab, Res Triangle Pk, NC 27709 USA. EM winuthayanonw@vetmed.wsu.edu; williamsc5@niehs.nih.gov FU National Institute of Environmental Health Sciences [1ZIAES70065, 1ZIAES025034, 1ZIAES050167, 1ZIAES102405] FX National Institute of 1ZIAES70065 Environmental Health Sciences Wipawee Winuthayanon Sylvia C Hewitt Kenneth S Korach; National Institute of 1ZIAES025034 Environmental Health Sciences Matthew L Edin; National Institute of 1ZIAES050167 Environmental Health Sciences Fred B Lih; National Institute of 1ZIAES102405 Environmental Health Sciences Miranda L Bernhardt Elizabeth Padilla-Banks Carmen J Williams; The funder had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 57 TC 0 Z9 0 U1 2 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 NOV 26 PY 2015 VL 4 AR e10453 DI 10.7554/eLife.10453 PG 28 WC Biology SC Life Sciences & Biomedicine - Other Topics GA CX7IG UT WOS:000365874800001 ER PT J AU Xu, P Xu, MM Jiang, LG Yang, QL Luo, ZP Dauter, Z Huang, MD Andreasent, PA AF Xu, Peng Xu, Mingming Jiang, Longguang Yang, Qinglan Luo, Zhipu Dauter, Zbigniew Huang, Mingdong Andreasent, Peter A. TI Design of Specific Serine Protease Inhibitors Based on a Versatile Peptide Scaffold: Conversion of a Urokinase Inhibitor to a Plasma Kallikrein Inhibitor SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID SUNFLOWER TRYPSIN-INHIBITOR; HEREDITARY ANGIOEDEMA; EXOSITE INHIBITORS; BICYCLIC PEPTIDES; CATALYTIC DOMAIN; DRUG DISCOVERY; ACTIVE-SITE; FACTOR VIIA; ANTICOAGULANTS; SELECTION AB All serine proteases hydrolyze peptide bonds by the same basic mechanism and have very similar active sites, in spite of the fact that individual proteases have different physiological functions. We here report a strategy for designing high-affinity and high-specificity serine protease inhibitors using a versatile peptide scaffold, a 10-mer. peptide, mupain-1 (CPAYSRYLDC). Mupain-1 was previously reported as a specific inhibitor of murine urokinase-type plasminogen activator (K-i = 0.55 mu M) without measurable affinity to plasma kallikrein (K-i > 1000 mu M). X-ray crystal structure analysis showed that the new peptide was able to adapt a new set of enzyme surface interactions by a slightly changed backbone conformation. Thus, with an appropriate re-engineering, mupain-1 can be redesigned to specific inhibitors of other serine proteases. C1 [Xu, Peng; Yang, Qinglan; Andreasent, Peter A.] Aarhus Univ, Dept Mol Biol & Genet, Danish Chinese Ctr Proteases & Canc, DK-8000 Aarhus, Denmark. [Xu, Mingming; Jiang, Longguang; Huang, Mingdong] Chinese Acad Sci, Fujian Inst Res Struct Matter, Danish Chinese Ctr Proteases & Canc, Fuzhou 350002, Peoples R China. [Luo, Zhipu; Dauter, Zbigniew] Argonne Natl Lab, Natl Canc Inst, Macromol Crystallog Lab, Synchrotron Radiat Res Sect, Argonne, IL 60439 USA. RP Andreasent, PA (reprint author), Aarhus Univ, Dept Mol Biol & Genet, Danish Chinese Ctr Proteases & Canc, DK-8000 Aarhus, Denmark. EM pa@mb.au.dk FU Danish National Research Foundation [26-331-6]; Natural Science Foundation of China [31161130356, 31170707, 31370737]; Natural Science Foundation of the Fujian Province [2012J05071]; Lundbeck Foundation [R83-A7826]; Carlsberg Foundation [2012_01_0642]; Cancer Research Foundation; Chinese Academy of Sciences visiting professorship for senior international scientists [2012T1G0023]; Aarhus University Research Foundation [10] FX This work was supported by the Danish National Research Foundation (Grant 26-331-6 to P.A.A.), the Natural Science Foundation of China (Grants 31161130356, 31170707, 31370737 to M.H.), the Natural Science Foundation of the Fujian Province (Grant 2012J05071 to L.J.), the Lundbeck Foundation (Grant R83-A7826 to P.A.A.), the Carlsberg Foundation (Grant 2012_01_0642 to P.A.A.), and the Cancer Research Foundation of 1989 (to P.A.A.). P.A.A. was awarded a Chinese Academy of Sciences visiting professorship for senior international scientists (Grant 2012T1G0023). M.H. was awarded an Aarhus University Research Foundation visiting professorship (Reference Number 10). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 3 Z9 3 U1 2 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD NOV 26 PY 2015 VL 58 IS 22 BP 8868 EP 8876 DI 10.1021/acs.jmedchem.5b01128 PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA CX9DG UT WOS:000366004600009 PM 26536069 ER PT J AU Monteiro, PA Chen, KY Lira, FS Saraiva, BTC Antunes, BMM Campos, EZ Freitas, IF AF Monteiro, Paula Alves Chen, Kong Y. Lira, Fabio Santos Cicotti Saraiva, Bruna Thamyres Mello Antunes, Barbara Moura Campos, Eduardo Zapaterra Freitas, Ismael Forte, Jr. TI Concurrent and aerobic exercise training promote similar benefits in body composition and metabolic profiles in obese adolescents SO LIPIDS IN HEALTH AND DISEASE LA English DT Article DE Body fat; Body composition; Exercise; Lipid profile; Obesity ID ADIPOSE-TISSUE INFLAMMATION; INSULIN-RESISTANCE; RISK-FACTORS; OVERWEIGHT; TRIAL; FAT; INTENSITY; STRENGTH; CHILDREN; FITNESS AB Background: The prevalence of obesity in pediatric population is increasing at an accelerated rate in many countries, and has become a major public health concern. Physical activity, particularly exercise training, remains to be a cornerstone of pediatric obesity interventions. The purpose of our current randomized intervention trial was to compare the effects of two types of training matched for training volume, aerobic and concurrent, on body composition and metabolic profile in obese adolescents. Thus the aim of the study was compare the effects of two types of training matched for training volume, aerobic and concurrent, on body composition and metabolic profile in obese adolescents. Methods: 32 obese adolescents participated in two randomized training groups, concurrent or aerobic, for 20 weeks (50 mins x 3 per week, supervised), and were compared to a 16-subject control group. We measured the percentage body fat (%BF, primary outcome), fat-free mass, percentage of android fat by dual energy x-ray absorptiometry, and others metabolic profiles at baseline and after interventions, and compared them between groups using the Intent-to-treat design. Results: In 20 weeks, both exercise training groups significantly reduced %BF by 2.9-3.6 % as compare to no change in the control group (p = 0.042). There were also positive changes in lipid levels in exercise groups. No noticeable changes were found between aerobic and concurrent training groups. Conclusions: The benefits of exercise in reducing body fat and metabolic risk profiles can be achieved by performing either type of training in obese adolescents. C1 [Monteiro, Paula Alves; Cicotti Saraiva, Bruna Thamyres; Freitas, Ismael Forte, Jr.] Univ Estadual Paulista, UNESP, Dept Phys Educ, Ctr & Prescript Motor Act Lab, BR-19060900 Presidente Prudente, SP, Brazil. [Monteiro, Paula Alves; Lira, Fabio Santos; Mello Antunes, Barbara Moura; Campos, Eduardo Zapaterra] Univ Estadual Paulista, Dept Phys Educ, Exercise & Immunometab Res Grp, BR-19060900 Presidente Prudente, SP, Brazil. [Monteiro, Paula Alves; Chen, Kong Y.] NIDDK, Diabetes Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. RP Monteiro, PA (reprint author), Univ Estadual Paulista, UNESP, Dept Phys Educ, Ctr & Prescript Motor Act Lab, Rua Roberto Simonsen 305, BR-19060900 Presidente Prudente, SP, Brazil. EM paulinha__1003@hotmail.com RI Freitas Jr, Ismael/D-1723-2012 OI Freitas Jr, Ismael/0000-0002-5071-0428 FU FAPESP [2013/25310-2] FX This work was supported by FAPESP (grants no 2013/25310-2). NR 34 TC 0 Z9 0 U1 3 U2 16 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-511X J9 LIPIDS HEALTH DIS JI Lipids Health Dis. PD NOV 26 PY 2015 VL 14 AR 153 DI 10.1186/s12944-015-0152-9 PG 9 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA CX2YY UT WOS:000365563900001 PM 26611872 ER PT J AU Wright, JT Williamson, JD Whelton, PK Snyder, JK Sink, KM Rocco, MV Reboussin, DM Rahman, M Oparil, S Lewis, CE Kimmel, PL Johnson, KC Goff, DC Fine, LJ Cutler, JA Cushman, WC Cheung, AK Ambrosius, WT AF Wright, Jackson T., Jr. Williamson, Jeff D. Whelton, Paul K. Snyder, Joni K. Sink, Kaycee M. Rocco, Michael V. Reboussin, David M. Rahman, Mahboob Oparil, Suzanne Lewis, Cora E. Kimmel, Paul L. Johnson, Karen C. Goff, David C., Jr. Fine, Lawrence J. Cutler, Jeffrey A. Cushman, William C. Cheung, Alfred K. Ambrosius, Walter T. CA SPRINT Res Grp TI A Randomized Trial of Intensive versus Standard Blood-Pressure Control SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ISOLATED SYSTOLIC HYPERTENSION; CONVERTING ENZYME-INHIBITOR; CORONARY-HEART-DISEASE; GLOBAL BURDEN; RISK; STROKE; METAANALYSIS; OUTCOMES; OLDER; PREVENTION AB BACKGROUND The most appropriate targets for systolic blood pressure to reduce cardiovascular morbidity and mortality among persons without diabetes remain uncertain. METHODS We randomly assigned 9361 persons with a systolic blood pressure of 130 mm Hg or higher and an increased cardiovascular risk, but without diabetes, to a systolic blood-pressure target of less than 120 mm Hg (intensive treatment) or a target of less than 140 mm Hg (standard treatment). The primary composite outcome was myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes. RESULTS At 1 year, the mean systolic blood pressure was 121.4 mm Hg in the intensive-treatment group and 136.2 mm Hg in the standard-treatment group. The intervention was stopped early after a median follow-up of 3.26 years owing to a significantly lower rate of the primary composite outcome in the intensive-treatment group than in the standard-treatment group (1.65% per year vs. 2.19% per year; hazard ratio with intensive treatment, 0.75; 95% confidence interval [CI], 0.64 to 0.89; P<0.001). All-cause mortality was also significantly lower in the intensive-treatment group (hazard ratio, 0.73; 95% CI, 0.60 to 0.90; P = 0.003). Rates of serious adverse events of hypotension, syncope, electrolyte abnormalities, and acute kidney injury or failure, but not of injurious falls, were higher in the intensive-treatment group than in the standard-treatment group. CONCLUSIONS Among patients at high risk for cardiovascular events but without diabetes, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, resulted in lower rates of fatal and nonfatal major cardiovascular events and death from any cause, although significantly higher rates of some adverse events were observed in the intensive-treatment group. C1 [Wright, Jackson T., Jr.; Rahman, Mahboob] Case Western Reserve Univ, Univ Hosp Case Med Ctr, Div Nephrol & Hypertens, Cleveland, OH 44106 USA. [Rahman, Mahboob] Louis Stokes Cleveland Vet Affairs VA, Med Ctr, Div Nephrol & Hypertens, Cleveland, OH USA. [Williamson, Jeff D.; Sink, Kaycee M.] Wake Forest Sch Med, Sticht Ctr Aging, Winston Salem, NC USA. [Rocco, Michael V.] Wake Forest Sch Med, Nephrol Sect, Winston Salem, NC USA. [Reboussin, David M.; Ambrosius, Walter T.] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC USA. [Whelton, Paul K.] Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA 70118 USA. [Snyder, Joni K.; Fine, Lawrence J.; Cutler, Jeffrey A.] NHLBI, Clin Applicat & Prevent Branch, Bethesda, MD 20892 USA. [Kimmel, Paul L.] NIDDK, Div Kidney Urol & Hematol Dis, Bethesda, MD 20892 USA. [Oparil, Suzanne] Univ Alabama Birmingham, Div Cardiovasc Dis, Birmingham, AL USA. [Lewis, Cora E.] Univ Alabama Birmingham, Div Prevent Med, Birmingham, AL USA. [Johnson, Karen C.] Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. [Cushman, William C.] VA Med Ctr, Prevent Med Sect, Memphis, TN USA. [Goff, David C., Jr.] Univ Colorado, Sch Publ Hlth, Aurora, CO USA. [Cheung, Alfred K.] Univ Utah, Div Nephrol & Hypertens, Salt Lake City, UT USA. RP Wright, JT (reprint author), Case Western Reserve Univ, Univ Hosp Case Med Ctr, Div Nephrol & Hypertens, 1100 Euclid Ave, Cleveland, OH 44106 USA. EM jackson.wright@case.edu RI Bhatt, Udayan/E-2754-2011; Gure, Tanya/J-8546-2012; OI Le, Viet/0000-0001-6659-5332 FU National Institutes of Health FX Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01206062. NR 38 TC 505 Z9 517 U1 17 U2 45 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 NOV 26 PY 2015 VL 373 IS 22 BP 2103 EP 2116 DI 10.1056/NEJMoa1511939 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA CW9YT UT WOS:000365354800005 ER PT J AU Horsburgh, CR Barry, CE Lange, C AF Horsburgh, C. Robert, Jr. Barry, Clifton E., III Lange, Christoph TI Treatment of Tuberculosis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID MULTIDRUG-RESISTANT TUBERCULOSIS; RESOURCE-LIMITED SETTINGS; MYCOBACTERIUM-TUBERCULOSIS; PULMONARY TUBERCULOSIS; ANTIRETROVIRAL THERAPY; HIV; PYRAZINAMIDE; CHEMOTHERAPY; REGIMEN; ADULTS C1 [Horsburgh, C. Robert, Jr.] Boston Univ, Dept Epidemiol, Boston, MA 02118 USA. [Horsburgh, C. Robert, Jr.] Boston Univ, Dept Biostat, Boston, MA 02118 USA. [Horsburgh, C. Robert, Jr.] Boston Univ, Dept Med, Boston, MA 02118 USA. [Horsburgh, C. Robert, Jr.] Boston Univ, Ctr Global Hlth & Dev, Boston, MA 02118 USA. [Barry, Clifton E., III] NIAID, TB Res Sect, NIH, Bethesda, MD 20892 USA. [Barry, Clifton E., III] Univ Cape Town, Inst Infect Dis & Mol Med, ZA-7925 Cape Town, South Africa. [Lange, Christoph] Res Ctr Borstel, German Ctr Infect Res DZIF TB Unit, Div Clin Infect Dis, Borstel, Germany. [Lange, Christoph] Univ Lubeck, Int Health Infect Dis, Lubeck, Germany. RP Horsburgh, CR (reprint author), Boston Univ, Sch Publ Hlth, Dept Epidemiol, 715 Albany St,T3E, Boston, MA 02118 USA. EM rhorsbu@bu.edu RI Barry, III, Clifton/H-3839-2012 FU Janssen; Chiesi; Gilead; AbbVie; Merck Sharp Dohme FX Dr. Horsburgh reports receiving fees from Janssen for serving on a data and safety monitoring board; and Dr. Lange, lecture fees from Chiesi, Gilead, AbbVie, and Merck Sharp & Dohme. No other potential conflict of interest relevant to this article was reported. NR 70 TC 29 Z9 30 U1 4 U2 35 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 NOV 26 PY 2015 VL 373 IS 22 BP 2149 EP 2160 DI 10.1056/NEJMra1413919 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA CW9YT UT WOS:000365354800009 PM 26605929 ER PT J AU Lee, CR Zeldin, DC AF Lee, Craig R. Zeldin, Darryl C. TI Resolvin Infectious Inflammation by Targeting the Host Response SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID SEPSIS C1 [Lee, Craig R.] Univ N Carolina, Eshelman Sch Pharm, Div Pharmacotherapy & Expt Therapeut, Chapel Hill, NC 27599 USA. [Zeldin, Darryl C.] Natl Inst Environm Hlth Sci, Div Intramural Res, NIH, Res Triangle Pk, NC USA. RP Lee, CR (reprint author), Univ N Carolina, Eshelman Sch Pharm, Div Pharmacotherapy & Expt Therapeut, Chapel Hill, NC 27599 USA. OI Lee, Craig/0000-0003-3595-5301 NR 5 TC 6 Z9 6 U1 4 U2 6 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 NOV 26 PY 2015 VL 373 IS 22 BP 2183 EP 2185 DI 10.1056/NEJMcibr1511280 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA CW9YT UT WOS:000365354800020 PM 26605933 ER PT J AU Huang, XP Karpiak, J Kroeze, WK Zhu, H Chen, X Moy, SS Saddoris, KA Nikolova, VD Farrell, MS Wang, S Mangano, TJ Deshpande, DA Jiang, A Penn, RB Jin, J Koller, BH Kenakin, T Shoichet, BK Roth, BL AF Huang, Xi-Ping Karpiak, Joel Kroeze, Wesley K. Zhu, Hu Chen, Xin Moy, Sheryl S. Saddoris, Kara A. Nikolova, Viktoriya D. Farrell, Martilias S. Wang, Sheng Mangano, Thomas J. Deshpande, Deepak A. Jiang, Alice Penn, Raymond B. Jin, Jian Koller, Beverly H. Kenakin, Terry Shoichet, Brian K. Roth, Bryan L. TI Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65 SO NATURE LA English DT Article ID PROTEIN-COUPLED RECEPTOR; SMOOTH-MUSCLE-CELLS; EXTRACELLULAR ACIDIFICATION; CAMP ACCUMULATION; OGR1; EXPRESSION; PH; CANCER; ACTIVATION; COMPLEX AB At least 120 non-olfactory G-protein-coupled receptors in the human genome are 'orphans' for which endogenous ligands are unknown, and many have no selective ligands, hindering the determination of their biological functions and clinical relevance. Among these is GPR68, a proton receptor that lacks small molecule modulators for probing its biology. Using yeast-based screens against GPR68, here we identify the benzodiazepine drug lorazepam as a non-selective GPR68 positive allosteric modulator. More than 3,000 GPR68 homology models were refined to recognize lorazepam in a putative allosteric site. Docking 3.1 million molecules predicted new GPR68 modulators, many of which were confirmed in functional assays. One potent GPR68 modulator, ogerin, suppressed recall in fear conditioning in wild-type but not in GPR68-knockout mice. The same approach led to the discovery of allosteric agonists and negative allosteric modulators for GPR65. Combining physical and structure-based screening may be broadly useful for ligand discovery for understudied and orphan GPCRs. C1 [Huang, Xi-Ping; Kroeze, Wesley K.; Zhu, Hu; Farrell, Martilias S.; Wang, Sheng; Mangano, Thomas J.; Jiang, Alice; Kenakin, Terry; Roth, Bryan L.] Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA. [Huang, Xi-Ping; Mangano, Thomas J.; Jiang, Alice; Roth, Bryan L.] Univ N Carolina, Sch Med, Natl Inst Mental Hlth, Psychoact Drug Screening Program, Chapel Hill, NC 27599 USA. [Karpiak, Joel; Shoichet, Brian K.] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94158 USA. [Chen, Xin; Jin, Jian] Univ N Carolina, Ctr Integrat Chem Biol & Drug Discovery CICBDD, Chapel Hill, NC 27599 USA. [Chen, Xin; Jin, Jian; Roth, Bryan L.] Univ N Carolina, Eshelman Sch Pharm, Div Chem Biol & Med Chem, Chapel Hill, NC 27599 USA. [Moy, Sheryl S.; Saddoris, Kara A.; Nikolova, Viktoriya D.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27599 USA. [Moy, Sheryl S.; Saddoris, Kara A.; Nikolova, Viktoriya D.] Univ N Carolina, Carolina Inst Dev Disabil CIDD, Chapel Hill, NC 27599 USA. [Deshpande, Deepak A.; Penn, Raymond B.] Thomas Jefferson Univ, Ctr Translat Med, Philadelphia, PA 19107 USA. [Deshpande, Deepak A.; Penn, Raymond B.] Thomas Jefferson Univ, Dept Med, Philadelphia, PA 19107 USA. [Koller, Beverly H.] Univ N Carolina, Sch Med, Dept Genet, Chapel Hill, NC 27599 USA. RP Roth, BL (reprint author), Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA. EM bshoichet@gmail.com; bryan_roth@med.unc.edu FU National Institutes of Health (NIH) [U01104974, R01 DA017204]; National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP); Michael Hooker Chair for Protein Therapeutics and Translational Proteomics; Genentech Foundation Predoctoral Fellowship; NIH [GM59957, GM71896, U19MH082441]; Structural Genomics Consortium; NICHD [U54 HD079124]; [P01 HL114471] FX This work was supported by National Institutes of Health (NIH) grants U01104974 (B.L.R., B.K.S. and W.K.K.), R01 DA017204 (B.L.R. and W.K.K.) and the National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP) (X.-P.H., H.Z., M.S.F., W.K.K., T.J.M., A.J. and B.L.R.), the Michael Hooker Chair for Protein Therapeutics and Translational Proteomics to B.L.R.; Genentech Foundation Predoctoral Fellowship (J.K.); NIH grants GM59957 and GM71896 (B.K.S.) and the Structural Genomics Consortium (B.K.S.); grant P01 HL114471 (R.B.P. and D.A.D.); NICHD grant U54 HD079124 (M.S.M., K.A.S., V.N.); NIH grant U19MH082441 (B.L.R., J.J. and X.C.). We thank Mark Pausch (Merck & Co.) for providing us Gs- and Gq-yeast strains for yeast screening assays. NR 44 TC 22 Z9 22 U1 13 U2 26 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 NOV 26 PY 2015 VL 527 IS 7579 BP 477 EP + DI 10.1038/nature15699 PG 23 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CW9XW UT WOS:000365352500039 PM 26550826 ER PT J AU Peng, YQ Gillis-Smith, S Jin, H Trankner, D Ryba, NJP Zuker, CS AF Peng, Yueqing Gillis-Smith, Sarah Jin, Hao Traenkner, Dimitri Ryba, Nicholas J. P. Zuker, Charles S. TI Sweet and bitter taste in the brain of awake behaving animals SO NATURE LA English DT Article ID GUSTATORY STIMULI; MIMETIC RESPONSES; MAMMALIAN SWEET; REACTIVITY TEST; UMAMI TASTE; RECEPTORS; RATS; REPRESENTATION; CIRCUIT; NEURONS AB Taste is responsible for evaluating the nutritious content of food, guiding essential appetitive behaviours, preventing the ingestion of toxic substances, and helping to ensure the maintenance of a healthy diet. Sweet and bitter are two of the most salient sensory percepts for humans and other animals; sweet taste allows the identification of energy-rich nutrients whereas bitter warns against the intake of potentially noxious chemicals(1). In mammals, information from taste receptor cells in the tongue is transmitted through multiple neural stations to the primary gustatory cortex in the brain(2). Recent imaging studies have shown that sweet and bitter are represented in the primary gustatory cortex by neurons organized in a spatial map(3,4), with each taste quality encoded by distinct cortical fields(4). Here we demonstrate that by manipulating the brain fields representing sweet and bitter taste we directly control an animal's internal representation, sensory perception, and behavioural actions. These results substantiate the segregation of taste qualities in the cortex, expose the innate nature of appetitive and aversive taste responses, and illustrate the ability of gustatory cortex to recapitulate complex behaviours in the absence of sensory input. C1 [Peng, Yueqing; Gillis-Smith, Sarah; Jin, Hao; Traenkner, Dimitri; Zuker, Charles S.] Columbia Univ Coll Phys & Surg, Howard Hughes Med Inst, New York, NY 10032 USA. [Peng, Yueqing; Gillis-Smith, Sarah; Jin, Hao; Traenkner, Dimitri; Zuker, Charles S.] Columbia Univ Coll Phys & Surg, Dept Biochem, New York, NY 10032 USA. [Peng, Yueqing; Gillis-Smith, Sarah; Jin, Hao; Traenkner, Dimitri; Zuker, Charles S.] Columbia Univ Coll Phys & Surg, Dept Mol Biophys, New York, NY 10032 USA. [Peng, Yueqing; Gillis-Smith, Sarah; Jin, Hao; Traenkner, Dimitri; Zuker, Charles S.] Columbia Univ Coll Phys & Surg, Dept Neurosci, New York, NY 10032 USA. [Traenkner, Dimitri; Zuker, Charles S.] HHMI Janelia Farm Res Campus, Ashburn, VA 20147 USA. [Ryba, Nicholas J. P.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. RP Zuker, CS (reprint author), Columbia Univ Coll Phys & Surg, Howard Hughes Med Inst, New York, NY 10032 USA. EM nick.ryba@nih.gov; cz2195@cumc.columbia.edu FU National Institute of Drug Abuse [DA035025]; Intramural Research Program of the National Institutes of Health, National Institute of Dental and Craniofacial Research FX We particularly thank H. Fischman and R. Lessard for suggestions, and members of the Zuker laboratory for comments. We also thank D. Salzman, K. Scott, and R. Axel for discussions. This research was supported in part by a grant from the National Institute of Drug Abuse (DA035025) to C.S.Z., and the Intramural Research Program of the National Institutes of Health, National Institute of Dental and Craniofacial Research (to N.J.P.R.). C.S.Z. is an investigator of the Howard Hughes Medical Institute and a Senior Fellow at Janelia Farms Research Campus, Howard Hughes Medical Institute. NR 27 TC 13 Z9 13 U1 13 U2 54 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 NOV 26 PY 2015 VL 527 IS 7579 BP 512 EP + DI 10.1038/nature15763 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CW9XW UT WOS:000365352500047 PM 26580015 ER PT J AU Nesin, M Read, J Koso-Thomas, M Isaacs, MB Sobanjo-ter Meulen, A AF Nesin, Mirjana Read, Jennifer Koso-Thomas, Marion Isaacs, Maggie Brewinski Sobanjo-ter Meulen, Ajoke TI Maternal Immunization: Current status and future prospects SO VACCINE LA English DT Editorial Material ID SAFETY C1 [Nesin, Mirjana; Read, Jennifer] NIAID, NIH, Rockville, MD 20852 USA. [Koso-Thomas, Marion; Isaacs, Maggie Brewinski] NICHD, NIH, Rockville, MD USA. [Sobanjo-ter Meulen, Ajoke] Bill & Melinda Gates Fdn, Seattle, WA USA. RP Nesin, M (reprint author), NIAID, OCRR, DMID, NIH, 5601 Fischers Lane,Off 7G38, Rockville, MD 20852 USA. EM nesinm@niaid.nih.gov; jennifer.read@nih.gov; kosomari@mail.nih.gov; maggie.brewinskiisaacs@nih.gov; Ajoke.sobanjo-termeulen@gatesfoundation.org NR 3 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 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD NOV 25 PY 2015 VL 33 IS 47 SI SI BP 6371 EP 6371 DI 10.1016/j.vaccine.2015.09.085 PG 1 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA DA0LT UT WOS:000367489300001 PM 26432914 ER PT J AU Rubin, FA Koso-Thomas, M Isaacs, MB Piper, J Read, J Nesin, M AF Rubin, Fran A. Koso-Thomas, Marion Isaacs, Maggie Brewinski Piper, Jeanna Read, Jennifer Nesin, Mirjana TI Maternal immunization efforts of the National Institutes of Health SO VACCINE LA English DT Article DE Maternal immunization; Vaccine development; Protocol development ID INFLUENZAE TYPE-B; TOXOID CONJUGATE VACCINE; PREGNANT-WOMEN; POLYSACCHARIDE VACCINE; STREPTOCOCCAL POLYSACCHARIDE; III POLYSACCHARIDE; REFERENCE SERUM; IMMUNOGENICITY; ANTIBODY; SAFETY AB Over the last 35 years, efforts at the National Institutes of Health (NIH) to protect mothers and their infants against infectious diseases have involved a bench-to-bedside approach. Basic and translational research that provided a foundation for clinical trials of vaccines in pregnancy include natural history and vaccine antigen identification studies. Development of laboratory assays and reagents have been funded by NIAID; these are critical for the advancement of vaccine candidates through the preclinical and clinical steps along the maternal immunization research pathway to support vaccine efficacy. Animal models of maternal immunization have been developed to evaluate efficacy of vaccine candidates. Clinical studies required development of maternal immunization protocols to address specific pregnancy related issues, for enrollment and safety assessment of mothers and their infants. NIH has organized and participated in meetings, workshops and other collaborative efforts with partners have advanced maternal immunization efforts. Partners have included many institutes and offices at NIH as well as other Department of Health and Human Services agencies and offices (Food and Drug Administration, Centers for Disease Control and Prevention, National Vaccine Program Office), World Health Organization, academic investigators, Biotech and pharmaceutical companies, and nonprofit organizations such as the Bill and Melinda Gates Foundation. These research and development partnership are essential for advancing maternal immunization. Continued efforts are needed to promote maternal immunization to protect pregnant women and their infants against vaccine-preventable infectious disease, especially in resource-limited settings where the burden of infections is high. (C) 2015 The Authors. Published by Elsevier Ltd. C1 [Rubin, Fran A.; Nesin, Mirjana] NIAID, DMID, NIH, Rockville, MD 20852 USA. [Koso-Thomas, Marion] NICHD, NIH, Rockville, MD USA. [Isaacs, Maggie Brewinski] NIH, ORWH, Bethesda, MD USA. [Piper, Jeanna] NIAID, DAIDS, NIH, Rockville, MD 20852 USA. [Read, Jennifer] NIAID, DAIT, NIH, Rockville, MD 20852 USA. RP Nesin, M (reprint author), NIAID, DMID, NIH, 5601 Fischers Lane,Off 7G38, Rockville, MD 20852 USA. EM farphd@comcast.net; kosomari@mail.nih.gov; brewinskiisaamm@mail.nih.gov; Jeanna.Piper@niaid.nih.gov; jennifer.read@nih.gov; nesinm@niaid.nih.gov NR 45 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD NOV 25 PY 2015 VL 33 IS 47 SI SI BP 6380 EP 6387 DI 10.1016/j.vaccine.2015.08.097 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA DA0LT UT WOS:000367489300005 PM 26458798 ER PT J AU White, A Madhi, SA AF White, Amina Madhi, Shabir A. TI Ethical considerations for designing GBS maternal vaccine efficacy trials in low-middle income countries SO VACCINE LA English DT Article DE Immunization; Group B Streptococcus; Pregnancy; Exploitation; Low-middle income countries; Research ethics; Trial design ID B STREPTOCOCCAL DISEASE; INTRAPARTUM ANTIBIOTIC-PROPHYLAXIS; INTERNATIONAL CONSENSUS OPINION; PREGNANT-WOMEN; CONJUGATE VACCINE; CARE DEBATE; CLINICAL-RESEARCH; INVASIVE DISEASE; INFANTS; STANDARD AB Many in the scientific community agree that a randomized, placebo-controlled trial would Offer the most scientifically rigorous study design for establishing the efficacy of a Group B Streptococcus (GBS) vaccine administered to pregnant women for the prevention of invasive GBS disease in young infants. There are compelling reasons to conduct such a trial in low-middle income countries (LMICs) with a high burden of disease, such as South Africa, and to adopt an add-on trial design in which participants are randomized to receive the GBS vaccine or placebo in addition to the locally available standard of care. Yet there is a longstanding debate about whether trials in LMICs should offer participants the worldwide best available standard of care. In this article, we examine both the risk-benefit profile and the potential for exploitation with an add-on trial design in the context of the locally available standard of care in South Africa. Our analysis suggests that providing the local standard of care to participants in this case may be not only more scientifically valuable but also more ethically acceptable than attempting to provide the worldwide best available standard of care in the South African setting. Moreover, the example of GBS in the South African setting can help to elucidate important ethical considerations for determining the acceptability of testing vaccine efficacy in the context of locally available rather than the worldwide best available standard of care in Phase III trials of other new maternal vaccines. (C) 2015 The Authors. Published by Elsevier Ltd. C1 [White, Amina] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. [Madhi, Shabir A.] MRC, Resp & Meningeal Pathogens Res Unit, Johannesburg, South Africa. [Madhi, Shabir A.] Univ Witwatersrand, Fac Hlth Sci, Dept Sci, Natl Res Fdn Vaccine Preventable Dis, Johannesburg, South Africa. RP White, A (reprint author), NIH, Dept Bioeth, 10 Ctr Dr,1C118, Bethesda, MD 20892 USA. EM Amina.white@nih.gov FU Intramural Program at the National Institutes of Health; Department of Bioethics FX This work is funded by the Intramural Program at the National Institutes of Health and the Department of Bioethics in particular. NR 31 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD NOV 25 PY 2015 VL 33 IS 47 SI SI BP 6396 EP 6400 DI 10.1016/j.vaccine,2015.07.108 PG 5 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA DA0LT UT WOS:000367489300007 PM 26271832 ER PT J AU Saloustros, E Salpea, P Qi, CF Gugliotti, LA Tsang, K Liu, S Starost, MF Morse, HC Stratakis, CA AF Saloustros, Emmanouil Salpea, Paraskevi Qi, Chen-Feng Gugliotti, Lina A. Tsang, Kitman Liu, Sisi Starost, Matthew F. Morse, Herbert C., III Stratakis, Constantine A. TI Hematopoietic neoplasms in Prkar2a-deficient mice SO JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH LA English DT Article DE Protein kinase A; Histiocytic sarcoma; Cyclic AMP; Diffuse large B cell lymphoma; Carney complex ID PROTEIN-KINASE-A; B-CELL LYMPHOMA; ALPHA REGULATORY SUBUNIT; CARNEY COMPLEX; NASOPHARYNGEAL CARCINOMA; SUSCEPTIBILITY LOCUS; BETHESDA PROPOSALS; CHROMOSOME 3P21; LEUKEMIA; PKA AB Background: Protein kinase A (PKA) is a holoenzyme that consists of a dimer of regulatory subunits and two inactive catalytic subunits that bind to the regulatory subunit dimer. Four regulatory subunits (RI alpha, RI beta, RII alpha, RII beta) and four catalytic subunits (C alpha, C beta, C gamma, Prkx) have been described in the human and mouse genomes. Previous studies showed that complete inactivation of the Prkar1a subunit (coding for RIa) in the germline leads to embryonic lethality, while Prkar1a-deficient mice are viable and develop schwannomas, thyroid, and bone neoplasms, and rarely lymphomas and sarcomas. Mice with inactivation of the Prkar2a and Prkar2b genes (coding for RII alpha and RII beta, respectively) are also viable but have not been studied for their susceptibility to any tumors. Methods: Cohorts of Prkar1a(+/-), Prkar2a(+/-), Prkar2a(-/-), Prkar2b(+/-) and wild type (WT) mice have been observed between 5 and 25 months of age for the development of hematologic malignancies. Tissues were studied by immunohistochemistry; tumor-specific markers were also used as indicated. Cell sorting and protein studies were also performed. Results: Both Prkar2a(-/-) and Prkar2a(+/-) mice frequently developed hematopoietic neoplasms dominated by histiocytic sarcomas (HS) with rare diffuse large B cell lymphomas (DLBCL). Southern blot analysis confirmed that the tumors diagnosed histologically as DLBCL were clonal B cell neoplasms. Mice with other genotypes did not develop a significant number of similar neoplasms. Conclusions: Prkar2a deficiency predisposes to hematopoietic malignancies in vivo. RII alpha's likely association with HS and DLBCL was hitherto unrecognized and may lead to better understanding of these rare neoplasms. C1 [Saloustros, Emmanouil; Salpea, Paraskevi; Tsang, Kitman; Liu, Sisi; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet PDEGEN, NIH, Bethesda, MD 20892 USA. [Saloustros, Emmanouil; Salpea, Paraskevi; Tsang, Kitman; Liu, Sisi; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Endocrinol Interinst Training Program, NIH, Bethesda, MD 20892 USA. [Qi, Chen-Feng; Morse, Herbert C., III] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Gugliotti, Lina A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom & Differentiat, NIH, Bethesda, MD 20892 USA. [Starost, Matthew F.] NIH, Div Vet Resources, OD, Bethesda, MD 20892 USA. RP Morse, HC (reprint author), NIAID, Immunogenet Lab, NIH, 5640 Fishers Lane, Rockville, MD 20852 USA. EM hmorse@niaid.nih.gov; stratakc@mail.nih.gov OI Saloustros, Emmanouil /0000-0002-0485-0120 FU Intramural Research Program (IRP) of the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD); National Institute of Allergy and Infectious Diseases (HCM, CQI), National Institutes of Health (NIH), Bethesda, MD; Hellenic Society of Medical Oncology FX This work was supported by the Intramural Research Program (IRP) of the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), and the National Institute of Allergy and Infectious Diseases (HCM, CQI), National Institutes of Health (NIH), Bethesda, MD 20892 and by a research grant from Hellenic Society of Medical Oncology (awardee: Emmanouil Saloustros). NR 35 TC 2 Z9 3 U1 1 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-9966 J9 J EXP CLIN CANC RES JI J. Exp. Clin. Cancer Res. PD NOV 25 PY 2015 VL 34 AR 143 DI 10.1186/s13046-015-0257-z PG 8 WC Oncology SC Oncology GA CY6BI UT WOS:000366491700001 PM 26608815 ER PT J AU Li, F Grishaev, A Ying, JF Bax, A AF Li, Fang Grishaev, Alexander Ying, Jinfa Bax, Ad TI Side Chain Conformational Distributions of a Small Protein Derived from Model-Free Analysis of a Large Set of Residual Dipolar Couplings SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID LIQUID-CRYSTALLINE MEDIUM; X-RAY CRYSTALLOGRAPHY; MAGNETIC-RESONANCE RELAXATION; NMR-SPECTROSCOPY; MOLECULAR-DYNAMICS; BINDING DOMAIN; METHYL-GROUPS; BIOLOGICAL MACROMOLECULES; CONSERVATIVE MUTAGENESIS; STAPHYLOCOCCAL NUCLEASE AB Accurate quantitative measurement of structural dispersion in proteins remains a prime challenge to both X-ray crystallography and NMR spectroscopy. Here we use a model-free approach based on measurement of many residual dipolar couplings (RDCs) in differentially orienting aqueous liquid crystalline solutions to obtain the side chain chi 1 distribution sampled by each residue in solution. Applied to the small well-ordered model protein GB3, our approach reveals that the RDC data are compatible with a single narrow distribution of side chain chi 1 angles for only about 40% of the residues. For more than half of the residues, populations greater than 10% for a second rotamer are observed, and four residues require sampling of three rotameric states to fit the RDC data. In virtually all cases, sampled chi 1 values are found to center closely around ideal g , g(+) and t rotameric angles, even though no rotamer restraint is used when deriving the sampled angles. The root-mean-square difference between experimental (3)J(H alpha H beta) couplings and those predicted by the Haasnoot-parametrized, motion-adjusted Karplus equation reduces from 2.05 to 0.75 Hz when using the new rotamer analysis instead of the 1.1-a X-ray structure as input for the dihedral angles. A comparison between observed and predicted (3)J(H alpha H beta) values suggests that the root-mean-square amplitude of chi 1 angle fluctuations within a given rotamer well is ca. 20. The quantitatively defined side chain rotamer equilibria obtained from our study set new benchmarks for evaluating improved molecular dynamics force fields, and also will enable further development of quantitative relations between side chain chemical shift and structure. C1 [Li, Fang; Ying, Jinfa; Bax, Ad] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Grishaev, Alexander] NIST, Inst Biosci & Biotechnol Res, Rockville, MD 20850 USA. RP Bax, A (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM bax@nih.gov FU Intramural Research Program of National Institute of Diabetes and Digestive and Kidney Diseases; Intramural Antiviral Target Program of Office of Director, NIH; China Scholarship Council FX We thank Dr. Yang Shen for assistance in data analysis and Dennis Torchia for useful discussions. This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases and by the Intramural Antiviral Target Program of the Office of the Director, NIH. F. Li acknowledges financial support from the China Scholarship Council. NR 91 TC 5 Z9 5 U1 4 U2 26 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 NOV 25 PY 2015 VL 137 IS 46 BP 14798 EP 14811 DI 10.1021/jacs.5b10072 PG 14 WC Chemistry, Multidisciplinary SC Chemistry GA CX9DH UT WOS:000366004700033 PM 26523828 ER PT J AU Chang, DC Piaggi, P Hanson, RL Knowler, WC Bucci, J Thio, G Hohenadel, MG Bogardus, C Krakoff, J AF Chang, Douglas C. Piaggi, Paolo Hanson, Robert L. Knowler, William C. Bucci, John Thio, Guene Hohenadel, Maximilian G. Bogardus, Clifton Krakoff, Jonathan TI Use of a High-Density Protein Microarray to Identify Autoantibodies in Subjects with Type 2 Diabetes Mellitus and an HLA Background Associated with Reduced Insulin Secretion SO PLOS ONE LA English DT Article ID T-CELL RESPONSES; PIMA-INDIANS; IDENTIFICATION; PATHOGENESIS; OBESITY; RESISTANCE; GAMMA; POLYMORPHISMS; AUTOANTIGENS; AUTOIMMUNITY AB New biomarkers for type 2 diabetes mellitus (T2DM) may aid diagnosis, drug development or clinical treatment. Evidence is increasing for the adaptive immune system's role in T2DM and suggests the presence of unidentified autoantibodies. While high-density protein microarrays have emerged as a useful technology to identify possible novel autoantigens in autoimmune diseases, its application in T2DM has lagged. In Pima Indians, the HLA haplotype (HLA-DRB1*02) is protective against T2DM and, when studied when they have normal glucose tolerance, subjects with this HLA haplotype have higher insulin secretion compared to those without the protective haplotype. Possible autoantibody biomarkers were identified using microarrays containing 9480 proteins in plasma from Pima Indians with T2DM without the protective haplotype (n = 7) compared with those with normal glucose regulation (NGR) with the protective haplotype (n = 11). A subsequent validation phase involving 45 cases and 45 controls, matched by age, sex and specimen storage time, evaluated 77 proteins. Eleven autoantigens had higher antibody signals among T2DM subjects with the lower insulin-secretion HLA background compared with NGR subjects with the higher insulin-secretion HLA background (p<0.05, adjusted for multiple comparisons). PPARG2 and UBE2M had lowest p-values (adjusted p = 0.023) while PPARG2 and RGS17 had highest case-to-control antibody signal ratios (1.7). A multi-protein classifier involving the 11 autoantigens had sensitivity, specificity, and area under the receiver operating characteristics curve of 0.73, 0.80, and 0.83 (95% CI 0.74-0.91, p = 3.4x10(-8)), respectively. This study identified 11 novel autoantigens which were associated with T2DM and an HLA background associated with reduced insulin secretion. While further studies are needed to distinguish whether these antibodies are associated with insulin secretion via the HLA background, T2DM more broadly, or a combination of the two, this study may aid the search for autoantibody biomarkers by narrowing the list of protein targets. C1 [Chang, Douglas C.; Piaggi, Paolo; Hanson, Robert L.; Knowler, William C.; Hohenadel, Maximilian G.; Bogardus, Clifton; Krakoff, Jonathan] NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ USA. [Bucci, John; Thio, Guene] Life Technol, Carlsbad, CA USA. RP Chang, DC (reprint author), NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ USA. EM changdc@mail.nih.gov FU Intramural Research Program of NIH, NIDDK; Life Technologies FX The research was solely funded by the Intramural Research Program of NIH, NIDDK. The funder provided support in the form of salaries for authors D.C.C., P.P, R.L.H., W.C.K., M.G.H., C.B, and J.K. The authors J.B. and G.T. are employed by Life Technologies, a commercial company. Life Technologies provided support in the form of salaries for authors J.B. and G.T, 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. NR 50 TC 1 Z9 1 U1 0 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 NOV 25 PY 2015 VL 10 IS 11 AR e0143551 DI 10.1371/journal.pone.0143551 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CX7ES UT WOS:000365865300079 PM 26606528 ER PT J AU Knight, JM Mak, G Shaw, J Porter, P McDermott, C Roberts, L You, R Yuan, XY Millien, VO Qian, YP Song, LZ Frazier, V Kim, C Kim, JJ Bond, RA Milner, JD Zhang, Y Mandal, PK Luong, A Kheradmand, F McMurray, JS Corry, DB AF Knight, John M. Mak, Garbo Shaw, Joanne Porter, Paul McDermott, Catherine Roberts, Luz You, Ran Yuan, Xiaoyi Millien, Valentine O. Qian, Yuping Song, Li-Zhen Frazier, Vincent Kim, Choel Kim, Jeong Joo Bond, Richard A. Milner, Joshua D. Zhang, Yuan Mandal, Pijus K. Luong, Amber Kheradmand, Farrah McMurray, John S. Corry, David B. TI Long-Acting Beta Agonists Enhance Allergic Airway Disease SO PLOS ONE LA English DT Article ID BETA(2)-ADRENERGIC RECEPTOR; MURINE MODEL; TRANSCRIPTION FACTOR; EXPERIMENTAL ASTHMA; SIGNALING PATHWAYS; LUNG-DISEASE; MILD ASTHMA; SH2 DOMAIN; MICE; INFLAMMATION AB Asthma is one of the most common of medical illnesses and is treated in part by drugs that activate the beta-2-adrenoceptor (beta 2-AR) to dilate obstructed airways. Such drugs include long acting beta agonists (LABAs) that are paradoxically linked to excess asthma-related mortality. Here we show that LABAs such as salmeterol and structurally related beta 2-AR drugs such as formoterol and carvedilol, but not short-acting agonists (SABAs) such as albuterol, promote exaggerated asthma-like allergic airway disease and enhanced airway constriction in mice. We demonstrate that salmeterol aberrantly promotes activation of the allergic disease-related transcription factor signal transducer and activator of transcription 6 (STAT6) in multiple mouse and human cells. A novel inhibitor of STAT6, PM-242H, inhibited initiation of allergic disease induced by airway fungal challenge, reversed established allergic airway disease in mice, and blocked salmeterol-dependent enhanced allergic airway disease. Thus, structurally related beta 2-AR ligands aberrantly activate STAT6 and promote allergic airway disease. This untoward pharmacological property likely explains adverse outcomes observed with LABAs, which may be overcome by agents that antagonize STAT6. C1 [Knight, John M.; You, Ran; Yuan, Xiaoyi] Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA. [Knight, John M.; You, Ran; Yuan, Xiaoyi] Baylor Coll Med, Dept Immunol & Med, Houston, TX 77030 USA. [Mak, Garbo; Porter, Paul; McDermott, Catherine; Roberts, Luz; Qian, Yuping; Song, Li-Zhen; Frazier, Vincent] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Shaw, Joanne] Univ Texas Med Sch Houston, Dept Otorhinolaryngolgy Head & Neck Surg, Houston, TX USA. [Millien, Valentine O.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Millien, Valentine O.] Baylor Coll Med, Translat Biol & Mol Med Program, Houston, TX 77030 USA. [Kim, Choel] Baylor Coll Med, Dept Pharmacol, Houston, TX 77030 USA. [Kim, Choel] Baylor Coll Med, Dept Biochem & Mol Biol, Houston, TX 77030 USA. [Kim, Jeong Joo] Baylor Coll Med, Dept Biochem & Mol Biol, Houston, TX 77030 USA. [Bond, Richard A.] Univ Houston, Coll Pharm, Dept Pharmacol & Pharmaceut Sci, Houston, TX 77030 USA. [Milner, Joshua D.; Zhang, Yuan] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Mandal, Pijus K.; McMurray, John S.] Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA. [Luong, Amber] Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA. [Luong, Amber] Univ Texas Med Sch Houston, Ctr Immunol & Autoimmune Dis, Brown Fdn Inst Mol Med Prevent Human Dis, Houston, TX USA. [Kheradmand, Farrah; Corry, David B.] Baylor Coll Med, Dept Med, Translat Biol & Mol Med Program, Houston, TX 77030 USA. [Kheradmand, Farrah; Corry, David B.] Baylor Coll Med, Dept Pathol & Immunol, Translat Biol & Mol Med Program, Houston, TX 77030 USA. [Kheradmand, Farrah; Corry, David B.] Baylor Coll Med, Biol Inflammat Ctr, Houston, TX 77030 USA. [Kheradmand, Farrah; Corry, David B.] Michael DeBakey VA Ctr Translat Res Inflammatory, Houston, TX USA. RP McMurray, JS (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA. EM jmcmurra@mdanderson.org; dcorry@bcm.edu FU American Asthma Foundation [11-0360]; Clayton Foundation for Research [Corr2012]; Cancer Center Support Grant [P30 CA16672-38]; Intramural Research Program of the United States National Institutes of Health, National Institute of Allergy and Infectious Diseases (NIH, NIAID) FX This study was supported by the American Asthma Foundation, grant 11-0360 http://www.americanasthmafoundation.org; Clayton Foundation for Research, Corr2012, http://www.claytonbiotech.com; Cancer Center Support Grant P30 CA16672-38; and the Intramural Research Program of the United States National Institutes of Health, National Institute of Allergy and Infectious Diseases (NIH, NIAID). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; Supported in part by the American Asthma Foundation (Award 11-0360) and the Intramural Research Program of the United States National Institutes of Health, National Institute of Allergy and Infectious Diseases (NIH, NIAID). We acknowledge the Cancer Center Support Grant (P30 CA16672-38) and the Translational Chemistry Core Facility for providing mass spectrometry services during the synthesis of PM-242H (both at MDACC). We thank Julia K. Walker, Ph.D., for providing beta arrestin 2-deficient mice. NR 62 TC 0 Z9 0 U1 1 U2 5 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 NOV 25 PY 2015 VL 10 IS 11 AR e0142212 DI 10.1371/journal.pone.0142212 PG 22 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CX7ES UT WOS:000365865300012 PM 26605551 ER PT J AU Prescott, J Setiawan, VW Wentzensen, N Schumacher, F Yu, H Delahanty, R Bernstein, L Chanock, SJ Chen, C Cook, LS Friedenreich, C Garcia-Closas, M Haiman, CA Le Marchand, L Liang, XL Lissowska, J Lu, LG Magliocco, AM Olson, SH Risch, HA Shu, XO Ursin, G Yang, HP Kraft, P De Vivo, I AF Prescott, Jennifer Setiawan, Veronica W. Wentzensen, Nicolas Schumacher, Fredrick Yu, Herbert Delahanty, Ryan Bernstein, Leslie Chanock, Stephen J. Chen, Chu Cook, Linda S. Friedenreich, Christine Garcia-Closas, Monserrat Haiman, Christopher A. Le Marchand, Loic Liang, Xiaolin Lissowska, Jolanta Lu, Lingeng Magliocco, Anthony M. Olson, Sara H. Risch, Harvey A. Shu, Xiao-Ou Ursin, Giske Yang, Hannah P. Kraft, Peter De Vivo, Immaculata TI Body Mass Index Genetic Risk Score and Endometrial Cancer Risk SO PLOS ONE LA English DT Article ID POSTMENOPAUSAL HORMONE-THERAPY; GENOME-WIDE ASSOCIATION; REPLACEMENT THERAPY; UNITED-STATES; VARIANTS; ESTROGEN; WOMEN; SUSCEPTIBILITY AB Genome-wide association studies (GWAS) have identified common variants that predispose individuals to a higher body mass index (BMI), an independent risk factor for endometrial cancer. Composite genotype risk scores (GRS) based on the joint effect of published BMI risk loci were used to explore whether endometrial cancer shares a genetic background with obesity. Genotype and risk factor data were available on 3,376 endometrial cancer case and 3,867 control participants of European ancestry from the Epidemiology of Endometrial Cancer Consortium GWAS. A BMI GRS was calculated by summing the number of BMI risk alleles at 97 independent loci. For exploratory analyses, additional GRSs were based on subsets of risk loci within putative etiologic BMI pathways. The BMI GRS was statistically significantly associated with endometrial cancer risk (P = 0.002). For every 10 BMI risk alleles a woman had a 13% increased endometrial cancer risk (95% CI: 4%, 22%). However, after adjusting for BMI, the BMI GRS was no longer associated with risk (per 10 BMI risk alleles OR = 0.99, 95% CI: 0.91, 1.07; P = 0.78). Heterogeneity by BMI did not reach statistical significance (P = 0.06), and no effect modification was noted by age, GWAS Stage, study design or between studies (P >= 0.58). In exploratory analyses, the GRS defined by variants at loci containing monogenic obesity syndrome genes was associated with reduced endometrial cancer risk independent of BMI (per BMI risk allele OR = 0.92, 95% CI: 0.88, 0.96; P = 2.1 x 10(-5)). Possessing a large number of BMI risk alleles does not increase endometrial cancer risk above that conferred by excess body weight among women of European descent. Thus, the GRS based on all current established BMI loci does not provide added value independent of BMI. Future studies are required to validate the unexpected observed relation between monogenic obesity syndrome genetic variants and endometrial cancer risk. C1 [Prescott, Jennifer; De Vivo, Immaculata] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Prescott, Jennifer; Kraft, Peter; De Vivo, Immaculata] Harvard Univ, Sch Med, Boston, MA USA. [Prescott, Jennifer; De Vivo, Immaculata] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Program Genet Epidemiol & Stat Genet, Boston, MA USA. [Setiawan, Veronica W.; Schumacher, Fredrick; Haiman, Christopher A.; Ursin, Giske] Univ Calif Los Angeles, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA. [Wentzensen, Nicolas; Chanock, Stephen J.; Yang, Hannah P.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Yu, Herbert] Univ Hawaii, Program Epidemiol, Ctr Canc, Honolulu, HI 96822 USA. [Yu, Herbert] Yale Univ, Dept Epidemiol & Publ Hlth, Yale Canc Ctr, Yale Sch Publ Hlth, New Haven, CT 06520 USA. [Delahanty, Ryan; Shu, Xiao-Ou] Vanderbilt Univ, Sch Med, Div Epidemiol, Dept Med, Nashville, TN 37212 USA. [Delahanty, Ryan; Shu, Xiao-Ou] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37212 USA. [Bernstein, Leslie] City Hope Natl Med Ctr, Beckman Res Inst, Duarte, CA USA. [Chen, Chu] Univ Washington, Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98195 USA. [Chen, Chu] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Cook, Linda S.] Univ New Mexico, Albuquerque, NM 87131 USA. [Friedenreich, Christine] Alberta Hlth Serv Canc Control Alberta, Dept Populat Hlth Res, Div Canc Care, Calgary, AB, Canada. [Garcia-Closas, Monserrat] Inst Canc Res, Div Genet & Epidemiol, Sutton, Surrey, England. [Liang, Xiaolin; Olson, Sara H.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Lissowska, Jolanta] Ctr Canc, Dept Epidemiol & Canc Prevent, Warsaw, Poland. [Lissowska, Jolanta] M Sklodowska Curie Inst Oncol, Warsaw, Poland. [Magliocco, Anthony M.] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [Ursin, Giske] Canc Registry Norway, Oslo, Norway. [Ursin, Giske] Univ Oslo, Inst Basic Med Sci, Dept Nutr, Oslo, Norway. RP Prescott, J (reprint author), Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. EM jennifer.prescott@channing.harvard.edu FU National Institutes of Health [R01 CA134958, U54 CA155626, R01 CA83918, P30 CA008748, R35 CA39779, R01 CA75977, R03 CA80636, N01 HD23166, N01 CN05230, N01 CN67009, R01 CA105212, R01 CA87538, P01 CA87969, R01 CA49449, R01 CA77398, CA091019, K05 CA136967]; Canadian Cancer Society; Canadian Institutes for Health Research; Health Senior Scholar, Alberta Innovates-Health Solutions; National Cancer Institute at the National Institutes of Health [R01 CA098346]; National Cancer Institute [R37 CA054281, R01 CA063464]; Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health FX This work was supported by the National Institutes of Health [grant R01 CA134958 (IDV)]. JP was supported by the National Institutes of Health [grant U54 CA155626]. The Alberta Health Services Study was funded by research grants from the Canadian Cancer Society and the Canadian Institutes for Health Research. CF was supported as a Health Senior Scholar by Alberta Innovates-Health Solutions. The Connecticut Endometrial Cancer Study was supported by the National Cancer Institute at the National Institutes of Health [grant R01 CA098346 (HY)]. The Estrogen, Diet, Genetics, and Endometrial Cancer study was supported by the National Institutes of Health [grants R01 CA83918 (SHO), P30 CA008748]. The Fred Hutchinson Cancer Research Center studies were supported by the National Institute of Health [grants R35 CA39779, R01 CA75977, R03 CA80636 (CC), N01 HD23166, N01 CN05230, N01 CN67009, R01 CA105212 (CC) and R01 CA87538]. The Multiethnic Cohort was supported by the National Cancer Institute [grants R37 CA054281, R01 CA063464]. The Nurses' Health Study was supported by the National Institutes of Health [grants P01 CA87969, R01 CA49449]. The California Teachers Study was supported by the National Institutes of Health [grants R01 CA77398 (LB), CA091019, and K05 CA136967 (LB)]. The Polish Endometrial Case-Control Study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 35 TC 4 Z9 4 U1 1 U2 8 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 NOV 25 PY 2015 VL 10 IS 11 AR e0143256 DI 10.1371/journal.pone.0143256 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CX7ES UT WOS:000365865300049 PM 26606540 ER PT J AU Rastinehad, AR Waingankar, N Turkbey, B Yaskiv, O Sonstegard, AM Fakhoury, M Olsson, CA Siegel, DN Choyke, PL Ben-Levi, E Villani, R AF Rastinehad, Ardeshir R. Waingankar, Nikhil Turkbey, Baris Yaskiv, Oksana Sonstegard, Anna M. Fakhoury, Mathew Olsson, Carl A. Siegel, David N. Choyke, Peter L. Ben-Levi, Eran Villani, Robert TI Comparison of Multiparametric MRI Scoring Systems and the Impact on Cancer Detection in Patients Undergoing MR US Fusion Guided Prostate Biopsies SO PLOS ONE LA English DT Article ID TRANSRECTAL ULTRASOUND BIOPSY; ACTIVE SURVEILLANCE; RISK; STRATIFICATION AB Introduction Multiple scoring systems have been proposed for prostate MRI reporting. We sought to review the clinical impact of the new Prostate Imaging Reporting and Data System v2 (PI- RADS) and compare those results to our proposed Simplified Qualitative System (SQS) score with respect to detection of prostate cancers and clinically significant prostate cancers. Methods All patients who underwent multiparametric prostate MRI (mpMRI) had their images interpreted using PI-RADS v1 and SQS score. PI-RADS v2 was calculated from prospectively collected data points. Patients with positive mpMRIs were then referred by their urologists for enrollment in an IRB-approved prospective phase III trial of mpMRI-Ultrasound (MR/TRUS) fusion biopsy of suspicious lesions. Standard 12-core biopsy was performed at the same setting. Clinical data were collected prospectively. Results 1060 patients were imaged using mpMRI at our institution during the study period. 341 participants were then referred to the trial. 312 participants underwent MR/TRUS fusion biopsy of 452 lesions and were included in the analysis. 202 participants had biopsy-proven cancer (64.7%) and 206 (45.6%) lesions were positive for cancer. Distribution of cancer detected at each score produced a Gaussian distribution for SQS while PI-RADS demonstrates a negatively skewed curve with 82.1% of cases being scored as a 4 or 5. Patient-level data demonstrated AUC of 0.702 (95% CI 0.65 to 0.73) for PI-RADS and 0.762 (95% CI 0.72 to 0.81) for SQS (p< 0.0001) with respect to the detection of prostate cancer. The analysis for clinically significant prostate cancer at a per lesion level resulted in an AUC of 0.725 (95% CI 0.69 to 0.76) and 0.829 (95% CI 0.79 to 0.87) for the PI-RADS and SQS score, respectively (p< 0.0001). Conclusions mpMRI is a useful tool in the workup of patients at risk for prostate cancer, and serves as a platform to guide further evaluation with MR/TRUS fusion biopsy. SQS score provided a more normal distribution of scores and yielded a higher AUC than PI-RADS v2. However until our findings are validated, we recommend reporting of detailed sequence-specific findings. This will allow for prospectively collected data to be utilized in determining the impact of ongoing changes to these scoring systems as our understanding of mpMRI interpretation evolves. C1 [Rastinehad, Ardeshir R.; Olsson, Carl A.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Waingankar, Nikhil] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Turkbey, Baris; Choyke, Peter L.] NIH, Mol Imaging Program, Bethesda, MD 20892 USA. [Yaskiv, Oksana; Sonstegard, Anna M.; Fakhoury, Mathew; Siegel, David N.; Ben-Levi, Eran; Villani, Robert] Hofstra North Shore LIJ Sch Med, New Hyde Pk, NY USA. RP Rastinehad, AR (reprint author), Icahn Sch Med Mt Sinai, New York, NY 10029 USA. EM art.rastinehad@mountsinai.org NR 20 TC 8 Z9 8 U1 2 U2 5 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 NOV 25 PY 2015 VL 10 IS 11 AR e0143404 DI 10.1371/journal.pone.0143404 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CX7ES UT WOS:000365865300062 PM 26605548 ER PT J AU Castro, FA Koshiol, J Quint, W Wheeler, CM Gillison, ML Vaughan, LM Kleter, B van Doorn, LJ Chaturvedi, AK Hildesheim, A Schiffman, M Wang, SS Zuna, RE Walker, JL Dunn, ST Wentzensen, N AF Castro, Felipe A. Koshiol, Jill Quint, Wim Wheeler, Cosette M. Gillison, Maura L. Vaughan, Laurence M. Kleter, Bernhard van Doorn, Leen-Jan Chaturvedi, Anil K. Hildesheim, Allan Schiffman, Mark Wang, Sophia S. Zuna, Rosemary E. Walker, Joan L. Dunn, S. Terence Wentzensen, Nicolas TI Detection of HPV DNA in paraffin-embedded cervical samples: a comparison of four genotyping methods SO BMC INFECTIOUS DISEASES LA English DT Article DE Genotyping; Formalin-fixed paraffin-embedded tissues; Cervical intraepithelial lesions; Exfoliated-cell ID GENITAL HUMAN-PAPILLOMAVIRUS; EARLY END-POINTS; PCR AMPLIFICATION; UNITED-STATES; INNO-LIPA; INTRAEPITHELIAL NEOPLASIA; BIOPSY SPECIMENS; BROAD-SPECTRUM; CANCER; TISSUES AB Background: Identification of human papillomavirus (HPV) DNA in cervical tissue is important for understanding cervical carcinogenesis and for evaluating cervical cancer prevention approaches. However, HPV genotyping using formalin-fixed, paraffin-embedded (FFPE) tissues is technically challenging. We evaluated the performance of four commonly used genotyping methods on FFPE cervical specimens conducted in different laboratories and compared to genotyping results from cytological samples. Methods: We included 60 pairs of exfoliated-cell and FFPE specimens from women with histologically confirmed cervical intraepithelial lesions grade 2 or 3. Cytology specimens were genotyped using the Linear Array assay. Four expert laboratories processed tissue specimens using different preparation methods and then genotyped the resultant sample preparations using four different HPV genotyping methods: SPF10-PCR DEIA LiPA25 (version 1), Inno-LiPA, Linear Array and the Onclarity assay. Percentage agreement, kappa statistics and McNemar's chi-square were calculated for each comparison of different methods and specimen types. Results: Overall agreement with respect to carcinogenic HPV status for FFPE samples between different methods was: 81.7, 86.7 and 91.7 % for Onclarity versus Inno-LiPA, Linear Array and SPF-LiPA25, respectively; 81.7 and 85.0 % for Linear Array versus Inno-LiPA and SPF-LiPA25, respectively; and 86.7 % for SPF-LiPA25 versus Inno-LiPA. Type-specific agreement was >88.3 % for all pair-wise comparisons. Comparisons with cytology specimens resulted in overall agreements from 80 to 95 % depending on the method and type-specific agreement was > 90 % for most comparisons. Conclusions: Our data demonstrate that the four genotyping methods run by expert laboratories reliably detect HPV DNA in FFPE specimens with some variation in genotype-specific detection. C1 [Castro, Felipe A.; Koshiol, Jill; Chaturvedi, Anil K.; Hildesheim, Allan; Schiffman, Mark; Wentzensen, Nicolas] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Quint, Wim; Kleter, Bernhard; van Doorn, Leen-Jan] DDL, Diagnost Lab, Rijswijk, Netherlands. [Gillison, Maura L.] Ohio State Univ, Ctr Comprehens Canc, Viral Oncol Program, Columbus, OH 43210 USA. [Wheeler, Cosette M.] Univ New Mexico, Sch Med, Dept Pathol, Albuquerque, NM 87131 USA. [Vaughan, Laurence M.] BD Diagnost, Sparks, MD USA. [Wang, Sophia S.] City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Div Canc Etiol, Duarte, CA 91010 USA. [Wang, Sophia S.] City Hope Natl Med Ctr, Duarte, CA USA. [Zuna, Rosemary E.; Walker, Joan L.; Dunn, S. Terence] Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK USA. [Zuna, Rosemary E.; Walker, Joan L.; Dunn, S. Terence] Univ Oklahoma, Hlth Sci Ctr, Dept Obstet & Gynecol, Oklahoma City, OK 73190 USA. [Wentzensen, Nicolas] NCI Shady Grove, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA. RP Wentzensen, N (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM wentzenn@mail.nih.gov FU Intramural Research Program of the NCI [Z01 CP010124] FX Intramural Research Program of the NCI (Z01 CP010124: Cervical cancer and human papillomavirus (HPV) infection). NR 40 TC 3 Z9 3 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2334 J9 BMC INFECT DIS JI BMC Infect. Dis. PD NOV 25 PY 2015 VL 15 AR 544 DI 10.1186/s12879-015-1281-5 PG 11 WC Infectious Diseases SC Infectious Diseases GA CX2CO UT WOS:000365502800001 PM 26607224 ER PT J AU Sikander, S Lazarus, A Bangash, O Fuhr, DC Weobong, B Krishna, RN Ahmad, I Weiss, HA Price, L Rahman, A Patel, V AF Sikander, Siham Lazarus, Anisha Bangash, Omer Fuhr, Daniela C. Weobong, Benedict Krishna, Revathi N. Ahmad, Ikhlaq Weiss, Helen A. Price, LeShawndra Rahman, Atif Patel, Vikram TI The effectiveness and cost-effectiveness of the peer-delivered Thinking Healthy Programme for perinatal depression in Pakistan and India: the SHARE study protocol for randomised controlled trials SO TRIALS LA English DT Article DE Thinking Healthy Programme; Psychological treatment; Peers; Non-mental health professionals; Perinatal depression; Task-shifting; Randomised trials; Low and middle income countries ID MIDDLE-INCOME COUNTRIES; MATERNAL MENTAL-HEALTH; POSTNATAL DEPRESSION; PRIMARY-CARE; ANXIETY DISORDERS; RURAL PAKISTAN; INFANT GROWTH; PREVALENCE; GOA; INTERVENTION AB Background: Rates of perinatal depression (antenatal and postnatal depression) in South Asia are among the highest in the world. The delivery of effective psychological treatments for perinatal depression through existing health systems is a challenge due to a lack of human resources. This paper reports on a trial protocol that aims to evaluate the effectiveness and cost-effectiveness of the Thinking Healthy Programme delivered by peers (Thinking Healthy Programme Peer-delivered; THPP), for women with moderate to severe perinatal depression in rural and urban settings in Pakistan and India. Methods/Design: THPP is evaluated with two randomised controlled trials: a cluster trial in Rawalpindi, Pakistan, and an individually randomised trial in Goa, India. Trial participants are pregnant women who are registered with the lady health workers in the study area in Pakistan and pregnant women attending outpatient antenatal clinics in India. They will be screened using the patient health questionnaire-9 (PHQ-9) for depression symptoms and will be eligible if their PHQ-9 is equal to or greater than 10 (PHQ-9 >= 10). The sample size will be 560 and 280 women in Pakistan and India, respectively. Women in the intervention arm (THPP) will be offered ten individual and four group sessions (Pakistan) or 6-14 individual sessions (India) delivered by a peer (defined as a mother from the same community who is trained and supervised in delivering the intervention). Women in the control arm (enhanced usual care) will receive health care as usual, enhanced by providing the gynaecologist or primary-health facilities with adapted WHO mhGAP guidelines for depression treatment, and providing the woman with her diagnosis and information on how to seek help for herself. The primary outcomes are remission and severity of depression symptoms at the 6-month postnatal follow-up. Secondary outcomes include remission and severity of depression symptoms at the 3-month postnatal follow-up, functional disability, perceived social support, breastfeeding rates, infant height and weight, and costs of health care at the 3- and 6-month postnatal follow-ups. The primary analysis will be intention-to-treat. Discussion: The trials have the potential to strengthen the evidence on the effectiveness and cost-effectiveness of an evidence-based psychological treatment recommended by the World Health Organisation and delivered by peers for perinatal depression. The trials have the unique opportunity to overcome the shortage of human resources in global mental health and may advance our understanding about the use of peers who work in partnership with the existing health systems in low-resource settings. C1 [Sikander, Siham; Bangash, Omer; Ahmad, Ikhlaq] Human Dev Res Fdn, Islamabad, Pakistan. [Lazarus, Anisha; Krishna, Revathi N.; Patel, Vikram] Sangath, Panaji, Goa, India. [Fuhr, Daniela C.; Weobong, Benedict; Weiss, Helen A.; Patel, Vikram] London Sch Hyg & Trop Med, Fac Epidemiol & Populat Hlth, London WC1, England. [Price, LeShawndra] NIMH, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. [Rahman, Atif] Univ Liverpool, Inst Psychol Hlth & Soc, Liverpool L69 3BX, Merseyside, England. [Patel, Vikram] Publ Hlth Fdn India, Ctr Chron Condit & Injuries, Delhi Ncr, India. RP Sikander, S (reprint author), Human Dev Res Fdn, Islamabad, Pakistan. EM siham.sikander@hdrfoundation.org FU NIMH, USA [U19MH95687]; NIMH [U19MH95687] FX The trials have been entirely funded by NIMH, USA, under award number U19MH95687. The authors would like to acknowledge Dan Chisholm, based at the Department of Mental Health and Substance Abuse, WHO, Switzerland, for his input in developing the economic evaluation model for the trials.; The views expressed are those of the authors and do not necessarily represent the official views of NIMH, the National Institutes of Health, the Department of Health and Human Services or the US Government. Research reported in this publication is supported by NIMH under award number U19MH95687. NR 48 TC 4 Z9 4 U1 5 U2 12 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 NOV 25 PY 2015 VL 16 AR 534 DI 10.1186/s13063-015-1063-9 PG 14 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CX6FL UT WOS:000365796500001 PM 26604001 ER PT J AU Cherukuri, PF Maduro, V Fuentes-Fajardo, KV Lam, K Adams, DR Tifft, CJ Mullikin, JC Gahl, WA Boerkoel, CF AF Cherukuri, Praveen F. Maduro, Valerie Fuentes-Fajardo, Karin V. Lam, Kevin Adams, David R. Tifft, Cynthia J. Mullikin, James C. Gahl, William A. Boerkoel, Cornelius F. CA NISC Comparative Sequencing TI Replicate exome-sequencing in a multiple-generation family: improved interpretation of next-generation sequencing data SO BMC GENOMICS LA English DT Article ID WHOLE-EXOME; MENDELIAN DISORDERS; CLINICAL EXOME; MUTATIONS; IDENTIFICATION; DIAGNOSIS; DISEASE; GENOME; BIAS; DISCOVERY AB Background: Whole-exome sequencing (WES) is rapidly evolving into a tool of choice for rapid, and inexpensive identification of molecular genetic lesions within targeted regions of the human genome. While biases in WES coverage of nucleotides in targeted regions are recognized, it is not well understood how repetition of WES improves the interpretation of sequencing results in a clinical diagnostic setting. Method: To address this, we compared independently generated exome-capture of six individuals from three-generations sequenced in triplicate. This generated between 48x-86x mean target depth of high-quality mapped bases (>Q20) for each technical replicate library. Cumulatively, we achieved 179 - 208x average target coverage for each individual in the pedigree. Using this experimental design, we evaluated stochastics in WES interpretation, genotyping sensitivity, and accuracy to detect de novo variants. Results: In this study, we show that repetition of WES improved the interpretation of the capture target regions after aggregating the data (93.5 - 93.9 %). Compared to 81.2 - 89.6 % (50.2-55.4 Mb of 61.7 M) coverage of targeted bases at >= 20x in the individual technical replicates, the aggregated data covered 93.5 - 93.9 % of targeted bases (57.7 - 58.0 of 61.7 M) at >= 20x threshold, suggesting a 4.3 - 12.7 % improvement in coverage. Each individual's aggregate dataset recovered 3.4 - 6.4 million bases within variable targeted regions. We uncovered technical variability (2-5 %) inherent to WES technique. We also show improved interpretation in assessing clinically important regions that lack interpretation under current conditions, affecting 12-16 of the 56 genes recommended for secondary analysis by American College of Medical Genetics (ACMG). We demonstrate that comparing technical replicate WES datasets and their derived aggregate data can effectively address overall WES genotyping discrepancies. Conclusion: We describe a method to evaluate the reproducibility and stochastics in exome library preparation, and delineate the advantages of aggregating the data derived from technical replicates. The implications of this study are directly applicable to improved experimental design and provide an opportunity to rapidly, efficiently, and accurately arrive at reliable candidate nucleotide variants. C1 [Cherukuri, Praveen F.; Maduro, Valerie; Fuentes-Fajardo, Karin V.; Lam, Kevin; Adams, David R.; Tifft, Cynthia J.; Gahl, William A.; Boerkoel, Cornelius F.] NIH, NIH Undiagnosed Dis Program, Common Fund, Off Director, Bethesda, MD 20892 USA. [Mullikin, James C.; NISC Comparative Sequencing] NHGRI, NIH Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA. [Adams, David R.; Tifft, Cynthia J.; Gahl, William A.] NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Cherukuri, Praveen F.] Inova Hlth Syst, Inova Translat Med Inst, Falls Church, VA USA. RP Adams, DR (reprint author), NIH, NIH Undiagnosed Dis Program, Common Fund, Off Director, Bldg 10, Bethesda, MD 20892 USA. EM david.adams@nih.gov FU Intramural Research Program of National Institutes of Health FX The authors thank Dr. Camilo Toro, Dr. Thomas Markello, Lynn Wolfe, and clinical staff for thoughtful discussions and feedback. We are extremely grateful to NIH Intramural Sequencing Center (NISC) for NGS library preparation, sequencing and data generation. We are extremely grateful to Drs. Ben Solomon, Thierry Vilboux, and Ram Iyer for thoughtful comments and discussion. We are extremely grateful to the participants of the Undiagnosed Diseases Program (UDP). Extensive use was made of the NIH Biowulf cluster, a GNU/Linux parallel processing system for computational analysis; we acknowledge the NIH Helix Systems Staff for management of this system. This study is supported by funds from the Intramural Research Program of the National Institutes of Health. NR 35 TC 0 Z9 0 U1 2 U2 5 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 NOV 25 PY 2015 VL 16 AR 998 DI 10.1186/s12864-015-2107-y PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA CW8YU UT WOS:000365286200001 PM 26602380 ER PT J AU Winogradoff, D Zhao, HQ Dalal, Y Papoian, GA AF Winogradoff, David Zhao, Haiqing Dalal, Yamini Papoian, Garegin A. TI Shearing of the CENP-A dimerization interface mediates plasticity in the octameric centromeric nucleosome SO SCIENTIFIC REPORTS LA English DT Article ID ANGSTROM RESOLUTION; CRYSTAL-STRUCTURE; BUDDING YEAST; CORE PARTICLE; FORCE-FIELD; NUCLEIC-ACIDS; HISTONE H3; DNA; PROTEIN; CHROMATIN AB The centromeric nucleosome is a key epigenetic determinant of centromere identity and function. Consequently, deciphering how CENP-A containing nucleosomes contribute structurally to centromere function is a fundamental question in chromosome biology. Here, we performed microsecond timescale all-atom molecular dynamics (MD) simulations of CENP-A and H3 nucleosomes, and report that the octameric CENP-A core particles and nucleosomes display different dynamics from their canonical H3-containing counterparts. The most significant motion observed is within key interactions at the heart of the CENP-A octameric core, wherein shearing of contacts within the CENP-A: CENP-A' dimerization interface results in a weaker four helix bundle, and an extrusion of 10-30 bp of DNA near the pseudo-dyad. Coupled to other local and global fluctuations, the CENP-A nucleosome occupies a more rugged free energy landscape than the canonical H3 nucleosome. Taken together, our data suggest that CENP-A encodes enhanced distortability to the octameric nucleosome, which may allow for enhanced flexing of the histone core in vivo. C1 [Winogradoff, David; Papoian, Garegin A.] Univ Maryland, Chem Phys Program, College Pk, MD 20742 USA. [Zhao, Haiqing; Papoian, Garegin A.] Univ Maryland, Biophys Program, College Pk, MD 20742 USA. [Zhao, Haiqing; Dalal, Yamini] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. [Papoian, Garegin A.] Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 USA. RP Dalal, Y (reprint author), NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. EM dalaly@mail.nih.gov; gpapoian@umd.edu RI Papoian, Garegin/D-6508-2011 OI Papoian, Garegin/0000-0001-8580-3790 FU National Science Foundation NSF [CHE-1363081]; University of Maryland; joint NCI-UMD Cancer Technology Partnership Program; intramural research program of the CCR/NCI FX G.A.P. is supported by the National Science Foundation NSF CHE-1363081. D.W. is supported by the University of Maryland. H.Z. is supported by the joint NCI-UMD Cancer Technology Partnership Program. Y.D. is supported by the intramural research program of the CCR/NCI. We thank Mary Pitman and Drs. Tom Misteli, Gordon Hager and Minh Bui for critical comments on the manuscript, and members of our laboratories for helpful discussions. Computational resources were provided by the Deepthought-II supercomputer at the University of Maryland. NR 75 TC 6 Z9 6 U1 0 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 NOV 25 PY 2015 VL 5 AR 17038 DI 10.1038/srep17038 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CW8VM UT WOS:000365277500001 PM 26602160 ER PT J AU Szabo, E AF Szabo, Eva TI Biomarkers in phase I-II chemoprevention trials: lessons from the NCI experience SO ECANCERMEDICALSCIENCE LA English DT Review DE biomarkers; chemoprevention; phase II clinical trials; National Cancer Institute ID SPORADIC COLORECTAL ADENOMAS; DETECTED LUNG NODULES; GROUND-GLASS OPACITY; INHALED BUDESONIDE; CANCER; PREVENTION; CT; DYSPLASIA; THERAPY; PLACEBO AB Early phase clinical trials are an essential component of chemopreventive drug development to identify signals of drug efficacy that can subsequently be explored definitively in phase III trials. Whereas phase I trials focus on safety and identification of optimal dose and schedule for cancer prevention, phase II trials focus on intermediate endpoints that are variably related to cancer development. The United States National Cancer Institute supports a programme devoted to early phase cancer prevention clinical trials. The experience, along with the benefits and limitations of the range of biomarker endpoints used in these studies, are reviewed here. C1 [Szabo, Eva] NCI, Lung & Upper Aerodigest Canc Res Grp, Canc Prevent Div, NIH, 9609 Med Ctr Dr,Room 5E-102, Bethesda, MD 20892 USA. RP Szabo, E (reprint author), NCI, Lung & Upper Aerodigest Canc Res Grp, Canc Prevent Div, NIH, 9609 Med Ctr Dr,Room 5E-102, Bethesda, MD 20892 USA. EM szaboe@mail.nih.gov NR 18 TC 0 Z9 0 U1 0 U2 0 PU CANCER INTELLIGENCE LTD PI BRISTOL PA 11 ALMA VALE RD,, BRISTOL, BS8 2HL, ENGLAND SN 1754-6605 J9 ECANCERMEDICALSCIENC JI eCancerMedicalScience PD NOV 24 PY 2015 VL 9 SI SI AR 599 DI 10.3332/ecancer.2015.599 PG 6 WC Oncology SC Oncology GA DC4IK UT WOS:000369184200005 PM 26635903 ER PT J AU Marquart, GD Tabor, KM Brown, M Strykowski, JL Varshney, GK LaFave, MC Mueller, T Burgess, SM Higashijima, S Burgess, HA AF Marquart, Gregory D. Tabor, Kathryn M. Brown, Mary Strykowski, Jennifer L. Varshney, Gaurav K. LaFave, Matthew C. Mueller, Thomas Burgess, Shawn M. Higashijima, Shin-ichi Burgess, Harold A. TI A 3D Searchable Database of Transgenic Zebrafish Gal4 and Cre Lines for Functional Neuroanatomy Studies SO FRONTIERS IN NEURAL CIRCUITS LA English DT Article DE zebratish; transgenic; Gal4; Cre; microRNA; 3D registration ID ENHANCER-TRAP LINES; GENE-EXPRESSION; SPINAL-CORD; NEURAL CIRCUITRY; IMAGE-ANALYSIS; IN-VIVO; NEURONS; DROSOPHILA; REVEALS; GENERATION AB Transgenic methods enable the selective manipulation of neurons for functional mapping of neuronal circuits. Using confocal microscopy, we have imaged the cellular-level expression of 109 transgenic lines in live 6 day post fertilization larvae, including 80 Gal4 enhancer trap lines, 9 Cre enhancer trap lines and 20 transgenic lines that express fluorescent proteins in defined gene-specific patterns. Image stacks were acquired at single micron resolution, together with a broadly expressed neural marker, which we used to align enhancer trap reporter patterns into a common 3-dimensional reference space. To facilitate use of this resource, we have written software that enables searching for transgenic lines that label cells within a selectable 3-dimensional region of interest (ROI) or neuroanatomical area. This software also enables the intersectional expression of transgenes to be predicted, a feature which we validated by detecting cells with co-expression of Cre and Gal4. Many of the imaged enhancer trap lines show intrinsic brain-specific expression. However, to increase the utility of lines that also drive expression in non neuronal tissue we have designed a novel UAS reporter, that suppresses expression in heart, muscle, and skin through the incorporation of microRNA binding sites in a synthetic 3' untranslated region. Finally, we mapped the site of transgene integration, thus providing molecular identification of the expression pattern for most lines. Cumulatively, this library of enhancer trap lines provides genetic access to 70% of the larval brain and is therefore a powerful and broadly accessible tool for the dissection of neural circuits in larval zebrafish. C1 [Marquart, Gregory D.; Tabor, Kathryn M.; Brown, Mary; Strykowski, Jennifer L.; Burgess, Harold A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Dev Biol, NIH, Bethesda, MD 20892 USA. [Marquart, Gregory D.; Burgess, Harold A.] Univ Maryland, Neurosci & Cognit Sci Program, College Pk, MD 20742 USA. [Varshney, Gaurav K.; LaFave, Matthew C.; Burgess, Shawn M.] NHGRI, Translat & Funct Genom Branch, NIH, Bethesda, MD 20892 USA. [Mueller, Thomas] Kansas State Univ, Div Biol, Manhattan, KS 66506 USA. [Higashijima, Shin-ichi] Natl Inst Physiol Sci, Okazaki Inst Integrat Biosci, Natl Inst Nat Sci, Aichi, Japan. RP Burgess, HA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Dev Biol, NIH, Bethesda, MD 20892 USA. EM haroldburgess@mail.nih.gov OI LaFave, Matthew/0000-0001-9165-041X; Varshney, Gaurav K./0000-0002-0429-1904 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute for Child Health and Human Development; Intramural Research Program of the National Human Genome Research Institute; Terry C. Johnson Center for Basic Cancer Research; Ministry of Education, Science, Technology, Sports and Culture of Japan FX We are grateful to Ben Feldman, Katie Kindt and Brant Weinstein for sharing transgenic lines. We thank Damian Dalle Nogare, Louis Leung and Kimberly McArthur for beta testing the brain browser software. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD (http://biowulf.nih.gov). This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute for Child Health and Human Development (HB), the Intramural Research Program of the National Human Genome Research Institute (SB), the Terry C. Johnson Center for Basic Cancer Research (TM) and grants from the Ministry of Education, Science, Technology, Sports and Culture of Japan (SH). NR 75 TC 5 Z9 5 U1 1 U2 4 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5110 J9 FRONT NEURAL CIRCUIT JI Front. Neural Circuits PD NOV 24 PY 2015 VL 9 AR 78 DI 10.3389/fncir.2015.00078 PG 17 WC Neurosciences SC Neurosciences & Neurology GA CY6UX UT WOS:000366545400002 PM 26635538 ER PT J AU Daimon, CM Jasien, JM Wood, WH Zhang, YQ Becker, KG Silverman, JL Crawley, JN Martin, B Maudsley, S AF Daimon, Caitlin M. Jasien, Joan M. Wood, William H., III Zhang, Yongqing Becker, Kevin G. Silverman, Jill L. Crawley, Jacqueline N. Martin, Bronwen Maudsley, Stuart TI Hippocampal Transcriptomic and Proteomic Alterations in the BTBR Mouse Model of Autism Spectrum Disorder SO FRONTIERS IN PHYSIOLOGY LA English DT Article DE autism spectrum disorder phenotype; BTBR mouse model; bioinformatics; etiology; behavior ID DEFICIT HYPERACTIVITY DISORDER; WOLFRAM-SYNDROME; INBRED STRAINS; NEURODEGENERATIVE DISORDERS; CEREBELLAR DYSFUNCTION; SOCIAL-INTERACTION; UNUSUAL REPERTOIRE; SYNAPTIC FUNCTION; MUTANT MICE; GENE SETS AB Autism spectrum disorders (ASD) are complex heterogeneous neurodevelopmental disorders of an unclear etiology, and no cure currently exists. Prior studies have demonstrated that the black and tan, brachyury (BTBR) T+ Itpr3tf/J mouse strain displays a behavioral phenotype with ASD-like features. BTBR T+ Itpr3tf/J mice (referred to simply as BTBR) display deficits in social functioning, lack of communication ability, and engagement in stereotyped behavior. Despite extensive behavioral phenotypic characterization, little is known about the genes and proteins responsible for the presentation of the ASD-like phenotype in the BTBR mouse model. In this study, we employed bioinformatics techniques to gain a wide-scale understanding of the transcriptomic and proteomic changes associated with the ASD-like phenotype in BTBR mice. We found a number of genes and proteins to be significantly altered in BTBR mice compared to C57BL/6J (B6) control mice controls such as BDNF, Shank3, and ERK1, which are highly relevant to prior investigations of ASD. Furthermore, we identified distinct functional pathways altered in BTBR mice compared to B6 controls that have been previously shown to be altered in both mouse models of ASD, some human clinical populations, and have been suggested as a possible etiological mechanism of ASD, including "axon guidance" and "regulation of actin cytoskeleton." In addition, our wide-scale bioinformatics approach also discovered several previously unidentified genes and proteins associated with the ASD phenotype in BTBR mice, such as Caskin1, suggesting that bioinformatics could be an avenue by which novel therapeutic targets for ASD are uncovered. As a result, we believe that informed use of synergistic bioinformatics applications represents an invaluable tool for elucidating the etiology of complex disorders like ASD. C1 [Daimon, Caitlin M.; Jasien, Joan M.; Martin, Bronwen] NIA, Metab Unit, NIH, Baltimore, MD 21224 USA. [Wood, William H., III; Zhang, Yongqing; Becker, Kevin G.] NIH, Gene Express & Genom Unit, Baltimore, MD 21224 USA. [Silverman, Jill L.; Crawley, Jacqueline N.] NIMH, Intramural Res Program, Lab Behav Neurosci, Bethesda, MD USA. [Silverman, Jill L.; Crawley, Jacqueline N.] Univ Calif Davis, MIND Inst, Sch Med, Sacramento, CA 95817 USA. [Maudsley, Stuart] NIA, Receptor Pharmacol Unit, NIH, Baltimore, MD 21224 USA. [Maudsley, Stuart] Univ Antwerp, VIB Dept Mol Genet, Translat Neurobiol Grp, B-2020 Antwerp, Belgium. [Maudsley, Stuart] Univ Antwerp, Inst Bom Bunge, Lab Neurogenet, B-2020 Antwerp, Belgium. RP Maudsley, S (reprint author), NIA, Receptor Pharmacol Unit, NIH, Baltimore, MD 21224 USA. EM stuart.maudsley@molgen.vib-ua.be FU Intramural Research Programs of the National Institute on Aging [NIH-AG000325-02]; National Institute of Mental Health at the National Institutes of Health FX This work was carried out with the support of the Intramural Research Programs of the National Institute on Aging (NIH-AG000325-02) and the National Institute of Mental Health at the National Institutes of Health. NR 92 TC 2 Z9 2 U1 3 U2 6 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-042X J9 FRONT PHYSIOL JI Front. Physiol. PD NOV 24 PY 2015 VL 6 DI 10.3389/fphys.2015.00324 PG 17 WC Physiology SC Physiology GA CY9SZ UT WOS:000366747900001 ER PT J AU Fabsitz, RR Papanicolaou, GJ Sholinsky, P Coady, SA Jaquish, CE Nelson, CR Olson, JL Puggal, MA Purkiser, KL Srinivas, PR Wei, GNS Wolz, M Sorlie, PD AF Fabsitz, Richard R. Papanicolaou, George J. Sholinsky, Phyliss Coady, Sean A. Jaquish, Cashell E. Nelson, Cheryl R. Olson, Jean L. Puggal, Mona A. Purkiser, Kevin L. Srinivas, Pothur R. Wei, Gina S. Wolz, Michael Sorlie, Paul D. TI Impact of National Heart, Lung, and Blood Institute-Supported Cardiovascular Epidemiology Research, 1998 to 2012 SO CIRCULATION LA English DT Article DE epidemiology; evaluation; health impact assessment; National Heart, Lung and Blood Institute (US); population characteristics; population dynamics; risk factors ID BIOMEDICAL-RESEARCH; TRANSLATION; MEDICINE; INNOVATION; COHORT; HEALTH C1 [Fabsitz, Richard R.; Papanicolaou, George J.; Sholinsky, Phyliss; Coady, Sean A.; Jaquish, Cashell E.; Nelson, Cheryl R.; Olson, Jean L.; Puggal, Mona A.; Purkiser, Kevin L.; Srinivas, Pothur R.; Wei, Gina S.; Wolz, Michael; Sorlie, Paul D.] NHLBI, Div Cardiovasc Sci, Epidemiol Branch, Bethesda, MD 20892 USA. RP Papanicolaou, GJ (reprint author), NHLBI, Epidemiol Branch, 6701 Rockledge Dr,Rm 10214, Bethesda, MD 20892 USA. EM gjp@nhlbi.nih.gov FU Intramural NIH HHS [Z99 HL999999] NR 22 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 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD NOV 24 PY 2015 VL 132 IS 21 BP 2028 EP 2033 DI 10.1161/CIRCULATIONAHA.114.014147 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA CX3DB UT WOS:000365574600012 PM 26508730 ER PT J AU Mills, JL Dimopoulos, A AF Mills, James L. Dimopoulos, Aggeliki TI Folic acid fortification for Europe? SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Editorial Material ID NEURAL-TUBE DEFECTS; FOLATE; IMPACT; FLOUR C1 [Mills, James L.; Dimopoulos, Aggeliki] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Mills, JL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM millsj@mail.nih.gov FU Intramural NIH HHS NR 12 TC 5 Z9 5 U1 0 U2 1 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 NOV 24 PY 2015 VL 351 AR h6198 DI 10.1136/bmj.h6198 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA CX4SX UT WOS:000365691700005 PM 26602789 ER PT J AU Vujkovic-Cvijin, I Swainson, LA Chu, SN Ortiz, AM Santee, CA Petriello, A Dunham, RM Fadrosh, DW Lin, DL Faruqi, AA Huang, Y Apetrei, C Pandrea, I Hecht, FM Pilcher, CD Klatt, NR Brenchley, JM Lynch, SV McCune, JM AF Vujkovic-Cvijin, Ivan Swainson, Louise A. Chu, Simon N. Ortiz, Alexandra M. Santee, Clark A. Petriello, Annalise Dunham, Richard M. Fadrosh, Douglas W. Lin, Din L. Faruqi, Ali A. Huang, Yong Apetrei, Cristian Pandrea, Ivona Hecht, Frederick M. Pilcher, Christopher D. Klatt, Nichole R. Brenchley, Jason M. Lynch, Susan V. McCune, Joseph M. TI Gut-Resident Lactobacillus Abundance Associates with IDO1 Inhibition and Th17 Dynamics in SIV-Infected Macaques SO CELL REPORTS LA English DT Article ID TRYPTOPHAN CATABOLISM; MICROBIAL TRANSLOCATION; IMMUNE ACTIVATION; HIV-1 INFECTION; CD4 COUNT; INFLAMMATION; MUCOSAL; HIV/AIDS; DISEASE; YOGURT AB Gut microbes can profoundly modulate mucosal barrier-promoting Th17 cells in mammals. A salient feature of HIV/simian immunodeficiency virus (SIV) immunopathogenesis is the loss of Th17 cells, which has been linked to increased activity of the immunomodulatory enzyme, indoleamine 2,3-dioxygenase 1 (IDO 1). The role of gut microbes in this system remains unknown, and the SIV-infected rhesus macaque provides a well-describedmodel for HIV-associated Th17 loss and mucosal immune disruption. We observed a specific depletion of gut-resident Lactobacillus during acute and chronic SIV infection of rhesus macaques, which was also seen in early HIV-infected humans. This depletion in rhesus macaques correlated with increased IDO1 activity and Th17 loss. Macaques supplemented with a Lactobacillus-containing probiotic exhibited decreased IDO1 activity during chronic SIV infection. We propose that Lactobacillus species inhibit mammalian IDO1 and thus may help to preserve Th17 cells during pathogenic SIV infection, providing support for Lactobacillus species as modulators of mucosal immune homeostasis. C1 [Vujkovic-Cvijin, Ivan; Swainson, Louise A.; Chu, Simon N.; Petriello, Annalise; Dunham, Richard M.; McCune, Joseph M.] Univ Calif San Francisco, Dept Med, Div Expt Med, San Francisco, CA 94143 USA. [Chu, Simon N.] Univ Calif Berkeley Univ Calif San Francisco Join, San Francisco, CA 94143 USA. [Ortiz, Alexandra M.; Brenchley, Jason M.] NIAID, Mol Microbiol Lab, Program Tissue Immun & Repair, NIH, Bethesda, MD 20892 USA. [Ortiz, Alexandra M.; Brenchley, Jason M.] NIAID, Mol Microbiol Lab, Immunopathogenesis Sect, NIH, Bethesda, MD 20892 USA. [Santee, Clark A.; Fadrosh, Douglas W.; Lin, Din L.; Faruqi, Ali A.; Lynch, Susan V.] Univ Calif San Francisco, Dept Med, Div Gastroenterol, San Francisco, CA 94143 USA. [Huang, Yong] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA. [Apetrei, Cristian; Pandrea, Ivona] Univ Pittsburgh, Sch Med, Ctr Vaccine Res, Pittsburgh, PA 15260 USA. [Hecht, Frederick M.; Pilcher, Christopher D.] Univ Calif San Francisco, Dept Med, Div HIV Infect Dis & Global Med, San Francisco, CA 94143 USA. [Klatt, Nichole R.] Univ Washington, Dept Pharmaceut, Seattle, WA 98121 USA. RP Lynch, SV (reprint author), Univ Calif San Francisco, Dept Med, Div Gastroenterol, San Francisco, CA 94143 USA. EM susan.lynch@ucsf.edu; mike.mccune@ucsf.edu OI Vujkovic-Cvijin, Ivan/0000-0002-8611-4900 FU CHRP [D13-SF-388]; NSF [1144247]; NIH [U19 AI96109]; Harvey V. Berneking Living Trust; Division of Intramural Research/NIAID/NIH; Bill and Melinda Gates Foundation [OPP1017716, P01 AI071713, R01 HD074511]; [R01HL117715-11] FX We thank P. Hunt, A. Sil, and J. Cyster for helpful discussions and K. Raehtz for assistance with AGM studies. The research reported herein was supported by CHRP D13-SF-388 (to I.V.-C.), NSF 1144247 (to I.V.-C.), NIH U19 AI96109 (to J.M.M.), the Harvey V. Berneking Living Trust (to J.M.M.), and R01HL117715-11 (to I. P.). Funding for this study was provided in part by the Division of Intramural Research/NIAID/NIH. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services (DHHS), nor does the mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Collection of human specimens was supported by Bill and Melinda Gates Foundation grant OPP1017716, P01 AI071713 (to F.M.H.), and R01 HD074511 (to C.D.P.). We thank M. Busch, G. Murphy, K. Marson, S. Facente, and A. Welte for aid in developing the human specimen and data repository. NR 31 TC 11 Z9 12 U1 0 U2 4 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 NOV 24 PY 2015 VL 13 IS 8 BP 1589 EP 1597 DI 10.1016/j.celrep.2015.10.026 PG 9 WC Cell Biology SC Cell Biology GA CX0RR UT WOS:000365404900009 PM 26586432 ER PT J AU Gross, JG Glassman, AR Jampol, LM Inusah, S Aiello, LP Antoszyk, AN Baker, CW Berger, BB Bressler, NM Browning, D Elman, MJ Ferris, FL Friedman, SM Marcus, DM Melia, M Stockdale, CR Sun, JK Beck, RW AF Gross, Jeffrey G. Glassman, Adam R. Jampol, Lee M. Inusah, Seidu Aiello, Lloyd Paul Antoszyk, Andrew N. Baker, Carl W. Berger, Brian B. Bressler, Neil M. Browning, David Elman, Michael J. Ferris, Frederick L., III Friedman, Scott M. Marcus, Dennis M. Melia, Michele Stockdale, Cynthia R. Sun, Jennifer K. Beck, Roy W. CA Diabet Retinopathy Clin Res Networ TI Panretinal Photocoagulation vs Intravitreous Ranibizumab for Proliferative Diabetic Retinopathy A Randomized Clinical Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID MACULAR EDEMA; RESEARCH-NETWORK; VISUAL-ACUITY; BEVACIZUMAB; AFLIBERCEPT; PROTOCOL AB IMPORTANCE Panretinal photocoagulation (PRP) is the standard treatment for reducing severe visual loss from proliferative diabetic retinopathy. However, PRP can damage the retina, resulting in peripheral vision loss or worsening diabetic macular edema (DME). OBJECTIVE To evaluate the noninferiority of intravitreous ranibizumab compared with PRP for visual acuity outcomes in patients with proliferative diabetic retinopathy. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial conducted at 55 US sites among 305 adults with proliferative diabetic retinopathy enrolled between February and December 2012 (mean age, 52 years; 44% female; 52% white). Both eyes were enrolled for 89 participants (1 eye to each study group), with a total of 394 study eyes. The final 2-year visit was completed in January 2015. INTERVENTIONS Individual eyes were randomly assigned to receive PRP treatment, completed in 1 to 3 visits (n = 203 eyes), or ranibizumab, 0.5mg, by intravitreous injection at baseline and as frequently as every 4 weeks based on a structured re-treatment protocol (n = 191 eyes). Eyes in both treatment groups could receive ranibizumab for DME. MAIN OUTCOMES AND MEASURES The primary outcome was mean visual acuity change at 2 years (5-letter noninferiority margin; intention-to-treat analysis). Secondary outcomes included visual acuity area under the curve, peripheral visual field loss, vitrectomy, DME development, and retinal neovascularization. RESULTS Mean visual acuity letter improvement at 2 years was +2.8 in the ranibizumab group vs +0.2 in the PRP group (difference, +2.2; 95% CI, -0.5 to +5.0; P < .001 for noninferiority). The mean treatment group difference in visual acuity area under the curve over 2 years was +4.2 (95% CI, +3.0 to +5.4; P < .001). Mean peripheral visual field sensitivity loss was worse (-23 dB vs -422 dB; difference, 372 dB; 95% CI, 213-531 dB; P < .001), vitrectomy was more frequent (15% vs 4%; difference, 9%; 95% CI, 4%-15%; P < .001), and DME development was more frequent (28% vs 9%; difference, 19%; 95% CI, 10%-28%; P < .001) in the PRP group vs the ranibizumab group, respectively. Eyes without active or regressed neovascularization at 2 years were not significantly different (35% in the ranibizumab group vs 30% in the PRP group; difference, 3%; 95% CI, -7% to 12%; P = .58). One eye in the ranibizumab group developed endophthalmitis. No significant differences between groups in rates of major cardiovascular events were identified. CONCLUSIONS AND RELEVANCE Among eyes with proliferative diabetic retinopathy, treatment with ranibizumab resulted in visual acuity that was noninferior to (not worse than) PRP treatment at 2 years. Although longer-term follow-up is needed, ranibizumab may be a reasonable treatment alternative, at least through 2 years, for patients with proliferative diabetic retinopathy. C1 [Gross, Jeffrey G.] Carolina Retina Ctr PA, Columbia, SC USA. [Glassman, Adam R.; Inusah, Seidu; Melia, Michele; Beck, Roy W.] Jaeb Ctr Hlth Res, Tampa, FL 33647 USA. [Jampol, Lee M.; Stockdale, Cynthia R.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Aiello, Lloyd Paul; Sun, Jennifer K.] Harvard Univ, Joslin Diabet Ctr, Beetham Eye Inst, Dept Ophthalmol, Boston, MA 02115 USA. [Antoszyk, Andrew N.; Browning, David] Charlotte Eye Ear Nose & Throat Associates PA, Charlotte, NC USA. [Baker, Carl W.] Paducah Retinal Ctr, Paducah, KY USA. [Berger, Brian B.] Retina Res Ctr, Austin, TX USA. [Bressler, Neil M.] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21205 USA. [Elman, Michael J.] Elman Retina Grp PA, Baltimore, MD USA. [Ferris, Frederick L., III] NEI, NIH, Bethesda, MD 20892 USA. [Friedman, Scott M.] Florida Retina Consultants, Lakeland, FL USA. [Marcus, Dennis M.] Southeast Retina Ctr PC, Augusta, GA USA. RP Glassman, AR (reprint author), Jaeb Ctr Hlth Res, 15310 Amberly Dr,Ste 350, Tampa, FL 33647 USA. EM drcrstat2@jaeb.org FU National Eye Institute; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, US Department of Health and Human Services [EY14231, EY23207, EY18817]; Genentech FX This study was supported through a cooperative agreement from the National Eye Institute and the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, US Department of Health and Human Services (grants EY14231, EY23207, and EY18817). Genentech provided ranibizumab for the study and funds to the DRCR.net to defray the study's clinical site costs. NR 23 TC 36 Z9 37 U1 1 U2 7 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 NOV 24 PY 2015 VL 314 IS 20 BP 2137 EP 2146 DI 10.1001/jama.2015.15217 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA CW9XQ UT WOS:000365351900017 ER PT J AU McLaren, PJ Coulonges, C Bartha, I Lenz, TL Deutsch, AJ Bashirova, A Buchbinder, S Carrington, MN Cossarizza, A Dalmau, J De Luca, A Goedert, JJ Gurdasani, D Haas, DW Herbeck, JT Johnson, EO Kirk, GD Lambotte, O Luo, M Mallal, S van Manen, D Martinez-Picado, J Meyer, L Miro, J Mullins, JI Obel, N Poli, G Sandhu, MS Schuitemaker, H Shea, PR Theodorou, I Walker, BD Weintrob, AC Winkler, CA Wolinsky, SM Raychaudhuri, S Goldstein, DB Telenti, A de Bakker, PIW Zagury, JF Fellay, J AF McLaren, Paul J. Coulonges, Cedric Bartha, Istvan Lenz, Tobias L. Deutsch, Aaron J. Bashirova, Arman Buchbinder, Susan Carrington, Mary N. Cossarizza, Andrea Dalmau, Judith De Luca, Andrea Goedert, James J. Gurdasani, Deepti Haas, David W. Herbeck, Joshua T. Johnson, Eric O. Kirk, Gregory D. Lambotte, Olivier Luo, Ma Mallal, Simon van Manen, Daniele Martinez-Picado, Javier Meyer, Laurence Miro, JoseM. Mullins, James I. Obel, Niels Poli, Guido Sandhu, Manjinder S. Schuitemaker, Hanneke Shea, Patrick R. Theodorou, Ioannis Walker, Bruce D. Weintrob, Amy C. Winkler, Cheryl A. Wolinsky, Steven M. Raychaudhuri, Soumya Goldstein, David B. Telenti, Amalio de Bakker, Paul I. W. Zagury, Jean-Francois Fellay, Jacques TI Polymorphisms of large effect explain the majority of the host genetic contribution to variation of HIV-1 virus load SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE HIV-1 control; GWAS; heritability; infectious disease; genomics ID GENOME-WIDE ASSOCIATION; DISEASE PROGRESSION; AFRICAN-AMERICANS; INFECTION; HLA; AIDS; CCR5; DETERMINANTS; RESTRICTION; HAPLOTYPES AB Previous genome-wide association studies (GWAS) of HIV-1-infected populations have been underpowered to detect common variants with moderate impact on disease outcome and have not assessed the phenotypic variance explained by genome-wide additive effects. By combining the majority of available genome-wide genotyping data in HIV-infected populations, we tested for association between similar to 8 million variants and viral load (HIV RNA copies per milliliter of plasma) in 6,315 individuals of European ancestry. The strongest signal of association was observed in the HLA class I region that was fully explained by independent effects mapping to five variable amino acid positions in the peptide binding grooves of the HLA-B and HLA-A proteins. We observed a second genome-wide significant association signal in the chemokine (C-C motif) receptor (CCR) gene cluster on chromosome 3. Conditional analysis showed that this signal could not be fully attributed to the known protective CCR5 Delta 32 allele and the risk P1 haplotype, suggesting further causal variants in this region. Heritability analysis demonstrated that common human genetic variation-mostly in the HLA and CCR5 regions-explains 25% of the variability in viral load. This study suggests that analyses in non-European populations and of variant classes not assessed by GWAS should be priorities for the field going forward. C1 [McLaren, Paul J.; Bartha, Istvan; Fellay, Jacques] Ecole Polytech Fed Lausanne, Sch Life Sci, Global Hlth Inst, CH-1015 Lausanne, Switzerland. [McLaren, Paul J.; Bartha, Istvan; Fellay, Jacques] Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland. [Coulonges, Cedric; Zagury, Jean-Francois] Conservatoire Natl Arts & Metiers, Chaire Bioinformat, EA4627, Lab Genom Bioinformat & Applicat, F-75003 Paris, France. [Coulonges, Cedric; Meyer, Laurence; Theodorou, Ioannis; Zagury, Jean-Francois] French Agcy Res AIDS & Hepatitis, ANRS Genom Grp, F-75013 Paris, France. [Lenz, Tobias L.] Max Planck Inst Evolutionary Biol, Dept Evolutionary Ecol, Evolutionary Immunogen, D-24306 Plon, Germany. [Deutsch, Aaron J.] Harvard Univ, Harvard MIT Div Hlth Sci & Technol, Boston, MA 02115 USA. [Deutsch, Aaron J.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Deutsch, Aaron J.; Raychaudhuri, Soumya] Brigham & Womens Hosp, Dept Med, Div Genet & Rheumatol, Boston, MA 02115 USA. [Deutsch, Aaron J.; Raychaudhuri, Soumya] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Bashirova, Arman; Carrington, Mary N.; Walker, Bruce D.] MIT, Massachusetts Gen Hosp, Ragon Inst, Boston, MA 02129 USA. [Bashirova, Arman; Carrington, Mary N.; Walker, Bruce D.] Harvard, Boston, MA 02129 USA. [Buchbinder, Susan] San Francisco Dept Publ Hlth, Bridge HIV 1, San Francisco, CA 94102 USA. [Carrington, Mary N.] Leidos Biomed Res Inc, Canc & Inflammat Program, Expt Immunol Lab, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Cossarizza, Andrea] Univ Modena & Reggio Emilia, Sch Med, Dept Surg Med Dent & Morphol Sci, I-41121 Modena, Italy. [Dalmau, Judith; Martinez-Picado, Javier] Univ Autonoma Barcelona, AIDS Res Inst IrsiCaixa, Inst Invest Ciencies Salut Germans Trias & Pujol, Badalona 08916, Spain. [De Luca, Andrea] Siena Univ Hosp, Univ Div Infect Dis, I-53100 Siena, Italy. Univ Siena, Dept Med Biotechnol, I-53100 Siena, Italy. [Goedert, James J.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA. [Gurdasani, Deepti; Sandhu, Manjinder S.] Wellcome Trust Sanger Inst, Human Genet, Hinxton CB10 1SA, England. [Gurdasani, Deepti; Sandhu, Manjinder S.] Univ Cambridge, Dept Med, Cambridge CB2 2QQ, England. [Haas, David W.] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Herbeck, Joshua T.] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. [Johnson, Eric O.] RTI Int, Behav Hlth Epidemiol, Res Triangle Pk, NC 27709 USA. [Kirk, Gregory D.] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD 21205 USA. [Lambotte, Olivier] INSERM, U1012, F-94270 Le Kremlin Bicetre, France. [Lambotte, Olivier] Univ Paris 11, F-94270 Le Kremlin Bicetre, France. [Lambotte, Olivier] Hop Bicetre, AP HP, Dept Internal Med & Infect Dis, F-94270 Le Kremlin Bicetre, France. [Luo, Ma] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB R3E 0J6, Canada. [Luo, Ma] Natl Microbiol Lab, Winnipeg, MB R3E 3P6, Canada. [Mallal, Simon] Murdoch Univ, Inst Immunol & Infect Dis, Perth, WA 6150, Australia. [Mallal, Simon] Pathwest, Perth, WA 6150, Australia. [van Manen, Daniele; Schuitemaker, Hanneke] Univ Amsterdam, Acad Med Ctr, Ctr Infect Dis & Immun Amsterdam, NL-1105 AZ Amsterdam, Netherlands. [Martinez-Picado, Javier] Inst Catalana Recerca & Estudis Avancats, Barcelona 08916, Spain. [Meyer, Laurence] INSERM, Ctr Rech Epidemiol & Sante Populat, U1018, F-94270 Le Kremlin Bicetre, Bicetre, France. [Meyer, Laurence] Univ Paris 11, Fac Med Paris Sud, UMRS 1018, F-94270 Le Kremlin Bicetre, Bicetre, France. [Meyer, Laurence] Hop Bicetre, AP HP, Epidemiol & Publ Hlth Serv, F-94270 Le Kremlin Bicetre, Bicetre, France. [Miro, JoseM.] Univ Barcelona, Hosp Clin, Inst Invest Biomed August Pi & Sunyer, Infect Dis Serv, E-08036 Barcelona, Spain. [Mullins, James I.] Univ Washington, Dept Microbiol, Seattle, WA 98195 USA. [Obel, Niels] Copenhagen Univ Hosp, Rigshosp, Dept Infect Dis, DK-2100 Copenhagen, Denmark. [Poli, Guido] Ist Sci San Raffaele, Div Immunol Transplantat & Infect Dis, I-20132 Milan, Italy. [Poli, Guido] Univ Vita Salute San Raffaele, Sch Med, I-20132 Milan, Italy. [Shea, Patrick R.; Goldstein, David B.] Columbia Univ, Inst Genom Med, New York, NY 10032 USA. [Theodorou, Ioannis] INSERM, UMRS 945, F-75014 Paris, France. [Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Weintrob, Amy C.] Uniformed Serv Univ Hlth Sci, Infect Dis Clin Res Program, Bethesda, MD 20814 USA. [Winkler, Cheryl A.] Leidos Biomed Res Inc, Bas Res Lab, Mol Genet Epidemiol Sect, Ctr Canc Res,NCI,Frederick Natl Lab, Frederick, MD 21702 USA. [Wolinsky, Steven M.] Northwestern Univ, Feinberg Sch Med, Div Infect Dis, Chicago, IL 60611 USA. [Raychaudhuri, Soumya] Univ Manchester, Fac Med & Human Sci, Manchester M13 9PL, Lancs, England. [Telenti, Amalio] J Craig Venter Inst, La Jolla, CA 92037 USA. [de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Dept Med Genet, NL-3584 CX Utrecht, Netherlands. [de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Dept Epidemiol, NL-3584 CX Utrecht, Netherlands. RP Fellay, J (reprint author), Ecole Polytech Fed Lausanne, Sch Life Sci, Global Hlth Inst, CH-1015 Lausanne, Switzerland. EM Jacques.Fellay@epfl.ch RI SHCS, all/G-4072-2011; SHCS, int. coll. A/G-4083-2011; Lenz, Tobias/D-1387-2009; Dalmau, Judith/I-7065-2016; Martinez-Picado, Javier/G-5507-2012; Fellay, Jacques/A-6681-2009; OI Deutsch, Aaron/0000-0001-6750-5335; Shea, Patrick/0000-0001-6804-5131; Lenz, Tobias/0000-0002-7203-0044; Dalmau, Judith/0000-0001-7513-3711; Martinez-Picado, Javier/0000-0002-4916-2129; Fellay, Jacques/0000-0002-8240-939X; McLaren, Paul/0000-0001-6019-7018; Wolinsky, Steven/0000-0002-9625-6697 FU Howard Hughes Medical Institute; NIAID NIH HHS [K24 AI118591]; NIDA NIH HHS [U01 DA036297] NR 39 TC 6 Z9 6 U1 1 U2 9 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 NOV 24 PY 2015 VL 112 IS 47 BP 14658 EP 14663 DI 10.1073/pnas.1514867112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CW7IY UT WOS:000365173100073 PM 26553974 ER PT J AU Duong, V Lambrechts, L Paul, RE Ly, S Lay, RS Long, KC Huy, R Tarantola, A Scott, TW Sakuntabhai, A Buchy, P AF Duong, Veasna Lambrechts, Louis Paul, Richard E. Ly, Sowath Lay, Rath Srey Long, Kanya C. Huy, Rekol Tarantola, Arnaud Scott, Thomas W. Sakuntabhai, Anavaj Buchy, Philippe TI Asymptomatic humans transmit dengue virus to mosquitoes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE mosquito experimental infection; Cambodia; Aedes aegypti; human-to-mosquito transmission; dengue ID DISEASE SEVERITY; AEDES-AEGYPTI; PCR ASSAY; INFECTIONS; INAPPARENT; VIREMIA; DETERMINANTS; OUTBREAK; CHILDREN; THAILAND AB Three-quarters of the estimated 390 million dengue virus (DENV) infections each year are clinically inapparent. People with inapparent dengue virus infections are generally considered dead-end hosts for transmission because they do not reach sufficiently high viremia levels to infect mosquitoes. Here, we show that, despite their lower average level of viremia, asymptomatic people can be infectious to mosquitoes. Moreover, at a given level of viremia, DENV-infected people with no detectable symptoms or before the onset of symptoms are significantly more infectious to mosquitoes than people with symptomatic infections. Because DENV viremic people without clinical symptoms may be exposed to more mosquitoes through their undisrupted daily routines than sick people and represent the bulk of DENV infections, our data indicate that they have the potential to contribute significantly more to virus transmission to mosquitoes than previously recognized. C1 [Duong, Veasna; Lay, Rath Srey; Buchy, Philippe] Inst Pasteur Cambodia, Int Network Pasteur Inst, Virol Unit, Phnom Penh 12201, Cambodia. [Lambrechts, Louis] Inst Pasteur, Dept Genomes & Genet, Insect Virus Interact Grp, F-75015 Paris, France. [Lambrechts, Louis; Paul, Richard E.; Sakuntabhai, Anavaj] CNRS, Unite Rech Associee 3012, F-75015 Paris, France. [Paul, Richard E.; Sakuntabhai, Anavaj] Inst Pasteur, Dept Genomes & Genet, Funct Genet Infect Dis Unit, F-75015 Paris, France. [Ly, Sowath; Tarantola, Arnaud] Inst Pasteur Cambodia, Int Network Pasteur Inst, Epidemiol & Publ Hlth Unit, Phnom Penh 12201, Cambodia. [Long, Kanya C.; Scott, Thomas W.] Univ Calif Davis, Dept Entomol & Nematol, Davis, CA 95616 USA. [Huy, Rekol] Minist Hlth, Natl Ctr Malariol, Phnom Penh 12302, Cambodia. [Scott, Thomas W.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Buchy, Philippe] GlaxoSmithKline, Vaccines Value Hlth Sci, Singapore 189720, Singapore. RP Buchy, P (reprint author), Inst Pasteur Cambodia, Int Network Pasteur Inst, Virol Unit, Phnom Penh 12201, Cambodia. EM buchyphilippe@hotmail.com RI Lambrechts, Louis/A-2057-2010; OI Lambrechts, Louis/0000-0001-5958-2138; Duong, Veasna/0000-0003-0353-1678; Tarantola, Arnaud/0000-0002-6946-7958 FU European Union [282 378]; French Government's Investissement d'Avenir Program, Laboratoire d'Excellence Integrative Biology of Emerging Infectious Diseases [ANR-10-LABX-62-IBEID]; Emergence(s) Program of the City of Paris; Research and Policy for Infectious Disease Dynamics Program of the Science and Technology Directory, Department of Homeland Security; Fogarty International Center, National Institutes of Health (NIH); NIH [1P01AI098670-01A1] FX We express our gratitude to patients who were eagerly willing to participate in the study, particularly in the mosquito transmission experiments. We also acknowledge the staff of Virology and Epidemiology Units at Institut Pasteur in Cambodia for their technical support. We thank doctors and nurses of the three hospitals in Kampong Cham Province for their contribution in patients' enrollment, sample collection, and patience. We extend our thanks to our entomology assistants, Mr. Neung Choueth and Mr. Chhin Deth, for their valuable assistance, and to all the team from the Dengue National Control Program. We thank A. Fontaine and S. Lequime for assistance with the figures, and three anonymous reviewers for constructive comments that significantly improved the manuscript. The research leading to these results received funding from the European Union Seventh Framework Programme (FP7/2007/2011) under Grant Agreement 282 378. L.L. received funding from the French Government's Investissement d'Avenir Program, Laboratoire d'Excellence Integrative Biology of Emerging Infectious Diseases (Grant ANR-10-LABX-62-IBEID), and from the Emergence(s) Program of the City of Paris. T.W.S. was supported by the Research and Policy for Infectious Disease Dynamics Program of the Science and Technology Directory, Department of Homeland Security, and Fogarty International Center, National Institutes of Health (NIH). L.L., K.C.L., and T.W.S. received support from NIH Grant 1P01AI098670-01A1. NR 38 TC 40 Z9 41 U1 4 U2 15 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 NOV 24 PY 2015 VL 112 IS 47 BP 14688 EP 14693 DI 10.1073/pnas.1508114112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CW7IY UT WOS:000365173100078 PM 26553981 ER PT J AU Meisel, C Schulze-Bonhage, A Freestone, D Cook, MJ Achermann, P Plenz, D AF Meisel, Christian Schulze-Bonhage, Andreas Freestone, Dean Cook, Mark James Achermann, Peter Plenz, Dietmar TI Intrinsic excitability measures track antiepileptic drug action and uncover increasing/decreasing excitability over the wake/sleep cycle SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE excitability; epilepsy; sleep ID TRANSCRANIAL MAGNETIC STIMULATION; MOTOR CORTEX EXCITABILITY; CORTICAL EXCITABILITY; NEURONAL AVALANCHES; SYNAPTIC HOMEOSTASIS; IN-VIVO; HUMAN BRAIN; EPILEPSY; SLEEP; RESPONSES AB Pathological changes in excitability of cortical tissue commonly underlie the initiation and spread of seizure activity in patients suffering from epilepsy. Accordingly, monitoring excitability and controlling its degree using antiepileptic drugs (AEDs) is of prime importance for clinical care and treatment. To date, adequate measures of excitability and action of AEDs have been difficult to identify. Recent insights into ongoing cortical activity have identified global levels of phase synchronization as measures that characterize normal levels of excitability and quantify any deviation therefrom. Here, we explore the usefulness of these intrinsic measures to quantify cortical excitability in humans. First, we observe a correlation of such markers with stimulation-evoked responses suggesting them to be viable excitability measures based on ongoing activity. Second, we report a significant covariation with the level of AED load and a wake-dependent modulation. Our results indicate that excitability in epileptic networks is effectively reduced by AEDs and suggest the proposed markers as useful candidates to quantify excitability in routine clinical conditions overcoming the limitations of electrical or magnetic stimulation. The wake-dependent time course of these metrics suggests a homeostatic role of sleep, to rebalance cortical excitability. C1 [Meisel, Christian; Plenz, Dietmar] NIMH, Sect Crit Brain Dynam, Bethesda, MD 20892 USA. [Schulze-Bonhage, Andreas] Univ Med Ctr Freiburg, Epilepsy Ctr, Neuroctr, D-79106 Freiburg, Germany. [Freestone, Dean] Univ Melbourne, Dept Elect & Elect Engn, Parkville, Vic 3010, Australia. [Cook, Mark James] St Vincents Hosp, Dept Neurol, Melbourne, Vic, Australia. [Cook, Mark James] Univ Melbourne, Fitzroy, Vic 3065, Australia. [Achermann, Peter] Univ Zurich, Inst Pharmacol & Toxicol, CH-8006 Zurich, Switzerland. [Achermann, Peter] Univ Zurich, Neurosci Ctr Zurich, CH-8057 Zurich, Switzerland. [Achermann, Peter] Swiss Fed Inst Technol, CH-8057 Zurich, Switzerland. [Achermann, Peter] Univ Zurich, Zurich Ctr Interdisciplinary Sleep Res, CH-8057 Zurich, Switzerland. RP Meisel, C (reprint author), NIMH, Sect Crit Brain Dynam, Bethesda, MD 20892 USA. EM christian@meisel.de RI Achermann, Peter/N-1215-2014; OI Achermann, Peter/0000-0002-0208-3511; Freestone, Dean/0000-0003-2411-5358; Cook, Mark/0000-0002-8875-4135 FU National Institute of Mental Health [ZIAMH002797]; Cluster of Excellence BrainLinks-BrainTools [EXC-1086] FX This study was supported by the Intramural Research Program of the National Institute of Mental Health (ZIAMH002797). This study used the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health. A.S.-B. would like to acknowledge support by the Cluster of Excellence BrainLinks-BrainTools (EXC-1086). NR 44 TC 9 Z9 9 U1 1 U2 10 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 NOV 24 PY 2015 VL 112 IS 47 BP 14694 EP 14699 DI 10.1073/pnas.1513716112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CW7IY UT WOS:000365173100079 PM 26554021 ER PT J AU Riazanski, V Gabdoulkhakova, AG Boynton, LS Eguchi, RR Deriy, LV Hogarth, DK Loaec, N Oumata, N Galons, H Brown, ME Shevchenko, P Gallan, AJ Yoo, SG Naren, AP Villereal, ML Beacham, DW Bindokas, VP Birnbaumer, L Meijer, L Nelson, DJ AF Riazanski, Vladimir Gabdoulkhakova, Aida G. Boynton, Lin S. Eguchi, Raphael R. Deriy, Ludmila V. Hogarth, D. Kyle Loaec, Nadege Oumata, Nassima Galons, Herve Brown, Mary E. Shevchenko, Pavel Gallan, Alexander J. Yoo, Sang Gune Naren, Anjaparavanda P. Villereal, Mitchel L. Beacham, Daniel W. Bindokas, Vytautas P. Birnbaumer, Lutz Meijer, Laurent Nelson, Deborah J. TI TRPC6 channel translocation into phagosomal membrane augments phagosomal function SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE phagosome; TRPC6; alveolar macrophage; cystic fibrosis; roscovitine ID CYSTIC-FIBROSIS; ALVEOLAR MACROPHAGES; RESPIRATORY-DISEASE; DRUG TARGETS; LIPID RAFTS; PHAGOCYTOSIS; ACIDIFICATION; CELLS; CFTR; IDENTIFICATION AB Defects in the innate immune system in the lung with attendant bacterial infections contribute to lung tissue damage, respiratory insufficiency, and ultimately death in the pathogenesis of cystic fibrosis (CF). Professional phagocytes, including alveolar macrophages (AMs), have specialized pathways that ensure efficient killing of pathogens in phagosomes. Phagosomal acidification facilitates the optimal functioning of degradative enzymes, ultimately contributing to bacterial killing. Generation of low organellar pH is primarily driven by the V-ATPases, proton pumps that use cytoplasmic ATP to load H+ into the organelle. Critical to phagosomal acidification are various channels derived from the plasma membrane, including the anion channel cystic fibrosis transmembrane conductance regulator, which shunt the transmembrane potential generated by movement of protons. Here we show that the transient receptor potential canonical-6 (TRPC6) calcium-permeable channel in the AM also functions to shunt the transmembrane potential generated by proton pumping and is capable of restoring microbicidal function to compromised AMs in CF and enhancement of function in non-CF cells. TRPC6 channel activity is enhanced via translocation to the cell surface (and then ultimately to the phagosome during phagocytosis) in response to G-protein signaling activated by the small molecule (R)-roscovitine and its derivatives. These data show that enhancing vesicular insertion of the TRPC6 channel to the plasma membrane may represent a general mechanism for restoring phagosome activity in conditions, where it is lost or impaired. C1 [Riazanski, Vladimir; Gabdoulkhakova, Aida G.; Boynton, Lin S.; Eguchi, Raphael R.; Deriy, Ludmila V.; Hogarth, D. Kyle; Brown, Mary E.; Shevchenko, Pavel; Gallan, Alexander J.; Yoo, Sang Gune; Villereal, Mitchel L.; Bindokas, Vytautas P.; Nelson, Deborah J.] Univ Chicago, Dept Pharmacol & Physiol Sci, Chicago, IL 60637 USA. [Riazanski, Vladimir; Gabdoulkhakova, Aida G.; Boynton, Lin S.; Eguchi, Raphael R.; Deriy, Ludmila V.; Hogarth, D. Kyle; Brown, Mary E.; Shevchenko, Pavel; Gallan, Alexander J.; Yoo, Sang Gune; Villereal, Mitchel L.; Bindokas, Vytautas P.; Nelson, Deborah J.] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Loaec, Nadege; Oumata, Nassima; Meijer, Laurent] Ctr Perharidy, Hotel Rech, Dept Res & Dev, ManRos Therapeut, F-29680 Roscoff, France. [Galons, Herve] Univ Paris 05, Unite Technol Chim & Biol Sante, UMR S INSERM 75270 1022, Paris 06, France. [Naren, Anjaparavanda P.] Cincinnati Childrens Hosp Med Ctr, Div Pulm Med & Gastroenterol, Dept Pediat, Cincinnati, OH 45229 USA. [Beacham, Daniel W.] Thermo Sci, Mol Probes, Eugene, OR 97402 USA. [Birnbaumer, Lutz] NIEHS, Neurobiol Lab, Res Triangle Pk, NC 27709 USA. RP Birnbaumer, L (reprint author), NIEHS, Neurobiol Lab, Res Triangle Pk, NC 27709 USA. EM Birnbau1@gmail.com; nelson@uchicago.edu OI Gabdoulkhakova, Aida/0000-0002-8437-4389 FU National Institutes of Health [R01 GM36823, R01 HL125076, R01 DK080364]; Cystic Fibrosis Foundation [12, 13PO]; NIH [Z01-ES-101684] FX The authors thank Dr. Rong Ma (University of North Texas, Fort Worth), who generously offered the use of his laboratory and animals in the first experiments involving the trpc6-/- mice; Drs. Radmila Sarac, Theodore Karrison, and Olga Zaborina, for many helpful conversations over the course of the study; Dr. G. Thinakaran for the gift of the many vesicle-directed antibodies; Yimei Chen in the Electron Microcopy Core at the University of Chicago, for his expertise; Dr. Richard D. Ye (University of Illinois at Chicago) for his help in the initial experiments examining whether (R)-roscovitine acted through the formyl peptide receptors; and Dr. Partha Kasturi (University of Kansas) for providing the initial experiments and analysis examining whether (R)-roscovitine modulated V-ATPase activity. This work was supported by National Institutes of Health Grants R01 GM36823, R01 HL125076, and R01 DK080364 (to D.J.N.); Cystic Fibrosis Foundation 12 and 13PO (to D.J.N.); and by the "Intramural Research Program of the NIH", Project Z01-ES-101684 (to L.B.). NR 50 TC 8 Z9 8 U1 1 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 NOV 24 PY 2015 VL 112 IS 47 BP E6486 EP E6495 DI 10.1073/pnas.1518966112 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CW7IY UT WOS:000365173100013 PM 26604306 ER PT J AU Tsai, SYA Chuang, JY Tsai, MS Wang, XF Xi, ZX Hung, JJ Chang, WC Bonci, A Su, TP AF Tsai, Shang-Yi A. Chuang, Jian-Ying Tsai, Meng-Shan Wang, Xiao-fei Xi, Zheng-Xiong Hung, Jan-Jong Chang, Wen-Chang Bonci, Antonello Su, Tsung-Ping TI Sigma-1 receptor mediates cocaine-induced transcriptional regulation by recruiting chromatin-remodeling factors at the nuclear envelope SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE sigma-1 receptor; cocaine; MAOB; emerin; deprenyl ID DEACETYLASE 3 HDAC3; DOPAMINE TRANSPORTER; HISTONE DEACETYLASE; ENDOPLASMIC-RETICULUM; BINDING-SITES; CELLS; EXPRESSION; PLASTICITY; MEMBRANE; PROTEINS AB The sigma-1 receptor (Sig-1R) chaperone at the endoplasmic reticulum (ER) plays important roles in cellular regulation. Here we found a new function of Sig-1R, in that it translocates from the ER to the nuclear envelope (NE) to recruit chromatin-remodeling molecules and regulate the gene transcription thereof. Sig-1Rs mainly reside at the ER-mitochondrion interface. However, on stimulation by agonists such as cocaine, Sig-1Rs translocate from ER to the NE, where Sig-1Rs bind NE protein emerin and recruit chromatin-remodeling molecules, including lamin A/C, barrier-to-autointegration factor (BAF), and histone deacetylase (HDAC), to form a complex with the gene repressor specific protein 3 (Sp3). Knockdown of Sig-1Rs attenuates the complex formation. Cocaine was found to suppress the gene expression of monoamine oxidase B (MAOB) in the brain of wild-type but not Sig-1R knockout mouse. A single dose of cocaine (20 mg/kg) in rats suppresses the level of MAOB at nuclear accumbens without affecting the level of dopamine transporter. Daily injections of cocaine in rats caused behavioral sensitization. Withdrawal from cocaine in cocaine-sensitized rats induced an apparent time-dependent rebound of theMAOB protein level to about 200% over control on day 14 after withdrawal. Treatment of cocaine-withdrawn rats with the MAOB inhibitor deprenyl completely alleviated the behavioral sensitization to cocaine. Our results demonstrate a role of Sig-1R in transcriptional regulation and suggest cocaine may work through this newly discovered genomic action to achieve its addictive action. Results also suggest theMAOB inhibitor deprenyl as a therapeutic agent to block certain actions of cocaine during withdrawal. C1 [Tsai, Shang-Yi A.; Chuang, Jian-Ying; Tsai, Meng-Shan; Su, Tsung-Ping] NIDA, Cellular Pathobiol Sect, Integrat Neurosci Res Branch, NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. [Chuang, Jian-Ying] Taipei Med Univ, PhD Program Neural Regenerat Med, Taipei 11031, Taiwan. [Wang, Xiao-fei; Xi, Zheng-Xiong] NIDA, Mol Targets & Medicat Discovery Branch, NIH, Dept Hlth & Human Serv, Baltimore, MD 21224 USA. [Hung, Jan-Jong] Natl Cheng Kung Univ, Inst Bioinformat & Biosignal Transduct, Tainan 70101, Taiwan. [Chang, Wen-Chang] Taipei Med Univ, Grad Inst Med Sci, Taipei 11031, Taiwan. [Bonci, Antonello] NIDA, Cellular Neurobiol Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. [Bonci, Antonello] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94608 USA. [Bonci, Antonello] Johns Hopkins Univ, Sch Med, Solomon H Snyder Neurosci Inst, Baltimore, MD 21205 USA. RP Su, TP (reprint author), NIDA, Cellular Pathobiol Sect, Integrat Neurosci Res Branch, NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. EM TSU@intra.nida.nih.gov OI Xi, Zheng-Xiong/0000-0001-6482-8104 FU National Institute on Drug Abuse, National Institutes of Health, US Department of Health and Human Services; Ministry of Science and Technology, Taiwan [MOST 103-2320-B-038-046, MOST 103-2321-B-038-001] FX We thank Brandon Harvey of the National Institute on Drug Abuse, Intramural Research Program for the supply of adeno-associated virus (AAV)-GFP and adeno-associated virus (AAV)-Sig-1R, and Diana Martinez, Roy Wise, and Yavin Shaham for helpful discussions. This work was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, US Department of Health and Human Services (S.-Y.A.T., J.-Y.C., M.-S.T., X.-f.W., Z.-X.X., A.B., and T.-P.S.). Supported was also provided by Grants MOST 103-2320-B-038-046 and MOST 103-2321-B-038-001 from the Ministry of Science and Technology, Taiwan (to J.-Y.C., J.-J.H., and W.-C.C.). NR 56 TC 6 Z9 6 U1 2 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 NOV 24 PY 2015 VL 112 IS 47 BP E6562 EP E6570 DI 10.1073/pnas.1518894112 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CW7IY UT WOS:000365173100021 PM 26554014 ER PT J AU Liu, W Hancock, CN Fischer, JW Harman, M Phang, JM AF Liu, Wei Hancock, Chad N. Fischer, Joseph W. Harman, Meredith Phang, James M. TI Proline biosynthesis augments tumor cell growth and aerobic glycolysis: involvement of pyridine nucleotides SO SCIENTIFIC REPORTS LA English DT Article ID PYRROLINE-5-CARBOXYLIC ACID; GLUTAMINE-METABOLISM; C-MYC; CANCER; OXIDASE; PATHWAY; EPIGENETICS; SUPPRESSOR; PROMOTES; SURVIVAL AB The metabolism of the nonessential amino acid proline contributes to tumor metabolic reprogramming. Previously we showed that MYC increases proline biosynthesis (PB) from glutamine. Here we show MYC increases the expression of the enzymes in PB at both protein and mRNA levels. Blockade of PB decreases tumor cell growth and energy production. Addition of Delta(1)-pyrroline- 5-carboxylate (P5C) or proline reverses the effects of P5C synthase knockdown but not P5C reductases knockdown. Importantly, the reversal effect of proline was blocked by concomitant proline dehydrogenase/oxidase (PRODH/POX) knockdown. These findings suggest that the important regulatory contribution of PB to tumor growth derives from metabolic cycling between proline and P5C rather than product proline or intermediate P5C. We further document the critical role of PB in maintaining pyridine nucleotide levels by connecting the proline cycle to glycolysis and to the oxidative arm of the pentose phosphate pathway. These findings establish a novel function of PB in tumorigenesis, linking the reprogramming of glucose, glutamine and pyridine nucleotides, and may provide a novel target for antitumor therapy. C1 [Liu, Wei; Hancock, Chad N.; Fischer, Joseph W.; Harman, Meredith; Phang, James M.] NCI, Metab & Canc Susceptibil Sect, Basic Res Lab, Ctr Canc Res,NIH, Frederick, MD 21702 USA. RP Phang, JM (reprint author), NCI, Metab & Canc Susceptibil Sect, Basic Res Lab, Ctr Canc Res,NIH, Frederick, MD 21702 USA. EM phangj@mail.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX We thank Gary Pauly at NCI for P5C synthesis, Dr. Anne Le from Johns Hopkins University School of Medicine for generous gift of glutaminase inhibitor BPTES, and Dr. Ziqiang Zhu for insightful comments. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. 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 35 TC 2 Z9 2 U1 4 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 NOV 24 PY 2015 VL 5 AR 17206 DI 10.1038/srep17206 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CW7ST UT WOS:000365200200002 PM 26598224 ER PT J AU Burbelo, PD Klimavicz, JS Deeks, SG Kovacs, JA Ragheb, JA AF Burbelo, Peter D. Klimavicz, James S. Deeks, Steve G. Kovacs, Joseph A. Ragheb, Jack A. TI Lack of Evidence for Molecular Mimicry in HIV-Infected Subjects SO PLOS ONE LA English DT Article ID LUCIFERASE IMMUNOPRECIPITATION SYSTEMS; COMMON IMMUNOLOGICAL EPITOPE; ANTIERYTHROPOIETIN ANTIBODIES; POSITIVE INDIVIDUALS; AUTOIMMUNE-DISEASE; AUTOANTIBODIES; IMMUNODEFICIENCY; ANEMIA; QUANTIFICATION; ERYTHROPOIETIN AB Previous studies in HIV patients have reported autoantibodies to several human proteins, including erythropoietin (EPO), interferon-alpha (IFN-alpha), interleukin-2 (IL-2), and HLA-DR, as potential mediators of anemia or immunosuppression. The etiology of these autoantibodies has been attributed to molecular mimicry between HIV epitopes and self-proteins. Here, the Luciferase Immunoprecipitation System (LIPS) was used to investigate the presence of such autoantibodies in HIV-infected adults. High levels of antibodies to HIV proteins such as capsid (p24), matrix (p17), envelope (gp41), and reverse transcriptase (RT) were detected using LIPS in both untreated and anti-retroviral-treated HIV-infected individuals but not in uninfected controls. LIPS readily detected anti-EPO autoantibodies in serum samples from subjects with presumptive pure red cell aplasia but not in any of the samples from HIV-infected or uninfected individuals. Similarly, subjects with HIV lacked autoantibodies to IFN-alpha, IL-2, HLA-DR and the immunoglobulin lambda light chain; all purported targets of molecular mimicry. While molecular mimicry between pathogen proteins and self-proteins is a commonly proposed mechanism for autoantibody production, the findings presented here indicate such a process is not common in HIV disease. C1 [Burbelo, Peter D.; Klimavicz, James S.] Natl Inst Dent & Craniofacial Res, Dent Clin Res Core, NIH, Bethesda, MD 20892 USA. [Deeks, Steve G.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Kovacs, Joseph A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Ragheb, Jack A.] US FDA, Off Biol Prod, OPQ, CDER, Silver Spring, MD USA. RP Burbelo, PD (reprint author), Natl Inst Dent & Craniofacial Res, Dent Clin Res Core, NIH, Bethesda, MD 20892 USA. EM burbelop@nidcr.nih.gov FU Divisions of Intramural Research, National Institute of Dental and Craniofacial Research; NIH Clinical Center; CDER, Food and Drug Administration, Foundation for AIDS Research (amFAR); Delaney AIDS Research Enterprise (DARE) [U19AI096109]; UCSF/Gladstone Institute of Virology & Immunology CFAR [P30 AI027763] FX This work was supported by the Divisions of Intramural Research, National Institute of Dental and Craniofacial Research, the NIH Clinical Center, and the CDER, Food and Drug Administration, Foundation for AIDS Research (amFAR), the Delaney AIDS Research Enterprise (DARE, U19AI096109), the UCSF/Gladstone Institute of Virology & Immunology CFAR (P30 AI027763). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 29 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 NOV 23 PY 2015 VL 10 IS 11 AR e0127662 DI 10.1371/journal.pone.0127662 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CX7AW UT WOS:000365853900001 PM 26599070 ER PT J AU Yu, HF Sui, YJ Wang, YC Sato, N Frey, B Xia, Z Waldmann, TA Berzofsky, J AF Yu, Huifeng Sui, Yongjun Wang, Yichuan Sato, Noriko Frey, Blake Xia, Zheng Waldmann, Thomas A. Berzofsky, Jay TI Interleukin-15 Constrains Mucosal T Helper 17 Cell Generation: Influence of Mononuclear Phagocytes SO PLOS ONE LA English DT Article ID INTESTINAL DENDRITIC CELLS; ACTIVATED KILLER-CELLS; IN-VIVO; IMMUNE-RESPONSES; RETINOIC-ACID; EXPRESSION CASSETTES; IL-15; DIFFERENTIATION; LYMPHOCYTES; SUBSETS AB Interleukin (IL)-15 has multiple roles in innate and adaptive immunity, especially regarding CD8(+) T cells and natural killer cells. However, the role of IL-15 in regulating differentiation of T helper cell subsets and mononuclear phagocytes (MPs) in different tissues in vivo is unknown. Here we report that IL-15 indirectly regulates Th17 but not other Th subsets in the intestinal lamina propria (LP), apparently through effects on MPs. Th17 cells in the LP were more prevalent in IL-15 KO mice than their wild-type counterparts, and less prevalent in IL-15 transgenic mice than their wild-type littermates, even co-caged. MPs from the LP of these mice were sufficient to mimic the in vivo finding in vitro by skewing of cocultured wild type OVA-specific CD4(+) T cells. However, production of IL-15 or lack thereof by these MPs was not sufficient to explain the skewing, as addition or blockade of IL- 15 in the cultures had no effect. Rather, a skewing of the relative proportion of CD11b(+), CD103(+) and double positive LP MP subsets in transgenic and KO could explain the differences in Th17 cells. Thus, IL-15 may influence MP subsets in the gut in a novel way that alters the frequency of LP Th17 cells. C1 [Yu, Huifeng; Sui, Yongjun; Wang, Yichuan; Frey, Blake; Xia, Zheng; Berzofsky, Jay] NIH, Vaccine Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Sato, Noriko] NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Waldmann, Thomas A.] NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Sui, YJ (reprint author), NIH, Vaccine Branch, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. EM suiy@niaid.nih.gov; berzofsj@mail.nih.gov FU National Cancer Institute (NCI) [ZO1 SC 004020] FX This work is supported by National Cancer Institute (NCI) intramural funding ZO1 SC 004020. NR 74 TC 1 Z9 1 U1 2 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 NOV 23 PY 2015 VL 10 IS 11 AR e0143001 DI 10.1371/journal.pone.0143001 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CX7AW UT WOS:000365853900055 PM 26600079 ER PT J AU Lei, HY Li, TW Li, BJ Tsai, S Biggar, RJ Nkrumah, F Neequaye, J Gutierrez, M Epelman, S Mbulaiteye, SM Bhatia, K Lo, SC AF Lei, Haiyan Li, Tianwei Li, Bingjie Tsai, Shien Biggar, Robert J. Nkrumah, Francis Neequaye, Janet Gutierrez, Marina Epelman, Sidnei Mbulaiteye, Sam M. Bhatia, Kishor Lo, Shyh-Ching TI Epstein-Barr virus from Burkitt Lymphoma biopsies from Africa and South America share novel LMP-1 promoter and gene variations SO SCIENTIFIC REPORTS LA English DT Article ID MEMBRANE PROTEIN-1 GENE; NUCLEAR ANTIGEN 1; V-VAL SUBTYPE; NASOPHARYNGEAL CARCINOMA; PERIPHERAL-BLOOD; MOLECULAR EPIDEMIOLOGY; SEQUENCE-ANALYSIS; EBV; GENOME; TUMOR AB Epstein Barr virus (EBV) sequence variation is thought to contribute to Burkitt lymphoma (BL), but lack of data from primary BL tumors hampers efforts to test this hypothesis. We directly sequenced EBV from 12 BL biopsies from Ghana, Brazil, and Argentina, aligned the obtained reads to the wildtype (WT) EBV reference sequence, and compared them with 100 published EBV genomes from normal and diseased people from around the world. The 12 BL EBVs were Type 1. Eleven clustered close to each other and to EBV from Raji BL cell line, but away from 12 EBVs reported from other BL-derived cell lines and away from EBV from NPC and healthy people from Asia. We discovered 23 shared novel nucleotide-base changes in the latent membrane protein (LMP)-1 promoter and gene (associated with 9 novel amino acid changes in the LMP-1 protein) of the 11 BL EBVs. Alignment of this region for the 112 EBV genomes revealed four distinct patterns, tentatively termed patterns A to D. The distribution of BL EBVs was 48%, 8%, 24% and 20% for patterns A to D, respectively; the NPC EBV's were Pattern B, and EBV-WT was pattern D. Further work is needed to investigate the association between EBV LMP-1 patterns with BL. C1 [Lei, Haiyan; Li, Tianwei; Li, Bingjie; Tsai, Shien; Lo, Shyh-Ching] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Biggar, Robert J.] NCI, Bethesda, MD 20892 USA. [Nkrumah, Francis] Noguchi Mem Inst, Accra, Ghana. [Neequaye, Janet] Univ Ghana, Dept Child Hlth, Accra, Ghana. [Gutierrez, Marina] Lab Stamboulian, Buenos Aires, DF, Argentina. [Epelman, Sidnei] St Marcelina Hosp, Dept Pediat Oncol, Sao Paulo, Brazil. [Mbulaiteye, Sam M.; Bhatia, Kishor] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20892 USA. RP Mbulaiteye, SM (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20892 USA. EM mbulaits@mail.nih.gov; ShyhChing.Lo@fda.hhs.gov FU Intramural Research Program of Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services [N01-CO-12400]; Food and Drug Administration in-house Modernizing Science Fund FX We would like to thank Dr. James J. Goedert and Charles Rabkin at the Infections and Immunoepidemiology Branch at the National Cancer Institute (Bethesda, Maryland) for editorial comments. We thank Drs. Hsiao-Mei Liao and Pengfei Guo at the Center for Biologics Evaluation and Research, Food and Drug Administration (Silver Spring, Maryland) for preparing the final Figures and Tables for publication. Support: The study was funded in part by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services; Grant number: N01-CO-12400, and in part by a Food and Drug Administration in-house Modernizing Science Fund. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD (http://biowulf.nih.gov). NR 47 TC 2 Z9 2 U1 0 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 NOV 23 PY 2015 VL 5 AR 16706 DI 10.1038/srep16706 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CW6CO UT WOS:000365085300001 PM 26593963 ER PT J AU Schiffman, M Wentzensen, N AF Schiffman, Mark Wentzensen, Nicolas TI Towards therapeutic vaccination against cervical precancer? SO LANCET LA English DT Editorial Material ID INTRAEPITHELIAL NEOPLASIA; FOLLOW-UP; CANCER; COLPOSCOPY; RISK; INFECTION C1 [Schiffman, Mark; Wentzensen, Nicolas] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Schiffman, M (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM schiffmm@mail.nih.gov NR 12 TC 1 Z9 1 U1 0 U2 1 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 NOV 21 PY 2015 VL 386 IS 10008 BP 2036 EP 2038 DI 10.1016/S0140-6736(15)00240-8 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA CX8XF UT WOS:000365987600007 PM 26386539 ER PT J AU Romero, R Deter, R AF Romero, Roberto Deter, Russell TI Should serial fetal biometry be used in all pregnancies? SO LANCET LA English DT Editorial Material C1 [Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Bethesda, MD 20892 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 48201 USA. [Deter, Russell] Baylor Coll Med, Dept Obstet & Gynecol, Houston, TX 77030 USA. RP Romero, R (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Bethesda, MD 20892 USA. EM prbchiefstaff@med.wayne.edu NR 13 TC 2 Z9 2 U1 0 U2 1 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 NOV 21 PY 2015 VL 386 IS 10008 BP 2038 EP 2040 DI 10.1016/S0140-6736(15)00148-8 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA CX8XF UT WOS:000365987600008 PM 26360241 ER PT J AU Nguyen, TT Yeom, YS Kim, HS Wang, ZJ Han, MC Kim, CH Lee, JK Zankl, M Petoussi-Henss, N Bolch, WE Lee, C Chung, BS AF Thang Tat Nguyen Yeom, Yeon Soo Kim, Han Sung Wang, Zhao Jun Han, Min Cheol Kim, Chan Hyeong Lee, Jai Ki Zankl, Maria Petoussi-Henss, Nina Bolch, Wesley E. Lee, Choonsik Chung, Beom Sun TI Incorporation of detailed eye model into polygon-mesh versions of ICRP-110 reference phantoms SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE ICRP reference phantom; detailed eye model; polygon-mesh phantom; lens dose coefficients; Monte Carlo ID DOSE CONVERSION COEFFICIENTS; COLOR SLICE IMAGES; ELECTRON EXPOSURE; LENS; RADIATION; SIMULATION; CATARACT; CADAVER AB The dose coefficients for the eye lens reported in ICRP 2010 Publication 116 were calculated using both a stylized model and the ICRP-110 reference phantoms, according to the type of radiation, energy, and irradiation geometry. To maintain consistency of lens dose assessment, in the present study we incorporated the ICRP-116 detailed eye model into the converted polygon-mesh (PM) version of the ICRP-110 reference phantoms. After the incorporation, the dose coefficients for the eye lens were calculated and compared with those of the ICRP-116 data. The results showed generally a good agreement between the newly calculated lens dose coefficients and the values of ICRP 2010 Publication 116. Significant differences were found for some irradiation cases due mainly to the use of different types of phantoms. Considering that the PM version of the ICRP-110 reference phantoms preserve the original topology of the ICRP-110 reference phantoms, it is believed that the PM version phantoms, along with the detailed eye model, provide more reliable and consistent dose coefficients for the eye lens. C1 [Thang Tat Nguyen; Yeom, Yeon Soo; Kim, Han Sung; Wang, Zhao Jun; Han, Min Cheol; Kim, Chan Hyeong; Lee, Jai Ki] Hanyang Univ, Dept Nucl Engn, Seoul 133791, South Korea. [Zankl, Maria; Petoussi-Henss, Nina] Deutsch Forschungszentrum Gesundheit & Umwelt Gmb, Helmholtz Zentrum Munchen, Res Unit Med Radiat Phys & Diagnost, D-85764 Neuherberg, Germany. [Bolch, Wesley E.] Univ Florida, J Crayton Pruitt Family Dept Biomed Engn, Gainesville, FL 32611 USA. [Lee, Choonsik] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Chung, Beom Sun] Ajou Univ, Sch Med, Dept Anat, Suwon 443380, South Korea. RP Nguyen, TT (reprint author), Hanyang Univ, Dept Nucl Engn, 222 Wangsimni Ro, Seoul 133791, South Korea. EM chkim@hanyang.ac.kr FU Nuclear Safety and Security Commission (NSSC) through Korea Radiation Safety Foundation (KORSAFe); Ministry of Science, ICT and Future Planning through the National Research Foundation of Korea [2011-0025496, 2012-K001146, 1403012]; Global PhD Fellowship program [2011-0007318, 2011-0030970] FX This project was supported by Nuclear Safety and Security Commission (NSSC) through Korea Radiation Safety Foundation (KORSAFe) and also by Ministry of Science, ICT and Future Planning through the National Research Foundation of Korea (Project No.: 2011-0025496, 2012-K001146, 1403012). Two of the authors were supported by the Global PhD Fellowship program (Project No.: 2011-0007318, 2011-0030970). NR 31 TC 1 Z9 3 U1 0 U2 2 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 NOV 21 PY 2015 VL 60 IS 22 BP 8695 EP 8707 DI 10.1088/0031-9155/60/22/8695 PG 13 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA CY0PV UT WOS:000366108900008 PM 26509407 ER PT J AU Zepeda-Mendoza, CJ Mukhopadhyay, S Wong, ES Harder, N Splinter, E de Wit, E Eckersley-Maslin, MA Ried, T Eils, R Rohr, K Mills, A de Laat, W Flicek, P Sengupta, AM Spector, DL AF Zepeda-Mendoza, Cinthya J. Mukhopadhyay, Swagatam Wong, Emily S. Harder, Nathalie Splinter, Erik de Wit, Elzo Eckersley-Maslin, Melanie A. Ried, Thomas Eils, Roland Rohr, Karl Mills, Alea de Laat, Wouter Flicek, Paul Sengupta, Anirvan M. Spector, David L. TI Quantitative analysis of chromatin interaction changes upon a 4.3 Mb deletion at mouse 4E2 SO BMC GENOMICS LA English DT Article ID CHROMOSOME CONFORMATION CAPTURE; NUCLEAR LAMINA INTERACTIONS; GENE-EXPRESSION; MONOSOMY 1P36; TUMOR-SUPPRESSOR; ORGANIZATION; GENOME; ARCHITECTURE; COHESIN; CELLS AB Background: Circular chromosome conformation capture (4C) has provided important insights into three dimensional (3D) genome organization and its critical impact on the regulation of gene expression. We developed a new quantitative framework based on polymer physics for the analysis of paired-end sequencing 4C (PE-4Cseq) data. We applied this strategy to the study of chromatin interaction changes upon a 4.3 Mb DNA deletion in mouse region 4E2. Results: A significant number of differentially interacting regions (DIRs) and chromatin compaction changes were detected in the deletion chromosome compared to a wild-type (WT) control. Selected DIRs were validated by 3D DNA FISH experiments, demonstrating the robustness of our pipeline. Interestingly, significant overlaps of DIRs with CTCF/Smc1 binding sites and differentially expressed genes were observed. Conclusions: Altogether, our PE-4Cseq analysis pipeline provides a comprehensive characterization of DNA deletion effects on chromatin structure and function. C1 [Zepeda-Mendoza, Cinthya J.; Eckersley-Maslin, Melanie A.; Mills, Alea; Spector, David L.] Cold Spring Harbor Lab, Watson Sch Biol Sci, Cold Spring Harbor, NY 11724 USA. [Mukhopadhyay, Swagatam; Mills, Alea; Spector, David L.] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. [Wong, Emily S.; Flicek, Paul] European Bioinformat Inst, European Mol Biol Lab, Hinxton CB10 1SD, Cambs, England. [Harder, Nathalie; Eils, Roland; Rohr, Karl] Heidelberg Univ, BioQuant, IPMB, Dept Bioinformat & Funct Genom,Biomed Comp Vis Gr, D-69120 Heidelberg, Germany. [Harder, Nathalie; Eils, Roland; Rohr, Karl] German Canc Res Ctr, D-69120 Heidelberg, Germany. [Splinter, Erik; de Wit, Elzo; de Laat, Wouter] Hubrecht Inst KNAW, NL-3584 CT Utrecht, Netherlands. [Splinter, Erik; de Wit, Elzo; de Laat, Wouter] Univ Med Ctr Utrecht, NL-3584 CT Utrecht, Netherlands. [Eckersley-Maslin, Melanie A.] Babraham Inst, Epigenet Programme, Cambridge CB22 3AT, England. [Ried, Thomas] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Sengupta, Anirvan M.] Rutgers State Univ, Dept Phys & Astron, Piscataway, NJ 08854 USA. RP Mukhopadhyay, S (reprint author), Cold Spring Harbor Lab, 1 Bungtown Rd, Cold Spring Harbor, NY 11724 USA. EM swagatam.mukhopadhyay@gmail.com; spector@cshl.edu RI Eils, Roland/B-6121-2009; OI Eils, Roland/0000-0002-0034-4036; Wong, Emily/0000-0003-0315-2942; de Wit, Elzo/0000-0003-2883-1415; Flicek, Paul/0000-0002-3897-7955 FU Gonzalo Rio Arronte Fellowship; NIGMS [42694]; NCI [2P30CA45508]; EMBO Long-term Fellowship program [ALTF 1518-2012]; Wellcome Trust [WT095908]; European Molecular Biology Laboratory FX C.Z-M. is supported by the Gonzalo Rio Arronte Fellowship. Research in the Spector lab is supported by NIGMS 42694 and NCI 2P30CA45508. ESW is supported by the EMBO Long-term Fellowship program (ALTF 1518-2012). PF is supported by the Wellcome Trust (WT095908) and the European Molecular Biology Laboratory. The authors have no competing interests to declare. NR 55 TC 0 Z9 0 U1 0 U2 6 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 NOV 21 PY 2015 VL 16 AR 982 DI 10.1186/s12864-015-2137-5 PG 17 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA CW8YH UT WOS:000365284900001 PM 26589460 ER PT J AU Gonzalez, FJ AF Gonzalez, Frank J. TI COLON AND LUNG CANCER BIOMARKERS: STUDIES IN MICE AND MAN SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 19th North American Meeting of the International-Society-for-the-Study-of-Xenobiotics (ISSX) / 29th Meeting of the Japanese-Society-for-the-Study-of-Xenobiotics (JSSX) CY OCT 19-23, 2014 CL San Francisco, CA SP Int Soc Study Xenobiot, Japan Soc Study Xenobiot C1 [Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0360-2532 EI 1097-9883 J9 DRUG METAB REV JI Drug Metab. Rev. PD NOV 20 PY 2015 VL 47 SU 1 SI SI MA S8 BP 14 EP 14 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CX3PQ UT WOS:000365611800021 ER PT J AU Waidyanatha, S McDonald, JA Doyle-Eisele, M McIntyre, BS Sanders, JM AF Waidyanatha, Suramya McDonald, Jacob A. Doyle-Eisele, Melanie McIntyre, Barry S. Sanders, J. Michael TI EFFECT OF VEHICLE ON THE DISPOSITION OF SUNSCREEN INGREDIENT 2-HYDROXY-4-METHOXYBENZOPHENONE IN RODENTS FOLLOWING DERMAL APPLICATION SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 19th North American Meeting of the International-Society-for-the-Study-of-Xenobiotics (ISSX) / 29th Meeting of the Japanese-Society-for-the-Study-of-Xenobiotics (JSSX) CY OCT 19-23, 2014 CL San Francisco, CA SP Int Soc Study Xenobiot, Japan Soc Study Xenobiot C1 [Waidyanatha, Suramya; McIntyre, Barry S.; Sanders, J. Michael] NIEHS, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [McDonald, Jacob A.; Doyle-Eisele, Melanie] Lovelace Resp Res Inst, Albuquerque, NM USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0360-2532 EI 1097-9883 J9 DRUG METAB REV JI Drug Metab. Rev. PD NOV 20 PY 2015 VL 47 SU 1 SI SI MA P111 BP 92 EP 92 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CX3PQ UT WOS:000365611800184 ER PT J AU Garg, AD Galluzzi, L Apetoh, L Baert, T Birge, RB Bravo-San Pedro, JM Breckpot, K Brough, D Chaurio, R Cirone, M Coosemans, A Coulie, PG De Ruysscher, D Dini, L de Witte, P Dudek-Peric, AM Faggioni, A Fucikova, J Gaipl, US Golab, J Gougeon, ML Hamblin, MR Hemminki, A Herrmann, M Hodge, JW Kepp, O Kroemer, G Krysko, DV Land, WG Madeo, F Manfredi, AA Mattarollo, SR Maueroder, C Merendino, N Multhoff, G Pabst, T Ricci, JE Riganti, C Romano, E Rufo, N Smyth, MJ Sonnemann, J Spisek, R Stagg, J Vacchelli, E Vandenabeele, P Vandenberk, L Van den Eynde, BJ Van Gool, S Velotti, F Zitvogel, L Agostinis, P AF Garg, Abhishek D. Galluzzi, Lorenzo Apetoh, Lionel Baert, Thais Birge, Raymond B. Bravo-San Pedro, Jose Manuel Breckpot, Karine Brough, David Chaurio, Ricardo Cirone, Mara Coosemans, An Coulie, Pierre G. De Ruysscher, Dirk Dini, Luciana de Witte, Peter Dudek-Peric, Aleksandra M. Faggioni, Alberto Fucikova, Jitka Gaipl, Udo S. Golab, Jakub Gougeon, Marie-Lise Hamblin, Michael R. Hemminki, Akseli Herrmann, Martin Hodge, James W. Kepp, Oliver Kroemer, Guido Krysko, Dmitri V. Land, Walter G. Madeo, Frank Manfredi, Angelo A. Mattarollo, Stephen R. Maueroder, Christian Merendino, Nicolo Multhoff, Gabriele Pabst, Thomas Ricci, Jean-Ehrland Riganti, Chiara Romano, Erminia Rufo, Nicole Smyth, Mark J. Sonnemann, Juergen Spisek, Radek Stagg, John Vacchelli, Erika Vandenabeele, Peter Vandenberk, Lien Van den Eynde, Benoit J. Van Gool, Stefaan Velotti, Francesca Zitvogel, Laurence Agostinis, Patrizia TI Molecular and Translational Classifications of DAMPs in Immunogenic Cell Death SO FRONTIERS IN IMMUNOLOGY LA English DT Article DE anti-tumor immunity; immunogenicity; immunotherapy; molecular dicine; oncoimmunology; patient prognosis; translational medicine ID HUMAN TUMOR-CELLS; HIGH HYDROSTATIC-PRESSURE; APOPTOTIC CALRETICULIN EXPOSURE; ANTICANCER IMMUNE-RESPONSES; ACTIVATING POLYPEPTIDE-II; FORMYL PEPTIDE RECEPTORS; RIBOSOMAL-PROTEIN DIMER; CYTOTOXIC T-LYMPHOCYTES; NEGATIVE BREAST-CANCER; PHOTODYNAMIC THERAPY AB The immunogenicity of malignant cells has recently been acknowledged as a critical determinant of efficacy in cancer therapy. Thus, besides developing direct immunostimulatory regimens, including dendritic cell-based vaccines, checkpoint-blocking therapies, and adoptive T-cell transfer, researchers have started to focus on the overall mmunobiology of neoplastic cells. It is now clear that cancer cells can succumb to some anticancer therapies by undergoing a peculiar form of cell death that is characterized by an increased immunogenic potential, owing to the emission of the so-called "damage-associated molecular patterns" (DAMPs). The emission of DAMPs and other mmunostimulatory factors by cells succumbing to immunogenic cell death (ICD) favors the establishment of a productive interface with the immune system. This results in the elicitation of tumor-targeting immune responses associated with the elimination of residual, treatment-resistant cancer cells, as well as with the establishment of immunological memory. Although ICD has been characterized with increased precision since its discovery, several questions remain to be addressed. Here, we summarize and tabulate the main molecular, immunological, preclinical, and clinical aspects of ICD, in an attempt to capture the essence of this phenomenon, and identify future challenges for this rapidly expanding field of investigation. C1 [Garg, Abhishek D.; Romano, Erminia; Rufo, Nicole; Agostinis, Patrizia] Univ Leuven, KU Leuven, Dept Cellular Mol Med, Cell Death Res & Therapy, Leuven, Belgium. [Galluzzi, Lorenzo; Bravo-San Pedro, Jose Manuel; Vacchelli, Erika] Ctr Rech Cordefiers, Equipe Labelsee Ligue Canc 11, Paris, France. [Galluzzi, Lorenzo; Bravo-San Pedro, Jose Manuel; Vacchelli, Erika] INSERM, U1138, Paris, France. [Galluzzi, Lorenzo; Bravo-San Pedro, Jose Manuel; Vacchelli, Erika] Univ Paris 05, Sorbonne Paris Cite, Paris, France. [Galluzzi, Lorenzo; Bravo-San Pedro, Jose Manuel; Vacchelli, Erika] Univ Paris 06, Paris, France. [Galluzzi, Lorenzo; Bravo-San Pedro, Jose Manuel; Vacchelli, Erika; Van den Eynde, Benoit J.] Gustave Roussy Comprehens Canc Inst, Villejuif, France. [Apetoh, Lionel] INSERM, U866, Dijon, France. [Apetoh, Lionel] Univ Bourgogne, Fac Med, Dijon, France. [Apetoh, Lionel] Ctr Georges Francois Leclerc, Dijon, France. [Baert, Thais; Coosemans, An] UZ Leuven, Dept Gynaecol & Obstet, Leuven, Belgium. [Baert, Thais; Coosemans, An] Katholieke Univ Leuven, Leuven Canc Inst, Dept Oncol, Lab Gynaecol Oncol, Leuven, Belgium. [Birge, Raymond B.] Univ Med & Dent New Jersey, New Jersey Med Sch, Rutgers Canc Inst New Jersey, Univ Hosp Canc Ctr,Dept Microbiol Biochem & Mol G, Newark, NJ 07103 USA. [Breckpot, Karine] Vrije Univ Brussel, Lab Mol & Cellular Therapy, Jette, Belgium. [Brough, David] Univ Manchester, Fac Life Sci, Manchester, Lancs, England. [Chaurio, Ricardo; Herrmann, Martin; Maueroder, Christian] Univ Erlangen Nurnberg, Dept Internal Med Rheumatol & Immunol 3, D-91054 Erlangen, Germany. [Cirone, Mara] Univ Roma La Sapienza, Dept Expt Med, I-00185 Rome, Italy. [Coulie, Pierre G.] Catholic Univ Louvain, Duve Inst, B-1200 Brussels, Belgium. [De Ruysscher, Dirk] Univ Leuven, KU Leuven, Univ Hosp Leuven, Dept Radiat Oncol, Leuven, Belgium. [Dini, Luciana] Univ Salento, Dept Biol & Environm Sci & Technol, Salento, Italy. [de Witte, Peter] Univ Leuven, KU Leuven, Dept Pharmaceut & Pharmacol Sci, Lab Mol Biodiscovery, Leuven, Belgium. [Faggioni, Alberto] Univ Roma La Sapienza, I-00185 Rome, Italy. [Fucikova, Jitka; Spisek, Radek] SOTIO, Prague, Czech Republic. [Fucikova, Jitka; Spisek, Radek] Charles Univ Prague, Univ Hosp Motol, Fac Med 2, Dept Immunol, Prague, Czech Republic. [Gaipl, Udo S.] Univ Klinikum Erlangen, Dept Radiat Oncol, Erlangen, Germany. [Golab, Jakub] Med Univ Warsaw, Dept Immunol, Warsaw, Poland. [Gougeon, Marie-Lise] Inst Pasteur, Biotherapy & Vaccine Unit, Paris, France. [Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Hemminki, Akseli] Univ Helsinki, Haartman Inst, Transplantat Lab, Canc Gene Therapy Grp, Helsinki, Finland. [Hemminki, Akseli] Helsinki Univ Hosp, Ctr Comprehens Canc, Helsinki, Finland. [Hemminki, Akseli] TILT Biotherapeut Ltd, Helsinki, Finland. [Hodge, James W.] NCI, NIH, Recombinant Vaccine Grp, Lab Tumor Immunol & Biol, Bethesda, MD 20892 USA. [Kepp, Oliver; Kroemer, Guido] Gustave Roussy Comprehens Canc Inst, Metabolom & Cell Biol Platforms, Villejuif, France. [Kroemer, Guido] Hop Europeen Georges Pompidou, AP HP, Pole Biol, Paris, France. [Kroemer, Guido] Karolinska Univ Hosp, Dept Womens & Chlldrens Hlth, Stockholm, Sweden. [Krysko, Dmitri V.; Vandenabeele, Peter] VIB, Inflammat Res Ctr, Mol Signaling & Cell Death Unit, Ghent, Belgium. [Krysko, Dmitri V.; Vandenabeele, Peter] Univ Ghent, Dept Biomed Mol Biol, B-9000 Ghent, Belgium. [Land, Walter G.] Univ Strasbourg, Lab Excellence Transplantex, INSERM UMRS1109, Mol ImmunoRheumatol, Strasbourg, France. [Madeo, Frank] Graz Univ, NAWI Graz, lnst Mol Biosci, Graz, Austria. [Madeo, Frank] BioTechMed Graz, Graz, Austria. [Manfredi, Angelo A.] Univ Vita Salute San Raffaele, IRRCS Ist Sci San Raffaele, Milan, Italy. [Mattarollo, Stephen R.] Univ Queensland, Univ Queensland Diamantina Inst, Translat Res Inst, Woolloongabba, Qld, Australia. [Merendino, Nicolo] Univ Tuscia, Dept Ecol & Biol Sci, Lab Cellular & Mol Nutr, Viterbo, Italy. [Multhoff, Gabriele] Tech Univ Munich, Klinikum Rechts Isar, Dept Radiat Oncol, D-80290 Munich, Germany. [Pabst, Thomas] Univ Hosp, Dept Med Oncol, Bern, Switzerland. [Ricci, Jean-Ehrland] Univ Nice Sophia Antipolis, IAISERM U1065, Ctr Med Med Mol C3M Equipe Controle Metabol Morts, F-06189 Nice, France. [Riganti, Chiara] Univ Turin, Dept Oncol, Turin, Italy. [Smyth, Mark J.] QIMR Berghofer Med Res Inst, Immunol Canc & Infect Lab, Herston, Qld, Australia. [Smyth, Mark J.] Univ Queensland, Sch Med, Herston, Qld, Australia. [Sonnemann, Juergen] Jena Univ Hosp, Childrens Clin, Dept Paediat Haematol & Oncol, Jena, Germany. [Stagg, John] Univ Montreal, Fac Pharm, Inst Canc Montreal, Ctr Rech,Ctr Hosp Univ Montreal, Montreal, PQ, Canada. [Vandenberk, Lien; Van Gool, Stefaan] Univ Leuven, KU Leuven, Dept Microbiol & Immunol, Lab Pediat Immunol, Leuven, Belgium. [Van den Eynde, Benoit J.] Catholic Univ Louvain, Ludwig Inst Canc Res, Duve Inst, B-1200 Brussels, Belgium. [Velotti, Francesca] Univ Tuscia, Dept Ecol & Biol Sci, Viterbo, Italy. [Zitvogel, Laurence] Univ Paris Sud, F-94275 Le Kremlin Bicetre, France. [Zitvogel, Laurence] INSERM, U1015, Villejuif, France. [Zitvogel, Laurence] Ctr Clin Invest Biotherapies Canc CICBT 507, Villejuif, France. RP Garg, AD (reprint author), Univ Leuven, KU Leuven, Dept Cellular Mol Med, Cell Death Res & Therapy, Leuven, Belgium. EM abhishek.garg@med.kuleuven.be; patrizia.agostinis@med.kuleuven.be RI Garg, Abhishek/D-5230-2012; Golab, Jakub/K-6974-2013; Vandenabeele, Peter/C-8597-2009; Maueroder, Christian/H-7412-2016; Krysko, Dmitri/G-9500-2013; Ricci, Jean Ehrland/I-7117-2016; herrmann, martin/A-9597-2013; Apetoh, Lionel/G-3310-2014; Hodge, James/D-5518-2015; OI Garg, Abhishek/0000-0002-9976-9922; Golab, Jakub/0000-0002-2830-5100; Maueroder, Christian/0000-0002-7563-883X; Krysko, Dmitri/0000-0002-9692-2047; Ricci, Jean Ehrland/0000-0003-1585-8117; herrmann, martin/0000-0002-0258-2484; Apetoh, Lionel/0000-0002-2774-438X; Hodge, James/0000-0001-5282-3154; Land, Walter/0000-0002-0090-0629; Bravo-San Pedro, Jose Manuel/0000-0002-5781-1133 FU Fund for Scientific Research Flanders (FWO-Vlaanderen) [G.0661.09, G.0728.10, G.0584.12N]; KU Leuven [GOA/11/009]; Inter university Attraction Poles Programme; Belgian State, Science Policy Office FX We would like to explicitly declare that this manuscript does not aim to describe guidelines for the fields of ICD and DAMP research. Rather, it is meant to be a comprehensive classification and review of relevant literature expressing consensus discussions, opinions, and conclusions endorsed and/or supported by a number of researchers and clinicians investigating ICI) and DAM Ps. We would also like to acknowledge the following colleagues for their support, reading and/or positive appraisal of this manuscript: Wee Han Ang, Vincenzo Barnaba, Marco E. Bianchi, Kariti de Visser, Sandra 0. Gollnick, Peter Henson, Polly Niatzinger, Niarek Michalak, Kodi Ravichandran, and Andrew Thorburn. ADC is a recipient of the FWO postdoctoral fellowship 2013. This work was supported by grants from the Fund for Scientific Research Flanders (FWO-Vlaanderen; (G.0661.09, G.0728.10 and G.0584.12N) and KU Leuven (GOA/11/009) to PA; This paper presents research results of the IAP7/32, funded by the Inter university Attraction Poles Programme, initiated by the Belgian State, Science Policy Office. NR 246 TC 26 Z9 26 U1 6 U2 28 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 NOV 20 PY 2015 VL 6 AR UNSP 588 DI 10.3389/fimmu.2015.00588 PG 24 WC Immunology SC Immunology GA CY0TW UT WOS:000366120100002 PM 26635802 ER PT J AU Ligibel, JA Alfano, CM Hershman, D Ballard, RM Bruinooge, SS Courneya, KS Daniels, EC Demark-Wahnefried, W Frank, ES Goodwin, PJ Irwin, ML Levit, LA McCaskill-Stevens, W Minasian, LM O'Rourke, MA Pierce, JP Stein, KD Thomson, CA Hudis, CA AF Ligibel, Jennifer A. Alfano, Catherine M. Hershman, Dawn Ballard, Rachel M. Bruinooge, Suanna S. Courneya, Kerry S. Daniels, Elvan C. Demark-Wahnefried, Wendy Frank, Elizabeth S. Goodwin, Pamela J. Irwin, Melinda L. Levit, Laura A. McCaskill-Stevens, Worta Minasian, Lori M. O'Rourke, Mark A. Pierce, John P. Stein, Kevin D. Thomson, Cynthia A. Hudis, Clifford A. TI Recommendations for Obesity Clinical Trials in Cancer Survivors: American Society of Clinical Oncology Statement SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID BODY-MASS INDEX; PHYSICAL-ACTIVITY; PROSTATE-CANCER; RANDOMIZED-TRIAL; BREAST; INTERVENTION; METAANALYSIS; WEIGHT; DIET; RECURRENCE C1 [Ligibel, Jennifer A.; Frank, Elizabeth S.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Alfano, Catherine M.; Daniels, Elvan C.; Stein, Kevin D.] Amer Canc Soc, Atlanta, GA 30329 USA. [Hershman, Dawn] Columbia Univ, New York, NY 10027 USA. [Hudis, Clifford A.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Ballard, Rachel M.] NIH, Bethesda, MD USA. [McCaskill-Stevens, Worta; Minasian, Lori M.] NCI, Bethesda, MD 20892 USA. [Bruinooge, Suanna S.; Levit, Laura A.] Amer Soc Clin Oncol, Alexandria, VA USA. [Courneya, Kerry S.] Univ Alberta, Edmonton, AB, Canada. [Goodwin, Pamela J.] Univ Toronto, Mt Sinai Hosp, Toronto, ON M5G 1X5, Canada. [Demark-Wahnefried, Wendy] Univ Alabama Birmingham, Birmingham, AL USA. [Irwin, Melinda L.] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [O'Rourke, Mark A.] Greenville Hosp Syst, Greenville, SC USA. [Pierce, John P.] Univ Calif San Diego, Moores Canc Ctr, San Diego, CA 92103 USA. [Thomson, Cynthia A.] Univ Arizona, Tucson, AZ USA. RP Ligibel, JA (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM jligibel@partners.org RI Goodwin, Pamela/K-1477-2013 FU NCI NIH HHS [P30 CA008748] NR 38 TC 12 Z9 12 U1 2 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 NOV 20 PY 2015 VL 33 IS 33 BP 3961 EP + DI 10.1200/JCO.2015.63.1440 PG 9 WC Oncology SC Oncology GA CX9JB UT WOS:000366020600020 PM 26324364 ER PT J AU Wiener, L Feudtner, C Hinds, P Wolfe, J Mack, J AF Wiener, Lori Feudtner, Chris Hinds, Pamela Wolfe, Joanne Mack, Jennifer TI Deeper Conversations Need Not Wait Until the End SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID OF-LIFE CARE; YOUNG-ADULTS; ADOLESCENTS; DISCUSSIONS; CHILDREN; CANCER C1 [Wiener, Lori] NCI, Bethesda, MD 20892 USA. [Feudtner, Chris] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Hinds, Pamela] Childrens Natl Hlth Syst, Washington, DC USA. [Hinds, Pamela] George Washington Univ, Washington, DC USA. [Wolfe, Joanne; Mack, Jennifer] Dana Farber Canc Inst, Boston, MA 02115 USA. [Wolfe, Joanne; Mack, Jennifer] Boston Childrens Hosp, Boston, MA USA. RP Wiener, L (reprint author), NCI, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 CA999999] NR 10 TC 1 Z9 1 U1 0 U2 3 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 NOV 20 PY 2015 VL 33 IS 33 BP 3974 EP + DI 10.1200/JCO.2015.62.3405 PG 2 WC Oncology SC Oncology GA CX9JB UT WOS:000366020600023 PM 26282649 ER PT J AU Shao, XM Liu, K Fan, Y Ding, ZH Chen, M Zhu, MY Weinstein, LS Li, HC Li, HS AF Shao, Ximing Liu, Ke Fan, Yi Ding, Zhihao Chen, Min Zhu, Minyan Weinstein, Lee S. Li, Hongchang Li, Huashun TI G alpha(s) Relays Sphingosine-1-Phosphate Receptor 1 Signaling to Stabilize Vascular Endothelial-Cadherin at Endothelial Junctions to Control Mouse Embryonic Vascular Integrity SO JOURNAL OF GENETICS AND GENOMICS LA English DT Article DE G alpha(s); VE-cadherin; S1PR1 signaling; adherens junctions; vascular integrity ID PROTEIN-COUPLED RECEPTORS; HETEROTRIMERIC G-PROTEINS; VE-CADHERIN; ADHERENS JUNCTIONS; SPROUTING ANGIOGENESIS; DOWN-REGULATION; IN-VIVO; S1PR1; MATURATION; CELLS AB Sphingosine-1-phosphate receptor 1 (S1PR1), a G protein-coupled receptor (GPCR), controls vascular stability by stabilizing vascular endothelial (VE)-cadherin junctional localization and inhibiting vascular endothelial growth factor receptor 2 (VEGFR2) signaling. However, the molecular mechanisms that link S1PR1 signaling to intracellular effectors remain unknown. In this study, we demonstrate that the heterotrimeric G protein subfamily member Gas, encoded by GNAS, acts as a relay mediator of S1PR1 signaling to control vascular integrity by stabilizing VE-cadherin at endothelial junctions. The endothelial cell-specific deletion of Gas in mice causes early embryonic lethality with massive hemorrhage and a disorganized vasculature. The immunostaining results revealed that Gas deletion remarkably reduces the junctional localization of VE-cadherin, whereas the mural cell coverage of the vessels is not impaired. In addition, we found that Gas depletion blocks the S1PR1-activation induced VE-cadherin stabilization at junctions, supporting that Gas acts downstream of S1PR1 signaling. Thus, our results demonstrate that Gas is an essential mediator to relay S1PR1 signaling and maintain vascular integrity. C1 [Shao, Ximing; Liu, Ke; Fan, Yi; Li, Huashun] Sichuan Univ, West China Hosp 2, West China Dev & Stem Cell Inst, Chengdu 610041, Peoples R China. [Shao, Ximing; Liu, Ke; Fan, Yi; Li, Huashun] Sichuan Univ, State Key Lab Biotherapy & Canc Ctr, West China Hosp, Chengdu 610041, Peoples R China. [Shao, Ximing; Liu, Ke; Fan, Yi; Li, Huashun] Collaborat Innovat Ctr Biotherapy, Chengdu 610041, Peoples R China. [Shao, Ximing; Liu, Ke; Ding, Zhihao; Li, Hongchang] Chinese Acad Sci, Shenzhen Key Lab Mol Biol Neural Dev, Shenzhen Inst Adv Technol, Lab Dev & Regenerat Biol,Inst Biomed & Biotechnol, Shenzhen 518055, Peoples R China. [Zhu, Minyan; Li, Huashun] Tongji Univ, Sch Med, Shanghai East Hosp, SARITEX Ctr Stem Cell Engn Translat Med, Shanghai 200123, Peoples R China. [Li, Huashun] Nerdbio Inc, SIP Biobay, Suzhou 215213, Peoples R China. [Weinstein, Lee S.] Natl Inst Diabet & Digest & Kidney Dis, NIH, Bethesda, MD 20892 USA. RP Li, HC (reprint author), Chinese Acad Sci, Shenzhen Key Lab Mol Biol Neural Dev, Shenzhen Inst Adv Technol, Lab Dev & Regenerat Biol,Inst Biomed & Biotechnol, Shenzhen 518055, Peoples R China. EM hc.li@siat.ac.cn; huashunli@tongji.edu.cn FU Ministry of Science & Technology-China [2014CB964600, 2012CB966800]; National Science Foundation of China [31301125, 31071283]; Shenzhen Peacock Plan [KQCX20130628112914292]; Shenzhen Key Laboratory for Molecular Biology of Neural Development [ZDSY20120617112838879]; SIAT Innovation Program for Excellent Young Researchers [201404] FX This work was partially supported by the grants from the Ministry of Science & Technology-China (Nos. 2014CB964600 and 2012CB966800), the National Science Foundation of China (Nos. 31301125 and 31071283), Shenzhen Peacock Plan (No. KQCX20130628112914292), Shenzhen Key Laboratory for Molecular Biology of Neural Development (No. ZDSY20120617112838879), and SIAT Innovation Program for Excellent Young Researchers (No. 201404). NR 42 TC 0 Z9 0 U1 2 U2 5 PU SCIENCE PRESS PI BEIJING PA 16 DONGHUANGCHENGGEN NORTH ST, BEIJING 100717, PEOPLES R CHINA SN 1673-8527 EI 1873-5533 J9 J GENET GENOMICS JI J. Genet. Genomics PD NOV 20 PY 2015 VL 42 IS 11 BP 613 EP 624 DI 10.1016/j.jgg.2015.08.006 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA CY0ZS UT WOS:000366136300003 PM 26674379 ER PT J AU Soliman, SE Kovac, P AF Soliman, Sameh E. Kovac, Pavol TI Synthesis of a Conjugation-Ready, Phosphorylated, Tetrasaccharide Fragment of the O-PS of Vibrio cholerae O139 SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID STRUCTURAL-ANALYSIS; SEROTYPES OGAWA; POLYSACCHARIDE; DISACCHARIDE; LIPOPOLYSACCHARIDE; TRISACCHARIDE; OLIGOSACCHARIDES; UPSTREAM; ANALOGS; RESIDUE AB A new pathway to the tetrasaccharide alpha-Colp-(1 -> 2)-4,6-P-beta-D-Galp-(1 -> 3)-[alpha-Colp-(1 -> 4)]-beta-D-GlcpNAc-1- (OCH2CH2)(3)NH2 has been developed. Glycosylation of 8-azido-3,6-dioxaoctyl 4,6-O-benzylidene-2-deoxy-2-trichloroacetamido-beta-D-glucopyranoside with 3,4,6-tri-O-acetyl-2-O-bromoacetyl-alpha-D-galactopyranosyl bromide afforded the beta-linked disaccharide. Debromoacetylation followed by reductive opening of the benzylidene acetal afforded the disaccharide diol acceptor. Halide-assisted glycosylation with 2,4-di-O-benzyl-alpha-colitosyl bromide gave the 1,2-cis-coupling product. Deacetylation followed by regioselective phosphorylation gave isomeric (R,S)-(P)-4(II),6(II)-cyclic phosphates, which were globally deprotected by one-step catalytic (Pd/C) hydrogenation/hydrogenolysis. The target tetrasaccharide, obtained in high overall yield, is amenable for conjugation to proteins. C1 [Soliman, Sameh E.; Kovac, Pavol] NIDDK, LBC, Sect Carbohydrates, NIH, Bethesda, MD 20892 USA. [Soliman, Sameh E.] Univ Alexandria, Fac Sci, Dept Chem, 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 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 the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). NR 21 TC 2 Z9 2 U1 2 U2 14 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 J9 J ORG CHEM JI J. Org. Chem. PD NOV 20 PY 2015 VL 80 IS 22 BP 11227 EP 11232 DI 10.1021/acs.joc.5b02105 PG 6 WC Chemistry, Organic SC Chemistry GA CX1NJ UT WOS:000365462600001 PM 26528773 ER PT J AU Wein, AN Peters, DE Valivullah, Z Hoover, BJ Tatineni, A Ma, Q Fattah, R Bugge, TH Leppla, SH Liu, SH AF Wein, Alexander N. Peters, Diane E. Valivullah, Zaheer Hoover, Benjamin J. Tatineni, Aparna Ma, Qian Fattah, Rasem Bugge, Thomas H. Leppla, Stephen H. Liu, Shihui TI An anthrax toxin variant with an improved activity in tumor targeting SO SCIENTIFIC REPORTS LA English DT Article ID PROTECTIVE ANTIGEN; LETHAL FACTOR; MATRIX; RECEPTOR; SPECIFICITY; TOXICITY; PROTEINS; INVASION; PROTEASE; SYSTEMS AB Anthrax lethal toxin (LT) is an A-B type toxin secreted by Bacillus anthracis, consisting of the cellular binding moiety, protective antigen (PA), and the catalytic moiety, lethal factor (LF). To target cells, PA binds to cell-surface receptors and is then proteolytically processed forming a LF-binding competent PA oligomer where each LF binding site is comprised of three subsites on two adjacent PA monomers. We previously generated PA-U2-R200A, a urokinase-activated PA variant with LF-binding subsite II residue Arg200 mutated to Ala, and PA-L1-I210A, a matrix metalloproteinase-activated PA variant with subsite III residue Ile210 mutated to Ala. PA-U2-R200A and PA-L1-I210A displayed reduced cytotoxicity when used singly. However, when combined, they formed LF-binding competent heterogeneous oligomers by intermolecular complementation, and achieved high specificity in tumor targeting. Nevertheless, each of these proteins, in particular PA-L1-I210A, retained residual LF-binding ability. In this work, we screened a library containing all possible amino acid substitutions for LF-binding site to find variants with activity strictly dependent upon intermolecular complementation. PA-I207R was identified as an excellent replacement for the original clockwise-side variant, PA-I210A. Consequently, the new combination of PA-L1-I207R and PA-U2-R200A showed potent anti-tumor activity and low toxicity, exceeding the performance of the original combination, and warranting further investigation. C1 [Wein, Alexander N.; Valivullah, Zaheer; Hoover, Benjamin J.; Tatineni, Aparna; Ma, Qian; Fattah, Rasem; Leppla, Stephen H.; Liu, Shihui] NIAID, Microbial Pathogenesis Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Peters, Diane E.; Bugge, Thomas H.] NIDCR, Proteases & Tissue Remodeling Sect, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. [Peters, Diane E.] Tufts Univ, Sch Med, Program Pharmacol & Expt Therapeut, Boston, MA 02111 USA. RP Leppla, SH (reprint author), NIAID, Microbial Pathogenesis Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM sleppla@niaid.nih.gov; shliu@niaid.nih.gov FU intramural research programs of the National Institute of Allergy and Infectious Diseases; National Institute of Dental and Craniofacial Research, National Institutes of Health FX This work was supported by the intramural research programs of the National Institute of Allergy and Infectious Diseases and the National Institute of Dental and Craniofacial Research, National Institutes of Health. The authors thank Dr. Clinton E. Leysath for assistance with crystal structure analysis. NR 34 TC 2 Z9 2 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 NOV 20 PY 2015 VL 5 AR 16267 DI 10.1038/srep16267 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CW5BO UT WOS:000365010600001 PM 26584669 ER PT J AU Imai, CM Halldorsson, TI Eiriksdottir, G Cotch, MF Steingrimsdottir, L Thorsdottir, I Launer, LJ Harris, T Gudnason, V Gunnarsdottir, I AF Imai, Cindy M. Halldorsson, Thorhallur I. Eiriksdottir, Gudny Cotch, Mary F. Steingrimsdottir, Laufey Thorsdottir, Inga Launer, Lenore J. Harris, Tamara Gudnason, Vilmundur Gunnarsdottir, Ingibjorg TI Depression and serum 25-hydroxyvitamin D in older adults living at northern latitudes - AGES-Reykjavik Study SO JOURNAL OF NUTRITIONAL SCIENCE LA English DT Article DE Vitamin D; Depression; Older adults; Cross-sectional analyses; Nutritional epidemiology ID FOOD FREQUENCY QUESTIONNAIRE; PARATHYROID-HORMONE LEVELS; VITAMIN-D SUPPLEMENTATION; D-RECEPTOR; ASSOCIATIONS; POPULATION; WOMEN; TRIAL; SYMPTOMS; HEALTH AB Low vitamin D status may be associated with depression. Few studies have examined vitamin D and depression in older adults living at northern latitudes. The present study cross-sectionally investigated serum 25-hydroxyvitamin D (25(OH) D) status and depression among 5006 community-dwelling older persons (66-96 years) living in Iceland (latitudes 64-66 degrees N). Depressive symptoms were measured by the fifteen-item Geriatric Depression Scale (GDS-15). Current major depressive disorder was assessed according to Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) criteria. Serum 25(OH) D was analysed using chemiluminescence immunoassay and categorised into three groups: deficient (<30 nmol/l); inadequate (30-49.9 nmol/l); and adequate (>= 50 nmol/l). There were twenty-eight (2%) men and fifty (1%) women with current major depressive disorder. Mean GDS-15 scores for men and women with adequate vitamin D concentrations were 2.1 and 2.2, respectively. Men and women with deficient v. adequate vitamin D status had more depressive symptoms (higher GDS-15 scores) (difference 0.7 (95 % CI 0.4, 0.9) and 0.4 (95 % CI 0.1, 0.6), respectively). Furthermore, men with deficient vitamin D status were more likely to have current major depressive disorder (adjusted OR 2.51; 95 % CI 1.03, 6.13) compared with men with adequate vitamin D status. Associations among women were not significant. In this older population living at northern latitudes, deficient vitamin D status may be associated with depression. Further investigations are warranted to evaluate the pathways that may be associated with risk of depression among older adults. C1 [Imai, Cindy M.; Halldorsson, Thorhallur I.; Steingrimsdottir, Laufey; Thorsdottir, Inga; Gunnarsdottir, Ingibjorg] Univ Iceland, Landspitali, Unit Nutr Res, IS-101 Reykjavik, Iceland. [Imai, Cindy M.; Halldorsson, Thorhallur I.; Steingrimsdottir, Laufey; Thorsdottir, Inga; Gunnarsdottir, Ingibjorg] Univ Iceland, Sch Hlth Sci, Fac Food Sci & Nutr, IS-101 Reykjavik, Iceland. [Halldorsson, Thorhallur I.] Statens Serum Inst, Ctr Fetal Programming, Dept Epidemiol Res, DK-2300 Copenhagen S, Denmark. [Eiriksdottir, Gudny; Gudnason, Vilmundur] Iceland Heart Assoc, IS-201 Kopavogur, Iceland. [Cotch, Mary F.] NEI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. [Launer, Lenore J.; Harris, Tamara] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. [Gudnason, Vilmundur] Univ Iceland, Sch Hlth Sci, Fac Med, IS-101 Reykjavik, Iceland. RP Gunnarsdottir, I (reprint author), Univ Iceland, Landspitali, Unit Nutr Res, Eiriksgata 29, IS-101 Reykjavik, Iceland. EM ingigun@landspitali.is RI Halldorsson, Tohrhallur/M-1823-2015 OI Halldorsson, Tohrhallur/0000-0001-5115-0162 FU Intramural NIH HHS [ZIA EY000401-10, Z99 EY999999, ZIA EY000401-08, ZIA EY000401-09, ZIA EY000401-11, ZIA EY000401-12, ZIA EY000401-13, ZIA EY000401-14, ZIA EY000401-15]; NEI NIH HHS [ZIA EY000401]; NIA NIH HHS [N01AG12100] NR 45 TC 0 Z9 0 U1 5 U2 7 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 2048-6790 J9 J NUTR SCI JI J. Nutr. Sci. PD NOV 20 PY 2015 VL 4 AR UNSP e37 DI 10.1017/jns.2015.27 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CW4LC UT WOS:000364961900001 PM 26688723 ER PT J AU Lichten, M AF Lichten, Michael TI Putting the breaks on meiosis SO SCIENCE LA English DT Editorial Material ID MEIOTIC RECOMBINATION; INITIATION C1 NCI, Bethesda, MD 20892 USA. RP Lichten, M (reprint author), NCI, Bethesda, MD 20892 USA. EM mlichten@helix.nih.gov RI Lichten, Michael/C-5795-2013 OI Lichten, Michael/0000-0001-9707-2956 NR 10 TC 4 Z9 4 U1 0 U2 6 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 NOV 20 PY 2015 VL 350 IS 6263 BP 913 EP 913 DI 10.1126/science.aad5404 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CW4IP UT WOS:000364955200023 PM 26586748 ER PT J AU Baingana, F al'Absi, M Becker, AE Pringle, B AF Baingana, Florence al'Absi, Mustafa Becker, Anne E. Pringle, Beverly TI Global research challenges and opportunities for mental health and substance-use disorders SO NATURE LA English DT Review ID MIDDLE-INCOME COUNTRIES; RANDOMIZED CONTROLLED-TRIAL; PSYCHIATRIC-DISORDERS; SCALE-UP; KNOWLEDGE TRANSLATION; SYSTEMATIC ANALYSIS; ANXIETY DISORDERS; DUAL DIAGNOSIS; DEPRESSION; SERVICES AB The research agenda for global mental health and substance-use disorders has been largely driven by the exigencies of high health burdens and associated unmet needs in low-and middle-income countries. Implementation research focused on context-driven adaptation and innovation in service delivery has begun to yield promising results that are improving the quality of, and access to, care in low-resource settings. Importantly, these efforts have also resulted in the development and augmentation of local, in-country research capacities. Given the complex interplay between mental health and substance-use disorders, medical conditions, and biological and social vulnerabilities, a revitalized research agenda must encompass both local variation and global commonalities in the impact of adversities, multi-morbidities and their consequences across the life course. We recommend priorities for research - as well as guiding principles for context-driven, intersectoral, integrative approaches - that will advance knowledge and answer the most pressing local and global mental health questions and needs, while also promoting a health equity agenda and extending the quality, reach and impact of scientific enquiry. C1 [Baingana, Florence] Makerere Univ, Sch Publ Hlth, POB 7072, Kampala, Uganda. [al'Absi, Mustafa] Univ Minnesota, Sch Med, DMRI, 311-1035 Univ Dr, Duluth, MN 55812 USA. [Becker, Anne E.] Harvard Univ, Sch Med, Dept Global Hlth & Social Med, Boston, MA 03115 USA. [Pringle, Beverly] NIMH, Off Res Dispar & Global Mental Hlth, Bethesda, MD 20892 USA. RP Baingana, F (reprint author), Makerere Univ, Sch Publ Hlth, POB 7072, Kampala, Uganda. EM kamayonza@gmail.com FU BRAIN R21 grant [R21DA024626]; Grand Challenges Canada [GMH 0094-04]; [R01DA016351]; [R01DA027232] FX The authors thank J. Dewit, A. Garton, Y. Bodenstein and J. Nguyen at the National Institute of Mental Health for construction of the interactive map. M. A. was supported in part by the following grants: R01DA016351 and R01DA027232, and a BRAIN R21 grant (R21DA024626). F. B. was supported in part by Grand Challenges Canada Grant GMH 0094-04. We are grateful to B. Good for his insightful review and suggestions. NR 71 TC 6 Z9 6 U1 8 U2 14 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 NOV 19 PY 2015 VL 527 IS 7578 BP S172 EP S177 DI 10.1038/nature16032 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CW9ZN UT WOS:000365356800013 PM 26580324 ER PT J AU Cottler, LB Zunt, J Weiss, B Kamal, AK Vaddiparti, K AF Cottler, Linda B. Zunt, Joseph Weiss, Bahr Kamal, Ayeesha Kamran Vaddiparti, Krishna TI Building global capacity for brain and nervous system disorders research SO NATURE LA English DT Review ID MIDDLE-INCOME COUNTRIES; HEALTH RESEARCH; EATING-DISORDERS; INTERNET; INTERVENTIONS; BURDEN; DISABILITY; DISEASES; WORLD; PREVALENCE AB The global burden of neurological, neuropsychiatric, substance-use and neurodevelopmental disorders in low-and middle-income countries is worsened, not only by the lack of targeted research funding, but also by the lack of relevant in-country research capacity. Such capacity, from the individual to the national level, is necessary to address the problems within a local context. As for many health issues in these countries, the ability to address this burden requires development of research infrastructure and a trained cadre of clinicians and scientists who can ask the right questions, and conduct, manage, apply and disseminate research for practice and policy. This Review describes some of the evolving issues, knowledge and programmes focused on building research capacity in low-and middle-income countries in general and for brain and nervous system disorders in particular. C1 [Cottler, Linda B.; Vaddiparti, Krishna] Univ Florida, Dept Epidemiol, Coll Publ Hlth & Hlth Profess, Gainesville, FL USA. [Cottler, Linda B.; Vaddiparti, Krishna] Univ Florida, Coll Med, Gainesville, FL USA. [Zunt, Joseph] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. [Weiss, Bahr] Vanderbilt Univ, Dept Psychol & Human Dev, Nashville, TN 37235 USA. [Kamal, Ayeesha Kamran] Aga Khan Univ, Int Cerebrovascular Translat Clin Res Training Pr, Fogarty Int Ctr, Stroke Serv,Sect Neurol,Dept Med,NIH, Karachi, Pakistan. RP Cottler, LB (reprint author), Univ Florida, Dept Epidemiol, Coll Publ Hlth & Hlth Profess, Gainesville, FL USA. EM lbcottler@ufl.edu FU FIC/NIMH/NIH [D43TW009120, D43TW009089, D43TW008660]; Fogarty International Center; National Institute on Drug Abuse of the National Institutes of Health [D43 TW009120] FX The authors were supported in part by the following grants: FIC/NIMH/NIH D43TW009120, Indo-US Training Program on Non-Communicable Diseases Across the Lifespan; FIC/NIMH/NIH D43TW009089, Increasing Mental Health Research Infrastructure in Southeast Asia; and FIC/NINDS/NIH D43TW008660, International Cerebrovascular Translational Clinical Research Training Program. Research reported in this publication was supported by the Fogarty International Center and the National Institute on Drug Abuse of the National Institutes of Health under Award Number D43 TW009120. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 34 TC 3 Z9 3 U1 2 U2 5 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 NOV 19 PY 2015 VL 527 IS 7578 BP S207 EP S213 DI 10.1038/nature16037 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CW9ZN UT WOS:000365356800018 PM 26580329 ER PT J AU Glass, RI AF Glass, Roger I. TI Brain disorders across the lifespan FOREWORD SO NATURE LA English DT Editorial Material C1 [Glass, Roger I.] NIH, Fogarty Int Ctr, 31 Ctr Dr, Bethesda, MD 20892 USA. RP Glass, RI (reprint author), NIH, Fogarty Int Ctr, 31 Ctr Dr, Bethesda, MD 20892 USA. NR 3 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 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD NOV 19 PY 2015 VL 527 IS 7578 BP S150 EP S150 DI 10.1038/nature16027 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CW9ZN UT WOS:000365356800008 PM 26580319 ER PT J AU Silberberg, D Anand, NP Michels, K Kalaria, RN AF Silberberg, Donald Anand, Nalini P. Michels, Kathleen Kalaria, Raj N. TI Brain and other nervous system disorders across the lifespan - global challenges and opportunitiesINTRODUCTION SO NATURE LA English DT Editorial Material ID BURDEN; DISEASE; DISABILITY; COUNTRIES; INJURIES AB This is an exciting time for scientific discovery that aims to reduce the frequency and impact of neurological, mental health and substance-use disorders. As it became increasingly clear that low-and middle-income countries have a disproportionate share of these disorders, and that many of the problems are best addressed by indigenous researchers who can seek context-sensitive solutions, the US National Institutes of Health and other research funders began to invest more in low-and middle-income country-focused research and research capacity-building to confront this significant public health challenge. In an effort to identify existing information, knowledge gaps, and emerging research and research capacity-building opportunities that are particularly relevant to low-and middle-income countries, in February 2014 the Center for Global Health Studies at the National Institutes of Health Fogarty International Center held a workshop to explore these issues with scientific experts from low-and middle-income countries and the United States. This evolved into the preparation of the Reviews in this supplement, which is designed to highlight opportunities and challenges associated with topical areas in brain-disorders research over the coming decade. This Introduction highlights some of the over-arching and intersecting priorities for addressing causes, prevention, treatment and rehabilitation as well as best practices to promote overall nervous system health. We review some brain disorders in low-and middle-income countries, while the Reviews describe relevant issues and the epidemiology of particular conditions in greater depth. C1 [Silberberg, Donald] Univ Penn, Dept Neurol, Philadelphia, PA 19104 USA. [Anand, Nalini P.] NIH, Div Int Sci Policy Planning & Evaluat, Bethesda, MD 20892 USA. [Anand, Nalini P.] NIH, Ctr Global Hlth Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Michels, Kathleen] NIH, Div Int Res & Training, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Kalaria, Raj N.] Newcastle Univ, Inst Neurosci, Newcastle Upon Tyne NE4 5PL, Tyne & Wear, England. RP Silberberg, D (reprint author), Univ Penn, Dept Neurol, Philadelphia, PA 19104 USA. EM silberbe@mail.med.upenn.edu; r.n.kalaria@ncl.ac.uk FU Medical Research Council [G0502157, G0400074, G0900652, G1100540, MR/L016451/1] NR 13 TC 11 Z9 11 U1 3 U2 8 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 NOV 19 PY 2015 VL 527 IS 7578 BP S151 EP S154 DI 10.1038/nature16028 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CW9ZN UT WOS:000365356800009 PM 26580320 ER PT J AU Arabi, Y Balkhy, H Hajeer, AH Bouchama, A Hayden, FG Al-Omari, A Al-Hameed, FM Taha, Y Shindo, N Whitehead, J Merson, L AlJohani, S Al-Khairy, K Carson, G Luke, TC Hensley, L Al-Dawood, A Al-Qahtani, S Modjarrad, K Sadat, M Rohde, G Leport, C Fowler, R AF Arabi, Yaseen Balkhy, Hanan Hajeer, Ali H. Bouchama, Abderrezak Hayden, Frederick G. Al-Omari, Awad Al-Hameed, Fahad M. Taha, Yusri Shindo, Nahoko Whitehead, John Merson, Laura AlJohani, Sameera Al-Khairy, Khalid Carson, Gail Luke, Thomas C. Hensley, Lisa Al-Dawood, Abdulaziz Al-Qahtani, Saad Modjarrad, Kayvon Sadat, Musharaf Rohde, Gernot Leport, Catherine Fowler, Robert TI Feasibility, safety, clinical, and laboratory effects of convalescent plasma therapy for patients with Middle East respiratory syndrome coronavirus infection: a study protocol SO SPRINGERPLUS LA English DT Article DE Middle east respiratory syndrome coronavirus; MERS-CoV; Viral pneumonia; Intensive care; Convalescent plasma; Serology; Genome; Neutralizing antibodies ID SAUDI-ARABIA; INFLUENZA; PNEUMONIA AB As of September 30, 2015, a total of 1589 laboratory-confirmed cases of infection with the Middle East respiratory syndrome coronavirus (MERS-CoV) have been reported to the World Health Organization (WHO). At present there is no effective specific therapy against MERS-CoV. The use of convalescent plasma (CP) has been suggested as a potential therapy based on existing evidence from other viral infections. We aim to study the feasibility of CP therapy as well as its safety and clinical and laboratory effects in critically ill patients with MERS-CoV infection. We will also examine the pharmacokinetics of the MERS-CoV antibody response and viral load over the course of MERS-CoV infection. This study will inform a future randomized controlled trial that will examine the efficacy of CP therapy for MERS-CoV infection. In the CP collection phase, potential donors will be tested by the enzyme linked immunosorbent assay (ELISA) and the indirect fluorescent antibody (IFA) techniques for the presence of anti-MERS-CoV antibodies. Subjects with anti-MERS-CoV IFA titer of >= 1:160 and no clinical or laboratory evidence of MERS-CoV infection will be screened for eligibility for plasma donation according to standard donation criteria. In the CP therapy phase, 20 consecutive critically ill patients admitted to intensive care unit with laboratory-confirmed MERS-CoV infection will be enrolled and each will receive 2 units of CP. Post enrollment, patients will be followed for clinical and laboratory outcomes that include anti-MERS-CoV antibodies and viral load. This protocol was developed collaboratively by King Abdullah International Medical Research Center (KAIMRC), Gulf Cooperation Council (GCC) Infection Control Center Group and the World Health Organization-International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC-WHO) MERS-CoV Working Group. It was approved in June 2014 by the Ministry of the National Guard Health Affairs Institutional Review Board (IRB). A data safety monitoring board (DSMB) was formulated. The study is registered at http://www.clinicaltrials.gov (NCT02190799). C1 [Arabi, Yaseen; Bouchama, Abderrezak; Al-Dawood, Abdulaziz; Al-Qahtani, Saad] King Saud bin Abdulaziz Univ Hlth Sci, King Abdulaziz Med City, King Abdullah Int Med Res Ctr, Intens Care Dept,Resp Serv,Coll Med, POB 22490, Riyadh 11426, Saudi Arabia. [Balkhy, Hanan] King Saud bin Abdulaziz Univ Hlth Sci, King Abdulaziz Med City, King Abdullah Int Med Res Ctr, Infect Control Dept, Riyadh, Saudi Arabia. [Hajeer, Ali H.; AlJohani, Sameera; Al-Khairy, Khalid] King Saud bin Abdulaziz Univ Hlth Sci, King Abdulaziz Med City, Pathol & Lab Dept, Riyadh, Saudi Arabia. [Hayden, Frederick G.] Univ Virginia, Sch Med, Dept Med, Div Infect Dis & Int Hlth, Charlottesville, VA 22908 USA. [Al-Omari, Awad] AlFaisal Univ, Secur Forces Hosp, Crit Care & Infect Control Dept, Riyadh, Saudi Arabia. [Al-Hameed, Fahad M.] King Saud bin Abdulaziz Univ Hlth Sci, King Abdulaziz Med City, Dept Intens Care, Jeddah, Saudi Arabia. [Taha, Yusri] King Abdul Aziz Med City, Dept Med Infect Dis, Al Hasa, Saudi Arabia. [Shindo, Nahoko] World Hlth Org, Pandem & Epidem Dis Dept, Geneva, Switzerland. [Whitehead, John] Univ Lancaster, Dept Math & Stat, Lancaster, England. [Merson, Laura] Univ Oxford, Clin Res Unit, Ho Chi Minh City, Vietnam. [Carson, Gail] Univ Oxford, Ctr Trop Med CCVTM, Oxford OX3 7LE, England. [Luke, Thomas C.] Henry Jackson Fdn, Naval Med Res Ctr, Viral & Rickettsial Dis Dept, Bethesda, MD 20817 USA. [Hensley, Lisa] NIAID, Integrated Res Facil, Frederick, MD USA. [Modjarrad, Kayvon] Walter Reed Army Inst Res, US Mil HIV Res Program, Silver Spring, MD 20910 USA. [Sadat, Musharaf] King Abdul Aziz Med City, Dept Intens Care, Riyadh, Saudi Arabia. [Rohde, Gernot] Maastricht Univ, Med Ctr, Dept Resp Med, NL-6202 AZ Maastricht, Netherlands. [Leport, Catherine] Univ Paris Diderot, French Infect Dis Soc, Paris, France. [Fowler, Robert] Univ Toronto, AMR Infect Control & Publicat AIP PED HSE HQ, Dept Med, Toronto, ON, Canada. [Fowler, Robert] Univ Toronto, AMR Infect Control & Publicat AIP PED HSE HQ, Inst Hlth Policy Management & Evaluat, Toronto, ON, Canada. [Fowler, Robert] Sunnybrook Hlth Sci Ctr, Dept Crit Care Med, Toronto, ON M4N 3M5, Canada. [Fowler, Robert] Sunnybrook Hlth Sci Ctr, Dept Med, Toronto, ON M4N 3M5, Canada. RP Arabi, Y (reprint author), King Saud bin Abdulaziz Univ Hlth Sci, King Abdulaziz Med City, King Abdullah Int Med Res Ctr, Intens Care Dept,Resp Serv,Coll Med, POB 22490, Riyadh 11426, Saudi Arabia. EM arabi@ngha.med.sa RI Rohde, Gernot/F-3060-2013; OI Rohde, Gernot/0000-0002-5193-7755; Hajeer, Ali/0000-0003-2727-9964 FU King Abdullah International Medical Research Center, Riyadh, Saudi Arabia FX This project is funded by King Abdullah International Medical Research Center, Riyadh, Saudi Arabia. NR 15 TC 7 Z9 7 U1 0 U2 5 PU SPRINGER INTERNATIONAL PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 2193-1801 J9 SPRINGERPLUS JI SpringerPlus PD NOV 19 PY 2015 VL 4 AR 709 DI 10.1186/s40064-015-1490-9 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DB7QA UT WOS:000368709400005 PM 26618098 ER PT J AU Montal, ED Dewi, R Bhalla, K Ou, LH Hwang, BJ Ropell, AE Gordon, C Liu, WJ DeBerardinis, RJ Sudderth, J Twaddel, W Boros, LG Shroyer, KR Duraisamy, S Drapkin, R Powers, RS Rohde, JM Boxer, MB Wong, KK Girnun, GD AF Montal, Emily D. Dewi, Ruby Bhalla, Kavita Ou, Lihui Hwang, Bor Jang Ropell, Ashley E. Gordon, Chris Liu, Wan-Ju DeBerardinis, Ralph J. Sudderth, Jessica Twaddel, William Boros, Laszlo G. Shroyer, Kenneth R. Duraisamy, Sekhar Drapkin, Ronny Powers, R. Scott Rohde, Jason M. Boxer, Matthew B. Wong, Kwok-Kin Girnun, Geoffrey D. TI PEPCK Coordinates the Regulation of Central Carbon Metabolism to Promote Cancer Cell Growth SO MOLECULAR CELL LA English DT Article ID CYTOSOLIC PHOSPHOENOLPYRUVATE CARBOXYKINASE; GLUTAMINE-METABOLISM; AEROBIC GLYCOLYSIS; COPY NUMBER; AMINO-ACID; GLUCOSE; MTORC1; PROLIFERATION; SURVIVAL; TUMORS AB Phosphoenolpyruvate carboxykinase (PEPCK) is well known for its role in gluconeogenesis. However, PEPCK is also a key regulator of TCA cycle flux. The TCA cycle integrates glucose, amino acid, and lipid metabolism depending on cellular needs. In addition, biosynthetic pathways crucial to tumor growth require the TCA cycle for the processing of glucose and glutamine derived carbons. We show here an unexpected role for PEPCK in promoting cancer cell proliferation in vitro and in vivo by increasing glucose and glutamine utilization toward anabolic metabolism. Unexpectedly, PEPCK also increased the synthesis of ribose from non-carbohydrate sources, such as glutamine, a phenomenon not previously described. Finally, we show that the effects of PEPCK on glucose metabolism and cell proliferation are in part mediated via activation of mTORC1. Taken together, these data demonstrate a role for PEPCK that links metabolic flux and anabolic pathways to cancer cell proliferation. C1 [Montal, Emily D.; Girnun, Geoffrey D.] SUNY Stony Brook, Dept Pharmacol Sci, Stony Brook, NY 11794 USA. [Dewi, Ruby; Bhalla, Kavita; Ou, Lihui; Hwang, Bor Jang; Liu, Wan-Ju] Univ Maryland, Sch Med, Marlene & Stewart Greenebaum Canc Ctr, Baltimore, MD 21201 USA. [Twaddel, William; Powers, R. Scott] Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. [Boros, Laszlo G.] Univ Calif Los Angeles, Los Angeles Sch Med, Los Angeles, CA 90095 USA. [Boros, Laszlo G.] Los Angeles Biomed Res Inst LA BioMed, Torrance, CA 90502 USA. [Boros, Laszlo G.] SIDMAP, Torrance, CA 90502 USA. [Duraisamy, Sekhar; Drapkin, Ronny] Dana Farber Canc Inst, Dept Pathol, Boston, MA 02115 USA. [Wong, Kwok-Kin] Dana Farber Canc Inst, Dept Med, Boston, MA 02115 USA. [Wong, Kwok-Kin] Harvard Univ, Sch Med, Boston, MA 02115 USA. [DeBerardinis, Ralph J.; Sudderth, Jessica] Univ Texas SW Med Ctr Dallas, Childrens Med Ctr, Res Inst, Dallas, TX 75390 USA. [Bhalla, Kavita; Ropell, Ashley E.; Gordon, Chris; Liu, Wan-Ju; Shroyer, Kenneth R.; Girnun, Geoffrey D.] SUNY Stony Brook, Sch Med, Dept Pathol, Stony Brook, NY 11794 USA. [Rohde, Jason M.; Boxer, Matthew B.] NIH, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. RP Girnun, GD (reprint author), SUNY Stony Brook, Dept Pharmacol Sci, Stony Brook, NY 11794 USA. EM geoffrey.girnun@stonybrookmedicine.edu RI Drapkin, Ronny/E-9944-2016 OI Drapkin, Ronny/0000-0002-6912-6977 FU NIH [CA169919, DK064685]; Maryland CRF; Stony Brook Research Foundation FX We thank Ms. Mallory for IHC work and Stony Brook Biorepository Core. Richard Hanson (OBM) for the PEPCK construct. This work was supported by NIH Grants CA169919 and DK064685, Maryland CRF and Stony Brook Research Foundation to G.D.G. The authors declare they have no conflict of interest related to the work presented. NR 36 TC 12 Z9 13 U1 3 U2 14 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 NOV 19 PY 2015 VL 60 IS 4 BP 571 EP 583 DI 10.1016/j.molcel.2015.09.025 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DB1SH UT WOS:000368288700008 PM 26481663 ER PT J AU Lenstra, TL Coulon, A Chow, CC Larson, DR AF Lenstra, Tineke L. Coulon, Antoine Chow, Carson C. Larson, Daniel R. TI Single-Molecule Imaging Reveals a Switch between Spurious and Functional ncRNA Transcription SO MOLECULAR CELL LA English DT Article ID RNA-POLYMERASE-II; ANTISENSE TRANSCRIPTION; GENE-EXPRESSION; SACCHAROMYCES-CEREVISIAE; NONCODING TRANSCRIPTION; BUDDING YEAST; IN-VIVO; INITIATION; ELONGATION; ACTIVATION AB Eukaryotic transcription is pervasive, and many of the resulting RNAs are non-coding. It is unknown whether ubiquitous transcription is functional or simply reflects stochastic transcriptional noise. By single-molecule visualization of the dynamic interplay between coding and non-coding transcription at the GAL locus in living yeast cells, we show that antisense GAL10 ncRNA transcription can switch between functional and spurious under different conditions. During galactose induction, GAL10 sense transcription occurs in short stochastic bursts, which are unaffected by transcription of antisense GAL10 ncRNA, even when both are present simultaneously at the same locus. In contrast, when GAL10 is not induced, ncRNA transcription is critical to prevent transcriptional leakage of GAL1 and GAL10. Suppression of ncRNA transcription by strand-specific CRISPR/dCas9 results in transcriptional leakage of the inducer GAL1, leading to a more sensitive transcription activation threshold, an alteration of metabolic switching, and a fitness defect in competition experiments. C1 [Lenstra, Tineke L.; Larson, Daniel R.] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. [Coulon, Antoine; Chow, Carson C.] Natl Inst Diabet & Digest & Kidney Dis, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. RP Larson, DR (reprint author), NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. EM dan.larson@nih.gov RI Larson, Daniel/B-9829-2008; Lenstra, Tineke/L-3958-2016; Coulon, Antoine/A-9006-2012 OI Larson, Daniel/0000-0001-9253-3055; Lenstra, Tineke/0000-0002-4440-9962; FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, National Institute of Diabetes and Digestive and Kidney Diseases; European Molecular Biology Organization; KWF Dutch Cancer Society [ALTF 37-2012, KWF 2012-5394] FX We thank M.A. Basrai, M. Vogelauer, C. Hittinger, V. Verkhusha, T.S. Karpova, G.L. Hager, M.H. Larson, J.S. Weissman, R.H. Singer, and D.R. Zenklusen for strains and plasmids. We thank T.S. Karpova for assistance with confocal imaging, K.M. McKinnon for assistance with flow cytometry, the NCI/CCR Sequencing Facility for RNA-seq, D.R. van Dijk and J. Rodriguez for help with RNA-seq analysis, and members of the D.R.L. lab and of the Janelia Research Campus/HHMI Transcription Imaging Consortium for helpful discussions. This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, National Institute of Diabetes and Digestive and Kidney Diseases, the European Molecular Biology Organization, and the KWF Dutch Cancer Society (grants ALTF 37-2012 and KWF 2012-5394 to T.L.L.). NR 38 TC 17 Z9 17 U1 7 U2 16 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 NOV 19 PY 2015 VL 60 IS 4 BP 597 EP 610 DI 10.1016/j.molcel.2015.09.028 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DB1SH UT WOS:000368288700010 PM 26549684 ER PT J AU Sun, N Yun, J Liu, J Malide, D Liu, CY Rovira, II Holmstrom, KM Fergusson, MM Yoo, YH Combs, CA Finkel, T AF Sun, Nuo Yun, Jeanho Liu, Jie Malide, Daniela Liu, Chengyu Rovira, Ilsa I. Holmstroem, Kira M. Fergusson, Maria M. Yoo, Young Hyun Combs, Christian A. Finkel, Toren TI Measuring In Vivo Mitophagy SO MOLECULAR CELL LA English DT Article ID HUNTINGTONS-DISEASE; QUALITY-CONTROL; RAT-LIVER; AUTOPHAGY; MITOCHONDRIA; PARKIN; PATHWAY; MACROAUTOPHAGY; MICE; PH AB Alterations in mitophagy have been increasingly linked to aging and age-related diseases. There are, however, no convenient methods to analyze mitophagy in vivo. Here, we describe a transgenic mouse model in which we expressed a mitochondrial-targeted form of the fluorescent reporter Keima (mt-Keima). Keima is a coral-derived protein that exhibits both pH-dependent excitation and resistance to lysosomal proteases. Comparison of a wide range of primary cells and tissues generated from the mt-Keima mouse revealed significant variations in basal mitophagy. In addition, we have employed the mt-Keima mice to analyze how mitophagy is altered by conditions including diet, oxygen availability, Huntingtin transgene expression, the absence of macroautophagy (ATG5 or ATG7 expression), an increase in mitochondrial mutational load, the presence of metastatic tumors, and normal aging. The ability to assess mitophagy under a host of varying environmental and genetic perturbations suggests that the mt-Keima mouse should be a valuable resource. C1 [Sun, Nuo; Yun, Jeanho; Liu, Jie; Rovira, Ilsa I.; Holmstroem, Kira M.; Fergusson, Maria M.; Finkel, Toren] NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. [Yun, Jeanho; Yoo, Young Hyun] Dong A Univ, Coll Med, Mitochondria Hub Regulat Ctr, Busan 602714, South Korea. [Malide, Daniela; Combs, Christian A.] NHLBI, Light Microscopy Core, NIH, Bethesda, MD 20892 USA. [Liu, Chengyu] NHLBI, Transgen Core, NIH, Bethesda, MD 20892 USA. RP Finkel, T (reprint author), NHLBI, Ctr Mol Med, NIH, Bldg 10, Bethesda, MD 20892 USA. EM finkelt@nih.gov OI Holmstrom, Kira/0000-0001-6434-7909 FU Leducq Foundation; NIH Intramural Research Program funds; National Research Foundation of Korea grant [2009-0093197]; Jackson Laboratory Repository [028072] FX We are grateful for Junhui Sun, Michele Allen (NHLBI Phenotyping Core), Zuxi Yu (NHLBI Pathology Core), Phil McCoy (NHLBI FACS Core), Pradeep Dagur, Natalie Porat Shilom, and Shihui Liu for experimental assistance. We thank T. Prolla and M. Komatsu for mice, R. Youle for the YFP-Parkin cell line, and A. Miyawaki for the original mt-Keima construct. This work was supported by a grant from the Leducq Foundation, NIH Intramural Research Program funds, and a National Research Foundation of Korea grant (2009-0093197). The mt-Keima mouse is being made available through The Jackson Laboratory Repository (stock no. 028072). NR 52 TC 23 Z9 23 U1 0 U2 5 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 NOV 19 PY 2015 VL 60 IS 4 BP 685 EP 696 DI 10.1016/j.molcel.2015.10.009 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DB1SH UT WOS:000368288700017 PM 26549682 ER PT J AU Kim, HF Ghazizadeh, A Hikosaka, O AF Kim, Hyoung F. Ghazizadeh, Ali Hikosaka, Okihide TI Dopamine Neurons Encoding Long-Term Memory of Object Value for Habitual Behavior SO CELL LA English DT Article ID PRIMATE SUPERIOR COLLICULUS; VENTRAL TEGMENTAL AREA; MONKEY CAUDATE NEURONS; BASAL GANGLIA CIRCUITS; NIGRA PARS RETICULATA; SUBSTANTIA-NIGRA; PARKINSONS-DISEASE; FUNCTIONAL-PROPERTIES; PROJECTION NEURONS; VISUAL RESPONSES AB Dopamine neurons promote learning by processing recent changes in reward values, such that reward may be maximized. However, such a flexible signal is not suitable for habitual behaviors that are sustained regardless of recent changes in reward outcome. We discovered a type of dopamine neuron in the monkey substantia nigra pars compacta (SNc) that retains past learned reward values stably. After reward values of visual objects are learned, these neurons continue to respond differentially to the objects, even when reward is not expected. Responses are strengthened by repeated learning and are evoked upon presentation of the objects long after learning is completed. These `` sustain-type'' dopamine neurons are confined to the caudal-lateral SNc and project to the caudate tail, which encodes long-term value memories of visual objects and guides gaze automatically to stably valued objects. This population of dopamine neurons thus selectively promotes learning and retention of habitual behavior. C1 [Kim, Hyoung F.; Ghazizadeh, Ali; Hikosaka, Okihide] NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. [Kim, Hyoung F.] Inst Basic Sci, CNIR, Suwon 440746, South Korea. [Kim, Hyoung F.] Sungkyunkwan Univ, Dept Biomed Engn, Suwon 440746, South Korea. [Hikosaka, Okihide] NIDA, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Kim, HF (reprint author), NEI, Sensorimotor Res Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM hyoung.f.kim@gmail.com FU Intramural Research Program at the National Institutes of Health, National Eye Institute FX We thank M. Yasuda for discussions and D. Parker, I. Bunea, M.K. Smith, G. Tansey, A.M. Nichols, T.W. Ruffner, J.W. McClurkin, and A.V. Hays for technical assistance. This research was supported by the Intramural Research Program at the National Institutes of Health, National Eye Institute. NR 45 TC 9 Z9 9 U1 3 U2 12 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 NOV 19 PY 2015 VL 163 IS 5 BP 1165 EP 1175 DI 10.1016/j.cell.2015.10.063 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CX9SD UT WOS:000366044700015 PM 26590420 ER PT J AU Shcherbakova, DM Baloban, M Pletnev, S Malashkevich, VN Xiao, H Dauter, Z Verkhusha, VV AF Shcherbakova, Daria M. Baloban, Mikhail Pletnev, Sergei Malashkevich, Vladimir N. Xiao, Hui Dauter, Zbigniew Verkhusha, Vladislav V. TI Molecular Basis of Spectral Diversity in Near-Infrared Phytochrome-Based Fluorescent Proteins SO CHEMISTRY & BIOLOGY LA English DT Article ID PSEUDOMONAS-AERUGINOSA BACTERIOPHYTOCHROME; IN-VIVO; BACTERIAL PHYTOCHROMES; BILIVERDIN CHROMOPHORE; CRYSTAL-STRUCTURE; FLASH-PHOTOLYSIS; QUANTUM YIELD; LIGHT; DOMAIN; AGP1 AB Near-infrared fluorescent proteins (NIR FPs) engineered from bacterial phytochromes (BphPs) are the probes of choice for deep-tissue imaging. Detection of several processes requires spectrally distinct NIR FPs. We developed an NIR FP, BphP1-FP, which has the most blue-shifted spectra and the highest fluorescence quantum yield among BphP-derived FPs. We found that these properties result from the binding of the biliverdin chromophore to a cysteine residue in the GAF domain, unlike natural BphPs and other BphP-based FPs. To elucidate the molecular basis of the spectral shift, we applied biochemical, structural and mass spectrometry analyses and revealed the formation of unique chromophore species. Mutagenesis of NIR FPs of different origins indicated that the mechanism of the spectral shift is general and can be used to design multicolor NIR FPs from other BphPs. We applied pairs of spectrally distinct point cysteine mutants to multicolor cell labeling and demonstrated that they perform well in model deep-tissue imaging. C1 [Shcherbakova, Daria M.; Baloban, Mikhail; Verkhusha, Vladislav V.] Albert Einstein Coll Med, Dept Anat & Struct Biol, Bronx, NY 10461 USA. [Pletnev, Sergei; Dauter, Zbigniew] NCI, Macromol Crystallog Lab, Basic Res Program, Argonne, IL 60439 USA. [Pletnev, Sergei; Dauter, Zbigniew] Leidos Biomed Res Inc, Argonne, IL 60439 USA. [Malashkevich, Vladimir N.] Albert Einstein Coll Med, Dept Biochem, Bronx, NY 10461 USA. [Xiao, Hui] Albert Einstein Coll Med, Dept Pathol, Bronx, NY 10461 USA. [Verkhusha, Vladislav V.] Univ Helsinki, Fac Med, Dept Biochem & Dev Biol, Helsinki 00029, Finland. RP Verkhusha, VV (reprint author), Albert Einstein Coll Med, Dept Anat & Struct Biol, Bronx, NY 10461 USA. EM vladislav.verkhusha@einstein.yu.edu FU US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; US Federal funds from the National Cancer Institute of the NIH [HHSN261200800001E]; NIH [CA164468, GM073913, GM108579]; EU FP7 program [ERC-2013-ADG-340233] FX We thank Eric Giraud (Institute for Research and Development, Montpellier, France) for the RpBphP1 gene, Clark Lagarias (University of California at Davis) and Richard Vierstra (University of Wisconsin at Madison) for the plasmids for production of BV and PFB in bacteria. We are grateful to Clark Lagarias for useful comments on the manuscript. We thank Jinghang Zhang for assistance with flow cytometry. Use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. W-31-109-Eng-38. This work was supported in part with US Federal funds from the National Cancer Institute of the NIH under contract HHSN261200800001E, the Intramural Research Program of the NIH, by the NIH grants CA164468, GM073913 and GM108579 (all to V.V.V.) and ERC-2013-ADG-340233 (to V.V.V.) grant from the EU FP7 program. NR 50 TC 9 Z9 9 U1 9 U2 28 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-5521 EI 1879-1301 J9 CHEM BIOL JI Chem. Biol. PD NOV 19 PY 2015 VL 22 IS 11 BP 1540 EP 1551 DI 10.1016/j.chembiol.2015.10.007 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CY1BO UT WOS:000366141800016 PM 26590639 ER PT J AU Zerze, GH Best, RB Mittal, J AF Zerze, Guel H. Best, Robert B. Mittal, Jeetain TI Sequence- and Temperature-Dependent Properties of Unfolded and Disordered Proteins from Atomistic Simulations SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID SINGLE-MOLECULE FRET; HYDROGEN-BOND FORMATION; REDUCED RIBONUCLEASE-A; X-RAY-SCATTERING; POLYPEPTIDE-CHAINS; DENATURED STATE; CONFORMATIONAL PROPERTIES; HYDROPHOBIC COLLAPSE; SECONDARY STRUCTURE; GLOBULE TRANSITION AB We use all-atom molecular simulation with explicit solvent to study the properties of selected intrinsically disordered proteins and unfolded states of foldable proteins, which include chain dimensions and shape, secondary structure propensity, solvent accessible surface area, and contact formation. We find that the qualitative scaling behavior of the chains matches expectations from theory under ambient conditions. In particular, unfolded globular proteins tend to be more collapsed under the same conditions than charged disordered sequences of the same length. However, inclusion of explicit solvent in addition naturally captures temperature-dependent solvation effects, which results in an initial collapse of the chains as temperature is increased, in qualitative agreement with experiment. There is a universal origin to the collapse, revealed in the change of hydration of individual residues as a function of temperature: namely, that the initial collapse is driven by unfavorable solvation free energy of individual residues, which in turn has a strong temperature dependence. We also observe that in unfolded globular proteins, increased temperature also initially favors formation of native-like (rather than non-native-like) structure. Our results help to establish how sequence encodes the degree of intrinsic disorder or order as well as its response to changes in environmental conditions. C1 [Zerze, Guel H.; Mittal, Jeetain] Lehigh Univ, Dept Chem & Biomol Engn, Bethlehem, PA 18015 USA. [Best, Robert B.] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Best, RB (reprint author), NIDDK, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. EM robertbe@helix.nih.gov; jeetain@lehigh.edu RI Best, Robert/H-7588-2016 OI Best, Robert/0000-0002-7893-3543 FU U.S. Department of Energy, Office of Basic Energy Science, Division of Material Sciences and Engineering [DE-SC0013979]; National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health; National Science Foundation (NSF) [TG-MCB-120014] FX We thank Prof. Ben Schuler for helpful discussions. J.M. acknowledges support from the U.S. Department of Energy, Office of Basic Energy Science, Division of Material Sciences and Engineering under Award (DE-SC0013979). R.B. is supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. Use of the high-performance computing capabilities of the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by the National Science Foundation (NSF) grant no. TG-MCB-120014, is gratefully acknowledged. This work utilized the computational resources of the NIH HPC Biowulf cluster. (http://hpc.nih.gov) NR 83 TC 6 Z9 6 U1 8 U2 22 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD NOV 19 PY 2015 VL 119 IS 46 BP 14622 EP 14630 DI 10.1021/acs.jpcb.5b08619 PG 9 WC Chemistry, Physical SC Chemistry GA CX1NP UT WOS:000365463200006 PM 26498157 ER PT J AU Sparano, JA Gray, RJ Makower, DF Pritchard, KI Albain, KS Hayes, DF Geyer, CE Dees, EC Perez, EA Olson, JA Zujewski, JA Lively, T Badve, SS Saphner, TJ Wagner, LI Whelan, TJ Ellis, MJ Paik, S Wood, WC Ravdin, P Keane, MM Moreno, HLG Reddy, PS Goggins, TF Mayer, IA Brufsky, AM Toppmeyer, DL Kaklamani, VG Atkins, JN Berenberg, JL Sledge, GW AF Sparano, J. A. Gray, R. J. Makower, D. F. Pritchard, K. I. Albain, K. S. Hayes, D. F. Geyer, C. E., Jr. Dees, E. C. Perez, E. A. Olson, J. A., Jr. Zujewski, J. A. Lively, T. Badve, S. S. Saphner, T. J. Wagner, L. I. Whelan, T. J. Ellis, M. J. Paik, S. Wood, W. C. Ravdin, P. Keane, M. M. Gomez Moreno, H. L. Reddy, P. S. Goggins, T. F. Mayer, I. A. Brufsky, A. M. Toppmeyer, D. L. Kaklamani, V. G. Atkins, J. N. Berenberg, J. L. Sledge, G. W. TI Prospective Validation of a 21-Gene Expression Assay in Breast Cancer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ADJUVANT CHEMOTHERAPY; RANDOMIZED-TRIALS; CLINICAL-PRACTICE; AMERICAN SOCIETY; GENE-EXPRESSION; TUMOR-MARKERS; TAMOXIFEN; RECURRENCE; EFFICACY; WOMEN AB BACKGROUND Prior studies with the use of a prospective-retrospective design including archival tumor samples have shown that gene-expression assays provide clinically useful prognostic information. However, a prospectively conducted study in a uniformly treated population provides the highest level of evidence supporting the clinical validity and usefulness of a biomarker. METHODS We performed a prospective trial involving women with hormone-receptor-positive, human epidermal growth factor receptor type 2 (HER2)-negative, axillary node-negative breast cancer with tumors of 1.1 to 5.0 cm in the greatest dimension (or 0.6 to 1.0 cm in the greatest dimension and intermediate or high tumor grade) who met established guidelines for the consideration of adjuvant chemotherapy on the basis of clinicopathologic features. A reverse-transcriptase-polymerase-chain-reaction assay of 21 genes was performed on the paraffin-embedded tumor tissue, and the results were used to calculate a score indicating the risk of breast-cancer recurrence; patients were assigned to receive endocrine therapy without chemotherapy if they had a recurrence score of 0 to 10, indicating a very low risk of recurrence (on a scale of 0 to 100, with higher scores indicating a greater risk of recurrence). RESULTS Of the 10,253 eligible women enrolled, 1626 women (15.9%) who had a recurrence score of 0 to 10 were assigned to receive endocrine therapy alone without chemotherapy. At 5 years, in this patient population, the rate of invasive disease-free survival was 93.8% (95% confidence interval [CI], 92.4 to 94.9), the rate of freedom from recurrence of breast cancer at a distant site was 99.3% (95% CI, 98.7 to 99.6), the rate of freedom from recurrence of breast cancer at a distant or local-regional site was 98.7% (95% CI, 97.9 to 99.2), and the rate of overall survival was 98.0% (95% CI, 97.1 to 98.6). CONCLUSIONS Among patients with hormone-receptor-positive, HER2-negative, axillary node-negative breast cancer who met established guidelines for the recommendation of adjuvant chemotherapy on the basis of clinicopathologic features, those with tumors that had a favorable gene-expression profile had very low rates of recurrence at 5 years with endocrine therapy alone. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00310180.) C1 [Sparano, J. A.; Makower, D. F.] Montefiore Med Ctr, Albert Einstein Coll Med, Bronx, NY 10467 USA. [Gray, R. J.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Pritchard, K. I.] Sunnybrook Res Inst, Toronto, ON, Canada. [Whelan, T. J.] Juravinski Canc Ctr, Hamilton, ON, Canada. [Albain, K. S.] Loyola Univ, Med Ctr, Maywood, IL 60153 USA. [Wagner, L. I.; Kaklamani, V. G.] Northwestern Univ, Chicago, IL 60611 USA. [Hayes, D. F.] Univ Michigan, Ann Arbor, MI 48109 USA. [Geyer, C. E., Jr.] Virginia Commonwealth Univ, Sch Med, Richmond, NC USA. [Geyer, C. E., Jr.] Massey Canc Ctr, Richmond, NC USA. [Dees, E. C.] Univ N Carolina, Chapel Hill, NC USA. [Olson, J. A., Jr.] Duke Univ, Med Ctr, Durham, NC USA. [Wagner, L. I.] Wake Forest Univ Hlth Serv, Winston Salem, NC USA. [Atkins, J. N.] Southeast Clin Oncol Res Consortium, Goldsboro, NC USA. [Perez, E. A.] Mayo Clin, Jacksonville, FL 32224 USA. [Olson, J. A., Jr.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Zujewski, J. A.; Lively, T.] NIH, Bethesda, MD 20892 USA. [Badve, S. S.] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Sledge, G. W.] Indiana Univ Hosp, Indianapolis, IN 46202 USA. [Saphner, T. J.] Vince Lombardi Canc Clin, Two Rivers, WI USA. [Goggins, T. F.] Fox Valley Hematol & Oncol, Appleton, WI USA. [Ellis, M. J.] Baylor Coll Med, Houston, TX 77030 USA. [Ravdin, P.] Univ Texas San Antonio, San Antonio, TX USA. [Ellis, M. J.] Washington Univ, St Louis, MO USA. [Paik, S.] Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. [Brufsky, A. M.] Univ Pittsburgh, Pittsburgh, PA USA. [Paik, S.] Yonsei Univ, Dept Med Oncol, Coll Med, Seoul, South Korea. [Paik, S.] Yonsei Univ, Breast Ctr, Coll Med, Seoul, South Korea. [Wood, W. C.] Emory Univ, Atlanta, GA 30322 USA. [Keane, M. M.] Irish Clin Oncol Res Grp, Dublin, Ireland. [Gomez Moreno, H. L.] Inst Nacl Enfermedades Neoplas, Lima, Peru. [Reddy, P. S.] Canc Ctr Kansas, Wichita, KS USA. [Mayer, I. A.] Vanderbilt Univ, Nashville, TN 37235 USA. [Toppmeyer, D. L.] Rutgers Canc Inst New Jersey, New Brunswick, NJ 08903 USA. [Berenberg, J. L.] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. [Sledge, G. W.] Stanford Univ, Stanford, CA 94305 USA. RP Sparano, JA (reprint author), Montefiore Med Ctr, Dept Oncol, 1695 Eastchester Rd, Bronx, NY 10461 USA. EM jsparano@montefiore.org RI Whelan, Timothy/D-3185-2017 FU National Cancer Institute FX Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00310180. NR 37 TC 112 Z9 115 U1 8 U2 23 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 NOV 19 PY 2015 VL 373 IS 21 BP 2005 EP 2014 DI 10.1056/NEJMoa1510764 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA CW4JN UT WOS:000364957700006 PM 26412349 ER PT J AU Gara, SK Kebebew, E AF Gara, Sudheer Kumar Kebebew, Electron TI HABP2 Mutation and Nonmedullary Thyroid Cancer REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Gara, Sudheer Kumar; Kebebew, Electron] NCI, Bethesda, MD 20892 USA. RP Gara, SK (reprint author), NCI, Bethesda, MD 20892 USA. EM kebebewe@mail.nih.gov RI Gara, Sudheer Kumar/E-8084-2016 NR 4 TC 1 Z9 1 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 NOV 19 PY 2015 VL 373 IS 21 BP 2086 EP 2087 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA CW4JN UT WOS:000364957700021 PM 26581001 ER PT J AU Li, HZ Liu, WL Chen, WP Zhu, JQ Deng, CX Rodgers, GP AF Li, Hongzhen Liu, Wenli Chen, Weiping Zhu, Jianqiong Deng, Chu-Xia Rodgers, Griffin P. TI Olfactomedin 4 deficiency promotes prostate neoplastic progression and is associated with upregulation of the hedgehogsignaling pathway SO SCIENTIFIC REPORTS LA English DT Article ID GENETICALLY-ENGINEERED MICE; STEM-CELLS; MYELOID-LEUKEMIA; TARGET GENE; CANCER; EXPRESSION; METASTASIS; HGC-1; PROLIFERATION; CARCINOMA AB Loss of olfactomedin 4 (OLFM4) gene expression is associated with the progression of human prostate cancer, but its role and the molecular mechanisms involved in this process have not been completely understood. In this study, we found that Olfm4-knockout mice developed prostatic intraepithelial neoplasia and prostatic adenocarcinoma. Importantly, we found that the hedgehogsignaling pathway was significantly upregulated in the Olfm4-knockout mouse model. We also found that restoration of OLFM4 in human prostate-cancer cells that lack OLFM4 expression significantly downregulated hedgehog signaling-pathway component expression. Furthermore, we demonstrated that the OLFM4 protein interacts with sonic hedgehog protein, as well as significantly inhibits GLI-reporter activity. Bioinformatic and immunohistochemistry analyses revealed that decreased OLFM4 and increased SHH expression was significantly associated with advanced human prostate cancer. Thus, olfactomedin 4 appears to play a critical role in regulating progression of prostate cancer, and has potential as a new biomarker for prostate cancer. C1 [Li, Hongzhen; Liu, Wenli; Zhu, Jianqiong; Rodgers, Griffin P.] NHLBI, Mol & Clin Hematol Branch, NIH, Bethesda, MD 20892 USA. [Chen, Weiping] NIDDK, Genom Core Facil, NIH, Bethesda, MD 20892 USA. [Deng, Chu-Xia] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. RP Rodgers, GP (reprint author), NHLBI, Mol & Clin Hematol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM gr5n@nih.gov RI deng, chuxia/N-6713-2016 FU Intramural Research Program, NIH/NIDDK FX We thank Dr. Victoria Hoffmann, DVM, DACVP (Division of Veterinary Resources/NIH) and Dr. Jaime Rodriguez-Canales MD (a pathologist in the Laboratory of Pathology, NCI, NIH [current address: Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX]) for help with histological evaluation of mouse prostate tissues, and Dr. Elizabeth Wright (NIDDK) for help with statistical analysis. We thank Dr. Chithra Keembiyehetty (Genomics Core Facility, NIDDK, NIH) for help with microarray analysis. We thank Drs. Ye Chen and Xujing Wang (Bioinformatics and Systems Biology Core, NHLBI, NIH) for their help with GSE35988 data download and analysis. We thank Dr. Ivan Ding (National Cancer Institute, NIH) for reading and providing comments on the manuscript. This work was supported by the Intramural Research Program, NIH/NIDDK. NR 29 TC 4 Z9 5 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 NOV 19 PY 2015 VL 5 AR 16974 DI 10.1038/srep16974 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CW4FS UT WOS:000364947400001 PM 26581960 ER PT J AU Shen, WX Plotkin, JL Francardo, V Ko, WKD Xie, Z Li, Q Fieblinger, T Wess, J Neubig, RR Lindsley, CW Conn, PJ Greengard, P Bezard, E Cenci, MA Surmeier, DJ AF Shen, Weixing Plotkin, Joshua L. Francardo, Veronica Ko, Wai Kin D. Xie, Zhong Li, Qin Fieblinger, Tim Wess, Juergen Neubig, Richard R. Lindsley, Craig W. Conn, P. Jeffrey Greengard, Paul Bezard, Erwan Cenci, M. Angela Surmeier, D. James TI M4 Muscarinic Receptor Signaling Ameliorates Striatal Plasticity Deficits in Models of L-DOPA-Induced Dyskinesia SO NEURON LA English DT Article ID MEDIUM SPINY NEURONS; BIDIRECTIONAL SYNAPTIC PLASTICITY; TIMING-DEPENDENT PLASTICITY; CHOLINERGIC INTERNEURONS; DOPAMINERGIC CONTROL; PARKINSONS-DISEASE; STRIATOPALLIDAL NEURONS; HUNTINGTONS-DISEASE; MOTOR DEFICITS; NMDA RECEPTOR AB A balanced interaction between dopaminergic and cholinergic signaling in the striatum is critical to goal-directed behavior. But how this interaction modulates corticostriatal synaptic plasticity underlying learned actions remains unclear-particularly in direct-pathway spiny projection neurons (dSPNs). Our studies show that in dSPNs, endogenous cholinergic signaling through M4 muscarinic receptors (M4Rs) promoted long-term depression of corticostriatal glutamatergic synapses, by suppressing regulator of G protein signaling type 4 (RGS4) activity, and blocked D1 dopamine receptor dependent long-term potentiation (LTP). Furthermore, in a mouse model of L-3,4-dihydroxyphenylalanine (L-DOPA)induced dyskinesia (LID) in Parkinson's disease (PD), boosting M4R signaling with positive allosteric modulator (PAM) blocked aberrant LTP in dSPNs, enabled LTP reversal, and attenuated dyskinetic behaviors. An M4R PAM also was effective in a primate LID model. Taken together, these studies identify an important signaling pathway controlling striatal synaptic plasticity and point to a novel pharmacological strategy for alleviating LID in PD patients. C1 [Shen, Weixing; Plotkin, Joshua L.; Xie, Zhong; Surmeier, D. James] Northwestern Univ, Dept Physiol, Feinberg Sch Med, Chicago, IL 60611 USA. [Francardo, Veronica; Fieblinger, Tim; Cenci, M. Angela] Lund Univ, Dept Expt Med Sci, Basal Ganglia Pathophysiol Unit, S-22184 Lund, Sweden. [Ko, Wai Kin D.; Bezard, Erwan] Univ Bordeaux, F-33000 Bordeaux, France. [Ko, Wai Kin D.; Bezard, Erwan] CNRS, Inst Malad Neurodegenerat, UMR 5293, F-33000 Bordeaux, France. [Ko, Wai Kin D.; Li, Qin; Bezard, Erwan] Motac Neurosci, Manchester M13 9XX, Lancs, England. [Wess, Juergen] NIDDK, Mol Signaling Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Neubig, Richard R.] Michigan State Univ, Dept Pharmacol & Toxicol, E Lansing, MI 48824 USA. [Lindsley, Craig W.; Conn, P. Jeffrey] Vanderbilt Univ, Dept Pharmacol, Nashville, TN 37232 USA. [Lindsley, Craig W.; Conn, P. Jeffrey] Vanderbilt Univ, Vanderbilt Ctr Neurosci Drug Discovery, Nashville, TN 37232 USA. [Greengard, Paul] Rockefeller Univ, Lab Mol & Cellular Neurosci, New York, NY 10065 USA. RP Surmeier, DJ (reprint author), Northwestern Univ, Dept Physiol, Feinberg Sch Med, Chicago, IL 60611 USA. EM j-surmeier@northwestern.edu RI Xie, Zhong/B-6829-2011 OI Bezard, Erwan/0000-0002-0410-4638; Cenci Nilsson, M. Angela/0000-0003-2216-2900; Xie, Zhong/0000-0002-8348-4455 FU Michael J. Fox Foundation; NIH [NS034696, MH074866, DA023252, MH073676, NS071669]; JPB Foundation; USAMRAA [W81XWH-09-1-0402]; NIH Intramural Research Program; Association France Parkinson; Foundation de France; LABEX BRAIN [ANR-10-LABX-43]; Swedish governmental [43301-ALF]; Basal Ganglia Disorders Linnaeus Consortium (BAGADILICO); Swedish Research Council; Swedish Foundation for International Cooperation in Research and Higher Education (STINT); Olle Engkvist Foundation; AstraZeneca FX This work was supported by the Michael J. Fox Foundation to W.S., D.J.S., the NIH NS034696 and MH074866 to D.J.S., the JPB Foundation to D.J.S., P.G., the USAMRAA grant W81XWH-09-1-0402 to P.G.; by the NIH Intramural Research Program to J.W.; by the grant to R.R.N. from NIH DA023252; by the grants to P.J.C. and C.W.L. from the NIH MH073676 and NS071669; by the grants from Association France Parkinson, the Foundation de France, and LABEX BRAIN ANR-10-LABX-43 to E.B.; and by the grants to M.A.C. from Swedish governmental funding of clinical research (grant 43301-ALF), the Basal Ganglia Disorders Linnaeus Consortium (BAGADILICO), the Swedish Research Council, the Swedish Foundation for International Cooperation in Research and Higher Education (STINT), and the Olle Engkvist Foundation. We thank Shenyu Zhai and Savio Chan for their comments on the manuscript and Sasha Ulrich for technical assistance. P.J.C. and C.W.L. receive research support from AstraZeneca and are inventors on patents that protect multiple classes of M4R PAMs. NR 63 TC 16 Z9 17 U1 2 U2 7 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 NOV 18 PY 2015 VL 88 IS 4 BP 762 EP 773 DI 10.1016/j.neuron.2015.10.039 PG 12 WC Neurosciences SC Neurosciences & Neurology GA CX5TR UT WOS:000365765900016 PM 26590347 ER PT J AU Tikkanen, R Tiihonen, J Rautiainen, MR Paunio, T Bevilacqua, L Panarsky, R Goldman, D Virkkunen, M AF Tikkanen, R. Tiihonen, J. Rautiainen, M. R. Paunio, T. Bevilacqua, L. Panarsky, R. Goldman, D. Virkkunen, M. TI Impulsive alcohol-related risk-behavior and emotional dysregulation among individuals with a serotonin 2B receptor stop codon SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID FLUID 5-HYDROXYINDOLEACETIC ACID; 5-HT2B RECEPTORS; FUNCTIONAL POLYMORPHISM; ANTISOCIAL-BEHAVIOR; HABITUALLY VIOLENT; INSULIN-SECRETION; HEALTHY CONTROLS; GENE; OFFENDERS; DISORDER AB A relatively common stop codon (Q20*) was identified in the serotonin 2B receptor gene (HTR2B) in a Finnish founder population in 2010 and it was associated with impulsivity. Here we examine the phenotype of HTR2B Q20* carriers in a setting comprising 14 heterozygous HTR2B Q20* carriers and 156 healthy controls without the HTR2B Q20*. The tridimensional personality questionnaire, Brown-Goodwin lifetime aggression scale, the Michigan alcoholism screening test and lifetime drinking history were used to measure personality traits, impulsive and aggressive behavior, both while sober and under the influence of alcohol, and alcohol consumption. Regression analyses showed that among the HTR2B Q20* carriers, temperamental traits resembled a passive-dependent personality profile, and the presence of the HTR2B Q20* predicted impulsive and aggressive behaviors particularly under the influence of alcohol. Results present examples of how one gene may contribute to personality structure and behaviors in a founder population and how personality may translate into behavior. C1 [Tikkanen, R.; Paunio, T.; Virkkunen, M.] Univ Helsinki, Dept Psychiat, Inst Clin Med, Helsinki 00260, Finland. [Tikkanen, R.] Rinnekoti Fdn, Res & Dev, Espoo, Finland. [Tiihonen, J.] Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden. [Tiihonen, J.] Univ Eastern Finland, Niuvaniemi Hosp, Dept Forens Psychiat, Kuopio, Finland. [Tiihonen, J.; Rautiainen, M. R.; Paunio, T.] Natl Inst Hlth & Welf, Helsinki, Finland. [Paunio, T.; Virkkunen, M.] Univ Helsinki, Cent Hosp, Dept Psychiat, SF-00260 Helsinki, Finland. [Bevilacqua, L.] NYU, Sch Med, Dept Psychiat, New York, NY USA. [Panarsky, R.; Goldman, D.] NIAAA, Lab Neurogenet, Rockville, MD 20852 USA. RP Tikkanen, R (reprint author), Univ Helsinki, Dept Psychiat, Inst Clin Med, Valskarinkatu 12,POB 22, Helsinki 00260, Finland. EM roope.tikkanen@helsinki.fi RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 NR 48 TC 3 Z9 3 U1 2 U2 6 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 NOV 17 PY 2015 VL 5 AR e681 DI 10.1038/tp.2015.170 PG 6 WC Psychiatry SC Psychiatry GA DA2ZQ UT WOS:000367666100003 PM 26575222 ER PT J AU Grenga, I Kwilas, AR Donahue, RN Farsaci, B Hodge, JW AF Grenga, Italia Kwilas, Anna R. Donahue, Renee N. Farsaci, Benedetto Hodge, James W. TI Inhibition of the angiopoietin/Tie2 axis induces immunogenic modulation, which sensitizes human tumor cells to immune attack SO JOURNAL FOR IMMUNOTHERAPY OF CANCER LA English DT Article DE Angiopoietin; Tie2; Immunogenic modulation; Immunotherapy ID OVARIAN-CANCER; ANTIANGIOGENIC THERAPY; SERUM ANGIOPOIETIN-2; GASTRIC-CANCER; BREAST-CANCER; ANGIOGENESIS; TIE2; EXPRESSION; RECEPTOR; VACCINE AB Background: The angiopoietin/Tie2 pathway is an attractive target for cancer therapy due to its well-known role in regulating angiogenesis. Trebananib, a recombinant peptide-Fc fusion protein, or peptibody, that binds to angiopoietin-1 (Ang1) and Ang2 to block their interaction with the Tie2 receptor, is under active clinical investigation. We investigated whether suppressing the angiopoietin/Tie2 pathway, using the preclinical version of Trebananib (mL4-3 and L1-7(N)), could increase the sensitivity of human tumor cells to immune-mediated lysis through immunogenic modulation, which would make Trebananib a promising candidate for combination with immunotherapy. Methods: We assessed human carcinoma cells for expression and activation of Ang1 and Ang2 and their receptor tyrosine kinase Tie2. In vitro, we exposed tumor cell lines expressing Tie2 to the peptibodies mL4-3 and L1-7(N), which inhibit the binding of Ang1 and Ang2 to Tie2, and assessed the cells for changes in viability, proliferation, surface phenotype, and sensitivity to attack by antigen-specific cytotoxic T lymphocytes (CTLs). Results: Suppression of the angiopoietin/Tie2 pathway using mL4-3 and L1-7(N) had no effect on the proliferation or viability of tumor cells. However, these inhibitors markedly altered tumor cell phenotype, rendering tumor cells significantly more sensitive to antigen-specific CTL killing. ICAM-1 was shown to be mechanistically involved in these inhibitors' ability to sensitize tumor cells to immune-mediated attack by functional blocking studies. Conclusion: Our findings provide a rationale for the combination of agents targeting the angiopoietin/Tie2 pathway with cancer immunotherapies. C1 [Grenga, Italia; Kwilas, Anna R.; Donahue, Renee N.; Farsaci, Benedetto; Hodge, James W.] NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Hodge, JW (reprint author), NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Ctr Dr,Room 8B13 MSC 1750, Bethesda, MD 20892 USA. EM hodgej@mail.nih.gov RI Farsaci, Benedetto/L-9837-2014; Hodge, James/D-5518-2015 OI Farsaci, Benedetto/0000-0001-8275-2561; Hodge, James/0000-0001-5282-3154 NR 55 TC 3 Z9 3 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2051-1426 J9 J IMMUNOTHER CANCER JI J. Immunother. Cancer PD NOV 17 PY 2015 VL 3 AR 52 DI 10.1186/s40425-015-0096-7 PG 11 WC Oncology SC Oncology GA CZ5QR UT WOS:000367157600001 PM 26579226 ER PT J AU Nagao, K Segre, JA AF Nagao, Keisuke Segre, Julia A. TI "Bringing Up Baby'' to Tolerate Germs SO IMMUNITY LA English DT Editorial Material ID ATOPIC-DERMATITIS; SKIN MICROBIOME; T-CELLS C1 [Nagao, Keisuke] NCI, Dermatol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Segre, Julia A.] NHGRI, Translat & Funct Genom Branch, NIH, Bethesda, MD 20892 USA. RP Nagao, K (reprint author), NCI, Dermatol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM keisuke.nagao@nih.gov; jsegre@nhgri.nih.gov RI Nagao, Keisuke/J-5116-2013 OI Nagao, Keisuke/0000-0002-7005-3138 NR 10 TC 2 Z9 2 U1 3 U2 6 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 NOV 17 PY 2015 VL 43 IS 5 BP 842 EP 844 DI 10.1016/j.immuni.2015.10.020 PG 4 WC Immunology SC Immunology GA CZ1DM UT WOS:000366846000006 PM 26588777 ER PT J AU Maltez, VI Tubbs, AL Cook, KD Aachoui, Y Falcone, EL Holland, SM Whitmire, JK Miao, EA AF Maltez, Vivien I. Tubbs, Alan L. Cook, Kevin D. Aachoui, Youssef Falcone, E. Liana Holland, Steven M. Whitmire, Jason K. Miao, Edward A. TI Inflammasomes Coordinate Pyroptosis and Natural Killer Cell Cytotoxicity to Clear Infection by a Ubiquitous Environmental Bacterium SO IMMUNITY LA English DT Article ID CHRONIC-GRANULOMATOUS-DISEASE; CHROMOBACTERIUM-VIOLACEUM INFECTION; III SECRETION APPARATUS; NK-CELLS; NLRC4 INFLAMMASOME; T-CELLS; LISTERIA INFECTION; INNATE IMMUNITY; ACTIVATION; CASPASE-1 AB Defective neutrophils in patients with chronic granulomatous disease (CGD) cause susceptibility to extracellular and intracellular infections. Microbes must first be ejected from intracellular niches to expose them to neutrophil attack, so we hypothesized that inflammasomes detect certain CGD pathogens upstream of neutrophil killing. Here, we identified one such ubiquitous environmental bacterium, Chromobacterium violaceum, whose extreme virulence was fully counteracted by the NLRC4 inflammasome. Caspase-1 protected via two parallel pathways that eliminated intracellular replication niches. Pyroptosis was the primary bacterial clearance mechanism in the spleen, but both pyroptosis and interleukin-18 (IL-18)-driven natural killer (NK) cell responses were required for liver defense. NK cells cleared hepatocyte replication niches via perforin-dependent cytotoxicity, whereas interferon-g was not required. These insights suggested a therapeutic approach: exogenous IL-18 restored perforin-dependent cytotoxicity during infection by the inflammasome-evasive bacterium Listeria monocytogenes. Therefore, inflammasomes can trigger complementary programmed cell death mechanisms, directing sterilizing immunity against intracellular bacterial pathogens. C1 [Maltez, Vivien I.; Tubbs, Alan L.; Aachoui, Youssef; Whitmire, Jason K.; Miao, Edward A.] Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA. [Maltez, Vivien I.; Tubbs, Alan L.; Aachoui, Youssef; Miao, Edward A.] Univ N Carolina, Ctr Gastrointestinal Biol & Dis, Chapel Hill, NC 27599 USA. [Maltez, Vivien I.; Tubbs, Alan L.; Aachoui, Youssef; Miao, Edward A.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Cook, Kevin D.; Whitmire, Jason K.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Falcone, E. Liana; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Miao, EA (reprint author), Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA. EM edmiao1@gmail.com OI Miao, Edward/0000-0001-7295-3490 FU NIH [AI097518, AI057141, AI119073, AI097518-02S1, R56AI110682, R01AI074862, T32 AI7273-27]; NCI Center Core Support Grant [P30CA016086] FX We wish to thank Vishva Dixit, Richard Flavell, Shizuo Akira, and David Chaplin for sharing mice. We also thank Dat Mao, Davis Trihn, and Taylor Atherton for upkeep of our mouse colony. This work was supported by the following NIH grants: AI097518, AI057141, and AI119073 (E.A.M.), AI097518-02S1 (V.I.M.), R56AI110682 and R01AI074862 (J.K.W.), and T32 AI7273-27 (K.D.C.). The UNC Flow Cytometry Core Facility is supported in part by an NCI Center Core Support Grant (P30CA016086) to the UNC Lineberger Comprehensive Cancer Center. NR 48 TC 12 Z9 12 U1 3 U2 7 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 NOV 17 PY 2015 VL 43 IS 5 BP 987 EP 997 DI 10.1016/j.immuni.2015.10.010 PG 11 WC Immunology SC Immunology GA CZ1DM UT WOS:000366846000018 PM 26572063 ER PT J AU Scharschmidt, TC Vasquez, KS Truong, HA Gearty, SV Pauli, ML Nosbaum, A Gratz, IK Otto, M Moon, JJ Liese, J Abbas, AK Fischbach, MA Rosenblum, MD AF Scharschmidt, Tiffany C. Vasquez, Kimberly S. Truong, Hong-An Gearty, Sofia V. Pauli, Mariela L. Nosbaum, Audrey Gratz, Iris K. Otto, Michael Moon, James J. Liese, Jan Abbas, Abul K. Fischbach, Michael A. Rosenblum, Michael D. TI A Wave of Regulatory T Cells into Neonatal Skin Mediates Tolerance to Commensal Microbes SO IMMUNITY LA English DT Article ID INTESTINAL MICROBIOTA; HAIR-FOLLICLES; IMMUNITY; DISEASE; INFLAMMATION; DIVERSITY; INFECTION; RESIDENT; BACTERIA; HOST AB The skin is a site of constant dialog between the immune system and commensal bacteria. However, the molecular mechanisms that allow us to tolerate the presence of skin commensals without eliciting destructive inflammation are unknown. Using a model system to study the antigen-specific response to S. epidermidis, we demonstrated that skin colonization during a defined period of neonatal life was required for establishing immune tolerance to commensal microbes. This crucial window was characterized by an abrupt influx of highly activated regulatory T (Treg) cells into neonatal skin. Selective inhibition of this Treg cell wave completely abrogated tolerance. Thus, the host-commensal relationship in the skin relied on a unique Treg cell population that mediated tolerance to bacterial antigens during a defined developmental window. This suggests that the cutaneous microbiome composition in neonatal life is crucial in shaping adaptive immune responses to commensals, and disrupting these interactions might have enduring health implications. C1 [Scharschmidt, Tiffany C.; Vasquez, Kimberly S.; Truong, Hong-An; Gearty, Sofia V.; Pauli, Mariela L.; Nosbaum, Audrey; Rosenblum, Michael D.] Univ Calif San Francisco, Dept Dermatol, San Francisco, CA 94143 USA. [Gratz, Iris K.] Salzburg Univ, Dept Mol Biol, A-5020 Salzburg, Austria. [Otto, Michael] NIAID, NIH, Bethesda, MD 20892 USA. [Moon, James J.] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Div Pulm & Crit Care Med, Boston, MA 02129 USA. [Moon, James J.] Harvard Univ, Sch Med, Boston, MA 02129 USA. [Liese, Jan] Univ Tubingen Hosp, Inst Med Microbiol & Hyg, D-72076 Tubingen, Germany. [Abbas, Abul K.] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA. [Fischbach, Michael A.] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA. [Fischbach, Michael A.] Univ Calif San Francisco, Calif Inst Quantitat Biosci, San Francisco, CA 94143 USA. RP Rosenblum, MD (reprint author), Univ Calif San Francisco, Dept Dermatol, San Francisco, CA 94143 USA. EM michael.rosenblum@ucsf.edu RI Gratz, Iris /L-6267-2015; OI Gratz, Iris /0000-0001-7470-7277; Otto, Michael/0000-0002-2222-4115; Scharschmidt, Tiffany/0000-0001-5517-089X FU Diabetes Research Center [NIH P30 DK063720]; NIH [5P30CA082103-15, K08-AR062064, R21-AR066821, DP2-AR068130]; Dermatology Foundation Career Development Award; UCSF Department of Dermatology; Intramural Research Program of the NIH National Institute of Allergy and Infectious Diseases; Burroughs Wellcome Fund [CAMS-1010934]; Scleroderma Research Foundation grant; National Psoriasis Foundation Translational Grant FX We thank C. Benetiz for assistance with animal husbandry and Creative Commons author Seans Potato Business for use of the mouse image in Figures S2 and S4 under the Attribution-ShareAlike license (https://creativecommons.org/licenses/by-sa/3.0/legalcode). Flow-cytometry data were generated in the UCSF Parnassus Flow Cytometry Core, which is supported by the Diabetes Research Center grant NIH P30 DK063720. Histology was performed with assistance from the UCSF Mouse Pathology Core, which is supported by NIH 5P30CA082103-15. T.C.S. is supported by a Dermatology Foundation Career Development Award and the UCSF Department of Dermatology. M.O. is supported by the Intramural Research Program of the NIH National Institute of Allergy and Infectious Diseases. This work was primarily funded by grants to M.D.R.: NIH K08-AR062064, Burroughs Wellcome Fund CAMS-1010934, NIH R21-AR066821, NIH DP2-AR068130, a Scleroderma Research Foundation grant, and a National Psoriasis Foundation Translational Grant. NR 54 TC 25 Z9 26 U1 3 U2 12 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 NOV 17 PY 2015 VL 43 IS 5 BP 1011 EP 1021 DI 10.1016/j.immuni.2015.10.016 PG 11 WC Immunology SC Immunology GA CZ1DM UT WOS:000366846000020 PM 26588783 ER PT J AU Shalabi, H Angiolillo, A Vezina, G Rubenstein, JL Pittaluga, S Raffeld, M Marcus, L AF Shalabi, Haneen Angiolillo, Anne Vezina, Gilbert Rubenstein, James L. Pittaluga, Stefania Raffeld, Mark Marcus, Leigh TI Prolonged Complete Response in a Pediatric Patient With Primary Peripheral T-Cell Lymphoma of the Central Nervous System SO PEDIATRIC HEMATOLOGY AND ONCOLOGY LA English DT Article DE CNS tumors; NHL; therapy ID PRIMARY-CNS-LYMPHOMA; DESCRIPTIVE ANALYSIS; COLLABORATIVE-GROUP; GAMMA-DELTA; ADOLESCENTS; CHILDREN; ORIGIN AB We describe a child with a 2-week history of progressive headaches, blurry vision, and intermittent vomiting. Magnetic resonance imaging (MRI) of the brain showed a deep left hemispheric lesion with extension into the corpus callosum. Histology and immunophenotyping of the lesion was consistent with peripheral T-cell lymphoma, not otherwise specified. Chemotherapy was initiated and a complete remission was achieved. This case illustrates that a chemotherapeutic regimen used in adults with central nervous system (CNS) lymphoma can achieve durable remissions in pediatric patients with peripheral T-cell lymphoma, not otherwise specified of the CNS. C1 [Shalabi, Haneen; Angiolillo, Anne] Childrens Natl Med Ctr, Ctr Canc & Blood Disorders, Div Pediat Hematol & Oncol, Washington, DC 20010 USA. [Vezina, Gilbert] Childrens Natl Med Ctr, Dept Radiol, Washington, DC 20010 USA. [Rubenstein, James L.] Univ Calif San Francisco, Div Hematol & Oncol, San Francisco, CA 94143 USA. [Pittaluga, Stefania; Raffeld, Mark] NIH, Pathol Lab, Bethesda, MD 20892 USA. [Marcus, Leigh] Food & Drug Adm, Silver Spring, MD USA. RP Shalabi, H (reprint author), Childrens Natl Med Ctr, Ctr Canc & Blood Disorders, Div Pediat Hematol & Oncol, 111 Michigan Ave NW, Washington, DC 20010 USA. EM hshalabi@childrensnational.org FU NCI NIH HHS [R01 CA139083, R21 CA184694] NR 18 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0888-0018 EI 1521-0669 J9 PEDIATR HEMAT ONCOL JI Pediatr. Hematol. Oncol. PD NOV 17 PY 2015 VL 32 IS 8 BP 529 EP 534 DI 10.3109/08880018.2015.1074325 PG 6 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA CZ2EC UT WOS:000366916900004 PM 26384083 ER PT J AU Banerjee, T Brosh, RM AF Banerjee, Taraswi Brosh, Robert M., Jr. TI RECQL: a new breast cancer susceptibility gene SO CELL CYCLE LA English DT Article DE breast cancer; RECQL; RECQ1; helicase; DNA damage; genomic instability; DNA repair ID DNA-REPAIR; PANCREATIC-CANCER; ROLES; POLYMORPHISMS; RECOMBINATION; REPLICATION; MUTATIONS; HELICASES; SURVIVAL; COMPLEX AB Identifying and characterizing novel genetic risk factors for BRCA1/2 negative breast cancers is highly relevant for early diagnosis and development of a management plan. Mutations in a number of DNA repair genes have been associated with genomic instability and development of breast and various other cancers. Whole exome sequencing efforts by 2 groups have led to the discovery in distinct populations of multiple breast cancer susceptibility mutations in RECQL, a gene that encodes a DNA helicase involved in homologous recombination repair and response to replication stress. RECQL pathogenic mutations were identified that truncated or disrupted the RECQL protein or introduced missense mutations in its helicase domain. RECQL mutations may serve as a useful biomarker for breast cancer. Targeting RECQL associated tumors with novel DNA repair inhibitors may provide a new strategy for anti-cancer therapy. C1 [Banerjee, Taraswi; Brosh, Robert M., Jr.] NIA, Lab Mol Gerontol, NIH, NIH Biomed Res Ctr, Baltimore, MD 21224 USA. RP Brosh, RM (reprint author), NIA, Lab Mol Gerontol, NIH, NIH Biomed Res Ctr, Baltimore, MD 21224 USA. EM broshr@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute on Aging FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. NR 41 TC 1 Z9 1 U1 0 U2 6 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1538-4101 EI 1551-4005 J9 CELL CYCLE JI Cell Cycle PD NOV 17 PY 2015 VL 14 IS 22 BP 3540 EP 3543 DI 10.1080/15384101.2015.1066539 PG 4 WC Cell Biology SC Cell Biology GA CY3PV UT WOS:000366322900011 PM 26125302 ER PT J AU Park, JE Kim, TS Kim, BY Lee, KS AF Park, Jung-Eun Kim, Tae-Sung Kim, Bo Yeon Lee, Kyung S. TI Selective blockade of cancer cell proliferation and anchorage-independent growth by Plk1 activity-dependent suicidal inhibition of its polo-box domain SO CELL CYCLE LA English DT Article DE anchorage-independent growth; Plk1; Polo-box domain; T78 peptide ID GREEN FLUORESCENT PROTEIN; ACUTE MYELOID-LEUKEMIA; KINASE 1; MITOTIC ENTRY; IN-VIVO; BI 6727; POLO-LIKE-KINASE-1; LOCALIZATION; VOLASERTIB; THERAPY AB Polo-like kinase 1 (Plk1) plays a critical role in proper M-phase progression and cell proliferation. Plk1 is overexpressed in a broad spectrum of human cancers and is considered an attractive anticancer drug target. Although a large number of inhibitors targeting the catalytic domain of Plk1 have been developed, these inhibitors commonly exhibit a substantial level of cross-reactivity with other structurally related kinases, thus narrowing their applicable dose for patient treatment. Plk1 contains a C-terminal polo-box domain (PBD) that is essentially required for interacting with its binding targets. However, largely due to the lack of both specific and membrane-permeable inhibitors, whether PBD serves as an alternative target for the development of anticancer therapeutics has not been rigorously examined. Here, we used an intracellularly expressed 29-mer-long PBIP1-derived peptide (i.e., PBIPtide), which can be converted into a suicidal PBD inhibitor via Plk1-dependent self-priming and binding. Using this highly specific and potent system, we showed that Plk1 PBD inhibition alone is sufficient for inducing mitotic arrest and apoptotic cell death in cancer cells but not in normal cells, and that cancer cell-selective killing can occur regardless of the presence or absence of oncogenic RAS mutation. Intriguingly, PBD inhibition also effectively prevented anchorage-independent growth of malignant cancer cells. Thus, targeting PBD represents an appealing strategy for anti-Plk1 inhibitor development. Additionally, PBD inhibition-induced cancer cell-selective killing may not simply stem from activated RAS alone but, rather, from multiple altered biochemical and physiological mechanisms, which may have collectively contributed to Plk1 addiction in cancer cells. C1 [Park, Jung-Eun; Kim, Tae-Sung; Lee, Kyung S.] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. [Kim, Bo Yeon] Korea Res Inst Biosci & Biotechnol, Incurable Dis Therapeut Res Ctr, Ochang, South Korea. RP Lee, KS (reprint author), NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. EM kyunglee@mail.nih.gov FU National Cancer Institute FX This work was supported in part by National Cancer Institute intramural grants awarded to K.S.L. NR 61 TC 1 Z9 1 U1 1 U2 5 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1538-4101 EI 1551-4005 J9 CELL CYCLE JI Cell Cycle PD NOV 17 PY 2015 VL 14 IS 22 BP 3624 EP 3634 DI 10.1080/15384101.2015.1104435 PG 11 WC Cell Biology SC Cell Biology GA CY3PV UT WOS:000366322900019 PM 26513691 ER PT J AU Hofmann, JN Beane Freeman, LE Lynch, CF Andreotti, G Thomas, KW Sandler, DP Savage, SA Alavanja, MC AF Hofmann, Jonathan N. Beane Freeman, Laura E. Lynch, Charles F. Andreotti, Gabriella Thomas, Kent W. Sandler, Dale P. Savage, Sharon A. Alavanja, Michael C. TI THE BIOMARKERS OF EXPOSURE AND EFFECT IN AGRICULTURE (BEEA) STUDY: RATIONALE, DESIGN, METHODS, AND PARTICIPANT CHARACTERISTICS SO JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH-PART A-CURRENT ISSUES LA English DT Article ID PESTICIDE EXPOSURE; URINARY CONCENTRATIONS; OCCUPATIONAL-EXPOSURE; TELOMERE LENGTH; NATIONAL-HEALTH; CANCER-RISK; METAANALYSIS; APPLICATORS; METABOLITES AB Agricultural exposures including pesticides, endotoxin, and allergens have been associated with risk of various cancers and other chronic diseases, although the biological mechanisms underlying these associations are generally unclear. To facilitate future molecular epidemiologic investigations, in 2010 the study of Biomarkers of Exposure and Effect in Agriculture (BEEA) was initiated within the Agricultural Health Study, a large prospective cohort in Iowa and North Carolina. Here the design and methodology of BEEA are described and preliminary frequencies for participant characteristics and current agricultural exposures are reported. At least 1,600 male farmers over 50 years of age will be enrolled in the BEEA study. During a home visit, participants are asked to complete a detailed interview about recent agricultural exposures and provide samples of blood, urine, and (since 2013) house dust. As of mid-September 2014, in total, 1,233 participants have enrolled. Most of these participants (83%) were still farming at the time of interview. Among those still farming, the most commonly reported crops were corn (81%) and soybeans (74%), and the most frequently noted animals were beef cattle (35%) and hogs (13%). There were 861 (70%) participants who reported occupational pesticide use in the 12 months prior to interview; among these participants, the most frequently noted herbicides were glyphosate (83%) and 2,4-D (72%), and most commonly reported insecticides were malathion (21%), cyfluthrin (13%), and permethrin (12%). Molecular epidemiologic investigations within BEEA have the potential to yield important new insights into the biological mechanisms through which these or other agricultural exposures influence disease risk. C1 [Hofmann, Jonathan N.; Beane Freeman, Laura E.; Andreotti, Gabriella; Alavanja, Michael C.] NCI, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, Bethesda, MD 20892 USA. [Lynch, Charles F.] Univ Iowa, Dept Epidemiol, Iowa City, IA USA. [Thomas, Kent W.] US EPA, Natl Exposure Res Lab, Res Triangle Pk, NC 27711 USA. [Sandler, Dale P.] Natl Inst Environm Hlth Sci, Epidemiol Branch, Res Triangle Pk, NC USA. [Savage, Sharon A.] NCI, Div Canc Epidemiol & Genet, Clin Genet Branch, Bethesda, MD 20892 USA. RP Hofmann, JN (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM hofmannjn@mail.nih.gov RI Savage, Sharon/B-9747-2015; Beane Freeman, Laura/C-4468-2015; OI Savage, Sharon/0000-0001-6006-0740; Beane Freeman, Laura/0000-0003-1294-4124; Sandler, Dale/0000-0002-6776-0018 FU NIH, National Cancer Institute [Z01CP010119]; National Institute of Environmental Health Sciences [Z01 ES 049030]; United States Environmental Protection Agency through an inter-Agency agreement FX This work was supported by the Intramural Research Program of the NIH, National Cancer Institute (Z01CP010119) and National Institute of Environmental Health Sciences (Z01 ES 049030), and by the United States Environmental Protection Agency through an inter-Agency agreement. The United States Environmental Protection Agency through its Office of Research and Development collaborated in the research described here. It has been subjected to Agency review and approved for publication. We gratefully acknowledge Amy Miller, Kate Torres, Sandor Balogh, Linda Gowen, Himanshi Singh, and Marsha Dunn (Westat, Inc., Rockville, Maryland) for study coordination, data management, and field research efforts. We also thank Debra Lande, Debra Podaril, and Jennifer Hamilton from the field research team at the University of Iowa for their efforts on this study. The ongoing participation of the Agricultural Health Study participants is indispensable and sincerely appreciated. NR 34 TC 1 Z9 1 U1 3 U2 13 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1528-7394 EI 1087-2620 J9 J TOXICOL ENV HEAL A JI J. Toxicol. Env. Health Part A PD NOV 17 PY 2015 VL 78 IS 21-22 BP 1338 EP 1347 DI 10.1080/15287394.2015.1091414 PG 10 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA CY2BD UT WOS:000366212900004 PM 26555155 ER PT J AU Anreddy, N Patel, A Zhang, YK Wang, YJ Shukla, S Kathawala, RJ Kumar, P Gupta, P Ambudkar, SV Wurpel, JD Chen, ZS Guo, HQ AF Anreddy, Nagaraju Patel, Atish Zhang, Yun-Kai Wang, Yi-Jun Shukla, Suneet Kathawala, Rishil J. Kumar, Priyank Gupta, Pranav Ambudkar, Suresh V. Wurpel, Johnn. D. Chen, Zhe-Sheng Guo, Huiqin TI A-803467, a tetrodotoxin-resistant sodium channel blocker, modulates ABCG2-mediated MDR in vitro and in vivo SO ONCOTARGET LA English DT Article DE multidrug resistance; ABCG2; ABC transporters; non-small cell lung cancer ID BREAST-CANCER RESISTANCE; REVERSES MULTIDRUG-RESISTANCE; ACUTE MYELOID-LEUKEMIA; SUBFAMILY-B MEMBER-1; DRUG-RESISTANCE; PROTEIN BCRP/ABCG2; LUNG-CANCER; GENE-EXPRESSION; P-GLYCOPROTEIN; ABCG2 AB ATP-binding cassette subfamily G member 2 (ABCG2) is a member of the ABC transporter superfamily proteins, which has been implicated in the development of multidrug resistance (MDR) in cancer, apart from its physiological role to remove toxic substances out of the cells. The diverse range of substrates of ABCG2 includes many antineoplastic agents such as topotecan, doxorubicin and mitoxantrone. ABCG2 expression has been reported to be significantly increased in some solid tumors and hematologic malignancies, correlated to poor clinical outcomes. In addition, ABCG2 expression is a distinguishing feature of cancer stem cells, whereby this membrane transporter facilitates resistance to the chemotherapeutic drugs. To enhance the chemosensitivity of cancer cells, attention has been focused on MDR modulators. In this study, we investigated the effect of a tetrodotoxin-resistant sodium channel blocker, A-803467 on ABCG2-overexpressing drug selected and transfected cell lines. We found that at non-toxic concentrations, A-803467 could significantly increase the cellular sensitivity to ABCG2 substrates in drug-resistant cells overexpressing either wild-type or mutant ABCG2. Mechanistic studies demonstrated that A-803467 (7.5 mu M) significantly increased the intracellular accumulation of [H-3]-mitoxantrone by inhibiting the transport activity of ABCG2, without altering its expression levels. In addition, A-803467 stimulated the ATPase activity in membranes overexpressed with ABCG2. In a murine model system, combination treatment of A-803467 (35 mg/kg) and topotecan (3 mg/kg) significantly inhibited the tumor growth in mice xenografted with ABCG2-overexpressing cancer cells. Our findings indicate that a combination of A-803467 and ABCG2 substrates may potentially be a novel therapeutic treatment in ABCG2-positive drug resistant cancers. C1 [Anreddy, Nagaraju; Patel, Atish; Zhang, Yun-Kai; Wang, Yi-Jun; Kathawala, Rishil J.; Kumar, Priyank; Gupta, Pranav; Wurpel, Johnn. D.; Chen, Zhe-Sheng] St Johns Univ, Coll Pharm & Hlth Sci, Dept Pharmaceut Sci, Queens, NY 11439 USA. [Shukla, Suneet; Ambudkar, Suresh V.] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Guo, Huiqin] Beijing Union Med Coll Hosp, Dept Thorac Surg, Beijing 100730, Peoples R China. RP Guo, HQ (reprint author), Beijing Union Med Coll Hosp, Dept Thorac Surg, Beijing 100730, Peoples R China. EM chenz@stjohns.edu; guohuiqin2@163.com RI Wang, Yi-Jun/K-3218-2016; OI Anreddy, Nagaraju/0000-0001-8914-8404 FU St. John's University; NIH grant [CA143701]; Wu Jieping Medical Foundation [320.6750.1297] FX We thank Dr. Mark F. Rosenberg and Dr. Zsolt Bikadi (Manchester Interdisciplinary Biocentre, 131 Princess Street, University of Manchester, Manchester, M17DN, UK) for providing coordinates of the ABCG2 homology model. We are thankful to Drs. Susan E. Bates and Robert W. Robey (NCI, NIH) for providing us HEK293/pcDNA3.1 (parental), HEK293/R482, HEK293/R482G and HEK293/R482T, H460 and H460/MX20 cell lines. We thank Anna Maria Barbuti (St. John's University, NY) for her critical reading and editing of the article. This work was supported by St. John's University and NIH grant (No: CA143701) to ZS. Chen, and Wu Jieping Medical Foundation (No: 320.6750.1297) to H. Guo. NR 54 TC 2 Z9 2 U1 0 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 NOV 17 PY 2015 VL 6 IS 36 BP 39276 EP 39291 PG 16 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CY0RS UT WOS:000366114000064 PM 26515463 ER PT J AU Lenardo, MJ Staudt, LM AF Lenardo, Michael J. Staudt, Louis M. TI Bill Paul: The heart of immunology SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material C1 [Lenardo, Michael J.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Staudt, Louis M.] NCI, Lymphoid Malignancies Branch, Nihon Univ, Bethesda, MD 20892 USA. RP Lenardo, MJ (reprint author), NIAID, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM lenardo@nih.gov NR 1 TC 0 Z9 0 U1 0 U2 0 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 NOV 17 PY 2015 VL 112 IS 46 BP 14117 EP 14118 DI 10.1073/pnas.1519815112 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CW7IA UT WOS:000365170400027 PM 26578754 ER PT J AU Cossio, P Hummer, G Szabo, A AF Cossio, Pilar Hummer, Gerhard Szabo, Attila TI On artifacts in single-molecule force spectroscopy SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE anisotropic diffusion; free energy surface; pulling device; unfolding rate ID PULLING EXPERIMENTS; FOLDING KINETICS; ADHESION BONDS; RNA HAIRPINS; DYNAMICS; BIOPOLYMERS; LANDSCAPES; COLLAPSE AB In typical force spectroscopy experiments, a small biomolecule is attached to a soft polymer linker that is pulled with a relatively large bead or cantilever. At constant force, the total extension stochastically changes between two (or more) values, indicating that the biomolecule undergoes transitions between two (or several) conformational states. In this paper, we consider the influence of the dynamics of the linker and mesoscopic pulling device on the force-dependent rate of the conformational transition extracted from the time dependence of the total extension, and the distribution of rupture forces in force-clamp and force-ramp experiments, respectively. For these different experiments, we derive analytic expressions for the observables that account for the mechanical response and dynamics of the pulling device and linker. Possible artifacts arise when the characteristic times of the pulling device and linker become comparable to, or slower than, the lifetimes of the metastable conformational states, and when the highly anharmonic regime of stretched linkers is probed at high forces. We also revisit the problem of relating force-clamp and force-ramp experiments, and identify a linker and loading rate-dependent correction to the rates extracted from the latter. The theory provides a framework for both the design and the quantitative analysis of force spectroscopy experiments by highlighting, and correcting for, factors that complicate their interpretation. C1 [Cossio, Pilar; Hummer, Gerhard] Max Planck Inst Biophys, Dept Theoret Biophys, D-60438 Frankfurt, Germany. [Szabo, Attila] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Cossio, P (reprint author), Max Planck Inst Biophys, Dept Theoret Biophys, D-60438 Frankfurt, Germany. EM pilar.cossio@biophys.mpg.de; gerhard.hummer@biophys.mpg.de; attilas@nih.gov RI Hummer, Gerhard/A-2546-2013; Szabo, Attila/H-3867-2012 OI Hummer, Gerhard/0000-0001-7768-746X; FU Max Planck Society; National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health FX P.C. and G.H. were supported by the Max Planck Society. A.S. was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. NR 40 TC 10 Z9 10 U1 5 U2 48 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 NOV 17 PY 2015 VL 112 IS 46 BP 14248 EP 14253 DI 10.1073/pnas.1519633112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CW7IA UT WOS:000365170400053 PM 26540730 ER PT J AU Vitre, B Holland, AJ Kulukian, A Shoshani, O Hirai, M Wang, Y Maldonado, M Cho, T Boubaker, J Swing, DA Tessarollo, L Evans, SM Fuchs, E Cleveland, DW AF Vitre, Benjamin Holland, Andrew J. Kulukian, Anita Shoshani, Ofer Hirai, Maretoshi Wang, Yin Maldonado, Marcus Cho, Thomas Boubaker, Jihane Swing, Deborah A. Tessarollo, Lino Evans, Sylvia M. Fuchs, Elaine Cleveland, Don W. TI Chronic centrosome amplification without tumorigenesis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE centrosome amplification; tumorigenesis; p53; Plk4 kinase ID CHROMOSOMAL INSTABILITY; CENTRIOLE DUPLICATION; GENOME INSTABILITY; EXTRA CENTROSOMES; MOUSE SKIN; KINASE 4; CELLS; MICE; P53; ANEUPLOIDY AB Centrosomes are microtubule-organizing centers that facilitate bipolar mitotic spindle assembly and chromosome segregation. Recognizing that centrosome amplification is a common feature of aneuploid cancer cells, we tested whether supernumerary centrosomes are sufficient to drive tumor development. To do this, we constructed and analyzed mice in which centrosome amplification can be induced by a Cre-recombinase-mediated increase in expression of Polo-like kinase 4 (Plk4). Elevated Plk4 in mouse fibroblasts produced supernumerary centrosomes and enhanced the expected mitotic errors, but proliferation continued only after inactivation of the p53 tumor suppressor. Increasing Plk4 levels in mice with functional p53 produced centrosome amplification in liver and skin, but this did not promote spontaneous tumor development in these tissues or enhance the growth of chemically induced skin tumors. In the absence of p53, Plk4 overexpression generated widespread centrosome amplification, but did not drive additional tumors or affect development of the fatal thymic lymphomas that arise in animals lacking p53. We conclude that, independent of p53 status, supernumerary centrosomes are not sufficient to drive tumor formation. C1 [Vitre, Benjamin; Holland, Andrew J.; Shoshani, Ofer; Wang, Yin; Maldonado, Marcus; Cho, Thomas; Boubaker, Jihane; Cleveland, Don W.] Ludwig Inst Canc Res, San Diego Branch, La Jolla, CA 92093 USA. [Kulukian, Anita; Fuchs, Elaine] Rockefeller Univ, Howard Hughes Med Inst, Lab Mammalian Cell Biol & Dev, New York, NY 10065 USA. [Hirai, Maretoshi; Evans, Sylvia M.] Univ Calif San Diego, Skaggs Sch Pharm, La Jolla, CA 92093 USA. [Swing, Deborah A.; Tessarollo, Lino] NCI, Mouse Canc Genet Program, Frederick, MD 21702 USA. [Cleveland, Don W.] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA. RP Cleveland, DW (reprint author), Ludwig Inst Canc Res, San Diego Branch, La Jolla, CA 92093 USA. EM dcleveland@ucsd.edu OI Vitre, Benjamin/0000-0001-5954-4270 FU Human Frontier Science Program Long-Term Fellowship [LT000855/2010]; Leukemia Lymphoma Society; Jane Coffins Child postdoctoral fellowship; National Institutes of Health (NIH) [GM29513, GM114119]; NIH [R37-AR27883, DP1HL117649] FX We thank Dr. Nissi Varki (University of California at San Diego Pathology Core) for histology sample preparation and analysis, and Melissa McAlonis-Downes (Ludwig Institute for Cancer Research) for valuable assistance in the management of the Cleveland laboratory mouse colony. We also thank N. Stokes, A. Aldeguer, and S. Hacker for valuable assistance with the DMBA/TPA treatments. B.V. was supported by a Human Frontier Science Program Long-Term Fellowship (LT000855/2010). A.J.H. was supported by a Leukemia Lymphoma Society Special Fellowship. A.K. was funded by a Jane Coffins Child postdoctoral fellowship. This work was supported by National Institutes of Health (NIH) Grants GM29513 (to D.W.C.) and GM114119 (to A.J.H), a Method to Extend Research in Time (MERIT) Award R37-AR27883 (to E.F.), and Grant DP1HL117649 from the NIH (to S.M.E.). NR 48 TC 10 Z9 10 U1 4 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 NOV 17 PY 2015 VL 112 IS 46 BP E6321 EP E6330 DI 10.1073/pnas.1519388112 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CW7IA UT WOS:000365170400011 PM 26578792 ER PT J AU Fitzhugh, CD Hsieh, MM Allen, D Coles, WA Seamon, C Ring, M Zhao, XC Minniti, CP Rodgers, GP Schechter, AN Tisdale, JF Taylor, JG AF Fitzhugh, Courtney D. Hsieh, Matthew M. Allen, Darlene Coles, Wynona A. Seamon, Cassie Ring, Michael Zhao, Xiongce Minniti, Caterina P. Rodgers, Griffin P. Schechter, Alan N. Tisdale, John F. Taylor, James G. TI Hydroxyurea-Increased Fetal Hemoglobin Is Associated with Less Organ Damage and Longer Survival in Adults with Sickle Cell Anemia SO PLOS ONE LA English DT Article ID PULMONARY-HYPERTENSION; DISEASE; MORTALITY; CHILDREN; DEATH; THERAPY; RISK; HYDROXYCARBAMIDE; COMPLICATIONS; MORBIDITY AB Background Adults with sickle cell anemia (HbSS) are inconsistently treated with hydroxyurea. Objectives We retrospectively evaluated the effects of elevating fetal hemoglobin with hydroxyurea on organ damage and survival in patients enrolled in our screening study between 2001 and 2010. Methods An electronic medical record facilitated development of a database for comparison of study parameters based on hydroxyurea exposure and dose. This study is registered with ClinicalTrials.gov, number NCT00011648. Results Three hundred eighty-three adults with homozygous sickle cell disease were analyzed with 59 deaths during study follow-up. Cox regression analysis revealed deceased subjects had more hepatic dysfunction (elevated alkaline phosphatase, Hazard Ratio = 1.005, 95% CI 1.003-1.006, p<0.0.0001), kidney dysfunction (elevated creatinine, Hazard Ratio = 1.13, 95% CI 1.00-1.27, p = 0.043), and cardiopulmonary dysfunction (elevated tricuspid jet velocity on echocardiogram, Hazard Ratio = 2.22, 1.23-4.02, p = 0.0082). Sixty-six percent of subjects were treated with hydroxyurea, although only 66% of those received a dose within the recommended therapeutic range. Hydroxyurea use was associated with improved survival (Hazard Ratio = 0.58, 95% CI 0.34-0.97, p = 0.040). This effect was most pronounced in those taking the recommended dose of 15-35 mg/kg/day (Hazard Ratio 0.36, 95% CI 0.17-0.73, p = 0.0050). Hydroxyurea use was not associated with changes in organ function over time. Further, subjects with higher fetal hemoglobin responses to hydroxyurea were more likely to survive (p = 0.0004). While alkaline phosphatase was lowest in patients with the best fetal hemoglobin response (95.4 versus 123.6, p = 0.0065 and 96.1 versus 113.6U/L, p = 0.041 at first and last visits, respectively), other markers of organ damage were not consistently improved over time in patients with the highest fetal hemoglobin levels. Conclusions Our data suggest that adults should be treated with the maximum tolerated hydroxyurea dose, ideally before organ damage occurs. Prospective studies are indicated to validate these findings. C1 [Fitzhugh, Courtney D.; Hsieh, Matthew M.; Coles, Wynona A.; Rodgers, Griffin P.; Tisdale, John F.] NHLBI, Mol & Clin Hematol Branch, NIDDK, NIH, Bethesda, MD 20892 USA. [Fitzhugh, Courtney D.; Allen, Darlene; Seamon, Cassie; Minniti, Caterina P.; Taylor, James G.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Ring, Michael] NIDDK, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Zhao, Xiongce] NIDDK, Intramural Res, NIH, Bethesda, MD 20892 USA. [Schechter, Alan N.] NIDDK, Mol Med Branch, NIH, Bethesda, MD 20892 USA. RP Taylor, JG (reprint author), NHLBI, Mol & Clin Hematol Branch, NIDDK, NIH, Bldg 10, Bethesda, MD 20892 USA. EM jamesta@mail.nih.gov OI Taylor, James/0000-0002-4421-1809 FU intramural programs of the Molecular and Clinical Hematology Branch, NHLBI; NIDDK, NIH; Hematology Branch, NHLBI, NIH [1ZIAHL006012-04] FX This research was funded by the intramural programs of the Molecular and Clinical Hematology Branch, NHLBI and NIDDK, NIH and the Hematology Branch, NHLBI, NIH (1ZIAHL006012-04). NR 31 TC 2 Z9 2 U1 1 U2 6 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 NOV 17 PY 2015 VL 10 IS 11 AR e0141706 DI 10.1371/journal.pone.0141706 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CW7BR UT WOS:000365153400007 PM 26576059 ER PT J AU Louis, JM Baber, JL Clore, GM AF Louis, John M. Baber, James L. Clore, G. Marius TI The C34 Peptide Fusion Inhibitor Binds to the Six-Helix Bundle Core Domain of HIV-1 gp41 by Displacement of the C-Terminal Helical Repeat Region SO BIOCHEMISTRY LA English DT Article ID ELECTRON-ELECTRON RESONANCE; HUMAN MONOCLONAL-ANTIBODY; MEDIATED CELL-FUSION; TRIMERIC COILED-COIL; VIRUS TYPE-1 ENTRY; MEMBRANE-FUSION; NEUTRALIZING ANTIBODIES; ENVELOPE GLYCOPROTEIN; PHAGE LIBRARY; POTENT INHIBITORS AB The conformational transition of the core domain of HIV-1 gp41 from a prehairpin intermediate to a six-helix bundle is responsible for virus-cell fusion. Several inhibitors which target the N-heptad repeat helical coiled-coil trimer that is fully accessible in the prehairpin intermediate have been designed. One such inhibitor is the peptide C34 derived from the C-heptad repeat of gp41 that forms the exterior of the six-helix bundle. Here, using a variety of biophysical techniques, including dye tagging, size-exclusion chromatography combined with multiangle light scattering, double electron-electron resonance EPR spectroscopy, and circular dichroism, we investigate the binding of C34 to two six-helix bundle mimetics comprising N- and C-heptad repeats either without (core(SP)) or with (core(SP)) a short spacer connecting the two. In the case of core(SP), C34 directly exchanges with the C-heptad repeat. For cores, up to two molecules of C34 bind the six-helix bundle via displacement of the C-heptad repeat. These results suggest that fusion inhibitors such as C34 can target a continuum of transitioning conformational states from the prehairpin intermediate to the six-helix bundle prior to the occurrence of irreversible fusion of viral and target cell membranes. C1 [Louis, John M.; Baber, James L.; Clore, G. Marius] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Louis, JM (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM johnl@niddk.nih.gov; mariusc@mail.nih.gov FU Intramural Research Program of National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; Intramural AIDS-Targeted Program of Office of the Director, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, and the Intramural AIDS-Targeted Program of the Office of the Director, National Institutes of Health (to G.M.C.). NR 66 TC 1 Z9 1 U1 3 U2 13 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD NOV 17 PY 2015 VL 54 IS 45 BP 6796 EP 6805 DI 10.1021/acs.biochem.5b01021 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CW7AP UT WOS:000365150600006 PM 26506247 ER PT J AU Yu, X Geer, LY Han, LY Bryant, SH AF Yu, Xiang Geer, Lewis Y. Han, Lianyi Bryant, Stephen H. TI Target enhanced 2D similarity search by using explicit biological activity annotations and profiles SO JOURNAL OF CHEMINFORMATICS LA English DT Article DE 2D similarity search; Iterative similarity search; Nearest neighbor; Iterative similarity search with classification; Profile ID CHEMICAL SIMILARITY; DATA FUSION; PSI-BLAST; DATA SETS; FINGERPRINT; COMPOUND; DATABASE; COEFFICIENTS; MOLECULES; METRICS AB Background: The enriched biological activity information of compounds in large and freely-accessible chemical databases like the PubChem Bioassay Database has become a powerful research resource for the scientific research community. Currently, 2D fingerprint based conventional similarity search (CSS) is the most common widely used approach for database screening, but it does not typically incorporate the relative importance of fingerprint bits to biological activity. Results: In this study, a large-scale similarity search investigation has been carried out on 208 well-defined compound activity classes extracted from PubChem Bioassay Database. An analysis was performed to compare the search performance of three types of 2D similarity search approaches: 2D fingerprint based conventional similarity search approach (CSS), iterative similarity search approach with multiple active compounds as references (ISS), and fingerprint based iterative similarity search with classification (ISC), which can be regarded as the combination of iterative similarity search with active references and a reversed iterative similarity search with inactive references. Compared to the search results returned by CSS, ISS improves recall but not precision. Although ISC causes the false rejection of active hits, it improves the precision with statistical significance, and outperforms both ISS and CSS. In a second part of this study, we introduce the profile concept into the three types of searches. We find that the profile based non-iterative search can significantly improve the search performance by increasing the recall rate. We also find that profile based ISS (PBISS) and profile based ISC (PBISC) significantly decreases ISS search time without sacrificing search performance. Conclusions: On the basis of our large-scale investigation directed against a wide spectrum of pharmaceutical targets, we conclude that ISC and ISS searches perform better than 2D fingerprint similarity searching and that profile based versions of these algorithms do nearly as well in less time. We also suggest that the profile version of the iterative similarity searches are both better performing and potentially quicker than the standard algorithm. C1 [Yu, Xiang; Geer, Lewis Y.; Han, Lianyi; Bryant, Stephen H.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Geer, LY (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM lewisg@ncbi.nlm.nih.gov FU Intramural Research Program of the NIH, National Library of Medicine FX This research was supported by the Intramural Research Program of the NIH, National Library of Medicine. We also thank Dr. Yanli Wang for her guide to correctly select high-quality bioassay data from PubChem Bioassay Database. NR 40 TC 5 Z9 5 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1758-2946 J9 J CHEMINFORMATICS JI J. Cheminformatics PD NOV 17 PY 2015 VL 7 AR 55 DI 10.1186/s13321-015-0103-5 PG 12 WC Chemistry, Multidisciplinary; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications SC Chemistry; Computer Science GA CW3SF UT WOS:000364911400001 PM 26583046 ER PT J AU Hogan, MC Lieske, JC Lienczewski, CC Nesbitt, LL Wickman, LT Heyer, CM Harris, PC Ward, CJ Sundsbak, JL Manganelli, L Ju, WJ Kopp, JB Nelson, PJ Adler, SG Reich, HN Holzmann, LB Kretzler, M Bitzer, M AF Hogan, Marie C. Lieske, John C. Lienczewski, Chrysta C. Nesbitt, Lisa L. Wickman, Larysa T. Heyer, Christina M. Harris, Peter C. Ward, Christopher J. Sundsbak, Jamie L. Manganelli, Luca Ju, Wenjun Kopp, Jeffrey B. Nelson, Peter J. Adler, Sharon G. Reich, Heather N. Holzmann, Lawrence B. Kretzler, Matthias Bitzer, Markus TI Strategy and rationale for urine collection protocols employed in the NEPTUNE study SO BMC NEPHROLOGY LA English DT Article DE Exosome; Urinalysis; Urine specimen collection ID GELATINASE-ASSOCIATED LIPOCALIN; FOCAL SEGMENTAL GLOMERULOSCLEROSIS; RETINOL-BINDING-PROTEIN; GLOMERULAR-DISEASE; NEPHROTIC SYNDROME; PROTEOMIC ANALYSIS; KIDNEY-DISEASE; EXOSOMES; INJURY; PODOCALYXIN AB Background: Glomerular diseases are potentially fatal, requiring aggressive interventions and close monitoring. Urine is a readily-accessible body fluid enriched in molecular signatures from the kidney and therefore particularly suited for routine clinical analysis as well as development of non-invasive biomarkers for glomerular diseases. Methods: The Nephrotic Syndrome Study Network (NEPTUNE; ClinicalTrials.gov Identifier NCT01209000) is a North American multicenter collaborative consortium established to develop a translational research infrastructure for nephrotic syndrome. This includes standardized urine collections across all participating centers for the purpose of discovering non-invasive biomarkers for patients with nephrotic syndrome due to minimal change disease, focal segmental glomerulosclerosis, and membranous nephropathy. Here we describe the organization and methods of urine procurement and banking procedures in NEPTUNE. Results: We discuss the rationale for urine collection and storage conditions, and demonstrate the performance of three experimental analytes (neutrophil gelatinase-associated lipocalin [NGAL], retinol binding globulin, and alpha-1 microglobulin) under these conditions with and without urine preservatives (thymol, toluene, and boric acid). We also demonstrate the quality of RNA and protein collected from the urine cellular pellet and exosomes. Conclusions: The urine collection protocol in NEPTUNE allows robust detection of a wide range of proteins and RNAs from urine supernatant and pellets collected longitudinally from each patient over 5 years. Combined with the detailed clinical and histopathologic data, this provides a unique resource for exploration and validation of new or accepted markers of glomerular diseases. C1 [Hogan, Marie C.; Lieske, John C.] Mayo Clin, Div Nephrol & Hypertens, Dept Med, Rochester, MN 55905 USA. [Lienczewski, Chrysta C.; Ju, Wenjun; Kretzler, Matthias; Bitzer, Markus] Univ Michigan Hlth Syst, Dept Internal Med Nephrol, Ann Arbor, MI USA. [Nesbitt, Lisa L.] Mayo Clin, Cardiovasc Res, Rochester, MN 55905 USA. [Wickman, Larysa T.] Univ Michigan, Pediat Nephrol, Ann Arbor, MI 48109 USA. [Heyer, Christina M.; Harris, Peter C.; Sundsbak, Jamie L.] Mayo Clin, Nephrol & Hypertens Res, Rochester, MN 55905 USA. [Ward, Christopher J.] Univ Kansas, Med Ctr, Dept Internal Med, Div Nephrol & Hypertens, Kansas City, KS 66103 USA. [Manganelli, Luca] Novartis Pharma AG, Oncol, Basel, Switzerland. [Kopp, Jeffrey B.] NIDDK, Kidney Dis Branch, NIH, Bethesda, MD 20892 USA. [Nelson, Peter J.] Univ Washington, Div Nephrol, Seattle, WA 98195 USA. [Nelson, Peter J.] Univ Washington, Kidney Res Inst, Seattle, WA 98195 USA. [Adler, Sharon G.] Harbor UCLA Med Ctr, Div Nephrol & Hypertens, Torrance, CA 90509 USA. [Reich, Heather N.] Univ Hlth Network, Dept Med, Toronto, ON, Canada. [Reich, Heather N.] Univ Toronto, Toronto, ON, Canada. [Holzmann, Lawrence B.] Univ Penn, Perelman Sch Med, Renal Elect & Hypertens Div, Philadelphia, PA USA. RP Hogan, MC (reprint author), Mayo Clin, Div Nephrol & Hypertens, Dept Med, 200 First St SW, Rochester, MN 55905 USA. EM hogan.marie@mayo.edu FU NEPTUNE study grants from the NIH Office of Rare Diseases [U54 DK083912]; O'Brien Kidney Center Grant [P30 DK081943]; NephCure; NCI; NIDDK; University of Michigan FX This work was supported by NEPTUNE study grants from the NIH Office of Rare Diseases, U54 DK083912; O'Brien Kidney Center Grant, P30 DK081943; NephCure; and by the Intramural Research programs of the NCI and NIDDK and The University of Michigan. NR 47 TC 2 Z9 2 U1 3 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2369 J9 BMC NEPHROL JI BMC Nephrol. PD NOV 17 PY 2015 VL 16 AR 190 DI 10.1186/s12882-015-0185-3 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA CW2ES UT WOS:000364804500001 PM 26577187 ER PT J AU Pursnani, A Massaro, JM Hoffmann, U AF Pursnani, Amit Massaro, Joseph M. Hoffmann, Udo TI Predicted vs Observed Clinical Event Risk for Cardiovascular Disease Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID CORONARY-ARTERY-DISEASE; OUTCOMES C1 [Pursnani, Amit] NorthShore Univ Hlth Syst, Div Cardiol, Evanston, IL USA. [Massaro, Joseph M.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Boston, MA 02114 USA. RP Hoffmann, U (reprint author), Massachusetts Gen Hosp, Cardiac MR PET CT Program, 100 Charles River Plaza, Boston, MA 02114 USA. EM uhoffmann@mgh.harvard.edu NR 4 TC 0 Z9 0 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 NOV 17 PY 2015 VL 314 IS 19 BP 2080 EP 2081 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA CW1PR UT WOS:000364764200028 ER PT J AU Ferrer, RA Taber, JM Klein, WMP Harris, PR Lewis, KL Biesecker, LG AF Ferrer, Rebecca A. Taber, Jennifer M. Klein, William M. P. Harris, Peter R. Lewis, Katie L. Biesecker, Leslie G. TI The role of current affect, anticipated affect and spontaneous self-affirmation in decisions to receive self-threatening genetic risk information SO COGNITION & EMOTION LA English DT Article DE Anticipated affect; Current affect; Self-affirmation; Defensiveness; Information seeking; Information avoidance ID HEALTH; AVOIDANCE; EMOTIONS; BEHAVIOR; ANXIETY; FAMILY AB One reason for not seeking personally threatening information may be negative current and anticipated affective responses. We examined whether current (e.g., worry) and anticipated negative affect predicted intentions to seek sequencing results in the context of an actual genomic sequencing trial (ClinSeq (R); n = 545) and whether spontaneous self-affirmation mitigated any (negative) association between affect and intentions. Anticipated affective response negatively predicted intentions to obtain and share results pertaining to both medically actionable and non-actionable disease, whereas current affect was only a marginal predictor. The negative association between anticipated affect and intentions to obtain results pertaining to non-actionable disease was weaker in individuals who were higher in spontaneous self-affirmation. These results have implications for the understanding of current and anticipated affect, self-affirmation and consequential decision-making and contribute to a growing body of evidence on the role of affect in medical decisions. C1 [Ferrer, Rebecca A.; Taber, Jennifer M.; Klein, William M. P.] NCI, Behav Res Program, NIH, Bethesda, MD 20892 USA. [Harris, Peter R.] Univ Sussex, Sch Psychol, Sussex, England. [Lewis, Katie L.; Biesecker, Leslie G.] NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA. RP Ferrer, RA (reprint author), NCI, Behav Res Program, NIH, Bethesda, MD 20892 USA. EM ferrerra@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 27 TC 6 Z9 6 U1 0 U2 14 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0269-9931 EI 1464-0600 J9 COGNITION EMOTION JI Cogn. Emot. PD NOV 17 PY 2015 VL 29 IS 8 BP 1456 EP 1465 DI 10.1080/02699931.2014.985188 PG 10 WC Psychology, Experimental SC Psychology GA CS5NN UT WOS:000362125100009 PM 25482843 ER PT J AU Evans, JS Stevens, MH Lumpe, JD Schneider, NM Stewart, AIF Deighan, J Jain, SK Chaffin, MS Crismani, M Stiepen, A McClintock, WE Holsclaw, GM Lefevre, F Lo, DY Clarke, JT Eparvier, FG Thiemann, EMB Chamberlin, PC Bougher, SW Bell, JM Jakosky, BM AF Evans, J. S. Stevens, M. H. Lumpe, J. D. Schneider, N. M. Stewart, A. I. F. Deighan, J. Jain, S. K. Chaffin, M. S. Crismani, M. Stiepen, A. McClintock, W. E. Holsclaw, G. M. Lefevre, F. Lo, D. Y. Clarke, J. T. Eparvier, F. G. Thiemann, E. M. B. Chamberlin, P. C. Bougher, S. W. Bell, J. M. Jakosky, B. M. TI Retrieval of CO2 and N-2 in the Martian thermosphere using dayglow observations by IUVS on MAVEN SO GEOPHYSICAL RESEARCH LETTERS LA English DT Article ID ULTRAVIOLET SPECTROMETER EXPERIMENT; TITANS UPPER-ATMOSPHERE; MARS UPPER-ATMOSPHERE; CROSS-SECTIONS; ERROR ANALYSIS; ATOMIC OXYGEN; MARINER 6; EMISSIONS; AIRGLOW; IMPACT AB We present direct number density retrievals of carbon dioxide (CO2) and molecular nitrogen (N-2) for the upper atmosphere of Mars using limb scan observations during October and November 2014 by the Imaging Ultraviolet Spectrograph on board NASA's Mars Atmosphere and Volatile EvolutioN (MAVEN) spacecraft. We use retrieved CO2 densities to derive temperature variability between 170 and 220 km. Analysis of the data shows (1) low-mid latitude northern hemisphere CO2 densities at 170km vary by a factor of about 2.5, (2) on average, the N-2/CO2 increases from 0.042 +/- 0.017 at 130 km to 0.12 +/- 0.06 at 200 km, and (3) the mean upper atmospheric temperature is 324 +/- 22 K for local times near 14:00. C1 [Evans, J. S.; Lumpe, J. D.] Computat Phys Inc, Springfield, VA 22151 USA. [Stevens, M. H.] Naval Res Lab, Washington, DC 20375 USA. [Schneider, N. M.; Stewart, A. I. F.; Deighan, J.; Jain, S. K.; Chaffin, M. S.; Crismani, M.; Stiepen, A.; McClintock, W. E.; Holsclaw, G. M.; Eparvier, F. G.; Thiemann, E. M. B.; Jakosky, B. M.] Univ Colorado, Lab Atmospher & Space Phys, Boulder, CO 80309 USA. [Lefevre, F.] CNRS, LATMOS, Paris, France. [Lo, D. Y.] Univ Arizona, Lunar & Planetary Lab, Tucson, AZ 85721 USA. [Clarke, J. T.] Boston Univ, Ctr Space Phys, Boston, MA 02215 USA. [Chamberlin, P. C.] NASA, Goddard Space Flight Ctr, Greenbelt, MD 20771 USA. [Bougher, S. W.] Univ Michigan, Dept Atmospher Ocean & Space Sci, Ann Arbor, MI 48109 USA. [Bell, J. M.] NIA, Hampton, VA USA. RP Evans, JS (reprint author), Computat Phys Inc, Springfield, VA 22151 USA. EM evans@cpi.com RI Chamberlin, Phillip/C-9531-2012; Clarke, John/C-8644-2013; Crismani, Matteo/H-3791-2016; OI Chamberlin, Phillip/0000-0003-4372-7405; Crismani, Matteo/0000-0003-3127-2466; SCHNEIDER, NICHOLAS/0000-0001-6720-5519 FU NASA; University of Colorado Laboratory for Atmospheric and Space Physics; Belgian American Educational Foundation; Rotary District FX The MAVEN project is supported by NASA through the Mars Exploration Program. J.S.E. acknowledges support from the University of Colorado Laboratory for Atmospheric and Space Physics and thanks John Correira for his assistance in generating figures for this paper. M.H.S. was supported by the NASA MAVEN Participating Scientist program. A. Stiepen is supported by the Belgian American Educational Foundation and the Rotary District 1630. The IUVS processing pipeline automatically generates level 2 retrieval data products, which are stored at the Planetary Atmospheres Node of the Planetary Data System (http://atmos.nmsu.edu/data_and_services/atmospheres_data/MAVEN/maven_iu vs.html). Data files can be identified by file names with the orbit numbers given, the word "periapse," and the identifier v03_r01. Data release v03_r01 includes CO2 and N2 density profiles and upper atmosphere temperatures. Later releases will include additional species and derived quantities. NR 68 TC 6 Z9 6 U1 0 U2 5 PU AMER GEOPHYSICAL UNION PI WASHINGTON PA 2000 FLORIDA AVE NW, WASHINGTON, DC 20009 USA SN 0094-8276 EI 1944-8007 J9 GEOPHYS RES LETT JI Geophys. Res. Lett. PD NOV 16 PY 2015 VL 42 IS 21 BP 9040 EP 9049 DI 10.1002/2015GL065489 PG 10 WC Geosciences, Multidisciplinary SC Geology GA DB2KK UT WOS:000368336800031 ER PT J AU Omilusik, KD Best, JA Yu, BF Goossens, S Weidemann, A Nguyen, JV Seuntjens, E Stryjewska, A Zweier, C Roychoudhuri, R Gattinoni, L Bird, LM Higashi, Y Kondoh, H Huylebroeck, D Haigh, J Goldrath, AW AF Omilusik, Kyla D. Best, J. Adam Yu, Bingfei Goossens, Steven Weidemann, Alexander Nguyen, Jessica V. Seuntjens, Eve Stryjewska, Agata Zweier, Christiane Roychoudhuri, Rahul Gattinoni, Luca Bird, Lynne M. Higashi, Yujiro Kondoh, Hisato Huylebroeck, Danny Haigh, Jody Goldrath, Ananda W. TI Transcriptional repressor ZEB2 promotes terminal differentiation of CD8(+) effector and memory T cell populations during infection SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID MENTAL RETARDATION SYNDROME; MOWAT-WILSON-SYNDROME; IL-7 RECEPTOR-ALPHA; LOOP-HELIX PROTEINS; HIRSCHSPRUNG-DISEASE; LYMPHOCYTE DEVELOPMENT; VIRAL-INFECTION; GENE-EXPRESSION; FATE DECISIONS; SMAD PROTEINS AB ZEB2 is a multi-zinc-finger transcription factor known to play a significant role in early neurogenesis and in epithelial-mesenchymal transition-dependent tumor metastasis. Although the function of ZEB2 in T lymphocytes is unknown, activity of the closely related family member ZEB1 has been implicated in lymphocyte development. Here, we find that ZEB2 expression is up-regulated by activated T cells, specifically in the KLRG1(hi) effector CD8(+) T cell subset. Loss of ZEB2 expression results in a significant loss of antigen-specific CD8(+) T cells after primary and secondary infection with a severe impairment in the generation of the KLRG1(hi) effector memory cell population. We show that ZEB2, which can bind DNA at tandem, consensus E-box sites, regulates gene expression of several E-protein targets and may directly repress Il7r and Il2 in CD8(+) T cells responding to infection. Furthermore, we find that T-bet binds to highly conserved T-box sites in the Zeb2 gene and that T-bet and ZEB2 regulate similar gene expression programs in effector T cells, suggesting that T-bet acts upstream and through regulation of ZEB2. Collectively, we place ZEB2 in a larger transcriptional network that is responsible for the balance between terminal differentiation and formation of memory CD8(+) T cells. C1 [Omilusik, Kyla D.; Best, J. Adam; Yu, Bingfei; Nguyen, Jessica V.; Goldrath, Ananda W.] Univ Calif San Diego, Rady Childrens Hosp San Diego, Div Biol Sci, La Jolla, CA 92093 USA. [Bird, Lynne M.] Univ Calif San Diego, Rady Childrens Hosp San Diego, Dept Pediat, La Jolla, CA 92093 USA. [Goossens, Steven; Haigh, Jody] Monash Univ, Australian Ctr Blood Dis, Div Blood Cancers, Mammalian Funct Genet Lab, Melbourne, Vic 3004, Australia. [Goossens, Steven] Univ Ghent, VIB Inflammat Res Ctr, B-9052 Ghent, Belgium. [Goossens, Steven] Univ Ghent, Dept Biomed Mol Biol, B-9052 Ghent, Belgium. [Weidemann, Alexander] Univ Erlangen Nurnberg, Dept Nephrol & Hypertens, Univ Klinikum Erlangen, D-91054 Erlangen, Germany. [Zweier, Christiane] Univ Erlangen Nurnberg, Univ Klinikum Erlangen, Inst Human Genet, D-91054 Erlangen, Germany. [Seuntjens, Eve; Stryjewska, Agata; Huylebroeck, Danny] Katholieke Univ Leuven, Dept Dev & Regenerat, Lab Mol Biol Celgen, B-3000 Leuven, Belgium. [Roychoudhuri, Rahul] NCI, Surg Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Gattinoni, Luca] NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Higashi, Yujiro] Aichi Human Serv Ctr, Dept Perinatol, Inst Dev Res, Kasugai, Aichi 4800392, Japan. [Kondoh, Hisato] Kyoto Sangyo Univ, Fac Life Sci, Kita Ku, Kyoto 6038555, Japan. [Huylebroeck, Danny] Erasmus MC, Dept Cell Biol, NL-3015 CN Rotterdam, Netherlands. RP Goldrath, AW (reprint author), Univ Calif San Diego, Rady Childrens Hosp San Diego, Div Biol Sci, La Jolla, CA 92093 USA. EM agoldrath@ucsd.edu RI Gattinoni, Luca/A-2281-2008; Zweier, Christiane/F-2202-2015; Roychoudhuri, Rahul/A-7442-2010; OI Gattinoni, Luca/0000-0003-2239-3282; Roychoudhuri, Rahul/0000-0002-5392-1853; Seuntjens, Eve/0000-0002-0126-461X; Huylebroeck, Danny/0000-0003-4862-1079 FU Leukemia and Lymphoma Society scholar award; Leukemia and Lymphoma Society fellow award; National Institutes of Health [AI067545]; KU Leuven [GOA-11/012]; Fund for Scientific Research-Flanders [FWO-V G.0954.11, G.0782.14]; Interuniversity Attraction Poles from the Belgian Science Policy Office [Belspo IUAP-VII-07]; InfraMouse Hercules Foundation [ZW09-03]; Erasmus MC FX This work was supported by a Leukemia and Lymphoma Society scholar award (to A.W. Goldrath), a Leukemia and Lymphoma Society fellow award (to K.D. Omilusik), and National Institutes of Health grant AI067545 (to A.W. Goldrath). The work of the DH-ES team was supported by KU Leuven (GOA-11/012), Fund for Scientific Research-Flanders (FWO-V G.0954.11 and G.0782.14), Interuniversity Attraction Poles from the Belgian Science Policy Office (Belspo IUAP-VII-07), InfraMouse Hercules Foundation (ZW09-03), and Erasmus MC. NR 56 TC 9 Z9 9 U1 1 U2 5 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD NOV 16 PY 2015 VL 212 IS 12 BP 2027 EP 2039 DI 10.1084/jem.20150194 PG 13 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA DB1DM UT WOS:000368248200008 PM 26503445 ER PT J AU Palmer, DC Guittard, GC Franco, Z Crompton, JG Eil, RL Patel, SJ Ji, Y Van Panhuys, N Klebanoff, CA Sukumar, M Clever, D Chichura, A Roychoudhuri, R Varma, R Wang, E Gattinoni, L Marincola, FM Balagopalan, L Samelson, LE Restifo, NP AF Palmer, Douglas C. Guittard, Geoffrey C. Franco, Zulmarie Crompton, Joseph G. Eil, Robert L. Patel, Shashank J. Ji, Yun Van Panhuys, Nicholas Klebanoff, Christopher A. Sukumar, Madhusudhanan Clever, David Chichura, Anna Roychoudhuri, Rahul Varma, Rajat Wang, Ena Gattinoni, Luca Marincola, Francesco M. Balagopalan, Lakshmi Samelson, Lawrence E. Restifo, Nicholas P. TI Cish actively silences TCR signaling in CD8(+) T cells to maintain tumor tolerance SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID GROWTH-HORMONE RECEPTOR; BLOOD MONONUCLEAR-CELLS; ADOPTIVE IMMUNOTHERAPY; VIRUS-INFECTION; SH2 DOMAIN; SOCS BOX; HOMEOSTATIC PROLIFERATION; INFILTRATING LYMPHOCYTES; SH2-CONTAINING PROTEIN; NEGATIVE REGULATION AB Improving the functional avidity of effector T cells is critical in overcoming inhibitory factors within the tumor microenvironment and eliciting tumor regression. We have found that Cish, a member of the suppressor of cytokine signaling ( SOCS) family, is induced by TCR stimulation in CD8(+) T cells and inhibits their functional avidity against tumors. Genetic deletion of Cish in CD8(+) T cells enhances their expansion, functional avidity, and cytokine polyfunctionality, resulting in pronounced and durable regression of established tumors. Although Cish is commonly thought to block STAT5 activation, we found that the primary molecular basis of Cish suppression is through inhibition of TCR signaling. Cish physically interacts with the TCR intermediate PLC-gamma 1, targeting it for proteasomal degradation after TCR stimulation. These findings establish a novel targetable interaction that regulates the functional avidity of tumor-specific CD8(+) T cells and can be manipulated to improve adoptive cancer immunotherapy. C1 [Palmer, Douglas C.; Guittard, Geoffrey C.; Franco, Zulmarie; Crompton, Joseph G.; Eil, Robert L.; Patel, Shashank J.; Ji, Yun; Klebanoff, Christopher A.; Sukumar, Madhusudhanan; Clever, David; Chichura, Anna; Roychoudhuri, Rahul; Gattinoni, Luca; Balagopalan, Lakshmi; Samelson, Lawrence E.; Restifo, Nicholas P.] NCI, Bethesda, MD 20892 USA. [Van Panhuys, Nicholas; Varma, Rajat] NIAID, Bethesda, MD 20892 USA. [Clever, David] Ohio State Univ, Coll Med, Med Scientist Training Program, Columbus, OH 43210 USA. [Wang, Ena; Marincola, Francesco M.] Sidra Med & Res Ctr, Doha, Qatar. RP Palmer, DC (reprint author), NCI, Bethesda, MD 20892 USA. EM palmerd@mail.nih.gov; restifo@nih.gov RI Gattinoni, Luca/A-2281-2008; van Panhuys, Nicholas/E-1812-2011; Ji, Yun/B-7245-2009; Roychoudhuri, Rahul/A-7442-2010; OI Gattinoni, Luca/0000-0003-2239-3282; Ji, Yun/0000-0001-6340-7009; Roychoudhuri, Rahul/0000-0002-5392-1853; van Panhuys, Nicholas/0000-0003-2199-852X FU Intramural Research Program of the National Cancer Institute, Center for Cancer Research of the US National Institutes of Health FX We thank A. Mixon and S. Farid of the Flow Cytometry Unit for help with flow cytometry analyses and sorting, Zhiya Yu and David Jones for technical animal support. We would like to thank Parthav Jailwala, Eric Stahlberg, and David Goldstein from the CCRIFX core (NCI) for expert microarray analysis. The microarray data are deposited at GEO (accession number: GSE56328, http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE56328). We also wish to thank Allen Bosley, Thorkel Andresson, Jim Ihle and Evan Parganas for significant material support. Megan Luckey and Jung-Hyun Park provided excellent discussions. Supported by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research of the US National Institutes of Health. NR 87 TC 10 Z9 10 U1 2 U2 7 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD NOV 16 PY 2015 VL 212 IS 12 BP 2095 EP 2113 DI 10.1084/jem.20150304 PG 19 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA DB1DM UT WOS:000368248200012 PM 26527801 ER PT J AU Chefer, S Thomasson, D Seidel, J Reba, RC Bohannon, JK Lackemeyer, MG Bartos, C Sayre, PJ Bollinger, L Hensley, LE Jahrling, PB Johnson, RF AF Chefer, Svetlana Thomasson, David Seidel, Jurgen Reba, Richard C. Bohannon, J. Kyle Lackemeyer, Mathew G. Bartos, Chris Sayre, Philip J. Bollinger, Laura Hensley, Lisa E. Jahrling, Peter B. Johnson, Reed F. TI Modeling [F-18]-FDG lymphoid tissue kinetics to characterize nonhuman primate immune response to Middle East respiratory syndrome-coronavirus aerosol challenge SO EJNMMI RESEARCH LA English DT Article DE [F-18]-FDG-PET; MERS-CoV; Animal models; Kinetic modeling ID RHESUS MACAQUES; EMISSION-TOMOGRAPHY; INFECTION; ALGORITHM; SCANNER; PET AB Background: The pathogenesis and immune response to Middle East respiratory syndrome (MERS) caused by a recently discovered coronavirus, MERS-CoV, have not been fully characterized because a suitable animal model is currently not available. F-18-Fluorodeoxyglucose ([F-18]-FDG)-positron emission tomography/computed tomography (PET/CT) as a longitudinal noninvasive approach can be beneficial in providing biomarkers for host immune response. [F-18]-FDG uptake is increased in activated immune cells in response to virus entry and can be localized by PET imaging. We used [F-18]-FDG-PET/CT to investigate the host response developing in nonhuman primates after MERS-CoV exposure and applied kinetic modeling to monitor the influx rate constant (K-i) in responsive lymphoid tissue. Methods: Multiple [F-18]-FDG-PET and CT images were acquired on a PET/CT clinical scanner modified to operate in a biosafety level 4 environment prior to and up to 29 days after MERS-CoV aerosol exposure. Time activity curves of various lymphoid tissues were reconstructed to follow the [F-18]-FDG uptake for approximately 60 min (3,600 s). Image-derived input function was used to calculate K-i for lymphoid tissues by Patlak plot. Results: Two-way repeated measures analysis of variance revealed alterations in K-i that was associated with the time point (p < 0.001) after virus exposure and the location of lymphoid tissue (p = 0.0004). As revealed by a statistically significant interaction (p < 0.0001) between these two factors, the pattern of K-i changes over time differed between three locations but not between subjects. A distinguished pattern of statistically significant elevation in K-i was observed in mediastinal lymph nodes (LNs) that correlated to K-i changes in axillary LNs. Changes in LNs K-i were concurrent with elevations of monocytes in peripheral blood. Conclusions: [F-18]-FDG-PET is able to detect subtle changes in host immune response to contain a subclinical virus infection. Full quantitative analysis is the preferred approach rather than semiquantitative analysis using standardized uptake value for detection of the immune response to the virus. C1 [Chefer, Svetlana; Thomasson, David; Seidel, Jurgen; Bohannon, J. Kyle; Lackemeyer, Mathew G.; Bartos, Chris; Sayre, Philip J.; Bollinger, Laura; Hensley, Lisa E.; Jahrling, Peter B.] NIAID, Integrated Res Facil, Div Clin Res, Frederick, MD 21702 USA. [Reba, Richard C.] NIH, Ctr Infect Dis Imaging Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Jahrling, Peter B.; Johnson, Reed F.] NIAID, Emerging Viral Pathogens Sect, Div Intramural Res, NIH, Frederick, MD USA. RP Chefer, S (reprint author), NIAID, Integrated Res Facil, Div Clin Res, Frederick, MD 21702 USA. EM schefer@mail.nih.gov FU NIAID; Division of Intramural Research (DIR); DCR; Battelle Memorial Institute's; US National Institute of Allergy and Infectious Diseases (NIAID) [HHSN272200700016I] FX This work was supported by NIAID, Division of Intramural Research (DIR), and DCR and was funded in part through Battelle Memorial Institute's prime contract with the US National Institute of Allergy and Infectious Diseases (NIAID) under Contract No. HHSN272200700016I. NR 24 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 2191-219X J9 EJNMMI RES JI EJNMMI Res. PD NOV 16 PY 2015 VL 5 AR 65 DI 10.1186/s13550-015-0143-x PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CW4LP UT WOS:000364963300001 PM 26573211 ER PT J AU Cugno, C Deola, S Filippini, P Stroncek, DF Rutella, S AF Cugno, Chiara Deola, Sara Filippini, Perla Stroncek, David F. Rutella, Sergio TI Granulocyte transfusions in children and adults with hematological malignancies: benefits and controversies SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Review DE Granulocyte transfusion; G-CSF; Dexamethasone; Hematopoietic stem cell transplantation; Febrile neutropenia; Infection ID COLONY-STIMULATING FACTOR; STEM-CELL TRANSPLANTATION; NEUTROPENIA-RELATED INFECTIONS; CHRONIC GRANULOMATOUS-DISEASE; INVASIVE FUNGAL-INFECTIONS; G-CSF; PEDIATRIC-PATIENTS; HEALTHY DONORS; LEUKOCYTE TRANSFUSIONS; PLUS DEXAMETHASONE AB Bacterial and fungal infections continue to pose a major clinical challenge in patients with prolonged severe neutropenia after chemotherapy or hematopoietic stem cell transplantation (HSCT). With the advent of granulocyte colony-stimulating factor (G-CSF) to mobilize neutrophils in healthy donors, granulocyte transfusions have been broadly used to prevent and/or treat life-threatening infections in patients with severe febrile neutropenia and/or neutrophil dysfunction. Although the results of randomized controlled trials are inconclusive, there are suggestions from pilot and retrospective studies that granulocyte transfusions may benefit selected categories of patients. We will critically appraise the evidence related to the use of therapeutic granulocyte transfusions in children and adults, highlighting current controversies in the field and discussing complementary approaches to modulate phagocyte function in the host. C1 [Cugno, Chiara; Deola, Sara; Rutella, Sergio] Sidra Med & Res Ctr, Out Patient Clin, Clin Res Ctr, Div Translat Med, Doha, Qatar. [Cugno, Chiara] IRCCS Fdn Policlin San Matteo, Dept Pediat Hematol & Oncol, Pavia, Italy. [Deola, Sara] Osped Cent Bolzano, Hematol & Bone Marrow Transplant Unit, Bolzano, Italy. [Filippini, Perla] Sidra Med & Res Ctr, Deep Immunophenotyping Core, Div Translat Med, Doha, Qatar. [Stroncek, David F.] NIH, Cell Proc Sect, Dept Transfus Med, Clin Ctr, Bethesda, MD 20892 USA. RP Rutella, S (reprint author), Sidra Med & Res Ctr, Out Patient Clin, Clin Res Ctr, Div Translat Med, Al Luqta St,Educ City North Campus,POB 26999, Doha, Qatar. EM srutella@sidra.org OI Rutella, Sergio/0000-0003-1970-7375 NR 91 TC 1 Z9 1 U1 0 U2 0 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 NOV 16 PY 2015 VL 13 AR 362 DI 10.1186/s12967-015-0724-5 PG 17 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CW1NC UT WOS:000364755900001 PM 26572736 ER PT J AU Hoskins, JW Ibrahim, A Emmanuel, M Manmiller, S Jia, JP Parikh, H Collins, I Ylaya, K Altekruse, SF Hewitt, SM Petersen, GM Amundadottir, LT AF Hoskins, Jason W. Ibrahim, Abdisamad Emmanuel, Mickey Manmiller, Sarah Jia, Jinping Parikh, Hemang Collins, Irene Ylaya, Kris Altekruse, Sean F. Hewitt, Stephen M. Petersen, Gloria M. Amundadottir, Laufey T. TI Functional analysis of the chr13q22.1 pancreatic cancer risk locus suggests allele-specific effects on DIS3 expression with prognostic implications SO CANCER RESEARCH LA English DT Meeting Abstract CT AACR Special Conference on Translation of the Cancer Genome CY FEB 07-09, 2015 CL San Francisco, CA SP Amer Assoc Canc Res C1 [Hoskins, Jason W.; Ibrahim, Abdisamad; Emmanuel, Mickey; Manmiller, Sarah; Jia, Jinping; Parikh, Hemang; Collins, Irene; Ylaya, Kris; Altekruse, Sean F.; Hewitt, Stephen M.; Amundadottir, Laufey T.] NCI, Bethesda, MD 20892 USA. [Petersen, Gloria M.] Mayo Clin, Rochester, MN USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD NOV 15 PY 2015 VL 75 IS 22 SU 1 MA A1-09 DI 10.1158/1538-7445.TRANSCAGEN-A1-09 PG 2 WC Oncology SC Oncology GA DE9QJ UT WOS:000370972600011 ER PT J AU Moore, L Lenz, P Yeager, M Pfeiffer, R Scelo, G Purdue, M Zaridze, D Schwartz, K Szeszenia-Dabrowska, N Davis, F Colt, J Janout, V Navritalova, M Boffetta, P Burdette, L Karami, S Brennan, P Hofmann, J Nickerson, M Chow, WH Tucker, M Chanock, S Hewitt, S Toro, J Rothman, N AF Moore, Lee Lenz, Petra Yeager, Meredith Pfeiffer, Ruth Scelo, Ghislaine Purdue, Mark Zaridze, David Schwartz, Kendra Szeszenia-Dabrowska, Neonilia Davis, Faith Colt, Joanne Janout, Vladimir Navritalova, Marie Boffetta, Paolo Burdette, Laurie Karami, Sara Brennan, Paul Hofmann, Jon Nickerson, Michael Chow, Wong-Ho Tucker, Margaret Chanock, Stephen Hewitt, Stephen Toro, Jorge Rothman, Nat TI Molecular characteristics and predictors of poor prognosis in sporadic clear cell renal cancer among central/eastern European and United States patients SO CANCER RESEARCH LA English DT Meeting Abstract CT AACR Special Conference on Translation of the Cancer Genome CY FEB 07-09, 2015 CL San Francisco, CA SP Amer Assoc Canc Res C1 [Moore, Lee; Lenz, Petra; Yeager, Meredith; Pfeiffer, Ruth; Purdue, Mark; Szeszenia-Dabrowska, Neonilia; Colt, Joanne; Burdette, Laurie; Karami, Sara; Hofmann, Jon; Nickerson, Michael; Tucker, Margaret; Chanock, Stephen; Toro, Jorge; Rothman, Nat] NCI, DCEG, NIH, DHHS, Rockville, MD USA. [Scelo, Ghislaine; Brennan, Paul] IARC, Lyon, France. [Zaridze, David] NN Blokhin Canc Res Ctr, Moscow, Russia. [Schwartz, Kendra] Univ MI, Detroit, MI USA. [Davis, Faith] Univ IL, Chicago, IL USA. [Janout, Vladimir] Palacky Univ, CR-77147 Olomouc, Czech Republic. [Navritalova, Marie] Masaryk Mem Canc Ctr, Brno, Czech Republic. [Boffetta, Paolo] ICAHN Med Inst, New York, NY USA. [Chow, Wong-Ho] MD Anderson CRC, Houston, TX USA. [Hewitt, Stephen] NCI, CCR, NIH, DHHS, Bethesda, MD 20892 USA. RI Janout, Vladimir/M-5133-2014 NR 0 TC 0 Z9 0 U1 1 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD NOV 15 PY 2015 VL 75 IS 22 SU 1 MA A1-31 DI 10.1158/1538-7445.TRANSCAGEN-A1-31 PG 2 WC Oncology SC Oncology GA DE9QJ UT WOS:000370972600028 ER PT J AU Nickerson, ML Im, KM Turan, S Guo, GW Moore, LE Theodorescu, D Dean, M AF Nickerson, Michael L. Im, Kate M. Turan, Sevilay Guo, Guangwu Moore, Lee E. Theodorescu, Dan Dean, Michael TI Translational genomics of urologic cancer genes SO CANCER RESEARCH LA English DT Meeting Abstract CT AACR Special Conference on Translation of the Cancer Genome CY FEB 07-09, 2015 CL San Francisco, CA SP Amer Assoc Canc Res C1 [Nickerson, Michael L.; Turan, Sevilay; Dean, Michael] NCI, Frederick, MD 21701 USA. [Im, Kate M.] Data Sci Genom, Ellicott City, MD USA. [Guo, Guangwu] Dana Farber Canc Inst, Boston, MA 02115 USA. [Moore, Lee E.] NCI, Rockville, MD USA. [Theodorescu, Dan] Univ Colorado, Aurora, CO USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD NOV 15 PY 2015 VL 75 IS 22 SU 1 MA A1-01 DI 10.1158/1538-7445.TRANSCAGEN-A1-01 PG 2 WC Oncology SC Oncology GA DE9QJ UT WOS:000370972600003 ER PT J AU Staudt, LM AF Staudt, Louis M. TI Therapy of lymphoma inspired by functional and structural genomics SO CANCER RESEARCH LA English DT Meeting Abstract CT AACR Special Conference on Translation of the Cancer Genome CY FEB 07-09, 2015 CL San Francisco, CA SP Amer Assoc Canc Res C1 [Staudt, Louis M.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD NOV 15 PY 2015 VL 75 IS 22 SU 1 MA IA09 DI 10.1158/1538-7445.TRANSCAGEN-IA09 PG 2 WC Oncology SC Oncology GA DE9QJ UT WOS:000370972600110 ER PT J AU Mookherjee, S Hiriyanna, S Kaneshiro, K Li, LJ Li, YC Li, W Qian, HH Li, TS Khanna, H Colosi, P Swaroop, A Wu, ZJ AF Mookherjee, Suddhasil Hiriyanna, Suja Kaneshiro, Kayleigh Li, Linjing Li, Yichao Li, Wei Qian, Haohua Li, Tiansen Khanna, Hemant Colosi, Peter Swaroop, Anand Wu, Zhijian TI Long-term rescue of cone photoreceptor degeneration in retinitis pigmentosa 2 (RP2)-knockout mice by gene replacement therapy SO HUMAN MOLECULAR GENETICS LA English DT Article ID ADENOASSOCIATED VIRUS VECTORS; TRANSGENIC MOUSE LINE; INSTITUTES-OF-HEALTH; IN-VIVO; PROTEIN RP2; CONGENITAL AMAUROSIS; PLASMA-MEMBRANE; RPGR; MUTATIONS; TRANSDUCTION AB Retinal neurodegenerative diseases are especially attractive targets for gene replacement therapy, which appears to be clinically effective for several monogenic diseases. X-linked forms of retinitis pigmentosa (XLRP) are relatively severe blinding disorders, resulting from progressive photoreceptor dysfunction primarily caused by mutations in RPGR or RP2 gene. With a goal to develop gene therapy for the XLRP-RP2 disease, we first performed detailed characterization of the Rp2-knockout (Rp2-KO) mice and observed early-onset cone dysfunction, which was followed by progressive cone degeneration, mimicking cone vision impairment in XLRP patients. The mice also exhibited distinct and significantly delayed falling phase of photopic b-wave of electroretinogram (ERG). Concurrently, we generated a self-complementary adeno-associated viral (AAV) vector carrying human RP2-coding sequence and demonstrated its ability to mediate stable RP2 protein expression in mouse photoreceptors. A long-term efficacy study was then conducted in Rp2-KO mice following AAV-RP2 vector administration. Preservation of cone function was achieved with a wide dose range over 18-month duration, as evidenced by photopic ERG and optomotor tests. The slower b-wave kinetics was also completely restored. Morphologically, the treatment preserved cone viability, corrected mis-trafficking of M-cone opsin and restored cone PDE6 expression. The therapeutic effect was achieved even in mice that received treatment at an advanced disease stage. The highest AAV-RP2 dose group demonstrated retinal toxicity, highlighting the importance of careful vector dosing in designing future human trials. The wide range of effective dose, a broad treatment window and long-lasting therapeutic effects should make the RP2 gene therapy attractive for clinical development. C1 [Mookherjee, Suddhasil; Hiriyanna, Suja; Kaneshiro, Kayleigh; Li, Yichao; Li, Wei; Qian, Haohua; Li, Tiansen; Colosi, Peter; Swaroop, Anand; Wu, Zhijian] NEI, NIH, Bethesda, MD 20892 USA. [Li, Linjing; Khanna, Hemant] Univ Massachusetts, Sch Med, Dept Ophthalmol, Worcester, MA 01605 USA. RP Wu, ZJ (reprint author), NEI, Ocular Gene Therapy Core, NIH, 6 Ctr Dr,Room 306,MSC 0610, Bethesda, MD 20892 USA. EM swaroopa@nei.nih.gov; wuzh@mail.nih.gov OI Swaroop, Anand/0000-0002-1975-1141 FU National Eye Institute, National Institutes of Health (NIH) [EY022372]; Foundation Fighting Blindness FX This work was supported by the intramural research program of the National Eye Institute, National Institutes of Health (NIH), NIH grant EY022372 and Foundation Fighting Blindness. NR 50 TC 3 Z9 3 U1 2 U2 4 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 NOV 15 PY 2015 VL 24 IS 22 BP 6446 EP 6458 DI 10.1093/hmg/ddv354 PG 13 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA DB2WK UT WOS:000368371000014 PM 26358772 ER PT J AU Chodick, G Levin, M Kleinerman, RA Shwarz, M Shalev, V Ashkenazi, S Horev, G AF Chodick, Gabriel Levin, Moran Kleinerman, Ruth A. Shwarz, Michael Shalev, Varda Ashkenazi, Shai Horev, Gad TI Differences in characteristics of pediatric patients undergoing computed tomography between hospitals and primary care settings: implications for assessing cancer follow-up studies SO ISRAEL JOURNAL OF HEALTH POLICY RESEARCH LA English DT Article DE Computed tomography; Pediatrics; Hospitalization; Israel ID RADIATION-EXPOSURE; CT SCANS; RISK; CHILDHOOD; COHORT AB Background: Recently published analyses showed that computed tomography (CT) scans in pediatric patients are associated with increased risk of radiation-related cancer. These analyses were based on data collected both from either hospitals and primary care services. Study objectives were to characterize cohorts of pediatric patients in Israel undergoing CT scans in primary care compared to hospitals settings. These cohorts will be further used for evaluating cancer risks. Methods: The present study was conducted in Schneider Children Medical Center in Israel (SCMCI), the largest tertiary pediatric hospital in the country. Data were collected directly from the listings of the pediatric radiology department for the period 1985-2005. Results were compared with previously published data on pediatric CT in the primary healthcare service performed between 1999 and 2003 in a large health organization, Maccabi Healthcare Services (MHS). Results: During the study observation periods, 38,351 and 22,223 examinations were documented in 13,726 and 18,075 pediatric patients in SCMCI and MHS, respectively. Compared to pediatric patients in the primary care, patients undergoing CT scans in the hospital were more likely to be younger, to have multiple CT scans, and to be scanned in the trunk. Also, cancer-related indications accounted for nearly 50 % of all CT scans conducted in the hospital compared to only 3 % in primary care settings. Conclusions: The results indicate major differences in the characteristics of children and adolescents scanned in hospitals compared to primary care settings. Some of these characteristics may be associated with cancer risk later in life, and should be taken into account in cancer risk assessments. C1 [Chodick, Gabriel; Shalev, Varda] Maccabi Healthcare Serv, Div Med, Tel Aviv, Israel. [Chodick, Gabriel; Kleinerman, Ruth A.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Chodick, Gabriel; Levin, Moran; Shalev, Varda; Ashkenazi, Shai; Horev, Gad] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. [Shwarz, Michael; Ashkenazi, Shai; Horev, Gad] Schneider Childrens Med Ctr Israel, Petah Tiqwa, Israel. RP Chodick, G (reprint author), Maccabi Healthcare Serv, Div Med, Tel Aviv, Israel.; Chodick, G (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA.; Chodick, G (reprint author), Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. EM Hodik_g@mac.org.il OI Kleinerman, Ruth/0000-0001-7415-2478 FU National Institutes of Health; National Cancer Institute; Maccabi Institute for Healthcare Services Research FX This study was supported in part by the intramural research program of the National Institutes of Health and the National Cancer Institute and through funding from the Maccabi Institute for Healthcare Services Research. NR 28 TC 0 Z9 0 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2045-4015 J9 ISR J HEALTH POLICY JI Isr. J. Health Policy Res. PD NOV 15 PY 2015 VL 4 AR 33 DI 10.1186/s13584-015-0031-x PG 6 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA DB6XS UT WOS:000368659600001 PM 26568819 ER PT J AU Thiara, DK Liu, CY Raman, F Mangat, S Purdy, JB Duarte, HA Schmidt, N Hur, J Sibley, CT Bluemke, DA Hadigan, C AF Thiara, Diana K. Liu, Chia Ying Raman, Fabio Mangat, Sabrina Purdy, Julia B. Duarte, Horacio A. Schmidt, Nancyanne Hur, Jamie Sibley, Christopher T. Bluemke, David A. Hadigan, Colleen TI Abnormal Myocardial Function Is Related to Myocardial Steatosis and Diffuse Myocardial Fibrosis in HIV-Infected Adults SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE HIV; intramyocardial lipid; myocardial strain; magnetic resonance spectroscopy; antiretroviral therapy ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; LEFT-VENTRICULAR DYSFUNCTION; MAGNETIC-RESONANCE; CARDIAC STEATOSIS; DILATED CARDIOMYOPATHY; PROTEASE INHIBITORS; PREDICT MORTALITY; DIABETES-MELLITUS; HEART-FAILURE AB Background. Impaired cardiac function persists in the era of effective human immunodeficiency virus (HIV) therapy, although the etiology is unclear. We used magnetic resonance imaging (MRI) to measure intramyocardial lipid levels and fibrosis as possible contributors to HIV-associated myocardial dysfunction. Methods. A cross-sectional study of 95 HIV-infected and 30 matched-healthy adults, without known cardiovascular disease (CVD) was completed. Intramyocardial lipid levels, myocardial fibrosis, and cardiac function (measured on the basis of strain) were quantified by MRI. Results. Systolic function was significantly decreased in HIV-infected subjects as compared to controls (mean radial strain [+/- SD], 21.7 +/- 8.6% vs 30.5 +/- 14.2%; P = .004). Intramyocardial lipid level and fibrosis index were both increased in HIV-infected subjects as compared to controls (P <=.04 for both) and correlated with the degree of myocardial dysfunction measured by strain parameters. Intramyocardial lipid levels correlated positively with antiretroviral therapy duration and visceral adiposity. Further, impaired myocardial function was strongly correlated with increased monocyte chemoattractant protein 1 levels (r = 0.396, P = .0002) and lipopolysaccharide binding protein levels (r = 0.25, P = .02). Conclusions. HIV-infected adults have reduced myocardial function as compared to controls in the absence of known CVD. Decreased cardiac function was associated with abnormal myocardial tissue composition characterized by increased lipid levels and diffuse myocardial fibrosis. Metabolic alterations related to antiretroviral therapy and chronic inflammation may be important targets for optimizing long-term cardiovascular health in HIV-infected individuals. C1 [Thiara, Diana K.; Mangat, Sabrina; Hur, Jamie; Hadigan, Colleen] NIAID, Immunoregulat Lab, Bldg 10, Bethesda, MD 20892 USA. [Liu, Chia Ying; Raman, Fabio; Bluemke, David A.] NIH, Radiol & Imaging Sci, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Purdy, Julia B.] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. [Raman, Fabio] Univ Alabama Birmingham, Med Scientist Training Program, Birmingham, AL USA. [Duarte, Horacio A.] Univ Washington, Seattle Childrens Hosp, Dept Pediat, Sch Med, Seattle, WA 98195 USA. [Sibley, Christopher T.] Oregon Hlth & Sci Univ, Knight Cardiovasc Inst, Portland, OR 97201 USA. RP Hadigan, C (reprint author), 10 Ctr Dr,Bldg 10,Rm 11C103, Bethesda, MD 20189 USA. EM hadiganc@niaid.nih.gov OI Raman, Fabio/0000-0003-2393-9937; Bluemke, David/0000-0002-8323-8086 FU National Institutes of Health (NIH) - National Institute of Allergy and Infectious Disease; National Institutes of Health (NIH) - NIH Clinical Center Departments of Imaging Sciences and Critical Care Medicine FX This work was supported by the National Institutes of Health (NIH; NIH Bench to Bedside Award and intramural NIH clinical researching funding from the National Institute of Allergy and Infectious Disease and the NIH Clinical Center Departments of Imaging Sciences and Critical Care Medicine). NR 36 TC 10 Z9 11 U1 0 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 NOV 15 PY 2015 VL 212 IS 10 BP 1544 EP 1551 DI 10.1093/infdis/jiv274 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DB7BE UT WOS:000368668600005 PM 25964507 ER PT J AU Kovacs, SB Sheikh, V Thompson, WL Morcock, DR Perez-Diez, A Yao, MD Rupert, AW Utay, NS Roby, G Freeman, AF Estes, JD Sereti, I AF Kovacs, Stephen B. Sheikh, Virginia Thompson, William L. Morcock, David R. Perez-Diez, Ainhoa Yao, Michael D. Rupert, Adam W. Utay, Netanya S. Roby, Gregg Freeman, Alexandra F. Estes, Jacob D. Sereti, Irini TI T-Cell Depletion in the Colonic Mucosa of Patients With Idiopathic CD4(+) Lymphopenia SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE idiopathic CD4(+) lymphopenia; HIV/AIDS; mucosal immunity; biomarkers; inflammation ID INFLAMMATORY-BOWEL-DISEASE; HIV-INFECTION; IN-VIVO; MICROBIAL TRANSLOCATION; SMALL-INTESTINE; IMMUNE-SYSTEM; LYMPHOCYTOPENIA; MICE; TH17; PHENOTYPE AB Idiopathic CD4(+) lymphopenia (ICL) is a rare syndrome characterized by low peripheral CD4(+) T-cell counts that can lead to serious opportunistic infections. The pathogenesis of ICL remains unclear, and whether effector sites are also lymphopenic is unknown. In this study, rectosigmoid mucosal biopsy specimens from patients with ICL and healthy controls were evaluated. Significant T-cell lymphopenia was observed in the mucosal tissue of patients with ICL by flow cytometry and immunohistochemistry, compared with healthy controls. Functional capacity of T cells, assessed by production of interferon. and interleukin 17, was preserved in the mucosa of patients with ICL. In contrast to T lymphocytes, the frequency of myeloid cells (neutrophils and macrophages) was elevated in the colonic mucosa of patients with ICL. Despite the observed mucosal abnormalities, plasma levels of intestinal fatty acid binding protein, a marker of enterocyte turnover and other inflammatory biomarkers, including interleukin 6, C-reactive protein, and tumor necrosis factor, were not elevated in patients with ICL, compared with healthy controls, whereas soluble CD14 levels were minimally elevated. These data suggest that patients with ICL, despite gut mucosal lymphopenia and local tissue inflammation, have preserved enterocyte turnover and T-helper type 17 cells with minimal systemic inflammation. These observations highlight differences from patients with human immunodeficiency virus infection, with or without AIDS, and may partially explain their distinct clinical prognosis. C1 [Kovacs, Stephen B.] NIH, Clin Res Directorate, Clin Monitoring Res Program, Bldg 10, Bethesda, MD 20892 USA. [Morcock, David R.; Estes, Jacob D.] NIH, Retroviral Immunopathol Sect, AIDS & Canc Virus Program, Bethesda, MD 20892 USA. [Rupert, Adam W.] NIH, AIDS Monitoring Lab, Leidos Biomed Res, Frederick Natl Lab Canc Res, Bethesda, MD 20892 USA. [Sheikh, Virginia; Thompson, William L.; Perez-Diez, Ainhoa; Yao, Michael D.; Roby, Gregg; Freeman, Alexandra F.; Sereti, Irini] NIH, NIAID, Bethesda, MD 20892 USA. [Utay, Netanya S.] Univ Texas Med Branch, Dept Internal Med, Div Infect Dis, Galveston, TX 77555 USA. RP Sereti, I (reprint author), NIH, NIAID, Bethesda, MD 20892 USA. EM isereti@niaid.nih.gov OI Utay, Netanya/0000-0002-6407-8670 FU National Cancer Institute [HHSN261200800001E]; National Institute of Allergy and Infectious Diseases Intramural Research Program, NIH FX This work was supported by the National Cancer Institute (contract HHSN261200800001E) and the National Institute of Allergy and Infectious Diseases Intramural Research Program, NIH. NR 42 TC 3 Z9 3 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 NOV 15 PY 2015 VL 212 IS 10 BP 1579 EP 1587 DI 10.1093/infdis/jiv282 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DB7BE UT WOS:000368668600009 PM 25995198 ER PT J AU Beachler, DC Guo, YS Xiao, WH Burk, RD Minkoff, H Strickler, HD Cranston, RD Wiley, DJ Jacobson, LP Weber, KM Margolick, JB Sugar, EA Reddy, S Gillison, ML D'Souza, G AF Beachler, Daniel C. Guo, Yingshi Xiao, Wiehong Burk, Robert D. Minkoff, Howard Strickler, Howard D. Cranston, Ross D. Wiley, Dorothy J. Jacobson, Lisa P. Weber, Kathleen M. Margolick, Joseph B. Sugar, Elizabeth A. Reddy, Susheel Gillison, Maura L. D'Souza, Gypsyamber TI High Oral Human Papillomavirus Type 16 Load Predicts Long-term Persistence in Individuals With or at Risk for HIV Infection SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE oral HPV; viral load; persistence; oropharyngeal cancer; HIV ID UNITED-STATES; HPV INFECTION; VIRAL LOAD; HEAD AB The association between oral human papillomavirus 16 (HPV16) DNA load and infection clearance was evaluated among 88 individuals with oral HPV16 infection who were identified within a prospective cohort of 1470 HIV-infected and uninfected individuals. Oral rinse specimens were collected semiannually for up to 5 years. The oral HPV16 load at the time of the first positive test result was significantly associated with the time to clearance of infection (continuous P trends <.01). Notably, clearance rates by 24 months were 41% and 94% in the highest and lowest HPV16 load tertiles (P = .03), respectively. High oral HPV16 load warrants consideration as a biomarker for infection persistence, the presumed precursor of HPV16-associated oropharyngeal cancer. C1 [Beachler, Daniel C.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Jacobson, Lisa P.; D'Souza, Gypsyamber] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Sugar, Elizabeth A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. [Guo, Yingshi; Xiao, Wiehong; Margolick, Joseph B.; Reddy, Susheel; Gillison, Maura L.] Ohio State Univ, Ctr Comprehens Canc, Viral Oncol Program, Columbus, OH 43210 USA. [Burk, Robert D.] Albert Einstein Coll Med, Dept Pediat, Bronx, NY 10467 USA. [Burk, Robert D.] Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10467 USA. [Burk, Robert D.] Albert Einstein Coll Med, Dept Obstet Gynecol & Womens Hlth, Bronx, NY 10467 USA. [Strickler, Howard D.] Albert Einstein Coll Med, Dept Epidemiol, Bronx, NY 10467 USA. [Strickler, Howard D.] Albert Einstein Coll Med, Dept Populat Hlth, Bronx, NY 10467 USA. [Minkoff, Howard] Maimonides Hosp, Dept Obstet & Gynecol, Brooklyn, NY 11219 USA. [Cranston, Ross D.] Univ Pittsburgh, Dept Med, Pittsburgh, PA 15260 USA. [Wiley, Dorothy J.] Univ Calif Los Angeles, Sch Nursing, Los Angeles, CA 90024 USA. [Weber, Kathleen M.] Northwestern Univ, Hektoen Inst Med, CORE Ctr John H Stroger Jr Hosp Cook Cty, Chicago, IL 60611 USA. [Reddy, Susheel] Northwestern Univ, Dept Infect Dis, Chicago, IL 60611 USA. RP D'Souza, G (reprint author), 615 N Wolfe St,E6132B, Baltimore, MD 21205 USA. EM gdsouza2@jhu.edu OI Cranston, Ross/0000-0002-2687-6217 FU National Institute of Dental and Craniofacial Research [R01 DE021395]; National Institute of Allergy and Infectious Disease [U01-A1-35043]; National Cancer Institute [T32 CA CA009314] FX This work was supported by the National Institute of Dental and Craniofacial Research (R01 DE021395 and related supplement to G. D. [principal investigator]), the National Institute of Allergy and Infectious Disease (U01-A1-35043), and the National Cancer Institute (T32 CA CA009314 and cancer prevention fellowship to D. C. B.). NR 15 TC 4 Z9 4 U1 0 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 NOV 15 PY 2015 VL 212 IS 10 BP 1588 EP 1591 DI 10.1093/infdis/jiv273 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DB7BE UT WOS:000368668600010 PM 25954049 ER PT J AU Grabowski, MK Kigozi, G Gray, RH Armour, B Manucci, J Serwadda, D Redd, AD Nalugoda, F Patel, EU Wawer, MJ Quinn, TC Tobian, AAR AF Grabowski, Mary K. Kigozi, Godfrey Gray, Ronald H. Armour, Benjamin Manucci, Jordyn Serwadda, David Redd, Andrew D. Nalugoda, Fred Patel, Eshan U. Wawer, Maria J. Quinn, Thomas C. Tobian, Aaron A. R. TI Herpes Simples Virus Type 2 Shedding From Male Circumcision Wounds in Rakai, Uganda SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE human immunodeficiency virus (HIV); herpes simplex virus type 2 (HSV-2); male circumcision; viral load; penile viral shedding; Uganda ID RANDOMIZED CONTROLLED-TRIAL; FEMALE PARTNERS; TRANSMISSION; INFECTION; HIV-1; HSV-2; MEN AB A prospective observational study of 176 men coinfected with human immunodeficiency virus and herpes simplex virus type 2 (HSV-2) was conducted to assess whether their sexual partners may be at an increased risk of HSV-2 from male circumcision (MC) wounds. Preoperative and weekly penile lavage samples were tested for penile HSV-2 shedding. Prevalence risk ratios (PRRs) were estimated using Poisson regression. Detectable penile HSV-2 shedding was present in 9.7% of men (17 of 176) before MC, compared with 12.9% (22 of 170) at 1 week (PRR, 1.33; 95% confidence interval [CI],.74-2.38) and 14.8% (23 of 155) at 2 weeks (PRR, 1.50; 95% CI,.86-2.62) after MC. HSV-2 shedding was lower among men with healed MC wounds (adjusted PRR, 0.62; 95% CI, .35-1.08). Men undergoing MC should be counseled on sexual abstinence and condom use. C1 [Grabowski, Mary K.; Gray, Ronald H.; Wawer, Maria J.; Tobian, Aaron A. R.] Johns Hopkins Univ, Sch Med, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Armour, Benjamin; Manucci, Jordyn; Redd, Andrew D.; Quinn, Thomas C.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD USA. [Tobian, Aaron A. R.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD USA. [Redd, Andrew D.; Patel, Eshan U.; Quinn, Thomas C.] NIAID, Div Intramural Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Serwadda, David; Nalugoda, Fred; Wawer, Maria J.; Quinn, Thomas C.; Tobian, Aaron A. R.] Rakai Hlth Sci Program, Entebbe, Uganda. [Serwadda, David] Makerere Univ, Inst Publ Hlth, Kampala, Uganda. RP Tobian, AAR (reprint author), Johns Hopkins Univ, Dept Pathol, Carnegie 437,600 N Wolfe St, Baltimore, MD 21287 USA. EM atobian1@jhmi.edu OI Patel, Eshan/0000-0003-2174-5004 FU Bill and Melinda Gates Foundation [22006.03]; Doris Duke Charitable Foundation [2011036]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases; Fogarty International Center [1D43TWOO9578-01]; National Institutes of Health [T32AI102, 1K23AI093152-01A1] FX This work was supported by the Bill and Melinda Gates Foundation grant 22006.03 for sample collection); the Doris Duke Charitable Foundation (grant 2011036 for laboratory work and Clinician Scientist Development awards to M. K. G. and A. A. R. T.); the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, and the Fogarty International Center (grant 1D43TWOO9578-01); and the National Institutes of Health (grants T32AI102 supported M. K. G. and 1K23AI093152-01A1 to A. A. R. T.). NR 15 TC 2 Z9 2 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 NOV 15 PY 2015 VL 212 IS 10 BP 1613 EP 1617 DI 10.1093/infdis/jiv259 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DB7BE UT WOS:000368668600014 PM 25943201 ER PT J AU Moran, TP Nakano, K Whitehead, GS Thomas, SY Cook, DN Nakano, H AF Moran, Timothy P. Nakano, Keiko Whitehead, Gregory S. Thomas, Seddon Y. Cook, Donald N. Nakano, Hideki TI Inhaled house dust programs pulmonary dendritic cells to promote type 2 T-cell responses by an indirect mechanism SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Article DE dendritic cells; allergic asthma; T helper 2 responses; environmental allergens; house dust ID THYMIC STROMAL LYMPHOPOIETIN; MITE ALLERGEN; PROTEOLYTIC ACTIVITY; IMMUNE-RESPONSES; TH2 POLARIZATION; GM-CSF; ASTHMA; EXPOSURE; SENSITIZATION; INFLAMMATION AB The induction of allergen-specific T helper 2 (Th2) cells by lung dendritic cells (DCs) is a critical step in allergic asthma development. Airway delivery of purified allergens or microbial products can promote Th2 priming by lung DCs, but how environmentally relevant quantities and combinations of these factors affect lung DC function is unclear. Here, we investigated the ability of house dust extract (HDE), which contains a mixture of environmental adjuvants, to prime Th2 responses against an innocuous inhaled antigen. Inhalational exposure to HDE conditioned lung conventional DCs, but not monocyte-derived DCs, to induce antigen-specific Th2 differentiation. Conditioning of DCs by HDE was independent of Toll-like receptor 4 signaling, indicating that environmental endotoxin is dispensable for programming DCs to induce Th2 responses. DCs directly treated with HDE underwent maturation but were poor stimulators of Th2 differentiation. In contrast, DCs treated with bronchoalveolar lavage fluid (BALF) from HDE-exposed mice induced robust Th2 differentiation. DC conditioning by BALF was independent of the proallergic cytokines IL-25, IL-33, and thymic stromal lymphopoietin. BALF treatment of DCs resulted in upregulation of CD80 but low expression of CD40, CD86, and IL-12p40, which was associated with Th2 induction. These findings support a model whereby environmental adjuvants in house dust indirectly program DCs to prime Th2 responses by triggering the release of endogenous soluble factor(s) by airway cells. Identifying these factors could lead to novel therapeutic targets for allergic asthma. C1 [Moran, Timothy P.; Nakano, Keiko; Whitehead, Gregory S.; Thomas, Seddon Y.; Cook, Donald N.; Nakano, Hideki] NIEHS, Immun Inflammat & Dis Lab, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. [Moran, Timothy P.] Univ N Carolina, Sch Med, Dept Pediat, Chapel Hill, NC USA. RP Moran, TP (reprint author), Univ N Carolina, Sch Med, 125 Mason Farm Rd,CB 7248, Chapel Hill, NC 27599 USA. EM tmoran@email.unc.edu OI Moran, Timothy/0000-0002-6832-9772; Thomas, Seddon/0000-0003-0075-0744 FU Intramural Research Program of the National Institutes of Health; National Institute of Environmental Health Sciences [ZIA ES102025-09]; National Center for Advancing Translational Sciences, National Institutes of Health [1KL2TR001109] FX This work was supported by the Intramural Research Program of the National Institutes of Health, the National Institute of Environmental Health Sciences (ZIA ES102025-09), and the National Center for Advancing Translational Sciences, National Institutes of Health (1KL2TR001109). NR 61 TC 1 Z9 1 U1 2 U2 7 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 NOV 15 PY 2015 VL 309 IS 10 BP L1208 EP L1218 DI 10.1152/ajplung.00256.2015 PG 11 WC Physiology; Respiratory System SC Physiology; Respiratory System GA CX7IZ UT WOS:000365876700017 PM 26386119 ER PT J AU Saldana-Caboverde, A Perera, EM Watkins-Chow, DE Hansen, NE Vemulapalli, M Mullikin, JC Pavan, WJ Kos, L AF Saldana-Caboverde, Amy Perera, Erasmo M. Watkins-Chow, Dawn E. Hansen, Nancy E. Vemulapalli, Meghana Mullikin, James C. Pavan, William J. Kos, Lidia CA NISC Comparative Sequencing Progra TI The transcription factors Ets1 and Sox10 interact during murine melanocyte development SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Melanocyte; Neural crest; Ets1; Sox10; Enteric ganglia ID ENTERIC NERVOUS-SYSTEM; CREST-DERIVED TISSUES; B RECEPTOR GENE; NEURAL CREST; HIRSCHSPRUNG-DISEASE; CHICK-EMBRYO; MOUSE MODEL; WAARDENBURG SYNDROME; MALIGNANT-MELANOMA; EXPRESSION AB Melanocytes, the pigment-producing cells, arise from multipotent neural crest (NC) cells during embryogenesis. Many genes required for melanocyte development were identified using mouse pigmentation mutants. The variable spotting mouse pigmentation mutant arose spontaneously at the Jackson Laboratory. We identified a G-to-A nucleotide transition in exon 3 of the Ets1 gene in variable spotting, which results in a missense G102E mutation. Homozygous variable spotting mice exhibit sporadic white spotting. Similarly, mice carrying a targeted deletion of Ets1 exhibit hypopigmentation; nevertheless, the function of Ets1 in melanocyte development is unknown. The transcription factor Ets1 is widely expressed in developing organs and tissues, including the NC. In the chick, Ets1 is required for the expression of Sox10, a transcription factor critical for the development of various NC derivatives, including melanocytes. We show that Ets1 is required early for murine NC cell and melanocyte precursor survival in vivo. Given the importance of Ets1 for Sox10 expression in the chick, we investigated a potential genetic interaction between these genes by comparing the hypopigmentation phenotypes of single and double heterozygous mice. The incidence of hypopigmentation in double heterozygotes was significantly greater than in single heterozygotes. The area of hypopigmentation in double heterozygotes was significantly larger than would be expected from the addition of the areas of hypopigmentation of single heterozygotes, suggesting that Ets1 and Sox10 interact synergistically in melanocyte development. Since Sox10 is also essential for enteric ganglia development, we examined the distal colons of Ets1 null mutants and found a significant decrease in enteric innervation, which was exacerbated by Sox10 heterozygosity. At the molecular level, Ets1 was found to activate an enhancer critical for Sox10 expression in NC-derived structures. Furthermore, enhancer activation was significantly inhibited by the variable spotting mutation. Together, these results suggest that Ets1 and Sox10 interact to promote proper melanocyte and enteric ganglia development from the NC. (C) 2015 Elsevier Inc. All rights reserved. C1 [Saldana-Caboverde, Amy; Perera, Erasmo M.; Kos, Lidia] Florida Int Univ, Dept Biol Sci, Miami, FL 33199 USA. [Watkins-Chow, Dawn E.; Pavan, William J.] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Hansen, Nancy E.; Mullikin, James C.] NHGRI, Comparat Genom Anal Unit, CGCGB, Bethesda, MD 20892 USA. [Vemulapalli, Meghana; Mullikin, James C.; NISC Comparative Sequencing Progra] NHGRI, NIH Intramural Sequencing Ctr, Rockville, MD USA. [Kos, Lidia] Florida Int Univ, Biomol Sci Inst, Miami, FL 33199 USA. RP Kos, L (reprint author), Florida Int Univ, Dept Biol Sci, Miami, FL 33199 USA. EM kosl@fiu.edu OI Watkins-Chow, Dawn/0000-0002-4355-0868 FU National Institutes of Health (NIH (NIAMS)) [R15AR062331]; NIH/NIGMS [R25GM061347] FX We thank Dr. Satrajit Sinha (State University of New York (SUNY) at Buffalo, Buffalo, NY) for providing the PCMV-HA-Ets1 and PCMV-HA vectors, and Dr. Eric Svensson (University of Chicago, Chicago, IL) for providing the Ets1 mutant mice. We also thank Dr. Paul Sharp from the Florida International University (FIU, Miami, FL) DNA Core for his help with direct sequencing, and Drs. Paulette Johnson and Jianbin Zhu from the FIU Statistical Consulting Department for their help with the statistical analyses of the hypopigmentation area data. We are also grateful to Dr. Fernando Noriega (FIU) for kindly allowing us to use his laboratory's real-time PCR system. This work was supported by the National Institutes of Health (NIH (NIAMS) R15AR062331 to L.K). Additional support for this project was provided by NIH/NIGMS R25GM061347. NR 56 TC 1 Z9 2 U1 2 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 EI 1095-564X J9 DEV BIOL JI Dev. Biol. PD NOV 15 PY 2015 VL 407 IS 2 BP 300 EP 312 DI 10.1016/j.ydbio.2015.04.012 PG 13 WC Developmental Biology SC Developmental Biology GA CY0AK UT WOS:000366068100011 PM 25912689 ER PT J AU Shakeri, R Malekzadeh, R Nasrollahzadeh, D Pawilta, M Murphy, G Islami, F Sotoudeh, M Michel, A Etemadi, A Waterboer, T Poustchi, H Brennan, P Boffetta, P Dawsey, SM Kamangar, F Abnet, CC AF Shakeri, Ramin Malekzadeh, Reza Nasrollahzadeh, Dariush Pawilta, Michael Murphy, Gwen Islami, Farhad Sotoudeh, Masoud Michel, Angelika Etemadi, Arash Waterboer, Tim Poustchi, Hossein Brennan, Paul Boffetta, Paolo Dawsey, Sanford M. Kamangar, Farin Abnet, Christian C. TI Multiplex H. pylori Serology and Risk of Gastric Cardia and Noncardia Adenocarcinomas SO CANCER RESEARCH LA English DT Article ID 2 DISTINCT ETIOLOGIES; HELICOBACTER-PYLORI; ESOPHAGEAL CANCER; ATROPHIC GASTRITIS; EPITHELIAL-CELLS; ANTIBODY-TITERS; TOOTH LOSS; INFECTION; CAGA; ASSOCIATION AB The reported associations with gastric adenocarcinoma and seropositivity to different Helicobacter pylori antigens using multiplex serology have not been consistent across studies. We aimed to investigate the association between 15 different multiplex serology antigens and the risk of gastric cardia (GCA) and gastric noncardia (GNCA) adenocarcinomas in northeastern Iran, a population with high rates of gastric adenocarcinoma. We included 272 cases of gastric adenocarcinoma (142 GCA, 103 GNCA, and 27 unspecified) and 524 controls who were individually matched to cases for age, sex, and place of residence in a population-based case-control study. Seropositivity to H. pylori was assessed using both multiplex serology and H. pylori IgG ELISA. Ninety-five percent of controls were seropositive to H. pylori. Of the 15 antibodies in the multiplex assay, 11 showed no significant association with gastric adenocarcinomas. CagA and VacA were associated with a significantly increased risk of all gastric adenocarcinoma and GNCA in multivariate models. Surprisingly, GroEL and NapA were significantly associated with a reduced risk of these tumors. Only CagA antigen was associated with significantly elevated risk of GCA. We found no associations between H. pylori seropositivity overall either by whole-cell ELISA test or multiplex serology, likely due to the high prevalence of seropositivity. Individual antigen testing showed that CagA positivity was associated with increased risk of both noncardia and cardia adenocarcinoma, which is similar to some other Asian populations, whereas two antigens were associated with lower risk of gastric cancer. This latter result was unexpected and should be retested in other populations. (C) 2015 AACR. C1 [Shakeri, Ramin; Malekzadeh, Reza; Nasrollahzadeh, Dariush; Islami, Farhad; Sotoudeh, Masoud; Etemadi, Arash; Kamangar, Farin] Univ Tehran Med Sci, Digest Oncol Res Ctr, Digest Dis Res Inst, Tehran, Iran. [Nasrollahzadeh, Dariush] Karolinska Inst, Med Epidemiol & Biostat, Stockholm, Sweden. [Pawilta, Michael; Michel, Angelika; Waterboer, Tim] German Canc Res Ctr, Heidelberg, Germany. [Murphy, Gwen; Etemadi, Arash; Dawsey, Sanford M.; Abnet, Christian C.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Islami, Farhad] Amer Canc Soc, Atlanta, GA 30329 USA. [Poustchi, Hossein] Univ Tehran Med Sci, Digest Dis Res Inst, Digest Dis Res Ctr, Tehran, Iran. [Brennan, Paul] Int Agcy Res Canc, F-69372 Lyon, France. [Boffetta, Paolo] Icahn Sch Med Mt Sinai, Inst Translat Epidemiol, New York, NY 10029 USA. [Boffetta, Paolo] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA. [Kamangar, Farin] Morgan State Univ, Sch Community Hlth & Policy, Dept Publ Hlth Anal, Baltimore, MD 21239 USA. RP Abnet, CC (reprint author), NCI, 9609 Med Ctr Dr,Room 6e430 MSC 9768, Bethesda, MD 20892 USA. EM malek@ams.ac.ir; abnetc@mail.nih.gov RI Abnet, Christian/C-4111-2015; Etemadi, Arash/C-1386-2016; Waterboer, Tim/G-1252-2010; OI Abnet, Christian/0000-0002-3008-7843; Etemadi, Arash/0000-0002-3458-1072; Pawlita, Michael/0000-0002-4720-8306 FU DDRI/TUMS [82-603]; Intramural Research Program of the National Cancer Institute, NIH FX This study was partly supported by grant No. 82-603 from DDRI/TUMS. It was also funded in part by the Intramural Research Program of the National Cancer Institute, NIH. NR 53 TC 3 Z9 3 U1 1 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD NOV 15 PY 2015 VL 75 IS 22 BP 4876 EP 4883 DI 10.1158/0008-5472.CAN-15-0556 PG 8 WC Oncology SC Oncology GA CX3MH UT WOS:000365602600020 PM 26383162 ER PT J AU Griffith, DE Adjemian, J Brown-Elliott, BA Prevots, DR Philley, JV Olivier, KN Wallace, RJ AF Griffith, David E. Adjemian, Jennifer Brown-Elliott, Barbara A. Prevots, D. Rebecca Philley, Julie V. Olivier, Kenneth N. Wallace, Richard J., Jr. TI Cure Not Possible, by Definition Reply SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Letter ID COMPLEX LUNG-DISEASE; THERAPY C1 [Griffith, David E.; Brown-Elliott, Barbara A.; Philley, Julie V.; Wallace, Richard J., Jr.] Univ Texas Hlth Sci Ctr, Tyler, TX 75708 USA. [Adjemian, Jennifer; Prevots, D. Rebecca; Olivier, Kenneth N.] NIH, Bethesda, MD 20892 USA. [Adjemian, Jennifer] US Public Hlth Serv Commissioned Corps, Rockville, MD USA. RP Griffith, DE (reprint author), Univ Texas Hlth Sci Ctr, Tyler, TX 75708 USA. NR 3 TC 0 Z9 0 U1 2 U2 2 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD NOV 15 PY 2015 VL 192 IS 10 BP 1256 EP 1257 PG 2 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA CW6XY UT WOS:000365142900022 PM 26568244 ER PT J AU Candice, SD Feng, TS van der Westhuyzen, R Gessner, RK Street, LJ Morgans, GL Warner, DF Moosa, A Naran, K Lawrence, N Boshoff, HIM Barry, CE Harris, CJ Gordon, R Chibale, K AF Candice, Soares de Melo Feng, Tzu-Shean van der Westhuyzen, Renier Gessner, Richard K. Street, Leslie J. Morgans, Garreth L. Warner, Digby F. Moosa, Atica Naran, Krupa Lawrence, Nina Boshoff, Helena I. M. Barry, Clifton E., III Harris, C. John Gordon, Richard Chibale, Kelly TI Aminopyrazolo[1,5-a]pyrimidines as potential inhibitors of Mycobacterium tuberculosis: Structure activity relationships and ADME characterization SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Mycobacterium tuberculosis; Antibacterial agent; Aminopyrazolopyrimidine; Infectious diseases ID EARLY BACTERICIDAL ACTIVITY; CYCLIN-DEPENDENT KINASE; BIOLOGICAL EVALUATION; LEAD OPTIMIZATION; IN-VITRO; ASSAY; DERIVATIVES; ETHAMBUTOL; OPC-67683; OXIDASE AB Whole-cell high-throughput screening of a diverse SoftFocus library against Mycobacterium tuberculosis (Mtb) generated a novel aminopyrazolo[1,5-a]pyrimidine hit series. The synthesis and structure activity relationship studies identified compounds with potent antimycobacterial activity. The SAR of over 140 compounds shows that the 2-pyridylmethylamine moiety at the C-7 position of the pyrazolopyrimidine scaffold was important for Mtb activity, whereas the C-3 position offered a higher degree of flexibility. The series was also profiled for in vitro cytotoxicity and microsomal metabolic stability as well as physicochemical properties. Consequently liabilities to be addressed in a future lead optimization campaign have been identified. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Candice, Soares de Melo; Feng, Tzu-Shean; van der Westhuyzen, Renier; Gessner, Richard K.; Street, Leslie J.; Chibale, Kelly] Univ Cape Town, Dept Chem, Drug Discovery & Dev Ctr H3D, ZA-7701 Rondebosch, South Africa. [Morgans, Garreth L.] iThemba Pharmaceut, ZA-1609 Modderfontein, South Africa. [Warner, Digby F.; Moosa, Atica; Naran, Krupa] Univ Cape Town, Dept Pathol, MRC NHLS UCT Mol Mycobacteriol Res Unit, ZA-7701 Rondebosch, South Africa. [Warner, Digby F.; Chibale, Kelly] Univ Cape Town, Inst Infect Dis & Mol Med, ZA-7701 Rondebosch, South Africa. [Lawrence, Nina] Univ Cape Town, Div Clin Pharmacol, ZA-7701 Rondebosch, South Africa. [Boshoff, Helena I. M.; Barry, Clifton E., III] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Harris, C. John] Cjh Consultants Pharmaceut R&D, Eynsford DA4 0AB, Kent, England. [Gordon, Richard] South African Med Res Council, SHIP, Parow Valley, South Africa. [Chibale, Kelly] Univ Cape Town, South African Med Res Council, Drug Discovery & Dev Res Unit, ZA-7701 Rondebosch, South Africa. RP Chibale, K (reprint author), Univ Cape Town, Dept Chem, Drug Discovery & Dev Ctr H3D, ZA-7701 Rondebosch, South Africa. EM kelly.chibale@uct.ac.za FU NIAID; Foundation for the National Institutes of Health; Bill & Melinda Gates Foundation; South African Medical Research Council (MRC); South African Tuberculosis Research and Innovation Initiative (SATRII); Strategic Health Innovation Partnerships (SHIP) initiative; University of Cape Town; South African Medical Research Council; South African Research Chairs Initiative of the Department of Science and Technology FX This work was funded, in part, by the Intramural Research Program of NIAID, by grants from the Foundation for the National Institutes of Health with support from the Bill & Melinda Gates Foundation, and by the South African Medical Research Council (MRC), the South African Tuberculosis Research and Innovation Initiative (SATRII) and the Strategic Health Innovation Partnerships (SHIP) initiative. The University of Cape Town, South African Medical Research Council, and South African Research Chairs Initiative of the Department of Science and Technology, administered through the South African National Research Foundation are gratefully acknowledged for support (K.C). Mathew Njoroge, Efrem Abay and Christel Brunschwig (H3-D ADME laboratories) are acknowledged for the metabolite identification studies and Carmen De Kock is acknowledged for the cytotoxicity studies. NR 49 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 0968-0896 EI 1464-3391 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD NOV 15 PY 2015 VL 23 IS 22 BP 7240 EP 7250 DI 10.1016/j.bmc.2015.10.021 PG 11 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA CW2TJ UT WOS:000364845500014 ER PT J AU Colbers, A Best, B Schalkwijk, S Wang, J Stek, A Tenorio, CH Hawkins, D Taylor, G Kreitchmann, R Burchett, S Haberl, A Kabeya, K van Kasteren, M Smith, E Capparelli, E Burger, D Mirochnick, M AF Colbers, Angela Best, Brookie Schalkwijk, Stein Wang, Jiajia Stek, Alice Tenorio, Carmen Hidalgo Hawkins, David Taylor, Graham Kreitchmann, Regis Burchett, Sandra Haberl, Annette Kabeya, Kabamba van Kasteren, Marjo Smith, Elizabeth Capparelli, Edmund Burger, David Mirochnick, Mark CA PANNA Network & IMPAACT Study TI Maraviroc Pharmacokinetics in HIV-1-Infected Pregnant Women SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE MTCT; pharmacokinetics; pregnancy; HIV; maraviroc ID TRANSMISSION AB Objective. To describe the pharmacokinetics of maraviroc in human immunodeficiency virus (HIV)-infected women during pregnancy and post partum. Methods. HIV-infected pregnant women receiving maraviroc as part of clinical care had intensive steady-state 12-hour pharmacokinetic profiles performed during the third trimester and >= 2 weeks after delivery. Cord blood samples and matching maternal blood samples were taken at delivery. The data were collected in 2 studies: P1026 (United States) and PANNA (Europe). Pharmacokinetic parameters were calculated. Results. Eighteen women were included in the analysis. Most women (12; 67%) received 150 mg of maraviroc twice daily with a protease inhibitor, 2 (11%) received 300 mg twice daily without a protease inhibitor, and 4 (22%) had an alternative regimen. The geometric mean ratios for third-trimester versus postpartum maraviroc were 0.72 (90% confidence interval, .60-.88) for the area under the curve overa dosing interval(AUC(tau)) and 0.70 (0.58-0.85) for the maximum maraviroc concentration. Only 1 patient showed a trough concentration (C-trough) below the suggested target of 50 ng/mL, both during pregnancy and post partum. The median ratio of maraviroc cord blood to maternal blood was 0.33 (range, 0.03-0.56). The viral load close to delivery was <50 copies/mL in 13 women (76%). All children were HIV negative at testing. Conclusions. Overall maraviroc exposure during pregnancy was decreased, with a reduction in AUC(tau) and maximum concentration of about 30%. C-trough was reduced by 15% but exceeded the minimum C-trough target concentration. Therefore, the standard adult dose seems sufficient in pregnancy. C1 [Colbers, Angela; Schalkwijk, Stein; Burger, David] Radboud Univ Nijmegen Med Ctr, Dept Pharm, NL-6525 GA Nijmegen, Netherlands. [Schalkwijk, Stein] Radboud Univ Nijmegen Med Ctr, Dept Pharmacol & Toxicol, NL-6525 GA Nijmegen, Netherlands. [van Kasteren, Marjo] St Elizabeth Hosp, Dept Internal Med, Tilburg, Netherlands. [Best, Brookie; Capparelli, Edmund] Univ Calif San Diego, UC San Diego Skaggs Sch Pharm & Pharmaceut Sci, Los Angeles, CA USA. [Best, Brookie; Capparelli, Edmund] Univ Calif San Diego, Sch Med, Los Angeles, CA USA. [Stek, Alice] Univ So Calif, Sch Med, Maternal Child & Adolescent Adult Ctr, Los Angeles, CA USA. [Wang, Jiajia] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Cambridge, MA 02138 USA. [Burchett, Sandra] Harvard Univ, Sch Med, Boston Childrens Hosp, Cambridge, MA 02138 USA. [Mirochnick, Mark] Boston Univ, Sch Med, Boston, MA 02118 USA. [Smith, Elizabeth] NIAID, Maternal Adolescent & Pediat Res Branch, Bethesda, MD 20892 USA. [Tenorio, Carmen Hidalgo] Hosp Univ Virgen Nieves Granada, Dept Infect Dis, Granada, Spain. [Hawkins, David] Chelsea & Westminster Hosp, London, England. [Taylor, Graham] Imperial Coll Healthcare NHS Trust, London, England. [Kreitchmann, Regis] Irmandade Santa Casa Misericordia Porto Alegre, HIV AIDS Res Dept, Porto Alegre, RS, Brazil. [Haberl, Annette] Goethe Univ Frankfurt, Dept Infect Dis, D-60054 Frankfurt, Germany. [Kabeya, Kabamba] Saint Pierre Univ Hosp, Dept Infect Dis, Brussels, Belgium. RP Colbers, A (reprint author), Radboud Univ Nijmegen Med Ctr, Dept Pharm, Geert Grooteplein Zuid 10, NL-6525 GA Nijmegen, Netherlands. EM angela.colbers@radboudumc.nl RI Schalkwijk, Stein/D-1055-2015; Colbers, A./L-4248-2015; OI nicastri, emanuele/0000-0002-5606-8712 FU European AIDS Treatment Network; European Commission; DG Research; Sixth Framework Programme [LSHP-CT-2006-037570]; Bristol-Myers Squibb; Merck Sharp Dohme; Janssen Research; National Institute of Allergy and Infectious Diseases, NIH [UM1AI068632, UM1AI068616, UM1AI106716]; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Mental Health FX The PANNA network is supported by the European AIDS Treatment Network, the European Commission, DG Research, Sixth Framework Programme (contract LSHP-CT-2006-037570), Bristol-Myers Squibb, Merck Sharp & Dohme, and Janssen Research. Overall support for IMPAACT was provided by the National Institute of Allergy and Infectious Diseases, NIH (grants UM1AI068632 [IMPAACT Leadership and Operations Center], UM1AI068616 [IMPAACT Statistical and Data Management Center], and UM1AI106716 [IMPAACT Laboratory Center]), with cofunding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health. NR 23 TC 0 Z9 0 U1 1 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 NOV 15 PY 2015 VL 61 IS 10 BP 1582 EP 1589 DI 10.1093/cid/civ587 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CW7EW UT WOS:000365161800016 PM 26202768 ER PT J AU Basta, NE Borrow, R Berthe, A Onwuchekwa, U Dembele, ATE Almond, R Frankland, S Patel, S Wood, D Nascimento, M Manigart, O Trotter, CL Greenwood, B Sow, SO AF Basta, Nicole E. Borrow, Ray Berthe, Abdoulaye Onwuchekwa, Uma Dembele, Awa Traore Eps Almond, Rachael Frankland, Sarah Patel, Sima Wood, Daniel Nascimento, Maria Manigart, Olivier Trotter, Caroline L. Greenwood, Brian Sow, Samba O. TI Higher Tetanus Toxoid Immunity 2 Years After PsA-TT Introduction in Mali SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE meningococcal vaccines; tetanus; conjugate; seroprevalence; Africa ID MENINGOCOCCAL CONJUGATE VACCINE; MENINGITIS; CARRIAGE AB Background. In 2010, mass vaccination with a then-new meningococcal A polysaccharide-tetanus toxoid protein conjugate vaccine (PsA-TT, or MenAfriVac) was undertaken in 1-to 29-year-olds in Bamako, Mali. Whether vaccination with PsA-TT effectively boosts tetanus immunity in a population with heterogeneous baseline tetanus immunity is not known. We assessed the impact of PsA-TT on tetanus toxoid (TT) immunity by quantifying ageand sex-specific immunity prior to and 2 years after introduction. Methods. Using a household-based, age-stratified design, we randomly selected participants for a prevaccination serological survey in 2010 and a postvaccination survey in 2012. TT immunoglobulin G (IgG) antibodies were quantified and geometric mean concentrations (GMCs) pre- and postvaccination among all age groups targeted for vaccination were compared. The probability of TT IgG levels a parts per thousand yen0.1 IU/mL (indicating short-term protection) and a parts per thousand yen1.0 IU/mL (indicating long-term protection) by age and sex was determined using logistic regression models. Results. Analysis of 793 prevaccination and 800 postvaccination sera indicated that while GMCs were low pre-PsA-TT, significantly higher GMCs in all age-sex strata were observed 2 years after PsA-TT introduction. The percentage with short-term immunity increased from 57.1% to 88.4% (31.3-point increase; 95% confidence interval [CI], 26.6-36.0;, P < .0001) and with long-term immunity increased from 20.0% to 58.5% (38.5-point increase; 95% CI, 33.7-43.3; P < .0001) pre- and postvaccination. Conclusions. Significantly higher TT immunity was observed among vaccine-targeted age groups up to 2 years after Mali's PsA-TT mass vaccination campaign. Our results, combined with evidence from clinical trials, strongly suggest that conjugate vaccines containing TT such as PsA-TT should be considered bivalent vaccines because of their ability to boost tetanus immunity. C1 [Basta, Nicole E.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN 55454 USA. [Basta, Nicole E.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Borrow, Ray; Almond, Rachael; Frankland, Sarah; Patel, Sima; Wood, Daniel] Manchester Royal Infirm, Vaccine Evaluat Unit, Publ Hlth England, Manchester, Lancs, England. [Berthe, Abdoulaye; Onwuchekwa, Uma; Dembele, Awa Traore Eps; Sow, Samba O.] Minist Sante, Ctr Dev Vaccins, Bamako, Mali. [Nascimento, Maria; Manigart, Olivier; Greenwood, Brian] London Sch Hyg & Trop Med, Fac Infect & Trop Dis, London, England. [Manigart, Olivier] MRC Unit, Fajara, Gambia. [Trotter, Caroline L.] Univ Cambridge, Dis Dynam Unit, Dept Vet Med, Cambridge CB2 1TN, England. RP Basta, NE (reprint author), Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, West Bank Off Bldg,1300 S 2nd St,Ste 300, Minneapolis, MN 55454 USA. EM nebasta@umn.edu OI Trotter, Caroline/0000-0003-4000-2708 FU US National Institutes of Health Early Independence Award from the Office of the Director and the National Institute of Dental and Craniofacial Research [1DP5OD009162]; RAPIDD program of the Science and Technology Directorate of the Department of Homeland Security and the Fogarty International Center; Bill & Melinda Gates Foundation [51251]; Wellcome Trust [086546] FX This work was supported by the US National Institutes of Health Early Independence Award from the Office of the Director and the National Institute of Dental and Craniofacial Research (1DP5OD009162 to N. E. B.); the RAPIDD program of the Science and Technology Directorate of the Department of Homeland Security and the Fogarty International Center (to N. E. B.); the Bill & Melinda Gates Foundation (51251 to B. G.); and the Wellcome Trust (086546 to B. G.). The content is solely the responsibility of the authors and does not necessarily represent the official views of funding agencies. NR 21 TC 3 Z9 3 U1 0 U2 1 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 NOV 15 PY 2015 VL 61 SU 5 BP S578 EP S585 DI 10.1093/cid/civ513 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CW7FF UT WOS:000365162700029 PM 26553691 ER PT J AU Basta, NE Borrow, R Berthe, A Dembele, ATE Onwuchekwa, U Townsend, K Boukary, RM Mabey, L Findlow, H Bai, XL Sow, SO AF Basta, Nicole E. Borrow, Ray Berthe, Abdoulaye Dembele, Awa Traore Eps Onwuchekwa, Uma Townsend, Kelly Boukary, Rahamatou M. Mabey, Lesley Findlow, Helen Bai, Xilian Sow, Samba O. TI Population-Level Persistence of Immunity 2 Years After the PsA-TT Mass-Vaccination Campaign in Mali SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE meningococcal vaccines; immunity; seroprevalence; Africa ID MENINGOCOCCAL CONJUGATE VACCINE; NEISSERIA-MENINGITIDIS SEROGROUP; EPIDEMIC MENINGITIS; ANTIBODY; IMMUNOGENICITY; CARRIAGE; RESPONSES; AFRICA; IMPACT; SAFETY AB Background. In 2010, Africa's first preventive meningococcal mass vaccination campaign was launched using a newly developed Neisseria meningitidis group A (NmA) polysaccharide-tetanus toxoid conjugate vaccine, PsA-TT (MenAfriVac), designed specifically for the meningitis belt. Given PsA-TT's recent introduction, the duration of protection against meningococcal group A is unknown. Methods. We conducted a household-based, age-stratified seroprevalence survey in Bamako, Mali, in 2012, 2 years after the vaccination campaign targeted all 1- to 29-year-olds. Randomly selected participants who had been eligible for PsA-TT provided a blood sample and responded to a questionnaire. Sera were analyzed to assess NmA-specific serum bactericidal antibody titers using rabbit complement (rSBA) and NmA-specific immunoglobulin G (IgG) by enzyme-linked immunosorbent assay. The proportion of participants putatively protected and the age group- and sex-specific rSBA geometric mean titers (GMTs) and IgG geometric mean concentrations (GMCs) were determined. Results. Two years postvaccination, nearly all of the 800 participants (99.0%; 95% confidence interval [CI], 98.3%-99.7%) maintained NmA-specific rSBA titers a parts per thousand yen8, the accepted threshold for protection; 98.6% (95% CI, 97.8%-99.4%) had titers a parts per thousand yen128, and 89.5% (95% CI, 87.4%-91.6%) had titers a parts per thousand yen1024. The rSBA GMTs were significantly higher in females than in males aged < 18 years at vaccination (P < .0001). NmA-specific IgG levels a parts per thousand yen2 A mu g/mL were found in 88.5% (95% CI, 86.3%-90.7%) of participants. Conclusions. Two years after PsA-TT introduction, a very high proportion of the population targeted for vaccination maintains high antibody titers against NmA. Assessing the duration of protection provided by PsA-TT is a priority for implementing evidence-based vaccination strategies. Representative, population-based seroprevalence studies complement clinical trials and provide this key evidence. C1 [Basta, Nicole E.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN 55454 USA. [Basta, Nicole E.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Borrow, Ray; Townsend, Kelly; Boukary, Rahamatou M.; Mabey, Lesley; Findlow, Helen; Bai, Xilian] Manchester Royal Infirm, Vaccine Evaluat Unit, Publ Hlth England, Manchester, Lancs, England. [Berthe, Abdoulaye; Dembele, Awa Traore Eps; Onwuchekwa, Uma; Sow, Samba O.] Minist Sante, Ctr Dev Vaccins, Bamako, Mali. RP Basta, NE (reprint author), Univ Minnesota, Div Epidemiol & Community Hlth, Sch Publ Hlth, West Bank Off Bldg,1300 S 2nd St,Ste 300, Minneapolis, MN 55454 USA. EM nebasta@umn.edu FU US National Institutes of Health Early Independence Award from the Office of the Director; National Institute of Dental and Craniofacial Research [1DP5OD009162]; RAPIDD program of the Science and Technology Directorate of the Department of Homeland Security and the Fogarty International Center FX This research was supported by the US National Institutes of Health Early Independence Award from the Office of the Director and the National Institute of Dental and Craniofacial Research (award number 1DP5OD009162 and supplement S1 to N. E. B.); and the RAPIDD program of the Science and Technology Directorate of the Department of Homeland Security and the Fogarty International Center (to N. E. B.). NR 39 TC 2 Z9 2 U1 0 U2 0 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 NOV 15 PY 2015 VL 61 SU 5 BP S547 EP S553 DI 10.1093/cid/civ602 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CW7FF UT WOS:000365162700025 PM 26553687 ER PT J AU Grunwald, JE Pistilli, M Ying, GS Maguire, M Daniel, E Whittock-Martin, R Parker-Ostroff, C Mohler, E Lo, JC Townsend, RR Gadegbeku, CA Lash, JP Fink, JC Rahman, M Feldman, H Kusek, JW Xie, DW AF Grunwald, Juan E. Pistilli, Maxwell Ying, Gui-Shuang Maguire, Maureen Daniel, Ebenezer Whittock-Martin, Revell Parker-Ostroff, Candace Mohler, Emile Lo, Joan C. Townsend, Raymond R. Gadegbeku, Crystal Ann Lash, James Phillip Fink, Jeffrey Craig Rahman, Mahboob Feldman, Harold Kusek, John W. Xie, Dawei CA CRIC Study Investigators TI Retinopathy and the Risk of Cardiovascular Disease in Patients With Chronic Kidney Disease (from the Chronic Renal Insufficiency Cohort Study) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID RETINAL VESSEL DIAMETERS; DIABETIC-RETINOPATHY; PROGRESSION; ASSOCIATION; ROTTERDAM; STROKE; GFR AB Patients with chronic kidney disease (CKD) experience other diseases such as cardiovascular disease (CVD) and retinopathy. The purpose of this study was to assess whether retinopathy predicts future CVD events in a subgroup of the participants of the Chronic Renal Insufficiency Cohort (CRIC) study. In this ancillary investigation, 2,605 participants of the CRIC study were invited to participate, and nonmydriatic fundus photographs were obtained in 1,936 subjects. Using standard protocols, presence and severity of retinopathy (diabetic, hypertensive, or other) and vessel diameter caliber were assessed at a central photograph reading center by trained graders masked to study participant's information. Patients with a self-reported history of cardiovascular disease were excluded. Incident CVD events were adjudicated using medical records. Kidney function measurements, traditional and nontraditional risk factors, for CVD were obtained. Presence and severity of retinopathy were associated with increased risk of development of any CVD in this population of CKD patients, and these associations persisted after adjustment for traditional risk factors for CVD. We also found a direct relation between increased venular diameter and risk of development of CVD; however, the relation was not statistically significant after adjustment for traditional risk factors. In conclusion, the presence of retinopathy was associated with future CVD events, suggesting that retinovascular pathology may be indicative of macro-vascular disease even after adjustment for renal dysfunction and traditional CVD risk factors. Assessment of retinal morphology may be valuable in assessing risk of CVD in patients with CKD, both clinically and in research settings. (C) 2015 Elsevier Inc. All rights reserved. C1 [Grunwald, Juan E.; Pistilli, Maxwell; Ying, Gui-Shuang; Maguire, Maureen; Daniel, Ebenezer; Whittock-Martin, Revell; Parker-Ostroff, Candace; Mohler, Emile; Townsend, Raymond R.; Feldman, Harold; Xie, Dawei] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Lo, Joan C.] Kaiser Permanente No Calif, Oakland, CA USA. [Gadegbeku, Crystal Ann] Temple Univ, Dept Med, Sch Med, Philadelphia, PA 19122 USA. [Lash, James Phillip] Univ Illinois, Chicago, IL USA. [Fink, Jeffrey Craig] Univ Maryland, Baltimore, MD 21201 USA. [Rahman, Mahboob] Maryland Case Western Univ, Cleveland, OH USA. [Kusek, John W.] NIDDK, Bethesda, MD 20892 USA. RP Grunwald, JE (reprint author), Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. EM juangrun@mail.med.upenn.edu OI Parker Ostroff, Candace/0000-0002-1590-1288; Fink, Jeffrey/0000-0002-5622-5052 FU National Institutes of Health [RO1 DK 74151]; NIDDK [U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, U01DK060902]; University of Pennsylvania Clinical and Translational Science Award NIH/NCATS [UL1TR000003]; Johns Hopkins University [UL1 TR000424]; University of Maryland GCRC [M01 RR-16500]; Clinical and Translational Science Collaborative of Cleveland [UL1TR000439]; Michigan Institute for Clinical and Health Research (MICHR) [UL1TR000433]; University of Illinois at Chicago CTSA [UL1RR029879]; Tulane University Translational Research in Hypertension and Renal Biology [P30GM103337]; Kaiser Permanente NIH/NCRR UCSF-CTSI [UL1 RR-024131]; Vivian S. Lasko Research Fund; Nina C. Mackall Trust; Research to Prevent Blindness FX This study was supported by Grant RO1 DK 74151 from National Institutes of Health. CRIC was funded by Grants U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, and U01DK060902 from NIDDK cooperative agreements, Grant UL1TR000003 from University of Pennsylvania Clinical and Translational Science Award NIH/NCATS, Grant UL1 TR000424 from Johns Hopkins University, Grant M01 RR-16500 from University of Maryland GCRC, Grant UL1TR000439 from Clinical and Translational Science Collaborative of Cleveland, Grant UL1TR000433 from Michigan Institute for Clinical and Health Research (MICHR), Grant UL1RR029879 from University of Illinois at Chicago CTSA, Grant P30GM103337 from Tulane University Translational Research in Hypertension and Renal Biology, Grant UL1 RR-024131 from Kaiser Permanente NIH/NCRR UCSF-CTSI, Vivian S. Lasko Research Fund, Nina C. Mackall Trust, and Research to Prevent Blindness. NR 20 TC 2 Z9 2 U1 0 U2 1 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 NOV 15 PY 2015 VL 116 IS 10 BP 1527 EP 1533 DI 10.1016/j.amjcard.2015.08.015 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CW7AU UT WOS:000365151100007 PM 26409637 ER PT J AU Spies, E Fichtner, M Muller, F Krasemann, S Illerhaus, G Glatzel, M Binder, M Trepel, M AF Spies, Elmar Fichtner, Michael Mueller, Fabian Krasemann, Susanne Illerhaus, Gerald Glatzel, Markus Binder, Mascha Trepel, Martin TI Comment on "Primary Central Nervous System (CNS) Lymphoma B Cell Receptors Recognize CNS Proteins" SO JOURNAL OF IMMUNOLOGY LA English DT Letter ID CHRONIC LYMPHOCYTIC-LEUKEMIA C1 [Spies, Elmar; Fichtner, Michael; Binder, Mascha; Trepel, Martin] Univ Med Ctr Hamburg Eppendorf, Univ Canc Ctr Hamburg, Hubertus Wald Tumor Ctr, Dept Hematol & Oncol, D-20246 Hamburg, Germany. [Mueller, Fabian] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Krasemann, Susanne; Glatzel, Markus] Univ Med Ctr Hamburg Eppendorf, Inst Neuropathol, D-20246 Hamburg, Germany. [Illerhaus, Gerald] Stuttgart Med Ctr, Dept Hematol & Oncol, D-70174 Stuttgart, Germany. [Trepel, Martin] Augsburg Med Ctr, Dept Hematol & Oncol, D-86165 Augsburg, Germany. RP Spies, E (reprint author), Univ Med Ctr Hamburg Eppendorf, Univ Canc Ctr Hamburg, Hubertus Wald Tumor Ctr, Dept Hematol & Oncol, Martinistr 52, D-20246 Hamburg, Germany. EM e.spies@uke.de RI Glatzel, Markus/G-3356-2011 OI Glatzel, Markus/0000-0002-7720-8817 NR 4 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD NOV 15 PY 2015 VL 195 IS 10 BP 4549 EP 4550 DI 10.4049/jimmunol.1501964 PG 2 WC Immunology SC Immunology GA CW2LC UT WOS:000364822800001 PM 26546683 ER PT J AU Wang, AJ Yang, ZH Grinchuk, V Smith, A Qin, BL Lu, NH Wang, D Wang, HB Ramalingam, TR Wynn, TA Urban, JF Shea-Donohue, T Zhao, AP AF Wang, An-Jiang Yang, Zhonghan Grinchuk, Viktoriya Smith, Allen Qin, Bolin Lu, Nonghua Wang, Duan Wang, Hongbing Ramalingam, Thirumalai R. Wynn, Thomas A. Urban, Joseph F., Jr. Shea-Donohue, Terez Zhao, Aiping TI IL-25 or IL-17E Protects against High-Fat Diet-Induced Hepatic Steatosis in Mice Dependent upon IL-13 Activation of STAT6 SO JOURNAL OF IMMUNOLOGY LA English DT Article ID LIVER-DISEASE; TYPE-2 IMMUNITY; KUPFFER CELLS; ALTERNATIVE ACTIVATION; NEMATODE INFECTION; INTERLEUKIN-25; INFLAMMATION; MACROPHAGES; RECEPTOR; PROGRESSION AB IL-25 or IL-17E is a member of IL-17 cytokine family and has immune-modulating activities. The role of IL-25 in maintaining lipid metabolic homeostasis remains unknown. We investigated the effects of exogenous IL-25 or deficiency of IL-25 on hepatic lipid accumulation. IL-25 expression was examined in paraffin-embedded tissue sections of liver from patients or in the livers from mice. Mouse model of steatosis was induced by feeding a high-fat diet (HFD). Extent of steatosis as well as expression of cytokines, key enzymes for lipid metabolic pathways, markers for Kupffer cells/macrophages, and lipid droplet (LD) proteins, were analyzed. Our results show that hepatic steatosis in mice was accompanied by increased LD proteins, but decreased IL-25 in the liver. Decreased hepatic IL-25 was also observed in patients with fatty liver. Administration of IL-25 to HFD-fed wild-type mice led to a significant improvement in hepatic steatosis. This effect was associated with increased expression of IL-13, development of alternatively activated Kupffer cells/macrophages, and decreased expression of LD proteins in the liver. In contrast, administration of IL-25 to HFD-fed mice deficient in STAT6 or IL-13 had no effects. In addition, stimulation of primary hepatocytes with IL-13, but not IL-25, resulted in downregulation of LD proteins. Finally, mice deficient in IL-25 had exacerbated hepatic lipid accumulation when fed the HFD. These data demonstrate that dysregulated IL-25 expression contributes to lipid accumulation, whereas exogenous IL-25 protects against hepatic steatosis through IL-13 activation of STAT6. IL-25 and IL-13 are potential therapeutic agents for hepatic steatosis and associated pathologies. C1 [Wang, An-Jiang; Yang, Zhonghan; Grinchuk, Viktoriya; Qin, Bolin; Shea-Donohue, Terez; Zhao, Aiping] Univ Maryland, Sch Med, Dept Radiat Oncol, Baltimore, MD 21201 USA. [Wang, An-Jiang; Yang, Zhonghan; Grinchuk, Viktoriya; Shea-Donohue, Terez; Zhao, Aiping] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Wang, An-Jiang; Lu, Nonghua] Nanchang Univ, Affiliated Hosp 1, Dept Gastroenterol & Hepatol, Nanchang 330006, Peoples R China. [Yang, Zhonghan] Sun Yat Sen Univ, Zhongshan Med Sch, Dept Biochem, Guangzhou 510080, Guangdong, Peoples R China. [Smith, Allen; Urban, Joseph F., Jr.] ARS, Diet Genom & Immunol Lab, Beltsville Human Nutr Res Ctr, USDA, Beltsville, MD 20705 USA. [Wang, Duan; Wang, Hongbing] Univ Maryland, Sch Med, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. [Ramalingam, Thirumalai R.; Wynn, Thomas A.] NIAID, Div Parasitol, NIH, Bethesda, MD 20892 USA. RP Zhao, AP (reprint author), NIH, Div Physiol & Pathol Sci, Ctr Sci Review, 6701 Rockledge Dr, Bethesda, MD 20892 USA. EM aiping.zhao@nih.gov FU National Institutes of Health [R01-DK083418, R01-AI/DK49316, R01-DK061652]; U.S. Department of Agriculture Current Research Information System project [8040-51000-058-00]; National Natural Science Fund of China [81460122] FX This work was supported by National Institutes of Health Grants R01-DK083418 (to A.Z.), R01-AI/DK49316 (to T.S.-D.), and R01-DK061652 (to H.W.), U.S. Department of Agriculture Current Research Information System project 8040-51000-058-00 (to A.S. and J.F.U.), and National Natural Science Fund of China Grant 81460122 (to A.-J.W.). NR 43 TC 3 Z9 3 U1 1 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD NOV 15 PY 2015 VL 195 IS 10 BP 4771 EP 4780 DI 10.4049/jimmunol.1500337 PG 10 WC Immunology SC Immunology GA CW2LC UT WOS:000364822800027 PM 26423151 ER PT J AU Anton, OM Vielkind, S Peterson, ME Tagaya, Y Long, EO AF Anton, Olga M. Vielkind, Susina Peterson, Mary E. Tagaya, Yutaka Long, Eric O. TI NK Cell Proliferation Induced by IL-15 Transpresentation Is Negatively Regulated by Inhibitory Receptors SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NATURAL-KILLER-CELLS; HUMAN DENDRITIC CELLS; LYMPHOID HOMEOSTASIS; MICE LACKING; GAMMA-CHAIN; T-CELLS; ACTIVATION; IL-15R-ALPHA; RECRUITMENT; SURVIVAL AB IL-15 bound to the IL-15R alpha-chain (IL-15R alpha) is presented in trans to cells bearing the IL-2R beta-chain and common gamma-chain. As IL-15 transpresentation occurs in the context of cell-to-cell contacts, it has the potential for regulation by and of other receptor-ligand interactions. In this study, human NK cells were tested for the sensitivity of IL-15 transpresentation to inhibitory receptors. Human cells expressing HLA class I ligands for inhibitory receptors KIR2DL1, KIR2DL2/3, or CD94-NKG2A were transfected with IL-15R alpha. Proliferation of primary NK cells in response to transpresented IL-15 was reduced by engagement of either KIR2DL1 or KIR2DL2/3 by cognate HLA-C ligands. Inhibitory KIR-HLA-C interactions did not reduce the proliferation induced by soluble IL-15. Therefore, transpresentation of IL-15 is subject to downregulation by MHC class I-specific inhibitory receptors. Similarly, proliferation of the NKG2A(+) cell line NKL induced by IL-15 transpresentation was inhibited by HLA-E. Coengagement of inhibitory receptors, either KIR2DL1 or CD94-NKG2A, did not inhibit phosphorylation of Stat5 but inhibited selectively phosphorylation of Akt and S6 ribosomal protein. IL-15R alpha was not excluded from, but was evenly distributed across, inhibitory synapses. These findings demonstrate a novel mechanism to attenuate IL-15-dependent NK cell proliferation and suggest that inhibitory NK cell receptors contribute to NK cell homeostasis. C1 [Anton, Olga M.; Vielkind, Susina; Peterson, Mary E.; Long, Eric O.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Tagaya, Yutaka] Univ Maryland, Sch Med, Inst Human Virol, Div Basic Sci & Vaccine Res, Baltimore, MD 21201 USA. RP Long, EO (reprint author), NIAID, Immunogenet Lab, NIH, 12441 Parklawn Dr, Rockville, MD 20852 USA. EM eLong@nih.gov FU Intramural Research Program at the National Institutes of Health, National Institute of Allergy and Infectious Diseases FX This work was supported by the Intramural Research Program at the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 52 TC 2 Z9 2 U1 1 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD NOV 15 PY 2015 VL 195 IS 10 BP 4810 EP 4821 DI 10.4049/jimmunol.1500414 PG 12 WC Immunology SC Immunology GA CW2LC UT WOS:000364822800031 PM 26453750 ER PT J AU Mukherjee, P Winkler, CW Taylor, KG Woods, TA Nair, V Khan, BA Peterson, KE AF Mukherjee, Piyali Winkler, Clayton W. Taylor, Katherine G. Woods, Tyson A. Nair, Vinod Khan, Burhan A. Peterson, Karin E. TI SARM1, Not MyD88, Mediates TLR7/TLR9-Induced Apoptosis in Neurons SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INNATE IMMUNE-RESPONSES; TOLL-LIKE RECEPTOR-3; CELL-DEATH; CAUSES NEURODEGENERATION; NEGATIVE REGULATOR; TLR7; ACTIVATION; MITOCHONDRIA; EXPRESSION; PROTECTION AB Neuronal apoptosis is a key aspect of many different neurologic diseases, but the mechanisms remain unresolved. Recent studies have suggested a mechanism of innate immune-induced neuronal apoptosis through the stimulation of endosomal TLRs in neurons. TLRs are stimulated both by pathogen-associated molecular patterns as well as by damage-associated molecular patterns, including microRNAs released by damaged neurons. In the present study, we identified the mechanism responsible for TLR7/TLR9-mediated neuronal apoptosis. TLR-induced apoptosis required endosomal localization of TLRs but was independent of MyD88 signaling. Instead, apoptosis required the TLR adaptor molecule SARM1, which localized to the mitochondria following TLR activation and was associated with mitochondrial accumulation in neurites. Deficiency in SARM1 inhibited both mitochondrial accumulation in neurites and TLR-induced apoptosis. These studies identify a non-MyD88 pathway of TLR7/TLR9 signaling in neurons and provide a mechanism for how innate immune responses in the CNS directly induce neuronal damage. C1 [Mukherjee, Piyali; Winkler, Clayton W.; Taylor, Katherine G.; Woods, Tyson A.; Khan, Burhan A.; Peterson, Karin E.] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Nair, Vinod] NIAID, Res Technol Branch, Microscopy Unit, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. RP Peterson, KE (reprint author), NIAID, Rocky Mt Labs, 903 South 4th St, Hamilton, MT 59840 USA. EM petersonka@niaid.nih.gov RI Peterson, Karin/D-1492-2016 OI Peterson, Karin/0000-0003-4177-7249 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases. NR 36 TC 5 Z9 5 U1 3 U2 6 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD NOV 15 PY 2015 VL 195 IS 10 BP 4913 EP 4921 DI 10.4049/jimmunol.1500953 PG 9 WC Immunology SC Immunology GA CW2LC UT WOS:000364822800041 PM 26423149 ER PT J AU Sun, L Hua, YN Vergarajauregui, S Diab, HI Puertollano, R AF Sun, Lu Hua, Yinan Vergarajauregui, Silvia Diab, Heba I. Puertollano, Rosa TI Novel Role of TRPML2 in the Regulation of the Innate Immune Response SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MUCOLIPIDOSIS TYPE-IV; LYSOSOMAL BIOGENESIS; TRANSCRIPTION FACTOR; ENDOSOMAL PATHWAY; PROTEIN TRPML1; TRAFFICKING; CHANNEL; GENE; AUTOPHAGY; CELLS AB TRPMLs (or mucolipins) constitute a family of endosomal cation channels with homology to the transient receptor potential superfamily. In mammals, the TRPML family includes three members: TRPML1-3. Although TRPML1 and TRPML3 have been well characterized, the cellular function of TRPML2 has remained elusive. To address TRPML2 function in a physiologically relevant cell type, we first analyzed TRPML2 expression in different mouse tissues and organs and found that it was predominantly expressed in lymphoid organs and kidney. Quantitative RT-PCR revealed tight regulation of TRPML2 at the transcriptional level. Although TRPML2 expression was negligible in resting macrophages, TRPML2 mRNA and protein levels dramatically increased in response to TLR activation both in vitro and in vivo. Conversely, TRPML1 and TRPML3 levels did not change upon TLR activation. Immunofluorescence analysis demonstrated that endogenous TRPML2 primarily localized to recycling endosomes both in culture and primary cells, in contrast with TRPML1 and TRPML3, which distribute to the late and early endosomal pathway, respectively. To better understand the in vivo function of TRPML2, we generated a TRPML2-knockout mouse. We found that the production of several chemokines, in particular CCL2, was severely reduced in TRPML2-knockout mice. Furthermore, TRPML2-knockout mice displayed impaired recruitment of peripheral macrophages in response to i.p. injections of LPS or live bacteria, suggesting a potential defect in the immune response. Overall, our study reveals interesting differences in the regulation and distribution of the members of the TRPML family and identifies a novel role for TRPML2 in the innate immune response. C1 [Sun, Lu; Hua, Yinan; Vergarajauregui, Silvia; Diab, Heba I.; Puertollano, Rosa] NHLBI, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. RP Puertollano, R (reprint author), NHLBI, Cell Biol & Physiol Ctr, NIH, 9000 Rockville Pike,Bldg 50-3537, Bethesda, MD 20892 USA. EM puertolr@mail.nih.gov RI di Ronza, Alberto/H-7674-2016 OI di Ronza, Alberto/0000-0002-9813-5143 FU Intramural Research Program of the National Institutes of Health, National Heart, Lung, and Blood Institute FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Heart, Lung, and Blood Institute. NR 40 TC 5 Z9 5 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD NOV 15 PY 2015 VL 195 IS 10 BP 4922 EP 4932 DI 10.4049/jimmunol.1500163 PG 11 WC Immunology SC Immunology GA CW2LC UT WOS:000364822800042 PM 26432893 ER PT J AU Liu, X Luo, DY Yang, N AF Liu, Xin Luo, Deyan Yang, Ning TI Cytosolic Low Molecular Weight FGF2 Orchestrates RIG-I-Mediated Innate Immune Response SO JOURNAL OF IMMUNOLOGY LA English DT Article ID FIBROBLAST-GROWTH-FACTOR; E3 UBIQUITIN LIGASE; INDUCIBLE GENE-I; FACTOR-BETA; INTERFERON INDUCTION; ADAPTER PROTEIN; VIRUS; FACTOR-2; PROLIFERATION; RECOGNITION AB Fibroblast growth factor (FGF)2, which is one of the 22 members of the FGF family, functions as an extracellular molecule involved in canonical receptor tyrosine kinase signaling. It has been implicated in angiogenesis and the development of the CNS. In this article, we reveal that cytosolic low m.w. isoform (LMW) FGF2 (18 kDa), not its secreted form, plays an unexpected role in the innate immune response. Cytosolic LMW FGF2 directly associated with inactivated RIG-I under physiological conditions, which enhanced RIG-I protein stability, thereby maintaining basal RIG-I levels. However, during RIG-I activation induced by viral RNA, cytosolic FGF2 bound to the caspase recruitment domains of activated RIG-I, which blocked RIG-I-MAVS complex formation. LMW FGF2 deficiency increased type I IFN production, whereas the overexpression of LMW FGF2 exerted the opposite effect. Cytosolic LMW FGF2 functions as a negative regulator in RIG-I-mediated antiviral signaling. This work provides insight into the role of FGF2 in innate immune response. C1 [Liu, Xin; Luo, Deyan] Beijing Inst Microbiol & Epidemiol, State Key Lab Pathogen & Biosecur, Beijing 100071, Peoples R China. [Yang, Ning] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Yang, N (reprint author), NIAID, Viral Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ldy612@126.com; skyyning@gmail.com FU Beijing Institute of Microbiology and Epidemiology [20110801] FX This work was supported by Beijing Institute of Microbiology and Epidemiology funding for overseas scholars (Grant 20110801). NR 30 TC 1 Z9 1 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD NOV 15 PY 2015 VL 195 IS 10 BP 4943 EP 4952 DI 10.4049/jimmunol.1501503 PG 10 WC Immunology SC Immunology GA CW2LC UT WOS:000364822800044 PM 26466960 ER PT J AU Seymour, L Groshen, S Rosner, GL Sullivan, DM Spriggs, DR Reeves, S Gravell, A Ivy, SP Ratain, MJ AF Seymour, Lesley Groshen, Susan Rosner, Gary L. Sullivan, Daniel M. Spriggs, David R. Reeves, Steven Gravell, Amy Ivy, S. Percy Ratain, Mark J. TI Impact of the 2010 Consensus Recommendations of the Clinical Trial Design Task Force of the NCI Investigational Drug Steering Committee SO CLINICAL CANCER RESEARCH LA English DT Review ID PHASE-I; THERAPEUTICS; CANCER AB Oncology phase III trials have a high failure rate, leading to high development costs. The Clinical Trials Design Task Force of the Investigational Drug Steering Committee of the NCI Cancer Therapy and Evaluation Program developed Recommendations regarding the design of phase II trials. We report here on the results of a Concordance Group review charged with documenting whether concordance rates improved after the publication of the Recommendations. One hundred and fifty-five trials were reviewed. Letter of Intents (LOI) from the post-Recommendation period were more likely to be randomized (44% vs. 34%) and biomarker selected (19% vs. 10%). Single-arm studies using time-to-event endpoints (bench-marked against historical data) were similar, as was the type of tumor. There was a significant improvement in the rate of concordance, with 74% of LOIs scored as concordant compared with 58% before the Recommendations (P = 0.042). This included a marked decrease in the use of single-arm designs to evaluate the activity of drug combinations (19% vs. 5%, P = 0.009). There were areas for which clarification was warranted, including the need for protocols to include further development plans, the use of realistic benchmarks, the careful evaluation of historical controls, and the use of a standard treatment option as a control. Ongoing critical evaluation of current trial design methodology and the development of new Guidelines when appropriate will continue to improve drug development ensuring that safe and effective cancer therapeutics are made available to our patients as quickly and efficiently as possible. (C) 2015 AACR. C1 [Seymour, Lesley] NCIC Clin Trials Grp, Kingston, ON, Canada. [Groshen, Susan] USC Keck Sch Med, Los Angeles, CA USA. [Rosner, Gary L.] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Sullivan, Daniel M.] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [Spriggs, David R.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Reeves, Steven; Ivy, S. Percy] NCI, Rockville, MD USA. [Gravell, Amy] Emmes Corp, Rockville, MD USA. [Ratain, Mark J.] Univ Chicago, Chicago, IL 60637 USA. RP Seymour, L (reprint author), Queens Univ, 10 Stuart St, Kingston, ON K7L 3N6, Canada. EM lseymour@ctg.queensu.ca FU NCATS NIH HHS [UL1 TR001079]; NCI NIH HHS [UM1 CA186691, U10 CA180863] NR 7 TC 0 Z9 0 U1 0 U2 0 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 NOV 15 PY 2015 VL 21 IS 22 BP 5057 EP 5063 DI 10.1158/1078-0432.CCR-15-0035 PG 7 WC Oncology SC Oncology GA CV7XB UT WOS:000364488700013 PM 26567365 ER PT J AU Saito, K Matsumoto, S Takakusagi, Y Matsuo, M Morris, HD Lizak, MJ Munasinghe, JP Devasahayam, N Subramanian, S Mitchell, JB Krishna, MC AF Saito, Keita Matsumoto, Shingo Takakusagi, Yoichi Matsuo, Masayuki Morris, H. Douglas Lizak, Martin J. Munasinghe, Jeeva P. Devasahayam, Nallathamby Subramanian, Sankaran Mitchell, James B. Krishna, Murali C. TI C-13-MR Spectroscopic Imaging with Hyperpolarized [1-C-13]pyruvate Detects Early Response to Radiotherapy in SCC Tumors and HT-29 Tumors SO CLINICAL CANCER RESEARCH LA English DT Article ID MAGNETIC-RESONANCE-SPECTROSCOPY; SQUAMOUS-CELL CARCINOMA; HYPERBARIC-OXYGEN; CYCLING HYPOXIA; MURINE TUMORS; IN-VIVO; IRRADIATION; RADIATION; CANCER; AGENT AB Purpose: X-ray irradiation of tumors causes diverse effects on the tumor microenvironment, including metabolism. Recent developments of hyperpolarized C-13-MRI enabled detecting metabolic changes in tumors using a tracer [1-C-13] pyruvate, which participates in important bioenergetic processes that are altered in cancers. Here, we investigated the effects of X-ray irradiation on pyruvate metabolism in squamous cell carcinoma (SCCVII) and colon cancer (HT-29) using hyperpolarized C-13-MRI. Experimental Design: SCCVII and HT-29 tumors were grown by injecting tumor cells into the hind legs of mice. [1-C-13] pyruvate was hyperpolarized and injected intravenously into tumor-bearing mice, and C-13-MR signals were acquired using a 4.7 T scanner. Results: [1-C-13] pyruvate and [1-C-13] lactate were detected in the tumor-bearing legs immediately after hyperpolarized [1-C-13] pyruvate administration. The [1-C-13] lactate to [1-C-13] pyruvate ratio (Lac/Pyr) increased as the tumors grew in nonirradiated SCCVII tumors. The increase in Lac/Pyr was suppressed modestly with a single 10 Gy of irradiation, but it significantly decreased by further irradiation (10 Gy x 3). Similar results were obtained in HT-29; Lac/Pyr significantly dropped with fractionated 30 Gy irradiation. Independent ex vivo measurements revealed that the lactate dehydrogenase (LDH) activity and protein level were significantly smaller in the irradiated SCCVII tumors compared with the nonirradiated tumors, indicating that a decrease in LDH activity was one of the main factors responsible for the decrease of Lac/Pyr observed on C-13-MRI. Conclusions: Robust changes of Lac/Pyr observed in the HT-29 after the radiation suggested that lactate conversion from pyruvate monitored with hyperpolarized C-13-MRI could be useful for the evaluation of early response to radiotherapy. (C) 2015 AACR. C1 [Saito, Keita; Matsumoto, Shingo; Takakusagi, Yoichi; Matsuo, Masayuki; Devasahayam, Nallathamby; Subramanian, Sankaran; Mitchell, James B.; Krishna, Murali C.] NCI, Radiat Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Morris, H. Douglas; Lizak, Martin J.; Munasinghe, Jeeva P.] NINDS, NIH, Bethesda, MD 20892 USA. RP Krishna, MC (reprint author), NCI, Radiat Biol Branch, Ctr Canc Res, NIH, Bldg 10,Room B3B69,10 Ctr Dr, Bethesda, MD 20892 USA. EM murali@helix.nih.gov OI Morris, H. Douglas/0000-0002-7942-3748 FU intramural research program of the NCI/NIH FX This study was supported by intramural research program of the NCI/NIH. NR 41 TC 6 Z9 6 U1 1 U2 7 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 NOV 15 PY 2015 VL 21 IS 22 BP 5073 EP 5081 DI 10.1158/1078-0432.CCR-14-1717 PG 9 WC Oncology SC Oncology GA CV7XB UT WOS:000364488700015 PM 25673698 ER PT J AU O'Donnell, PH Karovic, S Karrison, TG Janisch, L Levine, MR Harris, PJ Polite, BN Cohen, EEW Fleming, GF Ratain, MJ Maitland, ML AF O'Donnell, Peter H. Karovic, Sanja Karrison, Theodore G. Janisch, Linda Levine, Matthew R. Harris, Pamela J. Polite, Blase N. Cohen, Ezra E. W. Fleming, Gini F. Ratain, Mark J. Maitland, Michael L. TI Serum C-Telopeptide Collagen Crosslinks and Plasma Soluble VEGFR2 as Pharmacodynamic Biomarkers in a Trial of Sequentially Administered Sunitinib and Cilengitide SO CLINICAL CANCER RESEARCH LA English DT Article ID RENAL-CELL CARCINOMA; NONPEPTIDE ALPHA(V)BETA(3) ANTAGONISTS; TYROSINE KINASE INHIBITOR; ENDOTHELIAL GROWTH-FACTOR; BLOOD-BASED BIOMARKERS; BONE-MINERAL DENSITY; PHASE-II; ANTITUMOR-ACTIVITY; DRUG DEVELOPMENT; BETA-CROSSLAPS AB Purpose: Fit-for-purpose pharmacodynamic biomarkers could expedite development of combination antiangiogenic regimens. Plasma sVEGFR2 concentrations ([sVEGFR2]) mark sunitinib effects on the systemic vasculature. We hypothesized that cilengitide would impair microvasculature recovery during sunitinib withdrawal and could be detected through changes in [sVEGFR2]. Experimental Design: Advanced solid tumor patients received 50 mg sunitinib daily for 14 days. For the next 14 days, patients were randomized to arm A (cilengitide 2,000 mg administered intravenously twice weekly) or arm B (no treatment). The primary endpoint was change in [sVEGFR2] between days 14 and 28. A candidate pharmacodynamic biomarker of cilengitide inhibition of integrin avb3, serum c-telopeptide collagen crosslinks (CTx), was also measured. Results: Of 21 patients, 14 (7 per arm) received all treatments without interruption and had all blood samples available for analysis. The mean change and SD of [sVEGFR2] for all sunitinib-treated patients was consistent with previous data. There was no significant difference in the mean change in [sVEGFR2] from days 14 to 28 between the arms [armA: 2.8 ng/mL; 95% confidence interval (CI), 2.1-3.6 vs. arm B: 2.0 ng/mL; 95% CI, 0.72-3.4; P = 0.22, 2-sample t test]. Additional analyses suggested (i) prior bevacizumab therapy to be associated with unusually low baseline [sVEGFR2] and (ii) sunitinib causes measurable changes in CTx. Conclusions: Cilengitide had no measurable effects on any circulating biomarkers. Sunitinib caused measurable declines in serum CTx. The properties of [sVEGFR2] and CTx observed in this study inform the design of future combination antiangiogenic therapy trials. (C) 2015 AACR. C1 [O'Donnell, Peter H.; Karovic, Sanja; Janisch, Linda; Levine, Matthew R.; Polite, Blase N.; Cohen, Ezra E. W.; Fleming, Gini F.; Ratain, Mark J.; Maitland, Michael L.] Univ Chicago, Dept Med, Sect Hematol Oncol, Chicago, IL 60637 USA. [O'Donnell, Peter H.; Fleming, Gini F.; Ratain, Mark J.; Maitland, Michael L.] Univ Chicago, Comm Clin Pharmacol & Pharmacogen, Chicago, IL 60637 USA. [O'Donnell, Peter H.; Karrison, Theodore G.; Polite, Blase N.; Cohen, Ezra E. W.; Fleming, Gini F.; Ratain, Mark J.; Maitland, Michael L.] Univ Chicago, Comprehens Canc Ctr, Chicago, IL 60637 USA. [Karrison, Theodore G.] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. [Harris, Pamela J.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Maitland, ML (reprint author), Univ Chicago, 5841 South Maryland Ave,MC 2115, Chicago, IL 60637 USA. EM mmaitlan@medicine.bsd.uchicago.edu FU U.S. NIH [K23CA124802]; University of Chicago Comprehensive Cancer Center [P30 CA14599]; Translational Research Professorship from the Conquer Cancer Foundation of the American Society of Clinical Oncology; EMD Serono, Inc.; [U01CA69852]; [UM1 CA186705] FX The clinical trial was sponsored by U01CA69852 (M.J. Ratain). This project was additionally supported by U.S. NIH grants: K23CA124802 NCI Career Development Award (M.L. Maitland), the University of Chicago Comprehensive Cancer Center (P30 CA14599) Clinical Pharmacology Core Laboratory, and UM1 CA186705. Additional support was provided by a Translational Research Professorship from the Conquer Cancer Foundation of the American Society of Clinical Oncology (P.H. O'Donnell, M.J. Ratain, and M.L. Maitland). EMD Serono, Inc. provided funding to support the conduct of biomarker assays in the conduct of this trial. NR 52 TC 1 Z9 1 U1 0 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 NOV 15 PY 2015 VL 21 IS 22 BP 5092 EP 5099 DI 10.1158/1078-0432.CCR-15-0427 PG 8 WC Oncology SC Oncology GA CV7XB UT WOS:000364488700017 PM 26199386 ER PT J AU Amyot, F Arciniegas, DB Brazaitis, MP Curley, KC Diaz-Arrastia, R Gandjbakhche, A Herscovitch, P Hinds, SR Manley, GT Pacifico, A Razumovsky, A Riley, J Salzer, W Shih, R Smirniotopoulos, JG Stocker, D AF Amyot, Franck Arciniegas, David B. Brazaitis, Michael P. Curley, Kenneth C. Diaz-Arrastia, Ramon Gandjbakhche, Amir Herscovitch, Peter Hinds, Sidney R., II Manley, Geoffrey T. Pacifico, Anthony Razumovsky, Alexander Riley, Jason Salzer, Wanda Shih, Robert Smirniotopoulos, James G. Stocker, Derek TI A Review of the Effectiveness of Neuroimaging Modalities for the Detection of Traumatic Brain Injury SO JOURNAL OF NEUROTRAUMA LA English DT Review DE electrophysiology; imaging; spectroscopy; tomography; ultrasound ID POSITRON-EMISSION-TOMOGRAPHY; TRANSCRANIAL DOPPLER ULTRASONOGRAPHY; DIFFUSE AXONAL INJURY; CEREBRAL-BLOOD-FLOW; MINOR HEAD-INJURY; ANEURYSMAL SUBARACHNOID HEMORRHAGE; NEAR-INFRARED SPECTROSCOPY; POSTTRAUMATIC-STRESS-DISORDER; EVENT-RELATED POTENTIALS; OPERATION IRAQI FREEDOM AB The incidence of traumatic brain injury (TBI) in the United States was 3.5 million cases in 2009, according to the Centers for Disease Control and Prevention. It is a contributing factor in 30.5% of injury-related deaths among civilians. Additionally, since 2000, more than 260,000 service members were diagnosed with TBI, with the vast majority classified as mild or concussive (76%). The objective assessment of TBI via imaging is a critical research gap, both in the military and civilian communities. In 2011, the Department of Defense (DoD) prepared a congressional report summarizing the effectiveness of seven neuroimaging modalities (computed tomography [CT], magnetic resonance imaging [MRI], transcranial Doppler [TCD], positron emission tomography, single photon emission computed tomography, electrophysiologic techniques [magnetoencephalography and electroencephalography], and functional near-infrared spectroscopy) to assess the spectrum of TBI from concussion to coma. For this report, neuroimaging experts identified the most relevant peer-reviewed publications and assessed the quality of the literature for each of these imaging technique in the clinical and research settings. Although CT, MRI, and TCD were determined to be the most useful modalities in the clinical setting, no single imaging modality proved sufficient for all patients due to the heterogeneity of TBI. All imaging modalities reviewed demonstrated the potential to emerge as part of future clinical care. This paper describes and updates the results of the DoD report and also expands on the use of angiography in patients with TBI. C1 [Amyot, Franck; Gandjbakhche, Amir] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Amyot, Franck; Diaz-Arrastia, Ramon] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. [Smirniotopoulos, James G.] Uniformed Serv Univ Hlth Sci, Dept Radiol Neurol & Biomed Informat, Bethesda, MD 20814 USA. [Arciniegas, David B.] Baylor Coll Med, Beth K & Stuart C Yudofsky Div Neuropsychiat, Houston, TX 77030 USA. [Arciniegas, David B.] TIRR Mem Hermann, Brain Injury Res, Houston, TX USA. [Brazaitis, Michael P.] US States Army, Washington, DC USA. [Brazaitis, Michael P.] Geneva Fdn, Geneva, Switzerland. [Curley, Kenneth C.] US Army Med Res & Mat Command, Combat Casualty Care Directorate RAD2, Ft Detrick, MD USA. [Herscovitch, Peter] Natl Inst Hlth Clin Ctr, Positron Emiss Tomog Dept, Bethesda, MD USA. [Hinds, Sidney R., II] Def Ctr Excellence Psychol Hlth & Traumat Brain I, Def & Vet Brain Injury Ctr, Silver Spring, MD USA. [Manley, Geoffrey T.] Univ Calif San Francisco, Dept Neurol Surg, Brain & Spinal Injury Ctr, San Francisco, CA USA. [Pacifico, Anthony; Salzer, Wanda] MCMR CD, Congress Directed Med Res Programs, Ft Detrick, MD 21702 USA. [Razumovsky, Alexander] Sentient NeuroCare Serv Inc, Hunt Valley, MD USA. [Riley, Jason] Queens Univ, Kingston, ON, Canada. [Riley, Jason] ArcheOptix Inc, Picton, ON, Canada. [Shih, Robert; Stocker, Derek] Walter Reed Natl Mil Med Ctr, Bethesda, MD USA. RP Pacifico, A (reprint author), MCMR CD, Congress Directed Med Res Programs, 1077 Patchel St, Ft Detrick, MD 21702 USA. EM anthony.m.pacifico.civ@mail.mil FU ArcheOptix Inc., a biomedical devices company FX Alexander Razumovsky is a full time employee of Sentient Medical Systems, a for-profit company providing medical monitoring and diagnostic services. Jason Riley is partially funded and employed by ArcheOptix Inc., a biomedical devices company. For the remaining authors, no competing financial interests exist. NR 350 TC 7 Z9 7 U1 8 U2 28 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD NOV 15 PY 2015 VL 32 IS 22 BP 1693 EP 1721 DI 10.1089/neu.2013.3306 PG 29 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA CV6ST UT WOS:000364401500001 PM 26176603 ER PT J AU Smith, DH Hicks, RR Johnson, VE Bergstrom, DA Cummings, DM Noble, LJ Hovda, D Whalen, M Ahlers, ST LaPlaca, M Tortella, FC Duhaime, AC Dixon, CE AF Smith, Douglas H. Hicks, Ramona R. Johnson, Victoria E. Bergstrom, Debra A. Cummings, Diana M. Noble, Linda J. Hovda, David Whalen, Michael Ahlers, Stephen T. LaPlaca, Michelle Tortella, Frank C. Duhaime, Ann-Christine Dixon, C. Edward TI Pre-Clinical Traumatic Brain Injury Common Data Elements: Toward a Common Language Across Laboratories SO JOURNAL OF NEUROTRAUMA LA English DT Article DE common data elements; data dictionary; pre-clinical TBI models; traumatic brain injury ID DIFFUSE AXONAL INJURY; CONTROLLED CORTICAL IMPACT; CLOSED-HEAD-INJURY; CEREBRAL BLOOD-FLOW; ACUTE SUBDURAL-HEMATOMA; ADULT-RAT BRAIN; FLUID-PERCUSSION MODEL; LASTING IMPULSE NOISE; ALZHEIMERS-DISEASE; INTRACRANIAL-PRESSURE AB Traumatic brain injury (TBI) is a major public health issue exacting a substantial personal and economic burden globally. With the advent of big data approaches to understanding complex systems, there is the potential to greatly accelerate knowledge about mechanisms of injury and how to detect and modify them to improve patient outcomes. High quality, well-defined data are critical to the success of bioinformatics platforms, and a data dictionary of common data elements (CDEs), as well as unique data elements has been created for clinical TBI research. There is no data dictionary, however, for preclinical TBI research despite similar opportunities to accelerate knowledge. To address this gap, a committee of experts was tasked with creating a defined set of data elements to further collaboration across laboratories and enable the merging of data for meta-analysis. The CDEs were subdivided into a Core module for data elements relevant to most, if not all, studies, and Injury-Model-Specific modules for non-generalizable data elements. The purpose of this article is to provide both an overview of TBI models and the CDEs pertinent to these models to facilitate a common language for preclinical TBI research. C1 [Smith, Douglas H.; Johnson, Victoria E.] Univ Penn, Dept Neurosurg, Philadelphia, PA 19104 USA. [Hicks, Ramona R.] One Mind, Seattle, WA USA. [Hicks, Ramona R.; Bergstrom, Debra A.; Cummings, Diana M.] NINDS, NIH, Bethesda, MD 20892 USA. [Noble, Linda J.] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA USA. [Hovda, David] Univ Calif Los Angeles, Dept Neurosurg, Los Angeles, CA USA. [Whalen, Michael] Massachusetts Gen Hosp, Dept Pediat, Ctr Neurosci, Charlestown, MA USA. [Ahlers, Stephen T.] Naval Med Res Ctr, Operat & Undersea Med Directorate, Silver Spring, MD USA. [LaPlaca, Michelle] Georgia Tech, Dept Biomed Engn, Atlanta, GA USA. [LaPlaca, Michelle] Emory Univ, Atlanta, GA 30322 USA. [Tortella, Frank C.] Walter Reed Army Inst Res, Silver Spring, MD USA. [Duhaime, Ann-Christine] Harvard Univ, Sch Med, Dept Neurosurg, Boston, MA USA. [Dixon, C. Edward] Univ Pittsburgh, Dept Neurol Surg, Pittsburgh, PA 15260 USA. RP Smith, DH (reprint author), Univ Penn, Dept Neurosurg, 105 Hayden Hall,3320 Smith Walk, Philadelphia, PA 19104 USA. EM smithdou@mail.med.upenn.edu FU U.S. Department of Defense; National Institutes of Health FX We would like to acknowledge the U.S. Department of Defense and the National Institutes of Health who contributed funding for The Federal Interagency Traumatic Brain Injury Research (FIT-BIR) Informatics System. NR 131 TC 11 Z9 11 U1 2 U2 5 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD NOV 15 PY 2015 VL 32 IS 22 BP 1725 EP 1735 DI 10.1089/neu.2014.3861 PG 11 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA CV6ST UT WOS:000364401500003 PM 26058402 ER PT J AU Buonora, JE Mousseau, M Jacobowitz, DM Lazarus, RC Yarnell, AM Olsen, CH Pollard, HB Diaz-Arrastia, R Latour, L Mueller, GP AF Buonora, John E. Mousseau, Michael Jacobowitz, David M. Lazarus, Rachel C. Yarnell, Angela M. Olsen, Cara H. Pollard, Harvey B. Diaz-Arrastia, Ramon Latour, Lawrence Mueller, Gregory P. TI Autoimmune Profiling Reveals Peroxiredoxin 6 as a Candidate Traumatic Brain Injury Biomarker SO JOURNAL OF NEUROTRAUMA LA English DT Article DE autoantibodies; autoimmune profiling; biomarker; peroxiredoxin 6; traumatic brain injury ID C-TERMINAL HYDROLASE; CENTRAL-NERVOUS-SYSTEM; HUMAN PLATELETS; 2-DIMENSIONAL ELECTROPHORESIS; RHEUMATOID-ARTHRITIS; GEL-ELECTROPHORESIS; NEUROTROPHIC FACTOR; OXIDATIVE STRESS; SERUM-LEVELS; PROTEIN AB Autoimmune profiling in rats revealed the antioxidant enzyme, peroxiredoxin 6 (PRDX6), as a target for autoantibodies evoked in response to traumatic brain injury (TBI). Consistent with this proposal, immunohistochemical analysis of rat cerebral cortex demonstrated that PRDX6 is highly expressed in the perivascular space, presumably contained within astrocytic foot processes. Accordingly, an immunosorbent electrochemiluminescence assay was developed for investigating PRDX6 in human samples. PRDX6 was found to be measurable in human blood and highly expressed in human cerebral cortex and platelets. Circulating levels of PRDX6 were elevated fourfold over control values 4 to 24h following mild-to-moderate TBI. These findings suggest that PRDX6 may serve as a biomarker for TBI and that autoimmune profiling is a viable strategy for the discovery of novel TBI biomarkers. C1 [Buonora, John E.; Mousseau, Michael; Pollard, Harvey B.; Diaz-Arrastia, Ramon; Mueller, Gregory P.] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. [Buonora, John E.; Jacobowitz, David M.; Lazarus, Rachel C.; Yarnell, Angela M.; Pollard, Harvey B.; Diaz-Arrastia, Ramon; Mueller, Gregory P.] Uniformed Serv Univ Hlth Sci, Program Neurosci, Bethesda, MD 20814 USA. [Mousseau, Michael; Jacobowitz, David M.; Pollard, Harvey B.; Mueller, Gregory P.] Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, Bethesda, MD 20814 USA. [Olsen, Cara H.] Uniformed Serv Univ Hlth Sci, Biostat Consulting Ctr, Bethesda, MD 20814 USA. [Diaz-Arrastia, Ramon] Uniformed Serv Univ Hlth Sci, Dept Neurol, Bethesda, MD 20814 USA. [Latour, Lawrence] NINDS, Sect Stroke Diagnost & Therapeut, Bethesda, MD 20892 USA. RP Mueller, GP (reprint author), USUHS, C2117,4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM gregory.mueller@usuhs.edu FU Department of Defense in the Center for Neuroscience and Regenerative Medicine [G1703D]; Defense Medical Research and Development Command [D61_I_10_J6_152]; TriService Nursing Research Program [N12-P12] FX The authors would like to acknowledge the expert technical assistance of Ms. Tinghua Chen and Mr. James Freedy. Support for this work included funding from: Department of Defense in the Center for Neuroscience and Regenerative Medicine (G1703D), Defense Medical Research and Development Command (D61_I_10_J6_152) and TriService Nursing Research Program (N12-P12). NR 57 TC 3 Z9 3 U1 1 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD NOV 15 PY 2015 VL 32 IS 22 BP 1805 EP 1814 DI 10.1089/neu.2014.3736 PG 10 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA CV6ST UT WOS:000364401500011 PM 25938937 ER PT J AU Sutherland, MT Ray, KL Riedel, MC Yanes, JA Stein, EA Laird, AR AF Sutherland, Matthew T. Ray, Kimberly L. Riedel, Michael C. Yanes, Julio A. Stein, Elliot A. Laird, Angela R. TI Neurobiological Impact of Nicotinic Acetylcholine Receptor Agonists: An Activation Likelihood Estimation Meta-Analysis of Pharmacologic Neuroimaging Studies SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Activation likelihood estimation (ALE); Default mode network (DMN); Executive control network (ECN); Nicotine; Pharmacologic functional magnetic resonance imaging (fMRI); Withdrawal ID STATE FUNCTIONAL CONNECTIVITY; SCALE BRAIN NETWORKS; DEFAULT NETWORK; VISUOSPATIAL ATTENTION; SMOKING ABSTINENCE; COGNITIVE FUNCTION; CIGARETTE-SMOKING; PARIETAL CORTEX; WORKING-MEMORY; CUE REACTIVITY AB BACKGROUND: Nicotinic acetylcholine receptor (nAChR) agonists augment cognition among cigarette smokers and nonsmokers, yet the systems-level neurobiological mechanisms underlying such improvements are not fully understood. Aggregating neuroimaging results regarding nAChR agonists provides a means to identify common functional brain changes that may be related to procognitive drug effects. METHODS: We conducted a meta-analysis of pharmacologic neuroimaging studies within the activation likelihood estimation framework. We identified published studies contrasting a nAChR drug condition versus a baseline and coded each contrast by activity change direction (decrease or increase), participant characteristics (smokers or nonsmokers), and drug manipulation employed (pharmacologic administration or cigarette smoking). RESULTS: When considering all studies, nAChR agonist administration was associated with activity decreases in multiple regions, including the ventromedial prefrontal cortex (vmPFC), posterior cingulate cortex (PCC), parahippocampus, insula, and the parietal and precentral cortices. Conversely, activity increases were observed in lateral frontoparietal cortices, the anterior cingulate cortex, thalamus, and cuneus. Exploratory analyses indicated that both smokers and nonsmokers showed activity decreases in the vmPFC and PCC, and increases in lateral frontoparietal regions. Among smokers, both pharmacologic administration and cigarette smoking were associated with activity decreases in the vmPFC, PCC, and insula and increases in the lateral PFC, dorsal anterior cingulate cortex, thalamus, and cuneus. CONCLUSIONS: These results provide support for the systems-level perspective that nAChR agonists suppress activity in default-mode network regions and enhance activity in executive control network regions in addition to reducing activation of some task-related regions. We speculate these are potential mechanisms by which nAChR agonists enhance cognition. C1 [Sutherland, Matthew T.] Florida Int Univ, Dept Psychol, Miami, FL 33199 USA. [Ray, Kimberly L.] Univ Calif Davis, Dept Psychiat, Sacramento, CA 95817 USA. [Riedel, Michael C.] Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, San Antonio, TX 78229 USA. [Yanes, Julio A.; Laird, Angela R.] Florida Int Univ, Dept Phys, Miami, FL 33199 USA. [Stein, Elliot A.] NIDA, Neuroimaging Res Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, Baltimore, MD USA. RP Sutherland, MT (reprint author), Florida Int Univ, Dept Psychol, AHC-4,Room 312,11200 SW 8th St, Miami, FL 33199 USA. EM masuther@fiu.edu OI Ray, Kimberly/0000-0003-1302-2834 FU National Institute on Drug Abuse [K01-DA037819]; National Institute of Mental Health of the National Institutes of Health [R01-MH074457, R56-MH097870]; Intramural Research Program of the National Institute on Drug Abuse FX This work was supported by Grants from the National Institute on Drug Abuse (K01-DA037819, MTS) and the National Institute of Mental Health (R01-MH074457 and R56-MH097870, ARL) of the National Institutes of Health. EAS is supported by the Intramural Research Program of the National Institute on Drug Abuse. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 83 TC 6 Z9 6 U1 1 U2 17 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD NOV 15 PY 2015 VL 78 IS 10 BP 711 EP 720 DI 10.1016/j.biopsych.2014.12.021 PG 10 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA CU3VW UT WOS:000363455100009 PM 25662104 ER PT J AU Mai, S Welzel, G Ottstadt, M Lohr, F Severa, S Prigge, ES Wentzensen, N Trunk, MJ Wenz, F von Knebel-Doeberitz, M Reuschenbach, M AF Mai, Sabine Welzel, Grit Ottstadt, Martine Lohr, Frank Severa, Sebastin Prigge, Elena-Sophie Wentzensen, Nicolas Trunk, Marcus J. Wenz, Frederik von Knebel-Doeberitz, Magnus Reuschenbach, Miriam TI Prognostic Relevance of HPV Infection and p16 Overexpression in Squamous Cell Anal Cancer SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID HUMAN-PAPILLOMAVIRUS; CLINICAL-IMPLICATIONS; OROPHARYNGEAL CANCER; RETROSPECTIVE ANALYSIS; FUTURE-DIRECTIONS; CANAL CARCINOMA; UNITED-STATES; EXPRESSION; SURVIVAL; HEAD AB Purpose: Human papillomavirus (HPV) DNA and p16 status have both been reported as prognostic factors in anal cancer, but the prognostic relevance of combined detection and particularly HPV-/p16+ and HPV+/p16- signatures is unknown. We evaluated combined HPV DNA and p16 status as a prognostic factor of treatment response in anal cancer. Methods: 106 patients treated with radiochemotherapy (RCT+5-FU/MMC) with available paraffin-embedded tumor tissue specimens were evaluated regarding local control (LC) and overall survival (OS) at 5 years. In addition to HPV DNA/p16 status, the influence of age, gender, previous surgery, initial recurrence, T stage, N status, and tumor localization was analyzed. Results: 63 patients were HPV+/p16+, 9 were HPV+/p16-, 11 were HPV-/p16+, and 23 were HPV-/p16-. In univariate analysis, LC was significantly better in patients with T1/2 stage, female gender, and HPV/p16 status. HPV+/p16+ was associated with significantly better LC (88.1%; 95% confidence interval [CI]: 78.89-97.31) compared with HPV-/p16+ (63.6%; 95% CI: 35.18-92.02; P = .021) and especially HPV-/p16- (55.8%; 95% CI: 33.46-78.14; P = .002) but not with HPV+/p16- (77.8%; 95% CI: 50.56-105.04; P = .270). OS was influenced by T stage and LC. HPV+/p16+ patients showed a trend toward better OS compared with HPV -/p16- patients (HPV+/p16+: 81.1%; 95% CI: 70.12-92.08 vs HPV-/p16- : 68.8%; 95% CI: 47.44-90.16; P = .138). On multivariate analysis, T3/4 stage and HPV/p16 status (HPV-/p16+, HPV-/p16- vs HPV+/p16+) predicted poorer LC (T3/4: 50.3% vs T1/2: 86.6%, hazard ratio [HR] 0.22; 95% CI: 0.09-0.53; P < .001; HPV+/p16+ vs HPV-/p16+: HR 4.73; 95% CI: 1.33-16.82; PZ. 016, and HPV+/p16+ vs HPV-/p16- : HR 6.40; 95% CI: 2.23-18.35; P < .001), whereas local relapse dramatically influenced OS. Conclusion: Our data suggest that HPV/p16 signature determines prognosis. HPV+/p16+ patients had the best prognosis, and HPV-/p16+ and HPV-/p16- patients showed the worst outcome and therefore require therapy optimization, particularly given that LC is the most important factor for OS. (C) 2015 Elsevier Inc. All rights reserved. C1 [Mai, Sabine; Welzel, Grit; Ottstadt, Martine; Lohr, Frank; Severa, Sebastin; Wenz, Frederik] Heidelberg Univ, Univ Med Ctr Mannheim, Dept Radiat Oncol, Mannheim, Germany. [Prigge, Elena-Sophie; von Knebel-Doeberitz, Magnus; Reuschenbach, Miriam] Heidelberg Univ, Inst Pathol, Dept Appl Tumor Biol, Heidelberg, Germany. [Prigge, Elena-Sophie; von Knebel-Doeberitz, Magnus; Reuschenbach, Miriam] German Canc Res Ctr, Clin Cooperat Unit Appl Tumor Biol, Heidelberg, Germany. [Wentzensen, Nicolas] Natl Canc Inst, Div Canc Epidemiol & Genet, Bethesda, MD USA. [Trunk, Marcus J.] Heidelberg Univ, Univ Med Ctr Mannheim, Inst Pathol, Mannheim, Germany. RP Mai, S (reprint author), Univ Klinikum Mannheim, Klin Strahlentherapie & Radioonkol, Theodor Kutzer Ufer 1-3, D-68135 Mannheim, Germany. EM sabine.mai@umm.de RI von Knebel Doeberitz, Magnus/D-2372-2016 OI von Knebel Doeberitz, Magnus/0000-0002-0498-6781 FU Elekta; ORYX Fond GmbH FX F.L. has received research support and travel grants from Elekta and is a board member of C-Rad, F.W. reports grants and personal fees from Elekta, and M.v K.-D. has received research funding from ORYX Fond GmbH and has royalty sharing agreements with the University of Heidelberg. The other authors report no conflict of interest. NR 42 TC 7 Z9 7 U1 0 U2 10 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 NOV 15 PY 2015 VL 93 IS 4 BP 819 EP 827 DI 10.1016/j.ijrobp.2015.08.004 PG 9 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA CU0EL UT WOS:000363188700012 PM 26530750 ER PT J AU Braganza, MZ Potischman, N Park, Y Thompson, FE Hollenbeck, AR Kitahara, CM AF Braganza, Melissa Z. Potischman, Nancy Park, Yikyung Thompson, Frances E. Hollenbeck, Albert R. Kitahara, Cari M. TI Adolescent and mid-life diet and subsequent risk of thyroid cancer in the NIH-AARP diet and health study SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE adolescence; diet; nutrients; prospective study; thyroid cancer ID POOLED ANALYSIS; LARGE COHORT; ASSOCIATION; CHILDHOOD; PAPILLARY; EXPOSURE; OBESITY; GROWTH; WOMEN AB Although thyroid cancer is suspected to have a nutritional etiology, prospective studies examining the relationship between diet and thyroid cancer are lacking. During 1996-1997, NIH-AARP Diet and Health Study participants, ages 51-72 years, completed a 37-item food frequency questionnaire about diet at ages 12-13 years (adolescence) and 10 years before baseline (mid-life). Over a median 10 years of follow-up, 325 individuals (143 men and 182 women) were diagnosed with thyroid cancer. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for intakes of foods and food groups comparing the highest to the lowest quartiles. Adolescent intakes of chicken/turkey (HR=1.59, 95% CI: 0.97-2.60; p(trend) < 0.01) and sweet baked goods (HR=1.59, 95% CI: 1.09-2.34; p(trend)=0.04) were positively associated with thyroid cancer risk, while intake of butter/margarine was inversely associated with risk (HR=0.64, 95% CI: 0.44-0.91; p(trend) < 0.02). Similar to adolescent diet, mid-life intake of sweet baked goods was nonsignificantly associated with an increased risk of thyroid cancer (HR=1.39, 95% CI: 0.96-2.00; p(trend)=0.11), but intake of butter/margarine was inversely associated with risk (HR=0.66, 95% CI: 0.46-0.95; p(trend)=0.03). Among men, higher adolescent consumption of canned tuna was positively associated with risk of thyroid cancer (HR=1.69, 95% CI: 1.01-2.83; p(trend)=0.03), and greater mid-life intake of broccoli was associated with a twofold increased risk (HR52.13, 95% CI: 1.13-3.99; p(trend)<0.01). This large prospective study suggests that several components of the adolescent and mid-life diet, including iodine-rich foods and goitrogens, may influence thyroid cancer risk. C1 [Braganza, Melissa Z.; Park, Yikyung; Kitahara, Cari M.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Potischman, Nancy; Thompson, Frances E.] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Park, Yikyung] Washington Univ, Sch Med, Div Publ Hlth Sci, St Louis, MO 63110 USA. [Hollenbeck, Albert R.] AARP, AARP Res, Washington, DC USA. RP Kitahara, CM (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM meinholdc@mail.nih.gov RI Kitahara, Cari/R-8267-2016; OI Park, Yikyung/0000-0002-6281-489X FU National Institutes of Health (Intramural Research Program of the National Cancer Institute) FX Grant sponsor: National Institutes of Health (Intramural Research Program of the National Cancer Institute) NR 33 TC 1 Z9 1 U1 0 U2 8 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 NOV 15 PY 2015 VL 137 IS 10 BP 2413 EP 2423 DI 10.1002/ijc.29600 PG 11 WC Oncology SC Oncology GA CT5IQ UT WOS:000362842600014 PM 25974060 ER PT J AU Niciu, MJ Abdallah, CG Fenton, LR Fasula, MK Black, A Anderson, GM Sanacora, G AF Niciu, Mark J. Abdallah, Chadi G. Fenton, Lisa R. Fasula, Madonna K. Black, Anne Anderson, George M. Sanacora, Gerard TI A history of early life parental loss or separation is associated with successful cognitive-behavioral therapy in major depressive disorder SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Major depressive disorder; Cognitive-behavioral therapy; Parental loss; Parental separation; Hypothalamic-pituitary-adrenal axis; Cortisol ID COLLABORATIVE RESEARCH-PROGRAM; MENTAL-HEALTH TREATMENT; NATIONAL-INSTITUTE; TREATMENT RESPONSE; CHILDHOOD TRAUMA; PHARMACOTHERAPY; PSYCHOTHERAPY; INVENTORY; RELAPSE AB Background: There is a clinical need for evidence-based psychotherapy response biomarkers in major depressive disorder (MDD). Based on previous studies, we hypothesized that lower 24-h urinary cortisol levels and a history of early life stress/trauma would predict an improved antidepressant response to cognitive-behavioral therapy (CBT). Methods: 50 currently depressed MDD subjects were enrolled. 24-h urine was collected and measured for cortisol levels by radioimmunoassay (RIA). Subjects were also administered early life stress/trauma measures at baseline: Global Perceived Early-Life Stress (GPELS), The Early Life Trauma Inventory (ELTI) and Klein Loss Scale (KLS). The efficacy of a twelve-week course of once-weekly CBT was evaluated by the primary outcome measure, the 24-item Hamilton Depression Rating Scale (HDRS24), at baseline and every four weeks, and the Beck Depression Inventory at baseline and weekly thereafter. 42 subjects had at least one complete follow-up visit (>= 4 weeks of CBT), and 30 subjects completed the full 12-week course. Results: Baseline 24-h urinary cortisol levels did not correlate with CBT's antidepressant response. Higher KLS scores, a measure of early life parental loss or separation, correlated with delta HDRS24 (r(s)=-0.39. P-adjusted=0.05). Complementary general linear model analysis revealed enhanced CBT efficacy in patients with a history of early life parental loss or separation [F-(1,F- 3.5)=6.65, p=0.01] . Limitations: Small sample size, Treatment-naive population. Conclusions: Early life parental separation or loss positively correlated with CBT's antidepressant efficacy in our sample and may warrant further study in larger clinical samples. (C) 2015 Elsevier B.V. All rights reserved C1 [Niciu, Mark J.] NIMH, NIH, Expt Therapeut & Pathophysiol Branch, Bethesda, MD 20892 USA. [Abdallah, Chadi G.; Fasula, Madonna K.; Sanacora, Gerard] Yale Univ, Dept Psychiat, Connecticut Mental Hlth Ctr, Abraham Ribicoff Res Facil, New Haven, CT 06519 USA. [Abdallah, Chadi G.] Vet Affairs Natl Ctr PTSD, Vet Affairs Connecticut Healthcare Syst, Clin Neurosci Div, West Haven, CT 06516 USA. [Fenton, Lisa R.; Black, Anne] Vet Affairs Connecticut Healthcare Syst, West Haven, CT 06516 USA. [Anderson, George M.] Yale Child Study Ctr, West Haven, CT 06516 USA. RP Niciu, MJ (reprint author), NIMH, NIH, Expt Therapeut & Pathophysiol Branch, Bldg 10-CRC,10 Ctr Dr, Bethesda, MD 20892 USA. EM mark.niciu@nih.gov RI Niciu, Mark/J-1766-2014; OI Niciu, Mark/0000-0002-5612-3021; Abdallah, Chadi/0000-0001-5783-6181 FU NIMH NIH HHS [K02 MH076222, K23 MH101498, R01 MH071676] NR 27 TC 1 Z9 1 U1 0 U2 18 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 EI 1573-2517 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD NOV 15 PY 2015 VL 187 BP 241 EP 244 DI 10.1016/j.jad.2015.08.026 PG 4 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA CS1RL UT WOS:000361845300035 PM 26363143 ER PT J AU Gorai, AK Kanchan Upadhyay, A Tuluri, F Goyal, P Tchounwou, PB AF Gorai, Amit Kumar Kanchan Upadhyay, Abhishek Tuluri, Francis Goyal, Pramila Tchounwou, Paul B. TI An innovative approach for determination of air quality health index SO SCIENCE OF THE TOTAL ENVIRONMENT LA English DT Article DE Air quality health index; Fuzzy-AHP ID FUZZY SYNTHETIC EVALUATION; EXTENT ANALYSIS METHOD; DEVELOPING-COUNTRIES; POLLUTION; AHP; ASSOCIATION; CHILDREN; RANKING; ASTHMA AB Fuzzy-analytical hierarchical process (F-AHP) can be extended to determine fuzzy air quality health index (FAQHI) for deducing health risk associatedwith local air pollution levels, and subjective parameters. The present work aims at determining FAQHI by considering five air pollutant parameters (SO2, NO2, O-3, CO, and PM10) and three subjective parameters (population sensitivity, population density and location sensitivity). Each of the individual pollutants has varying impacts. Hence the combined health effects associated with the pollutants were estimated by aggregating the pollutants with different weights. Global weights for each evaluation alternatives were determined using fuzzy-AHP method. The developed model was applied to determine FAQHI in Howrah City, India from daily-observed concentrations of air pollutants over the three-year period between 2009 and 2011. The FAQHI values obtained through this method in Howrah City range from 1 to 3. Since the permissible value of FAQHI (as calculated for NAAQS) for residential areas is 1.78, higher index values are of public health concern to the exposed individuals. During the period of study, the observed FAQHI values were found to be higher than 1.78 in most of the day in the months of January to March, and October to December. However, the index values were below the recommended limit during rest of the months. In conclusion, FAQHI in Howrah city was above permissible limit in winter months and within acceptable values in summer and rainy months. Diurnal variations of FAQHI showed a similar trend during the three-year period of assessment. (C) 2015 Elsevier B.V. All rights reserved. C1 [Gorai, Amit Kumar] Natl Inst Technol, Dept Min Engn, Rourkela 769008, Odisha, India. [Kanchan] Birla Inst Technol, Dept Civil & Environm Engn, Ranchi 835215, Jharkhand, India. [Upadhyay, Abhishek; Goyal, Pramila] IIT Delhi, Ctr Atmospher Sci, Delhi 110016, India. [Tuluri, Francis] Jackson State Univ, Dept Technol, Jackson, MS 39217 USA. [Tchounwou, Paul B.] Jackson State Univ, NIH, NIMHD, RCMI Ctr Environm Hlth, Jackson, MS 39217 USA. RP Gorai, AK (reprint author), Natl Inst Technol, Dept Min Engn, Rourkela 769008, Odisha, India. EM amit_gorai@yahoo.co.uk FU DST, New Delhi [SR/FTP/ES-17/2012]; NIH/NIMHD [G12MD007581] FX The authors are grateful to West Bengal Pollution Control Board, India for providing the air quality data used in this study. The support from the DST, New Delhi Grant No. SR/FTP/ES-17/2012 and NIH/NIMHD Grant No. G12MD007581 are also acknowledged. NR 33 TC 2 Z9 2 U1 2 U2 37 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0048-9697 EI 1879-1026 J9 SCI TOTAL ENVIRON JI Sci. Total Environ. PD NOV 15 PY 2015 VL 533 BP 495 EP 505 DI 10.1016/j.scitotenv.2015.06.133 PG 11 WC Environmental Sciences SC Environmental Sciences & Ecology GA CQ0LV UT WOS:000360288300053 PM 26186464 ER PT J AU Luna, VM Daikoku, E Ono, F AF Luna, Victor M. Daikoku, Eriko Ono, Fumihito TI "Slow" skeletal muscles across vertebrate species SO CELL AND BIOSCIENCE LA English DT Review DE Zebrafish; Muscle; Slow fiber; Fast fiber; Acetylcholine receptor; Synapse ID EXTRA-OCULAR MUSCLES; NEUROMUSCULAR-JUNCTION; FROG-MUSCLE; LARVAL ZEBRAFISH; XENOPUS-LAEVIS; NERVE-ENDINGS; FIBERS; ACETYLCHOLINE; CURRENTS; RAT AB Skeletal muscle fibers are generally classified into two groups: slow (type I) and fast (type II). Fibers in each group are uniquely designed for specific locomotory needs based on their intrinsic cellular properties and the types of motor neurons that innervate them. In this review, we will focus on the current concept of slow muscle fibers which, unlike the originally proposed version based purely on amphibian muscles, varies widely depending on the animal model system studied. We will discuss recent findings from zebrafish neuromuscular junction synapses that may provide the framework for establishing a more unified view of slow muscles across mammalian and non-mammalian species. C1 [Luna, Victor M.] Columbia Univ, New York State Psychiat Inst, Div Integrat Neurosci, Dept Psychiat, New York, NY 10032 USA. [Daikoku, Eriko; Ono, Fumihito] Osaka Med Coll, Dept Mol Physiol, Takatsuki, Osaka 5698686, Japan. [Ono, Fumihito] NIAAA, Lab Mol Physiol, NIH, Bethesda, MD 20892 USA. RP Ono, F (reprint author), Osaka Med Coll, Dept Mol Physiol, 2-7 Daigaku Machi, Takatsuki, Osaka 5698686, Japan. EM onof@osaka-med.ac.jp OI ono, fumihito/0000-0001-7532-5262 FU intramural program at NIAAA; Research Support Center at OMC FX We thank Ms. Kasumi Minamimoto, Ms. Chika Murakami and Mr. Tomihiro Ono for their help in making figures and editing the text. This work was supported by the intramural program at NIAAA and the Research Support Center at OMC. NR 55 TC 2 Z9 2 U1 2 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2045-3701 J9 CELL BIOSCI JI Cell Biosci. PD NOV 14 PY 2015 VL 5 AR 62 DI 10.1186/s13578-015-0054-6 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CW9JB UT WOS:000365313900001 PM 26568818 ER PT J AU Chen, RJ Zhang, GF Garfield, SH Shi, YJ Chen, KG Robey, PG Leapman, RD AF Chen, Richard J. Zhang, Guofeng Garfield, Susan H. Shi, Yi-Jun Chen, Kevin G. Robey, Pamela G. Leapman, Richard D. TI Variations in Glycogen Synthesis in Human Pluripotent Stem Cells with Altered Pluripotent States SO PLOS ONE LA English DT Article ID HUMAN EMBRYONIC STEM; SELF-RENEWAL; GROUND-STATE; HUMAN ES; INDUCTION; LINES; MAINTENANCE; DIFFERENTIATION; EXPRESSION; NAIVE AB Human pluripotent stem cells (hPSCs) represent very promising resources for cell-based regenerative medicine. It is essential to determine the biological implications of some fundamental physiological processes (such as glycogen metabolism) in these stem cells. In this report, we employ electron, immunofluorescence microscopy, and biochemical methods to study glycogen synthesis in hPSCs. Our results indicate that there is a high level of glycogen synthesis (0.28 to 0.62 mu g/mu g proteins) in undifferentiated human embryonic stem cells (hESCs) compared with the glycogen levels (0 to 0.25 mu g/mu g proteins) reported in human cancer cell lines. Moreover, we found that glycogen synthesis was regulated by bone morphogenetic protein 4 (BMP-4) and the glycogen synthase kinase 3 (GSK-3) pathway. Our observation of glycogen bodies and sustained expression of the pluripotent factor Oct-4 mediated by the potent GSK-3 inhibitor CHIR-99021 reveals an altered pluripotent state in hPSC culture. We further confirmed glycogen variations under different naive pluripotent cell growth conditions based on the addition of the GSK-3 inhibitor BIO. Our data suggest that primed hPSCs treated with naive growth conditions acquire altered pluripotent states, similar to those naive-like hPSCs, with increased glycogen synthesis. Furthermore, we found that suppression of phosphorylated glycogen synthase was an underlying mechanism responsible for altered glycogen synthesis. Thus, our novel findings regarding the dynamic changes in glycogen metabolism provide new markers to assess the energetic and various pluripotent states in hPSCs. The components of glycogen metabolic pathways offer new assays to delineate previously unrecognized properties of hPSCs under different growth conditions. C1 [Chen, Richard J.; Zhang, Guofeng; Leapman, Richard D.] Natl Inst Biomed Imaging & Bioengn, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD 20892 USA. [Garfield, Susan H.] NCI, Expt Carcinogenesis, NIH, Bethesda, MD 20892 USA. [Shi, Yi-Jun; Chen, Kevin G.] NINDS, Stem Cell Unit, NIH, Bethesda, MD 20892 USA. [Robey, Pamela G.] Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. RP Leapman, RD (reprint author), Natl Inst Biomed Imaging & Bioengn, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD 20892 USA. EM leapmanr@mail.nih.gov RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 FU National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health FX This research was funded by the Intramural Program of the National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health. NR 50 TC 0 Z9 0 U1 1 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 NOV 13 PY 2015 VL 10 IS 11 AR e0142554 DI 10.1371/journal.pone.0142554 PG 22 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DA2MI UT WOS:000367628500032 PM 26565809 ER PT J AU Koehly, LM Morris, BA Skapinsky, K Goergen, A Ludden, A AF Koehly, Laura M. Morris, Bronwyn A. Skapinsky, Kaley Goergen, Andrea Ludden, Amanda TI Evaluation of the Families SHARE workbook: an educational tool outlining disease risk and healthy guidelines to reduce risk of heart disease, diabetes, breast cancer and colorectal cancer SO BMC PUBLIC HEALTH LA English DT Article DE Family health history; Disease risk; Chronic diseases; Family genomics health educator; Risk assessment; Breast cancer; Colorectal cancer; Diabetes; Heart disease ID CORONARY-ARTERY-DISEASE; MYOCARDIAL-INFARCTION; PARENTAL HISTORY; CARDIOVASCULAR-DISEASE; PHYSICAL-ACTIVITY; PREDICTIVE MODEL; AMERICAN WOMEN; SCORING SCHEME; OVARIAN-CANCER; PUBLIC-HEALTH AB Background: Common diseases such as heart disease, diabetes, and cancer are etiologically complex with multiple risk factors (e.g., environment, genetic, lifestyle). These risk factors tend to cluster in families, making families an important social context for intervention and lifestyle-focused disease prevention. The Families Sharing Health Assessment and Risk Evaluation (SHARE) workbook was designed as an educational tool outlining family health history based risk of heart disease, type 2 diabetes, breast cancer, and colorectal cancer. The current paper describes the steps taken to develop and evaluate the workbook employing a user-centered design approach. Methods: The workbook was developed in four steps, culminating in an evaluation focusing on understanding and usability of the tool. The evaluation was based on two Phases of data collected from a sample of mothers of young children in the Washington, D.C., area. A baseline assessment and follow-up approximately two weeks after receipt of the workbook were conducted, as well as focus groups with participants. The design of the workbook was refined in response to participant feedback from the first evaluation Phase and subsequently re-evaluated with a new sample. Results: After incorporating user-based feedback and revising the workbook, Phase 2 evaluation results indicated that understanding of the workbook components improved for all sections (from 6.26 to 6.81 on a 7-point scale). In addition, 100 % of users were able to use the algorithm to assess their disease risk and over 60 % used the algorithm to assess family members' disease risk. At follow-up, confidence to increase fruit, vegetable and fiber intake improved significantly, as well. Conclusions: The Families SHARE workbook was developed and evaluated resulting in a family health history tool that is both understandable and usable by key stakeholders. This educational tool will be used in intervention studies assessing the effectiveness of family genomics health educators who use the Families SHARE workbook to disseminate family risk information and encourage risk reducing behaviors. C1 [Koehly, Laura M.; Morris, Bronwyn A.; Skapinsky, Kaley; Goergen, Andrea; Ludden, Amanda] NHGRI, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA. RP Koehly, LM (reprint author), NHGRI, Social & Behav Res Branch, NIH, Bldg 31,Rm B1B54, Bethesda, MD 20892 USA. EM koehlyl@mail.nih.gov FU Division of Intramural Research of National Human Genome Research Institute, National Institutes of Health [Z01HG20335] FX This research was conducted and data analyzed at and supported by the Division of Intramural Research of the National Human Genome Research Institute, National Institutes of Health (Z01HG20335 to LMK). We thank Kayla de la Haye, Donald Hadley, Gillian Hooker, and Kimberly Kaphingst for their feedback on the Families SHARE workbook during its design step. Darryl Leja and Julia Fekecs were the graphic design team on this project; it could not have been accomplished without them. We express our gratitude to the participants of this study. NR 112 TC 4 Z9 4 U1 0 U2 3 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 NOV 13 PY 2015 VL 15 AR 1120 DI 10.1186/s12889-015-2483-x PG 15 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CW9FE UT WOS:000365303200001 PM 26566980 ER PT J AU Gowen, BG Chim, B Marceau, CD Greene, TT Burr, P Gonzalez, JR Hesser, CR Dietzen, PA Russell, T Iannello, A Coscoy, L Sentman, CL Carette, JE Muljo, SA Raulet, DH AF Gowen, Benjamin G. Chim, Bryan Marceau, Caleb D. Greene, Trever T. Burr, Patrick Gonzalez, Jeanmarie R. Hesser, Charles R. Dietzen, Peter A. Russell, Teal Iannello, Alexandre Coscoy, Laurent Sentman, Charles L. Carette, Jan E. Muljo, Stefan A. Raulet, David H. TI A forward genetic screen reveals novel independent regulators of ULBP1, an activating ligand for natural killer cells SO ELIFE LA English DT Article ID UNFOLDED PROTEIN RESPONSE; INNATE IMMUNE-SYSTEM; NKG2D RECEPTOR; ER-STRESS; TRANSCRIPTIONAL REGULATION; BINDING-PROTEIN; UP-REGULATION; OXIDATIVE STRESS; SELF-TOLERANCE; CANCER-CELLS AB Recognition and elimination of tumor cells by the immune system is crucial for limiting tumor growth. Natural killer (NK) cells become activated when the receptor NKG2D is engaged by ligands that are frequently upregulated in primary tumors and on cancer cell lines. However, the molecular mechanisms driving NKG2D ligand expression on tumor cells are not well defined. Using a forward genetic screen in a tumor-derived human cell line, we identified several novel factors supporting expression of the NKG2D ligand ULBP1. Our results show stepwise contributions of independent pathways working at multiple stages of ULBP1 biogenesis. Deeper investigation of selected hits from the screen showed that the transcription factor ATF4 drives ULBP1 gene expression in cancer cell lines, while the RNA-binding protein RBM4 supports ULBP1 expression by suppressing a novel alternatively spliced isoform of ULBP1 mRNA. These findings offer insight into the stress pathways that alert the immune system to danger. C1 [Gowen, Benjamin G.; Greene, Trever T.; Gonzalez, Jeanmarie R.; Hesser, Charles R.; Dietzen, Peter A.; Russell, Teal; Iannello, Alexandre; Coscoy, Laurent; Raulet, David H.] Univ Calif Berkeley, Canc Res Lab, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. [Chim, Bryan; Burr, Patrick; Muljo, Stefan A.] NIAID, Immunol Lab, Bethesda, MD 20892 USA. [Marceau, Caleb D.; Carette, Jan E.] Stanford Univ, Sch Med, Dept Microbiol & Immunol, Stanford, CA 94305 USA. [Sentman, Charles L.] Dartmouth Geisel Sch Med, Dept Microbiol & Immunol, Ctr Synthet Immun, Lebanon, NH USA. RP Raulet, DH (reprint author), Univ Calif Berkeley, Canc Res Lab, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. EM raulet@berkeley.edu OI Gonzalez, Jeanmarie/0000-0001-8998-7726 FU National Institutes of Health (NIH) [R01-AI039642, DP2 AI104557]; National Science Foundation (NSF) [NSF 0552996, DGE 1106400]; David and Lucile Packard Foundation; University of California Berkeley (UC Berkeley) FX National Institutes of Health (NIH) Intramural Research Program of the National Institute of Allergy and Infectious Diseases Stefan A Muljo; National Science Foundation (NSF) Research Experience for Undergraduates, NSF 0552996 Teal Russell; David and Lucile Packard Foundation Fellowship Jan E Carette; University of California Berkeley (UC Berkeley) K. Peter Hirth Chair, Graduate Student Fellowship Benjamin G Gowen; National Institutes of Health (NIH) R01-AI039642 David H Raulet; National Institutes of Health (NIH) DP2 AI104557 Jan E Carette; National Science Foundation (NSF) Graduate Research Fellowship DGE 1106400 Benjamin G Gowen; The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 73 TC 3 Z9 3 U1 1 U2 6 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD NOV 13 PY 2015 VL 4 AR e08474 DI 10.7554/eLife.08474 PG 26 WC Biology SC Life Sciences & Biomedicine - Other Topics GA CW2JI UT WOS:000364817600001 ER PT J AU Robinson, JP Roederer, M AF Robinson, J. Paul Roederer, Mario TI Flow cytometry strikes gold SO SCIENCE LA English DT Editorial Material ID CELLS; SEPARATION; SYSTEMS; IMMUNE C1 [Robinson, J. Paul] Purdue Univ, Dept Basic Med Sci, W Lafayette, IN 47907 USA. [Robinson, J. Paul] Purdue Univ, Weldon Sch Biomed Engn, W Lafayette, IN 47907 USA. [Roederer, Mario] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Robinson, JP (reprint author), Purdue Univ, Dept Basic Med Sci, W Lafayette, IN 47907 USA. EM jpr@flowcyt.cyto.purdue.edu; roederer@nih.gov NR 15 TC 9 Z9 9 U1 2 U2 11 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 NOV 13 PY 2015 VL 350 IS 6262 BP 739 EP 740 DI 10.1126/science.aad6770 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CW3MS UT WOS:000364897000019 PM 26564833 ER PT J AU Sluch, VM Davis, CHO Ranganathan, V Kerr, JM Krick, K Martin, R Berlinicke, CA Marsh-Armstrong, N Diamond, JS Mao, HQ Zack, DJ AF Sluch, Valentin M. Davis, Chung-ha O. Ranganathan, Vinod Kerr, Justin M. Krick, Kellin Martin, Russ Berlinicke, Cynthia A. Marsh-Armstrong, Nicholas Diamond, Jeffrey S. Mao, Hai-Quan Zack, Donald J. TI Differentiation of human ESCs to retinal ganglion cells using a CRISPR engineered reporter cell line SO SCIENTIFIC REPORTS LA English DT Article ID PLURIPOTENT STEM-CELLS; RNA-BINDING PROTEIN; TRANSCRIPTION FACTORS; AMACRINE CELLS; MAMMALIAN RETINA; COMPETENCE STATE; GENE-EXPRESSION; MOUSE RETINA; MATH5; PHOTORECEPTORS AB Retinal ganglion cell (RGC) injury and cell death from glaucoma and other forms of optic nerve disease is a major cause of irreversible vision loss and blindness. Human pluripotent stem cell (hPSC)-derived RGCs could provide a source of cells for the development of novel therapeutic molecules as well as for potential cell-based therapies. In addition, such cells could provide insights into human RGC development, gene regulation, and neuronal biology. Here, we report a simple, adherent cell culture protocol for differentiation of hPSCs to RGCs using a CRISPR-engineered RGC fluorescent reporter stem cell line. Fluorescence-activated cell sorting of the differentiated cultures yields a highly purified population of cells that express a range of RGC-enriched markers and exhibit morphological and physiological properties typical of RGCs. Additionally, we demonstrate that aligned nanofiber matrices can be used to guide the axonal outgrowth of hPSC-derived RGCs for in vitro optic nerve-like modeling. Lastly, using this protocol we identified forskolin as a potent promoter of RGC differentiation. C1 [Sluch, Valentin M.; Zack, Donald J.] Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21287 USA. [Davis, Chung-ha O.; Marsh-Armstrong, Nicholas] Kennedy Krieger Inst, Hugo W Moser Res Inst, Baltimore, MD 21205 USA. [Ranganathan, Vinod; Berlinicke, Cynthia A.; Zack, Donald J.] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Dept Ophthalmol, Baltimore, MD 21287 USA. [Kerr, Justin M.; Diamond, Jeffrey S.] NINDS, Synapt Physiol Sect, NIH, Bethesda, MD 20892 USA. [Krick, Kellin; Mao, Hai-Quan] Johns Hopkins Univ, Sch Med, Dept Biomed Engn, Baltimore, MD 21205 USA. [Krick, Kellin; Martin, Russ; Mao, Hai-Quan] Johns Hopkins Univ, Sch Med, Translat Tissue Engn Ctr, Baltimore, MD 21287 USA. [Martin, Russ; Mao, Hai-Quan] Johns Hopkins Univ, Whiting Sch Engn, Dept Mat Sci & Engn, Baltimore, MD 21218 USA. [Martin, Russ; Mao, Hai-Quan] Johns Hopkins Univ, Inst NanoBioTechnol, Baltimore, MD 21218 USA. [Marsh-Armstrong, Nicholas; Zack, Donald J.] Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD USA. [Zack, Donald J.] Johns Hopkins Univ, Sch Med, Inst Genet Med, Baltimore, MD 21287 USA. RP Zack, DJ (reprint author), Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21287 USA. EM dzack@jhmi.edu RI Diamond, Jeffrey/C-1835-2015; OI Diamond, Jeffrey/0000-0002-1770-2629; Jaskula-Ranga, Vinod/0000-0003-1202-634X FU Maryland Stem Cell Research Fund [2014-MSCRFI-0774]; NIH [T32-90040730, 1RO1EY02268001, 5T32EY007143, 5P30EY001765, R01EY023754]; Research to Prevent Blindness, Inc. FX This work was supported by grants from the Maryland Stem Cell Research Fund (2014-MSCRFI-0774), NIH (T32-90040730, 1RO1EY02268001, 5T32EY007143, 5P30EY001765, and R01EY023754), and unrestricted funds from Research to Prevent Blindness, Inc., and generous gifts from the Guerrieri Family Foundation and from Mr. and Mrs. Robert and Clarice Smith. NR 81 TC 9 Z9 10 U1 2 U2 14 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 NOV 13 PY 2015 VL 5 AR 16595 DI 10.1038/srep16595 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CV9ZN UT WOS:000364648200001 PM 26563826 ER PT J AU Kahn, RS Sommer, IE Murray, RM Meyer-Lindenberg, A Weinberger, DR Cannon, TD O'Donovan, M Correll, CU Kane, JM van Os, J Insel, TR AF Kahn, Rene S. Sommer, Iris E. Murray, Robin M. Meyer-Lindenberg, Andreas Weinberger, Daniel R. Cannon, Tyrone D. O'Donovan, Michael Correll, Christoph U. Kane, John M. van Os, Jim Insel, Thomas R. TI Schizophrenia SO NATURE REVIEWS DISEASE PRIMERS LA English DT Article ID SEVERE MENTAL-ILLNESS; TRANSCRANIAL MAGNETIC STIMULATION; TREATMENT-RESISTANT SCHIZOPHRENIA; AUDITORY VERBAL HALLUCINATIONS; ULTRA-HIGH RISK; DORSOLATERAL PREFRONTAL CORTEX; RANDOMIZED-CONTROLLED-TRIALS; PHYSICAL HEALTH-PROBLEMS; HIGH-CLINICAL-RISK; DE-NOVO MUTATIONS AB Schizophrenia is a chronic psychiatric disorder with a heterogeneous genetic and neurobiological background that influences early brain development, and is expressed as a combination of psychotic symptoms-such as hallucinations, delusions and disorganization-and motivational and cognitive dysfunctions. The mean lifetime prevalence of the disorder is just below 1%, but large regional differences in prevalence rates are evident owing to disparities in urbanicity and patterns of immigration. Although gross brain pathology is not a characteristic of schizophrenia, the disorder involves subtle pathological changes in specific neural cell populations and in cell-cell communication. Schizophrenia, as a cognitive and behavioural disorder, is ultimately about how the brain processes information. Indeed, neuroimaging studies have shown that information processing is functionally abnormal in patients with first-episode and chronic schizophrenia. Although pharmacological treatments for schizophrenia can relieve psychotic symptoms, such drugs generally do not lead to substantial improvements in social, cognitive and occupational functioning. Psychosocial interventions such as cognitive-behavioural therapy, cognitive remediation and supported education and employment have added treatment value, but are inconsistently applied. Given that schizophrenia starts many years before a diagnosis is typically made, the identification of individuals at risk and those in the early phases of the disorder, and the exploration of preventive approaches are crucial. C1 [Kahn, Rene S.; Sommer, Iris E.] Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Dept Psychiat, Utrecht, Netherlands. [Murray, Robin M.] Kings Coll London, Inst Psychiat Psychol & Neurosci, London, England. [Meyer-Lindenberg, Andreas] Heidelberg Univ, Cent Inst Mental Hlth, Mannheim, Germany. [Weinberger, Daniel R.] Johns Hopkins Univ, Sch Med, Lieber Inst Brain Dev, Baltimore, MD USA. [Weinberger, Daniel R.] Johns Hopkins Univ, Sch Med, Dept Psychiat, Dept Neurol, Baltimore, MD USA. [Weinberger, Daniel R.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD USA. [Weinberger, Daniel R.] Johns Hopkins Univ, Sch Med, Inst Med Genet, Baltimore, MD USA. [Cannon, Tyrone D.] Yale Univ, Dept Psychol, New Haven, CT USA. [O'Donovan, Michael] Cardiff Univ, MRC Ctr Psychiat Genet & Genom, Cardiff, S Glam, Wales. [O'Donovan, Michael] Cardiff Univ, Inst Psychol Med & Clin Neurosci, Cardiff, S Glam, Wales. [Correll, Christoph U.; Kane, John M.] Hofstra North Shore LIJ Sch Med, Hempstead, NY USA. [Correll, Christoph U.; Kane, John M.] Zucker Hillside Hosp, Glen Oaks, NY USA. [van Os, Jim] Maastricht Univ, Med Ctr, Dept Psychiat, Maastricht, Netherlands. [van Os, Jim] Maastricht Univ, Med Ctr, Dept Psychol, Maastricht, Netherlands. [van Os, Jim] Kings Coll London, Kings Hlth Partners, Inst Psychiat Psychol & Neurosci, Dept Psychosis Studies, London, England. [Insel, Thomas R.] US Natl Inst Mental Hlth, Bethesda, MD USA. RP Kahn, RS (reprint author), Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Dept Psychiat, Utrecht, Netherlands. EM r.kahn@umcutrecht.nl RI sommer, iris/D-1190-2014; Meyer-Lindenberg, Andreas/H-1076-2011 OI sommer, iris/0000-0002-2682-5313; Meyer-Lindenberg, Andreas/0000-0001-5619-1123 FU Genentech; Johnson and Johnson; Otsuka; Bristol-Myers Squibb; Takeda; Abbott; AstraZeneca; Aula Medica Congresos; BASF; Groupo Ferrer International; Janssen-Cilag; Lilly Deutschland; Hans-Jorg Weitbrecht Award; European College of Neuropsychopharmacology (ECNP) Neuropsychopharmacology Award; Prix ROGER DE SPOELBERCH; Eli Lilly; Lundbeck; Roche FX J.M.K. has received honoraria for lectures and/or consulting from Alkermes, Bristol-Myers Squibb, Eli Lilly, Forest Laboratories. FORUM Pharmaceuticals, Genentech, lntra-Cellular Therapies. Janssen, Johnson and Johnson. Lundbeck, Merck, Novartis, Otsuka, Pfizer, Reviva Pharmaceuticals. Roche and Sunovion Pharmaceuticals. He has received grant support from Genentech, Johnson and Johnson and Otsuka. He is a shareholder of MedAvante and the Vanguard Research Group. T.D.C. is a consultant to the Los Angeles County Department of Mental Health and Boehringer Ingelheim and is a co-inventor on a pending patent for a blood-based predictive biomaikei for psychosis. C.U.C. has been a consultant and/or adviser to, or has received honoraria from AbbVie Actavis, Alkermes, Bristol-Myers Squibb, Eli Lilly, Genentech, the Gerson Lehrman Group. Intra-Cellular Therapies, Janssen Pharmaceuticals. Johnson and Johnson, Lundbeck, MedAvante, Medscape, Otsuka, Pfizer, ProPhase, Reviva Pharmaceuticals, Roche, Sunovion Pharmaceuticals. Supernus Pharmaceuticals and Takeda. He has received grant support from Bristol-Myers Squibb, Otsuka and Takeda. A.M.-L. is a consultant for AstraZeneca. Elsevier. F. Hoffmann-La Roche. the Gerson Lehrman Group, Lundbeck, Outcome Europe Sarl, Outcome Sciences, Roche Pharma, Servier International and Thieme Verlag. He has held lectures that included the receipt of travel fees for Abbott, AstraZeneca, Aula Medica Congresos, BASF, Groupo Ferrer International, Janssen-Cilag, Lilly Deutschland. LVR Klinikum Dusseldorf, Servier Deutschland and Otsuka. He holds grants from Hans-Jorg Weitbrecht Award, European College of Neuropsychopharmacology (ECNP) Neuropsychopharmacology Award and Prix ROGER DE SPOELBERCH. R.S.K. has served as a member of the Data Safety Monitoring Board (DSMB) for Janssen-Cilag, Otsuka and Sunovion Pharmaceuticals, been consultant to Forrest, Gedeon Richter. FORUM Pharamaceuticals and Roche, and has received speaking fees from AstraZeneca, Eli Lilly and Lundbeck. M.O.D. has received a consultancy fee from Roche. R.M.M. has received honoraria for lectures from Janssen, Lundbeck, Otsuka and Roche I.E.S., T.R.I., D.R.W. and J.v.O. declare no competing interests. NR 246 TC 9 Z9 9 U1 27 U2 33 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2056-676X J9 NAT REV DIS PRIMERS JI Nat. Rev. Dis. Primers PD NOV 12 PY 2015 VL 1 AR 15067 DI 10.1038/nrdp.2015.67 PG 23 WC Medicine, General & Internal SC General & Internal Medicine GA DT2YK UT WOS:000381347500001 PM 27189524 ER PT J AU Fiandaca, MS Zhong, XG Cheema, AK Orquiza, MH Chidambaram, S Tan, MT Gresenz, CR FitzGerald, KT Nalls, MA Singleton, AB Mapstone, M Federoff, HJ AF Fiandaca, Massimo S. Zhong, Xiaogang Cheema, Amrita K. Orquiza, Michael H. Chidambaram, Swathi Tan, Ming T. Gresenz, Carole Roan FitzGerald, Kevin T. Nalls, Mike A. Singleton, Andrew B. Mapstone, Mark Federoff, Howard J. TI Plasma 24-metabolite Panel Predicts Preclinical Transition to Clinical Stages of Alzheimer's Disease SO FRONTIERS IN NEUROLOGY LA English DT Article DE Alzheimer's disease; biomarkers; economics; ethics; lipids; metabolomics; risk assessment ID DECLINING FINANCIAL CAPACITY; POLYUNSATURATED FATTY-ACIDS; INFUSION MASS-SPECTROMETRY; ACYL-COA CONCENTRATIONS; COGNITIVE IMPAIRMENT; CEREBROSPINAL-FLUID; HUMAN BRAIN; IN-VIVO; METABOLISM; MODEL AB We recently documented plasma lipid dysregulation in preclinical late-onset Alzheimer's disease (LOAD). A 10 plasma lipid panel, predicted phenoconversion and provided 90% sensitivity and 85% specificity in differentiating an at-risk group from those that would remain cognitively intact. Despite these encouraging results, low positive predictive values limit the clinical usefulness of this panel as a screening tool in subjects aged 70-80 years or younger. In this report, we re-examine our metabolomic data, analyzing baseline plasma specimens from our group of phenoconverters (n = 28) and a matched set of cognitively normal subjects (n = 73), and discover and internally validate a panel of 24 plasma metabolites. The new panel provides a classifier with receiver operating characteristic area under the curve for the discovery and internal validation cohort of 1.0 and 0.995 (95% confidence intervals of 1.0-1.0, and 0.981-1.0), respectively. Twenty-two of the 24 metabolites were significantly dysregulated lipids. While positive and negative predictive values were improved compared to our 10-lipid panel, low positive predictive values provide a reality check on the utility of such biomarkers in this age group (or younger). Through inclusion of additional significantly dysregulated analyte species, our new biomarker panel provides greater accuracy in our cohort but remains limited by predictive power. Unfortunately, the novel metabolite panel alone may not provide improvement in counseling and management of at-risk individuals but may further improve selection of subjects for LOAD secondary prevention trials. We expect that external validation will remain challenging due to our stringent study design, especially compared with more diverse subject cohorts. We do anticipate, however, external validation of reduced plasma lipid species as a predictor of phenoconversion to either prodromal or manifest LOAD. C1 [Fiandaca, Massimo S.; Mapstone, Mark; Federoff, Howard J.] Univ Calif Irvine, Dept Neurol, Irvine, CA 92717 USA. [Fiandaca, Massimo S.] Univ Calif Irvine, Dept Neurol Surg, Irvine, CA USA. [Zhong, Xiaogang; Tan, Ming T.] Georgetown Univ, Med Ctr, Dept Bioinformat Biostat & Biomath, Washington, DC 20007 USA. [Cheema, Amrita K.] Georgetown Univ, Med Ctr, Dept Oncol, Washington, DC 20007 USA. [Cheema, Amrita K.] Georgetown Univ, Med Ctr, Dept Biochem, Washington, DC 20007 USA. [Orquiza, Michael H.] Georgetown Univ, Med Ctr, Dept Neurosci, Washington, DC 20007 USA. [Chidambaram, Swathi] Georgetown Univ, Med Ctr, Sch Med, Washington, DC 20007 USA. [Gresenz, Carole Roan] RAND Corp, Dept Econ Sociol & Stat, Arlington, VA USA. [FitzGerald, Kevin T.] Georgetown Univ, Med Ctr, Pellegrino Ctr Clin Bioeth, Washington, DC 20007 USA. [Nalls, Mike A.; Singleton, Andrew B.] NIA, Lab Neurogenet, NIH, Bethesda, MD 20892 USA. RP Federoff, HJ (reprint author), Univ Calif Irvine, Dept Neurol, Irvine, CA 92717 USA. EM federoff@uci.edu RI Singleton, Andrew/C-3010-2009 FU National Institutes of Health [NIA R01 AG030753]; Department of Defense of the UnitedStates [W81XWH-09-1-0107]; Georgetown University through the Patricia J. Harvey Current Use Research Fund FX The National Institutes of Health (NIA R01 AG030753) and the Department of Defense of the UnitedStates (W81XWH-09-1-0107) provided grant funding to HF for this study. Additional support for this work was provided by a gift to Georgetown University through the Patricia J. Harvey Current Use Research Fund. NR 67 TC 4 Z9 4 U1 4 U2 5 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-2295 J9 FRONT NEUROL JI Front. Neurol. PD NOV 12 PY 2015 VL 6 AR 237 DI 10.3389/fneur.2015.00237 PG 13 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DA8YA UT WOS:000368091700001 PM 26617567 ER PT J AU Hathcock, KS Padilla-Nash, HM Camps, J Shin, DM Triner, D Shaffer, AL Maul, RW Steinberg, SM Gearhart, PJ Staudt, LM Morse, HC Ried, T Hodes, RJ AF Hathcock, Karen S. Padilla-Nash, Hesed M. Camps, Jordi Shin, Dong-Mi Triner, Daniel Shaffer, Arthur L., III Maul, Robert W. Steinberg, Seth M. Gearhart, Patricia J. Staudt, Louis M. Morse, Herbert C., III Ried, Thomas Hodes, Richard J. TI ATM deficiency promotes development of murine B-cell lymphomas that resemble diffuse large B-cell lymphoma in humans SO BLOOD LA English DT Article ID NF-KAPPA-B; CLASS SWITCH RECOMBINATION; SMALL-MOLECULE INHIBITORS; GENE-EXPRESSION; ATAXIA-TELANGIECTASIA; GERMINAL-CENTERS; IN-VIVO; SOMATIC HYPERMUTATION; MOUSE CHROMOSOMES; MICE AB The serine-threonine kinase ataxia-telangiectasia mutated (ATM) plays a central role in maintaining genomic integrity. In mice, ATM deficiency is exclusively associated with T-cell lymphoma development, whereas B-cell tumors predominate in human ataxia-telangiectasia patients. We demonstrate in this study that when T cells are removed as targets for lymphomagenesis and as mediators of immune surveillance, ATM-deficient mice exclusively develop early-onset immunoglobulin M+ B-cell lymphomas that do not transplant to immunocompetent mice and that histologically and genetically resemble the activated B cell-like (ABC) subset of human diffuse large B-cell lymphoma (DLBCL). These B-cell lymphomas show considerable chromosomal instability and a recurrent genomic amplification of a 4.48-Mb region on chromosome 18 that contains Malt1 and is orthologous to a region similarly amplified in human ABC DLBCL. Of importance, amplification of Malt1 in these lymphomas correlates with their dependence on nuclear factor (NF)-kappa B, MALT1, and B-cell receptor (BCR) signaling for survival, paralleling human ABC DLBCL. Further, like some human ABC DLBCLs, these mouse B-cell lymphomas also exhibit constitutive BCR-dependent NF-kappa B activation. This study reveals that ATM protects against development of B-cell lymphomas that model human ABC DLBCL and identifies a potential role for T cells in preventing the emergence of these tumors. C1 [Hathcock, Karen S.; Triner, Daniel; Hodes, Richard J.] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Padilla-Nash, Hesed M.; Camps, Jordi; Ried, Thomas] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. [Camps, Jordi] Inst Invest Biomed August Pi I Sunyer, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Gastrointestinal & Pancreat Oncol Grp, Barcelona, Spain. [Shin, Dong-Mi; Morse, Herbert C., III] NIAID, Immunopathol Lab, NIH, Bethesda, MD 20892 USA. [Shin, Dong-Mi] Seoul Natl Univ, Dept Food & Nutr, Seoul, South Korea. [Shaffer, Arthur L., III; Staudt, Louis M.] NCI, Lymphoid Malignancies Branch, NIH, Bethesda, MD 20892 USA. [Maul, Robert W.; Gearhart, Patricia J.] NIA, Lab Mol Biol & Immunol, NIH, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Hodes, Richard J.] NIA, NIH, Bethesda, MD 20892 USA. RP Hodes, RJ (reprint author), NCI, NIH, 10 Ctr Dr,Room 4B05, Bethesda, MD 20892 USA. EM richard_hodes@nih.gov FU Intramural Research Programs of the National Institutes of Health National Cancer Institute; National Institute of Allergy and Infectious Diseases; National Institute on Aging FX This study was supported by Intramural Research Programs of the National Institutes of Health National Cancer Institute, National Institute of Allergy and Infectious Diseases, and National Institute on Aging. NR 69 TC 2 Z9 2 U1 0 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 NOV 12 PY 2015 VL 126 IS 20 BP 2291 EP 2301 DI 10.1182/blood-2015-06-654749 PG 11 WC Hematology SC Hematology GA CY4PU UT WOS:000366391400007 PM 26400962 ER PT J AU Ben-Gedalya, T Moll, L Bejerano-Sagie, M Frere, S Cabral, WA Friedmann-Morvinski, D Slutsky, I Burstyn-Cohen, T Marini, JC Cohen, E AF Ben-Gedalya, Tziona Moll, Lorna Bejerano-Sagie, Michal Frere, Samuel Cabral, Wayne A. Friedmann-Morvinski, Dinorah Slutsky, Inna Burstyn-Cohen, Tal Marini, Joan C. Cohen, Ehud TI Alzheimer's disease-causing proline substitutions lead to presenilin 1 aggregation and malfunction SO EMBO JOURNAL LA English DT Article DE Alzheimer's disease; cyclophilin B; presenilin 1; proteostasis ID QUALITY-CONTROL COMPARTMENTS; AMYLOID PRECURSOR PROTEIN; GAMMA-SECRETASE ACTIVITY; NEUROFIBRILLARY TANGLES; CYCLOSPORINE-A; ENDOPLASMIC-RETICULUM; STRAUSSLER-SYNDROME; MISFOLDED PROTEINS; AGE-ONSET; PROTEOTOXICITY AB Do different neurodegenerative maladies emanate from the failure of a mutual protein folding mechanism? We have addressed this question by comparing mutational patterns that are linked to the manifestation of distinct neurodegenerative disorders and identified similar neurodegeneration-linked proline substitutions in the prion protein and in presenilin 1 that underlie the development of a prion disorder and of familial Alzheimer's disease (fAD), respectively. These substitutions were found to prevent the endoplasmic reticulum (ER)-resident chaperone, cyclophilin B, from assisting presenilin 1 to fold properly, leading to its aggregation, deposition in the ER, reduction of gamma-secretase activity, and impaired mitochondrial distribution and function. Similarly, reduced quantities of the processed, active presenilin 1 were observed in brains of cyclophilin B knockout mice. These discoveries imply that reduced cyclophilin activity contributes to the development of distinct neurodegenerative disorders, propose a novel mechanism for the development of certain fAD cases, and support the emerging theme that this disorder can stem from aberrant presenilin 1 function. This study also points at ER chaperones as targets for the development of counter-neurodegeneration therapies. C1 [Ben-Gedalya, Tziona; Moll, Lorna; Bejerano-Sagie, Michal; Cohen, Ehud] Hebrew Univ Jerusalem, Sch Med, IMRIC, Biochem & Mol Biol, Jerusalem, Israel. [Frere, Samuel; Slutsky, Inna] Tel Aviv Univ, Sackler Fac Med, Dept Physiol & Pharmacol, IL-69978 Tel Aviv, Israel. [Cabral, Wayne A.; Marini, Joan C.] NICHD, Bone & Extracellular Matrix Branch, NIH, Bethesda, MD USA. [Friedmann-Morvinski, Dinorah] Tel Aviv Univ, Wise Fac Life Sci, Biochem & Mol Biol, IL-69978 Tel Aviv, Israel. [Burstyn-Cohen, Tal] Hebrew Univ Jerusalem Hadassah Hosp & Med Sch, Fac Med Dent, Inst Dent Sci, Jerusalem, Israel. RP Cohen, E (reprint author), Hebrew Univ Jerusalem, Sch Med, IMRIC, Biochem & Mol Biol, Jerusalem, Israel. EM ehudc@ekmd.huji.ac.il RI Burstyn-Cohen, Tal/K-8846-2012; OI Burstyn-Cohen, Tal/0000-0002-2324-2921; Slutsky, Inna/0000-0002-0700-2266; Cohen, Ehud/0000-0001-5552-7086 FU Rosalinde and Arthur Gilbert Foundation (AFAR); European Research Council (ERC) [281010]; National Institute for Psychobiology in Israel (NIPI); Israel Science Foundation (ISF) [671/11, 1764/12] FX This study was generously supported by the Rosalinde and Arthur Gilbert Foundation (AFAR), the European Research Council (ERC, 281010), the National Institute for Psychobiology in Israel (NIPI), and the Israel Science Foundation (ISF, 671/11). This research was also partially supported by The Israel Science Foundation (ISF 1764/12 awarded to TBC). We thank Dr. Gerardo Lederkremer (Tel Aviv University) for providing us with the H2a-RFP plasmid, Dr. Alison Goate (Mount Sinai Hospital) for the APP-Myc expression vector, Dr. Jonathan Javitch (Colombia University) for the YFP-DAT plasmid, and Dr. Bart De Strooper (K.U. Leuven) for presenilin 1/2-KO MEF cells. We thank Mrs. Naomi Feinstein for expert assistance with EM experiments and Dr. Denes Agoston for assisting mouse procedures. We also thank Ms. Filipa Carvalhal Marques for critical reading of the manuscript. NR 67 TC 8 Z9 8 U1 3 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0261-4189 EI 1460-2075 J9 EMBO J JI Embo J. PD NOV 12 PY 2015 VL 34 IS 22 BP 2820 EP 2839 DI 10.15252/embj.201592042 PG 20 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CY7QR UT WOS:000366604300011 PM 26438723 ER PT J AU Lauer, MS Nakamura, R AF Lauer, Michael S. Nakamura, Richard TI Reviewing Peer Review at the NIH SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Lauer, Michael S.] NIH, Off Extramural Res, Bethesda, MD 20892 USA. [Nakamura, Richard] NIH, Ctr Sci Review, Bethesda, MD 20892 USA. RP Lauer, MS (reprint author), NIH, Off Extramural Res, Bldg 10, Bethesda, MD 20892 USA. NR 5 TC 3 Z9 3 U1 3 U2 13 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 NOV 12 PY 2015 VL 373 IS 20 BP 1893 EP 1895 DI 10.1056/NEJMp1507427 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA CV7IL UT WOS:000364445500001 PM 26559568 ER PT J AU Egan, JM AF Egan, Josephine M. TI Targeting Stem Cells in Chronic Myeloid Leukemia with a PPAR-gamma Agonist SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 NIA, Diabet Sect, Lab Clin Invest, NIH, Baltimore, MD 21224 USA. RP Egan, JM (reprint author), NIA, Diabet Sect, Lab Clin Invest, NIH, Baltimore, MD 21224 USA. NR 5 TC 2 Z9 2 U1 1 U2 3 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 NOV 12 PY 2015 VL 373 IS 20 BP 1973 EP 1975 DI 10.1056/NEJMcibr1511276 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA CV7IL UT WOS:000364445500015 PM 26559576 ER PT J AU Lateef, DM Xiao, CY Reitman, ML AF Lateef, Dalya M. Xiao, Cuiying Reitman, Marc L. TI Search for an Endogenous Bombesin-Like Receptor 3 (BRS-3) Ligand Using Parabiotic Mice SO PLOS ONE LA English DT Article ID SUBTYPE-3 BRS-3; OBESE; MOUSE; PHARMACOLOGY; EXPRESSION; CLONING; LEPTIN; GENES; RATS AB Bombesin-like receptor 3 (BRS-3) is an X-linked G protein-coupled receptor involved in the regulation of energy homeostasis. Brs3 null (Brs3(-/y)) mice become obese. To date, no high affinity endogenous ligand has been identified. In an effort to detect a circulating endogenous BRS-3 ligand, we generated parabiotic pairs of mice between Brs3(-/y) and wild type (WT) mice or between WT controls. Successful parabiosis was demonstrated by circulatory dye exchange. The Brs3(-/y)-WT and WT-WT pairs lost similar weight immediately after surgery. After 9 weeks on a high fat diet, the Brs3(-/y)-WT pairs weighed more than the WT-WT pairs. Within the Brs3(-/y)-WT pairs, the Brs3(-/y) mice had greater adiposity than the WT mice, but comparable lean and liver weights. Compared to WT mice in WT-WT pairs, Brs3(-/y) and WT mice in Brs3(-/y)-WT pairs each had greater lean mass, and the Brs3(-/y) mice also had greater adiposity. These results contrast to those reported for parabiotic pairs of leptin receptor null (Lepr(db/db)) and WT mice, where high leptin levels in the Lepr(db/db) mice cause the WT parabiotic partners to lose weight. Our data demonstrate that a circulating endogenous BRS-3 ligand, if present, is not sufficient to reduce adiposity in parabiotic partners of Brs3(-/y) mice. C1 [Lateef, Dalya M.; Xiao, Cuiying; Reitman, Marc L.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. RP Reitman, ML (reprint author), NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. EM marc.reitman@nih.gov RI Reitman, Marc/B-4448-2013 OI Reitman, Marc/0000-0002-0426-9475 FU Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health [DK075057] FX This research was supported by the Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (DK075057). NR 29 TC 2 Z9 2 U1 1 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 NOV 12 PY 2015 VL 10 IS 11 AR e0142637 DI 10.1371/journal.pone.0142637 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CV7UL UT WOS:000364480900052 PM 26562312 ER PT J AU Cai, Y Kimura, S AF Cai, Yan Kimura, Shioko TI Secretoglobin 3A2 Exhibits Anti-Fibrotic Activity in Bleomycin-Induced Pulmonary Fibrosis Model Mice SO PLOS ONE LA English DT Article ID SURFACTANT PROTEIN-A; UTEROGLOBIN-RELATED PROTEIN-1; ALLERGIC AIRWAY INFLAMMATION; LUNG DEVELOPMENT; MOUSE; EXPRESSION; GENE; SUPERFAMILY; MARKER AB Objective Secretoglobin (SCGB) 3A2 is a novel lung-enriched cytokine, previously shown to exhibit anti-inflammatory, growth factor, and anti-fibrotic activities. The latter activity was demonstrated using exogenously-administered recombinant SCGB3A2 in the bleomycin (BLM)induced pulmonary fibrosis model. Whether SCGB3A2 exhibits anti-fibrotic activity in vivo is not known. Methods Mice null for the Scgb3a2 gene were subjected to the BLM-induced pulmonary fibrosis model, and the severity of pulmonary fibrosis determined using histological and biochemical methods. Results BLM treatment caused weight loss of both Scgb3a2-null and wild-type mice, however, the loss was far more pronounced in BLM-treated Scgb3a2-null than wild-type mice, and the weight of day 21 of BLM-treated Scgb3a2-null mice was about half of that of BLM-treated wild-type mice. Hematoxylin & Eosin, Masson Trichrome, and Sirius Red staining of lung sections, Ashcroft fibrosis scores, hydroxyproline contents, and the levels of mRNAs encoding various collagens demonstrated that BLM-treated Scgb3a2-null mouse lungs had more severe fibrosis than those of wild-type mouse lungs. Total and differential inflammatory cell numbers in bronchoalveolar lavage fluids, and levels of lung mRNAs including those encoding Th2 cytokines such as IL-4 and profibrotic cytokines such as TGF beta were higher in BLM-treated Scgb3a2-null mouse lungs as compared to those of wild-type mouse lungs. In contrast, mRNAs encoding surfactant proteins A, B, C, and D, and SCGB1A1 did not differ between BLM-treated Scgb3a2-null and wild-type mouse lungs. Conclusion The role of SCGB3A2 in fibrosis was revisited using Scgb3a2-null mice and littermate controls in the BLM-induced pulmonary fibrosis model. The pulmonary fibrosis in the Scgb3a2-null mice was more severe than the wild-type controls, thus establishing that SCGB3A2 has anti-fibrotic activity in vivo. Importantly, surfactant proteins and SCGB1A1 appear not to be involved in the susceptibility of Scgb3a2-null mice to BLM-induced pulmonary fibrosis. C1 [Cai, Yan; Kimura, Shioko] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Kimura, S (reprint author), NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. EM kimuras@mail.nih.gov RI Cai, Yan/P-4383-2015 FU Intramural Research Program of the National Cancer Institute [ZIABC010449] FX Funding provided by ZIABC010449, Intramural Research Program of the National Cancer Institute, http://www.cancer.gov/, SK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 2 Z9 2 U1 0 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 NOV 11 PY 2015 VL 10 IS 11 AR e0142497 DI 10.1371/journal.pone.0142497 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CV7DR UT WOS:000364433100086 PM 26559674 ER PT J AU Gonzalez, CR Gonzalez, B Matzkin, ME Muniz, JA Cadet, JL Garcia-Rill, E Urbano, FJ Vitullo, AD Bisagno, V AF Gonzalez, Candela R. Gonzalez, Betina Matzkin, Maria E. Muniz, Javier A. Cadet, Jean Lud Garcia-Rill, Edgar Urbano, Francisco J. Vitullo, Alfredo D. Bisagno, Veronica TI Psychostimulant-Induced Testicular Toxicity in Mice: Evidence of Cocaine and Caffeine Effects on the Local Dopaminergic System SO PLOS ONE LA English DT Article ID ADENOSINE RECEPTOR EXPRESSION; RAT TESTIS; TYROSINE-HYDROXYLASE; LIPID-PEROXIDATION; DIFFERENT AGES; LEYDIG-CELLS; ADULT MICE; EXPOSURE; SPERMATOGENESIS; PATHWAY AB Several organ systems can be affected by psychostimulant toxicity. However, there is not sufficient evidence about the impact of psychostimulant intake on testicular physiology and catecholaminergic systems. The aim of the present study was to further explore potential toxic consequences of chronic exposure to cocaine, caffeine, and their combination on testicular physiology. Mice were injected with a 13-day chronic binge regimen of caffeine (3x5mg/kg), cocaine (3x10mg/kg), or combined administration. Mice treated with cocaine alone or combined with caffeine showed reduced volume of the seminiferous tubule associated to a reduction in the number of spermatogonia. Cocaine-only and combined treatments induced increased lipid peroxidation evaluated by TBARS assay and decreased glutathione peroxidase mRNA expression. Importantly, caffeine-cocaine combination potentiated the cocaine-induced germ cell loss, and induced pro-apoptotic BAX protein expression and diminished adenosine receptor A1 mRNA levels. We analyzed markers of dopaminergic function in the testis and detected the presence of tyrosine hydroxylase (TH) in the cytoplasm of androgen-producing Leydig cells, but also in meiotic germs cells within seminiferous tubules. Moreover, using transgenic BAC-Drd1a-tdTomato and D2R-eGFP mice, we report for the first time the presence of dopamine receptors (DRs) D1 and D2 in testicular mouse Leydig cells. Interestingly, the presence of DRD1 was also detected in the spermatogonia nearest the basal lamina of the seminiferous tubules, which did not show TH staining. We observed that psychostimulants induced downregulation of DRs mRNA expression and upregulation of TH protein expression in the testis. These findings suggest a potential role of the local dopaminergic system in psychostimulant-induced testicular pathology. C1 [Gonzalez, Candela R.; Vitullo, Alfredo D.] Univ Buenos Aires, Ctr Estudios Biomed Biotecnol Ambientales & Diagn, Buenos Aires, DF, Argentina. [Gonzalez, Betina; Muniz, Javier A.; Bisagno, Veronica] Univ Buenos Aires, Consejo Nacl Invest Cient & Tecn, Inst Invest Farmacol, Buenos Aires, DF, Argentina. [Matzkin, Maria E.] Univ Buenos Aires, Consejo Nacl Invest Cient & Tecn, Inst Biol & Med Expt, Buenos Aires, DF, Argentina. [Cadet, Jean Lud] NIDA, Intramural Program, Mol Neuropsychiat Res Branch, Baltimore, MD USA. [Garcia-Rill, Edgar] Univ Arkansas Med Sci, Dept Neurobiol & Dev Sci, Ctr Translat Neurosci, Little Rock, AR 72205 USA. [Urbano, Francisco J.] Univ Buenos Aires, Consejo Nacl Invest Cient & Tecn, Inst Fisiol Biol Mol & Neurociencias, Lab Fisiol & Biol Mol, Buenos Aires, DF, Argentina. RP Bisagno, V (reprint author), Univ Buenos Aires, Consejo Nacl Invest Cient & Tecn, Inst Invest Farmacol, Buenos Aires, DF, Argentina. EM vbisagno@ffyb.uba.ar FU [PICT 2012-0924]; [PICT-2012-1769] FX This work is supported by grants PICT 2012-0924 and PICT-2012-1769 (FU and VB), Argentina. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 63 TC 4 Z9 4 U1 4 U2 8 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 NOV 11 PY 2015 VL 10 IS 11 AR e0142713 DI 10.1371/journal.pone.0142713 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CV7DR UT WOS:000364433100113 PM 26560700 ER PT J AU Sastalla, I Datta, SK AF Sastalla, Inka Datta, Sandip K. TI Antibiotic Education: Not Just Another Brick in the Cell Wall SO CELL HOST & MICROBE LA English DT Editorial Material ID STAPHYLOCOCCUS-AUREUS; PEPTIDOGLYCAN; IL-1-BETA AB Methicillin-resistant Staphylococcus aureus (MRSA) are resistant to beta-lactam antibiotics, which inhibit bacterial cell wall synthesis. In this issue of Cell Host & Microbe, Muller et al. (2015) show that beta-lactam treatment of MRSA leads to synthesis of an altered cell wall that increases inflammasome activation and immunopathology during skin infection. C1 [Sastalla, Inka; Datta, Sandip K.] NIAID, Bacterial Pathogenesis Unit, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Datta, SK (reprint author), NIAID, Bacterial Pathogenesis Unit, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM dattas@niaid.nih.gov OI Datta, Sandip/0000-0003-0243-7815 FU Intramural NIH HHS NR 9 TC 0 Z9 0 U1 1 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 EI 1934-6069 J9 CELL HOST MICROBE JI Cell Host Microbe PD NOV 11 PY 2015 VL 18 IS 5 BP 520 EP 522 DI 10.1016/j.chom.2015.10.019 PG 3 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA CW6NA UT WOS:000365113100004 PM 26567505 ER PT J AU Fu, RQ Gill, RL Kim, EY Briley, NE Tyndall, ER Xu, J Li, CG Ramamurthi, KS Flanagan, JM Tian, F AF Fu, Riqiang Gill, Richard L., Jr. Kim, Edward Y. Briley, Nicole E. Tyndall, Erin R. Xu, Jie Li, Conggang Ramamurthi, Kumaran S. Flanagan, John M. Tian, Fang TI Spherical Nanoparticle Supported Lipid Bilayers for the Structural Study of Membrane Geometry-Sensitive Molecules SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID BACILLUS-SUBTILIS; CURVATURE; PROTEIN; NMR; LOCALIZATION; MECHANISMS; DIFFUSION; PEPTIDE; BEADS; STATE AB Many essential cellular processes including endocytosis and vesicle trafficking require alteration of membrane geometry. These changes are usually mediated by proteins that can sense and/or induce membrane curvature. Using spherical nanoparticle supported lipid bilayers (SSLBs), we characterize how SpoVM, a bacterial development factor, interacts with differently curved membranes by magic angle spinning solid-state NMR. Our results demonstrate that SSLBs are an effective system for structural and topological studies of membrane geometry-sensitive molecules. C1 [Gill, Richard L., Jr.; Briley, Nicole E.; Tyndall, Erin R.; Xu, Jie; Flanagan, John M.; Tian, Fang] Penn State Univ, Dept Biochem & Mol Biol, Hershey, PA 17033 USA. [Kim, Edward Y.; Ramamurthi, Kumaran S.] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Fu, Riqiang] Natl High Magnet Field Lab, Tallahassee, FL 32310 USA. [Li, Conggang] Chinese Acad Sci, Wuhan Inst Phys & Math, Natl Ctr Magnet Resonance Wuhan, Wuhan 430071, Peoples R China. RP Tian, F (reprint author), Penn State Univ, Dept Biochem & Mol Biol, Hershey, PA 17033 USA. EM ftian@psu.edu RI Ramamurthi, Kumaran/P-3516-2015; OI li, cong gang/0000-0002-5798-1722 FU NSF [DMR-1157490]; State of Florida; U.S. Department of Energy; National Institutes of Heath NIGMS [R01GM105963, R01GM094526]; NIH Intramural Research Program, National Cancer Institute, Center for Cancer Research FX We thank Drs. T. A. Cross and K. C. Huang for helpful discussions, and Nissan Chemical Industries, Ltd. for 50 and 100 nm silicon beads. The MAS ssNMR data were performed at the National High Magnetic Field Laboratory, which is supported by NSF Cooperative Agreement no. DMR-1157490, the State of Florida, and the U.S. Department of Energy. This work was supported by the National Institutes of Heath NIGMS (R01GM105963 to F.T. and R01GM094526 to J.M.F.) and the NIH Intramural Research Program, National Cancer Institute, Center for Cancer Research (K.S.R) NR 29 TC 1 Z9 1 U1 5 U2 28 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 NOV 11 PY 2015 VL 137 IS 44 BP 14031 EP 14034 DI 10.1021/jacs.5b08303 PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA CW1CQ UT WOS:000364727600008 PM 26488086 ER PT J AU Ho, S Sackett, DL Leighton, JL AF Ho, Stephen Sackett, Dan L. Leighton, James L. TI A "Methyl Extension" Strategy for Polyketide Natural Product Linker Site Validation and Its Application to Dictyostatin SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID BIOLOGICAL EVALUATION; STAUDINGER LIGATION; (-)-DICTYOSTATIN; ANALOGS; AZIDE; STEREOISOMERS; CATALYSTS; POWERFUL AB An approach to the validation of linker strategies for polyketide natural products with few or no obvious handles for linker attachment, and its application to dictyostatin, are described. Analogues in which the C(6)- and C(12)-methyl groups were replaced by 4-azidobutyl groups were prepared and shown to retain the low nanomolar potency of dictyostatin. Further, conjugation of the C(6) analogue with a cyclooctyne resulted in only minor attenuations in potency. Together, these results shed light on the binding of dictyostatin to beta-tubulin, establish a validated linker strategy for dictyostatin, and set the stage for the synthesis and study of dictyostatin conjugates. C1 [Ho, Stephen; Leighton, James L.] Columbia Univ, Dept Chem, New York, NY 10027 USA. [Sackett, Dan L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA. RP Leighton, JL (reprint author), Columbia Univ, Dept Chem, New York, NY 10027 USA. EM leighton@chem.columbia.edu FU National Institute of General Medical Sciences of the National Institutes of Health [R01GM058133]; Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH FX Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number R01GM058133, and was supported in part by the Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 32 TC 2 Z9 2 U1 2 U2 17 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 NOV 11 PY 2015 VL 137 IS 44 BP 14047 EP 14050 DI 10.1021/jacs.5b09869 PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA CW1CQ UT WOS:000364727600012 PM 26522184 ER PT J AU He, QJ Kiesewetter, DO Qu, Y Fu, X Fan, J Huang, P Liu, YJ Zhu, GZ Liu, Y Qian, ZY Chen, XY AF He, Qianjun Kiesewetter, Dale O. Qu, Ying Fu, Xiao Fan, Jing Huang, Peng Liu, Yijing Zhu, Guizhi Liu, Yi Qian, Zhiyong Chen, Xiaoyuan TI NIR-Responsive On-Demand Release of CO from Metal Carbonyl-Caged Graphene Oxide Nanomedicine SO ADVANCED MATERIALS LA English DT Article ID NITRIC-OXIDE; MONOXIDE; MOLECULES; PHOTOCORMS; LIGHT; NANOPARTICLES; SENSITIVITY; COMPLEXES; DELIVERY; CANCER AB On-demand release of carbon monoxide (CO) is realized through a novel near-infrared-responsive nanomedicine in favor of the enhancement of therapy efficacy and biosafety of CO therapy. C1 [He, Qianjun] Shenzhen Univ, Sch Med, Dept Biomed Engn, Guangdong Key Lab Biomed Measurements & Ultrasoun, Shenzhen 518060, Guangdong, Peoples R China. [He, Qianjun; Qu, Ying; Qian, Zhiyong] Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Chengdu 610041, Peoples R China. [He, Qianjun; Qu, Ying; Qian, Zhiyong] Sichuan Univ, West China Hosp, Ctr Canc, Chengdu 610041, Peoples R China. [He, Qianjun; Qu, Ying; Qian, Zhiyong] Collaborat Innovat Ctr Biotherapy, Chengdu 610041, Peoples R China. [He, Qianjun; Kiesewetter, Dale O.; Fu, Xiao; Fan, Jing; Huang, Peng; Liu, Yijing; Zhu, Guizhi; Liu, Yi; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. RP Qian, ZY (reprint author), Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Chengdu 610041, Peoples R China. EM anderson-qian@163.com; shawn.chen@nih.gov RI Liu, Yijing/D-6666-2016; Huang, Peng/R-2480-2016; HE, QIANJUN/M-2642-2013 OI Huang, Peng/0000-0003-3651-7813; HE, QIANJUN/0000-0003-0689-8838 FU National Nature Science Foundation of China [51102259, 31271021, 31222023]; Distinguished Young Scholars of Sichuan University [2011SCU04B18]; Intramural Research Program, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health FX The authors thank the financial support from the National Nature Science Foundation of China (Grant Nos. 51102259, 31271021, and 31222023), Distinguished Young Scholars of Sichuan University (Grant No. 2011SCU04B18), and the Intramural Research Program, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health. NR 30 TC 10 Z9 10 U1 39 U2 120 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 0935-9648 EI 1521-4095 J9 ADV MATER JI Adv. Mater. PD NOV 11 PY 2015 VL 27 IS 42 BP 6741 EP + DI 10.1002/adma.201502762 PG 7 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA CW0SR UT WOS:000364700200027 PM 26401893 ER PT J AU Yutin, N Shevchenko, S Kapitonov, V Krupovic, M Koonin, EV AF Yutin, Natalya Shevchenko, Sofiya Kapitonov, Vladimir Krupovic, Mart Koonin, Eugene V. TI A novel group of diverse Polinton-like viruses discovered by metagenome analysis SO BMC BIOLOGY LA English DT Article ID DNA VIRUSES; MAXIMUM-LIKELIHOOD; MICROBIAL ECOLOGY; GENETIC ELEMENTS; PROTEIN FAMILIES; CELL ENTRY; VIROPHAGE; TRANSPOSONS; EUKARYOTES; SEQUENCE AB Background: The rapidly growing metagenomic databases provide increasing opportunities for computational discovery of new groups of organisms. Identification of new viruses is particularly straightforward given the comparatively small size of viral genomes, although fast evolution of viruses complicates the analysis of novel sequences. Here we report the metagenomic discovery of a distinct group of diverse viruses that are distantly related to the eukaryotic virus-like transposons of the Polinton superfamily. Results: The sequence of the putative major capsid protein (MCP) of the unusual linear virophage associated with Phaeocystis globosa virus (PgVV) was used as a bait to identify potential related viruses in metagenomic databases. Assembly of the contigs encoding the PgVV MCP homologs followed by comprehensive sequence analysis of the proteins encoded in these contigs resulted in the identification of a large group of Polinton-like viruses (PLV) that resemble Polintons (polintoviruses) and virophages in genome size, and share with them a conserved minimal morphogenetic module that consists of major and minor capsid proteins and the packaging ATPase. With a single exception, the PLV lack the retrovirus-type integrase that is encoded in the genomes of all Polintons and the Mavirus group of virophages. However, some PLV encode a newly identified tyrosine recombinase-integrase that is common in bacteria and bacteriophages and is also found in the Organic Lake virophage group. Although several PLV genomes and individual genes are integrated into algal genomes, it appears likely that most of the PLV are viruses. Given the absence of protease and retrovirus-type integrase, the PLV could resemble the ancestral polintoviruses that evolved from bacterial tectiviruses. Apart from the conserved minimal morphogenetic module, the PLV widely differ in their genome complements but share a gene network with Polintons and virophages, suggestive of multiple gene exchanges within a shared gene pool. Conclusions: The discovery of PLV substantially expands the emerging class of eukaryotic viruses and transposons that also includes Polintons and virophages. This class of selfish elements is extremely widespread and might have been a hotbed of eukaryotic virus, transposon and plasmid evolution. New families of these elements are expected to be discovered. C1 [Yutin, Natalya; Shevchenko, Sofiya; Kapitonov, Vladimir; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Krupovic, Mart] Inst Pasteur, Dept Microbiol, Unite Biol Mol Gene Chez Extremophiles, Paris, France. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov RI Krupovic, Mart/I-4209-2012 OI Krupovic, Mart/0000-0001-5486-0098 FU US Department of Health and Human Services FX We thank Yuri Wolf for helpful advice on sequence assembly and analysis. NY, SS, VK and EVK were supported by intramural funds of the US Department of Health and Human Services (to the National Library of Medicine). NR 59 TC 6 Z9 6 U1 2 U2 16 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7007 J9 BMC BIOL JI BMC Biol. PD NOV 11 PY 2015 VL 13 AR 95 DI 10.1186/s12915-015-0207-4 PG 14 WC Biology SC Life Sciences & Biomedicine - Other Topics GA CV8NQ UT WOS:000364545300002 PM 26560305 ER PT J AU Kearney, MF Anderson, EM Coomer, C Smith, L Shao, W Johnson, N Kline, C Spindler, J Mellors, JW Coffin, JM Ambrose, Z AF Kearney, Mary F. Anderson, Elizabeth M. Coomer, Charles Smith, Luke Shao, Wei Johnson, Nicholas Kline, Christopher Spindler, Jonathan Mellors, John W. Coffin, John M. Ambrose, Zandrea TI Well-mixed plasma and tissue viral populations in RT-SHIV-infected macaques implies a lack of viral replication in the tissues during antiretroviral therapy SO RETROVIROLOGY LA English DT Article DE RT-SHIV; SIV or HIV evolution; HIV diversity; Single genome sequencing (SGS); Nonhuman primate model; Antiretroviral therapy; HIV compartmentalization; HIV persistence; SIV or HIV reservoir ID CENTRAL-NERVOUS-SYSTEM; FEMALE GENITAL-TRACT; CEREBROSPINAL-FLUID; DRUG-RESISTANCE; LYMPHOID-TISSUE; HIV-1 REPLICATION; VIRUS-REPLICATION; RESIDUAL VIREMIA; COMPARTMENTALIZATION; BLOOD AB Background: Determining the anatomic compartments that contribute to plasma HIV-1 is critical to understanding the sources of residual viremia during combination antiretroviral therapy (ART). We analyzed viral DNA and RNA populations in the plasma and tissues from macaques infected with SIV containing HIV-1 RT (RT-SHIV) to identify possible sources of persistent viremia and to investigate the effect of ART on viral replication in tissues. Tissues were collected at necropsy from four pigtailed macaques infected for 30 weeks with a diverse population of RT-SHIV. Two animals (6760 and 8232) were untreated and two animals (8030 and 8272) were treated with efavirenz, tenofovir, and emtricitabine for 20 weeks. Results: A total of 1800 single-genome RT-SHIV pol and env DNA and RNA sequences were analyzed from the plasma, PBMCs, axillary and mesenteric lymph nodes, spleen, thymus, small intestine, bone marrow, lung, and brain. Analyses of intracellular DNA and RNA populations revealed that the majority of proviruses in tissues from untreated animal 8232 were not expressed, whereas a greater proportion of proviruses in tissues were expressed from 6760. Few intracellular RNA sequences were detected in treated animals and most contained inactivating mutations, such as frame shifts or large deletions. Phylogenetics showed that RT-SHIV DNA populations in tissues were not different from virus in contemporary plasma samples in the treated or untreated animals, demonstrating a lack of anatomic compartmentalization and suggesting that plasma viremia is derived from multiple tissue sources. No sequence divergence was detected in the plasma or between tissues in the treated animals after 20 weeks of ART indicating a lack of ongoing replication in tissues during treatment. Conclusions: Virus populations in plasma and tissues did not differ significantly in either treated or untreated macaques, suggesting frequent exchange of virus or infected cells between tissues and plasma, consistent with non-compartmentalized and widely disseminated infection. There was no genetic evidence of ongoing replication in tissues during suppressive ART. C1 [Kearney, Mary F.; Anderson, Elizabeth M.; Coomer, Charles; Smith, Luke; Johnson, Nicholas; Spindler, Jonathan] NCI, HIV Dynam & Replicaton Program, Frederick, MD 21702 USA. [Shao, Wei] SAIC, Adv Biomed Comp Ctr, Frederick, MD USA. [Kline, Christopher; Mellors, John W.; Ambrose, Zandrea] Univ Pittsburgh, Sch Med, Dept Med, Div Infect Dis, Pittsburgh, PA 15213 USA. [Coffin, John M.] Tufts Univ, Dept Mol Biol & Microbiol, Boston, MA 02111 USA. RP Kearney, MF (reprint author), NCI, HIV Dynam & Replicaton Program, 1050 Boyles St,Bldg 535,Room 109, Frederick, MD 21702 USA. EM kearneym@mail.nih.gov FU National Cancer Institute's intramural Center for Cancer Research; NIH [AI080290]; Leidos contracts [25XS119, 13XS110]; Federal funds from the National Cancer Institute, NIH [HHSN261200800001E] FX The authors thank Joseph Meyer for help with generating figures. We also authors thank Ann Wiegand and Valerie Boltz for helpful discussions and Connie Kinna, Valerie Turnquist, and Susan Toms for administrative support. Funding for this research was provided by the National Cancer Institute's intramural Center for Cancer Research, by NIH R01 Grant AI080290 (ZA), by Leidos contracts 25XS119 (JWM) and 13XS110 (JMC) and with Federal funds from the National Cancer Institute, NIH, under contract HHSN261200800001E. JMC was a research Professor of the American Cancer Society. 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 55 TC 4 Z9 4 U1 1 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD NOV 11 PY 2015 VL 12 AR 93 DI 10.1186/s12977-015-0212-2 PG 17 WC Virology SC Virology GA CW1WB UT WOS:000364781500001 PM 26559632 ER PT J AU Jamshidi, M Fagerholm, R Khan, S Aittomaki, K Czene, K Darabi, H Li, JM Andrulis, IL Chang-Claude, J Devilee, P Fasching, PA Michailidou, K Bolla, MK Dennis, J Wang, Q Guo, Q Rhenius, V Cornelissen, S Rudolph, A Knight, JA Loehberg, CR Burwinkel, B Marme, F Hopper, JL Southey, MC Bojesen, SE Flyger, H Brenner, H Holleczek, B Margolin, S Mannermaa, A Kosma, VM Van Dyck, L Nevelsteen, I Couch, FJ Olson, JE Giles, GG McLean, C Haiman, CA Henderson, BE Winqvist, R Pylkas, K Tollenaar, RAEM Garcia-Closas, M Figueroa, J Hooning, MJ Martens, JWM Cox, A Cross, SS Simard, J Dunning, AM Easton, DF Pharoah, PDP Hall, P Blomqvist, C Schmidt, MK Nevanlinna, H AF Jamshidi, Maral Fagerholm, Rainer Khan, Sofia Aittomaki, Kristiina Czene, Kamila Darabi, Hatef Li, Jingmei Andrulis, Irene L. Chang-Claude, Jenny Devilee, Peter Fasching, Peter A. Michailidou, Kyriaki Bolla, Manjeet K. Dennis, Joe Wang, Qin Guo, Qi Rhenius, Valerie Cornelissen, Sten Rudolph, Anja Knight, Julia A. Loehberg, Christian R. Burwinkel, Barbara Marme, Frederik Hopper, John L. Southey, Melissa C. Bojesen, Stig E. Flyger, Henrik Brenner, Hermann Holleczek, Bernd Margolin, Sara Mannermaa, Arto Kosma, Veli-Matti Van Dyck, Laurien Nevelsteen, Ines Couch, Fergus J. Olson, Janet E. Giles, Graham G. McLean, Catriona Haiman, Christopher A. Henderson, Brian E. Winqvist, Robert Pylkas, Katri Tollenaar, Rob A. E. M. Garcia-Closas, Montserrat Figueroa, Jonine Hooning, Maartje J. Martens, John W. M. Cox, Angela Cross, Simon S. Simard, Jacques Dunning, Alison M. Easton, Douglas F. Pharoah, Paul D. P. Hall, Per Blomqvist, Carl Schmidt, Marjanka K. Nevanlinna, Heli CA kConFab Investigators TI SNP-SNP interaction analysis of NF-kappa B signaling pathway on breast cancer survival SO ONCOTARGET LA English DT Article DE breast cancer; survival analysis; SNP-SNP interaction; NF-kappa B pathway ID FALSE DISCOVERY RATE; ACTIVATION; CELLS; GENES; IDENTIFICATION; POLYMORPHISMS; TRANSCRIPTION; CHEMOTHERAPY; ANNOTATION; PROGNOSIS AB In breast cancer, constitutive activation of NF-kappa B has been reported, however, the impact of genetic variation of the pathway on patient prognosis has been little studied. Furthermore, a combination of genetic variants, rather than single polymorphisms, may affect disease prognosis. Here, in an extensive dataset (n = 30,431) from the Breast Cancer Association Consortium, we investigated the association of 917 SNPs in 75 genes in the NF-kappa B pathway with breast cancer prognosis. We explored SNP-SNP interactions on survival using the likelihood-ratio test comparing multivariate Cox' regression models of SNP pairs without and with an interaction term. We found two interacting pairs associating with prognosis: patients simultaneously homozygous for the rare alleles of rs5996080 and rs7973914 had worse survival (HRinteraction 6.98, 95% CI= 3.3-14.4, P=1.42E-07), and patients carrying at least one rare allele for rs17243893 and rs57890595 had better survival (HRinteraction 0.51, 95% CI= 0.3-0.6, P = 2.19E-05). Based on in silico functional analyses and literature, we speculate that the rs5996080 and rs7973914 loci may affect the BAFFR and TNFR1/TNFR3 receptors and breast cancer survival, possibly by disturbing both the canonical and non-canonical NF-kappa B pathways or their dynamics, whereas, rs17243893-rs57890595 interaction on survival may be mediated through TRAF2-TRAIL-R4 interplay. These results warrant further validation and functional analyses. C1 [Jamshidi, Maral; Fagerholm, Rainer; Khan, Sofia; Nevanlinna, Heli] Univ Helsinki, Dept Obstet & Gynecol, FI-00029 Helsinki, Finland. [Jamshidi, Maral; Fagerholm, Rainer; Khan, Sofia; Aittomaki, Kristiina; Nevanlinna, Heli] Helsinki Univ Hosp, FI-00029 Helsinki, Finland. [Aittomaki, Kristiina] Univ Helsinki, Dept Clin Genet, FI-00029 Helsinki, Finland. [Czene, Kamila; Darabi, Hatef; Li, Jingmei; Hall, Per] Karolinska Inst, Dept Med Epidemiol & Biostati, SE-17177 Stockholm, Sweden. [Andrulis, Irene L.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada. [Andrulis, Irene L.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Chang-Claude, Jenny] Univ Ulm, Dept Obstet & Gynecol, D-89069 Ulm, Germany. [Chang-Claude, Jenny; Rudolph, Anja] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Devilee, Peter] Leiden Univ, Dept Pathol, Med Ctr, Leiden, Netherlands. [Devilee, Peter] Leiden Univ, Dept Human Genet, Med Ctr, NL-2300 RA Leiden, Netherlands. [Fasching, Peter A.] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Dept Gynecol & Obstet, D-91054 Erlangen, Germany. [Fasching, Peter A.] Univ Calif Los Angeles, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90024 USA. [Michailidou, Kyriaki; Bolla, Manjeet K.; Dennis, Joe; Wang, Qin; Easton, Douglas F.; Pharoah, Paul D. P.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Guo, Qi; Rhenius, Valerie; Dunning, Alison M.; Easton, Douglas F.; Pharoah, Paul D. P.] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England. [Cornelissen, Sten; Schmidt, Marjanka K.] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands. [Knight, Julia A.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Prosserman Ctr Hlth Res, Toronto, ON M5G 1X5, Canada. [Knight, Julia A.] Univ Toronto, Dalla Lana Sch Publ Hlth, Div Epidemiol, Toronto, ON M5S 1A8, Canada. [Loehberg, Christian R.] Univ Erlangen Nurnberg, Comprehens Canc Ctr Erlangen EMN, Univ Hosp Erlangen, Dept Obstet & Gynaecol, D-91054 Erlangen, Germany. [Burwinkel, Barbara] German Canc Res Ctr, Mol Epidemiol Grp, Heidelberg, Germany. [Burwinkel, Barbara; Marme, Frederik] Heidelberg Univ, Dept Obstet & Gynecol, Heidelberg, Germany. [Marme, Frederik] Heidelberg Univ, Natl Ctr Tumor Dis, Heidelberg, Germany. [Hopper, John L.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia. [Southey, Melissa C.] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia. [Bojesen, Stig E.] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark. [Bojesen, Stig E.] Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, Herlev, Denmark. [Flyger, Henrik] Copenhagen Univ Hosp, Herlev Hosp, Dept Breast Surg, Herlev, Denmark. [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. [Holleczek, Bernd] Saarland Canc Registry, Saarbrucken, Germany. [Margolin, Sara] Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden. [Mannermaa, Arto; Kosma, Veli-Matti] Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Sch Med, Kuopio, Finland. [Mannermaa, Arto; Kosma, Veli-Matti] Univ Eastern Finland, Canc Ctr Eastern Finland, Kuopio, Finland. [Mannermaa, Arto; Kosma, Veli-Matti] Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, SF-70210 Kuopio, Finland. [kConFab Investigators] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [Van Dyck, Laurien] VIB, Vesalius Res Ctr VRC, Leuven, Belgium. [Van Dyck, Laurien] Univ Leuven, Dept Oncol, Lab Translat Genet, Leuven, Belgium. [Nevelsteen, Ines] Univ Hosp Leuven, Multidisciplinary Breast Ctr, Med Oncol, Leuven, Belgium. [Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Olson, Janet E.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Giles, Graham G.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Giles, Graham G.] Univ Melbourne, Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia. [McLean, Catriona] Monash Univ, Alfred Hosp, Anat Pathol, Melbourne, Vic 3181, Australia. [Haiman, Christopher A.; Henderson, Brian E.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Winqvist, Robert; Pylkas, Katri] Univ Oulu, Canc Res & Translat Med, Lab Canc Genet & Tumor Biol, Bioctr Oulu, Oulu, Finland. [Winqvist, Robert; Pylkas, Katri] Northern Finland Lab Ctr NordLab, Lab Canc Genet & Tumor Biol, Oulu, Finland. [Tollenaar, Rob A. E. M.] Leiden Univ, Med Ctr, Dept Surg Oncol, Leiden, Netherlands. [Garcia-Closas, Montserrat] Inst Canc Res, Div Genet & Epidemiol, Sutton SM2 5NG, Surrey, England. [Garcia-Closas, Montserrat] Inst Canc Res, Breakthrough Breast Canc Res Ctr, Div Breast Canc Res, London SW3 6JB, England. [Figueroa, Jonine] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Hooning, Maartje J.; Martens, John W. M.] Erasmus MC Canc Inst, Dept Med Oncol, Ae Rotterdam, Netherlands. [Cox, Angela] Univ Sheffield, Dept Oncol, Sheffield Canc Res, Sheffield, S Yorkshire, England. [Cross, Simon S.] Univ Sheffield, Dept Neurosci, Acad Unit Pathol, Sheffield, S Yorkshire, England. [Simard, Jacques] Univ Laval, Ctr Hosp Univ Quebec, Res Ctr, Quebec City, PQ, Canada. [Blomqvist, Carl] Univ Helsinki, Dept Oncol, Helsinki, HUS, Finland. [Blomqvist, Carl] Univ Helsinki, Cent Hosp, Helsinki, HUS, Finland. RP Nevanlinna, H (reprint author), Univ Helsinki, Dept Obstet & Gynecol, FI-00029 Helsinki, Finland. EM heli.nevanlinna@hus.fi RI Knight, Julia/A-6843-2012; Li, Jingmei/I-2904-2012; Andrulis, Irene/E-7267-2013; Van Dyck, Laurien/I-4018-2016; Brenner, Hermann/B-4627-2017; OI Li, Jingmei/0000-0001-8587-7511; Van Dyck, Laurien/0000-0002-1373-7656; Brenner, Hermann/0000-0002-6129-1572; Cross, Simon/0000-0003-2044-1754 FU NHMRC; National Breast Cancer Foundation; Cancer Australia; National Institute of Health (USA) FX We thank all the individuals who took part in these studies and all the researchers, clinicians, technicians and administrative staff who have enabled this work to be carried out. This study would not have been possible without the contributions of the following: Liisa Pelttari, Kirsimari Aaltonen, Karl von Smitten, Tuomas Heikkinen, Irja Erkkila (HEBCS); Peter Bugert, Medical Faculty Mannheim (BSUCH); Dorthe Uldall Andersen, Maria Birna Arnadottir, Anne Bank, Dorthe Kjeldgard Hansen (CGPS); Hartwig Ziegler, Sonja Wolf, Volker Hermann (ESTHER); Eija Myohanen, Helena Kemilainen (KBCP); Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study (which has received funding from the NHMRC, the National Breast Cancer Foundation, Cancer Australia, and the National Institute of Health (USA)) for their contributions to this resource, and the many families who contribute to kConFab (KConFab/AOCS); Gilian Peuteman, Dominiek Smeets, Thomas Van Brussel and Kathleen Corthouts (LMBC); Dieter Flesch-Janys, Petra Seibold, Judith Heinz, Nadia Obi, Alina Vrieling, Sabine Behrens, Ursula Eilber, Muhabbet Celik, Til Olchers and Stefan Nickels (MARIE); Meeri Otsukka, Kari Mononen (OBCS); Teresa Selander, Nayana Weerasooriya, Julia Knight, Gord Glendon (OFBCR); E. Krol-Warmerdam, and J. Blom for patient accrual, administering questionnaires, and managing clinical information; the LUMC survival data were retrieved from the Leiden hospital-based cancer registry system (ONCDOC) with the help of Dr. J. Molenaar (ORIGO); Louise Brinton, Mark Sherman, Neonila Szeszenia-Dabrowska, Beata Peplonska, Witold Zatonski, Pei Chao, Michael Stagner (PBCS); The Swedish Medical Research CounseL (Pkarma and SASBAC); Petra Bos, Jannet Blom, Ellen Crepin, Elisabeth Huijskens, Annette Heemskerk, the Erasmus MC Cancer Institute (RBCS); Sue Higham, Helen Cramp, Ian Brock, Malcolm W.R. Reed, Sabapathy Balasubramanian and Dan Connley (SBCS); and the SEARCH and EPIC teams (SEARCH); Andrew Lee, and Ed Dicks, Craig Luccarini and the staff of the Centre for Genetic Epidemiology Laboratory, Javier Benitez, Anna Gonzalez-Neira, the staff of the CNIO genotyping unit, Daniel C., Tessier, Francois Bacot, Daniel Vincent, Sylvie LaBoissiere and Frederic Robidoux and the staff of the McGill University and Genome Quebec Innovation Centre, Sune F. Nielsen, Borge G. Nordestgaard, and the staff of the Copenhagen DNA laboratory, and Julie M. Cunningham, Sharon A. Windebank, Christopher A. Hilker, Jeffrey Meyer and the staff of Mayo Clinic Genotyping Core Facility. NR 50 TC 0 Z9 0 U1 0 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 NOV 10 PY 2015 VL 6 IS 35 BP 37979 EP 37994 PG 16 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CY0RL UT WOS:000366113200075 PM 26317411 ER PT J AU Greaney, AJ Leppla, SH Moayeri, M AF Greaney, Allison J. Leppla, Stephen H. Moayeri, Mahtab TI Bacterial exotoxins and the inflammasome SO FRONTIERS IN IMMUNOLOGY LA English DT Review DE inflammasome; caspase-1; interleukin-1; pyroptosis; exotoxins; NLRP3; Nod-like receptors; anthrax lethal toxin ID ANTHRAX LETHAL TOXIN; FAMILIAL MEDITERRANEAN FEVER; PHENOL-SOLUBLE MODULINS; TUMOR-NECROSIS-FACTOR; PORE-FORMING TOXINS; NLRP3 INFLAMMASOME; CELL-DEATH; CASPASE-1 AUTOPROTEOLYSIS; TH17 RESPONSES; LISTERIA-MONOCYTOGENES AB The inflammasomes are intracellular protein complexes that play an important role in innate immune sensing. Activation of inflammasomes leads to activation of caspase-1 and maturation and secretion of the pro-inflammatory cytokines interleukin (IL)-1 alpha and IL-18. In certain myeloid cells, this activation can also lead to an inflammatory cell death (pyroptosis). Inflammasome sensor proteins have evolved to detect a range of microbial ligands and bacterial exotoxins either through direct interaction or by detection of host cell changes elicited by these effectors. Bacterial exotoxins activate the inflammasomes through diverse processes, including direct sensor cleavage, modulation of ion fluxes through plasma membrane pore formation, and perturbation of various host cell functions. In this review, we summarize the findings on some of the bacterial exotoxins that activate the inflammasomes. C1 [Greaney, Allison J.; Leppla, Stephen H.; Moayeri, Mahtab] NIAID, Microbial Pathogenesis Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Moayeri, M (reprint author), NIAID, Microbial Pathogenesis Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM mmoayeri@niaid.nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health. NR 103 TC 3 Z9 3 U1 6 U2 15 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 NOV 10 PY 2015 VL 6 AR UNSP 570 DI 10.3389/fimmu.2015.00570 PG 10 WC Immunology SC Immunology GA CY0SQ UT WOS:000366116700001 PM 26617605 ER PT J AU Chinyengetere, F Sekula, DJ Lu, Y Giustini, AJ Sanglikar, A Kawakami, M Ma, T Burkett, SS Eisenberg, BL Wells, WA Hoopes, PJ Demicco, EG Lazar, AJ Torres, KE Memoli, V Freemantle, SJ Dmitrovsky, E AF Chinyengetere, Fadzai Sekula, David J. Lu, Yun Giustini, Andrew J. Sanglikar, Aarti Kawakami, Masanori Ma, Tian Burkett, Sandra S. Eisenberg, Burton L. Wells, Wendy A. Hoopes, Paul J. Demicco, Elizabeth G. Lazar, Alexander J. Torres, Keila E. Memoli, Vincent Freemantle, Sarah J. Dmitrovsky, Ethan TI Mice null for the deubiquitinase USP18 spontaneously develop leiomyosarcomas SO BMC CANCER LA English DT Article DE USP18; ISG15; Leiomyosarcoma; Murine cancer model ID SOFT-TISSUE SARCOMA; UBIQUITIN PROTEASE UBP43; EUROPEAN-ORGANIZATION; EPITHELIAL-CELLS; CANCER; GROWTH; INACTIVATION; PATHWAY; ISG15; P53 AB Background: USP18 (ubiquitin-specific protease 18) removes ubiquitin-like modifier interferon stimulated gene 15 (ISG15) from conjugated proteins. USP18 null mice in a FVB/N background develop tumors as early as 2 months of age. These tumors are leiomyosarcomas and thus represent a new murine model for this disease. Methods: Heterozygous USP18 +/- FVB/N mice were bred to generate wild type, heterozygous and homozygous cohorts. Tumors were characterized immunohistochemically and two cell lines were derived from independent tumors. Cell lines were karyotyped and their responses to restoration of USP18 activity assessed. Drug testing arid tumorigenic assays were also performed. USP18 immunohistochemical staining in a large series of human leiomyosacomas was examined. Results: USP18 -/- FVB/N mice spontaneously develop tumors predominantly on the back of the neck with most tumors evident between 6-12 months (80% penetrance). Immunohistochemical characterization of the tumors confirmed they were leiomyosarcomas, which originate from smooth muscle. Restoration of USP18 activity in sarcoma-derived cell lines did not reduce anchorage dependent or independent growth or xenograft tumor formation demonstrating that these cells no longer require USP18 suppression for tumorigenesis. Karyotyping revealed that both tumor derived cell lines were aneuploid with extra copies of chromosomes 3 and 15. Chromosome 15 contains the Myc locus and MYC is also amplified in human leiomyosarcomas. MYC protein levels were elevated in both murine leiomyosarcoma cell lines. Stabilized P53 protein was detected in a subset of these murine tumors, another feature of human leiomyosarcomas. Immunohistochemical analyses of USP18 in human leiomyosarcomas revealed a range of staining intensities with the highest USP18 expression in normal vascular smooth muscle. USP18 tissue array analysis of primary leiomyosarcomas from 89 patients with a clinical database revealed cases with reduced USP18 levels had a significantly decreased time to metastasis (P = 0.0441). Conclusions: USP18 null mice develop leiomyosarcoma recapitulating key features of clinical leiomyosarcomas and patients with reduced-USP18 tumor levels have an unfavorable outcome. USP18 null mice and the derived cell lines represent clinically relevant models of leiomyosarcoma and can provide insights into both leiomyosarcoma biology and therapy. C1 [Chinyengetere, Fadzai; Sekula, David J.; Lu, Yun; Kawakami, Masanori; Ma, Tian; Freemantle, Sarah J.; Dmitrovsky, Ethan] Dartmouth, Dept Pharmacol & Toxicol, Hanover, NH USA. [Dmitrovsky, Ethan] Dartmouth, Dept Med, Hanover, NH USA. [Wells, Wendy A.; Memoli, Vincent] Dartmouth, Dept Pathol, Hanover, NH USA. [Eisenberg, Burton L.; Hoopes, Paul J.] Dartmouth, Dept Surg, Hanover, NH USA. [Sanglikar, Aarti; Eisenberg, Burton L.; Wells, Wendy A.; Hoopes, Paul J.; Memoli, Vincent; Dmitrovsky, Ethan] Norris Cotton Canc Ctr, Lebanon, NH USA. [Chinyengetere, Fadzai; Sekula, David J.; Lu, Yun; Giustini, Andrew J.; Kawakami, Masanori; Ma, Tian; Eisenberg, Burton L.; Wells, Wendy A.; Hoopes, Paul J.; Memoli, Vincent; Freemantle, Sarah J.; Dmitrovsky, Ethan] Dartmouth, Geisel Sch Med, Hanover, NH USA. [Chinyengetere, Fadzai; Sekula, David J.; Lu, Yun; Giustini, Andrew J.; Kawakami, Masanori; Ma, Tian; Eisenberg, Burton L.; Wells, Wendy A.; Hoopes, Paul J.; Memoli, Vincent; Freemantle, Sarah J.; Dmitrovsky, Ethan] Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 USA. [Giustini, Andrew J.; Hoopes, Paul J.] Dartmouth Coll, Thayer Sch Engn, Hanover, NH 03755 USA. [Burkett, Sandra S.] NCI, Comparat Mol Cytogenet Core, Mouse Canc Genet Program, Frederick, MD 21701 USA. [Demicco, Elizabeth G.] Mt Sinai Hosp, Dept Pathol, New York, NY 10029 USA. [Lazar, Alexander J.] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Lazar, Alexander J.; Torres, Keila E.] Univ Texas MD Anderson Canc Ctr, Sarcoma Res Ctr, Houston, TX 77030 USA. [Torres, Keila E.] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA. RP Dmitrovsky, E (reprint author), Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. EM ethan.dmitrovsky@dartmouth.edu RI Lazar, Alexander/A-3416-2008 OI Lazar, Alexander/0000-0002-6395-4499 FU National Institutes of Health (NIH); National Cancer Institute (NCI) [R01-CA087546, R01-CA062275, R01-CA190722]; Samuel Waxman Cancer Research Foundation (SWCRF); UT-STARS award; Uniting Against Lung Cancer; Mary Jo's Fund to Fight Cancer FX The flow cytometry was carried out in Dartlab, the Immunoassay and the Flow Cytometry Shared Resource at the Geisel School of Medicine at Dartmouth. We thank Dr. Jacqueline Smith and Gary Ward for analysis of data and technical assistance. Research reported in this publication was supported by National Institutes of Health (NIH) and National Cancer Institute (NCI) grants R01-CA087546 (E. Dmitrovsky), R01-CA062275 (E. Dmitrovsky), and R01-CA190722 (E. Dmitrovsky), by a Samuel Waxman Cancer Research Foundation (SWCRF) grant (E. Dmitrovsky), by a UT-STARS award (E. Dmitrovsky) and by a grant from Uniting Against Lung Cancer with Mary Jo's Fund to Fight Cancer (S.J. Freemantle). E. Dmitrovsky is an American Cancer Society Professor supported by a generous gift from the F.M. Kirby Foundation. The G-banding and SKY analysis was provided by the Center for Cancer Research, NCI, NIH. NR 46 TC 3 Z9 3 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD NOV 10 PY 2015 VL 15 AR 886 DI 10.1186/s12885-015-1883-8 PG 12 WC Oncology SC Oncology GA CW8TM UT WOS:000365272200005 PM 26555296 ER PT J AU Mou, ZY Hyde, TM Lipska, BK Martinowich, K Wei, P Ong, CJ Hunter, LA Palaguachi, GI Morgun, E Teng, R Lai, C Condarco, TA Demidowich, AP Krause, AJ Marshall, LJ Haack, K Voruganti, VS Cole, SA Butte, NF Comuzzie, AG Nalls, MA Zonderman, AB Singleton, AB Evans, MK Martin, B Maudsley, S Tsao, JW Kleinman, JE Yanovski, JA Han, JC AF Mou, Zongyang Hyde, Thomas M. Lipska, Barbara K. Martinowich, Keri Wei, Peter Ong, Chiew-Jen Hunter, Lindsay A. Palaguachi, Gladys I. Morgun, Eva Teng, Rujia Lai, Chen Condarco, Tania A. Demidowich, Andrew P. Krause, Amanda J. Marshall, Leslie J. Haack, Karin Voruganti, V. Saroja Cole, Shelley A. Butte, Nancy F. Comuzzie, Anthony G. Nalls, Michael A. Zonderman, Alan B. Singleton, Andrew B. Evans, Michele K. Martin, Bronwen Maudsley, Stuart Tsao, Jack W. Kleinman, Joel E. Yanovski, Jack A. Han, Joan C. TI Human Obesity Associated with an Intronic SNP in the Brain-Derived Neurotrophic Factor Locus SO CELL REPORTS LA English DT Article ID HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEIN; BINDING; TRANSCRIPTION; EXPRESSION; GENETICS; COMPLEX; BDNF AB Brain-derived neurotrophic factor (BDNF) plays a key role in energy balance. In population studies, SNPs of the BDNF locus have been linked to obesity, but the mechanism by which these variants cause weight gain is unknown. Here, we examined human hypothalamic BDNF expression in association with 44 BDNF SNPs. We observed that the minor C allele of rs12291063 is associated with lower human ventromedial hypothalamic BDNF expression (p < 0.001) and greater adiposity in both adult and pediatric cohorts (p values < 0.05). We further demonstrated that the major T allele for rs12291063 possesses a binding capacity for the transcriptional regulator, heterogeneous nuclear ribonucleoprotein D0B, knockdown of which disrupts transactivation by the T allele. Binding and transactivation functions are both disrupted by substituting C for T. These findings provide a rationale for BDNF augmentation as a targeted treatment for obesity in individuals who have the rs12291063 CC genotype. C1 [Mou, Zongyang; Wei, Peter; Ong, Chiew-Jen; Hunter, Lindsay A.; Palaguachi, Gladys I.; Morgun, Eva; Teng, Rujia; Lai, Chen; Han, Joan C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Metab & Neuroendocrinol, NIH, Bethesda, MD 20892 USA. [Mou, Zongyang; Morgun, Eva; Condarco, Tania A.; Demidowich, Andrew P.; Krause, Amanda J.; Tsao, Jack W.; Yanovski, Jack A.; Han, Joan C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, NIH, Bethesda, MD 20892 USA. [Hyde, Thomas M.; Martinowich, Keri; Kleinman, Joel E.] Johns Hopkins Univ, Sch Med, Lieber Inst Brain Dev, Baltimore, MD 21205 USA. [Hyde, Thomas M.; Martinowich, Keri; Kleinman, Joel E.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Hyde, Thomas M.; Kleinman, Joel E.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Lipska, Barbara K.] NIMH, Human Brain Collect Core, NIH, Bethesda, MD 20892 USA. [Wei, Peter; Ong, Chiew-Jen; Hunter, Lindsay A.; Palaguachi, Gladys I.] Uniformed Serv Univ Hlth Sci, Dept Neurol, Bethesda, MD 20814 USA. [Wei, Peter; Ong, Chiew-Jen; Hunter, Lindsay A.; Palaguachi, Gladys I.; Lai, Chen] Uniformed Serv Univ Hlth Sci, Dept Phys Med & Rehabil, Bethesda, MD 20814 USA. [Marshall, Leslie J.] NIAID, Preclin Microbicide & Prevent Res Branch, NIH, Bethesda, MD 20892 USA. [Haack, Karin; Voruganti, V. Saroja; Cole, Shelley A.; Comuzzie, Anthony G.] Texas Biomed Res Inst, Dept Genet, San Antonio, TX 78245 USA. [Haack, Karin; Voruganti, V. Saroja; Cole, Shelley A.; Comuzzie, Anthony G.] Southwest Natl Primate Res Ctr, San Antonio, TX 78245 USA. [Voruganti, V. Saroja] Univ N Carolina, Dept Nutr, Kannapolis, NC 28081 USA. [Voruganti, V. Saroja] Univ N Carolina, UNC Nutr Res Inst, Kannapolis, NC 28081 USA. [Butte, Nancy F.] Baylor Coll Med, USDA ARS Childrens Nutr Res Ctr, Houston, TX 77030 USA. [Nalls, Michael A.; Singleton, Andrew B.] NIA, Mol Genet Sect, Bethesda, MD 20892 USA. [Zonderman, Alan B.] NIA, Behav Epidemiol Sect, Baltimore, MD 21224 USA. [Evans, Michele K.] NIA, Hlth Dispar Res Sect, Baltimore, MD 21224 USA. [Martin, Bronwen] NIA, Metab Unit, Baltimore, MD 21224 USA. [Maudsley, Stuart] NIA, Receptor Pharmacol Unit, Baltimore, MD 21224 USA. [Maudsley, Stuart] Univ Antwerp, Translat Neurobiol Grp, VIB Dept Mol Genet, B-2610 Antwerp, Belgium. [Maudsley, Stuart] Univ Antwerp, Lab Neurogenet, Inst Born Bunge, B-2610 Antwerp, Belgium. [Tsao, Jack W.] Univ Tennessee, Hlth Sci Ctr, Dept Neurol, Memphis, TN 38163 USA. [Han, Joan C.] Univ Tennessee, Hlth Sci Ctr, Dept Pediat, Memphis, TN 38163 USA. [Han, Joan C.] Le Bonheur Childrens Hosp, Childrens Fdn Res Inst, Memphis, TN 38103 USA. RP Han, JC (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Metab & Neuroendocrinol, NIH, Bethesda, MD 20892 USA. EM jhan14@uthsc.edu RI Singleton, Andrew/C-3010-2009; Martinowich, Keri/F-9841-2012; Lipska, Barbara/E-4569-2017; OI Zonderman, Alan B/0000-0002-6523-4778 FU Intramural Research Program of NICHD; NIH [R01 DK59264, R01 DK080457]; NIMH; National Institute of Minority Health and Health Disparities; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); NIH Division of Nutrition Research Coordination; National Human Genome Research Institute (NHGRI); CALiCo [U01HG004803]; EAGLE [U01HG004798]; MEC [U01HG004802]; WHI [U01HG004790]; Coordinating Center [U01HG004801] FX This research was supported by the Intramural Research Program of NICHD and NIMH with supplemental funding from the NIH Bench to Bedside Program to J.C.H. and the National Institute of Minority Health and Health Disparities to J.A.Y. The Viva la Familia studies were supported by the NIH (R01 DK59264 and R01 DK080457 to N.F.B.). A.J.K. is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the NIH Division of Nutrition Research Coordination. The PAGE program is funded by National Human Genome Research Institute (NHGRI), supported by U01HG004803 (CALiCo), U01HG004798 (EAGLE), U01HG004802 (MEC), U01HG004790 (WHI), and U01HG004801 (Coordinating Center), and their respective NHGRI American Recovery and Reinvestment Act (ARRA) supplements. We thank Ms. Amy Deep-Soboslay and Drs. Lewellyn B. Bigelow and Mary M. Herman for their contributions in assembling the postmortem human brain cohorts for study, Dr. Amanda Preston for editorial assistance, and the families of the decedents for their generous donation of tissue. J.A.Y. is a Commissioned Officer of the United States Public Health Service. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Public Health Service, Department of the Navy, Department of Defense, or Department of Health and Human Services. NR 20 TC 8 Z9 8 U1 0 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 NOV 10 PY 2015 VL 13 IS 6 BP 1073 EP 1080 DI 10.1016/j.celrep.2015.09.065 PG 8 WC Cell Biology SC Cell Biology GA CW4UJ UT WOS:000364990600001 PM 26526993 ER PT J AU Kazanov, MD Roberts, SA Polak, P Stamatoyannopoulos, J Klimczak, LJ Gordenin, DA Sunyaev, SR AF Kazanov, Marat D. Roberts, Steven A. Polak, Paz Stamatoyannopoulos, John Klimczak, Leszek J. Gordenin, Dmitry A. Sunyaev, Shamil R. TI APOBEC-Induced Cancer Mutations Are Uniquely Enriched in Early-Replicating, Gene-Dense, and Active Chromatin Regions SO CELL REPORTS LA English DT Article ID BREAK-INDUCED REPLICATION; GENOMIC INSTABILITY; SUPER-ENHANCERS; ORGANIZATION; MUTAGENESIS; PATTERNS AB An antiviral component of the human innate immune system-the APOBEC cytidine deaminases-was recently identified as a prominent source of mutations in cancers. Here, we investigated the distribution of APOBEC-induced mutations across the genomes of 119 breast and 24 lung cancer samples. While the rate of most mutations is known to be elevated in late-replicating regions that are characterized by reduced chromatin accessibility and low gene density, we observed a marked enrichment of APOBEC mutations in early-replicating regions. This unusual mutagenesis profile may be associated with a higher propensity to form single-strand DNA substrates for APOBEC enzymes in early-replicating regions and should be accounted for in statistical analyses of cancer genome mutation catalogs aimed at understanding the mechanisms of carcinogenesis as well as highlighting genes that are significantly mutated in cancer. C1 [Kazanov, Marat D.] RAS, Res & Training Ctr Bioinformat, AA Kharkevich Inst Informat Transmiss Problems, Moscow 127051, Russia. [Roberts, Steven A.; Klimczak, Leszek J.; Gordenin, Dmitry A.] NIEHS, Durham, NC 27709 USA. [Roberts, Steven A.] Washington State Univ, Sch Mol Biosci, Pullman, WA 99164 USA. [Polak, Paz; Sunyaev, Shamil R.] Harvard Univ, Sch Med, Div Genet, Brigham & Womens Hosp, Boston, MA 02115 USA. [Stamatoyannopoulos, John] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Stamatoyannopoulos, John] Univ Washington, Dept Med, Seattle, WA 98195 USA. RP Gordenin, DA (reprint author), NIEHS, Durham, NC 27709 USA. EM gordenin@niehs.nih.gov; ssunyaev@rics.bwh.harvard.edu RI Kazanov, Marat/D-6381-2013 OI Kazanov, Marat/0000-0002-2314-5507 FU NIH [R01 MH101244]; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z1AES103266]; National Institute of Environmental Health Sciences (NIH/NIEHS) [4R00ES022633-02]; Russian Science Foundation [14-24-00155] FX This work was supported by NIH grant R01 MH101244 (S.R.S.); Intramural Research Program of the NIH, National Institute of Environmental Health Sciences, project Z1AES103266 (D.A.G.); the Pathway to Independence Award 4R00ES022633-02 from the National Institute of Environmental Health Sciences (NIH/NIEHS) (S.A.R.); and the Russian Science Foundation grant 14-24-00155 (M.D.K.). NR 30 TC 10 Z9 11 U1 0 U2 4 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 NOV 10 PY 2015 VL 13 IS 6 BP 1103 EP 1109 DI 10.1016/j.celrep.2015.09.077 PG 7 WC Cell Biology SC Cell Biology GA CW4UJ UT WOS:000364990600005 PM 26527001 ER PT J AU Farias, GG Guardia, CM Britt, DJ Guo, XL Bonifacino, JS AF Farias, Ginny G. Guardia, Carlos M. Britt, Dylan J. Guo, Xiaoli Bonifacino, Juan S. TI Sorting of Dendritic and Axonal Vesicles at the Pre-axonal Exclusion Zone SO CELL REPORTS LA English DT Article ID KINESIN LIGHT-CHAIN; AMYLOID PRECURSOR PROTEIN; INITIAL SEGMENT; HIPPOCAMPAL-NEURONS; MEMBRANE-PROTEINS; POLARIZED NEURONS; ACTIN-FILAMENTS; NERVOUS-SYSTEM; NMDA RECEPTOR; TRANSPORT AB Polarized sorting of newly synthesized proteins to the somatodendritic and axonal domains of neurons occurs by selective incorporation into distinct populations of vesicular transport carriers. An unresolved issue is how the vesicles themselves are sorted to their corresponding neuronal domains. Previous studies concluded that the axon initial segment (AIS) is an actin-based filter that selectively prevents passage of somatodendritic vesicles into the axon. We find, however, that most somatodendritic vesicles fail to enter the axon at a more proximal region in the axon hillock, herein referred to as the preaxonal exclusion zone (PAEZ). Forced coupling of a somatodendritic cargo protein to an axonally directed kinesin is sufficient to drive transport of whole somatodendritic vesicles through the PAEZ toward the distal axon. Based on these findings, we propose that polarized sorting of transport vesicles occurs at the PAEZ and depends on the ability of the vesicles to acquire an appropriately directed microtubule motor. C1 [Farias, Ginny G.; Guardia, Carlos M.; Britt, Dylan J.; Guo, Xiaoli; Bonifacino, Juan S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. RP Bonifacino, JS (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. EM bonifacinoj@helix.nih.gov OI Bonifacino, Juan S./0000-0002-5673-6370 FU Intramural Program of NICHD, NIH [ZIA HD001607] FX We thank K.E. Howell, P.J. Kammermeier, M. Komada, J. Lippincott-Schwartz, F. Perez, T.A. Rapoport, K.J. Verhey, and S. Vicini for gifts of reagents; X. Zhu and N. Tsai for technical assistance; and D.C. Gershlick for critical review of the manuscript. This work was funded by the Intramural Program of NICHD, NIH (ZIA HD001607). NR 63 TC 10 Z9 10 U1 2 U2 8 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 NOV 10 PY 2015 VL 13 IS 6 BP 1221 EP 1232 DI 10.1016/j.celrep.2015.09.074 PG 12 WC Cell Biology SC Cell Biology GA CW4UJ UT WOS:000364990600016 PM 26527003 ER PT J AU Salgado, MT Cao, ZL Nagababu, E Mohanty, JG Rifkind, JM AF Salgado, Maria T. Cao, Zeling Nagababu, Enika Mohanty, Joy G. Rifkind, Joseph M. TI Red Blood Cell Membrane-Facilitated Release of Nitrite-Derived Nitric Oxide Bioactivity SO BIOCHEMISTRY LA English DT Article ID HYPOXIC CONDITIONS; S-NITROSOHEMOGLOBIN; ENDOTHELIAL-CELLS; FLOW REGULATION; HEMOGLOBIN; DEOXYHEMOGLOBIN; REDUCTION; OXYGEN; ERYTHROCYTES; MECHANISM AB The reduction of nitrite by deoxyhemoglobin to nitric oxide (NO) has been proposed as a mechanism for the transfer of NO bioactivity from the red blood cell (RBC) to the vasculature. This transfer can increase vascular dilatation. The major challenge to this hypothesis is the very efficient scavenging of NO by hemoglobin, which prevents the release of NO from RBCs. Previous studies indicate that the reaction of nitrite with deoxyhemoglobin produces two metastable intermediates involving nitrite bound to deoxyhemoglobin and a hybrid intermediate [Hb(II)NO+ <-> Hb(III)NO] where the nitrite is reduced, but unavailable to react with hemoglobin. We have now shown how unique properties of these intermediates provide a pathway for the release of NO bioactivity from RBCs. The high membrane affinity of these intermediates (>100-fold greater than that of deoxyhemoglobin) places these intermediates on the membrane. Furthermore, membrane-induced conformational changes of the nitrite-reacted intermediates facilitate the release of NO from the hybrid intermediate and nitrite from the nitrite-bound intermediate. Increased membrane affinity, coupled with facilitated dissociation of NO and nitrite from the membrane-bound intermediates, provides the first realistic mechanism for the potential release of NO and nitrite from the RBC and their potential transfer to the vasculature. C1 [Salgado, Maria T.; Cao, Zeling; Nagababu, Enika; Mohanty, Joy G.; Rifkind, Joseph M.] NIA, Mol Dynam Sect, NIH, Baltimore, MD 21224 USA. RP Rifkind, JM (reprint author), NIA, Mol Dynam Sect, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM rifkind@verizon.net FU Intramural Research Program of National Institutes of Health (National Institute on Aging) FX This research was supported by the Intramural Research Program of the National Institutes of Health (National Institute on Aging). NR 42 TC 4 Z9 4 U1 3 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD NOV 10 PY 2015 VL 54 IS 44 BP 6712 EP 6723 DI 10.1021/acs.biochem.5b00643 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CV9NS UT WOS:000364614500007 PM 26478948 ER PT J AU Turkbey, EB Nacif, MS Guo, MY McClelland, RL Teixeira, PBRP Bild, DE Barr, RG Shea, S Post, W Burke, G Budoff, MJ Folsom, AR Liu, CY Lima, JA Bluemke, DA AF Turkbey, Evrim B. Nacif, Marcelo S. Guo, Mengye McClelland, Robyn L. Teixeira, Patricia B. R. P. Bild, Diane E. Barr, R. Graham Shea, Steven Post, Wendy Burke, Gregory Budoff, Matthew J. Folsom, Aaron R. Liu, Chia-Ying Lima, Joao A. Bluemke, David A. TI Prevalence and Correlates of Myocardial Scar in a US Cohort SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID CARDIAC MAGNETIC-RESONANCE; CARDIOVASCULAR RISK-FACTORS; CORONARY-ARTERY-DISEASE; INTIMA-MEDIA THICKNESS; ATHEROSCLEROSIS MESA; HEART-DISEASE; INFARCTION; CALCIUM; INDIVIDUALS; PREDICTION AB IMPORTANCE Myocardial scarring leads to cardiac dysfunction and poor prognosis. The prevalence of and factors associated with unrecognized myocardial infarction and scar have not been previously defined using contemporary methods in a multiethnic US population. OBJECTIVE To determine prevalence of and factors associated with myocardial scar in middle-and older-aged individuals in the United States. DESIGN, SETTING, AND PARTICIPANTS The Multi-Ethnic Study of Atherosclerosis (MESA) study is a population-based cohort in the United States. Participants were aged 45 through 84 years and free of clinical cardiovascular disease (CVD) at baseline in 2000-2002. In the 10th year examination (2010-2012), 1840 participants underwent cardiac magnetic resonance (CMR) imaging with gadolinium to detect myocardial scar. Cardiovascular disease risk factors and coronary artery calcium (CAC) scores were measured at baseline and year 10. Logistic regression models were used to estimate adjusted odds ratios (ORs) for myocardial scar. EXPOSURES Cardiovascular risk factors, CAC scores, left ventricle size and function, and carotid intima-media thickness. MAIN OUTCOMES AND MEASURES Myocardial scar detected by CMR imaging. RESULTS Of 1840 participants (mean [SD] age, 68 [9] years, 52% men), 146 (7.9%) had myocardial scars, of which 114 (78%) were undetected by electrocardiogram or by clinical adjudication. In adjusted models, age, male sex, body mass index, hypertension, and current smoking at baseline were associated with myocardial scar at year 10. The OR per 8.9-year increment was 1.61 (95% CI, 1.36-1.91; P < .001); for men vs women: OR, 5.76 (95% CI, 3.61-9.17; P < .001); per 4.8-SD body mass index: OR, 1.32 (95% CI, 1.09-1.61, P = .005); for hypertension: OR, 1.61 (95% CI, 1.12-2.30; P = .009); and for current vs never smokers: 2.00 (95% CI, 1.22-3.28; P = .006). Age-, sex-, and ethnicity-adjusted CAC scores at baseline were also associated with myocardial scar at year 10. Compared with a CAC score of 0, the OR for scores from 1 through 99 was 2.4 (95% CI, 1.5-3.9); from 100 through 399, 3.0 (95% CI, 1.7-5.1), and 400 or higher, 3.3 (95% CI, 1.7-6.1) (P < .001). The CAC score significantly added to the association of myocardial scar with age, sex, race/ethnicity, and traditional CVD risk factors (C statistic, 0.81 with CAC vs 0.79 without CAC, P =.01). CONCLUSIONS AND RELEVANCE The prevalence of myocardial scars in a US community-based multiethnic cohort was 7.9%, of which 78% were unrecognized by electrocardiography or clinical evaluation. Further studies are needed to understand the clinical consequences of these undetected scars. C1 [Turkbey, Evrim B.; Nacif, Marcelo S.; Liu, Chia-Ying; Bluemke, David A.] Natl Inst Biomed Imaging & Bioengn, Radiol & Imaging Sci, NIH, Ctr Clin, Bethesda, MD USA. [Turkbey, Evrim B.; Lima, Joao A.; Bluemke, David A.] Johns Hopkins Univ, Radiol & Radiol Sci, Baltimore, MD USA. [Guo, Mengye; McClelland, Robyn L.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Teixeira, Patricia B. R. P.; Post, Wendy; Lima, Joao A.] Johns Hopkins Univ, Sch Med, Dept Cardiol, Baltimore, MD USA. [Bild, Diane E.] Patient Ctr Outcomes Res Inst, Washington, DC USA. [Barr, R. Graham; Shea, Steven] Columbia Univ, Dept Med, New York, NY USA. [Barr, R. Graham; Shea, Steven] Columbia Univ, Dept Epidemiol, New York, NY USA. [Burke, Gregory] Wake Forest Univ Hlth Sci, Div Publ Hlth Sci, Winston Salem, NC USA. [Budoff, Matthew J.] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Div Cardiol, Torrance, CA 90509 USA. [Folsom, Aaron R.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. RP Bluemke, DA (reprint author), NIH, Ctr Clin, Radiol & Imaging Sci, 10 Ctr Dr,Bldg 10,Room 1C355, Bethesda, MD 20892 USA. EM david.bluemke@nih.gov OI Bluemke, David/0000-0002-8323-8086 FU National Heart, Lung, and Blood Institute [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]; National Center for Research Resources [UL1-TR-000040, UL1-TR-001079]; NIH Intramural Research Program; Bayer Healthcare; US Environmental Protection Agency [RD831697] 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-95167, N01-HC-95168 and N01-HC-95169 from the National Heart, Lung, and Blood Institute, by grants UL1-TR-000040 and UL1-TR-001079 from National Center for Research Resources the NIH Intramural Research Program, and by a grant from Bayer Healthcare for the use of gadolinium contrast agent. This publication was developed under a STAR research assistance agreement RD831697 (MESA Air) from the US Environmental Protection Agency. NR 30 TC 10 Z9 10 U1 2 U2 2 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 NOV 10 PY 2015 VL 314 IS 18 BP 1945 EP 1954 DI 10.1001/jama.2015.14849 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA CV7XQ UT WOS:000364490700017 PM 26547466 ER PT J AU Gan, L O'Hanlon, TP Lai, ZN Fannin, R Weller, ML Rider, LG Chiorini, JA Miller, FW AF Gan, Lu O'Hanlon, Terrance P. Lai, Zhennan Fannin, Rick Weller, Melodie L. Rider, Lisa G. Chiorini, John A. Miller, Frederick W. TI Gene Expression Profiles from Disease Discordant Twins Suggest Shared Antiviral Pathways and Viral Exposures among Multiple Systemic Autoimmune Diseases SO PLOS ONE LA English DT Article ID PERIPHERAL-BLOOD CELLS; LUPUS-ERYTHEMATOSUS; I INTERFERON; RHEUMATOID-ARTHRITIS; VIRUS INFECTION; PATHOGENESIS; DERMATOMYOSITIS; RECOGNITION; MECHANISMS; MYOSITIS AB Viral agents are of interest as possible autoimmune triggers due to prior reported associations and widely studied molecular mechanisms of antiviral immune responses in autoimmunity. Here we examined new viral candidates for the initiation and/or promotion of systemic autoimmune diseases (SAID), as well as possible related signaling pathways shared in the pathogenesis of those disorders. RNA isolated from peripheral blood samples from 33 twins discordant for SAID and 33 matched, unrelated healthy controls was analyzed using a custom viral-human gene microarray. Paired comparisons were made among three study groups-probands with SAID, their unaffected twins, and matched, unrelated healthy controls-using statistical and molecular pathway analyses. Probands and unaffected twins differed significantly in the expression of 537 human genes, and 107 of those were associated with viral infections. These 537 differentially expressed human genes participate in overlapping networks of several canonical, biologic pathways relating to antiviral responses and inflammation. Moreover, certain viral genes were expressed at higher levels in probands compared to either unaffected twins or unrelated, healthy controls. Interestingly, viral gene expression levels in unaffected twins appeared intermediate between those of probands and the matched, unrelated healthy controls. Of the viruses with over-expressed viral genes, herpes simplex virus-2 (HSV-2) was the only human viral pathogen identified using four distinct oligonucleotide probes corresponding to three HSV-2 genes associated with different stages of viral infection. Although the effects from immunosuppressive therapy on viral gene expression remain unclear, this exploratory study suggests a new approach to evaluate shared viral agents and antiviral immune responses that may be involved in the development of SAID. C1 [Gan, Lu; O'Hanlon, Terrance P.; Rider, Lisa G.; Miller, Frederick W.] NIEHS, Environm Autoimmun Grp, Clin Res Branch, NIH, Bethesda, MD USA. [Lai, Zhennan; Weller, Melodie L.; Chiorini, John A.] Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. [Fannin, Rick] NIEHS, Microarray Core, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. RP Miller, FW (reprint author), NIEHS, Environm Autoimmun Grp, Clin Res Branch, NIH, Bethesda, MD USA. EM millerf@mail.nih.gov OI Rider, Lisa/0000-0002-6912-2458; Miller, Frederick/0000-0003-2831-9593 FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences; National Institute of Dental and Craniofacial Research FX Funding: This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (http://www.niehs.nih.gov/) and National Institute of Dental and Craniofacial Research (http://www.nider.nih.gov/). Funding was received by FWM and JAC. NR 39 TC 1 Z9 1 U1 0 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 NOV 10 PY 2015 VL 10 IS 11 AR e0142486 DI 10.1371/journal.pone.0142486 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CV7CT UT WOS:000364430700113 PM 26556803 ER PT J AU Kyathanahalli, C Organ, K Moreci, RS Anamthathmakula, P Hassan, SS Caritis, SN Jeyasuria, P Condon, JC AF Kyathanahalli, Chandrashekara Organ, Kenna Moreci, Rebecca S. Anamthathmakula, Prashanth Hassan, Sonia S. Caritis, Steve N. Jeyasuria, Pancharatnam Condon, Jennifer C. TI Uterine endoplasmic reticulum stress-unfolded protein response regulation of gestational length is caspase-3 and-7-dependent SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE endoplasmic reticulum stress; caspase-3 and-7; unfolded protein response; preterm labor; uterus ID PROGESTERONE-RECEPTORS; MYOMETRIAL CELLS; PRETERM LABOR; APOPTOSIS; MICE; PREGNANCY; PARTURITION; UTERUS; ACTIVATION; EXPRESSION AB We previously identified myometrial caspase-3 (CASP3) as a potential regulator of uterine quiescence. We also determined that during pregnancy, the functional activation of uterine CASP3 is likely governed by an integrated endoplasmic reticulum stress response (ERSR) and is consequently limited by an increased unfolded protein response (UPR). The present study examined the functional relevance of uterine UPR-ERSR in maintaining myometrial quiescence and regulating the timing of parturition. In vitro analysis of the human uterine myocyte hTERT-HM cell line revealed that tunicamycin (TM)-induced ERSR modified uterine myocyte contractile responsiveness. Accordingly, alteration of in vivo uterine UPR-ERSR using a pregnant mouse model significantly modified gestational length. We determined that "normal" gestational activation of the ERSR-induced CASP3 and caspase 7 (CASP7) maintains uterine quiescence through previously unidentified proteolytic targeting of the gap junction protein, alpha 1 (GJA1); however, surprisingly, TM-induced uterine ERSR triggered an exaggerated UPR that eliminated uterine CASP3 and 7 tocolytic action precociously. These events allowed for a premature increase in myometrial GJA1 levels, elevated contractile responsiveness, and the onset of preterm labor. Importantly, a successful reversal of the magnified ERSR-induced preterm birth phenotype could be achieved by pretreatment with 4-phenylbutrate, a chaperone protein mimic. C1 [Kyathanahalli, Chandrashekara; Anamthathmakula, Prashanth; Hassan, Sonia S.; Jeyasuria, Pancharatnam; Condon, Jennifer C.] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Kyathanahalli, Chandrashekara; Anamthathmakula, Prashanth; Hassan, Sonia S.; Jeyasuria, Pancharatnam; Condon, Jennifer C.] Wayne State Univ, Sch Med, Dept Physiol, Detroit, MI 48201 USA. [Organ, Kenna; Moreci, Rebecca S.; Caritis, Steve N.; Jeyasuria, Pancharatnam; Condon, Jennifer C.] Univ Pittsburgh, Magee Womens Res Inst, Dept Obstet & Gynecol, Pittsburgh, PA 15213 USA. [Hassan, Sonia S.; Jeyasuria, Pancharatnam; Condon, Jennifer C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Bethesda, MD 20892 USA. RP Condon, JC (reprint author), Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. EM jcondon@med.wayne.edu RI Jeyasuria, Pancharatnam/B-4710-2008 OI Jeyasuria, Pancharatnam/0000-0002-1388-906X FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [1R01 HD065011]; March of Dimes [21FY12-152]; Wayne State University Perinatal Initiative FX This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Grant 1R01 HD065011), the March of Dimes (Grant 21FY12-152), and the Wayne State University Perinatal Initiative. NR 46 TC 4 Z9 4 U1 0 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 NOV 10 PY 2015 VL 112 IS 45 BP 14090 EP 14095 DI 10.1073/pnas.1518309112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CV7QY UT WOS:000364470300090 PM 26504199 ER PT J AU Zhang, PF Chen, YX Zeng, Y Shen, CG Li, R Guo, ZD Li, SW Zheng, QB Chu, CC Wang, ZT Zheng, ZZ Tian, R Ge, SX Zhang, XZ Xia, NS Liu, G Chen, XY AF Zhang, Pengfei Chen, Yixin Zeng, Yun Shen, Chenguang Li, Rui Guo, Zhide Li, Shaowei Zheng, Qingbing Chu, Chengchao Wang, Zhantong Zheng, Zizheng Tian, Rui Ge, Shengxiang Zhang, Xianzhong Xia, Ning-Shao Liu, Gang Chen, Xiaoyuan TI Virus-mimetic nanovesicles as a versatile antigen-delivery system SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE virus-mimetic vesicle; vaccine; nanobiotechnology; antigen delivery system; cell membrane ID DRUG-DELIVERY; BILE-SALTS; VACCINES; HEMAGGLUTININ; CELLS; NANOPARTICLES; VACCINATION; INFECTION; TRANSPORT; CARRIERS AB It is a critically important challenge to rapidly design effective vaccines to reduce the morbidity and mortality of unexpected pandemics. Inspired from the way that most enveloped viruses hijack a host cell membrane and subsequently release by a budding process that requires cell membrane scission, we genetically engineered viral antigen to harbor into cell membrane, then form uniform spherical virus-mimetic nanovesicles (VMVs) that resemble natural virus in size, shape, and specific immunogenicity with the help of surfactants. Incubation of major cell membrane vesicles with surfactants generates a large amount of nano-sized uniform VMVs displaying the native conformational epitopes. With the diverse display of epitopes and viral envelope glycoproteins that can be functionally anchored onto VMVs, we demonstrate VMVs to be straightforward, robust and tunable nanobiotechnology platforms for fabricating antigen delivery systems against a wide range of enveloped viruses. C1 [Zhang, Pengfei; Zeng, Yun; Shen, Chenguang; Li, Rui; Guo, Zhide; Li, Shaowei; Zheng, Qingbing; Chu, Chengchao; Wang, Zhantong; Zheng, Zizheng; Tian, Rui; Ge, Shengxiang; Zhang, Xianzhong; Xia, Ning-Shao; Liu, Gang] Xiamen Univ, Sch Publ Hlth, State Key Lab Mol Vaccinol & Mol Diagnost, Xiamen 361102, Peoples R China. [Zhang, Pengfei; Zeng, Yun; Shen, Chenguang; Li, Rui; Guo, Zhide; Li, Shaowei; Zheng, Qingbing; Chu, Chengchao; Wang, Zhantong; Zheng, Zizheng; Tian, Rui; Ge, Shengxiang; Zhang, Xianzhong; Xia, Ning-Shao; Liu, Gang] Xiamen Univ, Sch Publ Hlth, Ctr Mol Imaging & Translat Med, Xiamen 361102, Peoples R China. [Chen, Yixin; Shen, Chenguang; Li, Rui; Li, Shaowei; Zheng, Qingbing; Zheng, Zizheng; Ge, Shengxiang; Xia, Ning-Shao] Xiamen Univ, Sch Life Sci, Natl Inst Diagnost & Vaccine Dev Infect Dis, Xiamen 361102, Peoples R China. [Chen, Yixin; Shen, Chenguang; Li, Rui; Li, Shaowei; Zheng, Qingbing; Zheng, Zizheng; Ge, Shengxiang; Xia, Ning-Shao] Xiamen Univ, Sch Publ Hlth, Xiamen 361102, Peoples R China. [Chen, Yixin; Li, Shaowei; Xia, Ning-Shao; Liu, Gang] Xiamen Univ, Sch Life Sci, Innovat Ctr Cell Biol, State Key Lab Cellular Stress Biol, Xiamen 361102, Peoples R China. [Zeng, Yun] Sichuan Univ, West China Sch Preclin & Forens Med, Dept Pharmacol, Chengdu 610041, Peoples R China. [Wang, Zhantong; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. [Liu, Gang] Xiamen Univ, Coll Chem & Chem Engn, MOE Key Lab Spectrochem Anal & Instrumentat, Xiamen 361005, Peoples R China. RP Chen, XY (reprint author), Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. EM gangliu.cmitm@xmu.edu.cn; shawn.chen@nih.gov RI Zhang, Xianzhong/A-7754-2012 OI Zhang, Xianzhong/0000-0002-1001-1884 FU Ministry of Science and Technology of China (MOST) [2014CB744503, 2013CB733802, 2012DFH30020]; National Natural Science Foundation of China (NSFC) [81422023, 51273165, 81101101, 81371596, 81371817]; Program for New Century Excellent Talents in University [NCET-13-0502]; Fundamental Research Funds for the Central Universities [2013121039, 20720150141]; Intramural Research Program, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health FX We thank Dr. Henry S. Eden for careful proofreading of the manuscript. This work was supported by the Ministry of Science and Technology of China (MOST) (2014CB744503, 2013CB733802, and 2012DFH30020); the National Natural Science Foundation of China (NSFC) Grants 81422023, 51273165, 81101101, 81371596, and 81371817, Program for New Century Excellent Talents in University (NCET-13-0502); Fundamental Research Funds for the Central Universities (2013121039 and 20720150141); and the Intramural Research Program, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health. NR 32 TC 5 Z9 6 U1 4 U2 29 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 NOV 10 PY 2015 VL 112 IS 45 BP E6129 EP E6138 DI 10.1073/pnas.1505799112 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CV7QY UT WOS:000364470300010 PM 26504197 ER PT J AU Kristensen, DM Saeed, U Frishman, D Koonin, EV AF Kristensen, David M. Saeed, Usman Frishman, Dmitrij Koonin, Eugene V. TI A census of alpha-helical membrane proteins in double-stranded DNA viruses infecting bacteria and archaea SO BMC BIOINFORMATICS LA English DT Article DE Bacteriophages; Viruses; Comparative genomics; Transmembrane proteins; Membrane proteome ID TRANSMEMBRANE PROTEINS; COMPLETE GENOMES; SIGNAL PEPTIDES; SCALING LAWS; DATA-BANK; TOPOLOGY; PREDICTION; SEQUENCES; MARINE; GENERATION AB Background: Viruses are the most abundant and genetically diverse biological entities on earth, yet the repertoire of viral proteins remains poorly explored. As the number of sequenced virus genomes grows into the thousands, and the number of viral proteins into the hundreds of thousands, we report a systematic computational analysis of the point of first-contact between viruses and their hosts, namely viral transmembrane (TM) proteins. Results: The complement of a-helical TM proteins in double-stranded DNA viruses infecting bacteria and archaea reveals large-scale trends that differ from those of their hosts. Viruses typically encode a substantially lower fraction of TM proteins than archaea or bacteria, with the notable exception of viruses with virions containing a lipid component such as a lipid envelope, internal lipid core, or inner membrane vesicle. Compared to bacteriophages, archaeal viruses are substantially enriched in membrane proteins. However, this feature is not always stable throughout the evolution of a viral lineage; for example, TM proteins are not part of the common heritage shared between Lipothrixviridae and Rudiviridae. In contrast to bacteria and archaea, viruses almost completely lack proteins with complicated membrane topologies composed of more than 4 TM segments, with the few detected exceptions being obvious cases of relatively recent horizontal transfer from the host. Conclusions: The dramatic differences between the membrane proteomes of cells and viruses stem from the fact that viruses do not depend on essential membranes for energy transformation, ion homeostasis, nutrient transport and signaling. C1 [Kristensen, David M.; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Saeed, Usman; Frishman, Dmitrij] Tech Univ Munich, Wissensch Zentrum Weihenstephan, Dept Genome Oriented Bioinformat, D-85354 Freising Weihenstephan, Germany. [Saeed, Usman; Frishman, Dmitrij] Helmholtz Ctr Munich, German Res Ctr Environm Hlth, Inst Bioinformat & Syst Biol, D-85764 Neuherberg, Germany. RP Kristensen, DM (reprint author), Univ Iowa, Dept Biomed Engn, Iowa City, IA 52242 USA. EM david-kristensen@uiowa.edu FU US Department of Health and Human Services FX The authors are grateful to Arcady Mushegian for the creation of the initial POGs resource, as well as continued guidance in their application to study phage biology, and to Yuri Wolf for providing the dataset of representative bacterial and archaeal genomes. DMK and EVK are supported by intramural funds of the US Department of Health and Human Services (to the National Library of Medicine, NIH). NR 54 TC 1 Z9 1 U1 3 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD NOV 10 PY 2015 VL 16 AR 380 DI 10.1186/s12859-015-0817-4 PG 11 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA CV6GD UT WOS:000364367800001 PM 26554846 ER PT J AU Jolicoeur, EM Dunning, A Castelvecchio, S Dabrowski, R Waclawiw, MA Petrie, MC Stewart, R Jhund, PS Desvigne-Nickens, P Panza, JA Bonow, RO Sun, B San, TR Al-Khalidi, HR Rouleau, JL Velazquez, EJ Cleland, JGF AF Jolicoeur, E. Marc Dunning, Allison Castelvecchio, Serenella Dabrowski, Rafal Waclawiw, Myron A. Petrie, Mark C. Stewart, Ralph Jhund, Pardeep S. Desvigne-Nickens, Patrice Panza, Julio A. Bonow, Robert O. Sun, Benjamin San, Tan Ru Al-Khalidi, Hussein R. Rouleau, Jean L. Velazquez, Eric J. Cleland, John G. F. TI Importance of Angina in Patients With Coronary Disease, Heart Failure, and Left Ventricular Systolic Dysfunction Insights From STICH SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE coronary artery bypass grafting; coronary artery disease; heart failure; mortality ID ASSOCIATION TASK-FORCE; ARTERY-DISEASE; BYPASS-SURGERY; ISCHEMIC CARDIOMYOPATHY; PRACTICE GUIDELINES; ACCF/AHA GUIDELINE; SURGICAL-TREATMENT; TRIAL; PECTORIS; OUTCOMES AB BACKGROUND Patients with left ventricular (LV) systolic dysfunction, coronary artery disease (CAD), and angina are often thought to have a worse prognosis and a greater prognostic benefit from coronary artery bypass graft (CABG) surgery than those without angina. OBJECTIVES This study investigated: 1) whether angina was associated with a worse prognosis; 2) whether angina identified patients who had a greater survival benefit from CABG; and 3) whether CABG improved angina in patients with LV systolic dysfunction and CAD. METHODS We performed an analysis of the STICH (Surgical Treatment for Ischemic Heart Failure) trial, in which 1,212 patients with an ejection fraction <= 35% and CAD were randomized to CABG or medical therapy. Multivariable Cox and logistic models were used to assess long-term clinical outcomes. RESULTS At baseline, 770 patients (64%) reported angina. Among patients assigned to medical therapy, all-cause mortality was similar in patients with and without angina (hazard ratio [HR]: 1.05; 95% confidence interval [CI]: 0.79 to 1.38). The effect of CABG was similar whether the patient had angina (HR: 0.89; 95% CI: 0.71 to 1.13) or not (HR: 0.68; 95% CI: 0.50 to 0.94; p interaction = 0.14). Patients assigned to CABG were more likely to report improvement in angina than those assigned to medical therapy alone (odds ratio: 0.70; 95% CI: 0.55 to 0.90; p < 0.01). CONCLUSIONS Angina does not predict all-cause mortality in medically treated patients with LV systolic dysfunction and CAD, nor does it identify patients who have a greater survival benefit from CABG. However, CABG does improve angina to a greater extent than medical therapy alone. (Comparison of Surgical and Medical Treatment for Congestive Heart Failure and Coronary Artery Disease [STICH]; NCT00023595) (C) 2015 by the American College of Cardiology Foundation. C1 [Jolicoeur, E. Marc; Rouleau, Jean L.] Univ Montreal, Montreal Heart Inst, Dept Med, Montreal, PQ, Canada. [Dunning, Allison; Al-Khalidi, Hussein R.; Velazquez, Eric J.] Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC USA. [Castelvecchio, Serenella] IRCCS Policlin San Donato, Milan, Italy. [Dabrowski, Rafal] Natl Inst Cardiol, Warsaw, Poland. [Waclawiw, Myron A.; Desvigne-Nickens, Patrice] NHLBI, NIH, Bethesda, MD 20892 USA. [Petrie, Mark C.] Golden Jubilee Natl Hosp, Glasgow, Lanark, Scotland. [Stewart, Ralph] Auckland City Hosp, Auckland, New Zealand. [Jhund, Pardeep S.] Univ Glasgow, British Heart Fdn Cardiovasc Res Ctr, Glasgow, Lanark, Scotland. [Panza, Julio A.] Westchester Cty Med Ctr, Valhalla, NY 10595 USA. [Panza, Julio A.] New York Med Coll, Valhalla, NY 10595 USA. [Bonow, Robert O.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Sun, Benjamin] Allina Hlth, Minneapolis, MN USA. [San, Tan Ru] Natl Heart Ctr, Singapore, Singapore. [Cleland, John G. F.] Univ London Imperial Coll Sci Technol & Med, Royal Brompton Hosp, Natl Heart & Lung Inst, London, England. [Cleland, John G. F.] Univ London Imperial Coll Sci Technol & Med, Harefield Hosp, Natl Heart & Lung Inst, London, England. RP Cleland, JGF (reprint author), Univ London Imperial Coll Sci Technol & Med, Harefield Hosp, Natl Heart & Lung Inst, Heart Sci Bldg,Hill End Rd, London UB9 6JH, England. EM j.cleland@imperial.ac.uk OI castelvecchio, serenella/0000-0001-5365-7063; Jhund, Pardeep/0000-0003-4306-5317 FU Canadian Institutes of Health Research; NHLBI NIH HHS [U01 HL069013, U01 HL069015, U01HL69013, U01HL69015] NR 27 TC 10 Z9 10 U1 4 U2 10 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 NOV 10 PY 2015 VL 66 IS 19 BP 2092 EP 2100 DI 10.1016/j.jacc.2015.08.882 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CU9MO UT WOS:000363868800005 PM 26541919 ER PT J AU Peiris, D Thompson, SR Beratarrechea, A Cardenas, MK Diez-Canseco, F Goudge, J Gyamfi, J Kamano, JH Irazola, V Johnson, C Kengne, AP Keat, NK Miranda, JJ Mohan, S Mukasa, B Ng, E Nieuwlaat, R Ogedegbe, O Ovbiagele, B Plange-Rhule, J Praveen, D Salam, A Thorogood, M Thrift, AG Vedanthan, R Waddy, SP Webster, J Webster, R Yeates, K Yusoff, K AF Peiris, David Thompson, Simon R. Beratarrechea, Andrea Cardenas, Mara Kathia Diez-Canseco, Francisco Goudge, Jane Gyamfi, Joyce Kamano, Jemima Hoine Irazola, Vilma Johnson, Claire Kengne, Andre P. Keat, Ng Kien Miranda, J. Jaime Mohan, Sailesh Mukasa, Barbara Ng, Eleanor Nieuwlaat, Robby Ogedegbe, Olugbenga Ovbiagele, Bruce Plange-Rhule, Jacob Praveen, Devarsetty Salam, Abdul Thorogood, Margaret Thrift, Amanda G. Vedanthan, Rajesh Waddy, Salina P. Webster, Jacqui Webster, Ruth Yeates, Karen Yusoff, Khalid CA GACD Hypertension Res Programme Writing Grp TI Behaviour change strategies for reducing blood pressure-related disease burden: findings from a global implementation research programme SO IMPLEMENTATION SCIENCE LA English DT Article DE Implementation science; Hypertension; Behaviour change theory; Collaborative research; Low- and middle-income countries ID RANDOMIZED CONTROLLED-TRIAL; RESEARCH-COUNCIL GUIDANCE; CARDIOVASCULAR-DISEASE; NONCOMMUNICABLE DISEASES; COMPLEX INTERVENTIONS; PROTOCOL; HYPERTENSION; MANAGEMENT; CARE; PREVENTION AB Background: The Global Alliance for Chronic Diseases comprises the majority of the world's public research funding agencies. It is focussed on implementation research to tackle the burden of chronic diseases in low- and middle-income countries and amongst vulnerable populations in high-income countries. In its inaugural research call, 15 projects were funded, focussing on lowering blood pressure-related disease burden. In this study, we describe a reflexive mapping exercise to identify the behaviour change strategies undertaken in each of these projects. Methods: Using the Behaviour Change Wheel framework, each team rated the capability, opportunity and motivation of the various actors who were integral to each project (e.g. community members, non-physician health workers and doctors in projects focussed on service delivery). Teams then mapped the interventions they were implementing and determined the principal policy categories in which those interventions were operating. Guidance was provided on the use of Behaviour Change Wheel to support consistency in responses across teams. Ratings were iteratively discussed and refined at several group meetings. Results: There was marked variation in the perceived capabilities, opportunities and motivation of the various actors who were being targeted for behaviour change strategies. Despite this variation, there was a high degree of synergy in interventions functions with most teams utilising complex interventions involving education, training, enablement, environmental restructuring and persuasion oriented strategies. Similar policy categories were also targeted across teams particularly in the areas of guidelines, communication/marketing and service provision with few teams focussing on fiscal measures, regulation and legislation. Conclusions: The large variation in preparedness to change behaviour amongst the principal actors across these projects suggests that the interventions themselves will be variably taken up, despite the similarity in approaches taken. The findings highlight the importance of contextual factors in driving success and failure of research programmes. Forthcoming outcome and process evaluations from each project will build on this exploratory work and provide a greater understanding of factors that might influence scale-up of intervention strategies. C1 [Peiris, David; Johnson, Claire; Webster, Jacqui; Webster, Ruth] Univ Sydney, George Inst Global Hlth, Sydney, NSW, Australia. [Thompson, Simon R.] UCL Inst Global Hlth, London, England. [Beratarrechea, Andrea; Irazola, Vilma] Inst Clin Effectiveness & Heath Policy, Buenos Aires, DF, Argentina. [Cardenas, Mara Kathia; Diez-Canseco, Francisco; Miranda, J. Jaime] Univ Peruana Cayetano Heredia, Lima, Peru. [Goudge, Jane; Thorogood, Margaret] Univ Witwatersrand, Johannesburg, South Africa. [Gyamfi, Joyce; Ogedegbe, Olugbenga] NYU, Sch Med, New York, NY USA. [Kamano, Jemima Hoine] Moi Univ, Eldoret, Kenya. [Kengne, Andre P.] South African Med Res Council, Cape Town, South Africa. [Yusoff, Khalid] Univ Teknol Mara, Selangor, Malaysia. [Mohan, Sailesh] Publ Hlth Fdn India, New Delhi, India. [Mukasa, Barbara] Mildmay Uganda, Lweza, Uganda. [Ng, Eleanor] Populat Hlth Res Inst, Hamilton, ON, Canada. [Nieuwlaat, Robby] McMaster Univ, Hamilton, ON, Canada. [Ovbiagele, Bruce] Med Univ S Carolina, Charleston, SC 29425 USA. [Plange-Rhule, Jacob] Kwame Nkrumah Univ Sci & Technol, Kumasi, Ghana. [Praveen, Devarsetty; Salam, Abdul] George Inst Global Hlth, New Delhi, India. [Thorogood, Margaret] Univ Warwick, Coventry CV4 7AL, W Midlands, England. [Thrift, Amanda G.] Monash Univ, Sch Clin Sci Monash Hlth, Melbourne, Vic 3004, Australia. [Vedanthan, Rajesh] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Waddy, Salina P.] Natl Inst Hlth, Bethesda, MD USA. [Yeates, Karen] Queens Univ, Sch Med, Kingston, ON, Canada. RP Peiris, D (reprint author), Univ Sydney, George Inst Global Hlth, Sydney, NSW, Australia. EM dpeiris@georgeinstitute.org RI Thrift, Amanda/I-6251-2012; OI Thrift, Amanda/0000-0001-8533-4170; Oldenburg, Brian/0000-0002-7712-5413; Kalyesubula, Robert/0000-0003-3211-163X; Ponce Lucero, Vilarmina/0000-0002-8439-3096; Miranda, J. Jaime/0000-0002-4738-5468; Evans, Roger/0000-0002-9241-0757; Gebregziabher, Mulugeta/0000-0002-4826-481X; Yaya, Sanni/0000-0002-4876-6043 FU GACD Hypertension Programme funding agencies-Canadian Institutes of Health Research; Grand Challenges Canada; International Development Research Centre; Canadian Stroke Network; Australian National Health and Medical Research Council; US National Institutes of Health (National Heart, Lung and Blood Institute and National Institute of Neurological Disorders and Stroke); United Kingdom Medical Research Council; South African Medical Research Council FX The writing group would like to thank Eshe Jackson-Nyakasikana from the GACD Secretariat for invaluable logistical and administrative support. They would also like to thank all members of the GACD Hypertension Research Programme for their support and input throughout the preparation of this manuscript. Funding for the studies described and for manuscript submission was provided by the GACD Hypertension Programme funding agencies-Canadian Institutes of Health Research; Grand Challenges Canada; International Development Research Centre; Canadian Stroke Network; Australian National Health and Medical Research Council; the US National Institutes of Health (National Heart, Lung and Blood Institute and National Institute of Neurological Disorders and Stroke); the United Kingdom Medical Research Council; and the South African Medical Research Council. This report does not represent the official view of the National Institute of Neurological Disorders and Stroke (NINDS), the National Institutes of Health (NIH), or any part of the US Federal Government. No official support or endorsement of this article by the NINDS or NIH is intended or should be inferred. NR 33 TC 2 Z9 2 U1 7 U2 16 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-5908 J9 IMPLEMENT SCI JI Implement. Sci. PD NOV 9 PY 2015 VL 10 AR 158 DI 10.1186/s13012-015-0331-0 PG 15 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA CW7GC UT WOS:000365165000001 ER PT J AU Nani, RR Gorka, AP Nagaya, T Kobayashi, H Schnermann, MJ AF Nani, Roger R. Gorka, Alexander P. Nagaya, Tadanobu Kobayashi, Hisataka Schnermann, Martin J. TI Near-IR Light-Mediated Cleavage of Antibody-Drug Conjugates Using Cyanine Photocages SO ANGEWANDTE CHEMIE-INTERNATIONAL EDITION LA English DT Article DE antibodies; conjugation; cyanines; drug delivery; fluorescence ID IN-VIVO; RED-LIGHT; PHOTODYNAMIC THERAPY; COMBRETASTATIN A-4; PROTECTING GROUPS; VISIBLE-LIGHT; GREEN LIGHT; CANCER; FLUOROPHORES; STABILITY AB Despite significant progress in the clinical application of antibody drug conjugates (ADCs), novel cleavage strategies that provide improved selectivity are still needed. Herein is reported the first approach that uses near-IR light to cleave a small molecule from a biomacromolecule, and its application to the problem of ADC linkage. The preparation of cyanine antibody conjugates, drug cleavage mediated by 690nm light, and initial in vitro and in vivo evaluation is described. These studies provide the critical chemical underpinning from which to develop this near-IR light cleavable linker strategy. C1 [Nani, Roger R.; Gorka, Alexander P.; Schnermann, Martin J.] NCI, Biol Chem Lab, Ctr Canc Res, Frederick, MD 21701 USA. [Nagaya, Tadanobu; Kobayashi, Hisataka] NCI, Mol Imaging Program, Ctr Canc Res, Bethesda, MD 20892 USA. RP Schnermann, MJ (reprint author), NCI, Biol Chem Lab, Ctr Canc Res, Frederick, MD 21701 USA. EM martin.schnermann@nih.gov FU Intramural Research Program of the National Institutes of Health, Center for Cancer Research; National Cancer Institute, National Institutes of Health FX We thank Dr. Joseph Barchi for NMR assistance and Dr. James Kelley for mass spectrometric analysis. We thank the Optical Microscopy and Analysis Laboratory (Center for Cancer Research, NCI Frederick) for assistance in obtaining confocal fluorescence images and the CCR Flow Cytometry Core (Cancer and Inflammation Program, Center for Cancer Research, NCI-Frederick) for help with flow cytometry analysis. We thank Mr. James Shaum for synthesis of Umb. This work was supported by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, and the National Cancer Institute, National Institutes of Health. NR 44 TC 8 Z9 8 U1 14 U2 59 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 NOV 9 PY 2015 VL 54 IS 46 BP 13635 EP 13638 DI 10.1002/anie.201507391 PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA CV6QM UT WOS:000364395100026 PM 26403799 ER PT J AU Xia, D Ye, YH AF Xia, Di Ye, Yihong TI In Search of a Cure for Proteostasis-Addicted Cancer: A AAA Target Revealed SO CANCER CELL LA English DT Editorial Material ID INHIBITORS; ATPASE; THERAPY; SYSTEM C1 [Xia, Di] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Ye, Yihong] Natl Inst Diabet & Digest & Kidney Dis, Lab Mol Biol, NIH, Bethesda, MD 20892 USA. RP Xia, D (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM xiad@mail.nih.gov; yihongy@mail.nih.gov NR 10 TC 0 Z9 0 U1 1 U2 4 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 NOV 9 PY 2015 VL 28 IS 5 BP 550 EP 552 DI 10.1016/j.ccell.2015.10.006 PG 3 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CV9LQ UT WOS:000364609100003 PM 26555170 ER PT J AU Herriges, JC Verheyden, JM Zhang, Z Sui, PF Zhang, Y Anderson, MJ Swing, DA Zhang, Y Lewandoski, M Sun, X AF Herriges, John C. Verheyden, Jamie M. Zhang, Zhen Sui, Pengfei Zhang, Ying Anderson, Matthew J. Swing, Deborah A. Zhang, Yan Lewandoski, Mark Sun, Xin TI FGF-Regulated ETV Transcription Factors Control FGF-SHH Feedback Loop in Lung Branching SO DEVELOPMENTAL CELL LA English DT Article ID MOUSE EMBRYONIC LUNG; SONIC-HEDGEHOG; MORPHOGENESIS; EXPRESSION; LIMB; MECHANISMS; GROWTH; GENE; ORGANOGENESIS; PROGENITORS AB The mammalian lung forms its elaborate tree-like structure following a largely stereotypical branching sequence. While a number of genes have been identified to play essential roles in lung branching, what coordinates the choice between branch growth and new branch formation has not been elucidated. Here we show that loss of FGF-activated transcription factor genes, Etv4 and Etv5 (collectively Etv), led to prolonged branch tip growth and delayed new branch formation. Unexpectedly, this phenotype is more similar to mutants with increased rather than decreased FGF activity. Indeed, an increased Fgf10 expression is observed, and reducing Fgf10 dosage can attenuate the Etv mutant phenotype. Further evidence indicates that ETV inhibits Fgf10 via directly promoting Shh expression. SHH in turn inhibits local Fgf10 expression and redirects growth, thereby initiating new branches. Together, our findings establish EN as a key node in the FGF-ETV-SHH inhibitory feedback loop that dictates branching periodicity. C1 [Herriges, John C.; Verheyden, Jamie M.; Zhang, Zhen; Zhang, Yan; Sun, Xin] Univ Wisconsin, Genet Lab, Madison, WI 53706 USA. [Zhang, Zhen] Genentech Inc, Dept Physiol Chem, San Francisco, CA 94080 USA. [Zhang, Ying; Anderson, Matthew J.; Lewandoski, Mark] NCI, Canc & Dev Biol Lab, Frederick, MD 21702 USA. [Swing, Deborah A.] NCI, Mouse Canc Genet Program, Frederick, MD 21702 USA. RP Sun, X (reprint author), Univ Wisconsin, Genet Lab, Madison, WI 53706 USA. EM xsun@wisc.edu RI Zhang, Ying/Q-6956-2016 OI Zhang, Ying/0000-0002-8045-3821 FU NHLBI [HL113870, 119946, 122406]; Wisconsin Partnership Program Collaborative Research Award [2900]; American Heart predoctoral fellowship [11PRE5540006]; NIH predoctoral training grant [T32 GM007133]; National Institutes of Health, National Cancer Institute, and Center for Cancer Research FX We would like to thank members of the Sun lab for insightful discussions and critical readings of the manuscript, and Dr. Kevin Eliceri and Dr. Ruth Sullivan for the use of imaging instrumentation and lmaris software at UW Laboratory for Optical and Computational Instrumentation. We would like to thank Dr. Xuehua Zhong and Dr. Shuimin Qian for sharing expertise on chromatin immunoprecipitation. This work was supported by NHLBI HL113870, 119946, 122406, Wisconsin Partnership Program Collaborative Research Award #2900 (to X.S.); American Heart predoctoral fellowship #11PRE5540006 and NIH predoctoral training grant to University of Wisconsin Genetics program T32 GM007133 (to J.C.H); and intramural support by the National Institutes of Health, National Cancer Institute, and Center for Cancer Research (to ML.). NR 41 TC 4 Z9 5 U1 4 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 EI 1878-1551 J9 DEV CELL JI Dev. Cell PD NOV 9 PY 2015 VL 35 IS 3 BP 322 EP 332 DI 10.1016/j.devcel.2015.10.006 PG 11 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA CV9ND UT WOS:000364613000008 PM 26555052 ER PT J AU Honda, K Kobayashi, M Okusaka, T Rinaudo, JA Huang, Y Marsh, T Sanada, M Sasajima, Y Nakamori, S Shimahara, M Ueno, T Tsuchida, A Sata, N Ioka, T Yasunami, Y Kosuge, T Miura, N Kamita, M Sakamoto, T Shoji, H Jung, G Srivastava, S Yamada, T AF Honda, Kazufumi Kobayashi, Michimoto Okusaka, Takuji Rinaudo, Jo Ann Huang, Ying Marsh, Tracey Sanada, Mitsuaki Sasajima, Yoshiyuki Nakamori, Shoji Shimahara, Masashi Ueno, Takaaki Tsuchida, Akihiko Sata, Naohiro Ioka, Tatsuya Yasunami, Yohichi Kosuge, Tomoo Miura, Nami Kamita, Masahiro Sakamoto, Takako Shoji, Hirokazu Jung, Giman Srivastava, Sudhir Yamada, Tesshi TI Plasma biomarker for detection of early stage pancreatic cancer and risk factors for pancreatic malignancy using antibodies for apolipoprotein-All isoforms SO SCIENTIFIC REPORTS LA English DT Article ID LINKED-IMMUNOSORBENT-ASSAY; HIGH-DENSITY-LIPOPROTEIN; CELL MOTILITY; A-II; CARCINOMA; SERUM; EXPRESSION; ANTIGEN; MARKERS; ACTN4 AB We recently reported that circulating apolipoprotein AII (apoAII) isoforms apoAII-ATQ/AT (C-terminal truncations of the apoAII homo-dimer) decline significantly in pancreatic cancer and thus might serve as plasma biomarkers for the early detection of this disease. We report here the development of novel enzyme-linked immunosorbent assays (ELISAs) for measurement of apoAII-ATQ/AT and their clinical applicability for early detection of pancreatic cancer. Plasma and serum concentrations of apoAII-ATQ/AT were measured in three independent cohorts, which comprised healthy control subjects and patients with pancreatic cancer and gastroenterologic diseases (n = 1156). These cohorts included 151 cases of stage I/II pancreatic cancer. ApoAII-ATQ/AT not only distinguished the early stages of pancreatic cancer from healthy controls but also identified patients at high risk for pancreatic malignancy. AUC values of apoAII-ATQ/AT to detect early stage pancreatic cancer were higher than those of CA19-9 in all independent cohorts. ApoAII-ATQ/AT is a potential biomarker for screening patients for the early stage of pancreatic cancer and identifying patients at risk for pancreatic malignancy (161 words). C1 [Honda, Kazufumi; Miura, Nami; Kamita, Masahiro; Sakamoto, Takako; Shoji, Hirokazu; Yamada, Tesshi] Natl Canc Ctr, Res Inst, Div Chemotherapy & Clin Res, Tokyo 1040045, Japan. [Kobayashi, Michimoto; Sanada, Mitsuaki; Sasajima, Yoshiyuki; Jung, Giman] Toray Industries Ltd, New Frontiers Res Labs, Kamakura, Kanagawa 2488555, Japan. [Okusaka, Takuji] Natl Canc Ctr, Hepatobiliary & Pancreat Oncol Div, Tokyo 1040045, Japan. [Rinaudo, Jo Ann; Srivastava, Sudhir] NCI, Canc Prevent Div, Rockville, MD 20852 USA. [Huang, Ying; Marsh, Tracey] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Nakamori, Shoji] Natl Hosp Org, Osaka Natl Hosp, Dept Surg, Osaka 5400006, Japan. [Shimahara, Masashi; Ueno, Takaaki] Osaka Med Coll, Dept Oral Surg, Osaka 5698686, Japan. [Tsuchida, Akihiko] Tokyo Med Univ, Dept Gastrointestinal & Pediat Surg, Tokyo 1600023, Japan. [Sata, Naohiro] Jichi Med Univ, Dept Surg, Shimotsuke, Tochigi 3290498, Japan. [Ioka, Tatsuya] Osaka Med Ctr Canc & Cardiovasc Dis, Dept Hepatobiliary & Pancreat Oncol, Osaka 5370025, Japan. [Yasunami, Yohichi] Fukuoka Univ, Dept Regenerat Med & Transplantat, Fac Med, Fukuoka 8140018, Japan. [Kosuge, Tomoo] Natl Canc Ctr, Hepatobiliary & Pancreat Surg Div, Tokyo 1040045, Japan. [Honda, Kazufumi] Japan Agcy Med Res & Dev AMED CREST, Tokyo 1000004, Japan. RP Honda, K (reprint author), Natl Canc Ctr, Res Inst, Div Chemotherapy & Clin Res, Tokyo 1040045, Japan. EM khonda@ncc.go.jp FU Japan Agency for Medical Research and Development (AMED) Practical Research for Innovation Cancer Control [15ck0106101h0002]; Ministry of Health, Labour and Welfare of Japan; P-direct; AMED CREST; Ministry of Education, Culture, Sports, Science and Technology (METX) of Japan FX This work was supported by an Japan Agency for Medical Research and Development (AMED) Practical Research for Innovation Cancer Control (15ck0106101h0002, K.H.), Applied Research for Innovative Treatment of Cancer grant from the Ministry of Health, Labour and Welfare of Japan (K.H.), P-direct (K.H.), AMED CREST (K.H.), a Grant-in Aid for Scientific Research (B), and a Challenging Exploratory Research grant from the Ministry of Education, Culture, Sports, Science and Technology (METX) of Japan (K.H.). NR 24 TC 5 Z9 5 U1 2 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 NOV 9 PY 2015 VL 5 AR 15921 DI 10.1038/srep15921 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CV5DZ UT WOS:000364288700001 PM 26549697 ER PT J AU Makhnovskii, YA Berezhkovskii, AM Antipov, AE Zitserman, VY AF Makhnovskii, Yurii A. Berezhkovskii, Alexander M. Antipov, Anatoly E. Zitserman, Vladimir Yu. TI Biased diffusion in tubes of alternating diameter: Numerical study over a wide range of biasing force SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID BOUNDARY HOMOGENIZATION; TRANSPORT; SURFACES; ARRAYS AB This paper is devoted to particle transport in a tube formed by alternating wide and narrow sections, in the presence of an external biasing force. The focus is on the effective transport coefficients-mobility and diffusivity, as functions of the biasing force and the geometric parameters of the tube. Dependences of the effective mobility and diffusivity on the tube geometric parameters are known in the limiting cases of no bias and strong bias. The approximations used to obtain these results are inapplicable at intermediate values of the biasing force. To bridge the two limits Brownian dynamics simulations were run to determine the transport coefficients at intermediate values of the force. The simulations were performed for a representative set of tube geometries over a wide range of the biasing force. They revealed that there is a range of the narrow section length, where the force dependence of the mobility has a maximum. In contrast, the diffusivity is a monotonically increasing function of the force. A simple formula is proposed, which reduces to the known dependences of the diffusivity on the tube geometric parameters in both limits of zero and strong bias. At intermediate values of the biasing force, the formula catches the diffusivity dependence on the narrow section length, if the radius of these sections is not too small. (C) 2015 AIP Publishing LLC. C1 [Makhnovskii, Yurii A.] Russian Acad Sci, Topchiev Inst Petrochem Synth, Moscow 119991, Russia. [Berezhkovskii, Alexander M.] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20819 USA. [Antipov, Anatoly E.] Moscow MV Lomonosov State Univ, Fac Fundamental Phys & Chem Engn, Moscow 119991, Russia. [Zitserman, Vladimir Yu.] Russian Acad Sci, Joint Inst High Temp, Moscow 125412, Russia. RP Makhnovskii, YA (reprint author), Russian Acad Sci, Topchiev Inst Petrochem Synth, Leninsky Prospect 29, Moscow 119991, Russia. OI Makhnovskii, Yurii/0000-0002-1517-536X FU Russian Foundation for Basic Research [14-03-00343]; Ministry of Education and Science of Russia [14.607.21.0002]; Presidium of Russian Academy of Sciences "Fundamental Problems of Mathematical Modeling" [1]; NIH, Center for Information Technology FX A.E.A. and V.Yu.Z. thank the Russian Foundation for Basic Research for partial support (Grant No. 14-03-00343). A.E.A. gratefully acknowledges the support of the Ministry of Education and Science of Russia (Grant No. 14.607.21.0002). V.Yu.Z. is grateful for partial support to the Program of Basic Research no. 1 of Presidium of Russian Academy of Sciences "Fundamental Problems of Mathematical Modeling" (supervisor academician V.B. Betelin). A.M.B. was supported by the Intramural Research Program of the NIH, Center for Information Technology. NR 19 TC 0 Z9 0 U1 2 U2 6 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 NOV 7 PY 2015 VL 143 IS 17 AR 174102 DI 10.1063/1.4934728 PG 7 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA CV9CP UT WOS:000364585200006 PM 26547153 ER PT J AU Witte, S Bradley, A Enright, AJ Muljo, SA AF Witte, Steven Bradley, Allan Enright, Anton J. Muljo, Stefan A. TI High-density P300 enhancers control cell state transitions SO BMC GENOMICS LA English DT Article DE Transcriptional regulation; Lysine acetylation; Epigenetics; Long non-coding RNA; Systems biology; Inflammation; Cell differentiation; Super-enhancers ID LONG NONCODING RNAS; GENE-EXPRESSION; SUPER-ENHANCERS; PRIMED PLURIPOTENCY; IDENTITY GENES; HUMAN GENOME; TH17 CELLS; TRANSCRIPTION; ACTIVATION; MACROPHAGES AB Background: Transcriptional enhancers are frequently bound by a set of transcription factors that collaborate to activate lineage-specific gene expression. Recently, it was appreciated that a subset of enhancers comprise extended clusters dubbed stretch-or super-enhancers (SEs). These SEs are located near key cell identity genes, and enriched for non-coding genetic variations associated with disease. Previously, SEs have been defined as having the highest density of Med1, Brd4 or H3K27ac by ChIP-seq. The histone acetyltransferase P300 has been used as a marker of enhancers, but little is known about its binding to SEs. Results: We establish that P300 marks a similar SE repertoire in embryonic stem cells as previously reported using Med1 and H3K27ac. We also exemplify a role for SEs in mouse T helper cell fate decision. Similarly, upon activation of macrophages by bacterial endotoxin, we found that many SE-associated genes encode inflammatory proteins that are strongly up-regulated. These SEs arise from small, low-density enhancers in unstimulated macrophages. We also identified expression quantitative trait loci (eQTL) in human monocytes that lie within such SEs. In macrophages and Th17 cells, inflammatory SEs can be perturbed either genetically or pharmacologically thus revealing new avenues to target inflammation. Conclusions: Our findings support the notion that P300-marked SEs can help identify key nodes of transcriptional control during cell fate decisions. The SE landscape changes drastically during cell differentiation and cell activation. As these processes are crucial in immune responses, SEs may be useful in revealing novel targets for treating inflammatory diseases. C1 [Witte, Steven; Muljo, Stefan A.] NIAID, Integrat Immunobiol Unit, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Witte, Steven; Bradley, Allan] Wellcome Trust Sanger Inst, Cambridge, England. [Enright, Anton J.] EMBL European Bioinformat Inst, Cambridge, England. RP Enright, AJ (reprint author), EMBL European Bioinformat Inst, Wellcome Trust Genome Campus, Cambridge, England. EM aje@ebi.ac.uk; Stefan.Muljo@nih.gov OI Enright, Anton/0000-0002-6090-3100 FU NIH Intramural Research Program of the NIAID; Wellcome Trust; EMBL - European Bioinformatics Institute FX We would like to thank C. Kanellopoulou, E. Metzakopian, and G. Vassiliou for critically reading this manuscript, and John O'Shea for communicating results prior to publication. S.J.W. is a MSTP student and NIH-Cambridge Scholar. S.A.M. is supported by the NIH Intramural Research Program of the NIAID. A.B. is supported by the Wellcome Trust. A.J.E. is supported by the EMBL - European Bioinformatics Institute. NR 74 TC 2 Z9 2 U1 1 U2 6 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 NOV 6 PY 2015 VL 16 AR 903 DI 10.1186/s12864-015-1905-6 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA CW8WY UT WOS:000365281300001 PM 26546038 ER PT J AU Chiang, CY Ulrich, RL Ulrich, MP Eaton, B Ojeda, JF Lane, DJ Kota, KP Kenny, TA Ladner, JT Dickson, SP Kuehl, K Raychaudhuri, R Sun, M Bavari, S Wolcott, MJ Covell, D Panchal, RG AF Chiang, Chih-Yuan Ulrich, Ricky L. Ulrich, Melanie P. Eaton, Brett Ojeda, Jenifer F. Lane, Douglas J. Kota, Krishna P. Kenny, Tara A. Ladner, Jason T. Dickson, Samuel P. Kuehl, Kathleen Raychaudhuri, Rahul Sun, Mei Bavari, Sina Wolcott, Mark J. Covell, David Panchal, Rekha G. TI Characterization of the murine macrophage response to infection with virulent and avirulent Burkholderia species SO BMC MICROBIOLOGY LA English DT Article DE Burkholderia thailandensis; Burkholderia mallei; Burkholderia pseudomallei; Burkholderia oklahomensis; host response ID ACTIN-BASED MOTILITY; INTRACELLULAR LIFE-CYCLE; III SECRETION SYSTEM; PSEUDOMONAS-PSEUDOMALLEI; MALLEI INFECTION; IMMUNE-RESPONSE; GENE-EXPRESSION; MELIOIDOSIS; THAILANDENSIS; PROTEIN AB Background: Burkholderia pseudomallei (Bp) and Burkholderia mallei (Bm) are Gram-negative facultative intracellular pathogens, which are the causative agents of melioidosis and glanders, respectively. Depending on the route of exposure, aerosol or transcutaneous, infection by Bp or Bm can result in an extensive range of disease - from acute to chronic, relapsing illness to fatal septicemia. Both diseases are associated with difficult diagnosis and high fatality rates. About ninety five percent of patients succumb to untreated septicemic infections and the fatality rate is 50 % even when standard antibiotic treatments are administered. Results: The goal of this study is to profile murine macrophage-mediated phenotypic and molecular responses that are characteristic to a collection of Bp, Bm, Burkholderia thailandensis (Bt) and Burkholderia oklahomensis (Bo) strains obtained from humans, animals, environment and geographically diverse locations. Burkholderia spp. (N = 21) were able to invade and replicate in macrophages, albeit to varying degrees. All Bp (N = 9) and four Bm strains were able to induce actin polymerization on the bacterial surface following infection. Several Bp and Bm strains showed reduced ability to induce multinucleated giant cell (MNGC) formation, while Bo and Bp 776 were unable to induce this phenotype. Measurement of host cytokine responses revealed a statistically significant Bm mediated IL-6 and IL-10 production compared to Bp strains. Hierarchical clustering of transcriptional data from 84 mouse cytokines, chemokines and their corresponding receptors identified 29 host genes as indicators of differential responses between the Burkholderia spp. Further validation confirmed Bm mediated Il-1b, Il-10, Tnfrsf1b and Il-36a mRNA expressions were significantly higher when compared to Bp and Bt. Conclusions: These results characterize the phenotypic and immunological differences in the host innate response to pathogenic and avirulent Burkholderia strains and provide insight into the phenotypic alterations and molecular targets underlying host-Burkholderia interactions. C1 [Chiang, Chih-Yuan; Eaton, Brett; Ojeda, Jenifer F.; Lane, Douglas J.; Kenny, Tara A.; Bavari, Sina; Panchal, Rekha G.] USAMRIID, Mol & Translat Sci Div, Ft Detrick, MD 21702 USA. [Ulrich, Ricky L.] Univ Florida, Dept Med, Inst Therapeut Innovat, Orlando, FL USA. [Ulrich, Melanie P.] Florida SouthWestern State Coll, Ft Myers, FL USA. [Kota, Krishna P.] Perkin Elmer Corp, Waltham, MA USA. [Ladner, Jason T.] USAMRIID, Ctr Genome Sci, Ft Detrick, MD USA. [Dickson, Samuel P.] USAMRIID, Off Regulated Studies, Ft Detrick, MD USA. [Kuehl, Kathleen; Raychaudhuri, Rahul; Sun, Mei] USAMRIID, Pathol Div, Ft Detrick, MD USA. [Wolcott, Mark J.] USAMRIID, Diagnost Syst Div, Ft Detrick, MD USA. [Covell, David] NCI, Screening Technol Branch, Dev Therapeut Program, Frederick, MD 21701 USA. RP Panchal, RG (reprint author), USAMRIID, Mol & Translat Sci Div, Ft Detrick, MD 21702 USA. EM rekha.g.panchal.civ@mail.mil NR 69 TC 2 Z9 2 U1 1 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2180 J9 BMC MICROBIOL JI BMC Microbiol. PD NOV 6 PY 2015 VL 15 AR 259 DI 10.1186/s12866-015-0593-3 PG 15 WC Microbiology SC Microbiology GA CW9AZ UT WOS:000365292000002 PM 26545875 ER PT J AU Morris, SE Zelner, JL Fauquier, DA Rowles, TK Rosel, PE Gulland, F Grenfell, BT AF Morris, Sinead E. Zelner, Jonathan L. Fauquier, Deborah A. Rowles, Teresa K. Rosel, Patricia E. Gulland, Frances Grenfell, Bryan T. TI Partially observed epidemics in wildlife hosts: modelling an outbreak of dolphin morbillivirus in the northwestern Atlantic, June 2013-2014 SO JOURNAL OF THE ROYAL SOCIETY INTERFACE LA English DT Article DE dolphin morbillivirus; Poisson process; epidemiology; ecology; statistical modelling; marine mammal pathogen ID PHOCINE DISTEMPER VIRUS; GULF-OF-MEXICO; TURSIOPS-TRUNCATUS; WESTERN ATLANTIC; TRANSMISSION; DISEASE; INFECTION; CETACEANS; NETWORKS; DYNAMICS AB Morbilliviruses cause major mortality in marine mammals, but the dynamics of transmission and persistence are ill understood compared to terrestrial counterparts such as measles; this is especially true for epidemics in cetaceans. However, the recent outbreak of dolphin morbillivirus in the northwestern Atlantic Ocean can provide new insights into the epidemiology and spatio-temporal spread of this pathogen. To deal with uncertainties surrounding the ecology of this system (only stranded animals were observed), we develop a statistical framework that can extract key information about the underlying transmission process given only sparse data. Our self-exciting Poisson process model suggests that individuals are infectious for at most 24 days and can transfer infection up to two latitude degrees (220 km) within this time. In addition, the effective reproduction number is generally below one, but reaches 2.6 during a period of heightened stranding numbers near Virginia Beach, Virginia, in summer 2013. Network analysis suggests local movements dominate spatial spread, with seasonal migration facilitating wider dissemination along the coast. Finally, a low virus transmission rate or high levels of pre-existing immunity can explain the lack of viral spread into the Gulf of Mexico. More generally, our approach illustrates novel methodologies for analysing very indirectly observed epidemics. C1 [Morris, Sinead E.; Grenfell, Bryan T.] Princeton Univ, Dept Ecol & Evolut Biol, Princeton, NJ 08544 USA. [Zelner, Jonathan L.] Columbia Univ, Robert Wood Johnson Hlth & Soc Scholars Program, New York, NY USA. [Fauquier, Deborah A.; Rowles, Teresa K.] Natl Marine Fisheries Serv, Marine Mammal Hlth & Stranding Response Program, Silver Spring, MD USA. [Rosel, Patricia E.] Natl Marine Fisheries Serv, Southeast Fisheries Sci Ctr, Lafayette, LA USA. [Gulland, Frances] Marine Mammal Ctr, Sausalito, CA USA. [Gulland, Frances] US Marine Mammal Commiss, Bethesda, MD USA. [Grenfell, Bryan T.] NIH, Fogarty Int Ctr, Bethesda, MD USA. RP Morris, SE (reprint author), Princeton Univ, Dept Ecol & Evolut Biol, Princeton, NJ 08544 USA. EM semorris@princeton.edu FU RAPIDD program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; Bill and Melinda Gates Foundation; NOAA's Marine Mammal Unusual Mortality Event Contingency Fund; John H. Prescott Marine Mammal Rescue Assistance Grant Program FX B.T.G. and J.L.Z. were supported by the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security, the Fogarty International Center, National Institutes of Health; B.T.G. was supported by the Bill and Melinda Gates Foundation. Funding for dolphin data collection was provided by NOAA's Marine Mammal Unusual Mortality Event Contingency Fund, and the John H. Prescott Marine Mammal Rescue Assistance Grant Program. This publication does not constitute an endorsement of any commercial product or intend to be an opinion beyond scientific or other results obtained by NOAA. NR 54 TC 3 Z9 3 U1 1 U2 18 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 NOV 6 PY 2015 VL 12 IS 112 AR 20150676 DI 10.1098/rsif.2015.0676 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CW7HG UT WOS:000365168200004 ER PT J AU Panja, S Santiago-Frangos, A Schu, DJ Gottesman, S Woodson, SA AF Panja, Subrata Santiago-Frangos, Andrew Schu, Daniel J. Gottesman, Susan Woodson, Sarah A. TI Acidic Residues in the Hfq Chaperone Increase the Selectivity of sRNA Binding and Annealing SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE Hfq; small non-coding RNA; RNA chaperone; RNA-protein interactions; molecular beacon ID ESCHERICHIA-COLI HFQ; SM-LIKE PROTEIN; MESSENGER-RNA; INTERACTION SURFACES; E. COLI; RPOS; DSRA; RECOGNITION; TRANSLATION; MUTATIONS AB Hfq facilitates gene regulation by small non-coding RNAs (sRNAs), thereby affecting bacterial attributes such as biofilm formation and virulence. Escherichia coli Hfq recognizes specific U-rich and AAN motifs in sRNAs and target mRNAs, after which an arginine patch on the rim promotes base pairing between their complementary sequences. In the cell, Hfq must discriminate between many similar RNAs. Here, we report that acidic amino acids lining the sRNA binding channel between the inner pore and rim of the Hfq hexamer contribute to the selectivity of Hfq's chaperone activity. RNase footprinting, in vitro binding and stopped-flow fluorescence annealing assays showed that alanine substitution of D9, E18 or E37 strengthened RNA interactions with the rim of Hfq and increased annealing of non-specific or U-tailed RNA oligomers. Although the mutants were less able than wild-type Hfq to anneal sRNAs with wild-type rpoSmRNA, the D9A mutation bypassed recruitment of Hfq to an (AAN)4 motif in rpoS, both in vitro and in vivo. These results suggest that acidic residues normally modulate access of RNAs to the arginine patch. We propose that this selectivity limits indiscriminate target selection by E coli Hfq and enforces binding modes that favor genuine sRNA and mRNA pairs. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Panja, Subrata; Woodson, Sarah A.] Johns Hopkins Univ, Thomas C Jenkins Dept Biophys, Baltimore, MD 21218 USA. [Santiago-Frangos, Andrew] Johns Hopkins Univ, Cell Mol Dev Biol & Biophys Program, Baltimore, MD 21218 USA. [Schu, Daniel J.; Gottesman, Susan] NCI, Mol Biol Lab, Bethesda, MD 20892 USA. RP Woodson, SA (reprint author), Johns Hopkins Univ, 3400 N Charles St, Baltimore, MD 21218 USA. EM swoodson@jhu.edu OI Woodson, Sarah/0000-0003-0170-1987; Santiago-Frangos, Andrew/0000-0001-9615-065X FU National Institute of General Medicine [R01 GM46686]; Intramural Research Program of the National Cancer Institute, Center for Cancer Research FX This work was supported by a grant from the National Institute of General Medicine (R01 GM46686 to S.W.) and in part by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research (to S.G.) NR 42 TC 7 Z9 7 U1 0 U2 5 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 NOV 6 PY 2015 VL 427 IS 22 BP 3491 EP 3500 DI 10.1016/j.jmb.2015.07.010 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CW3MJ UT WOS:000364896100005 PM 26196441 ER PT J AU Mittal, SK Cho, KJ Ishido, S Roche, PA AF Mittal, Sharad K. Cho, Kyung-Jin Ishido, Satoshi Roche, Paul A. TI Interleukin 10 (IL-10)-mediated Immunosuppression: MARCH-I INDUCTION REGULATES ANTIGEN PRESENTATION BY MACROPHAGES BUT NOT DENDRITIC CELLS SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MHC CLASS-II; NEGATIVE REGULATION; PEPTIDE COMPLEXES; IMMUNE-RESPONSES; DOWN-REGULATION; T-CELLS; IL-10; UBIQUITINATION; EXPRESSION; MONOCYTES AB Efficient immune responses require regulated antigen presentation to CD4 T cells. IL-10 inhibits the ability of dendritic cells (DCs) and macrophages to stimulate antigen-specific CD4 T cells; however, the mechanisms by which IL-10 suppresses antigen presentation remain poorly understood. We now report that IL-10 stimulates expression of the E3 ubiquitin ligase March-I in activated macrophages, thereby down-regulating MHC-II, CD86, and antigen presentation to CD4 T cells. By contrast, IL-10 does not stimulate March-I expression in DCs, does not suppress MHC-II or CD86 expression on either resting or activated DCs, and does not affect antigen presentation by activated DCs. IL-10 does, however, inhibit the process of DC activation itself, thereby reducing the efficiency of antigen presentation in a March-I-independent manner. Thus, IL-10 suppression of antigen presenting cell function in macrophages is March-I-dependent, whereas in DCs, suppression is March- I-independent. C1 [Mittal, Sharad K.; Cho, Kyung-Jin; Roche, Paul A.] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Ishido, Satoshi] Showa Pharmaceut Univ, Lab Integrat Infect Immun, Machida, Tokyo 1948543, Japan. RP Roche, PA (reprint author), NIH, Bldg 10,Rm 4B36, Bethesda, MD 20892 USA. EM paul.roche@nih.gov FU Intramural Research Program of the National Institutes of Health; Ministry of Education, Culture, Sports, Science and Technology of Japan; Japan Society for the Promotion of Science FX This work was supported by the Intramural Research Program of the National Institutes of Health (to P. A. R.), the Ministry of Education, Culture, Sports, Science and Technology of Japan (to S. I.), and the Japan Society for the Promotion of Science (to S. I.). The authors declare that they have no conflicts of interest with the contents of this article. NR 39 TC 3 Z9 3 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 NOV 6 PY 2015 VL 290 IS 45 BP 27158 EP 27167 DI 10.1074/jbc.M115.682708 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CW2AS UT WOS:000364794000025 PM 26408197 ER PT J AU McIntyre, J McLenigan, MP Frank, EG Dai, XX Yang, W Wang, YS Woodgate, R AF McIntyre, Justyna McLenigan, Mary P. Frank, Ekaterina G. Dai, Xiaoxia Yang, Wei Wang, Yinsheng Woodgate, Roger TI Posttranslational Regulation of Human DNA Polymerase i SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CELL NUCLEAR ANTIGEN; LYSINE ACETYLTRANSFERASE KAT3B/P300; TRANSLESION SYNTHESIS; Y-FAMILY; STRUCTURAL BASIS; UBIQUITINATION SITES; OXIDATIVE STRESS; MAMMALIAN-CELLS; IOTA; ETA AB Background: Many proteins are subject to posttranslational regulation, such as ubiquitination. Results: Human DNA polymerase iota (pol iota) can be monoubiquitinated at >27 unique sites, and exposure to naphthoquinones results in polyubiquitination of pol iota. Conclusion: Ubiquitination sites are located across the entire pol iota polypeptide as well as various structural motifs. Significance: Ubiquitination at these sites is likely to alter cellular functions of pol iota in vivo. Human DNA polymerases (pols) eta and i are Y-family DNA polymerase paralogs that facilitate translesion synthesis past damaged DNA. Both pol eta and poli can be monoubiquitinated in vivo. Pol eta has been shown to be ubiquitinated at one primary site. When this site is unavailable, three nearby lysines may become ubiquitinated. In contrast, mass spectrometry analysis of monoubiquitinated poli revealed that it is ubiquitinated at over 27 unique sites. Many of these sites are localized in different functional domains of the protein, including the catalytic polymerase domain, the proliferating cell nuclear antigen-interacting region, the Rev1-interacting region, and its ubiquitin binding motifs UBM1 and UBM2. Poli monoubiquitination remains unchanged after cells are exposed to DNA-damaging agents such as UV light (generating UV photoproducts), ethyl methanesulfonate (generating alkylation damage), mitomycin C (generating interstrand cross-links), or potassium bromate (generating direct oxidative DNA damage). However, when exposed to naphthoquinones, such as menadione and plumbagin, which cause indirect oxidative damage through mitochondrial dysfunction, poli becomes transiently polyubiquitinated via Lys(11)- and Lys(48)-linked chains of ubiquitin and subsequently targeted for degradation. Polyubiquitination does not occur as a direct result of the perturbation of the redox cycle as no polyubiquitination was observed after treatment with rotenone or antimycin A, which both inhibit mitochondrial electron transport. Interestingly, polyubiquitination was observed after the inhibition of the lysine acetyltransferase KATB3/p300. We hypothesize that the formation of polyubiquitination chains attached to poli occurs via the interplay between lysine acetylation and ubiquitination of ubiquitin itself at Lys(11) and Lys(48) rather than oxidative damage per se. C1 [Woodgate, Roger] NICHD, Lab Genom Integr, NIH, Bethesda, MD 20892 USA. [McIntyre, Justyna] Polish Acad Sci, Inst Biochem & Biophys, PL-02106 Warsaw, Poland. [Dai, Xiaoxia; Wang, Yinsheng] Univ Calif Riverside, Dept Chem, Riverside, CA 92521 USA. [Yang, Wei] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Woodgate, R (reprint author), NICHD, Lab Genom Integr, NIH, Bethesda, MD 20892 USA. EM woodgate@nih.gov RI Regan, Clinton/E-6250-2012; McIntyre, Justyna/M-9186-2014 FU NICHD, National Institutes of Health Intramural Research Program; NIDDK, National Institutes of Health Intramural Research Program; Foundation for Polish Science [HOMING PLUS/2013-7/10]; National Institutes of Health [R01 DK082779] FX This work was supported by the NICHD, National Institutes of Health Intramural Research Program (to R.W.); the NIDDK, National Institutes of Health Intramural Research Program (to W.Y.); the Foundation for Polish Science HOMING PLUS/2013-7/10 (to J.M.); and National Institutes of Health Grant R01 DK082779 (to Y.W.). The authors declare that they have no conflicts of interest with the contents of this article. NR 70 TC 1 Z9 1 U1 1 U2 9 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 NOV 6 PY 2015 VL 290 IS 45 BP 27332 EP 27344 DI 10.1074/jbc.M115.675769 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CW2AS UT WOS:000364794000040 PM 26370087 ER PT J AU Mitchell, CJ Getnet, D Kim, MS Manda, SS Kumar, P Huang, TC Pinto, SM Nirujogi, RS Iwasaki, M Shaw, PG Wu, XY Zhong, J Chaerkady, R Marimuthu, A Muthusamy, B Sahasrabuddhe, NA Raju, R Bowman, C Danilova, L Cutler, J Kelkar, DS Drake, CG Prasad, TSK Marchionni, L Murakami, PN Scott, AF Shi, LM Thierry-Mieg, J Thierry-Mieg, D Irizarry, R Cope, L Ishihama, Y Wang, C Gowda, H Pandey, A AF Mitchell, Christopher J. Getnet, Derese Kim, Min-Sik Manda, Srikanth S. Kumar, Praveen Huang, Tai-Chung Pinto, Sneha M. Nirujogi, Raja Sekhar Iwasaki, Mio Shaw, Patrick G. Wu, Xinyan Zhong, Jun Chaerkady, Raghothama Marimuthu, Arivusudar Muthusamy, Babylakshmi Sahasrabuddhe, Nandini A. Raju, Rajesh Bowman, Caitlyn Danilova, Ludmila Cutler, Jevon Kelkar, Dhanashree S. Drake, Charles G. Prasad, T. S. Keshava Marchionni, Luigi Murakami, Peter N. Scott, Alan F. Shi, Leming Thierry-Mieg, Jean Thierry-Mieg, Danielle Irizarry, Rafael Cope, Leslie Ishihama, Yasushi Wang, Charles Gowda, Harsha Pandey, Akhilesh TI A multi-omic analysis of human naive CD4+T cells SO BMC SYSTEMS BIOLOGY LA English DT Article DE Whole genome sequencing; Epigenomics; Transcriptomics; Proteomics; Phosphoproteomics; Integrativeomics; Innate immunity ID SPECTROMETRY-BASED PROTEOMICS; KAPPA-B ACTIVATION; RNA-SEQ DATA; MASS-SPECTROMETRY; T-CELLS; GENE-EXPRESSION; PHOSPHORYLATION; DIFFERENTIATION; TRANSCRIPTOME; LYMPHOCYTES AB Background: Cellular function and diversity are orchestrated by complex interactions of fundamental biomolecules including DNA, RNA and proteins. Technological advances in genomics, epigenomics, transcriptomics and proteomics have enabled massively parallel and unbiased measurements. Such high-throughput technologies have been extensively used to carry out broad, unbiased studies, particularly in the context of human diseases. Nevertheless, a unified analysis of the genome, epigenome, transcriptome and proteome of a single human cell type to obtain a coherent view of the complex interplay between various biomolecules has not yet been undertaken. Here, we report the first multi-omic analysis of human primary naive CD4+ T cells isolated from a single individual. Results: Integrating multi-omics datasets allowed us to investigate genome-wide methylation and its effect on mRNA/protein expression patterns, extent of RNA editing under normal physiological conditions and allele specific expression in naive CD4+ T cells. In addition, we carried out a multi-omic comparative analysis of naive with primary resting memory CD4+ T cells to identify molecular changes underlying T cell differentiation. This analysis provided mechanistic insights into how several molecules involved in T cell receptor signaling are regulated at the DNA, RNA and protein levels. Phosphoproteomics revealed downstream signaling events that regulate these two cellular states. Availability of multi-omics data from an identical genetic background also allowed us to employ novel proteogenomics approaches to identify individual-specific variants and putative novel protein coding regions in the human genome. Conclusions: We utilized multiple high-throughput technologies to derive a comprehensive profile of two primary human cell types, naive CD4+ T cells and memory CD4+ T cells, from a single donor. Through vertical as well as horizontal integration of whole genome sequencing, methylation arrays, RNA-Seq, miRNA-Seq, proteomics, and phosphoproteomics, we derived an integrated and comparative map of these two closely related immune cells and identified potential molecular effectors of immune cell differentiation following antigen encounter. C1 [Mitchell, Christopher J.; Getnet, Derese; Kim, Min-Sik; Huang, Tai-Chung; Shaw, Patrick G.; Wu, Xinyan; Zhong, Jun; Chaerkady, Raghothama; Bowman, Caitlyn; Cutler, Jevon; Scott, Alan F.; Pandey, Akhilesh] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21218 USA. [Manda, Srikanth S.; Kumar, Praveen; Pinto, Sneha M.; Nirujogi, Raja Sekhar; Marimuthu, Arivusudar; Muthusamy, Babylakshmi; Sahasrabuddhe, Nandini A.; Raju, Rajesh; Kelkar, Dhanashree S.; Prasad, T. S. Keshava; Gowda, Harsha; Pandey, Akhilesh] Int Tech Pk, Inst Bioinformat, Bangalore, Karnataka, India. [Iwasaki, Mio; Ishihama, Yasushi] Kyoto Univ, Dept Mol & Cellular BioAnal, Kyoto, Japan. [Murakami, Peter N.] Johns Hopkins Univ, Dept Biostat, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Danilova, Ludmila; Drake, Charles G.; Marchionni, Luigi; Cope, Leslie] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Shi, Leming] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Thierry-Mieg, Jean; Thierry-Mieg, Danielle] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. [Irizarry, Rafael] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Wang, Charles] Loma Linda Univ, Ctr Genom, Loma Linda, CA 92350 USA. [Wang, Charles] Loma Linda Univ, Div Microbiol & Mol Genet, Loma Linda, CA 92350 USA. [Pandey, Akhilesh] Johns Hopkins Univ, Sch Med, Dept Biol Chem, Baltimore, MD 21205 USA. [Pandey, Akhilesh] Johns Hopkins Univ, Sch Med, Dept Pathol & Oncol, Baltimore, MD USA. RP Pandey, A (reprint author), Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21218 USA. EM pandey@jhmi.edu RI Ishihama, Yasushi/B-3101-2016; Kim, Min-Sik/M-3488-2016; Zhong, Jun/D-1662-2010; THIERRY-MIEG, Jean/F-1975-2017; OI Ishihama, Yasushi/0000-0001-7714-203X; Kim, Min-Sik/0000-0001-7317-5360; Zhong, Jun/0000-0003-3148-4143; THIERRY-MIEG, Jean/0000-0002-0396-6789; Huang, Tai-Chung/0000-0002-1625-7295 FU NIH [U54GM103520]; NCI's Clinical Proteomic Tumor Analysis Consortium initiative [U24CA160036]; National Heart, Lung and Blood Institute (NHLBI) [HHSN268201000032C]; Department of Biotechnology (DBT), Government of India FX We thank Dr. Barbara Migeon, Dr. Drew Pardoll, and Dr. Robert Siliciano for helpful discussions. We thank the Proteomics Core Facility at the Johns Hopkins University School of Medicine for data acquisition. This work was supported by a NIH roadmap grant for Technology Centers of Networks and Pathways (TCNP) (U54GM103520), NCI's Clinical Proteomic Tumor Analysis Consortium initiative (U24CA160036) and a contract (HHSN268201000032C) from the National Heart, Lung and Blood Institute (NHLBI). Harsha Gowda is a Wellcome Trust/DBT India Alliance Early Career Fellow. This work is also supported by research grants from the Department of Biotechnology (DBT), Government of India. NR 52 TC 3 Z9 3 U1 3 U2 16 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1752-0509 J9 BMC SYST BIOL JI BMC Syst. Biol. PD NOV 6 PY 2015 VL 9 AR 75 DI 10.1186/s12918-015-0225-4 PG 16 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA CV5BK UT WOS:000364280300001 PM 26542228 ER PT J AU Shmakov, S Abudayyeh, OO Makarova, KS Wolf, YI Gootenberg, JS Semenova, E Minakhin, L Joung, J Konermann, S Severinov, K Zhang, F Koonin, EV AF Shmakov, Sergey Abudayyeh, Omar O. Makarova, Kira S. Wolf, Yuri I. Gootenberg, Jonathan S. Semenova, Ekaterina Minakhin, Leonid Joung, Julia Konermann, Silvana Severinov, Konstantin Zhang, Feng Koonin, Eugene V. TI Discovery and Functional Characterization of Diverse Class 2 CRISPR-Cas Systems SO MOLECULAR CELL LA English DT Article ID MULTIPLE SEQUENCE ALIGNMENT; ADAPTIVE IMMUNITY; 3-DIMENSIONAL STRUCTURE; TARGET DNA; DUAL-RNA; EVOLUTION; ENDONUCLEASE; COMPLEX; IDENTIFICATION; PROKARYOTES AB Microbial CRISPR-Cas systems are divided into Class 1, with multisubunit effector complexes, and Class 2, with single protein effectors. Currently, only two Class 2 effectors, Cas9 and Cpf1, are known. We describe here three distinct Class 2 CRISPR-Cas systems. The effectors of two of the identified systems, C2c1 and C2c3, contain RuvC-like endonuclease domains distantly related to Cpf1. The third system, C2c2, contains an effector with two predicted HEPN RNase domains. Whereas production of mature CRISPR RNA (crRNA) by C2c1 depends on tracrRNA, C2c2 crRNA maturation is tracrRNA independent. We found that C2c1 systems can mediate DNA interference in a 50-PAM-dependent fashion analogous to Cpf1. However, unlike Cpf1, which is a single-RNA-guided nuclease, C2c1 depends on both crRNA and tracrRNA for DNA cleavage. Finally, comparative analysis indicates that Class 2 CRISPR-Cas systems evolved on multiple occasions through recombination of Class 1 adaptation modules with effector proteins acquired from distinct mobile elements. C1 [Shmakov, Sergey; Severinov, Konstantin] Skolkovo Inst Sci & Technol, Skolkovo 143025, Russia. [Shmakov, Sergey; Makarova, Kira S.; Wolf, Yuri I.; Koonin, Eugene V.] NLM, NIH, NCBI, Bethesda, MD 20894 USA. [Abudayyeh, Omar O.; Gootenberg, Jonathan S.; Joung, Julia; Konermann, Silvana; Zhang, Feng] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Abudayyeh, Omar O.; Gootenberg, Jonathan S.; Joung, Julia; Konermann, Silvana; Zhang, Feng] MIT, McGovern Inst Brain Res, Cambridge, MA 02139 USA. [Abudayyeh, Omar O.; Gootenberg, Jonathan S.; Joung, Julia; Konermann, Silvana; Zhang, Feng] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Abudayyeh, Omar O.; Gootenberg, Jonathan S.; Joung, Julia; Konermann, Silvana; Zhang, Feng] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Semenova, Ekaterina; Minakhin, Leonid; Severinov, Konstantin] Rutgers State Univ, Waksman Inst Microbiol, Piscataway, NJ 08854 USA. [Severinov, Konstantin] Russian Acad Sci, Inst Mol Genet, Moscow 123182, Russia. RP Zhang, F (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. EM zhang@broadinstitute.org; koonin@ncbi.nlm.nih.gov RI Severinov, Konstantin/C-8545-2016 FU US Department of Health and Human services; D.O.E. Computational Science Graduate Fellowship; NIMH [5DP1-MH100706, 1R01-MH110049]; NIDDK [5R01DK097768-03]; Poitras Center; Vallee Foundation; Simons Foundation; Paul G. Allen Foundation; New York Stem Cell Foundation; NIH [GM10407]; Russian Science Foundation [14-14-00988]; Skoltech; Skoltech Data-Intensive Biomedicine and Biotechnology Center for Research, Education, and Innovation FX We thank R. Macrae and F.A. Ran for critical reading of the manuscript and Lauren Solomon for the artistic rendering of the graphical abstract. S.S. is supported by the graduate program of Skoltech Data-Intensive Biomedicine and Biotechnology Center for Research, Education, and Innovation. K.S.M., Y.I.W., and E.V.K. are supported by the intramural program of the US Department of Health and Human services (to the national Library of Medicine). J.S.G. is supported by a D.O.E. Computational Science Graduate Fellowship. F.Z. is supported by the NIMH (5DP1-MH100706 and 1R01-MH110049), NIDDK (5R01DK097768-03), the Poitras Center, Vallee, Simons, Paul G. Allen, and New York Stem Cell Foundations, David R. Cheng, Tom Harriman, and Bob Metcalfe. F.Z. is a New York Stem Cell Foundation Robertson Investigator. K.S. is supported by an NIH grant GM10407, Russian Science Foundation grant 14-14-00988, and Skoltech. NR 59 TC 88 Z9 89 U1 25 U2 68 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 NOV 5 PY 2015 VL 60 IS 3 BP 385 EP 397 DI 10.1016/j.molcel.2015.10.008 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DB1RH UT WOS:000368286000009 PM 26593719 ER PT J AU Sun, C Tian, X Lee, YS Gunti, S Lipsky, A Herman, SEM Salem, D Stetler-Stevenson, M Yuan, C Kardava, L Moir, S Maric, I Valdez, J Soto, S Marti, GE Farooqui, MZ Notkins, AL Wiestner, A Aue, G AF Sun, Clare Tian, Xin Lee, Yuh Shan Gunti, Sreenivasulu Lipsky, Andrew Herman, Sarah E. M. Salem, Dalia Stetler-Stevenson, Maryalice Yuan, Constance Kardava, Lela Moir, Susan Maric, Irina Valdez, Janet Soto, Susan Marti, Gerald E. Farooqui, Mohammed Z. Notkins, Abner L. Wiestner, Adrian Aue, Georg TI Partial reconstitution of humoral immunity and fewer infections in patients with chronic lymphocytic leukemia treated with ibrutinib SO BLOOD LA English DT Article ID BRUTONS TYROSINE KINASE; B-CELL MALIGNANCIES; INITIAL THERAPY; TUMOR PROLIFERATION; OPEN-LABEL; BAFF; RITUXIMAB; CYCLOPHOSPHAMIDE; FLUDARABINE; EXPRESSION AB Chronic lymphocytic leukemia (CLL) is characterized by immune dysregulation, often including hypogammaglobulinemia, which contributes to a high rate of infections and morbidity. Ibrutinib, a covalent inhibitor of Bruton tyrosinekinase (BTK), inhibits B-cell receptor signaling and is an effective, US Food and Drug Administration (FDA)-approved treatment of CLL. Inactivating germline mutations in BTK cause a severe B-cell defect and agammaglobulinemia. Therefore, we assessed the impact of ibrutinib on immunoglobulin levels, normal B cells, and infection rate in patients with CLL treated with single-agent ibrutinib on a phase 2 investigator-initiated trial. Consistent with previous reports, immunoglobulin G (IgG) levels remained stable during the first 6 months on treatment, but decreased thereafter. In contrast, there were a transient increase in IgM and a sustained increase in IgA (median increase 45% at 12 months, P < .0001). To distinguish the effects on clonal B cells from normal B cells, we measured serum free light chains (FLCs). In kappa-clonal CLL cases, clonal (kappa) FLCs were elevated at baseline and normalized by 6 months. Nonclonal (lambda) FLCs, which were often depressed at baseline, increased, suggesting the recovery of normal B cells. Consistently, we observed normal B-cell precursors in the bone marrow and an increase in normal B-cell numbers in the peripheral blood. Patients with superior immune reconstitution, as defined by an increase in serum IgA of >= 50% from baseline to 12 months, had a significantly lower rate of infections (P = .03). These data indicate that ibrutinib allows for a clinically meaningful recovery of humoral immune function in patients with CLL. C1 [Sun, Clare; Lee, Yuh Shan; Lipsky, Andrew; Herman, Sarah E. M.; Valdez, Janet; Soto, Susan; Farooqui, Mohammed Z.; Wiestner, Adrian; Aue, Georg] NHLBI, Hematol Branch, Bethesda, MD 20892 USA. [Tian, Xin] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. [Gunti, Sreenivasulu; Notkins, Abner L.] Natl Inst Dent & Craniofacial Res, Lab Sensory Biol, Expt Med Sect, Bethesda, MD USA. [Salem, Dalia; Stetler-Stevenson, Maryalice; Yuan, Constance] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Kardava, Lela; Moir, Susan] NIAID, Lab Immunoregulat, Bethesda, MD 20892 USA. [Maric, Irina] NIH, Ctr Clin, Dept Lab Med, Bethesda, MD 20892 USA. [Marti, Gerald E.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP 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 RI Salem, Dalia/R-9314-2016 OI Salem, Dalia/0000-0002-4209-2260 FU Intramural Research Program of the National Heart, Lung, and Blood Institute of the National Institutes of Health FX This work was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute of the National Institutes of Health. NR 50 TC 15 Z9 15 U1 3 U2 6 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 NOV 5 PY 2015 VL 126 IS 19 BP 2213 EP 2219 DI 10.1182/blood-2015-04-639203 PG 7 WC Hematology SC Hematology GA CY4PP UT WOS:000366390900011 PM 26337493 ER PT J AU Shriner, D Kumkhaek, C Doumatey, AP Chen, GJ Bentley, AR Charles, BA Zhou, J Adeyemo, A Rodgers, GP Rotimi, CN AF Shriner, Daniel Kumkhaek, Chutima Doumatey, Ayo P. Chen, Guanjie Bentley, Amy R. Charles, Bashira A. Zhou, Jie Adeyemo, Adebowale Rodgers, Griffin P. Rotimi, Charles N. TI Evolutionary context for the association of gamma-globin, serum uric acid, and hypertension in African Americans SO BMC MEDICAL GENETICS LA English DT Article DE African American; Ancestry; Gamma-globin; Health disparity; Hypertension; Malaria; Uric acid ID GENOME-WIDE ASSOCIATION; NITRIC-OXIDE BIOAVAILABILITY; SICKLE-CELL DISEASE; URATE CONCENTRATIONS; FETAL-HEMOGLOBIN; CARDIOVASCULAR-DISEASE; PLASMODIUM-FALCIPARUM; GENETIC-VARIATION; HYPERURICEMIA; LOCI AB Background: Hyperuricemia and associated cardio-metabolic disorders are more prevalent in African Americans than in European Americans. We used genome-wide admixture mapping and association testing to identify loci with ancestry effects on serum uric acid levels. Methods: We analyzed 1,976 African Americans from Washington, D. C, including 1,322 individuals from 328 pedigrees and 654 unrelated individuals, enrolled in the Howard University Family Study. We performed admixture mapping and genome-wide association testing using similar to 800 k autosomal single-nucleotide polymorphisms (SNPs). We performed fine mapping by dense genotyping. We assessed functionality by a combination of bioinformatic annotation, reporter gene assays, and gel shift experiments. We also analyzed 12,641 individuals enrolled in the National Health and Nutrition Examination Survey. Results: We detected a genome-wide significant locus on chromosome 11p15.4 at which serum uric acid levels increased with increasing African ancestry, independent of kidney function. Fine-mapping identified two independent signals in the A-globin locus. The ancestral allele at SNP rs2855126, located upstream of the hemoglobin, gamma A gene HBG1, was associated with increased serum uric acid levels and higher expression of a reporter gene relative to the derived allele. Hyperuricemia was associated with increased risk of hypertension in 3,767 African Americans (Odds Ratio = 2.48, p = 2.71 x 10(-1)9). Conclusions: Given that increased expression of.-globin leads to increased levels of fetal hemoglobin which confers protection against malaria, we hypothesize that evolution in Africa of protection against malaria may have occurred at the cost of increased serum uric acid levels, contributing to the high rates of hyperuricemia and associated cardio-metabolic disorders observed in African Americans. C1 [Shriner, Daniel; Doumatey, Ayo P.; Chen, Guanjie; Bentley, Amy R.; Charles, Bashira A.; Zhou, Jie; Adeyemo, Adebowale; Rotimi, Charles N.] NHGRI, Ctr Res Genom & Global Hlth, Bethesda, MD 20892 USA. [Kumkhaek, Chutima; Rodgers, Griffin P.] NHLBI, Mol & Clin Hematol Branch, Bethesda, MD 20892 USA. RP Rotimi, CN (reprint author), NHGRI, Ctr Res Genom & Global Hlth, Bldg 12A Rm 4047,12 South Dr, Bethesda, MD 20892 USA. EM rotimic@mail.nih.gov FU National Institutes of Health [S06GM008016-320107, S06GM008016-380111, 2M01RR010284]; Intramural Research Program of the Center for Research on Genomics and Global Health (CRGGH); National Human Genome Research Institute; National Institute of Diabetes and Digestive and Kidney Diseases; Center for Information Technology; Office of the Director at the National Institutes of Health [Z01HG200362]; Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases FX The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official view of the National Institutes of Health. We thank Michael R. Erdos for assistance with dense genotyping. The Howard University Family Study was supported by the National Institutes of Health (grant numbers S06GM008016-320107, S06GM008016- 380111, and 2M01RR010284). Genotyping support was provided by the Coriell Institute for Medical Research. This research was supported by the Intramural Research Program of the Center for Research on Genomics and Global Health (CRGGH). The CRGGH is supported by the National Human Genome Research Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the Center for Information Technology, and the Office of the Director at the National Institutes of Health (grant number Z01HG200362, CNR). This research was also supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (GPR). The funders had no role in the collection, analysis, and interpretation of the data; in the writing of the manuscript; and in the decision to submit the manuscript for publication. NR 54 TC 0 Z9 0 U1 1 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2350 J9 BMC MED GENET JI BMC Med. Genet. PD NOV 5 PY 2015 VL 16 AR 103 DI 10.1186/s12881-015-0249-z PG 11 WC Genetics & Heredity SC Genetics & Heredity GA CY8WZ UT WOS:000366690700001 PM 26686224 ER PT J AU Im, HS Goltzer, O Sheehan, FT AF Im, Hyun Soo Goltzer, Oren Sheehan, Frances T. TI The effective quadriceps and patellar tendon moment arms relative to the tibiofemoral finite helical axis SO JOURNAL OF BIOMECHANICS LA English DT Article DE Musculoskeletal; MRI; Dynamics; In vivo; Patellofemoral; Torque; Muscle force; Modeling; Reliability ID KNEE EXTENSOR MECHANISM; CINE-PC MRI; IN-VIVO; CEREBRAL-PALSY; PATELLOFEMORAL JOINT; MODEL; FORCE; ALTA; ABNORMALITIES; KINEMATICS AB The moment arm is a crucial parameter for understanding musculoskeletal dynamics as it defines how linear muscle force is transformed into a moment. Yet, for the quadriceps tendon this parameter cannot be directly calculated, as the patella creates a dynamic fulcrum. Thus, the effective quadriceps moment arm (EQma) was developed to define the quadriceps force to tibial moment relationship. In vivo data in regards to the EQma are lacking and the critical question of how patellofemoral kinematics may influence the EQma remains unresolved. Therefore, the purpose of this study was to quantify the in vivo EQma during a knee extension exercise in asymptomatic controls and to correlate the EQma with sagittal plane patellofemoral kinematics. While subjects (30F/10M, 26.5 +/- 5.6 years, 167.5 +/- 10.2 cm, 62.6 +/- 10.7 kg) cyclically flexed-extended their knees within the MR scanner, dynamic cine-phase contrast and cine MR images were acquired. From these data, patellofemoral kinematics, the ratio of the patellar tendon to quadriceps force, the patellar tendon moment arm, and the EQma were quantified. The EQma trended upwards (32.9-45.5 mm (females) and 31.5-47.1 mm (males)) as the knee angle decreased (50-10 degrees). The quadriceps had a mechanical advantage (ratio of patellar to quadriceps tendon forces >1.0) for knee angles <= 20 degrees. The EQma did not correlate with sagittal plane patellofemoral kinematics. As this is the first study to characterize the EQma in vivo during dynamic volitional activity, in a large group of asymptomatic controls, it can serve as a foundation for future knee joint models and to explore how pathological conditions affect the EQma. Published by Elsevier Ltd. C1 [Im, Hyun Soo; Goltzer, Oren; Sheehan, Frances T.] NIH, Dept Rehabil Med, Funct & Appl Biomech, Bethesda, MD 20892 USA. RP Sheehan, FT (reprint author), NIH, Bldg 10,CRC RM 1-1469,10 Ctr Dr,MSC 1604, Bethesda, MD 20892 USA. EM fsheehan@cc.nih.gov FU Diagnostic Radiology Department at the NIH; NIH Clinical Center FX We thank Sara Sadeghi for her research support. We also thank the Diagnostic Radiology Department at the NIH for their support. This research was supported by the Intramural Research Program of the NIH Clinical Center. NR 27 TC 0 Z9 0 U1 1 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0021-9290 EI 1873-2380 J9 J BIOMECH JI J. Biomech. PD NOV 5 PY 2015 VL 48 IS 14 BP 3737 EP 3742 DI 10.1016/j.jbiomech.2015.04.003 PG 6 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA CX9YZ UT WOS:000366064000001 PM 26520912 ER PT J AU Lippincott-Schwartz, J AF Lippincott-Schwartz, Jennifer TI Interdisciplinary innovations are key to effective use of quantitative biological information SO MOLECULAR BIOLOGY OF THE CELL LA English DT Editorial Material C1 [Lippincott-Schwartz, Jennifer] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. RP Lippincott-Schwartz, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. EM jlippin@helix.nih.gov NR 1 TC 0 Z9 0 U1 2 U2 7 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PD NOV 5 PY 2015 VL 26 IS 22 BP 3893 EP 3893 DI 10.1091/mbc.E15-09-0644 PG 1 WC Cell Biology SC Cell Biology GA CY3QO UT WOS:000366324900001 PM 26543194 ER PT J AU Wu, L Zhang, XL Zhao, ZK Wang, L Li, B Li, GB Dean, M Yu, QC Wang, YH Lin, XX Rao, WJ Mei, ZL Li, Y Jiang, RZ Yang, H Li, FQ Xie, GY Xu, LQ Wu, K Zhang, J Chen, JH Wang, T Kristiansen, K Zhang, XQ Li, YR Yang, HM Wang, J Hou, Y Xu, X AF Wu, Liang Zhang, Xiaolong Zhao, Zhikun Wang, Ling Li, Bo Li, Guibo Dean, Michael Yu, Qichao Wang, Yanhui Lin, Xinxin Rao, Weijian Mei, Zhanlong Li, Yang Jiang, Runze Yang, Huan Li, Fuqiang Xie, Guoyun Xu, Liqin Wu, Kui Zhang, Jie Chen, Jianghao Wang, Ting Kristiansen, Karsten Zhang, Xiuqing Li, Yingrui Yang, Huanming Wang, Jian Hou, Yong Xu, Xun TI Full-length single-cell RNA-seq applied to a viral human cancer: applications to HPV expression and splicing analysis in HeLa S3 cells SO GIGASCIENCE LA English DT Article DE Single-cell transcriptome; HeLa; HPV; Virus; Tumor heterogeneity; Cancer; RNA splicing ID HUMAN-PAPILLOMAVIRUS TYPE-16; GENE-EXPRESSION; CERVICAL-CANCER; HEPATOCELLULAR-CARCINOMA; PROLIDASE ACTIVITY; PANCREATIC-CANCER; E7 ONCOPROTEIN; HUMAN GENOME; HETEROGENEITY; FUSION AB Background: Viral infection causes multiple forms of human cancer, and HPV infection is the primary factor in cervical carcinomas. Recent single-cell RNA-seq studies highlight the tumor heterogeneity present in most cancers, but virally induced tumors have not been studied. HeLa is a well characterized HPV+ cervical cancer cell line. Result: We developed a new high throughput platform to prepare single-cell RNA on a nanoliter scale based on a customized microwell chip. Using this method, we successfully amplified full-length transcripts of 669 single HeLa S3 cells and 40 of them were randomly selected to perform single-cell RNA sequencing. Based on these data, we obtained a comprehensive understanding of the heterogeneity of HeLa S3 cells in gene expression, alternative splicing and fusions. Furthermore, we identified a high diversity of HPV-18 expression and splicing at the single-cell level. By co-expression analysis we identified 283 E6, E7 co-regulated genes, including CDC25, PCNA, PLK4, BUB1B and IRF1 known to interact with HPV viral proteins. Conclusion: Our results reveal the heterogeneity of a virus-infected cell line. It not only provides a transcriptome characterization of HeLa S3 cells at the single cell level, but is a demonstration of the power of single cell RNA-seq analysis of virally infected cells and cancers. C1 [Wu, Liang; Zhang, Xiaolong; Zhao, Zhikun; Li, Bo; Li, Guibo; Yu, Qichao; Wang, Yanhui; Lin, Xinxin; Rao, Weijian; Mei, Zhanlong; Li, Yang; Jiang, Runze; Yang, Huan; Li, Fuqiang; Xie, Guoyun; Xu, Liqin; Wu, Kui; Zhang, Jie; Li, Yingrui; Yang, Huanming; Wang, Jian; Hou, Yong; Xu, Xun] BGI Shenzhen, Shenzhen 518083, Peoples R China. [Zhang, Xiaolong] Univ Chinese Acad Sci, Coll Life Sci, Beijing 100049, Peoples R China. [Zhao, Zhikun] Southeast Univ, State Key Lab Bioelect, Nanjing 210096, Jiangsu, Peoples R China. [Zhao, Zhikun] Southeast Univ, Sch Biol Sci & Med Engn, Nanjing 210096, Jiangsu, Peoples R China. [Wang, Ling; Chen, Jianghao; Wang, Ting] Fourth Mil Med Univ, Xijing Hosp, Dept Vasc & Endocrine Surg, Xian 710032, Peoples R China. [Li, Guibo; Kristiansen, Karsten; Hou, Yong] Univ Copenhagen, Dept Biol, DK-1599 Copenhagen, Denmark. [Dean, Michael] NCI, Canc & Inflammat Program, Frederick, MD 21702 USA. [Yu, Qichao] Univ Chinese Acad Sci, BGI Educ Ctr, Shenzhen 518083, Peoples R China. [Zhang, Xiuqing] BGI Shenzhen, Guangdong Enterprise Key Lab Human Dis Genom, Shenzhen 518083, Peoples R China. [Li, Yingrui] Univ Queensland, Inst Mol Biosci, Brisbane, Qld 4072, Australia. [Yang, Huanming; Wang, Jian] Zhejiang Univ, James D Watson Inst Genome Sci, Hangzhou 310058, Zhejiang, Peoples R China. RP Hou, Y (reprint author), BGI Shenzhen, Shenzhen 518083, Peoples R China. EM houyong@genomics.cn; xuxun@genomics.cn RI Kristiansen, Karsten/J-5148-2014; OI Kristiansen, Karsten/0000-0002-6024-0917; Zhao, Zhikun/0000-0001-5161-7818; hou, yong/0000-0002-0420-0726 FU National Basic Research Program of China [2011CB809203]; Chinese 863 Program [2012AA02A201, 2012AA02A502]; Guangdong Innovative Research Team Program [2009010016]; Guangdong Enterprise Key Laboratory of Human Disease Genomics; Shenzhen Municipal Government of China [CXB201108250094A, CXB201108250096A]; Science, Technology and Innovation Committee of Shenzhen Municipality [JSGG20140702161347218]; National Natural Science Fund [81272899, 81172510]; Discipline booster plan of Xi Jing Hospital [XJZT12Z07]; Shanxi Fund [2013K12-03-03]; Xi'an Fund [SF1323(3)]; Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH, DHHS, Bethesda, MD, USA FX The genome sequence and transcriptomic sequence described/used in this research were derived from a HeLa cell line. Henrietta Lacks, and the HeLa cell line that was established from her tumor cells without her knowledge or consent in 1951, have made significant contributions to scientific progress and advances in human health. We are grateful to Henrietta Lacks, now deceased, and to her surviving family members for their contributions to biomedical research. We thank L. Goodman for revising the manuscript. We also thank A. Krogh from University of Copenhagen for advices. We thank WaferGen Biosystems for providing the customized chips and suggestions. We thank X. Ye and S. Zhu for the help when developing MIRALCS. We thank L. R. Goldin and N. Caporaso for providing the frozen B cells. This work was supported by grants of the National Basic Research Program of China [2011CB809203]; Chinese 863 Program [2012AA02A201, 2012AA02A502]; Guangdong Innovative Research Team Program [2009010016]; the Guangdong Enterprise Key Laboratory of Human Disease Genomics, the Shenzhen Municipal Government of China [CXB201108250094A, CXB201108250096A]; the Science, Technology and Innovation Committee of Shenzhen Municipality [JSGG20140702161347218]; National Natural Science Fund [81272899, 81172510]; Discipline booster plan of Xi Jing Hospital [XJZT12Z07]; Shanxi Fund [2013K12-03-03]; and Xi'an Fund [SF1323(3)]. This research has been funded in part with federal funds from the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH, DHHS, Bethesda, MD, USA. NR 83 TC 3 Z9 4 U1 2 U2 15 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2047-217X J9 GIGASCIENCE JI GigaScience PD NOV 5 PY 2015 VL 4 AR 51 DI 10.1186/s13742-015-0091-4 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CX4KK UT WOS:000365668800001 PM 26550473 ER PT J AU Abeshouse, A Ahn, J Akbani, R Ally, A Amin, S Andry, CD Annala, M Aprikian, A Armenia, J Arora, A Auman, JT Balasundaram, M Balu, S Barbieri, CE Bauer, T Benz, CC Bergeron, A Beroukhim, R Berrios, M Bivol, A Bodenheimer, T Boice, L Bootwalla, MS dos Reis, RB Boutros, PC Bowen, J Bowlby, R Boyd, J Bradley, RK Breggia, A Brimo, F Bristow, CA Brooks, D Broom, BM Bryce, AH Bubley, G Burks, E Butterfield, YSN Button, M Canes, D Carlotti, CG Carlsen, R Carmel, M Carroll, PR Carter, SL Cartun, R Carver, BS Chan, JM Chang, MT Chen, Y Cherniack, AD Chevalier, S Chin, L Cho, J Chu, A Chuah, E Chudamani, S Cibulskis, K Ciriello, G Clarke, A Cooperberg, MR Corcoran, NM Costello, AJ Cowan, J Crain, D Curley, E David, K Demchok, JA Demichelis, F Dhalla, N Dhir, R Doueik, A Drake, B Dvinge, H Dyakova, N Felau, I Ferguson, ML Frazer, S Freedland, S Fu, Y Gabriel, SB Gao, JJ Gardner, J Gastier-Foster, JM Gehlenborg, N Gerken, M Gerstein, MB Getz, G Godwin, AK Gopalan, A Graefen, M Graim, K Gribbin, T Guin, R Gupta, M Hadjipanayis, A Haider, S Hamel, L Hayes, DN Heiman, DI Hess, J Hoadley, KA Holbrook, AH Holt, RA Holway, A Hovens, CM Hoyle, AP Huang, M Hutter, CM Ittmann, M Iype, L Jefferys, SR Jones, CD Jones, SJM Juhl, H Kahles, A Kane, CJ Kasaian, K Kerger, M Khurana, E Kim, J Klein, RJ Kucherlapati, R Lacombe, L Ladanyi, M Lai, PH Laird, PW Lander, ES Latour, M Lawrence, MS Lau, K LeBien, T Lee, D Lee, S Lehmann, KV Leraas, KM Leshchiner, I Leung, R Libertino, JA Lichtenberg, TM Lin, P Linehan, WM Ling, S Lippman, SM Liu, J Liu, W Lochovsky, L Loda, M Logothetis, C Lolla, L Longacre, T Lu, YL Luo, JH Ma, Y Mahadeshwar, HS Mallery, D Mariamidze, A Marra, MA Mayo, M McCall, S McKercher, G Meng, S Mes-Masson, AM Merino, MJ Meyersson, M Mieczkowski, PA Mills, GB Shaw, KRM Minner, S Moinzadeh, A Moore, RA Morris, S Morrison, C Mose, LE Mungall, AJ Murray, BA Myers, JB Naresh, R Nelson, J Nelson, MA Nelson, PS Newton, Y Noble, MS Noushmehr, H Nykter, M Pantazi, A Parfenov, M Park, PJ Parker, JS Paulauskis, J Penny, R Perou, CM Piche, A Pihl, T Pinto, PA Prandi, D Protopopov, A Ramirez, NC Rao, A Rathmell, WK Ratsch, G Ren, XJ Reuter, VE Reynolds, SM Rhie, SK Rieger-Christ, K Roach, J Robertson, AG Robinson, B Rubin, MA Saad, F Sadeghi, S Saksena, G Saller, C Salner, A Sanchez-Vega, F Sander, C Sandusky, G Sauter, G Sboner, A Scardino, PT Scarlata, E Schein, JE Schlomm, T Schmidt, LS Schultz, N Schumacher, SE Seidman, J Neder, L Seth, S Sharp, A Shelton, C Shelton, T Shen, H Shen, RL Sherman, M Sheth, M Shi, Y Shih, J Shmulevich, I Simko, J Simon, R Simons, JV Sipahimalani, P Skelly, T Sofia, HJ Soloway, MG Song, XZ Sorcini, A Sougnez, C Stepa, S Stewart, C Stewart, J Stuart, JM Sullivan, TB Sun, C Sun, HD Tam, A Tan, DH Tang, JB Tarnuzzer, R Tarvin, K Taylor, BS Teebagy, P Tenggara, I Tetu, B Tewari, A Thiessen, N Thompson, T Thorne, LB Tirapelli, DP Tomlins, SA Trevisan, FA Troncoso, P True, LD Tsourlakis, MC Tyekucheva, S Van Allen, E Van den Berg, DJ Veluvolu, U Verhaak, R Vocke, CD Voet, D Wan, YH Wang, QG Wang, WY Wang, ZN Weinhold, N Weinstein, JN Weisenberger, DJ Wilkerson, MD Wise, L Witte, J Wu, CC Wu, JY Wu, Y Xu, AW Yadav, SS Yang, LM Yang, LX Yau, C Ye, HH Yena, P Zeng, T Zenklusen, JC Zhang, HL Zhang, JH Zhang, JS Zhang, W Zhong, Y Zhu, K Zmuda, E AF Abeshouse, Adam Ahn, Jaeil Akbani, Rehan Ally, Adrian Amin, Samirkumar Andry, Christopher D. Annala, Matti Aprikian, Armen Armenia, Joshua Arora, Arshi Auman, J. Todd Balasundaram, Miruna Balu, Saianand Barbieri, Christopher E. Bauer, Thomas Benz, Christopher C. Bergeron, Alain Beroukhim, Rameen Berrios, Mario Bivol, Adrian Bodenheimer, Tom Boice, Lori Bootwalla, Moiz S. dos Reis, Rodolfo Borges Boutros, Paul C. Bowen, Jay Bowlby, Reanne Boyd, Jeffrey Bradley, Robert K. Breggia, Anne Brimo, Fadi Bristow, Christopher A. Brooks, Denise Broom, Bradley M. Bryce, Alan H. Bubley, Glenn Burks, Eric Butterfield, Yaron S. N. Button, Michael Canes, David Carlotti, Carlos G. Carlsen, Rebecca Carmel, Michel Carroll, Peter R. Carter, Scott L. Cartun, Richard Carver, Brett S. Chan, June M. Chang, Matthew T. Chen, Yu Cherniack, Andrew D. Chevalier, Simone Chin, Lynda Cho, Juok Chu, Andy Chuah, Eric Chudamani, Sudha Cibulskis, Kristian Ciriello, Giovanni Clarke, Amanda Cooperberg, Matthew R. Corcoran, Niall M. Costello, Anthony J. Cowan, Janet Crain, Daniel Curley, Erin David, Kerstin Demchok, John A. Demichelis, Francesca Dhalla, Noreen Dhir, Rajiv Doueik, Alexandre Drake, Bettina Dvinge, Heidi Dyakova, Natalya Felau, Ina Ferguson, Martin L. Frazer, Scott Freedland, Stephen Fu, Yao Gabriel, Stacey B. Gao, Jianjiong Gardner, Johanna Gastier-Foster, Julie M. Gehlenborg, Nils Gerken, Mark Gerstein, Mark B. Getz, Gad Godwin, Andrew K. Gopalan, Anuradha Graefen, Markus Graim, Kiley Gribbin, Thomas Guin, Ranabir Gupta, Manaswi Hadjipanayis, Angela Haider, Syed Hamel, Lucie Hayes, D. Neil Heiman, David I. Hess, Julian Hoadley, Katherine A. Holbrook, Andrea H. Holt, Robert A. Holway, Antonia Hovens, Christopher M. Hoyle, Alan P. Huang, Mei Hutter, Carolyn M. Ittmann, Michael Iype, Lisa Jefferys, Stuart R. Jones, Corbin D. Jones, Steven J. M. Juhl, Hartmut Kahles, Andre Kane, Christopher J. Kasaian, Katayoon Kerger, Michael Khurana, Ekta Kim, Jaegil Klein, Robert J. Kucherlapati, Raju Lacombe, Louis Ladanyi, Marc Lai, Phillip H. Laird, Peter W. Lander, Eric S. Latour, Mathieu Lawrence, Michael S. Lau, Kevin LeBien, Tucker Lee, Darlene Lee, Semin Lehmann, Kjong-Van Leraas, Kristen M. Leshchiner, Ignaty Leung, Robert Libertino, John A. Lichtenberg, Tara M. Lin, Pei Linehan, W. Marston Ling, Shiyun Lippman, Scott M. Liu, Jia Liu, Wenbin Lochovsky, Lucas Loda, Massimo Logothetis, Christopher Lolla, Laxmi Longacre, Teri Lu, Yiling Luo, Jianhua Ma, Yussanne Mahadeshwar, Harshad S. Mallery, David Mariamidze, Armaz Marra, Marco A. Mayo, Michael McCall, Shannon McKercher, Ginette Meng, Shaowu Mes-Masson, Anne-Marie Merino, Maria J. Meyersson, Matthew Mieczkowski, Piotr A. Mills, Gordon B. Shaw, Kenna R. Mills Minner, Sarah Moinzadeh, Alireza Moore, Richard A. Morris, Scott Morrison, Carl Mose, Lisle E. Mungall, Andrew J. Murray, Bradley A. Myers, Jerome B. Naresh, Rashi Nelson, Joel Nelson, Mark A. Nelson, Peter S. Newton, Yulia Noble, Michael S. Noushmehr, Houtan Nykter, Matti Pantazi, Angeliki Parfenov, Michael Park, Peter J. Parker, Joel S. Paulauskis, Joseph Penny, Robert Perou, Charles M. Piche, Alain Pihl, Todd Pinto, Peter A. Prandi, Davide Protopopov, Alexei Ramirez, Nilsa C. Rao, Arvind Rathmell, W. Kimryn Raetsch, Gunnar Ren, Xiaojia Reuter, Victor E. Reynolds, Sheila M. Rhie, Suhn K. Rieger-Christ, Kimberly Roach, Jeffrey Robertson, A. Gordon Robinson, Brian Rubin, Mark A. Saad, Fred Sadeghi, Sara Saksena, Gordon Saller, Charles Salner, Andrew Sanchez-Vega, Francisco Sander, Chris Sandusky, George Sauter, Guido Sboner, Andrea Scardino, Peter T. Scarlata, Eleonora Schein, Jacqueline E. Schlomm, Thorsten Schmidt, Laura S. Schultz, Nikolaus Schumacher, Steven E. Seidman, Jonathan Neder, Luciano Seth, Sahil Sharp, Alexis Shelton, Candace Shelton, Troy Shen, Hui Shen, Ronglai Sherman, Mark Sheth, Margi Shi, Yan Shih, Juliann Shmulevich, Ilya Simko, Jeffry Simon, Ronald Simons, Janae V. Sipahimalani, Payal Skelly, Tara Sofia, Heidi J. Soloway, Matthew G. Song, Xingzhi Sorcini, Andrea Sougnez, Carrie Stepa, Serghei Stewart, Chip Stewart, John Stuart, Joshua M. Sullivan, Travis B. Sun, Charlie Sun, Huandong Tam, Angela Tan, Donghui Tang, Jiabin Tarnuzzer, Roy Tarvin, Katherine Taylor, Barry S. Teebagy, Patrick Tenggara, Imelda Tetu, Bernard Tewari, Ashutosh Thiessen, Nina Thompson, Timothy Thorne, Leigh B. Tirapelli, Daniela P. Tomlins, Scott A. Trevisan, Felipe Amstalden Troncoso, Patricia True, Lawrence D. Tsourlakis, Maria Christina Tyekucheva, Svitlana Van Allen, Eliezer Van den Berg, David J. Veluvolu, Umadevi Verhaak, Roel Vocke, Cathy D. Voet, Doug Wan, Yunhu Wang, Qingguo Wang, Wenyi Wang, Zhining Weinhold, Nils Weinstein, John N. Weisenberger, Daniel J. Wilkerson, Matthew D. Wise, Lisa Witte, John Wu, Chia-Chin Wu, Junyuan Wu, Ye Xu, Andrew W. Yadav, Shalini S. Yang, Liming Yang, Lixing Yau, Christina Ye, Huihui Yena, Peggy Zeng, Thomas Zenklusen, Jean C. Zhang, Hailei Zhang, Jianhua Zhang, Jiashan Zhang, Wei Zhong, Yi Zhu, Kelsey Zmuda, Erik CA Canc Genome Atlas Res Network TI The Molecular Taxonomy of Primary Prostate Cancer SO CELL LA English DT Article ID ETS GENE FUSIONS; ACTIVE ANDROGEN RECEPTOR; DNA METHYLATION; RADICAL PROSTATECTOMY; GENOMIC ABERRATIONS; EXPRESSION PROFILES; WHOLE-GENOME; MUTATIONS; SPOP; RECURRENCE AB There is substantial heterogeneity among primary prostate cancers, evident in the spectrum of molecular abnormalities and its variable clinical course. As part of The Cancer Genome Atlas (TCGA), we present a comprehensive molecular analysis of 333 primary prostate carcinomas. Our results revealed a molecular taxonomy in which 74% of these tumors fell into one of seven subtypes defined by specific gene fusions (ERG, ETV1/4, and FLI1) or mutations (SPOP, FOXA1, and IDH1). Epigenetic profiles showed substantial heterogeneity, including an IDH1 mutant subset with a methylator phenotype. Androgen receptor (AR) activity varied widely and in a subtype-specific manner, with SPOP and FOXA1 mutant tumors having the highest levels of AR-induced transcripts. 25% of the prostate cancers had a presumed actionable lesion in the PI3K or MAPK signaling pathways, and DNA repair genes were inactivated in 19%. Our analysis reveals molecular heterogeneity among primary prostate cancers, as well as potentially actionable molecular defects. C1 [Canc Genome Atlas Res Network] NCI, Canc Genome Atlas Program Off, NIH, Bethesda, MD 20892 USA. RP Abeshouse, A (reprint author), NCI, Canc Genome Atlas Program Off, NIH, 31 Ctr Dr,Bldg 31,Suite 3A20, Bethesda, MD 20892 USA. EM massimo_loda@dfci.harvard.edu; sander.research@gmail.com; schultz@cbio.mskcc.org RI Carlotti, Carlos/C-1608-2012; Reis, Rodolfo/F-5877-2014; Lee, Semin/S-2629-2016; Marra, Marco/B-5987-2008; Holt, Robert/C-3303-2009; OI Rubin, Mark/0000-0002-8321-9950; Perou, Charles/0000-0001-9827-2247; Amin, Samir/0000-0002-3207-9505; Gehlenborg, Nils/0000-0003-0327-8297; Bryce, Alan H./0000-0002-0206-3895; Wang, Qingguo/0000-0002-5125-3724; Carlotti, Carlos/0000-0002-7055-0564; Reis, Rodolfo/0000-0003-0328-1840; Lee, Semin/0000-0002-9015-6046; Dvinge, Heidi/0000-0003-1741-0738; Barbieri, Christopher/0000-0002-0381-1947; Demichelis, Francesca/0000-0002-8266-8631; McCall, Shannon/0000-0003-3957-061X; Prandi, Davide/0000-0001-9885-6074; Bradley, Robert/0000-0002-8046-1063 FU NIH [5U24CA143799, 5U24CA143835, 5U24CA143840, 5U24CA143843, 5U24CA143845, 5U24CA143848, 5U24CA143858, 5U24CA143866, 5U24CA143867, 5U24CA143882, 5U24CA143883, 5U24CA144025, U54HG003067, U54HG003079, U54HG003273, P30CA16672]; Bayer, AG; Novartis; Bayer FX We are grateful to all the affected individuals and families who contributed to this study. We thank Margi Sheth and Ina Felau for project management. This work was supported by the following grants from the NIH: 5U24CA143799, 5U24CA143835, 5U24CA143840, 5U24CA143843, 5U24CA143845, 5U24CA143848, 5U24CA143858, 5U24CA143866, 5U24CA143867, 5U24CA143882, 5U24CA143883, 5U24CA144025, U54HG003067, U54HG003079, U54HG003273, and P30CA16672. D.J.W. is a consultant for Zymo Research Corporation. S.A.T., M.A.R., and F.D. are coauthors on a patent issued to the University of Michigan and the Brigham and Women's Hospital regarding ETS gene fusions in prostate cancer. The diagnostic field of use has been licensed to Hologic/Gen-Probe, Inc., who has sub-licensed some rights to Ventana Medical Systems. S.A.T. is a coauthor on a patent filed by the University of Michigan regarding SPINK1 in prostate cancer. The diagnostic field of use has been licensed to Hologic/Gen-Probe, Inc., who has sub-licensed some rights to Ventana Medical Systems. S.A.T. has served as a consultant and received honoraria from Ventana Medical Systems. M.A.R. is a co-inventor of the patent for the detection and therapeutic field of SPOP mutations in prostate cancer filed by Cornell University. E.V.A. is a consultant for Syapse and Ventana Medical Systems and owns equity in Syapse and Microsoft. A.D.C. has received research support from Bayer, AG. M.B.G. serves on the SAB of BINA. R. Beroukhim is a consultant for and received grant funding from Novartis. M. Meyerson received research support from Bayer and has equity in and is a consultant for Foundation Medicine. NR 91 TC 132 Z9 132 U1 19 U2 49 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 NOV 5 PY 2015 VL 163 IS 4 BP 1011 EP 1025 DI 10.1016/j.cell.2015.10.025 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CW2NS UT WOS:000364829700024 ER PT J AU Cheetham, CEJ Grier, BD Belluscio, L AF Cheetham, Claire E. J. Grier, Bryce D. Belluscio, Leonardo TI Bulk regional viral injection in neonatal mice enables structural and functional interrogation of defined neuronal populations throughout targeted brain areas SO FRONTIERS IN NEURAL CIRCUITS LA English DT Article DE adeno-associated virus; bulk labeling; neural circuit; olfactory bulb; tufted cell ID MAIN OLFACTORY-BULB; INTRABULBAR ASSOCIATIONAL SYSTEM; TUFTED CELLS; CEREBRAL-CORTEX; CRE RECOMBINASE; TRANSGENIC MICE; NERVOUS-SYSTEM; GRANULE CELLS; LONG-TERM; IN-VIVO AB The ability to label and manipulate specific cell types is central to understanding the structure and function of neuronal circuits. Here, we have developed a simple, affordable strategy for labeling of genetically defined populations of neurons throughout a targeted brain region: Bulk Regional Viral Injection (BReVI). Our strategy involves a large volume adeno-associated virus (AAV) injection in the targeted brain region of neonatal Gre driver mice. Using the mouse olfactory bulb (OB) as a model system, we tested the ability of BReVI to broadly and selectively label tufted cells, one of the two principal neuron populations of the OB, in CCK-IRES-Cre mice. BReVI resulted in labeling of neurons throughout the injected OB, with no spatial bias toward the injection site and no evidence of damage. The specificity of BReVI labeling was strikingly similar to that seen previously using immunohistochemical staining for cholecystokinin (CCK), an established tufted cell marker. Hence, the CCK-IRES-Cre line in combination with BReVI can provide an important tool for targeting and manipulation of OB tufted cells. We also found robust Cre-dependent reporter expression within three days of BReVI, which enabled us to assess developmental changes in the number and laminar distribution of OB tufted cells during the first three postnatal weeks. Furthermore, we demonstrate that BReVI permits structural and functional imaging in vivo, and can be combined with transgenic strategies to facilitate multi-color labeling of neuronal circuit components. BReVI is broadly applicable to different Cre driver lines and can be used to regionally manipulate genetically defined populations of neurons in any accessible brain region. C1 [Cheetham, Claire E. J.; Grier, Bryce D.; Belluscio, Leonardo] NINDS, Bethesda, MD 20892 USA. [Cheetham, Claire E. J.] Carnegie Mellon Univ, Dept Biol Sci, Pittsburgh, PA 15213 USA. RP Cheetham, CEJ (reprint author), NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM cheetham@andrew.cmu.edu; belluscl@ninds.nih.gov RI Cheetham, Claire/A-2612-2017; OI Cheetham, Claire/0000-0002-4038-1501; Grier, Bryce/0000-0002-7550-7784 FU NINDS Intramural Program [1-ZIA-NS003002]; Human Frontier Science Program Long-Term Fellowship FX This work was supported by the NINDS Intramural Program (1-ZIA-NS003002) and a Human Frontier Science Program Long-Term Fellowship to CC. NR 58 TC 1 Z9 1 U1 0 U2 2 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5110 J9 FRONT NEURAL CIRCUIT JI Front. Neural Circuits PD NOV 5 PY 2015 VL 9 AR 72 DI 10.3389/fncir.2015.00072 PG 13 WC Neurosciences SC Neurosciences & Neurology GA CW4AR UT WOS:000364934000001 PM 26594154 ER PT J AU Raza, MH Mattera, R Morell, R Sainz, E Rahn, R Gutierrez, J Paris, E Root, J Solomon, B Brewer, C Basra, MAR Khan, S Riazuddin, S Braun, A Bonifacino, JS Drayna, D AF Raza, M. Hashim Mattera, Rafael Morell, Robert Sainz, Eduardo Rahn, Rachel Gutierrez, Joanne Paris, Emily Root, Jessica Solomon, Beth Brewer, Carmen Basra, M. Asim Raza Khan, Shaheen Riazuddin, Sheikh Braun, Allen Bonifacino, Juan S. Drayna, Dennis TI Association between Rare Variants in AP4E1, a Component of Intracellular Trafficking, and Persistent Stuttering SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID PROTEIN COMPLEX; INTELLECTUAL DISABILITY; DEFICIENCY CAUSES; AP-4; MUTATIONS; ENZYME; LINKAGE; SUBUNIT; SIGNALS; LOCUS AB Stuttering is a common, highly heritable neurodevelopmental disorder characterized by deficits in the volitional control of speech. Whole-exome sequencing identified two heterozygous AP4E1 coding variants, c.1549G>A (p.Val517Ile) and c.2401G>A (p.Glu801Lys), that co-segregate with persistent developmental stuttering in a large Cameroonian family, and we observed the same two variants in unrelated Cameroonians with persistent stuttering. We found 23 other rare variants, including predicted loss-of-function variants, in AP4E1 in unrelated stuttering individuals in Cameroon, Pakistan, and North America. The rate of rare variants in AP4E1 was significantly higher in unrelated Pakistani and Cameroonian stuttering individuals than in population-matched control individuals, and coding variants in this gene are exceptionally rare in the general sub-Saharan West African, South Asian, and North American populations. Clinical examination of the Cameroonian family members failed to identify any symptoms previously reported in rare individuals carrying homozygous loss-of-function mutations in this gene. AP4E1 encodes the a subunit of the heterotetrameric (epsilon-beta 4-mu 4-sigma 4) AP-4 complex, involved in protein sorting at the trans-Golgi network. We found that the mu 4 subunit of AP-4 interacts with NAGPA, an enzyme involved in the synthesis of the mannose 6-phosphate signal that targets acid hydrolases to the lysosome and the product of a gene previously associated with stuttering. These findings implicate deficits in intracellular trafficking in persistent stuttering. C1 [Raza, M. Hashim; Morell, Robert; Sainz, Eduardo; Rahn, Rachel; Gutierrez, Joanne; Paris, Emily; Root, Jessica; Brewer, Carmen; Braun, Allen; Drayna, Dennis] NIDCD, NIH, Bethesda, MD 20892 USA. [Mattera, Rafael; Bonifacino, Juan S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. [Solomon, Beth] Clin Ctr Speech Language Pathol Serv, NIH, Bethesda, MD 20892 USA. [Basra, M. Asim Raza] Univ Punjab, Inst Chem, Lahore 54590, Pakistan. [Khan, Shaheen] Univ Punjab, Ctr Excellence Mol Biol, Lahore 54590, Pakistan. [Riazuddin, Sheikh] Alama Iqbal Med Res Ctr, Lahore 54550, Pakistan. RP Drayna, D (reprint author), NIDCD, NIH, Bethesda, MD 20892 USA. EM drayna@nidcd.nih.gov OI Morell, Robert/0000-0003-1537-7356; Bonifacino, Juan S./0000-0002-5673-6370 FU NIH National Institute of Child Health and Human Development (NICHD) [Z1A-DC000046-15, Z1A DC 000039-15, Z1A HD001607] FX This work was supported by NIH National Institute of Child Health and Human Development (NICHD) intramural grants Z1A-DC000046-15 (to D.D.), Z1A DC 000039-15 (to T.B. Friedman), and Z1A HD001607 (to J.B.). We thank the Stuttering Foundation of America, the Hollins Communications Research Institute, and the National Stuttering Association for assistance and M. Hallett, P. Friedman, S. Solomon, S. Inati, T. Lehky, L. Hathway, P. Penyakaew, S. Hove, J. Greenfield, S. Lischynsky, and H. Chow for assistance in clinical evaluations. NR 37 TC 2 Z9 2 U1 2 U2 8 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 NOV 5 PY 2015 VL 97 IS 5 BP 715 EP 725 DI 10.1016/j.ajhg.2015.10.007 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA CW2ED UT WOS:000364803000007 PM 26544806 ER PT J AU Zhui, YZ Yang, S Qi, RX Zou, Y Ma, BY Nussinov, R Zhang, QW AF Zhui, Yuzhen Yang, Shuang Qi, Ruxi Zou, Yu Ma, Buyong Nussinov, Ruth Zhang, Qingwen TI Effects of the C-Terminal Tail on the Conformational Dynamics of Human Neuronal Calcium Sensor-1 Protein SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID D2 DOPAMINE-RECEPTOR; BURIED SALT BRIDGES; MOLECULAR-DYNAMICS; WATER MODELS; STABILITY; NETWORKS; BINDING; RECOGNITION; SIMULATION; COLLAPSE AB Neuronal calcium sensor-1 (NCS-1) protein has been implicated in multiple neuronal functions by binding partners mostly through a largely exposed hydrophobic crevice (HC). In the absence of a ligand, the C-terminal tail (loop L3, residues D176 to V190) binds directly to the HC pocket as a ligand mimetic, occupying the HC and regulating its conformational stability. A recent experimental study reported that L3 deletion resulted in global structure destabilization. However, the influence of C-terminal tail on the conformations of NCS-1 protein is undear at the atomic level. In this study, we investigated the structural properties and the conformational dynamics of wild type NCS-1 and L3 truncation variant by extensive all-atom molecular dynamics (MD) simulations. Our cumulative 2 mu s MD simulations demonstrated that L3 deletion increased the structural flexibility of the C-domain and the distant N-domain. The community network analysis illustrated that C-terminal tail truncation weakened the interdomain correlation. Moreover, our data showed that the variant significantly disrupted the salt bridges network and expanded simultaneously the global structure and HC. These conformational changes caused by C-terminal tail truncation may affect the regulation of target interactions. Our study provides atomic details of the conformational dynamics effects of the C-terminal tail on human wild type NCS-1. C1 [Zhui, Yuzhen; Yang, Shuang; Zou, Yu; Zhang, Qingwen] Shanghai Univ Sport, Coll Phys Educ & Training, Shanghai 200438, Peoples R China. [Qi, Ruxi] Fudan Univ, Dept Phys, Shanghai 200433, Peoples R China. [Ma, Buyong; Nussinov, Ruth] Leidos Biomed Res Inc, NCI, Basic Sci Program, Canc & Inflammat Program, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Inst Mol Med, Dept Human Genet & Mol Med, Sackler Sch Med, IL-69978 Tel Aviv, Israel. RP Zhang, QW (reprint author), Shanghai Univ Sport, Coll Phys Educ & Training, 399 Chang Hai Rd, Shanghai 200438, Peoples R China. EM zqw@sus.edu.cn RI Ma, Buyong/F-9491-2011; OI Ma, Buyong/0000-0002-7383-719X; Zhang, Qingwen/0000-0002-8885-1066 FU Graduate Student Education Innovation Plan of Shanghai University of Sport [yjscx2015003]; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX We thank Dr. Cong Guo and Dr. Yin Luo for helpful discussions. This project has been funded from Graduate Student Education Innovation Plan of Shanghai University of Sport (Grant yjscx2015003). Simulations were performed at the High Performance Computing Server (PowerEdge T710) of Shanghai University of Sport. 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. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 2 Z9 2 U1 2 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD NOV 5 PY 2015 VL 119 IS 44 BP 14236 EP 14244 DI 10.1021/acs.jpcb.5b07962 PG 9 WC Chemistry, Physical SC Chemistry GA CV7EP UT WOS:000364435500028 ER PT J AU Worcester, DL Weinrich, M AF Worcester, David L. Weinrich, Michael TI Hydrostatic Pressure Promotes Domain Formation in Model Lipid Raft Membranes SO JOURNAL OF PHYSICAL CHEMISTRY LETTERS LA English DT Article ID ANGLE NEUTRON-SCATTERING; GENERAL-ANESTHESIA; PHASE-TRANSITIONS; NMDA RECEPTOR; BILAYERS; MIXTURES; PHOSPHOLIPIDS; CHOLESTEROL; LIPOSOMES; VESICLES AB Neutron diffraction measurements demonstrate that hydrostatic pressure promotes liquid-ordered (L-o) domain formation in lipid membranes prepared as both oriented multilayers and unilamellar vesicles made of a canonical ternary lipid mixture for which demixing transitions have been extensively studied. The results demonstrate an unusually large dependence of the mixing transition on hydrostatic pressure. Additionally, data at 28 degrees C show that the magnitude of increase in Lo caused by 10 MPa pressure is much the same as the decrease in Lo produced by twice minimum alveolar concentrations (MAC) of general anesthetics such as halothane, nitrous oxide, and xenon. Therefore, the results may provide a plausible explanation for the reversal of general anesthesia by hydrostatic pressure. C1 [Worcester, David L.; Weinrich, Michael] NIST, Ctr Neutron Res, Gaithersburg, MD 20899 USA. [Weinrich, Michael] Eunice Kennedy Shriver Natl Ctr Child Hlth & Huma, NIH, Bethesda, MD 20892 USA. [Worcester, David L.] Univ Calif Irvine, Dept Physiol & Biophys, Irvine, CA 92697 USA. RP Weinrich, M (reprint author), NIST, Ctr Neutron Res, Gaithersburg, MD 20899 USA. EM mw287k@nih.gov FU U.S. National Institutes of Health [GM 86685] FX We thank the National Science Foundation and the NIST Center for Neutron Research for access to neutron scattering facilities and Juscellino Leao for providing and helping with pressure equipment. We thank Boualem Hammouda and Jun Liu for help with SANS. Support to D.L.W. was provided by U.S. National Institutes of Health Grant GM 86685 (to Stephen H. White). We thank Dr. Sergey Bezmkov for useful discussions. The identification of any commercial product or trade name does not imply any endorsement or recommendation by the National Institute of Standards and Technology. NR 38 TC 1 Z9 1 U1 1 U2 13 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 NOV 5 PY 2015 VL 6 IS 21 BP 4417 EP 4421 DI 10.1021/acs.jpclett.5b02134 PG 5 WC Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Atomic, Molecular & Chemical SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA CV7ES UT WOS:000364435800020 PM 26538052 ER PT J AU Sharma, NK Kumar, A Kumari, A Tokar, EJ Waalkes, MP Bortner, CD Williams, J Ehrenshaft, M Mason, RP Sinha, BK AF Sharma, Nilesh K. Kumar, Ashutosh Kumari, Amrita Tokar, Erik J. Waalkes, Michael P. Bortner, Carl D. Williams, Jason Ehrenshaft, Marilyn Mason, Ronald P. Sinha, Birandra K. TI Nitric Oxide Down-Regulates Topoisomerase I and Induces Camptothecin Resistance in Human Breast MCF-7 Tumor Cells SO PLoS One LA English DT Article ID COLON-CARCINOMA CELLS; S-NITROSYLATION; ANTICANCER ACTIVITY; MELANOMA-CELLS; P53 FUNCTION; DNA-DAMAGE; WILD-TYPE; CANCER; PROTEIN; SENSITIVITY AB Camptothecin (CPT), a topoisomerase I poison, is an important drug for the treatment of solid tumors in the clinic. Nitric oxide ((NO)-N-center dot), a physiological signaling molecule, is involved in many cellular functions, including cell proliferation, survival and death. We have previously shown that (NO)-N-center dot plays a significant role in the detoxification of etoposide (VP-16), a topoisomerase II poison in vitro and in human melanoma cells. (NO)-N-center dot/(NO)-N-center dot-derived species are reported to modulate activity of several important cellular proteins. As topoisomerases contain a number of free sulfhydryl groups which may be targets of (NO)-N-center dot/(NO)-N-center dot-derived species, we have investigated the roles of (NO)-N-center dot/(NO)-N-center dot-derived species in the stability and activity of topo I. Here we show that (NO)-N-center dot/(NO)-N-center dot-derived species induces a significant down-regulation of topoisomerase I protein via the ubiquitin/26S proteasome pathway in human colon (HT29) and breast (MCF-7) cancer cell lines. Importantly, (NO)-N-center dot treatment induced a significant resistance to CPT only in MCF-7 cells. This resistance to CPT did not result from loss of topoisomerase I activity as there were no differences in topoisomerase I-induced DNA cleavage in vitro or in tumor cells, but resulted from the stabilization/induction of bcl2 protein. This up-regulation of bcl2 protein in MCF-7 cells was wtp53 dependent as pifithrine-alpha, a small molecule inhibitor of wtp53 function, completely reversed CPT resistance, suggesting that wtp53 and bcl2 proteins played important roles in CPT resistance. Because tumors in vivo are heterogeneous and contaminated by infiltrating macrophages, (NO)-N-center dot-induced down-regulation of topoisomerase I protein combined with bcl2 protein stabilization could render certain tumors highly resistant to CPT and drugs derived from it in the clinic. C1 [Sharma, Nilesh K.; Kumar, Ashutosh; Kumari, Amrita; Ehrenshaft, Marilyn; Mason, Ronald P.; Sinha, Birandra K.] NIEHS, Immun Inflammat & Dis Lab, NIH, Durham, NC 27713 USA. [Tokar, Erik J.; Waalkes, Michael P.] NIEHS, Natl Toxicol Program, NIH, Durham, NC USA. [Bortner, Carl D.] NIEHS, Lab Signal Transduct, NIH, Durham, NC USA. [Williams, Jason] NIEHS, Struct Biol Lab, NIH, Durham, NC USA. RP Sinha, BK (reprint author), NIEHS, Immun Inflammat & Dis Lab, NIH, Durham, NC 27713 USA. EM sinha1@niehs.nih.gov OI Sharma, Nilesh Kumar/0000-0002-8774-3020 FU National Institute of Environmental Health Sciences, NIH FX This research was supported [in part] by the intramural research program of the National Institute of Environmental Health Sciences, NIH. NR 53 TC 1 Z9 1 U1 3 U2 10 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 NOV 5 PY 2015 VL 10 IS 11 AR e0141897 DI 10.1371/journal.pone.0141897 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CV5IS UT WOS:000364303800034 PM 26540186 ER PT J AU Stoffers, D Diaz, BA Chen, G den Braber, A van 't Ent, D Boomsma, DI Mansvelder, HD de Geus, E Van Someren, EJW Linkenkaer-Hansen, K AF Stoffers, Diederick Diaz, B. Alexander Chen, Gang den Braber, Anouk van 't Ent, Dennis Boomsma, Dorret I. Mansvelder, Huibert D. de Geus, Eco Van Someren, Eus J. W. Linkenkaer-Hansen, Klaus TI Resting-State fMRI Functional Connectivity Is Associated with Sleepiness, Imagery, and Discontinuity of Mind SO PLOS ONE LA English DT Article ID INDEPENDENT COMPONENT ANALYSIS; HUMAN BRAIN-FUNCTION; DEFAULT-MODE; CORRELATED FLUCTUATIONS; WANDERING MINDS; VISUAL-CORTEX; NETWORK; EXPERIENCES; DYNAMICS; PATTERNS AB Resting-state functional magnetic resonance imaging (rs-fMRI) is widely used to investigate the functional architecture of the healthy human brain and how it is affected by learning, life-long development, brain disorders or pharmacological intervention. Non-sensory experiences are prevalent during rest and must arise from ongoing brain activity, yet little is known about this relationship. Here, we used two runs of rs-fMRI both immediately followed by the Amsterdam Resting-State Questionnaire (ARSQ) to investigate the relationship between functional connectivity within ten large-scale functional brain networks and ten dimensions of thoughts and feelings experienced during the scan in 106 healthy participants. We identified 11 positive associations between brain-network functional connectivity and ARSQ dimensions. 'Sleepiness' exhibited significant associations with functional connectivity within Visual, Sensorimotor and Default Mode networks. Similar associations were observed for 'Visual Thought' and 'Discontinuity of Mind', which may relate to variation in imagery and thought control mediated by arousal fluctuations. Our findings show that selfreports of thoughts and feelings experienced during a rs-fMRI scan help understand the functional significance of variations in functional connectivity, which should be of special relevance to clinical studies. C1 [Stoffers, Diederick; Diaz, B. Alexander; Mansvelder, Huibert D.; Van Someren, Eus J. W.; Linkenkaer-Hansen, Klaus] Vrije Univ Amsterdam, Dept Integrat Neurophysiol, CNCR, Amsterdam, Netherlands. [Stoffers, Diederick; Van Someren, Eus J. W.] Netherlands Inst Neurosci, Dept Sleep & Cognit, Amsterdam, Netherlands. [Chen, Gang] NIMH, Sci & Stat Comp Core, Bethesda, MD 20892 USA. [den Braber, Anouk; van 't Ent, Dennis; Boomsma, Dorret I.; de Geus, Eco] Vrije Univ Amsterdam, Fac Psychol & Educ, Dept Biol Psychol, Amsterdam, Netherlands. [Van Someren, Eus J. W.] Vrije Univ Amsterdam, Dept Med Psychol, Med Ctr, Amsterdam, Netherlands. RP Linkenkaer-Hansen, K (reprint author), Vrije Univ Amsterdam, Dept Integrat Neurophysiol, CNCR, Amsterdam, Netherlands. EM klaus.linkenkaer@cncr.vu.nl OI Mansvelder, Huib/0000-0003-1365-5340; de Geus, Eco/0000-0001-6022-2666 FU Netherlands Organization for Scientific Research [400-07-080, 433-08-121]; Neuroscience Campus Amsterdam [AC-2009-F2-3]; VU University Amsterdam (VU-CvB Financial Incentive Scheme) FX This work was supported by the Netherlands Organization for Scientific Research (MaGW-nr: 400-07-080 and 433-08-121), the Neuroscience Campus Amsterdam (AC-2009-F2-3), and VU University Amsterdam (VU-CvB Financial Incentive Scheme to KL-H). NR 74 TC 4 Z9 4 U1 1 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 NOV 5 PY 2015 VL 10 IS 11 AR e0142014 DI 10.1371/journal.pone.0142014 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CV5IS UT WOS:000364303800045 PM 26540239 ER PT J AU Zhang, L Zhan, SY Yao, J Lowery, FJ Zhang, QL Huang, WC Li, P Li, M Wang, X Zhang, CY Wang, H Ellis, K Cheerathodi, M McCarty, JH Palmieri, D Saunus, J Lakhani, S Huang, SY Sahin, AA Aldape, KD Steeg, PS Yu, DH AF Zhang, Lin Zhan, Siyuan Yao, Jun Lowery, Frank J. Zhang, Qingling Huang, Wen-Chien Li, Ping Li, Min Wang, Xiao Zhang, Chenyu Wang, Hai Ellis, Kenneth Cheerathodi, Mujeeburahiman McCarty, Joseph H. Palmieri, Diane Saunus, Jodi Lakhani, Sunil Huang, Suyun Sahin, Aysegul A. Aldape, Kenneth D. Steeg, Patricia S. Yu, Dihua TI Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth SO NATURE LA English DT Article ID BREAST-CANCER; CELLS; MIR-17-92; PHOSPHATASE; FAMILY AB The development of life-threatening cancer metastases at distant organs requires disseminated tumour cells' adaptation to, and co-evolution with, the drastically different microenvironments of metastatic sites(1). Cancer cells of common origin manifest distinct gene expression patterns after metastasizing to different organs(2). Clearly, the dynamic interaction between metastatic tumour cells and extrinsic signals at individual metastatic organ sites critically effects the subsequent metastatic outgrowth(3,4). Yet, it is unclear when and how disseminated tumour cells acquire the essential traits from the microenvironment of metastatic organs that prime their subsequent outgrowth. Here we show that both human and mouse tumour cells with normal expression of PTEN, an important tumour suppressor, lose PTEN expression after dissemination to the brain, but not to other organs. The PTEN level in PTEN-loss brain metastatic tumour cells is restored after leaving the brain microenvironment. This brain microenvironment-dependent, reversible PTEN messenger RNA and protein downregulation is epigenetically regulated by microRNAs from brain astrocytes. Mechanistically, astrocyte-derived exosomes mediate an intercellular transfer of PTEN-targeting microRNAs to metastatic tumour cells, while astrocyte-specific depletion of PTEN-targeting microRNAs or blockade of astrocyte exosome secretion rescues the PTEN loss and suppresses brain metastasis in vivo. Furthermore, this adaptive PTEN loss in brain metastatic tumour cells leads to an increased secretion of the chemokine CCL2, which recruits IBA1-expressing myeloid cells that reciprocally enhance the outgrowth of brain metastatic tumour cells via enhanced proliferation and reduced apoptosis. Our findings demonstrate a remarkable plasticity of PTEN expression in metastatic tumour cells in response to different organ microenvironments, underpinning an essential role of co-evolution between the metastatic cells and their microenvironment during the adaptive metastatic outgrowth. Our findings signify the dynamic and reciprocal cross-talk between tumour cells and the metastatic niche; importantly, they provide new opportunities for effective anti-metastasis therapies, especially of consequence for brain metastasis patients. C1 [Zhang, Lin; Zhan, Siyuan; Yao, Jun; Lowery, Frank J.; Zhang, Qingling; Huang, Wen-Chien; Li, Ping; Li, Min; Wang, Xiao; Zhang, Chenyu; Wang, Hai; Ellis, Kenneth; Yu, Dihua] Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA. [Zhang, Lin; Lowery, Frank J.; Yu, Dihua] Univ Texas Houston, Hlth Sci Ctr, Grad Sch Biomed Sci, Canc Biol Program, Houston, TX 77030 USA. [Zhan, Siyuan] Univ Notre Dame, Dept Biol Sci, Notre Dame, IN 46556 USA. [Cheerathodi, Mujeeburahiman; McCarty, Joseph H.; Huang, Suyun] Univ Texas MD Anderson Canc Ctr, Dept Neurosurg, Houston, TX 77030 USA. [Palmieri, Diane; Steeg, Patricia S.] NCI, Womans Malignancies Branch, Bethesda, MD 20892 USA. [Saunus, Jodi; Lakhani, Sunil] Univ Queensland, Clin Res Ctr, Brisbane, Qld 4029, Australia. [Lakhani, Sunil] Sch Med & Pathol Queensland, Brisbane, Qld 4029, Australia. [Lakhani, Sunil] Royal Brisbane & Womens Hosp, Brisbane, Qld 4029, Australia. [Sahin, Aysegul A.; Aldape, Kenneth D.] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Yu, Dihua] China Med Univ, Ctr Mol Med, Taichung 40402, Taiwan. RP Yu, DH (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA. EM dyu@mdanderson.org RI Zhang, Siyuan/A-1276-2014; OI Zhang, Siyuan/0000-0003-0910-3666; Lowery, Frank/0000-0002-4620-5293 FU DOD Center of Excellence [W81XWH-06-2-0033]; NIH [5R00CA158066-05]; DOD [W81XWH-11-1-0003]; Isaiah Fidler Fellowship in Cancer [PO1-CA099031]; Susan G. Komen Breast Cancer Foundation [KG091020]; METAvivor Research Grant; Breast and Ovarian Cancers Moon Shot program; China Medical University Research Fund; Sowell-Huggins Pre-doctoral Fellowship and Professorship in Cancer Research; [RO1-CA112567-06]; [R01CA184836] FX We thank M.-C. Hung, H.-K. Lin and Z. Lu for reading the manuscript, A. Yung for PTEN promoter constructs, MD Anderson Cancer Center (MDACC) shRNA and ORFome, FAGS, histology and high-resolution electron microscopy support, the animal core facilities (NIH CA16672) for technical support, and members of the Yu laboratory for helpful discussions. Thanks to A. Matsika for histological review and tissue microarray construction. This work was supported partially by DOD Center of Excellence grant (P.S.S.) subproject W81XWH-06-2-0033 (D.Y.), NIH Pathway to Independence Award 5R00CA158066-05 (S.Z.), DOD Postdoctoral Fellowship W81XWH-11-1-0003 (C.Z.), Isaiah Fidler Fellowship in Cancer Metastasis (F.J.L.), PO1-CA099031 project 4 (D.Y.), RO1-CA112567-06 (D.Y.), R01CA184836 (D.Y.), Susan G. Komen Breast Cancer Foundation Promise Grant KG091020 (D.Y), METAvivor Research Grant (D.Y.), Breast and Ovarian Cancers Moon Shot program, China Medical University Research Fund, and Sowell-Huggins Pre-doctoral Fellowship (L.Z.) and Professorship (D.Y.) in Cancer Research. D.Y. is the Hubert L. & Olive Stringer Distinguished Chair in Basic Science at the MDACC. NR 26 TC 91 Z9 98 U1 30 U2 112 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 NOV 5 PY 2015 VL 527 IS 7576 BP 100 EP 104 DI 10.1038/nature15376 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CV4XV UT WOS:000364270700051 PM 26479035 ER PT J AU Bourne, PE Lorsch, JR Green, ED AF Bourne, Philip E. Lorsch, Jon R. Green, Eric D. TI Sustaining the big-data ecosystem SO NATURE LA English DT Editorial Material C1 [Bourne, Philip E.] US Natl Inst Hlth, Data Sci, Bethesda, MD 20892 USA. [Bourne, Philip E.] Univ Calif San Diego, Off Res Affairs, Innovat & Ind Alliances, San Diego, CA 92103 USA. [Lorsch, Jon R.] Johns Hopkins Univ, Biophys & Biophys Chem, Baltimore, MD USA. [Green, Eric D.] NHGRI, Bethesda, MD 20892 USA. [Green, Eric D.] NIH, Intramural Sequencing Ctr, Bethesda, MD USA. RP Bourne, PE (reprint author), US Natl Inst Hlth, Data Sci, Bethesda, MD 20892 USA. EM philip.bourne@nih.gov NR 0 TC 17 Z9 17 U1 13 U2 28 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 NOV 5 PY 2015 VL 527 IS 7576 BP S16 EP S17 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CV4XV UT WOS:000364270700031 PM 26536219 ER PT J AU Hamaneh, MB Haber, J Yu, YK AF Hamaneh, Mehdi Bagheri Haber, Jonah Yu, Yi-Kuo TI Analytical solution and scaling of fluctuations in complex networks traversed by damped, interacting random walkers SO PHYSICAL REVIEW E LA English DT Article ID INFORMATION-FLOW; MODEL AB A general model for random walks (RWs) on networks is proposed. It incorporates damping and time-dependent links, and it includes standard (undamped, noninteracting) RWs (SRWs), coalescing RWs, and coalescing-branching RWs as special cases. The exact, time-dependent solutions for the average numbers of visits (w) to nodes and their fluctuations (sigma(2)) are given, and the long-term sigma-w relation is studied. Although sigma proportional to w(1/2) for SRWs, this power law can be fragile when coalescing-branching interaction is present. Damping, however, often strengthens it but with an exponent generally different from 1/2. C1 [Hamaneh, Mehdi Bagheri; Haber, Jonah; Yu, Yi-Kuo] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Hamaneh, MB (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM yyu@ncbi.nlm.nih.gov FU Intramural Research Program of the National Library of Medicine of the National Institutes of Health FX This work was supported by the Intramural Research Program of the National Library of Medicine of the National Institutes of Health. NR 26 TC 0 Z9 0 U1 1 U2 3 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 2470-0045 EI 2470-0053 J9 PHYS REV E JI Phys. Rev. E PD NOV 5 PY 2015 VL 92 IS 5 AR 052803 DI 10.1103/PhysRevE.92.052803 PG 8 WC Physics, Fluids & Plasmas; Physics, Mathematical SC Physics GA CV3LY UT WOS:000364161900007 PM 26651740 ER PT J AU Bar-Lev, TH Harris, D Tomic, M Stojilkovic, S Blumenfeld, Z Brown, P Seger, R Naor, Z AF Bar-Lev, Tali H. Harris, Dagan Tomic, Melanija Stojilkovic, Stanko Blumenfeld, Zeev Brown, Pamela Seger, Rony Naor, Zvi TI Role of PI4K and PI3K-AKT in ERK1/2 activation by GnRH in the pituitary gonadotropes SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article DE GnRH; PKC; PI3K; PI4K; ERK1/2; MAPK; Gonadotropes; L beta T2 cells; alpha T3-1 cells ID SIGNAL-REGULATED KINASE; N-TERMINAL KINASE; HORMONE-STIMULATED ACTIVITY; PROTEIN-COUPLED RECEPTORS; ALPHA-SUBUNIT PROMOTER; PHOSPHATIDYLINOSITOL 3-KINASE; BETA-GAMMA; C-SRC; MAPK CASCADES; CROSS-TALK AB The role of PI4K and PI3K-AKT in ERK1/2 activation by GnRH was examined. A relatively long pre-incubation (60 min) with wortmannin (10 nM and 10 mu M), and LY294002 (10 mu M and 100 mu M) (doses known to inhibit PI3K and PI4K, respectively), were required to inhibit GnRH-and PMA-stimulated ERK1/2 activity in alpha T3-1 and L beta T2 gonadotrope cells. A similar preincubation protocol was required to demonstrate inhibition of IGF-1-stimulated AKT activation lending support for the need of prolonged incubation (60 min) with wortmannin in contrast to other cellular systems. To rule out that the inhibitors acted upon PI(4,5)P-2 levels, we followed the [Ca2+](i) response to GnRH and found that wortmannin has no significant effect on GnRH-induced [Ca2+](i) responses. Surprisingly, GnRH and PMA reduced, while IGF-1 increased AKT phosphorylation. We suggest that PI3K inhibits GnRH-stimulated alpha GSU activity, has no effect upon GnRH-stimulated LH beta activity and enhanced the GnRH-stimulated FSH beta transcription. Hence, PI4K and PI3K-AKT play a role in GnRH to ERK1/2 signaling, while PI3K may regulate also GnRH-induced gonadotropin gene expression. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Bar-Lev, Tali H.; Harris, Dagan; Naor, Zvi] Tel Aviv Univ, George S Wise Fac Life Sci, Dept Biochem & Mol Biol, IL-69978 Tel Aviv, Israel. [Tomic, Melanija; Stojilkovic, Stanko] NICHHD, NIH, Bethesda, MD 20892 USA. [Blumenfeld, Zeev] Technion Fac Med, Reprod Endocrinol, OB GYN, IL-31096 Haifa, Israel. [Brown, Pamela] Univ Edinburgh, Queens Med Res Inst, Med Res Council, Ctr Reprod Hlth, Edinburgh EH16 4TJ, Midlothian, Scotland. [Seger, Rony] Weizmann Inst Sci, Dept Regulat Biol, IL-76100 Rehovot, Israel. RP Naor, Z (reprint author), Tel Aviv Univ, George S Wise Fac Life Sci, Dept Biochem & Mol Biol, IL-69978 Tel Aviv, Israel. EM ZviN@tauex.tau.ac.il RI Tomic, Melanija/C-3371-2016 FU Israel Science Foundation [221/05, 1932/15] FX The studies were supported by The Israel Science Foundation (Grants No. 221/05 and 1932/15). NR 44 TC 4 Z9 4 U1 0 U2 8 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD NOV 5 PY 2015 VL 415 IS C BP 12 EP 23 DI 10.1016/j.mce.2015.07.029 PG 12 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA CS5RB UT WOS:000362134600002 PM 26238084 ER PT J AU Dean, M Boland, J Yeager, M Im, KM Garland, L Rodriguez-Herrera, M Perez, M Mitchell, J Roberson, D Jones, K Lee, HJ Eggebeen, R Sawitzke, J Bass, S Zhang, XJ Robles, V Hollis, C Barajas, C Rath, E Arentz, C Figueroa, JA Nguyen, DD Nahleh, Z AF Dean, Michael Boland, Joseph Yeager, Meredith Im, Kate M. Garland, Lisa Rodriguez-Herrera, Maria Perez, Mylen Mitchell, Jason Roberson, David Jones, Kristine Lee, Hyo Jung Eggebeen, Rebecca Sawitzke, Julie Bass, Sara Zhang, Xijun Robles, Vivian Hollis, Celia Barajas, Claudia Rath, Edna Arentz, Candy Figueroa, Jose A. Nguyen, Diane D. Nahleh, Zeina TI Addressing health disparities in Hispanic breast cancer: accurate and inexpensive sequencing of BRCA1 and BRCA2 SO GIGASCIENCE LA English DT Article DE Breast cancer; Hispanic populations; Genetic testing; Underserved populations; Health disparity ID OVARIAN-CANCER; HEREDITARY BREAST; POLY(ADP-RIBOSE) POLYMERASE; MUTATION CARRIERS; RISK; WOMEN; GENES; PREVALENCE; RACE/ETHNICITY; PERFORMANCE AB Background: Germline mutations in the BRCA1 and BRCA2 genes account for 20-25 % of inherited breast cancers and about 10 % of all breast cancer cases. Detection of BRCA mutation carriers can lead to therapeutic interventions such as mastectomy, oophorectomy, hormonal prevention therapy, improved screening, and targeted therapies such as PARP-inhibition. We estimate that African Americans and Hispanics are 4-5 times less likely to receive BRCA screening, despite having similar mutation frequencies as non-Jewish Caucasians, who have higher breast cancer mortality. To begin addressing this health disparity, we initiated a nationwide trial of BRCA testing of Latin American women with breast cancer. Patients were recruited through community organizations, clinics, public events, and by mail and Internet. Subjects completed the consent process and questionnaire, and provided a saliva sample by mail or in person. DNA from 120 subjects was used to sequence the entirety of BRCA1 and BRCA2 coding regions and splice sites, and validate pathogenic mutations, with a total material cost of $85/subject. Subjects ranged in age from 23 to 81 years (mean age, 51 years), 6 % had bilateral disease, 57 % were ER/PR+, 23 % HER2+, and 17 % had triple-negative disease. Results: A total of seven different predicted deleterious mutations were identified, one newly described and the rest rare. In addition, four variants of unknown effect were found. Conclusions: Application of this strategy on a larger scale could lead to improved cancer care of minority and underserved populations. C1 [Dean, Michael; Im, Kate M.; Garland, Lisa; Rodriguez-Herrera, Maria; Perez, Mylen] NCI, Expt Immunol Lab, Frederick, MD 21702 USA. [Boland, Joseph; Yeager, Meredith; Mitchell, Jason; Roberson, David; Jones, Kristine; Lee, Hyo Jung; Eggebeen, Rebecca; Bass, Sara; Zhang, Xijun] NCI, Div Canc Epidemiol & Genet, Canc Genet Res Lab, Gaithersburg, MD USA. [Sawitzke, Julie] Leidos Biomed Res Inc, Basic Sci Program, Frederick, MD USA. [Robles, Vivian] Nueva Vida Richmond, Richmond, VA USA. [Hollis, Celia; Barajas, Claudia] Latino Community Dev Agcy, Oklahoma City, OK USA. [Rath, Edna; Nahleh, Zeina] Texas Tech Univ, Hlth Sci Ctr, El Paso, TX USA. [Arentz, Candy; Figueroa, Jose A.; Nguyen, Diane D.] Texas Tech Univ, Hlth Sci Ctr, Lubbock, TX 79430 USA. RP Dean, M (reprint author), NCI, Expt Immunol Lab, Frederick, MD 21702 USA. EM deanm@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; Leidos Biomedical Research, Inc. [HHSN261200800001E] FX The authors would like to thank the staff and health professionals from Nueva Vida (Baltimore, MD and Richmond, VA), the Latino Community Development Agency (Oklahoma City, OK), and the Texas Tech University Health Sciences Centers, in Lubbock and El Paso, TX; Mark Hurlbert (Avon Foundation); Dr Jennifer Loud for advice on approval of the study; Russ Hanson for managing study documents; and the BSP-CCR Genetics Core for technical support. The work was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, and by Leidos Biomedical Research, Inc., under contract # HHSN261200800001E. NR 52 TC 1 Z9 1 U1 2 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND EI 2047-217X J9 GIGASCIENCE JI GigaScience PD NOV 4 PY 2015 VL 4 AR 50 DI 10.1186/s13742-015-0088-z PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CX4KJ UT WOS:000365668700001 PM 26543556 ER PT J AU Karaca, E Harel, T Pehlivan, D Jhangiani, SN Gambin, T Akdemir, ZC Gonzaga-Jauregui, C Erdin, S Bayram, Y Campbell, IM Hunter, JV Atik, MM Van Esch, H Yuan, B Wiszniewski, W Isikay, S Yesil, G Yuregir, OO Bozdogan, ST Aslan, H Aydin, H Tos, T Aksoy, A De Vivo, DC Jain, P Geckinli, BB Sezer, O Gul, D Durmaz, B Cogulu, O Ozkinay, F Topcu, V Candan, S Cebi, AH Ikbal, M Gulec, EY Gezdirici, A Koparir, E Ekici, F Coskun, S Cicek, S Karaer, K Koparir, A Duz, MB Kirat, E Fenercioglu, E Ulucan, H Seven, M Guran, T Elcioglu, N Yildirim, MS Aktas, D Alikasifoglu, M Ture, M Yakut, T Overton, JD Yuksel, A Ozen, M Muzny, DM Adams, DR Boerwinkle, E Chung, WK Gibbs, RA Lupski, JR AF Karaca, Ender Harel, Tamar Pehlivan, Davut Jhangiani, Shalini N. Gambin, Tomasz Akdemir, Zeynep Coban Gonzaga-Jauregui, Claudia Erdin, Serkan Bayram, Yavuz Campbell, Ian M. Hunter, Jill V. Atik, Mehmed M. Van Esch, Hilde Yuan, Bo Wiszniewski, Wojciech Isikay, Sedat Yesil, Gozde Yuregir, Ozge O. Bozdogan, Sevcan Tug Aslan, Huseyin Aydin, Hatip Tos, Tulay Aksoy, Ayse De Vivo, Darryl C. Jain, Preti Geckinli, B. Bilge Sezer, Ozlem Gul, Davut Durmaz, Burak Cogulu, Ozgur Ozkinay, Ferda Topcu, Vehap Candan, Sukru Cebi, Alper Han Ikbal, Mevlit Gulec, Elif Yilmaz Gezdirici, Alper Koparir, Erkan Ekici, Fatma Coskun, Salih Cicek, Salih Karaer, Kadri Koparir, Asuman Duz, Mehmet Bugrahan Kirat, Emre Fenercioglu, Elif Ulucan, Hakan Seven, Mehmet Guran, Tulay Elcioglu, Nursel Yildirim, Mahmut Selman Aktas, Dilek Alikasifoglu, Mehmet Ture, Mehmet Yakut, Tahsin Overton, John D. Yuksel, Adnan Ozen, Mustafa Muzny, Donna M. Adams, David R. Boerwinkle, Eric Chung, Wendy K. Gibbs, Richard A. Lupski, James R. TI Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease SO NEURON LA English DT Article ID INTELLECTUAL-DISABILITY SYNDROME; CHROMATIN REMODELING COMPLEX; TRIPLE T COMPLEX; RNA HELICASES; PONTOCEREBELLAR HYPOPLASIA; ALZHEIMERS-DISEASE; SNX14 CAUSE; H-PRUNE; PROTEIN; MUTATIONS AB Development of the human nervous system involves complex interactions among fundamental cellular processes and requires a multitude of genes, many of which remain to be associated with human disease. We applied whole exome sequencing to 128 mostly consanguineous families with neurogenetic disorders that often included brain malformations. Rare variant analyses for both single nucleotide variant (SNV) and copy number variant (CNV) alleles allowed for identification of 45 novel variants in 43 known disease genes, 41 candidate genes, and CNVs in 10 families, with an overall potential molecular cause identified in >85% of families studied. Among the candidate genes identified, we found PRUNE, VARS, and DHX37 in multiple families and homozygous loss-of-function variants in AGBL2, SLC18A2, SMARCA1, UBQLN1, and CPLX1. Neuroimaging and in silico analysis of functional and expression proximity between candidate and known disease genes allowed for further understanding of genetic networks underlying specific types of brain malformations. C1 [Karaca, Ender; Harel, Tamar; Pehlivan, Davut; Jhangiani, Shalini N.; Gambin, Tomasz; Akdemir, Zeynep Coban; Bayram, Yavuz; Campbell, Ian M.; Atik, Mehmed M.; Yuan, Bo; Wiszniewski, Wojciech; Muzny, Donna M.; Gibbs, Richard A.; Lupski, James R.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Jhangiani, Shalini N.; Muzny, Donna M.; Boerwinkle, Eric; Gibbs, Richard A.; Lupski, James R.] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Gonzaga-Jauregui, Claudia; Overton, John D.] Regeneron Pharmaceut Inc, Regeneron Genet Ctr, Tarrytown, NY 10591 USA. [Erdin, Serkan] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Erdin, Serkan] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Hunter, Jill V.] Texas Childrens Hosp, Dept Pediat Radiol, Houston, TX 77030 USA. [Van Esch, Hilde] Univ Hosp Leuven, Ctr Human Genet, B-3000 Louvain, Belgium. [Isikay, Sedat] Gaziantep Childrens Hosp, Dept Child Neurol, TR-27560 Gaziantep, Turkey. [Yesil, Gozde] Bezmialem Univ, Dept Med Genet, TR-34093 Istanbul, Turkey. [Yuregir, Ozge O.] Ankara Numune Training & Res Hosp, Dept Med Genet, TR-01240 Adana, Turkey. [Bozdogan, Sevcan Tug] Mersin Univ, Dept Med Genet, TR-33343 Mersin, Turkey. [Aslan, Huseyin] Eskisehir Osmangazi Univ, Fac Med, Dept Med Genet, TR-26480 Eskisehir, Turkey. [Aydin, Hatip] Namik Kemal Univ, Fac Med, Dept Med Genet, TR-59100 Tekirdag, Turkey. [Tos, Tulay] Sami Ulus Childrens Hosp, Dept Med Genet, TR-06080 Ankara, Turkey. [Aksoy, Ayse] Sami Ulus Childrens Hosp, Dept Pediat Neurol, TR-06080 Ankara, Turkey. [De Vivo, Darryl C.] Columbia Univ, Med Ctr, Dept Neurol, New York, NY 10032 USA. [Jain, Preti] Columbia Univ, Med Ctr, Dept Pathol & Cell Biol, New York, NY 10032 USA. [Geckinli, B. Bilge] Marmara Univ, Sch Med, Dept Med Genet, TR-34722 Istanbul, Turkey. [Sezer, Ozlem] Samsun Educ & Res Hosp, Dept Med Genet, TR-55100 Samsun, Turkey. [Gul, Davut] Gulhane Mil Med Acad, Dept Med Genet, TR-06010 Ankara, Turkey. [Durmaz, Burak; Cogulu, Ozgur; Ozkinay, Ferda] Ege Univ, Fac Med, Dept Med Genet, TR-35040 Izmir, Turkey. [Topcu, Vehap] Zekai Tahir Burak Womens Hlth Training & Res Hosp, Dept Med Genet, TR-06230 Ankara, Turkey. [Candan, Sukru] Balikesir Ataturk Publ Hosp, Med Genet Sect, TR-10100 Balikesir, Turkey. [Cebi, Alper Han; Ikbal, Mevlit] Karadeniz Tech Univ, Dept Med Genet, TR-61310 Trabzon, Turkey. [Gulec, Elif Yilmaz; Gezdirici, Alper; Koparir, Erkan; Ekici, Fatma] Kanuni Sultan Suleyman Training & Res Hosp, Med Genet Sect, TR-34303 Istanbul, Turkey. [Coskun, Salih] Dicle Univ, Fac Med, Dept Med Genet, TR-21280 Diyarbakir, Turkey. [Cicek, Salih] Konya Numune Training & Res Hosp, Med Genet Sect, TR-42250 Konya, Turkey. [Karaer, Kadri] Intergen Genet Ctr, TR-06700 Ankara, Turkey. [Koparir, Asuman; Duz, Mehmet Bugrahan; Kirat, Emre; Fenercioglu, Elif; Ulucan, Hakan; Seven, Mehmet] Istanbul Univ, Cerrahpasa Med Sch, Dept Med Genet, TR-34098 Istanbul, Turkey. [Guran, Tulay] Marmara Univ Hosp, Dept Pediat Endocrinol & Diabet, TR-34899 Istanbul, Turkey. [Elcioglu, Nursel] Marmara Univ, Fac Med, Dept Pediat Genet, TR-34854 Istanbul, Turkey. [Yildirim, Mahmut Selman] Meram Med Fac, Necmettin Erbakan Univ, Dept Genet, TR-42060 Konya, Turkey. [Aktas, Dilek; Alikasifoglu, Mehmet] Hacettepe Univ, Sch Med, Damagen Genet Diagnost Ctr, TR-06230 Ankara, Turkey. [Aktas, Dilek; Alikasifoglu, Mehmet] Hacettepe Univ, Sch Med, Dept Med Genet, TR-06230 Ankara, Turkey. [Ture, Mehmet; Yakut, Tahsin] Uludag Univ, Fac Med, Dept Med Genet, TR-16120 Bursa, Turkey. [Yuksel, Adnan; Ozen, Mustafa] Biruni Univ, TR-34010 Istanbul, Turkey. [Adams, David R.] NIH, Off Director, Common Fund, Undiagnosed Dis Program, Bethesda, MD 20892 USA. [Boerwinkle, Eric] Univ Texas Houston, Hlth Sci Ctr, Ctr Human Genet, Houston, TX 77030 USA. [Chung, Wendy K.] Columbia Univ, Med Ctr, Dept Pediat & Med, New York, NY 10032 USA. [Lupski, James R.] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Lupski, James R.] Texas Childrens Hosp, Houston, TX 77030 USA. RP Lupski, JR (reprint author), Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. EM jlupski@bcm.edu RI Erdin, Serkan/B-4988-2008; ikbal, mevlit/D-5880-2015; Bayram, Cem/D-7403-2013; AYDIN, Hatip/A-2711-2017; Topcu, Vehap/E-5545-2015; Topcu, Vehap/E-5545-2015; OI Erdin, Serkan/0000-0001-6587-2625; Bayram, Cem/0000-0001-8717-4668; Topcu, Vehap/0000-0001-6881-3284; Topcu, Vehap/0000-0001-7224-5697; Gonzaga-Jauregui, Claudia/0000-0002-4667-3679 FU U.S. National Human Genome Research Institute (NHGRI) NHLBI grant [U54HG006542]; NINDS [RO1 NS058529, K23NS078056]; NHGRI [5U54HG003273]; Medical Genetics Research Fellowship Program [T32 GM07526]; Regeneron FX We thank all the family members and collaborators who participated in this study. This work was supported by U.S. National Human Genome Research Institute (NHGRI) NHLBI grant U54HG006542 to the Baylor-Hopkins Center for Mendelian Genomics, NINDS grant RO1 NS058529 to J. R. L., and NHGRI 5U54HG003273 to R. A. G. T. H. is supported by the Medical Genetics Research Fellowship Program (T32 GM07526). W. W. is supported by Career Development Award K23NS078056 from NINDS. The authors would like to thank the ExAC and the groups that provided exome variant data for comparison. A full list of contributing groups can be found at http://exac.broadinstitute.org/about. J.R.L. has stock ownership in 23andMe and Lasergen and is a paid consultant for Regeneron. J. R. L. is also a coinventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from the chromosomal microarray analysis and clinical exome sequencing offered in the Medical Genetics Laboratory (https://www.bcm.edu/geneticlabs/). W. K. C. is a paid consultant for Regeneron and BioReference Laboratories. C.G.-J. and J. D. O. are employees of the RGC. NR 60 TC 17 Z9 17 U1 3 U2 19 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 NOV 4 PY 2015 VL 88 IS 3 BP 499 EP 513 DI 10.1016/j.neuron.2015.09.048 PG 15 WC Neurosciences SC Neurosciences & Neurology GA CX5TM UT WOS:000365765400011 PM 26539891 ER PT J AU Beydoun, MA Fanelli-Kuczmarski, MT Allen, A Beydoun, HA Popkin, BM Evans, MK Zonderman, AB AF Beydoun, May A. Fanelli-Kuczmarski, Marie T. Allen, Allyssa Beydoun, Hind A. Popkin, Barry M. Evans, Michele K. Zonderman, Alan B. TI Monetary Value of Diet Is Associated with Dietary Quality and Nutrient Adequacy among Urban Adults, Differentially by Sex, Race and Poverty Status SO PLOS ONE LA English DT Article ID ENERGY-DENSE DIETS; SOCIOECONOMIC-STATUS; UNITED-STATES; FRENCH ADULTS; NUTRITIONAL QUALITY; FOOD EXPENDITURE; COST CONSTRAINT; HEALTHY DIET; US ADULTS; WOMEN AB Objective The association between monetary value of the diet (MVD, $/day) with dietary quality was examined using a large sample of urban US adults, differentially by socio-demographic factors. Methods This was a cross-sectional study of 2,111 participants, aged 30-64y, using data from the Healthy Aging in Neighborhoods of Diversity across the Life Span Study. Dietary quality indices included Healthy Eating Index-2010 (HEI-2010) and Mean Adequacy Ratio (MAR), (two 24-hr recalls). A national food price database was used to estimate MVD. Multiple linear/logistic regression analyses were conducted stratifying separately by sex, race and poverty status. Results Women had significantly higher HEI-2010 scores than men (43.35 vs 41.57 out of 100, respectively), whereas MAR scores were higher for men (76.8 vs 69.9, out of 100), reflecting energy intake gender differentials. Importantly, a $3/day higher MVD (IQR: $3.70/d (Q1) to $6.62/d (Q4)) was associated with a 4.98 +/- 0.35 higher total HEI-2010 and a 3.88 +/- 0.37 higher MAR score, after energy-adjustment and control for key confounders. For HEI-2010 and MAR, stronger associations were observed among participants above poverty and among women, whilethe MVD vs. HEI-2010 association was additionally stronger among Whites. Sex and poverty status differentials were observed for many MAR and some HEI2010 components. Conclusions Despite positive associations between measures of dietary quality and MVD, particularly above poverty and among women, approaching compliance with the Dietary Guidelines (80 or more for HEI-2010) requires a substantially higher MVD. Thus, nutrition education may further improve people's decision-making regarding food venues and dietary choices. C1 [Beydoun, May A.; Evans, Michele K.; Zonderman, Alan B.] NIA, Lab Epidemiol & Populat Sci, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Fanelli-Kuczmarski, Marie T.] Univ Delaware, Dept Behav Hlth & Nutr, Newark, DE USA. [Allen, Allyssa] Univ Maryland Baltimore Cty, Baltimore, MD 21228 USA. [Beydoun, Hind A.] Eastern Virginia Med Sch, Grad Program Publ Hlth, Norfolk, VA 23501 USA. [Popkin, Barry M.] Univ N Carolina, Dept Nutr, Chapel Hill, NC USA. [Popkin, Barry M.] Univ N Carolina, Carolina Populat Ctr, Chapel Hill, NC USA. RP Beydoun, MA (reprint author), NIA, Lab Epidemiol & Populat Sci, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM baydounm@mail.nih.gov OI Zonderman, Alan B/0000-0002-6523-4778 FU National Institute on Aging, NIA/NIH/IRP FX Funding: This work was fully supported by the Intramural Research Program of the National Institute on Aging, NIA/NIH/IRP. NR 73 TC 1 Z9 1 U1 2 U2 11 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 NOV 4 PY 2015 VL 10 IS 11 AR e0140905 DI 10.1371/journal.pone.0140905 PG 21 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CV5GZ UT WOS:000364298400044 PM 26536243 ER PT J AU McClurkin, MA Yingling, LR Ayers, C Cooper-McCann, R Suresh, V Nothwehr, A Barrington, DS Powell-Wiley, TM AF McClurkin, Michael A. Yingling, Leah Rae Ayers, Colby Cooper-McCann, Rebecca Suresh, Visakha Nothwehr, Ann Barrington, Debbie S. Powell-Wiley, Tiffany M. TI Health Insurance Status as a Barrier to Ideal Cardiovascular Health for US Adults: Data from the National Health and Nutrition Examination Survey (NHANES) SO PLOS ONE LA English DT Article ID AMERICAN-HEART-ASSOCIATION; UNITED-STATES; SCIENTIFIC STATEMENT; PHYSICAL-ACTIVITY; RISK-FACTORS; MORTALITY; COVERAGE; DISEASE; CARE; HYPERTENSION AB Background Little is known about the association between cardiovascular (CV) health and health insurance status. We hypothesized that U.S. adults without health insurance coverage would have a lower likelihood of ideal cardiovascular health. Methods and Results Using National Health and Nutrition Examination Survey (NHANES) data from 2007-2010, we examined the relationship between health insurance status and ideal CV health in U.S. adults aged >= 19 years and <65 (N = 3304). Ideal CV health was defined by the American Heart Association (AHA) as the absence of clinically manifested CV disease and the simultaneous presence of 6-7 "ideal" CV health factors and behaviors. Logistic regression modeling was used to determine the relationship between health insurance status and the odds of ideal CV health. Of the U.S. adult population, 5.4% attained ideal CV health, and 23.5% were without health insurance coverage. Those without health insurance coverage were more likely to be young (p<0.0001), male (p<0.0001), non-white (p<0.0001), with less than a high school degree (p<0.0001), have a poverty-to-income ratio less than 1 (p<0.0001) and unemployed (p<0.0001) compared to those with coverage. Lack of health insurance coverage was associated with a lower likelihood of ideal CV health; however, this relationship was attenuated by socioeconomic status. Conclusions U.S. adults without health insurance coverage are less likely to have ideal CV health. Population-based strategies and interventions directed at the community-level may be one way to improve overall CV health and reach this at-risk group. C1 [McClurkin, Michael A.; Yingling, Leah Rae; Cooper-McCann, Rebecca; Suresh, Visakha; Powell-Wiley, Tiffany M.] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. [Ayers, Colby] Univ Texas SW Med Ctr Dallas, Donald W Reynolds Cardiovasc Clin Res Ctr, Dallas, TX 75390 USA. [Nothwehr, Ann] Univ Maryland, College Pk, MD 20742 USA. [Barrington, Debbie S.] Natl Inst Minor Hlth & Hlth Dispar, Div Intramural Res, NIH, Bethesda, MD USA. RP Powell-Wiley, TM (reprint author), NHLBI, Cardiovasc & Pulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM tiffany.powell-wiley@nih.gov OI Suresh, Visakha/0000-0002-0950-2272; Yingling, Leah/0000-0002-7851-690X FU Division of Intramural Research of NHLBI at NIH [HHSN268201300173P]; National Institutes of Health (NIH) Medical Research Scholars Program; NIH; NIH from Pfizer Inc; Doris Duke Charitable Foundation; Alexandria Real Estate Equities, Inc.; Howard Hughes Medical Institute FX Funding for Colby Ayers is provided through a professional services contract (contract #HHSN268201300173P) through the Division of Intramural Research of NHLBI at NIH. Funding for Rebecca Cooper-McCann is provided through the National Institutes of Health (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., Mr. and Mrs. Joel S. Marcus, and the Howard Hughes Medical Institute, as well as other private donors. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Regarding the private donors, none of the research costs or authors' salaries were funded, in whole or in part, by a tobacco company. The identity of the private donors is not considered relevant to editors or reviewers' assessment of the validity of the work. The authors are not aware of any competing interests. NR 56 TC 2 Z9 2 U1 1 U2 5 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 NOV 4 PY 2015 VL 10 IS 11 AR e0141534 DI 10.1371/journal.pone.0141534 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CV5GZ UT WOS:000364298400068 PM 26535890 ER PT J AU Karron, RA Luongo, C Thumar, B Loehr, KM Englund, JA Collins, PL Buchholz, UJ AF Karron, Ruth A. Luongo, Cindy Thumar, Bhagvanji Loehr, Karen M. Englund, Janet A. Collins, Peter L. Buchholz, Ursula J. TI A gene deletion that up-regulates viral gene expression yields an attenuated RSV vaccine with improved antibody responses in children SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID RESPIRATORY SYNCYTIAL VIRUS; YOUNG-CHILDREN; IMMUNE GLOBULIN; M2-2 PROTEIN; LIVE; INFANTS; INFECTION; TRANSCRIPTION; GLYCOPROTEIN; IMMUNIZATION AB Respiratory syncytial virus (RSV) is the leading viral cause of severe pediatric respiratory illness, and a safe and effective vaccine for use in infancy and early childhood is needed. We previously showed that deletion of the coding sequence for the viral M2-2 protein (Delta M2-2) down-regulated viral RNA replication and up-regulated gene transcription and antigen synthesis, raising the possibility of development of an attenuated vaccine with enhanced immunogenicity. RSV MEDI DM2-2 was therefore evaluated as a live intranasal vaccine in adults, RSV-seropositive children, and RSV-seronegative children. When results in RSV-seronegative children were compared to those achieved with the previous leading live attenuated RSV candidate vaccine, vaccine virus shedding was significantly more restricted, yet the post-vaccination RSV-neutralizing serum antibody achieved [geometric mean titer (GMT) = 1: 97] was significantly greater. Surveillance during the subsequent RSV season showed that several seronegative RSV MEDI DM2-2 recipients had substantial antibody rises without reported illness, suggesting that the vaccine was protective yet primed for anamnestic responses to RSV. Rational design appears to have yielded a candidate RSV vaccine that is intrinsically superior at eliciting protective antibody in RSV-naive children and highlights an approach for the development of live attenuated RSV vaccines. C1 [Karron, Ruth A.; Thumar, Bhagvanji; Loehr, Karen M.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Ctr Immunizat Res, Baltimore, MD 21205 USA. [Luongo, Cindy; Collins, Peter L.; Buchholz, Ursula J.] NIH, RNA Viruses Sect, Infect Dis Lab, Natl Inst Allergy Immunol & Infect Dis, Bethesda, MD 20892 USA. [Englund, Janet A.] Univ Washington, Seattle Childrens Res Inst, Seattle, WA 98101 USA. RP Karron, RA (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Ctr Immunizat Res, Baltimore, MD 21205 USA. EM rkarron@jhu.edu FU NIAID [HHS 272200900010C]; NIAID; NIH; MedImmune; [UL1TR000423] FX R.A.K., K.M.L., B.T., and J.A.E. were funded by NIAID contract HHS 272200900010C. C.L., P.L.C., and U.J.B. were funded by the Intramural Program of the NIAID. This work was also supported in part by a Cooperative Research and Development Agreement between NIAID, NIH, and MedImmune. Clinical research support was also provided to J.A.E. by UL1TR000423. NR 27 TC 22 Z9 22 U1 0 U2 3 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 NOV 4 PY 2015 VL 7 IS 312 AR 312ra175 DI 10.1126/scitranslmed.aac8463 PG 9 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA CW8GK UT WOS:000365237300005 PM 26537255 ER PT J AU Lipsky, LM Haynie, DL Liu, DP Chaurasia, A Gee, B Li, KG Iannotti, RJ Simons-Morton, B AF Lipsky, Leah M. Haynie, Denise L. Liu, Danping Chaurasia, Ashok Gee, Benjamin Li, Kaigang Iannotti, Ronald J. Simons-Morton, Bruce TI Trajectories of eating behaviors in a nationally representative cohort of US adolescents during the transition to young adulthood SO INTERNATIONAL JOURNAL OF BEHAVIORAL NUTRITION AND PHYSICAL ACTIVITY LA English DT Article DE Eating behaviors; Body mass index; Emerging adults; Prospective research ID SCHOOL-AGED CHILDREN; BODY-MASS INDEX; VEGETABLE INTAKE; HEALTH BEHAVIOR; NUTRIENT-INTAKE; ENERGY-INTAKE; FOOD-INTAKE; PHYSICAL-ACTIVITY; DIETARY QUALITY; WHITE GIRLS AB Background: Diets of U.S. adolescents and adults do not meet recommendations, increasing risk of chronic disease. This study examined trajectories and predictors of eating behaviors in U.S. youth from age 16-20 years, and evaluated longitudinal associations of eating behaviors with weight outcomes. Methods: Data come from the first four waves (years) of the NEXT Generation Health Study, a nationally representative cohort of U.S. students in 10th grade during the 2009-2010 school year (n = 2785). Annual surveys queried frequency of food group intake (times/day of fruit and vegetables, whole grains, sugar-sweetened soda, sweet and salty snacks), and meal practices (days/week of breakfast, family meals, fast food, and television during meals). Body mass index (BMI, kg/m(2)) was calculated from self-reported height and weight. Adjusted generalized estimating equations and linear mixed models with multiple imputation for missing data estimated eating behavior trajectories overall and by baseline weight status (normal weight = 5 <= BMI%ile < 85, overweight = 85 <= BMI%ile < 95, obese = BMI%ile >= 95), accounting for the complex sampling design. Separate GEE models estimated longitudinal associations of food group frequencies with meal practices and of BMI with eating behaviors. Results: Eating behaviors tracked strongly from wave 1-4 (residual intraclass correlation = 41 % - 51 %). Across all baseline weight categories, frequency of food group intake and meal practices decreased over time, except for fast food, which remained stable. Fruit/vegetable intake frequency was associated positively with family meals (beta +/- SE = 0.33 +/- 0.05) and breakfast (0.18 +/- 0.03), and inversely with fast food (-0.31 +/- 0.04), while whole grain intake frequency was associated positively with family meals (0.07 +/- 0.02), television meals (0.02 +/- 0.009) and breakfast (0.04 +/- 0.01). Soda and snacks were positively associated with television meals (0.08 +/- 0.008 and 0.07 +/- 0.009, respectively) and fast food (0.24 +/- 0.02 and 0.20 +/- 0.03, respectively), while soda was inversely associated with breakfast frequency (-0.05 +/- 0.01). Time-varying BMI was unrelated to eating behaviors other than an inverse association with time-varying snacks (-0.33 +/- 0.12). Conclusions: Strong tracking over time supports the importance of early establishment of health-promoting eating behaviors in U.S. adolescents. Findings suggest meal practices may be important intervention targets. Lack of evidence for hypothesized associations of BMI and eating behaviors indicates the need for research confirming these findings using more precise measures of dietary intake. C1 [Lipsky, Leah M.; Haynie, Denise L.; Liu, Danping; Chaurasia, Ashok; Gee, Benjamin; Simons-Morton, Bruce] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, North Bethesda, MD 20852 USA. [Li, Kaigang] Colorado State Univ, Dept Hlth & Exercise Sci, Ft Collins, CO 80523 USA. [Iannotti, Ronald J.] CDM Grp, North Bethesda, MD 20814 USA. RP Lipsky, LM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, 6100 Execut Blvd, North Bethesda, MD 20852 USA. EM leah.lipsky@nih.gov RI Dey, Kamalesh/E-6568-2017; OI Simons-Morton, Bruce/0000-0003-1099-6617; Haynie, Denise/0000-0002-8270-6079; Lipsky, Leah/0000-0003-2645-4388 FU intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [HHSN267200800009C]; National Heart, Lung and Blood Institute (NHLBI); National Institute on Alcohol Abuse and Alcoholism (NIAAA); Maternal and Child Health Bureau (MCHB) of the Health Resources and Services Administration (HRSA) FX This research (contract number HHSN267200800009C) was supported in part by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Heart, Lung and Blood Institute (NHLBI), the National Institute on Alcohol Abuse and Alcoholism (NIAAA), and Maternal and Child Health Bureau (MCHB) of the Health Resources and Services Administration (HRSA), with supplemental support from the National Institute on Drug Abuse (NIDA). Intramural researchers were responsible for the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. NR 50 TC 2 Z9 2 U1 4 U2 15 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5868 J9 INT J BEHAV NUTR PHY JI Int. J. Behav. Nutr. Phys. Act. PD NOV 4 PY 2015 VL 12 AR 138 DI 10.1186/s12966-015-0298-x PG 11 WC Nutrition & Dietetics; Physiology SC Nutrition & Dietetics; Physiology GA CV1KP UT WOS:000364015600001 PM 26537771 ER PT J AU Takeuchi, JS Ren, F Yoshikawa, R Yamada, E Nakano, Y Kobayashi, T Matsuda, K Izumi, T Misawa, N Shintaku, Y Wetzel, KS Collman, RG Tanaka, H Hirsch, VM Koyanagi, Y Sato, K AF Takeuchi, Junko S. Ren, Fengrong Yoshikawa, Rokusuke Yamada, Eri Nakano, Yusuke Kobayashi, Tomoko Matsuda, Kenta Izumi, Taisuke Misawa, Naoko Shintaku, Yuta Wetzel, Katherine S. Collman, Ronald G. Tanaka, Hiroshi Hirsch, Vanessa M. Koyanagi, Yoshio Sato, Kei TI Coevolutionary dynamics between tribe Cercopithecini tetherins and their lentiviruses SO SCIENTIFIC REPORTS LA English DT Article ID SIMIAN-IMMUNODEFICIENCY-VIRUS; PRIMATE LENTIVIRUSES; RESTRICTION FACTORS; MAXIMUM-LIKELIHOOD; RETROVIRUS RELEASE; NONPANDEMIC HIV-1; CELL-SURFACE; VPU PROTEIN; EVOLUTION; CHIMPANZEES AB Human immunodeficiency virus, a primate lentivirus (PLV), causes AIDS in humans, whereas most PLVs are less or not pathogenic in monkeys. These notions suggest that the co-evolutionary process of PLVs and their hosts associates with viral pathogenicity, and therefore, that elucidating the history of virus-host co-evolution is one of the most intriguing topics in the field of virology. To address this, recent studies have focused on the interplay between intrinsic anti-viral proteins, such as tetherin, and viral antagonists. Through an experimental-phylogenetic approach, here we investigate the co-evolutionary interplay between tribe Cercopithecini tetherin and viral antagonists, Nef and Vpu. We reveal that tribe Cercopithecini tetherins are positively selected, possibly triggered by ancient Nef-like factor(s). We reconstruct the ancestral sequence of tribe Cercopithecini tetherin and demonstrate that all Nef proteins are capable of antagonizing ancestral Cercopithecini tetherin. Further, we consider the significance of evolutionary arms race between tribe Cercopithecini and their PLVs. C1 [Takeuchi, Junko S.; Yoshikawa, Rokusuke; Yamada, Eri; Nakano, Yusuke; Kobayashi, Tomoko; Misawa, Naoko; Koyanagi, Yoshio; Sato, Kei] Kyoto Univ, Inst Virus Res, Lab Viral Pathogenesis, Kyoto 6068507, Japan. [Ren, Fengrong; Tanaka, Hiroshi] Tokyo Med & Dent Univ, Med Res Inst, Dept Bioinformat, Tokyo 1138510, Japan. [Nakano, Yusuke] Kumamoto Univ, Fac Life Sci, Dept Med Virol, Kumamoto 8608556, Japan. [Matsuda, Kenta; Hirsch, Vanessa M.] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Izumi, Taisuke] Univ Tokushima, Inst Hlth Biosci, Dept Microbiol, Tokushima 7708503, Japan. [Shintaku, Yuta] Kyoto Univ, Wildlife Res Ctr, Kyoto 6068203, Japan. [Shintaku, Yuta] Japan Monkey Ctr, Aichi 4840081, Japan. [Wetzel, Katherine S.; Collman, Ronald G.] Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Sato, Kei] Japan Sci & Technol Agcy, CREST, Saitama 3220012, Japan. RP Sato, K (reprint author), Kyoto Univ, Inst Virus Res, Lab Viral Pathogenesis, Kyoto 6068507, Japan. EM ksato@virus.kyoto-u.ac.jp FU Aihara Innovative Mathematical Modeling Project; Japan Society for the Promotion of Science (JSPS); Council for Science and Technology Policy of Japan; CREST, Japan Science and Technology Agency; Health Labour Sciences Research Grant from the Ministry of Health, Labor and Welfare of Japan (MHLW) [26361601]; Takeda Science Foundation; Sumitomo Foundation Research Grant; Senshin Medical Research Foundation; Imai Memorial Trust for AIDS Research; Ichiro Kanehara Foundation; Kanae Foundation for the Promotion of Medical Science; Suzuken Memorial Foundation; Uehara Memorial Foundation; intramural research program of NIAID, NIH; NIH [R56-AI091516, R01-MH061139]; JSPS Research Fellowship [PD 15J06242]; JSPS [C15K07166, B24390112, S22220007]; Ministry of Education, Culture, Sports, Science and Technology of Japan [24115008]; Japan Agency for Medical Research and Development (AMED) [15Afk0410013h0001]; AMED; JSPS Core-to-Core Program; A. Advanced Research Networks FX We would like to thank Dr. Tomoyuki Miura (Institute for Virus Research, Kyoto University, Japan), Dr. Akio Adachi (Institute of Health Biosciences, The University of Tokushima), and Dr. Frank Kirchhoff (University of Ulm, Germany) for providing pSA212 and pCGCG vector, respectively, Dr. Sarah Elliott (University of Pennsylvania) for technical advice, Dr. Akira Kato (Japan Monkey Centre) for sampling and providing the body hair of Sykes' monkeys, and Dr. So Nakagawa (Tokai University) for helpful suggestion for the analyses on the molecular phylogenetic and evolution. This study was supported inpart by the following grants: the Aihara Innovative Mathematical Modeling Project, the Japan Society for the Promotion of Science (JSPS) through the "Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program)," initiated by the Council for Science and Technology Policy of Japan (to K.S.); CREST, Japan Science and Technology Agency (to K.S.); Health Labour Sciences Research Grant 26361601 from the Ministry of Health, Labor and Welfare of Japan (MHLW) (to K.S.); Takeda Science Foundation (to K.S.); Sumitomo Foundation Research Grant (to K.S.); Senshin Medical Research Foundation (to K.S.); Imai Memorial Trust for AIDS Research (to K.S.); Ichiro Kanehara Foundation (to K.S.); Kanae Foundation for the Promotion of Medical Science (to K.S.); Suzuken Memorial Foundation (to K.S.); Uehara Memorial Foundation (to K.S.); the intramural research program of NIAID, NIH (to K.M. and V.M.H.); NIH grants R56-AI091516 (to R.G.C.) and R01-MH061139 (to R.G.C.); JSPS Research Fellowship PD 15J06242 (to R.Y.); Grants-in-Aid for Research Activity Start-up (to T.I.) and Scientific Research C15K07166 (to K.S.), B24390112 (to Y.K.) and S22220007 (to Y.K.) from JSPS; a Grant-in-Aid for Scientific Research on Innovative Areas 24115008 (to Y.K.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan; Research on HIV/AIDS from Japan Agency for Medical Research and Development (AMED) 15Afk0410013h0001 (to Y.K.); the Platform Project for Supporting in Drug Discovery and Life Science Research (Platform for Dynamic Approaches to Living System) from AMED (to E.Y.); and JSPS Core-to-Core Program, A. Advanced Research Networks (to K.M., V.M.H. and Y.K.). NR 60 TC 3 Z9 3 U1 1 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 NOV 4 PY 2015 VL 5 AR 16021 DI 10.1038/srep16021 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CV1RY UT WOS:000364037000001 PM 26531727 ER PT J AU Bogen, D Wei, JS Azorsa, DO Ormanoglu, P Buehler, E Guha, R Keller, JM Griner, LAM Ferrer, M Song, YK Liao, HL Mendoza, A Gryder, BE Sindri, S He, JB Wen, XY Zhang, SL Shern, JF Yohe, ME Taschner-Mandl, S Shohet, JM Thomas, CJ Martin, SE Ambros, PF Khan, J AF Bogen, Dominik Wei, Jun S. Azorsa, David O. Ormanoglu, Pinar Buehler, Eugen Guha, Rajarshi Keller, Jonathan M. Griner, Lesley A. Mathews Ferrer, Marc Song, Young K. Liao, Hongling Mendoza, Arnulfo Gryder, Berkley E. Sindri, Sivasish He, Jianbin Wen, Xinyu Zhang, Shile Shern, John F. Yohe, Marielle E. Taschner-Mandl, Sabine Shohet, Jason M. Thomas, Craig J. Martin, Scott E. Ambros, Peter F. Khan, Javed TI Aurora B kinase is a potent and selective target in MYCN-driven neuroblastoma SO ONCOTARGET LA English DT Article DE neuroblastoma; MYCN; AURKB; high-throughput screening; barasertib ID PRECLINICAL TESTING PROGRAM; ACUTE MYELOID-LEUKEMIA; DIRECT TRANSCRIPTIONAL TARGET; SCALE RNAI SCREENS; CELLS IN-VITRO; BARASERTIB AZD1152; INHIBITOR AZD1152; PHASE-I; N-MYC; CHECKPOINT FUNCTION AB Despite advances in multimodal treatment, neuroblastoma (NB) is often fatal for children with high-risk disease and many survivors need to cope with long-term side effects from high-dose chemotherapy and radiation. To identify new therapeutic targets, we performed an siRNA screen of the druggable genome combined with a small molecule screen of 465 compounds targeting 39 different mechanisms of actions in four NB cell lines. We identified 58 genes as targets, including AURKB, in at least one cell line. In the drug screen, aurora kinase inhibitors (nine molecules) and in particular the AURKB-selective compound, barasertib, were the most discriminatory with regard to sensitivity for MYCN-amplified cell lines. In an expanded panel of ten NB cell lines, those with MYCN-amplification and wild-type TP53 were the most sensitive to low nanomolar concentrations of barasertib. Inhibition of the AURKB kinase activity resulted in decreased phosphorylation of the known target, histone H3, and upregulation of TP53 in MYCN-amplified, TP53 wild-type cells. However, both wild-type and TP53 mutant MYCN-amplified cell lines arrested in G2/M phase upon AURKB inhibition. Additionally, barasertib induced endoreduplication and apoptosis. Treatment of MYCN-amplified/TP53 wild-type neuroblastoma xenografts resulted in profound growth inhibition and tumor regression. Therefore, aurora B kinase inhibition is highly effective in aggressive neuroblastoma and warrants further investigation in clinical trials. C1 [Bogen, Dominik; Wei, Jun S.; Song, Young K.; Liao, Hongling; Gryder, Berkley E.; Sindri, Sivasish; He, Jianbin; Wen, Xinyu; Zhang, Shile; Shern, John F.; Yohe, Marielle E.; Khan, Javed] NCI, Oncogen Sect, Genet Branch, NIH, Bethesda, MD 20892 USA. [Bogen, Dominik; Taschner-Mandl, Sabine; Ambros, Peter F.] St Anna Kinderkrebsforsch, Childrens Canc Res Inst, Vienna, Austria. [Ormanoglu, Pinar; Buehler, Eugen; Guha, Rajarshi; Keller, Jonathan M.; Griner, Lesley A. Mathews; Ferrer, Marc; Thomas, Craig J.; Martin, Scott E.] Natl Ctr Adv Translat Sci, Div Preclin Innovat, NIH, Rockville, MD USA. [Azorsa, David O.] Translat Genom Res Inst TGen, Clin Translat Res Div, Scottsdale, AZ USA. [Mendoza, Arnulfo] NCI, Tumor & Metastasis Biol Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Shohet, Jason M.] Texas Childrens Canc Ctr, Houston, TX USA. [Shohet, Jason M.] Baylor Coll Med, Dept Pediat, Ctr Cell & Gene Therapy, Houston, TX 77030 USA. RP Khan, J (reprint author), NCI, Oncogen Sect, Genet Branch, NIH, Bethesda, MD 20892 USA. EM khanjav@mail.nih.gov OI Ambros, Peter F./0000-0002-5507-7211 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This study was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mentioning of trade names, commercial products, or organizations imply endorsement by the U.S. government. NR 61 TC 6 Z9 6 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 NOV 3 PY 2015 VL 6 IS 34 BP 35247 EP 35262 DI 10.18632/oncotarget.6208 PG 16 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CY0QZ UT WOS:000366111900021 PM 26497213 ER PT J AU Yao, PL Chen, LP Dobrzanski, TP Phillips, DA Zhu, BK Kang, BH Gonzalez, FJ Peters, JM AF Yao, Pei-Li Chen, Li Ping Dobrzanski, Tomasz P. Phillips, Dylan A. Zhu, Bokai Kang, Boo-Hyon Gonzalez, Frank J. Peters, Jeffrey M. TI Inhibition of testicular embryonal carcinoma cell tumorigenicity by peroxisome proliferator-activated receptor-beta/delta- and retinoic acid receptor-dependent mechanisms SO ONCOTARGET LA English DT Article DE peroxisome proliferator-activated receptor-beta/delta; testicular embryonal carcinoma; retinoic acid receptor; matrix metalloproteinase-2; tumorigenicity ID DELTA PPAR-DELTA; MATRIX METALLOPROTEINASES; CANCER; EXPRESSION; DIFFERENTIATION; INVASION; TUMORS; MMP-2; LINE; MIGRATION AB Peroxisome proliferator-activated receptor-beta/delta (PPAR beta/delta) has important physiological functions in control of cell growth, lipid and glucose homeostasis, differentiation and inflammation. To investigate the role of PPAR beta/delta in cancer, stable human testicular embryonal carcinoma cell lines were developed that constitutively express PPAR beta/delta. Expression of PPAR beta/delta caused enhanced activation of the receptor, and this significantly decreased proliferation, migration, invasion, anchorage-independent growth, and also reduced tumor mass and volume of ectopic xenografts derived from NT2/D1 cells compared to controls. The changes observed in xenografts were associated with decreased PPAR beta/delta-dependent expression of proliferating cell nuclear antigen and octamer-binding transcription factor-3/4, suggesting suppressed tumor proliferation and induction of differentiation. Inhibition of migration and invasion was mediated by PPAR beta/delta competing with formation of the retinoic acid receptor (RAR)/retinoid X receptor (RXR) complex, resulting in attenuation of RAR alpha-dependent matrix metalloproteinase-2 expression and activity. These results demonstrate that PPAR beta/delta mediates attenuation of human testicular embryonal carcinoma cell progression through a novel RAR-dependent mechanism and suggest that activation of PPAR beta/delta inhibits RAR/RXR dimerization and represents a new therapeutic strategy. C1 [Yao, Pei-Li; Chen, Li Ping; Dobrzanski, Tomasz P.; Phillips, Dylan A.; Zhu, Bokai; Peters, Jeffrey M.] Penn State Univ, Dept Vet & Biomed Sci, Ctr Mol Toxicol & Carcinogenesis, University Pk, PA 16802 USA. [Kang, Boo-Hyon] Chemon Nonclin Res Inst, Yongin, Gyeonggi Do, South Korea. [Gonzalez, Frank J.] NCI, Lab Metab, Bethesda, MD 20892 USA. RP Peters, JM (reprint author), Penn State Univ, Dept Vet & Biomed Sci, Ctr Mol Toxicol & Carcinogenesis, University Pk, PA 16802 USA. EM pxy11@psu.edu; jmp21@psu.edu FU National Institutes of Health; National Cancer Institute [R01-CA124533, R01-CA141029, 1ZIABC005561, 1ZIABC005562, 1ZIABC005708] FX This study was supported by the National Institutes of Health and National Cancer Institute grants R01-CA124533 (J. M. Peters), R01-CA141029 (J. M. Peters), 1ZIABC005561 (F.J. Gonzalez), 1ZIABC005562 (F.J. Gonzalez), and 1ZIABC005708 (F.J. Gonzalez). NR 55 TC 1 Z9 1 U1 3 U2 7 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD NOV 3 PY 2015 VL 6 IS 34 BP 36319 EP 36337 DI 10.18632/oncotarget.5415 PG 19 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CY0QZ UT WOS:000366111900099 PM 26431381 ER PT J AU Cash, H Shah, S Moore, E Caruso, A Uppaluri, R Van Waes, C Allen, C AF Cash, Harrison Shah, Sujay Moore, Ellen Caruso, Andria Uppaluri, Ravindra Van Waes, Carter Allen, Clint TI mTOR and MEK1/2 inhibition differentially modulate tumor growth and the immune microenvironment in syngeneic models of oral cavity cancer SO ONCOTARGET LA English DT Article DE head and neck/oral cancers; signal transduction pathways; inflammation and tumor development; animal models of cancer; immunomodulation ID SQUAMOUS-CELL CARCINOMA; T-CELL; HEAD; NECK; SYSTEM; PI3K; PI3K/AKT/MTOR; LYMPHOCYTES; COMBINATION; ACTIVATION AB We investigated the effects of mTOR and MEK1/2 inhibition on tumor growth and the tumor microenvironment in immunogenic and poorly immunogenic models of murine oral cancer. In vitro, rapamycin and PD901 inhibited signaling through expected downstream targets, but only PD901 reduced viability and altered function of MOC cells. Following transplantation of MOC cells into immune-competent mice, effects on both cancer and infiltrating immune cells were characterized following rapamycin and/or PD901 treatment for 21 days. In vivo, both rapamycin and PD901 inhibition reduced primary growth of established MOC tumors on treatment. Following withdrawal of PD901, rapid rebound of tumor growth limited survival, whereas durable tumor control was observed following rapamycin treatment in immunogenic MOC1 tumors despite more robust inhibition of oncogenic signaling by PD901. Characterization of the immune microenvironment revealed diminished infiltration and activation of antigen-specific CD8+ T-cells and other immune cells following PD901 but not rapamycin in immunogenic tumors. Subsequent in vitro T-cell assays validated robust inhibition of T-cell expansion and activation following MEK inhibition compared to mTOR inhibition. CD8 cell depletion abrogated rapamycin-induced primary tumor growth inhibition in MOC1 mice. These data have critical implications in the design of combination targeted and immune therapies in oral cancer. C1 [Cash, Harrison; Shah, Sujay; Moore, Ellen; Van Waes, Carter; Allen, Clint] NIDCD, Tumor Biol Sect, Head & Neck Surg Branch, NIH, Bethesda, MD 20892 USA. [Caruso, Andria] Walter Reed Natl Mil Med Ctr, Dept Otolaryngol Head & Neck Surg, Bethesda, MD USA. [Uppaluri, Ravindra] Washington Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, St Louis, MO USA. [Allen, Clint] Johns Hopkins Sch Med, Dept Otolaryngol Head & Neck Surg, Baltimore, MD USA. RP Allen, C (reprint author), NIDCD, Tumor Biol Sect, Head & Neck Surg Branch, NIH, Bethesda, MD 20892 USA. EM clint.allen@nih.gov FU Howard Hughes Medical Institute; Intramural NIH HHS NR 37 TC 3 Z9 4 U1 0 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 NOV 3 PY 2015 VL 6 IS 34 BP 36400 EP 36417 DI 10.18632/oncotarget.5063 PG 18 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CY0QZ UT WOS:000366111900104 PM 26506415 ER PT J AU Low, D Subramaniam, R Lin, L Aomatsu, T Mizoguchi, A Ng, A DeGruttola, AK Lee, CG Elias, JA Andoh, A Mino-Kenudson, M Mizoguchi, E AF Low, Daren Subramaniam, Renuka Lin, Li Aomatsu, Tomoki Mizoguchi, Atsushi Ng, Aylwin DeGruttola, Arianna K. Lee, Chun Geun Elias, Jack A. Andoh, Akira Mino-Kenudson, Mari Mizoguchi, Emiko TI Chitinase 3-like 1 induces survival and proliferation of intestinal epithelial cells during chronic inflammation and colitis-associated cancer by regulating S100A9 SO ONCOTARGET LA English DT Article DE mammalian chitinase; colitis-associated cancer; bone marrow chimeras; RAGE; intestinal epithelial cells ID COLORECTAL-CANCER; TISSUE RESPONSES; PROTEINS; CALPROTECTIN; APOPTOSIS; EXPRESSION; MECHANISM; PATHWAY; INJURY; MICE AB Many host-factors are inducibly expressed during the development of inflammatory bowel disease (IBD), each having their unique properties, such as immune activation, bacterial clearance, and tissue repair/remodeling. Dysregulation/imbalance of these factors may have pathogenic effects that can contribute to colitis-associated cancer (CAC). Previous reports showed that IBD patients inducibly express colonic chitinase 3-like 1 (CHI3L1) that is further upregulated during CAC development. However, little is known about the direct pathogenic involvement of CHI3L1 in vivo. Here we demonstrate that CHI3L1 (aka Brp39) knockout (KO) mice treated with azoxymethane (AOM)/dextran sulphate sodium (DSS) developed severe colitis but lesser incidence of CAC as compared to that in wild-type (WT) mice. Highest CHI3L1 expression was found during the chronic phase of colitis, rather than the acute phase, and is essential to promote intestinal epithelial cell (IEC) proliferation in vivo. This CHI3L1-mediated cell proliferation/survival involves partial downregulation of the pro-apoptotic S100A9 protein that is highly expressed during the acute phase of colitis, by binding to the S100A9 receptor, RAGE (Receptor for Advanced Glycation End products). This interaction disrupts the S100A9-associated expression positive feedback loop during early immune activation, creating a CHI3L1(hi) S100A9(low) colonic environment, especially in the later phase of colitis, which promotes cell proliferation/survival of both normal IECs and tumor cells. C1 [Low, Daren; Subramaniam, Renuka; Ng, Aylwin; DeGruttola, Arianna K.; Mizoguchi, Emiko] Massachusetts Gen Hosp, Dept Med, Gastrointestinal Unit, Boston, MA 02114 USA. [Low, Daren; Subramaniam, Renuka; Ng, Aylwin; DeGruttola, Arianna K.; Mino-Kenudson, Mari; Mizoguchi, Emiko] Harvard Univ, Sch Med, Boston, MA USA. [Lin, Li] NIA, Lab Cardiovasc Sci, NIH, Baltimore, MD 21224 USA. [Aomatsu, Tomoki; Andoh, Akira] Shiga Univ Med Sci, Grad Sch, Div Mucosal Immunol, Otsu, Shiga 52021, Japan. [Mizoguchi, Atsushi] Kurume Univ, Sch Med, Dept Immunol, Kurume, Fukuoka 830, Japan. [Lee, Chun Geun; Elias, Jack A.] Brown Univ, Warren Alpert Sch Med, Dept Microbiol & Immunol, Providence, RI 02912 USA. [Mino-Kenudson, Mari] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Mino-Kenudson, Mari] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Mizoguchi, Emiko] Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA. RP Mizoguchi, E (reprint author), Massachusetts Gen Hosp, Dept Med, Gastrointestinal Unit, Boston, MA 02114 USA. EM emizoguchi@mgh.harvard.edu FU Intramural NIH HHS; NIAID NIH HHS [R01 AI081807, AI81807]; NIDDK NIH HHS [R01 DK091247, DK91247, R01 DK080070, R01-DK80070] NR 34 TC 7 Z9 8 U1 1 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 NOV 3 PY 2015 VL 6 IS 34 BP 36535 EP 36550 DI 10.18632/oncotarget.5440 PG 16 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CY0QZ UT WOS:000366111900113 PM 26431492 ER PT J AU Jian, XY Tang, WK Zhai, P Roy, NS Luo, RB Gruschus, JM Yohe, ME Chen, PW Li, YF Byrd, RA Xia, D Randazzo, PA AF Jian, Xiaoying Tang, Wai-Kwan Zhai, Peng Roy, Neeladri Sekhar Luo, Ruibai Gruschus, James M. Yohe, Marielle E. Chen, Pei-Wen Li, Yifei Byrd, R. Andrew Xia, Di Randazzo, Paul A. TI Molecular Basis for Cooperative Binding of Anionic Phospholipids to the PH Domain of the Arf GAP ASAP1 SO STRUCTURE LA English DT Article ID ADP-RIBOSYLATION FACTOR; PLECKSTRIN HOMOLOGY DOMAIN; GTPASE-ACTIVATING PROTEIN; GUANINE-NUCLEOTIDE EXCHANGE; STRUCTURAL BASIS; INOSITOL PHOSPHATES; AKT ACTIVATION; CELL-SURFACE; MEMBRANE; KINASE AB We have defined the molecular basis for association of the PH domain of the Arf GAP ASAP1 with phospholipid bilayers. Structures of the unliganded and dibutyryl PtdIns(4,5)P-2-bound PH domain were solved. PtdIns(4,5)P-2 made contact with both a canonical site (C site) and an atypical site (A site). We hypothesized cooperative binding of PtdIns(4,5)P-2 to the C site and a nonspecific anionic phospholipid to the A site. PtdIns(4,5)P-2 dependence of binding to large unilamellar vesicles and GAP activity was sigmoidal, consistent with cooperative sites. In contrast, PtdIns(4,5)P-2 binding to the PH domain of PLC delta 1 was hyperbolic. Mutation of amino acids in either the C or A site resulted in decreased PtdIns(4,5)P-2-dependent binding to vesicles and decreased GAP activity. The results support the idea of cooperative phospholipid binding to the C and A sites of the PH domain of ASAP1. We propose that the mechanism underlies rapid switching between active and inactive ASAP1. C1 [Jian, Xiaoying; Zhai, Peng; Roy, Neeladri Sekhar; Luo, Ruibai; Chen, Pei-Wen] NCI, Lab Cellular & Mol Biol, NIH, Bethesda, MD 20892 USA. [Tang, Wai-Kwan; Xia, Di] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Gruschus, James M.] NHLBI, Lab Struct Biophys, NIH, Bethesda, MD 20892 USA. [Yohe, Marielle E.] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. [Li, Yifei; Byrd, R. Andrew] NCI, Struct Biophys Lab, NIH, Bethesda, MD 20892 USA. [Randazzo, Paul A.] NCI, Lab Cellular & Mol Biol, NIH, Bethesda, MD 20892 USA. [Xia, Di] NCI, Cell Biol Lab, Bethesda, MD 20892 USA. RP Xia, D (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. EM dixia@helix.nih.gov; randazzp@mail.nih.gov OI Byrd, R. Andrew/0000-0003-3625-4232 FU NIH Intramural Program [BC 007365] FX We thank Mark Lemmon for advice, critical review of the manuscript, and providing the plasmid for expression of the isolated PH domain of PLC delta 1, Tamas Balla for a plasmid for bacterial expression of GST fused to the PH domain of PLC delta 1, and David Lambright for advice and review of the data. We thank Shangjin Sun for preliminary NMR experiments. The work was supported by the NIH Intramural Program (Project BC 007365). NR 60 TC 7 Z9 7 U1 2 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 EI 1878-4186 J9 STRUCTURE JI Structure PD NOV 3 PY 2015 VL 23 IS 11 BP 1977 EP 1988 DI 10.1016/j.str.2015.08.008 PG 12 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA CY1MF UT WOS:000366170300005 PM 26365802 ER PT J AU Hoffman, NJ Parker, BL Chaudhuri, R Fisher-Wellman, KH Kleinert, M Humphrey, SJ Yang, PY Holliday, M Trefely, S Fazakerley, DJ Stockli, J Burchfield, JG Jensen, TE Jothi, R Kiens, B Wojtaszewski, JFP Richter, EA James, DE AF Hoffman, Nolan J. Parker, Benjamin L. Chaudhuri, Rima Fisher-Wellman, Kelsey H. Kleinert, Maximilian Humphrey, Sean J. Yang, Pengyi Holliday, Mira Trefely, Sophie Fazakerley, Daniel J. Stoeckli, Jacqueline Burchfield, James G. Jensen, Thomas E. Jothi, Raja Kiens, Bente Wojtaszewski, Jorgen F. P. Richter, Erik A. James, David E. TI Global Phosphoproteomic Analysis of Human Skeletal Muscle Reveals a Network of Exercise-Regulated Kinases and AMPK Substrates SO CELL METABOLISM LA English DT Article ID ACTIVATED PROTEIN-KINASE; POSTTRANSLATIONAL MODIFICATIONS; PHOSPHORYLATION SITES; SIGNALING PATHWAYS; GLUCOSE-UPTAKE; METFORMIN; HEALTH; IDENTIFICATION; METABOLISM; MICE AB Exercise is essential in regulating energy metabolism and whole-body insulin sensitivity. To explore the exercise signaling network, we undertook a global analysis of protein phosphorylation in human skeletal muscle biopsies from untrained healthy males before and after a single high-intensity exercise bout, revealing 1,004 unique exercise-regulated phosphosites on 562 proteins. These included substrates of known exercise-regulated kinases (AMPK, PKA, CaMK, MAPK, mTOR), yet the majority of kinases and substrate phosphosites have not previously been implicated in exercise signaling. Given the importance of AMPK in exercise-regulated metabolism, we performed a targeted in vitro AMPK screen and employed machine learning to predict exercise-regulated AMPK substrates. We validated eight predicted AMPK substrates, including AKAP1, using targeted phosphoproteomics. Functional characterization revealed an undescribed role for AMPK-dependent phosphorylation of AKAP1 in mitochondrial respiration. These data expose the unexplored complexity of acute exercise signaling and provide insights into the role of AMPK in mitochondrial biochemistry. C1 [Hoffman, Nolan J.; Parker, Benjamin L.; Chaudhuri, Rima; Holliday, Mira; Fazakerley, Daniel J.; Stoeckli, Jacqueline; Burchfield, James G.; James, David E.] Univ Sydney, Sch Mol Biosci, Charles Perkins Ctr, Sydney, NSW 2006, Australia. [Fisher-Wellman, Kelsey H.; Kleinert, Maximilian; Humphrey, Sean J.; Yang, Pengyi; Trefely, Sophie] Garvan Inst Med Res, Darlinghurst, NSW 2010, Australia. [Kleinert, Maximilian; Jensen, Thomas E.; Kiens, Bente; Wojtaszewski, Jorgen F. P.; Richter, Erik A.] Univ Copenhagen, August Krogh Ctr, Dept Nutr Exercise & Sports, DK-2100 Copenhagen, Denmark. [Yang, Pengyi; Jothi, Raja] NIEHS, Epigenet & Stem Cell Biol Lab, Syst Biol Sect, NIH, Res Triangle Pk, NC 27709 USA. [James, David E.] Univ Sydney, Sch Med, Sydney, NSW 2006, Australia. RP James, DE (reprint author), Univ Sydney, Sch Mol Biosci, Charles Perkins Ctr, Sydney, NSW 2006, Australia. EM david.james@sydney.edu.au RI Yang, Pengyi/B-1002-2010; Stoeckli, Jacqueline/D-7053-2016; OI Yang, Pengyi/0000-0003-1098-3138; Stoeckli, Jacqueline/0000-0002-6446-7350; Kleinert, Maximilian/0000-0002-8069-9055; Humphrey, Sean/0000-0002-2666-9744; Hoffman, Nolan/0000-0001-5168-7082 FU National Health and Medical Research Council (NHMRC) [GNT1061122, GNT1047067]; Diabetes Australia Research Trust; Lundbeck Foundation; Novo Nordisk Foundation; University of Copenhagen Excellence Programme for Interdisciplinary Research; Council for Independent Research/Medicine; NHMRC; European Molecular Biology Organization Long-Term Fellowship; NIH, National Institute of Environmental Health Sciences FX We thank John D. Scott for providing AKAP1 cDNA; Bruce E. Kemp and Jonathan S. Oakhill for AMPK alpha 1, beta 1, and gamma 2 cDNA; Kei Sakamoto for A-769662; Merck for ACC1/2 antibodies; and Vladislav V. Verkhusha for pMito-LSSmO-range. We thank Dorte E. Kristensen, James R. Krycer, and Xiao-Yi Zeng for help with enrolling human subjects, Seahorse experimental design, and mouse exercise experiments, respectively. This work was supported by National Health and Medical Research Council (NHMRC) project grants GNT1061122 and GNT1047067 (D.E.J.) and grants from the Diabetes Australia Research Trust (D.E.J., N.J.H., R.C.), Lundbeck Foundation, Novo Nordisk Foundation, University of Copenhagen Excellence Programme for Interdisciplinary Research (2016), and Council for Independent Research/Medicine (E. A. R.). D.E.J. is an NHMRC Senior Principal Research Fellow. B.L.P is a recipient of an NHMRC Early Career Fellowship, and S.J.H. is a recipient of a European Molecular Biology Organization Long-Term Fellowship. P.Y. and R.J. are supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. The contents of the published material are solely the responsibility of the individual authors and the Administering Institution and do not reflect the views of the NHMRC. NR 49 TC 25 Z9 26 U1 7 U2 18 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 NOV 3 PY 2015 VL 22 IS 5 BP 922 EP 935 DI 10.1016/j.cmet.2015.09.001 PG 14 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA CW7QJ UT WOS:000365193900018 PM 26437602 ER PT J AU Zhang, YY Xu, T Shan, B Hart, J Aslanian, A Han, XM Zong, N Li, HM Choi, H Wang, D Acharya, L Du, LS Vogt, PK Ping, PP Yates, JR AF Zhang, Yaoyang Xu, Tao Shan, Bing Hart, Jonathan Aslanian, Aaron Han, Xuemei Zong, Nobel Li, Haomin Choi, Howard Wang, Dong Acharya, Lipi Du, Lisa Vogt, Peter K. Ping, Peipei Yates, John R., III TI ProteinInferencer: Confident protein identification and multiple experiment comparison for large scale proteomics projects SO JOURNAL OF PROTEOMICS LA English DT Article DE Proteomics; Mass spectrometry; Database search; Protein inference; False discovery rate (FDR); Peptide-spectrum match (PSM) ID TANDEM MASS-SPECTROMETRY; AMINO-ACID-SEQUENCES; SHOTGUN PROTEOMICS; STATISTICAL-MODEL; DATABASE SEARCH; INFERENCE; PEPTIDES; ACCURACY; STRATEGY; DRAFT AB Shotgun proteomics generates valuable information from large-scale and target protein characterizations, including protein expression, protein quantification, protein post-translational modifications (PTMs), protein localization, and protein-protein interactions. Typically, peptides derived from proteolytic digestion, rather than intact proteins, are analyzed by mass spectrometers because peptides are more readily separated, ionized and fragmented. The amino acid sequences of peptides can be interpreted by matching the observed tandem mass spectra to theoretical spectra derived from a protein sequence database. Identified peptides serve as surrogates for their proteins and are often used to establish what proteins were present in the original mixture and to quantify protein abundance. Two major issues exist for assigning peptides to their originating protein. The first issue is maintaining a desired false discovery rate (FDR) when comparing or combining multiple large datasets generated by shotgun analysis and the second issue is properly assigning peptides to proteins when homologous proteins are present in the database. Herein we demonstrate a new computational tool, ProteinInferencer, which can be used for protein inference with both small- or large-scale data sets to produce a well-controlled protein FDR. In addition, ProteinInferencer introduces confidence scoring for individual proteins, which makes protein identifications evaluable. This article is part of a Special Issue entitled: Computational Proteomics. (C) 2015 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). C1 [Zhang, Yaoyang; Xu, Tao; Shan, Bing; Aslanian, Aaron; Han, Xuemei; Yates, John R., III] Scripps Res Inst, Dept Physiol Chem, La Jolla, CA 92037 USA. [Hart, Jonathan; Du, Lisa; Vogt, Peter K.] Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA 92037 USA. [Zong, Nobel; Li, Haomin; Choi, Howard; Ping, Peipei] Univ Calif Los Angeles, David Geffen Sch Med, NHLBI Prote Ctr, Dept Physiol, Los Angeles, CA 90095 USA. [Zong, Nobel; Li, Haomin; Choi, Howard; Ping, Peipei] Univ Calif Los Angeles, David Geffen Sch Med, NHLBI Prote Ctr, Dept Med, Los Angeles, CA 90095 USA. [Xu, Tao; Acharya, Lipi] Dow AgroSci LLC, Indianapolis, IN 46268 USA. [Wang, Dong] Vanderbilt Univ, Med Ctr, Nashville, TN 37232 USA. [Zhang, Yaoyang; Shan, Bing] Chinese Acad Sci, Interdisciplinary Res Ctr Biol & Chem, Shanghai Inst Organ Chem, Shanghai 200032, Peoples R China. RP Yates, JR (reprint author), Scripps Res Inst, Dept Physiol Chem, La Jolla, CA 92037 USA. EM zyy@sioc.ac.cn; txu2@dow.com; bingshan@scripps.edu; jhart@scripps.edu; aslanian@scripps.edu; xmhan@scripps.edu; zchghno1@gmail.com; haomin_li@yahoo.com; cjh9595@ucla.edu; DWang7@mdanderson.org; lachatya@dow.com; lisa13du@yahoo.com; pkvogt@scripps.edu; pping@mednet.ucla.edu; jyates@scripps.edu OI Vogt, Peter K/0000-0002-4519-7500 FU National Institutes of Health [P41 GM103533, R01 MH067880]; UCLA/NHLBI Proteomics Centers [HHSN268201000035C] FX Funding has been provided by the National Institutes of Health grants P41 GM103533 and R01 MH067880, and UCLA/NHLBI Proteomics Centers HHSN268201000035C. NR 32 TC 4 Z9 4 U1 3 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1874-3919 EI 1876-7737 J9 J PROTEOMICS JI J. Proteomics PD NOV 3 PY 2015 VL 129 SI SI BP 25 EP 32 DI 10.1016/j.jprot.2015.07.006 PG 8 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA CW3JD UT WOS:000364887600004 PM 26196237 ER PT J AU Gahl, WA Wise, AL Ashley, EA AF Gahl, William A. Wise, Anastasia L. Ashley, Euan A. TI The Undiagnosed Diseases Network of the National Institutes of Health A National Extension SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID PROGRAM C1 [Gahl, William A.; Wise, Anastasia L.] NHGRI, NIH, Bethesda, MD 20892 USA. [Ashley, Euan A.] Stanford Univ, Dept Med, Stanford, CA 94305 USA. [Ashley, Euan A.] Stanford Univ, Dept Genet, Stanford, CA 94305 USA. RP Ashley, EA (reprint author), Stanford Univ, Dept Med, Falk CVRB, 870 Quarry Rd, Stanford, CA 94305 USA. EM euan@stanford.edu FU NHGRI NIH HHS [U01 HG007672, U01 HG007530, U01 HG007674, U01 HG007690, U01 HG007703, U01 HG007708, U01 HG007709, U01 HG007942, U01 HG007943] NR 7 TC 11 Z9 11 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 NOV 3 PY 2015 VL 314 IS 17 BP 1797 EP 1798 DI 10.1001/jama.2015.12249 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA CV0RO UT WOS:000363960200008 PM 26375289 ER PT J AU Ambrose, BK Day, HR Rostron, B Conway, KP Borek, N Hyland, A Villanti, AC AF Ambrose, Bridget K. Day, Hannah R. Rostron, Brian Conway, Kevin P. Borek, Nicolette Hyland, Andrew Villanti, Andrea C. TI Flavored Tobacco Product Use Among US Youth Aged 12-17 Years, 2013-2014 SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Ambrose, Bridget K.; Day, Hannah R.; Rostron, Brian; Borek, Nicolette] US FDA, Ctr Tobacco Prod, Silver Spring, MD 20993 USA. [Conway, Kevin P.] NIDA, Div Epidemiol Serv & Prevent Res, Bethesda, MD 20892 USA. [Hyland, Andrew] Roswell Pk Canc Inst, Dept Hlth Behav, Buffalo, NY 14263 USA. [Villanti, Andrea C.] Truth Initiat, Schroeder Inst Tobacco Res & Policy Studies, Washington, DC USA. RP Ambrose, BK (reprint author), US FDA, Off Sci, Ctr Tobacco Prod, 10903 New Hampshire Ave,Bldg 75,Room 4432, Silver Spring, MD 20993 USA. EM bridget.ambrose@fda.hhs.gov OI Conway, Kevin/0000-0002-7638-339X; Villanti, Andrea/0000-0003-3104-966X FU PHS HHS [HHSN271201100027C] NR 5 TC 19 Z9 19 U1 1 U2 6 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 NOV 3 PY 2015 VL 314 IS 17 BP 1871 EP 1873 DI 10.1001/jama.2015.13802 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA CV0RO UT WOS:000363960200022 PM 26502219 ER PT J AU Nasser, HM Chen, YW Fiscella, K Calu, DJ AF Nasser, Helen M. Chen, Yu-Wei Fiscella, Kimberly Calu, Donna J. TI Individual variability in behavioral flexibility predicts sign-tracking tendency SO FRONTIERS IN BEHAVIORAL NEUROSCIENCE LA English DT Hardware Review DE sign-tracking; outcome devaluation; second-order conditioning; behavioral flexibility; Pavlovian incentive learning ID ATTRIBUTE INCENTIVE SALIENCE; GOAL-DIRECTED ACTIONS; REINFORCER DEVALUATION; BASOLATERAL AMYGDALA; UNCONDITIONED STIMULUS; NUCLEUS-ACCUMBENS; AMPHETAMINE EXPOSURE; ORBITOFRONTAL CORTEX; CENTERED BEHAVIOR; INSULAR CORTEX AB Sign-tracking rats show heightened sensitivity to food- and drug-associated cues, which serve as strong incentives for driving reward seeking. We hypothesized that this enhanced incentive drive is accompanied by an inflexibility when incentive value changes. To examine this we tested rats in Pavlovian outcome devaluation or second order conditioning prior to the assessment of sign-tracking tendency. To assess behavioral flexibility we trained rats to associate a light with a food outcome. After the food was devalued by pairing with illness, we measured conditioned responding (CR) to the light during an outcome devaluation probe test. The level of CR during outcome devaluation probe test correlated with the rats' subsequent tracking tendency, with sign-tracking rats failing to suppress CR to the light after outcome devaluation. To assess Pavlovian incentive learning, we trained rats on first-order (CS+, CS-) and second-order (SOCS+, SOCS-) discriminations. After second-order conditioning, we measured CR to the second-order cues during a probe test. Second-order conditioning was observed across all rats regardless of tracking tendency. The behavioral inflexibility of sign-trackers has potential relevance for understanding individual variation in vulnerability to drug addiction. C1 [Nasser, Helen M.; Chen, Yu-Wei; Fiscella, Kimberly; Calu, Donna J.] NIDA, Behav Neurosci Res Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, Baltimore, MD USA. [Nasser, Helen M.; Calu, Donna J.] Univ Maryland, Sch Med, Anat & Neurobiol, Baltimore, MD 21201 USA. RP Calu, DJ (reprint author), NIDA, Behav Neurosci Res Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, Baltimore, MD USA. EM dcalu@som.umaryland.edu OI Calu, Donna/0000-0003-2377-9494 NR 55 TC 4 Z9 4 U1 4 U2 7 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5153 J9 FRONT BEHAV NEUROSCI JI Front. Behav. Neurosci. PD NOV 3 PY 2015 VL 9 AR 289 DI 10.3389/fnbeh.2015.00289 PG 18 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA CV7BS UT WOS:000364427700001 PM 26578917 ER PT J AU Zhang, XY Ambale-Venkatesh, B Bluemke, DA Cowan, BR Finn, JP Kadish, AH Lee, DC Lima, JAC Hundley, WG Suinesiaputra, A Young, AA Medrano-Gracia, P AF Zhang, Xingyu Ambale-Venkatesh, Bharath Bluemke, David A. Cowan, Brett R. Finn, J. Paul Kadish, Alan H. Lee, Daniel C. Lima, Joao A. C. Hundley, William G. Suinesiaputra, Avan Young, Alistair A. Medrano-Gracia, Pau TI Information maximizing component analysis of left ventricular remodeling due to myocardial infarction SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article DE Cardiac remodeling; Information maximizing component analysis; Magnetic resonance imaging; Linear discriminant analysis; Logistic regression ID MAGNETIC-RESONANCE; DIMENSIONALITY REDUCTION; ENDOCARDIAL SURFACE; POPULATION; SHAPE; HEART; ATHEROSCLEROSIS; SURVIVAL; ATLASES; DESIGN AB Background: Although adverse left ventricular shape changes (remodeling) after myocardial infarction (MI) are predictive of morbidity and mortality, current clinical assessment is limited to simple mass and volume measures, or dimension ratios such as length to width ratio. We hypothesized that information maximizing component analysis (IMCA), a supervised feature extraction method, can provide more efficient and sensitive indices of overall remodeling. Methods: IMCA was compared to linear discriminant analysis (LDA), both supervised methods, to extract the most discriminatory global shape changes associated with remodeling after MI. Finite element shape models from 300 patients with myocardial infarction from the DETERMINE study (age 31-86, mean age 63, 20 % women) were compared with 1991 asymptomatic cases from the MESA study (age 44-84, mean age 62, 52 % women) available from the Cardiac Atlas Project. IMCA and LDA were each used to identify a single mode of global remodeling best discriminating the two groups. Logistic regression was employed to determine the association between the remodeling index and MI. Goodness-of-fit results were compared against a baseline logistic model comprising standard clinical indices. Results: A single IMCA mode simultaneously describing end-diastolic and end-systolic shapes achieved best results (lowest Deviance, Akaike information criterion and Bayesian information criterion, and the largest area under the receiver-operating-characteristic curve). This mode provided a continuous scale where remodeling can be quantified and visualized, showing that MI patients tend to present larger size and more spherical shape, more bulging of the apex, and thinner wall thickness. Conclusions: IMCA enables better characterization of global remodeling than LDA, and can be used to quantify progression of disease and the effect of treatment. These data and results are available from the Cardiac Atlas Project (http://www.cardiacatlas.org). C1 [Zhang, Xingyu; Cowan, Brett R.; Suinesiaputra, Avan; Young, Alistair A.; Medrano-Gracia, Pau] Univ Auckland, Dept Anat Radiol, Auckland 1148, New Zealand. [Ambale-Venkatesh, Bharath; Lima, Joao A. C.] Johns Hopkins Univ, Donald W Reynolds Cardiovasc Clin Res Ctr, Baltimore, MD USA. [Bluemke, David A.] Natl Inst Biomed Imaging & Bioengn, Bethesda, MD USA. [Finn, J. Paul] Univ Calif Los Angeles, Dept Radiol, Los Angeles, CA USA. [Kadish, Alan H.; Lee, Daniel C.] Northwestern Univ, Feinberg Cardiovasc Res Inst, Feinberg Sch Med, Chicago, IL 60611 USA. [Hundley, William G.] Cardiol Sect, Winston Salem, NC USA. RP Medrano-Gracia, P (reprint author), Univ Auckland, Dept Anat Radiol, Grafton Campus,85 Pk Rd, Auckland 1148, New Zealand. EM p.medrano@auckland.ac.nz RI Ambale Venkatesh, Bharath/F-4941-2016; OI Ambale Venkatesh, Bharath/0000-0002-2330-2373; Bluemke, David/0000-0002-8323-8086 FU National Heart, Lung, and Blood Institute [R01HL087773, R01HL121754]; NHLBI [N01-HC-95159, N01-HC-95169]; NCRR [UL1-RR-024156, UL1-RR-025005]; St. Jude Medical, Inc; National Heart, Lung and Blood Institute [R01HL91069]; NIH intramural research program; China Scholarship Council FX This project was supported by award numbers R01HL087773 and R01HL121754 from the National Heart, Lung, and Blood Institute. MESA was supported by contracts N01-HC-95159 through N01-HC-95169 from the NHLBI and by grants UL1-RR-024156 and UL1-RR-025005 from NCRR. DETERMINE was supported by St. Jude Medical, Inc; and the National Heart, Lung and Blood Institute (R01HL91069). A list of participating DETERMINE investigators can be found at http://www.clinicaltrials.gov. David A. Bluemke is supported by the NIH intramural research program. Xingyu Zhang would like to gratefully acknowledge financial support from the China Scholarship Council. NR 40 TC 0 Z9 0 U1 1 U2 5 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 NOV 3 PY 2015 VL 13 AR 343 DI 10.1186/s12967-015-0709-4 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CV1GM UT WOS:000364001700002 PM 26531126 ER PT J AU Goldstein, DS Holmes, C Sharabi, Y Wu, TX AF Goldstein, David S. Holmes, Courtney Sharabi, Yehonatan Wu, Tianxia TI Survival in synucleinopathies A prospective cohort study SO NEUROLOGY LA English DT Article ID MULTIPLE SYSTEM ATROPHY; NEUROGENIC ORTHOSTATIC HYPOTENSION; PARKINSONS-DISEASE; NATURAL-HISTORY; METAANALYSIS; DIAGNOSIS; MORTALITY AB Objectives:Parkinson disease (PD), multiple system atrophy (MSA), and pure autonomic failure (PAF) involve cytoplasmic deposition of -synuclein and are considered to be synucleinopathies. Approximately 40% of patients with PD, most patients with MSA, and all patients with PAF have neurogenic orthostatic hypotension (OH). This study compared long-term survival in these synucleinopathies.Methods:In this prospective cohort study, survival data were obtained for 97.6% of 206 referred patients evaluated between 1994 and 2014 (47 PD + OH, 54 PD no OH, 15 cerebellar MSA [MSA-C], 57 parkinsonian MSA [MSA-P], 28 PAF). Individual diagnoses were confirmed by clinical criteria and results of pharmacologic, neurochemical, and neuroimaging tests of sympathetic noradrenergic innervation. The Cox proportional hazard model was used to calculate hazard ratios (HRs) from symptom onset and from time of evaluation to death.Results:Patients with MSA-C or MSA-P had shorter survival from symptom onset than did patients with PD + OH (age- and sex-adjusted HR = 6.1, 5.6; p < 0.0001 each), PAF (HR = 10.8, 9.9; p < 0.0001 each) or PD no OH (HR = 14.9, 13.6; p < 0.0001 each). Among parkinsonian patients who died, median times from motor onset to death were 7.5 years in MSA-P, 11.6 years in PD + OH, and 15.8 years in PD no OH. Probabilities of survival for 10 years from onset of relevant symptoms were 0.39 in MSA-C, 0.33 in MSA-P, 0.74 in PD + OH, 0.87 in PAF, and 0.93 in PD no OH.Conclusions:In synucleinopathies, survival depends on the particular disease, with the risk of death greater in MSA-P than in PD + OH and in PD + OH than in PD no OH. C1 [Goldstein, David S.; Holmes, Courtney] NINDS, Clin Neurocardiol Sect, Clin Neurosci Program, Div Intramural Res,NIH, Bethesda, MD 20892 USA. [Wu, Tianxia] NINDS, Off Clin Director, Clin Neurosci Program, Div Intramural Res,NIH, Bethesda, MD 20892 USA. [Sharabi, Yehonatan] Chaim Sheba Med Ctr, Hypertens Unit, IL-52621 Tel Hashomer, Israel. [Sharabi, Yehonatan] Tel Aviv Univ, Tel Hashomer, Israel. RP Goldstein, DS (reprint author), NINDS, Clin Neurocardiol Sect, Clin Neurosci Program, Div Intramural Res,NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM goldsteind@ninds.nih.gov FU Division of Intramural Research (DIR), National Institute of Neurological Disorders and Stroke (NINDS), NIH FX The funding organization for this study was the Division of Intramural Research (DIR), National Institute of Neurological Disorders and Stroke (NINDS), NIH. The DIR, NINDS, NIH, supported the research reported here. NR 23 TC 6 Z9 6 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 NOV 3 PY 2015 VL 85 IS 18 BP 1554 EP 1561 DI 10.1212/WNL.0000000000002086 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA CV3VP UT WOS:000364194800006 PM 26432848 ER PT J AU Young, RM Wu, TY Schmitz, R Dawood, M Xiao, WM Phelan, JD Xu, WH Menard, L Meffre, E Chan, WCC Jaffe, ES Gascoyne, RD Campo, E Rosenwald, A Ott, G Delabie, J Rimsza, LM Staudt, LM AF Young, Ryan M. Wu, Tianyi Schmitz, Roland Dawood, Moez Xiao, Wenming Phelan, James D. Xu, Weihong Menard, Laurence Meffre, Eric Chan, Wing-Chung C. Jaffe, Elaine S. Gascoyne, Randy D. Campo, Elias Rosenwald, Andreas Ott, German Delabie, Jan Rimsza, Lisa M. Staudt, Louis M. TI Survival of human lymphoma cells requires B-cell receptor engagement by self-antigens SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE lymphoma; cancer biology; B-cell receptor ID CHRONIC LYMPHOCYTIC-LEUKEMIA; CENTRAL-NERVOUS-SYSTEM; CLASS SWITCH RECOMBINATION; NON-HODGKIN-LYMPHOMA; LUPUS-ERYTHEMATOSUS; MOLECULAR CHARACTERIZATION; GENE REARRANGEMENTS; SOMATIC MUTATION; IMMUNOGLOBULIN; REPERTOIRE AB The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) relies on chronic active B-cell receptor (BCR) signaling. BCR pathway inhibitors induce remissions in a subset of ABC DLBCL patients. BCR microclusters on the surface of ABC cells resemble those generated following antigen engagement of normal B cells. We speculated that binding of lymphoma BCRs to self-antigens initiates and maintains chronic active BCR signaling in ABC DLBCL. To assess whether antigenic engagement of the BCR is required for the ongoing survival of ABC cells, we developed isogenic ABC cells that differed solely with respect to the IgH V region of their BCRs. In competitive assays with wild-type cells, substitution of a heterologous V region impaired the survival of three ABC lines. The viability of one V(H)4-34(+) ABC line and the ability of its BCR to bind to its own cell surface depended on V region residues that mediate the intrinsic autoreactivity of V(H)4-34 to self-glycoproteins. The BCR of another ABC line reacted with self-antigens in apoptotic debris, and the survival of a third ABC line was sustained by reactivity of its BCR to an idiotypic epitope in its own V region. Hence, a diverse set of self-antigens is responsible for maintaining the malignant survival of ABC DLBCL cells. IgH V regions used by the BCRs of ABC DLBCL biopsy samples varied in their ability to sustain survival of these ABC lines, suggesting a screening procedure to identify patients who might benefit from BCR pathway inhibition. C1 [Young, Ryan M.; Wu, Tianyi; Schmitz, Roland; Dawood, Moez; Xiao, Wenming; Phelan, James D.; Xu, Weihong; Staudt, Louis M.] NCI, Lymphoid Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Menard, Laurence; Meffre, Eric] Yale Univ, Dept Immunobiol, Sch Med, New Haven, CT 06511 USA. [Chan, Wing-Chung C.] City Hope Natl Med Ctr, Dept Pathol, Duarte, CA 91010 USA. [Jaffe, Elaine S.] NCI, Lab Pathol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Gascoyne, Randy D.] British Columbia Canc Agcy, Ctr Lymphoid Canc, Vancouver, BC V5Z 4E6, Canada. [Campo, Elias] Univ Barcelona, Hosp Clin, Dept Pathol, Hematopathol Sect, E-08036 Barcelona, Spain. [Rosenwald, Andreas] Univ Wurzburg, Dept Pathol, D-97080 Wurzburg, Germany. [Ott, German] Robert Bosch Krankenhaus, Dept Clin Pathol, D-70376 Stuttgart, Germany. [Ott, German] Dr Margarete Fischer Bosch Inst Clin Pharmacol, D-70376 Stuttgart, Germany. [Delabie, Jan] Oslo Univ Hosp, Dept Pathol, N-0310 Oslo, Norway. [Rimsza, Lisa M.] Univ Arizona, Dept Pathol, Tucson, AZ 85724 USA. RP Staudt, LM (reprint author), NCI, Lymphoid Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM lstaudt@mail.nih.gov RI Campo, elias/O-7192-2016 OI Campo, elias/0000-0001-9850-9793 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute; Center for Cancer Research; Dr. Mildred Scheel Stiftung fur Krebsforschung (Deutsche Krebshilfe) FX This study used the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health. This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, and Center for Cancer Research; and the Dr. Mildred Scheel Stiftung fur Krebsforschung (Deutsche Krebshilfe) (R.S.). NR 56 TC 17 Z9 18 U1 2 U2 10 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 NOV 3 PY 2015 VL 112 IS 44 BP 13447 EP 13454 DI 10.1073/pnas.1514944112 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CV3NC UT WOS:000364164900036 PM 26483459 ER PT J AU McCauley, MJ Rouzina, I Manthei, KA Gorelick, RJ Musier-Forsyth, K Williams, MC AF McCauley, Micah J. Rouzina, Ioulia Manthei, Kelly A. Gorelick, Robert J. Musier-Forsyth, Karin Williams, Mark C. TI Targeted binding of nucleocapsid protein transforms the folding landscape of HIV-1 TAR RNA SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE single molecule; force spectroscopy; RNA stretching; RNA binding ID FREE-ENERGY DIFFERENCES; ACID CHAPERONE ACTIVITY; NUCLEIC-ACID; FLUCTUATION THEOREM; SECONDARY STRUCTURE; FORCE; MECHANISM; HAIRPINS; KINETICS; GAG AB Retroviral nucleocapsid (NC) proteins are nucleic acid chaperones that play a key role in the viral life cycle. During reverse transcription, HIV-1 NC facilitates the rearrangement of nucleic acid secondary structure, allowing the transactivation response (TAR) RNA hairpin to be transiently destabilized and annealed to a cDNA hairpin. It is not clear how NC specifically destabilizes TAR RNA but does not strongly destabilize the resulting annealed RNA-DNA hybrid structure, which must be formed for reverse transcription to continue. By combining single-molecule optical tweezers measurements with a quantitative mfold-based model, we characterize the equilibrium TAR stability and unfolding barrier for TAR RNA. Experiments show that adding NC lowers the transition state barrier height while also dramatically shifting the barrier location. Incorporating TAR destabilization by NC into the mfold-based model reveals that a subset of preferential protein binding sites is responsible for the observed changes in the unfolding landscape, including the unusual shift in the transition state. We measure the destabilization induced at these NC binding sites and find that NC preferentially targets TAR RNA by binding to specific sequence contexts that are not present on the final annealed RNA-DNA hybrid structure. Thus, specific binding alters the entire RNA unfolding landscape, resulting in the dramatic destabilization of this specific structure that is required for reverse transcription. C1 [McCauley, Micah J.; Williams, Mark C.] Northeastern Univ, Dept Phys, Boston, MA 02115 USA. [Rouzina, Ioulia; Manthei, Kelly A.] Univ Minnesota, Dept Biochem Mol Biol & Biophys, Minneapolis, MN 55455 USA. [Gorelick, Robert J.] Leidos Biomed Res Inc, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Musier-Forsyth, Karin] Ohio State Univ, Dept Chem & Biochem, Ctr Retroviral Res, Columbus, OH 43210 USA. [Musier-Forsyth, Karin] Ohio State Univ, Ctr RNA Biol, Columbus, OH 43210 USA. RP Williams, MC (reprint author), Northeastern Univ, Dept Phys, Boston, MA 02115 USA. EM mark@neu.edu OI Williams, Mark C./0000-0003-3219-376X FU National Institutes of Health (NIH) Grant [GM072462]; National Science Foundation Grant [MCB-1243883]; NIH Grant [GM065056]; National Cancer Institute, NIH [HHSN261200800001E]; Leidos Biomedical Research, Inc. FX This work was supported by National Institutes of Health (NIH) Grant GM072462 and National Science Foundation Grant MCB-1243883 (to M.C.W.) and NIH Grant GM065056 (to K.M.-F.). Additional funds were provided by the National Cancer Institute, NIH, under Contract HHSN261200800001E with Leidos Biomedical Research, Inc. (to R.J.G.). NR 35 TC 6 Z9 6 U1 3 U2 15 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 NOV 3 PY 2015 VL 112 IS 44 BP 13555 EP 13560 DI 10.1073/pnas.1510100112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CV3NC UT WOS:000364164900054 PM 26483503 ER PT J AU Alberstein, R Grey, R Zimmet, A Simmons, DK Mayer, ML AF Alberstein, Robert Grey, Richard Zimmet, Austin Simmons, David K. Mayer, Mark L. TI Glycine activated ion channel subunits encoded by ctenophore glutamate receptor genes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE NMDA receptors; ctenophores; crystal structures; evolution ID LIGAND-BINDING DOMAIN; CULTURED HIPPOCAMPAL-NEURONS; CRYSTAL-STRUCTURES; KAINATE RECEPTORS; DIMER INTERFACE; MODULATORY SITE; TERMINAL DOMAIN; NMDA-RECEPTORS; CONCANAVALIN-A; DESENSITIZATION AB Recent genome projects for ctenophores have revealed the presence of numerous ionotropic glutamate receptors (iGluRs) in Mnemiopsis leidyi and Pleurobrachia bachei, among our earliest metazoan ancestors. Sequence alignments and phylogenetic analysis show that these form a distinct clade from the well-characterized AMPA, kainate, and NMDA iGluR subtypes found in vertebrates. Although annotated as glutamate and kainate receptors, crystal structures of the ML032222a and PbiGluR3 ligand-binding domains (LBDs) reveal endogenous glycine in the binding pocket, whereas ligand-binding assays show that glycine binds with nanomolar affinity; biochemical assays and structural analysis establish that glutamate is occluded from the binding cavity. Further analysis reveals ctenophore-specific features, such as an interdomain Arg-Glu salt bridge, present only in subunits that bind glycine, but also a conserved disulfide in loop 1 of the LBD that is found in all vertebrate NMDA but not AMPA or kainate receptors. We hypothesize that ctenophore iGluRs are related to an early ancestor of NMDA receptors, suggesting a common evolutionary path for ctenophores and bilaterian species, and suggest that future work should consider both glycine and glutamate as candidate neurotransmitters in ctenophore species. C1 [Alberstein, Robert; Grey, Richard; Zimmet, Austin; Mayer, Mark L.] NICHHD, Lab Cellular & Mol Neurophysiol, NIH, Bethesda, MD 20892 USA. [Simmons, David K.] Univ Florida, Whitney Lab Marine Biosci, St Augustine, FL 32080 USA. RP Mayer, ML (reprint author), NICHHD, Lab Cellular & Mol Neurophysiol, NIH, Bethesda, MD 20892 USA. EM mayerm@mail.nih.gov FU US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; intramural research program of The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services; NASA [00093371] FX We thank Carla Glasser for technical assistance; Drs. Joy Zhao and Peter Schuck for help with analysis of isothermal titration calorimetry (ITC) experiments; and Dr. Albert Lau for performing the PROPKA calculations. Data were collected at Southeast Regional Collaborative Access Team (SER-CAT) 22-ID beamline at the Advanced Photon Source, Argonne National Laboratory. Use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract W-31-109-Eng-38. This work was supported the intramural research program of The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, and NASA Grant 00093371 for the study of the evolution of complex cell types. NR 66 TC 5 Z9 5 U1 0 U2 1 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 NOV 3 PY 2015 VL 112 IS 44 BP E6048 EP E6057 DI 10.1073/pnas.1513771112 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CV3NC UT WOS:000364164900020 PM 26460032 ER PT J AU Atayde, VD Aslan, H Townsend, S Hassani, K Kamhawi, S Olivier, M AF Atayde, Vanessa Diniz Aslan, Hamide Townsend, Shannon Hassani, Kasra Kamhawi, Shaden Olivier, Martin TI Exosome Secretion by the Parasitic Protozoan Leishmania within the Sand Fly Midgut SO CELL REPORTS LA English DT Article ID CUTANEOUS LEISHMANIASIS; IMMUNE-RESPONSES; VIRULENCE FACTORS; IN-VIVO; TRANSMISSION; MACROPHAGES; CELLS; FLIES; MICE; MECHANISMS AB Despite several studies describing the secretion of exosomes by Leishmania in vitro, observation of their formation and release in vivo has remained a major challenge. Herein, we show that Leishmania constitutively secretes exosomes within the lumen of the sand fly midgut through a mechanism homologous to the mammalian pathway. Through egestion experiments, we demonstrate that Leishmania exosomes are part of the sand fly inoculum and are co-egested with the parasite during the insect's bite, possibly influencing the host infectious process. Indeed, co-inoculation of mice footpads with L. major plus midgut-isolated or in-vitro-isolated L. major exosomes resulted in a significant increase in footpad swelling. Notably, co-injections produced exacerbated lesions through overinduction of inflammatory cytokines, in particular IL-17a. Our data indicate that Leishmania exosomes are an integral part of the parasite's infectious life cycle, and we propose to add these vesicles to the repertoire of virulence factors associated with vector-transmitted infections. C1 McGill Univ, Dept Med Microbiol & Immunol, Montreal, PQ H3A 2B4, Canada. [Aslan, Hamide; Townsend, Shannon; Kamhawi, Shaden] McGill Univ, Ctr Hlth, Res Inst, Infect Dis & Immun Global Heath Program, Montreal, PQ H4A 3J1, Canada. [Aslan, Hamide] Selahaddin Eyyubi Univ, Fac Hlth Sci, TR-21090 Diyarbakir, Baglar, Turkey. RP Kamhawi, S (reprint author), NIH, Vector Mol Biol Sect, 12735 Twinbrook Pkwy, Rockville, MD 20878 USA. EM skamhawi@niaid.nih.gov; martin.olivier@mcgill.ca FU Canadian Institutes of Health Research (CIHR); Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), NIH; Dr. David T.W. Lin Postdoctoral Fellowship; McGill University Faculty of Medicine; Research Institute of the McGill University Health Centre FX This research was supported by grants from the Canadian Institutes of Health Research (CIHR) to M.O. and by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), NIH, to S.K.M.O. is a Burroughs Welcome Fund Awardee in Molecular Parasitology. V.D.A. was supported by the Dr. David T.W. Lin Postdoctoral Fellowship, McGill University Faculty of Medicine, and by the Research Institute of the McGill University Health Centre. M.O. and V.D.A. are members of the Quebec province CHPI-FQRNT network in Host-Parasite Interaction. We thank the Facility for Electron Microscopy Research, McGill University, for assistance with TEM and the Institut de Recherches Cliniques de Montreal for the proteomics. We thank Dr. Jesus Valenzuela (NIAID, NIH) for his support; Mr. Claudio Meneses (NIAID, NIH) for providing the sand flies; and Dr. Greg Matlashewski (McGill University), Dr. Robert W. McMaster (University of British Columbia), Dr. Armando Jardim (McGill University), and Dr. Jose M. Requena (CSIC-UAM) for kindly providing us with antibodies. NR 45 TC 16 Z9 16 U1 2 U2 11 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 NOV 3 PY 2015 VL 13 IS 5 BP 957 EP 967 DI 10.1016/j.celrep.2015.09.058 PG 11 WC Cell Biology SC Cell Biology GA CV1BM UT WOS:000363988100011 PM 26565909 ER PT J AU Prince, P Mitchell, SA Wehrlen, L Childs, R Savani, B Yang, L Bevans, M AF Prince, Patricia Mitchell, Sandra A. Wehrlen, Leslie Childs, Richard Savani, Bipin Yang, Li Bevans, Margaret TI Spiritual Well-Being in Hispanic and Non-Hispanic Survivors of Allogeneic Hematopoietic Stem Cell Transplantation SO JOURNAL OF PSYCHOSOCIAL ONCOLOGY LA English DT Article DE coping; health related quality of life; Hispanic; spiritual well-being; stem cell transplant; survivorship ID QUALITY-OF-LIFE; SELF-REPORTED HEALTH; LONG-TERM HEALTH; CANCER SURVIVORS; FUNCTIONAL ASSESSMENT; FACIT-SP; MARROW TRANSPLANT; SYMPTOM DISTRESS; ADULT SURVIVORS; 3-FACTOR MODEL AB Research suggests that spiritual well-being positively contributes to quality of life during and following cancer treatment. This relationship has not been well-described in ethnically diverse survivors of allogeneic transplantation. This study compares spiritual well-being and quality of life of Hispanic (n = 69) and non-Hispanic (n = 102) survivors. Hispanic participants were significantly younger and reported significantly greater spiritual well-being than non-Hispanic survivors. Survivors with higher spiritual well-being had significantly better quality of life. Meaning and Peace significantly predicted quality of life. Although Hispanic survivors report greater spiritual well-being, Meaning and Peace, irrespective of ethnicity, have a salutary effect on quality of life. C1 [Prince, Patricia] NIH, Dept Social Work, Ctr Clin, Bethesda, MD 20892 USA. [Mitchell, Sandra A.] NCI, Div Canc Control & Populat Sci, Outcomes Res Branch, Rockville, MD USA. [Wehrlen, Leslie; Yang, Li; Bevans, Margaret] NIH, Dept Nursing, Ctr Clin, Bethesda, MD 20892 USA. [Childs, Richard] NHLBI, Bethesda, MD 20892 USA. [Savani, Bipin] Vanderbilt Univ, Dept Med, Nashville, TN USA. RP Bevans, M (reprint author), NIH, Dept Nursing, Ctr Clin, 10 Ctr Dr, Bethesda, MD 20892 USA. EM mbevans@cc.nih.gov FU Intramural Research Program of the NIH, Clinical Center FX This study was funded by the Intramural Research Program of the NIH, Clinical Center. NR 80 TC 2 Z9 2 U1 9 U2 11 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0734-7332 EI 1540-7586 J9 J PSYCHOSOC ONCOL JI J. Psychosoc. Oncol. PD NOV 2 PY 2015 VL 33 IS 6 BP 635 EP 654 DI 10.1080/07347332.2015.1082167 PG 20 WC Psychology, Social SC Psychology GA CX3FX UT WOS:000365582900003 PM 26315721 ER PT J AU Nussinov, R Tsai, CJ Muratcioglu, S Jang, H Gursoy, A Keskin, O AF Nussinov, Ruth Tsai, Chung-Jung Muratcioglu, Serena Jang, Hyunbum Gursoy, Attila Keskin, Ozlem TI Principles of K-Ras effector organization and the role of oncogenic K-Ras in cancer initiation through G1 cell cycle deregulation SO EXPERT REVIEW OF PROTEOMICS LA English DT Review DE K-Ras; KRAS4B; K-Ras4B; lung cancer; pancreatic cancer; calmodulin; Ras isoforms; cell cycle; Ras effectors; PI3K; Raf; RalGDS ID NUCLEOTIDE DISSOCIATION STIMULATOR; PROTEIN-PROTEIN INTERACTIONS; SIGNAL-REGULATED KINASE; TUMOR-SUPPRESSOR GENE; WEIBEL-PALADE BODIES; EXCHANGE FACTOR; PANCREATIC-CANCER; INDUCED SENESCENCE; BINDING DOMAIN; RESTRICTION POINT AB Illustrated here is the critical role of oncogenic KRAS in the initiation of cancer through deregulation of the G1 cell cycle, and elements and scenarios taking place under physiological conditions and in KRAS-driven cancer. Raf, PI3K and RalGDS are major K-Ras effectors. They bind at the same Ras site. What decides the cell selection among them? This temporal and spatial decision is critical since in some cellular context the outcome of their signaling pathways may oppose each other. Key among them is the concentration of calcium/calmodulin, negative feedback loops, where a downstream member of the pathway inhibits its upstream activator and cross-inhibition, where inhibition entails blocking another pathway. These three elements, in addition to spatial restrictions by K-Ras-membrane interactions, are not independent; they integrate to provide blueprints for cell decisions. Importantly, elucidation of signaling requires not only K-Ras binary interactions; but the structures and dynamics of its multiprotein complexes. C1 [Nussinov, Ruth; Tsai, Chung-Jung; Jang, Hyunbum] NCI, Basic Sci Program, Leidos Biomed Res Inc, Frederick Natl Lab Canc Res,Canc & Inflammat Prog, Frederick, MD 21701 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Mol Genet & Biochem, IL-69978 Tel Aviv, Israel. [Muratcioglu, Serena; Keskin, Ozlem] Koc Univ, Dept Chem, Istanbul, Turkey. [Muratcioglu, Serena; Keskin, Ozlem] Koc Univ, Dept Biol Engn, Istanbul, Turkey. [Gursoy, Attila] Koc Univ, Comp Engn, Istanbul, Turkey. RP Nussinov, R (reprint author), NCI, Basic Sci Program, Leidos Biomed Res Inc, Frederick Natl Lab Canc Res,Canc & Inflammat Prog, Frederick, MD 21701 USA. EM NussinoR@helix.nih.gov RI Gursoy, Attila/E-9565-2015 OI Gursoy, Attila/0000-0002-2297-2113 FU Frederick National Laboratory for Cancer Research, NIH [HHSN261200800001E]; Intramural Research Program of NIH, Frederick National Lab, Center for Cancer Research FX This project was funded by federal funds from the Frederick National Laboratory for Cancer Research, NIH, under contract HHSN261200800001E. This research was supported (in part) by the Intramural Research Program of NIH, Frederick National Lab, Center for Cancer Research. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 165 TC 10 Z9 10 U1 1 U2 17 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1478-9450 EI 1744-8387 J9 EXPERT REV PROTEOMIC JI Expert Rev. Proteomics PD NOV 2 PY 2015 VL 12 IS 6 BP 669 EP 682 DI 10.1586/14789450.2015.1100079 PG 14 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA CV8PT UT WOS:000364550800001 PM 26496174 ER PT J AU Faucette, AN Pawlitz, MD Pei, B Yao, FY Chen, K AF Faucette, Azure N. Pawlitz, Michael D. Pei, Bo Yao, Fayi Chen, Kang TI Immunization of pregnant women: Future of early infant protection SO HUMAN VACCINES & IMMUNOTHERAPEUTICS LA English DT Review DE antibody; B cell; clinical trial; immunization; infection; mucosal immunity; neonatal Fc receptor; pregnancy; vaccine; vaccine safety ID ACELLULAR PERTUSSIS-VACCINE; MATERNAL ANTIBODIES; IMMUNE-RESPONSES; FETOMATERNAL INTERFACE; INFLUENZA VACCINATION; ADVISORY-COMMITTEE; DNA IMMUNIZATION; VIRAL CHALLENGE; INNATE IMMUNITY; CTL RESPONSES AB Children in early infancy do not mount effective antibody responses to many vaccines against commons infectious pathogens, which results in a window of increased susceptibility or severity infections. In addition, vaccine-preventable infections are among the leading causes of morbidity in pregnant women. Immunization during pregnancy can generate maternal immune protection as well as elicit the production and transfer of antibodies cross the placenta and via breastfeeding to provide early infant protection. Several successful vaccines are now recommended to all pregnant women worldwide. However, significant gaps exist in our understanding of the efficacy and safety of other vaccines and in women with conditions associated with increased susceptible to high-risk pregnancies. Public acceptance of maternal immunization remained to be improved. Broader success of maternal immunization will rely on the integration of advances in basic science in vaccine design and evaluation and carefully planned clinical trials that are inclusive to pregnant women. C1 [Faucette, Azure N.; Pawlitz, Michael D.; Pei, Bo; Yao, Fayi; Chen, Kang] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI 48202 USA. [Faucette, Azure N.; Pawlitz, Michael D.; Pei, Bo; Yao, Fayi; Chen, Kang] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Detroit, MI USA. [Chen, Kang] Barbara Ann Karmanos Canc Inst, Tumor Biol & Microenvironm Program, Detroit, MI USA. [Chen, Kang] Wayne State Univ, Dept Immunol & Microbiol, Detroit, MI USA. [Chen, Kang] Wayne State Univ, Dept Oncol, Detroit, MI USA. [Chen, Kang] NIAID, Mucosal Immunol Studies Team, NIH, Bethesda, MD 20892 USA. RP Chen, K (reprint author), Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI 48202 USA. EM afaucett@med.wayne.edu; kchen@med.wayne.edu FU Wayne State University OVPR; American Congress of Obstetricians and Gynecologists Industrial Award on Immunization; Burroughs Wellcome Fund Preterm Birth Initiative; National Institutes of Health [U01AI95776]; Wayne State University Maternal Perinatal and Child Health Initiative; Wayne State University Office of the Vice President for Research (OVPR); Barbara Ann Karmanos Cancer Institute FX The authors acknowledge the funding support from the American Congress of Obstetricians and Gynecologists Industrial Award on Immunization, Burroughs Wellcome Fund Preterm Birth Initiative, National Institutes of Health U01AI95776 Young Investigator Award, Wayne State University Maternal Perinatal and Child Health Initiative, Wayne State University Office of the Vice President for Research (OVPR) and Barbara Ann Karmanos Cancer Institute (to K.C.). A.N.F. is supported partly by a fellowship from the Wayne State University OVPR. NR 84 TC 0 Z9 0 U1 1 U2 9 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 2164-5515 EI 2164-554X J9 HUM VACC IMMUNOTHER JI Human Vaccines Immunother. PD NOV 2 PY 2015 VL 11 IS 11 BP 2549 EP 2555 DI 10.1080/21645515.2015.1070984 PG 7 WC Biotechnology & Applied Microbiology; Immunology SC Biotechnology & Applied Microbiology; Immunology GA CV5VI UT WOS:000364339000015 PM 26366844 ER PT J AU Banerjee, T Sommers, JA Huang, J Seidman, MM Brosh, RM AF Banerjee, Taraswi Sommers, Joshua A. Huang, Jing Seidman, Michael M. Brosh, Robert M., Jr. TI Catalytic Strand Separation by RECQ1 Is Required for RPA-Mediated Response to Replication Stress SO CURRENT BIOLOGY LA English DT Article ID SQUAMOUS-CELL CARCINOMA; DNA-DAMAGE; HOMOLOGOUS RECOMBINATION; CANCER PROGRESSION; COLI RECQ; HELICASE; REPAIR; MUTATIONS; MIGRATION; PLAYS AB Three (BLM, WRN, and RECQ4) of the five human RecQ helicases are linked to genetic disorders characterized by genomic instability, cancer, and accelerated aging [1]. RECQ1, the first human RecQ helicase discovered [2-4] and the most abundant [5], was recently implicated in breast cancer [6, 7]. RECQ1 is an ATP-dependent DNA-unwinding enzyme (heli-case) [8, 9] with roles in replication [10-12] and DNA repair [13-16]. RECQ1 is highly expressed in various tumors and cancer cell lines (for review, see [17]), and its suppression reduces cancer cell proliferation [14], suggesting a target for anti-cancer drugs. RECQ1's assembly state plays a critical role in modulating its helicase, branch migration (BM), or strand annealing [18, 19]. The crystal structure of truncated RECQ1 [20, 21] resembles that of E. coli RecQ [22] with two RecA-like domains, a RecQ-specific zinc-binding domain and a winged-helix domain, the latter implicated in DNA strand separation and oligomer formation. In addition, a conserved aromatic loop (AL) is important for DNA unwinding by bacterial RecQ [23, 24] and truncated RECQ1 helicases [21]. To better understand the roles of RECQ1, two AL mutants (W227A and F231A) in full-length RECQ1 were characterized biochemically and genetically. The RECQ1 mutants were defective in helicase or BM but retained DNA binding, oligomerization, ATPase, and strand annealing. RECQ1-depleted HeLa cells expressing either AL mutant displayed reduced replication tract length, elevated dormant origin firing, and increased double-strand breaks that could be suppressed by exogenously expressed replication protein A (RPA). Thus, RECQ1 governs RPA's availability in order to maintain normal replication dynamics, suppress DNA damage, and preserve genome homeostasis. C1 [Banerjee, Taraswi; Sommers, Joshua A.; Huang, Jing; Seidman, Michael M.; Brosh, Robert M., Jr.] NIA, Lab Mol Gerontol, Biomed Res Ctr, NIH, Baltimore, MD 21224 USA. RP Brosh, RM (reprint author), NIA, Lab Mol Gerontol, Biomed Res Ctr, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM broshr@mail.nih.gov FU NIH, NIA, Intramural Research Program FX We wish to thank Dr. M. Wold (University of Iowa) for RPA expression constructs and Drs. M. Scheibye-Knudsen and K. Aly (NIA-NIH) for critical comments on the manuscript. This work was supported by NIH, NIA, Intramural Research Program. NR 44 TC 3 Z9 3 U1 1 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 EI 1879-0445 J9 CURR BIOL JI Curr. Biol. PD NOV 2 PY 2015 VL 25 IS 21 BP 2830 EP 2838 DI 10.1016/j.cub.2015.09.026 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CV4UR UT WOS:000364262500026 PM 26455304 ER PT J AU Sari, O Roy, V Metifiot, M Marchand, C Pommier, Y Bourg, S Bonnet, P Schinazi, RF Agrofoglio, LA AF Sari, Ozkan Roy, Vincent Metifiot, Mathieu Marchand, Christophe Pommier, Yves Bourg, Stephane Bonnet, Pascal Schinazi, Raymond F. Agrofoglio, Luigi A. TI Synthesis of dihydropyrimidine alpha, gamma-diketobutanoic acid derivatives targeting HIV integrase SO EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article DE Dihydropyrimidine alpha, gamma-diketobutanoic acid; Synthesis; Docking analysis; Antiviral activity; Integrase-HIV ID DUAL INHIBITORS; VIRUS; SITE; DNA AB The synthesis and antiviral evaluation of a series of dihydropyrimidinone and thiopyrimidine derivatives bearing aryl alpha, gamma-diketobutanoic acid moiety are described using the Biginelli multicomponent reaction as key step. The most active among 20 synthesized novel compounds were 4c, 4d and 5b, which possess nanomolar HIV-1 integrase (IN) stand transfer (ST) inhibition activities. In order to understand their mode of interactions within the IN active site, we docked all the compounds into the previously reported X-ray crystal structure of IN. We observed that compounds 4c, 4d and 5b occupied an area close to the two catalytic Mg2+ ions surrounded by their chelating triad (E221, D128 and D185), DC16, Y212 and the beta-diketo acid moiety of 4c, 4d and 5b chelating Mg2+. As those compounds lack anti-HIV activities in cell, their prodrugs were synthetized. The prodrug 4c' exhibited an anti-HIV activity of 0.19 mu M in primary human lymphocytes with some cytotoxicity. All together, these results indicate that the new analogs potentially interact within the catalytic site with highly conserved residues important for IN catalytic activity. (C) 2015 Elsevier Masson SAS. All rights reserved. C1 [Sari, Ozkan; Roy, Vincent; Bourg, Stephane; Bonnet, Pascal; Agrofoglio, Luigi A.] Univ Orleans, F-45067 Orleans, France. [Sari, Ozkan; Roy, Vincent; Bourg, Stephane; Bonnet, Pascal; Agrofoglio, Luigi A.] Univ Orleans, CNRS, UMR 7311, ICOA, F-45067 Orleans, France. [Metifiot, Mathieu; Marchand, Christophe; Pommier, Yves] NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Bourg, Stephane] Univ Orleans, CNRS, UPR 4301, CBM, F-45071 Orleans, France. [Schinazi, Raymond F.] Emory Univ, Sch Med, Biochem Pharmacol Lab, Ctr AIDS Res,Dept Pediat, Atlanta, GA 30322 USA. [Schinazi, Raymond F.] Vet Affairs Med Ctr, Atlanta, GA 30322 USA. RP Agrofoglio, LA (reprint author), Univ Orleans, F-45067 Orleans, France. EM luigi.agrofoglio@univ-orleans.fr RI Marchand, Christophe/D-8559-2016; Schinazi, Raymond/B-6777-2017 FU NIH Intramural Research Program, Center for Cancer Research, National Cancer Institute [Z01 BC 007333-09LMP]; French Ministere de l'Enseignement Superieur MNERST; LABEX SynOrg [ANR-11-LABX-0029]; NIH [5P30-AI-50409]; Department of Veterans Affairs FX This work was supported in part by the NIH Intramural Research Program, Center for Cancer Research, National Cancer Institute (Z01 BC 007333-09LMP). O.S. is grateful to the French Ministere de l'Enseignement Superieur MNERST for a Ph.D. scholarship. We thank the LABEX SynOrg (ANR-11-LABX-0029) for financial support. RFS is supported in part by the NIH Grant 5P30-AI-50409 (CFAR) and by the Department of Veterans Affairs. NR 28 TC 3 Z9 3 U1 1 U2 20 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 NOV 2 PY 2015 VL 104 BP 127 EP 138 DI 10.1016/j.ejmech.2015.09.015 PG 12 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA CU8XS UT WOS:000363828000012 PM 26451771 ER PT J AU Colombo, EA Carra, S Fontana, L Bresciani, E Cotelli, F Larizza, L AF Colombo, Elisa A. Carra, Silvia Fontana, Laura Bresciani, Erica Cotelli, Franco Larizza, Lidia TI A zebrafish model of Poikiloderma with Neutropenia recapitulates the human syndrome hallmarks and traces back neutropenia to the myeloid progenitor SO SCIENTIFIC REPORTS LA English DT Article ID CLERICUZIO-TYPE POIKILODERMA; ROTHMUND-THOMSON-SYNDROME; SMALL NUCLEAR-RNA; C16ORF57; GENE; EXPRESSION; MUTATIONS; PATHWAY; MYELODYSPLASIA; HEMATOPOIESIS AB Poikiloderma with Neutropenia (PN) is an autosomal recessive genodermatosis characterized by early-onset poikiloderma, pachyonychia, hyperkeratosis, bone anomalies and neutropenia, predisposing to myelodysplasia. The causative C16orf57/USB1 gene encodes a conserved phosphodiesterase that regulates the stability of spliceosomal U6-RNA. The involvement of USB1 in splicing has not yet allowed to unveil the pathogenesis of PN and how the gene defects impact on skin and bone tissues besides than on the haematological compartment. We established a zebrafish model of PN using a morpholino-knockdown approach with two different splicing morpholinos. Both usb1-depleted embryos displayed developmental abnormalities recapitulating the signs of the human syndrome. Besides the pigmentation and osteochondral defects, usb1-knockdown caused defects in circulation, manifested by a reduced number of circulating cells. The overall morphant phenotype was also obtained by co-injecting sub-phenotypic dosages of the two morpholinos and could be rescued by human USB1 RNA. Integrated in situ and real-time expression analyses of stage-specific markers highlighted defects of primitive haematopoiesis and traced back the dramatic reduction in neutrophil myeloperoxidase to the myeloid progenitors showing down-regulated pu.1 expression. Our vertebrate model of PN demonstrates the intrinsic requirement of usb1 in haematopoiesis and highlights PN as a disorder of myeloid progenitors associated with bone marrow dysfunction. C1 [Colombo, Elisa A.; Fontana, Laura; Larizza, Lidia] Univ Milan, Dipartimento Sci Salute, Milan, Italy. [Carra, Silvia; Bresciani, Erica; Cotelli, Franco] Univ Milan, Dipartimento Biosci, Milan, Italy. [Bresciani, Erica] NHGRI, Oncogenesis & Dev Sect, NIH, Bethesda, MD 20892 USA. [Larizza, Lidia] IRCCS Ist Auxol Italiano, Lab Citogenet Med & Genet Mol, Milan, Italy. RP Colombo, EA (reprint author), Univ Milan, Dipartimento Sci Salute, Milan, Italy. EM elisaadele.colombo@unimi.it RI Carra, Silvia/K-4643-2016; Colombo, Elisa/H-7091-2015 OI Carra, Silvia/0000-0002-9321-9508; Colombo, Elisa/0000-0001-9062-3188 FU Dote di Ricerca FSE, Regione Lombardia [16304]; Progetto Cariplo N.O.B.E.L. (Biological and molecular characterization of cancer stem cells) [Rif.2005.201610.9251] FX This work was supported by Dote di Ricerca FSE, Regione Lombardia funding, to EAC [ID project: 16304, 2011-2012] and Progetto Cariplo N.O.B.E.L. (Biological and molecular characterization of cancer stem cells, Rif.2005.201610.9251) to F.C. and to L.L. We thank dr. Ludovica Volpi (Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Universita degli Studi di Milano), for helpful discussion. NR 45 TC 0 Z9 0 U1 1 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 NOV 2 PY 2015 VL 5 AR 15814 DI 10.1038/srep15814 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CU9VL UT WOS:000363894100001 PM 26522474 ER PT J AU Gillette, WK Esposito, D Blanco, MA Alexander, P Bindu, L Bittner, C Chertov, O Frank, PH Grose, C Jones, JE Meng, ZJ Perkins, S Van, Q Ghirlando, R Fivash, M Nissley, DV McCormick, F Holderfield, M Stephen, AG AF Gillette, William K. Esposito, Dominic Blanco, Maria Abreu Alexander, Patrick Bindu, Lakshman Bittner, Cammi Chertov, Oleg Frank, Peter H. Grose, Carissa Jones, Jane E. Meng, Zhaojing Perkins, Shelley Van, Que Ghirlando, Rodolfo Fivash, Matthew Nissley, Dwight V. McCormick, Frank Holderfield, Matthew Stephen, Andrew G. TI Farnesylated and methylated KRAS4b: high yield production of protein suitable for biophysical studies of prenylated protein-lipid interactions SO SCIENTIFIC REPORTS LA English DT Article ID PLASMA-MEMBRANE; ESCHERICHIA-COLI; K-RAS; PDE-DELTA; H-RAS; ACTIVATION; MECHANISMS; EXPRESSION; BINDING; CHITINASE AB Prenylated proteins play key roles in several human diseases including cancer, atherosclerosis and Alzheimer's disease. KRAS4b, which is frequently mutated in pancreatic, colon and lung cancers, is processed by farnesylation, proteolytic cleavage and carboxymethylation at the C-terminus. Plasma membrane localization of KRAS4b requires this processing as does KRAS4b-dependent RAF kinase activation. Previous attempts to produce modified KRAS have relied on protein engineering approaches or in vitro farnesylation of bacterially expressed KRAS protein. The proteins produced by these methods do not accurately replicate the mature KRAS protein found in mammalian cells and the protein yield is typically low. We describe a protocol that yields 5-10 mg/L highly purified, farnesylated, and methylated KRAS4b from insect cells. Farnesylated and methylated KRAS4b is fully active in hydrolyzing GTP, binds RAF-RBD on lipid Nanodiscs and interacts with the known farnesyl-binding protein PDE delta. C1 [Gillette, William K.; Esposito, Dominic; Blanco, Maria Abreu; Alexander, Patrick; Bindu, Lakshman; Bittner, Cammi; Chertov, Oleg; Frank, Peter H.; Grose, Carissa; Jones, Jane E.; Meng, Zhaojing; Perkins, Shelley; Van, Que; Nissley, Dwight V.; McCormick, Frank; Holderfield, Matthew; Stephen, Andrew G.] Leidos Biomedical Res Inc, Frederick Natl Lab Canc Res, Canc Res Technol Program, Frederick, MD 21702 USA. [Ghirlando, Rodolfo] NIDDK, Mol Biol Lab, Bethesda, MD 20892 USA. [Fivash, Matthew] NCI Frederick, Data Management Syst, Frederick, MD 21702 USA. RP Stephen, AG (reprint author), Leidos Biomedical Res Inc, Frederick Natl Lab Canc Res, Canc Res Technol Program, POB B, Frederick, MD 21702 USA. EM andy.stephen@fnlcr.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Intramural Research Program of the NIH, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) FX We acknowledge the generous gift of Nanodiscs and protocols for their preparation from Drs. Stephen Sligar and Michael Gregory (University of Illinois at Urbana-Champaign). Jennifer Mehalko and Vanessa Wall provided technical support for cloning. Figures for this manuscript were prepared by Alan Kane, (Scientific Publications, Graphics and Media Frederick National Laboratory for Cancer Research.) Finally we appreciate critical reading of this manuscript by Drs. Jim Hartley and David Heimbrook (Frederick National Laboratory for Cancer Research). 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. In addition some of this work was funded in part by the Intramural Research Program of the NIH, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). 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 45 TC 3 Z9 3 U1 2 U2 11 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 NOV 2 PY 2015 VL 5 AR 15916 DI 10.1038/srep15916 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CU9OQ UT WOS:000363874400001 PM 26522388 ER PT J AU King, AJ Jensen, JD Carcioppolo, N Krakow, MM Sun, Y AF King, Andy J. Jensen, Jakob D. Carcioppolo, Nick Krakow, Melinda M. Sun, Ye TI Comparing Theories of Media Learning: Cognitive Mediation, Information Utility, and Knowledge Acquisition from Cancer News SO MASS COMMUNICATION AND SOCIETY LA English DT Article ID PUBLIC KNOWLEDGE; TELEVISION-NEWS; MODEL; COMMUNICATION; COMPREHENSION AB Determining what factors predict media learning is an important avenue of research for the field of mass communication. The present study provides a comparative investigation of two models of media learning: the cognitive mediation model and the information utility model. Participants (N=1,076) read a news article related to scientific discoveries relevant to cancer prevention and responded to all constructs of the two models. Recognition and comprehension were used to measure knowledge acquisition. Results generally support previous predictions of each model, though predicted variance remains small. In addition to testing the existing models, a modified cognitive mediation model using a key construct related to information utilityperceived relevancewas tested. The refined cognitive mediation model offered a more nuanced understanding of certain causal mechanisms but did not result in a meaningful change in predictive power of the model. Implications of the theoretical comparison and integration are discussed. C1 [King, Andy J.] Texas Tech Univ, Coll Media & Commun, Lubbock, TX 79409 USA. [Jensen, Jakob D.; Sun, Ye] Univ Utah, Dept Commun, Salt Lake City, UT 84112 USA. [Carcioppolo, Nick] Univ Miami, Dept Commun Studies, Coral Gables, FL 33124 USA. [Krakow, Melinda M.] NCI, Div Canc Prevent, Bethesda, MD 20892 USA. RP King, AJ (reprint author), Texas Tech Univ, Coll Media & Commun, 3003 15th St, Lubbock, TX 79409 USA. EM andy.king@ttu.edu NR 33 TC 0 Z9 0 U1 4 U2 5 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1520-5436 EI 1532-7825 J9 MASS COMMUN SOC JI Mass Commun. Soc. PD NOV 2 PY 2015 VL 18 IS 6 BP 753 EP 775 DI 10.1080/15205436.2015.1027406 PG 23 WC Communication SC Communication GA CT3OU UT WOS:000362717100003 ER PT J AU Halldorsdottir, T Ollendick, TH Ginsburg, G Sherrill, J Kendall, PC Walkup, J Sakolsky, DJ Piacentini, J AF Halldorsdottir, Thorhildur Ollendick, Thomas H. Ginsburg, Golda Sherrill, Joel Kendall, Philip C. Walkup, John Sakolsky, Dara J. Piacentini, John TI Treatment Outcomes in Anxious Youth with and without Comorbid ADHD in the CAMS SO JOURNAL OF CLINICAL CHILD AND ADOLESCENT PSYCHOLOGY LA English DT Article ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; COGNITIVE-BEHAVIORAL THERAPY; CHILDHOOD ANXIETY DISORDERS; DEFICIT HYPERACTIVITY DISORDER; INTERVIEW SCHEDULE; TREATMENT RESPONSE; DSM-IV; CHILDREN; ADOLESCENTS; MODERATORS AB The purpose of this study is to examine the influence of Attention-Deficit/Hyperactivity Disorder (ADHD), independent of Oppositional Defiant Disorder (ODD), on acute treatment response, remission rates and maintenance of gains at 6-month follow-up in anxious youth (ages 7-17, 76% Caucasian, 52% female) who received cognitive-behavioral therapy (CBT) alone, pharmacotherapy alone, the combination of CBT and pharmacotherapy or placebo pill in the Child/Adolescent Multimodal Study. Treatment response was defined as independent evaluator rated meaningful improvement in anxiety. Remission was operationalized as the absence of targeted anxiety disorders. ADHD and ODD were examined as moderators of outcomes at a diagnostic level. In the CBT group only, an ADHD diagnosis predicted poorer immediate treatment response and remission rates. However, these associations were not obtained for the pharmacotherapy groups. Participants with comorbid ODD were not less likely to achieve acute treatment response and remission rates than their counterparts across treatment conditions. Due to small sample size of the comorbid subgroups, our analyses must be considered preliminary. Nevertheless, our initial findings suggest further exploration of the separate roles of ADHD and ODD are worth pursuing, as they may be differentially associated with treatment outcomes in anxious youth treated with CBT but not youth treated with pharmacotherapy. If confirmed, findings may indicate that anxious youth with comorbid ADHD are less likely to benefit from CBT strategies alone and raise the possibility that these youth need adjunctive pharmacotherapy or psychosocial interventions. C1 [Halldorsdottir, Thorhildur; Ollendick, Thomas H.] Virginia Polytech Inst & State Univ, Dept Psychol, Blacksburg, VA 24060 USA. [Ginsburg, Golda] Johns Hopkins Univ, Sch Med, Div Child & Adolescent Psychiat, Baltimore, MD 21218 USA. [Sherrill, Joel] NIMH, Div Serv & Intervent Res, Bethesda, MD USA. [Kendall, Philip C.] Temple Univ, Dept Psychol, Philadelphia, PA 19122 USA. [Walkup, John] Weill Cornell Med Coll, Dept Psychiat, New York, NY USA. [Walkup, John] New York Presbyterian Hosp, New York, NY USA. [Sakolsky, Dara J.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15260 USA. [Piacentini, John] UCLA Psychiat & Behav Sci, Semel Inst, Los Angeles, CA USA. RP Halldorsdottir, T (reprint author), Virginia Polytech Inst & State Univ, Dept Psychol, Blacksburg, VA 24060 USA. EM thorhh1@vt.edu NR 33 TC 3 Z9 3 U1 3 U2 15 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1537-4416 EI 1537-4424 J9 J CLIN CHILD ADOLESC JI J. Clin. Child Adolesc. Psychol. PD NOV 2 PY 2015 VL 44 IS 6 BP 985 EP 991 DI 10.1080/15374416.2014.952008 PG 7 WC Psychology, Clinical; Psychology, Developmental SC Psychology GA CS5OY UT WOS:000362128800007 PM 25310142 ER PT J AU De Vita, F Maggio, M Lauretani, F Crucitti, L Bandinelli, S Mammarella, F Landi, F Ferrucci, L Ceda, GP AF De Vita, Francesca Maggio, Marcello Lauretani, Fulvio Crucitti, Lara Bandinelli, Stefania Mammarella, Federica Landi, Francesco Ferrucci, Luigi Ceda, Gian Paolo TI INSULIN-LIKE GROWTH FACTOR-1 AND ANEMIA IN OLDER SUBJECTS: THE INCHIANTI STUDY SO ENDOCRINE PRACTICE LA English DT Article ID BLOOD HEMOGLOBIN CONCENTRATION; PROINFLAMMATORY STATE; PHYSICAL PERFORMANCE; UNEXPLAINED ANEMIA; MUSCLE STRENGTH; UNITED-STATES; IGF-I; ERYTHROPOIESIS; SERUM; HORMONE AB Objective: Recent studies indicate a role for the age-related decline of anabolic hormones, especially testosterone, in the onset of "anemia of aging." Some of testosterone's erythropoietic activities are mediated by insulin-like growth factor (IGF)-1, which also seems to have independent erythropoietic effects. However, the associations among IGF-1, anemia, and hemoglobin (Hb) have not been adequately investigated in older populations. Methods: We used data from a representative sample of 953 subjects >= 65 years who participated in the InCHIANTI (Invecchiare in Chianti) Study and were not on growth hormone (GH) or erythropoietin therapy and were not diagnosed with hematologic malignancies or other cancers. Anemia was defined according to the World Health Organization (WHO) criteria by Hb level <= 13 g/dL in males and <= 12 g/dL in females. Backward multiple regression analyses including age, IGF binding protein (IGFBP)-3, testosterone, comorbidities, inflammatory markers, and anemia-related measures were used to address the relationship between IGF-1 and Hb and between IGF-1 and anemia in both sexes. Results: We found that 46/410 (11.2%) males and 71/543 (13.0%) females were defined as anemic. After adjustment for age, anemic males (100 +/- 54 vs. 130 +/- 56, P<.001) and females (89.1 +/- 48 vs. 110 +/- 52, P = .001) exhibited lower IGF-1 levels than their nonanemic counterparts. IGF-1 levels were independently and negatively associated with anemia in males (beta +/- SE = -0.0005 +/- 0.0002, P = .04) but not in females (beta +/- SE = -0.0002 +/- 0.0002, P = .40). In both males (beta +/- SE = 0.002 +/- 0.001, P = .03) and females (beta +/- SE = 0.002 +/- 0.0009, P = .03), IGF-1 levels were independently and positively associated with Hb levels. Conclusion: In older males but not in females, IGF-1 levels are negatively associated with anemia. IGF-1 levels are independent and positive determinants of Hb concentration in both sexes. C1 [De Vita, Francesca; Maggio, Marcello; Lauretani, Fulvio; Ceda, Gian Paolo] Univ Hosp Parma, Geriatr Rehabil Dept, Parma, Italy. [Maggio, Marcello; Ceda, Gian Paolo] Univ Parma, Dept Clin & Expt Med, Sect Geriatr, Food Sci Unit, I-43100 Parma, Italy. [Maggio, Marcello; Ceda, Gian Paolo] Univ Parma, Endocrinol Aging Unit, I-43100 Parma, Italy. [Crucitti, Lara] Ist Sci San Raffaele, Hematol & Bone Marrow Transplantat Unit, I-20132 Milan, Italy. [Bandinelli, Stefania] Azienda Sanit Firenze, Florence, Italy. [Mammarella, Federica; Landi, Francesco] Univ Cattolica Sacro Cuore, Dept Geriatr Neurosci & Orthoped, I-00168 Rome, Italy. [Ferrucci, Luigi] NIA, NIH, Baltimore, MD 21224 USA. RP Maggio, M (reprint author), Univ Parma, Dept Clin & Expt Med, Sect Geriatr, Endocrinol Aging Unit, Via Gramsci 14, I-43126 Parma, Emilia Romagna, Italy. EM marcellomaggio2001@yahoo.it RI Lauretani, Fulvio/K-5115-2016; OI Lauretani, Fulvio/0000-0002-5287-9972; Ceda, Gian Paolo/0000-0002-9648-8295 FU Italian Ministry of Health [ICS 110.1/RS97.71]; U.S. National Institute on Aging [N01-AG-916413, N01-AG-821336]; Intramural Research Program of the U.S. National Institute on Aging [263 MD 9164 13, 263 MD 821336] FX We thank all the study participants and Fabrizio Ablondi, Maurizio Conca, and Pietro Schianchi for their technical support. The InCHIANTI Study was supported as a "targeted project" (ICS 110.1/RS97.71) by the Italian Ministry of Health and in part by the U.S. National Institute on Aging (Contracts N01-AG-916413 and N01-AG-821336) and by the Intramural Research Program of the U.S. National Institute on Aging (Contracts 263 MD 9164 13 and 263 MD 821336). NR 40 TC 1 Z9 1 U1 0 U2 0 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 NOV PY 2015 VL 21 IS 11 BP 1211 EP 1218 DI 10.4158/EP14100.OR PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DO7MF UT WOS:000377966000003 PM 26214107 ER PT J AU Mills, KL Dumontheil, I Speekenbrink, M Blakemore, SJ AF Mills, Kathryn L. Dumontheil, Iroise Speekenbrink, Maarten Blakemore, Sarah-Jayne TI Multitasking during social interactions in adolescence and early adulthood SO ROYAL SOCIETY OPEN SCIENCE LA English DT Article DE cognitive load; development; dual task; egocentric bias; working memory ID CHILDREN; EGOCENTRISM; PERSPECTIVE; MIND AB Multitasking is part of the everyday lives of both adolescents and adults. We often multitask during social interactions by simultaneously keeping track of other non-social information. Here, we examined how keeping track of non-social information impacts the ability to navigate social interactions in adolescents and adults. Participants aged 11-17 and 22-30 years old were instructed to carry out two tasks, one social and one non-social, within each trial. The social task involved referential communication, requiring participants to use social cues to guide their decisions, which sometimes required taking a different perspective. The non-social task manipulated cognitive load by requiring participants to remember non-social information in the form of one two-digit number (low load) or three two-digit numbers (high load) presented before each social task stimulus. Participants showed performance deficits when under high cognitive load and when the social task involved taking a different perspective, and individual differences in both trait perspective taking and working memory capacity predicted performance. Overall, adolescents were less adept at multitasking than adults when under high cognitive load. These results suggest that multitasking during social interactions incurs performance deficits, and that adolescents are more sensitive than adults to the effects of cognitive load while multitasking. C1 [Mills, Kathryn L.; Dumontheil, Iroise; Blakemore, Sarah-Jayne] UCL, Inst Cognit Neurosci, London, England. [Mills, Kathryn L.; Dumontheil, Iroise; Blakemore, Sarah-Jayne] UCL, Expt Psychol, London, England. [Dumontheil, Iroise] Univ London Birkbeck Coll, Dept Psychol Sci, London WC1E 7HX, England. [Mills, Kathryn L.] NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. RP Mills, KL (reprint author), UCL, Inst Cognit Neurosci, London, England. EM kathryn.l.mills@gmail.com OI Speekenbrink, Maarten/0000-0003-3221-1091 FU NIH Graduate Partnership Program; Royal Society University Research Fellowship FX K.L.M. is supported by the NIH Graduate Partnership Program. S.-J.B. is funded by a Royal Society University Research Fellowship. NR 17 TC 2 Z9 2 U1 5 U2 6 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 2054-5703 J9 ROY SOC OPEN SCI JI R. Soc. Open Sci. PD NOV PY 2015 VL 2 IS 11 AR 150117 DI 10.1098/rsos.150117 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DO7MV UT WOS:000377967600001 PM 26715991 ER PT J AU Kueider, AM Palchamy, E Tanaka, T An, Y Kitner-Triolo, M Thambisetty, M AF Kueider, A. M. Palchamy, E. Tanaka, T. An, Y. Kitner-Triolo, M. Thambisetty, M. TI GENETIC PREDISPOSITION TO DECREASED SERUM VITAMIN D AND COGNITION: A MENDELIAN RANDOMIZATION ANALYSIS SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Kueider, A. M.; Palchamy, E.; Tanaka, T.; An, Y.; Kitner-Triolo, M.; Thambisetty, M.] NIA, Baltimore, MD 21224 USA. [Kueider, A. M.] Johns Hopkins Bloomberg Sch Publ Hlth, Mental Hlth, Baltimore, MD USA. NR 0 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 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2015 VL 55 SU 2 BP 60 EP 60 PG 1 WC Gerontology SC Geriatrics & Gerontology GA DJ5BV UT WOS:000374222700239 ER PT J AU Moore, AZ Ding, J Tuke, MA Wood, A Melzer, D Bandinelli, S Frayling, T Ferrucci, L AF Moore, A. Z. Ding, J. Tuke, M. A. Wood, A. Melzer, D. Bandinelli, S. Frayling, T. Ferrucci, L. TI DISTRIBUTION OF MITOCHONDRIAL DNA HETEROPLASMY IN PARTICIPANTS OF THE INCHIANTI STUDY SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Moore, A. Z.; Ding, J.; Ferrucci, L.] Natl Inst Aging, Baltimore, MD USA. [Tuke, M. A.; Wood, A.; Frayling, T.] Univ Exeter, Sch Med, Genet Complex Traits, Exeter, Devon, England. [Melzer, D.] Univ Exeter, Sch Med, Inst Biomed & Clin Sci, Exeter, Devon, England. [Bandinelli, S.] Azienda Sanit Firenze, Geriatr Rehabil Unit, Florence, Italy. NR 0 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 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2015 VL 55 SU 2 BP 67 EP 67 PG 1 WC Gerontology SC Geriatrics & Gerontology GA DJ5BV UT WOS:000374222700263 ER PT J AU Spira, AP Gonzalez, CE Venkatraman, V Wu, MN Pacheco, J Simonsick, EM Resnick, S AF Spira, A. P. Gonzalez, C. E. Venkatraman, V. Wu, M. N. Pacheco, J. Simonsick, E. M. Resnick, S. TI ASSOCIATION OF SLEEP DURATION WITH SUBSEQUENT GRAY MATTER ATROPHY IN COMMUNITY-DWELLING OLDER ADULTS SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Spira, A. P.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD USA. [Spira, A. P.; Wu, M. N.] Johns Hopkins Sch Med, Baltimore, MD USA. [Gonzalez, C. E.; Venkatraman, V.; Pacheco, J.; Simonsick, E. M.; Resnick, S.] NIA, Intramural Res Program, Baltimore, MD 21224 USA. [Pacheco, J.] Walter Reed Natl Mil Med Ctr, Bethesda, MD USA. NR 0 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 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2015 VL 55 SU 2 BP 70 EP 70 PG 1 WC Gerontology SC Geriatrics & Gerontology GA DJ5BV UT WOS:000374222700271 ER PT J AU Wennberg, AM Spira, AP Soldan, A Pettigrew, C Miller, MI Thambisetty, M Zipunnikov, V Albert, M AF Wennberg, A. M. Spira, A. P. Soldan, A. Pettigrew, C. Miller, M. I. Thambisetty, M. Zipunnikov, V. Albert, M. TI BLOOD GLUCOSE AND REDUCED CORTICAL THICKNESS IN AD VULNERABLE REGIONS IN MIDDLE AGED ADULTS SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Wennberg, A. M.; Spira, A. P.; Zipunnikov, V.; Albert, M.] Johns Hopkins Sch Publ Hlth, Mental Hlth, Baltimore, MD USA. [Soldan, A.; Pettigrew, C.] Johns Hopkins Sch Med, Baltimore, MD USA. [Thambisetty, M.] NIA, Unit Clin & Translat Neurosci, Baltimore, MD 21224 USA. [Miller, M. I.] Johns Hopkins Univ, Ctr Imaging Sci, Baltimore, MD USA. NR 0 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 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2015 VL 55 SU 2 BP 86 EP 86 PG 1 WC Gerontology SC Geriatrics & Gerontology GA DJ5BV UT WOS:000374222700321 ER PT J AU Rathbun, AM Shardell, M Orwig, D Gruber-Baldini, AL Johnson, R Hochberg, M Magaziner, J AF Rathbun, A. M. Shardell, M. Orwig, D. Gruber-Baldini, A. L. Johnson, R. Hochberg, M. Magaziner, J. TI THE IMPACT OF DEPRESSION ON PHYSICAL PERFORMANCE FOLLOWING HIP FRACTURE SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Rathbun, A. M.; Shardell, M.; Orwig, D.; Gruber-Baldini, A. L.; Johnson, R.; Hochberg, M.; Magaziner, J.] Univ Maryland, Sch Med, Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Shardell, M.] NIA, Bethesda, MD 20892 USA. NR 0 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 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2015 VL 55 SU 2 BP 88 EP 88 PG 1 WC Gerontology SC Geriatrics & Gerontology GA DJ5BV UT WOS:000374222700327 ER PT J AU Rawal, S Hoffman, HJ Bainbridge, KE Huedo-Medina, T Duffy, VB AF Rawal, S. Hoffman, H. J. Bainbridge, K. E. Huedo-Medina, T. Duffy, V. B. TI PREVALENCE AND RISK FACTORS OF SELF-REPORTED CHEMOSENSORY ALTERATIONS IN THE UNITED STATES: NHANES 2011-2012 SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Rawal, S.; Huedo-Medina, T.; Duffy, V. B.] Univ Connecticut, Allied Hlth Sci, Storrs, CT USA. [Hoffman, H. J.; Bainbridge, K. E.] Natl Inst Deafness & Other Commun Disorders, Epidemiol & Stat Program, NIH, Bethesda, MD USA. NR 0 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 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2015 VL 55 SU 2 BP 99 EP 99 PG 1 WC Gerontology SC Geriatrics & Gerontology GA DJ5BV UT WOS:000374222700364 ER PT J AU Best, JR Rosano, C Boudreau, R Simonsick, EM Studenski, S Yaffe, K Newman, AB Liu-Ambrose, T AF Best, J. R. Rosano, C. Boudreau, R. Simonsick, E. M. Studenski, S. Yaffe, K. Newman, A. B. Liu-Ambrose, T. TI THE IMPACT OF MAINTAINING WALKING IN LATE LIFE ON FUTURE CHANGE IN BRAIN MICRO- AND MACRO-STRUCTURE SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Rosano, C.; Boudreau, R.; Newman, A. B.] Univ Pittsburgh, Pittsburgh, PA USA. [Best, J. R.; Liu-Ambrose, T.] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Yaffe, K.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Simonsick, E. M.; Studenski, S.] NIA, NIH, Bethesda, MD 20892 USA. NR 0 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 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2015 VL 55 SU 2 BP 151 EP 152 PG 2 WC Gerontology SC Geriatrics & Gerontology GA DJ5BV UT WOS:000374222701005 ER PT J AU Flatt, JD Rosano, C Rosario, BL Rosso, AL Fowler, NR Aizenstein, HJ Newman, AB Simonsick, EM AF Flatt, J. D. Rosano, C. Rosario, B. L. Rosso, A. L. Fowler, N. R. Aizenstein, H. J. Newman, A. B. Simonsick, E. M. TI ASSOCIATION OF SOCIAL AND RECREATIONAL ACTIVITIES WITH BRAIN VOLUMES IN LATE LIFE SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Flatt, J. D.; Rosano, C.; Rosario, B. L.; Rosso, A. L.; Fowler, N. R.; Aizenstein, H. J.; Newman, A. B.] Univ Pittsburgh, Pittsburgh, PA USA. [Simonsick, E. M.] NIA, NIH, Bethesda, MD 20892 USA. NR 0 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 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2015 VL 55 SU 2 BP 151 EP 151 PG 1 WC Gerontology SC Geriatrics & Gerontology GA DJ5BV UT WOS:000374222701004 ER PT J AU O'Hare, CJ Kenny, R Rosano, C Boudreau, R Newman, AB Launer, LJ Yaffe, K Aizenstein, HJ AF O'Hare, C. J. Kenny, R. Rosano, C. Boudreau, R. Newman, A. B. Launer, L. J. Yaffe, K. Aizenstein, H. J. TI SELECTED VASCULAR RISK FACTORS AND FUTURE CEREBRAL BLOOD FLOW IN OLDER ADULTS SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Rosano, C.; Boudreau, R.; Newman, A. B.; Aizenstein, H. J.] Univ Pittsburgh, Pittsburgh, PA USA. [O'Hare, C. J.; Kenny, R.] Univ Dublin Trinity Coll, Dublin 2, Ireland. [Launer, L. J.] NIH, Bethesda, MD 20892 USA. [Yaffe, K.] Univ Calif San Francisco, San Francisco, CA 94143 USA. NR 0 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 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2015 VL 55 SU 2 BP 151 EP 151 PG 1 WC Gerontology SC Geriatrics & Gerontology GA DJ5BV UT WOS:000374222701003 ER PT J AU Barr, RA Hunter, C AF Barr, R. A. Hunter, C. TI RESEARCH AND TRAINING OPPORTUNITIES WITH THE NATIONAL INSTITUTE ON AGING SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Barr, R. A.] NIA, Bethesda, MD 20892 USA. NR 0 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 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2015 VL 55 SU 2 BP 164 EP 164 PG 1 WC Gerontology SC Geriatrics & Gerontology GA DJ5BV UT WOS:000374222701059 ER PT J AU Hill, CV AF Hill, C. V. TI ADDRESSING HEALTH DISPARITIES WITH THE NATIONAL INSTITUTE ON AGING SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Hill, C. V.] NIA, Bethesda, MD 20892 USA. NR 0 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 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2015 VL 55 SU 2 BP 164 EP 164 PG 1 WC Gerontology SC Geriatrics & Gerontology GA DJ5BV UT WOS:000374222701058 ER PT J AU Morissette-Thomas, V Cohen, AA Riesco, E Ferrucci, L AF Morissette-Thomas, V. Cohen, A. A. Riesco, E. Ferrucci, L. TI COMPLEX INTERACTIONS BETWEEN INFLAMMATION AND METABOLIC HORMONES DURING AGING SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Morissette-Thomas, V.; Cohen, A. A.] Univ Sherbrooke, Math, Sherbrooke, PQ J1K 2R1, Canada. [Riesco, E.] Res Ctr Aging, Sherbrooke, PQ, Canada. [Ferrucci, L.] Natl Inst Aging, Baltimore, MD USA. NR 0 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 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2015 VL 55 SU 2 BP 197 EP 197 PG 1 WC Gerontology SC Geriatrics & Gerontology GA DJ5BV UT WOS:000374222701177 ER PT J AU Armstrong, JJ Godin, J Mitnitski, AB Andrew, M Launer, LJ White, L Rockwood, K AF Armstrong, J. J. Godin, J. Mitnitski, A. B. Andrew, M. Launer, L. J. White, L. Rockwood, K. TI EXAMINING THE DYNAMIC ASSOCIATION BETWEEN FRAILTY AND COGNITIVE CHANGE IN OLDER MEN SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Armstrong, J. J.; Mitnitski, A. B.; Rockwood, K.] Dalhousie Univ, Halifax, NS, Canada. [Godin, J.; Andrew, M.] Capital Dist Hlth Author, Halifax, NS, Canada. [Launer, L. J.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [White, L.] Pacific Hlth Res & Educ Inst, Honolulu, HI USA. NR 0 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 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2015 VL 55 SU 2 BP 233 EP 234 PG 2 WC Gerontology SC Geriatrics & Gerontology GA DJ5BV UT WOS:000374222701299 ER PT J AU Nicklett, EJ Rostant, O Taylor, R AF Nicklett, E. J. Rostant, O. Taylor, R. TI FALL PROFILES OF OLDER AFRICAN AMERICAN ADULTS: AN EXAMINATION OF RISK AND PROTECTIVE FACTORS USING THE HEALTH & RETIREMENT STUDY SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Nicklett, E. J.; Taylor, R.] Univ Michigan, Sch Social Work, Ann Arbor, MI 48109 USA. [Rostant, O.] NIH, Baltimore, MD USA. [Taylor, R.] Univ Michigan, Inst Social Res, Ann Arbor, MI USA. NR 0 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 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2015 VL 55 SU 2 BP 237 EP 237 PG 1 WC Gerontology SC Geriatrics & Gerontology GA DJ5BV UT WOS:000374222701310 ER PT J AU Eymundsdottir, H Chang, M Jonsson, PV Launer, LJ Cotch, M Gudnason, V Ramel, A AF Eymundsdottir, H. Chang, M. Jonsson, P. V. Launer, L. J. Cotch, M. Gudnason, V. Ramel, A. TI ASSOCIATION BETWEEN SERUM 25 HYDROXY VITAMIN D AND LIFESTYLE FACTORS AMONG OLDER ADULTS IN ICELAND (AGES-REYKJAViK). SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Eymundsdottir, H.; Chang, M.; Ramel, A.] Univ Iceland, Fac Food Sci & Nutr, Reykjavik, Iceland. [Chang, M.] Reykjavik Univ, Sch Sci & Engn, Sports Sci, Reykjavik, Iceland. [Jonsson, P. V.] Univ Iceland, Fac Med, Reykjavik, Iceland. [Launer, L. J.] NIA, Intramural Res Program, Bethesda, MD 20892 USA. [Cotch, M.] NEI, Div Epidemiol & Clin Applicat, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Gudnason, V.] Iceland Heart Assoc Res Inst, Kopavogur, Iceland. NR 0 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 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2015 VL 55 SU 2 BP 252 EP 252 PG 1 WC Gerontology SC Geriatrics & Gerontology GA DJ5BV UT WOS:000374222701362 ER PT J AU Boot, WR Kueider, AM Gross, AL AF Boot, W. R. Kueider, A. M. Gross, A. L. TI DURABILITY, ADHERENCE AND LONGITUDINAL ANALYSES: CHALLENGES AND PROPOSED SOLUTIONS FOR COGNITIVE INTERVENTIONS SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Boot, W. R.] Florida State Univ, Psychol, Tallahassee, FL 32306 USA. [Kueider, A. M.] NIA, IRP Biomed Res Ctr, Baltimore, MD 21224 USA. [Gross, A. L.] Johns Hopkins Univ, Baltimore, MD USA. NR 0 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 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2015 VL 55 SU 2 BP 272 EP 272 PG 1 WC Gerontology SC Geriatrics & Gerontology GA DJ5BV UT WOS:000374222701431 ER PT J AU Shaffer, NC Fabbri, E Ferrucci, L Shardell, M Studenski, S AF Shaffer, N. Chiles Fabbri, E. Ferrucci, L. Shardell, M. Studenski, S. TI DISCRIMINANT VALIDITY OF MUSCLE QUALITY INDICATORS IN THE BALTIMORE LONGITUDINAL STUDY OF AGING SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Shaffer, N. Chiles; Fabbri, E.; Ferrucci, L.; Shardell, M.; Studenski, S.] NIA, NIH, Baltimore, MD 21224 USA. NR 0 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 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2015 VL 55 SU 2 BP 283 EP 283 PG 1 WC Gerontology SC Geriatrics & Gerontology GA DJ5BV UT WOS:000374222701474 ER PT J AU Marcum, CS Koehly, LM Lin, J AF Marcum, C. S. Koehly, L. M. Lin, J. TI THE EFFECT OF AGE ON PERCEPTIONS OF SOCIAL POSITIONS IN PERSONAL ACQUAINTANCE NETWORKS SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Marcum, C. S.; Koehly, L. M.; Lin, J.] NHGRI, SBRB, NIH, Bethesda, MD 20892 USA. NR 0 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 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2015 VL 55 SU 2 BP 295 EP 295 PG 1 WC Gerontology SC Geriatrics & Gerontology GA DJ5BV UT WOS:000374222701520 ER PT J AU Fabbri, E Shaffer, NC Gonzalez-Freire, M Shardell, M Zoli, M Studenski, S Ferrucci, L AF Fabbri, E. Shaffer, N. Chiles Gonzalez-Freire, M. Shardell, M. Zoli, M. Studenski, S. Ferrucci, L. TI BODY COMPOSITION, BUT NOT BMI, PREDICTS LONGITUDINAL DECLINE IN MUSCLE QUALITY IN OLDER MEN AND WOMEN FROM THE BALTIMORE LONGITUDINAL STUDY OF AGING SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Fabbri, E.; Shaffer, N. Chiles; Gonzalez-Freire, M.; Shardell, M.; Studenski, S.; Ferrucci, L.] NIA, Longitudinal Studies Sect, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. [Fabbri, E.; Zoli, M.] Univ Bologna, Dept Med & Surg Sci, Bologna, Italy. NR 0 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 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2015 VL 55 SU 2 BP 319 EP 320 PG 2 WC Gerontology SC Geriatrics & Gerontology GA DJ5BV UT WOS:000374222701618 ER PT J AU Cruz-Almeida, Y Rosso, AL Harris, TB Marcum, Z Yaffe, K Newman, AB Rosano, C AF Cruz-Almeida, Y. Rosso, A. L. Harris, T. B. Marcum, Z. Yaffe, K. Newman, A. B. Rosano, C. TI ASSOCIATIONS OF MUSCULOSKELETAL PAIN WITH MOBILITY IN OLDER ADULTS: POTENTIAL CEREBRAL MECHANISMS. SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Cruz-Almeida, Y.] Inst Aging Cognit Aging & Memory, Clin Translat Res Program, Gainesville, FL USA. [Rosso, A. L.; Marcum, Z.; Newman, A. B.; Rosano, C.] Univ Pittsburgh, Pittsburgh, PA USA. [Harris, T. B.] NIA, Bethesda, MD 20892 USA. [Yaffe, K.] Univ Calif San Francisco, San Francisco, CA 94143 USA. NR 0 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 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2015 VL 55 SU 2 BP 334 EP 334 PG 1 WC Gerontology SC Geriatrics & Gerontology GA DJ5BV UT WOS:000374222701671 ER PT J AU Rosso, AL Tudorascu, DL Aizenstein, HJ Newman, AB Harris, T Satterfield, S Yaffe, K Rosano, C AF Rosso, A. L. Tudorascu, D. L. Aizenstein, H. J. Newman, A. B. Harris, T. Satterfield, S. Yaffe, K. Rosano, C. TI AGE-RELATED CHANGES IN GREY MATTER VOLUME AND CHANGES IN GAIT VARIABILITY SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Rosso, A. L.; Tudorascu, D. L.; Aizenstein, H. J.; Newman, A. B.; Rosano, C.] Univ Pittsburgh, Pittsburgh, PA USA. [Harris, T.] NIA, Bethesda, MD 20892 USA. [Satterfield, S.] Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. [Yaffe, K.] Univ Calif San Francisco, San Francisco, CA 94143 USA. NR 0 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 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2015 VL 55 SU 2 BP 334 EP 334 PG 1 WC Gerontology SC Geriatrics & Gerontology GA DJ5BV UT WOS:000374222701673 ER PT J AU Wright, RS Kuczmarski, M Waldstein, SR Pohlig, RT Evans, MK Zonderman, AB AF Wright, R. S. Kuczmarski, M. Waldstein, S. R. Pohlig, R. T. Evans, M. K. Zonderman, A. B. TI POVERTY STATUS MODERATES RELATIONS OF DIET QUALITY TO COGNITIVE PERFORMANCE AMONG AFRICAN AMERICAN AND WHITE URBAN DWELLING ADULTS SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Wright, R. S.; Kuczmarski, M.; Pohlig, R. T.] Univ Delaware, Sch Nursing, Newark, DE USA. [Waldstein, S. R.] Univ Maryland Baltimore Cty, Baltimore, MD 21228 USA. [Evans, M. K.; Zonderman, A. B.] NIA, Baltimore, MD 21224 USA. NR 0 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 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2015 VL 55 SU 2 BP 346 EP 346 PG 1 WC Gerontology SC Geriatrics & Gerontology GA DJ5BV UT WOS:000374222701723 ER PT J AU Lin, J Marcum, CS Myers, MF Koehly, LM AF Lin, J. Marcum, C. S. Myers, M. F. Koehly, L. M. TI MULTIPLE-INFORMANT FAMILY HEALTH HISTORY ASSESSMENT: CONSISTENT PERCEPTIONS ACROSS FAMILY MEMBERS? SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Lin, J.; Marcum, C. S.; Koehly, L. M.] NHGRI, Bethesda, MD 20892 USA. [Myers, M. F.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. NR 0 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 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2015 VL 55 SU 2 BP 376 EP 377 PG 2 WC Gerontology SC Geriatrics & Gerontology GA DJ5BV UT WOS:000374222701840 ER PT J AU O'Hare, CJ Kenny, R Aizenstein, HJ Boudreau, R Newman, AB Launer, LJ Yaffe, K Rosano, C AF O'Hare, C. J. Kenny, R. Aizenstein, H. J. Boudreau, R. Newman, A. B. Launer, L. J. Yaffe, K. Rosano, C. TI COGNITIVE STATUS, GRAY MATTER ATROPHY AND ORTHOSTATIC BLOOD PRESSURE RESPONSE IN ADULTS AGED 83+ SO GERONTOLOGIST LA English DT Meeting Abstract C1 [O'Hare, C. J.; Kenny, R.] Univ Dublin Trinity Coll, Irish Longitudinal Study Ageing, Dublin 2, Ireland. [Aizenstein, H. J.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. [Boudreau, R.; Newman, A. B.; Rosano, C.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Launer, L. J.] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. [Yaffe, K.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Yaffe, K.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Yaffe, K.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. NR 0 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 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2015 VL 55 SU 2 BP 410 EP 411 PG 2 WC Gerontology SC Geriatrics & Gerontology GA DJ5BV UT WOS:000374222702117 ER PT J AU Huizer-Pajkos, A Kane, AE Howlett, SE Mach, J Mitchell, S De Cabo, R Le Couteur, D Hilmer, S AF Huizer-Pajkos, A. Kane, A. E. Howlett, S. E. Mach, J. Mitchell, S. De Cabo, R. Le Couteur, D. Hilmer, S. TI THE INFLUENCE OF AGING ON ADVERSE GERIATRIC OUTCOMES SECONDARY TO POLYPHARMACY IN A MOUSE MODEL SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Huizer-Pajkos, A.; Kane, A. E.; Mach, J.; Hilmer, S.] Univ Sydney, Royal N Shore Hosp, Kolling Insitute Med Res, St Leonards, NSW 2065, Australia. [Howlett, S. E.] Dalhousie Univ, Halifax, NS, Canada. [Mitchell, S.; De Cabo, R.] NIA, Baltimore, MD 21224 USA. [Le Couteur, D.] Concord Hosp, Sydney, NSW, Australia. [Le Couteur, D.] Univ Sydney, Sydney, NSW 2006, Australia. NR 0 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 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2015 VL 55 SU 2 BP 461 EP 461 PG 1 WC Gerontology SC Geriatrics & Gerontology GA DJ5BV UT WOS:000374222702283 ER PT J AU McCabe, E Murabito, JM Cheng, S Larson, MG AF McCabe, E. Murabito, J. M. Cheng, S. Larson, M. G. TI THE HEALTHY AGING INDEX PREDICTS MORTALITY IN THE FRAMINGHAM OFFSPRING STUDY SO GERONTOLOGIST LA English DT Meeting Abstract C1 [McCabe, E.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Murabito, J. M.; Cheng, S.; Larson, M. G.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Murabito, J. M.; Cheng, S.; Larson, M. G.] Boston Univ, Sch Med, Framingham, MA USA. [Cheng, S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiovasc, Boston, MA 02115 USA. [Larson, M. G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Murabito, J. M.] Boston Univ, Sch Med, Dept Med, Gen Internal Med, Boston, MA 02118 USA. NR 0 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 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2015 VL 55 SU 2 BP 650 EP 650 PG 1 WC Gerontology SC Geriatrics & Gerontology GA DJ5BV UT WOS:000374222703150 ER PT J AU Schrack, JA Simonsick, EM Studenski, S Ferrucci, L AF Schrack, J. A. Simonsick, E. M. Studenski, S. Ferrucci, L. TI RISING SERUM IL-6 PREDICTS DECLINING WALKING EFFICIENCY IN MID-TO-LATE LIFE SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Schrack, J. A.] Johns Hopkins Sch Publ Hlth, Epidemiol, Baltimore, MD USA. [Schrack, J. A.; Simonsick, E. M.; Studenski, S.; Ferrucci, L.] NIA, Baltimore, MD 21224 USA. NR 0 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 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2015 VL 55 SU 2 BP 733 EP 733 PG 1 WC Gerontology SC Geriatrics & Gerontology GA DJ5BV UT WOS:000374222703436 ER PT J AU Winger, M Caserotti, P Ward, R Boudreau, R Harris, T Strotmeyer, ES AF Winger, M. Caserotti, P. Ward, R. Boudreau, R. Harris, T. Strotmeyer, E. S. TI CORRELATIONS BETWEEN TASK-BASED POWER AND LEG PRESS POWER AND STRENGTH MEASURES IN DECOS SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Winger, M.; Boudreau, R.; Strotmeyer, E. S.] Univ Pittsburgh, Grad Sch Publ Hlth, Epidemiol, Pittsburgh, PA USA. [Caserotti, P.] Univ Southern Denmark, Odense, Denmark. [Ward, R.] Boston Univ, Spaulding Rehabil Hosp, Boston, MA 02215 USA. [Harris, T.] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. NR 0 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 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2015 VL 55 SU 2 BP 734 EP 734 PG 1 WC Gerontology SC Geriatrics & Gerontology GA DJ5BV UT WOS:000374222703441 ER PT J AU Nicklett, EJ Evans, L Rostant, O AF Nicklett, E. J. Evans, L. Rostant, O. TI NEIGHBORHOOD CONTEXT AND RECURRENT FALLS AMONG OLDER ADULTS AGING IN PLACE SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Nicklett, E. J.; Evans, L.] Univ Michigan, Sch Social Work, Ann Arbor, MI 48109 USA. [Rostant, O.] NIH, Baltimore, MD USA. NR 0 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 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2015 VL 55 SU 2 BP 753 EP 753 PG 1 WC Gerontology SC Geriatrics & Gerontology GA DJ5BV UT WOS:000374222703517 ER PT J AU Shaffer, NC Gruber-Baldini, AL Guralnik, J Magaziner, J Orwig, D AF Shaffer, N. Chiles Gruber-Baldini, A. L. Guralnik, J. Magaziner, J. Orwig, D. TI SARCOPENIA POST HIP FRACTURE: ARE MALES AND FEMALES DIFFERENT? SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Shaffer, N. Chiles] NIA, NIH, Baltimore, MD 21224 USA. [Gruber-Baldini, A. L.; Guralnik, J.; Magaziner, J.; Orwig, D.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. NR 0 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 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2015 VL 55 SU 2 BP 765 EP 765 PG 1 WC Gerontology SC Geriatrics & Gerontology GA DJ5BV UT WOS:000374222704024 ER PT J AU Lange-Maia, B Newman, AB Jakicic, JM Cauley, JA Simonsick, EM Vinik, AI Harris, T Strotmeyer, ES AF Lange-Maia, B. Newman, A. B. Jakicic, J. M. Cauley, J. A. Simonsick, E. M. Vinik, A. I. Harris, T. Strotmeyer, E. S. TI SENSORIMOTOR AND CARDIOVASCULAR AUTONOMIC PERIPHERAL NERVOUS SYSTEM FUNCTION IN OLDER ADULTS SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Lange-Maia, B.; Newman, A. B.; Jakicic, J. M.; Cauley, J. A.; Strotmeyer, E. S.] Univ Pittsburgh, Pittsburgh, PA USA. [Simonsick, E. M.] NIA, Baltimore, MD 21224 USA. [Vinik, A. I.] Eastern Virginia Med Sch, Norfolk, VA 23501 USA. [Harris, T.] NIA, Bethesda, MD 20892 USA. NR 0 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 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2015 VL 55 SU 2 BP 770 EP 771 PG 2 WC Gerontology SC Geriatrics & Gerontology GA DJ5BV UT WOS:000374222704047 ER PT J AU Plater, E Deshpande, N Hewston, P Simonsick, EM Studenski, S Ferrucci, L AF Plater, E. Deshpande, N. Hewston, P. Simonsick, E. M. Studenski, S. Ferrucci, L. TI DECLINE IN LOWER LIMB SOMATOSENSORY FUNCTIONS: EFFECTS OF AGE AND TYPE 2 DIABETES SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Plater, E.; Deshpande, N.; Hewston, P.] Queens Univ, Fac Hlth Sci, Kingston, ON, Canada. [Simonsick, E. M.; Studenski, S.; Ferrucci, L.] NIA, Baltimore, MD 21224 USA. NR 0 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 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2015 VL 55 SU 2 BP 770 EP 770 PG 1 WC Gerontology SC Geriatrics & Gerontology GA DJ5BV UT WOS:000374222704045 ER PT J AU Schaap, L Harris, T Satterfield, S Schwartz, AV Simonsick, EM Vinik, AI Yaffe, K Strotmeyer, ES AF Schaap, L. Harris, T. Satterfield, S. Schwartz, A. V. Simonsick, E. M. Vinik, A. I. Yaffe, K. Strotmeyer, E. S. TI THE ASSOCIATION BETWEEN NOCICEPTIVE AND NEUROPATHIC PAIN AND COGNITIVE FUNCTION IN OLDER PERSONS SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Schaap, L.] Vrije Univ Amsterdam, Dept Hlth Sci, Amsterdam, Netherlands. [Harris, T.] NIA, Bethesda, MD 20892 USA. [Satterfield, S.] Univ Tennessee, Hlth Sci Ctr, Memphis, TN USA. [Schwartz, A. V.] Univ San Francisco, San Francisco, CA 94117 USA. [Simonsick, E. M.] NIA, Baltimore, MD 21224 USA. [Vinik, A. I.] Eastern Virginia Med Sch, Norfolk, VA 23501 USA. [Yaffe, K.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Strotmeyer, E. S.] Univ Pittsburgh, Pittsburgh, PA USA. NR 0 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 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2015 VL 55 SU 2 BP 770 EP 770 PG 1 WC Gerontology SC Geriatrics & Gerontology GA DJ5BV UT WOS:000374222704046 ER PT J AU Lin, J Kelley-Moore, J AF Lin, J. Kelley-Moore, J. TI AGE-GRADED TRAJECTORIES IN HEALTH AND AGING RESEARCH: EMBRACING THE PROMISES, AVOIDING THE PITFALLS SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Lin, J.] NIH, Bethesda, MD 20892 USA. [Kelley-Moore, J.] Case Western Reserve Univ, Cleveland, OH 44106 USA. NR 0 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 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2015 VL 55 SU 2 BP 823 EP 824 PG 2 WC Gerontology SC Geriatrics & Gerontology GA DJ5BV UT WOS:000374222704266 ER PT J AU Harris, TB Koster, A Caserotti, P Arnardottir, NY Sveinsson, T Brychta, RJ Chen, KY AF Harris, T. B. Koster, A. Caserotti, P. Arnardottir, N. Y. Sveinsson, T. Brychta, R. J. Chen, K. Y. TI PATTERNS OF FUNCTION IN OLD AGE: THE AGE, GENE/ENVIRONMENT REYKJAVIK STUDY SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Harris, T. B.] NIA, Bethesda, MD 20892 USA. [Koster, A.] Maastricht Univ, NL-6200 MD Maastricht, Netherlands. [Caserotti, P.] Univ Southern Denmark, Odense, Denmark. [Arnardottir, N. Y.; Sveinsson, T.] Univ Iceland, Reykjavik, Iceland. [Brychta, R. J.; Chen, K. Y.] NIDDK, Bethesda, MD 20892 USA. RI Sveinsson, Thorarinn/F-7554-2010 OI Sveinsson, Thorarinn/0000-0001-8989-5514 NR 0 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 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2015 VL 55 SU 2 BP 837 EP 837 PG 1 WC Gerontology SC Geriatrics & Gerontology GA DJ5BV UT WOS:000374222704323 ER PT J AU Morissette-Thomas, V Cohen, AA Riesco, E Ferrucci, L AF Morissette-Thomas, V. Cohen, A. A. Riesco, E. Ferrucci, L. TI COMPLEX INTERACTIONS BETWEEN INFLAMMATION AND METABOLIC HORMONES DURING AGING SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Morissette-Thomas, V.; Cohen, A. A.] Univ Sherbrooke, Sherbrooke, PQ J1K 2R1, Canada. [Riesco, E.] Res Ctr Aging, Sherbrooke, PQ, Canada. [Ferrucci, L.] NIA, Baltimore, MD 21224 USA. NR 0 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 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2015 VL 55 SU 2 BP 858 EP 859 PG 2 WC Gerontology SC Geriatrics & Gerontology GA DJ5BV UT WOS:000374222704416 ER PT J AU Bluethmann, SM Ferrer, R Alfano, CM Green, P AF Bluethmann, Shirley M. Ferrer, Rebecca Alfano, Catherine M. Green, Paige TI Frailty and self-rated health: A comparison between cancer survivors and other older adults SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Bluethmann, Shirley M.; Ferrer, Rebecca; Green, Paige] NCI, Behav Res Program, Bethesda, MD 20892 USA. [Alfano, Catherine M.] Amer Canc Soc, Survivorship, Atlanta, GA 30329 USA. NR 0 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 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2015 VL 55 SU 2 MA 364 PG 2 WC Gerontology SC Geriatrics & Gerontology GA DJ5BV UT WOS:000374222704484 ER PT J AU Files, DC Rushing, J Harris, TB Morris, P Newman, AB Young, M Miller, ME Kritchevsky, SB AF Files, D. Clark Rushing, Julia Harris, Tamara B. Morris, Peter Newman, Anne B. Young, Michael Miller, Michael E. Kritchevsky, Stephen B. TI Pre-hospital physical function and hospital outcomes in critically ill older adults SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Files, D. Clark; Young, Michael] Wake Forest Sch Med, Pulm & Crit Care Med, Winston Salem, NC USA. [Files, D. Clark; Kritchevsky, Stephen B.] Wake Forest Sch Med, Geriatr, Winston Salem, NC USA. [Rushing, Julia; Miller, Michael E.] Wake Forest Sch Med, Publ Hlth Sci, Winston Salem, NC USA. [Harris, Tamara B.] NIA, NIH, Bethesda, MD 20892 USA. [Morris, Peter] Univ Kentucky, Pulm & Crit Care, Lexington, KY 40506 USA. [Newman, Anne B.] Univ Pittsburgh, Epidemiol, Pittsburgh, PA 15260 USA. NR 0 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 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2015 VL 55 SU 2 MA 342 PG 1 WC Gerontology SC Geriatrics & Gerontology GA DJ5BV UT WOS:000374222704516 ER PT J AU Fukui, K De Cabo, R AF Fukui, Koji De Cabo, Rafael TI Chronic Vitamin E-deficiency Induces Cognitive Dysfunction via Brain Oxidation SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Fukui, Koji] Shibaura Inst Technol, Tokyo, Japan. [De Cabo, Rafael] NIA, Bethesda, MD 20892 USA. NR 0 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 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2015 VL 55 SU 2 MA 333 PG 2 WC Gerontology SC Geriatrics & Gerontology GA DJ5BV UT WOS:000374222704622 ER PT J AU Mitchell, S Saffari, A Sioutas, C Morgan, T Finch, C AF Mitchell, Sarah Saffari, Arian Sioutas, Constantinos Morgan, Todd Finch, Caleb TI Interventions for Healthy Aging in Mice: The Role of Sex, Dose, and Parental Genotype in the Response to Calorie Restriction SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Mitchell, Sarah; Saffari, Arian; Sioutas, Constantinos; Morgan, Todd; Finch, Caleb] NIA, Translat Gerontol Branch, Bethesda, MD 20892 USA. NR 0 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 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2015 VL 55 SU 2 MA 367 PG 1 WC Gerontology SC Geriatrics & Gerontology GA DJ5BV UT WOS:000374222704487 ER PT J AU Petr, M Mitchell, S Fishbein, K Krawcyzk, M Gonzalez-Freire, M Scalzo, P De Cabo, R Spencer, R AF Petr, Michael Mitchell, Sarah Fishbein, Kenneth Krawcyzk, Melissa Gonzalez-Freire, Marta Scalzo, Paul De Cabo, Rafael Spencer, Richard TI How Fast Can My Mouse Run? Uncovering The Biological Mechanisms Of Gait Trends As Predictors Of Mortality In Mice SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Petr, Michael; Mitchell, Sarah; De Cabo, Rafael] NIA, Expt Gerontol Sect, NIH, Bethesda, MD 20892 USA. [Fishbein, Kenneth; Spencer, Richard] NIA, Clin Invest Lab, Magnet Resonanc Imaging & Spect Sect, NIH, Bethesda, MD 20892 USA. [Krawcyzk, Melissa] NIA, Cardiovasc Sci Lab, NIH, Bethesda, MD 20892 USA. [Gonzalez-Freire, Marta; Scalzo, Paul] NIA, Longitudinal Studies Sect, NIH, Bethesda, MD 20892 USA. NR 0 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 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2015 VL 55 SU 2 MA 367 PG 2 WC Gerontology SC Geriatrics & Gerontology GA DJ5BV UT WOS:000374222704599 ER PT J AU Salimi, S Shardell, M Miller, R Gruber-Baldini, AL Orwig, D Rathbun, AM Yerges-Armstrong, L Hochberg, MC AF Salimi, Shabnam Shardell, Michelle Miller, Ram Gruber-Baldini, Ann L. Orwig, Denise Rathbun, Alan M. Yerges-Armstrong, Laura Hochberg, Marc C. TI Association of Tumor Necrosis Factor alpha Receptor with Trajectories of Bone Turnover Markers in Older Adults with Hip Fracture SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Salimi, Shabnam; Shardell, Michelle; Miller, Ram; Gruber-Baldini, Ann L.; Orwig, Denise; Rathbun, Alan M.; Yerges-Armstrong, Laura; Hochberg, Marc C.] Univ Maryland, Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Salimi, Shabnam; Shardell, Michelle] NIA, Translat Gerontol Branch, NIH, Bethesda, MD 20892 USA. NR 0 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 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2015 VL 55 SU 2 MA 370 PG 2 WC Gerontology SC Geriatrics & Gerontology GA DJ5BV UT WOS:000374222704546 ER PT J AU Shaaban, CE Aizenstein, HJ Rosso, AL Launer, LJ Kritchevsky, SB Yaffe, K Newman, AB Rosano, C AF Shaaban, C. Elizabeth Aizenstein, Howard J. Rosso, Andrea L. Launer, Lenore J. Kritchevsky, Stephen B. Yaffe, Kristine Newman, Anne B. Rosano, Caterina TI Long-Term Relationship of BDNF With Brain Microstructural Integrity of Community-Dwelling Older Adults SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Shaaban, C. Elizabeth; Rosso, Andrea L.; Newman, Anne B.; Rosano, Caterina] Univ Pittsburgh, Epidemiol, Pittsburgh, PA 15260 USA. [Aizenstein, Howard J.] Univ Pittsburgh, Psychiat, Pittsburgh, PA 15260 USA. [Launer, Lenore J.] NIA, NIH, Bethesda, MD 20892 USA. [Kritchevsky, Stephen B.] Wake Forest Univ, Bowman Gray Sch Med, Internal Med, Winston Salem, NC 27109 USA. [Yaffe, Kristine] Univ Calif San Francisco, Psychiat Neurol & Epidemiol, San Francisco, CA 94143 USA. NR 0 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 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2015 VL 55 SU 2 MA 365 PG 2 WC Gerontology SC Geriatrics & Gerontology GA DJ5BV UT WOS:000374222704597 ER PT J AU Shardell, M Semba, R Kalyani, R Bandinelli, S Chia, CW Ferrucci, L AF Shardell, Michelle Semba, Richard Kalyani, Rita Bandinelli, Stefania Chia, Chee W. Ferrucci, Luigi TI Prospective Association of Plasma Klotho with the Frailty Syndrome: Findings from the InCHIANTI Study SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Shardell, Michelle; Chia, Chee W.; Ferrucci, Luigi] NIA, Translat Gerontol Branch, Bethesda, MD 20892 USA. [Semba, Richard] Johns Hopkins Med Inst, Wilmer Eye Inst, Baltimore, MD USA. [Kalyani, Rita] Johns Hopkins Med Inst, Dept Med, Baltimore, MD USA. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Rehabil Unit, Florence, Italy. NR 0 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 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2015 VL 55 SU 2 MA 341 PG 1 WC Gerontology SC Geriatrics & Gerontology GA DJ5BV UT WOS:000374222704573 ER PT J AU Shardell, M Semba, R Kalyani, R Bandinelli, S Chia, CW Ferrucci, L AF Shardell, Michelle Semba, Richard Kalyani, Rita Bandinelli, Stefania Chia, Chee W. Ferrucci, Luigi TI Prospective Association of Plasma Klotho with Bone Health: Findings from the InCHIANTI Study SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Shardell, Michelle; Chia, Chee W.; Ferrucci, Luigi] NIA, Translat Gerontol Branch, Bethesda, MD 20892 USA. [Semba, Richard] Johns Hopkins Med Inst, Wilmer Eye Inst, Baltimore, MD USA. [Kalyani, Rita] Johns Hopkins Med Inst, Dept Med, Baltimore, MD USA. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Rehabil Unit, Florence, Italy. NR 0 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 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2015 VL 55 SU 2 MA 340 PG 1 WC Gerontology SC Geriatrics & Gerontology GA DJ5BV UT WOS:000374222704572 ER PT J AU Williams, JP Miller, CB AF Williams, John P. Miller, Craig B. TI NIH Common Fund Explanation of the Molecular Transducers of Physical Activity Consortium SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Williams, John P.; Miller, Craig B.] NIH, NIH MoTrPac Working Grp, Bethesda, MD USA. NR 0 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 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2015 VL 55 SU 2 MA 335 PG 2 WC Gerontology SC Geriatrics & Gerontology GA DJ5BV UT WOS:000374222704567 ER PT J AU Baker, BR Cosgrove, CM Altekruse, SF Mohiuddin, JJ Chen, RC AF Baker, B. R. Cosgrove, C. M. Altekruse, S. F. Mohiuddin, J. J. Chen, R. C. TI Association Between Socioeconomic Status (SES) Variables and Outcomes Using Registry Data: Is Regional or Individual SES More Important? SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT 57th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) CY OCT 18-21, 2015 CL San Antonio, TX SP Amer Soc Radiat Oncol C1 [Baker, B. R.; Mohiuddin, J. J.; Chen, R. C.] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Baker, B. R.; Mohiuddin, J. J.; Chen, R. C.] Census Bur, Suitland, MD USA. [Altekruse, S. F.] NCI, Rockville, MD 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 NOV 1 PY 2015 VL 93 IS 3 SU S MA 2892 BP E358 EP E358 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DI0VL UT WOS:000373215300887 ER PT J AU Bernstein, MB Gameiro, SR Malamas, A Wolfe, T Sahoo, N Tailor, RC Pidikiti, R Guha, C Hahn, SM Hodge, JW Krishnan, S AF Bernstein, M. B. Gameiro, S. R. Malamas, A. Wolfe, T. Sahoo, N. Tailor, R. C. Pidikiti, R. Guha, C. Hahn, S. M. Hodge, J. W. Krishnan, S. TI Proton Irradiation Modulates Tumor Phenotype Leading to Enhanced Immune-Mediated Cell Killing SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT 57th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) CY OCT 18-21, 2015 CL San Antonio, TX SP Amer Soc Radiat Oncol C1 [Bernstein, M. B.; Wolfe, T.; Sahoo, N.; Tailor, R. C.; Pidikiti, R.; Hahn, S. M.; Krishnan, S.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Gameiro, S. R.; Malamas, A.; Hodge, J. W.] NIH, Bethesda, MD 20892 USA. [Guha, C.] Montefiore Med Ctr, Albert Einstein Coll Med, Bronx, NY 10467 USA. RI Hodge, James/D-5518-2015 OI Hodge, James/0000-0001-5282-3154 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 NOV 1 PY 2015 VL 93 IS 3 SU S MA 3360 BP E542 EP E542 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DI0VL UT WOS:000373215301425 ER PT J AU Chung, EJ Sowers, AL Thetford, A McKay-Corkum, G Mitchell, JB Citrin, DE AF Chung, E. J. Sowers, A. L. Thetford, A. McKay-Corkum, G. Mitchell, J. B. Citrin, D. E. TI mTOR Inhibition With Rapamycin Mitigates Radiation-Induced Pulmonary Fibrosis in a Murine Model SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT 57th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) CY OCT 18-21, 2015 CL San Antonio, TX SP Amer Soc Radiat Oncol C1 [Chung, E. J.; Sowers, A. L.; Thetford, A.; McKay-Corkum, G.; Mitchell, J. B.; Citrin, D. E.] 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 NOV 1 PY 2015 VL 93 IS 3 SU S MA 3324 BP E528 EP E529 PG 2 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DI0VL UT WOS:000373215301390 ER PT J AU Dong, T Jones, GC Scoble, D Bajaj, GK AF Dong, T. Jones, G. C. Scoble, D. Bajaj, G. K. TI Retrospective Analysis of Diminished Narcotic Dependency and Weight Loss With Prophylactic Gabapentin Use in Patients Undergoing Radiation Therapy for Oropharyngeal Cancer SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT 57th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) CY OCT 18-21, 2015 CL San Antonio, TX SP Amer Soc Radiat Oncol C1 [Dong, T.] Howard Univ, Coll Med, Washington, DC USA. [Jones, G. C.] NCI, Bethesda, MD 20892 USA. [Scoble, D.; Bajaj, G. K.] Inova Comprehens Canc & Res Inst, Falls Church, VA 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 NOV 1 PY 2015 VL 93 IS 3 SU S MA 2754 BP E303 EP E303 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DI0VL UT WOS:000373215300750 ER PT J AU Kesarwala, AH Miura, N DeGraff, WG Mitchell, JB AF Kesarwala, A. H. Miura, N. DeGraff, W. G. Mitchell, J. B. TI Effect of Differential DNA Repair Process Inhibition on Radiosensitization SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT 57th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) CY OCT 18-21, 2015 CL San Antonio, TX SP Amer Soc Radiat Oncol C1 [Kesarwala, A. H.; Miura, N.; DeGraff, W. G.; Mitchell, J. B.] 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 NOV 1 PY 2015 VL 93 IS 3 SU S MA 3284 BP E513 EP E513 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DI0VL UT WOS:000373215301350 ER PT J AU Krauze, AV Ning, H Cheng, JY Zhuge, Y Cooley-Zgela, T Smart, DK Camphausen, KA AF Krauze, A. V. Ning, H. Cheng, J. Y. Zhuge, Y. Cooley-Zgela, T. Smart, D. K. Camphausen, K. A. TI Dose Volume Toxicity Analysis for Organs at Risk in Patients Receiving Reirradiation for Recurrent High Grade Glioma SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT 57th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) CY OCT 18-21, 2015 CL San Antonio, TX SP Amer Soc Radiat Oncol C1 [Krauze, A. V.; Ning, H.; Cheng, J. Y.; Zhuge, Y.; Cooley-Zgela, T.; Smart, D. K.; Camphausen, K. A.] 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 NOV 1 PY 2015 VL 93 IS 3 SU S MA 2219 BP E86 EP E86 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DI0VL UT WOS:000373215300219 ER PT J AU Lee, C Jung, JW Pelletier, C Pyakuryal, A Kim, JO Lee, C AF Lee, C. Jung, J. W. Pelletier, C. Pyakuryal, A. Kim, J. O. Lee, C. TI Reconstruction of Out-of-Field Normal Tissue Dose for Intensity Modulated Radiation Therapy Patients for Large Scale Retrospective Epidemiological Studies of Late Effects SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT 57th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) CY OCT 18-21, 2015 CL San Antonio, TX SP Amer Soc Radiat Oncol C1 [Lee, C.] Univ Michigan, Ann Arbor, MI 48109 USA. [Jung, J. W.; Pelletier, C.] E Carolina Univ, Greenville, NC USA. [Pyakuryal, A.; Lee, C.] NCI, NIH, Rockville, MD USA. [Kim, J. O.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA 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 NOV 1 PY 2015 VL 93 IS 3 SU S MA 3351 BP E539 EP E539 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DI0VL UT WOS:000373215301417 ER PT J AU Padro, D Eisch, R Bates, S Simone, CB Ning, H Smart, DK Jones, JC Krauze, AV Citrin, DE Kesarwala, AH AF Padro, D. Eisch, R. Bates, S. Simone, C. B., II Ning, H. Smart, D. K. Jones, J. C. Krauze, A. V. Citrin, D. E. Kesarwala, A. H. TI Salvage Radiation Therapy for Chemotherapy Refractory Cutaneous Mycosis Fungoides SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT 57th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) CY OCT 18-21, 2015 CL San Antonio, TX SP Amer Soc Radiat Oncol C1 [Padro, D.; Eisch, R.; Bates, S.; Ning, H.; Smart, D. K.; Krauze, A. V.; Citrin, D. E.; Kesarwala, A. H.] NCI, NIH, Bethesda, MD 20892 USA. [Ning, H.] Univ Penn, Philadelphia, PA 19104 USA. [Jones, J. C.] NCI, Vaccine Branch, 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 NOV 1 PY 2015 VL 93 IS 3 SU S MA 3128 BP E452 EP E452 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DI0VL UT WOS:000373215301196 ER PT J AU Pyakuryal, A Sio, TTW Narayanasamy, G Lee, C AF Pyakuryal, A. Sio, T. T. W. Narayanasamy, G. Lee, C. TI Clinical Application of Radiobiological Modeling in the Histogram Analysis in Radiation Therapy (HART): An Open-source Software System in Radiation Oncology SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT 57th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) CY OCT 18-21, 2015 CL San Antonio, TX SP Amer Soc Radiat Oncol C1 [Pyakuryal, A.; Lee, C.] NCI, NIH, Rockville, MD USA. [Sio, T. T. W.] Mayo Clin, Scottsdale, AZ USA. [Narayanasamy, G.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 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 NOV 1 PY 2015 VL 93 IS 3 SU S MA 3347 BP E537 EP E537 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DI0VL UT WOS:000373215301413 ER PT J AU Wenger, C Salvador, R Basser, P Miranda, P AF Wenger, C. Salvador, R. Basser, P. Miranda, P. TI Modeling Intersubject Differences in Tumor Treating Fields (TTFields) Treatment of GBM Patients SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT 57th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) CY OCT 18-21, 2015 CL San Antonio, TX SP Amer Soc Radiat Oncol C1 [Wenger, C.; Salvador, R.; Miranda, P.] Univ Lisbon, Fac Sci, P-1699 Lisbon, Portugal. [Basser, P.] NICHD, NIH, STBB, Bethesda, MD USA. OI Wenger, Cornelia/0000-0001-7889-9093 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 NOV 1 PY 2015 VL 93 IS 3 SU S MA 2177 BP E71 EP E71 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DI0VL UT WOS:000373215300178 ER PT J AU Zhuge, Y Ning, H Cheng, JY Kirkland, RS Arora, B Miller, RW Kaushal, A Camphausen, KA Krauze, AV AF Zhuge, Y. Ning, H. Cheng, J. Y. Kirkland, R. S. Arora, B. Miller, R. W. Kaushal, A. Camphausen, K. A. Krauze, A. V. TI A Novel Approach to Diffusion Weighted Imaging Analysis in Newly Diagnosed GBM SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT 57th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) CY OCT 18-21, 2015 CL San Antonio, TX SP Amer Soc Radiat Oncol C1 [Zhuge, Y.; Ning, H.; Cheng, J. Y.; Arora, B.; Miller, R. W.; Kaushal, A.; Camphausen, K. A.; Krauze, A. V.] NCI, NIH, Bethesda, MD 20892 USA. [Kirkland, R. S.] Univ Missouri, Columbia, MO 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 NOV 1 PY 2015 VL 93 IS 3 SU S MA 2228 BP E90 EP E90 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DI0VL UT WOS:000373215300228 ER PT J AU Azghadi, S Candas, D Fan, M Li, JJ AF Azghadi, S. Candas, D. Fan, M. Li, J. J. TI NF-kappa B Controlled CD47 Overexpression in Immuno/Radioresistance of HER-2 Breast Cancer Cells SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT 57th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) CY OCT 18-21, 2015 CL San Antonio, TX SP Amer Soc Radiat Oncol C1 [Azghadi, S.; Candas, D.; Fan, M.; Li, J. J.] Univ Calif Davis, Sch Med, Sacramento, CA 95817 USA. [Li, J. J.] NCI, Designated Comprehens Canc Ctr, Sacramento, CA 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 NOV 1 PY 2015 VL 93 IS 3 SU S MA 316 BP S139 EP S139 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DI0VL UT WOS:000373215302012 ER PT J AU Hall, WA Pugh, SL Gilbert, MR Wefel, JS Armstrong, T Wendland, MM Brachman, DG Roof, KS Brown, PD Crocker, IR Robins, HI Lee, RJ Chao, ST Kim, L Srkalovic, G Fisch, BM Mehta, MP Curran, WJ Movsas, B AF Hall, W. A. Pugh, S. L. Gilbert, M. R. Wefel, J. S. Armstrong, T. Wendland, M. M. Brachman, D. G. Roof, K. S. Brown, P. D. Crocker, I. R. Robins, H. I. Lee, R. J. Chao, S. T. Kim, L. Srkalovic, G. Fisch, B. M. Mehta, M. P. Curran, W. J., Jr. Movsas, B. TI Bevacizumab Use in Patients With Subtotal Resection of Newly Diagnosed Glioblastoma (GBM): A Secondary Analysis of NRG Oncology/RTOG 0825 SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT 57th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) CY OCT 18-21, 2015 CL San Antonio, TX SP Amer Soc Radiat Oncol C1 [Hall, W. A.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Pugh, S. L.] NRG Oncol Stat & Data Management Ctr, Philadelphia, PA USA. [Gilbert, M. R.] NIH, Bethesda, MD 20892 USA. [Wefel, J. S.; Brown, P. D.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Armstrong, T.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Wendland, M. M.] Willamette Valley Canc Inst & Res Ctr, Eugene, OR USA. [Brachman, D. G.] Arizona Oncol Serv Mesa, Mesa, AZ USA. [Roof, K. S.] Southeast Radiat Oncol Grp PA, Charlotte, NC USA. [Crocker, I. R.; Curran, W. J., Jr.] Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. [Robins, H. I.] Univ Wisconsin Hosp, Madison, WI USA. [Lee, R. J.] Intermt Healthcare, Murray, UT USA. [Chao, S. T.] Cleveland Clin, Cleveland, OH 44106 USA. [Kim, L.] Thomas Jefferson Univ, Sidney Kimmel Med Coll, Philadelphia, PA 19107 USA. [Srkalovic, G.] Michigan Canc Res Consortium CCOP, Ann Arbor, MI USA. [Fisch, B. M.] Kaiser Permanente No Calif, Kaiser Santa Clara, CA USA. [Mehta, M. P.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Movsas, B.] Henry Ford Hlth Syst, Detroit, MI USA. RI Gilbert, Mark/J-7494-2016 OI Gilbert, Mark/0000-0003-2556-9722 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 NOV 1 PY 2015 VL 93 IS 3 SU S MA 250 BP S110 EP S110 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DI0VL UT WOS:000373215301921 ER PT J AU Josefsson, A Kiess, AP Minn, I Mease, RC Brummet, ME Baidoo, K Brechbiel, M Sgouros, G Pomper, MG Hobbs, RF AF Josefsson, A. Kiess, A. P. Minn, I. Mease, R. C. Brummet, M. E. Baidoo, K. Brechbiel, M. Sgouros, G. Pomper, M. G. Hobbs, R. F. TI Macro to Microdosimetric Analysis for Alpha Particle Radiopharmaceutical Therapy for [At-211]YC-I-27, a PSMA-Targeting Ligand for Metastatic Prostate Cancer SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT 57th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) CY OCT 18-21, 2015 CL San Antonio, TX SP Amer Soc Radiat Oncol C1 [Josefsson, A.; Kiess, A. P.; Minn, I.; Mease, R. C.; Brummet, M. E.; Sgouros, G.; Pomper, M. G.] Johns Hopkins Univ, Baltimore, MD USA. [Baidoo, K.; Brechbiel, M.] NCI, NIH, Bethesda, MD 20892 USA. [Hobbs, R. F.] Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. NR 0 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 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD NOV 1 PY 2015 VL 93 IS 3 SU S MA 338 BP S148 EP S149 PG 2 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DI0VL UT WOS:000373215302034 ER PT J AU McCloskey, SA Mitchell, S Basch, E Sharif, J Kupelian, PA Malin, J AF McCloskey, S. A. Mitchell, S. Basch, E. Sharif, J. Kupelian, P. A. Malin, J. TI Development of Anatomic Site-Specific Item Sets for Acute Toxicity Assessment in Radiation Oncology Using the US National Cancer Institute PRO-CTCAE SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT 57th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) CY OCT 18-21, 2015 CL San Antonio, TX SP Amer Soc Radiat Oncol C1 [McCloskey, S. A.; Sharif, J.; Kupelian, P. A.; Malin, J.] Univ Calif Los Angeles, Los Angeles, CA USA. [Mitchell, S.] NCI, Bethesda, MD 20892 USA. [Basch, E.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 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 NOV 1 PY 2015 VL 93 IS 3 SU S MA 78 BP S35 EP S35 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DI0VL UT WOS:000373215301749 ER PT J AU Zhang, HH Zhang, P Gilbert, MR Aldape, K Chakravarti, A Magliocco, A Klimowicz, A D'Souza, WD Corn, BW Hunter, GK Muanza, TM Dicker, AP Vigneault, E Brachman, DG Bovi, JA Robins, HI Sahijdak, WM Won, M Mehta, MP AF Zhang, H. H. Zhang, P. Gilbert, M. R. Aldape, K. Chakravarti, A. Magliocco, A. Klimowicz, A. D'Souza, W. D. Corn, B. W. Hunter, G. K. Muanza, T. M. Dicker, A. P. Vigneault, E. Brachman, D. G. Bovi, J. A. Robins, H. I. Sahijdak, W. M. Won, M. Mehta, M. P. TI NRG Oncology/RTOG 0525 Role of Machine Learning Analytic Tools for Survival Prediction of GBM Patients Using Clinical Parameters SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT 57th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) CY OCT 18-21, 2015 CL San Antonio, TX SP Amer Soc Radiat Oncol C1 [Zhang, H. H.; D'Souza, W. D.; Mehta, M. P.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Zhang, P.; Won, M.] NRG, Philadelphia, PA USA. [Gilbert, M. R.] NIH, Bethesda, MD 20892 USA. [Aldape, K.] Univ Toronto, Univ Hlth Network, Toronto, ON, Canada. [Chakravarti, A.] Ohio State Univ, Wexner Med Ctr, Columbus, OH 43210 USA. [Magliocco, A.] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [Klimowicz, A.] Boehringer Ingelheim Pharmaceut, Ridgefield, CT USA. [Corn, B. W.] Tel Aviv Med Ctr & Sch Med, Tel Aviv, Israel. [Hunter, G. K.] Intermt Healthcare, Murray, UT USA. [Muanza, T. M.] McGill Univ, Jewish Gen Hosp, Montreal, PQ H3T 1E2, Canada. [Dicker, A. P.] Thomas Jefferson Univ, Sidney Kimmel Med Coll, Philadelphia, PA 19107 USA. [Vigneault, E.] CHUQ, Hotel Dieu Quebec, Quebec City, PQ, Canada. [Brachman, D. G.] Arizona Oncol Serv Mesa, Mesa, AZ USA. [Bovi, J. A.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Robins, H. I.] Univ Wisconsin, Madison, WI USA. [Sahijdak, W. M.] Huron River Radiat Oncol, Ann Arbor, MI USA. RI Gilbert, Mark/J-7494-2016 OI Gilbert, Mark/0000-0003-2556-9722 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 NOV 1 PY 2015 VL 93 IS 3 SU S MA 324 BP S142 EP S143 PG 2 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DI0VL UT WOS:000373215302020 ER PT J AU Bourne, PE Bonazzi, V Dunn, M Green, ED Guyer, M Komatsoulis, G Larkin, J Russell, B AF Bourne, Philip E. Bonazzi, Vivien Dunn, Michelle Green, Eric D. Guyer, Mark Komatsoulis, George Larkin, Jennie Russell, Beth TI The NIH Big Data to Knowledge (BD2K) initiative SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Editorial Material C1 [Bourne, Philip E.; Green, Eric D.] NHGRI, Bethesda, MD USA. [Komatsoulis, George] Natl Ctr Biotechnol Informat, NIH, Bethesda, MD USA. RP Bourne, PE (reprint author), NHGRI, Bethesda, MD USA. EM philip.bourne@nih.gov NR 1 TC 5 Z9 5 U1 1 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1067-5027 EI 1527-974X J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD NOV PY 2015 VL 22 IS 6 BP 1114 EP 1114 DI 10.1093/jamia/ocv136 PG 1 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA DI8AF UT WOS:000373722400002 PM 26555016 ER PT J AU Shirts, BH Salama, JS Aronson, SJ Chung, WK Gray, SW Hindorff, LA Jarvik, GP Plon, SE Stoffel, EM Tarczy-Hornoch, PZ Van Allen, EM Weck, KE Chute, CG Freimuth, RR Grundmeier, RW Hartzler, AL Li, RL Peissig, PL Peterson, JF Rasmussen, LV Starren, JB Williams, MS Overby, CL AF Shirts, Brian H. Salama, Joseph S. Aronson, Samuel J. Chung, Wendy K. Gray, Stacy W. Hindorff, Lucia A. Jarvik, Gail P. Plon, Sharon E. Stoffel, Elena M. Tarczy-Hornoch, Peter Z. Van Allen, Eliezer M. Weck, Karen E. Chute, Christopher G. Freimuth, Robert R. Grundmeier, Robert W. Hartzler, Andrea L. Li, Rongling Peissig, Peggy L. Peterson, Josh F. Rasmussen, Luke V. Starren, Justin B. Williams, Marc S. Overby, Casey L. TI CSER and eMERGE: current and potential state of the display of genetic information in the electronic health record SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article DE genetics; electronic health records; translational research; clinical decision support; survey ID CLINICAL DECISION-SUPPORT; GENOMIC DATA; INDIVIDUALIZED MEDICINE; PERSONALIZED MEDICINE; TECHNICAL DESIDERATA; IMPLEMENTATION; PHARMACOGENOMICS; INTEGRATION; CHALLENGES; ATTITUDES AB Objective Clinicians' ability to use and interpret genetic information depends upon how those data are displayed in electronic health records (EHRs). There is a critical need to develop systems to effectively display genetic information in EHRs and augment clinical decision support (CDS). Materials and Methods The National Institutes of Health (NIH)-sponsored Clinical Sequencing Exploratory Research and Electronic Medical Records & Genomics EHR Working Groups conducted a multiphase, iterative process involving working group discussions and 2 surveys in order to determine how genetic and genomic information are currently displayed in EHRs, envision optimal uses for different types of genetic or genomic information, and prioritize areas for EHR improvement. Results There is substantial heterogeneity in how genetic information enters and is documented in EHR systems. Most institutions indicated that genetic information was displayed in multiple locations in their EHRs. Among surveyed institutions, genetic information enters the EHR through multiple laboratory sources and through clinician notes. For laboratory-based data, the source laboratory was the main determinant of the location of genetic information in the EHR. The highest priority recommendation was to address the need to implement CDS mechanisms and content for decision support for medically actionable genetic information. Conclusion Heterogeneity of genetic information flow and importance of source laboratory, rather than clinical content, as a determinant of information representation are major barriers to using genetic information optimally in patient care. Greater effort to develop interoperable systems to receive and consistently display genetic and/or genomic information and alert clinicians to genomic-dependent improvements to clinical care is recommended. C1 [Shirts, Brian H.] Univ Washington, Dept Lab Med, Box 357110,1959 NE Pacific St,NW120, Seattle, WA 98195 USA. [Salama, Joseph S.; Jarvik, Gail P.] Univ Washington, Dept Med, Div Med Genet, Seattle, WA 98195 USA. [Aronson, Samuel J.] Partners Healthcare, Personalized Med, Boston, MA USA. [Chung, Wendy K.] Columbia Univ, Dept Pediat, Med Ctr, New York, NY 10027 USA. [Gray, Stacy W.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Gray, Stacy W.; Van Allen, Eliezer M.] Dana Farber Canc Inst, Boston, MA USA. [Hindorff, Lucia A.; Li, Rongling] NHGRI, NIH, Rockville, MD USA. [Jarvik, Gail P.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Plon, Sharon E.] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Stoffel, Elena M.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Tarczy-Hornoch, Peter Z.] Univ Washington, Dept Biomed Informat & Med Educ, Seattle, WA 98195 USA. [Van Allen, Eliezer M.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Weck, Karen E.] Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC USA. [Weck, Karen E.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Chute, Christopher G.; Freimuth, Robert R.] Mayo Clin, Div Biomed Stat & Informat, Dept Hlth Sci Res, Rochester, MN USA. [Freimuth, Robert R.] Childrens Hosp Philadelphia, Dept Biomed & Hlth Informat, Philadelphia, PA 19104 USA. [Hartzler, Andrea L.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Peissig, Peggy L.] Marshfield Clin Res Fdn, Biomed Informat Res Ctr, Marshfield, WI USA. [Peterson, Josh F.] Dept Biomed Informat, Nashville, TN USA. [Rasmussen, Luke V.; Starren, Justin B.] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Div Hlth & Biomed Informat, Chicago, IL 60611 USA. [Williams, Marc S.; Overby, Casey L.] Geisinger Med Ctr, Genome Med Inst, Danville, PA 17822 USA. [Overby, Casey L.] Univ Maryland, Sch Med, Program Personalized & Genom Med, Dept Med, Baltimore, MD 21201 USA. [Overby, Casey L.] Univ Maryland, Sch Med, Ctr Health Related Informat & Bioimaging, Baltimore, MD 21201 USA. RP Shirts, BH (reprint author), Univ Washington, Dept Lab Med, Box 357110,1959 NE Pacific St,NW120, Seattle, WA 98195 USA. EM shirtsb@uw.edu OI Rasmussen, Luke/0000-0002-4497-8049; Overby, Casey/0000-0001-9302-5968; Tarczy-Hornoch, Peter/0000-0003-1047-179X FU NHGRI; NCI [U01 HG006485, U01 HG006500, U01 HG006546, R01 HG006600, U01 HG006492, UM1 HG007301, UM1 HG007292, UM1 HG006508, U01 HG006487, U01 HG006507, U01 HG007307]; National Human Genome Research Institute [U01HG006828, U01HG006830, U01HG006389, U01HG006382, U01HG006375, U01HG006379, U01HG006380, U01HG006388, U01HG006378, U01HG006385] FX CSER: The Clinical Sequencing Exploratory Research Program (CSER) was initiated and funded by NHGRI and the NCI through the following grants: U01 HG006485 (Baylor College of Medicine); U01 HG006500 (Brigham & Women's Hospital); U01 HG006546 (Children's Hospital of Philadelphia); R01 HG006600 (Columbia University); U01 HG006492 (Dana-Farber Cancer Institute); UM1 HG007301 (HudsonAlpha Institute); UM1 HG007292 (Kaiser Permanente); UM1 HG006508 (University of Michigan); U01 HG006487 (University of North Carolina); U01 HG006507 (University of Washington); and U01 HG007307 (University of Washington serving as the Coordinating Center).; eMERGE: The eMERGE Network was initiated and funded by National Human Genome Research Institute through the following grants: U01HG006828 (Cincinnati Children's Hospital Medical Center/Boston Children's Hospital); U01HG006830 (Children's Hospital of Philadelphia); U01HG006389 (Essentia Institute of Rural Health); U01HG006382 (Geisinger Clinic); U01HG006375 (Group Health Cooperative); U01HG006379 (Mayo Clinic); U01HG006380 (Icahn School of Medicine at Mount Sinai); U01HG006388 (Northwestern University); U01HG006378 (Vanderbilt University Medical Center); and U01HG006385 (Vanderbilt University Medical Center serving as the Coordinating Center). NR 35 TC 9 Z9 9 U1 6 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1067-5027 EI 1527-974X J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD NOV PY 2015 VL 22 IS 6 BP 1231 EP 1242 DI 10.1093/jamia/ocv065 PG 12 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA DI8AF UT WOS:000373722400021 PM 26142422 ER PT J AU Frey, LJ Sward, KA Newth, CJL Khemani, RG Cryer, ME Thelen, JL Enriquez, R Shaoyu, S Pollack, MM Harrison, RE Meert, KL Berg, RA Wessel, DL Shanley, TP Dalton, H Carcillo, J Jenkins, TL Dean, JM AF Frey, Lewis J. Sward, Katherine A. Newth, Christopher J. L. Khemani, Robinder G. Cryer, Martin E. Thelen, Julie L. Enriquez, Rene Shaoyu, Su Pollack, Murray M. Harrison, Rick E. Meert, Kathleen L. Berg, Robert A. Wessel, David L. Shanley, Thomas P. Dalton, Heidi Carcillo, Joseph Jenkins, Tammara L. Dean, J. Michael TI Virtualization of open-source secure web services to support data exchange in a pediatric critical care research network SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article DE electronic health record; secure web services; grid; virtualization; pediatric critical care; data governance; pediatric network; virtual machines; learning health care system ID ELECTRONIC HEALTH RECORDS; MINI-SENTINEL; INFRASTRUCTURE; SYSTEM; INTEROPERABILITY; ARCHITECTURE; INFORMATICS; ARCHETYPES; ENTERPRISE; PCORNET AB Objectives To examine the feasibility of deploying a virtual web service for sharing data within a research network, and to evaluate the impact on data consistency and quality. Material and Methods Virtual machines (VMs) encapsulated an open-source, semantically and syntactically interoperable secure web service infrastructure along with a shadow database. The VMs were deployed to 8 Collaborative Pediatric Critical Care Research Network Clinical Centers. Results Virtual web services could be deployed in hours. The interoperability of the web services reduced format misalignment from 56% to 1% and demonstrated that 99% of the data consistently transferred using the data dictionary and 1% needed human curation. Conclusions Use of virtualized open-source secure web service technology could enable direct electronic abstraction of data from hospital databases for research purposes. C1 [Frey, Lewis J.] Univ S Carolina, Dept Publ Hlth Sci, Biomed Informat Ctr, Columbia, SC 29208 USA. [Sward, Katherine A.] Univ Utah, Coll Nursing, Dept Biomed Informat, Salt Lake City, UT 84112 USA. [Newth, Christopher J. L.; Khemani, Robinder G.] Childrens Hosp Angeles, Dept Anesthesiol & Crit Care Med, USC Keck Sch Med, Los Angeles, CA USA. [Cryer, Martin E.] Univ Utah, Sch Med, Dept Biomed Informat, Salt Lake City, UT USA. [Thelen, Julie L.; Enriquez, Rene; Shaoyu, Su] Univ Utah, Dept Pediat, Sch Med, Salt Lake City, UT USA. [Pollack, Murray M.] Univ Arizona, Phoenix Childrens Hosp, Dept Pediat, Phoenix, AZ USA. [Harrison, Rick E.] Univ Calif Los Angeles, Dept Pediat, Los Angeles, CA 90024 USA. [Meert, Kathleen L.] Childrens Hosp Michigan, Dept Pediat, Detroit, MI 48201 USA. [Berg, Robert A.] Univ Penn, Childrens Hosp Philadelphia, Dept Anesthesiol & Crit Care, Perelman Sch Med, Philadelphia, PA 19104 USA. [Wessel, David L.] Childrens Natl Med Ctr, Dept Pediat, Washington, DC 20010 USA. [Shanley, Thomas P.] Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA. [Dalton, Heidi] Univ Arizona, Phoenix Childrens Hosp, Coll Med Phoenix, Dept Child Hlth, Phoenix, AZ USA. [Carcillo, Joseph] Childrens Hosp Pittsburgh, Dept Crit Care Med, Pittsburgh, PA 15213 USA. [Jenkins, Tammara L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Dean, J. Michael] Univ Utah, Dept Pediat, NICHD Collaborat Pediat Crit Care Res Network, Div Pediat Crit Care Med,Sch Med, Salt Lake City, UT USA. RP Frey, LJ (reprint author), Med Univ S Carolina, Dept Publ Hlth Sci, Biomed Informat Ctr, 135 Cannon St,Suite 405K,MUSC 200, Charleston, SC 29425 USA. EM frey@musc.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, Department of Health and Human Services [U10HD050096, U10HD049981, U10HD063108, U10HD063106, U10HD063114, U10HD049983, U10HD050012, U01HD049934] FX This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Department of Health and Human Services, through cooperative agreements (U10HD050096, U10HD049981, U10HD063108, U10HD063106, U10HD063114, U10HD049983, U10HD050012, and U01HD049934). NR 29 TC 2 Z9 2 U1 4 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1067-5027 EI 1527-974X J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD NOV PY 2015 VL 22 IS 6 BP 1271 EP 1276 DI 10.1093/jamia/ocv009 PG 6 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA DI8AF UT WOS:000373722400025 PM 25796596 ER PT J AU Brooks, SE Muller, CY Robinson, W Walker, EM Yeager, K Cook, ED Friedman, S Somkin, CP Brown, CL McCaskill-Stevens, W AF Brooks, Sandra E. Muller, Carolyn Y. Robinson, William Walker, Eleanor M. Yeager, Kate Cook, Elise D. Friedman, Sue Somkin, Carol P. Brown, Carol Leslie McCaskill-Stevens, Worta TI Increasing Minority Enrollment Onto Clinical Trials: Practical Strategies and Challenges Emerge From the NRG Oncology Accrual Workshop SO JOURNAL OF ONCOLOGY PRACTICE LA English DT Article ID HEALTH-CARE-SYSTEMS; CANCER; PARTICIPATION; DISPARITIES; SURVIVAL AB Racial and ethnic diversity has historically been difficult to achieve in National Cancer Institute-sponsored clinical trials, even while as many as 80% of those trials have faced difficulty in meeting overall recruitment targets. In an attempt to address these issues, NRG Oncology recently convened a comprehensive workshop titled "Clinical Trials Enrollment: Challenges and Opportunities." Discussants at the workshop included representatives of the three legacy groups of the NRG (ie, Gynecologic Oncology Group, National Surgical Adjuvant Breast and Bowel Program, and Radiation Therapy Oncology Group), a minority-based community clinical oncology program, a large integrated health care system, the leadership of the National Cancer Institute, and a large patient advocacy group. This article summarizes the concepts discussed at the workshop, which included: needs assessments, infrastructural support, training of investigators and research staff, specific clinical trial recruitment strategies (both system and community based), and development and mentoring of young investigators. Many new, more specific tactics, including use of diverse cancer care settings, direct-to-consumer communication, and the need for centralized information technology such as the use of software to match trials to special populations, are presented. It was concluded that new, innovative trial designs and the realities of limited funding would require the adoption of effective and efficient recruiting strategies, specialized training, and stakeholder engagement. US clinical research programs must generate and embrace new ideas and pilot test novel recruitment strategies if they are to maintain their historic role as world leaders in cancer care innovation and delivery. C1 [Brooks, Sandra E.] CompleteCare Hlth Network, 53 South Laurel St,Floor 2, Bridgeton, NJ 08302 USA. Univ New Mexico, Albuquerque, NM 87131 USA. Tulane Univ, New Orleans, LA 70118 USA. Henry Ford Hosp, Detroit, MI 48202 USA. Emory Univ, Atlanta, GA 30322 USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Facing Our Risk Canc Empowered, Tampa, FL USA. Kaiser Permanente, Oakland, CA USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. NCI, Bethesda, MD 20892 USA. RP Brooks, SE (reprint author), CompleteCare Hlth Network, 53 South Laurel St,Floor 2, Bridgeton, NJ 08302 USA. EM sandraebrooks40@aol.com FU NCI NIH HHS [P30 CA008748, U10 CA180822, U10 CA180868, U10CA180822, U10CA180868] NR 16 TC 6 Z9 6 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 1554-7477 EI 1935-469X J9 J ONCOL PRACT JI J. Oncol. Pract. PD NOV PY 2015 VL 11 IS 6 BP 486 EP + DI 10.1200/JOP.2015.005934 PG 6 WC Health Care Sciences & Services SC Health Care Sciences & Services GA DG5CS UT WOS:000372091100011 PM 26464496 ER PT J AU Stavreva, DA Hager, GL AF Stavreva, Diana A. Hager, Gordon L. TI Chromatin structure and gene regulation: a dynamic view of enhancer function SO NUCLEUS LA English DT Article DE chromatin accessibility; DNase I; enhancers; gene pulsing; glucocorticoid receptor; long-range interactions; transcription; ultradian ID PITUITARY-ADRENAL AXIS; GLUCOCORTICOID-RECEPTOR; TRANSCRIPTIONAL REGULATION; GENOMIC INTERACTIONS; TOPOLOGICAL DOMAINS; SUBCUTANEOUS TISSUE; IN-VIVO; EXCHANGE; CELLS; ARCHITECTURE AB Localized chromatin organization is now recognized as an important determinant of cell identity and developmental pathways. Recent studies have demonstrated that these epigenetic states are unexpectedly dynamic and malleable. In this Extra view we will highlight the transient nature of stimulus-induced enhancer accessibility and its importance for transcription regulation. Using glucocorticoid receptor (GR) as a model system we will discuss spatiotemporal relationships between receptor/chromatin interactions, lifetimes of the DNase I hypersensitivity sites (DHSs), long-range interactions, and gene regulation. We propose that differential temporal activation and utilization of distal regulatory elements plays a role in directing divergent stimulus-induced transcriptional programs. C1 [Stavreva, Diana A.; Hager, Gordon L.] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. RP Stavreva, DA (reprint author), NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. EM stavrevd@mail.nih.gov; hagerg@exchange.nih.gov FU Intramural Research Program of NIH, National Cancer Institute, Center for Cancer Research FX This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 59 TC 1 Z9 1 U1 2 U2 7 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1949-1034 EI 1949-1042 J9 NUCLEUS-PHILA JI Nucleus PD NOV-DEC PY 2015 VL 6 IS 6 BP 442 EP 448 DI 10.1080/19491034.2015.1107689 PG 7 WC Cell Biology SC Cell Biology GA DE5WX UT WOS:000370705000004 PM 26765055 ER PT J AU Coyne, GO Chen, A Kummar, S AF Coyne, Geraldine O'Sullivan Chen, Alice Kummar, Shivaani TI Delivering on the promise: poly ADP ribose polymerase inhibition as targeted anticancer therapy SO CURRENT OPINION IN ONCOLOGY LA English DT Review DE BRCA1/2; chemopotentiation; combination strategies; DNA damage repair; ovarian cancer; radiation sensitizer ID PARP INHIBITORS; PHASE-I; POLY(ADP-RIBOSE) POLYMERASE; OVARIAN-CANCER; SOLID TUMORS; OPEN-LABEL; COMBINATION; TEMOZOLOMIDE; OLAPARIB; REPAIR AB Purpose of review The article presents the rationale, clinical development, and current status of poly (ADP ribose) polymerase inhibitors (PARPis) as anticancer agents. Recent findings The recent approval of olaparib in heavily pretreated patients with advanced ovarian cancer carrying a BRCA1/2 mutation represents a significant therapeutic advance for patients with this difficult to treat disease. Though olaparib is the first agent in this class to be approved, multiple PARPis are in various stages of clinical development, including in combination with other treatment modalities such as radiation, antiangiogenic agents, and cytotoxic chemotherapies. Summary Clinical benefit has been observed with PARPis in patients with advanced BRCA1/2 mutant ovarian and breast cancers. Various PARPis, either as single agents or in combination, are being evaluated in the neoadjuvant, adjuvant, and metastatic settings. C1 [Coyne, Geraldine O'Sullivan; Chen, Alice] NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Kummar, Shivaani] Stanford Univ, Dept Med, Div Med Oncol, Stanford, CA 94305 USA. RP Kummar, S (reprint author), Stanford Univ, Sch Med, Med, 780 Welch Rd,Rm CJ250L, Palo Alto, CA 94304 USA. EM skummar@stanford.edu FU Division of Oncology, Stanford University FX 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. G.O.C. and A.C. - This work was performed by federal employees as part of their official duty. S.K. - This work was supported by the Division of Oncology, Stanford University. There are no conflicts of interest. NR 33 TC 3 Z9 3 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1040-8746 EI 1531-703X J9 CURR OPIN ONCOL JI Curr. Opin. Oncol. PD NOV PY 2015 VL 27 IS 6 BP 475 EP 481 DI 10.1097/CCO.0000000000000238 PG 7 WC Oncology SC Oncology GA DD0QI UT WOS:000369624100007 ER PT J AU Fakhrejahani, F Tomita, Y Maj-Hes, A Trepel, JB De Santis, M Apolo, AB AF Fakhrejahani, Farhad Tomita, Yusuke Maj-Hes, Agnes Trepel, Jane B. De Santis, Maria Apolo, Andrea B. TI Immunotherapies for bladder cancer: a new hope SO CURRENT OPINION IN UROLOGY LA English DT Review DE advanced bladder cancer; combination therapy; immunotherapy; programmed death ligand-1; tumor-infiltrating lymphocytes ID BACILLUS-CALMETTE-GUERIN; CELL LUNG-CANCER; REGULATORY T-CELLS; EXOME ANALYSIS REVEALS; ADVANCED MELANOMA; CTLA-4 BLOCKADE; UROTHELIAL CARCINOMA; ANTITUMOR IMMUNITY; PD-1 BLOCKADE; DOUBLE-BLIND AB Purpose of review We review recent data on immunotherapies for bladder cancer and discuss strategies to maximize the antitumor effect of immunotherapy in solid tumors. Recent findings Anti-programmed death ligand 1 has shown promise in advanced bladder cancer. Clinical trials of immune checkpoint inhibitors as monotherapy or in combination are underway. Here we review strategies for enhancing antitumor immunity using immunomodulating agents or combination treatments that may increase tumor response. Summary Combining immune checkpoint inhibitors with other treatment modalities may lead to the development of new treatment strategies in advanced bladder cancer; however, identifying predictive biomarkers is essential for appropriate patient selection. C1 [Fakhrejahani, Farhad; Apolo, Andrea B.] NCI, Genitourinary Malignancies Branch, Ctr Canc Res, NIH, 10 Ctr Dr,Rm 12N226,MSC 1906, Bethesda, MD 20892 USA. [Tomita, Yusuke; Trepel, Jane B.] NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Maj-Hes, Agnes] Med Univ Vienna, Dept Urol, Vienna, Austria. [De Santis, Maria] Univ Warwick, Canc Res Unit, Sch Med, Coventry CV4 7AL, W Midlands, England. RP Apolo, AB (reprint author), NCI, Genitourinary Malignancies Branch, Ctr Canc Res, NIH, 10 Ctr Dr,Rm 12N226,MSC 1906, Bethesda, MD 20892 USA. EM andrea.apolo@nih.gov FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 130 TC 2 Z9 2 U1 3 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0963-0643 EI 1473-6586 J9 CURR OPIN UROL JI Curr. Opin. Urol. PD NOV PY 2015 VL 25 IS 6 BP 586 EP 596 DI 10.1097/MOU.0000000000000213 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA DC5HU UT WOS:000369252900016 PM 26372038 ER PT J AU Jobes, ML Aharonovich, E Epstein, DH Phillips, KA Reamer, D Anderson, M Preston, KL AF Jobes, Michelle L. Aharonovich, Efrat Epstein, David H. Phillips, Karran A. Reamer, David Anderson, Micheline Preston, Kenzie L. TI Effects of Prereactivation Propranolol on Cocaine Craving Elicited by Imagery Script/Cue Sets in Opioid-dependent Polydrug Users: A Randomized Study SO JOURNAL OF ADDICTION MEDICINE LA English DT Article DE cocaine; cue-induced craving; imagery scripts; memory reconsolidation; propranolol ID MORPHINE PLACE PREFERENCE; MEMORY RECONSOLIDATION; EMOTIONAL MEMORY; HUMAN FEAR; HUMANS; REACTIVATION; EXTINCTION; REACTIVITY; RETRIEVAL; QUESTIONNAIRE AB Objectives: Relapse to drug misuse may follow exposure to drug cues that elicit craving. The learned associations, or "emotional memories,'' that underlie responses to cues may be attenuated or erased by the beta-adrenergic antagonist propranolol during a "reconsolidation window'' shortly after the memories are reactivated by cues. Methods: We evaluated the effects of propranolol on cue-induced drug cravings in healthy opioid-dependent individuals who used cocaine while receiving methadone maintenance (n = 33). Participants were asked to recall specific cocaine use and neutral events in an interview; these events were used to develop personalized auditory script/cue sets. Approximately 1 week later, propranolol (40 mg) or placebo (random assignment, double blind) was administered orally before presentation of the script/cue sets; the presentation of the script/cue sets were tested 1 week and 5 weeks after the propranolol/placebo session. Ongoing drug use was monitored via urine screens and self-report in twice-weekly visits. Results: Cue reactivity, as assessed by craving scales and physiological responses, was unexpectedly greater in the propranolol group than in the placebo group. This counterhypothesized group difference was present acutely during propranolol administration and seemed to persist (without reaching statistical significance) during the subsequent test sessions. Conclusions: Our results do not support the use of propranolol for cue-induced cocaine craving in opioid-maintained patients. C1 [Jobes, Michelle L.; Phillips, Karran A.; Reamer, David; Anderson, Micheline; Preston, Kenzie L.] NIDA, Clin Pharmacol & Therapeut Res Branch, Intramural Res Program, Baltimore, MD USA. [Aharonovich, Efrat] Columbia Univ, Coll Physicians & Surgeons, Dept Psychiat, New York, NY USA. RP Preston, KL (reprint author), NIDA, Intramural Res Program, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM kpreston@intra.nida.nih.gov FU National Institute on Drug Abuse (NIDA), National Institutes of Health; NIDA [DA-020647] FX This research was supported by the Intramural Research Program (IRP) of the National Institute on Drug Abuse (NIDA), National Institutes of Health, and a NIDA R01 (grant number DA-020647) (Aharonovich). NR 36 TC 1 Z9 1 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1932-0620 EI 1935-3227 J9 J ADDICT MED JI J. Addict. Med. PD NOV-DEC PY 2015 VL 9 IS 6 BP 491 EP 498 DI 10.1097/ADM.0000000000000169 PG 8 WC Substance Abuse SC Substance Abuse GA DC9CR UT WOS:000369519000012 PM 26501788 ER PT J AU Chin, LMK Chan, L Woolstenhulme, JG Christensen, EJ Shenouda, CN Keyser, RE AF Chin, Lisa M. K. Chan, Leighton Woolstenhulme, Joshua G. Christensen, Eric J. Shenouda, Christian N. Keyser, Randall E. TI Improved Cardiorespiratory Fitness With Aerobic Exercise Training in Individuals With Traumatic Brain Injury SO JOURNAL OF HEAD TRAUMA REHABILITATION LA English DT Article DE endurance training; exercise tolerance; fatigue; physical activity; (V)over dotO(2) ID FATIGUE SEVERITY SCALE; PHYSICAL-ACTIVITY; ANAEROBIC THRESHOLD; MULTIPLE-SCLEROSIS; SLEEP DISTURBANCE; ADULTS; ENDURANCE; CAPACITY; METAANALYSIS; HEALTH AB Objective: To examine cardiorespiratory fitness in individuals with traumatic brain injury (TBI), before and following participation in a supervised 12-week aerobic exercise training program. Methods: Ten subjects with nonpenetrating TBI (TBI severity: mild, 50%; moderate, 40%; severe, 10%; time since injury [mean +/- SD]: 6.6 +/- 6.8 years) performed exercise training on a treadmill 3 times a week for 30 minutes at vigorous intensity (70%-80% of heart rate reserve). All subjects completed a cardiopulmonary exercise test, with pulmonary gas exchange measured and a questionnaire related to fatigue (Fatigue Severity Scale) at baseline and following exercise training. Results: After training, increases (P <.01) in peak oxygen consumption ((V)over dotO(2); + 3.1 +/- 2.4 mL/min/kg), time to volitional fatigue (+ 1.4 +/- 0.8 minutes), and peak work rate (+ 59 +/- 43 W) were observed. At the anaerobic threshold, (V)over dotO(2) (+ 3.6 +/- 2.1 mL/kg/min), treadmill time (+ 1.8 +/- 1.1 minutes), and work rate (+ 37 +/- 39 W) were higher (P <.01) following exercise training. Subjects also reported significantly lower (P <.05) Fatigue Severity Scale composite scores (-0.9 +/- 1.3) following exercise training. Conclusion: These findings suggest that individuals with TBI may benefit from participation in vigorous aerobic exercise training with improved cardiorespiratory fitness and diminished fatigue. C1 [Chin, Lisa M. K.; Woolstenhulme, Joshua G.; Keyser, Randall E.] George Mason Univ, Dept Rehabil Sci, 4400 Univ Dr, Fairfax, VA 22030 USA. [Chin, Lisa M. K.; Chan, Leighton; Woolstenhulme, Joshua G.; Christensen, Eric J.; Keyser, Randall E.] NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. [Chan, Leighton; Shenouda, Christian N.] Ctr Neurosci & Regenerat Med, Bethesda, MD USA. RP Chin, LMK (reprint author), George Mason Univ, Dept Rehabil Sci, 4400 Univ Dr, Fairfax, VA 22030 USA. EM lchin2@gmu.edu RI Chin, Lisa/O-4706-2014 OI Chin, Lisa/0000-0002-0178-739X FU Center for Neuroscience and Regenerative Medicine [G192HI-H]; National Institutes of Health Clinical Center (Rehabilitation Medicine Department Intramural Funds) FX This study was supported by the Center for Neuroscience and Regenerative Medicine (G192HI-H) and the National Institutes of Health Clinical Center (Rehabilitation Medicine Department Intramural Funds). The authors thank Bart Drinkard and Anne Quinn for their assistance with the exercise training sessions and data collection. They also thank Beth Kvochak for initial recruitment efforts. NR 67 TC 3 Z9 3 U1 2 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0885-9701 EI 1550-509X J9 J HEAD TRAUMA REHAB JI J. Head Trauma Rehabil. PD NOV-DEC PY 2015 VL 30 IS 6 BP 382 EP 390 DI 10.1097/HTR.0000000000000062 PG 9 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA DD0JN UT WOS:000369606300010 PM 24901330 ER PT J AU Dong, J Yang, JY Tranah, G Franceschini, N Parimi, N Alkorta-Aranburu, G Xu, ZL Alonso, A Cummings, SR Fornage, M Huang, XM Kritchevsky, S Liu, YM London, S Niu, L Wilson, RS De Jager, PL Yu, L Singleton, AB Harris, T Mosley, TH Pinto, JM Bennett, DA Chen, HL AF Dong, Jing Yang, Jingyun Tranah, Greg Franceschini, Nora Parimi, Neeta Alkorta-Aranburu, Gorka Xu, Zongli Alonso, Alvaro Cummings, Steven R. Fornage, Myriam Huang, Xuemei Kritchevsky, Stephen Liu, Yongmei London, Stephanie Niu, Liang Wilson, Robert S. De Jager, Philip L. Yu, Lei Singleton, Andrew B. Harris, Tamara Mosley, Thomas H., Jr. Pinto, Jayant M. Bennett, David A. Chen, Honglei TI Genome-wide Meta-analysis on the Sense of Smell Among US Older Adults SO MEDICINE LA English DT Article ID ODOR IDENTIFICATION; PARKINSONS-DISEASE; OLFACTORY DYSFUNCTION; ALZHEIMERS-DISEASE; APOLIPOPROTEIN-E; RISK LOCI; ASSOCIATION; IMPAIRMENT; POPULATION; EPITHELIUM AB Olfactory dysfunction is common among older adults and affects their safety, nutrition, quality of life, and mortality. More importantly, the decreased sense of smell is an early symptom of neurodegenerative diseases such as Parkinson disease (PD) and Alzheimer disease. However, the genetic determinants for the sense of smell have been poorly investigated. We here performed the first genome-wide meta-analysis on the sense of smell among 6252 US older adults of European descent from the Atherosclerosis Risk in Communities (ARIC) study, the Health, Aging, and Body Composition (Health ABC) study, and the Religious Orders Study and the Rush Memory and Aging Project (ROS/MAP). Genome-wide association study analysis was performed first by individual cohorts and then meta-analyzed using fixed-effect models with inverse variance weights. Although no SNPs reached genome-wide statistical significance, we identified 13 loci with suggestive evidence for an association with the sense of smell (P-meta<1x10(-5)). Of these, 2 SNPs at chromosome 17q21.31 (rs199443 in NSF, P=3.02x10(-6); and rs2732614 in KIAA1267-LRRC37A, P=6.65x10(-6)) exhibited cis effects on the expression of microtubule-associated protein tau (MAPT, 17q21.31) in 447 frontal-cortex samples obtained postmortem and profiled by RNA-seq (P<1x10(-15)). Gene-based and pathway-enrichment analyses further implicated MAPT in regulating the sense of smell in older adults. Similar results were obtained after excluding participants who reported a physician-diagnosed PD or use of PD medications. In conclusion, we provide preliminary evidence that the MAPT locus may play a role in regulating the sense of smell in older adults and therefore offer a potential genetic link between poor sense of smell and major neurodegenerative diseases. C1 [Dong, Jing; Xu, Zongli; London, Stephanie; Chen, Honglei] NIEHS, Epidemiol Branch, 111 TW Alexander Dr,POB 12233,Mail Drop A3-05, Res Triangle Pk, NC 27709 USA. [Niu, Liang] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. [Yang, Jingyun; Wilson, Robert S.; Yu, Lei; Bennett, David A.] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA. [Tranah, Greg; Parimi, Neeta; Cummings, Steven R.] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. [Franceschini, Nora] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [Alkorta-Aranburu, Gorka] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Alonso, Alvaro] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Hershey, PA 17033 USA. [Kritchevsky, Stephen] Wake Forest Sch Med, Sticht Ctr Aging, Winston Salem, NC USA. [Liu, Yongmei] Wake Forest Sch Med, Div Publ Hlth Sci, Winston Salem, NC USA. Brigham & Womens Hosp, Inst Neurosci, Dept Neurol, Program Translat Neuro Psychiat Gen, Boston, MA 02115 USA. Brigham & Womens Hosp, Inst Neurosci, Dept Psychiat, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. [De Jager, Philip L.] Broad Inst, Program Med & Populat Genet, Boston, MA USA. [Singleton, Andrew B.] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. [Harris, Tamara] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Mosley, Thomas H., Jr.] Univ Mississippi, Med Ctr, Dept Med, Div Geriatr, Jackson, MS 39216 USA. [Pinto, Jayant M.] Univ Chicago Med & Biol Sci, Dept Surg, Sect Otolaryngol Head & Neck Surg, Chicago, IL USA. [Yang, Jingyun; Yu, Lei; Bennett, David A.] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. [Wilson, Robert S.] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. [Wilson, Robert S.] Rush Univ, Med Ctr, Dept Behav Sci, Chicago, IL 60612 USA. RP Dong, J (reprint author), NIEHS, Epidemiol Branch, 111 TW Alexander Dr,POB 12233,Mail Drop A3-05, Res Triangle Pk, NC 27709 USA. EM dongj4@mail.nih.gov RI Singleton, Andrew/C-3010-2009; OI xu, zongli/0000-0002-9034-8902; London, Stephanie/0000-0003-4911-5290; Chen, Honglei/0000-0003-3446-7779 FU NIH [Z01 ES101986]; National Institute of Environmental Health Sciences; National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C]; National Human Genome Research Institute [U01HG004402]; National Institutes of Health [HHSN268200625226C, UL1RR025005, HHSN268200782096C]; NIH, National Institute on Aging (NIA); NIA [N01AG62101, N01AG62103, N01AG62106, 1R01AG032098-01A1]; National Institutes of Aging [R01 AG30146, P30 AG10161, R01 AG17917, R01 AG15819]; Illinois Department of Public Health; Translational Genomics Research Institute; National Institute on Aging [K23 AG036762]; McHugh Otolaryngology Research Fund; American Geriatrics Society; Center on the Demography and Economics of Aging; Institute of Translational Medicine at the University of Chicago [KL2RR025000, UL1RR024999]; NIEHS; NIH; GE; [R01HL087641]; [R01HL59367]; [R01HL086694]; [U01HL075572-01]; [R01-HL70825]; [R01-HL093029]; [R01-NS087541] FX The study was supported by the Intramural Research Program of NIH (Z01 ES101986) and the National Institute of Environmental Health Sciences.; 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, with the ARIC carotid MRI examination funded by U01HL075572-01; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. Neurocognitive data are collected by U01 HL096812, HL096814, HL096899, HL096902, and HL096917 with previous brain MRI examinations funded by R01-HL70825. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. Additional support for this project includes grants R01-HL093029 and R01-NS087541.; The Health ABC Study research was supported by in part by the Intramural Research Program of the NIH, National Institute on Aging (NIA) and 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.; The Religious Orders Study and Rush Memory and Aging Project were supported by grants from the National Institutes of Aging (R01 AG30146, P30 AG10161, R01 AG17917, R01 AG15819), the Illinois Department of Public Health, and the Translational Genomics Research Institute.; JMP was supported by the National Institute on Aging (K23 AG036762), the McHugh Otolaryngology Research Fund, the American Geriatrics Society, the Center on the Demography and Economics of Aging, and the Institute of Translational Medicine at the University of Chicago (KL2RR025000 and UL1RR024999).; XH received research grants and consultation fees from NIEHS, NIH, and GE. Other authors declare no competing financial interests. NR 43 TC 1 Z9 1 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0025-7974 EI 1536-5964 J9 MEDICINE JI Medicine (Baltimore) PD NOV PY 2015 VL 94 IS 47 AR e1892 DI 10.1097/MD.0000000000001892 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA DC9KB UT WOS:000369539300008 PM 26632684 ER PT J AU Schulz, SC AF Schulz, S. Charles TI This issue: First-Episode Psychosis SO PSYCHIATRIC ANNALS LA English DT Editorial Material C1 [Schulz, S. Charles] Univ Minnesota, Dept Psychiat, F282-2A West B,2450 Riverside Ave, Minneapolis, MN 55454 USA. [Schulz, S. Charles] Univ Minnesota, Psychiat, Minneapolis, MN 55454 USA. [Schulz, S. Charles] Univ Minnesota, Minneapolis, MN 55454 USA. [Schulz, S. Charles] NIMH, Neuropsychopharmacol Sect, Clin Ctr, Bethesda, MD USA. [Schulz, S. Charles] Virginia Commonwealth Univ Med Coll Virginia, Richmond, VA USA. [Schulz, S. Charles] Univ Pittsburgh, Schizophrenia Module, Pittsburgh, PA 15260 USA. RP Schulz, SC (reprint author), Univ Minnesota, Dept Psychiat, F282-2A West B,2450 Riverside Ave, Minneapolis, MN 55454 USA. EM scs@umn.edu NR 1 TC 0 Z9 0 U1 1 U2 1 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0048-5713 EI 1938-2456 J9 PSYCHIAT ANN JI Psychiatr. Ann. PD NOV PY 2015 VL 45 IS 11 BP 545 EP 546 DI 10.3928/00485713-20151103-04 PG 2 WC Psychiatry SC Psychiatry GA DC9EE UT WOS:000369523100004 ER PT J AU Azrin, ST Goldstein, AB Heinssen, RK AF Azrin, Susan T. Goldstein, Amy B. Heinssen, Robert K. TI Early Intervention for Psychosis: The Recovery After an Initial Schizophrenia Episode Project SO PSYCHIATRIC ANNALS LA English DT Article ID COGNITIVE-BEHAVIORAL THERAPY; RANDOMIZED CONTROLLED-TRIAL; 1ST-EPISODE PSYCHOSIS; UNTREATED PSYCHOSIS; MENTAL-ILLNESS; 1ST EPISODE; PREVALENCE; SERVICES; RISK; PREVENTION AB First-episode psychosis (FEP) is a traumatic event that often foreshadows a schizophrenia spectrum diagnosis. FEP treatment responsiveness depends on rapid initiation of care, but substantial delays between the onset of psychosis and effective antipsychotic intervention are common. In 2008, the National Institute of Mental Health launched the Recovery After an Initial Schizophrenia Episode (RAISE) initiative to develop and test coordinated specialty care (CSC)-a team-based, multicomponent treatment program for FEP-in "real world" US community clinics. RAISE demonstrates that mental health professionals from various disciplines can be trained to deliver CSC and that the approach significantly improves symptoms and functioning for patient's with FEP. Furthermore, clinical impact is greater when treatment is initiated soon after psychosis onset. With recent federal legislation, the number of CSC programs in the US is growing rapidly. A national learning health care network among US early psychosis clinics will further align science and clinical practice in early psychosis. C1 [Azrin, Susan T.] NIMH, Primary Care Res Program, Div Serv & Intervent Res, Rockville, MD 20852 USA. [Goldstein, Amy B.] NIMH, Prevent Res, Div Serv & Intervent Res, Rockville, MD 20852 USA. [Heinssen, Robert K.] NIMH, Div Serv & Intervent Res, 6001 Execut Blvd,Room 7145,MSC 9631, Rockville, MD 20852 USA. RP Azrin, ST (reprint author), NIMH, Div Serv & Intervent Res, 6001 Execut Blvd,Room 7145,MSC 9631, Rockville, MD 20852 USA. EM Susan.Azrin@nih.gov NR 44 TC 2 Z9 2 U1 4 U2 11 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0048-5713 EI 1938-2456 J9 PSYCHIAT ANN JI Psychiatr. Ann. PD NOV PY 2015 VL 45 IS 11 BP 548 EP 553 DI 10.3928/00485713-20151103-05 PG 6 WC Psychiatry SC Psychiatry GA DC9EE UT WOS:000369523100005 ER PT J AU Bohl, DD Ahn, J Tabaraee, E Ahn, J Jain, A Grauer, JN Singh, K AF Bohl, Daniel D. Ahn, Junyoung Tabaraee, Ehsan Ahn, Junho Jain, Akshay Grauer, Jonathan N. Singh, Kern TI Urinary Tract Infection Following Posterior Lumbar Fusion Procedures An American College of Surgeons National Surgical Quality Improvement Program Study SO SPINE LA English DT Article DE age; diabetes mellitus; functional status; malnutrition; National Patient Safety Goal; National Surgical Quality Improvement Program; operative duration; posterior lumbar fusion procedures; preventable adverse event; readmission; sex; systemic sepsis; urinary catheterization; urinary tract infection ID ORTHOPEDIC-SURGERY; SPINAL SURGERY; NUTRITION; RISK; SUPPLEMENTATION; COMPLICATIONS; PREVENTION; HOSPITALS; DIAGNOSIS; ALBUMIN AB Study Design. Retrospective review of prospectively collected data. Objective. To determine the incidence and risk factors for the development of a urinary tract infection (UTI) after a posterior lumbar fusion procedure. Summary of Background Data. UTI after surgery is common and has important clinical consequences for both patients and the health care system. Few studies have examined UTI after spinal fusion procedures. Methods. Patients undergoing posterior lumbar fusion procedures during 2011 to 2013 were identified in the American College of Surgeons National Surgical Quality Improvement Program database. Statistical comparisons were made using multivariate regression with adjustment for demographic, comorbidity, and operative characteristics. Results. A total of 10,825 patients met inclusion criteria. The incidence of a UTI was 1.77% (95% confidence interval = 1.52%-2.02%). Independent risk factors for a UTI were greater age (for 50 59 yr, relative risk [RR] = 1.0; 60 69 yr, RR = 2.1; >= 70 yr, RR = 3.5; P < 0.001), female sex (RR = 2.2, P < 0.001), dependent functional status (RR = 2.1, P = 0.010), malnutrition (RR = 2.3, P = 0.004), diabetic status (for non-insulin-dependent diabetes, RR = 1.5; for insulin-dependent diabetes, RR = 1.9; P = 0.011), and increased operative duration (for 120-179 min, RR = 1.4; 180-239 min, RR = 2.3; and for >= 240 min, RR = 2.7; P < 0.001). Patients who developed a UTI had a greater risk for systemic sepsis than other patients (11.5% vs. 0.63%; adjusted RR = 14.4, P < 0.001). Patients who developed a UTI had a greater risk for readmission than other patients (36.7% vs. 5.0%; adjusted RR = 6.1, P < 0.001). Conclusion. UTIs occur in nearly 1 in 50 patients undergoing posterior lumbar fusion procedures. Patients who are older, female, dependent, malnourished, or diabetic are at greater risk and should be counseled and monitored accordingly. In addition, morbidity associated with a UTI in this population is substantial, as demonstrated by a 14-fold increase in the risk for systemic sepsis and a 6-fold increase in the risk for readmission. As such, increased preventative measures should be targeted to the patients identified here to be at greatest risk. C1 [Bohl, Daniel D.; Grauer, Jonathan N.] Yale Univ, Sch Med, Dept Orthopaed & Rehabil, New Haven, CT 06510 USA. [Ahn, Junyoung; Tabaraee, Ehsan; Jain, Akshay; Singh, Kern] Rush Univ, Dept Orthopaed Surg, Med Ctr, 1611W Harrison St,Ste 300, Chicago, IL 60612 USA. [Ahn, Junho] NIA, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. RP Singh, K (reprint author), Rush Univ, Dept Orthopaed Surg, Med Ctr, 1611W Harrison St,Ste 300, Chicago, IL 60612 USA. EM kern.singh@rushortho.com NR 28 TC 2 Z9 2 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0362-2436 EI 1528-1159 J9 SPINE JI SPINE PD NOV PY 2015 VL 40 IS 22 BP 1785 EP 1791 DI 10.1097/BRS.0000000000001003 PG 7 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA DC4WR UT WOS:000369221500017 PM 26020850 ER PT J AU Kulakov, IV Matsukevich, MV Shulgau, ZT Sergazy, S Seilkhanov, TM Puzari, A Fisyuk, AS AF Kulakov, Ivan V. Matsukevich, Mariya V. Shulgau, Zarina T. Sergazy, Shyngys Seilkhanov, Tulegen M. Puzari, Amrit Fisyuk, Alexander S. TI Synthesis and antiradical activity of 4-aryl(hetaryl)-substituted 3-aminopyridin-2(1H)-ones SO CHEMISTRY OF HETEROCYCLIC COMPOUNDS LA English DT Article DE 3-aminopyridin-2(1H)-ones; 1,3-diketones; N-(3-oxoalkenyl)chloroacetamides; antiradical activity; intramolecular cyclization ID REVERSE-TRANSCRIPTASE INHIBITORS; 2-PYRIDINONE DERIVATIVES; BIOLOGICAL EVALUATION; IN-VITRO; DESIGN; PEPTIDOMIMETICS; ANALOGS AB The reaction of aryl(hetaryl)-substituted 1,3-diketones with chloroacetamide gave the respective N-(3-oxoalkenyl)chloroacetamides, which were converted to 3-pyridinium-substituted pyridin-2(1De)-ones upon heating with excess of pyridine in n-butanol. The decomposition of pyridinium salts with hydrazine hydrate resulted in new 4-aryl(hetaryl)-substituted 3-aminopyridin-2(1De)-ones, which showed strong antiradical activity with respect to ABTS and DPPH radicals. C1 [Kulakov, Ivan V.; Matsukevich, Mariya V.; Fisyuk, Alexander S.] FM Dostoevskii Omsk State Univ, Dept Organ Chem, 55a Mira Ave, Omsk 644077, Russia. [Fisyuk, Alexander S.] Omsk State Tech Univ, Omsk 644050, Russia. [Shulgau, Zarina T.; Sergazy, Shyngys] Minist Educ & Sci, RSE Natl Ctr Biotechnol, Astana 010000, Kazakhstan. [Seilkhanov, Tulegen M.] Sh Ualikhanov Kokshetau State Univ, Kokshetau 020000, Kazakhstan. [Puzari, Amrit] Natl Inst Technol Nagaland, Dept Sci & Humanities, Dimapur 797103, Nagaland, India. RP Kulakov, IV (reprint author), FM Dostoevskii Omsk State Univ, Dept Organ Chem, 55a Mira Ave, Omsk 644077, Russia. EM kulakov@chemomsu.ru; shulgau@biocenter.kz; tseilkhanov@mail.ru; amrit09us@yahoo.com; fisyuk@chemomsu.ru RI Fisyuk, Alexander/K-4544-2013; Kulakov, Ivan/A-7471-2014 OI Fisyuk, Alexander/0000-0001-6191-9297; Kulakov, Ivan/0000-0001-5772-2096 FU Russian Foundation for Basic Research [15-53-45084 IND_a] FX This study was performed with financial support from the Russian Foundation for Basic Research (project 15-53-45084 IND_a). NR 35 TC 1 Z9 1 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-3122 EI 1573-8353 J9 CHEM HETEROCYCL COM+ JI Chem. Heterocycl. Compds. PD NOV PY 2015 VL 51 IS 11-12 BP 991 EP 996 DI 10.1007/s10593-016-1809-7 PG 6 WC Chemistry, Organic SC Chemistry GA DC1VI UT WOS:000369005200006 ER PT J AU Farese, AM Hankey, KG Cohen, MV MacVittie, TJ AF Farese, Ann M. Hankey, Kim G. Cohen, Melanie Veirs MacVittie, Thomas J. TI LYMPHOID AND MYELOID RECOVERY IN RHESUS MACAQUES FOLLOWING TOTAL BODY X-IRRADIATION SO HEALTH PHYSICS LA English DT Article DE blood; laboratory animals; whole body irradiation; x rays ID BONE-MARROW-TRANSPLANTATION; RADIATION-INDUCED MYELOSUPPRESSION; T-CELL RECONSTITUTION; COLONY-STIMULATING FACTOR; NONHUMAN PRIMATE MODEL; G-CSF; HEMATOPOIETIC RECOVERY; INTENSIVE CHEMOTHERAPY; POTENTIALLY LETHAL; GATED IMPORTATION AB Recovery from severe immunosuppression requires hematopoietic stem cell reconstitution and effective thymopoiesis to restore a functional immune cell repertoire. Herein, a model of immune cell reconstitution consequent to potentially lethal doses of irradiation is described, which may be valuable in evaluating potential medical countermeasures. Male rhesus macaques were total body irradiated by exposure to 6.00 Gy 250 kVp x-radiation (midline tissue dose, 0.13 Gy min(-1)), resulting in an approximate LD10/60 (n = 5/59). Animals received medical management, and hematopoietic and immune cell recovery was assessed (n <= 14) through 370 d post exposure. A subset of animals (n <= 8) was examined through 700 d. Myeloid recovery was assessed by neutrophil and platelet-related parameters. Lymphoid recovery was assessed by the absolute lymphocyte count and FACS-based phenotyping of B- and T-cell subsets. Recent thymic emigrants were identified by T cell receptor excision circle quantification. Severe neutropenia, lymphopenia, and thrombocytopenia resolved within 30 d. Total CD3+ cells mu L-1 required 60 d to reach values 60% of normal, followed by subsequent slow recovery to approximately normal by 180 d post irradiation. Recovery of CD3+4+ and CD3+8+ cell memory and naive subsets were markedly different. Memory populations were >= 100% of normal by day 60, whereas naive populations were only 57% normal at 180 d and never fully recovered to baseline post irradiation. Total (CD20+) B cells mu L-1 were within normal levels by 77 d post exposure. This animal model elucidates the variable T- and B- cell subset recovery kinetics after a potentially lethal dose of total-body irradiation that are dependent on marrow-derived stem and progenitor cell recovery, peripheral homeostatic expansion, and thymopoiesis. C1 [Farese, Ann M.; Hankey, Kim G.; MacVittie, Thomas J.] Univ Maryland, Sch Med, Dept Radiat Oncol, Baltimore, MD 21201 USA. [Cohen, Melanie Veirs] NIAID, Integrated Res Facil, Frederick, MD USA. RP Farese, AM (reprint author), 10 S Pine St,MSTF Rm 6-34D, Baltimore, MD 21201 USA. EM afarese@som.umaryland.edu FU Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [R01 A167503-1] FX This project has been funded in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under R01 A167503-1. Authors gratefully acknowledge the superb technical assistance of Carrie Redinger, Michael E. Flynn, and all the members of our Preclincial Radiobiology Laboratory for their dedication to the health and wellbeing of our animals. NR 65 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD NOV PY 2015 VL 109 IS 5 BP 414 EP 426 DI 10.1097/HP.0000000000000348 PG 13 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA DC2VE UT WOS:000369075100007 PM 26425902 ER PT J AU Housman, G Malukiewicz, J Boere, V Grativol, AD Pereira, LCM Silva, IDE Ruiz-Miranda, CR Truman, R Stone, AC AF Housman, Genevieve Malukiewicz, Joanna Boere, Vanner Grativol, Adriana D. Pereira, Luiz Cezar M. e Silva, Ita de Oliveira Ruiz-Miranda, Carlos R. Truman, Richard Stone, Anne C. TI Validation of qPCR Methods for the Detection of Mycobacterium in New World Animal Reservoirs SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID POLYMERASE-CHAIN-REACTION; LEPRAE DNA; TUBERCULOSIS COMPLEX; INFECTIOUS-DISEASES; SPONTANEOUS LEPROSY; CALLITHRIX-JACCHUS; NONHUMAN-PRIMATES; REAL-TIME; PCR; DIAGNOSIS AB Zoonotic pathogens that cause leprosy (Mycobacterium leprae) and tuberculosis (Mycobacterium tuberculosis complex, MTBC) continue to impact modern human populations. Therefore, methods able to survey mycobacterial infection in potential animal hosts are necessary for proper evaluation of human exposure threats. Here we tested for mycobacterial-specific single-and multi-copy loci using qPCR. In a trial study in which armadillos were artificially infected with M. leprae, these techniques were specific and sensitive to pathogen detection, while more traditional ELISAs were only specific. These assays were then employed in a case study to detect M. leprae as well as MTBC in wild marmosets. All marmosets were negative for M. leprae DNA, but 14 were positive for the mycobacterial rpoB gene assay. Targeted capture and sequencing of rpoB and other MTBC genes validated the presence of mycobacterial DNA in these samples and revealed that qPCR is useful for identifying mycobacterial-infected animal hosts. C1 [Housman, Genevieve; Malukiewicz, Joanna; Stone, Anne C.] Arizona State Univ, Sch Human Evolut & Social Change, Tempe, AZ 85281 USA. [Malukiewicz, Joanna; Boere, Vanner] Univ Fed Vicosa, Dept Bioquim & Biol Mol, Vicosa, MG, Brazil. [Grativol, Adriana D.; Ruiz-Miranda, Carlos R.] Univ Estadual Norte Fluminense, Ctr Biociencias & Biotecnol, Lab Ciencias Ambientias, Rio De Janeiro, Brazil. [Pereira, Luiz Cezar M.] Univ Fed Vale Sao Francisco, Ctr Conservacao & Manejo Fauna Caatinga, Petrolina, PE, Brazil. [e Silva, Ita de Oliveira] Univ Fed Vicosa, Dept Biol Anim, Vicosa, MG, Brazil. [Truman, Richard] NIAID, HHS HRSA HSB Natl Hansens Dis Program, IAA 2646, Baton Rouge, LA USA. RP Housman, G (reprint author), Arizona State Univ, Sch Human Evolut & Social Change, Tempe, AZ 85281 USA. EM ghousman@asu.edu RI Ruiz, Carlos/I-4446-2016; OI Housman, Genevieve/0000-0002-3482-7511 FU National Institute of Allergy and Infectious Diseases [NIAID IAA-2646]; National Science Foundation [NSF BCS-1063939, NSF DDIG-1061508]; Fulbright Scholar Program; International Primatological Society; Arizona State University Chapter of Sigma Xi; Arizona State University Graduate and Professional Student Association FX This work was supported by the National Institute of Allergy and Infectious Diseases (www.niaid.nih.gov) [NIAID IAA-2646 to RT]; the National Science Foundation (www.nsf.gov) [NSF BCS-1063939 to ACS and NSF DDIG-1061508 to JM]; the Fulbright Scholar Program (www.cies.org) [Fellowship to JM]; the International Primatological Society (www.internationalprimatologicalsociety.org) [Research Grant to JM]; the Arizona State University Chapter of Sigma Xi (sigmaxi.asu.edu) [GIAR to JM]; and the Arizona State University Graduate and Professional Student Association (gpsa.asu.edu) [Jumpstart and Research Grant to JM]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 0 Z9 0 U1 2 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD NOV PY 2015 VL 9 IS 11 AR e0004198 DI 10.1371/journal.pntd.0004198 PG 13 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA DB2NA UT WOS:000368344400022 PM 26571269 ER PT J AU Howes, RE Reiner, RC Battle, KE Longbottom, J Mappin, B Ordanovich, D Tatem, AJ Drakeley, C Gething, PW Zimmerman, PA Smith, DL Hay, SI AF Howes, Rosalind E. Reiner, Robert C., Jr. Battle, Katherine E. Longbottom, Joshua Mappin, Bonnie Ordanovich, Dariya Tatem, Andrew J. Drakeley, Chris Gething, Peter W. Zimmerman, Peter A. Smith, David L. Hay, Simon I. TI Plasmodium vivax Transmission in Africa SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID DUFFY-BLOOD-GROUP; MALARIA TRANSMISSION; GLOBAL DISTRIBUTION; G6PD DEFICIENCY; SPATIAL-DISTRIBUTION; CLINICAL SPECTRUM; RISK-FACTORS; ELIMINATION; FALCIPARUM; PARASITE AB Malaria in sub-Saharan Africa has historically been almost exclusively attributed to Plasmodium falciparum (Pf). Current diagnostic and surveillance systems in much of sub-Saharan Africa are not designed to identify or report non-Pf human malaria infections accurately, resulting in a dearth of routine epidemiological data about their significance. The high prevalence of Duffy negativity provided a rationale for excluding the possibility of Plasmodium vivax (Pv) transmission. However, review of varied evidence sources including traveller infections, community prevalence surveys, local clinical case reports, entomological and serological studies contradicts this viewpoint. Here, these data reports are weighted in a unified framework to reflect the strength of evidence of indigenous Pv transmission in terms of diagnostic specificity, size of individual reports and corroboration between evidence sources. Direct evidence was reported from 21 of the 47 malaria-endemic countries studied, while 42 countries were attributed with infections of visiting travellers. Overall, moderate to conclusive evidence of transmission was available from 18 countries, distributed across all parts of the continent. Approximately 86.6 million Duffy positive hosts were at risk of infection in Africa in 2015. Analysis of the mechanisms sustaining Pv transmission across this continent of low frequency of susceptible hosts found that reports of Pv prevalence were consistent with transmission being potentially limited to Duffy positive populations. Finally, reports of apparent Duffy-independent transmission are discussed. While Pv is evidently not a major malaria parasite across most of sub-Saharan Africa, the evidence presented here highlights its widespread low-level endemicity. An increased awareness of Pv as a potential malaria parasite, coupled with policy shifts towards species-specific diagnostics and reporting, will allow a robust assessment of the public health significance of Pv, as well as the other neglected non-Pf parasites, which are currently invisible to most public health authorities in Africa, but which can cause severe clinical illness and require specific control interventions. C1 [Howes, Rosalind E.; Battle, Katherine E.; Mappin, Bonnie; Gething, Peter W.; Smith, David L.] Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Oxford, England. [Howes, Rosalind E.; Zimmerman, Peter A.] Case Western Reserve Univ, Ctr Global Hlth & Dis, Cleveland, OH 44106 USA. [Reiner, Robert C., Jr.] Indiana Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Bloomington, IN USA. [Reiner, Robert C., Jr.; Tatem, Andrew J.; Smith, David L.; Hay, Simon I.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Longbottom, Joshua; Hay, Simon I.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Ordanovich, Dariya; Tatem, Andrew J.] Univ Southampton, Dept Geog & Environm, Southampton, Hants, England. [Tatem, Andrew J.] Flowminder Fdn, Stockholm, Sweden. [Drakeley, Chris] London Sch Hyg & Trop Med, Malaria Ctr, London WC1, England. [Smith, David L.] Sanaria Inst Global Hlth & Trop Med, Rockville, MD USA. [Smith, David L.; Hay, Simon I.] Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA. RP Howes, RE (reprint author), Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, S Parks Rd, Oxford, England. EM rosalind.howes@zoo.ox.ac.uk RI Hay, Simon/F-8967-2015; OI Hay, Simon/0000-0002-0611-7272; Zimmerman, Peter/0000-0002-5349-4513; Gething, Peter/0000-0001-6759-5449; Longbottom, Joshua/0000-0002-4151-9031 FU Wellcome Trust [095066, 091924]; NIH [R01 AI097366]; Bill & Melinda Gates Foundation [OPP1106427, 1032350, OPP1068048, OPP1106023, OPP1110495]; UK Medical Research Council (MRC) [K00669X]; UK Department for International Development (DFID) [K00669X]; RAPIDD program of the Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health, USA FX REH is funded by a Wellcome Trust (www.wellcome.ac.uk) Senior Research Fellowship to SIH (095066) and an NIH (www.nih.gov) grant to PAZ (R01 AI097366). The Wellcome Trust Senior Research Fellowship to SIH (095066) also supports KEB and JL. AJT is funded by grants from the Bill & Melinda Gates Foundation (#OPP1106427, #1032350) (www.gatesfoundation.org). CD is funded by the Wellcome Trust (091924). PWG is a Career Development Fellow (K00669X) jointly funded by the UK Medical Research Council (MRC; www.mrc.ac.uk) and the UK Department for International Development (DFID; www.gov.uk/government/organisations/department-for-international-develop ment) under the MRC/DFID Concordat agreement and receives support from the Bill and Melinda Gates Foundation (OPP1068048, OPP1106023), which also supports BM. DLS is funded by a grant from the Bill & Melinda Gates Foundation (OPP1110495), which also supports RCR. RCR, AJT, DLS and SIH also acknowledge funding support from the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health, USA (www.fic.nih.gov). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 85 TC 9 Z9 10 U1 2 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD NOV PY 2015 VL 9 IS 11 AR e0004222 DI 10.1371/journal.pntd.0004222 PG 27 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA DB2NA UT WOS:000368344400035 PM 26587988 ER PT J AU Leitner, WW Wali, T Kincaid, R Denis, ACS AF Leitner, Wolfgang W. Wali, Tonu Kincaid, Randall Denis, Adriana Costero-Saint TI Arthropod Vectors and Disease Transmission: Translational Aspects SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID PLASMODIUM INFECTION; IXODES-SCAPULARIS; SALIVARY ANTIGEN; TICK; REFRACTORINESS; AUTOIMMUNITY; MALARIA; VACCINE; BITES; GLAND C1 [Leitner, Wolfgang W.] NIAID, Div Allergy Immunol & Transplantat, NIH, Bethesda, MD 20892 USA. [Wali, Tonu; Kincaid, Randall; Denis, Adriana Costero-Saint] NIAID, Div Microbiol & Infect Dis, NIH, Bethesda, MD 20892 USA. RP Leitner, WW (reprint author), NIAID, Div Allergy Immunol & Transplantat, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM wleitner@niaid.nih.gov RI Leitner, Wolfgang/F-5741-2011 OI Leitner, Wolfgang/0000-0003-3125-5922 FU NIAID/NIH FX The workshop reported here was supported by the NIAID/NIH. The funders had no role in study design, data collection and analysis of the studies presented by the workshop presenters which are discussed in this article. NR 32 TC 3 Z9 3 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD NOV PY 2015 VL 9 IS 11 AR e0004107 DI 10.1371/journal.pntd.0004107 PG 11 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA DB2NA UT WOS:000368344400010 PM 26583380 ER PT J AU Schousboe, ML Ranjitkar, S Rajakaruna, RS Amerasinghe, PH Morales, F Pearce, R Ord, R Leslie, T Rowland, M Gadalla, NB Konradsen, F Bygbjerg, IC Roper, C Alifrangis, M AF Schousboe, Mette L. Ranjitkar, Samir Rajakaruna, Rupika S. Amerasinghe, Priyanie H. Morales, Francisco Pearce, Richard Ord, Rosalyn Leslie, Toby Rowland, Mark Gadalla, Nahla B. Konradsen, Flemming Bygbjerg, Ib C. Roper, Cally Alifrangis, Michael TI Multiple Origins of Mutations in the mdr1 Gene-A Putative Marker of Chloroquine Resistance in P. vivax SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID SINGLE-NUCLEOTIDE POLYMORPHISMS; ANTIMALARIAL-DRUG-RESISTANCE; PLASMODIUM-VIVAX; DIHYDROFOLATE-REDUCTASE; CONFERRING MUTATIONS; SOUTH-AMERICA; PFMDR1 GENE; FALCIPARUM; MALARIA; DIVERSITY AB Background Chloroquine combined with primaquine has been the recommended antimalarial treatment of Plasmodium vivax malaria infections for six decades but the efficacy of this treatment regimen is threatened by chloroquine resistance (CQR). Single nucleotide polymorphisms (SNPs) in the multidrug resistance gene, Pvmdr1 are putative determinants of CQR but the extent of their emergence at population level remains to be explored. Objective In this study we describe the prevalence of SNPs in the Pvmdr1 among samples collected in seven P. vivax endemic countries and we looked for molecular evidence of drug selection by characterising polymorphism at microsatellite (MS) loci flanking the Pvmdr1 gene. Methods We examined the prevalence of SNPs in the Pvmdr1 gene among 267 samples collected from Pakistan, Afghanistan, Sri Lanka, Nepal, Sudan, Sao Tome and Ecuador. We measured and diversity in four microsatellite (MS) markers flanking the Pvmdr1 gene to look evidence of selection on mutant alleles. Results SNP polymorphism in the Pvmdr1 gene was largely confined to codons T958M, Y976F and F1076L. Only 2.4% of samples were wildtype at all three codons (TYF, n = 5), 13.3% (n = 28) of the samples were single mutant MYF, 63.0% of samples (n = 133) were double mutant MYL, and 21.3%(n = 45) were triple mutant MFL. Clear geographic differences in the prevalence of these Pvmdr mutation combinations were observed. Significant linkage disequilibrium (LD) between Pvmdr1 and MS alleles was found in populations sampled in Ecuador, Nepal and Sri Lanka, while significant LD between Pvmdr1 and the combined 4 MS locus haplotype was only seen in Ecuador and Sri Lanka. When combining the 5 loci, high level diversity, measured as expected heterozygosity (He), was seen in the complete sample set (H-e = 0.99), while H-e estimates for individual loci ranged from 0.00-0.93. Although Pvmdr1 haplotypes were not consistently associated with specific flanking MS alleles, there was significant differentiation between geographic sites which could indicate directional selection through local drug pressure. Conclusions Our observations suggest that Pvmdr1 mutations emerged independently on multiple occasions even within the same population. In Sri Lanka population analysis at multiple sites showed evidence of local selection and geographical dispersal of Pvmdr1 mutations between sites. C1 [Schousboe, Mette L.; Ranjitkar, Samir; Alifrangis, Michael] Univ Copenhagen, Inst Microbiol & Immunol, Ctr Med Parasitol, Copenhagen, Denmark. [Schousboe, Mette L.; Ranjitkar, Samir; Alifrangis, Michael] Copenhagen Univ Hosp, Dept Infect Dis, Copenhagen, Denmark. [Rajakaruna, Rupika S.] Univ Peradeniya, Dept Zool, Peradeniya, Sri Lanka. [Amerasinghe, Priyanie H.] Int Water Management Inst, Hyderabad, Andhra Pradesh, India. [Morales, Francisco] Univ San Francisco Quito Robles & Pampite, Cumbaya, Ecuador. [Pearce, Richard; Leslie, Toby; Rowland, Mark; Roper, Cally] London Sch Hyg & Trop Med, Fac Infect & Trop Dis, London WC1, England. [Ord, Rosalyn] New York Blood Ctr, Lindsley F Kimball Res Inst, Blood Borne Parasites, New York, NY 10021 USA. [Gadalla, Nahla B.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Konradsen, Flemming; Bygbjerg, Ib C.] Univ Copenhagen, Inst Publ Hlth, Sect Global Hlth, Copenhagen, Denmark. RP Schousboe, ML (reprint author), Univ Copenhagen, Inst Microbiol & Immunol, Ctr Med Parasitol, Copenhagen, Denmark. EM Cally.Roper@lshtm.ac.uk OI Bygbjerg, Ib/0000-0001-9100-2754; Alifrangis, Michael/0000-0002-3835-3333; Konradsen, Flemming/0000-0003-1036-6949 FU Danish Agency for Science, Technology and Innovation FX The study have received funding from the Danish Agency for Science, Technology and Innovation (MLS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 4 Z9 4 U1 3 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD NOV PY 2015 VL 9 IS 11 AR e0004196 DI 10.1371/journal.pntd.0004196 PG 17 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA DB2NA UT WOS:000368344400020 PM 26539821 ER PT J AU Morse, CG McLaughlin, M Proschan, M Koh, C Kleiner, DE Heller, T Kovacs, JA AF Morse, Caryn G. McLaughlin, Mary Proschan, Michael Koh, Christopher Kleiner, David E. Heller, Theo Kovacs, Joseph A. TI Transient elastography for the detection of hepatic fibrosis in HIV-monoinfected adults with elevated aminotransferases on antiretroviral therapy SO AIDS LA English DT Article DE hepatotoxicity; liver biopsy; liver stiffness measurements ID LIVER STIFFNESS MEASUREMENT; SIMPLE NONINVASIVE INDEX; SAMPLING VARIABILITY; CIRRHOSIS; BIOPSY; COINFECTION; PREDICT; DISEASE; SYSTEM AB Objective:Vibration-controlled transient elastography (VCTE) is increasingly used to assess liver fibrosis in viral hepatitis and fatty liver disease populations. Because the accuracy of VCTE in HIV-monoinfected populations has not been established, we evaluated its performance in assessing liver fibrosis in a cohort of HIV-monoinfected adults undergoing liver biopsy as part of a recently published clinical trial.Methods:HIV-infected adults with elevated aminotransferase levels for at least 6 months while receiving antiretroviral therapy, and without chronic viral hepatitis or other known causes of liver disease, were prospectively evaluated by VCTE, other noninvasive markers of fibrosis, and percutaneous liver biopsy as part of a cross-sectional study examining liver pathology.Results:Sixty-six patients were evaluated by VCTE and liver biopsy. The cohort was in the majority male (92%), with a median age of 50 years (range 17-68). Biopsy identified bridging fibrosis in 14 (21%) and nonalcoholic steatohepatitis in 38 (58%) participants. VCTE was unsuccessful or unreliable in seven participants (11%). In the 59 participants with reliable results, median liver stiffness measurement (LSM) was 5.9kPa (range 3.3-29.2kPa); 25 participants (42%) had a LSM above 7.1kPa, a value consistent with increased liver stiffness in other populations. VCTE had good sensitivity and specificity with an area under the receiver-operating characteristic curve (AUROC) of 93% for detection of moderate fibrosis (Ishak F2; 95% confidence interval 86-99%).Conclusions:In HIV-monoinfected adults with biopsy-proven liver disease, LSM by VCTE was the best noninvasive predictor of fibrosis. Our findings support the continued use of VCTE for fibrosis screening in HIV-monoinfected patients with elevated aminotransferases. C1 [Morse, Caryn G.; Kovacs, Joseph A.] NIH, Ctr Clin, Dept Crit Care Med, AIDS Sect, Bethesda, MD 20892 USA. [McLaughlin, Mary] NIAID, Immunoregulat Lab, Bethesda, MD 20892 USA. [Proschan, Michael] NIAID, Biostat Res Branch, Bethesda, MD 20892 USA. [Kleiner, David E.] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Koh, Christopher; Heller, Theo] NIDDK, Liver Dis Branch, Bethesda, MD 20892 USA. RP Morse, CG (reprint author), NIH, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM cmorse@mail.nih.gov OI Morse, Caryn/0000-0002-1177-4365 FU NIH Intramural Research Program; NIH Clinical Center; NIAID; NIDDK; NCI; NIH Bench to Bedside Award - Office of AIDS Research FX This study is supported by the NIH Intramural Research Program, NIH Clinical Center, NIAID, NIDDK, NCI, and, in part, by an NIH Bench to Bedside Award funded by the Office of AIDS Research. NR 22 TC 3 Z9 3 U1 0 U2 0 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 NOV PY 2015 VL 29 IS 17 BP 2297 EP 2302 DI 10.1097/QAD.0000000000000841 PG 6 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA DB4BG UT WOS:000368457100001 PM 26544701 ER PT J AU Shearer, GM Clerici, M Graham, DR Boasso, A AF Shearer, Gene M. Clerici, Mario Graham, David R. Boasso, Adriano TI Curing HIV/AIDS beyond hematopoietic stem cell transplant SO AIDS LA English DT Letter ID T-LYMPHOCYTES; HIV; DISEASE; REACTIVATION; STIMULATION; EXPRESSION; RESERVOIR C1 [Shearer, Gene M.] NIH, Expt Immunol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Clerici, Mario] Univ Milan, Dept Physiopathol & Transplants, Milan, Italy. [Clerici, Mario] IRCCS, Don C Gnocchi Fdn ONLUS, Milan, Italy. [Graham, David R.] Johns Hopkins Univ, Sch Med, Dept Mol & Comparat Pathobiol, Baltimore, MD USA. [Boasso, Adriano] Univ London Imperial Coll Sci Technol & Med, Ctr Immunol & Vaccinol, Chelsea & Westminster Hosp, London, England. RP Shearer, GM (reprint author), NIH, Expt Immunol Branch, Ctr Canc Res, Bldg 10,RM 4B-36, Bethesda, MD 20892 USA. EM shearerg@dc10a.nci.nih.gov NR 16 TC 0 Z9 0 U1 0 U2 1 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 NOV PY 2015 VL 29 IS 17 BP 2364 EP 2366 DI 10.1097/QAD.0000000000000861 PG 3 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA DB4BO UT WOS:000368457900003 PM 26544708 ER PT J AU More, ES Fee, E AF More, Ellen S. Fee, Elizabeth TI Mary Steichen Calderone (1904-1998): Advocate for Sex Education SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material C1 [More, Ellen S.] Univ Massachusetts, Sch Med, Dept Psychiat, Worcester, MA 01655 USA. [More, Ellen S.] Univ Massachusetts, Sch Med, Off Med Hist & Arch, Worcester, MA 01655 USA. [Fee, Elizabeth] NIH, Natl Lib Med, Bethesda, MD 20892 USA. RP More, ES (reprint author), Univ Massachusetts, Sch Med, 55 Lake Ave N, Worcester, MA 01655 USA. EM ellen.more@umassmed.edu NR 8 TC 0 Z9 0 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD NOV PY 2015 VL 105 IS 11 BP 2255 EP 2255 DI 10.2105/AJPH.2015.302822 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DB2KJ UT WOS:000368336700030 PM 26378827 ER PT J AU Shikani, AH Miller, AC Elamin, EM AF Shikani, Alan H. Miller, Andrew C. Elamin, Elamin M. TI Experimental Assessment and Future Applications of the Shikani Tracheostomy Speaking Valve SO AMERICAN JOURNAL OF SPEECH-LANGUAGE PATHOLOGY LA English DT Article ID VENTILATOR-DEPENDENT PATIENTS; AERODYNAMIC CHARACTERISTICS; AIR-FLOW; TRACHEOTOMY; MECHANICS; PRESSURE AB Purpose: Tracheostomy speaking valve use may increase airflow resistance and work of breathing. It remains unclear which valve offers the best performance characteristics. We compared the performance characteristics of the Shikani speaking valve (SSV; unidirectional-flow ball valve) with those of the Passy-Muir valve (PMV; bias-closed flapper valve). Method: Airflow resistance was measured for both the SSV and the PMV at 8 flow amplitudes and in 3 orientations (-15 degrees, 0 degrees, +20 degrees) in the bias-open and bias-closed configurations. Results: Significantly lower airflow resistance was observed for the SSV (bias open) compared with the PMV at -15 degrees (p < .001), 0 degrees (p < .001), and +20 degrees (p = .006) from the horizon. No significant difference was observed between the PMV and the SSV (bias-closed) configuration at any of the tested angles. A nonsignificant trend toward decreased airflow resistance was observed between the SSV bias-open and bias-closed configurations at each of the angles tested. Conclusions: The SSV demonstrated lower airflow resistance compared with the PMV across 8 flow amplitudes in the biasopen configuration at -15 degrees, 0 degrees, and +20 degrees from the horizon. Further investigation is needed to determine the clinical impact of these findings on patient comfort, work of breathing, phonation, and airway protection during swallowing. C1 [Shikani, Alan H.] Maryland Nose & Sinus Ctr, Baltimore, MD USA. [Shikani, Alan H.] Union Mem Hosp, Baltimore, MD USA. [Shikani, Alan H.] Sinai Hosp, Baltimore, MD 21215 USA. [Miller, Andrew C.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Miller, Andrew C.] W Virginia Univ, Morgantown, WV 26506 USA. [Elamin, Elamin M.] James A Haley Vet Hosp, Tampa, FL 33612 USA. [Elamin, Elamin M.] Univ S Florida, Tampa, FL USA. RP Elamin, EM (reprint author), James A Haley Vet Hosp, Tampa, FL 33612 USA. EM eelamin@health.usf.edu OI Miller, Andrew/0000-0001-8474-5090 FU SuperDimension FX The opinions expressed are the view of the authors and do not represent any position or policy of the U.S. National Institutes of Health, the Public Health Service, the Department of Health and Human Services, the Veterans Administration, the State of West Virginia, or the U.S. Government. Elamin M. Elamin received support for travel from SuperDimension. NR 21 TC 0 Z9 0 U1 0 U2 1 PU AMER SPEECH-LANGUAGE-HEARING ASSOC PI ROCKVILLE PA 10801 ROCKVILLE PIKE, ROCKVILLE, MD 20852-3279 USA SN 1058-0360 EI 1558-9110 J9 AM J SPEECH-LANG PAT JI Am. J. Speech-Lang. Pathol. PD NOV PY 2015 VL 24 IS 4 BP 733 EP 738 DI 10.1044/2015_AJSLP-14-0115 PG 6 WC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation SC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation GA DB3RW UT WOS:000368430100029 PM 26140360 ER PT J AU Schovanek, J Bullova, P Tayem, Y Giubellino, A Wesley, R Lendvai, N Nolting, S Kopacek, J Frysak, Z Pommier, Y Kummar, S Pacak, K AF Schovanek, Jan Bullova, Petra Tayem, Yasin Giubellino, Alessio Wesley, Robert Lendvai, Nikoletta Noelting, Svenja Kopacek, Juraj Frysak, Zdenek Pommier, Yves Kummar, Shivaani Pacak, Karel TI Inhibitory Effect of the Noncamptothecin Topoisomerase I Inhibitor LMP-400 on Female Mice Models and Human Pheochromocytoma Cells SO ENDOCRINOLOGY LA English DT Article ID HYPOXIA-INDUCIBLE FACTOR-1; METASTATIC PHEOCHROMOCYTOMA; MALIGNANT PHEOCHROMOCYTOMA; PARAGANGLIOMA FOCUS; SIGNALING PATHWAYS; HIF2A MUTATIONS; CANCER-THERAPY; TARGET GENES; CHEMOTHERAPY; HEREDITARY AB Metastatic pheochromocytoma continues to be an incurable disease, and treatment with conventional cytotoxic chemotherapy offers limited efficacy. In the present study, we evaluated a novel topoisomerase I inhibitor, LMP-400, as a potential treatment for this devastating disease. We found a high expression of topoisomerase I in human metastatic pheochromocytoma, providing a basis for the evaluation of a topoisomerase 1 inhibitor as a therapeutic strategy. LMP-400 inhibited the cell growth of established mouse pheochromocytoma cell lines and primary human tumor tissue cultures. In a study performed in athymic female mice, LMP-400 demonstrated a significant inhibitory effect on tumor growth with two drug administration regimens. Furthermore, low doses of LMP-400 decreased the protein levels of hypoxia-inducible factor 1 (HIF-1 alpha), one of a family of factors studied as potential metastatic drivers in these tumors. The HIF-1 alpha decrease resulted in changes in the mRNA levels of HIF-1 transcriptional targets. In vitro, LMP-400 showed an increase in the growth-inhibitory effects in combination with other chemotherapeutic drugs that are currently used for the treatment of pheochromocytoma. We conclude that LMP-400 has promising antitumor activity in preclinical models of metastatic pheochromocytoma and its use should be considered in future clinical trials. C1 [Schovanek, Jan; Bullova, Petra; Tayem, Yasin; Giubellino, Alessio; Lendvai, Nikoletta; Noelting, Svenja; Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, Bethesda, MD 20892 USA. [Wesley, Robert] NIH, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. [Pommier, Yves; Kummar, Shivaani] NCI, NIH, Bethesda, MD 20892 USA. [Schovanek, Jan; Frysak, Zdenek] Palacky Univ, Fac Med & Dent, Dept Internal Med Nephrol Rheumatol & Endocrinol, CR-77147 Olomouc, Czech Republic. [Bullova, Petra; Kopacek, Juraj] Slovak Acad Sci, Inst Virol, Dept Mol Med, Bratislava 84505, Slovakia. [Noelting, Svenja] Univ Munich, Univ Hosp, Dept Internal Med 2, D-80539 Munich, Germany. RP Pacak, K (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Med Neuroendocrinol, NIH, CRC, Bldg 10,Room 1E-3140,10 Ctr Dr,MSC-1109, Bethesda, MD 20892 USA. EM karel@mail.nih.gov FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health FX This work was supported the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health. NR 57 TC 2 Z9 2 U1 0 U2 2 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD NOV PY 2015 VL 156 IS 11 BP 4094 EP 4104 DI 10.1210/en.2015-1476 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DB3JV UT WOS:000368408100023 PM 26267380 ER PT J AU Bando, H Takebe, N AF Bando, Hideaki Takebe, Naoko TI Recent innovations in the USA National Cancer Institute-sponsored investigator initiated Phase I and II anticancer drug development SO JAPANESE JOURNAL OF CLINICAL ONCOLOGY LA English DT Review DE Phase I and II clinical trial; translational research; experimental therapeutics; clinical trial network; next-generation sequencing; molecular characterization ID ONCOLOGY; THERAPEUTICS; TRIALS; DESIGN AB Exciting recent advancements in deep-sequencing technology have enabled a rapid and cost-effective molecular characterization of patient-derived tumor samples. Incorporating these innovative diagnostic technologies into early clinical trials could significantly propel implementation of precision medicine by identifying genetic markers predictive of sensitivity to agents. It may also markedly accelerate drug development and subsequent regulatory approval of novel agents. Particularly noteworthy, a high-response rate in a Phase II trial involving a biomarker-enriched patient cohort could result in a regulatory treatment approval in rare histologies, which otherwise would not be a candidate for a large randomized clinical trial. Furthermore, even if a trial does not meet its statistical endpoint, tumors from a few responders should be molecularly characterized as part of the new biomarker-mining processes. In order to accommodate patient screening and accelerate the accrual process, institutions conducting early clinical trials need to be a part of a multi-institution clinical trials network. Future clinical trial design will incorporate new biomarkers discovered by a 'phenotype-to-genotype' effort with an appropriate statistical design. To help advance such changes, the National Cancer Institute has recently reformed the existing early phase clinical trials network. A new clinical trial network, the Experimental Therapeutics Clinical Trials Network (ET-CTN), was begun and, in addition to its pre-existing infrastructure, an up-to-date clinical trial registration system, clinical trial monitoring system including electronic database and a central Institutional Review Board were formed. Ultimately, these reforms support identifying the most appropriate therapy for each tumor type by incorporating state-of-the-art molecular diagnostic tools into early clinical trials. C1 [Bando, Hideaki] Natl Canc Ctr Hosp East, Dept Gastroenterol & Gastrointestinal Oncol, 6-5-1 Kashiwanoha, Kashiwa, Chiba 2778577, Japan. [Takebe, Naoko] NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Bethesda, MD 20852 USA. RP Bando, H (reprint author), Natl Canc Ctr Hosp East, Dept Gastroenterol & Gastrointestinal Oncol, 6-5-1 Kashiwanoha, Kashiwa, Chiba 2778577, Japan. EM hbando@east.ncc.go.jp; takeben@mail.nih.gov NR 12 TC 1 Z9 1 U1 2 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0368-2811 EI 1465-3621 J9 JPN J CLIN ONCOL JI Jpn. J. Clin. Oncol. PD NOV PY 2015 VL 45 IS 11 BP 1001 EP 1006 DI 10.1093/jjco/hyv144 PG 6 WC Oncology SC Oncology GA DB3IV UT WOS:000368405300001 PM 26423340 ER PT J AU Han, B Compton, WM AF Han, Beth Compton, Wilson M. TI Report Ignores Risk Factor of Tobacco in Assessing Suicidality Reply SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Letter DE Smoking; Suicide ID CIGARETTE-SMOKING; COMPLETED SUICIDE; ADULTS C1 [Han, Beth] Subst Abuse & Mental Hlth Serv Adm, Rockville, MD 20857 USA. [Compton, Wilson M.] NIDA, NIH, Bethesda, MD 20892 USA. RP Han, B (reprint author), Subst Abuse & Mental Hlth Serv Adm, Rockville, MD 20857 USA. EM Beth.Han@samhsa.hhs.gov NR 6 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 NOV PY 2015 VL 76 IS 11 BP 1571 EP 1572 DI 10.4088/JCP.15lr10027a PG 2 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA DB2QF UT WOS:000368353400029 PM 26646035 ER PT J AU Smith, SJ Horstick, EJ Davidson, AE Dowling, J AF Smith, Sarah J. Horstick, Eric J. Davidson, Ann E. Dowling, James TI Analysis of Zebrafish Larvae Skeletal Muscle Integrity with Evans Blue Dye SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Developmental Biology; Issue 105; congenital muscular dystrophies; Evans Blue Dye; zebrafish; sarcolemma integrity; myopathy; Duchenne muscular dystrophy; dystroglycanopathies ID DUCHENNE MUSCULAR-DYSTROPHY; GLYCOPROTEIN COMPLEX; MODEL; MUTANT; MYOPATHY; SARCOLEMMA; DISEASE; MOUSE AB The zebrafish model is an emerging system for the study of neuromuscular disorders. In the study of neuromuscular diseases, the integrity of the muscle membrane is a critical disease determinant. To date, numerous neuromuscular conditions display degenerating muscle fibers with abnormal membrane integrity; this is most commonly observed in muscular dystrophies. Evans Blue Dye (EBD) is a vital, cell permeable dye that is rapidly taken into degenerating, damaged, or apoptotic cells; in contrast, it is not taken up by cells with an intact membrane. EBD injection is commonly employed to ascertain muscle integrity in mouse models of neuromuscular diseases. However, such EBD experiments require muscle dissection and/or sectioning prior to analysis. In contrast, EBD uptake in zebrafish is visualized in live, intact preparations. Here, we demonstrate a simple and straightforward methodology for performing EBD injections and analysis in live zebrafish. In addition, we demonstrate a co-injection strategy to increase efficacy of EBD analysis. Overall, this video article provides an outline to perform EBD injection and characterization in zebrafish models of neuromuscular disease. C1 [Smith, Sarah J.; Davidson, Ann E.; Dowling, James] Hosp Sick Children, Program Genet & Genome Biol, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. [Smith, Sarah J.; Davidson, Ann E.; Dowling, James] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A1, Canada. [Horstick, Eric J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, Bethesda, MD USA. [Horstick, Eric J.; Dowling, James] Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA. [Horstick, Eric J.; Dowling, James] Univ Michigan, Dept Neurol, Ann Arbor, MI 48109 USA. RP Dowling, J (reprint author), Hosp Sick Children, Program Genet & Genome Biol, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. EM james.dowling@sickkids.ca FU Department of Pediatrics at the Hospital for Sick Children; Cure Congenital Muscular Dystrophy (CMD) FX We wish to thank Trent Waugh for his technical assistance. We also acknowledge the Department of Pediatrics at the Hospital for Sick Children and Cure Congenital Muscular Dystrophy (CMD) for their generous funding for this project. NR 32 TC 0 Z9 0 U1 0 U2 0 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD NOV PY 2015 IS 105 AR e53183 DI 10.3791/53183 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DB5SM UT WOS:000368573900033 ER PT J AU Reardon, DA Gilbert, MR Wick, W Liau, LD AF Reardon, David A. Gilbert, Mark R. Wick, Wolfgang Liau, Linda TI Immunotherapy for neuro-oncology: the critical rationale for combinatorial therapy SO NEURO-ONCOLOGY LA English DT Article DE glioblastoma; immunotherapy; immune checkpoint; programmed-death 1; vaccine ID REGULATORY T-CELLS; ENDOTHELIAL GROWTH-FACTOR; ANTITUMOR IMMUNE-RESPONSES; PULSED DENDRITIC CELLS; LYMPHOCYTE-ASSOCIATED ANTIGEN-4; TUMOR-INFILTRATING LYMPHOCYTES; HUMAN GLIOBLASTOMA-MULTIFORME; NEWLY-DIAGNOSED GLIOBLASTOMA; CANCER-IMMUNOTHERAPY; SUPPRESSOR-CELLS AB A successful therapeutic paradigm established historically in oncology involves combining agents with potentially complementary mechanisms of antitumor activity into rationally designed regimens. For example, cocktails of cytotoxic agents, which were carefully designed based on mechanisms of action, dose, and scheduling considerations, have led to dramatic improvements in survival including cures for childhood leukemia, Hodgkin's lymphoma, and several other complex cancers. Outcome for glioblastoma, the most common primary malignant CNS cancer, has been more modest, but nonetheless our current standard of care derives from confirmation that combination therapy surpasses single modality therapy. Immunotherapy has recently come of age for medical oncology with exciting therapeutic benefits achieved by several types of agents including vaccines, adoptive T cells, and immune checkpoint inhibitors against several types of cancers. Nonetheless, most benefits are relatively short, while others are durable but are limited to a minority of treated patients. Critical factors limiting efficacy of immunotherapeutics include insufficient immunogenicity and/or inadequate ability to overcome immunosuppressive factors exploited by tumors. The paradigm of rationally designed combinatorial regimens, originally established by cytotoxic therapy for oncology, may also prove relevant for immunotherapy. Realization of the true therapeutic potential of immunotherapy for medical oncology and neuro-oncology patients may require development of combinatorial regimens that optimize immunogenicity and target tumor adaptive immunosuppressive factors. C1 [Reardon, David A.] Dana Farber Brigham & Womens Canc Ctr, Ctr Neurooncol, Boston, MA USA. [Reardon, David A.] Dana Farber Brigham & Womens Canc Ctr, Dept Med Oncol, Boston, MA USA. [Gilbert, Mark R.] NCI, Neurol Clin, Bethesda, MD 20892 USA. [Gilbert, Mark R.] NCI, Natl Ctr Canc Res, Bethesda, MD 20892 USA. [Wick, Wolfgang] Heidelberg Univ, Neurol Clin, Heidelberg, Germany. [Wick, Wolfgang] Heidelberg Univ, Natl Ctr Tumor Dis, Heidelberg, Germany. [Wick, Wolfgang] German Canc Res Ctr, German Consortium Translat Canc Res DKTK, Heidelberg, Germany. [Liau, Linda] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurosurg, Brain Tumor Program, Los Angeles, CA 90095 USA. RP Reardon, DA (reprint author), Dana Farber Canc Inst, Ctr Neurooncol, 450 Brookline Ave,D2134, Boston, MA 02215 USA. EM david_reardon@dfci.harvard.edu RI Gilbert, Mark/J-7494-2016 OI Gilbert, Mark/0000-0003-2556-9722 FU Celldex Pharmaceuticals; Incyte, Inc.; GlaxoSmithKline; Genentech; Apogenix [APG101]; Boehringer Ingelheim; Eli Lilly; immatics; MSD; Roche; Northwest Biotherapeutics, Inc. FX David A. Reardon, MD, has served as a speakers' bureau member for Merck and Genentech/Roche and has received research support from Celldex Pharmaceuticals and Incyte, Inc. He has also served on advisory boards for Abbvie, Amgen, Cavion, EMD Serono, Genentech/Roche, Merck, Midatech, Momenta Pharmaceuticals, Novocure, Novartis, Regeneron, and Stemline Therapeutics.; Mark R. Gilbert, MD, has served on advisory boards for Abbvie, EMD Serono, Genentech/Roche, Merck, and Cell Medica. He has received research support from GlaxoSmithKline and Genentech.; Wolfgang Wick, MD, has received research grants from Apogenix, Boehringer Ingelheim, Eli Lilly, immatics, MSD, and Roche as well as honoraria for lectures or advisory board participation from MSD and Roche. He is or has been the coordinating investigator for sponsored clinical trials evaluating APG101 (Apogenix), bevacizumab (Roche), galunisertib (Eli Lilly), temozolomide (MSD), and temsirolimus (Pfizer).; Linda Liau, MD, PhD, has received research funding from Northwest Biotherapeutics, Inc. NR 133 TC 3 Z9 3 U1 2 U2 10 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD NOV PY 2015 VL 17 SU 7 BP 32 EP 40 DI 10.1093/neuonc/nov178 PG 9 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA DB3OO UT WOS:000368421200007 PM 26516225 ER PT J AU Choi, HS Jain, V Krueger, B Marshall, V Kim, CH Shisler, JL Whitby, D Renne, R AF Choi, Hong Seok Jain, Vaibhav Krueger, Brian Marshall, Vickie Kim, Chang Hee Shisler, Joanna L. Whitby, Denise Renne, Rolf TI Kaposi's Sarcoma-Associated Herpesvirus (KSHV) Induces the Oncogenic miR-17-92 Cluster and Down-Regulates TGF-beta Signaling SO PLOS PATHOGENS LA English DT Article ID ENDOTHELIAL-CELLS; NUCLEAR ANTIGEN; DNA-SEQUENCES; MALIGNANT-LYMPHOMA; MICRORNA CLUSTER; IN-VITRO; VIRUS; LATENCY; EXPRESSION; MIR-155 AB KSHV is a DNA tumor virus that causes Kaposi's sarcoma. Upon KSHV infection, only a limited number of latent genes are expressed. We know that KSHV infection regulates host gene expression, and hypothesized that latent genes also modulate the expression of host miRNAs. Aberrant miRNA expression contributes to the development of many types of cancer. Array-based miRNA profiling revealed that all six miRNAs of the oncogenic miR-17-92 cluster are up-regulated in KSHV infected endothelial cells. Among candidate KSHV latent genes, we found that vFLIP and vCyclin were shown to activate the miR-17-92 promoter, using luciferase assay and western blot analysis. The miR-17-92 cluster was previously shown to target TGF-beta signaling. We demonstrate that vFLIP and vCyclin induce the expression of the miR-17-92 cluster to strongly inhibit the TGF-beta signaling pathway by down-regulating SMAD2. Moreover, TGF-beta activity and SMAD2 expression were fully restored when antagomirs ( inhibitors) of miR-17-92 cluster were transfected into cells expressing either vFLIP or vCyclin. In addition, we utilized viral genetics to produce vFLIP or vCyclin knock-out viruses, and studied the effects in infected TIVE cells. Infection with wildtype KSHV abolished expression of SMAD2 protein in these endothelial cells. While single-knockout mutants still showed a marked reduction in SMAD2 expression, TIVE cells infected by a double-knockout mutant virus were fully restored for SMAD2 expression, compared to non-infected TIVE cells. Expression of either vFLIP or vCycIin was sufficient to downregulate SMAD2. In summary, our data demonstrate that vFLIP and vCyclin induce the oncogenic miR-17-92 cluster in endothelial cells and thereby interfere with the TGF-beta signaling pathway. Manipulation of the TGF-beta pathway via host miRNAs represents a novel mechanism that may be important for KSHV tumorigenesis and angiogenesis, a hallmark of KS. C1 [Choi, Hong Seok; Jain, Vaibhav; Krueger, Brian; Renne, Rolf] Univ Florida, Dept Mol Genet & Microbiol, Gainesville, FL 32611 USA. [Marshall, Vickie; Kim, Chang Hee; Whitby, Denise] Leidos Biomed, Frederick Natl Lab Canc Res, AIDS & Canc Virus Program, Frederick, MD USA. [Shisler, Joanna L.] Univ Illinois, Coll Med, Dept Microbiol, Urbana, IL 61801 USA. [Renne, Rolf] Univ Florida, UF Hlth Canc Ctr, Gainesville, FL USA. [Renne, Rolf] Univ Florida, UF Inst Genet, Gainesville, FL USA. RP Choi, HS (reprint author), Univ Florida, Dept Mol Genet & Microbiol, Gainesville, FL 32611 USA. EM rrenne@ufl.edu FU National Institutes of Health NCI [R01CA 119917]; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work was supported by grants from National Institutes of Health NCI R01CA 119917 to RR and with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E to DW. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 59 TC 4 Z9 4 U1 2 U2 4 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 NOV PY 2015 VL 11 IS 11 AR e1005255 DI 10.1371/journal.ppat.1005255 PG 19 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA DB2IR UT WOS:000368332000019 PM 26545119 ER PT J AU Harper, MS Guo, KJ Gibbert, K Lee, EJ Dillon, SM Barrett, BS McCarter, MD Hasenkrug, KJ Dittmer, U Wilson, CC Santiago, ML AF Harper, Michael S. Guo, Kejun Gibbert, Kathrin Lee, Eric J. Dillon, Stephanie M. Barrett, Bradley S. McCarter, Martin D. Hasenkrug, Kim J. Dittmer, Ulf Wilson, Cara C. Santiago, Mario L. TI Interferon-alpha Subtypes in an Ex Vivo Model of Acute HIV-1 Infection: Expression, Potency and Effector Mechanisms SO PLOS PATHOGENS LA English DT Article ID PLASMACYTOID DENDRITIC CELLS; IFN-ALPHA; I INTERFERON; INHIBITS HIV-1; GASTROINTESTINAL-TRACT; DISEASE PROGRESSION; ANTI-HIV-1 ACTIVITY; RESTRICTION FACTORS; VPU PROTEIN; LYMPHOCYTES AB HIV-1 is transmitted primarily across mucosal surfaces and rapidly spreads within the intestinal mucosa during acute infection. The type I interferons (IFNs) likely serve as a first line of defense, but the relative expression and antiviral properties of the 12 IFN alpha subtypes against HIV-1 infection of mucosal tissues remain unknown. Here, we evaluated the expression of all IFN alpha subtypes in HIV-1-exposed plasmacytoid dendritic cells by next-generation sequencing. We then determined the relative antiviral potency of each IFN alpha subtype ex vivo using the human intestinal Lamina Propria Aggregate Culture model. IFN alpha subtype transcripts from the centromeric half of the IFNA gene complex were highly expressed in pDCs following HIV-1 exposure. There was an inverse relationship between IFNA subtype expression and potency. IFN alpha 8, IFN alpha 6 and IFN alpha 14 were the most potent in restricting HIV-1 infection. IFN alpha 2, the clinically-approved subtype, and IFN alpha 1 were both highly expressed but exhibited relatively weak antiviral activity. The relative potencies correlated with binding affinity to the type I IFN receptor and the induction levels of HIV-1 restriction factors Mx2 and Tetherin/ BST-2 but not APOBEC3G, F and D. However, despite the lack of APOBEC3 transcriptional induction, the higher relative potency of IFN alpha 8 and IFN alpha 14 correlated with stronger inhibition of virion infectivity, which is linked to deaminase-independent APOBEC3 restriction activity. By contrast, both potent (IFN alpha 8) and weak (IFN alpha 1) subtypes significantly induced HIV-1 GG-to-AG hypermutation. The results unravel non-redundant functions of the IFN alpha subtypes against HIV-1 infection, with strong implications for HIV-1 mucosal immunity, viral evolution and IFN alpha-based functional cure strategies. C1 [Harper, Michael S.; Guo, Kejun; Lee, Eric J.; Dillon, Stephanie M.; Barrett, Bradley S.; Wilson, Cara C.; Santiago, Mario L.] Univ Colorado Denver, Dept Med, Aurora, CO 80045 USA. [Harper, Michael S.; Wilson, Cara C.; Santiago, Mario L.] Univ Colorado Denver, Dept Immunol & Microbiol, Aurora, CO USA. [Gibbert, Kathrin; Dittmer, Ulf] Univ Duisburg Essen, Univ Hosp Essen, Inst Virol, Essen, Germany. [McCarter, Martin D.] Univ Colorado Denver, Dept Surg, Aurora, CO USA. [Hasenkrug, Kim J.] NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Harper, MS (reprint author), Univ Colorado Denver, Dept Med, Aurora, CO 80045 USA. EM ulf.dittmer@uni-due.de; cara.wilson@ucdenver.edu; mario.santiago@ucdenver.edu FU University of Colorado Department of Medicine Early Career Program; NIAID; German Research Association [DFG-TRR60]; Tim Gill Foundation endowment; [R56 AI116271]; [R01 AI108404] FX This work was supported by R56 AI116271 (MLS and CCW), R01 AI108404 (CCW), the University of Colorado Department of Medicine Early Career Program (MLS), the Intramural Research Program at the NIAID (KJH) and the German Research Association DFG-TRR60 (KGi and UD). MSH was supported in part by a Tim Gill Foundation endowment to the University of Colorado Division of Infectious Diseases. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 79 TC 7 Z9 7 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 NOV PY 2015 VL 11 IS 11 AR e1005254 DI 10.1371/journal.ppat.1005254 PG 24 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA DB2IR UT WOS:000368332000018 PM 26529416 ER PT J AU de Gonzalez, AB Kleinerman, RA McAreavey, D Rajaraman, P AF de Gonzalez, Amy Berrington Kleinerman, Ruth A. McAreavey, Dorothea Rajaraman, Preetha TI Cardiac MR Imaging and the Specter of Double-Strand Breaks SO RADIOLOGY LA English DT Editorial Material ID CARDIOVASCULAR MAGNETIC-RESONANCE; CORONARY CT ANGIOGRAPHY; COMPUTED-TOMOGRAPHY; BLOOD-LYMPHOCYTES; HEART-DISEASE; DNA; RISK; FAILURE; CANCER; REPAIR C1 [de Gonzalez, Amy Berrington; Kleinerman, Ruth A.; Rajaraman, Preetha] NCI, Div Canc Epidemiol & Genet, Radiat Epidemiol Branch, Bethesda, MD 20892 USA. [McAreavey, Dorothea] NIH, Dept Cardiol, Ctr Clin, Bethesda, MD 20892 USA. RP de Gonzalez, AB (reprint author), NCI, Div Canc Epidemiol & Genet, Radiat Epidemiol Branch, 6120 Executive Blvd, Bethesda, MD 20892 USA. EM berringtona@mail.nih.gov OI Kleinerman, Ruth/0000-0001-7415-2478 NR 25 TC 2 Z9 2 U1 3 U2 4 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 NOV PY 2015 VL 277 IS 2 BP 329 EP 331 DI 10.1148/radiol.2015151943 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DB3TQ UT WOS:000368435100004 ER PT J AU Liu, F Choi, KW Samsonov, A Spencer, RG Wilson, JJ Block, WF Kijowski, R AF Liu, Fang Choi, Kwang Won Samsonov, Alexey Spencer, Richard G. Wilson, John J. Block, Walter F. Kijowski, Richard TI Articular Cartilage of the Human Knee Joint: In Vivo Multicomponent T2 Analysis at 3.0 T SO RADIOLOGY LA English DT Article ID RELAXATION ANALYSIS; PATELLAR CARTILAGE; OSTEOARTHRITIS; MRI; T-2; TIME; MATRIX; COLLAGEN; BRAIN; EPIDEMIOLOGY AB Purpose: To compare multicomponent T2 parameters of the articular cartilage of the knee joint measured by using multicomponent driven equilibrium single-shot observation of T1 and T2 (mcDESPOT) in asymptomatic volunteers and patients with osteoarthritis. Materials and Methods: This prospective study was performed with institutional review board approval and with written informed consent from all subjects. The mcDESPOT sequence was performed in the knee joint of 13 asymptomatic volunteers and 14 patients with osteoarthritis of the knee. Single-component T2 (T2(Single)), T2 of the fast-relaxing water component (T2(F)) and of the slow-relaxing water component (T2(S)), and the fraction of the fast-relaxing water component (F-F) of cartilage were measured. Wilcoxon rank-sum tests and multivariate linear regression models were used to compare mcDESPOT parameters between volunteers and patients with osteoarthritis. Receiver operating characteristic analysis was used to assess diagnostic performance with mcDESPOT parameters for distinguishing morphologically normal cartilage from morphologically degenerative cartilage identified at magnetic resonance imaging in eight cartilage subsections of the knee joint. Results: Higher cartilage T2(Single) (P < .001), lower cartilage F-F (P < .001), and similar cartilage T2(F) (P = .079) and T2(S) (P = .124) values were seen in patients with osteoarthritis compared with those in asymptomatic volunteers. Differences in T2(Single) and F-F remained significant (P < .05) after consideration of age differences between groups of subjects. Diagnostic performance was higher with F-F than with T2(Single) for distinguishing between normal and degenerative cartilage (P < .05), with greater areas under the curve at receiver operating characteristic analysis. Conclusion: Patients with osteoarthritis of the knee had significantly higher cartilage T2(Single) and significantly lower cartilage F-F than did asymptomatic volunteers, and receiver operating characteristic analysis results suggested that F-F may allow greater diagnostic performance than that with T2(Single) for distinguishing between normal and degenerative cartilage. (C) RSNA, 2015 C1 [Liu, Fang; Samsonov, Alexey; Block, Walter F.] Univ Wisconsin, Dept Med Phys, Sch Med & Publ Hlth, Madison, WI 53706 USA. [Choi, Kwang Won] Univ Wisconsin, Dept Biomech Engn, Sch Med & Publ Hlth, Madison, WI USA. [Samsonov, Alexey; Kijowski, Richard] Univ Wisconsin, Dept Radiol, Sch Med & Publ Hlth, Madison, WI 53706 USA. [Wilson, John J.] Univ Wisconsin, Dept Orthoped, Sch Med & Publ Hlth, Madison, WI USA. [Spencer, Richard G.] NIA, Magnet Resonance Imaging & Spect Sect, NIH, Baltimore, MD 21224 USA. RP Liu, F (reprint author), Wisconsin Inst Med Res, Dept Med Phys, 1111 Highland Ave, Madison, WI 53705 USA. EM fliu37@wisc.edu FU National Institutes of Health [R01NS065034] FX This research was supported by the National Institutes of Health (grant R01NS065034). NR 51 TC 4 Z9 4 U1 5 U2 7 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 NOV PY 2015 VL 277 IS 2 BP 477 EP 488 DI 10.1148/radiol.2015142201 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DB3TQ UT WOS:000368435100024 PM 26024307 ER PT J AU Brenner, P Mayr, T Guethoff, S Buchholz, S Poettinger, T Lutzmann, I Werner, F Bauer, A Klymiuk, N Wolf, E Reimann, K Mohiuddin, M Hermanns, W Ayares, D McGregor, C Lambris, JD Hagl, C Reichart, B Lambris, JD Hagl, C Reichart, B Abicht, JM AF Brenner, Paolo Mayr, Tanja Guethoff, Sonja Buchholz, Stefan Poettinger, Thomas Lutzmann, Isabelle Werner, Fabian Bauer, Andreas Klymiuk, Nikolai Wolf, Eckhard Reimann, Keith Mohiuddin, Muhammad Hermanns, Walter Ayares, David McGregor, Christopher Lambris, John D. Hagl, Christian Reichart, Bruno Lambris, John D. Hagl, Christian Reichart, Bruno Abicht, Jan-Michael TI CD40MAB COSTIMULATION BLOCKADE IN (LIFE-SUPPORTING) HETEROTOPIC AND ORTHOTOPIC CARDIAC XENOTRANSPLANTATION MODELS WITH GALT-KO/HCD46/HTM TRANSGENIC DONOR PIGS INTO THE BABOON SO TRANSPLANTATION LA English DT Meeting Abstract CT Joint Congress of the International-Pancreas-and-Islet-Transplantation-Association, International-Xenotransplantation-Association and Cell-Transplant-Society CY NOV 15-19, 2015 CL Melbourne, AUSTRALIA SP Int Pancreas & Islet Transplantat Assoc, Int Xenotransplantat Assoc, Cell Transplant Soc C1 [Brenner, Paolo; Mayr, Tanja; Guethoff, Sonja; Buchholz, Stefan; Poettinger, Thomas; Lutzmann, Isabelle; Werner, Fabian] Univ Munich, Dept Cardiac Surg, Munich, Germany. [Bauer, Andreas; Abicht, Jan-Michael] Univ Munich, Dept Anaesthesiol, Munich, Germany. [Brenner, Paolo; Mayr, Tanja; Guethoff, Sonja; Poettinger, Thomas; Lutzmann, Isabelle; Werner, Fabian; Reichart, Bruno; Abicht, Jan-Michael] Univ Munich, Walter Brendel Ctr, Munich, Germany. [Klymiuk, Nikolai; Wolf, Eckhard] Univ Munich, Dept Mol Anim Breeding & Biotechnol, Munich, Germany. [Reimann, Keith] Univ Massachusetts, MassBiol, Sch Med, Boston, MA 02125 USA. [Mohiuddin, Muhammad] NHLBI, Cardiothorac Surg Res Lab, NIH, Bethesda, WA 20892 USA. [Hermanns, Walter] Univ Munich, Dept Vet Pathol, Munich, Germany. [Ayares, David] Revivicor Inc, Blacksburg, VA USA. [McGregor, Christopher] UCL, Dept Cardiothorac Surg, London, England. [Lambris, John D.] Univ Penn, Pathol & Lab Med, Philadelphia, PA 19104 USA. RI Mohiuddin, Muhammad/M-4642-2013 OI Mohiuddin, Muhammad/0000-0003-4654-783X NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD NOV PY 2015 VL 99 IS 11 SU 2 MA 815 BP S238 EP S239 PG 2 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA DB6LE UT WOS:000368625700348 ER PT J AU Miller, J Singh, A Eckhaus, M Corcoran, P Thomas, M Lewis, B Reimann, K Ayares, D Horvath, K Mohiuddin, M AF Miller, Justin Singh, Avneesh Eckhaus, Michael Corcoran, Philip Thomas, Marvin Lewis, Billeta Reimann, Keith Ayares, David Horvath, Keith Mohiuddin, Muhammad TI HISTOLOGICAL EVIDENCE OF ACUTE REJECTION AFTER TERMINATING ANTI CD40 ANTIBODY (2C10R4) TREATMENT IN GTKO.HCD46.HTBM PIG TO BABOON CARDIAC XENOGRAFTS SURVIVING FOR OVER ONE YEAR SO TRANSPLANTATION LA English DT Meeting Abstract CT Joint Congress of the International-Pancreas-and-Islet-Transplantation-Association, International-Xenotransplantation-Association and Cell-Transplant-Society CY NOV 15-19, 2015 CL Melbourne, AUSTRALIA SP Int Pancreas & Islet Transplantat Assoc, Int Xenotransplantat Assoc, Cell Transplant Soc C1 [Miller, Justin; Singh, Avneesh; Corcoran, Philip; Horvath, Keith; Mohiuddin, Muhammad] NHLBI, Cardiothorac Surg Res Program, NIH, Bethesda, MD 20892 USA. [Eckhaus, Michael; Thomas, Marvin; Lewis, Billeta] NIH, Div Vet Res, ORS, Bethesda, MD 20892 USA. [Reimann, Keith] Univ Massachusetts, Boston, MA 02125 USA. [Ayares, David] Revivicor Inc, Blacksburg, VA USA. RI Mohiuddin, Muhammad/M-4642-2013 OI Mohiuddin, Muhammad/0000-0003-4654-783X 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 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD NOV PY 2015 VL 99 IS 11 SU 2 MA 811 BP S236 EP S236 PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA DB6LE UT WOS:000368625700344 ER PT J AU Mohiuddin, M Singh, A Corcoran, P Thomas, M Lewis, B Clark, T Eckhaus, M Belli, A Reimann, K Klymuik, N Wolf, E Ayares, D Horvath, K AF Mohiuddin, Muhammad Singh, Avneesh Corcoran, Philip Thomas, Marvin Lewis, Billeta Clark, Tannia Eckhaus, Michael Belli, Aaron Reimann, Keith Klymuik, Nikolai Wolf, Eckhard Ayares, David Horvath, Keith TI CRITICAL NEED OF CONTINUOUS CO-STIMULATION BLOCKADE WITH ANTI CD40 ANTIBODY (2C10.R4) FOR LONG-TERM MAINTENANCE OF GTKO.HCD46.HTBM PIG CARDIAC XENOGRAFT SURVIVAL IN BABOONS SO TRANSPLANTATION LA English DT Meeting Abstract CT Joint Congress of the International-Pancreas-and-Islet-Transplantation-Association, International-Xenotransplantation-Association and Cell-Transplant-Society CY NOV 15-19, 2015 CL Melbourne, AUSTRALIA SP Int Pancreas & Islet Transplantat Assoc, Int Xenotransplantat Assoc, Cell Transplant Soc C1 [Mohiuddin, Muhammad; Singh, Avneesh; Corcoran, Philip; Horvath, Keith] NHLBI, Cardiothorac Surg Res Program, NIH, Bldg 10, Bethesda, MD 20892 USA. [Klymuik, Nikolai; Wolf, Eckhard] LMU, Munich, Germany. [Belli, Aaron; Reimann, Keith] Univ Massachusetts, Boston, MA 02125 USA. [Thomas, Marvin; Lewis, Billeta; Clark, Tannia; Eckhaus, Michael] NIH, DVR ORS, Bldg 10, Bethesda, MD 20892 USA. [Ayares, David] Revivicor Inc, Blacksburg, VA USA. RI Mohiuddin, Muhammad/M-4642-2013 OI Mohiuddin, Muhammad/0000-0003-4654-783X NR 0 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 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD NOV PY 2015 VL 99 IS 11 SU 2 MA 810 BP S236 EP S236 PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA DB6LE UT WOS:000368625700343 ER PT J AU Singh, A Corcoran, P Lewis, B Thomas, M Ayares, D Horvath, K Mohiuddin, M AF Singh, Avneesh Corcoran, Philip Lewis, Billeta Thomas, Marvin Ayares, David Horvath, Keith Mohiuddin, Muhammad TI CARDIAC XENOTRANSPLANTATION: ROLE OF CD4+CD25HIFOXP3+T REGULATORY CELLS IN LONG-TERM CARDIAC XENOGRAFT SURVIVORS. SO TRANSPLANTATION LA English DT Meeting Abstract CT Joint Congress of the International-Pancreas-and-Islet-Transplantation-Association, International-Xenotransplantation-Association and Cell-Transplant-Society CY NOV 15-19, 2015 CL Melbourne, AUSTRALIA SP Int Pancreas & Islet Transplantat Assoc, Int Xenotransplantat Assoc, Cell Transplant Soc C1 [Singh, Avneesh; Corcoran, Philip; Horvath, Keith; Mohiuddin, Muhammad] NHLBI, Cardiothorac Surg Res Program, NIH, Bethesda, MD 20892 USA. [Lewis, Billeta; Thomas, Marvin] NIH, DVR ORS, Bethesda, MD 20892 USA. [Ayares, David] Revivicor Inc, Blacksburg, VA USA. RI Mohiuddin, Muhammad/M-4642-2013 OI Mohiuddin, Muhammad/0000-0003-4654-783X 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 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD NOV PY 2015 VL 99 IS 11 SU 2 MA 1058 BP S327 EP S327 PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA DB6LE UT WOS:000368625700481 ER PT J AU Singh, A Corcoran, P Lewis, B Thomas, M Ayares, D Horvath, K Mohiuddin, M AF Singh, Avneesh Corcoran, Philip Lewis, Billeta Thomas, Marvin Ayares, David Horvath, Keith Mohiuddin, Muhammad TI CARDIAC XENOTRANSPLANTATION: RE-EMERGED B CELLS AFTER TRANSIENT DEPLETION BY RITUXAN TREATMENT MAINTAINS THEIR REPERTOIRE BUT HAVE A MUTED IMMUNE RESPONSE SO TRANSPLANTATION LA English DT Meeting Abstract CT Joint Congress of the International-Pancreas-and-Islet-Transplantation-Association, International-Xenotransplantation-Association and Cell-Transplant-Society CY NOV 15-19, 2015 CL Melbourne, AUSTRALIA SP Int Pancreas & Islet Transplantat Assoc, Int Xenotransplantat Assoc, Cell Transplant Soc C1 [Singh, Avneesh; Corcoran, Philip; Horvath, Keith; Mohiuddin, Muhammad] NHLBI, Cardiothorac Surg Res Program, NIH, Bethesda, MD 20892 USA. [Lewis, Billeta; Thomas, Marvin] NIH, DvR ORS, Bethesda, MD 20892 USA. [Ayares, David] Revivicor Inc, Blacksburg, VA USA. RI Mohiuddin, Muhammad/M-4642-2013 OI Mohiuddin, Muhammad/0000-0003-4654-783X 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 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD NOV PY 2015 VL 99 IS 11 SU 2 MA 812 BP S237 EP S237 PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA DB6LE UT WOS:000368625700345 ER PT J AU Qian, WJ Park, JE Grant, R Lai, CC Kelley, JA Yaffe, MB Lee, KS Burke, TR AF Qian, Wen-Jian Park, Jung-Eun Grant, Robert Lai, Christopher C. Kelley, James A. Yaffe, Michael B. Lee, Kyung S. Burke, Terrence R., Jr. TI Neighbor-directed histidine N (tau)-alkylation: A route to imidazolium-containing phosphopeptide macrocycles SO BIOPOLYMERS LA English DT Article DE Plk1; polo kinase; polo-box domain; crystal structure; cationic dialkyl histidine; peptide macrocycles; phosphopeptides ID RING-CLOSING METATHESIS; POLO-BOX DOMAIN; KINASE 1; PEPTIDES; ALKYLATION; CATALYSTS; FRAGMENTATION; SELECTIVITY; CYCLIZATION; REDUCTION AB Our recently discovered, selective, on-resin route to N()-alkylated imidazolium-containing histidine residues affords new strategies for peptide mimetic design. In this, we demonstrate the use of this chemistry to prepare a series of macrocyclic phosphopeptides, in which imidazolium groups serve as ring-forming junctions. Interestingly, these cationic moieties subsequently serve to charge-mask the phosphoamino acid group that directed their formation. Neighbor-directed histidine N()-alkylation opens the door to new families of phosphopeptidomimetics for use in a range of chemical biology contexts. (c) 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 104: 663-673, 2015. C1 [Qian, Wen-Jian; Lai, Christopher C.; Kelley, James A.; Burke, Terrence R., Jr.] NCI, Biol Chem Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Park, Jung-Eun; Lee, Kyung S.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Grant, Robert; Yaffe, Michael B.] MIT, Dept Biol & Biol Engn, Ctr Canc Res, Cambridge, MA 02139 USA. RP Burke, TR (reprint author), NCI, NIH, Bldg 376 Boyles St, Frederick, MD 21702 USA. EM tburke@helix.nih.gov FU National Institutes of Health [ES015339, GM68762]; National Institute of General Medical Sciences, National Institutes of Health [P41 GM103403]; U.S. Department of Energy (DOE) Office of Science by Argonne National Laboratory, U.S. DOE [DE-AC02-06CH11357]; NIH, Center for Cancer Research, NCI-Frederick; National Cancer Institute, National Institutes of Health FX Contract grant sponsor: National Institutes of Health; Contract grant number: ES015339, GM68762; Contract grant sponsor: National Institute of General Medical Sciences, National Institutes of Health; Contract grant number: P41 GM103403; Contract grant sponsor: U.S. Department of Energy (DOE) Office of Science by Argonne National Laboratory, U.S. DOE; Contract grant number: DE-AC02-06CH11357; Contract grant sponsors: Intramural Research Program of the NIH, Center for Cancer Research, NCI-Frederick and the National Cancer Institute, National Institutes of Health, an NCI Director';s Innovation Career Development Award NR 40 TC 2 Z9 2 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-3525 EI 1097-0282 J9 BIOPOLYMERS JI Biopolymers PD NOV PY 2015 VL 104 IS 6 BP 663 EP 673 DI 10.1002/bip.22698 PG 11 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA DB2NZ UT WOS:000368347600001 PM 26152807 ER PT J AU Grady, C AF Grady, Christine TI Institutional Review Boards Purpose and Challenges SO CHEST LA English DT Review ID MULTICENTER CLINICAL-TRIALS; HUMAN RESEARCH PARTICIPANTS; NETWORK; SUPPORT; REFORM; IRBS AB Institutional review boards (IRBs) or research ethics committees provide a core protection for human research participants through advance and periodic independent review of the ethical acceptability of proposals for human research. IRBs were codified in US regulation just over three decades ago and are widely required by law or regulation in jurisdictions globally. Since the inception of IRBs, the research landscape has grown and evolved, as has the system of IRB review and oversight. Evidence of inconsistencies in IRB review and in application of federal regulations has fueled dissatisfaction with the IRB system. Some complain that IRB review is time-consuming and burdensome without clear evidence of effectiveness at protecting human subjects. Multiple proposals have been offered to reform or update the current IRB system, and many alternative models are currently being tried. Current focus on centralizing and sharing reviews requires more attention and evidence. Proposed changes to the US federal regulations may bring more changes. Data and resourcefulness are needed to further develop and test review and oversight models that provide adequate and respectful protections of participant rights and welfare and that are appropriate, efficient, and adaptable for current and future research. C1 [Grady, Christine] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. RP Grady, C (reprint author), NIH, Dept Bioeth, Ctr Clin, Bldg 10 IC118, Bethesda, MD 20892 USA. EM cgrady@nih.gov FU Intramural NIH HHS NR 50 TC 0 Z9 0 U1 2 U2 6 PU AMER COLL CHEST PHYSICIANS PI GLENVIEW PA 2595 PATRIOT BLVD, GLENVIEW, IL 60026 USA SN 0012-3692 J9 CHEST JI Chest PD NOV PY 2015 VL 148 IS 5 BP 1148 EP 1155 DI 10.1378/chest.15-0706 PG 8 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DB1MZ UT WOS:000368273600023 PM 26042632 ER PT J AU Wiggins, JL Mitchell, C Hyde, LW Monk, CS AF Wiggins, Jillian Lee Mitchell, Colter Hyde, Luke W. Monk, Christopher S. TI Identifying early pathways of risk and resilience: The codevelopment of internalizing and externalizing symptoms and the role of harsh parenting SO DEVELOPMENT AND PSYCHOPATHOLOGY LA English DT Article ID EARLY CONDUCT PROBLEMS; EARLY-CHILDHOOD; DEVELOPMENTAL PSYCHOPATHOLOGY; DEPRESSIVE SYMPTOMS; ANTISOCIAL-BEHAVIOR; PHYSICAL AGGRESSION; MIDDLE CHILDHOOD; MULTIPLE-LEVELS; SUBSTANCE USE; TRAJECTORIES AB Psychological disorders co-occur often in children, but little has been done to document the types of conjoint pathways internalizing and externalizing symptoms may take from the crucial early period of toddlerhood or how harsh parenting may overlap with early symptom codevelopment. To examine symptom codevelopment trajectories, we identified latent classes of individuals based on internalizing and externalizing symptoms across ages 3-9 and found three symptom codevelopment classes: normative symptoms (low), severe-decreasing symptoms (initially high but rapidly declining), and severe symptoms (high) trajectories. Next, joint models examined how parenting trajectories overlapped with internalizing and externalizing symptom trajectories. These trajectory classes demonstrated that, normatively, harsh parenting increased after toddlerhood, but the severe symptoms class was characterized by a higher level and a steeper increase in harsh parenting and the severe-decreasing class by high, stable harsh parenting. In addition, a transactional model examined the bidirectional relationships among internalizing and externalizing symptoms and harsh parenting because they may cascade over time in this early period. Harsh parenting uniquely contributed to externalizing symptoms, controlling for internalizing symptoms, but not vice versa. In addition, internalizing symptoms appeared to be a mechanism by which externalizing symptoms increase. Results highlight the importance of accounting for both internalizing and externalizing symptoms from an early age to understand risk for developing psychopathology and the role harsh parenting plays in influencing these trajectories. C1 [Wiggins, Jillian Lee; Mitchell, Colter; Hyde, Luke W.; Monk, Christopher S.] Univ Michigan, Ann Arbor, MI 48109 USA. RP Wiggins, JL (reprint author), NIMH, Emot & Dev Branch, NIH, 9000 Rockville Pike,Bldg 15K, Bethesda, MD 20892 USA. EM jillian.wiggins@nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [R01HD36916, R01HD39135, R01HD40421] FX The authors thank the Eunice Kennedy Shriver National Institute of Child Health and Human Development through Grants R01HD36916, R01HD39135, and R01HD40421, as well as a consortium of private foundations for their support of the Fragile Families and Child Well-Being Study. The authors also thank the families who participated and are grateful to Ellen Leibenluft for encouragement on the manuscript. NR 86 TC 5 Z9 5 U1 4 U2 20 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0954-5794 EI 1469-2198 J9 DEV PSYCHOPATHOL JI Dev. Psychopathol. PD NOV PY 2015 VL 27 IS 4 BP 1295 EP 1312 DI 10.1017/S0954579414001412 PN 1 PG 18 WC Psychology, Developmental SC Psychology GA DB0YZ UT WOS:000368236000023 PM 26439075 ER PT J AU Lansford, JE Godwin, J Tirado, LMU Zelli, A Al-Hassan, SM Bacchini, D Bombi, AS Bornstein, MH Chang, L Deater-Deckard, K Di Giunta, L Dodge, KA Malone, PS Oburu, P Pastorelli, C Skinner, AT Sorbring, E Tapanya, S Alampay, LP AF Lansford, Jennifer E. Godwin, Jennifer Uribe Tirado, Liliana Maria Zelli, Arnaldo Al-Hassan, Suha M. Bacchini, Dario Bombi, Anna Silvia Bornstein, Marc H. Chang, Lei Deater-Deckard, Kirby Di Giunta, Laura Dodge, Kenneth A. Malone, Patrick S. Oburu, Paul Pastorelli, Concetta Skinner, Ann T. Sorbring, Emma Tapanya, Sombat Pena Alampay, Liane TI Individual, family, and culture level contributions to child physical abuse and neglect: A longitudinal study in nine countries SO DEVELOPMENT AND PSYCHOPATHOLOGY LA English DT Article ID CORPORAL PUNISHMENT; DISCIPLINE; ATTITUDES; ATTRIBUTIONS; BEHAVIORS; VIOLENCE; PARENTS; MOTHERS; FATHERS; MALTREATMENT AB This study advances understanding of predictors of child abuse and neglect at multiple levels of influence. Mothers, fathers, and children (N = 1,418 families, M age of children = 8.29 years) were interviewed annually in three waves in 13 cultural groups in nine countries (China, Colombia, Italy, Jordan, Kenya, Philippines, Sweden, Thailand, and the United States). Multilevel models were estimated to examine predictors of (a) within-family differences across the three time points, (b) between-family within-culture differences, and (c) between-cultural group differences in mothers' and fathers' reports of corporal punishment and children's reports of their parents' neglect. These analyses addressed to what extent mothers' and fathers' use of corporal punishment and children's perceptions of their parents' neglect were predicted by parents' belief in the necessity of using corporal punishment, parents' perception of the normativeness of corporal punishment in their community, parents' progressive parenting attitudes, parents' endorsement of aggression, parents' education, children's externalizing problems, and children's internalizing problems at each of the three levels. Individual-level predictors (especially child externalizing behaviors) as well as cultural-level predictors (especially normativeness of corporal punishment in the community) predicted corporal punishment and neglect. Findings are framed in an international context that considers how abuse and neglect are defined by the global community and how countries have attempted to prevent abuse and neglect. C1 [Lansford, Jennifer E.; Godwin, Jennifer; Dodge, Kenneth A.; Malone, Patrick S.; Skinner, Ann T.] Duke Univ, Durham, NC 27708 USA. [Uribe Tirado, Liliana Maria] Univ San Buenaventura, Bogota, Colombia. [Zelli, Arnaldo] Univ Rome Foro Italico, Rome, Italy. [Al-Hassan, Suha M.] Hashemite Univ, Zarqa, Jordan. [Al-Hassan, Suha M.] Emirates Coll Adv Educ, Abu Dhabi, U Arab Emirates. [Bacchini, Dario] Univ Naples 2, Naples, Italy. [Bombi, Anna Silvia; Di Giunta, Laura; Pastorelli, Concetta] Univ Roma La Sapienza, Rome, Italy. [Bornstein, Marc H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Rockville, MD USA. [Chang, Lei] Hong Kong Inst Educ, Hong Kong, Hong Kong, Peoples R China. [Deater-Deckard, Kirby] Virginia Polytech Inst & State Univ, Blacksburg, VA 24061 USA. [Oburu, Paul] Maseno Univ, Maseno, Kenya. [Sorbring, Emma] Univ West, Trollhattan, Sweden. [Tapanya, Sombat] Chiang Mai Univ, Chiang Mai, Thailand. [Pena Alampay, Liane] Ateneo Manila Univ, Quezon City, Philippines. RP Lansford, JE (reprint author), Duke Univ, Ctr Child & Family Policy, Box 90545, Durham, NC 27708 USA. EM lansford@duke.edu OI ZELLI, Arnaldo/0000-0003-4020-8159 FU FIC NIH HHS [R03 TW008141]; NICHD NIH HHS [R01 HD054805] NR 44 TC 3 Z9 3 U1 10 U2 25 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0954-5794 EI 1469-2198 J9 DEV PSYCHOPATHOL JI Dev. Psychopathol. PD NOV PY 2015 VL 27 IS 4 SI SI BP 1417 EP 1428 DI 10.1017/S095457941500084X PN 2 PG 12 WC Psychology, Developmental SC Psychology GA DB0ZL UT WOS:000368237500004 PM 26535934 ER PT J AU Zinzow-Kramer, WM Horton, BM McKee, CD Michaud, JM Tharp, GK Thomas, JW Tuttle, EM Yi, S Maney, DL AF Zinzow-Kramer, W. M. Horton, B. M. McKee, C. D. Michaud, J. M. Tharp, G. K. Thomas, J. W. Tuttle, E. M. Yi, S. Maney, D. L. TI Genes located in a chromosomal inversion are correlated with territorial song in white-throated sparrows SO GENES BRAIN AND BEHAVIOR LA English DT Article DE Behavioral polymorphism; estrogen receptor alpha; RNA-seq; social behavior; WGCNA ID ALTERNATIVE REPRODUCTIVE STRATEGIES; ZONOTRICHIA-ALBICOLLIS GMELIN; COEXPRESSION NETWORK ANALYSIS; ESTROGEN-RECEPTOR-ALPHA; SOCIAL-BEHAVIOR NETWORK; HISTORY TRADE-OFFS; NEURAL RESPONSES; POLYMORPHISM; BRAIN; AGGRESSION AB The genome of the white-throated sparrow (Zonotrichia albicollis) contains an inversion polymorphism on chromosome 2 that is linked to predictable variation in a suite of phenotypic traits including plumage color, aggression and parental behavior. Differences in gene expression between the two color morphs, which represent the two common inversion genotypes (ZAL2/ZAL2 and ZAL2/ZAL2(m)), may therefore advance our understanding of the molecular underpinnings of these phenotypes. To identify genes that are differentially expressed between the two morphs and correlated with behavior, we quantified gene expression and terrirorial aggression, including song, in a population of free-living white-throated sparrows. We analyzed gene expression in two brain regions, the medial amygdala (MeA) and hypothalamus. Both regions are part of a 'social behavior network', which is rich in steroid hormone receptors and previously linked with territorial behavior. Using weighted gene co-expression network analyses, we identified modules of genes that were correlated with both morph and singing behavior. The majority of these genes were located within the inversion, showing the profound effect of the inversion on the expression of genes captured by the rearrangement. These modules were enriched with genes related to retinoic acid signaling and basic cellular functioning. In the MeA, the most prominent pathways were those related to steroid hormone receptor activity. Within these pathways, the only gene encoding such a receptor was ESR1 (estrogen receptor 1), a gene previously shown to predict song rate in this species. The set of candidate genes we identified may mediate the effects of a chromosomal inversion on territorial behavior. C1 [Zinzow-Kramer, W. M.; Horton, B. M.; McKee, C. D.; Michaud, J. M.; Maney, D. L.] Emory Univ, Dept Psychol, Atlanta, GA 30322 USA. [Tharp, G. K.] Emory Univ, Yerkes Nonhuman Primate Genom Core, Atlanta, GA 30322 USA. [Thomas, J. W.] NHGRI, Intramural Sequencing Ctr, NIH, Rockville, MD USA. [Tuttle, E. M.] Indiana State Univ, Dept Biol, Terre Haute, IN 47809 USA. [Tuttle, E. M.] Indiana State Univ, Ctr Genom Advocacy, Terre Haute, IN 47809 USA. [Yi, S.] Georgia Inst Technol, Sch Biol, Atlanta, GA 30332 USA. RP Zinzow-Kramer, WM (reprint author), Emory Univ, Dept Psychol, Atlanta, GA 30322 USA. EM wzinzow@emory.edu RI Maney, Donna/G-3706-2011; Tuttle, Elaina/A-1485-2016 OI Tuttle, Elaina/0000-0002-2465-918X FU NSF [SMA-1306132]; NIH [R01MH082833, 1R21NIMH102677]; National Human Genome Research Institute Intramural Research program at the NIH FX Sequencing of the superwhite genome and SNP calling between the reference assembly and the superwhite assembly were performed by the Roy J. Carver Biotechnology Center of the University of Illinois. RNA-seq for the HYP and MeA samples was conducted at the Yerkes Nonhuman Primate Genomics Core Laboratory. This work was supported by NSF grant SMA-1306132 to W.M.Z.-K. and D.L.M. and NIH grants R01MH082833 to D.L.M. and 1R21NIMH102677 to D.L.M and S.V.Y. The National Human Genome Research Institute Intramural Research program at the NIH supported J.W.T. The authors have no conflicts of interest to report. NR 78 TC 2 Z9 2 U1 7 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1601-1848 EI 1601-183X J9 GENES BRAIN BEHAV JI Genes Brain Behav. PD NOV PY 2015 VL 14 IS 8 BP 641 EP 654 DI 10.1111/gbb.12252 PG 14 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA DB1DQ UT WOS:000368248600008 PM 26463687 ER PT J AU Blenkinsop, TA Saini, JS Maminishkis, A Bharti, K Wan, Q Banzon, T Lotfi, M Davis, J Singh, D Rizzolo, LJ Miller, S Temple, S Stern, JH AF Blenkinsop, Timothy A. Saini, Janmeet S. Maminishkis, Arvydas Bharti, Kapil Wan, Qin Banzon, Tina Lotfi, Mostafa Davis, Janine Singh, Deepti Rizzolo, Lawrence J. Miller, Sheldon Temple, Sally Stern, Jeffrey H. TI Human Adult Retinal Pigment Epithelial Stem Cell-Derived RPE Monolayers Exhibit Key Physiological Characteristics of Native Tissue SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article DE human; retinal pigment epithelium; cell culture; fluid transport ID ION-TRANSPORT MECHANISMS; GROWTH-FACTOR EXPRESSION; FLUID TRANSPORT; IMMUNOCYTOCHEMICAL LOCALIZATION; MACULAR DEGENERATION; FUNCTIONAL-ANALYSIS; APICAL MEMBRANE; VISUAL FUNCTION; BASAL MEMBRANE; CIRCUIT STATE AB PURPOSE. We tested what native features have been preserved with a new culture protocol for adult human RPE. METHODS. We cultured RPE from adult human eyes. Standard protocols for immunohistochemistry, electron microscopy, electrophysiology, fluid transport, and ELISA were used. RESULTS. Confluent monolayers of adult human RPE cultures exhibit characteristics of native RPE. Immunohistochemistry demonstrated polarized expression of RPE markers. Electron microscopy illustrated characteristics of native RPE. The mean transepithelial potential (TEP) was 1.19 +/- 0.24 mV (mean +/- SEM, n = 31), apical positive, and the mean transepithelial resistance (R-T) was 178.7 +/- 9.9 Omega.cm(2) (mean +/- SEM, n = 31). Application of 100 mu M adenosine triphosphate (ATP) apically increased net fluid absorption (Jv) by 6.11 +/- 0.53 mu L.cm(2). h(-1) (mean +/- SEM, n = 6) and TEP by 0.33 +/- 0.048 mV (mean +/- SEM, n = 25). Gene expression of cultured RPE was comparable to native adult RPE (n = 5); however, native RPE RNA was harvested between 24 and 40 hours after death and, therefore, may not accurately reflect healthy native RPE. Vascular endothelial growth factor secreted preferentially basally 2582 6 146 pg/mL/d, compared to an apical secretion of 1548 +/- 162 pg/mL/d (n = 14, P < 0.01), while PEDF preferentially secreted apically 1487 +/- 280 ng/mL/d compared to a basolateral secretion of 864 +/- 132 ng/mL/d (n = 14, P < 0.01). CONCLUSIONS. The new culture model preserves native RPE morphology, electrophysiology, and gene and protein expression patterns, and may be a useful model to study RPE physiology, disease, and transplantation. C1 [Blenkinsop, Timothy A.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Saini, Janmeet S.; Temple, Sally; Stern, Jeffrey H.] Neural Stem Cell Inst, Rensselaer, NY 12144 USA. [Maminishkis, Arvydas; Bharti, Kapil; Wan, Qin; Banzon, Tina; Lotfi, Mostafa; Davis, Janine; Miller, Sheldon] NEI, NIH, Bethesda, MD 20892 USA. [Singh, Deepti; Rizzolo, Lawrence J.] Yale Univ, New Haven, CT USA. RP Stern, JH (reprint author), Neural Stem Cell Inst, One Discovery Dr, Rensselaer, NY 12144 USA. EM timothy.blenkinsop@mssm.edu; jeffreystern@neuralsci.org OI Rizzolo, Lawrence/0000-0002-2393-8419 FU Intramural NIH HHS; NEI NIH HHS [R01 EY022079, 1R01EY022079] NR 106 TC 3 Z9 3 U1 0 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 NOV PY 2015 VL 56 IS 12 BP 7085 EP 7099 DI 10.1167/iovs.14-16246 PG 15 WC Ophthalmology SC Ophthalmology GA DB0ZS UT WOS:000368238200014 PM 26540654 ER PT J AU Vergara-Jaque, A Fenollar-Ferrer, C Mulligan, C Mindell, JA Forrest, LR AF Vergara-Jaque, Ariela Fenollar-Ferrer, Cristina Mulligan, Christopher Mindell, Joseph A. Forrest, Lucy R. TI Family resemblances: A common fold for some dimeric ion-coupled secondary transporters SO JOURNAL OF GENERAL PHYSIOLOGY LA English DT Article ID DEPENDENT DICARBOXYLATE TRANSPORTER; CRYSTAL-STRUCTURE; NEUROTRANSMITTER TRANSPORTERS; NEISSERIA-GONORRHOEAE; MEMBRANE-PROTEINS; VIBRIO-CHOLERAE; MECHANISM; NA+; ALIGNMENT; BINDING AB Membrane transporter proteins catalyze the passage of a broad range of solutes across cell membranes, allowing the uptake and efflux of crucial compounds. Because of the difficulty of expressing, purifying, and crystallizing integral membrane proteins, relatively few transporter structures have been elucidated to date. Although every membrane transporter has unique characteristics, structural and mechanistic similarities between evolutionarily diverse transporters have been identified. Here, we compare two recently reported structures of membrane proteins that act as antimicrobial efflux pumps, namely MtrF from Neisseria gonorrhoeae and YdaH from Alcanivorax borkumensis, both with each other and with the previously published structure of a sodium-dependent dicarboxylate transporter from Vibrio cholerae, VcINDY. MtrF and YdaH belong to the p-aminobenzoyl-glutamate transporter (AbgT) family and have been reported as having architectures distinct from those of all other families of transporters. However, our comparative analysis reveals a similar structural arrangement in all three proteins, with highly conserved secondary structure elements. Despite their differences in biological function, the overall "design principle" of MtrF and YdaH appears to be almost identical to that of VcINDY, with a dimeric quaternary structure, helical hairpins, and clear boundaries between the transport and scaffold domains. This observation demonstrates once more that the same secondary transporter architecture can be exploited for multiple distinct transport modes, including cotransport and antiport. Based on our comparisons, we detected conserved motifs in the substrate-binding region and predict specific residues likely to be involved in cation or substrate binding. These findings should prove useful for the future characterization of the transport mechanisms of these families of secondary active transporters. C1 [Vergara-Jaque, Ariela; Fenollar-Ferrer, Cristina; Forrest, Lucy R.] NINDS, Computat Struct Biol Unit, NIH, Bethesda, MD 20824 USA. [Mulligan, Christopher; Mindell, Joseph A.] NINDS, Membrane Transport Biophys Sect, NIH, Bethesda, MD 20824 USA. RP Forrest, LR (reprint author), NINDS, Computat Struct Biol Unit, NIH, Bethesda, MD 20824 USA. EM lucy.forrest@nih.gov FU Division of Intramural Research of the National Institutes of Health, National Institute of Neurological Disorders and Stroke; L'Oreal Chile-The United Nations Educational, Scientific and Cultural Organization (UNESCO) Women in Science Fellowship; L'Oreal-UNESCO Rising Talent Award FX This research was supported by the Division of Intramural Research of the National Institutes of Health, National Institute of Neurological Disorders and Stroke. A. Vergara-Jaque is recipient of the L'Oreal Chile-The United Nations Educational, Scientific and Cultural Organization (UNESCO) Women in Science Fellowship and the L'Oreal-UNESCO Rising Talent Award. NR 41 TC 2 Z9 2 U1 1 U2 5 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0022-1295 EI 1540-7748 J9 J GEN PHYSIOL JI J. Gen. Physiol. PD NOV PY 2015 VL 146 IS 5 BP 423 EP 434 DI 10.1085/jgp.201511481 PG 12 WC Physiology SC Physiology GA DB1EA UT WOS:000368249600008 PM 26503722 ER PT J AU Feng, S Bucuvalas, J Kanaparthi, S Burrell, B Jake, DA Spain, K AF Feng, Sandy Bucuvalas, John Kanaparthi, Sai Burrell, Bryna Jake, Demetris A. Spain, Katharine CA Iwith Investigators TI CLASS II (ANTI-DQ/ANTI-DR) DONOR SPECIFIC ANTIBODY (DSA): PREVALENCE AND ASSOCIATION WITH HISTOPATHOLOGY IN LONG-TERM PEDIATRIC LIVER TRANSPLANT (TX) RECIPIENTS WITH NORMAL LIVER TESTS: IWITH TRIAL SO TRANSPLANT INTERNATIONAL LA English DT Meeting Abstract C1 [Feng, Sandy] UCSF, San Francisco, CA USA. [Bucuvalas, John] Cincinnati Childrens Hosp, Cincinnati, OH USA. [Kanaparthi, Sai; Burrell, Bryna] Immune Tolerance Network, London, England. [Jake, Demetris A.] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Spain, Katharine] Rho Inc, Chapel Hill, NC USA. [Iwith Investigators] NIDDK, NIAID, ITN, 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 0934-0874 EI 1432-2277 J9 TRANSPL INT JI Transpl. Int. PD NOV PY 2015 VL 28 SU 4 SI SI MA O320 BP 116 EP 116 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA DA3VE UT WOS:000367726700316 ER PT J AU Rosa, C Campbell, ANC Miele, GM Brunner, M Winstanley, EL AF Rosa, Carmen Campbell, Aimee N. C. Miele, Gloria M. Brunner, Meg Winstanley, Erin L. TI Using e-technologies in clinical trials SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE Clinical trials; E-technology; Social media; Apps; Smartphones; Internet ID RANDOMIZED CONTROLLED-TRIAL; SUBSTANCE USE DISORDERS; COMPUTER-BASED INTERVENTIONS; COGNITIVE-BEHAVIORAL THERAPY; CORONARY-ARTERY-DISEASE; WEB-BASED INTERVENTIONS; IMPROVE PATIENT-CARE; ONLINE SOCIAL MEDIA; DRINKERS CHECK-UP; FACE-TO-FACE AB Clinical trials have been slow to incorporate e-technology (digital and electronic technology that utilizes mobile devices or the Internet) into the design and execution of studies. In the meantime, individuals and corporations are relying more on electronic platforms and most have incorporated such technology into their daily lives. This paper provides a general overview of the use of e-technologies in clinical trials research, specifically within the last decade, marked by rapid growth of mobile and Internet-based tools. Benefits of and challenges to the use of e-technologies in data collection, recruitment and retention, delivery of interventions, and dissemination are provided, as well as a description of the current status of regulatory oversight of e-technologies in clinical trials research. As an example of ways in which e-technologies can be used for intervention delivery, a summary of e-technologies for treatment of substance use disorders is presented. Using e-technologies to design and implement clinical trials has the potential to reach a wide audience, making trials more efficient while also reducing costs; however, researchers should be cautious when adopting these tools given the many challenges in using new technologies, as well as threats to participant privacy/confidentiality. Challenges of using e-technologies can be overcome with careful planning, useful partnerships, and forethought. The role of web- and smartphone-based applications is expanding, and the increasing use of those platforms by scientists and the public alike make them tools that cannot be ignored. Published by Elsevier Inc. C1 [Rosa, Carmen] NIDA, NIH, Bethesda, MD 20892 USA. [Campbell, Aimee N. C.] Columbia Univ, Dept Psychiat, New York State Psychiat Inst, Med Ctr, New York, NY USA. [Campbell, Aimee N. C.] Mt Sinai St Lukes Hosp, Dept Psychiat & Behav Hlth, New York, NY USA. [Miele, Gloria M.] Columbia Univ Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. [Brunner, Meg] Univ Washington, Inst Alcohol & Drug Abuse, Seattle, WA 98195 USA. [Winstanley, Erin L.] Univ Cincinnati, James L Winkle Coll Pharm, Cincinnati, OH USA. RP Rosa, C (reprint author), 6001 Execut Blvd, Bethesda, MD USA. EM crosa@nida.nih.gov; anc2002@cumc.columbia.edu; gmm23@columbia.edu; meganw@uw.edu; erin.winstanley@uc.edu RI Emchi, Karma/Q-1952-2016; OI Brunner, Meg/0000-0001-6923-1833 FU National Institute on Drug Abuse Clinical Trials Network [U10 DA013035, U10 DA013714] FX This work was supported by grants from the National Institute on Drug Abuse Clinical Trials Network: U10 DA013035 (PIs: Nunes, Rotrosen); U10 DA013714 (PIs: Donovan, Roll). NR 140 TC 7 Z9 7 U1 4 U2 17 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7144 EI 1559-2030 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD NOV PY 2015 VL 45 SI SI BP 41 EP 54 DI 10.1016/j.cct.2015.07.007 PN A PG 14 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA DA4FE UT WOS:000367754700008 PM 26176884 ER PT J AU DerSimonian, R Laird, N AF DerSimonian, Rebecca Laird, Nan TI Meta-analysis in clinical trials revisited SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE Random-effects model; Meta-analysis; Heterogeneity; Clinical trials; Genome Wide Association Studies; Big Data ID RANDOM-EFFECTS MODEL; GENOME-WIDE ASSOCIATION; EFFECTS META-REGRESSION; BETWEEN-STUDY VARIANCE; STATISTICAL-METHODS; HETEROGENEITY; MOMENTS; PERFORMANCE; CONFIDENCE; INTERVALS AB In this paper, we revisit a 1986 article we published in this Journal, Meta-Analysis in Clinical Trials, where we introduced a random-effects model to summarize the evidence about treatment efficacy from a number of related clinical trials. Because of its simplicity and ease of implementation, our approach has been widely used (with more than 12,000 citations to date) and the "DerSimonian and Laird method" is now often referred to as the 'standard approach' or a 'popular' method for meta-analysis in medical and clinical research. The method is especially useful for providing an overall effect estimate and for characterizing the heterogeneity of effects across a series of studies. Here, we review the background that led to the original 1986 article, briefly describe the random-effects approach for meta-analysis, explore its use in various settings and trends over time and recommend a refinement to the method using a robust variance estimator for testing overall effect. We conclude with a discussion of repurposing the method for Big Data meta-analysis and Genome Wide Association Studies for studying the importance of genetic variants in complex diseases. Published by Elsevier Inc. C1 [DerSimonian, Rebecca] NIAID, Bethesda, MD 20892 USA. [Laird, Nan] Harvard Univ, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. RP DerSimonian, R (reprint author), NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM DerSimonian@nih.gov; nanlaird@gmail.com FU Intramural NIH HHS [Z99 AI999999] NR 32 TC 56 Z9 57 U1 11 U2 21 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7144 EI 1559-2030 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD NOV PY 2015 VL 45 SI SI BP 139 EP 145 DI 10.1016/j.cct.2015.09.002 PN A PG 7 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA DA4FE UT WOS:000367754700019 PM 26343745 ER PT J AU Usadi, RS Diamond, MP Legro, RS Schlaff, WD Hansen, KR Casson, P Christman, G Bates, GW Baker, V Seungdamrong, A Rosen, MP Lucidi, S Thomas, T Huang, H Santoro, N Eisenberg, E Zhang, H Alvero, R AF Usadi, Rebecca S. Diamond, Michael P. Legro, Richard S. Schlaff, William D. Hansen, Karl R. Casson, Peter Christman, Gregory Bates, G. Wright Baker, Valerie Seungdamrong, Aimee Rosen, Mitchell P. Lucidi, Scott Thomas, Tracey Huang, Hao Santoro, Nanette Eisenberg, Esther Zhang, Heping Alvero, Ruben CA Reproductive Med Network TI Recruitment strategies in two reproductive medicine network infertility trials SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE Clinical trial; Recruitment; Subjects ID RANDOMIZED CONTROLLED-TRIAL; RETENTION; WOMEN AB Background: Recruitment of individuals into clinical trials is a critical step in,completing studies. Reports examining the effectiveness of different recruitment strategies, and specifically in infertile couples, are limited. Methods: We investigated recruitment methods used in two NIH sponsored trials, Pregnancy in Polycystic Ovary Syndrome (PPCOS II) and Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS), and examined which strategies yielded the greatest number of participants completing the trials. Results: 3683 couples were eligible for screening. 1650 participants were randomized and 1339 completed the trials. 750 women were randomized in PPCOS II; 212 of the participants who completed the trial were referred by physicians. Participants recruited from radio ads (84/750) and the internet (81/750) resulted in similar rates of trial completion in PPCOS II. 900 participants were randomized in AMIGOS. 440 participants who completed the trial were referred to the study by physicians. The next most successful method in AMIGOS was the use of the internet, achieving 78 completed participants. Radio ads proved the most successful strategy in both trials for participants who earned <$50,000 annually. Radio ads were most successful in enrolling white patients in PPCOS II and black patients in AMIGOS. Seven ancillary Clinical Research Scientist Training (CREST) sites enrolled 324 of the participants who completed the trials. Conclusions: Physician referral was the most successful recruitment strategy. Radio ads and the internet were the next most successful strategies, particularly for women of limited income. Ancillary clinical sites were important for overall recruitment. (C) 2015 Elsevier Inc. All rights reserved. C1 [Usadi, Rebecca S.] Carolinas Healthcare Syst Reprod Med & Infertil, Charlotte, NC 28232 USA. [Diamond, Michael P.] Georgia Regents Univ, Dept Obstet & Gynecol, Augusta, GA 30912 USA. [Legro, Richard S.] Penn State Coll Med, Dept Obstet & Gynecol, Hershey, PA 17033 USA. [Schlaff, William D.] Thomas Jefferson Univ, Dept Obstet & Gynecol, Philadelphia, PA 19107 USA. [Hansen, Karl R.] Univ Oklahoma, Dept Obstet & Gynecol, Coll Med, Oklahoma City, OK 73104 USA. [Casson, Peter] Northeastern Reprod Med, Colchester 05446, Essex, England. [Christman, Gregory] Univ Florida, Dept Obstet & Gynecol, Gainesville, FL 32606 USA. [Bates, G. Wright] Univ Alabama Birmingham, Dept Obstet & Gynecol, Birmingham, AL 35233 USA. [Baker, Valerie] Stanford Univ, Dept Obstet & Gynecol, Med Ctr, Stanford, CA 94304 USA. [Seungdamrong, Aimee] Univ Med & Dent New Jersey, Newark, NJ 07101 USA. [Rosen, Mitchell P.] Univ Calif San Francisco, Dept Reprod Endocrinol & Infertil, San Francisco, CA 94115 USA. [Lucidi, Scott] Virginia Commonwealth Univ, Dept Obstet & Gynecol, Richmond, VA 23235 USA. [Thomas, Tracey] Yale Univ, Collaborat Ctr Stat Sci, Sch Publ Hlth, New Haven, CT 06511 USA. [Huang, Hao; Zhang, Heping] Yale Univ, Sch Publ Hlth, Dept Biostat, New Haven, CT 06520 USA. [Santoro, Nanette; Alvero, Ruben] Univ Colorado Denver, Dept Obstet & Gynecol, Aurora, CO 80045 USA. [Eisenberg, Esther] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Fertil & Infertil Branch, Rockville, MD 20847 USA. RP Usadi, RS (reprint author), Carolinas Healthcare Syst Reprod Med & Infertil, 1025 Morehead Med Dr, Charlotte, NC 28232 USA. EM Rebecca.Usadi@carolinashealthcare.org OI Diamond, Michael/0000-0001-6353-4489 FU National Institutes of Health (NIH)/Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [5R25HD075737]; National Center for Research Resources and the National Center for Advancing Translational Sciences through an NIH [UL1 TR000127]; American Recovery and Reinvestment Act [U10HD039005-0851, U10HD055925-02W1]; [U10 HD39005]; [U10 HD38992]; [U10 HD27049]; [U10 HD38998]; [HD055944]; [U10 HD055936]; [U10 U54-HD29834] FX Supported by the National Institutes of Health (NIH)/Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) grant 5R25HD075737. Also supported by U10 HD39005 (to M.P.D.), U10 HD38992 (to R.S.L), U10 HD27049 (to CC.), U10 HD38998 (to W.D.S and RA), HD055944 (to P.C.), U10 HD055936 (to G.C.), U10 U54-HD29834 (to the University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core of the Specialized Cooperative Centers Program in Reproduction and Infertility Research) and by the National Center for Research Resources and the National Center for Advancing Translational Sciences through an NIH grant (UL1 TR000127) to Pennsylvania State University. This research also was made possible by the funding by American Recovery and Reinvestment Act (U10HD039005-0851 to M.P.D., U10HD055925-02W1 to H.Z.). NR 14 TC 0 Z9 0 U1 2 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7144 EI 1559-2030 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD NOV PY 2015 VL 45 BP 196 EP 200 DI 10.1016/j.cct.2015.09.010 PN B PG 5 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA DA4FJ UT WOS:000367755200009 PM 26386293 ER PT J AU Resnik, DB AF Resnik, David B. TI Some reflections on evaluating institutional review board effectiveness SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE Institutional review boards; Effectiveness; Ethics; Oversight; Empirical research; Randomized controlled trials; Prospective cohort studies ID TRIALS; REFORM AB Most commentators agree that it is important to conduct empirical research on the effectiveness of institutional review board (IRB) review and oversight but the studies that have been published so far do not directly address this question because they do not attempt to measure the impact of the IRB on the welfare or rights of human subjects. Additional studies on IRB composition, staffing, review times, consistency, and so forth will not yield that evidence that is needed to measure IRB effectiveness if they do not also collect data on the welfare and rights of human research subjects. Researchers should consider developing studies, such as randomized, controlled trials, or prospective, cohort designs, which directly measure IRB effectiveness. Such studies could yield information that will be invaluable in improving IRB review and oversight and protecting human research subjects. Published by Elsevier Inc. C1 [Resnik, David B.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Resnik, DB (reprint author), NIEHS, NIH, 111 Alexander Dr,Box 12233, Res Triangle Pk, NC 27709 USA. EM resnikd@niehs.nih.gov FU Intramural Program of the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH) [ZIA-ES-102646-07] FX I am grateful to Christine Grady for helpful comments. This research was supported by the Intramural Program of the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH) (ZIA-ES-102646-07). It does not represent the views of the NIEHS, NIH, or federal government. NR 18 TC 1 Z9 1 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7144 EI 1559-2030 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD NOV PY 2015 VL 45 BP 261 EP 264 DI 10.1016/j.cct.2015.09.018 PN B PG 4 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA DA4FJ UT WOS:000367755200018 PM 26408053 ER PT J AU Anderson, BE Naujokas, MF Suk, WA AF Anderson, Beth Ellen Naujokas, Marisa F. Suk, William A. TI Interweaving Knowledge Resources to Address Complex Environmental Health Challenges SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID TRANSDISCIPLINARY RESEARCH; HYDROXY-PAHS; EXPOSURE; COMMUNITIES; SCIENCE; PARENT AB BACKGROUND: Complex problems do not respect academic disciplinary boundaries. Environmental health research is complex and often moves beyond these boundaries, integrating diverse knowledge resources to solve such challenges. Here we describe an evolving paradigm for interweaving approaches that integrates widely diverse resources outside of traditional academic environments in full partnerships of mutual respect and understanding. We demonstrate that scientists, social scientists, and engineers can work with government agencies, industry, and communities to interweave their expertise into metaphorical knowledge fabrics to share understanding, resources, and enthusiasm. OBJECTIVE: Our goal is to acknowledge and validate how interweaving research approaches can contribute to research-driven, solution-oriented problem solving in environmental health, and to inspire more members of the environmental health community to consider this approach. DISCUSSION: The National Institutes of Healths National Institute of Environmental Health Sciences Superfund Research Program (SRP), as mandated by Congress, has evolved to become a program that reaches across a wide range of knowledge resources. SRP fosters interweaving multiple knowledge resources to develop innovative multidirectional partnerships for research and training. Here we describe examples of how motivation, ideas, knowledge, and expertise from different people, institutions, and agencies can integrate to tackle challenges that can be as complex as the resources they bring to bear on it. CONCLUSIONS: By providing structure for interweaving science with its stakeholders, we are better able to leverage resources, increase potential for innovation, and proactively ensure a more fully developed spectrum of beneficial outcomes of research investments. C1 [Anderson, Beth Ellen; Suk, William A.] NIEHS, Superfund Res Program, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Naujokas, Marisa F.] MDB Inc, Durham, NC 27713 USA. RP Naujokas, MF (reprint author), MDB Inc, Meridian Corp Ctr 2525, Suite 50, Durham, NC 27713 USA. EM mnaujokas@michaeldbaker.com FU National Institutes of Health's (NIH) National Institute of Environmental Health Sciences (NIEHS) FX This work was supported in part by the National Institutes of Health's (NIH) National Institute of Environmental Health Sciences (NIEHS). M.F.N. is employed by MDB, Inc., Durham, North Carolina. NR 36 TC 1 Z9 1 U1 0 U2 5 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD NOV PY 2015 VL 123 IS 11 BP 1095 EP 1099 DI 10.1289/ehp.1409525 PG 5 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA DA1VW UT WOS:000367584600009 PM 25910282 ER PT J AU Lam, T Williams, PL Lee, MM Korrick, SA Birnbaum, LS Burns, JS Sergeyev, O Revich, B Altshul, LM Patterson, DG Hauser, R AF Lam, Thuy Williams, Paige L. Lee, Mary M. Korrick, Susan A. Birnbaum, Linda S. Burns, Jane S. Sergeyev, Oleg Revich, Boris Altshul, Larisa M. Patterson, Donald G., Jr. Hauser, Russ TI Prepubertal Serum Concentrations of Organochlorine Pesticides and Age at Sexual Maturity in Russian Boys SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID BLOOD LEAD LEVELS; POLYCHLORINATED-BIPHENYLS; REPRODUCTIVE DEVELOPMENT; HEXACHLOROBENZENE HCB; PUBERTAL DEVELOPMENT; CHILDRENS HEALTH; LIPID ADJUSTMENT; CRITICAL WINDOWS; EXPOSURE; MATURATION AB Background: Few human studies have evaluated the impact of childhood exposure to organochlorine pesticides (OCP) on pubertal development. Objective: We evaluated associations of serum OCP concentrations [hexachlorobenzene (HCB), ?-hexachlorocyclohexane (beta HCH), and p,p-dichlorodiphenyldichloroethylene (p,p'-DDE)] with age at attainment of sexual maturity among boys. Methods: From 2003 through 2005, 350 8- to 9-year-old boys from Chapaevsk, Russia, with measured OCPs were enrolled and followed annually for 8 years. We used multivariable interval-censored models to evaluate associations of OCPs (quartiles) with three physician-assessed measures of sexual maturity: Tanner stage 5 for genitalia growth, Tanner stage 5 for pubic hair growth, or testicular volume (TV) >= 20 mL in either testis. Results: In adjusted models, boys with higher HCB concentrations achieved sexual maturity reflected by TV >= 20 mL a mean of 3.1 months (95% CI: 1.7, 7.8), 5.3 months (95% CI: 0.6, 10.1), and 5.0 months (95% CI: 0.2, 9.8) later for quartiles Q2, Q3, and Q4, respectively, compared with Q1 (p trend = 0.04). Tanner stage 5 for genitalia growth was attained a mean of 2.2 months (95% CI: 3.1, 7.5), 5.7 months (95% CI: 0.4, 11.0), and 3.7 months (95% CI: 1.7, 9.1) later for quartiles Q2, Q3, and Q4, respectively, of ?HCH compared with Q1 (p trend = 0.09). Tanner stage 5 for pubic hair growth occurred 69 months later on average for boys in the highest versus lowest quartile for HCB (p trend < 0.001), beta HCH (trend p = 0.01), and p,p'-DDE (p trend = 0.04). No associations were observed between p,p-DDE and Tanner stage 5 for genitalia growth or TV >= 20 mL. Conclusions and Relevance: Higher prepubertal serum HCB and beta HCH concentrations were associated with a later age at attainment of sexual maturity. Only the highest quartile of serum p,p'-DDE was associated with later pubic hair maturation. C1 [Lam, Thuy; Korrick, Susan A.; Burns, Jane S.; Hauser, Russ] Harvard Univ, TH Chan Sch Publ Hlth, Environm & Occupat Med & Epidemiol Program, Dept Environm Hlth, Boston, MA 02115 USA. [Lam, Thuy] Gradient Corp, Cambridge, MA 02138 USA. [Williams, Paige L.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Williams, Paige L.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Lee, Mary M.] Univ Massachusetts, Sch Med, Dept Pediat, Pediat Endocrine Div, Worcester, MA USA. [Lee, Mary M.] Univ Massachusetts, Sch Med, Dept Cell & Dev Biol, Worcester, MA USA. [Korrick, Susan A.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Div Network Med,Dept Med, Boston, MA 02115 USA. [Birnbaum, Linda S.] NCI, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC USA. [Sergeyev, Oleg] Russian Acad Sci, Vavilov Inst Gen Genet, Dept Genom & Human Genet, Moscow, Russia. [Sergeyev, Oleg] Chapaevsk Med Assoc, Chapaevsk, Samara Region, Russia. [Revich, Boris] Russian Acad Sci, Inst Forecasting, Moscow, Russia. [Altshul, Larisa M.] Harvard Univ, TH Chan Sch Publ Hlth, Exposure Epidemiol & Risk Program, Boston, MA 02115 USA. [Altshul, Larisa M.] Environm Hlth & Engn Inc, Needham, MA USA. [Patterson, Donald G., Jr.] EnviroSolut Consulting Inc, Auburn, GA USA. [Patterson, Donald G., Jr.] Axys Analyt Solut, Sidney, BC, Canada. [Patterson, Donald G., Jr.] Exponent Inc, Maynard, MA USA. RP Hauser, R (reprint author), Harvard Univ, TH Chan Sch Publ Hlth, Environm & Occupat Med & Epidemiol Program, 668 Huntington Ave,Bldg 1,Room 1409, Boston, MA 02115 USA. EM rhauser@hsph.harvard.edu OI Sergeyev, Oleg/0000-0002-5745-3348 FU U.S. Environmental Protection Agency [R82943701]; National Institute of Environmental Health Sciences [R01 ES014370, P30 E5000002, R03 E50171 17]; National Institute for Occupational Safety and Health [T42-0H008416-09]; intramural program of the National Cancer Institute, National Institutes of Health FX This work was funded by the U.S. Environmental Protection Agency (grant R82943701), the National Institute of Environmental Health Sciences (grants R01 ES014370, P30 E5000002, and R03 E50171 17), and the intramural program of the National Cancer Institute, National Institutes of Health. T.L. was supported by the National Institute for Occupational Safety and Health (training grant T42-0H008416-09). NR 53 TC 1 Z9 1 U1 3 U2 7 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD NOV PY 2015 VL 123 IS 11 BP 1216 EP 1221 DI 10.1289/ehp.1409022 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA DA1VW UT WOS:000367584600026 PM 26009253 ER PT J AU Langley, G Austin, CP Balapure, AK Birnbaum, LS Bucher, JR Fentem, J Fitzpatrick, SC Fowle, JR Kavlock, RJ Kitano, H Lidbury, BA Muotri, AR Peng, SQ Sakharov, D Seidle, T Trez, T Tonevitsky, A van De Stolpe, A Whelan, M Willett, C AF Langley, Gill Austin, Christopher P. Balapure, Anil K. Birnbaum, Linda S. Bucher, John R. Fentem, Julia Fitzpatrick, Suzanne C. Fowle, John R. Kavlock, Robert J. Kitano, Hiroaki Lidbury, Brett A. Muotri, Alysson R. Peng, Shuang-Qing Sakharov, Dmitry Seidle, Troy Trez, Thales Tonevitsky, Alexander van de Stolpe, Anja Whelan, Maurice Willett, Catherine TI Lessons from Toxicology: Developing a 21st-Century Paradigm for Medical Research SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID PLURIPOTENT STEM-CELLS; ALZHEIMERS-DISEASE; MODELS; PATHWAYS; PROTEIN AB Biomedical developments in the 21st century provide an unprecedented opportunity to gain a dynamic systems-level and human-specific understanding of the causes and pathophysiologies of disease. This understanding is a vital need, in view of continuing failures in health research, drug discovery, and clinical translation. The full potential of advanced approaches may not be achieved within a 20th-century conceptual framework dominated by animal models. Novel technologies are being integrated into environmental health research and are also applicable to disease research, but these advances need a new medical research and drug discovery paradigm to gain maximal benefits. We suggest a new conceptual framework that repurposes the 21st-century transition underway in toxicology. Human disease should be conceived as resulting from integrated extrinsic and intrinsic causes, with research focused on modern human-specific models to understand disease pathways at multiple biological levels that are analogous to adverse outcome pathways in toxicology. Systems biology tools should be used to integrate and interpret data about disease causation and pathophysiology. Such an approach promises progress in overcoming the current roadblocks to understanding human disease and successful drug discovery and translation. A discourse should begin now to identify and consider the many challenges and questions that need to be solved. C1 [Langley, Gill] Humane Soc Int, Res & Toxicol Dept, London N1 7LY, England. [Austin, Christopher P.] NIH, Natl Ctr Adv Translat Sci, US Dept HHS, Bethesda, MD 20892 USA. [Balapure, Anil K.] CSIR Cent Drug Res Inst, Div Biochem, Lucknow, Uttar Pradesh, India. [Birnbaum, Linda S.] NIEHS, Res Triangle Pk, NC 27709 USA. [Birnbaum, Linda S.] NIH, NTP, DHHS, Res Triangle Pk, NC USA. [Bucher, John R.] NIEHS, Div NTP, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Fentem, Julia] Unilever R&D, SEAC, Sharnbrook, Beds, England. [Fitzpatrick, Suzanne C.] US FDA, Off Ctr Director, Ctr Food Safety & Appl Nutr, Rockville, MD 20857 USA. [Fowle, John R.] Sci Inform LLC, Pittsboro, NC USA. [Kavlock, Robert J.] US EPA, Off Res & Dev, Washington, DC 20460 USA. [Kitano, Hiroaki] Syst Biol Inst, Tokyo, Japan. [Lidbury, Brett A.] Australian Natl Univ, John Curtin Sch Med Res, Genom & Predict Med, Canberra, ACT 2601, Australia. [Muotri, Alysson R.] Univ Calif San Diego, Sch Med, Dept Pediat, Rady Childrens Hosp San Diego,Dept Cellular & Mol, La Jolla, CA 92093 USA. [Peng, Shuang-Qing] Acad Mil Med Sci, Inst Dis Control & Prevent, Evaluat & Res Ctr Toxicol, Beijing, Peoples R China. [Sakharov, Dmitry] Sci Res Ctr Bioclinicum, Moscow, Russia. [Seidle, Troy] Humane Soc Int, Res & Toxicol Dept, Montreal, PQ, Canada. [Trez, Thales] Univ Fed Alfenas, Inst Sci & Technol, Alfenas, Brazil. [Tonevitsky, Alexander] Natl Ctr Med Radiol Res, Obninsk, Russia. [van de Stolpe, Anja] Philips Res, Eindhoven, Netherlands. [Whelan, Maurice] Commiss European Communities, Joint Res Ctr, Inst Hlth & Consumer Protect, I-21020 Ispra, Italy. [Willett, Catherine] Humane Soc United States, Regulatory Toxicol Risk Assessment & Alternat, Washington, DC USA. RP Langley, G (reprint author), Humane Soc Int, 5 Underwood St, London N1 7LY, England. EM glangley@hsi.org OI Seidle, Troy/0000-0002-1341-2181; Tonevitsky, Alexander/0000-0002-7079-7145 NR 41 TC 11 Z9 12 U1 6 U2 9 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD NOV PY 2015 VL 123 IS 11 BP A268 EP A272 DI 10.1289/ehp.1510345 PG 5 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA DA1VW UT WOS:000367584600001 PM 26523530 ER PT J AU Rao, AS Scher, AI Vieira, RVA Merikangas, KR Metti, AL Peterlin, BL AF Rao, Aruna S. Scher, Ann I. Vieira, Rebeca V. A. Merikangas, Kathleen R. Metti, Andrea L. Peterlin, B. Lee TI The Impact of Post-Traumatic Stress Disorder on the Burden of Migraine: Results From the National Comorbidity Survey-Replication SO HEADACHE LA English DT Article DE migraine; post-traumatic stress disorder; disability; economic burden; societal burden ID UNITED-STATES; NCS-R; AMERICAN MIGRAINE; SOCIOECONOMIC-STATUS; EPISODIC MIGRAINE; PREVALENCE; HEADACHE; DISABILITY; ASSOCIATIONS; LIFE AB Background.-Post-traumatic stress disorder (PTSD) has been linked with migraine in prior studies. Objective.-To evaluate the individual and joint burdens of migraine and PTSD in a population-based cohort. Methods.-The National Comorbidity Survey-Replication (NCS-R) is a general population study conducted in the United States from February 2001-April 2003. PTSD and migraine were assessed, and four groups defined based on their migraine and PTSD status. The four groups included those with no migraine and no PTSD (controls, n=4535), those with migraine and without PTSD (migraine alone, n=236), those with PTSD and without migraine (PTSD alone, n=244), and those with both migraine and PTSD (mig+PTSD, n=68). Logistic and Poisson regression models were used to assess the association between dichotomous/multilevel outcome variables indicating financial, health, and interpersonal burdens and each migraine/PTSD group. Results.-Compared to controls, those with Mig+PTSD were more likely to be in the low poverty index (48% vs 41%, AOR 2.16; CI: 1.10, 4.24) and were less likely to be working for pay or profit in the past week (50% vs 68%, AOR 0.42; CI: 0.24, 0.74) but not those with migraine or PTSD alone. Additionally, the number of days where work quality was cut due to physical or mental health or substance abuse in the past month was greater in all groups compared to controls: (1) migraine alone: mean 2.57 (SEM 0.32) vs mean 1.09 (SEM 0.08) days, ARR=2.39; CI: 2.19, 2.62; (2) PTSD alone: mean 2.43 (SEM 0.33) vs mean 1.09 (SEM 0.08) days, ARR=2.09; CI: 1.91, 2.29; (3) mig+PTSD: mean 8.2 (SEM 0.79) vs 1.09 (SEM 0.08) days, ARR 6.79; CI 6.16, 7.49; and was over 2.5-fold greater in those mig+PTSD than migraine alone (mean 8.0 [SEM 0.79] vs 2.6 days [SEM 0.72], ARR 2.77; CI: 2.45, 3.14). The likelihood of having difficulty getting along or maintaining a social life was also increased in all groups relative to controls: (1) migraine alone: 21% vs 5.4%, AOR 4.20; CI: 2.62, 6.74; (2) PTSD alone: 18% vs 5.4%, AOR 3.40; CI: 2.40, 4.82; (3) Mig+PTSD: 39% vs 5.4%, AOR 9.95; CI: 5.72, 17.32, and was 2-fold greater in those with Mig+PTSD as compared to those with migraine alone (AOR 2.32; CI: 1.15, 4.69). Conclusions.-These findings support the need for those who treat migraine patients to be aware of the comorbidity with PTSD, as these patients may be particularly prone to adverse financial, health, and interpersonal disease burdens. C1 [Rao, Aruna S.; Peterlin, B. Lee] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Scher, Ann I.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Vieira, Rebeca V. A.] Univ Fed Rio Grande do Sul, Dept Psychol, Porto Alegre, RS, Brazil. [Merikangas, Kathleen R.] NIMH, NIH, Bethesda, MD 20892 USA. [Metti, Andrea L.] Metti Consulting, Pittsburgh, PA USA. RP Peterlin, BL (reprint author), Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. EM lpeterlin@jhmi.edu FU United States (U.S.) National Institute of Mental Health (NIMH) [U01-MH60220]; Robert Wood Johnson Foundation [044780]; National Institute of Health/National Institute of Neurological Disorders and Stroke [K23-NS078345] FX The National Comorbidity Survey-Replication (NCS-R) is supported by the United States (U.S.) National Institute of Mental Health (NIMH; U01-MH60220) with supplemental support from the National Institute of Drug Abuse, the Substance Abuse and Mental Health Services Administration, the Robert Wood Johnson Foundation (Grant#044780) and the John W. Alden Trust. Collaborating NCS-R investigators include Dr. Merikangas (co-principal investigator, NIMH). This study was also supported by funding from the National Institute of Health/National Institute of Neurological Disorders and Stroke (K23-NS078345) to Dr. Peterlin. The views and opinions expressed in this report are those of the authors and should not be construed to represent the views of any of the sponsoring organizations, agencies, or the U.S. government. Dr. Peterlin had full access to all of the data in the study and takes responsibility of the integrity of the data and the accuracy of the data analysis. NR 42 TC 3 Z9 3 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0017-8748 EI 1526-4610 J9 HEADACHE JI Headache PD NOV-DEC PY 2015 VL 55 IS 10 BP 1323 EP 1341 DI 10.1111/head.12698 PG 19 WC Clinical Neurology SC Neurosciences & Neurology GA DA3DG UT WOS:000367675800003 PM 26473981 ER PT J AU Brown, AN Drusano, GL Adams, JR Rodriquez, JL Jambunathan, K Baluya, DL Brown, DL Kwara, A Mirsalis, JC Hafner, R Louie, A AF Brown, Ashley N. Drusano, George L. Adams, Jonathan R. Rodriquez, Jaime L. Jambunathan, Kalyani Baluya, Dodge L. Brown, David L. Kwara, Awewura Mirsalis, Jon C. Hafner, Richard Louie, Arnold TI Preclinical Evaluations To Identify Optimal Linezolid Regimens for Tuberculosis Therapy SO MBIO LA English DT Article ID MITOCHONDRIAL PROTEIN-SYNTHESIS; DRUG-RESISTANT TUBERCULOSIS; INFECTION MODEL SYSTEM; PHARMACODYNAMICS; INHIBITION; EMERGENCE AB Linezolid is an oxazolidinone with potent activity against Mycobacterium tuberculosis. Linezolid toxicity in patients correlates with the dose and duration of therapy. These toxicities are attributable to the inhibition of mitochondrial protein synthesis. Clinically relevant linezolid regimens were simulated in the in vitro hollow-fiber infection model (HFIM) system to identify the linezolid therapies that minimize toxicity, maximize antibacterial activity, and prevent drug resistance. Linezolid inhibited mitochondrial proteins in an exposure-dependent manner, with toxicity being driven by trough concentrations. Once-daily linezolid killed M. tuberculosis in an exposure-dependent manner. Further, 300 mg linezolid given every 12 hours generated more bacterial kill but more toxicity than 600 mg linezolid given once daily. None of the regimens prevented linezolid resistance. These findings show that with linezolid monotherapy, a clear tradeoff exists between antibacterial activity and toxicity. By identifying the pharmacokinetic parameters linked with toxicity and antibacterial activity, these data can provide guidance for clinical trials evaluating linezolid in multidrug antituberculosis regimens. IMPORTANCE The emergence and spread of multidrug-resistant M. tuberculosis are a major threat to global public health. Linezolid is an oxazolidinone that is licensed for human use and has demonstrated potent activity against multidrug-resistant M. tuberculosis. However, long-term use of linezolid has shown to be toxic in patients, often resulting in thrombocytopenia. We examined therapeutic linezolid regimens in an in vitro model to characterize the exposure-toxicity relationship. The antibacterial activity against M. tuberculosis was also assessed for these regimens, including the amplification or suppression of resistant mutant subpopulations by the chosen regimen. Higher exposures of linezolid resulted in greater antibacterial activity, but with more toxicity and, for some regimens, increased resistant mutant subpopulation amplification, illustrating the trade-off between activity and toxicity. These findings can provide valuable insight for designing optimal dosage regimens for linezolid that are part of the long combination courses used to treat multidrug-resistant M. tuberculosis. C1 [Brown, Ashley N.; Drusano, George L.; Adams, Jonathan R.; Rodriquez, Jaime L.; Baluya, Dodge L.; Brown, David L.; Louie, Arnold] Univ Florida, Inst Therapeut Innovat, Dept Med, Orlando, FL 32816 USA. [Jambunathan, Kalyani; Mirsalis, Jon C.] SRI Int, Biosci Div, Harrisonburg, VA USA. [Kwara, Awewura] Brown Univ, Miriam Hosp, Alpert Med Sch, Div Infect Dis, Providence, RI USA. [Hafner, Richard] NIAID, Div Aids, Bethesda, MD 20892 USA. RP Brown, AN (reprint author), Univ Florida, Inst Therapeut Innovat, Dept Med, Orlando, FL 32816 USA. EM Ashley.Brown@medicine.ufl.edu FU Lifespan/Tufts/Brown Center for AIDS Research (CFAR); NIH/NIAID/Miriam Hospital limited program [P30-AI-042853]; NIAID/DAIDS of the National Institutes of Health [HHSN266200700043C, HHSN272201400006I] FX This work was supported by a 2012 grant from the Lifespan/Tufts/Brown Center for AIDS Research (CFAR), an NIH/NIAID/Miriam Hospital limited program (P30-AI-042853) and also by the NIAID/DAIDS of the National Institutes of Health under contract award No HHSN266200700043C and HHSN272201400006I. NR 24 TC 7 Z9 7 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD NOV-DEC PY 2015 VL 6 IS 6 AR e01741-15 DI 10.1128/mBio.01741-15 PG 8 WC Microbiology SC Microbiology GA DA0YY UT WOS:000367524700040 PM 26530386 ER PT J AU Dai, KF He, LL Khan, SN O'Dell, S McKee, K Tran, KR Li, YX Sundling, C Morris, CD Mascola, JR Hedestam, GBK Wyatt, RT Zhu, J AF Dai, Kaifan He, Linling Khan, Salar N. O'Dell, Sijy McKee, Krisha Tran, Karen Li, Yuxing Sundling, Christopher Morris, Charles D. Mascola, John R. Hedestam, Gunilla B. Karlsson Wyatt, Richard T. Zhu, Jiang TI Rhesus Macaque B-Cell Responses to an HIV-1 Trimer Vaccine Revealed by Unbiased Longitudinal Repertoire Analysis SO MBIO LA English DT Article ID NEUTRALIZING ANTIBODIES; HIV-1-NEUTRALIZING ANTIBODIES; ENVELOPE TRIMER; PRIMATE MODELS; POTENT NEUTRALIZATION; SINGLE-CELL; ENV TRIMERS; BROAD; GENERATION; DESIGN AB Next-generation sequencing (NGS) has been used to investigate the diversity and maturation of broadly neutralizing antibodies (bNAbs) in HIV-1-infected individuals. However, the application of NGS to the preclinical assessment of human vaccines, particularly the monitoring of vaccine-induced B-cell responses in a nonhuman primate (NHP) model, has not been reported. Here, we present a longitudinal NGS analysis of memory B-cell responses to an HIV-1 trimer vaccine in a macaque that has been extensively studied by single B-cell sorting and antibody characterization. We first established an NHP antibodyomics pipeline using the available 454 pyrosequencing data from this macaque and developed a protocol to sequence the NHP antibody repertoire in an unbiased manner. Using these methods, we then analyzed memory B-cell repertoires at four time points of NHP immunization and traced the lineages of seven CD4-binding site (CD4bs)-directed monoclonal antibodies previously isolated from this macaque. Longitudinal analysis revealed distinct patterns of B-cell lineage development in response to an HIV-1 trimer vaccine. While the temporal B-cell repertoire profiles and lineage patterns provide a baseline for comparison with forthcoming HIV-1 trimer vaccines, the newly developed NHP antibody NGS technologies and antibodyomics tools will facilitate future evaluation of human vaccine candidates. IMPORTANCE The nonhuman primate model has been widely used in the preclinical assessment of human vaccines. Next-generation sequencing of B-cell repertoires provides a quantitative tool to analyze B-cell responses to a vaccine. In this study, the longitudinal B-cell repertoire analysis of a rhesus macaque immunized with an HIV-1 trimer vaccine revealed complex B-cell lineage patterns and showed the potential to facilitate the evaluation of future HIV-1 vaccines. The repertoire sequencing technologies and antibodyomics methods reported here can be extended to vaccine development for other human pathogens utilizing the nonhuman primate model. C1 [Dai, Kaifan; He, Linling; Khan, Salar N.; Morris, Charles D.; Wyatt, Richard T.; Zhu, Jiang] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [O'Dell, Sijy; McKee, Krisha; Mascola, John R.] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Tran, Karen; Wyatt, Richard T.] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA. [Li, Yuxing] Univ Maryland, Inst Biosci & Biotechnol Res, Rockville, MD USA. [Sundling, Christopher; Hedestam, Gunilla B. Karlsson] Karolinska Inst, Dept Microbiol & Tumor Cell Biol, Stockholm, Sweden. [Wyatt, Richard T.; Zhu, Jiang] Scripps Res Inst, Ctr HIV AIDS Vaccine Immunol & Immunogen Discover, La Jolla, CA 92037 USA. [Zhu, Jiang] Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA. RP Wyatt, RT (reprint author), Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. EM wyatt@scripps.edu; jiang@scripps.edu OI Sundling, Christopher/0000-0002-6138-690X; Khan, Salar/0000-0002-9531-6918 FU Scripps Center for HIV/AIDS immunology & Immunogen Discovery [CHAVI-ID UM1 AI 100663]; International AIDS Vaccine initiative (IAVI); NIH/NIAID [HIVRAD P01 AI04722, R01AI102766] FX This work was supported by grants from the Scripps Center for HIV/AIDS immunology & Immunogen Discovery (CHAVI-ID UM1 AI 100663), the International AIDS Vaccine initiative (IAVI) and its generous donors (who can be found at http://www.iavi.org), and NIH/NIAID grants HIVRAD P01 AI04722 and R01AI102766. NR 55 TC 2 Z9 2 U1 2 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD NOV-DEC PY 2015 VL 6 IS 6 AR e01375-15 DI 10.1128/mBio.01375-15 PG 17 WC Microbiology SC Microbiology GA DA0YY UT WOS:000367524700015 PM 26530382 ER PT J AU Dowd, KA DeMaso, CR Pierson, TC AF Dowd, Kimberly A. DeMaso, Christina R. Pierson, Theodore C. TI Genotypic Differences in Dengue Virus Neutralization Are Explained by a Single Amino Acid Mutation That Modulates Virus Breathing SO MBIO LA English DT Article ID WEST-NILE-VIRUS; ANTIBODY-MEDIATED NEUTRALIZATION; COXSACKIEVIRUS B3; MONOCLONAL-ANTIBODIES; STRUCTURAL INSIGHTS; MOLECULAR EVOLUTION; SYNTHETIC PEPTIDES; ENVELOPE PROTEIN; EPITOPE EXPOSURE; ANTIGENIC SITES AB Flaviviruses sample an ensemble of virion conformations resulting from the conformational flexibility of their structural proteins. To investigate how sequence variation among strains impacts virus breathing, we performed studies with the monoclonal antibody (MAb) E111, which binds an inaccessible domain III envelope (E) protein epitope of dengue virus serotype 1 (DENV1). Prior studies indicated that an observed similar to 200-fold difference in neutralization between the DENV1 strains Western Pacific-74 (West Pac-74) and 16007 could not be explained by differences in the affinity of MAb E111 for each strain. Through neutralization studies with wild-type and variant viruses carrying genes encoding reciprocal mutations at all 13 amino acid differences between the E proteins of West Pac-74 and 16007, we found that E111 neutralization susceptibility mapped solely to the presence of a lysine or arginine at E domain II residue 204, located distally from the E111 epitope. This same residue correlated with neutralization differences observed for MAbs specific for epitopes distinct from E111, suggesting that this amino acid dictates changes in the conformational ensembles sampled by the virus. Furthermore, an observed twofold difference in the stability of infectious West Pac-74 versus 16007 in solution also mapped to E residue 204. Our results demonstrate that neutralization susceptibility can be altered in an epitope-independent manner by natural strain variation that influences the structures sampled by DENV. That different conformational ensembles of flaviviruses may affect the landscape available for antibody binding, as well as virus stability, has important implications for functional studies of antibody potency, a critical aspect of vaccine development. IMPORTANCE The global burden of dengue virus (DENV) is growing, with recent estimates of similar to 390 million human infections each year. Antibodies play a crucial role in protection from DENV infection, and vaccines that elicit a robust antibody response are being actively pursued. We report here the identification of a single amino acid residue in the envelope protein of DENV serotype 1 that results in global changes to virus structure and stability when it is changed. Our results indicate that naturally occurring variation at this particular site among virus strains impacts the ensemble of structures sampled by the virus, a process referred to as virus breathing. The finding that such limited and conservative sequence changes can modulate the landscape available for antibody binding has important implications for both vaccine development and the study of DENV-reactive antibodies. C1 [Dowd, Kimberly A.; DeMaso, Christina R.; Pierson, Theodore C.] NIAID, Viral Pathogenesis Sect, Viral Dis Lab, NIH, 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 National Institute of Allergy and Infectious Diseases FX This research was funded by the intramural Research Program of the National Institute of Allergy and Infectious Diseases. NR 62 TC 7 Z9 7 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD NOV-DEC PY 2015 VL 6 IS 6 AR e01559-15 DI 10.1128/mBio.01559-15 PG 11 WC Microbiology SC Microbiology GA DA0YY UT WOS:000367524700027 PM 26530385 ER PT J AU Yang, CF Starr, T Song, LH Carlson, JH Sturdevant, GL Beare, PA Whitmire, WM Caldwell, HD AF Yang, Chunfu Starr, Tregei Song, Lihua Carlson, John H. Sturdevant, Gail L. Beare, Paul A. Whitmire, William M. Caldwell, Harlan D. TI Chlamydial Lytic Exit from Host Cells Is Plasmid Regulated SO MBIO LA English DT Article ID TRACHOMATIS PLASMID; TRANSCRIPTIONAL REGULATOR; INTERMEDIATE-FILAMENTS; MEMBRANE-PROTEIN; VIRULENCE FACTOR; III SECRETION; INCLUSION; GENES; ACTIN; IDENTIFICATION AB Chlamydia trachomatis is an obligate intracellular bacterium that is a globally important human pathogen. The chlamydial plasmid is an attenuating virulence factor, but the molecular basis for attenuation is not understood. Chlamydiae replicate within a membrane-bound vacuole termed an inclusion, where they undergo a biphasic developmental growth cycle and differentiate from noninfectious into infectious organisms. Late in the developmental cycle, the fragile chlamydia-laden inclusion retains its integrity by surrounding itself with scaffolds of host cytoskeletal proteins. The ability of chlamydiae to developmentally free themselves from this cytoskeleton network is a fundamental virulence trait of the pathogen. Here, we show that plasmidless chlamydiae are incapable of disrupting their cytoskeletal entrapment and remain intracellular as stable mature inclusions that support high numbers of infectious organisms. By using deletion mutants of the eight plasmid-carried genes (Delta pgp1 to Delta pgp8), we show that Pgp4, a transcriptional regulator of multiple chromosomal genes, is required for exit. Exit of chlamydiae is dependent on protein synthesis and is inhibited by the compound C1, an inhibitor of the type III secretion system (T3S). Exit of plasmid-free and Delta pgp4 organisms, which failed to lyse infected cells, was rescued by latrunculin B, an inhibitor of actin polymerization. Our findings describe a genetic mechanism of chlamydial exit from host cells that is dependent on an unknown pgp4-regulated chromosomal T3S effector gene. IMPORTANCE Chlamydia's obligate intracellular life style requires both entry into and exit from host cells. Virulence factors that function in exiting are unknown. The chlamydial inclusion is stabilized late in the infection cycle by F-actin. A prerequisite of chlamydial exit is its ability to disassemble actin from the inclusion. We show that chlamydial plasmid-free organisms, and also a plasmid gene protein 4 (pgp4) null mutant, do not disassociate actin from the inclusion and fail to exit cells. We further provide evidence that Pgp4-regulated exit is dependent on the chlamydial type III secretion system. This study is the first to define a genetic mechanism that functions in chlamydial lytic exit from host cells. The findings also have practical implications for understanding why plasmid-free chlamydiae are highly attenuated and have the ability to elicit robust protective immune responses. C1 [Yang, Chunfu; Whitmire, William M.; Caldwell, Harlan D.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Starr, Tregei; Carlson, John H.; Beare, Paul A.] NIAID, Bacteriol Lab, NIH, Hamilton, MT USA. [Song, Lihua] Inst Microbiol & Epidemiol, State Key Lab Pathogen & Biosecur, Beijing, Peoples R China. [Sturdevant, Gail L.] NIAID, Virol Lab, NIH, Hamilton, MT USA. RP Caldwell, HD (reprint author), NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM hcaldwell@niaid.nih.gov FU 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 34 TC 1 Z9 1 U1 1 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD NOV-DEC PY 2015 VL 6 IS 6 AR e01648-15 DI 10.1128/mBio.01648-15 PG 9 WC Microbiology SC Microbiology GA DA0YY UT WOS:000367524700034 PM 26556273 ER PT J AU Heery, CR Singh, BH Rauckhorst, M Marte, JL Donahue, RN Grenga, I Rodell, TC Dahut, W Arlen, PM Madan, RA Schlom, J Gulley, JL AF Heery, Christopher R. Singh, B. Harpreet Rauckhorst, Myrna Marte, Jennifer L. Donahue, Renee N. Grenga, Italia Rodell, Timothy C. Dahut, William Arlen, Philip M. Madan, Ravi A. Schlom, Jeffrey Gulley, James L. TI Phase I Trial of a Yeast-Based Therapeutic Cancer Vaccine (GI-6301) Targeting the Transcription Factor Brachyury SO CANCER IMMUNOLOGY RESEARCH LA English DT Article ID EPITHELIAL-MESENCHYMAL TRANSITION; PROSTATE-CANCER; ADVANCED CHORDOMA; E-CADHERIN; METASTASIS; IMATINIB; CELLS; IDENTIFICATION; REGULATOR; PHENOTYPE AB The nuclear transcription factor brachyury has previously been shown to be a strong mediator of the epithelial-to-mesenchymal transition (EMT) in human carcinoma cells and a strong negative prognostic factor in several tumor types. Brachyury is overexpressed in a range of human carcinomas as well as in chordoma, a rare tumor for which there is no standard systemic therapy. Preclinical studies have shown that a recombinant Saccharomyces cerevisiae (yeast) vaccine encoding brachyury (GI-6301) can activate human T cells in vitro. A phase I dose-escalation (3-3 design) trial enrolled 34 patients at 4 dose levels [3, 3, 16, and 11 patients, respectively, at 4, 16, 40, and 80 yeast units (YU)]. Expansion cohorts were enrolled at 40-and 80-YU dose levels for analysis of immune response and clinical activity. We observed brachyury-specific T-cell immune responses in the majority of evaluable patients despite most having been heavily pretreated. No evidence of autoimmunity or other serious adverse events was observed. Two chordoma patients showed evidence of disease control (one mixed response and one partial response). A patient with colorectal carcinoma, who enrolled on study with a large progressing pelvic mass and rising carcinoembryonic antigen (CEA), remains on study for greater than 1 year with stable disease, evidence of decreased tumor density, and decreased serum CEA. This is the first-in-human study to demonstrate the safety and immunogenicity of this therapeutic cancer vaccine and provides the rationale for exploration in phase II studies. A randomized phase II chordoma study is now enrolling patients. (C) 2015 AACR. C1 [Heery, Christopher R.; Donahue, Renee N.; Grenga, Italia; Schlom, Jeffrey] NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Singh, B. Harpreet; Rauckhorst, Myrna; Marte, Jennifer L.; Dahut, William; Arlen, Philip M.; Madan, Ravi A.; Gulley, James L.] NCI, Genitourinary Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Rodell, Timothy C.] GlobeImmune Inc, Louisville, CO USA. RP Gulley, JL (reprint author), NCI, 9000 Rockville Pike,Bldg 10,Rm 12N226, Bethesda, MD 20892 USA. EM gj50i@nih.gov RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 FU Intramural NIH HHS [Z01 BC010661-04, Z01 BC010666-04] NR 32 TC 14 Z9 14 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2326-6066 EI 2326-6074 J9 CANCER IMMUNOL RES JI Cancer Immunol. Res. PD NOV PY 2015 VL 3 IS 11 BP 1248 EP 1256 DI 10.1158/2326-6066.CIR-15-0119 PG 9 WC Oncology; Immunology SC Oncology; Immunology GA DA1KV UT WOS:000367555600007 PM 26130065 ER PT J AU Morris, SE Vaidyanathan, U Cuthbert, BN AF Morris, Sarah E. Vaidyanathan, Uma Cuthbert, Bruce N. TI Psychophysiological science and the research domain criteria: A commentary SO INTERNATIONAL JOURNAL OF PSYCHOPHYSIOLOGY LA English DT Editorial Material AB The current special issue, devoted to the Research Domain Criteria (RDoC) initiative of the US National Institute of Mental Health, showcases a variety of empirical and review articles that address issues related to this dimensional and multi-method approach to research on mental disorders. Here, we provide an integrative perspective on various aspects of these articles, focused around the primary principles of the RDoC approach and the practical and methodological issues related to conducting RDoC-informed research. The chief point we wish to highlight is that these articles demonstrate the ways in which the field of psychophysiology already thinks along the lines of RDoC in terms of using biobehavioral constructs, looking for convergence among constructs using various methodologies, and utilizing dimensional measurements in studies. In this sense, RDoC is not novel; however, by specifying a formal research platform it provides explicit encouragement and guidance for using such principles in understanding psychiatric phenomena, rather than continuing to focus research efforts on traditional diagnostic categories alone. Published by Elsevier B.V. C1 [Morris, Sarah E.; Vaidyanathan, Uma; Cuthbert, Bruce N.] NIMH, Bethesda, MD 20892 USA. RP Morris, SE (reprint author), NIMH, Div Translat Res, 6001 Execut Blvd, Bethesda, MD 20892 USA. EM sarah.morris@nih.gov FU Intramural NIH HHS [Z99 MH999999] NR 15 TC 3 Z9 3 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-8760 EI 1872-7697 J9 INT J PSYCHOPHYSIOL JI Int. J. Psychophysiol. PD NOV PY 2015 VL 98 IS 2 SI SI BP 378 EP 380 DI 10.1016/j.ijpsycho.2015.11.002 PN 2 PG 3 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA DA0NG UT WOS:000367493400015 PM 26546860 ER PT J AU Yahiro, K Hirayama, T Moss, J Noda, M AF Yahiro, K. Hirayama, T. Moss, J. Noda, M. TI Helicobacter pylori VacA toxin causes cell death by inducing accumulation of cytoplasmic connexin 43 SO CELL DEATH & DISEASE LA English DT Editorial Material ID VACUOLATING CYTOTOXIN; PROTEIN C1 [Yahiro, K.; Noda, M.] Chiba Univ, Grad Sch Med, Dept Mol Infectiol, Chiba 2608670, Japan. [Hirayama, T.] Nagasaki Univ, Inst Trop Med, Dept Bacteriol, Nagasaki 8528523, Japan. [Moss, J.] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. RP Yahiro, K (reprint author), Chiba Univ, Grad Sch Med, Dept Mol Infectiol, Chuo Ku, 1-8-1 Inohana, Chiba 2608670, Japan. EM yahirok@faculty.chiba-u.jp FU Intramural NIH HHS NR 10 TC 3 Z9 3 U1 0 U2 0 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 NOV PY 2015 VL 6 AR e1971 DI 10.1038/cddis.2015.329 PG 2 WC Cell Biology SC Cell Biology GA CZ5PU UT WOS:000367155300010 PM 26561781 ER PT J AU Aggleton, JP Wright, NF Rosene, DL Saunders, RC AF Aggleton, John P. Wright, Nicholas F. Rosene, Douglas L. Saunders, Richard C. TI Complementary Patterns of Direct Amygdala and Hippocampal Projections to the Macaque Prefrontal Cortex SO CEREBRAL CORTEX LA English DT Article DE anatomy; emotion; fornix; hippocampus; memory; subiculum ID MAGNETIC-RESONANCE-SPECTROSCOPY; MONKEY RETROSPLENIAL CORTEX; RHESUS-MONKEY; CEREBRAL-CORTEX; TEMPORAL-LOBE; MACACA-FASCICULARIS; PARAHIPPOCAMPAL CORTICES; AUTOBIOGRAPHICAL MEMORY; EFFERENT PROJECTIONS; MAMMILLARY BODIES AB The projections from the amygdala and hippocampus (including subiculum and presubiculum) to prefrontal cortex were compared using anterograde tracers injected into macaque monkeys (Macaca fascicularis, Macaca mulatta). Almost all prefrontal areas were found to receive some amygdala inputs. These connections, which predominantly arose from the intermediate and magnocellular basal nucleus, were particularly dense in parts of the medial and orbital prefrontal cortex. Contralateral inputs were not, however, observed. The hippocampal projections to prefrontal areas were far more restricted, being confined to the ipsilateral medial and orbital prefrontal cortex (within areas 11, 13, 14, 24a, 32, and 25). These hippocampal projections principally arose from the subiculum, with the fornix providing the sole route. Thus, while the lateral prefrontal cortex essentially receives only amygdala inputs, the orbital prefrontal cortex receives both amygdala and hippocampal inputs, though these typically target different areas. Only in medial prefrontal cortex do direct inputs from both structures terminate in common sites. But, even when convergence occurs within an area, the projections predominantly terminate in different lamina (hippocampal inputs to layer III and amygdala inputs to layers I, II, and VI). The resulting segregation of prefrontal inputs could enable the parallel processing of different information types in prefrontal cortex. C1 [Aggleton, John P.; Wright, Nicholas F.] Cardiff Univ, Sch Psychol, Cardiff CF10 3AT, S Glam, Wales. [Rosene, Douglas L.] Boston Univ, Dept Anat & Neurobiol, Sch Med, Boston, MA 02118 USA. [Saunders, Richard C.] NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. RP Aggleton, JP (reprint author), Cardiff Univ, Sch Psychol, Pk Pl, Cardiff CF10 3AT, S Glam, Wales. EM aggleton@cf.ac.uk OI Rosene, Douglas/0000-0001-8719-1441; Aggleton, John/0000-0002-5573-1308 FU Royal Society/Wolfson Research Merit Award [MA09R2/HLL] FX The research was partly supported by a joint Royal Society/Wolfson Research Merit Award (MA09R2/HLL). Funding to pay the Open Access publication charges for this article was provided by a Royal Society Wolfson Research Merit Award to JPA. NR 94 TC 10 Z9 10 U1 2 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 EI 1460-2199 J9 CEREB CORTEX JI Cereb. Cortex PD NOV PY 2015 VL 25 IS 11 BP 4351 EP 4373 DI 10.1093/cercor/bhv019 PG 23 WC Neurosciences SC Neurosciences & Neurology GA CY5QW UT WOS:000366463300029 PM 25715284 ER PT J AU Venable, RM Brown, FLH Pastor, RW AF Venable, Richard M. Brown, Frank L. H. Pastor, Richard W. TI Mechanical properties of lipid bilayers from molecular dynamics simulation SO CHEMISTRY AND PHYSICS OF LIPIDS LA English DT Review DE Area per lipid; Bending modulus; Area compressibility modulus; Spontaneous curvature; Gaussian curvature modulus; CHARMM 36 force field ID X-RAY-SCATTERING; ADDITIVE FORCE-FIELD; COMPUTER-SIMULATION; BENDING ELASTICITY; MEMBRANE CURVATURE; FLUID MEMBRANES; SURFACE-TENSION; LIQUID/LIQUID INTERFACES; CHAIN-LENGTH; CHARMM AB Lipid areas (A(l)), bilayer area compressibilities (K-A), bilayer bending constants (K-C), and monolayer spontaneous curvatures (c(0)) from simulations using the CHARMM36 force field are reported for 12 representative homogenous lipid bilayers. A(l) (or their surrogate, the average deuterium order parameter in the "plateau region" of the chain) agree very well with experiment, as do the K-A. Simulated K-C are in near quantitative agreement with vesicle flicker experiments, but are somewhat larger than K-C from X-ray, pipette aspiration, and neutron spin echo for saturated lipids. Spontaneous curvatures of bilayer leaflets from the simulations are approximately 30% smaller than experimental values of monolayers in the inverse hexagonal phase. Published by Elsevier Ireland Ltd. C1 [Venable, Richard M.; Pastor, Richard W.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. [Brown, Frank L. H.] Univ Calif Santa Barbara, Dept Chem & Biochem, Santa Barbara, CA 93106 USA. [Brown, Frank L. H.] Univ Calif Santa Barbara, Dept Phys, Santa Barbara, CA 93106 USA. RP Pastor, RW (reprint author), NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. EM pastorr@nhlbi.nih.gov FU Intramural Research Program of the NIH, National Heart, Lung and Blood Institute; National Science Foundation [CHE-1153096, CHE-1465162] FX We thank Alexander Sodt and Markus Deserno for helpful conversations during the preparation of this manuscript, Max Watson for critical technical advice on obtaining neutral surfaces, and we acknowledge our codevelopers of the CHARMM lipid force field, particularly Jeffery Klauda, Alexander MacKerell, Jr., and Douglas Tobias. The generous advice over many years from Michael Brown, Evan Evans, Klaus Gawrisch, Stuart McLaughlin, John Nagle, Adrian Parsegian, and Steven White regarding experimental data has been invaluable to our efforts. This research was supported by the Intramural Research Program of the NIH, National Heart, Lung and Blood Institute, and by the National Science Foundation (Grant Nos. CHE-1153096 and CHE-1465162), and used the high-performance computational capabilities at the National Institutes of Health, Bethesda, MD (NHLBI LoBoS and Biowulf clusters). NR 89 TC 14 Z9 14 U1 15 U2 55 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0009-3084 EI 1873-2941 J9 CHEM PHYS LIPIDS JI Chem. Phys. Lipids PD NOV PY 2015 VL 192 SI SI BP 60 EP 74 DI 10.1016/j.chemphyslip.2015.07.014 PG 15 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA CZ4YJ UT WOS:000367108800008 PM 26238099 ER PT J AU Patlolla, AK Hackett, D Tchounwou, PB AF Patlolla, Anita K. Hackett, Diahanna Tchounwou, Paul B. TI Genotoxicity study of silver nanoparticles in bone marrow cells of Sprague-Dawley rats SO FOOD AND CHEMICAL TOXICOLOGY LA English DT Article DE Silver nanoparticles; Genotoxicity; Sprague-Dawley rats; Bone marrow cells; Chromosomal aberrations; Micronuclei; DNA damage mitotic index ID STRESS-DEPENDENT TOXICITY; HUMAN HEPATOMA-CELLS; IN-VITRO TOXICITY; OXIDATIVE STRESS; DNA-DAMAGE; CHROMOSOME-ABERRATIONS; WISTAR RATS; VIVO; CYTOTOXICITY; EXPOSURE AB The antimicrobial properties of silver nanoparticles (Ag-NPs) have resulted in their extensive application in consumer and health care products. Although Ag-NPs have great potential benefits, their side effects are unknown and seem inevitable due to their ability to reach the nucleus and damage genetic material. This study aimed to determine genotoxic potential of Ag-NPs using mitotic index (MI), DNA damage (comet assay), structural chromosome aberrations (SCA), micronuclei (MN) formation as genetic end-points and induction of reactive oxygen species (ROS) as oxidative stress endpoint in bone marrow of Sprague Dawley rats. Four groups of five male rats were orally administered Ag-NPs, once a day for five days with doses of 5, 25, 50, 100, mg/Kg. A control group was also made of five rats. Bone marrow samples were collected 24 h after the last treatment following standard protocols. Ag-NPs exposure significantly increased (p <0.05) the induction of ROS, number of SCA, the frequency of micro-nucleated cells, damaged the DNA and decreased the mitotic index compared to negative control. The results suggest that Ag-NPs may have the potential to induce oxidative stress mediated genotoxicity in rats. Further characterization of their genotoxicity and also their potential health implications should be monitored regularly. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Patlolla, Anita K.; Hackett, Diahanna; Tchounwou, Paul B.] Jackson State Univ, Coll Sci Engn & Technol, NIH RCMI Ctr Environm Hlth, Jackson, MS 39217 USA. [Hackett, Diahanna] Jackson State Univ, CSET, Dept Biol, LS MAMP Program, Jackson, MS USA. RP Patlolla, AK (reprint author), Jackson State Univ, Coll Sci Engn & Technol, NIH RCMI Ctr Environm Hlth, Jackson, MS 39217 USA. EM anita.k.patlolla@jsums.edu FU U.S. DOD through the U.S. Department of Army [W912HZ-10-2-0045]; NIH-Center for Environmental Health at Jackson State University [2G12MD007581-16] FX This research was supported in part by grants from U.S. DOD through the U.S. Department of Army #W912HZ-10-2-0045 (CMCM) and in part by NIH-Center for Environmental Health (Grant No. 2G12MD007581-16) at Jackson State University. NR 59 TC 3 Z9 3 U1 1 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-6915 EI 1873-6351 J9 FOOD CHEM TOXICOL JI Food Chem. Toxicol. PD NOV PY 2015 VL 85 BP 52 EP 60 DI 10.1016/j.fct.2015.05.005 PG 9 WC Food Science & Technology; Toxicology SC Food Science & Technology; Toxicology GA CZ2RC UT WOS:000366951300007 PM 26032631 ER PT J AU Figueroa, JD Koutros, S Colt, JS Kogevinas, M Garcia-Closas, M Real, FX Friesen, MC Baris, D Stewart, P Schwenn, M Johnson, A Karagas, MR Armenti, KR Moore, LE Schned, A Lenz, P Prokunina-Olsson, L Banday, AR Paquin, A Ylaya, K Chung, JY Hewitt, SM Nickerson, ML Tardon, A Serra, C Carrato, A Garcia-Closas, R Lloreta, J Malats, N Fraumeni, JF Chanock, SJ Chatterjee, N Rothman, N Silverman, DT AF Figueroa, Jonine D. Koutros, Stella Colt, Joanne S. Kogevinas, Manolis Garcia-Closas, Montserrat Real, Francisco X. Friesen, Melissa C. Baris, Dalsu Stewart, Patricia Schwenn, Molly Johnson, Alison Karagas, Margaret R. Armenti, Karla R. Moore, Lee E. Schned, Alan Lenz, Petra Prokunina-Olsson, Ludmila Banday, A. Rouf Paquin, Ashley Ylaya, Kris Chung, Joon-Yong Hewitt, Stephen M. Nickerson, Michael L. Tardon, Adonina Serra, Consol Carrato, Alfredo Garcia-Closas, Reina Lloreta, Josep Malats, Nuria Fraumeni, Joseph F., Jr. Chanock, Stephen J. Chatterjee, Nilanjan Rothman, Nathaniel Silverman, Debra T. TI Modification of Occupational Exposures on Bladder Cancer Risk by Common Genetic Polymorphisms SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID GENOME-WIDE ASSOCIATION; CONFERS SUSCEPTIBILITY; SEQUENCE VARIANT; LOCUS; SMOKING; SLC14A1 AB Few studies have demonstrated gene/environment interactions in cancer research. Using data on high-risk occupations for 2258 case patients and 2410 control patients from two bladder cancer studies, we observed that three of 16 known or candidate bladder cancer susceptibility variants displayed statistically significant and consistent evidence of additive interactions; specifically, the GSTM1 deletion polymorphism (P-interaction <= .001), rs11892031 (UGT1A, P-interaction = .01), and rs798766 (TMEM129-TACC3-FGFR3, P-interaction = .03). There was limited evidence for multiplicative interactions. When we examined detailed data on a prevalent occupational exposure associated with increased bladder cancer risk, straight metalworking fluids, we also observed statistically significant additive interaction for rs798766 (TMEM129-TACC3-FGFR3, P-interaction = .02), with the interaction more apparent in patients with tumors positive for FGFR3 expression. All statistical tests were two-sided. The interaction we observed for rs798766 (TMEM129-TACC3-FGFR3) with specific exposure to straight metalworking fluids illustrates the value of integrating germline genetic variation, environmental exposures, and tumor marker data to provide insight into the mechanisms of bladder carcinogenesis. C1 [Figueroa, Jonine D.; Koutros, Stella; Colt, Joanne S.; Garcia-Closas, Montserrat; Friesen, Melissa C.; Baris, Dalsu; Stewart, Patricia; Moore, Lee E.; Prokunina-Olsson, Ludmila; Banday, A. Rouf; Paquin, Ashley; Fraumeni, Joseph F., Jr.; Chanock, Stephen J.; Chatterjee, Nilanjan; Silverman, Debra T.] NIH, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Ylaya, Kris; Chung, Joon-Yong; Hewitt, Stephen M.] NIH, Expt Pathol Lab, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Nickerson, Michael L.] NIH, Canc & Inflammat Program, Bethesda, MD 20892 USA. [Figueroa, Jonine D.] Univ Edinburgh, Sch Med, Usher Inst Populat Hlth Sci & Informat, Edinburgh EH8 9A8, Midlothian, Scotland. [Kogevinas, Manolis; Tardon, Adonina; Lloreta, Josep] CIBERESP, Madrid, Spain. [Kogevinas, Manolis] Ctr Res Environm Epidemiol CREAL, Barcelona, Spain. [Kogevinas, Manolis] Hosp del Mar, Municipal Inst Med Res IMIM, Barcelona, Spain. [Garcia-Closas, Montserrat] Inst Canc Res, Div Genet & Epidemiol, London SW3 6JB, England. [Real, Francisco X.; Malats, Nuria] Spanish Natl Canc Res Ctr CNIO, Madrid, Spain. [Real, Francisco X.; Serra, Consol] Univ Pompeu Fabra, Dept Ciencies Expt & Salut, Barcelona, Spain. [Schwenn, Molly] Maine Canc Registry, Augusta, ME USA. [Johnson, Alison] Vermont Canc Registry, Burlington, VT USA. [Karagas, Margaret R.; Schned, Alan] Geisel Sch Med Dartmouth, Hanover, NH USA. [Armenti, Karla R.] New Hampshire Dept Hlth & Human Serv, Concord, NH 03301 USA. [Lenz, Petra] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Clin Res Directorate, Clin Monitoring Res Program, Frederick, MD USA. [Tardon, Adonina] Univ Oviedo, Mol Epidemiol Grp, Inst Univ Oncol, Oviedo, Asturias, Spain. [Carrato, Alfredo] Hosp Ramon & Cajal, E-28034 Madrid, Spain. [Garcia-Closas, Reina] Hosp Univ Canarias, Unidad Invest, San Cristobal la Laguna, Spain. RP Figueroa, JD (reprint author), Univ Edinburgh, Sch Med, Usher Inst Populat Hlth Sci & Informat, Teviot Pl, Edinburgh EH8 9A8, Midlothian, Scotland. EM jonine.figueroa@ed.ac.uk RI Friesen, Melissa/A-5362-2009; Kogevinas, Manolis/C-3918-2017; Real, Francisco X/H-5275-2015; OI Hewitt, Stephen/0000-0001-8283-1788; Real, Francisco X/0000-0001-9501-498X; Chung, Joon-Yong/0000-0001-5041-5982; Malats, Nuria/0000-0003-2538-3784 FU Intramural Research Program of the National Institutes of Health; Division of Cancer Epidemiology and Genetics, National Cancer Institute FX This work was supported by the Intramural Research Program of the National Institutes of Health and the Division of Cancer Epidemiology and Genetics, National Cancer Institute. NR 22 TC 6 Z9 6 U1 1 U2 14 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 NOV PY 2015 VL 107 IS 11 AR djv223 DI 10.1093/jnci/djv223 PG 5 WC Oncology SC Oncology GA CZ2YZ UT WOS:000366972300008 ER PT J AU Freidlin, B Little, RF Korn, EL AF Freidlin, Boris Little, Richard F. Korn, Edward L. TI Design Issues in Randomized Clinical Trials of Maintenance Therapies SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID PROGRESSION-FREE SURVIVAL; CELL LUNG-CANCER; BURDEN FOLLICULAR LYMPHOMA; ADVANCED OVARIAN-CANCER; END-POINTS; PHASE-III; RITUXIMAB MAINTENANCE; TREATMENT STRATEGIES; COLORECTAL-CANCER; MULTIPLE-MYELOMA AB A potential therapeutic strategy for patients who respond (or have stable disease) on a fixed-duration induction therapy is to receive maintenance therapy, typically given for a prolonged period of time. To enable patients and clinicians to make informed treatment decisions, the designs of phase III randomized clinical trials (RCTs) assessing maintenance strategies need to be such that their results will provide clear assessment of the relevant risks and benefits of these strategies. We review the key aspects of maintenance RCT designs. Important design considerations include choice of first-line and second-line therapies, minimizing between-arm differences in follow-up schedules, and choice of the primary endpoint. In order to change clinical practice, RCTs should be designed to accurately isolate and quantify the clinical benefit of maintenance as compared with the standard approach of fixed-duration induction followed by the second-line treatment at progression. To accomplish this, RCTs need to utilize an overall survival (or quality of life) endpoint or, in settings where this is not feasible, endpoints that incorporate the effects of the subsequent line of therapy (eg, time from randomization to second progression or death). Toxicity and symptom information over both the study treatment (maintenance) and the second-line treatment should also be collected and reported. C1 [Freidlin, Boris; Korn, Edward L.] NCI, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Little, Richard F.] NCI, Clin Invest Branch, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Freidlin, B (reprint author), NCI, Biometr Res Branch, Div Canc Treatment & Diag, 9609 Med Ctr Dr,Room 5W102,MSC 9735, Bethesda, MD 20892 USA. EM freidlinb@ctep.nci.nih.gov NR 56 TC 0 Z9 0 U1 3 U2 3 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 NOV PY 2015 VL 107 IS 11 AR djv225 DI 10.1093/jnci/djv225 PG 9 WC Oncology SC Oncology GA CZ2YZ UT WOS:000366972300010 ER PT J AU Hung, RJ Ulrich, CM Goode, EL Brhane, Y Muir, K Chan, AT Le Marchand, L Schildkraut, J Witte, JS Eeles, R Boffetta, P Spitz, MR Poirier, JG Rider, DN Fridley, BL Chen, ZH Haiman, C Schumacher, F Easton, DF Landi, MT Brennan, P Houlston, R Christiani, DC Field, JK Bickeboller, H Risch, A Kote-Jarai, Z Wiklund, F Gronberg, H Chanock, S Berndt, SI Kraft, P Lindstrom, S Al Olama, AA Song, HL Phelan, C Wentzensen, N Peters, U Slattery, ML Sellers, TA Casey, G Gruber, SB Hunter, DJ Amos, CI Henderson, B AF Hung, Rayjean J. Ulrich, Cornelia M. Goode, Ellen L. Brhane, Yonathan Muir, Kenneth Chan, Andrew T. Le Marchand, Loic Schildkraut, Joellen Witte, John S. Eeles, Rosalind Boffetta, Paolo Spitz, Margaret R. Poirier, Julia G. Rider, David N. Fridley, Brooke L. Chen, Zhihua Haiman, Christopher Schumacher, Fredrick Easton, Douglas F. Landi, Maria Teresa Brennan, Paul Houlston, Richard Christiani, David C. Field, John K. Bickeboeller, Heike Risch, Angela Kote-Jarai, Zsofia Wiklund, Fredrik Gronberg, Henrik Chanock, Stephen Berndt, Sonja I. Kraft, Peter Lindstrom, Sara Al Olama, Ali Amin Song, Honglin Phelan, Catherine Wentzensen, Nicholas Peters, Ulrike Slattery, Martha L. Sellers, Thomas A. Casey, Graham Gruber, Stephen B. Hunter, David J. Amos, Christopher I. Henderson, Brian CA GECCO FOCI CORECT DRIVE GAME-ON Network TI Cross Cancer Genomic Investigation of Inflammation Pathway for Five Common Cancers: Lung, Ovary, Prostate, Breast, and Colorectal Cancer SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; TELOMERE DYSFUNCTION; GENOTYPE IMPUTATION; TERT-CLPTM1L LOCUS; SEQUENCE VARIANTS; GENETIC-VARIATION; INNATE IMMUNITY; IDENTIFIES 2; RISK LOCI AB Background: Inflammation has been hypothesized to increase the risk of cancer development as an initiator or promoter, yet no large-scale study of inherited variation across cancer sites has been conducted. Methods: We conducted a cross-cancer genomic analysis for the inflammation pathway based on 48 genome-wide association studies within the National Cancer Institute GAME-ON Network across five common cancer sites, with a total of 64 591 cancer patients and 74 467 control patients. Subset-based meta-analysis was used to account for possible disease heterogeneity, and hierarchical modeling was employed to estimate the effect of the subcomponents within the inflammation pathway. The network was visualized by enrichment map. All statistical tests were two-sided. Results: We identified three pleiotropic loci within the inflammation pathway, including one novel locus in Ch12q24 encoding SH2B3 (rs3184504), which reached GWAS significance with a P value of 1.78 x 10(-8), and it showed an association with lung cancer (P = 2.01 x 10(-6)), colorectal cancer (GECCO P = 6.72x10(-6); CORECT P = 3.32x10(-5)), and breast cancer (P = .009). We also identified five key subpathway components with genetic variants that are relevant for the risk of these five cancer sites: inflammatory response for colorectal cancer (P = .006), inflammation related cell cycle gene for lung cancer (P = 1.35x10(-6)), and activation of immune response for ovarian cancer (P = .009). In addition, sequence variations in immune system development played a role in breast cancer etiology (P = .001) and innate immune response was involved in the risk of both colorectal (P = .022) and ovarian cancer (P = .003). Conclusions: Genetic variations in inflammation and its related subpathway components are keys to the development of lung, colorectal, ovary, and breast cancer, including SH2B3, which is associated with lung, colorectal, and breast cancer. C1 [Hung, Rayjean J.; Brhane, Yonathan; Poirier, Julia G.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5T 3L9, Canada. [Ulrich, Cornelia M.; Risch, Angela] Natl Ctr Tumor Dis, Heidelberg, Germany. [Ulrich, Cornelia M.; Risch, Angela] German Canc Res Ctr, Heidelberg, Germany. [Goode, Ellen L.; Rider, David N.] Mayo Clin, Rochester, MN USA. [Muir, Kenneth] Univ Warwick, Coventry CV4 7AL, W Midlands, England. [Chan, Andrew T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Le Marchand, Loic] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. [Schildkraut, Joellen] Duke Univ, Durham, NC USA. [Witte, John S.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Eeles, Rosalind; Houlston, Richard; Kote-Jarai, Zsofia] Inst Canc Res, London SW3 6JB, England. [Boffetta, Paolo] Mt Sinai Sch Med, New York, NY USA. [Spitz, Margaret R.] Baylor Coll Med, Houston, TX 77030 USA. [Fridley, Brooke L.] Univ Kansas, Med Ctr, Dept Biostat, Kansas City, KS 66103 USA. [Chen, Zhihua; Phelan, Catherine; Sellers, Thomas A.] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [Haiman, Christopher; Schumacher, Fredrick; Casey, Graham; Gruber, Stephen B.; Henderson, Brian] Univ South Calif, Los Angeles, CA USA. [Easton, Douglas F.; Al Olama, Ali Amin; Song, Honglin] Univ Cambridge, Cambridge, England. [Landi, Maria Teresa; Chanock, Stephen; Berndt, Sonja I.; Wentzensen, Nicholas] NCI, Bethesda, MD 20892 USA. [Brennan, Paul] Int Agcy Res Canc, F-69372 Lyon, France. [Christiani, David C.; Kraft, Peter; Lindstrom, Sara; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Field, John K.] Univ Liverpool, Liverpool L69 3BX, Merseyside, England. [Bickeboeller, Heike] Univ Gottingen, Sch Med, D-37073 Gottingen, Germany. [Wiklund, Fredrik; Gronberg, Henrik] Karolinska Inst, Stockholm, Sweden. [Peters, Ulrike] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Ulrich, Cornelia M.; Slattery, Martha L.] Univ Utah, Hlth Sci Ctr, Salt Lake City, UT USA. [Ulrich, Cornelia M.; Slattery, Martha L.] Huntsman Canc Inst, Salt Lake City, UT USA. [Amos, Christopher I.] Dartmouth Coll, Geisel Sch Med, Lebanon, NH 03756 USA. RP Hung, RJ (reprint author), Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, 60 Murray St, Toronto, ON M5T 3L9, Canada. EM rayjean.hung@lunenfeld.ca RI Hung, Rayjean/A-7439-2013; Risch, Angela/H-2669-2013; OI Eeles, Rosalind/0000-0002-3698-6241; Risch, Angela/0000-0002-8026-5505; Houlston, Richard/0000-0002-5268-0242 FU TRICL (Transdisciplinary Research for Cancer of Lung); International Lung Cancer Consortium (ILCCO): National Institute of Health [U19 CA148127-01]; Canadian Cancer Society Research Institute [020214]; DRIVE (Discovery, Biology, and Risk of Inherited Variants in Breast Cancer): National Institute of Health [U19 CA148065]; CORECT (ColoRectal Transdisciplinary Study): National Institute of Health [U19 CA148107, R01 CA81488, P30 CA014089]; GAME-ON U19 initiative for prostate cancer (ELLIPSE) [U19 CA148537]; FOCI (Transdisciplinary Cancer Genetic Association and Interacting Studies): National Institutes of Health [U19 CA148112-01, R01-CA122443, P50-CA136393, P30-CA15083]; Cancer Research UK [C490/A8339, C490/A16561, C490/A10119, C490/A10124]; GECCO (Genetics and Epidemiology of Colorectal Cancer Consortium): National Cancer Institute, National Institutes of Health, US Department of Health and Human Services [U01 CA137088, R01 CA059045]; ASTERISK: a 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); DACHS: 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]; DALS: National Institutes of Health [R01 CA48998]; National Institutes of Health [P01 CA 055075, UM1 CA167552, R01 137178, R01 CA 151993, R01 CA137178, P01 CA 087969, R01 CA151993, P50 CA 127003, R01 CA042182, R01 CA076366, K05 CA154337]; OFCCR: National Institutes of Health [U01 CA074783]; Ontario Ministry of Research and Innovation; 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, GEI U01 HG 004438]; National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C] FX TRICL (Transdisciplinary Research for Cancer of Lung) and International Lung Cancer Consortium (ILCCO): National Institute of Health U19 CA148127-01 (PI: Amos), Canadian Cancer Society Research Institute (no. 020214, PI: Hung).; DRIVE (Discovery, Biology, and Risk of Inherited Variants in Breast Cancer): National Institute of Health U19 CA148065.; CORECT (ColoRectal Transdisciplinary Study): National Institute of Health U19 CA148107; R01 CA81488, P30 CA014089.; ELLIPSE (ELLIPSE, Elucidating Loci in Prostate Cancer Susceptibility): This work was support by the GAME-ON U19 initiative for prostate cancer (ELLIPSE), U19 CA148537.; FOCI (Transdisciplinary Cancer Genetic Association and Interacting Studies): National Institutes of Health U19 CA148112-01 (PI: Sellers), R01-CA122443, P50-CA136393, P30-CA15083 (PI: Goode), Cancer Research UK (C490/A8339, C490/A16561, C490/A10119, C490/A10124 [PI: Pharoah]).; GECCO (Genetics and Epidemiology of Colorectal Cancer Consortium): National Cancer Institute, National Institutes of Health, US Department of Health and Human Services (U01 CA137088; R01 CA059045). ASTERISK: a Hospital Clinical Research Program (PHRC) and supported by 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). DACHS: 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: 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, and P50 CA 127003), NHS by the National Institutes of Health (R01 CA137178, P01 CA 087969, R01 CA151993, and P50 CA 127003), and PHS by the National Institutes of Health (R01 CA042182). OFCCR: National Institutes of Health, through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783); see CFR section. 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: 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. Nat Genet. 2007;39(5):645-649), Colon CGEMS pancreatic cancer scan (PanScan) (Amundadottir L, et al. Nat Genet. 2009;41(9):986-990 and Petersen GM, et al. Nat Genet. 2010;42(3):224-228), and the Lung Cancer and Smoking study. 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: National Institutes of Health (R01 CA076366 to PA Newcomb). VITAL: National Institutes of Health (K05 CA154337). WHI: The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. NR 90 TC 5 Z9 6 U1 1 U2 5 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 NOV PY 2015 VL 107 IS 11 AR djv246 DI 10.1093/jnci/djv246 PG 10 WC Oncology SC Oncology GA CZ2YZ UT WOS:000366972300014 ER PT J AU Pinsky, PF Kramer, BS AF Pinsky, Paul F. Kramer, Barnett S. TI Lung Cancer Risk and Demographic Characteristics of Current 20-29 Pack-Year Smokers: Implications for Screening SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID SMOKING-CESSATION; UNITED-STATES; EXCESS RISK; MORTALITY; PATTERNS; MODEL AB Background: Based on current recommendations, 30+ pack-years of smoking are required for eligibility for low-dose CT (LDCT) lung cancer screening; former smokers must have quit within 15 years. We investigated whether current smokers with 20 to 29 pack-years have similar lung cancer risks as eligible former smokers and also whether they have a different demographic profile. Methods: The Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) was a randomly assigned screening trial of subjects age 55 to 74 years with chest radiographs (CXR) used for lung cancer. Subjects completed a baseline questionnaire containing smoking history questions. Cox proportional hazards models, adjusted for age and sex, were utilized to estimate hazard ratios (HRs) for various smoking history groups. Next, we utilized the National Health Interview Survey (NHIS), which inquired about smoking history and race/ethnicity, to analyze the demographic profiles of various high-risk smoking history categories. All statistical tests were two-sided. Results: The PLCO cohort included 18 114 former and 12 243 current LDCT-eligible smokers, plus 2283 20- to 29-pack-year current smokers. The hazard ratio for 20-to 29-pack-year current smokers compared with eligible (30+ pack-year) former smokers was 1.07 (95% confidence interval [CI] = 0.75 to 1.5). Based on the NHIS, 10 million persons in the United States are currently LDCT eligible; an additional 1.6 million (16%, 95% CI = 13.6% to 19.0%) are 20-to 29-pack-year current smokers. The percentage increase in eligibles if 20-to 29-pack-year current smokers were included was substantially greater for women than men (22.2%, 95% CI = 17.9% to 26.7%; vs 12.2%, 95% CI = 9.3% to 15.3%, P < .001) and for minorities than non-Hispanic whites (30.0%, 95% CI = 24.2% to 36.0%; vs 14.1%, 95% CI = 11.1% to 17.0%, P < .001). Conclusion: The potential benefits and harms of recommending LDCT screening for 20 to 29-pack-year current smokers should be assessed. C1 [Pinsky, Paul F.; Kramer, Barnett S.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Pinsky, PF (reprint author), NCI, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM pp4f@nih.gov NR 18 TC 4 Z9 4 U1 0 U2 0 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 NOV PY 2015 VL 107 IS 11 AR djv226 DI 10.1093/jnci/djv226 PG 5 WC Oncology SC Oncology GA CZ2YZ UT WOS:000366972300018 ER PT J AU Wright, JD Cui, RR Wang, AQ Chen, L Tergas, AI Burke, WM Ananth, CV Hou, JY Neugut, AI Temkin, SM Wang, YC Hershman, DL AF Wright, Jason D. Cui, Rosa R. Wang, Anqi Chen, Ling Tergas, Ana I. Burke, William M. Ananth, Cande V. Hou, June Y. Neugut, Alfred I. Temkin, Sarah M. Wang, Y. Claire Hershman, Dawn L. TI Economic and Survival Implications of Use of Electric Power Morcellation for Hysterectomy for Presumed Benign Gynecologic Disease SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID ASSISTED VAGINAL HYSTERECTOMY; TOTAL ABDOMINAL HYSTERECTOMY; QUALITY-OF-LIFE; TOTAL LAPAROSCOPIC HYSTERECTOMY; COST-EFFECTIVENESS ANALYSIS; UTERINE LEIOMYOSARCOMA; PREVENTION STRATEGIES; BRCA1/2 MUTATIONS; CONTROLLED-TRIAL; WOMEN AB Background: Electric power morcellation during laparoscopic hysterectomy allows some women to undergo minimally invasive surgery but may disrupt underlying occult malignancies and increase the risk of tumor dissemination. Methods: We developed a state transition Markov cohort simulation model of the risks and benefits of hysterectomy (abdominal, laparoscopic, and laparoscopic with electric power morcellation) for women with presumed benign gynecologic disease. The model considered perioperative morbidity, mortality, risk of cancer and dissemination, and outcomes in women with an underlying malignancy. We explored the effectiveness from a societal perspective stratified by age (<40, 40-49, 50-59, and >= 60 years). Results: Under all scenarios, modeled laparoscopic hysterectomy without morcellation was the most beneficial strategy. Laparoscopic hysterectomy with morcellation was associated with 80.83 more intraoperative complications, 199.64 fewer perioperative complications, and 241.80 fewer readmissions than abdominal hysterectomy per 10 000 women. Per 10 000 women younger than age 40 years, laparoscopic hysterectomy with morcellation was associated with 1.57 more cases of disseminated cancer and 0.97 fewer deaths than abdominal hysterectomy. The excess cases of disseminated cancer per 10 000 women with morcellation compared with abdominal hysterectomy increased with age to 47.54 per 10 000 in women age 60 years and older. Compared with abdominal hysterectomy, this resulted in 0.30 (age 40-49 years), 5.07 (age 50-59 years), and 18.14 (age 60 years and older) excess deaths per 10 000 women in the respective age groups. Conclusion: Laparoscopic hysterectomy without morcellation is the most beneficial approach of the three methods of hysterectomy studied. In older women, the risks of electric power morcellation may outweigh the benefits of minimally invasive hysterectomy. C1 [Wright, Jason D.; Cui, Rosa R.; Chen, Ling; Tergas, Ana I.; Burke, William M.; Ananth, Cande V.; Hou, June Y.] Columbia Univ, Coll Phys & Surg, Dept Obstet & Gynecol, New York, NY 10032 USA. [Neugut, Alfred I.; Hershman, Dawn L.] Columbia Univ, Coll Phys & Surg, Dept Med, New York, NY 10032 USA. [Tergas, Ana I.; Ananth, Cande V.; Neugut, Alfred I.; Hershman, Dawn L.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10032 USA. [Wang, Anqi; Wang, Y. Claire] Columbia Univ, Mailman Sch Publ Hlth, Dept Hlth Policy & Management, New York, NY 10032 USA. [Wright, Jason D.; Tergas, Ana I.; Burke, William M.; Hou, June Y.; Neugut, Alfred I.; Hershman, Dawn L.] Columbia Univ, Coll Phys & Surg, Herbert Irving Comprehens Canc Ctr, New York, NY 10032 USA. [Wright, Jason D.; Tergas, Ana I.; Burke, William M.; Hou, June Y.; Neugut, Alfred I.; Hershman, Dawn L.] New York Presbyterian Hosp, New York, NY USA. [Temkin, Sarah M.] NCI, Bethesda, MD 20892 USA. RP Wright, JD (reprint author), Columbia Univ, Coll Phys & Surg, Dept Obstet & Gynecol, Div Gynecol Oncol, 161 Ft Washington Ave,8th Floor, New York, NY 10032 USA. EM jw2459@columbia.edu FU National Cancer Institute [NCI R01CA169121-01A1, NCI R01CA134964, NCI R25 CA094061-11] FX Dr. Wright (NCI R01CA169121-01A1) and Dr. Hershman (NCI R01CA134964) are recipients of grants and Dr. Tergas is the recipient of a fellowship (NCI R25 CA094061-11) from the National Cancer Institute. NR 56 TC 1 Z9 1 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 NOV PY 2015 VL 107 IS 11 AR djv251 DI 10.1093/jnci/djv251 PG 9 WC Oncology SC Oncology GA CZ2YZ UT WOS:000366972300026 ER PT J AU Zhang, B Shu, XO Delahanty, RJ Zeng, CJ Michailidou, K Bolla, MK Wang, Q Dennis, J Wen, WQ Long, JR Li, C Dunning, AM Chang-Claude, J Shah, M Perkins, BJ Czene, K Darabi, H Eriksson, M Bojesen, SE Nordestgaard, BG Nielsen, SF Flyger, H Lambrechts, D Neven, P Wildiers, H Floris, G Schmidt, MK Rookus, MA van den Hurk, K de Kort, WLAM Couch, FJ Olson, JE Hallberg, E Vachon, C Rudolph, A Seibold, P Flesch-Janys, D Peto, J dos-Santos-Silva, I Fletcher, O Johnson, N Nevanlinna, H Muranen, TA Aittomaki, K Blomqvist, C Li, JM Humphreys, K Brand, J Guenel, P Truong, T Cordina-Duverger, E Menegaux, F Burwinkel, B Marme, F Yang, RX Surowy, H Benitez, J Zamora, MP Perez, JIA Cox, A Cross, SS Reed, MWR Andrulis, IL Knight, JA Glendon, G Tchatchou, S Sawyer, EJ Tomlinson, I Kerin, MJ Miller, N Chenevix-Trench, G Haiman, CA Henderson, BE Schumacher, F Le Marchand, L Lindblom, A Margolin, S Hooning, MJ Martens, JWM Tilanus-Linthorst, MMA Collee, JM Hopper, JL Southey, MC Tsimiklis, H Apicella, C Slager, S Toland, AE Ambrosone, CB Yannoukakos, D Giles, GG Milne, RL McLean, C Fasching, PA Haeberle, L Ekici, AB Beckmann, MW Brenner, H Dieffenbach, AK Arndt, V Stegmaier, C Swerdlow, AJ Ashworth, A Orr, N Jones, M Figueroa, J Garcia-Closas, M Brinton, L Lissowska, J Dumont, M Winqvist, R Pylkas, K Jukkola-Vuorinen, A Grip, M Brauch, H Bruning, T Ko, YD Peterlongo, P Manoukian, S Bonanni, B Radice, P Bogdanova, N Antonenkova, N Dork, T Mannermaa, A Kataja, V Kosma, VM Hartikainen, JM Devilee, P Seynaeve, C Van Asperen, CJ Jakubowska, A Lubinski, J Jaworska-Bieniek, K Durda, K Hamann, U Torres, D Schmutzler, RK Neuhausen, SL Anton-Culver, H Kristensen, VN Alnaes, GIG Pierce, BL Kraft, P Peters, U Lindstrom, S Seminara, D Burgess, S Ahsan, H Whittemore, AS John, EM Gammon, MD Malone, KE Tessier, DC Vincent, D Bacot, F Luccarini, C Baynes, C Ahmed, S Maranian, M Healey, CS Gonzalez-Neira, A Pita, G Alonso, MR Alvarez, N Herrero, D Pharoah, PDP Simard, J Hall, P Hunter, DJ Easton, DF Zheng, W AF Zhang, Ben Shu, Xiao-Ou Delahanty, Ryan J. Zeng, Chenjie Michailidou, Kyriaki Bolla, Manjeet K. Wang, Qin Dennis, Joe Wen, Wanqing Long, Jirong Li, Chun Dunning, Alison M. Chang-Claude, Jenny Shah, Mitul Perkins, Barbara J. Czene, Kamila Darabi, Hatef Eriksson, Mikael Bojesen, Stig E. Nordestgaard, Borge G. Nielsen, Sune F. Flyger, Henrik Lambrechts, Diether Neven, Patrick Wildiers, Hans Floris, Giuseppe Schmidt, Marjanka K. Rookus, Matti A. van den Hurk, Katja de Kort, Wim L. A. M. Couch, Fergus J. Olson, Janet E. Hallberg, Emily Vachon, Celine Rudolph, Anja Seibold, Petra Flesch-Janys, Dieter Peto, Julian dos-Santos-Silva, Isabel Fletcher, Olivia Johnson, Nichola Nevanlinna, Heli Muranen, Taru A. Aittomaki, Kristiina Blomqvist, Carl Li, Jingmei Humphreys, Keith Brand, Judith Guenel, Pascal Truong, Therese Cordina-Duverger, Emilie Menegaux, Florence Burwinkel, Barbara Marme, Frederik Yang, Rongxi Surowy, Harald Benitez, Javier Pilar Zamora, M. Perez, Jose I. A. Cox, Angela Cross, Simon S. Reed, Malcolm W. R. Andrulis, Irene L. Knight, Julia A. Glendon, Gord Tchatchou, Sandrine Sawyer, Elinor J. Tomlinson, Ian Kerin, Michael J. Miller, Nicola Chenevix-Trench, Georgia Haiman, Christopher A. Henderson, Brian E. Schumacher, Fredrick Le Marchand, Loic Lindblom, Annika Margolin, Sara Hooning, Maartje J. Martens, John W. M. Tilanus-Linthorst, Madeleine M. A. Collee, J. Margriet Hopper, John L. Southey, Melissa C. Tsimiklis, Helen Apicella, Carmel Slager, Susan Toland, Amanda E. Ambrosone, Christine B. Yannoukakos, Drakoulis Giles, Graham G. Milne, Roger L. McLean, Catriona Fasching, Peter A. Haeberle, Lothar Ekici, Arif B. Beckmann, Matthias W. Brenner, Hermann Dieffenbach, Aida Karina Arndt, Volker Stegmaier, Christa Swerdlow, Anthony J. Ashworth, Alan Orr, Nick Jones, Michael Figueroa, Jonine Garcia-Closas, Montserrat Brinton, Louise Lissowska, Jolanta Dumont, Martine Winqvist, Robert Pylkas, Katri Jukkola-Vuorinen, Arja Grip, Mervi Brauch, Hiltrud Bruening, Thomas Ko, Yon-Dschun Peterlongo, Paolo Manoukian, Siranoush Bonanni, Bernardo Radice, Paolo Bogdanova, Natalia Antonenkova, Natalia Doerk, Thilo Mannermaa, Arto Kataja, Vesa Kosma, Veli-Matti Hartikainen, Jaana M. Devilee, Peter Seynaeve, Caroline Van Asperen, Christi J. Jakubowska, Anna Lubinski, Jan Jaworska-Bieniek, Katarzyna Durda, Katarzyna Hamann, Ute Torres, Diana Schmutzler, Rita K. Neuhausen, Susan L. Anton-Culver, Hoda Kristensen, Vessela N. Alnaes, Grethe I. Grenaker Pierce, Brandon L. Kraft, Peter Peters, Ulrike Lindstrom, Sara Seminara, Daniela Burgess, Stephen Ahsan, Habibul Whittemore, Alice S. John, Esther M. Gammon, Marilie D. Malone, Kathleen E. Tessier, Daniel C. Vincent, Daniel Bacot, Francois Luccarini, Craig Baynes, Caroline Ahmed, Shahana Maranian, Mel Healey, Catherine S. Gonzalez-Neira, Anna Pita, Guillermo Rosario Alonso, M. Alvarez, Nuria Herrero, Daniel Pharoah, Paul D. P. Simard, Jacques Hall, Per Hunter, David J. Easton, Douglas F. Zheng, Wei CA kConFab Investigators Australian Ovarian Study Grp DRIVE Project TI Height and Breast Cancer Risk: Evidence From Prospective Studies and Mendelian Randomization SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID GENOME-WIDE ASSOCIATION; MULTIPLE GENETIC-VARIANTS; DIFFERENT ANATOMIC SITES; CORONARY-ARTERY-DISEASE; BODY-FAT DISTRIBUTION; ADULT HUMAN HEIGHT; PROSPECTIVE COHORT; INTERLEUKIN-6 RECEPTOR; SUSCEPTIBILITY LOCI; COMMON VARIANTS AB Background: Epidemiological studies have linked adult height with breast cancer risk in women. However, the magnitude of the association, particularly by subtypes of breast cancer, has not been established. Furthermore, the mechanisms of the association remain unclear. Methods: We performed a meta-analysis to investigate associations between height and breast cancer risk using data from 159 prospective cohorts totaling 5 216 302 women, including 113 178 events. In a consortium with individual-level data from 46 325 case patients and 42 482 control subjects, we conducted a Mendelian randomization analysis using a genetic score that comprised 168 height-associated variants as an instrument. This association was further evaluated in a second consortium using summary statistics data from 16 003 case patients and 41 335 control subjects. Results: The pooled relative risk of breast cancer was 1.17 (95% confidence interval [CI] = 1.15 to 1.19) per 10 cm increase in height in the meta-analysis of prospective studies. In Mendelian randomization analysis, the odds ratio of breast cancer per 10 cm increase in genetically predicted height was 1.22 (95% CI = 1.13 to 1.32) in the first consortium and 1.21 (95% CI = 1.05 to 1.39) in the second consortium. The association was found in both premenopausal and postmenopausal women but restricted to hormone receptor-positive breast cancer. Analyses of height-associated variants identified eight new loci associated with breast cancer risk after adjusting for multiple comparisons, including three loci at 1q21.2, DNAJC27, and CCDC91 at genome-wide significance level P < 5 x 10(-8). Conclusions: Our study provides strong evidence that adult height is a risk factor for breast cancer in women and certain genetic factors and biological pathways affecting adult height have an important role in the etiology of breast cancer. C1 [Zhang, Ben; Shu, Xiao-Ou; Delahanty, Ryan J.; Zeng, Chenjie; Wen, Wanqing; Long, Jirong; Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, Vanderbilt Ingram Canc Ctr,Dept Med,Div Epidemiol, Nashville, TN 37203 USA. [Li, Chun] Vanderbilt Univ, Sch Med, Dept Biostat, Nashville, TN 37203 USA. [Michailidou, Kyriaki; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Pharoah, Paul D. P.; Easton, Douglas F.] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge, England. [Li, Chun; Dunning, Alison M.; Shah, Mitul; Perkins, Barbara J.; Blomqvist, Carl; Ahmed, Shahana; Maranian, Mel; Healey, Catherine S.; Pharoah, Paul D. P.; Easton, Douglas F.] Univ Cambridge, Dept Oncol, Cambridge, England. [Czene, Kamila; Darabi, Hatef; Eriksson, Mikael] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Bojesen, Stig E.; Nordestgaard, Borge G.; Nielsen, Sune F.] Herlev Hosp, Copenhagen Gen Populat Study, Copenhagen, Denmark. [Bojesen, Stig E.; Nordestgaard, Borge G.; Nielsen, Sune F.] Herlev Hosp, Dept Clin Biochem, Copenhagen, Denmark. [Flyger, Henrik] Herlev Hosp, Dept Breast Surg, Copenhagen, Denmark. [Bojesen, Stig E.; Nordestgaard, Borge G.] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark. [Lambrechts, Diether] VIB, Vesalius Res Ctr, Leuven, Belgium. [Lambrechts, Diether] Univ Leuven, Dept Oncol, Lab Translat Genet, Leuven, Belgium. [Neven, Patrick; Wildiers, Hans; Floris, Giuseppe] Univ Hosp Leuven, Leuven, Belgium. [Neven, Patrick; Wildiers, Hans; Floris, Giuseppe] Dept Oncol, Leuven, Belgium. [Schmidt, Marjanka K.; Rookus, Matti A.] Netherlands Canc Inst, Amsterdam, Netherlands. [van den Hurk, Katja; de Kort, Wim L. A. M.] Sanquin Blood Supply, Dept Donor Studies, Div Res, Amsterdam, Netherlands. [Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Olson, Janet E.; Hallberg, Emily; Vachon, Celine; Slager, Susan] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Chang-Claude, Jenny; Rudolph, Anja; Seibold, Petra] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Flesch-Janys, Dieter] Univ Med Ctr Hamburg Eppendorf, Dept Canc Epidemiol, Clin Canc Registry, Hamburg, Germany. [Flesch-Janys, Dieter] Univ Med Ctr Hamburg Eppendorf, Inst Med Biometr & Epidemiol, Hamburg, Germany. [Peto, Julian; dos-Santos-Silva, Isabel] London Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, London WC1, England. [Fletcher, Olivia; Johnson, Nichola] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England. [Nevanlinna, Heli; Muranen, Taru A.] Univ Helsinki, Dept Obstet & Gynecol, Helsinki, Finland. [Aittomaki, Kristiina] Univ Helsinki, Dept Clin Genet, Helsinki, Finland. [Blomqvist, Carl] Univ Helsinki, Dept Oncol, Helsinki, Finland. [Blomqvist, Carl] Univ Helsinki, Cent Hosp, Helsinki, Finland. [Humphreys, Keith; Brand, Judith; Hall, Per] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Li, Jingmei] Genome Inst Singapore, Div Human Genet, Singapore, Singapore. [Guenel, Pascal; Truong, Therese; Cordina-Duverger, Emilie; Menegaux, Florence] CESP Ctr Res Epidemiol & Populat Hlth, Inserm Natl Inst Hlth & Med Res, Environm Epidemiol Canc, Villejuif, France. [Guenel, Pascal; Truong, Therese; Cordina-Duverger, Emilie; Menegaux, Florence] Univ Paris Sud, Villejuif, France. [Burwinkel, Barbara; Marme, Frederik; Yang, Rongxi; Surowy, Harald] Heidelberg Univ, Dept Obstet & Gynecol, Heidelberg, Germany. [Marme, Frederik] Heidelberg Univ, Natl Ctr Tumor Dis, Heidelberg, Germany. [Burwinkel, Barbara; Yang, Rongxi; Surowy, Harald] German Canc Res Ctr, Mol Epidemiol Grp, Heidelberg, Germany. [Benitez, Javier] Spanish Natl Res Ctr CNIO, Human Genotyping Ctr, Human Genet Grp, Madrid, Spain. [Pilar Zamora, M.] Hosp La Paz, Oncol Serv, Madrid, Spain. [Perez, Jose I. A.] Hosp Monte Naranco, Surg Serv, Oviedo, Spain. [Cox, Angela; Reed, Malcolm W. R.] Univ Sheffield, Dept Oncol, Sheffield, S Yorkshire, England. [Cross, Simon S.] Univ Sheffield, Dept Neurosci, Sheffield, S Yorkshire, England. [Andrulis, Irene L.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Glendon, Gord; Tchatchou, Sandrine] Univ Toronto, Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada. [Knight, Julia A.] Univ Toronto, Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst,Div Epidemiol, Prosserman Ctr Hlth Res,Dalla Lana Sch Publ Hlth, Toronto, ON M5G 1X5, Canada. [Sawyer, Elinor J.] Kings Coll London, Guys Hosp, Div Canc Studies, Res Oncol, London WC2R 2LS, England. [Tomlinson, Ian] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX1 2JD, England. [Tomlinson, Ian] Univ Oxford, Oxford Biomed Res Ctr, Oxford OX1 2JD, England. [Kerin, Michael J.; Miller, Nicola] Univ Coll Hosp Galway, Inst Clin Sci, Galway, Ireland. [Chenevix-Trench, Georgia] QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia. [kConFab Investigators; Australian Ovarian Study Grp] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [Haiman, Christopher A.; Henderson, Brian E.; Schumacher, Fredrick] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Le Marchand, Loic] Univ Hawaii, Canc Res Ctr, Program Epidemiol, Honolulu, HI 96822 USA. [Lindblom, Annika] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. [Margolin, Sara] Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden. [Hooning, Maartje J.; Martens, John W. M.] Erasmus MC Canc Inst, Dept Med Oncol, Family Canc Clin, Rotterdam, Netherlands. [Tilanus-Linthorst, Madeleine M. A.] Erasmus MC Canc Inst, Dept Surg Oncol, Rotterdam, Netherlands. [Collee, J. Margriet] Erasmus MC Canc Inst, Dept Clin Genet, Rotterdam, Netherlands. [Hopper, John L.; Apicella, Carmel; Giles, Graham G.; Milne, Roger L.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Biostat & Epidemiol, Melbourne, Vic, Australia. [Southey, Melissa C.; Tsimiklis, Helen] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia. [Giles, Graham G.; Milne, Roger L.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [McLean, Catriona] Alfred Hosp, Anat Pathol, Melbourne, Vic, Australia. [Toland, Amanda E.] Ohio State Univ, Ctr Comprehens Canc, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA. [Ambrosone, Christine B.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Yannoukakos, Drakoulis] Natl Ctr Sci Res Demokritos, IRRP, Mol Diagnost Lab, Athens, Greece. [Fasching, Peter A.; Haeberle, Lothar; Beckmann, Matthias W.] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Comprehens Canc Ctr Erlangen EMN, Dept Gynecol & Obstet, Erlangen, Germany. [Fasching, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. [Ekici, Arif B.] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Inst Human Genet, Erlangen, Germany. [Brenner, Hermann; Dieffenbach, Aida Karina; Arndt, Volker] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Stegmaier, Christa] Saarland Canc Registry, Saarbrucken, Germany. [Swerdlow, Anthony J.; Ashworth, Alan; Orr, Nick] Inst Canc Res, Div Breast Canc Res, London SW3 6JB, England. [Swerdlow, Anthony J.; Jones, Michael] Inst Canc Res, Div Genet & Epidemiol, London SW3 6JB, England. [Figueroa, Jonine; Brinton, Louise] NCI, Div Canc Epidemiol & Genet, Gaithersburg, MD USA. [Garcia-Closas, Montserrat] Inst Canc Res, Div Genet & Epidemiol, London SW3 6JB, England. [Garcia-Closas, Montserrat] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England. [Lubinski, Jan] M Sklodowska Curie Mem Canc Ctr, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Lubinski, Jan] Inst Oncol, Warsaw, Poland. [Dumont, Martine; Simard, Jacques] Ctr Hosp Univ Quebec, Res Ctr, Quebec City, PQ, Canada. [Dumont, Martine; Simard, Jacques] Univ Laval, Quebec City, PQ, Canada. [Winqvist, Robert; Pylkas, Katri] Univ Oulu, Dept Clin Chem, Lab Canc Genet & Tumor Biol, Oulu, Finland. [Winqvist, Robert; Pylkas, Katri] Univ Oulu, Oulu Univ Hosp, NordLab Oulu, Bioctr Oulu, Oulu, Finland. [Jukkola-Vuorinen, Arja] Univ Oulu, Dept Oncol, Oulu, Finland. [Grip, Mervi] Univ Oulu, Dept Surg, Oulu, Finland. [Brauch, Hiltrud] Univ Tubingen, German Canc Consortium DKTK, Dr Margarete Fischer Bosch Inst Clin Pharmacol St, Heidelberg, Germany. [Brauch, Hiltrud] German Canc Res Ctr, Heidelberg, Germany. [Bruening, Thomas] Inst Ruhr Univ Bochum IPA, Inst Prevent & Occupat Med German Social Accid In, Bochum, Germany. [Ko, Yon-Dschun] Johanniter Krankenhaus, Evangel Kliniken Bonn gGmbH, Dept Internal Med, Bonn, Germany. Deutsch Krebsforschungszentrum DKFZ, Mol Genet Breast Canc, Heidelberg, Germany. [Peterlongo, Paolo] Fdn Ist FIRC Oncol Mol, IFOM, Milan, Italy. [Manoukian, Siranoush] Fdn IRCCS INT, Dept Prevent & Predict Med, Unit Med Genet, Milan, Italy. [Radice, Paolo] Fdn IRCCS INT, Dept Prevent & Predict Med, Unit Mol Bases Genet Risk & Genet Testing, Milan, Italy. [Manoukian, Siranoush] Fdn IRCCS INT, Dept Prevent & Predict Med, Milan, Italy. [Bonanni, Bernardo] IEO, Div Canc Prevent & Genet, Milan, Italy. [Doerk, Thilo] Hannover Med Sch, Dept Radiat Oncol, Hannover, Germany. [Doerk, Thilo] Hannover Med Sch, Dept Obstet & Gynaecol, Hannover, Germany. [Antonenkova, Natalia] NN Alexandrov Res Inst Oncol & Med Radiol, Minsk, Byelarus. [Mannermaa, Arto; Kosma, Veli-Matti; Hartikainen, Jaana M.] Kuopio Univ Hosp, Imaging Ctr, Dept Clin Pathol, SF-70210 Kuopio, Finland. [Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M.] Kuopio Univ Hosp, Ctr Canc, SF-70210 Kuopio, Finland. [Mannermaa, Arto; Kosma, Veli-Matti; Hartikainen, Jaana M.] Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Kuopio, Finland. [Kataja, Vesa] Jyvaskyla Cent Hosp, Cent Finland Hosp Dist, Jyvaskyla, Finland. [Devilee, Peter] Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands. [Devilee, Peter] Leiden Univ, Med Ctr, Dept Pathol, Leiden, Netherlands. [Van Asperen, Christi J.] Leiden Univ, Med Ctr, Dept Clin Genet, Leiden, Netherlands. [Devilee, Peter] Leiden Univ, Med Ctr, Leiden, Netherlands. [Seynaeve, Caroline] Erasmus MC Daniel Den Hoed Canc Ctr, Dept Med Oncol, Family Canc Clin, Rotterdam, Netherlands. [Jakubowska, Anna; Lubinski, Jan; Jaworska-Bieniek, Katarzyna; Durda, Katarzyna] Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland. [Hamann, Ute; Torres, Diana] German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany. [Torres, Diana] Pontificia Univ Javeriana, Inst Human Genet, Bogota, Colombia. [Schmutzler, Rita K.] Univ Hosp Cologne, Dept Obstet & Gynaecol, Div Mol Gynecooncol, Cologne, Germany. [Schmutzler, Rita K.] Univ Hosp Cologne, Ctr Familial Breast & Ovarian Canc, Cologne, Germany. [Schmutzler, Rita K.] Univ Hosp Cologne, Ctr Integrated Oncol, Cologne, Germany. [Schmutzler, Rita K.] Univ Cologne, Ctr Mol Med Cologne, D-50931 Cologne, Germany. [Neuhausen, Susan L.] City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Duarte, CA 91010 USA. [Anton-Culver, Hoda] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA. [Kristensen, Vessela N.; Alnaes, Grethe I. Grenaker] Oslo Univ Hosp, Radiumhosp, Inst Canc Res, Dept Genet, Oslo, Norway. [Kristensen, Vessela N.] Univ Oslo, Inst Clin Med, Oslo, Norway. [Kristensen, Vessela N.] Univ Oslo, Dept Clin Mol Biol, Oslo, Norway. [Pierce, Brandon L.; Ahsan, Habibul] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. [Kraft, Peter; Lindstrom, Sara; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Program Genet Epidemiol & Stat Genet, Boston, MA 02115 USA. [Peters, Ulrike] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Seminara, Daniela] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Burgess, Stephen] Univ Cambridge, Dept Publ Hlth & Primary Care, Strangeways Res Lab, Cambridge, England. [Ahsan, Habibul] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Ahsan, Habibul] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Ahsan, Habibul] Univ Chicago, Ctr Comprehens Canc, Chicago, IL 60637 USA. [Whittemore, Alice S.; John, Esther M.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Whittemore, Alice S.; John, Esther M.] Stanford Univ, Sch Med, Stanford Canc Inst, Stanford, CA 94305 USA. [John, Esther M.] Canc Prevent Inst Calif, Fremont, CA USA. [Gammon, Marilie D.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Malone, Kathleen E.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Program Epidemiol, Seattle, WA 98104 USA. [Tessier, Daniel C.; Vincent, Daniel; Bacot, Francois] McGill Univ, Montreal, PQ, Canada. [Tessier, Daniel C.; Vincent, Daniel; Bacot, Francois] Genome Quebec Innovat Ctr, Montreal, PQ, Canada. [Gonzalez-Neira, Anna; Pita, Guillermo; Rosario Alonso, M.; Alvarez, Nuria; Herrero, Daniel] Spanish Natl Canc Res Ctr, Human Canc Genet Program, Human Genotyping CEGEN Unit, Madrid, Spain. RP Zheng, W (reprint author), Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, 2525 West End Ave,Eighth Floor, Nashville, TN 37203 USA. EM wei.zheng@vanderbilt.edu RI Li, Jingmei/I-2904-2012; Bruning, Thomas/G-8120-2015; Andrulis, Irene/E-7267-2013; Knight, Julia/A-6843-2012; Hartikainen, Jaana/E-6256-2015; Dork, Thilo/J-8620-2012; Brenner, Hermann/B-4627-2017; manoukian, siranoush/E-7132-2017; OI Dunning, Alison Margaret/0000-0001-6651-7166; Burgess, Stephen/0000-0001-5365-8760; Li, Jingmei/0000-0001-8587-7511; Bruning, Thomas/0000-0001-9560-5464; Brenner, Hermann/0000-0002-6129-1572; manoukian, siranoush/0000-0002-6034-7562; dos Santos Silva, Isabel/0000-0002-6596-8798; Cox, Angela/0000-0002-5138-1099; Pierce, Brandon/0000-0002-7829-952X; Yannoukakos, Drakoulis/0000-0001-7509-3510 FU US National Institutes of Health (NIH) [R37CA070867]; Ingram Professorship endowment; Anne Potter Wilson endowment; European Community's Seventh Framework Programme [223175, HEALTH-F2-2009-223175]; European Community's Seventh Framework Programme (COGS) [223175 (HEALTH-F2-2009-223175)]; Cancer Research UK (CR-UK) [C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692]; National Institutes of Health [CA128978, R01 CA77398]; Post-Cancer GWAS initiative (GAME-ON 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; Breast Cancer Research Foundation; Ovarian Cancer Research Fund; National Cancer Institute (NCI) [U19 CA148065]; National Cancer Institute [UM1 CA164920]; National Health and Medical Research Council of Australia; New South Wales Cancer Council; Victorian Health Promotion Foundation (Australia); Victorian Breast Cancer Research Consortium; Dutch Cancer Society [NKI 2007-3839, 2009 4363, RUL 1997-1505, DDHK 2004-3124, DDHK 2009-4318]; BBMRI-NL - Dutch government [NWO 184.021.007]; Dutch National Genomics Initiative; ELAN-Fond of the University Hospital of Erlangen; Breakthrough Breast Cancer; National Health Service (NHS); CR-UK [C1287/A10118, C1287/A12014]; European Union European Cooperation in Science and Technology (COST) programme [BM0606]; NIHR Comprehensive Biomedical Research Centre; Guy's & St. Thomas' NHS Foundation Trust; King's College London, United Kingdom; Oxford Biomedical Research Centre; Dietmar-Hopp Foundation; Helmholtz Society; German Cancer Research Center (DKFZ); Fondation de France; Institut National du Cancer (INCa); Ligue Nationale contre le Cancer; Ligue contre le Cancer Grand Ouest; Agence Nationale de Securite Sanitaire (ANSES); Agence Nationale de la Recherche (ANR); Chief Physician Johan Boserup and Lise Boserup Fund; Danish Medical Research Council; Herlev Hospital; Genome Spain Foundation; Red Tematica de Investigacion Cooperativa en Cancer; Asociacion Espanola Contra el Cancer; Fondo de Investigacion Sanitario [PI11/00923, PI081120]; Instituto de Salud Carlos III; California Breast Cancer Act of 1993; California Breast Cancer Research Fund [97-10500]; Lon V Smith Foundation [LVS39420]; Baden Wurttemberg Ministry of Science, Research and Arts; German Cancer Aid (Deutsche Krebshilfe); Deutsche Krebshilfe [107 352]; Federal Ministry of Education and Research (BMBF) Germany [01KW9975/5, 01KW9976/8, 01KW9977/0, 01KW0114, 01KH0402]; Robert Bosch Foundation, Stuttgart; Deutsches Krebsforschungszentrum (DKFZ), Heidelberg; Institute for Prevention and Occupational Medicine of the German Social Accident Insurance (IPA), Bochum; Department of Internal Medicine; Evangelische Kliniken Bonn gGmbH; Johanniter Krankenhaus, Bonn, Germany; Helsinki University Central Hospital Research Fund; Academy of Finland [266528]; Finnish Cancer Society; Nordic Cancer Union; Sigrid Juselius Foundation; Friends of Hannover Medical School; Rudolf Bartling Foundation; Stockholm County Council; Karolinska Institutet; Swedish Cancer Society; Gustav V Jubilee Foundation; Bert von Kantzows Foundation; special Government Funding (EVO) of Kuopio University Hospital grants; Cancer Fund of North Savo; Finnish Cancer Organizations; University of Eastern Finland; National Breast Cancer Foundation; National Health and NHMRC; Queensland Cancer Fund; Cancer Council of New South Wales; Cancer Council of Victoria; Cancer Council of Tasmania; Cancer Council of South Australia; Cancer Foundation of Western Australia; NHMRC [145684, 288704, 454508, 199600]; United States Army Medical Research and Materiel Command [DAMD17-01-1-0729]; Cancer Council of Tasmania and Cancer Foundation of Western Australia; Stichting tegen Kanker [232-2008, 196-2010]; Flemish Fund for Scientific Research; KULPFV/10/016-SymBioSysII; Deutsche Krebshilfe e.V. [70-2892-BR I, 106332, 108253, 10841]; Hamburg Cancer Society; German Cancer Research Center; Italian Association for Cancer Research (AIRC); Fondazione IRCCS Istituto Nazionale Tumori; NIH [CA128978, CA116167, CA176785, CA63464, CA54281, CA098758, CA132839]; NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]; VicHealth; Cancer Council Victoria; Australian NHMRC [209057, 251553, 504711]; Quebec Breast Cancer Foundation; Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program [CRN-87521]; Ministry of Economic Development, Innovation and Export Trade [PSR-SIIRI-701]; Norwegian Research council [155218/V40, 175240/S10]; FUGE-NFR [181600/V11]; Swizz Bridge Award; Finnish Cancer Foundation; Academy of Finland; University of Oulu; Oulu University Hospital; Biobanking and Biomolecular Resources Research Infrastructure [BBMRI-NL CP16]; Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services; Marit and Hans Rausings Initiative Against Breast Cancer; Agency for Science, Technology and Research of Singapore (A*STAR); US National Institute of Health; Susan G. Komen Breast Cancer Foundation; Yorkshire Cancer Research [S295, S299, S305PA]; UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge; Cancer Research UK [C490/A10124]; DKFZ; Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]; Hellenic Cooperative Oncology Group research grant [HR R_BG/04]; Stefanie Spielman Breast Cancer fund; OSU Comprehensive Cancer Center; DBBR (a CCSG Share Resource by National Institutes of Health) [P30 CA016056]; Greek General Secretary for Research and Technology (GSRT) Program; Research Excellence II; European Union (European Social Fund); Greek national funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF), ARISTEIA; Institute of Cancer Research (ICR); NHS; [PBZ_KBN_122/P05/2004] FX The work for this project at Vanderbilt University was supported primarily by US National Institutes of Health (NIH) grant R37CA070867 and funds from Ingram Professorship and Anne Potter Wilson endowments. This work was partly supported by the European Community's Seventh Framework Programme under grant agreement number 223175 (grant number HEALTH-F2-2009-223175) (Collaborative Oncological Gene-Environment Study [COGS]). 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 (CR-UK; C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692), 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.; The Genetic Associations and Mechanisms in Oncology Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (GAME-ON DRIVE) Consortium was supported by National Cancer Institute (NCI) Grant number U19 CA148065. The work of the Breast Cancer Family Registry (BCFR) included in DRIVE was supported by grant UM1 CA164920 from the National Cancer Institute. 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 BCFR, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government or the BCFR.; The Australian Breast Cancer Family Study (ABCFS), NC-BCFR, and Ontario Familial Breast Cancer Registry (OFBCR) work was supported by grant UM1 CA164920 from the National Cancer Institute. The ABCFS was also supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia), and the Victorian Breast Cancer Research Consortium. John. L. Hopper is a National Health and Medical Research Council (NHMRC) Australia Fellow and a Victorian Breast Cancer Research Consortium Group Leader. Melissa C. Southey is an NHMRC Senior Research Fellow and a Victorian Breast Cancer Research Consortium Group Leader. The Amsterdam Breast Cancer Study (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 work of the Bavarian Breast Cancer Cases and Controls (BBCC) was partly funded by ELAN-Fond of the University Hospital of Erlangen. The Bavarian British Breast Cancer Study (BBCS) is funded by Cancer Research UK and Breakthrough Breast Cancer and acknowledges National Health Service (NHS) funding to the National Institute for Health Research (NIHR) Biomedical Research Centre, and the National Cancer Research Network (NCRN). The Breast Cancer Association Consortium (BCAC) is funded by CR-UK (C1287/A10118 and C1287/A12014). Meetings of BCAC have been funded by the European Union European Cooperation in Science and Technology (COST) programme (BM0606). Douglas F. Easton is a Principal Research Fellow of CR-UK. In the Breast Cancer in Galway Genetic Study (BIGGS), Elinor Sawyer is supported by NIHR Comprehensive Biomedical Research Centre, Guy's & St. Thomas' NHS Foundation Trust in partnership with King's College London, United Kingdom. Ian Tomlinson is supported by the Oxford Biomedical Research Centre. The Breast Cancer Study of the University of Heidelberg (BSUCH) study was supported by the Dietmar-Hopp Foundation, the Helmholtz Society, and the German Cancer Research Center (DKFZ).; The CECILE Breast Cancer Study was funded by Fondation de France, Institut National du Cancer (INCa), Ligue Nationale contre le Cancer, Ligue contre le Cancer Grand Ouest, Agence Nationale de Securite Sanitaire (ANSES), Agence Nationale de la Recherche (ANR). The Copenhagen General Population Study (CGPS) was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council, and Herlev Hospital. The Spanish National Cancer Centre Breast Cancer Study (CNIO-BCS) was supported by the Genome Spain Foundation, the Red Tematica de Investigacion Cooperativa en Cancer, and grants from the Asociacion Espanola Contra el Cancer and the Fondo de Investigacion Sanitario (PI11/00923 and PI081120). The Human Genotyping-CEGEN Unit (CNIO) is supported by the Instituto de Salud Carlos III. The California Teachers Study (CTS) was initially supported by the California Breast Cancer Act of 1993 and the California Breast Cancer Research Fund (contract 97-10500) and is currently funded through the National Institutes of Health (R01 CA77398). Collection of cancer incidence data was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885. Hoda Anton-Culver receives support from the Lon V Smith Foundation (LVS39420). The Esther Breast Cancer Study (ESTHER) study was supported by a grant from the Baden Wurttemberg Ministry of Science, Research and Arts. Additional case patients were recruited in the context of the Verlauf der diagnostischen Abklarung study, which was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe). The German Consortium for Hereditary Breast & Ovarian Cancer (GC-HBOC) was supported by Deutsche Krebshilfe (107 352). The Gene Environment Interaction and Breast Cancer in Germany (GENICA) was funded by the Federal Ministry of Education and Research (BMBF) Germany grants 01KW9975/5, 01KW9976/8, 01KW9977/0, and 01KW0114, the Robert Bosch Foundation, Stuttgart, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Institute for Prevention and Occupational Medicine of the German Social Accident Insurance (IPA), Bochum, as well as the Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany. The Helsinki Breast Cancer Study (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 Hannover-Minsk Breast Cancer Study (HMBCS) was supported by a grant from the Friends of Hannover Medical School and by the Rudolf Bartling Foundation. Financial support for Karolinska Breast Cancer Study (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 Kuopio Breast Cancer Project (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.; The Kathleen Cuningham Foundation Consortium for research into Familial Breast Cancer (kConFab) is supported by a grant from the National Breast Cancer Foundation, and previously by the National Health and NHMRC, the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia, and the Cancer Foundation of Western Australia. The kConFab Clinical Follow Up Study was funded by the NHMRC (145684, 288704, 454508). Financial support for the Australian Ovarian Cancer Study (AOCS) was provided by the United States Army Medical Research and Materiel Command (DAMD17-01-1-0729), the Cancer Council of Tasmania and Cancer Foundation of Western Australia, and the NHMRC [199600]. Georgia Chenevix-Trench and Penelope M. Webb are supported by the NHMRC. Leuven Multidisciplinary Breast Centre (LMBC) is supported by the 'Stichting tegen Kanker' (232-2008 and 196-2010). Diether Lambrechts is supported by the Flemish Fund for Scientific Research and the KULPFV/10/016-SymBioSysII. The Mammary Carcinoma Risk Factor Investigation (MARIE) study was supported by the Deutsche Krebshilfe e.V. (70-2892-BR I, 106332, 108253, 10841), the Hamburg Cancer Society, the German Cancer Research Center, and the Federal Ministry of Education and Research (BMBF) Germany (01KH0402). Milan Breast Cancer Study Group (MBCSG) is supported by grants from the Italian Association for Cancer Research (AIRC) and by funds from the Italian citizens who allocated the 5/1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects "5x1000"). The Mayo Clinic Breast Cancer Study (MCBCS) Clinic Breast Cancer Study (MCBCS) was supported by the NIH grants CA128978, CA116167, CA176785, an NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), the Breast Cancer Research Foundation, and a generous gift from the David F. and Margaret T. Grohne Family Foundation and the Ting Tsung and Wei Fong Chao Foundation. Melbourne Collaborative Cohort Study (MCCS) cohort recruitment in the study was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057, 251553, and 504711 and by infrastructure provided by Cancer Council Victoria. The Multi-ethnic Cohort (MEC) was support by NIH grants CA63464, CA54281, CA098758, and CA132839. The work of Montreal Gene-Environment Breast Cancer Study (MTLGEBCS) was supported by the Quebec Breast Cancer Foundation, the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program (grant number CRN-87521), and the Ministry of Economic Development, Innovation and Export Trade (grant number PSR-SIIRI-701). The Norwegian Breast Cancer Study was supported by grants from the Norwegian Research council, 155218/V40, 175240/S10 to ALBD, FUGE-NFR 181600/V11 to VNK and a Swizz Bridge Award to ALBD. The Oulu Breast Cancer Study (OBCS) was supported by research grants from the Finnish Cancer Foundation, the Academy of Finland, the University of Oulu, and the Oulu University Hospital. The OFBCR was supported by grant UM1 CA164920 from the National Cancer Institute. The Leiden University Medical Centre Breast Cancer Study (ORIGO) study was supported by the Dutch Cancer Society (RUL 1997-1505) and the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL CP16).; The NCI Polish Breast Cancer Study (PBCS) was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services. The Karolinska Mammography Project for Risk Prediction of Breast Cancer - prevalent cases (pKARMA) study was supported by Marit and Hans Rausings Initiative Against Breast Cancer. The Rotterdam Breast Cancer Study (RBCS) was funded by the Dutch Cancer Society (DDHK 2004-3124, DDHK 2009-4318). The Singapore and Sweden Breast Cancer Study (SASBAC) study was supported by funding from the Agency for Science, Technology and Research of Singapore (A*STAR), the US National Institute of Health, and the Susan G. Komen Breast Cancer Foundation. The Sheffield Breast Cancer Study (SBCS) was supported by Yorkshire Cancer Research S295, S299, and S305PA. Study of Epidemiology and Risk factors in Cancer Heredity (SEARCH) is funded by a program 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. Stadtisches Klinikum Karlsruhe Deutsches Krebsforschungszentrum Study (SKKDKFZS) is supported by the DKFZ. The IHCC-Szczecin Breast Cancer Study (SZBCS) was supported by Grant PBZ_KBN_122/P05/2004. The Triple Negative Breast Cancer Consortium Study (TNBCC) was supported by: a Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a grant from the Breast Cancer Research Foundation, a generous gift from the David F. and Margaret T. Grohne Family Foundation and the Ting Tsung and Wei Fong Chao Foundation, the Stefanie Spielman Breast Cancer fund and the OSU Comprehensive Cancer Center, DBBR (a CCSG Share Resource by National Institutes of Health Grant P30 CA016056), the Hellenic Cooperative Oncology Group research grant (HR R_BG/04) and the Greek General Secretary for Research and Technology (GSRT) Program, Research Excellence II, the European Union (European Social Fund), and Greek national funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF), ARISTEIA. The UK Breakthrough Generations Study (UKBGS) is funded by Breakthrough Breast Cancer and the Institute of Cancer Research (ICR). ICR acknowledges NHS funding to the NIHR Biomedical Research Centre. NR 74 TC 6 Z9 6 U1 3 U2 16 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 NOV PY 2015 VL 107 IS 11 AR djv219 DI 10.1093/jnci/djv219 PG 17 WC Oncology SC Oncology GA CZ2YZ UT WOS:000366972300027 ER PT J AU Yekta, Z Xie, DW Bogner, HR Weber, DR Zhang, XZ Harhay, M Reese, PP AF Yekta, Zahra Xie, Dawei Bogner, Hillary R. Weber, David R. Zhang, Xinzhi Harhay, Michael Reese, Peter P. TI The association of antidepressant medications and diabetic retinopathy among people with diabetes SO JOURNAL OF DIABETES AND ITS COMPLICATIONS LA English DT Article DE Antidepressant medication; Retinopathy; Type 2 diabetes; Pharmacoepidemiology; Depression ID C-REACTIVE PROTEIN; SEROTONIN REUPTAKE INHIBITORS; INFLAMMATORY MARKERS; ENDOTHELIAL DYSFUNCTION; DEPRESSIVE SYMPTOMS; PROSPECTIVE COHORT; NITRIC-OXIDE; EXPRESSION; AMITRIPTYLINE; COMPLICATIONS AB Objective: To determine if the use of antidepressants was associated with lower odds of diabetic retinopathy and if so, to determine if this association was mediated by decreased inflammation as measured by C-reactive protein (CRP). Design: This was a cross sectional study of 1,041 participants with type 2 diabetes 40-85 years old from the 2005-2008 National Health and Nutrition Examination Survey (NHANES). Multiple logistic regression was used to examine the association between the outcome of diabetic retinopathy and the primary exposure of antidepressant medication usage. We also determined whether CRP meets standard criteria as a mediator between antidepressant use and diabetic retinopathy. Results: Participants using antidepressants were less likely to have diabetic retinopathy (OR 0.50, 95% CI: 0.31-0.82). CRP did not meet one of the criteria for mediation. However, CRP was an effect modifier such that the association of antidepressant use and diabetic retinopathy was only present among participants with CRP mg/d1. Among the antidepressant drug classes, selective serotonin reuptake inhibitor (SSRI) users had significantly lower odds of developing diabetic retinopathy compared to non-users of antidepressants. Conclusions: Using representative survey data of US adults with type-2 diabetes, this study found that antidepressant use was associated with lower odds of diabetic retinopathy. Further longitudinal and experimental studies are necessary to confirm this finding and to determine if there is a role for antidepressants in preventing diabetic retinopathy in select patient populations. (C) 2015 Elsevier Inc. All rights reserved. C1 [Yekta, Zahra; Xie, Dawei; Bogner, Hillary R.; Harhay, Michael; Reese, Peter P.] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Weber, David R.] Univ Rochester, Sch Med & Dent, Rochester, NY 14627 USA. [Zhang, Xinzhi] NIH, Bethesda, MD 20892 USA. [Reese, Peter P.] Univ Penn, Perelman Sch Med, Renal Electrolyte & Hypertens Div, Philadelphia, PA 19104 USA. RP Yekta, Z (reprint author), Univ Penn, 917 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM yekta@mail.med.upenn.edu; dxie@mail.med.upenn.edu; bogner@mail.med.upenn.edu; david_weber@urmc.rochester.edu; xinzhi.zhang@nih.gov; mharhay@mail.med.upenn.edu; peter.reese@uphs.upenn.edu OI Harhay, Michael/0000-0002-0553-674X NR 47 TC 2 Z9 2 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1056-8727 EI 1873-460X J9 J DIABETES COMPLICAT JI J. Diabetes Complications PD NOV-DEC PY 2015 VL 29 IS 8 BP 1077 EP 1084 DI 10.1016/j.jdiacomp.2015.06.009 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CZ1SF UT WOS:000366884900019 PM 26233573 ER PT J AU Kosa, P Komori, M Waters, R Wu, TX Cortese, I Ohayon, J Fenton, K Cherup, J Gedeon, T Bielekova, B AF Kosa, Peter Komori, Mika Waters, Ryan Wu, Tianxia Cortese, Irene Ohayon, Joan Fenton, Kaylan Cherup, Jamie Gedeon, Tomas Bielekova, Bibiana TI Novel composite MRI scale correlates highly with disability in multiple sclerosis patients SO MULTIPLE SCLEROSIS AND RELATED DISORDERS LA English DT Article DE Multiple sclerosis; MRI; Clinical disability ID DISEASE SEVERITY SCALE; BRAIN ATROPHY; FOLLOW-UP; LESION LOAD; COGNITIVE IMPAIRMENT; CLINICAL PROGRESSION; RELAPSE ONSET; CORD ATROPHY; EDSS; ABNORMALITIES AB Understanding genotype-phenotype relationships or development/validation of biomarkers requires large multicenter cohorts integrated by universal quantification of crucial phenotypical traits, such as central nervous system (CNS) tissue destruction. We hypothesized that mathematical modeling-guided combination of biologically meaningful, semi-quantitative MRI elements characterized by high signal-to-noise ratio will provide such reliable, universal tool for measuring CNS tissue destruction. We retrospectively graded 15 elements in MRI scans performed in 419 untreated subjects with or without neurological diseases, while being blinded to their prospectively acquired clinical scores. We then used 305 subjects for disability-guided mathematical modeling to select and combine MRI elements that had non-redundant contributions to clinical disability, resulting in Combinatorial MRI Scale (COMRIS). We validated our model on the remaining 114 independent subjects. COMRIS requires 5-10 min per scan on average to compute and demonstrates highly significant (p < 0.0001) and validation-consistent Spearman correlation coefficients (0.75, 0.76, and 0.65) for the expanded disability status scale (EDSS), Scripps neurological rating scale (SNRS), and symbol digit modality test (SDMT) measures of neurological disability, respectively. Because COMRIS is not greatly influenced by MRI scanners or protocols and can be computed even in the presence of some motion artifacts, it does not require censoring out patients and it provides comparable results across different cohorts. As such, it represents a broadly available clinical and research tool that can facilitate multicenter research studies and comparative analyses across patient cohorts and research projects. Published by Elsevier B.V. C1 [Kosa, Peter; Komori, Mika; Cherup, Jamie; Bielekova, Bibiana] Natl Inst Neurol Disorders & Stroke, Neuroimmunol Dis Unit, NIH, Bethesda, MD USA. [Waters, Ryan; Gedeon, Tomas] Montana State Univ, Dept Math Sci, Bozeman, MT 59717 USA. [Wu, Tianxia] Natl Inst Neurol Disorders & Stroke, Clin Neurosci Program, NIH, Bethesda, MD USA. [Cortese, Irene; Ohayon, Joan; Fenton, Kaylan] Natl Inst Neurol Disorders & Stroke, Neuroimmunol Clin, NIH, Bethesda, MD USA. RP Bielekova, B (reprint author), Natl Inst Neurol Disorders & Stroke, Neuroimmunol Dis Unit, NIH, Bldg 10,Room 5C103, Bethesda, MA 20892 USA. EM kosap@mail.nih.gov; mika.komori2@nih.gov; waters@math.montana.edu; wuti@mail.nih.gov; corteseir@ninds.nih.gov; ohayonj@ninds.nih.gov; kaylan.fenton@gmail.com; jamie.cherup@nih.gov; Gedeon@math.montana.edu; Bibi.Bielekova@nih.gov FU National Institute of Neurological Disorders and Stroke of the National Institutes of Health FX This work was supported by the Intramural research program of the National Institute of Neurological Disorders and Stroke of the National Institutes of Health. We thank Govind Bhagavatheeshwaran, Alison Wichman, and Muktha Natrajan for critical review of the manuscript and clinical team members who did not fulfill co-authorship criteria (Jenifer Dwyer, Alison Wichman and Anne Mayfield) for expert patient care and support. NR 43 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2211-0348 EI 2211-0356 J9 MULT SCLER RELAT DIS JI Mult. Scler. Relat. Disord. PD NOV PY 2015 VL 4 IS 6 BP 526 EP 535 DI 10.1016/j.msard.2015.08.009 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA CZ2QL UT WOS:000366949600009 PM 26590659 ER PT J AU Schweitzer, JB Riggins, T Ross, TJ Black, MM Salmeron, BJ AF Schweitzer, Julie B. Riggins, Tracy Ross, Thomas J. Black, Maureen M. Salmeron, Betty Jo TI Interpretation of prenatal drug exposure functional imaging data SO NEUROTOXICOLOGY AND TERATOLOGY LA English DT Letter ID COCAINE EXPOSURE C1 [Schweitzer, Julie B.] Univ Calif Davis, Sch Med, Dept Psychiat & Behav Sci, Sacramento, CA 95817 USA. [Schweitzer, Julie B.] Univ Calif Davis, Sch Med, MIND Inst, Sacramento, CA 95817 USA. [Riggins, Tracy] Univ Maryland Coll Pk, Dept Psychol, College Pk, MD USA. [Riggins, Tracy; Ross, Thomas J.; Salmeron, Betty Jo] Natl Inst Drug Abuse, Intramural Res Program, Neuroimaging Res Branch, Bethesda, MD USA. [Black, Maureen M.] Univ Maryland, Sch Med, Dept Pediat, College Pk, MD USA. RP Schweitzer, JB (reprint author), Univ Calif Davis, MIND Inst, 2825 50th St, Sacramento, CA 95817 USA. EM Jschwetizer@ucdavis.edu RI Salmeron, Betty Jo/M-1793-2016 OI Salmeron, Betty Jo/0000-0003-1699-9333 FU Intramural NIH HHS; NIDA NIH HHS [R01 DA021059, R01 DA07432] NR 6 TC 0 Z9 0 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0892-0362 EI 1872-9738 J9 NEUROTOXICOL TERATOL JI Neurotoxicol. Teratol. PD NOV-DEC PY 2015 VL 52 BP 58 EP 59 DI 10.1016/j.ntt.2015.10.006 PN A PG 2 WC Neurosciences; Toxicology SC Neurosciences & Neurology; Toxicology GA CZ4YE UT WOS:000367108300009 PM 26518758 ER PT J AU Behl, M Hsieh, JH Shafer, TJ Mundy, WR Rice, JR Boyd, WA Freedman, JH Hunter, ES Jarema, KA Padilla, S Tice, RR AF Behl, Mamta Hsieh, Jui-Hua Shafer, Timothy J. Mundy, William R. Rice, Julie R. Boyd, Windy A. Freedman, Jonathan H. Hunter, E. Sidney, III Jarema, Kimberly A. Padilla, Stephanie Tice, Raymond R. TI Use of alternative assays to identify and prioritize organophosphorus flame retardants for potential developmental and neurotoxicity SO NEUROTOXICOLOGY AND TERATOLOGY LA English DT Article DE Flame retardants; neurotoxicity; developmental toxicity; embryonic stem cells; Caenorhabditis elegans; zebrafish ID NEMATODE CAENORHABDITIS-ELEGANS; MESSENGER-RNA EXPRESSION; MICROELECTRODE ARRAYS; LOCOMOTOR-ACTIVITY; BRAIN-DEVELOPMENT; THYROID-HORMONE; PHASE-OUT; EXPOSURE; ZEBRAFISH; PHOSPHATE AB Due to their toxicity and persistence in the environment, brominated flame retardants (BFRs) are being phased out of commercial use, leading to the increased use of alternative chemicals such as the organophosphorus flame retardants (OPERs). There is, however, limited information on the potential health effects of OPFRs. Due to the structural similarity of the OPFRs to organophosphorus insecticides, there is concern regarding developmental toxicity and neurotoxicity. In response, we evaluated a set of OPERs (triphenyl phosphate [TPHP]), isopropylated phenyl phosphate [IPP], 2-ethylhexyl diphenyl phosphate [EHDP], tert-butylated phenyl diphenyl phosphate [BPDP], trimethyl phenyl phosphate [TMPP], isodecyl diphenyl phosphate [IDDP], (tris(1,3-dichloroisopropyl) phosphate [TDCIPP], and tris(2-chloroethyl)phosphate [TCEP]) in a battery of cell-based in vitro assays and alternative model organisms and compared the results to those obtained for two classical BFRs (3,3',5,5'-tetrabromobisphenol A [TBBPA] and 2,2'4,4'-brominated diphenyl ether [BDE-47]). The assays used evaluated the effects of chemicals on the differentiation of mouse embryonic stem cells, the proliferation and growth of human neural stem cells, rat neuronal growth and network activity, and development of nematode (Caenorhabditis elegans) and zebrafish (Danio rerio). All assays were performed in a concentration-response format, allowing for the determination of the point of departure (POD: the lowest concentration where a chemically-induced response exceeds background noise). The majority of OPERs (8/9) were active in multiple assays in the range of 1-10 mu M, most of which had comparable activity to the BFRs TBBPA and BDE-47. TCEP was negative in all assays. The results indicate that the replacement OPFRs, with the exception of TCEP, showed comparable activity to the two BFRs in the assays tested. Based on these results, more comprehensive studies are warranted to further characterize the potential hazard of some of these OPFR compounds. Published by Elsevier Inc. C1 [Behl, Mamta; Rice, Julie R.; Boyd, Windy A.; Tice, Raymond R.] NIEHS, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Shafer, Timothy J.; Mundy, William R.; Hunter, E. Sidney, III; Jarema, Kimberly A.; Padilla, Stephanie] US EPA, Integrated Syst Toxicol Div, Off Res & Dev, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. [Freedman, Jonathan H.] Univ Louisville, Hlth Sci Ctr, Dept Pharmacol & Toxicol, Louisville, KY 40292 USA. [Hsieh, Jui-Hua] Kelly Govt Solut, Res Triangle Pk, NC USA. RP Behl, M (reprint author), NIEHS, Div Natl Toxicol Program, POB 12233, Res Triangle Pk, NC 27709 USA. EM behlmv@niehs.nih.gov OI Boyd, Windy/0000-0003-3803-3716 NR 66 TC 17 Z9 17 U1 15 U2 52 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0892-0362 EI 1872-9738 J9 NEUROTOXICOL TERATOL JI Neurotoxicol. Teratol. PD NOV-DEC PY 2015 VL 52 SI SI BP 181 EP 193 DI 10.1016/j.ntt.2015.09.003 PN B PG 13 WC Neurosciences; Toxicology SC Neurosciences & Neurology; Toxicology GA CZ4YF UT WOS:000367108400009 PM 26386178 ER PT J AU Jarema, KA Hunter, DL Shaffer, RM Behl, M Padilla, S AF Jarema, Kimberly A. Hunter, Deborah L. Shaffer, Rachel M. Behl, Mamta Padilla, Stephanie TI Acute and developmental behavioral effects of flame retardants and related chemicals in zebrafish SO NEUROTOXICOLOGY AND TERATOLOGY LA English DT Article DE Zebrafish; Neurotoxicity; Flame retardants; Developmental; Acute ID INDUCED DELAYED NEUROTOXICITY; HALOGENATED BISPHENOL-A; JUVENILE RAT-BRAIN; DANIO-RERIO; LARVAL ZEBRAFISH; CHLORPYRIFOS EXPOSURE; LOCOMOTOR-ACTIVITY; PENTABDE REPLACEMENT; TRIPHENYL PHOSPHATE; HEPTACHLOR EXPOSURE AB As polybrominated diphenyl ethers are phased out, numerous compounds are emerging as potential replacement flame retardants for use in consumer and electronic products. Little is known, however, about the neurobehavioral toxicity of these replacements. This study evaluated the neurobehavioral effects of acute or developmental exposure to t-butylphenyl diphenyl phosphate (BPDP), 2-ethylhexyl diphenyl phosphate (EHDP), isodecyl diphenyl phosphate (IDDP), isopropylated phenyl phosphate (IPP), tricresyl phosphate (TMPP; also abbreviated TCP), triphenyl phosphate (TPHP; also abbreviated TPP), tetrabromobisphenol A (TBBPA), tris (2-chloroethyl) phosphate (TCEP), tris (1,3-dichloroisopropyl) phosphate (TDCIPP; also abbreviated TDCPP), tri-o-cresyl phosphate (TOCP), and 2,2-,4,4'-tetrabromodiphenyl ether (BDE-47) in zebrafish (Danio redo) larvae. Larvae (n approximate to 24 per dose per compound) were exposed to test compounds (0.4-120 mu M) at subteratogenic concentrations either developmentally or acutely, and locomotor activity was assessed at 6 days post fertilization. When given developmentally, all chemicals except BPDP, IDDP and TBBPA produced behavioral effects. When given acutely, all chemicals produced behavioral effects, with TPHP, TBBPA, EHDP, IPP, and BPDP eliciting the most effects at the most concentrations. The results indicate that these replacement flame retardants may have developmental or pharmacological effects on the vertebrate nervous system. Published by Elsevier Inc. C1 [Jarema, Kimberly A.] US EPA, Toxicol Assessment Div, NHEERL, Res Triangle Pk, NC 27711 USA. [Hunter, Deborah L.; Shaffer, Rachel M.; Padilla, Stephanie] US EPA, Integrated Syst Toxicol Div, NHEERL, Res Triangle Pk, NC 27711 USA. [Shaffer, Rachel M.] Univ N Carolina, Sch Med, Curriculum Toxicol, Chapel Hill, NC USA. [Behl, Mamta] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Padilla, S (reprint author), US EPA, Integrated Syst Toxicol Div, NHEERL, Res Triangle Pk, NC 27711 USA. EM Padilla.stephanie@epa.gov OI Shaffer, Rachel/0000-0003-2917-7865 FU NIEHS NIH HHS [T32 ES007126] NR 87 TC 12 Z9 12 U1 11 U2 30 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0892-0362 EI 1872-9738 J9 NEUROTOXICOL TERATOL JI Neurotoxicol. Teratol. PD NOV-DEC PY 2015 VL 52 SI SI BP 194 EP 209 DI 10.1016/j.ntt.2015.08.010 PN B PG 16 WC Neurosciences; Toxicology SC Neurosciences & Neurology; Toxicology GA CZ4YF UT WOS:000367108400010 PM 26348672 ER PT J AU Fang, EF Scheibye-Knudsen, M Jahn, HJ Li, J Ling, L Guo, HW Zhu, XQ Preedy, V Lu, HM Bohr, VA Chan, WY Liu, YL Ng, TB AF Fang, Evandro Fei Scheibye-Knudsen, Morten Jahn, Heiko J. Li, Juan Ling, Li Guo, Hongwei Zhu, Xinqiang Preedy, Victor Lu, Huiming Bohr, Vilhelm A. Chan, Wai Yee Liu, Yuanli Ng, Tzi Bun TI A research agenda for aging in China in the 21st century SO AGEING RESEARCH REVIEWS LA English DT Review DE Aging; Public health; Chronic non-communicable diseases; Mental health; Geriatric care; Policy; Physical exercise; Pharmacological interventions ID CHRONIC NONCOMMUNICABLE DISEASES; HEALTH-CARE; OLDEST-OLD; HONG-KONG; DEPRESSIVE SYMPTOMS; RURAL CHINA; POPULATION; SYSTEM; POLICY; DEMENTIA AB China is encountering formidable healthcare challenges brought about by the problem of aging. By 2050, there will be 400 million Chinese citizens aged 65+, 150 million of whom will be 80+. The undesirable consequences of the one-child policy, rural-to-urban migration, and expansion of the population of 'empty nest' elders are eroding the traditional family care of the elders, further exacerbating the burden borne by the current public healthcare system. The challenges of geriatric care demand prompt attention by proposing strategies for improvement in several key areas. Major diseases of the elderly that need more attention include chronic non-communicable diseases and mental health disorders. We suggest the establishment of a home care-dominated geriatric care system, and a proactive role for researchers on aging in reforming geriatric care through policy dialogs. We propose ideas for preparation of the impending aging burden and the creation of a nurturing environment conducive to healthy aging in China. (C) 2015 Elsevier B.V. All rights reserved. C1 [Fang, Evandro Fei; Ng, Tzi Bun] Chinese Univ Hong Kong, Sch Biomed Sci, Fac Med, Hong Kong, Hong Kong, Peoples R China. [Fang, Evandro Fei; Scheibye-Knudsen, Morten; Lu, Huiming; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. [Jahn, Heiko J.] Univ Bielefeld, Dept Publ Hlth Med, Sch Publ Hlth, D-33615 Bielefeld, Germany. [Li, Juan] Chinese Acad Sci, Ctr Aging Psychol, Key Lab Mental Hlth, Inst Psychol, Beijing 100101, Peoples R China. [Ling, Li] Sun Yat Sen Univ, Dept Med Stat & Epidemiol, Sch Publ Hlth, Guangzhou 510080, Guangdong, Peoples R China. [Ling, Li] Sun Yat Sen Ctr Migrant Hlth Policy, Guangzhou 510080, Guangdong, Peoples R China. [Guo, Hongwei] Fudan Univ, Sch Publ Hlth, Shanghai 200032, Peoples R China. [Zhu, Xinqiang] Zhejiang Univ, Inst Nutr & Food Safety, Hangzhou 310058, Zhejiang, Peoples R China. [Zhu, Xinqiang] Zhejiang Univ, Dept Toxicol & Nutr, Sch Publ Hlth, Hangzhou 310058, Zhejiang, Peoples R China. [Preedy, Victor] Kings Coll London, Diabet & Nutr Sci Div, Sch Med, London WC2R 2LS, England. [Liu, Yuanli] Chinese Acad Med Sci, Peking Union Sch Publ Hlth, Beijing 100006, Peoples R China. [Liu, Yuanli] Peking Union Med Coll, Beijing 100006, Peoples R China. [Liu, Yuanli] Harvard TH Chan Sch Publ Hlth, Dept Global Hlth & Populat, Boston, MA 02115 USA. RP Liu, YL (reprint author), Chinese Acad Med Sci, Peking Union Sch Publ Hlth, Beijing 100006, Peoples R China. EM evandro.fang@nih.gov; scheibyem@mail.nih.gov; heiko.jahn@uni-bielefeld.de; lijuan@psych.ac.cn; lingli@mail.sysu.edu.cn; hwguo@shmu.edu.cn; zhuxq@zju.edu.cn; victor.preedy@kcl.ac.uk; huiming.lu@nih.gov; BohrV@grc.nia.nih.gov; chanwy@cuhk.edu.hk; yuanliu@hsph.harvard.edu; b021770@mailserv.cuhk.edu.hk OI Scheibye-Knudsen, Morten/0000-0002-6637-1280 FU Intramural Research Program of the NIH, National Institute on Ageing, USA [Z01-AG000723-02] FX This research was supported in part by the Intramural Research Program (Grant number: Z01-AG000723-02) of the NIH, National Institute on Ageing, USA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank Drs. Peter Sykora and Joseph Hsu at NIA, NIH for reading of the manuscript. NR 67 TC 6 Z9 6 U1 6 U2 27 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1568-1637 EI 1872-9649 J9 AGEING RES REV JI Ageing Res. Rev. PD NOV PY 2015 VL 24 BP 197 EP 205 DI 10.1016/j.arr.2015.08.003 PN B PG 9 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA CZ0AY UT WOS:000366768700009 PM 26304837 ER PT J AU van der Pals, J Hammer-Hansen, S Nielles-Vallespin, S Kellman, P Taylor, J Kozlov, S Hsu, LY Chen, MY Arai, AE AF van der Pals, Jesper Hammer-Hansen, Sophia Nielles-Vallespin, Sonia Kellman, Peter Taylor, Joni Kozlov, Shawn Hsu, Li-Yueh Chen, Marcus Y. Arai, Andrew E. TI Temporal and spatial characteristics of the area at risk investigated using computed tomography and T-1-weighted magnetic resonance imaging SO EUROPEAN HEART JOURNAL-CARDIOVASCULAR IMAGING LA English DT Article DE area at risk; myocardial perfusion; MRI; CT; myocardial infarction; myocardial ischaemia ID ACUTE MYOCARDIAL-INFARCTION; COLLATERAL BLOOD-FLOW; CORONARY-ARTERY OCCLUSION; LATTICE RELAXATION-TIMES; ISCHEMIC CELL-DEATH; END-CAPILLARY LOOPS; WAVEFRONT PHENOMENON; BORDER ZONE; DOG; HEART AB Aims Cardiovascular magnetic resonance (CMR) imaging can measure the myocardial area at risk (AAR), but the technique has received criticism for inadequate validation. CMR commonly depicts an AAR that is wider than the infarct, which in turn would require a lateral perfusion gradient within the AAR. We investigated the presence of a lateral perfusion gradient within the AAR and validated CMR measures of AAR against three independent reference standards of high quality. Methods and results Computed tomography (CT) perfusion imaging, microsphere blood flow analysis, T-1-weighted 3T CMR and fluorescent microparticle pathology were used to investigate the AAR in a canine model (n = 10) of ischaemia and reperfusion. AAR size by CMR correlated well with CT (R-2 = 0.80), microsphere blood flow (R-2 = 0.80), and pathology (R-2 = 0.74) with good limits of agreement [-0.79 +/- 4.02% of the left ventricular mass (LVM) vs. CT; -1.49 +/- 4.04% LVM vs. blood flow and -1.01 +/- 4.18% LVM vs. pathology]. The lateral portion of the AAR had higher perfusion than the core of the AAR by CT perfusion imaging (40.7 +/- 11.8 vs. 25.2 +/- 17.7 Hounsfield units, P = 0.0008) and microsphere blood flow (0.11 +/- 0.04 vs. 0.05 +/- 0.02 mL/g/min, lateral vs. core, P = 0.001). The transmural extent of MI was lower in the lateral portion of the AAR than the core (28.2 +/- 10.2 vs. 17.4 +/- 8.4% of the wall, P = 0.001). Conclusion T-1-weighted CMR accurately quantifies size of the AAR with excellent agreement compared with three independent reference standards. A lateral perfusion gradient results in lower transmural extent of infarction at the edges of the AAR compared with the core. C1 [van der Pals, Jesper; Hammer-Hansen, Sophia; Nielles-Vallespin, Sonia; Kellman, Peter; Taylor, Joni; Kozlov, Shawn; Hsu, Li-Yueh; Chen, Marcus Y.; Arai, Andrew E.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Arai, AE (reprint author), NHLBI, NIH, Bldg 10,Room B1D416,MSC 1061,10 Ctr Dr, Bethesda, MD 20892 USA. EM araia@nih.gov FU Division of Intramural Research, National Heart, Lung and Blood Institute, National Institutes of Health [ZIA HL004607-15, ZIC HL005909-06, ZIA HL006136-03, ZIA HL006138-03, ZIA HL006136-04]; National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, Maryland, USA FX This work was funded by the Division of Intramural Research, National Heart, Lung and Blood Institute, National Institutes of Health (grant numbers ZIA HL004607-15, ZIC HL005909-06, ZIA HL006136-03, ZIA HL006138-03 and ZIA HL006136-04). The contents and views of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. Funding to pay the Open Access publication charges for this article was provided by the National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, Maryland, USA. NR 31 TC 1 Z9 1 U1 1 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 2047-2404 EI 2047-2412 J9 EUR HEART J-CARD IMG JI Eur. Heart J.-Cardiovasc. Imaging PD NOV PY 2015 VL 16 IS 11 BP 1232 EP 1240 DI 10.1093/ehjci/jev072 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CY7KB UT WOS:000366586100015 PM 25881901 ER PT J AU Kuang, HY Jin, SS Thomas, T Engmann, L Hansen, KR Coutifaris, C Casson, P Christman, G Alvero, R Santoro, N Eisenberg, E Diamond, MP Legro, RS Zhang, HP AF Kuang, Hongying Jin, Susan Thomas, Tracey Engmann, Lawrence Hansen, Karl R. Coutifaris, Christos Casson, Peter Christman, Gregory Alvero, Ruben Santoro, Nanette Eisenberg, Esther Diamond, Michael P. Legro, Richard S. Zhang, Heping CA Reproductive Med Network TI Predictors of participant retention in infertility treatment trials SO FERTILITY AND STERILITY LA English DT Article DE Randomized controlled clinical trial; dropout; logistic regression; retention ID INTENT-TO-TREAT; CLINICAL-TRIAL; PREVENTION; RACE; RECRUITMENT; DISTRUST; REASONS; PROGRAM; DROPOUT AB Objective: To identify variables associated with retention (or dropout) in infertility clinical trials. Retention of subjects in randomized controlled clinical trials (RCTs) has received considerable attention, but there have been few consistent findings. Design: Secondary analysis of data from RCTs. Setting: Academic medical centers. Patient(s): Women with polycystic ovary syndrome (PCOS) or couples with unexplained infertility, aged 18-40 years. Intervention(s): This study is not an intervention study, but the patients in the original RCTs were treated with any or combination of metformin, clomiphene citrate (CC), letrozole, and gonadotropins. Main Outcome Measure(s): Successful retention versus dropout during the RCTs. Result(s): Race, ethnicity, body mass index (BMI), insurance coverage, history of smoking, and history of alcohol use were significantly associated with retention whether they were considered in bivariate analyses or a multivariable logistic model. Specifically, white race, higher income, having graduate degrees, normal weight, better insurance coverage, nonsmokers, and those who reported current use of alcohol at the start of the trial, had higher retention rates. Conclusion(s): We identified several additive and persistent predictors of retention that can be used to guide the conduct of RCTs and improve the retention rate. Given the limitation of our association analysis, methodologically sound and theoretically grounded research are warranted so that high quality data can be collected to improve our understanding on the causes of dropout. (C) 2015 by American Society for Reproductive Medicine. C1 [Kuang, Hongying] Affiliated Hosp 1, Dept Obstet & Gynecol, Harbin, Peoples R China. [Kuang, Hongying] Heilongjiang Univ Chinese Med, Harbin, Peoples R China. [Kuang, Hongying; Jin, Susan; Thomas, Tracey; Zhang, Heping] Yale Univ, Sch Publ Hlth, Dept Biostat, New Haven, CT 06520 USA. [Engmann, Lawrence] Univ Connecticut, Sch Med, Dept Obstet & Gynecol, Farmington, CT USA. [Hansen, Karl R.] Univ Oklahoma, Coll Med, Dept Obstet & Gynecol, Oklahoma City, OK 73190 USA. [Coutifaris, Christos] Univ Penn, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA. [Casson, Peter] Univ Vermont, Dept Obstet & Gynecol, Burlington, VT USA. [Christman, Gregory] Univ Florida, Dept Obstet & Gynecol, Shands Hosp, Gainesville, FL 32611 USA. [Alvero, Ruben; Santoro, Nanette] Univ Colorado, Dept Obstet & Gynecol, Aurora, CO USA. [Eisenberg, Esther] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Diamond, Michael P.] Georgia Regents Univ, Dept Obstet & Gynecol, Augusta, GA USA. [Legro, Richard S.] Penn State Coll Med, Dept Obstet & Gynecol, Hershey, PA USA. RP Zhang, HP (reprint author), Yale Univ, Sch Publ Hlth, Dept Biostat, New Haven, CT 06520 USA. EM Heping.Zhang@yale.edu OI Diamond, Michael/0000-0001-6353-4489 FU National Institutes of Health (NIH)/Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [U10 HD27049, U10 HD38992, U10HD055925, U10 HD39005, U10 HD33172, U10 HD38998, U10 HD055936, U10 HD055942, U10 HD055944, U54-HD29834]; American Recovery and Reinvestment Act; General Clinical Research Center Grants [MO1RR10732, C06 RR016499] FX Supported by National Institutes of Health (NIH)/Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Grants U10 HD27049 (to C.C.), U10 HD38992 (to R.S.L.), U10HD055925 (to H.Z.), U10 HD39005 (to M.P.D.), U10 HD33172 (to M.P.S.), U10 HD38998 (to W.D.S), U10 HD055936 (to G.M.C.), U10 HD055942 (to R.G.B.), and U10 HD055944 (to P.R.C.); U54-HD29834 (to the University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core of the Specialized Cooperative Centers Program in Reproduction and Infertility Research); Funds were received from American Recovery and Reinvestment Act. General Clinical Research Center Grants MO1RR10732 and construction grant C06 RR016499 (to Pennsylvania State University). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NICHD or NIH. NR 27 TC 1 Z9 1 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD NOV PY 2015 VL 104 IS 5 BP 1236 EP + DI 10.1016/j.fertnstert.2015.08.001 PG 10 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CY5ZK UT WOS:000366486400031 PM 26354094 ER PT J AU Vatsalya, V Gowin, JL Schwandt, ML Momenan, R Coe, MA Cooke, ME Hommer, DW Bartlett, S Heilig, M Ramchandani, VA AF Vatsalya, Vatsalya Gowin, Joshua L. Schwandt, Melanie L. Momenan, Reza Coe, Marion A. Cooke, Megan E. Hommer, Daniel W. Bartlett, Selena Heilig, Markus Ramchandani, Vijay A. TI Effects of Varenicline on Neural Correlates of Alcohol Salience in Heavy Drinkers SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Article DE Alcohol-Food Incentive Delay (AFID) task; intravenous (IV) infusion; heavy drinkers; neuroimaging; ventral striatum ID NICOTINIC ACETYLCHOLINE-RECEPTORS; USE DISORDERS; SMOKING-CESSATION; NUCLEUS-ACCUMBENS; DOPAMINE RELEASE; CONTROLLED-TRIAL; PARTIAL AGONIST; INSULA; ADDICTION; ANTICIPATION AB Background: Preclinical and emerging clinical evidence indicates that varenicline, a nicotinic partial agonist approved for smoking cessation, attenuates alcohol seeking and consumption. Reductions of alcohol craving have been observed under varenicline treatment and suggest effects of the medication on alcohol reward processing, but this hypothesis remains untested. Methods: In this double-blind, placebo-controlled randomized experimental medicine study, 29 heavy drinkers underwent a functional magnetic resonance imaging scan after 2 weeks of varenicline (2 mg/d) or placebo administration. During functional magnetic resonance imaging, participants performed the Alcohol-Food Incentive Delay task, where they could earn points for snacks or alcohol. At baseline and after 3 weeks of medication, participants underwent intravenous alcohol self-administration sessions in the laboratory. Results: During the functional magnetic resonance imaging scan, participants in the varenicline group (N = 17) reported lower feelings of happiness and excitement on subjective mood scales when anticipating alcohol reward compared with the placebo group (N = 12). Linear mixed effects analysis revealed that anticipation of alcohol reward was associated with significant blood oxygen level dependent activation of the ventral striatum, amygdala, and posterior insula in the placebo group; this activation was attenuated in the varenicline group. The varenicline group showed no difference in intravenous alcohol self-administration relative to the placebo group for either session. Participants with higher insula activation when anticipating alcohol reward showed higher alcohol self-administration behavior across groups. Conclusions: Our findings suggest that varenicline decreases blood oxygen level dependent activation in striato-corticolimbic regions associated with motivation and incentive salience of alcohol in heavy drinkers. This mechanism may underlie the clinical effectiveness of varenicline in reducing alcohol intake and indicates its potential utility as a pharmacotherapy for alcohol use disorders. C1 [Vatsalya, Vatsalya; Gowin, Joshua L.; Coe, Marion A.; Cooke, Megan E.; Ramchandani, Vijay A.] NIAAA, Sect Human Psychopharmacol, Lab Clin & Translat Studies, Bethesda, MD USA. [Schwandt, Melanie L.; Heilig, Markus] NIAAA, Lab Clin & Translat Studies, Bethesda, MD USA. [Momenan, Reza; Hommer, Daniel W.] NIAAA, Sect Brain Electrophysiol & Imaging, Lab Clin & Translat Studies, Bethesda, MD USA. [Bartlett, Selena] Queensland Univ Technol, Inst Hlth & Biomed Innovat, Translat Res Inst, Brisbane, Qld 4001, Australia. RP Ramchandani, VA (reprint author), 10 Ctr Dr,Rm 2-2352, Bethesda, MD 20892 USA. EM vijayr@mail.nih.gov RI Bartlett, Selena/J-1345-2012 OI Bartlett, Selena/0000-0002-1741-3958 FU NIAAA Division of Intramural Clinical and Biological Research [Z1A AA000466] FX This study was supported by the NIAAA Division of Intramural Clinical and Biological Research (Z1A AA000466). Medication supply was provided by Pfizer Inc. under agreement with Dr. Bartlett. Development of the CAIS software used for the IV-ASA session was supported by Sean O'Connor, MD, at the Indiana Alcohol Research Center (NIH P60 AA007611). NR 47 TC 1 Z9 1 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 NOV PY 2015 VL 18 IS 12 AR UNSP pyv068 DI 10.1093/ijnp/pyv068 PG 10 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CY6DV UT WOS:000366499000006 ER PT J AU Mohiuddin, MM Reichart, B Byrne, GW McGregor, CGA AF Mohiuddin, Muhammad M. Reichart, Bruno Byrne, Guerard W. McGregor, Christopher G. A. TI Current status of pig heart xenotransplantation SO INTERNATIONAL JOURNAL OF SURGERY LA English DT Review DE Cardiac xenotransplantation; Heterotopic; Orthotopic; Intrathoracic heterotopic; Anti CD40 antibody; Anti CD154 antibody; Anti CD20 antibody ID CARDIAC XENOGRAFT SURVIVAL; TO-BABOON MODEL; MECHANICAL CIRCULATORY SUPPORT; MEMBRANE COFACTOR PROTEIN; DECAY-ACCELERATING FACTOR; GENE-KNOCKOUT PIGS; COSTIMULATION BLOCKADE; TRANSGENIC EXPRESSION; HYPERACUTE REJECTION; NONHUMAN-PRIMATES AB Significant progress in understanding and overcoming cardiac xenograft rejection using a clinically relevant large animal pig-to-baboon model has accelerated in recent years. This advancement is based on improved immune suppression, which attained more effective regulation of B lymphocytes and possibly newer donor genetics. These improvements have enhanced heterotopic cardiac xenograft survival from a few weeks to over 2 years, achieved intrathoracic heterotopic cardiac xenograft survival of 50 days and orthotopic survival of 57 days. This encouraging progress has rekindled interest in xenotransplantation research and refocused efforts on preclinical orthotopic cardiac xenotransplantation. (C) 2015 IJS Publishing Group Limited. Published by Elsevier Ltd. All rights reserved. C1 [Mohiuddin, Muhammad M.] NHLBI, CSRP, NIH, Bethesda, MD 20892 USA. [Reichart, Bruno] Univ Munich, Walter Brendel Ctr Expt Med, Munich, Germany. [Byrne, Guerard W.; McGregor, Christopher G. A.] UCL, Inst Cardiovasc Sci, London, England. [Byrne, Guerard W.; McGregor, Christopher G. A.] Mayo Clin, Dept Surg, Rochester, MN USA. RP Mohiuddin, MM (reprint author), NHLBI, CSRP, NIH, Bldg 10,Rm B1D47G,10 Ctr Dr,MSC 1550, Bethesda, MD 20892 USA. EM mohiuddinm@mail.nih.gov RI Mohiuddin, Muhammad/M-4642-2013 OI Mohiuddin, Muhammad/0000-0003-4654-783X FU NHLBI/NIH [HHSN268201300001C]; Revivicor Inc; German Research Foundation [TRR127]; NIAID [AI066310]; National Institute for Health Research University College London Hospitals Biomedical Research Centre FX NHLBI/NIH (Mohiuddin) contract # HHSN268201300001C.; Revivicor Inc (Mohiuddin).; German Research Foundation (Bruno Reichart) TRR127.; NIAID (AI066310) (Guerard Byrne and Christopher McGregor).; National Institute for Health Research University College London Hospitals Biomedical Research Centre. (Guerard Byrne and Christopher McGregor). NR 56 TC 3 Z9 3 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1743-9191 EI 1743-9159 J9 INT J SURG JI Int. J. Surg. PD NOV PY 2015 VL 23 SI SI BP 234 EP 239 DI 10.1016/j.ijsu.2015.08.038 PN B PG 6 WC Surgery SC Surgery GA CY8ME UT WOS:000366661900008 PM 26318967 ER PT J AU Chiou, VL Burotto, M AF Chiou, Victoria L. Burotto, Mauricio TI Pseudoprogression and Immune-Related Response in Solid Tumors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID ADVANCED MELANOMA; ANTI-PD-L1 ANTIBODY; CLINICAL ACTIVITY; PHASE-I; CANCER; SAFETY; NIVOLUMAB; IPILIMUMAB; TRIAL; GUIDELINES C1 [Chiou, Victoria L.; Burotto, Mauricio] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Chiou, VL (reprint author), NCI, Ctr Canc Res, Bethesda, MD 20892 USA. EM mauricioburotto@yahoo.com NR 22 TC 44 Z9 44 U1 1 U2 2 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 NOV 1 PY 2015 VL 33 IS 31 BP 3541 EP + DI 10.1200/JCO.2015.61.6870 PG 5 WC Oncology SC Oncology GA CX9IU UT WOS:000366019800008 PM 26261262 ER PT J AU Ford, JS Chou, JF Sklar, CA Oeffinger, KC Friedman, DN McCabe, M Robison, LL Kleinerman, RA Li, YL Marr, BP Abramson, DH Dunkel, IJ AF Ford, Jennifer S. Chou, Joanne F. Sklar, Charles A. Oeffinger, Kevin C. Friedman, Danielle Novetsky McCabe, Mary Robison, Leslie L. Kleinerman, Ruth A. Li, Yuelin Marr, Brian P. Abramson, David H. Dunkel, Ira J. TI Psychosocial Outcomes in Adult Survivors of Retinoblastoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CHILDHOOD-CANCER SURVIVOR; LONG-TERM SURVIVORS; QUALITY-OF-LIFE; EVENT SCALE; HEREDITARY RETINOBLASTOMA; HOROWITZS IMPACT; INCREASED RISK; NETHERLANDS; LEUKEMIA; STRESS AB Purpose Survival rates for individuals diagnosed with retinoblastoma (RB) exceed 95% in the United States; however, little is known about the long-term psychosocial outcomes of these survivors. Patients and Methods Adult RB survivors, diagnosed from 1932 to 1994 and treated in New York, completed a comprehensive questionnaire adapted from the Childhood Cancer Survivor Study (CCSS), by mail or telephone. Psychosocial outcomes included psychological distress, anxiety, depression, somatization, fear of cancer recurrence, satisfaction with facial appearance, post-traumatic growth, and post-traumatic stress symptoms; noncancer CCSS siblings served as a comparison group. Results A total of 470 RB survivors (53.6% with bilateral RB; 52.1% female) and 2,820 CCSS siblings were 43.3 (standard deviation [SD], 11) years and 33.2 (SD, 8.4) years old at the time of study, respectively. After adjusting for sociodemographic factors, RB survivors did not have significantly higher rates of depression, somatization, distress, or anxiety compared with CCSS siblings. Although RB survivors were more likely to report post-traumatic stress symptoms of avoidance and/or hyperarousal (both P < .01), only five (1.1%) of 470 met criteria for post-traumatic stress disorder. Among survivors, having a chronic medical condition did not increase the likelihood of psychological problems. Bilateral RB survivors were more likely than unilateral RB survivors to experience fears of cancer recurrence (P < .01) and worry about their children being diagnosed with RB (P < .01). However, bilateral RB survivors were no more likely to report depression, anxiety, or somatic complaints than unilateral survivors. Conclusion Most RB survivors do not have poorer psychosocial functioning compared with a noncancer sample. In addition, bilateral and unilateral RB survivors seem similar with respect to their psychological symptoms. (C) 2015 by American Society of Clinical Oncology C1 [Ford, Jennifer S.; Chou, Joanne F.; Sklar, Charles A.; Oeffinger, Kevin C.; Friedman, Danielle Novetsky; McCabe, Mary; Li, Yuelin; Marr, Brian P.; Abramson, David H.] Mem Sloan Kettering Canc Ctr, New York, NY 10022 USA. [Ford, Jennifer S.; Sklar, Charles A.; Abramson, David H.; Dunkel, Ira J.] Weill Cornell Med Coll, New York, NY USA. [Robison, Leslie L.] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Kleinerman, Ruth A.] NCI, Bethesda, MD 20892 USA. RP Ford, JS (reprint author), Mem Sloan Kettering Canc Ctr, Dept Psychiat & Behav Sci, 641 Lexington Ave,7th Floor, New York, NY 10022 USA. EM fordj@mskcc.org RI Friedman, Danielle Novetsky/B-7551-2016; OI Friedman, Danielle Novetsky/0000-0003-4668-9176; Dunkel, Ira/0000-0001-8091-6067; Kleinerman, Ruth/0000-0001-7415-2478 FU New York Community Trust; Pearl Vision; Frueauff Foundation; Perry's Promise Fund; St Jude Grant [U24CA55727]; Memorial Sloan Kettering Cancer Grant [P30CA008748]; Memorial Sloan Kettering Cancer Center Grant [K05CA160724]; National Cancer Institute/National Institutes of Health of the Clinical Trial and Translational Science Center at Weill Cornell Medical College, the intramural program of the National Institutes of Health, National Cancer Institute [KL2TR000458] FX Supported by the New York Community Trust, Pearl Vision, Frueauff Foundation, Perry's Promise Fund, St Jude Grant No. U24CA55727 (G.T. Armstrong, principal investigator), Memorial Sloan Kettering Cancer Grant No. P30CA008748 (C.B. Thompson, principal investigator), and Memorial Sloan Kettering Cancer Center Grant No. K05CA160724 (K.C.O., principal investigator); D.N.F. is supported in part by National Cancer Institute/National Institutes of Health Grant No. KL2TR000458 of the Clinical Trial and Translational Science Center at Weill Cornell Medical College, the intramural program of the National Institutes of Health, National Cancer Institute. NR 30 TC 1 Z9 1 U1 0 U2 8 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 NOV 1 PY 2015 VL 33 IS 31 BP 3608 EP + DI 10.1200/JCO.2014.60.5733 PG 9 WC Oncology SC Oncology GA CX9IU UT WOS:000366019800017 PM 26417002 ER PT J AU Canepa, M AlGhatrif, M AF Canepa, Marco AlGhatrif, Majd TI From Arterial Stiffness to Heart Failure: Still a Long Way to Go SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Editorial Material ID PULSE-WAVE VELOCITY; CARDIOVASCULAR EVENTS; DIASTOLIC FUNCTION; EJECTION FRACTION; REFLECTIONS; WOMEN; MEN C1 [Canepa, Marco] Univ Genoa, Cardiovasc Unit, Dept Internal Med, I-16132 Genoa, Italy. [Canepa, Marco; AlGhatrif, Majd] NIA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Canepa, M (reprint author), Univ Genoa, IRCCS AOU San Martino IST, Dept Internal Med, Cardiovasc Unit, Viale Benedetto XV 6, I-16132 Genoa, Italy. EM marco.canepa@unige.it NR 14 TC 2 Z9 2 U1 0 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 NOV PY 2015 VL 4 IS 11 AR e002807 DI 10.1161/JAHA.115.002807 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CY7UU UT WOS:000366615600031 ER PT J AU Gooding, HC Shay, CM Ning, HY Gillman, MW Chiuve, SE Reis, JP Allen, NB Lloyd-Jones, DM AF Gooding, Holly C. Shay, Christina M. Ning, Hongyan Gillman, Matthew W. Chiuve, Stephanie E. Reis, Jared P. Allen, Norrina B. Lloyd-Jones, Donald M. TI Optimal Lifestyle Components in Young Adulthood Are Associated With Maintaining the Ideal Cardiovascular Health Profile Into Middle Age SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE cardiovascular disease; cardiovascular health; health behaviors; young adults ID ARTERY RISK DEVELOPMENT; PRIMARY PREVENTION; HEART-ASSOCIATION; PHYSICAL-ACTIVITY; FACTOR BURDEN; DISEASE RISK; ALL-CAUSE; MORTALITY; WOMEN; CARDIA AB Background-Middle-aged adults with ideal blood pressure, cholesterol, and glucose levels exhibit substantially lower cardiovascular mortality than those with unfavorable levels. Four healthy lifestyle components-optimal body weight, diet, physical activity, and not smoking-are recommended for cardiovascular health (CVH). This study quantified associations between combinations of healthy lifestyle components measured in young adulthood and loss of the ideal CVH profile into middle age. Methods and Results-Analyses included 2164 young adults in the Coronary Artery Risk Development in Young Adults study with the ideal CVH profile (defined as untreated blood pressure <120/80 mm Hg, total cholesterol <200 mg/dL, fasting blood glucose <100 mg/dL, and absence of cardiovascular disease) at baseline. Cox proportional hazards regression models estimated hazard ratios for loss of the ideal CVH profile over 25 years according to 4 individual and 16 combinations of optimal healthy lifestyle components measured in young adulthood: body mass index, physical activity, nonsmoking status, and diet quality. Models were adjusted for age, sex, race, education, study center, and baseline blood pressure, cholesterol, and glucose. Eighty percent (n=1737) of participants lost the ideal CVH profile by middle age; loss was greatest for young adults with no optimal healthy lifestyle components at baseline. Relative to young adults with no optimal healthy lifestyle components, those with all 4 were less likely to lose the ideal CVH profile (hazard ratio 0.59, 95% CI 0.44-0.80). Combinations that included optimal body mass index and nonsmoking status were each associated with lower risk. Conclusions-Optimal body mass index and not smoking in young adulthood were protective against loss of the ideal CVH profile through middle age. Importance of diet and physical activity may be included through their effects on healthy weight. C1 [Gooding, Holly C.] Harvard Univ, Sch Med, Div Adolescent, Young Adult Med,Boston Childrens Hosp, Boston, MA 02115 USA. [Gillman, Matthew W.] Harvard Univ, Sch Med, Harvard Pilgrim Healthcare Inst, Dept Populat Med, Boston, MA USA. [Shay, Christina M.] Univ N Carolina, Gillings Sch Global Hlth, Chapel Hill, NC USA. [Ning, Hongyan; Allen, Norrina B.; Lloyd-Jones, Donald M.] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Chiuve, Stephanie E.] Brigham & Womens Hosp, Dept Med, Div Prevent Med, Boston, MA 02115 USA. [Reis, Jared P.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. RP Gooding, HC (reprint author), Boston Childrens Hosp, Div Adolescent, 300 Longwood Ave, Boston, MA 02115 USA. EM holly.gooding@childrens.harvard.edu FU National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201300025C, HHSN268201300026C]; Northwestern University [HHSN268201300027C]; University of Minnesota [HHSN268201300028C]; Kaiser Foundation Research Institute [HHSN268201300029C]; Johns Hopkins University School of Medicine [HHSN268200900041C]; Intramural Research Program of the National Institute on Aging (NIA); NIA [AG0005]; NHLBI [AG0005] FX The Coronary Artery Risk Development in Young Adults Study (CARDIA) is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with the University of Alabama at Birmingham (HHSN268201300025C & HHSN268201300026C), Northwestern University (HHSN268201300027C), University of Minnesota (HHSN268201300028C), Kaiser Foundation Research Institute (HHSN268201300029C), and Johns Hopkins University School of Medicine (HHSN268200900041C). CARDIA is also partially supported by the Intramural Research Program of the National Institute on Aging (NIA) and an intra-agency agreement between NIA and NHLBI (AG0005). This manuscript has been reviewed by CARDIA for scientific content. NR 33 TC 2 Z9 2 U1 1 U2 6 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 NOV PY 2015 VL 4 IS 11 AR e002048 DI 10.1161/JAHA.115.002048 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CY7UU UT WOS:000366615600004 ER PT J AU Tsao, CW Lyass, A Larson, MG Levy, D Hamburg, NM Vita, JA Benjamin, EJ Mitchell, GF Vasan, RS AF Tsao, Connie W. Lyass, Asya Larson, Martin G. Levy, Daniel Hamburg, Naomi M. Vita, Joseph A. Benjamin, Emelia J. Mitchell, Gary F. Vasan, Ramachandran S. TI Relation of Central Arterial Stiffness to Incident Heart Failure in the Community SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE aortic stiffness; epidemiology; heart failure; pressure pulsatility ID PREDICTS CARDIOVASCULAR EVENTS; PRESERVED EJECTION FRACTION; PULSE-WAVE VELOCITY; AORTIC STIFFNESS; BLOOD-PRESSURE; DIASTOLIC DYSFUNCTION; OLDER-ADULTS; RISK-FACTORS; FRAMINGHAM; DISEASE AB Background-Arterial stiffness, pressure pulsatility, and wave reflection are associated with cardiovascular disease. Left ventricular function is coupled to proximal aortic properties, but the association of central aortic stiffness and hemodynamics with incident clinical heart failure (HF) is not well described. Methods and Results-Framingham Study participants without clinical HF (n=2539, mean age 64 years, 56% women) underwent applanation tonometry to measure carotid-femoral pulse wave velocity (CFPWV), central pulse pressure, forward wave amplitude, and augmentation index. CFPWV was inverse-transformed to reduce heteroscedasticity and multiplied by -1 to restore effect direction (iCFPWV). Over 10.1 (range 0.04-12.9) years, 170 HF events developed. In multivariable-adjusted analyses, iCFPWV was associated with incident HF in a continuous, graded fashion (hazards ratio [HR] per SD unit [SDU] 1.29, 95% confidence interval [CI] 1.02-1.64, P=0.037). iCFPWV was associated with HF with reduced ejection fraction (HR=1.69/SDU, 95% CI 1.19-2.42, P=0.0037) in age-and sex-adjusted models, which was attenuated in multivariable-adjusted models (P=0.065). Central pulse pressure and forward wave amplitude were associated with HF in age-and sex-adjusted models (per SDU, HR=1.20, 95% CI 1.06-1.37, P=0.006, and HR=1.15, 95% CI 1.01-1.31, P=0.036, respectively), but not in multivariable-adjusted models (both P >= 0.28). Augmentation index was not associated with HF risk (P >= 0.19 in all models). Conclusions-In our prospective investigation of a large community-based sample of middle-aged to elderly individuals, greater aortic stiffness (reflected by higher iCFPWV) was associated with increased risk of HF. Future studies may investigate the impact of modifying aortic stiffness in reducing the community burden of HF. C1 [Tsao, Connie W.] Beth Israel Deaconess Med Ctr, Dept Med, Div Cardiovasc, Boston, MA 02215 USA. [Lyass, Asya; Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Levy, Daniel] NHLBI, Bethesda, MD 20892 USA. [Hamburg, Naomi M.; Vita, Joseph A.; Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Cardiol Sect, Boston, MA 02118 USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Sect Preventat Med, Boston, MA 02118 USA. [Mitchell, Gary F.] Cardiovasc Engn Inc, Norwood, MA USA. [Tsao, Connie W.; Lyass, Asya; Larson, Martin G.; Levy, Daniel; Benjamin, Emelia J.; Vasan, Ramachandran S.] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. RP Tsao, CW (reprint author), 330 Brookline Ave,RW-453, Boston, MA 02215 USA. EM ctsao1@bidmc.harvard.edu FU National Heart, Lung and Blood Institute [HHSN268201500001I, NO1-HC-25195, HL076784, AG028321, HL070100, HL060040, HL080124, HL071039, HL077447, 6R01-NS-17950, HL107385]; American Heart Association [13SDG14250015]; National Institutes of Health [1K23 HL118259] FX The Framingham Heart Study is funded by the National Heart, Lung and Blood Institute (HHSN268201500001I, NO1-HC-25195, HL076784, AG028321, HL070100, HL060040, HL080124, HL071039, HL077447, 6R01-NS-17950, and HL107385). This work was also supported by the American Heart Association (13SDG14250015 to Tsao), and National Institutes of Health (1K23 HL118259 to Tsao). NR 38 TC 12 Z9 13 U1 0 U2 0 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 NOV PY 2015 VL 4 IS 11 AR e002189 DI 10.1161/JAHA.115.002189 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CY7UU UT WOS:000366615600007 ER PT J AU Borgia, A Kemplen, KR Borgia, MB Soranno, A Shammas, S Wunderlich, B Nettels, D Best, RB Clarke, J Schuler, B AF Borgia, Alessandro Kemplen, Katherine R. Borgia, Madeleine B. Soranno, Andrea Shammas, Sarah Wunderlich, Bengt Nettels, Daniel Best, Robert B. Clarke, Jane Schuler, Benjamin TI Transient misfolding dominates multidomain protein folding SO NATURE COMMUNICATIONS LA English DT Article ID SINGLE-MOLECULE FLUORESCENCE; INTERMOLECULAR INTERACTIONS; TRANSITION-STATES; ENERGY LANDSCAPES; DOMAIN; TITIN; SPECTROSCOPY; AGGREGATION; FRUSTRATION; PATHWAY AB Neighbouring domains of multidomain proteins with homologous tandem repeats have divergent sequences, probably as a result of evolutionary pressure to avoid misfolding and aggregation, particularly at the high cellular protein concentrations. Here we combine microfluidic-mixing single-molecule kinetics, ensemble experiments and molecular simulations to investigate how misfolding between the immunoglobulin-like domains of titin is prevented. Surprisingly, we find that during refolding of tandem repeats, independent of sequence identity, more than half of all molecules transiently form a wide range of misfolded conformations. Simulations suggest that a large fraction of these misfolds resemble an intramolecular amyloid-like state reported in computational studies. However, for naturally occurring neighbours with low sequence identity, these transient misfolds disappear much more rapidly than for identical neighbours. We thus propose that evolutionary sequence divergence between domains is required to suppress the population of long-lived, potentially harmful misfolded states, whereas large populations of transient misfolded states appear to be tolerated. C1 [Borgia, Alessandro; Borgia, Madeleine B.; Soranno, Andrea; Wunderlich, Bengt; Nettels, Daniel; Schuler, Benjamin] Univ Zurich, Dept Biochem, CH-8057 Zurich, Switzerland. [Kemplen, Katherine R.; Shammas, Sarah; Clarke, Jane] Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England. [Best, Robert B.] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Borgia, A (reprint author), Univ Zurich, Dept Biochem, Winterthurerstr 190, CH-8057 Zurich, Switzerland. EM a.borgia@bioc.uzh.ch; jc162@cam.ac.uk; schuler@bioc.uzh.ch RI Best, Robert/H-7588-2016; Schuler, Benjamin/E-7342-2011; OI Best, Robert/0000-0002-7893-3543; Schuler, Benjamin/0000-0002-5970-4251; Soranno, Andrea/0000-0001-8394-7993 FU Swiss National Science Foundation; European Research Council; Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney diseases of the National Institutes of Health; Wellcome Trust [WT095195]; Engineering and Physical Sciences Research Council (UK) FX We thank Hagen Hofmann for helpful comments on the manuscript. B.S. was supported by the Swiss National Science Foundation and the European Research Council. 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. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD, USA (http://biowulf.nih.gov). This work was supported by the Wellcome Trust (WT095195; J.C. and S.S.), and an Engineering and Physical Sciences Research Council (UK) studentship (K.R.K.). J.C. is a Wellcome Trust Senior Research fellow. NR 55 TC 11 Z9 11 U1 8 U2 44 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 NOV PY 2015 VL 6 AR 8861 DI 10.1038/ncomms9861 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CY3GG UT WOS:000366296300006 PM 26572969 ER PT J AU Abdelmohsen, K Panda, AC De, S Grammatikakis, I Kim, J Ding, J Noh, JH Kim, KM Mattison, JA de Cabo, R Gorospe, M AF Abdelmohsen, Kotb Panda, Amaresh C. De, Supriyo Grammatikakis, Ioannis Kim, Jiyoung Ding, Jun Noh, Ji Heon Kim, Kyoung Mi Mattison, Julie A. de Cabo, Rafael Gorospe, Myriam TI Circular RNAs in monkey muscle: age-dependent changes SO AGING-US LA English DT Article DE post-transcriptional gene regulation; aging; splicing; RNA-sequencing; ribonucleoprotein complex ID SKELETAL-MUSCLE; DIFFERENTIATION; DISEASE; CANCER AB Circular RNAs (circRNAs) have been identified in numerous species, including human, mouse, nematode, and coelacanth. They are believed to function as regulators of gene expression at least in part by sponging microRNAs. Here, we describe the identification of circRNAs in monkey (Rhesus macaque) skeletal muscle. RNA sequencing analysis was employed to identify and annotate similar to 12,000 circRNAs, including numerous circular intronic RNAs (ciRNAs), from skeletal muscle of monkeys of a range of ages. Reverse transcription followed by real-time quantitative (q)PCR analysis verified the presence of these circRNAs, including the existence of several highly abundant circRNAs, and the differential abundance of a subset of circRNAs as a function of age. Taken together, our study has documented systematically circRNAs expressed in skeletal muscle and has identified circRNAs differentially abundant with advancing muscle age. We propose that some of these circRNAs might influence muscle function. C1 [Abdelmohsen, Kotb; Panda, Amaresh C.; De, Supriyo; Grammatikakis, Ioannis; Kim, Jiyoung; Ding, Jun; Noh, Ji Heon; Kim, Kyoung Mi; Gorospe, Myriam] NIA, Genet Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Mattison, Julie A.; de Cabo, Rafael] NIA, Translat Gerontol Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Abdelmohsen, K (reprint author), NIA, Genet Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM abdelmohsenk@mail.nih.gov RI de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; De, Supriyo/0000-0002-2075-7655 FU National Institute on Aging Intramural Research Program of the National Institutes of Health FX This research was supported in full by the National Institute on Aging Intramural Research Program of the National Institutes of Health. We appreciate the animal care staff and technicians at the NIH Animal Center in Poolesville, specifically Mark Szarowicz, Kelli Vaughan, and Ed Tilmont. NR 24 TC 7 Z9 8 U1 2 U2 6 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1945-4589 J9 AGING-US JI Aging-US PD NOV PY 2015 VL 7 IS 11 BP 903 EP 910 PG 8 WC Cell Biology SC Cell Biology GA CY4HR UT WOS:000366369700006 PM 26546448 ER PT J AU Reardon, ES Hong, JA Straughan, DM Azoury, SC Zhang, M Schrump, DS AF Reardon, Emily S. Hong, Julie A. Straughan, David M. Azoury, Said C. Zhang, Mary Schrump, David S. TI Pulmonary Metastases Exhibit Epigenetic Clonality: Implications for Precision Cancer Therapy SO ANNALS OF THORACIC SURGERY LA English DT Article; Proceedings Paper CT 51st Annual Meeting of the Society-of-Thoracic-Surgeons CY JAN 24-28, 2015 CL San Diego, CA SP Soc Thorac Surg ID STEM-CELLS; GENE-EXPRESSION; LUNG-CANCER; ADOPTIVE IMMUNOTHERAPY; HETEROGENEITY; MECHANISMS; RESISTANCE; EPIGENOME; EXPERIENCE; DORMANCY AB Background. Development of effective cancer therapies may be limited by intratumoral heterogeneity, which facilitates outgrowth and organ-specific dissemination of treatment resistant clones. At present, limited information is available regarding epigenetic landscapes of pulmonary metastases. This study was undertaken to characterize epigenetic signatures of pulmonary metastases and to identify potential therapeutic targets. Methods. RNA and DNA were extracted from 65 pulmonary metastases resected from 12 patients (5 with sarcoma, 7 with adrenocortical carcinoma). Quantitative reverse transcription polymerase chain reaction techniques were used to evaluate expression levels of cancertestis (CT) genes (NY-ESO-1, MAGE-A3, MAGE-A9, MAGE-A12, GAGE1, CT-45, SSX-1, and SSX-2), tumor suppressor (TS) genes (p16 and RASSF1A), and genes encoding epigenetic modifiers (DNMT1, DNMT3A, DNMT3B, EZH2, EED, and SUZ12), aberrantly expressed in human malignant diseases. Pyrosequencing techniques were used to quantitate DNA methylation levels in LINE1, NBL2, and D4Z4 repetitive sequences and promoter methylation status of differentially regulated genes. Results of these analyses were compared with a standardized panel of normal lung tissues. Results. Pulmonary metastases exhibited histologically related and patient-specific global DNA demethylation. Significant interpatient heterogeneity of gene expression was observed even among patients with similar tumor histologic features. Epigenetic signatures appeared consistent among metastases from the same patient, irrespective of the time of resection (synchronous/metachronous) or the anatomic location. EZH2, EED, and SUZ12 (core components of Polycomb repressive complex-2 [PRC-2]) were upregulated in the majority of metastases. Conclusions. Pulmonary metastases exhibit patientspecific epigenetic clonality, which may be exploited for precision therapies targeting aberrant CT or TS gene expression. PRC-2 may be a shared target for epigenetic therapy of pulmonary metastases. (C) 2015 by The Society of Thoracic Surgeons C1 [Reardon, Emily S.; Hong, Julie A.; Straughan, David M.; Azoury, Said C.; Zhang, Mary; Schrump, David S.] NCI, Ctr Canc Res, Thorac & GI Oncol Branch, Thorac Epigenet Lab, Bethesda, MD 20892 USA. RP Schrump, DS (reprint author), Thorac & GI Oncol Branch, CCR-NCI Bldg 10,Rm 4-3942,10 Ctr Dr,MSC 1201, Bethesda, MD 20892 USA. EM david.schrump@nih.gov FU Intramural NIH HHS; NCI NIH HHS [ZIA BC 011122, ZIA BC 011418] NR 39 TC 1 Z9 1 U1 3 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-4975 EI 1552-6259 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD NOV PY 2015 VL 100 IS 5 BP 1839 EP 1848 DI 10.1016/j.athoracsur.2015.05.089 PG 10 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA CX6OM UT WOS:000365820400058 PM 26298164 ER PT J AU Bocarsly, ME Jiang, WC Wang, C Dudman, JT Ji, N Aponte, Y AF Bocarsly, Miriam E. Jiang, Wan-chen Wang, Chen Dudman, Joshua T. Ji, Na Aponte, Yeka TI Minimally invasive microendoscopy system for in vivo functional imaging of deep nuclei in the mouse brain SO BIOMEDICAL OPTICS EXPRESS LA English DT Article ID FLUORESCENCE MICROENDOSCOPY; CELLULAR RESOLUTION; PUPIL-SEGMENTATION; ADAPTIVE OPTICS; ENDOSCOPY; MICE; LENS AB The ability to image neurons anywhere in the mammalian brain is a major goal of optical microscopy. Here we describe a minimally invasive microendoscopy system for studying the morphology and function of neurons at depth. Utilizing a guide cannula with an ultrathin wall, we demonstrated in vivo two-photon fluorescence imaging of deeply buried nuclei such as the striatum (2.5 mm depth), substantia nigra (4.4 mm depth) and lateral hypothalamus (5.0 mm depth) in mouse brain. We reported, for the first time, the observation of neuronal activity with subcellular resolution in the lateral hypothalamus and substantia nigra of head-fixed awake mice. (C) 2015 Optical Society of America C1 [Bocarsly, Miriam E.; Aponte, Yeka] NIDA, Intramural Res Program, Neuronal Circuits & Behav Unit, Baltimore, MD 21224 USA. [Bocarsly, Miriam E.; Jiang, Wan-chen; Wang, Chen; Dudman, Joshua T.; Ji, Na; Aponte, Yeka] Howard Hughes Med Inst, Ashburn, VA 20147 USA. RP Bocarsly, ME (reprint author), NIAAA, Sect Neuronal Struct, NIH, Bethesda, MD 20892 USA. EM jin@janelia.hhmi.org; yeka.aponte@nih.gov OI Dudman, Joshua/0000-0002-4436-1057 FU Janelia Visitor Program; Howard Hughes Medical Institute; NIDA Intramural Research Program FX This project was supported by the Janelia Visitor Program and funded by the Howard Hughes Medical Institute and NIDA Intramural Research Program. M. E. B. and Y. A. were supported by the NIDA Intramural Research Program, W-C. J., C. W., J. T. D., and N. J. were supported by Howard Hughes Medical Institute. We thank J. Rouchard, K. Morris for mouse breeding and procedures; M. Copeland, A. Hu, B. Shields for histology support; S. Sarsfield for help with figures and comments on the manuscript; Branka Prijovic, Sead Doric, and Jean-Luc Neron from Doric Lenses Inc. for assistance with guide cannula assembly. NR 27 TC 3 Z9 3 U1 5 U2 16 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 2156-7085 J9 BIOMED OPT EXPRESS JI Biomed. Opt. Express PD NOV 1 PY 2015 VL 6 IS 11 BP 4546 EP 4556 DI 10.1364/BOE.6.004546 PG 11 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA CY0UQ UT WOS:000366122400031 PM 26601017 ER PT J AU Ji, XM Gui, J Han, YH Brennan, P Li, YF McKay, J Caporaso, NE Bertazzi, PA Landi, MT Amos, CI AF Ji, Xuemei Gui, Jiang Han, Younghun Brennan, Paul Li, Yafang McKay, James Caporaso, Neil E. Bertazzi, Pier Alberto Landi, Maria Teresa Amos, Christopher I. TI The role of haplotype in 15q25.1 locus in lung cancer risk: results of scanning chromosome 15 SO CARCINOGENESIS LA English DT Article ID GENOME-WIDE ASSOCIATION; NICOTINE DEPENDENCE; ADENOCARCINOMA RISK; SUSCEPTIBILITY LOCI; MESSENGER-RNA; VARIANTS; SMOKING; POPULATION; CHRNA5; POLYMORPHISMS AB The role of haplotypes and the interaction of haplotypes and smoking in lung cancer risk have not been well characterized. We analyzed data from an Italian population-based, case-control study with 1815 lung cancer patients and 1959 healthy controls in discovery, and performed a validation using a case-control study with 2983 lung cancer patients and 3553 healthy controls of European ancestry for replication. Sliding window haplotype analysis within chromosome 15, evaluating 4 722 250 haplotypes and pair-wise haplotype analysis identified that CHRNA5 rs588765-rs16969968 was the most significant haplotype associated with lung cancer risk (omnibus P = 8.35 x 10(-15) in discovery and 7.26 x 10(-14) in replication), and improved the prediction of case status over that provided by the individual SNPs rs16969968 or rs588765 (likelihood ratio test P = 0.006 for rs16969968 and 3.83 x 10(-14) for rs588765 in discovery, 0.009 for rs16969968 and 4.62 x 10(-13) for rs588765 in replication, compared with rs588765-rs16969968). Compared with the wild-type homozygous diplotype, CA/CA homozygote exhibited an approximately 2-fold increase risk for lung cancer (OR = 2.12; 95% CI 1.46-3.07 in discovery, and OR = 2.01; 95% CI 1.51-2.67 in replication). Even among never-smokers, CA/CA homozygote showed an increased risk of lung cancer with borderline significance in discovery (adjusted OR = 1.75, 95% CI 0.96-3.19) and statistical significance in replication (adjusted OR = 2.10, 95% CI 1.12-3.96), compared with combined genotypes (CG/CG + CG/TG). Accordingly, rs588765-rs16969968 may be a genetic marker to lung cancer risk, even among never-smokers. C1 [Ji, Xuemei; Gui, Jiang; Han, Younghun; Li, Yafang; Amos, Christopher I.] Dartmouth Coll, Geisel Sch Med Dartmouth, Dept Biomed Data Sci, Hanover, NH 03755 USA. [Brennan, Paul; McKay, James] Int Agcy Res Canc, F-69372 Lyon, France. [Caporaso, Neil E.; Landi, Maria Teresa] NCI, Dept Hlth & Human Serv, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Bertazzi, Pier Alberto] Univ Milan, Fdn IRCCS Ca Granda Policlin Hosp, Dept Prevent Med, Dept Clin Sci & Community Hlth, I-20122 Milan, Italy. RP Amos, CI (reprint author), Dartmouth Coll, Geisel Sch Med Dartmouth, Dept Biomed Data Sci, Hanover, NH 03755 USA. EM Christopher.I.Amos@Dartmouth.edu FU National Institutes of Health (NIH) [P30CA023108, P20GM103534, R01LM012012]; Trandisciplinary Research in Cancer of the Lung (TRICL) [U19CA148127]; UICC American Cancer Society Beginning Investigators Fellowship - Union for International Cancer Control (UICC) FX National Institutes of Health (NIH) for the research of lung cancer (grant P30CA023108, P20GM103534 and R01LM012012); Trandisciplinary Research in Cancer of the Lung (TRICL) (grant U19CA148127); UICC American Cancer Society Beginning Investigators Fellowship funded by the Union for International Cancer Control (UICC) (to X.J.). NR 27 TC 3 Z9 3 U1 1 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 EI 1460-2180 J9 CARCINOGENESIS JI Carcinogenesis PD NOV PY 2015 VL 36 IS 11 BP 1275 EP 1283 DI 10.1093/carcin/bgv118 PG 9 WC Oncology SC Oncology GA CY4OF UT WOS:000366386800003 PM 26282330 ER PT J AU Brenner, DR Amos, CI Brhane, Y Timofeeva, MN Caporaso, N Wang, YF Christiani, DC Bickeboller, H Yang, P Albanes, D Stevens, VL Gapstur, S McKay, J Boffetta, P Zaridze, D Szeszenia-Dabrowska, N Lissowska, J Rudnai, P Fabianova, E Mates, D Bencko, V Foretova, L Janout, V Krokan, HE Skorpen, F Gabrielsen, ME Vatten, L Njolstad, I Chen, C Goodman, G Lathrop, M Vooder, T Valk, K Nelis, M Metspalu, A Broderick, P Eisen, T Wu, XF Zhang, D Chen, W Spitz, MR Wei, YY Su, L Xie, D She, J Matsuo, K Matsuda, F Ito, H Risch, A Heinrich, J Rosenberger, A Muley, T Dienemann, H Field, JK Raji, O Chen, Y Gosney, J Liloglou, T Davies, MPA Marcus, M McLaughlin, J Orlow, I Han, YH Li, YF Zong, XC Johansson, M Liu, G Tworoger, SS Le Marchand, L Henderson, BE Wilkens, LR Dai, JC Shen, HB Houlston, RS Landi, MT Brennan, P Hung, RJ AF Brenner, Darren R. Amos, Christopher I. Brhane, Yonathan Timofeeva, Maria N. Caporaso, Neil Wang, Yufei Christiani, David C. Bickeboeller, Heike Yang, Ping Albanes, Demetrius Stevens, Victoria L. Gapstur, Susan McKay, James Boffetta, Paolo Zaridze, David Szeszenia-Dabrowska, Neonilia Lissowska, Jolanta Rudnai, Peter Fabianova, Eleonora Mates, Dana Bencko, Vladimir Foretova, Lenka Janout, Vladimir Krokan, Hans E. Skorpen, Frank Gabrielsen, Maiken E. Vatten, Lars Njolstad, Inger Chen, Chu Goodman, Gary Lathrop, Mark Vooder, Tonu Valk, Kristjan Nelis, Mari Metspalu, Andres Broderick, Peter Eisen, Timothy Wu, Xifeng Zhang, Di Chen, Wei Spitz, Margaret R. Wei, Yongyue Su, Li Xie, Dong She, Jun Matsuo, Keitaro Matsuda, Fumihiko Ito, Hidemi Risch, Angela Heinrich, Joachim Rosenberger, Albert Muley, Thomas Dienemann, Hendrik Field, John K. Raji, Olaide Chen, Ying Gosney, John Liloglou, Triantafillos Davies, Michael P. A. Marcus, Michael McLaughlin, John Orlow, Irene Han, Younghun Li, Yafang Zong, Xuchen Johansson, Mattias Liu, Geoffrey Tworoger, Shelley S. Le Marchand, Loic Henderson, Brian E. Wilkens, Lynne R. Dai, Juncheng Shen, Hongbing Houlston, Richard S. Landi, Maria T. Brennan, Paul Hung, Rayjean J. CA EPIC Investigators TI Identification of lung cancer histology-specific variants applying Bayesian framework variant prioritization approaches within the TRICL and ILCCO consortia SO CARCINOGENESIS LA English DT Article ID GENOME-WIDE ASSOCIATION; NEVER-SMOKERS; SUSCEPTIBILITY LOCUS; FALSE DISCOVERY; DNA-REPAIR; RISK; POPULATION; DISEASE; PATHWAYS; MATRIX-METALLOPROTEINASE-1 AB Large-scale genome-wide association studies (GWAS) have likely uncovered all common variants at the GWAS significance level. Additional variants within the suggestive range (0.0001> P > 5 x 10(-8)) are, however, still of interest for identifying causal associations. This analysis aimed to apply novel variant prioritization approaches to identify additional lung cancer variants that may not reach the GWAS level. Effects were combined across studies with a total of 33 456 controls and 6756 adenocarcinoma (AC; 13 studies), 5061 squamous cell carcinoma (SCC; 12 studies) and 2216 small cell lung cancer cases (9 studies). Based on prior information such as variant physical properties and functional significance, we applied stratified false discovery rates, hierarchical modeling and Bayesian false discovery probabilities for variant prioritization. We conducted a fine mapping analysis as validation of our methods by examining top-ranking novel variants in six independent populations with a total of 3128 cases and 2966 controls. Three novel loci in the suggestive range were identified based on our Bayesian framework analyses: KCNIP4 at 4p15.2 (rs6448050, P = 4.6 x 10(-7)) and MTMR2 at 11q21 (rs10501831, P = 3.1 x 10(-6)) with SCC, as well as GAREM at 18q12.1 (rs11662168, P = 3.4 x 10(-7)) with AC. Use of our prioritization methods validated two of the top three loci associated with SCC (P = 1.05 x 10(-4) for KCNIP4, represented by rs9799795) and AC (P = 2.16 x 10(-4) for GAREM, represented by rs3786309) in the independent fine mapping populations. This study highlights the utility of using prior functional data for sequence variants in prioritization analyses to search for robust signals in the suggestive range. C1 [Brenner, Darren R.; Brhane, Yonathan; McLaughlin, John; Zong, Xuchen; Hung, Rayjean J.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5T 3L9, Canada. [Brenner, Darren R.; McKay, James; Johansson, Mattias; Brennan, Paul] Int Agcy Res Canc, Genet Sect, F-69372 Lyon, France. [Brenner, Darren R.] Alberta Hlth Serv, Canc Control Alberta, Dept Canc Epidemiol & Prevent Res, Calgary, AB T2T 5C7, Canada. [Amos, Christopher I.; Han, Younghun; Li, Yafang] Dartmouth Coll, Geisel Sch Med, Ctr Genom Med, Dept Community & Family Med, Lebanon, NH 03766 USA. [Timofeeva, Maria N.] Univ Edinburgh, Inst Genet & Mol Med, Edinburgh EH8 9YL, Midlothian, Scotland. [Caporaso, Neil; Albanes, Demetrius; Landi, Maria T.] NCI, Dept Hlth & Human Serv, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Wang, Yufei; Broderick, Peter; Houlston, Richard S.] Inst Canc Res, Div Genet & Epidemiol, Sutton SM2 5NG, Surrey, England. [Christiani, David C.; Wei, Yongyue; Su, Li] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Christiani, David C.; Wei, Yongyue; Su, Li] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Bickeboeller, Heike] Univ Gottingen, Univ Med Ctr, Dept Genet Epidemiol, D-37073 Gottingen, Germany. [Yang, Ping; Xie, Dong; She, Jun] Mayo Clin, Ctr Canc, Div Hlth Sci, Rochester, NY 55905 USA. [Yang, Ping; Xie, Dong; She, Jun] Mayo Clin, Coll Med, Rochester, NY 55905 USA. [Stevens, Victoria L.; Gapstur, Susan] Amer Canc Soc Epidemiol & Surveillance Res, Epidemiol Res Program, Atlanta, GA 30301 USA. [Boffetta, Paolo] Icahn Sch Med Mt Sinai, Tisch Canc Ctr, Populat Sci, New York, NY 10029 USA. [Boffetta, Paolo] Icahn Sch Med Mt Sinai, Inst Translat Epidemiol, New York, NY 10029 USA. [Zaridze, David] Russian NN Blokhin Canc Res Ctr, Inst Carcinogenesis, Moscow 115478, Russia. [Szeszenia-Dabrowska, Neonilia] Inst Occupat Med, Dept Epidemiol, PL-91348 Lodz, Poland. [Lissowska, Jolanta] M Sklodowska Curie Mem Canc Ctr, Dept Epidemiol & Canc Prevent, PL-02781 Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, PL-02781 Warsaw, Poland. [Rudnai, Peter] Natl Inst Environm Hlth, H-1097 Budapest, Hungary. [Fabianova, Eleonora] Reg Author Publ Hlth, Dept Hlth Risk Assessment, Banska Bystrica 97556, Slovakia. [Mates, Dana] Natl Inst Publ Hlth, Bucharest 050463, Romania. [Bencko, Vladimir] Charles Univ Prague, Fac Med 1, Inst Hyg & Epidemiol, Prague 12800 2, Czech Republic. [Foretova, Lenka] Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Brno 65653, Czech Republic. [Janout, Vladimir] Palacky Univ, Dept Prevent Med, Olomouc 77515, Czech Republic. [Krokan, Hans E.] Norwegian Univ Sci & Technol, Fac Med, Dept Canc Res & Mol Med, N-7489 Trondheim, Norway. [Skorpen, Frank; Gabrielsen, Maiken E.] Norwegian Univ Sci & Technol, Fac Med, Dept Lab Med, Childrens & Womens Hlth, N-7489 Trondheim, Norway. [Vatten, Lars] Norwegian Univ Sci & Technol, Fac Med, Dept Publ Hlth & Gen Practice, N-7489 Trondheim, Norway. [Njolstad, Inger] Univ Tromso, Dept Community Med, N-9037 Tromso, Norway. [Chen, Chu; Goodman, Gary] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Lathrop, Mark] McGill Univ, Montreal, PQ, Canada. [Lathrop, Mark] Genome Quebec Innovat Ctr, Montreal, PQ, Canada. [Vooder, Tonu] Univ Tartu, Inst Mol & Cell Biol, EE-51010 Tartu, Estonia. [Valk, Kristjan] Univ Bergen, Dept Biomed, N-5009 Bergen, Norway. [Nelis, Mari; Metspalu, Andres] Estonian Bioctr, Genotyping Core Facil, Inst Mol & Cell Biol, EE-51010 Tartu, Estonia. [Eisen, Timothy] Cambridge Biomed Res Ctr, Dept Oncol, Cambridge CB2 0QQ, England. [Wu, Xifeng; Zhang, Di] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Chen, Wei] Univ Texas MD Anderson Canc Ctr, Dept Genet, Houston, TX 77030 USA. [Spitz, Margaret R.] Baylor Coll Med, Duncan Canc Ctr, Houston, TX 77030 USA. [Matsuo, Keitaro] Kyushu Univ, Grad Sch Med, Dept Prevent Med, Fukuoka 8190395, Japan. [Matsuda, Fumihiko] Kyoto Univ, Grad Sch Med, Ctr Genom Med, Kyoto 6068501, Japan. [Ito, Hidemi] Aichi Canc Ctr, Res Inst, Dept Epidemiol & Prevent, Chikusa Ku, Nagoya, Aichi 4640021, Japan. [Risch, Angela] DKFZ, Div Epigen & Canc Risk Factors, D-69121 Heidelberg, Germany. [Risch, Angela; Muley, Thomas; Dienemann, Hendrik] German Ctr Lung Res DZL, Translat Lung Res Ctr Heidelberg TLRC H, Div Epigenom & Canc Risk Factors, D-69121 Heidelberg, Germany. [Heinrich, Joachim] Helmholtz Zentrum Munchen, Environm Epidemiol Unit, D-85764 Neuherberg, Germany. [Rosenberger, Albert] Univ Gottingen, Univ Med Ctr, Dept Genet Epidemiol, D-37073 Gottingen, Germany. [Muley, Thomas] Univ Klinikum Heidelberg, Thoraxklin, Translat Res Unit, D-69117 Heidelberg, Germany. [Dienemann, Hendrik] Univ Klinikum Heidelberg, Thoraxklin, Dept Thorac Surg, D-69117 Heidelberg, Germany. [Field, John K.; Raji, Olaide; Chen, Ying; Gosney, John; Liloglou, Triantafillos; Davies, Michael P. A.; Marcus, Michael] Univ Liverpool, Canc Res Ctr, Dept Mol & Clin Canc Med, Inst Translat Med,Roy Castle Lung Canc Res Progra, Liverpool L69 3BX, Merseyside, England. [Orlow, Irene] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10065 USA. [Liu, Geoffrey] Princess Margaret Hosp, Dept Med, Med Oncol & Haematol, Toronto, ON M5G 2M9, Canada. [Tworoger, Shelley S.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Tworoger, Shelley S.] Brigham & Womens Hosp, Channing Div, Med Network, Boston, MA 02115 USA. [Tworoger, Shelley S.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Le Marchand, Loic; Wilkens, Lynne R.] Univ Hawaii, Ctr Canc, Canc Epidemiol Program, Honolulu, HI 96813 USA. [Henderson, Brian E.] Univ South Calif, Keck Sch Med, Los Angeles, CA 90089 USA. [Dai, Juncheng; Shen, Hongbing] Nanjing Med Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Nanjing 210029, Jiangsu, Peoples R China. RP Hung, RJ (reprint author), Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, 60 Murray St Rm L5-215, Toronto, ON M5T 3L9, Canada. EM rayjean.hung@lunenfeld.ca RI Hung, Rayjean/A-7439-2013; U-ID, Kyushu/C-5291-2016; Janout, Vladimir/M-5133-2014; Liu, Geoffrey/N-4421-2016; Chen, Ying/I-4349-2013; Risch, Angela/H-2669-2013; OI Johansson, Mattias/0000-0002-3116-5081; Risch, Angela/0000-0002-8026-5505; Orlow, Irene/0000-0001-6234-6961; Matsuo, Keitaro/0000-0003-1761-6314; Houlston, Richard/0000-0002-5268-0242 FU IARC; Mayo Foundation funds; U.S. National Institutes of Health [CA-80127, CA-84354]; NIH, Bethesda, MD USA [CA 097193, CA 34944, CA 40360, HL 26490, HL 34595]; Cancer Research UK [C1298/A8780, C1298/A8362]; National Cancer Research Network (NCRN); HEAL; Sanofi-Aventis; National Health Service; National Institute for Health Research Biomedical Research Centre; NIH [GM103534, CA074386, CA092824, CA090578]; Institute for Quantitative Biomedical Sciences at Dartmouth; National Cancer Institute [P50-CA070907]; NCI CCSG award [P30-CA008748]; China National High-Tech Research and Development Program Grant [2009AA022705]; National Key Basic Research Program Grant [2011CB503805]; National Natural Science Foundation of China [30730080, 30972541, 30901233, 30872178]; Canadian Cancer Society Research Institute [020214]; Ontario Institute of Cancer and Cancer Care Ontario Chair Award; Deutsche Krebshilfe [70-2919]; Helmholtz-DAAD fellowship [A/07/97379]; NIH (USA) [U19CA148127]; GSF - German Federal Ministry of Education, Science, Research and Technology; State of Bavaria; National Genome Research Network (NGFN); DFG [BI 576/2-1, BI 576/2-2]; Helmholtzgemeinschaft (HGF); Federal office for Radiation Protection [BfS: STSch4454]; Institut National du Cancer, France; Cancer Care Ontario Research Chair; US Public Health Service (National Cancer Institute) [R37 CA54281]; MEC Infrastructure Grant [UM1 CA164973]; Roy Castle Lung Cancer Foundation, UK; Europe Against Cancer Program of the European Commission (SANCO); Deutsche Krebshilfe; Deutsches Krebsforschungszentrum; German Federal Ministry of Education and Research; Danish Cancer Society; Health Research Fund (FIS) of the Spanish Ministry of Health, Spanish Regional Government of Andalucia; Health Research Fund (FIS) of the Spanish Ministry of Health, Spanish Regional Government of Asturias; Health Research Fund (FIS) of the Spanish Ministry of Health, Spanish Regional Government of Basque Country; Health Research Fund (FIS) of the Spanish Ministry of Health, Spanish Regional Government of Murcia; Health Research Fund (FIS) of the Spanish Ministry of Health, Spanish Regional Government of Navarra; Catalan Institute of Oncology, Spain; ISCIII of the Spanish Ministry of Health [RETICC DR06/0020]; Cancer Research UK; Medical Research Council, United Kingdom; Greek Ministry of Health; Stavros Niarchos Foundation; Hellenic Health Foundation; Italian Association for Research on Cancer (AIRC); Italian National Research Council, Fondazione-Istituto Banco Napoli, Italy; Associazione Italiana per la Ricerca sul Cancro-AIRC-Milan; Compagnia di San Paolo; Dutch Ministry of Public Health, Welfare and Sports; World Cancer Research Fund; Swedish Cancer Society; Swedish Scientific Council; Regional Government of Vasterbotten, Sweden; NordForsk (Centre of excellence programme HELGA), Norway; French League against Cancer (LNCC), France; National Institute for Health and Medical Research (INSERM), France; Mutuelle Generale de l'Education Nationale (MGEN), France; 3M Co, France; Gustave Roussy Institute (IGR), France; General Councils of France; National Cancer Center Research and Development Fund [H23-A-4]; Health and Labor Sciences Research Grants for Research on Applying Health Technology [201136002A]; Ministry of Health, Labor and Welfare [H26-Innovative Cancer-General-094]; Japanese Ministry of Education, Culture, Sports, Science and Technology [17015018, 221S0001]; 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, NO1-4992, 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, U01 HG004438, NIH HHSN268200782096C, U01 HG004446]; [P01-CA087969] FX The work reported in this article was partly undertaken during the tenure of a Postdoctoral Fellowship from the IARC (for D.R.B.). The statistical analysis and data management of this project was partially supported by National Institutes of Health (NIH) (U19-CA148127-01). Work carried out at Mayo was supported by the Mayo Foundation funds and U.S. National Institutes of Health (R01 grants CA-80127, CA-84354). The Nurses' Health Study (NHS) was supported by the grant (P01-CA087969). PHS is supported by (CA 097193, CA 34944, CA 40360, HL 26490 and HL 34595) from the NIH, Bethesda, MD USA. The work performed at ICR was supported by Cancer Research UK (C1298/A8780 and C1298/A8362); National Cancer Research Network (NCRN); HEAL; Sanofi-Aventis and National Health Service funding to the Royal Marsden Hospital and Institute of Cancer Research, as well as the National Institute for Health Research Biomedical Research Centre. Work at ICR was also supported by NIH (GM103534) and the Institute for Quantitative Biomedical Sciences at Dartmouth to C.I.A. The work performed at the M.D. Anderson Cancer Center (MDACC) was supported by the National Cancer Institute grant (P50-CA070907). The work done at the Memorial Sloan Kettering Cancer Center (MSKCC) was supported by NCI CCSG award (P30-CA008748). Work performed at Harvard was supported by the NIH (CA074386, CA092824 and CA090578). The Nanjing study and Beijing studies were funded by the China National High-Tech Research and Development Program Grant (2009AA022705); the National Key Basic Research Program Grant (2011CB503805) and the National Natural Science Foundation of China (30730080, 30972541, 30901233 and 30872178). The LTRI study was supported by Canadian Cancer Society Research Institute (020214); Ontario Institute of Cancer and Cancer Care Ontario Chair Award to R.H. 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 M.N.T.) and by the NIH (USA) (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 (BI 576/2-1, 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 Munchen. Support for the IARC genome-wide studies was provided by Institut National du Cancer, France. The MSH-PMH study is supported by Canadian Cancer Society Research Institute (no. 020214, PI: Hung) and Cancer Care Ontario Research Chair (Hung, Liu). The Multiethnic Cohort Study has been supported by US Public Health Service (National Cancer Institute) grant (R37 CA54281) and MEC Infrastructure Grant (UM1 CA164973). The Liverpool Lung Project (LLP) was supported by the Roy Castle Lung Cancer Foundation, UK.; The EPIC study has been supported by the Europe Against Cancer Program of the European Commission (SANCO); Deutsche Krebshilfe, Deutsches Krebsforschungszentrum, German Federal Ministry of Education and Research; Danish Cancer Society; Health Research Fund (FIS) of the Spanish Ministry of Health, Spanish Regional Governments of Andalucia, Asturias, Basque Country, Murcia and Navarra; Catalan Institute of Oncology, Spain; the ISCIII of the Spanish Ministry of Health (RETICC DR06/0020); Cancer Research UK; Medical Research Council, United Kingdom; Greek Ministry of Health; Stavros Niarchos Foundation; Hellenic Health Foundation; Italian Association for Research on Cancer (AIRC); Italian National Research Council, Fondazione-Istituto Banco Napoli, Italy; Associazione Italiana per la Ricerca sul Cancro-AIRC-Milan; Compagnia di San Paolo; Dutch Ministry of Public Health, Welfare and Sports; World Cancer Research Fund; Swedish Cancer Society; Swedish Scientific Council; Regional Government of Vasterbotten, Sweden; NordForsk (Centre of excellence programme HELGA), Norway; French League against Cancer (LNCC), France; National Institute for Health and Medical Research (INSERM), France; Mutuelle Generale de l'Education Nationale (MGEN), France; 3M Co, France; Gustave Roussy Institute (IGR), France and General Councils of France.; Aichi's study was supported by the National Cancer Center Research and Development Fund (no. H23-A-4); Health and Labor Sciences Research Grants for Research on Applying Health Technology (no. 201136002A) and H26-Innovative Cancer-General-094 from the Ministry of Health, Labor and Welfare and a Research on Grant-in-Aid for Scientific Priority Areas of Cancer (no. 17015018) and on Innovative Areas (no. 221S0001) from the Japanese Ministry of Education, Culture, Sports, Science and Technology.; 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 (NO1-4992 Human Molecular Genetics, 2012, Vol. 21, No. 22, downloaded from http://hmg.oxfordjournals.org/ at Mount Sinai Hospital on January 11, 2013, 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) and 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 and RO1HL091172-01), genotyping at the Johns Hopkins University Center for Inherited Disease Research (U01 HG004438 and NIH HHSN268200782096C) and study coordination at the GENEVA Coordination Center (U01 HG004446) for EAGLE and part of PLCO studies. NR 67 TC 1 Z9 1 U1 1 U2 16 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 EI 1460-2180 J9 CARCINOGENESIS JI Carcinogenesis PD NOV PY 2015 VL 36 IS 11 BP 1314 EP 1326 DI 10.1093/carcin/bgv128 PG 13 WC Oncology SC Oncology GA CY4OF UT WOS:000366386800008 PM 26363033 ER PT J AU Lawrenson, K Iversen, ES Tyrer, J Weber, RP Concannon, P Hazelett, DJ Li, QY Marks, JR Berchuck, A Lee, JM Aben, KKH Anton-Culver, H Antonenkova, N Bandera, EV Bean, Y Beckmann, MW Bisogna, M Bjorge, L Bogdanova, N Brinton, LA Brooks-Wilson, A Bruinsma, F Butzow, R Campbell, IG Carty, K Chang-Claude, J Chenevix-Trench, G Chen, A Chen, ZH Cook, LS Cramer, DW Cunningham, JM Cybulski, C Plisiecka-Halasa, J Dennis, J Dicks, E Doherty, JA Dork, T du Bois, A Eccles, D Easton, DT Edwards, RP Eilber, U Ekici, AB Fasching, PA Fridley, BL Gao, YT Gentry-Maharaj, A Giles, GG Glasspool, R Goode, EL Goodman, MT Gronwald, J Harter, P Hasmad, HN Hein, A Heitz, F Hildebrandt, MAT Hillemanns, P Hogdall, E Hogdall, C Hosono, S Jakubowska, A Paul, J Jensen, A Karlan, BY Kjaer, SK Kelemen, LE Kellar, M Kelley, JL Kiemeney, LA Krakstad, C Lambrechts, D Lambrechts, S Le, ND Lee, AW Cannioto, R Leminen, A Lester, J Levine, DA Liang, D Lissowska, J Lu, KR Lubinski, J Lundvall, L Massuger, LFAG Matsuo, K McGuire, V McLaughlin, JR Nevanlinna, H McNeish, I Menon, U Modugno, F Moysich, KB Narod, SA Nedergaard, L Ness, RB Azmi, MAN Odunsi, K Olson, SH Orlow, I Orsulic, S Pearce, CL Pejovic, T Pelttari, LM Permuth-Wey, J Phelan, CM Pike, MC Poole, EM Ramus, SJ Risch, HA Rosen, B Rossing, MA Rothstein, JH Rudolph, A Runnebaum, IB Rzepecka, IK Salvesen, HB Budzilowska, A Sellers, TA Shu, XO Shvetsov, YB Siddiqui, N Sieh, W Song, HL Southey, MC Sucheston, L Tangen, IL Teo, SH Terry, KL Thompson, PJ Timorek, A Tworoger, SS Van Nieuwenhuysen, E Vergote, I Vierkant, RA Wang-Gohrke, S Walsh, C Wentzensen, N Whittemore, AS Wicklund, KG Wilkens, LR Woo, YL Wu, XF Wu, AH Yang, HN Zheng, W Ziogas, A Coetzee, GA Freedman, ML Monteiro, ANA Moes-Sosnowska, J Kupryjanczyk, J Pharoah, PD Gayther, SA Schildkraut, JM AF Lawrenson, Kate Iversen, Edwin S. Tyrer, Jonathan Weber, Rachel Palmieri Concannon, Patrick Hazelett, Dennis J. Li, Qiyuan Marks, Jeffrey R. Berchuck, Andrew Lee, Janet M. Aben, Katja K. H. Anton-Culver, Hoda Antonenkova, Natalia Bandera, Elisa V. 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 Chang-Claude, Jenny Chenevix-Trench, Georgia Chen, Ann Chen, Zhihua Cook, Linda S. Cramer, Daniel W. Cunningham, Julie M. Cybulski, Cezary Plisiecka-Halasa, Joanna Dennis, Joe Dicks, Ed Doherty, Jennifer A. Doerk, Thilo du Bois, Andreas Eccles, Diana Easton, Douglas T. Edwards, Robert P. Eilber, Ursula Ekici, Arif B. Fasching, Peter A. Fridley, Brooke L. Gao, Yu-Tang Gentry-Maharaj, Aleksandra Giles, Graham G. Glasspool, Rosalind Goode, Ellen L. Goodman, Marc T. Gronwald, Jacek Harter, Philipp Hasmad, Hanis Nazihah Hein, Alexander Heitz, Florian Hildebrandt, Michelle A. T. Hillemanns, Peter Hogdall, Estrid Hogdall, Claus Hosono, Satoyo Jakubowska, Anna Paul, James Jensen, Allan Karlan, Beth Y. Kjaer, Susanne Kruger Kelemen, Linda E. Kellar, Melissa Kelley, Joseph L. Kiemeney, Lambertus A. Krakstad, Camilla Lambrechts, Diether Lambrechts, Sandrina Le, Nhu D. Lee, Alice W. Cannioto, Rikki Leminen, Arto Lester, Jenny Levine, Douglas A. Liang, Dong Lissowska, Jolanta Lu, Karen Lubinski, Jan Lundvall, Lene Massuger, Leon F. A. G. Matsuo, Keitaro McGuire, Valerie McLaughlin, John R. Nevanlinna, Heli McNeish, Iain Menon, Usha Modugno, Francesmary Moysich, Kirsten B. Narod, Steven A. Nedergaard, Lotte Ness, Roberta B. Azmi, Mat Adenan Noor Odunsi, Kunle Olson, Sara H. Orlow, Irene Orsulic, Sandra Pearce, Celeste L. Pejovic, Tanja Pelttari, Liisa M. Permuth-Wey, Jennifer Phelan, Catherine M. Pike, Malcolm C. Poole, Elizabeth M. Ramus, Susan J. Risch, Harvey A. Rosen, Barry Rossing, Mary Anne Rothstein, Joseph H. Rudolph, Anja Runnebaum, Ingo B. Rzepecka, Iwona K. Salvesen, Helga B. Budzilowska, Agnieszka Sellers, Thomas A. Shu, Xiao-Ou Shvetsov, Yurii B. Siddiqui, Nadeem Sieh, Weiva Song, Honglin Southey, Melissa C. Sucheston, Lara Tangen, Ingvild L. Teo, Soo-Hwang Terry, Kathryn L. Thompson, Pamela J. Timorek, Agnieszka Tworoger, Shelley S. Van Nieuwenhuysen, Els Vergote, Ignace Vierkant, Robert A. Wang-Gohrke, Shan Walsh, Christine Wentzensen, Nicolas Whittemore, Alice S. Wicklund, Kristine G. Wilkens, Lynne R. Woo, Yin-Ling Wu, Xifeng Wu, Anna H. Yang, Hannah Zheng, Wei Ziogas, Argyrios Coetzee, Gerhard A. Freedman, Matthew L. Monteiro, Alvaro N. A. Moes-Sosnowska, Joanna Kupryjanczyk, Jolanta Pharoah, Paul D. Gayther, Simon A. Schildkraut, Joellen M. CA Australian Canc Study Ovarian Canc Australian Ovarian Canc Study Grp TI Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer SO CARCINOGENESIS LA English DT Article ID GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; GERMLINE MUTATIONS; FALLOPIAN-TUBE; REPAIR GENES; DNA-DAMAGE; IN-VITRO; BREAST; BRCA1; CELLS AB Genome-wide association studies have identified 20 genomic regions associated with risk of epithelial ovarian cancer (EOC), but many additional risk variants may exist. Here, we evaluated associations between common genetic variants [single nucleotide polymorphisms (SNPs) and indels] in DNA repair genes and EOC risk. We genotyped 2896 common variants at 143 gene loci in DNA samples from 15 397 patients with invasive EOC and controls. We found evidence of associations with EOC risk for variants at FANCA, EXO1, E2F4, E2F2, CREB5 and CHEK2 genes (P = 0.001). The strongest risk association was for CHEK2 SNP rs17507066 with serous EOC (P = 4.74 x 10(-7)). Additional genotyping and imputation of genotypes from the 1000 genomes project identified a slightly more significant association for CHEK2 SNP rs6005807 (r(2) with rs17507066 = 0.84, odds ratio (OR) 1.17, 95% CI 1.11-1.24, P = 1.1 x 10(-7)). We identified 293 variants in the region with likelihood ratios of less than 1: 100 for representing the causal variant. Functional annotation identified 25 candidate SNPs that alter transcription factor binding sites within regulatory elements active in EOC precursor tissues. In The Cancer Genome Atlas dataset, CHEK2 gene expression was significantly higher in primary EOCs compared to normal fallopian tube tissues (P = 3.72 x 10(-8)). We also identified an association between genotypes of the candidate causal SNP rs12166475 (r(2) = 0.99 with rs6005807) and CHEK2 expression (P = 2.70 x 10(-8)). These data suggest that common variants at 22q12.1 are associated with risk of serous EOC and CHEK2 as a plausible target susceptibility gene. C1 [Lee, Janet M.; Lee, Alice W.; Ramus, Susan J.; Wu, Anna H.] Univ So Calif, Norris Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Iversen, Edwin S.; Anton-Culver, Hoda; Pike, Malcolm C.] Duke Univ, Dept Stat Sci, Durham, NC 27708 USA. [Tyrer, Jonathan; Song, Honglin; Pharoah, Paul D.] Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Dept Oncol, Cambridge CB2 1TN, England. [Weber, Rachel Palmieri; Schildkraut, Joellen M.] Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC 27710 USA. [Concannon, Patrick; du Bois, Andreas] Univ Florida, Genet Inst, Gainesville, FL 32611 USA. [Concannon, Patrick; du Bois, Andreas] Univ Florida, Dept Pathol Immunol & Lab Med, Gainesville, FL 32611 USA. [Hazelett, Dennis J.; Coetzee, Gerhard A.] Univ So Calif, Keck Sch Med, Norris Canc Ctr, Dept Urol, Los Angeles, CA 90089 USA. [Hazelett, Dennis J.; Coetzee, Gerhard A.] Univ So Calif, Keck Sch Med, Norris Canc Ctr, Dept Prevent Med, Los Angeles, CA 90089 USA. [Li, Qiyuan] Xiamen Univ, Sch Med, Xiamen 361000, Peoples R China. [Marks, Jeffrey R.] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. [Berchuck, Andrew] Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC 27710 USA. [Aben, Katja K. H.] Dept Hlth Evidence, NL-6500 HB Nijmegen, Netherlands. [Aben, Katja K. H.; Ziogas, Argyrios] Ctr Comprehens Canc, NL-3542 EG Utrecht, Netherlands. [Anton-Culver, Hoda] Univ Calif Irvine, Sch Med, Genet Epidemiol Res Inst, Dept Epidemiol, Irvine, CA 92697 USA. [Antonenkova, Natalia] Byelorussian Inst Oncol & Med Radiol Aleksandrov, Minsk 223052, Byelarus. [Australian Canc Study Ovarian Canc] QIMR Berghofer Med Res Inst, Canc Div, Brisbane, Qld 4006, Australia. [Australian Ovarian Canc Study Grp] Peter MacCallum Canc Inst, East Melbourne, Vic 3002, Australia. [Bandera, Elisa V.] Rutgers Canc Inst New Jersey, Canc Prevent & Control, New Brunswick, NJ 08903 USA. [Bean, Yukie; Kellar, Melissa; Pejovic, Tanja] Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Portland, OR 97239 USA. [Bean, Yukie; Pejovic, Tanja] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97239 USA. [Beckmann, Matthias W.; Fasching, Peter A.; Hein, Alexander] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Comprehens Canc Ctr Erlangen EMN, Dept Gynecol & Obstet, D-91054 Erlangen, Germany. [Bisogna, Maria; Levine, Douglas A.] Mem Sloan Kettering Canc Ctr, Dept Surg, Gynecol Serv, New York, NY 10065 USA. [Bjorge, Line; Krakstad, Camilla; Salvesen, Helga B.; Tangen, Ingvild L.] Haukeland Hosp, Dept Gynecol & Obstet, N-5021 Bergen, Norway. [Bjorge, Line; Krakstad, Camilla; Salvesen, Helga B.; Tangen, Ingvild L.] Univ Bergen, Ctr Canc Biomarkers, Dept Clin Sci, N-5020 Bergen, Norway. [Bogdanova, Natalia; Doerk, Thilo] Hannover Med Sch, Gynaecol Res Unit, D-30625 Hannover, Germany. [Brinton, Louise A.; Wentzensen, Nicolas; Yang, Hannah] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20852 USA. [Brooks-Wilson, Angela] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC V5Z 1L3, Canada. [Brooks-Wilson, Angela] Simon Fraser Univ, Dept Biomed Physiol & Kinesiol, Burnaby, BC V5A 1S6, Canada. [Bruinsma, Fiona; Giles, Graham G.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic 3004, Australia. [Butzow, Ralf; Leminen, Arto; Nevanlinna, Heli; Pelttari, Liisa M.] Univ Helsinki, Dept Obstet & Gynecol, Helsinki 00029, Finland. [Butzow, Ralf; Leminen, Arto; Nevanlinna, Heli; Pelttari, Liisa M.] Univ Helsinki, Cent Hosp, Helsinki 00029, Finland. [Butzow, Ralf] Univ Helsinki, Cent Hosp, Dept Pathol, Helsinki 00029, Finland. [Campbell, Ian G.] Peter MacCallum Canc Ctr, Div Res, Canc Genet Lab, Melbourne, Vic 8006, Australia. [Campbell, Ian G.; Southey, Melissa C.] Univ Melbourne, Dept Pathol, Parkville, Vic 3002, Australia. [Campbell, Ian G.; Paul, James] Univ Melbourne, Dept Oncol, Sir Peter MacCallum Dept Oncol, Parkville, Vic 3002, Australia. Beatson West Scotland Canc Ctr, Canc Res UK Clin Trials Unit, Glasgow G12 0YN, Lanark, Scotland. [Chang-Claude, Jenny; Eilber, Ursula; Rudolph, Anja] German Canc Res Ctr, Div Canc Epidemiol, D-69009 Heidelberg, Germany. [Chenevix-Trench, Georgia] QIMR Berghofer Med Res Inst, Canc Div, Brisbane, Qld 4029, Australia. [Chen, Ann; Chen, Zhihua] H Lee Moffitt Canc Ctr & Res Inst, Dept Biostat, Tampa, FL 33612 USA. [Cook, Linda S.] Univ New Mexico, Dept Internal Med, Div Epidemiol & Biostat, Albuquerque, NM 87131 USA. [Cramer, Daniel W.; Terry, Kathryn L.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Cramer, Daniel W.; Terry, Kathryn L.] Brigham & Womens Hosp, Obstet & Gynecol Epidemiol Ctr, Boston, MA 02115 USA. [Cramer, Daniel W.; Terry, Kathryn L.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Cunningham, Julie M.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA. Pomeranian Med Univ, Dept Genet & Pathol, PL-70115 Szczecin, Poland. [Plisiecka-Halasa, Joanna; Lissowska, Jolanta; Budzilowska, Agnieszka; Moes-Sosnowska, Joanna; Kupryjanczyk, Jolanta] Maria Sklodowska Curie Mem Canc Ctr, Dept Canc Epidemiol & Prevent, PL-02781 Warsaw, Poland. [Plisiecka-Halasa, Joanna; Lissowska, Jolanta; Budzilowska, Agnieszka; Moes-Sosnowska, Joanna; Kupryjanczyk, Jolanta] Inst Oncol, PL-02781 Warsaw, Poland. [Dennis, Joe; Dicks, Ed; Easton, Douglas T.] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England. [Doherty, Jennifer A.] Geisel Sch Med Dartmouth, Sect Biostat & Epidemiol, Dept Community & Family Med, Lebanon, NH 03756 USA. [Harter, Philipp; Heitz, Florian] Kliniken Essen Mitte, Dept Gynecol & Gynecol Oncol, D-45136 Essen, Germany. [du Bois, Andreas; Harter, Philipp; Heitz, Florian] Dr Horst Schmidt Kliniken Wiesbaden, Dept Gynecol & Gynecol Oncol, D-65199 Wiesbaden, Germany. [Eccles, Diana; Edwards, Robert P.] Princess Anne Hosp, Wessex Clin Genet Serv, Southampton SO16 5YA, Hants, England. [Edwards, Robert P.; Cannioto, Rikki; Modugno, Francesmary] Univ Pittsburgh, Ovarian Canc Ctr Excellence, Pittsburgh, PA 15222 USA. [Ekici, Arif B.] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Inst Human Genet, D-91054 Erlangen, Germany. [Fasching, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Div Hematol & Oncol, Dept Med, Los Angeles, CA 90095 USA. [Fridley, Brooke L.] Univ Kansas, Med Ctr, Biostat & Informat Shared Resource, Kansas City, KS 66160 USA. [Gao, Yu-Tang] Shanghai Canc Inst, Shanghai 200032, Peoples R China. [Gentry-Maharaj, Aleksandra; Menon, Usha] UCL, Inst Womens Hlth, Dept Womens Canc, London W1T 7DN, England. [Giles, Graham G.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic 3010, Australia. [Goode, Ellen L.; Vierkant, Robert A.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA. [Goodman, Marc T.; Thompson, Pamela J.] 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, Community & Populat Hlth Res Inst, Dept Biomed Sci, Los Angeles, CA 90048 USA. [Hasmad, Hanis Nazihah] Canc Res Initiat Fdn, Sime Darby Med Ctr, Subang Jaya 47500, Malaysia. [Hildebrandt, Michelle A. T.; Teo, Soo-Hwang; Wu, Xifeng] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Hillemanns, Peter] Hannover Med Sch, Dept Obstet, D-30625 Hannover, Germany. [Hillemanns, Peter] Hannover Med Sch, Dept Gynaecol, D-30625 Hannover, Germany. [Hogdall, Estrid] Danish Canc Soc, Inst Canc Epidemiol, DK-2100 Copenhagen, Denmark. [Hogdall, Estrid] Univ Copenhagen, Herlev Hosp, Dept Pathol, Mol Unit, DK-2100 Copenhagen, Denmark. Univ Copenhagen, Rigshosp, Gyn Clin, DK-2100 Copenhagen, Denmark. [Hosono, Satoyo] Aichi Canc Ctr Res Inst, Div Epidemiol & Prevent, Nagoya, Aichi 4648681, Japan. [Jensen, Allan; Kjaer, Susanne Kruger] Danish Canc Soc Res Ctr, Dept Virus Lifestyle & Genes, DK-2100 Copenhagen, Denmark. [Karlan, Beth Y.; Lester, Jenny; Orsulic, Sandra; Walsh, Christine] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Los Angeles, CA 90048 USA. [Kjaer, Susanne Kruger] Univ Copenhagen, Rigshosp, Dept Gynecol, DK-2100 Copenhagen, Denmark. [Kelemen, Linda E.; Kellar, Melissa] Med Univ S Carolina, Dept Publ Hlth Sci, Charleston, SC USA. [Kelley, Joseph L.] Univ Pittsburgh, Sch Med, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA 15222 USA. [Kiemeney, Lambertus A.] Radboud Univ Nijmegen, Med Ctr, Dept Hlth Evidence, NL-6500 HB Nijmegen, Netherlands. [Kiemeney, Lambertus A.] Radboud Univ Nijmegen, Med Ctr, Dept Urol, NL-6500 HB Nijmegen, Netherlands. [Lambrechts, Diether] VIB, Vesalius Res Ctr, B-3000 Leuven, Belgium. [Lambrechts, Diether] Univ Leuven, Dept Oncol, Lab Translat Genet, B-3000 Louvain, Belgium. [Lambrechts, Sandrina; Van Nieuwenhuysen, Els; Vergote, Ignace] Univ Hosp Leuven, Dept Oncol, Div Gynecol Oncol, B-3000 Louvain, Belgium. [Le, Nhu D.] BC Canc Agcy, Canc Control Res, Vancouver, BC V5Z 1L3, Canada. [Moysich, Kirsten B.] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Liang, Dong; Sucheston, Lara] Texas So Univ, Coll Pharm & Hlth Sci, Houston, TX 77004 USA. [Lu, Karen] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA. [Massuger, Leon F. A. G.] Radboud Univ Nijmegen, Med Ctr, Dept Gynaecol, NL-6500 HB Nijmegen, Netherlands. [Matsuo, Keitaro] Kyushu Univ, Fac Med Sci, Dept Prevent Med, Fukuoka 8128582, Japan. [McGuire, Valerie; Rothstein, Joseph H.; Sieh, Weiva; Whittemore, Alice S.] Stanford Univ, Sch Med, Dept Hlth Res & Policy Epidemiol, Stanford, CA 94305 USA. [McLaughlin, John R.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Prosserman Ctr Hlth Res, Toronto, ON M5G 1X5, Canada. [McNeish, Iain] Univ Glasgow, Wolfson Wohl Canc Res Ctr, Beatson Inst Canc Res, Inst Canc Sci, Glasgow G61 1QH, Lanark, Scotland. [Modugno, Francesmary] Magee Womens Res Inst, Womens Canc Res Program, Pittsburgh, PA 15222 USA. [Modugno, Francesmary] Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15222 USA. [Modugno, Francesmary] Univ Pittsburgh, Sch Med, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA 15222 USA. [Modugno, Francesmary] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15222 USA. [Narod, Steven A.] Womens Coll Res Inst, Toronto, ON M5G 1N8, Canada. [Nedergaard, Lotte] Univ Copenhagen, Rigshosp, Dept Pathol, DK-2100 Copenhagen, Denmark. [Ness, Roberta B.] Univ Texas Houston, Sch Publ Hlth, Houston, TX 77225 USA. [Azmi, Mat Adenan Noor; Woo, Yin-Ling] Univ Malaya, Med Ctr, Dept Obstet & Gynaecol, Kuala Lumpur 50603, Malaysia. [Odunsi, Kunle] Roswell Pk Canc Inst, Dept Gynecol Oncol, Buffalo, NY 14263 USA. [Olson, Sara H.; Orlow, Irene; Pike, Malcolm C.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10065 USA. [Pearce, Celeste L.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Permuth-Wey, Jennifer; Phelan, Catherine M.; Sellers, Thomas A.] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL 33612 USA. [Poole, Elizabeth M.; Tworoger, Shelley S.] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Poole, Elizabeth M.; Tworoger, Shelley S.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Poole, Elizabeth M.; Tworoger, Shelley S.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Risch, Harvey A.] Yale Univ, Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT 06520 USA. [Rosen, Barry] Princess Margaret Hosp, Dept Gynecol Oncol, Toronto, ON M5G 1X6, Canada. [Rosen, Barry] Univ Toronto, Fac Med, Dept Obstet & Gynecol, Toronto, ON M5G 1X6, Canada. [Rossing, Mary Anne] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Program Epidemiol, Seattle, WA 98109 USA. [Rossing, Mary Anne; Wicklund, Kristine G.] Univ Washington, Dept Epidemiol, Seattle, WA 98109 USA. [Runnebaum, Ingo B.] Univ Jena, Jena Univ Hosp, Dept Gynaecol, D-07743 Jena, Germany. [Shu, Xiao-Ou; Zheng, Wei] Vanderbilt Univ, Sch Med, Div Epidemiol, Dept Med,Vanderbilt Epidemiol Ctr, Nashville, TN 37203 USA. [Shu, Xiao-Ou; Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37203 USA. [Shvetsov, Yurii B.; Wilkens, Lynne R.] Univ Hawaii, Ctr Canc, Canc Epidemiol Program, Honolulu, HI 96826 USA. [Siddiqui, Nadeem] Glasgow Royal Infirm, Dept Gynaecol Oncol, Glasgow G4 0SF, Lanark, Scotland. [Teo, Soo-Hwang; Woo, Yin-Ling] Univ Malaya, Canc Res Inst, Fac Med, Med Ctr, Kuala Lumpur 50603, Malaysia. [Timorek, Agnieszka] Med Univ Warsaw, IInd Fac Med, Dept Obstet Gynecol & Oncol, PL-03242 Warsaw, Poland. [Timorek, Agnieszka] Brodnowski Hosp, PL-03242 Warsaw, Poland. [Wang-Gohrke, Shan] Univ Ulm, Dept Obstet & Gynecol, D-89075 Ulm, Germany. Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Monteiro, Alvaro N. A.] H Lee Moffitt Canc Ctr & Res Inst, Div Populat Sci, Canc Epidemiol Program, Tampa, FL 33612 USA. [Monteiro, Alvaro N. A.] Res Inst, Tampa, FL 33612 USA. [Schildkraut, Joellen M.] Duke Canc Inst, Canc Control & Populat Sci, Durham, NC 27710 USA. RP Schildkraut, JM (reprint author), Duke Canc Inst, Canc Control & Populat Sci, Durham, NC 27710 USA. EM jms2yf@virginia.edu RI U-ID, Kyushu/C-5291-2016; Teo, Soo-hwang/H-2353-2014; Aben, Katja/G-9686-2016; Bowtell, David/H-1007-2016; Hein, Alexander/F-6999-2010; Dork, Thilo/J-8620-2012; Gronwald, Jacek/A-4576-2017; Bjorge, Line/C-1307-2017; salvesen, Helga/C-1187-2017; Bandera, Elisa/M-4169-2014; Brooks-Wilson, Angela/E-9399-2012; OI Aben, Katja/0000-0002-0214-2147; Bowtell, David/0000-0001-9089-7525; Hein, Alexander/0000-0003-2601-3398; Gronwald, Jacek/0000-0002-3643-2871; Bjorge, Line/0000-0002-0240-2770; salvesen, Helga/0000-0002-4438-8831; Glasspool, Rosalind/0000-0002-5000-1680; Bandera, Elisa/0000-0002-8789-2755; Brooks-Wilson, Angela/0000-0003-1009-6408; Orlow, Irene/0000-0001-6234-6961; Krakstad, Camilla/0000-0002-0174-8139 FU Genetic Associations and Mechanisms in Oncology (GAME-ON): a NCI Cancer Post-GWAS Initiative [U19-CA148112]; COGS project through a European Commission's Seventh Framework Programme grant [223175-HEALTH-F2-2009-223175]; Ovarian Cancer Research Fund [PPD/RPCI.07]; Department of Defense Award [W81XWH-12-1-0561, W81XWH-07-0449]; National Institutes of Health [K07-CA080668, K07-CA095666, K07-CA143047, K22-CA138563]; Department of Defense [W81XWH-12-1-0561, DAMD17-02-1-0666, DAMD17-02-1-0669, W81XWH-10-1-02802]; California Cancer Research Program [00-01389V-20170, 2II0200]; Cancer Prevention Institute of California; 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, R01-CA092044, R01-CA112523, R01-CA122443, R01-CA126841, R01-CA16056]; Rutgers Cancer Institute of New Jersey; US Public Health Service [PSA-042205]; National Cancer Institute [1K99CA184415-01]; National Health and Medical Research Council; National Center for Advancing Translational Sciences (NCATS) [UL1TR000124]; National Center for Research Resources / General Clinical Research Center [R01-CA54419, R01-CA58598, R01-CA61132, R01-CA76016, R01-CA83918, R01-CA87538, R01-CA95023, R01-CA063678, R01 CA114343, R03-CA113148, R03-CA115195, U01-CA69417, U01-CA71966, UM1-CA182910] FX The scientific development and funding for this project were supported by the following: the Genetic Associations and Mechanisms in Oncology (GAME-ON): a NCI Cancer Post-GWAS Initiative (U19-CA148112); the COGS project 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 (PPD/RPCI.07); and Department of Defense Award (W81XWH-12-1-0561, W81XWH-07-0449). F.M. was supported by National Institutes of Health K07-CA080668; S.S.T. and E.M.P. were supported in part by Department of Defense Award W81XWH-12-1-0561. Funding of the constituent studies was provided by: 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 grant LVS-39420; Mayo Foundation; Minnesota Ovarian Cancer Alliance; National Institutes of Health (K07-CA095666, K07-CA143047, K22-CA138563); 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, R01-CA063678, R01 CA114343, R03-CA113148, R03-CA115195, U01-CA69417, U01-CA71966), UM1-CA182910; Rutgers Cancer Institute of New Jersey; and the US Public Health Service (PSA-042205). Personal support: K.L is supported by a K99/R00 grant from the National Cancer Institute (Grant number 1K99CA184415-01). D.F.E. is a Principal Research Fellow of Cancer Research UK. G.C.-T. and P.M.W. are supported by the National Health and Medical Research Council. B.K. holds an American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124. NR 51 TC 5 Z9 5 U1 2 U2 11 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 EI 1460-2180 J9 CARCINOGENESIS JI Carcinogenesis PD NOV PY 2015 VL 36 IS 11 BP 1341 EP 1353 DI 10.1093/carcin/bgv138 PG 13 WC Oncology SC Oncology GA CY4OF UT WOS:000366386800011 PM 26424751 ER PT J AU Selmansberger, M Braselmann, H Hess, J Bogdanova, T Abend, M Tronko, M Brenner, A Zitzelsberger, H Unger, K AF Selmansberger, Martin Braselmann, Herbert Hess, Julia Bogdanova, Tetiana Abend, Michael Tronko, Mykola Brenner, Alina Zitzelsberger, Horst Unger, Kristian TI Genomic copy number analysis of Chernobyl papillary thyroid carcinoma in the Ukrainian-American Cohort SO CARCINOGENESIS LA English DT Article ID ARRAY-CGH; GENE-EXPRESSION; CANCER; ACCIDENT; RET/PTC; RADIATION; I-131; RISK; REARRANGEMENTS; EXPOSURE AB One of the major consequences of the 1986 Chernobyl reactor accident was a dramatic increase in papillary thyroid carcinoma (PTC) incidence, predominantly in patients exposed to the radioiodine fallout at young age. The present study is the first on genomic copy number alterations (CNAs) of PTCs of the Ukrainian-American cohort (UkrAm) generated by array comparative genomic hybridization (aCGH). Unsupervised hierarchical clustering of CNA profiles revealed a significant enrichment of a subgroup of patients with female gender, long latency (>17 years) and negative lymph node status. Further, we identified single CNAs that were significantly associated with latency, gender, radiation dose and BRAF V600E mutation status. Multivariate analysis revealed no interactions but additive effects of parameters gender, latency and dose on CNAs. The previously identified radiation-associated gain of the chromosomal bands 7q11.22-11.23 was present in 29% of cases. Moreover, comparison of our radiation-associated PTC data set with the TCGA data set on sporadic PTCs revealed altered copy numbers of the tumor driver genes NF2 and CHEK2. Further, we integrated the CNA data with transcriptomic data that were available on a subset of the herein analyzed cohort and did not find statistically significant associations between the two molecular layers. However, applying hierarchical clustering on a 'BRAF-like/RAS-like' transcriptome signature split the cases into four groups, one of which containing all BRAF-positive cases validating the signature in an independent data set. C1 [Selmansberger, Martin; Braselmann, Herbert; Hess, Julia; Zitzelsberger, Horst; Unger, Kristian] German Res Ctr Environm Hlth GmbH, Res Unit Radiat Cytogenet, Helmholtz Zentrum Munchen, D-85764 Neuherberg, Germany. [Bogdanova, Tetiana; Tronko, Mykola] Natl Acad Med Sci Ukraine, Inst Endocrinol & Metab, UA-254114 Kiev, Ukraine. [Abend, Michael] Bundeswehr Inst Radiobiol, D-80937 Munich, Germany. [Brenner, Alina] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Unger, K (reprint author), German Res Ctr Environm Hlth GmbH, Res Unit Radiat Cytogenet, Helmholtz Zentrum Munchen, D-85764 Neuherberg, Germany. EM unger@helmholtz-muenchen.de OI HeSS, Julia/0000-0001-9860-1426; Unger, Kristian/0000-0002-0374-2320 FU European Commission, EpiRadBio project [FP7 269553]; European Commission, DoReMi project [249689] FX European Commission, EpiRadBio project (FP7 269553); European Commission, DoReMi project (249689). NR 38 TC 2 Z9 4 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 EI 1460-2180 J9 CARCINOGENESIS JI Carcinogenesis PD NOV PY 2015 VL 36 IS 11 BP 1381 EP 1387 DI 10.1093/carcin/bgv119 PG 7 WC Oncology SC Oncology GA CY4OF UT WOS:000366386800015 PM 26320103 ER PT J AU Meeks, KAC Stronks, K Beune, EJAJ Adeyemo, A Henneman, P Mannens, MMAM Nicolaou, M Peters, RJG Rotimi, CN Snijder, MB Agyemang, C AF Meeks, Karlijn A. C. Stronks, Karien Beune, Erik J. A. J. Adeyemo, Adebowale Henneman, Peter Mannens, Marcel M. A. M. Nicolaou, Mary Peters, Ron J. G. Rotimi, Charles N. Snijder, Marieke B. Agyemang, Charles TI Prevalence of type 2 diabetes and its association with measures of body composition among African residents in the Netherlands - The HELIUS study SO DIABETES RESEARCH AND CLINICAL PRACTICE LA English DT Article DE Type 2 diabetes; Africans; Body fat; Body fat distribution ID BIOELECTRICAL-IMPEDANCE ANALYSIS; DIFFERENT ETHNIC-GROUPS; HEALTH; OBESITY; RISK; ADULTS; AMERICAN; GLUCOSE; WOMEN; FAT AB Aims: To compare type 2 diabetes prevalence among three ethnic groups resident in the Netherlands: Ghanaians, African Surinamese and Dutch origin. Secondly, to determine the contribution of measures of body composition to ethnic differences in type 2 diabetes. Methods: Baseline data from Ghanaian (n = 1873), African Surinamese (n = 2189) and Dutch (n = 2151) origin participants of the HELIUS study (aged 18-70 years) were analyzed. Type 2 diabetes was determined according to the WHO criteria. Logistic regression tested ethnic differences in type 2 diabetes and the contribution of body fat percentage and waist-to-hip ratio. Results: Among men, type 2 diabetes prevalence was higher in Ghanaians (14.9%) than in African Surinamese (10.4%) and Dutch (5.0%). Among women, type 2 diabetes prevalence in Ghanaian (11.1%) was higher than in Dutch (2.3%), but similar to African Surinamese (11.5%). After adjusting for age, body fat percentage and waist-to-hip ratio, the odds ratios for having type 2 diabetes were 1.55 (95% CI: 1.12-2.15) for Ghanaian men compared with African Surinamese and 4.19 (95% CI: 2.86-6.12) compared with Dutch. Among women these odds ratios were 0.94 (95% CI: 0.70-1.26) and 4.78 (95% CI: 2.82-8.11). Conclusions: The higher prevalence of type 2 diabetes among Ghanaian compared with African Surinamese men suggests a need to distinguish between African descent populations when assessing their type 2 diabetes risk. The higher odds for type 2 diabetes among Ghanaians cannot be attributed to differences in body composition. Further research on the contribution of lifestyle factors as well as genetic and epigenetic factors is needed to identify the reasons for the observed disparities. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Meeks, Karlijn A. C.; Stronks, Karien; Beune, Erik J. A. J.; Nicolaou, Mary; Snijder, Marieke B.; Agyemang, Charles] Univ Amsterdam, Acad Med Ctr, Dept Publ Hlth, NL-1105 AZ Amsterdam, Netherlands. [Adeyemo, Adebowale; Rotimi, Charles N.] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. [Henneman, Peter; Mannens, Marcel M. A. M.] Univ Amsterdam, Acad Med Ctr, Dept Clin Genet, NL-1105 AZ Amsterdam, Netherlands. [Peters, Ron J. G.] Univ Amsterdam, Acad Med Ctr, Dept Cardiol, NL-1105 AZ Amsterdam, Netherlands. RP Meeks, KAC (reprint author), Meibergdreef 15, NL-1105 AZ Amsterdam, Netherlands. EM k.a.meeks@amc.uva.nl; k.stronks@amc.uva.nl; e.j.beune@amc.uva.nl; adeyemoa@mail.nih.gov; p.henneman@amc.uva.nl; m.a.mannens@amc.uva.nl; m.nicolaou@amc.uva.nl; r.j.peters@amc.uva.nl; rotimic@mail.nih.gov; m.b.snijder@amc.uva.nl; c.o.agyemang@amc.uva.nl OI Adeyemo, Adebowale/0000-0002-3105-3231 FU Dutch Heart Foundation [2010T084]; the Netherlands Organization for Health Research and Development (ZonMw) [200500003]; European Union (FP-7) [278901] FX The HELIUS study is conducted by the Academic Medical Centre Amsterdam and the Public Health Service of Amsterdam. Both organizations provided core support for HELIUS. The HELIUS study is also funded by the Dutch Heart Foundation (grant number: 2010T084), the Netherlands Organization for Health Research and Development (ZonMw) (grant number: 200500003), and the European Union (FP-7) (grant number: 278901). We gratefully acknowledge the AMC Biobank for their support in biobank management and high-quality storage of collected samples. We are most grateful to the participants of the HELIUS study and the management team, research nurses, interviewers, research assistants and other staff who have taken part in gathering the data of this study. We thank Wim B. Busschers of Academic Medical Centre, Department of Public Health, for helping with the statistical analysis for this manuscript. NR 47 TC 2 Z9 2 U1 0 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 NOV PY 2015 VL 110 IS 2 BP 137 EP 146 DI 10.1016/j.diabres.2015.09.017 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CY3NS UT WOS:000366317100005 PM 26432411 ER PT J AU Donigan, KA Cerritelli, SM McDonald, JP Vaisman, A Crouch, RJ Woodgate, R AF Donigan, Katherine A. Cerritelli, Susana M. McDonald, John P. Vaisman, Alexandra Crouch, Robert J. Woodgate, Roger TI Unlocking the steric gate of DNA polymerase eta leads to increased genomic instability in Saccharomyces cerevisiae SO DNA REPAIR LA English DT Article DE Y-family DNA polymerase; Translesion DNA synthesis; Ribonucleotide excision repair; DNA polymerase eta; Cyclobutane pyrimidine timer; RNase H2 ID RIBONUCLEOTIDE EXCISION-REPAIR; FRAGILE SITE STABILITY; ESCHERICHIA-COLI DINB; INTACT YEAST-CELLS; Y-FAMILY; RNASE H2; POL-ETA; THYMINE DIMER; ERROR-PRONE; BYPASS AB DNA polymerase eta (pol eta) is best characterized for its ability to perform accurate and efficient translesion DNA synthesis (TLS) through cyclobutane pyrimidine dimers (CPDs). To ensure accurate bypass the polymerase is not only required to select the correct base, but also discriminate between NTPs and dNTPs. Most DNA polymerases have a conserved "steric gate" residue which functions to prevent incorporation of NMPs during DNA synthesis. Here, we demonstrate that the Phe35 residue of Saccharomyces cerevisiae pol eta functions as a steric gate to limit the use of ribonucleotides during polymerization both in vitro and in vivo. Unlike the related pol eta enzyme, wild-type pol eta does not readily incorporate NMPs in vitro. In contrast, a pol eta F35A mutant incorporates NMPs on both damaged and undamaged DNA in vitro with a high degree of base selectivity. An S.cerevisiae strain expressing pol eta F35A (rad30-F35A) that is also deficient for nucleotide excision repair (rad1 Delta) and the TLS polymerase, pol zeta (rev3 Delta), is extremely sensitive to UV-light. The sensitivity is due, in part, to RNase H2 activity, as an isogenic rnh201 Delta strain is roughly 50-fold more UV-resistant than its RNH201(+) counterpart. Interestingly the rad1 Delta rev3 Delta rad30-F35A rnh201 Delta strain exhibits a significant increase in the extent of spontaneous mutagenesis with a spectrum dominated by 1 bp deletions at runs of template Ts. We hypothesize that the increased mutagenesis is due to rA incorporation at these sites and that the short poly rA tract is subsequently repaired in an error-prone manner by a novel repair pathway that is specifically targeted to polyribonucleotide tracks. These data indicate that under certain conditions, pol eta can compete with the cell's replicases and gain access to undamaged genomic DNA. Such observations are consistent with a role for pol eta in replicating common fragile sites (CFS) in human cells. Published by Elsevier B.V. C1 [Donigan, Katherine A.; McDonald, John P.; Vaisman, Alexandra; Woodgate, Roger] NICHHD, Lab Genom Integr, NIH, Bethesda, MD 20892 USA. [Cerritelli, Susana M.; Crouch, Robert J.] NICHHD, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. RP Woodgate, R (reprint author), NICHHD, Lab Genom Integr, NIH, Bethesda, MD 20892 USA. EM woodgate@nih.gov FU National Institute of Child Health and Human Development/National Institutes of Health Intramural Research Program; National Institute of Child Health and Human Development Intramural Research Program FX This work was supported by the National Institute of Child Health and Human Development/National Institutes of Health Intramural Research Program to R.W. and R.C. Funding for open access charge: National Institute of Child Health and Human Development Intramural Research Program. NR 52 TC 5 Z9 5 U1 4 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 EI 1568-7856 J9 DNA REPAIR JI DNA Repair PD NOV PY 2015 VL 35 BP 1 EP 12 DI 10.1016/j.dnarep.2015.07.002 PG 12 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA CX9YO UT WOS:000366062900002 PM 26340535 ER PT J AU Caglayan, M Wilson, SH AF Caglayan, Melike Wilson, Samuel H. TI Oxidant and environmental toxicant-induced effects compromise DNA ligation during base excision DNA repair SO DNA REPAIR LA English DT Article DE Base excision repair (BER); DNA polymerase beta (pol beta); DNA ligase; 8-oxo-7,8-dihydro-2 '-deoxyguanosine (8-oxoG); Ligation failure; Abortive ligation products ID STRAND BREAK REPAIR; TEMPLATING 8-OXOGUANINE LESION; POLYMERASE ACTIVE-SITE; ABASIC SITES; APURINIC/APYRIMIDINIC ENDONUCLEASE-1; NEURODEGENERATIVE DISEASE; APRATAXIN DEFICIENCY; CATALYTIC MECHANISM; AP ENDONUCLEASE-1; OXIDATIVE DAMAGE AB DNA lesions arise from many endogenous and environmental agents, and such lesions can promote deleterious events leading to genomic instability and cell death. Base excision repair (BER) is the main DNA repair pathway responsible for repairing single strand breaks, base lesions and abasic sites in mammalian cells. During BER, DNA substrates and repair intermediates are channeled from one step to the next in a sequential fashion so that release of toxic repair intermediates is minimized. This includes handoff of the product of gap-filling DNA synthesis to the DNA ligation step. The conformational differences in DNA polymerase beta (pol beta) associated with incorrect or oxidized nucleotide (8-oxodGMP) insertion could impact channeling of the repair intermediate to the final step of BER, i.e., DNA ligation by DNA ligase I or the DNA Ligase III/XRCC1 complex. Thus, modified DNA ligase substrates produced by faulty pol beta gap-filling could impair coordination between pol beta and DNA ligase. Ligation failure is associated with 5'-AMP addition to the repair intermediate and accumulation of strand breaks that could be more toxic than the initial DNA lesions. Here, we provide an overview of the consequences of ligation failure in the last step of BER. We also discuss DNA-end processing mechanisms that could play roles in reversal of impaired BER. Published by Elsevier B.V. C1 [Caglayan, Melike; Wilson, Samuel H.] NIEHS, Genome Integr & Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Wilson, SH (reprint author), NIEHS, Genome Integr & Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01-ES050158, Z01-ES050159] FX This research was supported by grants Z01-ES050158 and Z01-ES050159 from the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 73 TC 5 Z9 7 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 EI 1568-7856 J9 DNA REPAIR JI DNA Repair PD NOV PY 2015 VL 35 BP 85 EP 89 DI 10.1016/j.dnarep.2015.09.010 PG 5 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA CX9YO UT WOS:000366062900011 PM 26466358 ER PT J AU Song, T Lee, M Jeon, HS Park, Y Dodd, LE Dartois, V Follman, D Wang, J Cai, Y Goldfeder, LC Olivier, KN Xie, YD Via, LE Cho, SN Barry, CE Chen, RY AF Song, Taeksun Lee, Myungsun Jeon, Han-Seung Park, Yumi Dodd, Lori E. Dartois, Veronique Follman, Dean Wang, Jing Cai, Ying Goldfeder, Lisa C. Olivier, Kenneth N. Xie, Yingda Via, Laura E. Cho, Sang Nae Barry, Clifton E., III Chen, Ray Y. TI Linezolid Trough Concentrations Correlate with Mitochondrial Toxicity-Related Adverse Events in the Treatment of Chronic Extensively Drug-Resistant Tuberculosis SO EBIOMEDICINE LA English DT Article DE Mitochondrial toxicity; Adverse events; Linezolid; Tuberculosis; Drug resistant; Therapeutic drug monitoring ID DNA A2706G POLYMORPHISM; PROTEIN-SYNTHESIS; LACTIC-ACIDOSIS; XDR-TB; INHIBITION; SAFETY; OXAZOLIDINONES; TOLERABILITY; INFECTIONS; EFFICACY AB Long-term linezolid use is limited by mitochondrial toxicity-associated adverse events (AEs). Within a prospective, randomized controlled trial of linezolid to treat chronic extensively drug-resistant tuberculosis, we serially monitored the translational competence of mitochondria isolated from peripheral blood of participants by determining the cytochrome c oxidase/citrate synthase activity ratio. We compared this ratio with AEs associated with mitochondrial dysfunction. Linezolid trough concentrations were determined for 38 participants at both 600 mg and 300 mg doses. Those on 600 mg had a significantly higher risk of AE than those on 300 mg (HR 3 . 10, 95% CI 1 . 23-7 . 86). Mean mitochondrial function levels were significantly higher in patients before starting linezolid compared to their concentrations on 300 mg (P = 0 . 004) or 600 mg (P < 0 . 0001). Increasing mean linezolid trough concentrations were associated with lower mitochondrial function levels (Spearman's rho = -0.48; P = 0.005). Mitochondrial toxicity risk increased with increasing linezolid trough concentrations, with all patients with mean linezolid trough >2 mu g/ml developing an AE related to mitochondrial toxicity, whether on 300 mg or 600mg. Therapeutic drug monitoring may be useful to prevent the development of mitochondrial toxicity associated with long-term linezolid use. Published by Elsevier B.V. C1 [Song, Taeksun; Lee, Myungsun; Jeon, Han-Seung; Park, Yumi] Int TB Res Ctr, Chang Won, South Korea. [Dodd, Lori E.; Follman, Dean] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Dartois, Veronique] Rutgers, Publ Hlth Res Inst, New Jersey Med Sch, Newark, NJ USA. [Wang, Jing] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Clin Res Directorate, Clin Monitoring Res Program, Frederick, MD USA. [Cai, Ying; Goldfeder, Lisa C.; Xie, Yingda; Via, Laura E.; Barry, Clifton E., III; Chen, Ray Y.] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Olivier, Kenneth N.] NHLBI, Cardiovasc & Pulm Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Cho, Sang Nae] Yonsei Univ, Coll Med, Dept Microbiol, Seoul, South Korea. [Cho, Sang Nae] Yonsei Univ, Coll Med, Inst Immunol & Immunol Dis, Seoul, South Korea. [Via, Laura E.; Barry, Clifton E., III] Univ Cape Town, Fac Hlth Sci, Dept Clin Lab Sci, ZA-7701 Cape Town, South Africa. RP Chen, RY (reprint author), 9000 Rockville Pike,MSC 3206,Bldg 33,Rm 2W20, Bethesda, MD 20892 USA. EM ray.chen@nih.gov FU CCR NIH HHS [HHSN261200800001C]; NCI NIH HHS [HHSN261200800001E]; PHS HHS [HHSN261200800001E] NR 34 TC 9 Z9 9 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2352-3964 J9 EBIOMEDICINE JI EBioMedicine PD NOV PY 2015 VL 2 IS 11 BP 1627 EP 1633 DI 10.1016/j.ebiom.2015.09.051 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA CX8OA UT WOS:000365962100027 PM 26870788 ER PT J AU Huang, RY Wei, YY Hung, RJ Liu, G Su, L Zhang, RY Zong, XC Zhang, ZF Morgenstern, H Bruske, I Heinrich, J Hong, YC Kim, JH Cote, M Wenzlaff, A Schwartz, AG Stucker, I Mclaughlin, LJ Marcus, MW Davies, MPA Liloglou, T Field, JK Matsuo, K Barnett, M Thornquist, M Goodman, G Wang, Y Chen, SZ Yang, P Duell, EJ Andrew, AS Lazarus, P Muscat, J Woll, P Horsman, J Teare, MD Flugelman, A Rennert, G Zhang, Y Brenner, H Stegmaier, C van der Heijden, EHFM Aben, K Kiemeney, L Barros-Dios, J Perez-Rios, M Ruano-Ravina, A Caporaso, NE Bertazzi, PA Landi, MT Dai, JC Shen, HB Fernandez-Tardon, G Rodriguez-Suarez, M Tardon, A Christiani, DC AF Huang, Ruyi Wei, Yongyue Hung, Rayjean J. Liu, Geoffrey Su, Li Zhang, Ruyang Zong, Xuchen Zhang, Zuo-Feng Morgenstern, Hal Brueske, Irene Heinrich, Joachim Hong, Yun-Chul Kim, Jin Hee Cote, Michele Wenzlaff, Angela Schwartz, Ann G. Stucker, Isabelle Mclaughlin, L. John Marcus, Michael W. Davies, Michael P. A. Liloglou, Triantafillos Field, John K. Matsuo, Keitaro Barnett, Matt Thornquist, Mark Goodman, Gary Wang, Yi Chen, Size Yang, Ping Duell, Eric J. Andrew, Angeline S. Lazarus, Philip Muscat, Joshua Woll, Penella Horsman, Janet Teare, M. Dawn Flugelman, Anath Rennert, Gad Zhang, Yan Brenner, Hermann Stegmaier, Christa van der Heijden, Erik H. F. M. Aben, Katja Kiemeney, Lambertus Barros-Dios, Juan Perez-Rios, Monica Ruano-Ravina, Alberto Caporaso, Neil E. Bertazzi, Pier Alberto Landi, Maria Teresa Dai, Juncheng Shen, Hongbing Fernandez-Tardon, Guillermo Rodriguez-Suarez, Marta Tardon, Adonina Christiani, David C. TI Associated Links Among Smoking, Chronic Obstructive Pulmonary Disease, and Small Cell Lung Cancer: A Pooled Analysis in the International Lung Cancer Consortium SO EBIOMEDICINE LA English DT Article DE Smoking behaviors; Chronic obstructive pulmonary disease; Small cell lung cancer risk; Multicenter pooling; Causal mediation analysis ID GENETIC SUSCEPTIBILITY; RESIDENTIAL RADON; HEAVY SMOKERS; DNA-REPAIR; RISK; POPULATION; COPD; COHORT; VARIANTS; HEALTH AB Background: The high relapse and mortality rate of small-cell lung cancer (SCLC) fuels the need for epidemiologic study to aid in its prevention. Methods: We included 24 studies from the ILCCO collaboration. Random-effects panel logistic regression and cubic spline regression were used to estimate the effects of smoking behaviors on SCLC risk and explore their non-linearity. Further, we explored whether the risk of smoking on SCLC was mediated through COPD. Findings: Significant dose-response relationships of SCLC risk were observed for all quantitative smoking variables. Smoking pack-years were associated with a sharper increase of SCLC risk for pack-years ranged 0 to approximately 50. The former smokers with longer cessation showed a 43%(quit_for_5-9 years) to 89%(quit_for_>= 20 years) declined SCLC risk vs. subjects who had quit smoking <5 years. Compared with non-COPD subjects, smoking behaviors showed a significantly higher effect on SCLC risk among COPD subjects, and further, COPD patients showed a 1.86-fold higher risk of SCLC. Furthermore, smoking behaviors on SCLC risk were significantly mediated through COPD which accounted for 0.70% to 7.55% of total effects. Interpretation: This is the largest pooling study that provides improved understanding of smoking on SCLC, and further demonstrates a causal pathway through COPD that warrants further experimental study. (C) 2015 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 [Huang, Ruyi; Wei, Yongyue; Su, Li; Zhang, Ruyang; Christiani, David C.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Huang, Ruyi] E Da Hosp, Dept Med Educ, Kaohsiung, Taiwan. [Huang, Ruyi] I Shou Univ, Kaohsiung, Taiwan. [Hung, Rayjean J.; Zong, Xuchen] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada. [Liu, Geoffrey] Univ Toronto, Princess Margaret Canc Ctr, Univ Hlth Network, Toronto, ON, Canada. [Zhang, Zuo-Feng] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Jonsson Comprehens Canc Ctr, Dept Epidemiol, Los Angeles, CA USA. [Morgenstern, Hal] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Morgenstern, Hal] Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA. [Brueske, Irene; Heinrich, Joachim] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 1, Neuherberg, Germany. [Hong, Yun-Chul] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul 151, South Korea. [Kim, Jin Hee] Seoul Natl Univ, Grad Sch Publ Hlth, Dept Environm Hlth, Seoul, South Korea. [Cote, Michele; Wenzlaff, Angela; Schwartz, Ann G.] Wayne State Univ, Barbara Ann Karmanos Canc Inst, Detroit, MI USA. [Cote, Michele; Wenzlaff, Angela; Schwartz, Ann G.] Wayne State Univ, Dept Oncol, Detroit, MI USA. [Stucker, Isabelle] French Inst Hlth & Med Res, Ctr Res Epidemiol & Populat Hlth, Villejuif, France. [Mclaughlin, L. John] Publ Hlth Ontario, Toronto, ON, Canada. [Marcus, Michael W.; Davies, Michael P. A.; Liloglou, Triantafillos; Field, John K.] Univ Liverpool, Inst Translat Med, Dept Mol & Clin Canc Med, Liverpool L69 3BX, Merseyside, England. [Matsuo, Keitaro] Aichi Canc Ctr, Res Inst, Div Mol Med, Nagoya, Aichi 464, Japan. [Barnett, Matt; Thornquist, Mark; Goodman, Gary] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Wang, Yi; Chen, Size; Yang, Ping] Mayo Clin, Dept Hlth Sci Res, Div Epidemiol, Rochester, MN USA. [Wang, Yi] Wenzhou Med Univ, Sch Environm Sci & Publ Hlth, Wenzhou, Peoples R China. [Chen, Size] Guangdong Pharmaceut Univ, Affiliated Hosp 1, Dept Oncol, Guangzhou, Guangdong, Peoples R China. [Duell, Eric J.] Catalan Inst Oncol ICO IDIBELL, Unit Nutr & Canc, Barcelona, Spain. [Andrew, Angeline S.] Dartmouth Coll, Norris Cotton Canc Ctr, Geisel Sch Med, Lebanon, NH 03756 USA. [Lazarus, Philip; Muscat, Joshua] Penn State Coll Med, Hershey, PA USA. [Woll, Penella; Horsman, Janet; Teare, M. Dawn] Univ Sheffield, Sheffield Sch Hlth & Related Res, Expt Canc Med Ctr, Sheffield, S Yorkshire, England. [Flugelman, Anath; Rennert, Gad] Carmel Hosp, Clalit Natl Israeli Canc Control Ctr, Haifa, Israel. [Flugelman, Anath; Rennert, Gad] Technion Israel Inst Technol, IL-32000 Haifa, Israel. [Zhang, Yan; Brenner, Hermann] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Brenner, Hermann] German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany. [Stegmaier, Christa] Saarland Canc Registry, Saarbrucken, Germany. [van der Heijden, Erik H. F. M.; Aben, Katja; Kiemeney, Lambertus] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, NL-6525 ED Nijmegen, Netherlands. [Aben, Katja] Netherlands Comprehens Canc Org, Utrecht, Netherlands. [Barros-Dios, Juan; Perez-Rios, Monica; Ruano-Ravina, Alberto] Univ Hosp Complex Santiago Compostela, Serv Prevent Med, Santiago De Compostela, Spain. [Caporaso, Neil E.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. [Bertazzi, Pier Alberto; Landi, Maria Teresa] Osped Maggiore Policlin, Fdn IRCCS Ca Granda, Epidemiol Unit, Milan, Italy. [Bertazzi, Pier Alberto; Landi, Maria Teresa] Univ Milan, Dept Clin Sci & Community Hlth, Milan, Italy. [Wei, Yongyue; Zhang, Ruyang; Dai, Juncheng; Shen, Hongbing] Nanjing Med Univ, Collaborat Innovat Ctr Canc Personalized Med, Jiangsu Key Lab Canc Biomarkers Prevent & Treatme, Dept Epidemiol & Biostat,Sch Publ Hlth, Nanjing, Jiangsu, Peoples R China. [Fernandez-Tardon, Guillermo; Tardon, Adonina; Christiani, David C.] Univ Oviedo, Dept Prevent Med & Publ Hlth, Spanish Consortium Res Epidemiol & Publ Hlth CIBE, Oviedo, Spain. [Rodriguez-Suarez, Marta] CSIC, Dept Conservat Biol, Estn Biol Donana, E-41080 Seville, Spain. [Christiani, David C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pulm & Crit Care Div,Dept Med, Boston, MA USA. [Wei, Yongyue; Zhang, Ruyang] Nanjing Med Univ, Sch Publ Hlth, Joint Lab Hlth & Environm Risk Assessment HERA, Nanjing, Jiangsu, Peoples R China. RP Christiani, DC (reprint author), 665 Huntington Ave,Bldg 1 Room, Boston, MA 02115 USA. EM dchris@hsph.harvard.edu RI van der Heijden, H.F.M. (Erik)/D-3774-2009; Hung, Rayjean/A-7439-2013; Aben, Katja/G-9686-2016; CSIC, EBD Donana/C-4157-2011; bertazzi, pietro alberto/D-5039-2017; OI van der Heijden, H.F.M. (Erik)/0000-0003-3596-518X; Aben, Katja/0000-0002-0214-2147; CSIC, EBD Donana/0000-0003-4318-6602; bertazzi, pietro alberto/0000-0003-3475-2449; Huang, Ruyi/0000-0001-6867-7171 FU Intramural NIH HHS; NCI NIH HHS [CA060691, CA074386, CA090578, CA09142, CA092824, CA167462, CA68384, CA77954, CA80127, CA84354, CA90833, CA96134, P30 CA022453, P30 CA023108, P30CA022453, R35 CA197449, U01 CA063673, UM1 CA167462]; NIDA NIH HHS [DA11386]; NIEHS NIH HHS [ES00002, ES011667]; PHS HHS [HHSN261201000028C] NR 71 TC 6 Z9 6 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2352-3964 J9 EBIOMEDICINE JI EBioMedicine PD NOV PY 2015 VL 2 IS 11 BP 1677 EP 1685 DI 10.1016/j.ebiom.2015.09.031 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA CX8OA UT WOS:000365962100033 PM 26870794 ER PT J AU Tu, HB Li, HY Wang, Y Niyyati, M Wang, YH Leshin, J Levine, M AF Tu, Hongbin Li, Hongyan Wang, Yu Niyyati, Mahtab Wang, Yaohui Leshin, Jonathan Levine, Mark TI Low Red Blood Cell Vitamin C Concentrations Induce Red Blood Cell Fragility: A Link to Diabetes Via Glucose, Glucose Transporters, and Dehydroascorbic Acid SO EBIOMEDICINE LA English DT Article DE Ascorbic Acid; Dehydroascorbic Acid; Red Blood Cells; Diabetes; Glucose Transport; beta-Spectrin ID RECOMMENDED DIETARY ALLOWANCE; ASCORBIC-ACID; HUMAN-ERYTHROCYTES; ENDOTHELIAL DYSFUNCTION; MEMBRANE-TRANSPORT; INSULIN-RESISTANCE; WATER-CONTENT; DEFORMABILITY; MELLITUS; HEMOGLOBIN AB Strategies to prevent diabetic microvascular angiopathy focus on the vascular endothelium. Because red blood cells (RBCs) are less deformable in diabetes, we explored an original concept linking decreased RBC deformability to RBC ascorbate and hyperglycemia. We characterized ascorbate concentrations from human and mouse RBCs and plasma, and showed an inverse relationship between RBC ascorbate concentrations and deformability, measured by osmotic fragility. RBCs from ascorbate deficient mice were osmotically sensitive, appeared as spherocytes, and had decreased beta-spectrin. These aberrancies reversed with ascorbate repletion in vivo. Under physiologic conditions, only ascorbate's oxidation product dehydroascorbic acid (DHA), a substrate for facilitated glucose transporters, was transported into mouse and human RBCs, with immediate intracellular reduction to ascorbate. In vitro, glucose inhibited entry of physiologic concentrations of dehydroascorbic acid into mouse and human RBCs. In vivo, plasma glucose concentrations in normal and diabetic mice and humans were inversely related to respective RBC ascorbate concentrations, as was osmotic fragility. Human RBC beta-spectrin declined as diabetes worsened. Taken together, hyperglycemia in diabetes produced lower RBC ascorbate with increased RBC rigidity, a candidate to drive microvascular angiopathy. Because glucose transporter expression, DHA transport, and its inhibition by glucose differed for mouse versus human RBCs, human experimentation is indicated. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). C1 [Tu, Hongbin; Li, Hongyan; Wang, Yu; Niyyati, Mahtab; Wang, Yaohui; Leshin, Jonathan; Levine, Mark] NIDDK, Mol & Clin Nutr Sect, Digest Dis Branch, Intramural Res Program,NIH, Bethesda, MD 20892 USA. RP Levine, M (reprint author), NIDDK, Mol & Clin Nutr Sect, Digest Dis Branch, Intramural Res Program,NIH, Bethesda, MD 20892 USA. FU Intramural NIH HHS NR 81 TC 5 Z9 5 U1 3 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2352-3964 J9 EBIOMEDICINE JI EBioMedicine PD NOV PY 2015 VL 2 IS 11 BP 1735 EP 1750 DI 10.1016/j.ebiom.2015.09.049 PG 16 WC Medicine, General & Internal SC General & Internal Medicine GA CX8OA UT WOS:000365962100039 PM 26870799 ER PT J AU Bontemps-Gallo, S Madec, E Lacroix, JM AF Bontemps-Gallo, Sebastien Madec, Edwige Lacroix, Jean-Marie TI The two-component system CpxAR is essential for virulence in the phytopathogen bacteria Dickeya dadantii EC3937 SO ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID OSMOREGULATED PERIPLASMIC GLUCANS; ENVELOPE STRESS-RESPONSE; RCSCD-RCSB PHOSPHORELAY; ERWINIA-CHRYSANTHEMI; ESCHERICHIA-COLI; SIGNAL-TRANSDUCTION; PHOP-PHOQ; ANTIMICROBIAL PEPTIDES; HAEMOPHILUS-DUCREYI; III SECRETION AB The CpxAR two-component system is present in many Proteobacteria. It controls expression of genes required to maintain envelope integrity in response to environmental injury. Consequently, this two-component system was shown to be required for virulence of several zoo-pathogens, but it has never been investigated in phyto-pathogens. In this paper, we investigate the role of the CpxAR two-component system in vitro and in vivo in Dickeya dadantii, an enterobacterial phytopathogen that causes soft-rot disease in a large variety of plant species. cpxA null mutant displays a constitutively phosphorylated CpxR phenotype as shown by direct analysis of phosphorylation of CpxR by a Phos-Tag retardation gel approach. Virulence in plants is completely abolished in cpxA or cpxR mutants of D.dadantii. In planta, CpxAR is only activated at an early stage of the infection process as shown by Phos-Tag and gene fusion analyses. To our knowledge, this is the first time that the timing of CpxAR phosphorelay activation has been investigated during the infection process by direct monitoring of response regulator phosphorylation. C1 [Bontemps-Gallo, Sebastien; Madec, Edwige; Lacroix, Jean-Marie] Univ Lille, Univ Sci & Technol Lille, UMR CNRS 8576, Unite Glycobiol Struct & Fonct, F-59655 Villeneuve Dascq, France. RP Bontemps-Gallo, S (reprint author), NIAID, Lab Zoonot Pathogens, NIH, Hamilton, MT 59840 USA. EM sebastien.bontemps-gallo@nih.gov OI bontemps-gallo, sebastien/0000-0002-1834-5416 FU Centre National de la Recherche Scientifique (CNRS); Universite de Lille 1; Ministere de l'Enseignement Superieur et de la Recherche; Lille 1 University FX The authors would like to thank Lucas Briche for technical assistance. We are grateful to Martha Thayer for the English corrections. The 'A strains' were kindly provided by Dr N. Cotte-Pattat and Dr G. Condemine (CNRS UMR 5240, University of Lyon 1). This work was supported by grants from the Centre National de la Recherche Scientifique (CNRS), the Universite de Lille 1 and the Ministere de l'Enseignement Superieur et de la Recherche. SBG was funded by post-doctoral fellowship of the Lille 1 University. The funders were not involved in the study design, data collection and analysis, decision to publish or preparation of the manuscript. NR 47 TC 4 Z9 4 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1462-2912 EI 1462-2920 J9 ENVIRON MICROBIOL JI Environ. Microbiol. PD NOV PY 2015 VL 17 IS 11 SI SI BP 4415 EP 4428 DI 10.1111/1462-2920.12874 PG 14 WC Microbiology SC Microbiology GA CY1AV UT WOS:000366139500021 PM 25856505 ER PT J AU Zimmermann, M Kuehne, A Boshoff, HI Barry, CE Zamboni, N Sauer, U AF Zimmermann, Michael Kuehne, Andreas Boshoff, Helena I. Barry, Clifton E., III Zamboni, Nicola Sauer, Uwe TI Dynamic exometabolome analysis reveals active metabolic pathways in non-replicating mycobacteria SO ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID TANDEM MASS-SPECTROMETRY; ESCHERICHIA-COLI; FUNCTIONAL GENOMICS; HIGH-THROUGHPUT; TUBERCULOSIS; SMEGMATIS; DORMANCY; MUTANTS; GROWTH; HOST AB An organism's metabolic activity leaves an extracellular footprint and dynamic changes in this exometabolome inform about nutrient uptake, waste disposal and signalling activities. Using non-targeted mass spectrometry, we report exometabolome dynamics of hypoxia-induced, non-replicating mycobacteria that are thought to play a role in latent tuberculosis. Despite evidence of active metabolism, little is known about the mechanisms enabling obligate aerobic mycobacteria to cope with hypoxia, resulting in long-term survival and increased chemotherapeutic tolerance. The dynamics of 379 extracellular compounds of Mycobacterium smegmatis were deconvoluted with a genome-scale metabolic reaction-pair network to generate hypotheses about intracellular pathway usage. Time-resolved C-13-tracing and mutant experiments then demonstrated a crucial, energy-generating role of asparagine utilization and non-generic usage of the glyoxylate shunt for hypoxic fitness. Experiments with M.bovis and M.tuberculosis revealed the general relevance of asparagine fermentation and a variable contribution of the glyoxylate shunt to non-replicative, hypoxic survival between the three species. C1 [Zimmermann, Michael; Kuehne, Andreas; Zamboni, Nicola; Sauer, Uwe] ETH, Inst Mol Syst Biol, Zurich, Switzerland. [Zimmermann, Michael; Kuehne, Andreas] Life Sci Zurich Grad Sch, PhD Program Syst Biol, Zurich, Switzerland. [Boshoff, Helena I.; Barry, Clifton E., III] NIAID, Lab Clin Infect Dis, TB Res Sect, NIH, Bethesda, MD 20892 USA. RP Sauer, U (reprint author), ETH, Inst Mol Syst Biol, Zurich, Switzerland. EM sauer@imsb.biol.ethz.ch RI Barry, III, Clifton/H-3839-2012 FU EU FP7 project SysteMTb; NIAID FX John D McKinney for genetic deletion strains of M. smegmatis and M. tuberculosis. This research was, in part, funded by EU FP7 project SysteMTb (MZ and US) and by the Intramural Research Program of NIAID (HIB and CEB). NR 42 TC 4 Z9 4 U1 4 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1462-2912 EI 1462-2920 J9 ENVIRON MICROBIOL JI Environ. Microbiol. PD NOV PY 2015 VL 17 IS 11 SI SI BP 4802 EP 4815 DI 10.1111/1462-2920.13056 PG 14 WC Microbiology SC Microbiology GA CY1AV UT WOS:000366139500047 PM 26373870 ER PT J AU Bandara, G Beaven, MA Olivera, A Gilfillan, AM Metcalfe, DD AF Bandara, Geethani Beaven, Michael A. Olivera, Ana Gilfillan, Alasdair M. Metcalfe, Dean D. TI Activated mast cells synthesize and release soluble ST2-a decoy receptor for IL-33 SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE Antigen; Human mast cells; sST2; IL-33; Stem cell factor ID FC-EPSILON-RI; ATOPIC-DERMATITIS; AIRWAY INFLAMMATION; PROMOTER USAGE; LYMPHOID-CELLS; BONE-MARROW; INTERLEUKIN-33; EXPRESSION; GENE; CYTOKINE AB IL-33 released from damaged cells plays a central role in allergic inflammation by acting through its membrane-bound receptor, ST2 receptor (ST2L). IL-33 activity can be neutralized by the soluble spliced variant of ST2 (sST2) that has been associated with allergic inflammation but its source is not well defined. We investigated whether mast cells (MCs) are a significant source of sST2 following activation through Fc epsilon RI or ST2. We find that antigen and IL-33 induce substantial production and release of sST2 from human and mouse MCs in culture and do so synergistically when added together or in combination with stem cell factor. Moreover, increases in circulating sST2 during anaphylaxis in mice were dependent on the presence of MCs. Human MCs activated via Fc epsilon RI failed to generate IL-33 and IL-33 produced by mouse bone marrow-derived MCs was retained within the cells. Therefore, Fc epsilon RI-mediated sST2 production is independent of MC-derived IL-33 acting in an autocrine manner. These results are consistent with the conclusion that both mouse and human MCs when activated are a significant inducible source of sST2 but not IL-33 and thus have the ability to modulate the biologic impact of IL-33 produced locally by other cell types during allergic inflammation. C1 [Bandara, Geethani; Olivera, Ana; Gilfillan, Alasdair M.; Metcalfe, Dean D.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Beaven, Michael A.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Bandara, G (reprint author), NIAID, Lab Allerg Dis, NIH, Bldg 10,Room 11C206,10 Ctr Dr,MSC 1881, Bethesda, MD 20892 USA. EM bandarag@niaid.nih.gov FU Division of Intramural Research programs within the National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute FX This work was supported by the Division of Intramural Research programs within the National Institute of Allergy and Infectious Diseases (to G.B., A.O., A.M.G., and D.D.M,) and National Heart, Lung, and Blood Institute (to M.A.B.). We also thank Rosa Munoz-Cano and Avanti Desai for assistance in flow cytometry analysis. NR 69 TC 6 Z9 6 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 EI 1521-4141 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD NOV PY 2015 VL 45 IS 11 BP 3034 EP 3044 DI 10.1002/eji.201545501 PG 11 WC Immunology SC Immunology GA CY4TJ UT WOS:000366401000010 PM 26256265 ER PT J AU He, XM Tillo, D Vierstra, J Syed, KS Deng, C Ray, GJ Stamatoyannopoulos, J FitzGerald, PC Vinson, C AF He, Ximiao Tillo, Desiree Vierstra, Jeff Syed, Khund-Sayeed Deng, Callie Ray, G. Jordan Stamatoyannopoulos, John FitzGerald, Peter C. Vinson, Charles TI Methylated Cytosines Mutate to Transcription Factor Binding Sites that Drive Tetrapod Evolution SO GENOME BIOLOGY AND EVOLUTION LA English DT Article DE tissue specific; TFBS; AP-1; CG methylation; coelacanth; TG dinucleotide ID NUCLEAR FACTOR-I; DNA METHYLATION; REGULATORY EVOLUTION; NUCLEOSOME OCCUPANCY; ESCHERICHIA-COLI; CPG METHYLATION; FACTOR AP-1; SP-FAMILY; GENOME; PROTEINS AB In mammals, the cytosine in CG dinucleotides is typically methylated producing 5-methylcytosine (5mC), a chemically less stable form of cytosine that can spontaneously deaminate to thymidine resulting in a T center dot G mismatched base pair. Unlike other eukaryotes that efficiently repair this mismatched base pair back to C center dot G, in mammals, 5mCG deamination is mutagenic, sometimes producing TG dinucleotides, explaining the depletion of CG dinucleotides in mammalian genomes. It was suggested that new TG dinucleotides generate genetic diversity that may be critical for evolutionary change. We tested this conjecture by examining the DNA sequence properties of regulatory sequences identified by DNase I hypersensitive sites (DHSs) in human and mouse genomes. We hypothesized that the new TG dinucleotides generate transcription factor binding sites (TFBS) that become tissue-specific DHSs (TS-DHSs). We find that 8-mers containing the CG dinucleotide are enriched in DHSs in both species. However, 8-mers containing a TG and no CG dinucleotide are preferentially enriched in TS-DHSs when compared with 8-mers with neither a TG nor a CG dinucleotide. The most enriched 8-mer with a TG and no CG dinucleotide in tissue-specific regulatory regions in both genomes is the AP-1 motif (TGA(C)/(G)TCAN), and we find evidence that TG dinucleotides in the AP-1 motif arose from CG dinucleotides. Additional TS-DHS-enriched TFBS containing the TG/CA dinucleotide are the E-Box motif (GCAGCTGC), the NF-1 motif (GGCA-TGCC), and the GR (glucocorticoid receptor) motif (G-ACA-TGT-C). Our results support the suggestion that cytosine methylation is mutagenic in tetrapods producing TG dinucleotides that create TFBS that drive evolution. C1 [He, Ximiao; Tillo, Desiree; Syed, Khund-Sayeed; Deng, Callie; Ray, G. Jordan; Vinson, Charles] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. [Vierstra, Jeff; Stamatoyannopoulos, John] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [FitzGerald, Peter C.] NCI, Genome Anal Unit, Genet Branch, NIH, Bethesda, MD 20892 USA. RP Vinson, C (reprint author), NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. EM vinsonc@mail.nih.gov FU National Institute of Health (NIH), Center for Cancer Research, National Cancer Institute FX This work was supported by the Intramural Research Program of the National Institute of Health (NIH), Center for Cancer Research, National Cancer Institute. The authors thank Dr Alison P. Lee for providing the annotations for conserved non-coding elements (CNEs) in tetrapods and Dr Sanjit Mukherjee for helpful discussion. They also thank the high-performance computational capabilities of the Helix & Biowulf Systems at the NIH, Bethesda, MD (http://helix.nih.gov). NR 81 TC 4 Z9 4 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1759-6653 J9 GENOME BIOL EVOL JI Genome Biol. Evol. PD NOV PY 2015 VL 7 IS 11 BP 3155 EP 3169 DI 10.1093/gbe/evv205 PG 15 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA CY6DR UT WOS:000366498500009 PM 26507798 ER PT J AU Jia, P Sankoh, O Tatem, AJ AF Jia, Peng Sankoh, Osman Tatem, Andrew J. TI Mapping the environmental and socioeconomic coverage of the INDEPTH international health and demographic surveillance system network SO HEALTH & PLACE LA English DT Article DE Health; Remote sensing; Africa; Asia; Demographic surveillance sites ID LAND-SURFACE TEMPERATURE; NEIGHBORHOOD GREENNESS; MALARIA TRANSMISSION; VEGETATION INDEX; DISEASE; AFRICA; EPIDEMIOLOGY; MIGRATION; BURDEN; MODIS AB The International Network for the Demographic Evaluation of Populations and their Health (INDEPTH) has produced reliable longitudinal data about the lives of people in low- and middle-income countries (LMICs) through a global network of health and demographic surveillance system (HDSS) sites. Since reliable demographic data are scarce across many LMICs, we examine the environmental and socioeconomic (ES) similarities between existing HDSS sites and the rest of the LMICs. The HDSS sites were hierarchically grouped by the similarity of their ES conditions to quantify the ES variability between sites. The entire Africa and Asia region was classified to identify which regions were most similar to existing sites, based on available ES data. Results show that the current INDEPTH network architecture does a good job in representing ES conditions, but that great heterogeneities exist, even within individual countries. The results provide valuable information in determining the confidence with which relationships derived from present HDSS sites can be broadly extended to other areas, and to highlight areas where the new HDSS sites would improve significantly the ES coverage of the network. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Jia, Peng] SUNY Buffalo, Dept Epidemiol & Environm Hlth, Buffalo, NY 14260 USA. [Sankoh, Osman] INDEPTH, Accra, Ghana. [Tatem, Andrew J.] Univ Southampton, Dept Geog & Environm, Southampton, Hants, England. [Tatem, Andrew J.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Tatem, Andrew J.] Flowminder Fdn, Stockholm, Sweden. RP Tatem, AJ (reprint author), Univ Southampton, Dept Geog & Environm, Southampton, Hants, England. OI Jia, Peng/0000-0003-0110-3637 FU NIH/NIAID [U19AI089674]; Bill & Melinda Gates Foundation [OPP1106427, 1032350]; RAPIDD program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX AJT is supported by funding from NIH/NIAID (U19AI089674), the Bill & Melinda Gates Foundation (OPP1106427, 1032350), and the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. This work forms part of the WorldPop Project (www.worldpop.org.uk) and Flowminder (www.flowminder.org). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 53 TC 1 Z9 1 U1 4 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8292 EI 1873-2054 J9 HEALTH PLACE JI Health Place PD NOV PY 2015 VL 36 BP 88 EP 96 DI 10.1016/j.healthplace.2015.09.009 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CX9BW UT WOS:000366000700010 PM 26454610 ER PT J AU Lyles, RH Van Domelen, D Mitchell, EM Schisterman, EF AF Lyles, Robert H. Van Domelen, Dane Mitchell, Emily M. Schisterman, Enrique F. TI A Discriminant Function Approach to Adjust for Processing and Measurement Error When a Biomarker is Assayed in Pooled Samples SO INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH LA English DT Article DE epidemiology; errors-in-variables; odds ratio; pooling ID BINARY REGRESSION; BIOSPECIMENS; PREVALENCE; SUBJECT; DISEASE; DESIGN; BLOOD; MODEL; SERA; RISK AB Pooling biological specimens prior to performing expensive laboratory assays has been shown to be a cost effective approach for estimating parameters of interest. In addition to requiring specialized statistical techniques, however, the pooling of samples can introduce assay errors due to processing, possibly in addition to measurement error that may be present when the assay is applied to individual samples. Failure to account for these sources of error can result in biased parameter estimates and ultimately faulty inference. Prior research addressing biomarker mean and variance estimation advocates hybrid designs consisting of individual as well as pooled samples to account for measurement and processing (or pooling) error. We consider adapting this approach to the problem of estimating a covariate-adjusted odds ratio (OR) relating a binary outcome to a continuous exposure or biomarker level assessed in pools. In particular, we explore the applicability of a discriminant function-based analysis that assumes normal residual, processing, and measurement errors. A potential advantage of this method is that maximum likelihood estimation of the desired adjusted log OR is straightforward and computationally convenient. Moreover, in the absence of measurement and processing error, the method yields an efficient unbiased estimator for the parameter of interest assuming normal residual errors. We illustrate the approach using real data from an ancillary study of the Collaborative Perinatal Project, and we use simulations to demonstrate the ability of the proposed estimators to alleviate bias due to measurement and processing error. C1 [Lyles, Robert H.; Van Domelen, Dane] Emory Univ, Rollins Sch Publ Hlth, Dept Biostat & Bioinformat, Atlanta, GA 30322 USA. [Mitchell, Emily M.; Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Res, Bethesda, MD 20892 USA. RP Lyles, RH (reprint author), Emory Univ, Rollins Sch Publ Hlth, Dept Biostat & Bioinformat, 1518 Clifton Rd NE,Mailstop 1518-002-3AA, Atlanta, GA 30322 USA. EM rlyles@sph.emory.edu; dvandom@emory.edu; emily.mitchell@nih.gov; schistee@mail.nih.gov OI Schisterman, Enrique/0000-0003-3757-641X FU National Center for Advancing Translational Sciences [UL1TR000454]; National Institute of Allergy and Infectious Diseases [P30AI050409]; Intramural Research Program of the National Institute of Environmental Health Sciences [Z01-ES040006]; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; Long-Range Research Initiative of the American Chemistry Council FX This research was supported in part by the National Center for Advancing Translational Sciences (UL1TR000454), the National Institute of Allergy and Infectious Diseases (P30AI050409), the Intramural Research Program of the National Institute of Environmental Health Sciences (Z01-ES040006), the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, and by the Long-Range Research Initiative of the American Chemistry Council. NR 27 TC 0 Z9 0 U1 0 U2 1 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1660-4601 J9 INT J ENV RES PUB HE JI Int. J. Environ. Res. Public Health PD NOV PY 2015 VL 12 IS 11 BP 14723 EP 14740 DI 10.3390/ijerph121114723 PG 18 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA CX4CJ UT WOS:000365645500072 PM 26593934 ER PT J AU Wubshet, SG Brighente, IMC Moaddel, R Staerk, D AF Wubshet, Sileshi G. Brighente, Ines M. C. Moaddel, Ruin Staerk, Dan TI Magnetic Ligand Fishing as a Targeting Tool for HPLC-HRMS-SPE-NMR: alpha-Glucosidase Inhibitory Ligands and Alkylresorcinol Glycosides from Eugenia catharinae SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID PROOF-OF-CONCEPT; PLANT-EXTRACTS; AERIAL PARTS; IDENTIFICATION; CONSTITUENTS; ASSAY; LEAVES; NANOPARTICLES; MYRTACEAE; MECHANISM AB A bioanalytical platform combining magnetic ligand fishing for alpha-glucosidase inhibition profiling and HPLC-HRMS-SPE-NMR for structural identification of alpha-glucosidase inhibitory ligands, both directly from crude plant extracts, is presented. Magnetic beads with N-terminus-coupled alpha-glucosidase were synthesized and characterized for their inherent catalytic activity. Ligand fishing with the immobilized enzyme was optimized using an artificial test mixture consisting of caffeine, ferulic acid, and luteolin before proof-of-concept with the crude extract of Eugenia catharinae. The combination of ligand fishing and HPLC-HRMS-SPE-NMR identified myricetin 3-O-alpha-L-rhamnopyranoside, myricetin, quercetin, and kaempferol as ?-glucosidase inhibitory ligands in E. catharinae. Furthermore, HPLC-HRMS-SPE-NMR analysis led to identification of six new alkylresorcinol glycosides, i.e., 5-(2-oxopentyl)resorcinol 4-O-beta-D-glucopyranoside, 5-propylresorcinol 4-O-beta-D-glucopyranoside, 5-pentylresorcinol 4-O-[alpha-D-apiofuranosyl-(1 -> 6)]-beta-d-glucopyranoside, 5-pentylresorcinol 4-O-beta-D-glucopyranoside, 4-hydroxy-3-O-methyl-5-pentylresorcinol 1-O-beta-D-glucopyranoside, and 3-O-methyl-5-pentylresorcinol 1-O-[beta-D-glucopyranosyl-(1 -> 6)]-beta-D-glucopyranoside. C1 [Wubshet, Sileshi G.; Staerk, Dan] Univ Copenhagen, Fac Hlth & Med Sci, Dept Drug Design & Pharmacol, DK-2100 Copenhagen, Denmark. [Brighente, Ines M. C.] Univ Fed Santa Catarina, Dept Quim, Lab Quim Prod Nat, BR-88040900 Florianopolis, SC, Brazil. [Moaddel, Ruin] NIA, Biomed Res Ctr, NIH, Baltimore, MD 21224 USA. RP Moaddel, R (reprint author), NIA, Biomed Res Ctr, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM moaddelru@grc.nia.nih.gov; ds@sund.ku.dk FU Carlsberg Foundation; Apotekerfonden af 1991; Danish Agency for Science, Technology and Innovation via National Research Infrastructure funds; NIA; Danish Research Council for Independent Research I Technology and Production [SGW: DFF - 4005-00387] FX HPLC equipment used for high-resolution bioassay profiles was obtained via a grant from The Carlsberg Foundation. The 600 MHz HPLC-HRMS-SPE-NMR system used in this work was acquired through a grant from Apotekerfonden af 1991, The Carlsberg Foundation, and the Danish Agency for Science, Technology and Innovation via the National Research Infrastructure funds. This research was supported in part by the Intramural Research Program of the NIA (R.M.) and by a grant from The Danish Research Council for Independent Research I Technology and Production (SGW: DFF - 4005-00387). NR 36 TC 7 Z9 7 U1 10 U2 31 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 EI 1520-6025 J9 J NAT PROD JI J. Nat. Prod. PD NOV PY 2015 VL 78 IS 11 BP 2657 EP 2665 DI 10.1021/acs.jnatprod.5b00603 PG 9 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA CX9DS UT WOS:000366005800019 PM 26496505 ER PT J AU Henrich, CJ Cartner, LK Wilson, JA Fuller, RW Rizzo, AE Reilly, KM McMahon, JB Gustafson, KR AF Henrich, Curtis J. Cartner, Laura K. Wilson, Jennifer A. Fuller, Richard W. Rizzo, Anthony E. Reilly, Karlyne M. McMahon, James B. Gustafson, Kirk R. TI Deguelins, Natural Product Modulators of NF1-Defective Astrocytoma Cell Growth Identified by High-Throughput Screening of Partially Purified Natural Product Extracts SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID DRUG DISCOVERY; CANCER CELLS; LIBRARIES; APOPTOSIS; ROTENONE; PLANT; MICE; INHIBITOR; INDUCTION; MARINE AB A high-throughput screening assay for modulators of Trp53/NF1 mutant astrocytoma cell growth was adapted for use with natural product extracts and applied to a novel collection of prefractionated/partially purified extracts. Screening 68 427 samples identified active fractions from 95 unique extracts, including the terrestrial plant Millettia ichthyotona. Only three of these extracts showed activity in the crude extract form, thus demonstrating the utility of a partial purification approach for natural product screening. The NF1 screening assay was used to guide purification of active compounds from the M. ichthyotona extract, which yielded the two rotenones deguelin (1) and dehydrodeguelin (2). The deguelins have been reported to affect growth of a number of cancer cell lines. They potently inhibited growth of only one of a panel of NF1/Trp53 mutant murine astrocytoma cell lines, possibly related to epigenetic factors, but had no effect on the growth of normal astrocytes. These results suggest the potential utility of deguelins as tools for further investigating NF1 astrocytoma cell growth. These bioprobes were identified only as a result of screening partially purified natural product extracts. C1 [Henrich, Curtis J.; Cartner, Laura K.; Wilson, Jennifer A.; Fuller, Richard W.; McMahon, James B.; Gustafson, Kirk R.] NCI, Ctr Canc Res, Mol Targets Lab, Frederick, MD 21702 USA. [Rizzo, Anthony E.; Reilly, Karlyne M.] NCI, Ctr Canc Res, Mouse Canc Genet Program, Frederick, MD 21702 USA. [Henrich, Curtis J.; Cartner, Laura K.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Basic Sci Program, Frederick, MD 21702 USA. RP Henrich, CJ (reprint author), NCI, Ctr Canc Res, Mol Targets Lab, Frederick, MD 21702 USA. EM curtis.henrich2@nih.gov; gustafki@mail.nih.gov FU Intramural Research Program of NIH; National Cancer Institute; Center for Cancer Research; Federal funds from Frederick National Laboratory for Cancer Research; National Institutes of Health [HHSN261200800001E] FX We thank the Natural Products Support Group at NCI-Frederick for extract preparation and S. Tarasov and M. Dyba (Biophysics Resource Core, Structural Biophysics Laboratory, CCR) and H. Bokesch (MTL) for assistance with high-resolution mass spectrometry. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. This project was also 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 35 TC 1 Z9 1 U1 3 U2 13 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 EI 1520-6025 J9 J NAT PROD JI J. Nat. Prod. PD NOV PY 2015 VL 78 IS 11 BP 2776 EP 2781 DI 10.1021/acs.jnatprod.5b00753 PG 6 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA CX9DS UT WOS:000366005800035 PM 26467198 ER PT J AU Serpe, M AF Serpe, Mihaela TI What does it take to get the job done? SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID DROSOPHILA NEUROMUSCULAR-JUNCTION; GLUTAMATE RECEPTORS AB I am extremely honored to be the recipient of the 2015 Women in Cell Biology Junior Award. When I reflect on my journey in science, many great people and memorable experiences come to mind. Some of these encounters were truly career-defining moments. Others provided priceless lessons. In this essay, I recount some of the moments and experiences that influenced my scientific trajectory with the hope that they may inspire others. C1 [Serpe, Mihaela] NICHHD, Unit Cellular Commun, Program Cellular Regulat & Metab, NIH, Bethesda, MD 20892 USA. RP Serpe, M (reprint author), NICHHD, Unit Cellular Commun, Program Cellular Regulat & Metab, NIH, Bethesda, MD 20892 USA. EM mihaela.serpe@nih.gov FU ASCB Women in Cell Biology Junior Award FX Mihaela Serpe is the recipient of the 2015 ASCB Women in Cell Biology Junior Award. NR 14 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PD NOV 1 PY 2015 VL 26 IS 21 BP 3684 EP 3686 DI 10.1091/mbc.E15-06-0428 PG 3 WC Cell Biology SC Cell Biology GA CY3PO UT WOS:000366322200003 PM 26515970 ER PT J AU Van de Mark, D Kong, D Loncarek, J Stearns, T AF Van de Mark, Daniel Kong, Dong Loncarek, Jadranka Stearns, Tim TI MDM1 is a microtubule-binding protein that negatively regulates centriole duplication SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID TRACHEAL EPITHELIAL-CELLS; HAMSTER OVARY CELLS; CENTROSOME AMPLIFICATION; INTERACTIVE TREE; MOUSE; PLK4; REDUPLICATION; CILIOGENESIS; RECRUITMENT; BIOGENESIS AB Mouse double-minute 1 (Mdm1) was originally identified as a gene amplified in transformed mouse cells and more recently as being highly up-regulated during differentiation of multiciliated epithelial cells, a specialized cell type having hundreds of centrioles and motile cilia. Here we show that the MDM1 protein localizes to centrioles of dividing cells and differentiating multiciliated cells. 3D-SIM microscopy showed that MDM1 is closely associated with the centriole barrel, likely residing in the centriole lumen. Overexpression of MDM1 suppressed centriole duplication, whereas depletion of MDM1 resulted in an increase in granular material that likely represents early intermediates in centriole formation. We show that MDM1 binds microtubules in vivo and in vitro. We identified a repeat motif in MDM1 that is required for efficient microtubule binding and found that these repeats are also present in CCSAP, another microtubule-binding protein. We propose that MDM1 is a negative regulator of centriole duplication and that its function is mediated through microtubule binding. C1 [Van de Mark, Daniel; Stearns, Tim] Stanford Univ, Dept Biol, Stanford, CA 94305 USA. [Kong, Dong; Loncarek, Jadranka] NCI, Lab Prot Dynam & Signaling, Ctr Canc Research Frederick, NIH, Frederick, MD 21702 USA. [Stearns, Tim] Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA. RP Stearns, T (reprint author), Stanford Univ, Dept Biol, Stanford, CA 94305 USA. EM stearns@stanford.edu RI Kong, Dong/O-4465-2016 OI Kong, Dong/0000-0002-7144-3808 FU National Institutes of Health [R01GM52022]; Stanford Genome Training Program Grant NIH [5 T32 HG000044]; National Center for Research Resources [1S10OD01227601]; Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX We thank the following for gifts of antibodies: Bryan Dynlacht (New York University, New York, NY), Jeremy Reiter (University of California, San Francisco, San Francisco, CA), and Eszter Vladar and Jeffrey Axelrod (Stanford University, Stanford, CA). We also thank Eszter Vladar for help and guidance in working with the MTEC culture system. This work was supported by National Institutes of Health Grant R01GM52022 (T.S.) and Stanford Genome Training Program Grant NIH 5 T32 HG000044 (D.V.). The 3D-SIM superresolution experiments were supported in part by Award 1S10OD01227601 from the National Center for Research Resources. The CLEM imaging was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research (J.L.). NR 64 TC 2 Z9 7 U1 1 U2 4 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PD NOV 1 PY 2015 VL 26 IS 21 BP 3788 EP 3802 DI 10.1091/mbc.E15-04-0235 PG 15 WC Cell Biology SC Cell Biology GA CY3PO UT WOS:000366322200016 PM 26337392 ER PT J AU Doyle, AD Carvajal, N Jin, A Matsumoto, K Yamada, KM AF Doyle, Andrew D. Carvajal, Nicole Jin, Albert Matsumoto, Kazue Yamada, Kenneth M. TI Local 3D matrix microenvironment regulates cell migration through spatiotemporal dynamics of contractility-dependent adhesions SO NATURE COMMUNICATIONS LA English DT Article ID 3-DIMENSIONAL COLLAGEN MATRICES; ATOMIC-FORCE MICROSCOPY; FOCAL ADHESIONS; ACTIN CYTOSKELETON; NASCENT ADHESIONS; POISSONS RATIO; INTEGRIN; MECHANICS; LIMITS; MODEL AB The physical properties of two-dimensional (2D) extracellular matrices (ECMs) modulate cell adhesion dynamics and motility, but little is known about the roles of local microenvironmental differences in three-dimensional (3D) ECMs. Here we generate 3D collagen gels of varying matrix microarchitectures to characterize their regulation of 3D adhesion dynamics and cell migration. ECMs containing bundled fibrils demonstrate enhanced local adhesion-scale stiffness and increased adhesion stability through balanced ECM/adhesion coupling, whereas highly pliable reticular matrices promote adhesion retraction. 3D adhesion dynamics are locally regulated by ECM rigidity together with integrin/ECM association and myosin II contractility. Unlike 2D migration, abrogating contractility stalls 3D migration regardless of ECM pore size. We find force is not required for clustering of activated integrins on 3D native collagen fibrils. We propose that efficient 3D migration requires local balancing of contractility with ECM stiffness to stabilize adhesions, which facilitates the detachment of activated integrins from ECM fibrils. C1 [Doyle, Andrew D.; Matsumoto, Kazue; Yamada, Kenneth M.] Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, Cell Biol Sect, NIH, Bethesda, MD 20892 USA. [Carvajal, Nicole; Jin, Albert] Natl Inst Biomed Imaging & Bioengn, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD 20892 USA. RP Doyle, AD (reprint author), Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, Cell Biol Sect, NIH, Bethesda, MD 20892 USA. EM adoyle@mail.nih.gov; kyamada@dir.nidcr.nih.gov FU NIDCR Division of Intramural Research; NIBIB Division of Intramural Research FX We thank Raimon Sunyer, Shannon Doyle and Vinay Swaminathan for helpful suggestions and comments, Brain Duchez, Emily Joo and Will Daley for critical reading of the manuscript and mouse dissection, Hari Shroff and Andrew York for help with SIM imaging, and Lauren Sheehy for technical help. A.D.D., K.M. and K.M.Y. are supported by the NIDCR Division of Intramural Research. N.C. and A.J. are supported by the NIBIB Division of Intramural Research. NR 64 TC 19 Z9 19 U1 8 U2 25 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 NOV PY 2015 VL 6 AR 8720 DI 10.1038/ncomms9720 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CY3EC UT WOS:000366290200001 PM 26548801 ER PT J AU Haetscher, N Feuermann, Y Wingert, S Rehage, M Thalheimer, FB Weiser, C Bohnenberger, H Jung, K Schroeder, T Serve, H Oellerich, T Hennighausen, L Rieger, MA AF Haetscher, Nadine Feuermann, Yonatan Wingert, Susanne Rehage, Maike Thalheimer, Frederic B. Weiser, Christian Bohnenberger, Hanibal Jung, Klaus Schroeder, Timm Serve, Hubert Oellerich, Thomas Hennighausen, Lothar Rieger, Michael A. TI STAT5-regulated microRNA-193b controls haematopoietic stem and progenitor cell expansion by modulating cytokine receptor signalling SO NATURE COMMUNICATIONS LA English DT Article ID ACUTE MYELOID-LEUKEMIA; C-KIT; TRANSCRIPTION FACTORS; LINEAGE CHOICE; SELF-RENEWAL; STAT5; MIR-193B; MOUSE; DIFFERENTIATION; MAINTENANCE AB Haematopoietic stem cells (HSCs) require the right composition of microRNAs (miR) for proper life-long balanced blood regeneration. Here we show a regulatory circuit that prevents excessive HSC self-renewal by upregulation of miR-193b upon self-renewal promoting thrombopoietin (TPO)-MPL-STAT5 signalling. In turn, miR-193b restricts cytokine signalling, by targeting the receptor tyrosine kinase c-KIT. We generated a miR-193b knockout mouse model to unravel the physiological function of miR-193b in haematopoiesis. MiR-193b(-/-) mice show a selective gradual enrichment of functional HSCs, which are fully competent in multilineage blood reconstitution upon transplantation. The absence of miR-193b causes an accelerated expansion of HSCs, without altering cell cycle or survival, but by decelerating differentiation. Conversely, ectopic miR-193b expression restricts long-term repopulating HSC expansion and blood reconstitution. MiR-193b-deficient haematopoietic stem and progenitor cells exhibit increased basal and cytokine-induced STAT5 and AKT signalling. This STAT5-induced microRNA provides a negative feedback for excessive signalling to restrict uncontrolled HSC expansion. C1 [Haetscher, Nadine; Feuermann, Yonatan; Wingert, Susanne; Rehage, Maike; Thalheimer, Frederic B.; Serve, Hubert; Oellerich, Thomas; Rieger, Michael A.] Goethe Univ Frankfurt, LOEWE Ctr Cell & Gene Therapy, D-60590 Frankfurt, Germany. [Haetscher, Nadine; Feuermann, Yonatan; Wingert, Susanne; Rehage, Maike; Thalheimer, Frederic B.; Serve, Hubert; Oellerich, Thomas; Rieger, Michael A.] Goethe Univ Frankfurt, Dept Med, Hematol Oncol, D-60590 Frankfurt, Germany. [Feuermann, Yonatan; Hennighausen, Lothar] NIDDK, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. [Bohnenberger, Hanibal] Univ Med Ctr Gottingen, Dept Pathol, D-37075 Gottingen, Germany. [Jung, Klaus] Univ Med Ctr Gottingen, Dept Med Stat, D-37073 Gottingen, Germany. [Schroeder, Timm] Swiss Fed Inst Technol, Dept Biosyst Sci & Engn, CH-4058 Basel, Switzerland. [Serve, Hubert; Oellerich, Thomas; Rieger, Michael A.] German Canc Consortium DKTK, Heidelberg, Germany. [Serve, Hubert; Oellerich, Thomas; Rieger, Michael A.] German Canc Res Ctr, D-69120 Heidelberg, Germany. RP Rieger, MA (reprint author), Goethe Univ Frankfurt, LOEWE Ctr Cell & Gene Therapy, Theodor Stern Kai 7, D-60590 Frankfurt, Germany. EM m.rieger@em.uni-frankfurt.de OI Feuermann, Yonatan/0000-0002-6561-6397 FU Jose Carreras Leukamie-Stiftung [DJCLS R11/02]; Boehringer Ingelheim Foundation; Intramural Research Program of the National Institute of Diabetes, Digestive and Kidney Diseases; LOEWE Center for Cell and Gene Therapy Frankfurt, Hessisches Ministerium fur Wissenschaft und Kunst [III L 4-518/17.004] FX We thank C. Jourdan, S. Bothur, T. Merovci, B. Brill, C. Molenda, K. Pesek, P. Schwab and M. Engel for the excellent technical assistance. This study was funded in part by the Jose Carreras Leukamie-Stiftung (DJCLS R11/02). N.H. received a travel grant from the Boehringer Ingelheim Foundation. L.H. was supported by the Intramural Research Program of the National Institute of Diabetes, Digestive and Kidney Diseases. M.A.R. received support by the LOEWE Center for Cell and Gene Therapy Frankfurt, Hessisches Ministerium fur Wissenschaft und Kunst (III L 4-518/17.004 (2014)). NR 40 TC 5 Z9 5 U1 1 U2 3 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 NOV PY 2015 VL 6 AR 8928 DI 10.1038/ncomms9928 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CY4LK UT WOS:000366379400010 PM 26603207 ER PT J AU Zhang, PS Abdelmohsen, K Liu, Y Tominaga-Yamanaka, K Yoon, JH Ioannis, G Martindale, JL Zhang, YQ Becker, KG Yang, IH Gorospe, M Mattson, MP AF Zhang, Peisu Abdelmohsen, Kotb Liu, Yong Tominaga-Yamanaka, Kumiko Yoon, Je-Hyun Ioannis, Grammatikakis Martindale, Jennifer L. Zhang, Yongqing Becker, Kevin G. Yang, In Hong Gorospe, Myriam Mattson, Mark P. TI Novel RNA- and FMRP-binding protein TRF2-S regulates axonal mRNA transport and presynaptic plasticity SO NATURE COMMUNICATIONS LA English DT Article ID FRAGILE-X-SYNDROME; MENTAL-RETARDATION PROTEIN; SYNAPTIC PLASTICITY; HUMAN TELOMERES; GROWTH CONES; TRANSLATION; LOCALIZATION; NEURONS; VESICLE; PATHOPHYSIOLOGY AB Despite considerable evidence that RNA-binding proteins (RBPs) regulate mRNA transport and local translation in dendrites, roles for axonal RBPs are poorly understood. Here we demonstrate that a non-telomeric isoform of telomere repeat-binding factor 2 (TRF2-S) is a novel RBP that regulates axonal plasticity. TRF2-S interacts directly with target mRNAs to facilitate their axonal delivery. The process is antagonized by fragile X mental retardation protein (FMRP). Distinct from the current RNA-binding model of FMRP, we show that FMRP occupies the GAR domain of TRF2-S protein to block the assembly of TRF2-S-mRNA complexes. Overexpressing TRF2-S and silencing FMRP promotes mRNA entry to axons and enhances axonal outgrowth and neurotransmitter release from presynaptic terminals. Our findings suggest a pivotal role for TRF2-S in an axonal mRNA localization pathway that enhances axon outgrowth and neurotransmitter release. C1 [Zhang, Peisu; Liu, Yong; Mattson, Mark P.] Natl Inst Aging Intramural Res Program, Lab Neurosci, NIH, Baltimore, MD 21224 USA. [Abdelmohsen, Kotb; Tominaga-Yamanaka, Kumiko; Yoon, Je-Hyun; Ioannis, Grammatikakis; Martindale, Jennifer L.; Zhang, Yongqing; Becker, Kevin G.; Gorospe, Myriam] Natl Inst Aging Intramural Res Program, Genet Lab, NIH, Baltimore, MD 21224 USA. [Yang, In Hong] Natl Univ Singapore, Dept Biomed Engn, Singapore 117465, Singapore. [Yang, In Hong] Natl Univ Singapore, SINAPSE, Singapore 117465, Singapore. [Mattson, Mark P.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Zhang, PS (reprint author), Natl Inst Aging Intramural Res Program, Lab Neurosci, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM zhangpe@grc.nia.nih.gov; mark.mattson@nih.gov OI Liu, Yong/0000-0003-1278-7114 FU Intramural Research Program of the National Institute on Aging; Glenn Foundation for Medical Research FX This work was supported by the Intramural Research Program of the National Institute on Aging and by a grant to M.P.M. from the Glenn Foundation for Medical Research. We thank Haiyang Jiang, Min Geol Joo, Elin Lehrmann and William Wood for technical support, and Erez Eitan, Sana Siddiqui and Su Zhang for critical comments on the manuscript. NR 56 TC 5 Z9 5 U1 1 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 NOV PY 2015 VL 6 AR 8888 DI 10.1038/ncomms9888 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CY3GK UT WOS:000366296800002 PM 26586091 ER PT J AU Soekadar, SR Birbaumer, N Slutzky, MW Cohen, LG AF Soekadar, Surjo R. Birbaumer, Niels Slutzky, Marc W. Cohen, Leonardo G. TI Brain-machine interfaces in neurorehabilitation of stroke SO NEUROBIOLOGY OF DISEASE LA English DT Article DE Brain machine interface (BMI); Neurorehabilitation; Stroke; Robotics; Assistive technology; Brain stimulation ID TRANSCRANIAL MAGNETIC STIMULATION; LOCAL-FIELD POTENTIALS; PRIMARY MOTOR CORTEX; FUNCTIONAL ELECTRICAL-STIMULATION; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; UPPER-LIMB RECOVERY; REAL-TIME FMRI; COMPUTER-INTERFACE; SELF-REGULATION; NEUROLOGICAL REHABILITATION AB Stroke is among the leading causes of long-term disabilities leaving an increasing number of people with cognitive, affective and motor impairments depending on assistance in their daily life. While function after stroke can significantly improve in the first weeks and months, further recovery is often slow or non-existent in the more severe cases encompassing 30-50% of all stroke victims. The neurobiological mechanisms underlying recovery in those patients are incompletely understood. However, recent studies demonstrated the brain's remarkable capacity for functional and structural plasticity and recovery even in severe chronic stroke. As all established rehabilitation strategies require some remaining motor function, there is currently no standardized and accepted treatment for patients with complete chronic muscle paralysis. The development of brain-machine interfaces (BMIs) that translate brain activity into control signals of computers or external devices provides two new strategies to overcome stroke-related motor paralysis. First, BMIs can establish continuous high-dimensional brain-control of robotic devices or functional electric stimulation (FES) to assist in daily life activities (assistive BMI). Second, BMIs could facilitate neuroplasticity, thus enhancing motor learning and motor recovery (rehabilitative BMI). Advances in sensor technology, development of non-invasive and implantable wireless BMI-systems and their combination with brain stimulation, along with evidence for BMI systems' clinical efficacy suggest that BMI-related strategies will play an increasing role in neurorehabilitation of stroke. (C) 2014 The Authors. Published by Elsevier Inc. C1 [Soekadar, Surjo R.] Univ Tubingen Hosp, Dept Psychiat & Psychotherapy, Appl Neurotechnol Lab, Tubingen, Germany. [Soekadar, Surjo R.; Birbaumer, Niels] Univ Tubingen, Inst Med Psychol & Behav Neurobiol, Tubingen, Germany. [Birbaumer, Niels] IRCCS, Osped San Camillo, Venice, Italy. [Slutzky, Marc W.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Cohen, Leonardo G.] NIH, Human Cort Physiol & Neurorehabil Sect, NINDS, Bethesda, MD 20892 USA. RP Soekadar, SR (reprint author), Univ Tubingen Hosp, Dept Psychiat & Psychotherapy, Appl Neurotechnol Lab, Tubingen, Germany. EM surjo.soekadar@uni-tuebingen.de; niels.birbaumer@uni-tuebingen.de; mslutzky@northwestern.edu; cohenl@ninds.nih.gov FU National Institute of Neurological Disorders and Stroke (NINDS), USA; German Federal Ministry of Education and Research (BMBF) [01GQ0831, 16SV5838K]; BMBF [01GI0925]; Deutsche Forschungsgemeinschaft (DFG) [SO932-2]; European Commission [288551]; Volkswagenstiftung (VW); Baden-Wurttemberg Stiftung, Germany FX This work was supported by the Intramural Research Program (IRP) of the National Institute of Neurological Disorders and Stroke (NINDS), USA; the German Federal Ministry of Education and Research (BMBF, grant number 01GQ0831, 16SV5838K to SRS and NB); the BMBF to the German Center for Diabetes Research (DZD e.V., grant number 01GI0925), the Deutsche Forschungsgemeinschaft (DFG, grant number SO932-2 to SRS and Reinhart Koselleck support to NB); the European Commission under the project WAY (grant number 288551 to SRS and NB); the Volkswagenstiftung (VW) and the Baden-Wurttemberg Stiftung, Germany. NR 128 TC 14 Z9 15 U1 6 U2 30 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 EI 1095-953X J9 NEUROBIOL DIS JI Neurobiol. Dis. PD NOV PY 2015 VL 83 BP 172 EP 179 DI 10.1016/j.nbd.2014.11.025 PG 8 WC Neurosciences SC Neurosciences & Neurology GA CY2HS UT WOS:000366230000017 PM 25489973 ER PT J AU Ciruela, F Fernandez-Duehas, V Jacobson, KA AF Ciruela, Francisco Fernandez-Duehas, Victor Jacobson, Kenneth A. TI Lighting up G protein-coupled purinergic receptors with engineered fluorescent ligands SO NEUROPHARMACOLOGY LA English DT Review DE Fluorescent ligands; Purinergic receptors; FRET; GPCR oligomerization ID A(3) ADENOSINE RECEPTORS; SINGLE LIVING CELLS; PROBING MOLECULAR-INTERACTIONS; TIME-RESOLVED FRET; ALLOSTERIC INTERACTIONS; ENERGY-TRANSFER; GPCR LIGANDS; MEMBRANE MICRODOMAINS; AGONIST BINDING; A(2A) RECEPTORS AB The use of G protein-coupled receptors fluorescent ligands is undergoing continuous expansion. In line with this, fluorescent agonists and antagonists of high affinity for G protein-coupled adenosine and P2Y receptors have been shown to be useful pharmacological probe compounds. Fluorescent ligands for AIR, A(2A)R, and A(3)R (adenosine receptors) and P2Y(2)R, P2Y(4)R, P2Y(6)R, and P2Y(14)R (nucleotide receptors) have been reported. Such ligands have been successfully applied to drug discovery and to GPCR characterization by flow cytometry, fluorescence correlation spectroscopy, fluorescence microscopy, fluorescence polarization, fluorescence resonance energy transfer and scanning confocal microscopy. Here we summarize recently reported and readily available representative fluorescent ligands of purinergic receptors. In addition, we pay special attention on the use of this family of fluorescent ligands revealing two main aspects of purinergic receptor biology, namely ligand binding and receptor oligomerization. This article is part of the Special Issue entitled 'Fluorescent Tools in Neuropharmacology'. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Ciruela, Francisco; Fernandez-Duehas, Victor] Univ Barcelona, IDIBELL, Unitat Farmacol, Dept Patol & Terapeut Expt,Fac Med, Lhospitalet De Llobregat 08907, Spain. [Ciruela, Francisco] Univ Ghent, Fac Sci, Dept Physiol, B-9000 Ghent, Belgium. [Jacobson, Kenneth A.] NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Ciruela, F (reprint author), Univ Barcelona, IDIBELL, Unitat Farmacol, Dept Patol & Terapeut Expt,Fac Med, Lhospitalet De Llobregat 08907, Spain. EM fciruela@ub.edu; kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU NIDDK-NIH Intramural Research Program [N01DK031115]; Ministerio de Economia y Competitividad/Instituto de Salud Carlos III [PIE14/00034, SAF2011-24779, SAF2014-55700-P, CSD2008-00005, PCIN-2013-019-C03-03]; Institucio Catalana de Recerca i Estudis Avancats (ICREA Academia); Agentschap voor Innovatie door Wetenschap en Technologie [SBO-140028] FX This work was supported by NIDDK-NIH Intramural Research Program (N01DK031115) to KAJ. Also, supported by Ministerio de Economia y Competitividad/Instituto de Salud Carlos III (PIE14/00034) (SAF2011-24779, SAF2014-55700-P, Consolider-Ingenio CSD2008-00005, PCIN-2013-019-C03-03 and PIE14/00034), Institucio Catalana de Recerca i Estudis Avancats (ICREA Academia-2010) and Agentschap voor Innovatie door Wetenschap en Technologie (SBO-140028) to FC. VF-D and FC belong to the "Neuropharmacology and Pain" accredited research group (Generalitat de Catalunya, 2014 SGR 1251). NR 88 TC 3 Z9 3 U1 2 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 EI 1873-7064 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD NOV PY 2015 VL 98 SI SI BP 58 EP 67 DI 10.1016/j.neuropharm.2015.04.001 PG 10 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA CY2HF UT WOS:000366228700008 PM 25890205 ER PT J AU Wu, GX Zhao, H Li, CH Rajapakse, MP Wong, WC Xu, J Saunders, CW Reeder, NL Reilman, RA Scheynius, A Sun, S Billmyre, BR Li, WJ Averette, AF Mieczkowski, P Heitman, J Theelen, B Schroder, MS De Sessions, PF Butler, G Maurer-Stroh, S Boekhout, T Nagarajan, N Dawson, TL AF Wu, Guangxi Zhao, He Li, Chenhao Rajapakse, Menaka Priyadarsani Wong, Wing Cheong Xu, Jun Saunders, Charles W. Reeder, Nancy L. Reilman, Raymond A. Scheynius, Annika Sun, Sheng Billmyre, Blake Robert Li, Wenjun Averette, Anna Floyd Mieczkowski, Piotr Heitman, Joseph Theelen, Bart Schroeder, Markus S. De Sessions, Paola Florez Butler, Geraldine Maurer-Stroh, Sebastian Boekhout, Teun Nagarajan, Niranjan Dawson, Thomas L., Jr. TI Genus-Wide Comparative Genomics of Malassezia Delineates Its Phylogeny, Physiology, and Niche Adaptation on Human Skin SO PLOS GENETICS LA English DT Article ID MAXIMUM-LIKELIHOOD; DOMESTIC-ANIMALS; SEBORRHEIC DERMATITIS; MICROBIAL COMMUNITIES; PROTEIN FAMILIES; HIGH-THROUGHPUT; SEQUENCE; DANDRUFF; FUNGAL; PACHYDERMATIS AB Malassezia is a unique lipophilic genus in class Malasseziomycetes in Ustilaginomycotina, (Basidiomycota, fungi) that otherwise consists almost exclusively of plant pathogens. Malassezia are typically isolated from warm-blooded animals, are dominant members of the human skin mycobiome and are associated with common skin disorders. To characterize the genetic basis of the unique phenotypes of Malassezia spp., we sequenced the genomes of all 14 accepted species and used comparative genomics against a broad panel of fungal genomes to comprehensively identify distinct features that define the Malassezia gene repertoire: gene gain and loss; selection signatures; and lineage-specific gene family expansions. Our analysis revealed key gene gain events (64) with a single gene conserved across all Malassezia but absent in all other sequenced Basidiomycota. These likely horizontally transferred genes provide intriguing gain-of-function events and prime candidates to explain the emergence of Malassezia. A larger set of genes (741) were lost, with enrichment for glycosyl hydrolases and carbohydrate metabolism, concordant with adaptation to skin's carbohydrate-deficient environment. Gene family analysis revealed extensive turnover and underlined the importance of secretory lipases, phospholipases, aspartyl proteases, and other peptidases. Combining genomic analysis with a re-evaluation of culture characteristics, we establish the likely lipid-dependence of all Malassezia. Our phylogenetic analysis sheds new light on the relationship between Malassezia and other members of Ustilaginomycotina, as well as phylogenetic lineages within the genus. Overall, our study provides a unique genomic resource for understanding Malassezia niche-specificity and potential virulence, as well as their abundance and distribution in the environment and on human skin. C1 [Wu, Guangxi; Li, Chenhao; Rajapakse, Menaka Priyadarsani; De Sessions, Paola Florez; Nagarajan, Niranjan] ASTAR, Genome Inst Singapore, Computat & Syst Biol, Singapore, Singapore. [Zhao, He] Procter & Gamble Singapore Innovat Ctr, Singapore, Singapore. [Li, Chenhao; Maurer-Stroh, Sebastian] ASTAR, Bioinformat Inst, Singapore, Singapore. [Xu, Jun; Saunders, Charles W.; Reeder, Nancy L.; Reilman, Raymond A.] Procter & Gamble Mason Business Ctr, Mason, OH USA. [Scheynius, Annika] Karolinska Inst, Dept Med Solna, Translat Immunol Unit, Stockholm, Sweden. [Scheynius, Annika] Univ Hosp, Stockholm, Sweden. [Sun, Sheng; Billmyre, Blake Robert; Averette, Anna Floyd; Heitman, Joseph] Duke Univ Med Ctr, Durham, NC USA. [Li, Wenjun] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Mieczkowski, Piotr] Univ N Carolina, Chapel Hill, NC USA. [Theelen, Bart] CBS KNAW, Fungal Biodivers Ctr, Utrecht, Netherlands. [Schroeder, Markus S.; Butler, Geraldine] Univ Coll Dublin, Dublin 2, Ireland. [Maurer-Stroh, Sebastian] Nanyang Technol Univ, Sch Biol Sci, Singapore 639798, Singapore. [Dawson, Thomas L., Jr.] ASTAR, Inst Med Biol, Singapore, Singapore. RP Wu, GX (reprint author), ASTAR, Genome Inst Singapore, Computat & Syst Biol, Singapore, Singapore. EM nagarajann@gis.a-star.edu.sg; thomas.dawson@imb.a-star.edu.sg RI Wu, Guangxi/J-4516-2016 FU NIH/NIAID R37 award [AI39115-18]; NIH/NIAID R01 award [AI50113-11]; Swedish Research Council; Agency for Science Technology and Research (A*STAR), Singapore FX Studies in the JH lab were supported by NIH/NIAID R37 award AI39115-18 and R01 award AI50113-11. AS is supported by the Swedish Research Council. Studies in the NN lab were supported by grants from the Agency for Science Technology and Research (A*STAR), Singapore. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 76 TC 17 Z9 17 U1 3 U2 9 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 NOV PY 2015 VL 11 IS 11 AR e1005614 DI 10.1371/journal.pgen.1005614 PG 26 WC Genetics & Heredity SC Genetics & Heredity GA CY1PF UT WOS:000366179000012 PM 26539826 ER PT J AU Fox, JC Tyler, RC Guzzo, C Tuinstra, RL Peterson, FC Lusso, P Volkman, BF AF Fox, Jamie C. Tyler, Robert C. Guzzo, Christina Tuinstra, Robbyn L. Peterson, Francis C. Lusso, Paolo Volkman, Brian F. TI Engineering Metamorphic Chemokine Lymphotactin/XCL1 into the GAG-Binding, HIV-Inhibitory Dimer Conformation SO ACS CHEMICAL BIOLOGY LA English DT Article ID C-CHEMOKINE; GLYCOSAMINOGLYCAN-BINDING; NATIVE-STATE; PROTEIN; SYSTEM; INTERCONVERSION; IDENTIFICATION AB Unlike other chemokines, XCL1 undergoes a distinct metamorphic interconversion between a canonical monomeric chemokine fold and a unique beta-sandwich dimer. The monomeric conformation binds and activates the receptor XCR1, whereas the dimer binds extracellular matrix glycosaminoglycans and has been associated with anti-human immunodeficiency virus (HIV) activity. Functional studies of WT-XCL1 are complex, as both conformations are populated in solution. To overcome this limitation, we engineered a stabilized dimeric variant of XCL1 designated CC5. This variant features a new disulfide bond (A36CA49C) that prevents structural interconversion by locking the chemokine into the beta-sandwich dimeric conformation, as demonstrated by NMR structural analysis and hydrogen/deuterium exchange experiments. Functional studies analyzing glycosaminoglycan binding demonstrate that CC5 binds with high affinity to heparin. In addition, CC5 exhibits potent inhibition of HIV-1 activity in primary peripheral blood mononuclear cells (PBMCs), demonstrating the importance of the dimer in blocking viral infection. Conformational variants like CC5 are valuable tools for elucidating the biological relevance of the XCL1 native-state interconversion and will assist in future antiviral and functional studies. C1 [Fox, Jamie C.; Tyler, Robert C.; Tuinstra, Robbyn L.; Peterson, Francis C.; Volkman, Brian F.] Med Coll Wisconsin, Dept Biochem, Milwaukee, WI 53226 USA. [Guzzo, Christina; Lusso, Paolo] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Volkman, BF (reprint author), Med Coll Wisconsin, Dept Biochem, Milwaukee, WI 53226 USA. EM bvolkman@mcw.edu FU NIH [Al103225, Al05802]; Intramural Program of the NIAID FX This work was supported by NIH grant nos. Al103225 and Al05802 to B.F.V. and by the Intramural Program of the NIAID. NR 32 TC 6 Z9 6 U1 0 U2 3 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 NOV PY 2015 VL 10 IS 11 BP 2580 EP 2588 DI 10.1021/acschembio.5b00542 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CX1NK UT WOS:000365462700019 PM 26302421 ER PT J AU Lieberman, P Nicklas, RA Randolph, C Oppenheimer, J Bernstein, D Bernstein, J Ellis, A Golden, DBK Greenberger, P Kemp, S Khan, D Ledford, D Lieberman, J Metcalfe, D Nowak-Wegrzyn, A Sicherer, S Wallace, D Blessing-Moore, J Lang, D Portnoy, JM Schuller, D Spector, S Tilles, SA AF Lieberman, Phillip Nicklas, Richard A. Randolph, Christopher Oppenheimer, John Bernstein, David Bernstein, Jonathan Ellis, Anne Golden, David B. K. Greenberger, Paul Kemp, Steven Khan, David Ledford, Dennis Lieberman, Jay Metcalfe, Dean Nowak-Wegrzyn, Anna Sicherer, Scott Wallace, Dana Blessing-Moore, Joann Lang, David Portnoy, Jay M. Schuller, Diane Spector, Sheldon Tilles, Stephen A. TI Anaphylaxis-a practice parameter update 2015 SO ANNALS OF ALLERGY ASTHMA & IMMUNOLOGY LA English DT Article ID EXERCISE-INDUCED ANAPHYLAXIS; HUMAN SEMINAL PLASMA; HYMENOPTERA VENOM ALLERGY; ANGIOTENSIN-CONVERTING ENZYME; EMERGENCY-DEPARTMENT PATIENTS; AMERICAN-HEART-ASSOCIATION; LARGE LOCAL REACTIONS; INSECT STING ALLERGY; SELF-INJECTABLE EPINEPHRINE; BETA-ADRENERGIC-BLOCKADE C1 [Lieberman, Phillip] Univ Tennessee, Coll Med, Med & Pediat, Memphis, TN USA. [Nicklas, Richard A.] George Washington Med Ctr, Med, Washington, DC USA. [Bernstein, David] Univ Cincinnati, Coll Med, Div Allergy Immunol, Clin Med & Environm Hlth, Cincinnati, OH USA. [Blessing-Moore, Joann] Stanford Univ, Med Ctr, Dept Immunol, Med & Pediat, Palo Alto, CA 94304 USA. [Khan, David] Univ Texas SW Med Ctr Dallas, Internal Med, Dallas, TX 75390 USA. [Lang, David] Cleveland Clin Fdn, Div Med, Allergy Immunol Sect, Cleveland, OH 44195 USA. [Lang, David] Cleveland Clin Fdn, Allergy & Immunol Fellowship Training Program, Allergy Immunol Sect, Cleveland, OH 44195 USA. [Oppenheimer, John] Pulm & Allergy Associates, New Jersey Med Sch, Dept Internal Med, Morristown, NJ USA. [Portnoy, Jay M.] Childrens Mercy Hosp, Div Allergy Asthma & Immunol, Kansas City, MO 64108 USA. [Portnoy, Jay M.] Univ Missouri, Kansas City Sch Med, Pediat, Kansas City, MO 64110 USA. [Randolph, Christopher] Yale Affiliated Hosp, Pediat, Ctr Allergy Asthma & Immunol, Waterbury, CT USA. [Schuller, Diane] Penn State Univ, Milton S Hershey Med Coll, Allergy & Immunol, Hershey, PA USA. [Spector, Sheldon] Univ Calif Los Angeles, Sch Med, Med, Los Angeles, CA USA. [Tilles, Stephen A.] Univ Washington, Sch Med, Med, Redmond, WA USA. [Wallace, Dana] Nova SE Univ, Med, Coll Osteopath Med, Davie, FL USA. [Bernstein, Jonathan] Univ Cincinnati, Coll Med, Dept Internal Med, Clin Med,Div Immunol,Allergy Sect, Cincinnati, OH USA. [Ellis, Anne] Queens Univ, Dept Med, Div Allergy & Immunol, Dept Biomed & Mol Sci, Kingston, ON K7L 3N6, Canada. [Golden, David B. K.] Johns Hopkins Univ, Med, Baltimore, MD USA. [Greenberger, Paul] Northwestern Univ, Feinberg Sch Med, Div Allergy Immunol, Med, Chicago, IL 60611 USA. [Kemp, Steven] Univ Mississippi, Coll Med, Med, Jackson, MS 39216 USA. [Ledford, Dennis] Univ S Florida, Morsani Coll Med, Allergy Immunol, Tampa, FL USA. [Lieberman, Jay] Univ Tennessee, Coll Med, Pediat, Memphis, TN USA. [Metcalfe, Dean] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Metcalfe, Dean] NIAID, Mast Cell Biol Sect LAD, NIH, Bethesda, MD 20892 USA. [Nowak-Wegrzyn, Anna] Icahn Sch Med Mt Sinai, Pediat, Div Pediat Allergy & Immunol, Jaffe Food Allergy Inst, New York, NY 10029 USA. [Sicherer, Scott] Icahn Sch Med Mt Sinai, Dept Pediat Pediat Allergy & Immunol, Jaffee Food Allergy Inst, New York, NY 10029 USA. RP Lieberman, P (reprint author), Care of Grupe SL, Joint Task Force Practice Parameters, 50 N Brockway St,304, Palatine, IL 60067 USA. EM SueGrupe@ACAAI.org FU Centers for Disease Control and Prevention; National Institute for Occupational Safety and Health; Teva; Merck; Glaxo; Pfizer; Genentech; Novartis; Astra Zeneca; Amgon; Savoy; Cephalon; Circassia Ltd; Siemens; Targacept; Merck Schering; Schering; Chiltern; Forest; ViroPharma; Nutucia FX The following is a summary of interests disclosed on work group members' Conflict of Interest Disclosure Statements (not including information concerning family member interests). Completed Conflict of Interest Disclosure Statements are available upon request. David Bernstein, MD, is on the advisory boards of Teva and Circassion; is on the board of the American Board of Allergy and Immunology; is a consultant for Proctor & Gamble, Science Strategies, Guidepoint Federal, and Merck; provides legal support for Fowler, Whited, & Barrett; is speaker for Merck; and has received financial support from the Centers for Disease Control and Prevention and the National Institute for Occupational Safety and Health (principal investigator) and Teva, Merck, Glaxo, Pfizer, Genentech, Novartis, Astra Zeneca, Amgon, Savoy, and Cephalon. Jonathan Bernstein, MD, has consulted for and received honorarium and gifts from Sanofi Aventis; served as consultant, speaker and researcher for Dyax, Shire, CSL Behring, ViroPharma, and research for Pharming, is the editor of the Journal of Asthma; serves on the AAAAI Board of Directors; is a committee member of the ACAAI, and is chair of the Allergists for Israel. Anne Ellis, MD, is s speaker for Pfizer Canada, Merck, and Astra; is on the advisory board of Palladin Labs; received a research grant from Circassia Ltd; and is on the Drug, Allergy & Anaphylaxis Committee of the ACAAI. David B.K. Golden, MD, is a consultant for Sanofi and GlaxoSmithKline, speaker for Genentech, and has received financial support from Siemens for a clinical trial. Paul Greenberger, MD, has consulted for Mylan (Day) and is a committee member of the Food and Drug Administration Pulmonary Allergy Drugs Advisory Committee. Kevin J. Kelly, MD, received research grants from Targacept, Merck Schering, Schering, Chiltern, and Glaxo; has consulted for the University of North Carolina; and is a leadership board member of the American Lung Association of Wisconsin. Steven Kemp, MD, is a committee member, assembly member, and speaker for the AAAAI; is an editorial board member and committee member of the ACAAI; and is on the board of directors for the American Board of Allergy & Immunology. David Khan, MD, is a speaker for Baxter and Genentech. Dennis Ledford, MD, is a speaker for the South Carolina Allergy & Immunology Society and Meda Pharmaceutical; has received research grants from Teva, Forest, Genentech, Merck, and ViroPharma; has consulted for Shook Hardy Bacon, Saieva and Stine, and Genentech; is on the advisory board of AstraZeneca. Jay Lieberman, MD, reports no conflicts. Philip Lieberman, MD, consults for Sanofi Aventis, Neyian, Merck, Genentech, Teva, Meda, and the Asthma and Allergy Foundation of America; serves on the advisory boards of Sanofi Aventis, Neyian, Merck, Teva, and Meda; and served as speaker for Neyina, Teva, and Meda. Dean Metcalfe, MD, reports no conflicts. Anna Nowak-Wegrzyn, MD, is on the advisory boards of Merck and Nutricia; has served as speaker for Thermofisher Scientific; and received a research grant from Nutucia.; Scott Sicherer, MD, consults for Novartis; edits and receives honorarium from the Journal of Allergy and Clinical Immunology and is associate editor of the Journal of Allergy and Clinical Immunology In Practice; serves as speaker for and receives honorarium from the American Academy of Pediatrics; received honorarium from the American Board of Allergy and Immunology; is on the advisory board of Sanofi; edits and contributes to UpToDate; consults for the Food Allergy Initiative; received research grants from the National Institute of Allergy and Infectious Diseases, National Institutes of Health; is on the executive committee of the American Academy of Pediatrics; and is a medical advisor for the Food Allergy and Anaphylaxis Network and Food Allergy Research and Education. Dana Wallace, MD, is on the advisory board of Sanofi, Sunovion, and Mylan; serves as speaker for Sunovion, Teva, and Meda; and is on the board of directors of the World Allergy Organization. The Joint Task Force recognizes that experts in a field are likely to have interests that could come into conflict with development a completely unbiased and objective practice parameter. To take advantage of that expertise, a process has been developed to prevent potential conflicts from influencing the final document in a negative way. At the workgroup level, members who have a potential conflict of interest do not participate in discussions concerning topics related to the potential conflict; or if they do write a section on that topic, the workgroup completely rewrites it without their involvement to remove potential bias. In addition, the entire document is reviewed by the Joint Task Force and any apparent bias is removed at that level. Moreover, the practice parameter is sent for review by invited reviewers and by anyone with an interest in the topic by posting the document on the Web sites of the ACAAI and the AAAAI. The Joint Task Force has made a concerted effort to acknowledge all contributors to this parameter. If any contributors have been excluded inadvertently, the Task Force will ensure that appropriate recognition of such contributions is made subsequently. NR 525 TC 22 Z9 22 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1081-1206 EI 1534-4436 J9 ANN ALLERG ASTHMA IM JI Ann. Allergy Asthma Immunol. PD NOV PY 2015 VL 115 IS 5 BP 341 EP 384 DI 10.1016/j.anai.2015.07.019 PG 44 WC Allergy; Immunology SC Allergy; Immunology GA CX3PP UT WOS:000365611700004 PM 26505932 ER PT J AU Guo, XY Long, JR Zeng, CJ Michailidou, K Ghoussaini, M Bolla, MK Wang, Q Milne, RL Shu, XO Cai, QY Beesley, J Kar, SP Andrulis, IL Anton-Culver, H Arndt, V Beckmann, MW Beeghly-Fadiel, A Benitez, J Blot, W Bogdanova, N Bojesen, SE Brauch, H Brenner, H Brinton, L Broeks, A Bruning, T Burwinkel, B Cai, H Canisius, S Chang-Claude, J Choi, JY Couch, FJ Cox, A Cross, SS Czene, K Darabi, H Devilee, P Droit, A Dork, T Fasching, PA Fletcher, O Flyger, H Fostira, F Gaborieau, V Garcia-Closas, M Giles, GG Grip, M Guenel, P Haiman, CA Hamann, U Hartman, M Hollestelle, A Hopper, JL Hsiung, CN Ito, H Jakubowska, A Johnson, N Kabisch, M Kang, D Khan, S Knight, JA Kosma, VM Lambrechts, D Le Marchand, L Li, JM Lindblom, A Lophatananon, A Lubinski, J Mannermaa, A Manoukian, S Margolin, S Marme, F Matsuo, K McLean, CA Meindl, A Muir, K Neuhausen, SL Nevanlinna, H Nord, S Olson, JE Orr, N Peterlongo, P Putti, TC Rudolph, A Sangrajrang, S Sawyer, EJ Schmidt, MK Schmutzler, RK Shen, CY Shi, JJ Shrubsole, MJ Southey, MC Swerdlow, A Teo, SH Thienpont, B Toland, AE Tollenaar, RAEM Tomlinson, IPM Truong, T Tseng, CC van den Ouweland, A Wen, WQ Winqvist, R Wu, A Yip, CH Zamora, MP Zheng, Y Hall, P Pharoah, PDP Simard, J Chenevix-Trench, G Dunning, AM Easton, DF Zheng, W AF Guo, Xingyi Long, Jirong Zeng, Chenjie Michailidou, Kyriaki Ghoussaini, Maya Bolla, Manjeet K. Wang, Qin Milne, Roger L. Shu, Xiao-Ou Cai, Qiuyin Beesley, Jonathan Kar, Siddhartha P. Andrulis, Irene L. Anton-Culver, Hoda Arndt, Volker Beckmann, Matthias W. Beeghly-Fadiel, Alicia Benitez, Javier Blot, William Bogdanova, Natalia Bojesen, Stig E. Brauch, Hiltrud Brenner, Hermann Brinton, Louise Broeks, Annegien Bruening, Thomas Burwinkel, Barbara Cai, Hui Canisius, Sander Chang-Claude, Jenny Choi, Ji-Yeob Couch, Fergus J. Cox, Angela Cross, Simon S. Czene, Kamila Darabi, Hatef Devilee, Peter Droit, Arnaud Doerk, Thilo Fasching, Peter A. Fletcher, Olivia Flyger, Henrik Fostira, Florentia Gaborieau, Valerie Garcia-Closas, Montserrat Giles, Graham G. Grip, Mervi Guenel, Pascal Haiman, Christopher A. Hamann, Ute Hartman, Mikael Hollestelle, Antoinette Hopper, John L. Hsiung, Chia-Ni Ito, Hidemi Jakubowska, Anna Johnson, Nichola Kabisch, Maria Kang, Daehee Khan, Sofia Knight, Julia A. Kosma, Veli-Matti Lambrechts, Diether Le Marchand, Loic Li, Jingmei Lindblom, Annika Lophatananon, Artitaya Lubinski, Jan Mannermaa, Arto Manoukian, Siranoush Margolin, Sara Marme, Frederik Matsuo, Keitaro McLean, Catriona A. Meindl, Alfons Muir, Kenneth Neuhausen, Susan L. Nevanlinna, Heli Nord, Silje Olson, Janet E. Orr, Nick Peterlongo, Paolo Putti, Thomas Choudary Rudolph, Anja Sangrajrang, Suleeporn Sawyer, Elinor J. Schmidt, Marjanka K. Schmutzler, Rita K. Shen, Chen-Yang Shi, Jiajun Shrubsole, Martha J. Southey, Melissa C. Swerdlow, Anthony Teo, Soo Hwang Thienpont, Bernard Toland, Amanda Ewart Tollenaar, Robert A. E. M. Tomlinson, Ian P. M. Truong, Therese Tseng, Chiu-chen van den Ouweland, Ans Wen, Wanqing Winqvist, Robert Wu, Anna Yip, Cheng Har Zamora, M. Pilar Zheng, Ying Hall, Per Pharoah, Paul D. P. Simard, Jacques Chenevix-Trench, Georgia Dunning, Alison M. Easton, Douglas F. Zheng, Wei CA kConFab Investigators TI Fine-Scale Mapping of the 4q24 Locus Identifies Two Independent Loci Associated with Breast Cancer Risk SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID GENOME-WIDE ASSOCIATION; CELL SELF-RENEWAL; SUSCEPTIBILITY LOCI; MYELOID CANCERS; FUNCTIONAL VARIANTS; STEM-CELLS; CYCLIN D1; TET2; EXPRESSION; ENHANCERS AB Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 x 10(-4); OR, 1.04; 95% confidence interval (CI), 1.02-1.07] and rs77928427 (P = 1.86 x 10(-4); OR, 1.04; 95% CI, 1.02-1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r(2) >= 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor-binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk. (C) 2015 AACR. C1 [Guo, Xingyi; Long, Jirong; Zeng, Chenjie; Shu, Xiao-Ou; Cai, Qiuyin; Beeghly-Fadiel, Alicia; Blot, William; Cai, Hui; Shi, Jiajun; Shrubsole, Martha J.; Wen, Wanqing; Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, Div Epidemiol,Dept Med,Vanderbilt Ingram Canc Ctr, Nashville, TN 37203 USA. [Michailidou, Kyriaki; Bolla, Manjeet K.; Wang, Qin; Pharoah, Paul D. P.; Easton, Douglas F.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Ghoussaini, Maya; Kar, Siddhartha P.; Pharoah, Paul D. P.; Dunning, Alison M.; Easton, Douglas F.] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England. [Milne, Roger L.; Giles, Graham G.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Milne, Roger L.; Giles, Graham G.; Hopper, John L.] Univ Melbourne, Sch Populat & Global Hlth, Ctr Biostat & Epidemiol, Melbourne, Vic, Australia. [Beesley, Jonathan; Chenevix-Trench, Georgia] QIMR Berghofer Med Res Inst, Dept Genet, Brisbane, Qld, Australia. [Andrulis, Irene L.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada. [Andrulis, Irene L.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Anton-Culver, Hoda] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA. [Arndt, Volker; Brenner, Hermann] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Beckmann, Matthias W.; Fasching, Peter A.] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Dept Obstet & Gynaecol, D-91054 Erlangen, Germany. [Benitez, Javier] Spanish Natl Canc Res Ctr, Human Canc Genet Program, Madrid, Spain. [Benitez, Javier] Ctr Invest Red Enfermedades Raras, Valencia, Spain. [Blot, William] Int Epidemiol Inst, Rockville, MD USA. [Bogdanova, Natalia] Hannover Med Sch, Dept Radiat Oncol, Hannover, Germany. [Bojesen, Stig E.] Herlev Hosp, Copenhagen Gen Populat Study, DK-2730 Herlev, Denmark. [Bojesen, Stig E.] Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, Herlev, Denmark. [Bojesen, Stig E.] Univ Copenhagen, Fac Med & Hlth Sci, Copenhagen, Denmark. [Brauch, Hiltrud] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany. [Brauch, Hiltrud] Univ Tubingen, Tubingen, Germany. [Brauch, Hiltrud; Brenner, Hermann] German Canc Res Ctr, German Canc Consortium, Heidelberg, Germany. [Brenner, Hermann] German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany. [Brinton, Louise] Natl Canc Inst, Div Canc Epidemiol & Genet, Rockville, MD USA. [Broeks, Annegien; Canisius, Sander; Schmidt, Marjanka K.] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands. [Bruening, Thomas] German Social Accid Insurance, Inst Prevent & Occupat Med, Bochum, Germany. [Burwinkel, Barbara] German Canc Res Ctr, Div Mol Genet Epidemiol, Heidelberg, Germany. [Burwinkel, Barbara] German Canc Res Ctr, Mol Epidemiol Grp, Heidelberg, Germany. [Chang-Claude, Jenny; Rudolph, Anja] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Choi, Ji-Yeob; Kang, Daehee] Seoul Natl Univ, Coll Med, Dept Biomed Sci, Seoul, South Korea. [Choi, Ji-Yeob; Kang, Daehee] Seoul Natl Univ, Coll Med, Canc Res Inst, Seoul, South Korea. [Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Cox, Angela] Univ Sheffield, Dept Oncol, Sheffield Canc Res Ctr, Sheffield, S Yorkshire, England. [Cross, Simon S.] Univ Sheffield, Dept Neurosci, Acad Unit Pathol, Sheffield, S Yorkshire, England. [Czene, Kamila; Darabi, Hatef; Li, Jingmei; Hall, Per] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Devilee, Peter] Leiden Univ, Med Ctr, Dept Pathol, Leiden, Netherlands. [Devilee, Peter] Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands. [Droit, Arnaud; Simard, Jacques] Univ Laval, CHU Quebec, Res Ctr, Quebec City, PQ, Canada. [Doerk, Thilo] Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany. [Fasching, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. [Fletcher, Olivia; Garcia-Closas, Montserrat; Johnson, Nichola] Inst Canc Res, Breakthrough Breast Canc Res Ctr, Div Canc Studies, London SW3 6JB, England. [Flyger, Henrik] Copenhagen Univ Hosp, Herlev Hosp, Dept Breast Surg, Herlev, Denmark. [Fostira, Florentia] IRRP, Natl Ctr Sci Res Demokritos, Mol Diagnost Lab, Athens, Greece. [Gaborieau, Valerie] Int Agcy Res Canc, F-69372 Lyon, France. [Garcia-Closas, Montserrat] Inst Canc Res, Div Genet & Epidemiol, London SW3 6JB, England. [Grip, Mervi] Oulu Univ Hosp, Dept Surg, Oulu, Finland. [Grip, Mervi] Univ Oulu, Oulu, Finland. [Guenel, Pascal; Truong, Therese] INSERM, Ctr Res Epidemiol & Populat Hlth, Environm Epidemiol Canc, Villejuif, France. [Guenel, Pascal; Truong, Therese] Univ Paris 11, Villejuif, France. [Haiman, Christopher A.; Tseng, Chiu-chen; Wu, Anna] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Hamann, Ute; Kabisch, Maria] German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany. [Hartman, Mikael] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore. [Hartman, Mikael] Natl Univ Hlth Syst, Dept Surg, Singapore, Singapore. [Hollestelle, Antoinette] Erasmus Univ, Med Ctr, Dept Med Oncol, Rotterdam, Netherlands. [Hsiung, Chia-Ni] Acad Sinica, Inst Biomed Sci, Taipei, Taiwan. [kConFab Investigators] Peter MacCallum Canc Inst, East Melbourne, Vic, Australia. [Ito, Hidemi] Aichi Canc Ctr, Res Inst, Div Epidemiol & Prevent, Aichi, Japan. [Jakubowska, Anna; Lubinski, Jan] Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland. [Kang, Daehee] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea. [Khan, Sofia; Nevanlinna, Heli] Univ Helsinki, Cent Hosp, Dept Obstet & Gynecol, FIN-00290 Helsinki, Finland. [Knight, Julia A.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Prosserman Ctr Hlth Res, Toronto, ON M5G 1X5, Canada. [Knight, Julia A.] Univ Toronto, Dalla Lana Sch Publ Hlth, Div Epidemiol, Toronto, ON, Canada. [Kosma, Veli-Matti; Mannermaa, Arto] Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Sch Med, Kuopio, Finland. [Kosma, Veli-Matti; Mannermaa, Arto] Univ Eastern Finland, Canc Ctr Eastern Finland, Kuopio, Finland. [Kosma, Veli-Matti; Mannermaa, Arto] Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, SF-70210 Kuopio, Finland. [Lambrechts, Diether; Thienpont, Bernard] Vesalius Res Ctr, Leuven, Belgium. [Lambrechts, Diether; Thienpont, Bernard] Univ Leuven, Dept Oncol, Lab Translat Genet, Leuven, Belgium. [Le Marchand, Loic] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. [Lindblom, Annika] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. [Lophatananon, Artitaya] Univ Warwick, Warwick Med Sch, Div Hlth Sci, Coventry CV4 7AL, W Midlands, England. [Manoukian, Siranoush; Muir, Kenneth] Ist Nazl Tumori, Fdn IRCCS, Dept Prevent & Predict Med, Unit Med Genet, I-20133 Milan, Italy. [Margolin, Sara] Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden. [Marme, Frederik] Heidelberg Univ, Natl Ctr Tumor Dis, Heidelberg, Germany. [Marme, Frederik] Heidelberg Univ, Dept Obstet & Gynecol, Heidelberg, Germany. [Matsuo, Keitaro] Kyushu Univ, Fac Med Sci, Dept Prevent Med, Fukuoka 812, Japan. [McLean, Catriona A.] Alfred Hosp, Anat Pathol, Melbourne, Vic, Australia. [Meindl, Alfons] Tech Univ Munich, Div Gynaecol & Obstet, D-80290 Munich, Germany. [Muir, Kenneth] Univ Manchester, Inst Populat Hlth, Manchester, Lancs, England. [Neuhausen, Susan L.] Beckman Res Inst City Hope, Duarte, CA USA. [Nord, Silje] Oslo Univ Hosp, Radiumhosp, Inst Canc Res, Dept Genet, Oslo, Norway. [Nord, Silje] Univ Oslo, Fac Med, Inst Clin Med, KG Jebsen Ctr Breast Canc Res, Oslo, Norway. [Olson, Janet E.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Orr, Nick] Inst Canc Res, Div Breast Canc Res, London, England. [Orr, Nick] Inst Canc Res, Canc Res, London, England. [Peterlongo, Paolo] FIRC Inst Mol Oncol, IFOM, Milan, Italy. [Putti, Thomas Choudary] Natl Univ Hlth Syst, Dept Pathol, Singapore, Singapore. [Sangrajrang, Suleeporn] Natl Canc Inst, Bangkok, Thailand. [Sawyer, Elinor J.] Kings Coll London, Guys Hosp, Res Oncol, London, England. [Schmutzler, Rita K.] Univ Hosp Cologne, Dept Obstet & Gynaecol, Div Mol Gynecooncol, Cologne, Germany. [Schmutzler, Rita K.] Univ Hosp Cologne, Ctr Integrated Oncol, Cologne, Germany. [Schmutzler, Rita K.] Univ Hosp Cologne, Ctr Mol Med, Cologne, Germany. [Schmutzler, Rita K.] Univ Hosp Cologne, Ctr Familial Breast & Ovarian Canc, Cologne, Germany. [Shen, Chen-Yang] China Med Univ, Sch Publ Hlth, Taichung, Taiwan. [Shen, Chen-Yang] Acad Sinica, Inst Biomed Sci, Taiwan Biobank, Taipei, Taiwan. [Southey, Melissa C.] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia. [Swerdlow, Anthony] Inst Canc Res, Div Genet & Epidemiol, London SW3 6JB, England. [Swerdlow, Anthony] Inst Canc Res, Div Breast Canc Res, London SW3 6JB, England. [Teo, Soo Hwang] Canc Res Initiat Fdn, Selangor, Malaysia. [Teo, Soo Hwang; Yip, Cheng Har] Univ Malaya, Med Ctr, Canc Res Inst, Breast Canc Res Unit, Kuala Lumpur, Malaysia. [Toland, Amanda Ewart] Ohio State Univ, Ctr Comprehens Canc, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA. [Tollenaar, Robert A. E. M.] Leiden Univ, Med Ctr, Dept Surg Oncol, Leiden, Netherlands. [Tomlinson, Ian P. M.] Univ Oxford, Wellcome Trust, Ctr Human Genet, Oxford, England. [Tomlinson, Ian P. M.] Univ Oxford, Oxford Biomed Res Ctr, Oxford, England. [van den Ouweland, Ans] Erasmus Univ, Med Ctr, Dept Clin Genet, Rotterdam, Netherlands. [Winqvist, Robert] Univ Oulu, Dept Clin Chem, Lab Canc Genet & Tumor Biol, Oulu, Finland. [Winqvist, Robert] Northern Finland Lab Ctr NordLab, Lab Canc Genet & Tumor Biol, Oulu, Finland. [Zamora, M. Pilar] Hosp Univ La Paz, Med Oncol Serv, Madrid, Spain. [Zheng, Ying] Shanghai Municipal Ctr Dis Control & Prevent, Shanghai, Peoples R China. RP Zheng, W (reprint author), Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, 2525 West End Ave,8th Floor, Nashville, TN 37203 USA. EM wei.zheng@vanderbilt.edu RI Peissel, Bernard/E-8187-2017; Hartman, Mikael/B-4324-2011; Knight, Julia/A-6843-2012; Li, Jingmei/I-2904-2012; Yip, Cheng-Har/B-1909-2010; Teo, Soo-hwang/H-2353-2014; Bruning, Thomas/G-8120-2015; Andrulis, Irene/E-7267-2013; Shrubsole, Martha/K-5052-2015; Dork, Thilo/J-8620-2012; Nord, Silje/R-5212-2016; Brenner, Hermann/B-4627-2017; manoukian, siranoush/E-7132-2017 OI Peissel, Bernard/0000-0001-9233-3571; Dunning, Alison Margaret/0000-0001-6651-7166; Khan, Sofia/0000-0003-4185-8882; Cox, Angela/0000-0002-5138-1099; Arndt, Volker/0000-0001-9320-8684; Li, Jingmei/0000-0001-8587-7511; Bruning, Thomas/0000-0001-9560-5464; Shrubsole, Martha/0000-0002-5591-7575; Nord, Silje/0000-0002-3271-5356; Brenner, Hermann/0000-0002-6129-1572; manoukian, siranoush/0000-0002-6034-7562 FU NIH [R37CA070867, CA128978, CA122340, CA63464, CA54281, CA098758, CA132839, R01CA100374, R01CA64277, R01CA148667, R37CA70867, R01 CA092447]; endowment funds for the Ingram Professorship; Anne Potter Wilson Chair; Cancer Research UK [C1287/A10118, C1287/A12014, C8197/A16565, C1287/A10710, C490/A10124]; European Community's Seventh Framework Programme [223175, HEALTH-F2-2009-223175]; European Union [HEALTH-F2-2009-223175, BM0606]; Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program; Ministry of Economic Development, Innovation and Export Trade of Quebec [PSR-SIIRI-701]; Post-Cancer GWAS initiative [1U19 CA148537, 1U19 CA148065, 1U19 CA148112]; Department of Defence [W81XWH-10-1-0341]; Komen Foundation for the Cure; Breast Cancer Research Foundation; Ovarian Cancer Research Fund; National Cancer Institute [UM1 CA164920]; National Health and Medical Research Council of Australia; New South Wales Cancer Council; Victorian Health Promotion Foundation (Australia); Victorian Breast Cancer Research Consortium; Canadian Institutes of Health Research "CIHR Team in Familial Risks of Breast Cancer" program; Dutch Cancer Society [NKI2007-3839, NKI2009-4363, RUL 1997-1505, DDHK 2004-3124, DDHK 2009-4318]; Breast Cancer Research Trust, UK; ELAN-Programme of the University Hospital of Erlangen; Breakthrough Breast Cancer; NHS; NIHR Comprehensive Biomedical Research Centre, Guy's & St. Thomas' NHS Foundation Trust in partnership with King's College London, UK; Wellcome Trust [090532/Z/09/Z]; Oxford Biomedical Research Centre; Dietmar-Hopp Foundation; Helmholtz Society; German Cancer Research Center (DKFZ); Fondation de France, Institut National du Cancer (INCa); LigueNationale contre le Cancer, Agence Nationale de Securite Sanitaire (ANSES); Agence Nationale de la Recherche (ANR); Chief Physician Johan Boserup and Lise Boserup Fund; Danish Medical Research Council; Herlev Hospital; Genome Spain Foundation; Red Tematica de Investigacion Cooperativa en Cancer; Asociacion Espanola Contra el Cancer; Fondo de Investigacion Sanitario [PI11/00923, PI081120]; Instituto de Salud Carlos III; Michael Manzella Foundation (MMF); California Breast Cancer Act; California Breast Cancer Research Fund [97-10500]; National Institutes of Health [R01 CA77398]; California Department of Public Health as part of the statewide cancer reporting program [103885]; Lon V Smith Foundation [LVS39420]; Baden Wurttemberg Ministry of Science, Research and Arts; German Cancer Aid (Deutsche Krebshilfe); Federal Ministry of Education and Research (BMBF) Germany [01KW9975/5, 01KW9976/8, 01KW9977/0, 01KW0114, 01KH0402]; Robert Bosch Foundation, Stuttgart; Deutsches Krebsforschungszentrum (DKFZ), Heidelberg; Institute for Prevention and Occupational Medicine of the German Social Accident Insurance; Institute of the Ruhr University Bochum (IPA); Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus Bonn, Germany; Academy of Finland [266528, 250083, 122715, 251314]; Finnish Cancer Society; Nordic Cancer Union; Sigrid Juselius Foundation; Helsinki University Central Hospital Research Fund; Ministry of Education, Science, Sports, Culture and Technology of Japan; Ministry Health, Labour and Welfare of Japan; Takeda Science Foundation; National Cancer Center Research and Development Fund; Rudolf Bartling Foundation; Stockholm County Council; Karolinska Institutet; Stockholm Cancer Foundation; Swedish Cancer Society; Kuopio University Hospital grants; Cancer Fund of North Savo; Finnish Cancer Organizations; University of Eastern Finland; National Breast Cancer Foundation; NHMRC; Queensland Cancer Fund; Cancer Council of New South Wales; Cancer Council of Victoria; Cancer Council of Tasmania; Cancer Council of South Australia; Cancer Foundation of Western Australia; NHMRC [145684, 288704, 454508, 199600]; United States Army Medical Research and Materiel Command [DAMD17-01-1-0729]; Cancer Council of Tasmania and Cancer Foundation of Western Australia; California Breast Cancer Research Program [1RB-0287, 3PB-0102, 5PB-0018, 10PB-0098]; California Department of Health; National Cancer Institute's Division of Cancer Prevention and Control Surveillance, Epidemiology, and End Results Program [N01CN25403]; Stichting tegen Kanker [232-2008, 196-2010]; FWO; ERC; Deutsche Krebshilfe e.V. [70-2892-BR I, 106332, 108253, 108419]; Hamburg Cancer Society; German Cancer Research Center; Italian Association for Cancer Research (AIRC); Fondazione IRCCS Istituto Nazionale Tumori; Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]; VicHealth; Cancer Council Victoria; Australian NHMRC [209057, 251553, 504711]; Quebec Breast Cancer Foundation; Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program [CRN-87521]; Ministry of Economic Development, Innovation and Export Trade-grant [PSR-SIIRI-701]; Malaysian Ministry of Science, Technology and Innovation (MOSTI), Malaysian Ministry of Higher Education [UM.C/HlR/MOHE/06]; Cancer Research Initiatives Foundation (CARIF); Biomedical Research Council, Singapore [BMRC08/1/35/19/550]; National Medical Research Council, Singapore [NMRC/CG/SERI/2010]; Norwegian Research council [155218/V40, 175240/S10, FUGE-NFR 181600/V11]; Health Region South East (HSO) [2014061]; Finnish Cancer Foundation; University of Oulu; special Governmental EVO funds for Oulu University Hospital; Biobanking and Biomolecular Resources Research Infrastructure [BBMRI-NL CP16]; Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA; Marit and Hans Rausings Initiative Against Breast Cancer; Cancer Risk Prediction Center (CRisP); Swedish Research Council [70867902]; Agency for Science, Technology, and Research of Singapore (A*STAR); US National Institute of Health (NIH); Susan G. Komen Breast Cancer Foundation; Swedish Cancer Society [5128-B07-01PAF]; Yorkshire Cancer Research [S305PA, S299, S295]; Sheffield Experimental Cancer Medicine Centre; National Program of Cancer Registries; Centers for Disease Control and Prevention (CDC); UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge; National Research Foundation of Korea -unded by the Ministry of Education, Science, and Technology [2012-0000347]; NUS start-up Grant; NCIS Centre Grant; Biomedical Research Council [05/1/21/19/425]; DKFZ; Polish Foundation of Science; Ohio State University Comprehensive Cancer Center; Stefanie Spielman Fund for Breast Cancer Research; European Union (European Social Fund-ESF); Greek National Funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF)-Research Funding Program of the General Secretariat for Research & Technology: ARISTEIA; Institute of Biomedical Sciences; Academia Sinica; National Science Council, Taiwan; Institute of Cancer Research (ICR); [KULPFV/10/016-SymBioSysII]; [P30 CA68485]; [PBZ_KBN_122/P05/2004] FX The work conducted for this project at Vanderbilt Epidemiology Center is supported in part by NIH grant R37CA070867 and endowment funds for the Ingram Professorship and Anne Potter Wilson Chair. BCAC is funded by Cancer Research UK (C1287/A10118, C1287/A12014) and by the European Community's Seventh Framework Programme under grant agreement no 223175 (HEALTH-F2-2009-223175; COGS). Meetings of the BCAC have been funded by the European Union COST programme (BM0606). Genotyping of the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C8197/A16565 and C1287/A10710), the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program and the Ministry of Economic Development, Innovation and Export Trade of Quebec (PSR-SIIRI-701). Additional support for the iCOGS infrastructure was provided by the NIH (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), Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. This work was supported by grant UM1 CA164920 from the National Cancer Institute. The ABCFS was also supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia), and the Victorian Breast Cancer Research Consortium. J.L.H. is a National Health and Medical Research Council (NHMRC) Senior Principal Research Fellow and M.C.S. is a NHMRC Senior Research Fellow. The OFBCR work was also supported by the Canadian Institutes of Health Research "CIHR Team in Familial Risks of Breast Cancer" program. The ABCS was funded by the Dutch Cancer Society Grant no. NKI2007-3839 and NKI2009-4363. The ACP study is funded by the Breast Cancer Research Trust, UK. The work of the BBCC was partly funded by ELAN-Programme of the University Hospital of Erlangen. The BBCS is funded by Cancer Research UK and Breakthrough Breast Cancer and acknowledges NHS funding to the NIHR Biomedical Research Centre, and the National Cancer Research Network (NCRN). E.J. Sawyer is supported by NIHR Comprehensive Biomedical Research Centre, Guy's & St. Thomas' NHS Foundation Trust in partnership with King's College London, UK. Core funding to the Wellcome Trust Centre for Human Genetics was provided by the Wellcome Trust (090532/Z/09/Z). I.P.M. Tomlison is supported by the Oxford Biomedical Research Centre. The BSUCH study was supported by the Dietmar-Hopp Foundation, the Helmholtz Society and the German Cancer Research Center (DKFZ). The CECILE study was funded by Fondation de France, Institut National du Cancer (INCa), LigueNationale contre le Cancer, Agence Nationale de Securite Sanitaire (ANSES), Agence Nationale de la Recherche (ANR). The CGPS was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council, and Herlev Hospital. The CNIO-BCS was supported by the Genome Spain Foundation, the Red Tematica de Investigacion Cooperativa en Cancer and grants from the Asociacion Espanola Contra el Cancer and the Fondo de Investigacion Sanitario (PI11/00923 and PI081120). The Human Genotyping-CEGEN Unit, CNIO is supported by the Instituto de Salud Carlos III. Divyansh Agarwal was supported by a Fellowship from the Michael Manzella Foundation (MMF) and was a participant in the CNIO Summer Training Program.; The CTS was initially supported by the California Breast Cancer Act of 1993 and the California Breast Cancer Research Fund (contract 97-10500) and is currently funded through the National Institutes of Health (R01 CA77398). Collection of cancer incidence data was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885. H. Anton-Culver receives support from the Lon V Smith Foundation (LVS39420). 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 GENICA was funded by the Federal Ministry of Education and Research (BMBF) Germany grants 01KW9975/5, 01KW9976/8, 01KW9977/0 and 01KW0114, the Robert Bosch Foundation, Stuttgart, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), as well as the Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus Bonn, Germany. The HEBCS was 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 HERPACC was supported by a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Science, Sports, Culture and Technology of Japan, by a Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control from Ministry Health, Labour and Welfare of Japan, by a research grant from Takeda Science Foundation, by Health and Labour Sciences Research Grants for Research on Applying Health Technology from Ministry Health, Labour and Welfare of Japan and by National Cancer Center Research and Development Fund. The HMBCS was supported by the Rudolf Bartling Foundation. 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 Stockholm Cancer Foundation and the Swedish Cancer Society. 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, the Academy of Finland, and by the strategic funding of the University of Eastern Finland. kConFab is supported by grants from the National Breast Cancer Foundation, the NHMRC, the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia, and the Cancer Foundation of Western Australia. The kConFab Clinical Follow Up Study was funded by the NHMRC (145684, 288704, 454508). Financial support for the AOCS was provided by the United States Army Medical Research and Materiel Command (DAMD17-01-1-0729), the Cancer Council of Tasmania and Cancer Foundation of Western Australia, and the NHMRC(199600). G.C.T. and P.W. are supported by the NHMRC. LAABC is supported by grants (1RB-0287, 3PB-0102, 5PB-0018 and 10PB-0098) from the California Breast Cancer Research Program. Incident breast cancer cases were collected by the USC Cancer Surveillance Program (CSP), which is supported under subcontract by the California Department of Health.; The CSP is also part of the National Cancer Institute's Division of Cancer Prevention and Control Surveillance, Epidemiology, and End Results Program, under contract number N01CN25403. LMBC is supported by the 'Stichting tegen Kanker' (232-2008 and 196-2010). D. Lambrechts is supported by the FWO and the KULPFV/10/016-SymBioSysII and by an ERC consolidator grant. 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, and the Federal Ministry of Education and Research (BMBF) Germany [01KH0402]. MBCSG is supported by grants from the Italian Association for Cancer Research (AIRC) and by funds from the Italian citizens who allocated a 5/1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects "5 x 1000"). The MCBCS was supported by the NIH grants (CA122340, CA128978) and a Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), the Breast Cancer Research Foundation, and a generous gift from the David F. and Margaret T. Grohne Family Foundation and the Ting Tsung and Wei Fong Chao Foundation. MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057, 251553, and 504711 and by infrastructure provided by Cancer Council Victoria. The MEC was supported by NIH grants CA63464, CA54281, CA098758, and CA132839. The work of MTLGEBCS was supported by the Quebec Breast Cancer Foundation, the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program-grant CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade-grant PSR-SIIRI-701. MYBRCA is funded by research grants from the Malaysian Ministry of Science, Technology and Innovation (MOSTI), Malaysian Ministry of Higher Education (UM.C/HlR/MOHE/06), and Cancer Research Initiatives Foundation (CARIF). Additional controls were recruited by the Singapore Eye Research Institute, which was supported by a grant from the Biomedical Research Council (BMRC08/1/35/19/550), Singapore and the National Medical Research Council, Singapore (NMRC/CG/SERI/2010). The NBCS was supported by grants from the Norwegian Research council (155218/V40, 175240/S10 to Anne-Lise Borresen-Dale, FUGE-NFR 181600/V11 to V.-M. Kosma and a Swizz Bridge Award to Anne-Lise Borresen-Dale). S. Nord has a carrier grant from the Health Region South East (HSO, grant nr 2014061). The NBHS was supported by NIH grant R01CA100374. Biological sample preparation was conducted the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485. OBCS was supported by the Academy of Finland (grant number 250083, 122715 and Center of Excellence grant number 251314), the Finnish Cancer Foundation, 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 ORIGO study was supported by the Dutch Cancer Society (RUL 1997-1505) and the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL CP16). The PBCS was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. pKARMA is a combination of the KARMA and LIBRO-1 studies. KARMA was supported by Marit and Hans Rausings Initiative Against Breast Cancer.; KARMA and LIBRO-1 were supported the Cancer Risk Prediction Center (CRisP; www.crispcenter.org), a Linnaeus Centre (Contract ID 70867902) financed by the Swedish Research Council. The RBCS was funded by the Dutch Cancer Society (DDHK 2004-3124, DDHK 2009-4318). SASBAC 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. KC was financed by the Swedish Cancer Society (5128-B07-01PAF). The SBCGS was supported primarily by NIH grants R01CA64277, R01CA148667, and R37CA70867. Biological sample preparation was conducted the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485. The SBCS was supported by Yorkshire Cancer Research S305PA, S299 and S295, and the Sheffield Experimental Cancer Medicine Centre. Funding for the SCCS was provided by NIH grant R01 CA092447. The Arkansas Central Cancer Registry is fully funded by a grant from National Program of Cancer Registries, Centers for Disease Control and Prevention (CDC). Data on SCCS cancer cases from Mississippi were collected by the Mississippi Cancer Registry, which participates in the National Program of Cancer Registries (NPCR) of the Centers for Disease Control and Prevention (CDC). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the CDC or the Mississippi Cancer Registry. 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 SEBCS was supported by the BRL (Basic Research Laboratory) program through the National Research Foundation of Korea funded by the Ministry of Education, Science, and Technology (2012-0000347). SGBCC is funded by the NUS start-up Grant, NCIS Centre Grant, and NMRC Clinician Scientist Award. Additional controls were recruited by the Singapore Consortium of Cohort Studies-Multi-ethnic cohort (SCCS-MEC), which was funded by the Biomedical Research Council, grant number: 05/1/21/19/425. SKKDKFZS is supported by the DKFZ. The SZBCS was supported by Grant PBZ_KBN_122/P05/2004. K.J. is a fellow of International PhD program, Postgraduate School of Molecular Medicine, Warsaw Medical University, supported by the Polish Foundation of Science. The TNBCC was supported by the NIH grant (CA128978), the Breast Cancer Research Foundation, Komen Foundation for the Cure, the Ohio State University Comprehensive Cancer Center, the Stefanie Spielman Fund for Breast Cancer Research, and a generous gift from the David F. and Margaret T. Grohne Family Foundation and the Ting Tsung and Wei Fong Chao Foundation. Part of the TNBCC (DEMOKRITOS) has been co-financed by the European Union (European Social Fund-ESF) and Greek National Funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF)-Research Funding Program of the General Secretariat for Research & Technology: ARISTEIA. The TWBCS is supported by the Institute of Biomedical Sciences, Academia Sinica and the National Science Council, Taiwan. The UKBGS is funded by Breakthrough Breast Cancer and the Institute of Cancer Research (ICR). ICR acknowledges NHS funding to the NIHR Biomedical Research Centre. NR 49 TC 2 Z9 2 U1 4 U2 18 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD NOV PY 2015 VL 24 IS 11 BP 1680 EP 1691 DI 10.1158/1055-9965.EPI-15-0363 PG 12 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CX3KV UT WOS:000365598600006 PM 26354892 ER PT J AU Szulkin, R Karlsson, R Whitington, T Aly, M Gronberg, H Eeles, RA Easton, DF Kote-Jarai, Z Al Olama, AA Benlloch, S Muir, K Giles, GG Southey, MC FitzGerald, LM Henderson, BE Schumacher, FR Haiman, CA Sipeky, C Tammela, TLJ Nordestgaard, BG Key, TJ Travis, RC Neal, DE Donovan, JL Hamdy, FC Pharoah, PDP Pashayan, N Khaw, KT Stanford, JL Thibodeau, SN McDonnell, SK Schaid, DJ Maier, C Vogel, W Luedeke, M Herkommer, K Kibel, AS Cybulski, C Lubinski, J Kluzniak, W Cannon-Albright, L Brenner, H Herrmann, V Holleczek, B Park, JY Sellers, TA Lim, HY Slavov, C Kaneva, RP Mitev, VI Spurdle, A Teixeira, MR Paulo, P Maia, S Pandha, H Michael, A Kierzek, A Batra, J Clements, JA Albanes, D Andriole, GL Berndt, SI Chanock, S Gapstur, SM Giovannucci, EL Hunter, DJ Kraft, P Le Marchand, L Ma, J Mondul, AM Penney, KL Stampfer, MJ Stevens, VL Weinstein, SJ Trichopoulou, A Bueno-De-Mesquita, BH Tjonneland, A Cox, DG Maehle, L Schleutker, J Lindstrom, S Wiklund, F AF Szulkin, Robert Karlsson, Robert Whitington, Thomas Aly, Markus Gronberg, Henrik Eeles, Rosalind A. Easton, Douglas F. Kote-Jarai, Zsofia Al Olama, Ali Amin Benlloch, Sara Muir, Kenneth Giles, Graham G. Southey, Melissa C. FitzGerald, Liesel M. Henderson, Brian E. Schumacher, Fredrick R. Haiman, Christopher A. Sipeky, Csilla Tammela, Teuvo L. J. Nordestgaard, Borge G. Key, Timothy J. Travis, Ruth C. Neal, David E. Donovan, Jenny L. Hamdy, Freddie C. Pharoah, Paul D. P. Pashayan, Nora Khaw, Kay-Tee Stanford, Janet L. Thibodeau, Stephen N. McDonnell, Shannon K. Schaid, Daniel J. Maier, Christiane Vogel, Walther Luedeke, Manuel Herkommer, Kathleen Kibel, Adam S. Cybulski, Cezary Lubinski, Jan Kluzniak, Wojciech Cannon-Albright, Lisa Brenner, Hermann Herrmann, Volker Holleczek, Bernd Park, Jong Y. Sellers, Thomas A. Lim, Hui-Yi Slavov, Chavdar Kaneva, Radka P. Mitev, Vanio I. Spurdle, Amanda Teixeira, Manuel R. Paulo, Paula Maia, Sofia Pandha, Hardev Michael, Agnieszka Kierzek, Andrzej Batra, Jyotsna Clements, Judith A. Albanes, Demetrius Andriole, Gerald L. Berndt, Sonja I. Chanock, Stephen Gapstur, Susan M. Giovannucci, Edward L. Hunter, David J. Kraft, Peter Le Marchand, Loic Ma, Jing Mondul, Alison M. Penney, Kathryn L. Stampfer, Meir J. Stevens, Victoria L. Weinstein, Stephanie J. Trichopoulou, Antonia Bueno-de-Mesquita, Bas H. Tjonneland, Anne Cox, David G. Maehle, Lovise Schleutker, Johanna Lindstroem, Sara Wiklund, Fredrik CA PRACTICAL Consortium Australian Prostate Canc BioResour BPC3 Consortium TI Genome-Wide Association Study of Prostate Cancer-Specific Survival SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID SUSCEPTIBILITY LOCI; METAANALYSIS; COHORT AB Background: Unnecessary intervention and overtreatment of indolent disease are common challenges in clinical management of prostate cancer. Improved tools to distinguish lethal from indolent disease are critical. Methods: We performed a genome-wide survival analysis of cause-specific death in 24,023 prostate cancer patients (3,513 disease-specific deaths) from the PRACTICAL and BPC3 consortia. Top findings were assessed for replication in a Norwegian cohort (CONOR). Results: We observed no significant association between genetic variants and prostate cancer survival. Conclusions: Common genetic variants with large impact on prostate cancer survival were not observed in this study. Impact: Future studies should be designed for identification of rare variants with large effect sizes or common variants with small effect sizes. (C) 2015 AACR. C1 [Szulkin, Robert; Karlsson, Robert; Whitington, Thomas; Aly, Markus; Gronberg, Henrik; Wiklund, Fredrik] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden. [Szulkin, Robert] Karolinska Inst, Stockholm Cty Council, Acad Primary Healthcare Ctr, SE-17177 Stockholm, Sweden. [Eeles, Rosalind A.; Kote-Jarai, Zsofia] Inst Canc Res, London SW3 6JB, England. [Eeles, Rosalind A.] Royal Marsden Natl Hlth Serv NHS Fdn Trust, London, England. [Eeles, Rosalind A.] Royal Marsden Natl Hlth Serv NHS Fdn Trust, Sutton, Surrey, England. [Easton, Douglas F.; Al Olama, Ali Amin; Benlloch, Sara] Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Muir, Kenneth] Univ Manchester, Inst Populat Hlth, Manchester, Lancs, England. [Muir, Kenneth] Univ Warwick, Warwick Med Sch, Coventry CV4 7AL, W Midlands, England. [Giles, Graham G.; FitzGerald, Liesel M.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Giles, Graham G.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Biostat & Epidemiol, Melbourne, Vic, Australia. [Southey, Melissa C.] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Parkville, Vic 3052, Australia. [Henderson, Brian E.; Schumacher, Fredrick R.; Haiman, Christopher A.] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Sipeky, Csilla; Schleutker, Johanna] Univ Turku, Inst Biomed, Dept Med Biochem & Genet, Turku, Finland. [Tammela, Teuvo L. J.] Tampere Univ Hosp, Dept Urol, Tampere, Finland. [Tammela, Teuvo L. J.] Univ Tampere, Sch Med, FIN-33101 Tampere, Finland. [Nordestgaard, Borge G.] Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, Herlev, Denmark. [Nordestgaard, Borge G.] Univ Copenhagen, Fac Med & Hlth Sci, Copenhagen, Denmark. [Key, Timothy J.; Travis, Ruth C.] Univ Oxford, Nuffield Dept Populat Hlth, Canc Epidemiol, Oxford, England. [Neal, David E.] Univ Cambridge, Addenbrookes Hosp, Dept Oncol, Cambridge CB2 2QQ, England. [Neal, David E.] Canc Res UK Cambridge Res Inst, Li Ka Shing Ctr, Cambridge, England. [Donovan, Jenny L.] Univ Bristol, Sch Social & Community Med, Bristol, Avon, England. [Hamdy, Freddie C.] Univ Oxford, Nuffield Dept Surg Sci, Oxford, England. [Hamdy, Freddie C.] Univ Oxford, John Radcliffe Hosp, Fac Med Sci, Oxford OX3 9DU, England. [Pharoah, Paul D. P.; Pashayan, Nora] Univ Cambridge, Strangeways Res Lab, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England. [Pashayan, Nora] UCL, Dept Appl Hlth Res, London, England. [Khaw, Kay-Tee] Univ Cambridge, Clin Gerontol Unit, Cambridge, England. [Stanford, Janet L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Stanford, Janet L.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Thibodeau, Stephen N.; McDonnell, Shannon K.; Schaid, Daniel J.] Mayo Clin, Rochester, MN USA. [Maier, Christiane; Luedeke, Manuel] Univ Hosp Ulm, Dept Urol, Ulm, Germany. [Vogel, Walther] Univ Hosp Ulm, Inst Human Genet, Ulm, Germany. [Herkommer, Kathleen] Tech Univ Munich, Klinikum Rechts Isar, Dept Urol, D-80290 Munich, Germany. [Kibel, Adam S.] Brigham & Womens Hosp, Dana Farber Canc Inst, Div Urol Surg, Boston, MA 02115 USA. [Cybulski, Cezary; Lubinski, Jan; Kluzniak, Wojciech] Pomeranian Med Univ, Dept Genet & Pathol, Int Hereditary Canc Ctr, Szczecin, Poland. [Cannon-Albright, Lisa] Univ Utah, Sch Med, Dept Med, Div Genet Epidemiol, Salt Lake City, UT USA. [Cannon-Albright, Lisa] Vet Affairs Med Ctr, George E Wahlen Dept, Salt Lake City, UT 84148 USA. [Brenner, Hermann; Herrmann, Volker] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Brenner, Hermann] German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany. [Brenner, Hermann] German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany. [Holleczek, Bernd] Saarland Canc Registry, Saarbrucken, Germany. [Park, Jong Y.; Sellers, Thomas A.] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Canc Epidemiol, Tampa, FL 33682 USA. [Lim, Hui-Yi] Univ S Florida, H Lee Moffitt Canc Ctr, Biostat Program, Tampa, FL 33682 USA. [Slavov, Chavdar] Med Univ Sofia, Dept Urol, Sofia, Bulgaria. [Slavov, Chavdar] Med Univ Sofia, Alexandrovska Univ Hosp, Sofia, Bulgaria. [Kaneva, Radka P.; Mitev, Vanio I.] Med Univ, Mol Med Ctr, Dept Med Chem & Biochem, Sofia, Bulgaria. [Spurdle, Amanda] Queensland Inst Med Res, Mol Canc Epidemiol Lab, Brisbane, Qld 4006, Australia. [Teixeira, Manuel R.; Paulo, Paula; Maia, Sofia] Portuguese Oncol Inst, Dept Genet, Oporto, Portugal. [Teixeira, Manuel R.] Univ Porto, Biomed Sci Inst ICBAS, Oporto, Portugal. [Pandha, Hardev; Michael, Agnieszka; Kierzek, Andrzej] Univ Surrey, Surrey, England. [Batra, Jyotsna; Clements, Judith A.] Queensland Univ Technol, Inst Hlth & Biomed Innovat, Australian Prostate Canc Res Ctr Qld, Brisbane, Qld 4001, Australia. [Batra, Jyotsna; Clements, Judith A.] Queensland Univ Technol, Sch Biomed Sci, Brisbane, Qld 4001, Australia. [Australian Prostate Canc BioResour] Australian Prostate Canc BioResource, Brisbane, Qld, Australia. [Albanes, Demetrius; Berndt, Sonja I.; Chanock, Stephen; Mondul, Alison M.; Weinstein, Stephanie J.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Andriole, Gerald L.] Washington Univ, Sch Med, St Louis, MO USA. [Chanock, Stephen] Frederick Natl Lab Canc Res, Core Genotyping Facil, Gaithersburg, MD USA. [Gapstur, Susan M.; Stevens, Victoria L.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Giovannucci, Edward L.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Giovannucci, Edward L.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Giovannucci, Edward L.; Ma, Jing] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Hunter, David J.; Kraft, Peter; Lindstroem, Sara] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Program Genet Epidemiol & Stat Genet, Boston, MA 02115 USA. [Le Marchand, Loic] Univ Hawaii, Canc Res Ctr Hawaii, Honolulu, HI 96813 USA. [Ma, Jing; Penney, Kathryn L.] Brigham & Womens Hosp, Channing Lab, Dept Epidemiol, Boston, MA 02115 USA. [Ma, Jing; Penney, Kathryn L.; Stampfer, Meir J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Trichopoulou, Antonia] Hellen Hlth Fdn, Athens, Greece. [Trichopoulou, Antonia] Univ Athens, Sch Med, Dept Hyg Epidemiol & Med Stat, GR-11527 Athens, Greece. [Trichopoulou, Antonia] Acad Athens, Bureau Epidemiol Res, Athens, Greece. [Bueno-de-Mesquita, Bas H.] Natl Inst Publ Hlth & Environm RIVM, Dept Determinants Chron Dis DCD, Bilthoven, Netherlands. [Bueno-de-Mesquita, Bas H.] Univ Med Ctr, Dept Gastroenterol & Hepatol, Utrecht, Netherlands. [Bueno-de-Mesquita, Bas H.] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. [Bueno-de-Mesquita, Bas H.] Univ Malaya, Fac Med, Dept Social & Prevent Med, Kuala Lumpur, Malaysia. [Tjonneland, Anne] Danish Canc Soc, Res Ctr, Copenhagen, Denmark. [Cox, David G.] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. [Cox, David G.] Ctr Leon Berard, INSERM, Canc Res Ctr Lyon, UMR1052, F-69373 Lyon, France. [Maehle, Lovise] Oslo Univ Hosp, Norwegian Radium Hosp, Dept Med Genet, Inherited Canc Res Grp, Oslo, Norway. [Schleutker, Johanna] Univ Tampere, BioMediTech, FIN-33101 Tampere, Finland. [Schleutker, Johanna] FimLab Labs, Tampere, Finland. RP Szulkin, R (reprint author), Karolinska Inst, Box 281, SE-17177 Stockholm, Sweden. EM robert.szulkin@ki.se RI Teixeira, Manuel/E-4885-2011; Paulo, Paula/F-1441-2016; Batra, Jyotsna/B-4130-2011; Cox, David/A-2023-2009; Brenner, Hermann/B-4627-2017; OI albright, lisa/0000-0003-2602-3668; Teixeira, Manuel/0000-0002-4896-5982; Paulo, Paula/0000-0001-8387-2127; Giles, Graham/0000-0003-4946-9099; Clements, Judith/0000-0001-6026-1964; Karlsson, Robert/0000-0002-8949-2587; Cox, David/0000-0002-2152-9259; Brenner, Hermann/0000-0002-6129-1572; Eeles, Rosalind/0000-0002-3698-6241; Mondul, Alison/0000-0002-8843-1416 FU Swedish Cancer Society [2012/823]; Swedish Research Council [2014/2269] FX F. Wiklund was recipient of the Swedish Cancer Society grant 2012/823 and Swedish Research Council grant 2014/2269. NR 8 TC 7 Z9 7 U1 5 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD NOV PY 2015 VL 24 IS 11 BP 1796 EP 1800 DI 10.1158/1055-9965.EPI-15-0543 PG 5 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CX3KV UT WOS:000365598600020 PM 26307654 ER PT J AU Robbins, PF AF Robbins, Paul F. TI T-Cell Receptor-Transduced T Cells Clinical Experience SO CANCER JOURNAL LA English DT Review DE Adoptive immunotherapies; T-cell epitopes; T-cell receptors (TCRs); tumor regression ID WILMS-TUMOR GENE; METASTATIC MELANOMA; CANCER REGRESSION; CD34(+) PROGENITORS; ANTIGEN NY-ESO-1; IN-VITRO; LYMPHOCYTES; THERAPY; IMMUNOTHERAPY; PEPTIDE AB The large number of T-cell epitopes that have been found to be processed and presented on human tumors, now numbering in the hundreds, provides a rich source of targets for therapeutic interventions aimed at inducing durable tumor regression. Vaccination strategies aimed at inducing responses to these antigens have been largely ineffective, and it has been challenging to generate large numbers of T cells with the functional capacity to mediate durable tumor regressions in adoptive immunotherapy strategies in patients who have common epithelial malignancies. The ability to generate T-cell receptors that recognize shared as well as unique antigens expressed in a wide variety of common tumor types that include lung, breast, ovarian, gastrointestinal, urothelial, and genitourinary cancers provides an opportunity to develop widely applicable therapies based on the adoptive transfer of autologous T cells transduced with those receptors. C1 [Robbins, Paul F.] NCI, NIH, Surg Branch, Bethesda, MD 20892 USA. RP Robbins, PF (reprint author), NCI, NIH, Surg Branch, CRC 3-5744, Bethesda, MD 20892 USA. EM paulrobbins@mail.nih.gov NR 41 TC 2 Z9 2 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1528-9117 EI 1540-336X J9 CANCER J JI Cancer J. PD NOV-DEC PY 2015 VL 21 IS 6 BP 480 EP 485 DI 10.1097/PPO.0000000000000160 PG 6 WC Oncology SC Oncology GA CX5BE UT WOS:000365714800007 PM 26588680 ER PT J AU Yang, JC AF Yang, James C. TI Toxicities Associated With Adoptive T-Cell Transfer for Cancer SO CANCER JOURNAL LA English DT Review DE Acute cytokine release; autoimmune complications; cancer; cultured immune cells; infection; off-target toxicities; toxicities ID CHIMERIC-ANTIGEN-RECEPTOR; METASTATIC MELANOMA; GENE-THERAPY; IMMUNOTHERAPY; LYMPHOCYTES; REGRESSION; AUTOIMMUNITY; TRIAL; SPECIFICITY; LEUKEMIA AB This review describes the toxicities associated with the therapeutic administration of cultured immune cells for the treatment of cancer by review of the literature. The toxicities seen are of 4 types: infection associated with preparative host immunosuppression with chemotherapy prior to cell administration, acute cytokine release by the infused cells, autoimmune complications from attacking self-antigens also expressed by some normal tissues, and off-target toxicities where antigens, other than the intended, are attacked. Complications from immunosuppression and cytokine release are often short-lived and currently best addressed by supportive care. Autoimmunity, either on target, off tumor or off target, is the result of the selection of imperfect target antigens. In some cases, this can be tolerated because the benefits outweigh the costs. In other cases, alternative target antigens must be found. New strategies targeting viral antigens for virally induced cancers and antigens encoded by tumor-specific mutations seem to have promise as safe and potentially effective targets for adoptive cell transfer. C1 [Yang, James C.] NCI, Surg Branch, Clin Res Ctr, Bethesda, MD 20892 USA. RP Yang, JC (reprint author), NCI, Surg Branch, Clin Res Ctr, Bldg 10A CRC,Rm 3-5952, Bethesda, MD 20892 USA. EM jamesyang@mail.nih.gov FU National Institutes of Health FX Funding was provided by the National Institutes of Health. NR 33 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 1528-9117 EI 1540-336X J9 CANCER J JI Cancer J. PD NOV-DEC PY 2015 VL 21 IS 6 BP 506 EP 509 DI 10.1097/PPO.0000000000000157 PG 4 WC Oncology SC Oncology GA CX5BE UT WOS:000365714800011 PM 26588684 ER PT J AU Rath, BH Wahba, A Camphausen, K Tofilon, PJ AF Rath, Barbara H. Wahba, Amy Camphausen, Kevin Tofilon, Philip J. TI Coculture with astrocytes reduces the radiosensitivity of glioblastoma stem-like cells and identifies additional targets for radiosensitization SO CANCER MEDICINE LA English DT Article DE Astrocytes; glioblastoma stem-like cells; microenvironment; radiosensitization; STAT3 ID TUMOR-INITIATING CELLS; HUMAN BRAIN; IN-VITRO; ADJUVANT TEMOZOLOMIDE; SIGNAL TRANSDUCERS; CANCER; LINES; RADIATION; RADIOTHERAPY; RADIORESISTANCE AB Toward developing a model system for investigating the role of the microenvironment in the radioresistance of glioblastoma (GBM), human glioblastoma stem-like cells (GSCs) were grown in coculture with human astrocytes. Using a trans-well assay, survival analyses showed that astrocytes significantly decreased the radiosensitivity of GSCs compared to standard culture conditions. In addition, when irradiated in coculture, the initial level of radiation-induced H2AX foci in GSCs was reduced and foci dispersal was enhanced suggesting that the presence of astrocytes influenced the induction and repair of DNA double-strand breaks. These data indicate that astrocytes can decrease the radiosensitivity of GSCs in vitro via a paracrine-based mechanism and further support a role for the microenvironment as a determinant of GBM radioresponse. Chemokine profiling of coculture media identified a number of bioactive molecules not present under standard culture conditions. The gene expression profiles of GSCs grown in coculture were significantly different as compared to GSCs grown alone. These analyses were consistent with an astrocyte-mediated modification in GSC phenotype and, moreover, suggested a number of potential targets for GSC radiosensitization that were unique to coculture conditions. Along these lines, STAT3 was activated in GSCs grown with astrocytes; the JAK/STAT3 inhibitor WP1066 enhanced the radiosensitivity of GSCs under coculture conditions and when grown as orthotopic xenografts. Further, this coculture system may also provide an approach for identifying additional targets for GBM radiosensitization. C1 [Rath, Barbara H.; Wahba, Amy; Camphausen, Kevin; Tofilon, Philip J.] NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. RP Tofilon, PJ (reprint author), NCI, 10 Ctr Drive MSC 1002,Bldg 10,B3B69B, Bethesda, MD 20892 USA. EM tofionp@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, and Center for Cancer Research FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, and Center for Cancer Research. NR 42 TC 1 Z9 1 U1 1 U2 1 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 NOV PY 2015 VL 4 IS 11 BP 1705 EP 1716 DI 10.1002/cam4.510 PG 12 WC Oncology SC Oncology GA CX6XB UT WOS:000365843900011 PM 26518290 ER PT J AU Lebov, JF Engel, LS Richardson, D Hogan, SL Sandler, DP Hoppin, JA AF Lebov, Jill F. Engel, Lawrence S. Richardson, David Hogan, Susan L. Sandler, Dale P. Hoppin, Jane A. TI Pesticide exposure and end-stage renal disease risk among wives of pesticide applicators in the Agricultural Health Study SO ENVIRONMENTAL RESEARCH LA English DT Article DE Pesticide exposure; End-stage renal disease; Farm women; Agricultural exposures ID FARM FAMILY EXPOSURE; OXIDATIVE STRESS; RAT-KIDNEY; SRI-LANKA; PATHWAYS; CONTAMINATION; CHLORPYRIFOS; PROXIMITY; COMMUNITY; EPIDEMIC AB Background: Pesticide exposure has been found to cause renal damage and dysfunction in experimental studies, but epidemiological research on the renal effects of chronic low-level pesticide exposure is limited. We investigated the relationships between end-stage renal disease (ESRD) among wives of licensed pesticide applicators (N=31,142) in the Agricultural Health Study (AHS) and (1) personal pesticide use, (2) exposure to the husband's pesticide use, and (3) other pesticide-associated farming and household activities. Methods: AHS participants reported pesticide exposure via self-administered questionnaires at enrollment (1993-1997). ESRD cases were identified via linkage to the United States Renal Data System. Associations between ESRD and pesticide exposures were estimated with Cox proportional hazard regression models controlling for age at enrollment. Models of associations with farming and household factors were additionally adjusted for personal use of pesticides. Results: We identified 98 ESRD cases diagnosed between enrollment and 31 December 2011. Although women who ever applied pesticides (56% of cohort) were less likely than those who did not apply to develop ESRD (Hazard Ratio (HR): 0.42; 95% CI: 0.28, 0.64), among women who did apply pesticides, the rate of ESRD was significantly elevated among those who reported the highest (vs. lowest) cumulative general pesticide use (HR: 4.22; 95% CI: 1.26, 14.20). Among wives who never applied pesticides, ESRD was associated with husbands' ever use of paraquat (HR=1.99; 95% CI: 1.14, 3.47) and butylate (HR=1.71; 95% CI: 1.00, 2.95), with a positive exposure-response pattern for husband's cumulative use of these pesticides. Conclusions: ESRD may be associated with direct and/or indirect exposure to pesticides among farm women. Future studies should evaluate indirect exposure risk among other rural populations. Published by Elsevier Inc. C1 [Lebov, Jill F.; Engel, Lawrence S.; Richardson, David] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Hogan, Susan L.] Univ N Carolina, Dept Med, Div Nephrol & Hypertens, Chapel Hill, NC USA. [Sandler, Dale P.] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Hoppin, Jane A.] N Carolina State Univ, Dept Biol Sci, Ctr Human Hlth & Environm, Raleigh, NC 27695 USA. RP Sandler, DP (reprint author), NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. EM jlebov@email.unc.edu; larry.engel@unc.edu; david.richardson@unc.edu; Susan_hogan@med.unc.edu; sandler@niehs.nih.gov; jahoppin@ncsu.edu OI Sandler, Dale/0000-0002-6776-0018; Engel, Lawrence/0000-0001-9268-4830 FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [ZO1 ES 049030]; NIH, National Institute of Diabetes and Digestive and Kidney Diseases Ruth L. Kirschstein National Research Service Award (NRSA) Institutional Research Training Grant [T32 DK 007750] FX This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (ZO1 ES 049030) and by an NIH, National Institute of Diabetes and Digestive and Kidney Diseases Ruth L. Kirschstein National Research Service Award (NRSA) Institutional Research Training Grant (T32 DK 007750; PI RJ Falk). NR 52 TC 0 Z9 0 U1 1 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0013-9351 EI 1096-0953 J9 ENVIRON RES JI Environ. Res. PD NOV PY 2015 VL 143 BP 198 EP 210 DI 10.1016/j.envres.2015.10.002 PN A PG 13 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA CX6SJ UT WOS:000365831400026 PM 26505650 ER PT J AU Prasad, V Goldstein, JA AF Prasad, Vinay Goldstein, Jeffery A. TI Clinical trial spots for cancer patients by tumour type: The cancer trials portfolio at clinicaltrials.gov SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE Cancer clinical trials; Clinicaltrials.gov; Cancer trials; Phase I, phase II and phase III; Burden of disease; Cancer trials portfolio ID LYMPHOMA; PARTICIPATION AB Background: Although participation in cancer clinical trials is low, little is known about the number of available clinical trials, and open spots for patients. Moreover, it is unclear what the relationship is between clinical trial openings and the incidence and mortality of cancer subtypes. Methodology: We identified the number of phase I, phase II and phase III registered at clinicaltrials.gov by cancer (tumour) type. All counts were over the preceding 5 years (2008-2013). We compared these counts against the incidence and prevalence of disease reported by Surveillance, Epidemiology and End Results (SEER) database for 32 common cancers. Results: From 2008 to 2013, 3879 phase I trials, 4982 phase II trials and 1379 phase III trials concerning a cancer subtype were registered in clinicaltrials.gov. These trials had a cumulative proposed recruitment of 203,396, 421,502 and 697,787 patients, respectively. Trial enrolment varied by tumour type, with both over and under-representation occurring. Conclusion: Opportunities to enrol in clinical trials vary by phase and tumour type. Oncologists must remain committed to clinical trials. Published by Elsevier Ltd. C1 [Prasad, Vinay] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Goldstein, Jeffery A.] Vanderbilt Univ, Med Ctr, Dept Pathol Microbiol & Immunol, Nashville, TN 37232 USA. RP Prasad, V (reprint author), NCI, Med Oncol Branch, NIH, 10 Ctr Dr 10-12N226, Bethesda, MD 20892 USA. EM vinayakkprasad@gmail.com; jeffery.a.goldstein@vanderbilt.edu FU Intramural NIH HHS [Z99 CA999999] NR 18 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD NOV PY 2015 VL 51 IS 17 BP 2718 EP 2723 DI 10.1016/j.ejca.2015.07.045 PG 6 WC Oncology SC Oncology GA CX3UC UT WOS:000365623900028 PM 26321010 ER PT J AU Harari, S Torre, O Cassandro, R Moss, J AF Harari, Sergio Torre, Olga Cassandro, Roberto Moss, Joel TI The changing face of a rare disease: lymphangioleiomyomatosis SO EUROPEAN RESPIRATORY JOURNAL LA English DT Article ID TUBEROUS SCLEROSIS COMPLEX; GROWTH FACTOR-D; PLACEBO-CONTROLLED TRIAL; PULMONARY-FUNCTION TESTS; GIANT-CELL ASTROCYTOMAS; AIR-FLOW OBSTRUCTION; SERUM VEGF-D; LUNG-FUNCTION; MATRIX METALLOPROTEINASES; RENAL ANGIOMYOLIPOMAS AB Lymphangioleiomyomatosis is a rare disease characterised by cystic destruction of the lung, lymphatic abnormalities and abdominal tumours. It affects almost exclusively females and can occur sporadically or in patients with tuberous sclerosis complex. In the past decade remarkable progress has been made in understanding of the pathogenesis of this disease leading to a new therapeutic approach. This review summarises recent advances regarding pathogenic mechanisms and clinical manifestations, and highlights the current and the most promising future therapeutic strategies. C1 [Harari, Sergio; Torre, Olga; Cassandro, Roberto] Osped San Giuseppe, Unita Operat Pneumol & Terapia Semiintens Resp, Serv Fisiopatol Resp & Emodinam Polmonare, MultiMed IRCCS, Milan, Italy. [Moss, Joel] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MA USA. RP Harari, S (reprint author), Osped San Giuseppe MultiMed, Unita Operat Pneumol & Terapia Semiintens Resp, Via San Vittore 12, I-20123 Milan, Italy. EM sharari@ilpolmone.it OI Harari, Sergio/0000-0001-8629-7391 NR 147 TC 9 Z9 9 U1 0 U2 4 PU EUROPEAN RESPIRATORY SOC JOURNALS LTD PI SHEFFIELD PA 442 GLOSSOP RD, SHEFFIELD S10 2PX, ENGLAND SN 0903-1936 EI 1399-3003 J9 EUR RESPIR J JI Eur. Resp. J. PD NOV PY 2015 VL 46 IS 5 BP 1471 EP 1485 DI 10.1183/13993003.00412-2015 PG 15 WC Respiratory System SC Respiratory System GA CX1KB UT WOS:000365454000033 PM 26405290 ER PT J AU Hickey, A Esnault, C Majumdar, A Chatterjee, AG Iben, JR McQueen, PG Yang, AX Mizuguchi, T Grewal, SIS Levin, HL AF Hickey, Anthony Esnault, Caroline Majumdar, Anasuya Chatterjee, Atreyi Ghatak Iben, James R. McQueen, Philip G. Yang, Andrew X. Mizuguchi, Takeshi Grewal, Shiv I. S. Levin, Henry L. TI Single-Nucleotide-Specific Targeting of the Tf1 Retrotransposon Promoted by the DNA-Binding Protein Sap1 of Schizosaccharomyces pombe SO GENETICS LA English DT Article DE Sap1; Tf1; integration; transposition; Schizosaccharomyces pombe ID RNA-POLYMERASE-III; TERMINAL REPEAT RETROTRANSPOSON; POSITION-SPECIFIC INTEGRATION; LEUKEMIA-VIRUS INTEGRATION; REPLICATION FORK ARREST; FISSION YEAST; REVERSE TRANSCRIPTION; SILENT CHROMATIN; TRANSPOSABLE ELEMENTS; TY5 RETROTRANSPOSON AB Transposable elements (TEs) constitute a substantial fraction of the eukaryotic genome and, as a result, have a complex relationship with their host that is both adversarial and dependent. To minimize damage to cellular genes, TEs possess mechanisms that target integration to sequences of low importance. However, the retrotransposon Tf1 of Schizosaccharomyces pombe integrates with a surprising bias for promoter sequences of stress-response genes. The clustering of integration in specific promoters suggests that Tf1 possesses a targeting mechanism that is important for evolutionary adaptation to changes in environment. We report here that Sap1, an essential DNA-binding protein, plays an important role in Tf1 integration. A mutation in Sap1 resulted in a 10-fold drop in Tf1 transposition, and measures of transposon intermediates support the argument that the defect occurred in the process of integration. Published ChIP-Seq data on Sap1 binding combined with high-density maps of Tf1 integration that measure independent insertions at single-nucleotide positions show that 73.4% of all integration occurs at genomic sequences bound by Sap1. This represents high selectivity because Sap1 binds just 6.8% of the genome. A genome-wide analysis of promoter sequences revealed that Sap1 binding and amounts of integration correlate strongly. More important, an alignment of the DNA-binding motif of Sap1 revealed integration clustered on both sides of the motif and showed high levels specifically at positions +19 and -9. These data indicate that Sap1 contributes to the efficiency and position of Tf1 integration. C1 [Hickey, Anthony; Esnault, Caroline; Majumdar, Anasuya; Chatterjee, Atreyi Ghatak; Yang, Andrew X.; Levin, Henry L.] NCI, Sect Eukaryot Transposable Elements, Program Cellular Regulat & Metab, NIH, Bethesda, MD 20892 USA. [Iben, James R.] NCI, Program Genom Differentiat, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [McQueen, Philip G.] NCI, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol,NIH, Bethesda, MD 20892 USA. [Mizuguchi, Takeshi; Grewal, Shiv I. S.] NCI, Lab Biochem & Mol Biol, NIH, Bethesda, MD 20892 USA. RP Levin, HL (reprint author), NIH, 18 Lib Dr,Rm 106, Bethesda, MD 20892 USA. EM henry_levin@nih.gov FU Intramural Research Programs of the National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Cancer Institute; Intramural Research Program of the National Institutes of Health, Center for Information Technology FX We thank Amnon Hizi for purifying Sap1 protein, conducting pull-down experiments, and providing helpful discussions. We thank Yabin Guo for the use of his computer programs and scripts in the bioinformatic analysis of our data. We thank Chanan Rubin for his helpful contributions. This research was supported by the Intramural Research Programs of the National Institutes of Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (H.L.L.), and the National Cancer Institute (S.I.S.G.). P.G.M. was supported by the Intramural Research Program of the National Institutes of Health, Center for Information Technology. This study used the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD (http://biowulf.nih.gov). NR 60 TC 2 Z9 2 U1 3 U2 5 PU GENETICS SOCIETY AMERICA PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 0016-6731 EI 1943-2631 J9 GENETICS JI Genetics PD NOV PY 2015 VL 201 IS 3 BP 905 EP U203 DI 10.1534/genetics.115.181602 PG 45 WC Genetics & Heredity SC Genetics & Heredity GA CX2HH UT WOS:000365517200009 PM 26358720 ER PT J AU Conover, HN Lujan, SA Chapman, MJ Cornelio, DA Sharif, R Williams, JS Clark, AB Camilo, F Kunkel, TA Argueso, JL AF Conover, Hailey N. Lujan, Scott A. Chapman, Mary J. Cornelio, Deborah A. Sharif, Rabab Williams, Jessica S. Clark, Alan B. Camilo, Francheska Kunkel, Thomas A. Argueso, Juan Lucas TI Stimulation of Chromosomal Rearrangements by Ribonucleotides SO GENETICS LA English DT Article DE LOH; NAHR; genome stability; recombination; ribonucleotides ID DNA-POLYMERASE EPSILON; SACCHAROMYCES-CEREVISIAE; MISMATCH REPAIR; GENOME INSTABILITY; RNASE H2; YEAST; RECOMBINATION; REPLICATION; MUTATIONS; MECHANISMS AB We show by whole genome sequence analysis that loss of RNase H2 activity increases loss of heterozygosity (LOH) in Saccharomyces cerevisiae diploid strains harboring the pol2-M644G allele encoding a mutant version of DNA polymerase epsilon that increases ribonucleotide incorporation. This led us to analyze the effects of loss of RNase H2 on LOH and on nonallelic homologous recombination (NAHR) in mutant diploid strains with deletions of genes encoding RNase H2 subunits (rnh201 Delta, rnh202 Delta, and rnh203 Delta), topoisomerase 1 (TOP1 Delta), and/or carrying mutant alleles of DNA polymerases e, a, and delta. We observed an similar to 7-fold elevation of the LOH rate in RNase H2 mutants encoding wild-type DNA polymerases. Strains carrying the pol2-M644G allele displayed a 7-fold elevation in the LOH rate, and synergistic 23-fold elevation in combination with rnh201 Delta. In comparison, strains carrying the pol2-M644L mutation that decreases ribonucleotide incorporation displayed lower LOH rates. The LOH rate was not elevated in strains carrying the pol1-L868M or pol3-L612M alleles that result in increased incorporation of ribonucleotides during DNA synthesis by polymerases a and d, respectively. A similar trend was observed in an NAHR assay, albeit with smaller phenotypic differentials. The ribonucleotide-mediated increases in the LOH and NAHR rates were strongly dependent on TOP1. These data add to recent reports on the asymmetric mutagenicity of ribonucleotides caused by topoisomerase 1 processing of ribonucleotides incorporated during DNA replication. C1 [Conover, Hailey N.; Chapman, Mary J.; Cornelio, Deborah A.; Sharif, Rabab; Camilo, Francheska; Argueso, Juan Lucas] Colorado State Univ, Dept Environm & Radiol Hlth Sci, Ft Collins, CO 80523 USA. [Conover, Hailey N.; Chapman, Mary J.; Cornelio, Deborah A.; Sharif, Rabab; Camilo, Francheska; Argueso, Juan Lucas] Colorado State Univ, Inst Genome Architecture & Funct, Ft Collins, CO 80523 USA. [Conover, Hailey N.] Colorado State Univ, Cell & Mol Biol Grad Program, Ft Collins, CO 80523 USA. [Lujan, Scott A.; Williams, Jessica S.; Clark, Alan B.; Kunkel, Thomas A.; Argueso, Juan Lucas] NIEHS, Genome Integr & Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Argueso, JL (reprint author), Colorado State Univ, 493 MRB,1618 Campus Delivery, Ft Collins, CO 80523 USA. EM kunkel@niehs.nih.gov; lucas.argueso@colostate.edu FU Division of Intramural Research of the National Institutes of Health [Z01 ES065070]; NIEHS; Boettcher Foundation; CNPq/Brazil; National Science Foundation Research Experience for Undergraduates program at Colorado State University FX We thank Clinton Orebaugh and Marta Garbacz for helpful comments on the manuscript; Adam Burkholder and the National Institute of Environmental Health Sciences (NIEHS) Integrative Bioinformatics Support Group for help with whole genome mutation calling; Matheus A. Pichorim for offering technical support during the recombination rate assays; and Karen O'Connell, Sue Jinks-Robertson, and Tom Petes for helpful discussions and for sharing unpublished data. We are also thankful for the valuable feedback provided by the associate editor and anonymous reviewers. This work was supported by project Z01 ES065070 to T.A.K. from the Division of Intramural Research of the National Institutes of Health, NIEHS, and by a Webb-Waring biomedical research award from the Boettcher Foundation (to J.L.A.). D.A.C. received a postdoctoral fellowship from CNPq/Brazil. F.C. was supported by the National Science Foundation Research Experience for Undergraduates program at Colorado State University. The authors have no conflict of interest. NR 37 TC 5 Z9 5 U1 0 U2 5 PU GENETICS SOCIETY AMERICA PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 0016-6731 EI 1943-2631 J9 GENETICS JI Genetics PD NOV PY 2015 VL 201 IS 3 BP 951 EP U278 DI 10.1534/genetics.115.181149 PG 19 WC Genetics & Heredity SC Genetics & Heredity GA CX2HH UT WOS:000365517200012 PM 26400612 ER PT J AU Wiestner, A AF Wiestner, Adrian TI The role of B-cell receptor inhibitors in the treatment of patients with chronic lymphocytic leukemia SO HAEMATOLOGICA LA English DT Review ID TYROSINE KINASE INHIBITOR; NON-HODGKIN-LYMPHOMA; TOLL-LIKE RECEPTORS; TUMOR PROLIFERATION; OPEN-LABEL; IN-VIVO; PHOSPHATIDYLINOSITOL 3-KINASE-DELTA; WALDENSTROMS MACROGLOBULINEMIA; ANTIGEN RECEPTORS; T-LYMPHOCYTES AB Chronic lymphocytic leukemia is a malignancy of mature auto-reactive B cells. Genetic and functional studies implicate B-cell receptor signaling as a pivotal pathway in its pathogenesis. Full B-cell receptor activation requires tumor-microenvironment interactions in lymphoid tissues. Spleen tyrosine kinase, Bruton's tyrosine kinase, and the phosphatidylinositol 3-kinase (PI3K) delta isoform are essential for B-cell receptor signal transduction but also mediate the effect of other pathways engaged in chronic lymphocytic leukemia cells in the tissue-microenvironment. Orally bioavailable inhibitors of spleen tyrosine kinase, Bruton's tyrosine kinase, or PI3K delta, induce high rates of durable responses. Ibrutinib, a covalent inhibitor of Bruton's tyrosine kinase, and idelalisib, a selective inhibitor of PI3Kd, have obtained regulatory approval in chronic lymphocytic leukemia. Ibrutinib and idelalisib are active in patients with high-risk features, achieving superior disease control in difficult-to-treat patients than prior best therapy, making them the preferred agents for chronic lymphocytic leukemia with TP53 aberrations and for patients resistant to chemoimmunotherapy. In randomized trials, both ibrutinib, versus ofatumumab, and idelalisib in combination with rituximab, versus placebo with rituximab improved survival in relapsed/refractory chronic lymphocytic leukemia. Responses to B-cell receptor inhibitors are mostly partial, and within clinical trials treatment is continued until progression or occurrence of intolerable side effects. Ibrutinib and idelalisib are, overall, well tolerated; notable adverse events include increased bruising and incidence of atrial fibrillation on ibrutinib and colitis, pneumonitis and transaminase elevations on idelalisib. Randomized trials investigate the role of B-cell receptor inhibitors in first-line therapy and the benefit of combinations. This review discusses the biological basis for targeted therapy of chronic lymphocytic leukemia with B-cell receptor inhibitors, and summarizes the clinical experience with these agents. C1 [Wiestner, Adrian] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Wiestner, A (reprint author), NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. EM wiestnera@mail.nih.gov FU Heart, Lung, and Blood Institute, National Institutes of Health FX The author is supported by the intramural research program of the Heart, Lung, and Blood Institute, National Institutes of Health. NR 117 TC 16 Z9 17 U1 1 U2 13 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD NOV PY 2015 VL 100 IS 12 BP 1495 EP 1507 DI 10.3324/haematol.2014.119123 PG 13 WC Hematology SC Hematology GA CX5YH UT WOS:000365777900013 PM 26628631 ER PT J AU Hosokawa, K Muranski, P Feng, XM Keyvanfar, K Townsley, DM Dumitriu, B Chen, JC Kajigaya, S Taylor, JG Hourigan, CS Barrett, AJ Young, NS AF Hosokawa, Kohei Muranski, Pawel Feng, Xingmin Keyvanfar, Keyvan Townsley, Danielle M. Dumitriu, Bogdan Chen, Jichun Kajigaya, Sachiko Taylor, James G. Hourigan, Christopher S. Barrett, A. John Young, Neal S. TI Identification of novel microRNA signatures linked to acquired aplastic anemia SO HAEMATOLOGICA LA English DT Article ID PAROXYSMAL-NOCTURNAL HEMOGLOBINURIA; REGULATORY T-CELLS; TRANSCRIPTION FACTOR; FLOW-CYTOMETRY; EXPRESSION; PATHOGENESIS; RESPONSES; GENE; INDUCTION; ARTHRITIS AB Emerging evidence indicates that microRNA control and modulate immunity. MicroRNA have not been investigated in acquired aplastic anemia, a T-cell-mediated immune disease. Analysis of 84 microRNA expression levels in CD4(+) and CD8(+) T cells of patients with aplastic anemia revealed concurrent down-regulation of miR-126-3p, miR-145-5p, miR-223-3p, and miR-199a-5p (>3-fold change, P<0.05) in both T-cell populations, which were unique in aplastic anemia compared to other hematologic disorders. MiR-126-3p and miR-223-3p were down-regulated in CD4(+) T effector memory cells, and miR-126-3p, miR-145-5p, and miR-223-3p were down-regulated in CD8(+) T effector memory and terminal effector cells. Successful immunosuppressive therapy was associated with restoration to normal expression levels of miR-126-3p, miR-145-5p, and miR-223-3p (> 2-fold change, P<0.05). In CD4(+) and CD8(+) T cells in aplastic anemia patients, MYC and PIK3R2 were up-regulated and proved to be targets of miR-145-5p and miR-126-3p, respectively. MiR-126-3p and miR-145-5p knockdown promoted proliferation and increased interferon-gamma and granzyme B production in both CD4(+) and CD8(+) T cells. Our work describes previously unknown regulatory roles of microRNA in T-cell activation in aplastic anemia, which may open a new perspective for development of effective therapy. C1 [Hosokawa, Kohei; Muranski, Pawel; Feng, Xingmin; Keyvanfar, Keyvan; Townsley, Danielle M.; Dumitriu, Bogdan; Chen, Jichun; Kajigaya, Sachiko; Taylor, James G.; Hourigan, Christopher S.; Barrett, A. John; Young, Neal S.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Hosokawa, K (reprint author), NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. EM kohei.hosokawa@nih.gov RI Hourigan, Christopher/S-2476-2016; OI Hourigan, Christopher/0000-0002-6189-8067; Taylor, James/0000-0002-4421-1809 FU NIH, National Heart, Lung, and Blood Institute FX This research was supported by the Intramural Research Program of the NIH, National Heart, Lung, and Blood Institute. NR 56 TC 4 Z9 5 U1 0 U2 5 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD NOV PY 2015 VL 100 IS 12 BP 1534 EP 1545 DI 10.3324/haematol.2015.126128 PG 12 WC Hematology SC Hematology GA CX5YH UT WOS:000365777900017 PM 26354756 ER PT J AU Lipsky, AH Farooqui, MZH Tian, X Martyr, S Cullinane, AM Nghiem, K Sun, C Valdez, J Niemann, CU Herman, SEM Saba, N Soto, S Marti, G Uzel, G Holland, SM Lozier, JN Wiestner, A AF Lipsky, Andrew H. Farooqui, Mohammed Z. H. Tian, Xin Martyr, Sabrina Cullinane, Ann M. Nghiem, Khanh Sun, Clare Valdez, Janet Niemann, Carsten U. Herman, Sarah E. M. Saba, Nakhle Soto, Susan Marti, Gerald Uzel, Gulbu Holland, Steve M. Lozier, Jay N. Wiestner, Adrian TI Incidence and risk factors of bleeding-related adverse events in patients with chronic lymphocytic leukemia treated with ibrutinib SO HAEMATOLOGICA LA English DT Article ID BRUTON TYROSINE KINASE; MANTLE-CELL LYMPHOMA; PLATELET ACTIVATION; THERAPEUTIC TARGET; SIGNALING PATHWAY; FAMILY KINASES; BTK INHIBITOR; COLLAGEN; PCI-32765; TUMOR AB Ibrutinib is associated with bleeding-related adverse events of grade <= 2 in severity, and infrequently with grade >= 3 events. To investigate the mechanisms of bleeding and identify patients at risk, we prospectively assessed platelet function and coagulation factors in our investigator-initiated trial of single-agent ibrutinib for chronic lymphocytic leukemia. At a median follow-up of 24 months we recorded grade <= 2 bleeding-related adverse events in 55% of 85 patients. No grade >= 3 events occurred. Median time to event was 49 days. The cumulative incidence of an event plateaued by 6 months, suggesting that the risk of bleeding decreases with continued therapy. At baseline, von Willebrand factor and factor VIII levels were often high and normalized on treatment. Platelet function measured via the platelet function analyzer (PFA-100 (TM) ) was impaired in 22 patients at baseline and in an additional 19 patients on ibrutinib (often transiently). Collagen and adenosine diphosphate induced platelet aggregation was tested using whole blood aggregometry. Compared to normal controls, response to both agonists was decreased in all patients with chronic lymphocytic leukemia, whether on ibrutinib or not. Compared to untreated chronic lymphocytic leukemia patients, response to collagen showed a mild further decrement on ibrutinib, while response to adenosine diphosphate improved. All parameters associated with a significantly increased risk of bleeding-related events were present at baseline, including prolonged epinephrine closure time (HR 2.74, P=0.012), lower levels of von Willebrand factor activity (HR 2.73, P=0.009) and factor VIII (HR 3.73, P=0.0004). In conclusion, both disease and treatment-related factors influence the risk of bleeding. Patients at greater risk for bleeding of grade <= 2 can be identified by clinical laboratory tests and counseled to avoid aspirin, non-steroidal anti-inflammatory drugs and fish oils. C1 [Lipsky, Andrew H.; Farooqui, Mohammed Z. H.; Martyr, Sabrina; Sun, Clare; Valdez, Janet; Niemann, Carsten U.; Herman, Sarah E. M.; Saba, Nakhle; Soto, Susan; Marti, Gerald; Wiestner, Adrian] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Tian, Xin] NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. [Cullinane, Ann M.; Nghiem, Khanh; Lozier, Jay N.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Uzel, Gulbu; Holland, Steve M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Lipsky, Andrew H.] Montefiore Med Ctr, Dept Internal Med, New York, NY USA. RP Wiestner, A (reprint author), NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. EM lozierjn@cc.nih.gov; wiestnera@mail.nih.gov FU Intramural Research Program of NHLBI; Danish Cancer Society FX This work was supported by the Intramural Research Program of NHLBI. Pharmacyclics provided ibrutinib and research support. CUN was supported by the Danish Cancer Society. NR 29 TC 10 Z9 10 U1 0 U2 2 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD NOV PY 2015 VL 100 IS 12 BP 1571 EP 1578 DI 10.3324/haematol.2015.126672 PG 8 WC Hematology SC Hematology GA CX5YH UT WOS:000365777900021 PM 26430171 ER PT J AU Aarhus, L Engdahl, B Tambs, K Kvestad, E Hoffman, HJ AF Aarhus, Lisa Engdahl, Bo Tambs, Kristian Kvestad, Ellen Hoffman, Howard J. TI Association Between Childhood Hearing Disorders and Tinnitus in Adulthood SO JAMA OTOLARYNGOLOGY-HEAD & NECK SURGERY LA English DT Article ID OTITIS-MEDIA; RISK-FACTORS; AGE; POPULATION AB IMPORTANCE The association between childhood hearing disorders and adult tinnitus has not been examined in longitudinal cohort studies. OBJECTIVES To determine the association between different types of childhood hearing loss and tinnitus in adulthood and evaluate whether tinnitus risk is mediated by adult hearing loss. DESIGN, SETTING, AND PARTICIPANTS Population-based cohort study of 32 430 adults (aged 20-56 years) who underwent pure-tone audiometry and completed a tinnitus questionnaire in the Nord-Trondelag Hearing Loss Study, which was a part of the Nord-Trondelag Health Study 2 (HUNT2). The study was conducted from January 1, 2014, to April 1, 2015. Data analysis was performed from April 1, 2014, to April 1, 2015. As children, the same individuals had undergone screening audiometry in a longitudinal primary school hearing investigation, including ear, nose, and throat examinations when indicated. INTERVENTIONS Pure-tone audiometry, questionnaires, and ear, nose, and throat examinations. MAIN OUTCOMES AND MEASURES Self-reported tinnitus (yes or no) in adulthood measured by questionnaires. RESULTS Adults who had hearing loss at the time of the school investigation (n = 3026) reported more tinnitus, measured as odds ratio (95% CI), than did adults with normal childhood hearing (n = 29 404) (1.4 [1.3-1.6]). Childhood hearing disorders associated with tinnitus in adulthood included sensorineural hearing loss, chronic suppurative otitis media, and hearing loss associated with a history of recurrent acute otitis media (2.4 [1.9-3.0], 2.4 [1.5-3.9], and 1.6 [1.3-2.0], respectively). These estimates were adjusted for age, sex, and noise exposure in adulthood. After further analyses that included adjustment for adult hearing threshold, none of these childhood hearing disorders remained positively associated with tinnitus. CONCLUSIONS AND RELEVANCE Childhood hearing disorders associated with tinnitus in adulthood include sensorineural hearing loss, chronic suppurative otitis media, and hearing loss associated with a history of recurrent acute otitis media. After adjustment for the adult hearing threshold, none of the childhood hearing disorders was positively associated with tinnitus. Hence, it appears that these significant associations are mediated or transmitted through adult hearing loss. C1 [Aarhus, Lisa; Engdahl, Bo; Tambs, Kristian; Kvestad, Ellen] Norwegian Inst Publ Hlth, Div Mental Hlth, N-0403 Oslo, Norway. [Hoffman, Howard J.] NIDCD, Epidemiol & Stat Program, NIH, Bethesda, MD USA. RP Aarhus, L (reprint author), Norwegian Inst Publ Hlth, Div Mental Hlth, POB 4404, N-0403 Oslo, Norway. EM lisa.aarhus@me.com FU National Institute on Deafness and Other Communication Disorders, National Institutes of Health [N01-DC-6-2104]; Extra Foundation: Health and Rehabilitation [2012/F0M9336]; National Association of Hard of Hearing FX The Nord-Trondelag Hearing Loss Study, which is a part of the Nord-Trondelag Health Study, was funded by the National Institute on Deafness and Other Communication Disorders, National Institutes of Health research contract N01-DC-6-2104. This study was supported by research contract 2012/F0M9336 to the National Institute of Public Health from the Extra Foundation: Health and Rehabilitation through the member organization, the National Association of Hard of Hearing. NR 26 TC 0 Z9 0 U1 2 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6181 EI 2168-619X J9 JAMA OTOLARYNGOL JI JAMA Otolaryngol-Head Neck Surg. PD NOV PY 2015 VL 141 IS 11 BP 983 EP 989 DI 10.1001/jamaoto.2015.2378 PG 7 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA CX1PZ UT WOS:000365469400006 PM 26540147 ER PT J AU Wardell, JD Ramchandani, VA Hendershot, CS AF Wardell, Jeffrey D. Ramchandani, Vijay A. Hendershot, Christian S. TI A Multilevel Structural Equation Model of Within- and Between-Person Associations Among Subjective Responses to Alcohol, Craving, and Laboratory Alcohol Self-Administration SO JOURNAL OF ABNORMAL PSYCHOLOGY LA English DT Article DE adolescent; intoxication; urge; alcohol dependence; alcohol sensitivity ID INDIVIDUAL-DIFFERENCES; IMPAIRED CONTROL; LOW-LEVEL; DEPENDENCE SYMPTOMS; DRINKING BEHAVIOR; EFFECTS SCALE; YOUNG-ADULTS; ETHANOL; VALIDATION; CHALLENGE AB Subjective responses to alcohol are important determinants of drinking behavior and have been linked with risk for alcohol use disorders. However, few attempts have been made to examine proximal within-person associations among state changes in subjective responses and ongoing alcohol self-administration in the laboratory. This study disaggregated within-and between-person associations among subjective responses and alcohol self-administration, while also examining the mediating role of craving and the moderating role of trait impaired control over alcohol. Sixty young heavy drinkers (mean age = 19.90, SD = 0.86) completed self-report measures including the Impaired Control Scale, then participated in a 2-hr intravenous alcohol self-administration session using the Computer-Assisted Self-infusion of Ethanol (CASE) paradigm. Repeated assessments of subjective stimulation, subjective sedation, and craving were examined in relation to ongoing in-session self-administration, as indexed by breath alcohol concentration (BrAC) assessed 15 min later. Multilevel structural equation modeling was used to isolate within-person and between-person associations. The results showed few significant associations at the between-person level, except for a direct negative association between sedation and BrAC. At the within-person level, state fluctuations in stimulation were positively associated with both craving and subsequent BrAC, whereas state changes in sedation were negatively associated with craving and positively associated with BrAC. Within-person indirect associations from subjective stimulation and sedation to subsequent BrAC mediated via craving were statistically significant. Also, participants higher on impaired control showed stronger within-person associations between craving and greater subsequent BrAC. The results suggest that subjective responses to alcohol and craving have proximal associations with self-administration behavior, the strength of which is linked with trait impaired control over alcohol. C1 [Wardell, Jeffrey D.; Hendershot, Christian S.] Ctr Addict & Mental Hlth, Campbell Family Mental Hlth Res Inst, Toronto, ON, Canada. [Ramchandani, Vijay A.] NIAAA, Sect Human Psychopharmacol, Lab Clin & Translat Studies, NIH, Bethesda, MD USA. [Hendershot, Christian S.] Univ Toronto, Dept Psychol, Toronto, ON M5S 1A1, Canada. [Hendershot, Christian S.] Univ Toronto, Dept Psychiat, Toronto, ON M5S 1A1, Canada. RP Hendershot, CS (reprint author), 100 Stokes St,3rd Floor, Toronto, ON M6J 1H4, Canada. EM christian.hendershot@utoronto.ca FU ABMRF/The Foundation for Alcohol Research; Canadian Institutes of Health Research [MOP-119444, MSH-130189, MFE-140817]; Canada Foundation for Innovation; Ministry of Research and Innovation; Ontario Mental Health Foundation; NIAAA Division of Intramural Clinical and Biological Research FX This study was supported by a grant from ABMRF/The Foundation for Alcohol Research (CSH). The authors also acknowledge support from Canadian Institutes of Health Research Grants MOP-119444 (CSH), MSH-130189 (CSH) and MFE-140817 (JDW); the Canada Foundation for Innovation and Ministry of Research and Innovation (CSH), and the Ontario Mental Health Foundation (CSH); as well as the NIAAA Division of Intramural Clinical and Biological Research (VAR). The authors thank Sean O'Connor and Victor Vitvitsky at the Indiana Alcohol Research Center (NIH P60 AA007611) for software support. The authors also express appreciation to Ariel Graff, Vanessa Garofalo, Mike Markovich, and Matthew McPhee for their assistance with data collection. NR 65 TC 3 Z9 3 U1 1 U2 7 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0021-843X EI 1939-1846 J9 J ABNORM PSYCHOL JI J. Abnorm. Psychol. PD NOV PY 2015 VL 124 IS 4 BP 1050 EP 1063 DI 10.1037/abn0000121 PG 14 WC Psychology, Clinical; Psychology, Multidisciplinary SC Psychology GA CX3OQ UT WOS:000365609000024 PM 26595481 ER PT J AU Picard, C Al-Herz, W Bousfiha, A Casanova, JL Chatila, T Conley, ME Cunningham-Rundles, C Etzioni, A Holland, SM Klein, C Nonoyama, S Ochs, HD Oksenhendler, E Puck, JM Sullivan, KE Tang, MLK Franco, JL Gaspar, HB AF Picard, Capucine Al-Herz, Waleed Bousfiha, Aziz Casanova, Jean-Laurent Chatila, Talal Conley, Mary Ellen Cunningham-Rundles, Charlotte Etzioni, Amos Holland, Steven M. Klein, Christoph Nonoyama, Shigeaki Ochs, Hans D. Oksenhendler, Eric Puck, Jennifer M. Sullivan, Kathleen E. Tang, Mimi L. K. Franco, Jose Luis Gaspar, H. Bobby TI Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015 SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Article DE Primary immunodeficiencies; classification; genetic defects AB We report the updated classification of primary immunodeficiencies compiled by the Primary Immunodeficiency Expert Committee (PID EC) of the International Union of Immunological Societies (IUIS). In the two years since the previous version, 34 new gene defects are reported in this updated version. For each disorder, the key clinical and laboratory features are provided. In this new version we continue to see the increasing overlap between immunodeficiency, as manifested by infection and/or malignancy, and immune dysregulation, as manifested by auto-inflammation, auto-immunity, and/or allergy. There is also an increased number of genetic defects that lead to susceptibility to specific organisms which reflects the finely tuned nature of immune defense systems. This classification is the most up to date catalogue of all known and published primary immunodeficiencies and acts as a current reference of the knowledge of these conditions and is an important aid for the genetic and molecular diagnosis of patients with these rare diseases. C1 [Picard, Capucine; Casanova, Jean-Laurent] Necker Hosp Sick Children, Lab Human Genet Infect Dis, Necker Branch, INSERM UMR1163, Paris, France. [Picard, Capucine] Hop Necker Enfants Malad, AP HP, Ctr Etude Deficits Immunitaires, Paris, France. [Al-Herz, Waleed] Kuwait Univ, Fac Med, Dept Pediat, Kuwait, Kuwait. [Al-Herz, Waleed] Al Sabah Hosp, Allergy & Clin Immunol Unit, Dept Pediat, Kuwait, Kuwait. [Bousfiha, Aziz] King Hassan II Univ, Ibn Rochd Med Sch, Clin Immunol Unit, Casablanca Childrens Hosp, Casablanca, Morocco. [Casanova, Jean-Laurent; Conley, Mary Ellen] Rockefeller Univ, St Giles Lab Human Genet Infect Dis, Rockefeller Branch, New York, NY 10021 USA. [Casanova, Jean-Laurent] Howard Hughes Med Inst, New York, NY USA. [Casanova, Jean-Laurent] Univ Paris 05, Imagine Inst, Paris, France. [Casanova, Jean-Laurent] Necker Hosp Sick Children, Pediat Hematol & Immunol Unit, Paris, France. [Chatila, Talal] Childrens Hosp, Div Immunol, Boston, MA 02115 USA. [Cunningham-Rundles, Charlotte] Mt Sinai Sch Med, Dept Med & Pediat, New York, NY USA. [Etzioni, Amos] Technion Israel Inst Technol, Meyer Childrens Hospital, Haifa, Israel. [Holland, Steven M.] NIAID, Lab Clin Infect Dis, Bethesda, MD 20892 USA. [Klein, Christoph] Univ Munich, Dr von Hauner Childrens Hosp, Munich, Germany. [Nonoyama, Shigeaki] Natl Def Med Coll, Dept Pediat, Saitama, Japan. [Ochs, Hans D.] Univ Washington, Dept Pediat, Seattle, WA 98195 USA. [Ochs, Hans D.] Seattle Childrens Res Inst, Seattle, WA USA. [Oksenhendler, Eric] Hop St Louis, AP HP, Dept Clin Immunol, Paris, France. [Oksenhendler, Eric] Univ Paris Diderot, Sorbonne Paris Cite, Paris, France. [Puck, Jennifer M.] Univ Calif San Francisco, Dept Pediat, San Francisco, CA USA. [Puck, Jennifer M.] UCSF Benioff Childrens Hosp, San Francisco, CA USA. [Sullivan, Kathleen E.] Childrens Hosp Philadelphia, Dept Pediat, Div Allergy Immunol, Philadelphia, PA 19104 USA. [Tang, Mimi L. K.] Murdoch Childrens Res Inst, Melbourne, Vic, Australia. [Tang, Mimi L. K.] Univ Melbourne, Dept Paediat, Melbourne, Vic, Australia. [Tang, Mimi L. K.] Royal Childrens Hosp, Dept Allergy & Immunol, Melbourne, Vic, Australia. [Franco, Jose Luis] Univ Antioquia, Grp Primary Immunodeficiencies, Medellin, Colombia. [Gaspar, H. Bobby] UCL Inst Child Hlth, London WC1N 1EH, England. RP Gaspar, HB (reprint author), UCL Inst Child Hlth, 30 Guilford St, London WC1N 1EH, England. EM h.gaspar@ucl.ac.uk FU NIAID NIH HHS [R18 AI048693] NR 0 TC 79 Z9 85 U1 7 U2 12 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 EI 1573-2592 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD NOV PY 2015 VL 35 IS 8 BP 696 EP 726 DI 10.1007/s10875-015-0201-1 PG 31 WC Immunology SC Immunology GA CX7HN UT WOS:000365872900003 PM 26482257 ER EF