FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Arem, H Yu, K Xiong, X Moy, K Freedman, ND Mayne, ST Albanes, D Arslan, AA Austin, M Bamlet, WR Beane-Freeman, L Bracci, P Canzian, F Cotterchio, M Duell, EJ Gallinger, S Giles, GG Goggins, M Goodman, PJ Hartge, P Hassan, M Helzlsouer, K Henderson, B Holly, EA Hoover, R Jacobs, EJ Kamineni, A Klein, A Klein, E Kolonel, LN Li, D Malats, N Mannistoo, S McCullough, ML Olson, SH Orlow, I Peters, U Petersen, GM Porta, M Severi, G Shu, XO Visvanathan, K White, E Yu, H Zeleniuch-Jacquotte, A Zheng, W Tobias, GS Maeder, D Brotzman, M Risch, H Sampson, JN Stolzenberg-Solomon, RZ AF Arem, Hannah Yu, Kai Xiong, Xiaoqin Moy, Kristin Freedman, Neal D. Mayne, Susan T. Albanes, Demetrius Arslan, Alan A. Austin, Melissa Bamlet, William R. Beane-Freeman, Laura Bracci, Paige Canzian, Federico Cotterchio, Michelle Duell, Eric J. Gallinger, Steve Giles, Graham G. Goggins, Michael Goodman, Phyllis J. Hartge, Patricia Hassan, Manal Helzlsouer, Kathy Henderson, Brian Holly, Elizabeth A. Hoover, Robert Jacobs, Eric J. Kamineni, Aruna Klein, Alison Klein, Eric Kolonel, Laurence N. Li, Donghui Malats, Nuria Mannisto, Satu McCullough, Marjorie L. Olson, Sara H. Orlow, Irene Peters, Ulrike Petersen, Gloria M. Porta, Miquel Severi, Gianluca Shu, Xiao-Ou Visvanathan, Kala White, Emily Yu, Herbert Zeleniuch-Jacquotte, Anne Zheng, Wei Tobias, Geoffrey S. Maeder, Dennis Brotzman, Michelle Risch, Harvey Sampson, Joshua N. Stolzenberg-Solomon, Rachael Z. TI Vitamin D Metabolic Pathway Genes and Pancreatic Cancer Risk SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; UNITED-STATES; MORTALITY; SUSCEPTIBILITY; COHORT; DETERMINANTS; CONSORTIUM; RADIATION; JAPAN AB Evidence on the association between vitamin D status and pancreatic cancer risk is inconsistent. This inconsistency may be partially attributable to variation in vitamin D regulating genes. We selected 11 vitamin D-related genes (GC, DHCR7, CYP2R1, VDR, CYP27B1, CYP24A1, CYP27A1, RXRA, CRP2, CASR and CUBN) totaling 213 single nucleotide polymorphisms (SNPs), and examined associations with pancreatic adenocarcinoma. Our study included 3,583 pancreatic cancer cases and 7,053 controls from the genome-wide association studies of pancreatic cancer PanScans-I-III. We used the Adaptive Joint Test and the Adaptive Rank Truncated Product statistic for pathway and gene analyses, and unconditional logistic regression for SNP analyses, adjusting for age, sex, study and population stratification. We examined effect modification by circulating vitamin D concentration (<= 50, >50 nmol/L) for the most significant SNPs using a subset of cohort cases (n = 713) and controls (n = 878). The vitamin D metabolic pathway was not associated with pancreatic cancer risk (p = 0.830). Of the individual genes, none were associated with pancreatic cancer risk at a significance level of p<0.05. SNPs near the VDR (rs2239186), LRP2 (rs4668123), CYP24A1 (rs2762932), GC (rs2282679), and CUBN (rs1810205) genes were the top SNPs associated with pancreatic cancer (p-values 0.008-0.037), but none were statistically significant after adjusting for multiple comparisons. Associations between these SNPs and pancreatic cancer were not modified by circulating concentrations of vitamin D. These findings do not support an association between vitamin D-related genes and pancreatic cancer risk. Future research should explore other pathways through which vitamin D status might be associated with pancreatic cancer risk. C1 [Arem, Hannah; Yu, Kai; Moy, Kristin; Freedman, Neal D.; Albanes, Demetrius; Beane-Freeman, Laura; Hartge, Patricia; Hoover, Robert; Tobias, Geoffrey S.; Sampson, Joshua N.; Stolzenberg-Solomon, Rachael Z.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Xiong, Xiaoqin] Informat Management Syst Inc, Calverton, MD USA. [Mayne, Susan T.; Risch, Harvey] Yale Univ, Sch Publ Hlth, Yale Canc Ctr, New Haven, CT USA. [Arslan, Alan A.; Zeleniuch-Jacquotte, Anne] NYU, Dept Populat Hlth, New York, NY USA. [Arslan, Alan A.; Zeleniuch-Jacquotte, Anne] NYU, Dept Obstet & Gynecol, New York, NY 10016 USA. [Arslan, Alan A.; Zeleniuch-Jacquotte, Anne] NYU, Dept Environm Med, New York, NY 10016 USA. [Austin, Melissa] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Bamlet, William R.; Petersen, Gloria M.] Mayo Clin, Dept Epidemiol, Rochester, MN USA. [Bracci, Paige; Holly, Elizabeth A.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Canzian, Federico] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Cotterchio, Michelle] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON M5S 1A1, Canada. [Cotterchio, Michelle] Canc Care Ontario Toronto, Prevent & Canc Control, Toronto, ON, Canada. [Duell, Eric J.] Catalan Inst Oncol ICO IDIBELL, Barcelona, Spain. [Gallinger, Steve] Univ Toronto, Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Giles, Graham G.; Severi, Gianluca] Univ Melbourne, Sch Populat Hlth, Canc Council Victoria & Ctr MEGA Epidemiol, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Goggins, Michael] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Goggins, Michael] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Goggins, Michael] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Goodman, Phyllis J.; Klein, Eric; Peters, Ulrike; White, Emily] Cleveland Clin, Glickman Urol & Kidney Inst, Cleveland, OH 44106 USA. [Hassan, Manal; Li, Donghui] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX 77030 USA. [Helzlsouer, Kathy; Visvanathan, Kala] MD Mercy, Baltimore, MD USA. [Henderson, Brian] Univ So Calif, Sch Med, Dept Preventat Med, Los Angeles, CA USA. [Jacobs, Eric J.; McCullough, Marjorie L.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Kamineni, Aruna] Grp Hlth Res Inst, Seattle, WA USA. [Kolonel, Laurence N.; Yu, Herbert] Univ Hawaii, Ctr Canc, Manoa, HI USA. [Malats, Nuria] Spanish Natl Canc Res Ctr, Mol Pathol Program, Madrid, Spain. [Mannisto, Satu] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Olson, Sara H.; Orlow, Irene] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Porta, Miquel] Hosp Mar Inst Med Res IMIM, Barcelona, Spain. [Porta, Miquel] Sch Med, Barcelona, Spain. [Shu, Xiao-Ou; Zheng, Wei] Vanderbilt Univ, Vanderbilt Epidemiol Ctr, Dept Med, Div Epidemiol, Nashville, TN 37235 USA. [Shu, Xiao-Ou; Zheng, Wei] Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Nashville, TN 37235 USA. [Maeder, Dennis] NCI, Canc Genom Res Lab, Div Canc Epidemiol & Genet, Leidos Biomed Res Inc,Frederick Natl Lab Canc Res, Frederick, MD 21701 USA. [Brotzman, Michelle] WESTAT Corp, Rockville, MD 20850 USA. RP Arem, H (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM Hannah.arem@nih.gov RI Porta, Miquel/B-5787-2008; Freedman, Neal/B-9741-2015; Gallinger, Steven/E-4575-2013; Tobias, Geoffrey/M-4135-2016; Beane Freeman, Laura/C-4468-2015; OI Porta, Miquel/0000-0003-1684-7428; Orlow, Irene/0000-0001-6234-6961; Malats, Nuria/0000-0003-2538-3784; Freedman, Neal/0000-0003-0074-1098; Giles, Graham/0000-0003-4946-9099; Tobias, Geoffrey/0000-0002-2878-8253; Beane Freeman, Laura/0000-0003-1294-4124; Mannisto, Satu/0000-0002-8668-3046; Zeleniuch-Jacquotte, Anne/0000-0001-9350-1303 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Please see the Supplemental Information section for a detailed listing of study-specific funding. Co-authors Xiaoqin Xiong (Information Management Systems, Inc.), Dennis Maeder (Leidos Biomedical Research, Inc.) and Michelle Brotzman (Westat) are employed by commercial enterprises, and received salary from these companies to support this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 TC 8 Z9 8 U1 0 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 MAR 23 PY 2015 VL 10 IS 3 AR e0117574 DI 10.1371/journal.pone.0117574 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CE6ZS UT WOS:000351987300005 PM 25799011 ER PT J AU Azroyan, A Cortez-Retamozo, V Bouley, R Liberman, R Ruan, YC Kiselev, E Jacobson, KA Pittet, MJ Brown, D Breton, S AF Azroyan, Anie Cortez-Retamozo, Virna Bouley, Richard Liberman, Rachel Ruan, Ye Chun Kiselev, Evgeny Jacobson, Kenneth A. Pittet, Mikael J. Brown, Dennis Breton, Sylvie TI Renal Intercalated Cells Sense and Mediate Inflammation via the P2Y(14) Receptor SO PLOS ONE LA English DT Article ID VACUOLAR H+-ATPASE; LYSOPHOSPHATIDIC ACID RECEPTOR; PROTEIN-COUPLED RECEPTOR; EPIDIDYMAL CLEAR CELLS; DUCT EPITHELIAL-CELLS; V-ATPASE; COLLECTING DUCT; UDP-GLUCOSE; RAT-KIDNEY; FUNCTIONAL EXPRESSION AB Uncontrolled inflammation is one of the leading causes of kidney failure. Pro-inflammatory responses can occur in the absence of infection, a process called sterile inflammation. Here we show that the purinergic receptor P2Y(14) (GPR105) is specifically and highly expressed in collecting duct intercalated cells (ICs) and mediates sterile inflammation in the kidney. P2Y(14) is activated by UDP-glucose, a damage-associated molecular pattern molecule (DAMP) released by injured cells. We found that UDP-glucose increases pro-inflammatory chemokine expression in ICs as well as MDCK-C11 cells, and UDP-glucose activates the MEK1/2-ERK1/2 pathway in MDCK-C11 cells. These effects were prevented following inhibition of P2Y(14) with the small molecule PPTN. Tail vein injection of mice with UDP-glucose induced the recruitment of neutrophils to the renal medulla. This study identifies ICs as novel sensors, mediators and effectors of inflammation in the kidney via P2Y(14). C1 [Azroyan, Anie; Cortez-Retamozo, Virna; Bouley, Richard; Liberman, Rachel; Ruan, Ye Chun; Pittet, Mikael J.; Brown, Dennis; Breton, Sylvie] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA 02114 USA. [Azroyan, Anie; Bouley, Richard; Liberman, Rachel; Ruan, Ye Chun; Brown, Dennis; Breton, Sylvie] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Program Membrane Biol,Nephrol Div, Boston, MA USA. [Kiselev, Evgeny; Jacobson, Kenneth A.] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Breton, S (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA 02114 USA. EM Breton.Sylvie@MGH.Harvard.edu RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU NIH [HD040793, DK097124, DK042956]; Boston Area Diabetes and Endocrinology Research Center [DK57521]; Center for the Study of Inflammatory Bowel Disease [DK43351]; Charles and Ann Sanders Research Scholar Award at MGH; Intramural Research Program of the NIH, NIDDK; PRAT Program, NIGMS FX This work was supported by NIH grants HD040793 and DK097124 (to S.B.) and NIH grant DK042956 (to D.B.). The Microscopy Core facility of the MGH Program in Membrane Biology receives support from the Boston Area Diabetes and Endocrinology Research Center (DK57521) and the Center for the Study of Inflammatory Bowel Disease (DK43351). S.B. is a recipient of the Charles and Ann Sanders Research Scholar Award at MGH. K.A.J. is funded by the Intramural Research Program of the NIH, NIDDK. E.K. is funded by the PRAT Program, NIGMS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 77 TC 4 Z9 4 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 MAR 23 PY 2015 VL 10 IS 3 AR e0121419 DI 10.1371/journal.pone.0121419 PG 24 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CE6ZS UT WOS:000351987300250 PM 25799465 ER PT J AU Gong, Z Schwieters, CD Tang, C AF Gong, Zhou Schwieters, Charles D. Tang, Chun TI Conjoined Use of EM and NMR in RNA Structure Refinement SO PLOS ONE LA English DT Article ID SPECTROSCOPY; DYNAMICS; RIBOSOME; ELEMENT AB More than 40% of the RNA structures have been determined using nuclear magnetic resonance (NMR) technique. NMR mainly provides local structural information of protons and works most effectively on relatively small biomacromolecules. Hence structural characterization of large RNAs can be difficult for NMR alone. Electron microscopy (EM) provides global shape information of macromolecules at nanometer resolution, which should be complementary to NMR for RNA structure determination. Here we developed a new energy term in Xplor-NIH against the density map obtained by EM. We conjointly used NMR and map restraints for the structure refinement of three RNA systems-U2/U6 small-nuclear RNA, genome-packing motif (psi(CD)) 2 from Moloney murine leukemia virus, and ribosome-binding element from turnip crinkle virus. In all three systems, we showed that the incorporation of a map restraint, either experimental or generated from known PDB structure, greatly improves structural precision and accuracy. Importantly, our method does not rely on an initial model assembled from RNA duplexes, and allows full torsional freedom for each nucleotide in the torsion angle simulated annealing refinement. As increasing number of macromolecules can be characterized by both NMR and EM, the marriage between the two techniques would enable better characterization of RNA three-dimensional structures. C1 [Gong, Zhou; Tang, Chun] Chinese Acad Sci, CAS Key Lab Magnet Resonance Biol Syst, State Key Lab Magnet Resonance & Atom Mol Phys, Natl Magnet Resonance Ctr Wuhan,Wuhan Inst Phys &, Wuhan 430071, Hubei Province, Peoples R China. [Schwieters, Charles D.] NIH, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Tang, C (reprint author), Chinese Acad Sci, CAS Key Lab Magnet Resonance Biol Syst, State Key Lab Magnet Resonance & Atom Mol Phys, Natl Magnet Resonance Ctr Wuhan,Wuhan Inst Phys &, Wuhan 430071, Hubei Province, Peoples R China. EM tanglab@wipm.ac.cn FU Chinese Ministry of Science and Technology [2013CB910200]; National Natural Sciences Foundation of China [31400735, 31225007, 31170728]; International Early Career Scientist program from the Howard Hughes Medical Institute; NIH CIT Intramural Research Program FX C.T. is supported by grants from the Chinese Ministry of Science and Technology (2013CB910200) and the National Natural Sciences Foundation of China (31400735, 31225007, and 31170728), and supported in part by the International Early Career Scientist program from the Howard Hughes Medical Institute. C.D.S. is supported by the NIH CIT Intramural Research Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 31 TC 6 Z9 6 U1 1 U2 12 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 MAR 23 PY 2015 VL 10 IS 3 AR e0120445 DI 10.1371/journal.pone.0120445 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CE6ZS UT WOS:000351987300144 PM 25798848 ER PT J AU Harris, DA Patel, SH Gucek, M Hendrix, A Westbroek, W Taraska, JW AF Harris, Dinari A. Patel, Sajni H. Gucek, Marjan Hendrix, An Westbroek, Wendy Taraska, Justin W. TI Exosomes Released from Breast Cancer Carcinomas Stimulate Cell Movement SO PLOS ONE LA English DT Article ID METASTASIS SUPPRESSOR GENE; HEPATOCELLULAR-CARCINOMA; MEMBRANE-VESICLES; TUMOR-METASTASIS; PROSTATE-CANCER; MICROVESICLES; GROWTH; PROGRESSION; BIOMARKERS; MIGRATION AB For metastasis to occur cells must communicate with to their local environment to initiate growth and invasion. Exosomes have emerged as an important mediator of cell-to-cell signalling through the transfer of molecules such as mRNAs, microRNAs, and proteins between cells. Exosomes have been proposed to act as regulators of cancer progression. Here, we study the effect of exosomes on cell migration, an important step in metastasis. We performed cell migration assays, endocytosis assays, and exosome proteomic profiling on exosomes released from three breast cancer cell lines that model progressive stages of metastasis. Results from these experiments suggest: (1) exosomes promote cell migration and (2) the signal is stronger from exosomes isolated from cells with higher metastatic potentials; (3) exosomes are endocytosed at the same rate regardless of the cell type; (4) exosomes released from cells show differential enrichment of proteins with unique protein signatures of both identity and abundance. We conclude that breast cancer cells of increasing metastatic potential secrete exosomes with distinct protein signatures that proportionally increase cell movement and suggest that released exosomes could play an active role in metastasis. C1 [Harris, Dinari A.; Taraska, Justin W.] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. [Patel, Sajni H.; Gucek, Marjan] NHLBI, Prote Core Facil, NIH, Bethesda, MD 20892 USA. [Hendrix, An] Ghent Univ Hosp, Lab Expt Canc Res, Dept Radiat Oncol & Expt Canc Res, Ghent, Belgium. [Westbroek, Wendy] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Taraska, JW (reprint author), NHLBI, Lab Mol Biophys, NIH, Bldg 10, Bethesda, MD 20892 USA. EM justin.taraska@nih.gov RI Taraska, Justin/H-8876-2016 OI Taraska, Justin/0000-0001-5355-9535 FU National Heart Lung and Blood Institute, National Institutes of Health [HL006098-02] FX All Authors were supported by the Intramural Research Program of the National Heart Lung and Blood Institute, National Institutes of Health, HL006098-02. (http://www.nhlbi.nih.gov/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 62 TC 12 Z9 15 U1 2 U2 23 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 MAR 23 PY 2015 VL 10 IS 3 AR e0117495 DI 10.1371/journal.pone.0117495 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CE6ZS UT WOS:000351987300004 PM 25798887 ER PT J AU Maawy, AA Hiroshima, Y Zhang, Y Heim, R Makings, L Garcia-Guzman, M Luiken, GA Kobayashi, H Hoffman, RM Bouvet, M AF Maawy, Ali A. Hiroshima, Yukihiko Zhang, Yong Heim, Roger Makings, Lew Garcia-Guzman, Miguel Luiken, George A. Kobayashi, Hisataka Hoffman, Robert M. Bouvet, Michael TI Near Infra-Red Photoimmunotherapy with Anti-CEA-IR700 Results in Extensive Tumor Lysis and a Significant Decrease in Tumor Burden in Orthotopic Mouse Models of Pancreatic Cancer SO PLOS ONE LA English DT Article ID FLUORESCENCE-GUIDED SURGERY; ANTI-CEA ANTIBODY; HUMAN COLON-CANCER; IMAGING-SYSTEM; NUDE-MICE; PATIENT; RESECTION; SURVIVAL; GROWTH AB Photoimmunotherapy (PIT) of cancer utilizes tumor-specific monoclonal antibodies conjugated to a photosensitizer phthalocyanine dye IR700 which becomes cytotoxic upon irradiation with near infrared light. In this study, we aimed to evaluate the efficacy of PIT on human pancreatic cancer cells in vitro and in vivo in an orthotopic nude mouse model. The binding capacity of anti-CEA antibody to BxPC-3 human pancreatic cancer cells was determined by FACS analysis. An in vitro cytotoxicity assay was used to determine cell death following treatment with PIT. For in vivo determination of PIT efficacy, nude mice were orthotopically implanted with BxPC-3 pancreatic tumors expressing green fluorescent protein (GFP). After tumor engraftment, the mice were divided into two groups: (1) treatment with anti-CEA-IR700 + 690 nm laser and (2) treatment with 690 nm laser only. Anti-CEA-IR700 (100 mu g) was administered to group (1) via tail vein injection 24 hours prior to therapy. Tumors were then surgically exposed and treated with phototherapy at an intensity of 150 mW/cm(2) for 30 minutes. Whole body imaging was done subsequently for 5 weeks using an OV-100 small animal imaging system. Anti-CEA-IR700 antibody bound to the BxPC3 cells to a high degree as shown by FACS analysis. Anti-CEA-IR700 caused extensive cancer cell killing after light activation compared to control cells in cytotoxicity assays. In the orthotopic models of pancreatic cancer, the anti-CEA-IR700 group had significantly smaller tumors than the control after 5 weeks (p<0.001). There was no significant difference in the body weights of mice in the anti-CEA-IR700 and control groups indicating that PIT was well tolerated by the mice. C1 [Maawy, Ali A.; Hiroshima, Yukihiko; Hoffman, Robert M.; Bouvet, Michael] Univ Calif San Diego, Dept Surg, San Diego, CA 92103 USA. [Hiroshima, Yukihiko; Zhang, Yong; Hoffman, Robert M.] AntiCancer Inc, San Diego, CA USA. [Hiroshima, Yukihiko] Yokohama City Univ, Dept Surg, Yokohama, Kanagawa 232, Japan. [Heim, Roger; Makings, Lew; Garcia-Guzman, Miguel] Aspyrian Therapeut, San Diego, CA USA. [Luiken, George A.] OncoFluor Inc, San Diego, CA USA. [Kobayashi, Hisataka] NIH, Bethesda, MD 20892 USA. [Bouvet, Michael] VA Healthcare Syst, Surg Serv, San Diego, CA USA. RP Bouvet, M (reprint author), Univ Calif San Diego, Dept Surg, San Diego, CA 92103 USA. EM mbouvet@ucsd.edu FU National Cancer Institute [CA142669, CA132971]; AntiCancer, Inc.; Aspyrian Therapeutics FX This work was supported by grants from the National Cancer Institute CA142669 and CA132971 (to M.B. and AntiCancer, Inc). AntiCancer, Inc. and Aspyrian Therapeutics provided support in the form of salaries for authors YZ, RH, LM, and MG-G but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 23 TC 10 Z9 10 U1 0 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 MAR 23 PY 2015 VL 10 IS 3 AR e0121989 DI 10.1371/journal.pone.0121989 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CE6ZS UT WOS:000351987300307 PM 25799218 ER PT J AU Stram, DO Preston, DL Sokolnikov, M Napier, B Kopecky, KJ Boice, J Beck, H Till, J Bouville, A AF Stram, Daniel O. Preston, Dale L. Sokolnikov, Mikhail Napier, Bruce Kopecky, Kenneth J. Boice, John Beck, Harold Till, John Bouville, Andre TI Shared Dosimetry Error in Epidemiological Dose-Response Analyses SO PLOS ONE LA English DT Article ID ATOMIC-BOMB SURVIVORS; ESTIMATING UNCERTAINTY; LUNG-CANCER; RADIATION; REGRESSION; DISEASE; COHORT; RISK; METHODOLOGY; LIKELIHOOD AB Radiation dose reconstruction systems for large-scale epidemiological studies are sophisticated both in providing estimates of dose and in representing dosimetry uncertainty. For example, a computer program was used by the Hanford Thyroid Disease Study to provide 100 realizations of possible dose to study participants. The variation in realizations reflected the range of possible dose for each cohort member consistent with the data on dose determinates in the cohort. Another example is the Mayak Worker Dosimetry System 2013 which estimates both external and internal exposures and provides multiple realizations of "possible" dose history to workers given dose determinants. This paper takes up the problem of dealing with complex dosimetry systems that provide multiple realizations of dose in an epidemiologic analysis. In this paper we derive expected scores and the information matrix for a model used widely in radiation epidemiology, namely the linear excess relative risk (ERR) model that allows for a linear dose response (risk in relation to radiation) and distinguishes between modifiers of background rates and of the excess risk due to exposure. We show that treating the mean dose for each individual (calculated by averaging over the realizations) as if it was true dose (ignoring both shared and unshared dosimetry errors) gives asymptotically unbiased estimates (i.e. the score has expectation zero) and valid tests of the null hypothesis that the ERR slope beta is zero. Although the score is unbiased the information matrix (and hence the standard errors of the estimate of beta) is biased for beta not equal 0 when ignoring errors in dose estimates, and we show how to adjust the information matrix to remove this bias, using the multiple realizations of dose. The use of these methods in the context of several studies including, the Mayak Worker Cohort, and the U.S. Atomic Veterans Study, is discussed. C1 [Stram, Daniel O.] Univ So Calif, Dept Prevent Med, Los Angeles, CA 90089 USA. [Preston, Dale L.] Hirosoft Int, Eureka, CA USA. [Sokolnikov, Mikhail] Southern Urals Biophys Inst, Ozersk, Russia. [Napier, Bruce] Pacific NW Natl Lab, Richland, WA 99352 USA. [Kopecky, Kenneth J.] Fred Hutchinson Canc Ctr, Seattle, WA USA. [Boice, John] Vanderbilt Univ, Nashville, TN 37235 USA. [Beck, Harold] US DOE, New York, NY USA. [Till, John] Risk Assessment Corp, Neeses, SC USA. [Bouville, Andre] NCI, Radiat Epidemiol Branch, Rockville, MD USA. RP Stram, DO (reprint author), Univ So Calif, Dept Prevent Med, Los Angeles, CA 90089 USA. EM Daniel.Stram@med.usc.edu FU National Cancer Institute [U01 CA137026]; U.S. Department of Energy [DE-HS0000091, DE-SC0008944 (doe.gov)]; Discovery Grant from the Vanderbilt-Ingram Cancer Center [404-357-9682 (vicc.org)] FX This research was supported in part by contracts and grants from the National Cancer Institute (grant no. U01 CA137026) (www.cancer.gov), the U.S. Department of Energy (grant nos. DE-HS0000091, and DE-SC0008944) (doe.gov) and a Discovery Grant from the Vanderbilt-Ingram Cancer Center (Center no. 404-357-9682) (vicc.org). Risk Assessment Corporation and Hirosoft International provided support in the form of salaries for authors [JT and DP], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the "author contributions" section. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 38 TC 6 Z9 6 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 23 PY 2015 VL 10 IS 3 AR e0119418 DI 10.1371/journal.pone.0119418 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CE6ZS UT WOS:000351987300048 PM 25799311 ER PT J AU Knosp, WM Knox, SM Lombaert, IMA Haddox, CL Patel, VN Hoffman, MP AF Knosp, Wendy M. Knox, Sarah M. Lombaert, Isabelle M. A. Haddox, Candace L. Patel, Vaishali N. Hoffman, Matthew P. TI Submandibular Parasympathetic Gangliogenesis Requires Sprouty-Dependent Wnt Signals from Epithelial Progenitors SO DEVELOPMENTAL CELL LA English DT Article ID GLAND BRANCHING MORPHOGENESIS; SALIVARY-GLAND; NEURAL CREST; GROWTH-FACTOR; FGF; ORGANOGENESIS; CELLS; GENE; INVOLVEMENT; MUTATIONS AB Parasympathetic innervation is critical for submandibular gland (SMG) development and regeneration. Parasympathetic ganglia (PSG) are derived from Schwann cell precursors that migrate along nerves, differentiate into neurons, and coalesce within their target tissue to form ganglia. However, signals that initiate gangliogenesis after the precursors differentiate into neurons are unknown. We found that deleting negative regulators of FGF signaling, Sprouty1 and Sprouty2 (Spry1/2DKO), resulted in a striking loss of gangliogenesis, innervation, and keratin 5-positive (K5+) epithelial progenitors in the SMG. Here we identify Wnts produced by K5+ progenitors in the SMG as key mediators of gangliogenesis. Wnt signaling increases survival and proliferation of PSG neurons, and inhibiting Wnt signaling disrupts gangliogenesis and organ innervation. Activating Wnt signaling and reducing FGF gene dosage rescues gangliogenesis and innervation in both the Spry1/2DKO SMG and pancreas. Thus, K5+ progenitors produce Wnt signals to establish the PSG-epithelial communication required for organ innervation and progenitor cell maintenance. C1 [Knosp, Wendy M.; Knox, Sarah M.; Lombaert, Isabelle M. A.; Haddox, Candace L.; Patel, Vaishali N.; Hoffman, Matthew P.] NIDCR, Matrix & Morphogenesis Sect, NIH, Bethesda, MD 20892 USA. [Knox, Sarah M.] UCSF, Dept Cell & Tissue Biol, San Francisco, CA 94143 USA. RP Hoffman, MP (reprint author), NIDCR, Matrix & Morphogenesis Sect, NIH, Bethesda, MD 20892 USA. EM mhoffman@mail.nih.gov OI Knox, Sarah/0000-0002-7567-083X FU Intramural Research Program of the National Institute of Dental and Craniofacial Research at the NIH FX The authors would like to thank Dr. Gail R. Martin, in whose laboratory at UCSF this collaboration started, for providing critical input into the design and experimental details and for sharing many of the mouse strains used; Prajakta Ghatpande and Elsa Berenstein for technical assistance and maintenance of the mouse colonies required for these studies; and Joao Ferreira, Ryan Petrie, and Kelly Ten Hagen for critical reading of the manuscript. This research was supported by the Intramural Research Program of the National Institute of Dental and Craniofacial Research at the NIH. NR 49 TC 10 Z9 10 U1 2 U2 10 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 MAR 23 PY 2015 VL 32 IS 6 BP 667 EP 677 DI 10.1016/j.devcel.2015.01.023 PG 11 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA CE5AK UT WOS:000351841900006 PM 25805134 ER PT J AU Rambold, AS Cohen, S Lippincott-Schwartz, J AF Rambold, Angelika S. Cohen, Sarah Lippincott-Schwartz, Jennifer TI Fatty Acid Trafficking in Starved Cells: Regulation by Lipid Droplet Lipolysis, Autophagy, and Mitochondrial Fusion Dynamics SO DEVELOPMENTAL CELL LA English DT Article ID BETA-OXIDATION; ENDOPLASMIC-RETICULUM; SKELETAL-MUSCLE; METABOLISM; DEGRADATION; PROTEIN; STARVATION; HEART; HETEROGENEITY; LOCALIZATION AB Fatty acids (FAs) provide cellular energy under starvation, yet how they mobilize and move into mitochondria in starved cells, driving oxidative respiration, is unclear. Here, we clarify this process by visualizing FA trafficking with a fluorescent FA probe. The labeled FA accumulated in lipid droplets (LDs) in well-fed cells but moved from LDs into mitochondria when cells were starved. Autophagy in starved cells replenished LDs with FAs, increasing LD number over time. Cytoplasmic lipases removed FAs from LDs, enabling their transfer into mitochondria. This required mitochondria to be highly fused and localized near LDs. When mitochondrial fusion was prevented in starved cells, FAs neither homogeneously distributed within mitochondria nor became efficiently metabolized. Instead, FAs reassociated with LDs and fluxed into neighboring cells. Thus, FAs engage in complex trafficking itineraries regulated by cytoplasmic lipases, autophagy, and mitochondrial fusion dynamics, ensuring maximum oxidative metabolism and avoidance of FA toxicity in starved cells. C1 [Rambold, Angelika S.; Cohen, Sarah; 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 lippincj@mail.nih.gov FU Deutsche Forschungsgemeinschaft FX We thank N. Mizushima and D. C. Chan for contributing the Atg5KO and Mfn-deficient cell lines, respectively. We thank S. van Engelenburg, T. Lammermann, and G. Diering for helpful discussions and technical assistance. We are thankful to C. Stratakis for providing access to the Seahorse Flux Analyzer. We thank A. Hoofring for help with illustrations. A.S.R. was supported by a postdoctoral fellowship from the Deutsche Forschungsgemeinschaft. NR 66 TC 58 Z9 59 U1 12 U2 44 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 MAR 23 PY 2015 VL 32 IS 6 BP 678 EP 692 DI 10.1016/j.devcel.2015.01.029 PG 15 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA CE5AK UT WOS:000351841900007 PM 25752962 ER PT J AU Ma, YP Wen, XB Hoshino, Y Yuan, L AF Ma, Yongping Wen, Xiaobo Hoshino, Yasutaka Yuan, L. TI Cloning and nucleotide sequence analyses of 11 genome segments of two American and one British equine rotavirus strains SO VETERINARY MICROBIOLOGY LA English DT Article DE Equine rotavirus; Genome sequence; Genotype constellations ID GROUP-A ROTAVIRUSES; MOLECULAR CHARACTERIZATION; INTERSPECIES RELATEDNESS; SPECIES-SPECIFICITY; VP4 GENOTYPE; CLASSIFICATION; JAPAN; CONSTELLATION; TRANSMISSION; REVEAL AB Group A equine rotavirus (ERV) is the main cause of diarrhea in foals and causes severe economic loss due to morbidity and mortality on stud farming worldwide. Molecular evolution of equine rotaviruses remains understudies. In this study, whole-genomic analysis of 2 group A ERV, FI-14 (G3P[12]), H-2 (G3P[12]) isolated from American, and FI23 (G14P[12]) from British was carried out and genotype constellations were determined as G3-P[12]-I6-R2-C2-M3-A10-N2-T3-E2-H7 for FI-14; G14-P[12]-12-R2-C2-M3-A10-N2-T3-E2-H7 for FI23; and G3-P[12]-16-R2-C2-M3-A10-N2-T3-E2-H7 for H-2, respectively. With the exception of the VP7 and VP6 gene, 2 G3P[12] strains (FI-14 and H-2) and one G14P[12] strain (FI23) were highly related genetically. Of note, the VP6 genotype of H-2 strain was previously reported to be I2, however, sequence and phylogenetic analyses demonstrated that it was 16. Therefore, it showed that G3P[12] ERV strains and G14P[12] ERV strains bore a distinct VP6 genotype: 16 for G3P[12] strains and 12 for G14P[12] strains. Moreover, it demonstrated that T-cell epitope 299P-300P/Q residues (PP/Q) of VP6 may be considered as 12 ERV typical molecular marker, which facilitates the analysis of the molecular evolution of equine rotaviruses. (C) 2015 Elsevier B.V. All rights reserved. C1 [Ma, Yongping] Chongqing Med Univ, Dept Biochem & Mol Biol, Mol Med & Canc Res Ctr, Chongqing 400016, Peoples R China. [Ma, Yongping; Wen, Xiaobo; Hoshino, Yasutaka] NIAID, Epidemiol Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Wen, Xiaobo] Heilongjiang Bayi Agr Univ, Coll Anim Sci & Vet Med, Daqing 163319, Heilongjiang Pr, Peoples R China. [Yuan, L.] Virginia Polytech Inst & State Univ, Virginia Maryland Reg Coll Vet Med, Dept Biomed Sci & Pathobiol, Blacksburg, VA 24060 USA. RP Yuan, L (reprint author), Virginia Polytech Inst & State Univ, Virginia Maryland Reg Coll Vet Med, Dept Biomed Sci & Pathobiol, Blacksburg, VA 24060 USA. EM lyuan@vt.edu FU National Natural Science Foundation of China (NSFC) [30671865] FX The research was partially funded by a research grant from the National Natural Science Foundation of China (NSFC no. 30671865). NR 25 TC 2 Z9 2 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1135 EI 1873-2542 J9 VET MICROBIOL JI Vet. Microbiol. PD MAR 23 PY 2015 VL 176 IS 1-2 BP 172 EP 178 DI 10.1016/j.vetmic.2015.01.008 PG 7 WC Microbiology; Veterinary Sciences SC Microbiology; Veterinary Sciences GA CC1GK UT WOS:000350089000020 PM 25631250 ER PT J AU Khare, R Burger, JD Aberdeen, JS Tresner-Kirsch, DW Corrales, TJ Hirchman, L Lu, ZY AF Khare, Ritu Burger, John D. Aberdeen, John S. Tresner-Kirsch, David W. Corrales, Theodore J. Hirchman, Lynette Lu, Zhiyong TI Scaling drug indication curation through crowdsourcing SO DATABASE-THE JOURNAL OF BIOLOGICAL DATABASES AND CURATION LA English DT Article ID BIOCREATIVE III; NORMALIZATION; INFORMATION; MEDICATIONS; DEFINITION; QUALITY; TASK AB Motivated by the high cost of human curation of biological databases, there is an increasing interest in using computational approaches to assist human curators and accelerate the manual curation process. Towards the goal of cataloging drug indications from FDA drug labels, we recently developed LabeledIn, a human-curated drug indication resource for 250 clinical drugs. Its development required over 40 h of human effort across 20 weeks, despite using well-defined annotation guidelines. In this study, we aim to investigate the feasibility of scaling drug indication annotation through a crowdsourcing technique where an unknown network of workers can be recruited through the technical environment of Amazon Mechanical Turk (MTurk). To translate the expert-curation task of cataloging indications into human intelligence tasks (HITs) suitable for the average workers on MTurk, we first simplify the complex task such that each HIT only involves a worker making a binary judgment of whether a highlighted disease, in context of a given drug label, is an indication. In addition, this study is novel in the crowdsourcing interface design where the annotation guidelines are encoded into user options. For evaluation, we assess the ability of our proposed method to achieve high-quality annotations in a time-efficient and cost-effective manner. We posted over 3000 HITs drawn from 706 drug labels on MTurk. Within 8 h of posting, we collected 18 775 judgments from 74 workers, and achieved an aggregated accuracy of 96% on 450 control HITs (where gold-standard answers are known), at a cost of $1.75 per drug label. On the basis of these results, we conclude that our crowdsourcing approach not only results in significant cost and time saving, but also leads to accuracy comparable to that of domain experts. C1 [Khare, Ritu; Corrales, Theodore J.; Lu, Zhiyong] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Burger, John D.; Aberdeen, John S.; Tresner-Kirsch, David W.; Hirchman, Lynette] Mitre Corp, Bedford, MA 01730 USA. [Corrales, Theodore J.] Montgomery Blair High Sch, Silver Spring, MD 20901 USA. RP Lu, ZY (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM zhiyong.lu@nih.gov FU Intramural Research Program of the National Institutes of Health, National Library of Medicine; NIH Intramural Research Training Award; MITRE's Internal Research and Development Program FX The work was supported by the Intramural Research Program of the National Institutes of Health, National Library of Medicine (R.K., Z.L.). T.C. was a summer intern at the NIH and supported by the NIH Intramural Research Training Award. The work was also funded under MITRE's Internal Research and Development Program (J.A., J.B., D.T.K., L.H.). Funding for open access charge: The Intramural Research Program of the National Institutes of Health, National Library of Medicine. NR 50 TC 7 Z9 7 U1 3 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1758-0463 J9 DATABASE-OXFORD JI Database PD MAR 22 PY 2015 AR bav016 DI 10.1093/database/bav016 PG 10 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA CR0XG UT WOS:000361046300001 ER PT J AU Lee, C Jung, JW Pelletier, C Pyakuryal, A Lamart, S Kim, JO Lee, C AF Lee, Choonik Jung, Jae Won Pelletier, Christopher Pyakuryal, Anil Lamart, Stephanie Kim, Jong Oh Lee, Choonsik TI Reconstruction of organ dose for external radiotherapy patients in retrospective epidemiologic studies SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE organ dose reconstruction; phantom; radiotherapy; DICOM ID TREATMENT PLANNING SYSTEM; CANCER-RISK-ASSESSMENT; CARLO-BASED PHOTON; MONTE-CARLO; RADIATION-THERAPY; COMPUTATIONAL PHANTOMS; HUMAN ANATOMY; DOSIMETRY; FIELD; MODELS AB Organ dose estimation for retrospective epidemiological studies of late effects in radiotherapy patients involves two challenges: radiological images to represent patient anatomy are not usually available for patient cohorts who were treated years ago, and efficient dose reconstruction methods for large-scale patient cohorts are not well established. In the current study, we developed methods to reconstruct organ doses for radiotherapy patients by using a series of computational human phantoms coupled with a commercial treatment planning system (TPS) and a radiotherapy-dedicated Monte Carlo transport code, and performed illustrative dose calculations. First, we developed methods to convert the anatomy and organ contours of the pediatric and adult hybrid computational phantom series to Digital Imaging and Communications in Medicine (DICOM)-image and DICOM-structure files, respectively. The resulting DICOM files were imported to a commercial TPS for simulating radiotherapy and dose calculation for in-field organs. The conversion process was validated by comparing electron densities relative to water and organ volumes between the hybrid phantoms and the DICOM files imported in TPS, which showed agreements within 0.1 and 2%, respectively. Second, we developed a procedure to transfer DICOM-RT files generated from the TPS directly to a Monte Carlo transport code, x-ray Voxel Monte Carlo (XVMC) for more accurate dose calculations. Third, to illustrate the performance of the established methods, we simulated a whole brain treatment for the 10 year-old male phantom and a prostate treatment for the adult male phantom. Radiation doses to selected organs were calculated using the TPS and XVMC, and compared to each other. Organ average doses from the two methods matched within 7%, whereas maximum and minimum point doses differed up to 45%. The dosimetry methods and procedures established in this study will be useful for the reconstruction of organ dose to support retrospective epidemiological studies of late effects in radiotherapy patients. C1 [Lee, Choonik] Univ Michigan, Dept Radiat Oncol, Ann Arbor, MI 48109 USA. [Jung, Jae Won; Pelletier, Christopher] E Carolina Univ, Dept Phys, Greenville, NC 27858 USA. [Pyakuryal, Anil; Lamart, Stephanie; Lee, Choonsik] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA. [Kim, Jong Oh] Univ Pittsburgh, Inst Canc, Radiat Oncol, Pittsburgh, PA 15232 USA. RP Lee, C (reprint author), Univ Michigan, Dept Radiat Oncol, Ann Arbor, MI 48109 USA. EM leechoonsik@mail.nih.gov RI Lee, Choonsik/C-9023-2015 OI Lee, Choonsik/0000-0003-4289-9870 FU National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics FX This work was supported by the intramural research program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics. This study utilized the high-performance computational capabilities of the Helix Linux computing system at the National Institutes of Health, Bethesda, MD (http://helix.nih.gov). NR 38 TC 2 Z9 2 U1 0 U2 1 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 EI 1361-6560 J9 PHYS MED BIOL JI Phys. Med. Biol. PD MAR 21 PY 2015 VL 60 IS 6 BP 2309 EP 2324 DI 10.1088/0031-9155/60/6/2309 PG 16 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA CI6OV UT WOS:000354880900004 PM 25715852 ER PT J AU Dang, H Steinway, SN Ding, W Rountree, CB AF Dang, Hien Steinway, Steven N. Ding, Wei Rountree, Carl B. TI Induction of tumor initiation is dependent on CD44s in c-Met(+) hepatocellular carcinoma SO BMC CANCER LA English DT Article ID CANCER STEM-CELLS; EPITHELIAL-MESENCHYMAL TRANSITION; HEPATOCYTE GROWTH-FACTOR; C-MET; LIVER-CANCER; PHOSPHATIDYLINOSITOL 3-KINASE; STEM/PROGENITOR CELLS; FACTOR/SCATTER FACTOR; EXPRESSION SIGNATURE; THERAPEUTIC TARGET AB Background: Hepatocellular carcinoma (HCC) patients with active hepatocyte growth factor (HGF)/c-Met signaling have a significantly worse prognosis. c-Met, a high affinity receptor for HGF, plays a critical role in cancer growth, invasion and metastasis. c-Met and CD44 have been utilized as cell surface markers to identify mesenchymal tumor-initiating stem-like cells (TISC) in several cancers including HCC. In this work, we examine the complex relationship between c-Met and CD44s (standard form), and investigate the specific role of CD44s as a tumor initiator and stemness marker in HCC. Methods: Gene and protein expression assays were utilized to investigate the relationship between CD44s and c-Met in HCC cell lines. Tumor-sphere assays and in vivo tumor assays were performed to investigate the role of CD44+ cells as TISCs. Student's t-test or one-way ANOVA with Tukeys post-hoc test was performed to test for differences amongst groups with a p < .05 as significant. Results: In an immunohistochemical and immunoblot analysis of human HCC samples, we observed that more than 39% of human HCC samples express c-Met and CD44. To study the relationship between c-Met and CD44, we used MHCC97-H cells, which are CD44(+)/c-Met(+). The knockdown of c-Met in MHCC97-H cells decreased CD44s, reduced TISC characteristics and decreased tumorsphere formation. Furthermore, we demonstrate that the inhibition of PI3K/AKT signaling decreased CD44s expression and subsequently decreased tumorsphere formation. The down-regulation of CD44s leads to a significant loss of a TISC and mesenchymal phenotype. Finally, the down-regulation of CD44s in MHCC97-H cells decreased tumor initiation in vivo compared with the scrambled control. Conclusions: In summary, our data suggest that CD44s is modulated by the c-Met-PI3K-AKT signaling cascade to support a mesenchymal and TISC phenotype in HCC cells. Moreover, c-Met could be a potential therapeutic drug for targeting HCC cells with TISC and mesenchymal phenotypes. C1 [Dang, Hien; Steinway, Steven N.; Ding, Wei; Rountree, Carl B.] Penn State Univ, Penn State Childrens Hosp, Coll Med, Dept Pediat & Pharmacol, Hershey, PA 17033 USA. [Dang, Hien] NCI, Human Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Rountree, Carl B.] Bon Secours St Marys Hosp, Richmond, VA 23226 USA. RP Dang, H (reprint author), Penn State Univ, Penn State Childrens Hosp, Coll Med, Dept Pediat & Pharmacol, Hershey, PA 17033 USA. EM danghi@mail.nih.gov; carl_rountree@bshsi.org FU National Institute of Health [R03DK088013, 1F30DK093234-01]; American Cancer Society [RSG-10-073-01-TBG]; Four Diamonds Foundation FX We acknowledge Drs. Kent Vrana and Willard Freeman of the Functional Genomics Core (The Pennsylvania State University College of Medicine) for technical and editorial input of the manuscript. Important Functional Genomics Core Facility instrumentation purchases were made possible through Tobacco Settlement Funds. This work was made possible by generous support from the National Institute of Health, R03DK088013 (CBR); the American Cancer Society, Research Scholar Award, RSG-10-073-01-TBG (CBR); and the Four Diamonds Foundation (CBR); National Institute of Health, 1F30DK093234-01 (SS). NR 52 TC 8 Z9 8 U1 0 U2 6 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 MAR 21 PY 2015 VL 15 AR 161 DI 10.1186/s12885-015-1166-4 PG 11 WC Oncology SC Oncology GA CE7ZH UT WOS:000352060000001 PM 25886575 ER PT J AU Lee, J Lee, K Joung, I Joo, K Brooks, BR Lee, J AF Lee, Juyong Lee, Kiho Joung, InSuk Joo, Keehyoung Brooks, Bernard R. Lee, Jooyoung TI Sigma-RF: prediction of the variability of spatial restraints in template-based modeling by random forest SO BMC BIOINFORMATICS LA English DT Article DE Template-based modeling; Homology modeling; Random forest; Machine learning; Protein structure; Protein structure prediction; Protein sequence; Bioinformatics; Statistics ID PROTEIN-STRUCTURE PREDICTION; GLOBAL OPTIMIZATION; STRUCTURE INFORMATION; ENERGY FUNCTION; ACCURACY; CASP8; ALIGNMENTS AB Background: In template-based modeling when using a single template, inter-atomic distances of an unknown protein structure are assumed to be distributed by Gaussian probability density functions, whose center peaks are located at the distances between corresponding atoms in the template structure. The width of the Gaussian distribution, the variability of a spatial restraint, is closely related to the reliability of the restraint information extracted from a template, and it should be accurately estimated for successful template-based protein structure modeling. Results: To predict the variability of the spatial restraints in template-based modeling, we have devised a prediction model, Sigma-RF, by using the random forest (RF) algorithm. The benchmark results on 22 CASP9 targets show that the variability values from Sigma-RF are of higher correlations with the true distance deviation than those from Modeller. We assessed the effect of new sigma values by performing the single-domain homology modeling of 22 CASP9 targets and 24 CASP10 targets. For most of the targets tested, we could obtain more accurate 3D models from the identical alignments by using the Sigma-RF results than by using Modeller ones. Conclusions: We find that the average alignment quality of residues located between and at two aligned residues, quasi-local information, is the most contributing factor, by investigating the importance of input features used in the RF machine learning. This average alignment quality is shown to be more important than the previously identified quantity of a local information: the product of alignment qualities at two aligned residues. C1 Korea Inst Adv Study, Ctr Silico Prot Sci, Seoul, South Korea. [Lee, Juyong; Lee, Kiho; Joung, InSuk; Joo, Keehyoung; Lee, Jooyoung] Korea Inst Adv Study, Ctr Silico Prot Sci, Seoul, South Korea. [Joo, Keehyoung] Korea Inst Adv Study, Ctr Adv Computat, Seoul, South Korea. [Joung, InSuk; Lee, Jooyoung] Korea Inst Adv Study, Sch Computat Sci, Seoul, South Korea. [Lee, Juyong; Brooks, Bernard R.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20852 USA. RP Lee, J (reprint author), Korea Inst Adv Study, Ctr Silico Prot Sci, Seoul, South Korea. EM jlee@kias.re.kr RI Lee, Juyong/A-7869-2013 OI Lee, Juyong/0000-0003-1174-4358 FU National Research Foundation of Korea (NRF) - Korea government (MEST) [20120001222]; KISTI Supercomputing Center [KSC-2012-C3-02] FX This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. 20120001222). We thank Korea Institute for Advanced Study for providing computing resources (KIAS Center for Advanced Computation Linux Cluster) for this work. We also like to acknowledge the support from the KISTI Supercomputing Center (KSC-2012-C3-02). NR 41 TC 4 Z9 4 U1 2 U2 7 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 MAR 21 PY 2015 VL 16 AR 94 DI 10.1186/s12859-015-0526-z PG 12 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA CE4RX UT WOS:000351818900001 PM 25886990 ER PT J AU Baller, JB McGinty, EE Azrin, ST Juliano-Bult, D Daumit, GL AF Baller, Julia B. McGinty, Emma E. Azrin, Susan T. Juliano-Bult, Denise Daumit, Gail L. TI Screening for cardiovascular risk factors in adults with serious mental illness: a review of the evidence SO BMC PSYCHIATRY LA English DT Article ID QUALITY-OF-CARE; 2ND-GENERATION ANTIPSYCHOTIC-DRUGS; COMMUNITY PSYCHIATRIC-SERVICES; DECISION-SUPPORT-SYSTEMS; HEALTH-CARE; METABOLIC SYNDROME; UNITED-STATES; MEDICAL-CARE; SCHIZOPHRENIA; MORTALITY AB Background: Adults with serious mental illness have a mortality rate two to three times higher than the overall US population, much of which is due to somatic conditions, especially cardiovascular disease. Given the disproportionately high prevalence of cardiovascular risk factors in the population with SMI, screening for these conditions is an important first step for timely diagnosis and appropriate treatment. This comprehensive literature review summarizes screening rates for cardiovascular risk factors in the population with serious mental illness. Methods: Relevant articles published between 2000 and 2013 were identified using the EMBASE, PsychInfo, PubMed, SCOPUS and Web of Science databases. We reviewed 10 studies measuring screening rates for obesity, diabetes, dyslipidemia, and hypertension in the population with serious mental illness. Two reviewers independently extracted information on screening rates, study population, and study setting. Results: Rates of screening varied considerably by time period, study population, and data source for all medical conditions. For example, rates of lipid testing for antipsychotic users ranged from 6% to 85%. For some conditions, rates of screening were consistently high. For example, screening rates for hypertension ranged from 79% - 88%. Conclusions: There is considerable variation in screening of cardiovascular risk factors in the population with serious mental illness, with significant need for improvement in some study populations and settings. Implementation of standard screening protocols triggered by diagnosis of serious mental illness or antipsychotic use may be promising avenues for ensuring timely diagnosis and treatment of cardiovascular risk factors in this population. C1 [Baller, Julia B.; McGinty, Emma E.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Azrin, Susan T.; Juliano-Bult, Denise] NIMH, Rockville, MD 20852 USA. [Daumit, Gail L.] Johns Hopkins Sch Med, Baltimore, MD 21205 USA. RP Daumit, GL (reprint author), Johns Hopkins Sch Med, 2024 Monument St,Suite 2-620, Baltimore, MD 21205 USA. EM gdaumit@jhmi.edu FU NIMH [HHSN271201200576P] FX This study was funded through NIMH contract HHSN271201200576P. NR 61 TC 6 Z9 6 U1 5 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-244X J9 BMC PSYCHIATRY JI BMC Psychiatry PD MAR 21 PY 2015 VL 15 AR 55 DI 10.1186/s12888-015-0416-y PG 13 WC Psychiatry SC Psychiatry GA CE3KO UT WOS:000351725400001 PM 25885367 ER PT J AU Kurochkina, NA Iadarola, MJ AF Kurochkina, Natalya A. Iadarola, Michael J. TI Helical assemblies: Structure determinants SO JOURNAL OF THEORETICAL BIOLOGY LA English DT Article DE Protein conformation; Repeats; Helix-helix interface; Assembly; Enantiomer-selective ligand binding ID 4-HELIX BUNDLE PROTEINS; ENERGETIC APPROACH; ALPHA-HELICES; TRP CHANNELS; BETA-BARRELS; PACKING; REPEAT; MECHANISM; BINDING; DISPOSITION AB Protein structural motifs such as helical assemblies and alpha/beta barrels combine secondary structure elements with various types of interactions. Helix-helix interfaces of assemblies - Anlcyrin, ARM/HEAT, PUM, LRR, and TPR repeats - exhibit unique amino acid composition and patterns of interactions that correlate with curvature of solenoids, surface geometry and mutual orientation of the helical edges. Inner rows of ankyrin, ARM/HEAT, and PUM-HD repeats utilize edges (i-1, i) and (i+1, i+2) for the interaction of the given a-helix with preceding and following helices correspondingly, whereas outer rows of these proteins and LRR repeats invert this pattern and utilize edges (i-1, i) and (i-3, i-2). Arrangement of contacts observed in protein ligands that bind helical assemblies has to mimic the assembly pattern to provide the same curvature as a determinant of binding specificity. These characteristics are important for understanding fold recognition, specificity of protein-protein interactions, and design of new drugs and materials. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Kurochkina, Natalya A.] Sch Theoret Modeling, Washington, DC 20006 USA. [Iadarola, Michael J.] NIH, Anesthesia Sect, Dept Perioperat Med, Ctr Clin, Bethesda, MD 20892 USA. RP Kurochkina, NA (reprint author), Sch Theoret Modeling, 1629 K St NW S 300, Washington, DC 20006 USA. EM info@schtm.org; michael.iadarola@nih.gov FU Clinical Center, National Institutes of Health, Bethesda, MD, USA; School of Theoretical Modeling, Washington, DC, USA FX The Intramural Research programs of the Clinical Center, National Institutes of Health, Bethesda, MD, USA and Research Funds of The School of Theoretical Modeling, Washington, DC, USA. NR 50 TC 1 Z9 1 U1 2 U2 6 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-5193 EI 1095-8541 J9 J THEOR BIOL JI J. Theor. Biol. PD MAR 21 PY 2015 VL 369 BP 80 EP 84 DI 10.1016/j.jtbi.2015.01.012 PG 5 WC Biology; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology GA CE2ND UT WOS:000351651400008 PM 25613414 ER PT J AU Kohli, A Osinusi, A Sims, Z Nelson, A Meissner, EG Barrett, LL Bon, D Marti, MM Silk, R Kotb, C Gross, C Jolley, TA Sidharthan, S Petersen, T Townsend, K Egerson, D Kapoor, R Spurlin, E Sneller, M Proschan, M Herrmann, E Kwan, R Teferi, G Talwani, R Diaz, G Kleiner, DE Wood, BJ Chavez, J Abbott, S Symonds, WT Subramanian, GM Pang, PS McHutchison, J Polis, MA Fauci, AS Masur, H Kottilil, S AF Kohli, Anita Osinusi, Anuoluwapo Sims, Zayani Nelson, Amy Meissner, Eric G. Barrett, Lisa L. Bon, Dimitra Marti, Miriam M. Silk, Rachel Kotb, Colleen Gross, Chloe Jolley, Tim A. Sidharthan, Sreetha Petersen, Tess Townsend, Kerry Egerson, D'Andrea Kapoor, Rama Spurlin, Emily Sneller, Michael Proschan, Michael Herrmann, Eva Kwan, Richard Teferi, Gebeyehu Talwani, Rohit Diaz, Gabbie Kleiner, David E. Wood, Brad J. Chavez, Jose Abbott, Stephen Symonds, William T. Subramanian, G. Mani Pang, Phillip S. McHutchison, John Polis, Michael A. Fauci, Anthony S. Masur, Henry Kottilil, Shyam TI Virological response after 6 week triple-drug regimens for hepatitis C: a proof-of-concept phase 2A cohort study SO LANCET LA English DT Article ID GENOTYPE 1 INFECTION; INHIBITOR SOFOSBUVIR PLUS; DIRECT-ACTING ANTIVIRALS; TREATMENT-NAIVE PATIENTS; INTERFERON-FREE THERAPY; PEGYLATED INTERFERON; PROTEASE INHIBITOR; VIRUS-INFECTION; CHRONIC HCV; OPEN-LABEL AB Background Direct-acting antiviral drugs have a high cure rate and favourable tolerability for patients with hepatitis C virus (HCV). Shorter courses could improve affordability and adherence. Sofosbuvir and ledipasvir with ribavirin have high efficacy when taken for 8 weeks but not for 6 weeks. We assessed whether the addition of a third direct-acting antiviral drug to sofosbuvir and ledipasvir would allow a shorter treatment duration. Methods In this single-centre, open-label, phase 2A trial, we sequentially enrolled treatment-naive patients with HCV genotype 1 infection into three treatment groups: 12 weeks of sofosbuvir and ledipasvir; 6 weeks of sofosbuvir, ledipasvir, and GS-9669; or 6 weeks of sofosbuvir, ledipasvir, and GS-9451. Patients and investigators were not masked to treatment assignment. The primary endpoint was the propotion of patients with sustained viral response at 12 weeks after treatment completion (SVR12), assessed by serum HCV RNA concentrations lower than 43 IU/mL (the lower limit of quantification). We did an intention-to-treat analysis for the primary endpoint and adverse events. This study is registered with ClinicalTrials. gov, number NCT01805882. Findings Between Jan 11, 2013, and Dec 17, 2013, we enrolled 60 patients, and sequentially assigned them into three groups of 20. We noted an SVR12 in all 20 patients (100%, 95% CI 83-100) allocated to sofosbuvir and ledipasvir for 12 weeks; in 19 (95%, 75-100) of the 20 patients allocated to sofosbuvir, ledipasvir, and GS-9669 for 6 weeks (one patient relapsed 2 weeks after completion of treatment); and in 19 (95%, 75-100%) of the 20 patients allocated to sofosbuvir, ledipasvir, and GS-9451 for 6 weeks (one patient was lost to follow-up after reaching sustained viral response at 4 weeks). Most adverse events were mild and no patients discontinued treatment. Two serious adverse events occurred (pain after a post-treatment liver biopsy and vertigo), both unrelated to study drugs. Interpretation In this small proof-of-concept study, two different three-drug regimens that were given for 6 weeks resulted in high cure rates for HCV infection with excellent tolerability. Addition of a third potent direct-acting antiviral drug can reduce the duration of treatment required to achieve sustained viral response in patients with chronic HCV genotype 1 infection without cirrhosis. C1 [Kohli, Anita; Sims, Zayani; Sidharthan, Sreetha; Petersen, Tess; Masur, Henry] NIH, NIH Clin Ctr, Dept Crit Care Med, Bethesda, MD 20892 USA. [Kohli, Anita; Osinusi, Anuoluwapo; Silk, Rachel; Kotb, Colleen; Gross, Chloe; Egerson, D'Andrea; Kapoor, Rama; Diaz, Gabbie] Frederick Natl Lab Canc Res, Clin Monitoring Res Program, Clin Res Directorate, Leidos Biomed Res, Frederick, MD USA. [Nelson, Amy; Meissner, Eric G.; Barrett, Lisa L.; Marti, Miriam M.; Jolley, Tim A.; Townsend, Kerry; Spurlin, Emily; Sneller, Michael; Kwan, Richard; Polis, Michael A.; Fauci, Anthony S.; Kottilil, Shyam] Immunoregulat Lab, New York, NY USA. [Proschan, Michael] Biostat Res Branch, Baltimore, MD USA. [Talwani, Rohit] NIH, NIAID, Bethesda, MD USA. [Talwani, Rohit] Univ Maryland, Inst Human Virol, Div Infect Dis, Bethesda, MD USA. [Osinusi, Anuoluwapo; Barrett, Lisa L.] Dalhousie Univ, Dept Med, Halifax, NS, Canada. [Bon, Dimitra; Herrmann, Eva] Goethe Univ Frankfurt, Inst Biostat & Math Modeling, D-60054 Frankfurt, Germany. [Teferi, Gebeyehu; Chavez, Jose; Abbott, Stephen] Unity Hlth Care, Washington, DC USA. [Diaz, Gabbie] NCI, NIH, Bethesda, MD 20892 USA. [Kleiner, David E.] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Wood, Brad J.] NIH, Ctr Clin, Ctr Intervent Oncol Radiol & Imaging Sci, Bethesda, MD USA. [Wood, Brad J.] NCI, Bethesda, MD 20892 USA. [Symonds, William T.; Subramanian, G. Mani; Pang, Phillip S.; McHutchison, John] Gilead Sci, Foster City, CA USA. RP Kottilil, S (reprint author), NIH, NIAID, Immunoregulat Lab, Immunopathogenesis Sect, Bethesda, MD 20892 USA. EM skottilil@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases (NIAID); National Cancer Institute and Clinical Center Intramural Program; German Research Foundation; National Institutes of Health; Gilead Sciences FX National Institute of Allergy and Infectious Diseases (NIAID), National Cancer Institute and Clinical Center Intramural Program, German Research Foundation, National Institutes of Health, Gilead Sciences. NR 32 TC 53 Z9 53 U1 1 U2 13 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 MAR 21 PY 2015 VL 385 IS 9973 BP 1107 EP 1113 DI 10.1016/S0140-6736(14)61228-9 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA CD7KX UT WOS:000351270400028 PM 25591505 ER PT J AU Ramot, Y Kodavanti, UP Kissling, GE Ledbetter, AD Nyska, A AF Ramot, Yuval Kodavanti, Urmila P. Kissling, Grace E. Ledbetter, Allen D. Nyska, Abraham TI Clinical and pathological manifestations of cardiovascular disease in rat models: the influence of acute ozone exposure SO INHALATION TOXICOLOGY LA English DT Article DE Cardiovascular disease models; clinical biomarkers; kidney; ozone; pathology; rat models ID SPONTANEOUSLY HYPERTENSIVE-RATS; FAWN-HOODED RAT; LA-CORPULENT RAT; PARTICULATE MATTER; AIR-POLLUTION; METABOLIC SYNDROME; JOINT PUBLICATION; REVISED GUIDES; NACAD GROUPS; VASCULAR DYSFUNCTION AB Rodent models of cardiovascular diseases (CVD) and metabolic disorders are used for examining susceptibility variations to environmental exposures. However, cross-model organ pathologies and clinical manifestations are often not compared. We hypothesized that genetic CVD rat models will exhibit baseline pathologies and will thus express varied lung response to acute ozone exposure. Male 12-14-week-old healthy Wistar Kyoto (WKY), Wistar (WIS), and Sprague-Dawley (SD) rats and CVD-compromised spontaneously hypertensive (SH), fawn-hooded hypertensive (FHH), stroke-prone SH (SHSP), obese SH heart-failure (SHHF), obese diabetic JCR (JCR) rats were exposed to 0.0, 0.25, 0.5, or 1.0ppm ozone for 4h and clinical biomarkers, and lung, heart and kidney pathologies were compared immediately following (0-h) or 20-h later. Strain differences were observed between air-exposed CVD-prone and WKY rats in clinical biomarkers and in kidney and heart pathology. Serum cholesterol was higher in air-exposed obese SHHF and JCR compared to other air-exposed strains. Ozone did not produce lesions in the heart or kidney. CVD-prone and SD rats demonstrated glomerulopathy and kidney inflammation (WKY=WIS=SH= 1-year old who participated in a partially randomized, open-label, 96-week combination antire-troviral therapy (cART)-algorithmstudy. Methods Participants were categorized as CMV-naive, CMV-positive (CMV+) viremic, and CMV+ aviremic, based on blood, urine, or throat culture, CMV IgG and DNA polymerase chain reaction measured at baseline. At weeks 0, 12, 20 and 40, T-cell subsets including naive (CD62L+CD45RA+; CD95-CD28+), activated (CD38+HLA-DR+) and terminally differentiated (CD62L-CD45RA+; CD95+CD28-) CD4+ and CD8+ T-cells were measured by flow cytometry. Results Of the 107 participants included in the analysis, 14% were CMV+ viremic; 49% CMV+ aviremic; 37% CMV-naive. In longitudinal adjusted models, compared with CMV+ status, baseline CMV-naive status was significantly associated with faster recovery of CD8+CD62L +CD45RA+% and CD8+CD95-CD28+% and faster decrease of CD8+CD95+CD28-%, independent of HIV VL response to treatment, cART regimen and baseline CD4%. Surprisingly, CMV status did not have a significant impact on longitudinal trends in CD8+CD38+HLA-DR+%. CMV status did not have a significant impact on any CD4+ T-cell subsets. Conclusions In this cohort of PHIV+ children, the normalization of naive and terminally differentiated CD8+ T-cell subsets in response to cART was detrimentally affected by the presence of CMV co-infection. These findings may have implications for adjunctive treatment strategies targeting CMV co-infection in PHIV+ children, especially those that are now adults or reaching young adulthood and may have accelerated immunologic aging, increased opportunistic infections and aging diseases of the immune system. C1 [Kapetanovic, Suad] NIMH, NIH, Bethesda, MD 20892 USA. [Aaron, Lisa; Montepiedra, Grace] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Anthony, Patricia; Thuvamontolrat, Kasalyn; Kovacs, Andrea] Univ So Calif, Keck Sch Med, Maternal Child & Adolescent Ctr Infect Dis & Viro, Los Angeles, CA 90033 USA. [Pahwa, Savita] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Burchett, Sandra] Childrens Hosp Boston, Boston, MA USA. [Burchett, Sandra] Harvard Univ, Sch Med, Boston, MA USA. [Weinberg, Adriana] Univ Colorado, Denver, CO 80202 USA. RP Kapetanovic, S (reprint author), NIMH, NIH, Bethesda, MD 20892 USA. EM suad.kapetanovic@nih.gov OI Bonagura, Vincent/0000-0002-0681-2099 FU National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) [UM1AI068632, UM1AI068616, UM1AI106716]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute of Mental Health (NIMH); Intramural Research Program of the NIMH FX Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) was provided by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) under Award Numbers UM1AI068632 (IMPAACT LOC), UM1AI068616 (IMPAACT SDMC) and UM1AI106716 (IMPAACT LC), with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Mental Health (NIMH). This project was also supported in part by the Intramural Research Program of the NIMH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 24 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 MAR 20 PY 2015 VL 10 IS 3 AR e0120474 DI 10.1371/journal.pone.0120474 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CE8HY UT WOS:000352083900038 PM 25794163 ER PT J AU Korzeniewski, SJ Allred, E Logan, JW Fichorova, RN Engelke, S Kuban, KCK O'Shea, TM Paneth, N Holm, M Dammann, O Leviton, A AF Korzeniewski, Steven J. Allred, Elizabeth Logan, J. Wells Fichorova, Raina N. Engelke, Stephen Kuban, Karl C. K. O'Shea, T. Michael Paneth, Nigel Holm, Mari Dammann, Olaf Leviton, Alan CA ELGAN Study Investigators TI Elevated Endogenous Erythropoietin Concentrations Are Associated with Increased Risk of Brain Damage in Extremely Preterm Neonates SO PLOS ONE LA English DT Article ID INFLAMMATION-RELATED PROTEINS; LOW-BIRTH-WEIGHT; EPITHELIAL-CELLS; GESTATIONAL-AGE; IN-VITRO; INFANTS; ANGIOGENESIS; INJURY; ISCHEMIA; NEWBORNS AB Background We sought to determine, in very preterm infants, whether elevated perinatal erythropoietin (EPO) concentrations are associated with increased risks of indicators of brain damage, and whether this risk differs by the co-occurrence or absence of intermittent or sustained systemic inflammation (ISSI). Methods Protein concentrations were measured in blood collected from 786 infants born before the 28th week of gestation. EPO was measured on postnatal day 14, and 25 inflammation-related proteins were measured weekly during the first 2 postnatal weeks. We defined ISSI as a concentration in the top quartile of each of 25 inflammation-related proteins on two separate days a week apart. Hypererythropoietinemia (hyperEPO) was defined as the highest quartile for gestational age on postnatal day 14. Using logistic regression and multinomial logistic regression models, we compared risks of brain damage among neonates with hyperEPO only, ISSI only, and hyperEPO+ISSI, to those who had neither hyperEPO nor ISSI, adjusting for gestational age. Results Newborns with hyperEPO, regardless of ISSI, were more than twice as likely as those without to have very low (<55) Mental (OR 2.3; 95% CI 1.5-3.5) and/or Psychomotor (OR 2.4; 95% CI 1.6-3.7) Development Indices (MDI, PDI), and microcephaly at age two years (OR 2.4; 95% CI 1.5-3.8). Newborns with both hyperEPO and ISSI had significantly increased risks of ventriculomegaly, hemiparetic cerebral palsy, microcephaly, and MDI and PDI <55 (ORs ranged from 2.2-6.3), but not hypoechoic lesions or other forms of cerebral palsy, relative to newborns with neither hyperEPO nor ISSI. Conclusion hyperEPO, regardless of ISSI, is associated with elevated risks of very low MDI and PDI, and microcephaly, but not with any form of cerebral palsy. Children with both hyperEPO and ISSI are at higher risk than others of very low MDI and PDI, ventriculomegaly, hemiparetic cerebral palsy, and microcephaly. C1 [Korzeniewski, Steven J.] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD 20892 USA. [Korzeniewski, Steven J.] NICHD, Perinatol Res Branch, NIH, Detroit, MI USA. [Korzeniewski, Steven J.] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Korzeniewski, Steven J.; Paneth, Nigel] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Allred, Elizabeth; Leviton, Alan] Boston Childrens Hosp, Dept Neurol, Boston, MA USA. [Allred, Elizabeth; Fichorova, Raina N.; Leviton, Alan] Harvard Univ, Sch Med, Boston, MA USA. [Logan, J. Wells] Nationwide Childrens Hosp, Dept Neonatol, Columbus, OH USA. [Fichorova, Raina N.] Brigham & Womens Hosp, Dept Obstet, Boston, MA 02115 USA. [Fichorova, Raina N.] Brigham & Womens Hosp, Dept Gynecol, Boston, MA 02115 USA. [Fichorova, Raina N.] Brigham & Womens Hosp, Dept Reprod Biol, Boston, MA 02115 USA. [Engelke, Stephen] E Carolina Univ, Brody Sch Med, Dept Pediat, Greenville, NC USA. [Kuban, Karl C. K.] Boston Med Ctr, Dept Pediat, Boston, MA USA. [Kuban, Karl C. K.] Boston Univ, Boston, MA 02215 USA. [O'Shea, T. Michael] Wake Forest Univ, Dept Pediat, Winston Salem, NC 27109 USA. [Paneth, Nigel] Michigan State Univ, Dept Pediat & Human Dev, E Lansing, MI 48824 USA. [Holm, Mari] Norwegian Univ Sci & Technol, Fac Med, Dept Lab Med Childrens & Womens Hlth, N-7034 Trondheim, Norway. [Holm, Mari; Dammann, Olaf] Tufts Univ, Sch Med, Dept Publ Hlth & Community Med, Boston, MA 02111 USA. [Dammann, Olaf] Hannover Med Sch, Neuroepidemiol Unit, Hannover, Germany. RP Korzeniewski, SJ (reprint author), NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD 20892 USA. EM sKorzeni@med.wayne.edu FU National Institute of Neurological Disorders and Stroke [5U01NS040069-05, 2R01NS040069-06A2]; National Eye Institute [1-R01-EY021820-01]; National Institute of Child Health and Human Development [5P30HD018655-28]; Wayne State University Perinatal Initiative FX This study was supported by The National Institute of Neurological Disorders and Stroke (5U01NS040069-05; 2R01NS040069-06A2), The National Eye Institute (1-R01-EY021820-01), the National Institute of Child Health and Human Development (5P30HD018655-28), and the Wayne State University Perinatal Initiative. NR 48 TC 4 Z9 5 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 MAR 20 PY 2015 VL 10 IS 3 AR e0115083 DI 10.1371/journal.pone.0115083 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CE8IA UT WOS:000352084200003 PM 25793991 ER PT J AU Tiano, JP Springer, DA Rane, SG AF Tiano, Joseph P. Springer, Danielle A. Rane, Sushil G. TI SMAD3 Negatively Regulates Serum Irisin and Skeletal Muscle FNDC5 and Peroxisome Proliferator-activated Receptor gamma Coactivator 1-alpha (PGC-1 alpha) during Exercise SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Exercise; Obesity; Skeletal Muscle; SMAD Transcription Factor; Transforming Growth Factor Beta (TGF-B); Irisin ID BROWN ADIPOSE-TISSUE; TGF-BETA; TRANSCRIPTION FACTORS; TARGETED DISRUPTION; SIGNAL-TRANSDUCTION; INSULIN-RESISTANCE; AEROBIC EXERCISE; WHITE FAT; IN-VIVO; OBESITY AB Background: Mothers against decapentaplegic homolog 3 (SMAD3) and FNDC5/irisin are molecules that modulate energy metabolism and body weight regulation. Results: SMAD3 negatively regulates irisin during exercise and suppresses FNDC5 and PGC-1 in cultured skeletal muscle cells. Conclusion: SMAD3 suppresses irisin/FNDC5 in skeletal muscle. Significance: This study sheds light on the poorly understood regulation of irisin/FNDC5 in skeletal muscle. Beige adipose cells are a distinct and inducible type of thermogenic fat cell that express the mitochondrial uncoupling protein-1 and thus represent a powerful target for treating obesity. Mice lacking the TGF- effector protein SMAD3 are protected against diet-induced obesity because of browning of their white adipose tissue (WAT), leading to increased whole body energy expenditure. However, the role SMAD3 plays in WAT browning is not clearly understood. Irisin is an exercise-induced skeletal muscle hormone that induces WAT browning similar to that observed in SMAD3-deficient mice. Together, these observations suggested that SMAD3 may negatively regulate irisin production and/or secretion from skeletal muscle. To address this question, we used wild-type and SMAD3 knock-out (Smad3(-/-)) mice subjected to an exercise regime and C2C12 myotubes treated with TGF-, a TGF- receptor 1 pharmacological inhibitor, adenovirus expressing constitutively active SMAD3, or siRNA against SMAD3. We find that in Smad3(-/-) mice, exercise increases serum irisin and skeletal muscle FNDC5 (irisin precursor) and its upstream activator peroxisome proliferator-activated receptor coactivator 1- (PGC-1) to a greater extent than in wild-type mice. In C2C12 myotubes, TGF- suppresses FNDC5 and PGC-1 mRNA and protein levels via SMAD3 and promotes SMAD3 binding to the FNDC5 and PGC-1 promoters. These data establish that SMAD3 suppresses FNDC5 and PGC-1 in skeletal muscle cells. These findings shed light on the poorly understood regulation of irisin/FNDC5 by demonstrating a novel association between irisin and SMAD3 signaling in skeletal muscle. C1 [Tiano, Joseph P.; Rane, Sushil G.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Springer, Danielle A.] NHLBI, Murine Phenotyping Core, NIH, Bethesda, MD 20892 USA. RP Rane, SG (reprint author), NIDDK, Cell Growth & Metab Sect, Diabet Endocrinol & Obes Branch, NIH,Clin Res Ctr, West Labs 5-5940,10 Ctr Dr, Bethesda, MD 20892 USA. EM ranes@niddk.nih.gov FU National Institutes of Health intramural program FX This work was supported, in whole or in part, by the National Institutes of Health intramural program. NR 66 TC 9 Z9 10 U1 2 U2 11 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 MAR 20 PY 2015 VL 290 IS 12 BP 7671 EP 7684 DI 10.1074/jbc.M114.617399 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CE2AC UT WOS:000351613600029 PM 25648888 ER PT J AU Li, CW Bazzano, LAL Rao, DC Hixson, JE He, J Gu, DF Gu, CC Shimmin, LC Jaquish, CE Schwander, K Liu, DP Huang, JF Lu, FH Cao, J Chong, S Lu, XF Kelly, TN AF Li, Changwei Bazzano, Lydia A. L. Rao, Dabeeru C. Hixson, James E. He, Jiang Gu, Dongfeng Gu, Charles C. Shimmin, Lawrence C. Jaquish, Cashell E. Schwander, Karen Liu, De-Pei Huang, Jianfeng Lu, Fanghong Cao, Jie Chong, Shen Lu, Xiangfeng Kelly, Tanika N. TI Genome-Wide Linkage and Positional Association Analyses Identify Associations of Novel AFF3 and NTM Genes with Triglycerides: The GenSalt Study SO JOURNAL OF GENETICS AND GENOMICS LA English DT Article DE Lipids; Linkage analysis; Positional association analysis; Gene-based analysis ID ACETYLCHOLINE-RECEPTOR GENES; ACUTE LYMPHOBLASTIC-LEUKEMIA; CORONARY-ARTERY-DISEASE; SUSCEPTIBILITY LOCI; AMERICAN-INDIANS; FAMILY ANALYSIS; LIPID-LEVELS; RISK; POPULATION; VARIANTS AB We conducted a genome-wide linkage scan and positional association study to identify genes and variants influencing blood lipid levels among participants of the Genetic Epidemiology Network of Salt-Sensitivity (GenSalt) study. The GenSalt study was conducted among 1906 participants from 633 Han Chinese families. Lipids were measured from overnight fasting blood samples using standard methods. Multipoint quantitative trait genome-wide linkage scans were performed on the high-density lipoprotein, low-density lipoprotein, and log-transformed triglyceride phenotypes. Using dense panels of single nucleotide polymorphisms (SNPs), single-marker and gene-based association analyses were conducted to follow-up on promising linkage signals. Additive associations between each SNP and lipid phenotypes were tested using mixed linear regression models. Gene-based analyses were performed by combining P-values from single-marker analyses within each gene using the truncated product method (TPM). Significant associations were assessed for replication among 777 Asian participants of the Multi-ethnic Study of Atherosclerosis (MESA). Bonferroni correction was used to adjust for multiple testing. In the GenSalt study, suggestive linkage signals were identified at 2p11.2-2q12.1 [maximum multipoint LOD score (MML) = 2.18 at 2q11.2] and 11q24.3-11q25 (MML = 2.29 at 11q25) for the log-transformed triglyceride phenotype. Follow-up analyses of these two regions revealed gene-based associations of charged multivesicular body protein 3 (CHMP3), ring finger protein 103 (RNF103), AF4/FMR2 family, member 3 (AFF3), and neurotrimin (NTM) with triglycerides (P = 4 x 10(-4), 1.00 x 10(-5), 2.00 x 10(-5), and 1.00 x 10(-7), respectively). Both the AFF3 and NTM triglyceride associations were replicated among MESA study participants (P = 1.00 x 10(-7) and 8.00 x 10(-5), respectively). Furthermore, NTM explained the linkage signal on chromosome 11. In conclusion, we identified novel genes associated with lipid phenotypes in linkage regions on chromosomes 2 and 11. C1 [Li, Changwei; Bazzano, Lydia A. L.; He, Jiang; Kelly, Tanika N.] Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA 70112 USA. [Bazzano, Lydia A. L.; He, Jiang] Tulane Univ, Sch Med, Dept Med, New Orleans, LA 70112 USA. [Rao, Dabeeru C.; Gu, Charles C.; Schwander, Karen] Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA. [Hixson, James E.; Shimmin, Lawrence C.] Univ Texas Houston, Sch Publ Hlth, Dept Epidemiol Human Genet & Environm Sci, Houston, TX 77030 USA. [Gu, Dongfeng; Huang, Jianfeng; Cao, Jie; Lu, Xiangfeng] Chinese Acad Med Sci, Fuwai Hosp, Natl Ctr Cardiovasc Dis, State Key Lab Cardiovasc Dis, Beijing 100037, Peoples R China. [Gu, Dongfeng; Huang, Jianfeng; Cao, Jie; Lu, Xiangfeng] Peking Union Med Coll, Beijing 100037, Peoples R China. [Jaquish, Cashell E.] NHLBI, Div Prevent & Populat Sci, Bethesda, MD 20892 USA. [Liu, De-Pei] Chinese Acad Med Sci, Inst Basic Med Sci, Natl Lab Med Mol Biol, Beijing 100730, Peoples R China. [Liu, De-Pei] Peking Union Med Coll, Beijing 100730, Peoples R China. [Lu, Fanghong] Shandong Acad Med Sci, Inst Basic Med, Jinan 250062, Peoples R China. [Chong, Shen] Nanjing Med Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Nanjing 210029, Jiangsu, Peoples R China. RP Kelly, TN (reprint author), Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA 70112 USA. EM tkelly@tulane.edu RI Li, Changwei/S-5615-2016 OI Li, Changwei/0000-0002-9203-304X FU National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health, Bethesda, MD [U01HL072507, R01HL087263, R01HL090682]; NHLBI [K08HL091108, N02-HL-64278]; CTSA [UL1-RR-024156]; [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] FX The GenSalt is supported by a cooperative agreement project grant (Nos. U01HL072507, R01HL087263, and R01HL090682) from the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health, Bethesda, MD. Dr. Bazzano was supported by a career development award (No. K08HL091108) from NHLBI. MESA and the MESA SHARe project were conducted and supported by NHLBI in collaboration with MESA investigators. Support for MESA is provided by contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169 and CTSA UL1-RR-024156. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, California, USA) and the Broad Institute of Harvard and MIT (Boston, Massachusetts, USA) using the Affymetric Genome-Wide Human SNP Array 6.0. NR 53 TC 2 Z9 2 U1 0 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 MAR 20 PY 2015 VL 42 IS 3 BP 107 EP 117 DI 10.1016/j.jgg.2015.02.003 PG 11 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA CE5GD UT WOS:000351858300003 PM 25819087 ER PT J AU Lonnrot, M Lynch, K Larsson, HE Lernmark, A Rewers, M Hagopian, W She, JX Simell, O Ziegler, AG Akolkar, B Krischer, J Hyoty, H AF Lonnrot, Maria Lynch, Kristian Larsson, Helena Elding Lernmark, Ake Rewers, Marian Hagopian, William She, Jin-Xiong Simell, Olli Ziegler, Anette-G Akolkar, Beena Krischer, Jeffrey Hyoty, Heikki CA TEDDY Study Grp TI A method for reporting and classifying acute infectious diseases in a prospective study of young children: TEDDY SO BMC PEDIATRICS LA English DT Article DE Childhood infections; Prospective study; Type 1 diabetes ID RESPIRATORY-TRACT INFECTIONS; OUTCOMES AB Background: Early childhood environmental exposures, possibly infections, may be responsible for triggering islet autoimmunity and progression to type 1 diabetes (T1D). The Environmental Determinants of Diabetes in the Young (TEDDY) follows children with increased HLA-related genetic risk for future T1D. TEDDY asks parents to prospectively record the child's infections using a diary book. The present paper shows how these large amounts of partially structured data were reduced into quantitative data-sets and further categorized into system-specific infectious disease episodes. The numbers and frequencies of acute infections and infectious episodes are shown. Methods: Study subjects (n = 3463) included children who had attended study visits every three months from age 3 months to 4 years, without missing two or more consecutive visits during the follow-up. Parents recorded illnesses prospectively in a TEDDY Book at home. The data were entered into the study database during study visits using ICD-10 codes by a research nurse. TEDDY investigators grouped ICD-10 codes and fever reports into infectious disease entities and further arranged them into four main categories of infectious episodes: respiratory, gastrointestinal, other, and unknown febrile episodes. Incidence rate of infections was modeled as function of gender, HLA-DQ genetic risk group and study center using the Poisson regression. Results: A total of 113,884 ICD-10 code reports for infectious diseases recorded in the database were reduced to 71,578 infectious episodes, including 74.0% respiratory, 13.1% gastrointestinal, 5.7% other infectious episodes and 7.2% febrile episodes. Respiratory and gastrointestinal infectious episodes were more frequent during winter. Infectious episode rates peaked at 6 months and began declining after 18 months of age. The overall infectious episode rate was 5.2 episodes per person-year and varied significantly by country of residence, sex and HLA genotype. Conclusions: The data reduction and categorization process developed by TEDDY enables analysis of single infectious agents as well as larger arrays of infectious agents or clinical disease entities. The preliminary descriptive analyses of the incidence of infections among TEDDY participants younger than 4 years fits well with general knowledge of infectious disease epidemiology. This protocol can be used as a template in forthcoming time-dependent TEDDY analyses and in other epidemiological studies. C1 [Lonnrot, Maria; Hyoty, Heikki] Univ Tampere, FIN-33101 Tampere, Finland. [Lonnrot, Maria] Seinajoki Cent Hosp, Seinajoki, Finland. [Lynch, Kristian; Krischer, Jeffrey] Univ S Florida, Tampa, FL USA. [Larsson, Helena Elding; Lernmark, Ake] Lund Univ, Malmo, Sweden. [Rewers, Marian] Barbara Davis Ctr Childhood Diabet, Denver, CO USA. [Hagopian, William] Pacific Northwest Diabet Res Inst, Seattle, WA USA. [She, Jin-Xiong] Georgia Regents Univ, Augusta, GA USA. [Simell, Olli] Univ Turku, Turku, Finland. [Ziegler, Anette-G] Helmholtz Zentrum Munchen, Diabet Res Inst, Neuherberg, Germany. [Ziegler, Anette-G] Tech Univ Munich, Klinikum Rechts Isar, Neuherberg, Germany. [Ziegler, Anette-G] Forschergrp Diabet eV, Neuherberg, Germany. [Akolkar, Beena] NIH, Bethesda, MD 20892 USA. [Hyoty, Heikki] Pirkanmaa Hosp Dist, Fimlab Labs, Tampere, Finland. RP Lonnrot, M (reprint author), Univ Tampere, FIN-33101 Tampere, Finland. EM maria.lonnrot@uta.fi RI Ziegler, Anette-Gabriele/M-4614-2014; Bonifacio, Ezio/E-7700-2010 OI Ziegler, Anette-Gabriele/0000-0002-6290-5548; Bonifacio, Ezio/0000-0002-8704-4713 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [U01 DK63829, U01 DK63861, U01 DK63821, U01 DK63865, U01 DK63863, U01 DK63836, U01 DK63790, UC4 DK63829, UC4 DK63861, UC4 DK63821, UC4 DK63865, UC4 DK63863, UC4 DK63836, UC4 DK95300, HHSN267200700014C]; National Institute of Allergy and Infectious Diseases (NIAID); National Institute of Child Health and Human Development (NICHD); National Institute of Environmental Health Sciences (NIEHS); Juvenile Diabetes Research Foundation (JDRF); Centers for Disease Control and Prevention (CDC) FX Funded by U01 DK63829, U01 DK63861, U01 DK63821, U01 DK63865, U01 DK63863, U01 DK63836, U01 DK63790, UC4 DK63829, UC4 DK63861, UC4 DK63821, UC4 DK63865, UC4 DK63863, UC4 DK63836, and UC4 DK95300 and Contract No. HHSN267200700014C from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Child Health and Human Development (NICHD), National Institute of Environmental Health Sciences (NIEHS), Juvenile Diabetes Research Foundation (JDRF), and Centers for Disease Control and Prevention (CDC). NR 18 TC 2 Z9 2 U1 1 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2431 J9 BMC PEDIATR JI BMC Pediatr. PD MAR 20 PY 2015 VL 15 AR 24 DI 10.1186/s12887-015-0333-8 PG 10 WC Pediatrics SC Pediatrics GA CE3KF UT WOS:000351724500001 PM 25884839 ER PT J AU Huang, XF Barchi, JJ AF Huang, Xuefei Barchi, Joseph J., Jr. TI Preface SO CARBOHYDRATE RESEARCH LA English DT Editorial Material C1 [Huang, Xuefei] Michigan State Univ, E Lansing, MI 48824 USA. [Barchi, Joseph J., Jr.] Natl Canc Inst, Rockville, MD USA. RP Huang, XF (reprint author), Michigan State Univ, E Lansing, MI 48824 USA. RI Huang, Xuefei/G-3371-2014; OI Huang, Xuefei/0000-0002-6468-5526 NR 0 TC 1 Z9 1 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0008-6215 EI 1873-426X J9 CARBOHYD RES JI Carbohydr. Res. PD MAR 20 PY 2015 VL 405 BP 1 EP 1 DI 10.1016/j.carres.2014.12.008 PG 1 WC Biochemistry & Molecular Biology; Chemistry, Applied; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA CD0GJ UT WOS:000350748400001 PM 25605502 ER PT J AU Biswas, S Medina, SH Barchi, JJ AF Biswas, Souvik Medina, Scott H. Barchi, Joseph J., Jr. TI Synthesis and cell-selective antitumor properties of amino acid conjugated tumor-associated carbohydrate antigen-coated gold nanoparticles SO CARBOHYDRATE RESEARCH LA English DT Article DE Thomsen Friedenreich; Tumor-associated carbohydrate antigens; Gold nanoparticles; Galectin-3; Cytotoxicity ID THOMSEN-FRIEDENREICH DISACCHARIDE; PHASE PEPTIDE-SYNTHESIS; O-LINKED GLYCOSYLATION; GROWTH-FACTOR RECEPTOR; BREAST-CANCER CELLS; PANCREATIC-CANCER; PROSTATE-CANCER; CARCINOMA CELLS; MUCIN-TYPE; IN-VITRO AB The Thomsen Friedenreich antigen (TFag) disaccharide is a tumor-associated carbohydrate antigen (TACA) found primarily on carcinoma cells and rarely expressed in normal tissue. The TFag has been shown to interact with Galectin-3 (Gal-3), one in a family of beta-galactoside binding proteins. Galectins have a variety of cellular functions, and Gal-3 has been shown to be the sole galectin with anti-apoptotic activity. We have previously prepared gold nanoparticles (AuNP) coated with the TFag in various presentations as potential anti-adhesive therapeutic tools or antitumor vaccine platforms. Here we describe the synthesis of TFag-glycoamino acid conjugates attached to gold nanoparticles through a combined alkane/PEG linker, where the TFag was attached to either a serine or threonine amino acid. Particles were fully characterized by a host of biophysical techniques, and along with a control particle carrying hydroxyl-terminated linker units, were evaluated in both Gal-3 positive and negative cell lines. We show that the particles bearing the saccharides selectively inhibited tumor cell growth of the Gal-3 positive cells significantly more than the Gal-3 negative cells. In addition, the threonine-attached TF particles were more potent than the serine-attached constructs. These results support the use of AuNP as antitumor therapeutic platforms, targeted against cell lines that express specific lectins that interact with TFag. Published by Elsevier Ltd. C1 [Biswas, Souvik; Medina, Scott H.; Barchi, Joseph J., Jr.] NCI, Ctr Canc Res, Biol Chem Lab, Frederick, MD 21702 USA. RP Barchi, JJ (reprint author), NCI, Ctr Canc Res, Biol Chem Lab, Frederick, MD 21702 USA. EM barchij@mail.nih.gov FU Intramural Program of the National Cancer Institute, Frederick, MD of the National Institutes of Health FX The authors would like to thank the Dr. Kunio Nagashima and Ulrich Baxa of the Electron Microscopy laboratory of Leidos Biomedical Inc. for help with the TEM data, Dr. Anu Puri and Mr. Kshitij Gupta for help with acquiring DLS and zeta potential data and Jared Orwenyo and Lai-Xi Wang of the University of Maryland, Baltimore for help with the carbohydrate analysis of our particles. Funding for this work was supplied by The Intramural Program of the National Cancer Institute, Frederick, MD of the National Institutes of Health. NR 88 TC 10 Z9 10 U1 4 U2 30 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0008-6215 EI 1873-426X J9 CARBOHYD RES JI Carbohydr. Res. PD MAR 20 PY 2015 VL 405 BP 93 EP 101 DI 10.1016/j.carres.2014.11.002 PG 9 WC Biochemistry & Molecular Biology; Chemistry, Applied; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA CD0GJ UT WOS:000350748400013 PM 25556664 ER PT J AU Tse, ZTH Xu, S Fung, ICH Wood, BJ AF Tse, Zion Tsz Ho Xu, Sheng Fung, Isaac Chun-Hai Wood, Bradford J. TI Cyber-attack risk low for medical devices SO SCIENCE LA English DT Letter C1 [Tse, Zion Tsz Ho] Univ Georgia, Coll Engn, Athens, GA 30602 USA. [Xu, Sheng; Wood, Bradford J.] NIH, Ctr Intervent Oncol, Bethesda, MD 20892 USA. [Fung, Isaac Chun-Hai] Georgia So Univ, Dept Epidemiol, Jiann Ping Hsu Coll Publ Hlth, Statesboro, GA 30460 USA. RP Tse, ZTH (reprint author), Univ Georgia, Coll Engn, Athens, GA 30602 USA. EM ziontse@uga.edu OI Fung, Isaac Chun-Hai/0000-0001-5496-2529 NR 5 TC 0 Z9 0 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 MAR 20 PY 2015 VL 347 IS 6228 BP 1323 EP 1324 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CD6SM UT WOS:000351219600029 PM 25792321 ER PT J AU Samanovic, MI Tu, SJ Novak, O Iyer, LM McAllister, FE Aravind, L Gygi, SP Hubbard, SR Strnad, M Darwin, KH AF Samanovic, Marie I. Tu, Shengjiang Novak, Ondrej Iyer, Lakshminarayan M. McAllister, Fiona E. Aravind, L. Gygi, Steven P. Hubbard, Stevan R. Strnad, Miroslav Darwin, K. Heran TI Proteasomal Control of Cytokinin Synthesis Protects Mycobacterium tuberculosis against Nitric Oxide SO MOLECULAR CELL LA English DT Article ID TANDEM MASS-SPECTROMETRY; IDENTIFICATION; BIOSYNTHESIS; PUP; PUPYLATION; RESISTANCE; INHIBITORS; PROTEOME; SYNTHASE; PLATFORM AB One of several roles of the Mycobacterium tuberculosis proteasome is to defend against host-produced nitric oxide (NO), a free radical that can damage numerous biological macromolecules. Mutations that inactivate proteasomal degradation in Mycobacterium tuberculosis result in bacteria that are hypersensitive to NO and attenuated for growth in vivo, but it was not known why. To elucidate the link between proteasome function, NO resistance, and pathogenesis, we screened for suppressors of NO hypersensitivity in a mycobacterial proteasome ATPase mutant and identified mutations in Rv1205. We determined that Rv1205 encodes a pupylated proteasome substrate. Rv1205 is a homolog of the plant enzyme LONELY GUY, which catalyzes the production of hormones called cytokinins. Remarkably, we report that an obligate human pathogen secretes several cytokinins. Finally, we determined that the Rv1205-dependent accumulation of cytokinin breakdown products is likely responsible for the sensitization of Mycobacterium tuberculosis proteasome-associated mutants to NO. C1 [Samanovic, Marie I.; Darwin, K. Heran] NYU, Sch Med, Dept Microbiol, New York, NY 10016 USA. [Tu, Shengjiang] NYU, Sch Med, Dept Biochem & Mol Pharmacol, Howard Hughes Med Inst, New York, NY 10016 USA. [Novak, Ondrej; Strnad, Miroslav] Palacky Univ, Ctr Reg Hana Biotechnol & Agr Res, Dept Metabol, Olomouc 78371, Czech Republic. [Novak, Ondrej; Strnad, Miroslav] Inst Expt Bot AS CR, Lab Growth Regulators, Olomouc 78371, Czech Republic. [Iyer, Lakshminarayan M.; Aravind, L.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [McAllister, Fiona E.; Gygi, Steven P.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Hubbard, Stevan R.] NYU, Sch Med, Dept Biochem & Mol Pharmacol, Skirball Inst, New York, NY 10016 USA. RP Darwin, KH (reprint author), NYU, Sch Med, Dept Microbiol, New York, NY 10016 USA. EM heran.darwin@med.nyu.edu RI Novak, Ondrej/F-7031-2014; OI Novak, Ondrej/0000-0003-3452-0154; Hubbard, Stevan/0000-0002-2707-9383 FU NIH [R01HL092774]; Jan T. Vilcek Endowed Fellowship fund; Intramural Research Program of the National Library of Medicine (NIH); Ministry of Education, Youth and Sport of the Czech Republic from the National Program of Sustainability I [LO1204]; Internal Grant Agency of Palacky University [IGA_PrF_2015_021]; Burroughs Wellcome Fund FX We are grateful to A. Darwin and C. Nathan for review of draft versions of this manuscript and to V. DiRita, I. Mohr, T. Richardson, and V. Torres for helpful suggestions. We thank D. Reinberg for generous support, W. Houry for E. coli LDC andadvice, H. Li for purified PafA, S. Ehrt for the Delta prcBA::hygmutant, B. Bennett and S. Butler-Wufor cloning assistance, J. McKinney for pMV306.Strep, H. Martinkova and B. Parizkova for technical assistance in cytokinin detection, K. Rhee for metabolomics advice, R. Michalek at Metabolon for outstanding data analysis, and the Rockefeller Proteomics Resource Center for use of their facilities. We are eternally grateful to Charlie Rice and The Rockefeller University for providing laboratory space and support for the 15 months after Superstorm Sandy. This work was supported by NIH grant R01HL092774 (awarded to K. H. D.) and the Jan T. Vilcek Endowed Fellowship fund (awarded to M.I.S.). L.A. and L.M.I. are funded by the Intramural Research Program of the National Library of Medicine (NIH). For O.N. and M.S., work is supported by the Ministry of Education, Youth and Sport of the Czech Republic (grant LO1204 from the National Program of Sustainability I) and the Internal Grant Agency of Palacky University (IGA_PrF_2015_021). K. H. D holds an Investigators in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund. NR 54 TC 13 Z9 13 U1 2 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 MAR 19 PY 2015 VL 57 IS 6 BP 984 EP 994 DI 10.1016/j.molcel.2015.01.024 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CE3GP UT WOS:000351715000007 PM 25728768 ER PT J AU Dambach, M Sandoval, M Updegrove, TB Anantharaman, V Aravind, L Waters, LS Storz, G AF Dambach, Michael Sandoval, Melissa Updegrove, Taylor B. Anantharaman, Vivek Aravind, L. Waters, Lauren S. Storz, Gisela TI The Ubiquitous yybP-ykoY Riboswitch Is a Manganese-Responsive Regulatory Element SO MOLECULAR CELL LA English DT Article ID ENTERICA SEROVAR TYPHIMURIUM; ESCHERICHIA-COLI; TRANSCRIPTIONAL REGULATION; COMPARATIVE GENOMICS; BACILLUS-SUBTILIS; GENE-EXPRESSION; RNA ELEMENT; BINDING; BACTERIA; SALMONELLA AB The highly structured, cis-encoded RNA elements known as riboswitches modify gene expression upon binding a wide range of molecules. The yybP-ykoY motif was one of the most broadly distributed and numerous bacterial riboswitches for which the cognate ligand was unknown. Using a combination of in vivo reporter and in vitro expression assays, equilibrium dialysis, and northern analysis, we show that the yybP-ykoY motif responds directly to manganese ions in both Escherichia coli and Bacillus subtilis. The identification of the yybP-ykoY motif as a manganese ion sensor suggests that the genes that are preceded by this motif and encode a diverse set of poorly characterized membrane proteins have roles in metal homeostasis. C1 [Dambach, Michael; Sandoval, Melissa; Updegrove, Taylor B.; Waters, Lauren S.; Storz, Gisela] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, Bethesda, MD 20892 USA. [Waters, Lauren S.] Univ Wisconsin, Dept Chem, Oshkosh, WI 54901 USA. [Anantharaman, Vivek; Aravind, L.] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Waters, LS (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, Bethesda, MD 20892 USA. EM watersl@uwosh.edu; storzg@mail.nih.gov OI Storz, Gisela/0000-0001-6698-1241; Anantharaman, Vivek/0000-0001-8395-0009 FU Intramural Research Programs of the Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Library of Medicine as well as the Pharmacology Research Associate Program; NIH Undergraduate Scholarship Program FX We thank S. Altuvia, N. Baird, A. Banerjee, C. Beisel, A. Ferre-d'Amare, S. Gottesman, J. Imlay, B. Rosen, W. Winkler, and J. Zhang for helpful discussions and D.-Y. Lee for the atomic absorbance analysis. This work was supported by the Intramural Research Programs of the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Library of Medicine as well as the Pharmacology Research Associate Program (to L.S.W.) and the NIH Undergraduate Scholarship Program (to M.S.). NR 43 TC 16 Z9 16 U1 1 U2 11 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 MAR 19 PY 2015 VL 57 IS 6 BP 1099 EP 1109 DI 10.1016/j.molcel.2015.01.035 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CE3GP UT WOS:000351715000016 PM 25794618 ER PT J AU Fredriksson, K Van Itallie, CM Aponte, A Gucek, M Tietgens, AJ Anderson, JM AF Fredriksson, Karin Van Itallie, Christina M. Aponte, Angel Gucek, Marjan Tietgens, Amber J. Anderson, James M. TI Proteomic Analysis of Proteins Surrounding Occludin and Claudin-4 Reveals Their Proximity to Signaling and Trafficking Networks SO PLOS ONE LA English DT Article ID TIGHT JUNCTION PROTEIN; CANINE KIDNEY-CELLS; ADHESION MOLECULE; EPITHELIAL-CELLS; INTERCELLULAR-JUNCTIONS; REGULATED EXPRESSION; ACTIN CYTOSKELETON; MEMBRANE-PROTEIN; IMMUNOGLOBULIN SUPERFAMILY; PARACELLULAR PERMEABILITY AB Tight junctions are complex membrane structures that regulate paracellular movement of material across epithelia and play a role in cell polarity, signaling and cytoskeletal organization. In order to expand knowledge of the tight junction proteome, we used biotin ligase (BioID) fused to occludin and claudin-4 to biotinylate their proximal proteins in cultured MDCK II epithelial cells. We then purified the biotinylated proteins on streptavidin resin and identified them by mass spectrometry. Proteins were ranked by relative abundance of recovery by mass spectrometry, placed in functional categories, and compared not only among the N- and C-termini of occludin and the N-terminus of claudin-4, but also with our published inventory of proteins proximal to the adherens junction protein E-cadherin and the tight junction protein ZO-1. When proteomic results were analyzed, the relative distribution among functional categories was similar between occludin and claudin-4 proximal proteins. Apart from already known tight junction-proteins, occludin and claudin-4 proximal proteins were enriched in signaling and trafficking proteins, especially endocytic trafficking proteins. However there were significant differences in the specific proteins comprising the functional categories near each of the tagging proteins, revealing spatial compartmentalization within the junction complex. Taken together, these results expand the inventory of known and unknown proteins at the tight junction to inform future studies of the organization and physiology of this complex structure. C1 [Fredriksson, Karin; Van Itallie, Christina M.; Tietgens, Amber J.; Anderson, James M.] NHLBI, Lab Tight Junct Struct & Funct, NIH, Bethesda, MD 20892 USA. [Aponte, Angel; Gucek, Marjan] NHLBI, Prote Core Facil, NIH, Bethesda, MD 20892 USA. RP Fredriksson, K (reprint author), NHLBI, Lab Tight Junct Struct & Funct, NIH, Bldg 10, Bethesda, MD 20892 USA. EM fredrikssonk@nhlbi.nih.gov FU Intramural Program of the National Institutes of Health FX This study was funded by the Intramural Program of the National Institutes of Health to JMA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 123 TC 13 Z9 13 U1 1 U2 9 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 MAR 19 PY 2015 VL 10 IS 3 AR e0117074 DI 10.1371/journal.pone.0117074 PG 35 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CD9NQ UT WOS:000351425400022 PM 25789658 ER PT J AU Kocarnik, JM Park, SL Han, JL Dumitrescu, L Cheng, IN Wilkens, LR Schumacher, FR Kolonel, L Carlson, CS Crawford, DC Goodloe, RJ Dilks, HH Baker, P Richardson, D Matise, TC Ambite, JL Song, FJ Qureshi, AA Zhang, MF Duggan, D Hutter, C Hindorff, L Bush, WS Kooperberg, C Le Marchand, L Peters, U AF Kocarnik, Jonathan M. Park, S. Lani Han, Jiali Dumitrescu, Logan Cheng, Iona Wilkens, Lynne R. Schumacher, Fredrick R. Kolonel, Laurence Carlson, Chris S. Crawford, Dana C. Goodloe, Robert J. Dilks, Holli H. Baker, Paxton Richardson, Danielle Matise, Tara C. Ambite, Jose Luis Song, Fengju Qureshi, Abrar A. Zhang, Mingfeng Duggan, David Hutter, Carolyn Hindorff, Lucia Bush, William S. Kooperberg, Charles Le Marchand, Loic Peters, Ulrike TI Pleiotropic and Sex-Specific Effects of Cancer GWAS SNPs on Melanoma Risk in the Population Architecture Using Genomics and Epidemiology (PAGE) Study SO PLOS ONE LA English DT Article ID BASAL-CELL CARCINOMA; WIDE ASSOCIATION; PROSTATE-CANCER; SUSCEPTIBILITY LOCI; NURSES HEALTH; VARIANTS; PIGMENTATION; METAANALYSIS; GENETICS; 5P15.33 AB Background Several regions of the genome show pleiotropic associations with multiple cancers. We sought to evaluate whether 181 single-nucleotide polymorphisms previously associated with various cancers in genome-wide association studies were also associated with melanoma risk. Methods We evaluated 2,131 melanoma cases and 20,353 controls from three studies in the Population Architecture using Genomics and Epidemiology (PAGE) study (EAGLE-BioVU, MEC, WHI) and two collaborating studies (HPFS, NHS). Overall and sex-stratified analyses were performed across studies. Results We observed statistically significant associations with melanoma for two lung cancer SNPs in the TERT-CLPTM1L locus (Bonferroni-corrected p<2.8x10(-4)), replicating known pleiotropic effects at this locus. In sex-stratified analyses, we also observed a potential male-specific association between prostate cancer risk variant rs12418451 and melanoma risk (OR=1.22, p=8.0x10(-4)). No other variants in our study were associated with melanoma after multiple comparisons adjustment (p>2.8e(-4)). Conclusions We provide confirmatory evidence of pleiotropic associations with melanoma for two SNPs previously associated with lung cancer, and provide suggestive evidence for a male-specific association with melanoma for prostate cancer variant rs12418451. This SNP is located near TPCN2, an ion transport gene containing SNPs which have been previously associated with hair pigmentation but not melanoma risk. Previous evidence provides biological plausibility for this association, and suggests a complex interplay between ion transport, pigmentation, and melanoma risk that may vary by sex. If confirmed, these pleiotropic relationships may help elucidate shared molecular pathways between cancers and related phenotypes. C1 [Kocarnik, Jonathan M.; Carlson, Chris S.; Kooperberg, Charles; Peters, Ulrike] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Park, S. Lani; Schumacher, Fredrick R.] Univ So Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Dept Prevent Med, Los Angeles, CA 90033 USA. [Han, Jiali] Indiana Univ, Melvin & Bren Simon Canc Ctr, Richard M Fairbanks Sch Publ Hlth, Dept Epidemiol, Indianapolis, IN 46204 USA. [Dumitrescu, Logan; Goodloe, Robert J.; Dilks, Holli H.; Baker, Paxton; Richardson, Danielle; Bush, William S.] Vanderbilt Univ, Ctr Human Genet Res, Nashville, TN 37235 USA. [Dumitrescu, Logan] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. [Cheng, Iona] Canc Prevent Inst Calif, Fremont, CA USA. [Wilkens, Lynne R.; Kolonel, Laurence; Le Marchand, Loic] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96822 USA. [Crawford, Dana C.] Case Western Reserve Univ, Dept Epidemiol, Cleveland, OH 44106 USA. [Crawford, Dana C.] Case Western Reserve Univ, Biosta Inst Computat Biol, Cleveland, OH 44106 USA. [Matise, Tara C.] Rutgers State Univ, Dept Genet, Piscataway, NJ USA. [Ambite, Jose Luis] Univ So Calif, Inst Informat Sci, Marina Del Rey, CA 90292 USA. [Song, Fengju] Tianjin Med Univ, Canc Inst & Hosp, Dept Epidemiol, Tianjin, Peoples R China. [Song, Fengju] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Channing Lab, Boston, MA 02115 USA. [Qureshi, Abrar A.; Zhang, Mingfeng] Brigham & Womens Hosp, Dept Dermatol, Boston, MA 02115 USA. [Duggan, David] Translat Genom Res Inst, Phoenix, AZ USA. [Hutter, Carolyn] NCI, Epidemiol & Genom Res Program, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Hindorff, Lucia] NHGRI, Div Genom Med, NIH, Bethesda, MD 20892 USA. [Bush, William S.] Vanderbilt Univ, Dept Biomed Informat, Nashville, TN 37235 USA. RP Kocarnik, JM (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. EM jkocarni@fhcrc.org OI Bush, William/0000-0002-9729-6519 FU National Human Genome Research Institute (NHGRI) [U01HG004803, U01HG004798, U01HG004802, U01HG004790, U01HG004801]; "Epidemiologic Architecture for Genes Linked to Environment (EAGLE)" through the NHGRI PAGE program [U01HG004798-01]; NCATS/NIH [UL1 TR000445]; Multiethnic Cohort study (MEC) [U01HG004802]; National Cancer Institute [R37CA54281, R01 CA63, P01CA33619, U01CA136792, U01CA98758]; "Epidemiology of putative genetic variants: The Women's Health Initiative" study is provided through the NHGRI PAGE program [U01HG004790]; National Heart, Lung, and Blood Institute; NIH; U.S. Department of Health and Human Services [N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221]; PAGE Coordinating Center [U01HG004801-01]; National Institutes of Mental Health; NCI [R25CA94880]; NIH [CA122838, CA87969, CA055075, CA49449, CA100264, CA093459] FX The Population Architecture Using Genomics and Epidemiology (PAGE) program is funded by the National Human Genome Research Institute (NHGRI), supported by U01HG004803 (CALiCo), U01HG004798 (EAGLE), U01HG004802 (MEC), U01HG004790 (WHI), and U01HG004801 (Coordinating Center), and their respective NHGRI ARRA supplements. The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. The complete list of PAGE members can be found at http://www.pagestudy.org. The data and materials included in this report results from collaboration between the following studies: The "Epidemiologic Architecture for Genes Linked to Environment (EAGLE)" is funded through the NHGRI PAGE program (U01HG004798-01 and its NHGRI ARRA supplement). The dataset(s) used for the analyses described were obtained from Vanderbilt University Medical; Center's BioVU which is supported by institutional funding and by the Vanderbilt CTSA grant UL1 TR000445 from NCATS/NIH. The Vanderbilt University Center for Human Genetics Research, Computational Genomics Core provided computational and/or analytical support for this work; The Multiethnic Cohort study (MEC) characterization of epidemiological architecture is funded through the NHGRI PAGE program (U01HG004802 and its NHGRI ARRA supplement). The MEC study is funded through the National Cancer Institute (R37CA54281, R01 CA63, P01CA33619, U01CA136792, and U01CA98758). Funding support for the "Epidemiology of putative genetic variants: The Women's Health Initiative" study is provided through the NHGRI PAGE program (U01HG004790 and its NHGRI ARRA supplement). The WHI program is funded by the National Heart, Lung, and Blood Institute; NIH; and U.S. Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. The authors thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators can be found at: http://www.whiscience.org/publications/WHI_investigators_ shortlist.pdf. Assistance with phenotype harmonization, SNP selection and annotation, data cleaning, data management, integration and dissemination, and general study coordination was provided by the PAGE Coordinating Center (U01HG004801-01 and its NHGRI ARRA supplement). The National Institutes of Mental Health also contributes to the support for the Coordinating Center. Author JMK was supported by grant R25CA94880 from NCI. The Nurses' Health Study and the Health Professionals Followup Study were funded by NIH grants CA122838, CA87969, CA055075, CA49449, CA100264, and CA093459. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 5 Z9 5 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 MAR 19 PY 2015 VL 10 IS 3 AR e0120491 DI 10.1371/journal.pone.0120491 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CD9NQ UT WOS:000351425400160 PM 25789475 ER PT J AU Xu, JH Chen, BB Callis, P Muino, PL Rozeboom, H Broos, J Toptygin, D Brand, L Knutson, JR AF Xu, Jianhua Chen, Binbin Callis, Patrik Muino, Pedro L. Rozeboom, Henriette Broos, Jaap Toptygin, Dmitri Brand, Ludwig Knutson, Jay R. TI Picosecond Fluorescence Dynamics of Tryptophan and 5-Fluorotryptophan in Monellin: Slow Water-Protein Relaxation Unmasked SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID NORMALIZED EMISSION-SPECTROSCOPY; TIME-RESOLVED FLUORESCENCE; STOKES SHIFT; HYDRATION DYNAMICS; ENERGY-TRANSFER; BIOSYNTHETIC INCORPORATION; FEMTOSECOND RESOLUTION; MOLECULAR-DYNAMICS; BIOLOGICAL WATER; SPECTRA AB Time dependent fluorescence Stokes (emission wavelength) shifts (TDFSS) from tryptophan (Trp) following sub-picosecond excitation are increasingly used to investigate protein dynamics, most recently enabling active research interest into water dynamics near the surface of proteins. Unlike many fluorescence probes, both the efficiency and the wavelength of Trp fluorescence in proteins are highly sensitive to microenvironment, and Stokes shifts can be dominated by the well-known heterogeneous nature of protein structure, leading to what we call pseudo-TDFSS: shifts that arise from differential decay rates of subpopulations. Here we emphasize a novel, general method that obviates pseudo-TDFSS by replacing Trp by 5-fluorotryptophan (5Ftrp), a fluorescent analogue with higher ionization potential and greatly suppressed electron-transfer quenching. 5FTrp slows and suppresses pseudo-TDFSS, thereby providing a clearer view of genuine relaxation caused by solvent and protein response. This procedure is applied to the sweet-tasting protein monellin which has uniquely been the subject of ultrafast studies in two different laboratories (Peon, J.; et al. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 10964; Xu, J.; et al. J. Am. Chem. Soc. 2006, 128, 1214) that led to disparate interpretations of a 20 ps transient. They differed because of the pseudo-TDFSS present. The current study exploiting special properties of 5FTrp strongly supports the conclusion that both lifetime heterogeneity-based TDFSS and environment relaxation-based TDFSS are present in monellin and 5FTrp-monellin. The original experiments on monellin were most likely dominated by pseudo-TDFSS, whereas, in the present investigation of 5FTrp-monellin, the TDFSS is dominated by relaxation and any residual pseudo-TDFSS is overwhelmed and/or slowed to irrelevance. C1 [Xu, Jianhua; Chen, Binbin; Knutson, Jay R.] NHLBI, Opt Spect Sect, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. [Callis, Patrik] Montana State Univ, Dept Chem & Biochem, Bozeman, MT 59717 USA. [Muino, Pedro L.] St Francis Univ, Dept Chem, Loretto, PA 15940 USA. [Rozeboom, Henriette; Broos, Jaap] Univ Groningen, Groningen Biomol Sci & Biotechnol Inst, Dept Biophys Chem, Groningen, Netherlands. [Toptygin, Dmitri; Brand, Ludwig] Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. RP Knutson, JR (reprint author), NHLBI, Opt Spect Sect, Lab Mol Biophys, NIH, Bldg 10, Bethesda, MD 20892 USA. EM knutsonj@helix.nih.gov FU NIH, NHLBI; National Science Foundation [OCI-1053575, MCB090176] FX This research was supported (in part) by the Intramural Research Program of the NIH, NHLBI. The MD + QM simulations were supported by the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by National Science Foundation Grant No. OCI-1053575 through Project No. MCB090176. We thank Dr. Temussi and Dr. Esposito for providing the plasmid containing the MENE1 gene. NR 69 TC 3 Z9 3 U1 4 U2 38 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 MAR 19 PY 2015 VL 119 IS 11 BP 4230 EP 4239 DI 10.1021/acs.jpcb.5b01651 PG 10 WC Chemistry, Physical SC Chemistry GA CE1FL UT WOS:000351557400008 PM 25710196 ER PT J AU Koren, G Clark, S Hankins, GDV Caritis, SN Umans, JG Miodovnik, M Mattison, DR Matok, I AF Koren, Gideon Clark, Shannon Hankins, Gary D. V. Caritis, Steve N. Umans, Jason G. Miodovnik, Menachem Mattison, Donald R. Matok, Ilan TI Maternal safety of the delayed-release doxylamine and pyridoxine combination for nausea and vomiting of pregnancy; a randomized placebo controlled trial SO BMC PREGNANCY AND CHILDBIRTH LA English DT Article DE Doxylamine; Pyridoxine; Nausea and vomiting of pregnancy; Diclegis; Safety; Toxicology ID BENDECTIN; DICLECTIN AB Background: Nausea and vomiting of pregnancy (NVP) is the most common medical condition in pregnancy, affecting up to 80% of expecting mothers. In April 2013 the FDA approved the delayed release combination of doxylamine succinate and -pyridoxine hydrochloride (Diclegis (R)) for NVP, following a phase 3 randomized trial in pregnant women. The fetal safety of this medication has been proven by numerous studies. However, because it is the only FDA-approved medication for NVP that is likely to be used by a large number of pregnant women, its maternal safety is an important public health question. The Objective is to evaluate the maternal safety of doxylamine succinate -pyridoxine hydrochloride delayed-release preparation (Diclegis (R) as compared to placebo. Methods: We randomized women suffering from NVP to receive Diclegis (R) (n = 131) or placebo (n = 125) for 14 days at doses ranging from 2-4 tablets a day, based on a pre-specified titration protocol response to symptoms. Adverse events were collected through patient diaries, clinical examination and laboratory testing. Results: Doxylamine succinate 10 mg and pyridoxine hydrochloride 10 mg use was not associated with an increased rate of any adverse event over placebo, including CNS depression, gastrointestinal or cardiovascular involvement. Conclusions: Doxylamine succinate-pyridoxine hydrochloride delayed release combination is safe and well tolerated by pregnant women when used in the recommended dose of up to 4 tablets daily in treating nausea and vomiting of pregnancy. C1 [Koren, Gideon; Matok, Ilan] Hosp Sick Children, Motherisk Program, Toronto, ON M5G 1X8, Canada. [Koren, Gideon; Matok, Ilan] Univ Toronto, Toronto, ON, Canada. [Clark, Shannon; Hankins, Gary D. V.] Univ Texas Med Branch, Dept Obstet & Gynecol, Galveston, TX 77555 USA. [Caritis, Steve N.] Univ Pittsburgh, Med Ctr, Dept Obstet & Gynecol, Pittsburgh, PA USA. [Umans, Jason G.; Miodovnik, Menachem] Medstar Hlth Res Inst, Hyattsville, MD USA. [Umans, Jason G.; Miodovnik, Menachem] Georgetown Howard Univ, Ctr Clin & Translat Sci, Washington, DC USA. [Koren, Gideon; Clark, Shannon; Hankins, Gary D. V.; Caritis, Steve N.; Umans, Jason G.; Miodovnik, Menachem; Mattison, Donald R.] Eunice Kennedy Shriver, Natl Inst Child & Human Dev, Obstetr Pharmacol Res Unit Network, Bethesda, MD USA. [Matok, Ilan] Hebrew Univ Jerusalem, Fac Med, Sch Pharm, Inst Drug Res,Div Clin Pharm, Jerusalem, Israel. [Koren, Gideon] Hosp Sick Children, Div Clin Pharmacol Toxicol, Toronto, ON M5G 1X8, Canada. RP Koren, G (reprint author), Hosp Sick Children, Motherisk Program, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. EM gkoren@sickkids.ca FU Duchesnay Inc., Blainville, Quebec, Canada FX The study was supported by Duchesnay Inc., Blainville, Quebec, Canada and executed by Premier Research Group, Philadelphia, PA. NR 19 TC 2 Z9 2 U1 1 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2393 J9 BMC PREGNANCY CHILDB JI BMC Pregnancy Childbirth PD MAR 18 PY 2015 VL 15 AR 59 DI 10.1186/s12884-015-0488-1 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CF5IW UT WOS:000352591700001 PM 25884778 ER PT J AU Baydyuk, M Wu, XS He, LM Wu, LG AF Baydyuk, Maryna Wu, Xin-Sheng He, Liming Wu, Ling-Gang TI Brain-Derived Neurotrophic Factor Inhibits Calcium Channel Activation, Exocytosis, and Endocytosis at a Central Nerve Terminal SO JOURNAL OF NEUROSCIENCE LA English DT Article DE BDNF; calcium channels; calyx of Held; endocytosis; exocytosis ID SYNAPTIC-TRANSMISSION; TRANSMITTER RELEASE; RETT-SYNDROME; VESICLE ENDOCYTOSIS; HELD SYNAPSE; FACTOR BDNF; HIPPOCAMPUS; CALYX; CURRENTS; TRKB AB Brain-derived neurotrophic factor (BDNF) is a neurotrophin that regulates synaptic function and plasticity and plays important roles in neuronal development, survival, and brain disorders. Despite such diverse and important roles, how BDNF, or more generally speaking, neurotrophins affect synapses, particularly nerve terminals, remains unclear. By measuring calcium currents and membrane capacitance during depolarization at a large mammalian central nerve terminal, the rat calyx of Held, we report for the first time that BDNF slows down calcium channel activation, including P/Q-type channels, and inhibits exocytosis induced by brief depolarization or single action potentials, inhibits slow and rapid endocytosis, and inhibits vesicle mobilization to the readily releasable pool. These presynaptic mechanisms may contribute to the important roles of BDNF in regulating synapses and neuronal circuits and suggest that regulation of presynaptic calcium channels, exocytosis, and endocytosis are potential mechanisms by which neurotrophins achieve diverse neuronal functions. C1 [Baydyuk, Maryna; Wu, Xin-Sheng; He, Liming; Wu, Ling-Gang] NINDS, Bethesda, MD 20892 USA. RP Wu, LG (reprint author), NINDS, 35 Convent Dr,Bldg 35,Room 2B-1012, Bethesda, MD 20892 USA. EM wul@ninds.nih.gov FU National Institute of Neurological Disorders and Stroke Intramural Research Program FX This research was supported by the National Institute of Neurological Disorders and Stroke Intramural Research Program. We thank Dr. Baoji Xu for reagents and BdnfLacZ/+ and TrkBLacZ/+ brains. NR 43 TC 4 Z9 5 U1 0 U2 6 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAR 18 PY 2015 VL 35 IS 11 BP 4676 EP 4682 DI 10.1523/JNEUROSCI.2695-14.2015 PG 7 WC Neurosciences SC Neurosciences & Neurology GA CE9ZM UT WOS:000352202300018 PM 25788684 ER PT J AU Bradfute, SB Anthony, SM Stuthman, KS Ayithan, N Tailor, P Shaia, CI Bray, M Ozato, K Bavari, S AF Bradfute, Steven B. Anthony, Scott M. Stuthman, Kelly S. Ayithan, Natarajan Tailor, Prafullakumar Shaia, Carl I. Bray, Mike Ozato, Keiko Bavari, Sina TI Mechanisms of Immunity in Post-Exposure Vaccination against Ebola Virus Infection SO PLOS ONE LA English DT Article ID PROTECTS NONHUMAN-PRIMATES; T-CELL RESPONSES; MARBURG HEMORRHAGIC-FEVER; DENDRITIC CELLS; GUINEA-PIGS; CRYPTOCOCCUS-NEOFORMANS; FILOVIRUS INFECTION; MOUSE MODEL; PATHOGENESIS; ANTIBODIES AB Ebolaviruses can cause severe hemorrhagic fever that is characterized by rapid viral replication, coagulopathy, inflammation, and high lethality rates. Although there is no clinically proven vaccine or treatment for Ebola virus infection, a virus-like particle (VLP) vaccine is effective in mice, guinea pigs, and non-human primates when given pre-infection. In this work, we report that VLPs protect Ebola virus-infected mice when given 24 hours post-infection. Analysis of cytokine expression in serum revealed a decrease in pro-inflammatory cytokine and chemokine levels in mice given VLPs post-exposure compared to infected, untreated mice. Using knockout mice, we show that VLP-mediated post-exposure protection requires perforin, B cells, macrophages, conventional dendritic cells (cDCs), and either CD4+ or CD8+ T cells. Protection was Ebola virus-specific, as marburgvirus VLPs did not protect Ebola virus-infected mice. Increased antibody production in VLP-treated mice correlated with protection, and macrophages were required for this increased production. However, NK cells, IFN-gamma, and TNF-alpha were not required for post-exposure-mediated protection. These data suggest that a non-replicating Ebola virus vaccine can provide post-exposure protection and that the mechanisms of immune protection in this setting require both increased antibody production and generation of cytotoxic T cells. C1 [Bradfute, Steven B.; Anthony, Scott M.; Stuthman, Kelly S.; Shaia, Carl I.; Bavari, Sina] US Army Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA. [Ayithan, Natarajan; Ozato, Keiko] NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. [Tailor, Prafullakumar] Natl Inst Immunol, New Delhi 110067, India. [Bray, Mike] NIAID, Div Clin Res, NIH, Bethesda, MD 20892 USA. RP Bavari, S (reprint author), US Army Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA. EM sina.bavari.civ@mail.mil FU Defense Threat Reduction Agency [1.1C003_08_RD_B] FX This work was supported by a grant from the Defense Threat Reduction Agency to SB (1.1C003_08_RD_B). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 69 TC 3 Z9 3 U1 0 U2 15 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 MAR 18 PY 2015 VL 10 IS 3 AR UNSP e0118434 DI 10.1371/journal.pone.0118434 PG 21 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CE9BN UT WOS:000352138500034 PM 25785602 ER PT J AU Chikaev, AN Bakulina, AY Burdick, RC Karpenko, LI Pathak, VK Ilyichev, AA AF Chikaev, Anton N. Bakulina, Anastasiya Yu. Burdick, Ryan C. Karpenko, Larisa I. Pathak, Vinay K. Ilyichev, Alexander A. TI Selection of Peptide Mimics of HIV-1 Epitope Recognized by Neutralizing Antibody VRC01 SO PLOS ONE LA English DT Article ID MONOCLONAL-ANTIBODIES; PHAGE DISPLAY; MIMOTOPE; GP120; DESIGN; VACCINE; FEATURES; PROTEIN; 2G12 AB The ability to induce anti-HIV-1 antibodies that can neutralize a broad spectrum of viral isolates from different subtypes seems to be a key requirement for development of an effective HIV-1 vaccine. The epitopes recognized by the most potent broadly neutralizing antibodies that have been characterized are largely discontinuous. Mimetics of such conformational epitopes could be potentially used as components of a synthetic immunogen that can elicit neutralizing antibodies. Here we used phage display technology to identify peptide motifs that mimic the epitope recognized by monoclonal antibody VRC01, which is able to neutralize up to 91% of circulating primary isolates. Three rounds of biopanning were performed against 2 different phage peptide libraries for this purpose. The binding specificity of selected phage clones to monoclonal antibody VRC01 was estimated using dot blot analysis. The putative peptide mimics exposed on the surface of selected phages were analyzed for conformational and linear homology to the surface of HIV-1 gp120 fragment using computational analysis. Corresponding peptides were synthesized and checked for their ability to interfere with neutralization activity of VRC01 in a competitive inhibition assay. One of the most common peptides selected from 12-mer phage library was found to partially mimic a CD4-binding loop fragment, whereas none of the circular C7C-mer peptides was able to mimic any HIV-1 domains. However, peptides identified from both the 12-mer and C7C-mer peptide libraries showed rescue of HIV-1 infectivity in the competitive inhibition assay. The identification of epitope mimics may lead to novel immunogens capable of inducing broadly reactive neutralizing antibodies. C1 [Chikaev, Anton N.; Bakulina, Anastasiya Yu.; Karpenko, Larisa I.; Ilyichev, Alexander A.] State Res Ctr Virol & Biotechnol VECTOR, Koltsov 630559, Novosibirsk Reg, Russia. [Burdick, Ryan C.; Pathak, Vinay K.] NCI, HIV Drug Resistance Program, Viral Mutat Sect, Frederick, MD 21702 USA. RP Chikaev, AN (reprint author), State Res Ctr Virol & Biotechnol VECTOR, Koltsov 630559, Novosibirsk Reg, Russia. EM chikaev@vector.nsc.ru RI Ilyichev, Alexander/B-1327-2012; Karpenko, Larisa/A-9682-2014 OI Ilyichev, Alexander/0000-0001-5356-0843; FU National Institute of Allergy and Infectious Diseases (NIAID); Russian Foundation for Basic Research (RFBR) [RUB1-31084-NO-12]; Russian Science Foundation [14-14-00660] FX This work was supported by the joint grant from the National Institute of Allergy and Infectious Diseases (NIAID) and the Russian Foundation for Basic Research (RFBR) RUB1-31084-NO-12. http://www.rfbr.ru/rffi/eng/contests international announcement/o 60903. Homology modeling and molecular docking experiments were also supported by Russian Science Foundation grant 14-14-00660. http://www.rscf.ru/sites/default/files/docfiles/Spisok pobediteley.pdf. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 0 Z9 0 U1 3 U2 12 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 MAR 18 PY 2015 VL 10 IS 3 AR e0120847 DI 10.1371/journal.pone.0120847 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CE9BN UT WOS:000352138500196 PM 25785734 ER PT J AU Kines, RC Zarnitsyn, V Johnson, TR Pang, YYS Corbett, KS Nicewonger, JD Gangopadhyay, A Chen, M Liu, J Prausnitz, MR Schiller, JT Graham, BS AF Kines, Rhonda C. Zarnitsyn, Vladimir Johnson, Teresa R. Pang, Yuk-Ying S. Corbett, Kizzmekia S. Nicewonger, John D. Gangopadhyay, Anu Chen, Man Liu, Jie Prausnitz, Mark R. Schiller, John T. Graham, Barney S. TI Vaccination with Human Papillomavirus Pseudovirus-Encapsidated Plasmids Targeted to Skin Using Microneedles SO PLOS ONE LA English DT Article ID RESPIRATORY SYNCYTIAL VIRUS; T-CELL RESPONSES; WEST-NILE-VIRUS; INFLUENZA VACCINE; NEUTRALIZING ANTIBODY; FUSION GLYCOPROTEIN; MONOCLONAL-ANTIBODY; DNA VACCINATION; YOUNG-CHILDREN; MOUSE MODEL AB Human papilloma virus-like particles (HPV VLP) serve as the basis of the current licensed vaccines for HPV. We have previously shown that encapsidation of DNA expressing the model antigen M/M2 from respiratory syncytial virus (RSV) in HPV pseudovirions (PsV) is immunogenic when delivered intravaginally. Because the HPV capsids confer tropism for basal epithelium, they represent attractive carriers for vaccination targeted to the skin using microneedles. In this study we asked: 1) whether HPV16 VLP administered by microneedles could induce protective immune responses to HPV16 and 2) whether HPV16 PsV-encapsidated plasmids delivered by microneedles could elicit immune responses to both HPV and the antigen delivered by the transgene. Mice immunized with HPV16 VLP coated microneedles generated robust neutralizing antibody responses and were protected from HPV16 challenge. Microneedle arrays coated with HPV16-M/M2 or HPV16-F protein (genes of RSV) were then tested and dose-dependent HPV and F-specific antibody responses were detected post-immunization, and M/M2-specific T-cell responses were detected post RSV challenge, respectively. HPV16 PsV-F immunized mice were fully protected from challenge with HPV16 PsV and had reduced RSV viral load in lung and nose upon intranasal RSV challenge. In summary, HPV16 PsV-encapsidated DNA delivered by microneedles induced neutralizing antibody responses against HPV and primed for antibody and T-cell responses to RSV antigens encoded by the encapsidated plasmids. Although the immunogenicity of the DNA component was just above the dose response threshold, the HPV-specific immunity was robust. Taken together, these data suggest microneedle delivery of lyophilized HPV PsV could provide a practical, thermostable combined vaccine approach that could be developed for clinical evaluation. C1 [Kines, Rhonda C.; Pang, Yuk-Ying S.; Schiller, John T.] NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. [Zarnitsyn, Vladimir; Prausnitz, Mark R.] Georgia Inst Technol, Sch Chem & Biomol Engn, Atlanta, GA 30332 USA. [Johnson, Teresa R.; Corbett, Kizzmekia S.; Nicewonger, John D.; Gangopadhyay, Anu; Chen, Man; Liu, Jie; Graham, Barney S.] NIAID, Viral Pathogenesis Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Graham, BS (reprint author), NIAID, Viral Pathogenesis Lab, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM bgraham@nih.gov FU National Institute of Allergy and Infectious Diseases; National Cancer Institute FX This work was supported by intramural funding from the National Institute of Allergy and Infectious Diseases and the National Cancer Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 46 TC 8 Z9 8 U1 4 U2 29 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 MAR 18 PY 2015 VL 10 IS 3 AR e0120797 DI 10.1371/journal.pone.0120797 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CE9BN UT WOS:000352138500190 PM 25785935 ER PT J AU Li, RH Hempel, LU Jiang, TB AF Li, Renhua Hempel, Leonie U. Jiang, Tingbo TI A Non-Parametric Peak Calling Algorithm for DamID-Seq SO PLOS ONE LA English DT Article ID PROTEIN-DNA INTERACTIONS; GENOME AB Protein-DNA interactions play a significant role in gene regulation and expression. In order to identify transcription factor binding sites (TFBS) of double sex (DSX)-an important transcription factor in sex determination, we applied the DNA adenine methylation identification (DamID) technology to the fat body tissue of Drosophila, followed by deep sequencing (DamID-Seq). One feature of DamID-Seq data is that induced adenine methylation signals are not assured to be symmetrically distributed at TFBS, which renders the existing peak calling algorithms for ChIP-Seq, including SPP and MACS, inappropriate for DamID-Seq data. This challenged us to develop a new algorithm for peak calling. A challenge in peaking calling based on sequence data is estimating the averaged behavior of background signals. We applied a bootstrap resampling method to short sequence reads in the control (Dam only). After data quality check and mapping reads to a reference genome, the peaking calling procedure compromises the following steps: 1) reads resampling; 2) reads scaling (normalization) and computing signal-to-noise fold changes; 3) filtering; 4) Calling peaks based on a statistically significant threshold. This is a non-parametric method for peak calling (NPPC). We also used irreproducible discovery rate (IDR) analysis, as well as ChIP-Seq data to compare the peaks called by the NPPC. We identified approximately 6,000 peaks for DSX, which point to 1,225 genes related to the fat body tissue difference between female and male Drosophila. Statistical evidence from IDR analysis indicated that these peaks are reproducible across biological replicates. In addition, these peaks are comparable to those identified by use of ChIP-Seq on S2 cells, in terms of peak number, location, and peaks width. C1 [Li, Renhua; Jiang, Tingbo] Northeast Forestry Univ, State Key Lab Tree Genet & Breeding, Harbin 150040, Peoples R China. [Li, Renhua; Hempel, Leonie U.] NIDDK, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. RP Jiang, TB (reprint author), Northeast Forestry Univ, State Key Lab Tree Genet & Breeding, Harbin 150040, Peoples R China. EM tbjiang@yahoo.com NR 17 TC 2 Z9 2 U1 4 U2 9 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 MAR 18 PY 2015 VL 10 IS 3 AR e0117415 DI 10.1371/journal.pone.0117415 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CE9BN UT WOS:000352138500017 PM 25785608 ER PT J AU Yuan, LX Sun, LG Fortin, D Wang, YH Yin, XB AF Yuan, Linxi Sun, Liguang Fortin, Danielle Wang, Yuhong Yin, Xuebin TI Microscale Characterization and Trace Element Distribution in Bacteriogenic Ferromanganese Coatings on Sand Grains from an Intertidal Zone of the East China Sea SO PLOS ONE LA English DT Article ID RARE-EARTH-ELEMENTS; BIOGENIC MN OXIDES; SP STRAIN SG-1; MANGANESE OXIDE; PINAL-CREEK; IRON-OXYHYDROXIDE; DIAGENETIC IRON; NATURAL-WATERS; HEAVY-METALS; HUMIC-ACID AB An ancient wood layer dated at about 5600 yr BP by accelerator mass spectrometry (AMS) C-14 was discovered in an intertidal zone of the East China Sea. Extensive and horizontally stratified sediments with black color on the top and yellowish-red at the bottom, and some nodule-cemented concretions with brown surface and black inclusions occurred in this intertidal zone. Microscale analysis methods were employed to study the microscale characterization and trace element distribution in the stratified sediments and concretions. Light microscopy, scanning electron microscopy (SEM) and backscattered electron imaging (BSE) revealed the presence of different coatings on the sand grains. The main mineral compositions of the coatings were ferrihydrite and goethite in the yellowish-red parts, and birnessite in the black parts using X-ray powder diffraction (XRD). SEM observations showed that bacteriogenic products and bacterial remnants extensively occurred in the coatings, indicating that bacteria likely played an important role in the formation of ferromanganese coatings. Post-Archean Australian Shale (PAAS)-normalized middle rare earth element (MREE) enrichment patterns of the coatings indicated that they were caused by two sub-sequential processes: (1) preferentially release of Fe-Mn from the beach rocks by fermentation of ancient woods and colloidal flocculation in the mixing water zone and (2) preferential adsorption of MREE by Fe-Mn oxyhydroxides from the seawater. The chemical results indicated that the coatings were enriched with Sc, V, Cr, Co, Ni, Cu, Zn, Ba, especially with respect to Co, Ni. The findings of the present study provide an insight in the microscale features of ferromanganese coatings and the Fe-Mn biogeochemical cycling during the degradation of buried organic matter in intertidal zones or shallow coasts. C1 [Yuan, Linxi; Sun, Liguang; Yin, Xuebin] Univ Sci & Technol China, Sch Earth & Space Sci, Hefei 230026, Peoples R China. [Yuan, Linxi; Yin, Xuebin] Jiangsu Bioengn Res Ctr Selenium, Suzhou 215123, Peoples R China. [Yuan, Linxi; Yin, Xuebin] Univ Sci & Technol China, Suzhou Inst Adv Study, Adv Lab Selenium & Human Hlth, Suzhou 215123, Peoples R China. [Fortin, Danielle] Univ Ottawa, Dept Earth Sci, Ottawa, ON K1N 6N5, Canada. [Wang, Yuhong] NIH, Bethesda, MD 20892 USA. RP Yuan, LX (reprint author), Univ Sci & Technol China, Sch Earth & Space Sci, Hefei 230026, Peoples R China. EM yuanli@ustc.edu.cn; slg@ustc.edu.cn FU Natural Science Youth Foundation of Jiangsu Province for Youth, China [BK2012202]; National 973 Program [2010CB428902]; Chinese Postdoctoral Science Foundation [2013M540518]; Jiangsu Provincial Postdoctoral Science Foundation [1302080C] FX This work was supported by Natural Science Youth Foundation of Jiangsu Province for Youth, China (BK2012202) (http://www.jstd.gov.cn/), National 973 Program (Grant No 2010CB428902) (http://www.most.gov.cn/), Chinese Postdoctoral Science Foundation (2013M540518) (http://res.chinapostdoctor.org.cn/BshWeb/index.shtml) and Jiangsu Provincial Postdoctoral Science Foundation (1302080C) (http://www.jsbsh.gov.cn/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 75 TC 1 Z9 2 U1 13 U2 48 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 MAR 18 PY 2015 VL 10 IS 3 AR e0119080 DI 10.1371/journal.pone.0119080 PG 21 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CE9BN UT WOS:000352138500071 PM 25786213 ER PT J AU Pelkey, KA Barksdale, E Craig, MT Yuan, XQ Sukumaran, M Vargish, GA Mitchell, RM Wyeth, MS Petralia, RS Chittajallu, R Karlsson, RM Cameron, HA Murata, Y Colonnese, MT Worley, PF McBain, CJ AF Pelkey, Kenneth A. Barksdale, Elizabeth Craig, Michael T. Yuan, Xiaoqing Sukumaran, Madhav Vargish, Geoffrey A. Mitchell, Robert M. Wyeth, Megan S. Petralia, Ronald S. Chittajallu, Ramesh Karlsson, Rose-Marie Cameron, Heather A. Murata, Yasunobu Colonnese, Matthew T. Worley, Paul F. McBain, Chris J. TI Pentraxins Coordinate Excitatory Synapse Maturation and Circuit Integration of Parvalbumin Interneurons SO NEURON LA English DT Article ID DEVELOPING VISUAL-SYSTEM; AMPA RECEPTORS; RAT HIPPOCAMPUS; GABAERGIC INTERNEURONS; GABA(A) RECEPTORS; NEURONAL-ACTIVITY; STARGAZER MOUSE; PYRAMIDAL CELLS; SELECTIVE LOSS; NARP AB Circuit computation requires precision in the timing, extent, and synchrony of principal cell (PC) firing that is largely enforced by parvalbumin-expressing, fast-spiking interneurons (PVFSIs). To reliably coordinate network activity, PVFSIs exhibit specialized synaptic and membrane properties that promote efficient afferent recruitment such as expression of high-conductance, rapidly gating, GluA4-containing AMPA receptors (AMPARs). We found that PVFSIs upregulate GluA4 during the second postnatal week coincident with increases in the AMPAR clustering proteins NPTX2 and NPTXR. Moreover, GluA4 is dramatically reduced in NPTX2(-/-)/NPTXR-/- mice with consequent reductions in PVFSI AMPAR function. Early postnatal NPTX2(-/-)/NPTXR-/- mice exhibit delayed circuit maturation with a prolonged critical period permissive for giant depolarizing potentials. Juvenile NPTX2(-/-)/NPTXR-/- mice display reduced feed-forward inhibition yielding a circuit deficient in rhythmogenesis and prone to epileptiform discharges. Our findings demonstrate an essential role for NPTXs in controlling network dynamics highlighting potential therapeutic targets for disorders with inhibition/excitation imbalances such as schizophrenia. C1 [Pelkey, Kenneth A.; Barksdale, Elizabeth; Craig, Michael T.; Yuan, Xiaoqing; Sukumaran, Madhav; Vargish, Geoffrey A.; Mitchell, Robert M.; Wyeth, Megan S.; Chittajallu, Ramesh; McBain, Chris J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. [Petralia, Ronald S.] NIDCD, Adv Imaging Core, NIH, Bethesda, MD 20892 USA. [Karlsson, Rose-Marie; Cameron, Heather A.] NIMH, Sect Neuroplast, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. [Murata, Yasunobu; Colonnese, Matthew T.] George Washington Univ, Dept Pharmacol & Physiol, Washington, DC 20037 USA. [Murata, Yasunobu; Colonnese, Matthew T.] George Washington Univ, Inst Neurosci, Washington, DC 20037 USA. [Worley, Paul F.] Johns Hopkins Univ, Solomon H Snyder Dept Neurosci, Baltimore, MD 21205 USA. RP Pelkey, KA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Neurosci, NIH, 35 Lincoln Dr, Bethesda, MD 20892 USA. EM pelkeyk2@mail.nih.gov RI Cameron, Heather/E-6221-2011; Craig, Michael/E-7070-2011; OI Cameron, Heather/0000-0002-3245-5777; Craig, Michael/0000-0001-8481-6709; Murata, Yasunobu/0000-0001-5757-2497; Colonnese, Matthew/0000-0002-2480-1270 FU PRAT; NICHD; NIDCD; NIMH; NIH [PAR-02-059, NS 039156, EY022730] FX We thank Dr. Ya-Xian Wang (NIH/NIDCD IR) for expert technical assistance with immunogold EM experiments. Work was supported by a PRAT fellowship to M.S.W., an NICHD intramural award to C.J.M., NIDCD intramural research program funding to R.S.P., an NIMH intramural award to H.A.C., NIH grants (PAR-02-059, NS 039156) to P.F.W., and an NIH grant (EY022730) to M.T. Colonnese. NR 58 TC 20 Z9 20 U1 4 U2 20 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 MAR 18 PY 2015 VL 85 IS 6 BP 1257 EP 1272 DI 10.1016/j.neuron.2015.02.020 PG 16 WC Neurosciences SC Neurosciences & Neurology GA CD8BA UT WOS:000351319000013 PM 25754824 ER PT J AU Davis, JM Smoyer, WE Connor, EM Huskins, WC Pastern, C Purucker, M Schrader, EC Jackson, CR Kaskel, FJ Hirschfeld, S AF Davis, Jonathan M. Smoyer, William E. Connor, Edward M. Huskins, W. Charles Pastern, Cindy Purucker, Mary Schrader, Elisabeth C. Jackson, Cynthia R. Kaskel, Frederick J. Hirschfeld, Steven TI Sponsors meet scientists to speed pediatric medicines development SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Editorial Material ID TIME C1 [Davis, Jonathan M.] Floating Hosp Children, Dept Pediat, Boston, MA 02111 USA. [Davis, Jonathan M.] Tufts Clin & Translat Sci Inst, Boston, MA 02111 USA. [Smoyer, William E.] Nationwide Childrens Hosp, Ctr Clin & Translat Res, Columbus, OH 43205 USA. [Smoyer, William E.; Connor, Edward M.] Childrens Natl Med Ctr, Clin & Translat Res Inst, Washington, DC 20010 USA. [Huskins, W. Charles] Mayo Clin, Div Pediat Infect Dis, Rochester, MN 55905 USA. [Pastern, Cindy] Vanderbilt Univ, CTSA Consortium Coordinating Ctr, Nashville, TN 37232 USA. [Purucker, Mary] Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Schrader, Elisabeth C.; Jackson, Cynthia R.] Quintiles Inc, Pediat Ctr Excellence, Durham, NC 27703 USA. [Jackson, Cynthia R.] Duke Univ, Med Ctr, Div Pediat Infect Dis, Dept Pediat, Durham, NC 27710 USA. [Kaskel, Frederick J.] Montefiore Med Ctr, Dept Pediat, New York, NY 10467 USA. [Hirschfeld, Steven] NICHHD, Bethesda, MD 20892 USA. RP Davis, JM (reprint author), Floating Hosp Children, Dept Pediat, Boston, MA 02111 USA. EM jdavis@tuftsmedicalcenter.org RI Hirschfeld, Steven/E-2987-2016 OI Hirschfeld, Steven/0000-0003-0627-7249 NR 7 TC 0 Z9 0 U1 0 U2 0 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 MAR 18 PY 2015 VL 7 IS 279 PG 3 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA CD9UH UT WOS:000351443500001 ER PT J AU Tan, AWL Francischetti, IMB Slovak, M Kini, RM Ribeiro, JMC AF Tan, Angelina W. L. Francischetti, Ivo M. B. Slovak, Mirko Kini, R. Manjunatha Ribeiro, Jose M. C. TI Sexual differences in the sialomes of the zebra tick, Rhipicephalus pulchellus SO JOURNAL OF PROTEOMICS LA English DT Article DE Salivary glands; Tick; Transcriptome ID DIFFERENTIALLY EXPRESSED GENES; HISTAMINE-BINDING PROTEINS; SALIVARY-GLAND TRANSCRIPTS; PROSTATE-SPECIFIC ANTIGEN; VECTOR IXODES-SCAPULARIS; AMBLYOMMA-AMERICANUM L.; RNA-SEQ DATA; BOOPHILUS-MICROPLUS; DROSOPHILA-MELANOGASTER; CATTLE TICK AB Ticks rely exclusively on vertebrate blood for their survival. During feeding ticks inject into their hosts a sophisticated salivary potion that overcomes host hemostasis and adverse inflammatory responses. These mediators may also enhance pathogen transmission. Knowledge of the tick salivary protein repertoire may lead to vaccine targets to disrupt feeding and/or parasite transmission as well as to the discovery of novel pharmacological agents. Male saliva may also assist reproduction because males use their mouthparts to lubricate and introduce their spermatophores into the females' genital pore. The analyses of the sialomes of male and female ticks independently allow us to understand the strategy used by each gender to feed successfully. We sequenced cDNA libraries from pools of salivary glands from adult male and female Rhipicephalus pulchellus feeding at different time points, using the Illumina HiSeq protocol. De novo assembly of a total of 241,229,128 paired-end reads lead to extraction of 50,460 coding sequences (CDS), 11,277 of which had more than 75% coverage to known transcripts, or represented novel sequences, and were submitted to GenBank. Additionally, we generated the proteome, from the salivary gland extracts of male and female R. pulchellus, yielding a total of 454 and 2063 proteins respectively which were identified by one or more peptides with at least 95% confidence. The data set is presented as an annotated hyperlinked Excel spreadsheet, describing 121 putative secreted protein families. Female and male specific transcripts were identified. Biological significance This annotated R. pulchellus database represents a mining field for future experiments involving the resolution of time-dependent transcript expression in this tick species, as well as to define novel vaccine targets and discover novel pharmaceuticals. Gender specific proteins may represent different repertoires of pharmacological reagents to assist feeding by each sex, and in males may represent proteins that assist reproduction similarly to seminal proteins in other animals. (C) 2015 Elsevier B.V. All rights reserved. C1 [Tan, Angelina W. L.; Kini, R. Manjunatha] Natl Univ Singapore, NUS Grad Sch Integrat Sci & Engn, Singapore 117456, Singapore. [Tan, Angelina W. L.; Kini, R. Manjunatha] Natl Univ Singapore, Fac Sci, Dept Biol Sci, Singapore 117543, Singapore. [Francischetti, Ivo M. B.; Ribeiro, Jose M. C.] NIAID, Vector Biol Sect, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Slovak, Mirko] Slovak Acad Sci, Inst Zool, Bratislava 84206, Slovakia. [Kini, R. Manjunatha] Virginia Commonwealth Univ, Dept Biochem & Mol Biol, Med Coll Virginia, Richmond, VA 23298 USA. [Kini, R. Manjunatha] Univ S Australia, Sch Pharm & Med Sci, Adelaide, SA 5001, Australia. RP Kini, RM (reprint author), Natl Univ Singapore, NUS Grad Sch Integrat Sci & Engn, Singapore 117456, Singapore. EM tan.angelina@u.nus.edu; ifrancischetti@niaid.nih.gov; mirko.slovak@savba.sk; dbskinim@nus.edu.sg; jribeiro@niaid.nih.gov OI Ribeiro, Jose/0000-0002-9107-0818 FU Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH, USA) [ZIA AI000810-16]; VEGA (Vedecka grantova agentura) [2/0060/12]; Singapore Ministry of Education [MOE2010-T2-2-023] FX J.M.C.R. and I.F. were supported by the Intramural Research Program of the Division of Intramural Research (ZIA AI000810-16), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH, USA). MS was supported by grant VEGA (Vedecka grantova agentura) 2/0060/12. AWLT and RMK were supported by grant MOE2010-T2-2-023 from the Singapore Ministry of Education. NR 135 TC 7 Z9 7 U1 3 U2 8 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 MAR 18 PY 2015 VL 117 BP 120 EP 144 DI 10.1016/j.jprot.2014.12.014 PG 25 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA CD2VS UT WOS:000350937700010 PM 25576852 ER PT J AU Homan, P Neumeister, A Nugent, AC Charney, DS Drevets, WC Hasler, G AF Homan, P. Neumeister, A. Nugent, A. C. Charney, D. S. Drevets, W. C. Hasler, G. TI Serotonin versus catecholamine deficiency: behavioral and neural effects of experimental depletion in remitted depression SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID DORSAL RAPHE NUCLEUS; TRYPTOPHAN-DEPLETION; PREFRONTAL CORTEX; ANTIDEPRESSANT DRUGS; SELECTIVE SEROTONIN; PSYCHIATRIC-DISORDERS; REUPTAKE INHIBITORS; MAJOR DEPRESSION; HEALTHY-SUBJECTS; THALAMIC NUCLEI AB Despite immense efforts into development of new antidepressant drugs, the increases of serotoninergic and catecholaminergic neurotransmission have remained the two major pharmacodynamic principles of current drug treatments for depression. Consequently, psychopathological or biological markers that predict response to drugs that selectively increase serotonin and/or catecholamine neurotransmission hold the potential to optimize the prescriber's selection among currently available treatment options. The aim of this study was to elucidate the differential symptomatology and neurophysiology in response to reductions in serotonergic versus catecholaminergic neurotransmission in subjects at high risk of depression recurrence. Using identical neuroimaging procedures with [F-18] fluorodeoxyglucose positron emission tomography after tryptophan depletion (TD) and catecholamine depletion (CD), subjects with remitted depression were compared with healthy controls in a double-blind, randomized, crossover design. Although TD induced significantly more depressed mood, sadness and hopelessness than CD, CD induced more inactivity, concentration difficulties, lassitude and somatic anxiety than TD. CD specifically increased glucose metabolism in the bilateral ventral striatum and decreased glucose metabolism in the bilateral orbitofrontal cortex, whereas TD specifically increased metabolism in the right prefrontal cortex and the posterior cingulate cortex. Although we found direct associations between changes in brain metabolism and induced depressive symptoms following CD, the relationship between neural activity and symptoms was less clear after TD. In conclusion, this study showed that serotonin and catecholamines have common and differential roles in the pathophysiology of depression. C1 [Homan, P.; Hasler, G.] Univ Bern, Univ Hosp Psychiat, Div Mol Psychiat, Translat Res Ctr, CH-3000 Bern, Switzerland. [Neumeister, A.] NYU, Sch Med, Dept Psychiat & Radiol, Mol Imaging Program, New York, NY USA. [Nugent, A. C.] NIMH, Intramural Res Program, Expt Therapeut & Pathophysiol Branch, NIH, Bethesda, MD 20892 USA. [Nugent, A. C.] Dept Hlth & Human Serv, Bethesda, MD USA. [Charney, D. S.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Drevets, W. C.] Laureate Inst Brain Res, Tulsa, OK USA. [Drevets, W. C.] Janssen Pharmaceut Res & Dev, Titusville, NJ USA. RP Hasler, G (reprint author), Univ Bern, Univ Hosp Psychiat, Div Mol Psychiat, Translat Res Ctr, Bolligenstr 111, CH-3000 Bern, Switzerland. EM gregor.hasler@puk.unibe.ch RI Hasler, Gregor/E-4845-2012 OI Hasler, Gregor/0000-0002-8311-0138 FU National Institutes of Mental Health; University Hospital and Hermann Klaus Foundation, Zurich FX This research was supported by the Intramural Research Program of the National Institutes of Mental Health and the University Hospital and Hermann Klaus Foundation, Zurich. We thank Eveline Nuesch for statistical advice. NR 71 TC 2 Z9 2 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 MAR 17 PY 2015 VL 5 AR e532 DI 10.1038/tp.2015.25 PG 9 WC Psychiatry SC Psychiatry GA DA2VK UT WOS:000367654700006 PM 25781231 ER PT J AU Atalla, H Lysnyansky, I Raviv, Y Rottem, S AF Atalla, Hazem Lysnyansky, Inna Raviv, Yossef Rottem, Shlomo TI Mycoplasma gallisepticum Inactivated by Targeting the Hydrophobic Domain of the Membrane Preserves Surface Lipoproteins and Induces a Strong Immune Response SO PLOS ONE LA English DT Article ID STRUCTURAL INTEGRITY; CELLS; PROTEINS; VACCINES; HYOPNEUMONIAE; VACCINATION; CHICKENS; INVASION; DISEASE; CULTURE AB An innovative approach for inactivation of Mycoplasma gallisepticum using the hydrophobic photoinduced alkylating probe 1, 5-iodonaphthylazide (INA) is described. Treatment of washed M. gallisepticum mid-exponential culture (0.2 mg cell protein / mL) with INA followed by irradiation with far-ultraviolet light (310-380 nm) completely abolished viability. Transmission electron microscopy showed that the majority of the inactivated M. gallisepticum were comparable in size to intact cells, but that part of the INA-treated M. gallisepticum preparation also contained low density cells and membrane vesicles. Confocal microscopy revealed that untreated M. gallisepticum cells were internalized by chicken red blood cells (c-RBCs), whereas the INA-inactivated cells remained attached to the outer surface of the c-RBCs. INA treatment of M. gallisepticum resulted in a complete inactivation of F0F1 - ATPase and of the L-arginine uptake system, but the cytoplasmatic soluble NADH2 dehydrogenase was only partially affected. Western blot analysis of the lipoprotein fraction showed that the INA-treated M. gallisepticum retained their lipoproteins. Following subcutaneous injection of M. gallisepticum INA-bacterin, 100% and 68.8% of chickens were positive by the rapid serum agglutination test and enzyme-linked immunosorbent assay respectively, 2 weeks post-injection. These data suggest that the photoinducible alkylating agent INA inactivates M. gallisepticum but preserves its surface lipoproteins and thus has the potential to be used as a general approach for the inactivation of mycoplasmas for vaccine development. C1 [Atalla, Hazem; Rottem, Shlomo] Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Microbiol & Mol Genet, IL-91010 Jerusalem, Israel. [Lysnyansky, Inna] Kimron Vet Inst, Div Avian & Aquat Dis, Bet Dagan, Israel. [Raviv, Yossef] SAIC Frederick Inc, Natl Canc Inst, Frederick, MD USA. RP Lysnyansky, I (reprint author), Kimron Vet Inst, Div Avian & Aquat Dis, Bet Dagan, Israel. EM innal@moag.gov.il FU SAIC-Frederick FX The authors received no specific funding for this work. SAIC-Frederick provided support in the form of salaries for Dr. Y. Raviv, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 0 Z9 0 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 MAR 17 PY 2015 VL 10 IS 3 AR e0120462 DI 10.1371/journal.pone.0120462 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CD7QC UT WOS:000351284600163 PM 25781939 ER PT J AU Hua, Y Wang, B Wallen, GR Shao, P Ni, CP Hua, QZ AF Hua, Yan Wang, Bo Wallen, Gwenyth R. Shao, Pei Ni, Chunping Hua, Qianzhen TI Health-Promoting Lifestyles and Depression in Urban Elderly Chinese SO PLOS ONE LA English DT Article ID OLDER-ADULTS; PRIMARY-CARE; SCALE GDS; SYMPTOMS; VALIDATION; PREVALENCE; BEHAVIORS; DISEASE; PROFILE; VERSION AB Objective To explore health-promoting lifestyles, depression and provide further insight into the relationship between health-promoting lifestyles and depression in an urban community sample of elderly Chinese people. Methods A cross-sectional descriptive and correlational study of 954 community-dwelling urban elderly Chinese (aged >= 60) was conducted from July to December 2010. Lifestyles and depression were assessed using the revised Chinese Version of the Health-Promoting Lifestyle Profile (HPLP-C) and the Geriatric Depression Scale (GDS), respectively. Results In this cohort, 15.8% of elderly urban adults met the criteria for depression. Over half of the sample (62.1%) scored greater than 100 on the HPLP-C, with range of score sum from 55 to 160. There were significant correlations between self-actualization (OR = 1.167, 95%CI: 1.111-1.226), nutrition (OR = 1.118, 95%CI: 1.033-1.209), physical activity (OR = 1.111, 95%CI: 1.015-1.216) and depression among community-dwelling elderly Chinese. Limitations This was a cross-sectional study. The significant associations found do not represent directional causation. Further longitudinal follow-up is recommended to investigate the specific causal relationship between lifestyles and depression. Conclusions Depression was common with medium to high levels of health-promoting lifestyles among urban elderly Chinese people. Lifestyle behaviors such as self-actualization, good nutrition habits and frequent physical activity were correlated to fewer depressive symptoms. Healthy lifestyles should be further developed in this population and measures should be taken for improving their depression. C1 [Hua, Yan; Shao, Pei; Ni, Chunping; Hua, Qianzhen] Fourth Mil Med Univ, Sch Nursing, Xian 710032, Shaanxi Provinc, Peoples R China. [Wang, Bo] Fourth Mil Med Univ, Dept Epidemiol, Sch Prevent Med, Xian 710032, Shaanxi Provinc, Peoples R China. [Wallen, Gwenyth R.] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Ni, CP (reprint author), Fourth Mil Med Univ, Sch Nursing, Xian 710032, Shaanxi Provinc, Peoples R China. EM pingchuni@163.com; qianzhen@fmmu.edu.cn NR 40 TC 1 Z9 1 U1 7 U2 15 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 MAR 17 PY 2015 VL 10 IS 3 AR e0117998 DI 10.1371/journal.pone.0117998 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CD7QC UT WOS:000351284600019 PM 25781326 ER PT J AU Kottilil, S Wright, M Polis, MA Masur, H AF Kottilil, Shyam Wright, Mary Polis, Michael A. Masur, Henry TI Treatment of Hepatitis C Virus Infection RESPONSE SO ANNALS OF INTERNAL MEDICINE LA English DT Letter ID LIVER FIBROSIS C1 [Kottilil, Shyam] Univ Maryland, Inst Human Virol, Baltimore, MD 21201 USA. [Wright, Mary; Polis, Michael A.] NIAID, NIH, Bethesda, MD 20892 USA. [Masur, Henry] NIH, Bethesda, MD 20892 USA. RP Kottilil, S (reprint author), Univ Maryland, Inst Human Virol, Baltimore, MD 21201 USA. NR 2 TC 1 Z9 1 U1 0 U2 0 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD MAR 17 PY 2015 VL 162 IS 6 BP 459 EP 459 DI 10.7326/L15-5064-4 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA CD7OH UT WOS:000351279600029 PM 25775329 ER PT J AU Palin, AC Love, PE AF Palin, Amy C. Love, Paul E. TI CD5 Helps Aspiring Regulatory T Cells Ward Off Unwelcome Cytokine Advances SO IMMUNITY LA English DT Editorial Material ID SELECTION; DISEASE C1 [Palin, Amy C.; Love, Paul E.] NICHHD, NIH, Bethesda, MD 20892 USA. RP Love, PE (reprint author), NICHHD, NIH, Bethesda, MD 20892 USA. EM lovep@mail.nih.gov NR 11 TC 1 Z9 1 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD MAR 17 PY 2015 VL 42 IS 3 BP 395 EP 396 DI 10.1016/j.immuni.2015.02.018 PG 2 WC Immunology SC Immunology GA CD7VE UT WOS:000351301900002 PM 25786168 ER PT J AU Shalova, IN Lim, JY Chittezhath, M Zinkernagel, AS Beasley, F Hernandez-Jimenez, E Toledano, V Cubillos-Zapata, C Rapisarda, A Chen, JM Duan, KB Yang, H Poidinger, M Melillo, G Nizet, V Arnalich, F Lopez-Collazo, E Biswas, SK AF Shalova, Irina N. Lim, Jyue Yuan Chittezhath, Manesh Zinkernagel, Annelies S. Beasley, Federico Hernandez-Jimenez, Enrique Toledano, Victor Cubillos-Zapata, Carolina Rapisarda, Annamaria Chen, Jinmiao Duan, Kaibo Yang, Henry Poidinger, Michael Melillo, Giovanni Nizet, Victor Arnalich, Francisco Lopez-Collazo, Eduardo Biswas, Subhra K. TI Human Monocytes Undergo Functional Re-programming during Sepsis Mediated by Hypoxia-Inducible Factor-1 alpha SO IMMUNITY LA English DT Article ID MOUSE MACROPHAGES; GENE-EXPRESSION; SEPTIC SHOCK; KAPPA-B; IRAK-M; HIF-1-ALPHA; IMMUNOSUPPRESSION; POLARIZATION; TOLERANCE; CELLS AB Sepsis is characterized by a dysregulated inflammatory response to infection. Despite studies in mice, the cellular and molecular basis of human sepsis remains unclear and effective therapies are lacking. Blood monocytes serve as the first line of host defense and are equipped to recognize and respond to infection by triggering an immune-inflammatory response. However, the response of these cells in human sepsis and their contribution to sepsis pathogenesis is poorly understood. To investigate this, we performed a transcriptomic, functional, and mechanistic analysis of blood monocytes from patients during sepsis and after recovery. Our results revealed the functional plasticity of monocytes during human sepsis, wherein they transited from a pro-inflammatory to an immunosuppressive phenotype, while enhancing protective functions like phagocytosis, anti-microbial activity, and tissue remodeling. Mechanistically, hypoxia inducible factor-1 alpha (HIF1 alpha) mediated this functional re-programming of monocytes, revealing a potential mechanism for their therapeutic targeting to regulate human sepsis. C1 [Shalova, Irina N.; Lim, Jyue Yuan; Chittezhath, Manesh; Chen, Jinmiao; Duan, Kaibo; Yang, Henry; Poidinger, Michael; Biswas, Subhra K.] Biopolis, Agcy Sci Technol & Res, Singapore Immunol Network SIgN, Singapore 138648, Singapore. [Zinkernagel, Annelies S.; Beasley, Federico; Nizet, Victor] Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA. [Hernandez-Jimenez, Enrique; Toledano, Victor; Cubillos-Zapata, Carolina; Lopez-Collazo, Eduardo] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USA. [Hernandez-Jimenez, Enrique; Toledano, Victor; Cubillos-Zapata, Carolina; Lopez-Collazo, Eduardo] La Paz Hosp, IdiPAZ, Tumor Immunol Lab, Madrid 28046, Spain. [Rapisarda, Annamaria; Melillo, Giovanni] La Paz Hosp, IdiPAZ, Innate Immun Grp, Madrid 28046, Spain. [Rapisarda, Annamaria; Melillo, Giovanni] NCI, Dev Therapeut Program, Tumor Hypoxia Lab, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21701 USA. [Arnalich, Francisco] La Paz Hosp, Dept Internal Med, Madrid 28046, Spain. RP Biswas, SK (reprint author), Biopolis, Agcy Sci Technol & Res, Singapore Immunol Network SIgN, 04-06 Immunos Bldg,8A Biomed Grove, Singapore 138648, Singapore. EM subhra_biswas@immunol.a-star.edu.sg RI Infektiologie, USZ/A-6921-2011; Zinkernagel, Annelies/F-1780-2017 FU SIgN; A*STAR; Fondos de Investigacion Sanitaria [PI11/00350]; Health Sciences Authority, Singapore FX S.K.B. thanks core funding of SIgN, A*STAR, and E.L.-C. thanks Fondos de Investigacion Sanitaria (PI11/00350) for the funding this research. We thank the Health Sciences Authority, Singapore, for their kind support with the blood supply. We are grateful to Ms. Josephine Lum and Dr. Francesca Zolezzi for their kind help with the transcriptomics. We also thank the Flow Cytometry and Immunomonitoring Platforms (SIgN). We thank Dr. John Common and Professor Birgitte Lane (Institute of Medical Biology, A*STAR) for their help in providing human fibroblasts for wound healing assay. Dr. Neil McCarthy of Insight Editing London edited the manuscript. G.M. is presently an employee of AstraZeneca and has no conflict of interest related to this work. NR 40 TC 31 Z9 31 U1 3 U2 25 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 MAR 17 PY 2015 VL 42 IS 3 BP 484 EP 498 DI 10.1016/j.immuni.2015.02.001 PG 15 WC Immunology SC Immunology GA CD7VE UT WOS:000351301900013 PM 25746953 ER PT J AU Hickman, HD Reynoso, GV Ngudiankama, BF Cush, SS Gibbs, J Bennink, JR Yewdell, JW AF Hickman, Heather D. Reynoso, Glennys V. Ngudiankama, Barbara F. Cush, Stephanie S. Gibbs, James Bennink, Jack R. Yewdell, Jonathan W. TI CXCR3 Chemokine Receptor Enables Local CD8(+) T Cell Migration for the Destruction of Virus-Infected Cells SO IMMUNITY LA English DT Article ID LYMPH-NODES; LEUKOCYTE MIGRATION; IN-VIVO; EFFECTOR; GENERATION; DIFFERENTIATION; INFLAMMATION; RECRUITMENT; MATURATION; RESPONSES AB CD8(+) T cells play a critical role in limiting peripheral virus replication, yet how they locate virus-infected cells within tissues is unknown. Here, we have examined the environmental signals that CD8(+) T cells use to localize and eliminate virus-infected skin cells. Epicutaneous vaccinia virus (VV) infection, mimicking human smallpox vaccination, greatly increased expression of the CXCR3 chemokine receptor ligands CXCL9 and CXCL10 in VV-infected skin. Despite normal T cell numbers in the skin, Cxcr3(-/-) mice exhibited dramatically impaired CD8(+)-T-cell-dependent virus clearance. Intravital microscopy revealed that Cxcr3(-/-) T cells were markedly deficient in locating, engaging, and killing virus-infected cells. Further, transfer of wild-type CD8(+) T cells restored viral clear-ance in Cxcr3(-/-) animals. These findings demonstrate a function for CXCR3 in enhancing the ability of tissue-localized CD8(+) T cells to locate virus-infected cells and thereby exert anti-viral effector functions. C1 [Hickman, Heather D.; Reynoso, Glennys V.; Ngudiankama, Barbara F.; Cush, Stephanie S.; Gibbs, James; Bennink, Jack R.; Yewdell, Jonathan W.] NIAID, Cell Biol Sect, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Hickman, Heather D.; Reynoso, Glennys V.; Ngudiankama, Barbara F.; Cush, Stephanie S.; Gibbs, James; Bennink, Jack R.; Yewdell, Jonathan W.] NIAID, Viral Immunol Sect, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Hickman, HD (reprint author), NIAID, Cell Biol Sect, Viral Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM hhickman@mail.nih.gov FU Intramural Research Program of the NIAID, NIH FX The authors would like to thank members of the Comparative Medicine Branch for excellence in animal husbandry, the NIAID flow cytometry facility (Bishop Hague and Elina Stregevsky) for cell sorting, and the NIAID Biological Imaging facility (Owen Schwartz) for assistance with microscopy. This work was supported by the Intramural Research Program of the NIAID, NIH. NR 40 TC 29 Z9 29 U1 1 U2 16 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 MAR 17 PY 2015 VL 42 IS 3 BP 524 EP 537 DI 10.1016/j.immuni.2015.02.009 PG 14 WC Immunology SC Immunology GA CD7VE UT WOS:000351301900016 PM 25769612 ER PT J AU Kim, HS Kim, AR Kim, DK Kim, HW Park, YH Jang, GH Kim, B Park, YM You, JS Kim, HS Beaven, MA Kim, YM Choi, WS AF Kim, Hyuk Soon Kim, A-Ram Kim, Do Kyun Kim, Hyun Woo Park, Young Hwan Jang, Geun Hyo Kim, Bokyung Park, Yeong Min You, Jueng Soo Kim, Hyung Sik Beaven, Michael A. Kim, Young Mi Choi, Wahn Soo TI Interleukin-10-producing CD5(+) B cells inhibit mast cells during immunoglobulin E-mediated allergic responses SO SCIENCE SIGNALING LA English DT Article ID T-HELPER-CELL; NONOBESE DIABETIC MICE; HYPERSENSITIVITY REACTIONS; B10 CELLS; IN-VIVO; DISEASE; ACTIVATION; IGE; LYMPHOCYTES; IMMUNITY AB Subsets of B cells inhibit various immune responses through their production of the cytokine interleukin-10 (IL-10). We found that IL-10-producing CD5(+) B cells suppressed the immunoglobulin E (IgE)- and antigen-mediated activation of mast cells in vitro as well as allergic responses in mice in an IL-10-dependent manner. Furthermore, the suppressive effect of these B cells on mast cells in vitro and in vivo depended on direct cell-to-cell contact through the costimulatory receptor CD40 on CD5(+) B cells and the CD40 ligand on mast cells. This contact enhanced the production of IL-10 by the CD5(+) B cells. Through activation of the Janus-activated kinase-signal transducer and activator of transcription 3 pathway, IL-10 decreased the abundance of the kinases Fyn and Fgr and inhibited the activation of the downstream kinase Syk in mast cells. Together, these findings suggest that an important function of IL-10-producing CD5(+) B cells is inhibiting mast cells and IgE-mediated allergic responses. C1 [Kim, Hyuk Soon; Kim, A-Ram; Kim, Do Kyun; Kim, Hyun Woo; Park, Young Hwan; Jang, Geun Hyo; Kim, Bokyung; Park, Yeong Min; You, Jueng Soo; Choi, Wahn Soo] Konkuk Univ, Sch Med, Chungju 380701, South Korea. [Kim, Hyung Sik] Sungkyunkwan Univ, Coll Pharm, Suwon 440746, South Korea. [Beaven, Michael A.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Kim, Young Mi] Duksung Womens Univ, Coll Pharm, Seoul 132714, South Korea. RP Choi, WS (reprint author), Konkuk Univ, Sch Med, Chungju 380701, South Korea. EM wahnchoi@kku.ac.kr FU National Research Foundation of Korea (NRF) grant [Ministry of Science, ICT, and Future Planning (MSIP)] [2012R1A2A1A03670516]; NRF grant (MSIP) - Korean government [NRF-2013R1A4A1069575]; Intramural Program of the National Heart, Lung, and Blood Institute, NIH FX This work was supported by the National Research Foundation of Korea (NRF) grant [Ministry of Science, ICT, and Future Planning (MSIP), No. 2012R1A2A1A03670516] and in part by an NRF grant (MSIP, NRF-2013R1A4A1069575) funded by the Korean government. M.A.B. was supported by the Intramural Program of the National Heart, Lung, and Blood Institute, NIH. NR 45 TC 6 Z9 6 U1 0 U2 1 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1945-0877 EI 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD MAR 17 PY 2015 VL 8 IS 368 AR ra28 DI 10.1126/scisignal.2005861 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CD6QR UT WOS:000351214700004 PM 25783157 ER PT J AU Murphy, TP Cutlip, DE Regensteiner, JG Mohler, ER Cohen, DJ Reynolds, MR Massaro, JM Lewis, BA Cerezo, J Oldenburg, NC Thum, CC Jaff, MR Comerota, AJ Steffes, MW Abrahamsen, IH Goldberg, S Hirsch, AT AF Murphy, Timothy P. Cutlip, Donald E. Regensteiner, Judith G. Mohler, Emile R., III Cohen, David J. Reynolds, Matthew R. Massaro, Joseph M. Lewis, Beth A. Cerezo, Joselyn Oldenburg, Niki C. Thum, Claudia C. Jaff, Michael R. Comerota, Anthony J. Steffes, Michael W. Abrahamsen, Ingrid H. Goldberg, Suzanne Hirsch, Alan T. TI Supervised Exercise, Stent Revascularization, or Medical Therapy for Claudication Due to Aortoiliac Peripheral Artery Disease The CLEVER Study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE angioplasty; ankle-brachial index; cilostazol; exercise rehabilitation; quality of life; walking ID PERCUTANEOUS TRANSLUMINAL ANGIOPLASTY; RANDOMIZED CONTROLLED TRIAL; INTERMITTENT CLAUDICATION; RISK-FACTORS; PREVALENCE; HEALTH; REHABILITATION; PLACEMENT; OUTCOMES; PROGRAM AB BACKGROUND Treatment for claudication that is due to aortoiliac peripheral artery disease (PAD) often relies on stent revascularization (ST). However, supervised exercise (SE) is known to provide comparable short-term (6-month) improvements in functional status and quality of life. Longer-term outcomes are not known. OBJECTIVES The goal of this study was to report the longer-term (18-month) efficacy of SE compared with ST and optimal medical care (OMC). METHODS Of 111 patients with aortoiliac PAD randomly assigned to receive OMC, OMC plus SE, or OMC plus ST, 79 completed the 18-month clinical and treadmill follow-up assessment. SE consisted of 6 months of SE and an additional year of telephone-based exercise counseling. Primary clinical outcomes included objective treadmill-based walking performance and subjective quality of life. RESULTS Peak walking time improved from baseline to 18 months for both SE (5.0 +/- 5.4 min) and ST (3.2 +/- 4.7 min) significantly more than for OMC (0.2 +/- 2.1 min; p < 0.001 and p = 0.04, respectively). The difference between SE and ST was not significant (p = 0.16). Improvement in claudication onset time was greater for SE compared with OMC, but not for ST compared with OMC. Many disease-specific quality-of-life scales demonstrated durable improvements that were greater for ST compared with SE or OMC. CONCLUSIONS Both SE and ST had better 18-month outcomes than OMC. SE and ST provided comparable durable improvement in functional status and in quality of life up to 18 months. The durability of claudication exercise interventions merits its consideration as a primary PAD claudication treatment. (C) 2015 by the American College of Cardiology Foundation. C1 [Murphy, Timothy P.; Cerezo, Joselyn] Rhode Isl Hosp, Vasc Dis Res Ctr, Dept Diagnost Imaging, Providence, RI 02903 USA. [Cutlip, Donald E.] Beth Israel Deaconess Med Ctr, Div Cardiol, Boston, MA 02215 USA. [Cutlip, Donald E.; Reynolds, Matthew R.; Massaro, Joseph M.; Thum, Claudia C.] Harvard Clin Res Inst, Boston, MA USA. [Regensteiner, Judith G.] Univ Colorado, Sch Med Aurora, Ctr Womens Hlth Res, Aurora, CO USA. [Mohler, Emile R., III] Univ Penn, Perelman Sch Med, Div Cardiovasc, Sect Vasc Med, Philadelphia, PA 19104 USA. [Cohen, David J.] Univ Missouri, Div Cardiol, Kansas City, MO 64110 USA. [Massaro, Joseph M.] Boston Univ, Dept Biostat, Boston, MA 02215 USA. [Lewis, Beth A.] Univ Minnesota, Sch Kinesiol, Minneapolis, MN USA. [Oldenburg, Niki C.; Steffes, Michael W.; Hirsch, Alan T.] Univ Minnesota, Sch Med, Div Cardiovasc, Lillehei Heart Inst, Minneapolis, MN 55455 USA. [Jaff, Michael R.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Comerota, Anthony J.] Toledo Hosp, Jobst Vasc Inst, Toledo, OH USA. [Goldberg, Suzanne] NHLBI, Bethesda, MD 20892 USA. RP Murphy, TP (reprint author), Rhode Isl Hosp, Vasc Dis Res Ctr, Gerry 337,593 Eddy St, Providence, RI 02903 USA. EM tmurphy@lifespan.org FU National Heart, Lung, and Blood Institute [HL77221, HL081656]; eV3; Boston Scientific; Abbott Vascular; Cordis/Johnson Johnson; Otsuka Pharmaceuticals; Medtronic; Cardiovascular Systems, Inc.; Aastrom Biosciences; Viromed; AstraZeneca; pedometers FX The CLEVER study was sponsored primarily by the National Heart, Lung, and Blood Institute (grants HL77221 and HL081656), and also received financial support from Cordis/Johnson & Johnson, eV3, and Boston Scientific. Throughout the study, Otsuka America donated cilostazol for all study participants. Omron Healthcare donated pedometers. Krames Stay well donated print materials on exercise and diet for study participants. Dr. Murphy has received research grant support from Abbott Vascular, Cordis/Johnson & Johnson, and Otsuka Pharmaceuticals. Dr. Cutlip has received either a research contract or grant support paid to his institution from Medtronic, Boston Scientific, and Abbott Vascular. Dr. Cohen has received research grant support from Medtronic, Boston Scientific, Abbott Vascular, and Cardiovascular Systems, Inc.; and has served as a consultant to Medtronic, Abbott Vascular, and Cardiovascular Systems, Inc. Dr. Reynolds has served as a consultant to Medtronic, Inc. Dr. Jaff has equity in Micell, Inc. and PQ Bypass; has served on the board of VIVA Physicians, Inc.; and has served as a consultant to Becker Venture Services Group, Abbott Vascular, Boston Scientific, Cordis Corporation, Covidien/eV3, and Medtronic Vascular. Dr. Hirsch has received research grants from Abbott Vascular, Aastrom Biosciences, Viromed, and AstraZeneca; and served as a consultant to Novartis and Merck & Co. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 36 TC 29 Z9 31 U1 2 U2 11 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 MAR 17 PY 2015 VL 65 IS 10 BP 999 EP 1009 DI 10.1016/j.jacc.2014.12.043 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CC8RK UT WOS:000350635600007 PM 25766947 ER PT J AU Jinsmaa, Y Cooney, A Sullivan, P Sharabi, Y Goldstein, DS AF Jinsmaa, Yunden Cooney, Adele Sullivan, Patricia Sharabi, Yehonatan Goldstein, David S. TI The serotonin aldehyde, 5-HIAL, oligomerizes alpha-synuclein SO NEUROSCIENCE LETTERS LA English DT Article DE Serotonin; Dopamine; 5-Hydroxyindolealdehyde; 3,4-Dihydroxyphenylacetaldehyde; Parkinson' disease ID REDUCED VESICULAR STORAGE; PARKINSONS-DISEASE; DOPAMINE; NORADRENALINE; METABOLITE; DOPAL AB In Parkinson's disease (PD) alpha-synuclein oligomers are thought to be pathogenic, and 3,4-dihydroxyphenylacetaldehyde (DOPAL), an obligate aldehyde intermediate in neuronal dopamine metabolism, potently oligomerizes alpha-synuclein. PD involves alpha-synuclein deposition in brain-stem raphe nuclei; however, whether 5-hydroxyindoleacetaldehyde (5-HIAL), the aldehyde of serotonin, oligomerizes alpha-synuclein has been unknown. In this study we tested whether 5-HIAL oligomerizes alpha-synuclein in vitro and in PC12 cells conditionally over-expressing alpha-synuclein. Alpha-synuclein oligomers were quantified by western blotting after incubation of alpha-synuclein with serotonin and monoamine oxidase-A (MAO-A) to generate 5-HIAL or dopamine to generate DOPAL. Oligomerization of alpha-synuclein in PC12 cells over-expressing the protein was compared between vehicle-treated cells and cells incubated with levodopa to generate DOPAL or 5-hydroxytryptophan to generate 5-HIAL. Monoamine aldehyde mediation of the oligomerization was assessed using the MAO inhibitor, pargyline. Dopamine and serotonin incubated with MAO-A both strongly oligomerized alpha-synuclein (more than 10 times control); pargyline blocked the oligomerization. In synuclein overexpressing PC12 cells, levodopa and 5-hydroxytryptophan elicited pargyline-sensitive alpha-synuclein oligomerization. 5-HIAL oligomerizes alpha-synuclein both in vitro and in synuclein-overexpressing PC12 cells, in a manner similar to DOPAL. The findings may help explain loss of serotonergic neurons in PD. (c) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Jinsmaa, Yunden; Cooney, Adele; Sullivan, Patricia; Goldstein, David S.] NINDS, Clin Neurocardiol Sect, CNP, DIR,NIH, Bethesda, MD 20892 USA. [Sharabi, Yehonatan] Chaim Sheba Med Ctr, Dept Internal Med, IL-52621 Tel Hashomer, Israel. RP Goldstein, DS (reprint author), NINDS, Clin Neurocardiol Sect, CNP, DIR,NIH, 9000 Rockville Pike,10-5N220, Bethesda, MD 20892 USA. EM goldsteind@ninds.nih.gov FU Intramural Research Program of the National Institute of Neurological Disorders and Stroke, NIH FX The research reported here was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, NIH. NR 11 TC 1 Z9 1 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 EI 1872-7972 J9 NEUROSCI LETT JI Neurosci. Lett. PD MAR 17 PY 2015 VL 590 BP 134 EP 137 DI 10.1016/j.neulet.2015.01.064 PG 4 WC Neurosciences SC Neurosciences & Neurology GA CD2QW UT WOS:000350925100026 PM 25637699 ER PT J AU Deshmukh, L Ghirlando, R Clore, GM AF Deshmukh, Lalit Ghirlando, Rodolfo Clore, G. Marius TI Conformation and dynamics of the Gag polyprotein of the human immunodeficiency virus 1 studied by NMR spectroscopy SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE HIV-1 Gag; interdomain motion; proteolytic processing; residual dipolar couplings; real time NMR ID HIV-1 CAPSID PROTEIN; DIPOLAR COUPLINGS; BIOLOGICAL MACROMOLECULES; NUCLEOCAPSID PROTEIN; CRYSTAL-STRUCTURES; CLEAVAGE SITES; DOMAIN; BINDING; ALIGNMENT; MEMBRANE AB Assembly and maturation of the human immunodeficiency virus type 1 (HIV-1) are governed by the Gag polyprotein. Here we study the conformation and dynamics of a large HIV-1 Gag fragment comprising the matrix, capsid, spacer peptide 1 and nucleocapsid domains (referred to as Delta Gag) by heteronuclear multidimensional NMR spectroscopy. In solution, Delta Gag exists in a dynamic equilibrium between monomeric and dimeric states. In the presence of nucleic acids and at low ionic strength Delta Gag assembles into immature virus-like particles. The structured domains of Delta Gag (matrix, the N- and C-terminal domains of capsid, and the N- and C-terminal zinc knuckles of nucleocapsid) retain their fold and reorient semi-independently of one another; the linkers connecting the structural domains, including spacer peptide 1 that connects capsid to nucleocapsid, are intrinsically disordered. Structural changes in Delta Gag upon proteolytic processing by HIV-1 protease, monitored by NMR in real-time, demonstrate that the conformational transition of the N-terminal 13 residues of capsid from an intrinsically disordered coil to a beta-hairpin upon cleavage at the matrix vertical bar capsid junction occurs five times faster than cleavage at the capsid vertical bar spacer peptide 1 vertical bar unction. Finally, nucleic acids interact with both nucleocapsid and matrix domains, and proteolytic processing at the spacer peptide 1 vertical bar nucleocapsid junction by HIV-1 protease is accelerated in the presence of single-stranded DNA. C1 [Deshmukh, Lalit; Clore, G. Marius] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Ghirlando, Rodolfo] NIDDK, Mol Biol, NIH, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDK, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. EM mariusc@mail.nih.gov RI Deshmukh, Lalit/C-5073-2015 FU NIH, NIDDK; Intramural AIDS Targeted Antiviral Program of the Office of the Director of the NIH FX We thank M. Bayro, M. Cai, V. Tugarinov, and V. Venditti for useful discussions; W. Sundquist for the gift of Delta Gag cDNA; and D. Garrett for technical support. This work was supported by funds from the Intramural Program of the NIH, NIDDK, and from the Intramural AIDS Targeted Antiviral Program of the Office of the Director of the NIH (to G.M.C.). NR 47 TC 11 Z9 11 U1 0 U2 20 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 MAR 17 PY 2015 VL 112 IS 11 BP 3374 EP 3379 DI 10.1073/pnas.1501985112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CD4NM UT WOS:000351060000068 PM 25713345 ER PT J AU Ament, SA Szelinger, S Glusman, G Ashworth, J Hou, LP Akula, N Shekhtman, T Badner, JA Brunkow, ME Mauldin, DE Stittrich, AB Rouleau, K Detera-Wadleigh, SD Nurnberger, JI Edenberg, HJ Gershon, ES Schork, N Price, ND Gelinas, R Hood, L Craig, D McMahon, FJ Kelsoe, JR Roach, JC AF Ament, Seth A. Szelinger, Szabolcs Glusman, Gustavo Ashworth, Justin Hou, Liping Akula, Nirmala Shekhtman, Tatyana Badner, Judith A. Brunkow, Mary E. Mauldin, Denise E. Stittrich, Anna-Barbara Rouleau, Katherine Detera-Wadleigh, Sevilla D. Nurnberger, John I., Jr. Edenberg, Howard J. Gershon, Elliot S. Schork, Nicholas Price, Nathan D. Gelinas, Richard Hood, Leroy Craig, David McMahon, Francis J. Kelsoe, John R. Roach, Jared C. CA Bipolar Genome Study TI Rare variants in neuronal excitability genes influence risk for bipolar disorder SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE bipolar disorder; family genomics; regulatory variants; GABA(A) receptor; voltage-gated calcium channel ID GENOME-WIDE ASSOCIATION; ADAMS-OLIVER SYNDROME; MAJOR DEPRESSION; SEQUENCING DATA; SCHIZOPHRENIA; EXPRESSION; MUTATIONS; DNA; FRAMEWORK; GENETICS AB We sequenced the genomes of 200 individuals from 41 families multiply affected with bipolar disorder (BD) to identify contributions of rare variants to genetic risk. We initially focused on 3,087 candidate genes with known synaptic functions or prior evidence from genome-wide association studies. BD pedigrees had an increased burden of rare variants in genes encoding neuronal ion channels, including subunits of GABA(A) receptors and voltage-gated calcium channels. Four uncommon coding and regulatory variants also showed significant association, including a missense variant in GABRA6. Targeted sequencing of 26 of these candidate genes in an additional 3,014 cases and 1,717 controls confirmed rare variant associations in ANK3, CACNA1B, CACNA1C, CACNA1D, C4CNG2, CAMK2A and NGF. Variants in promoters and 5' and 3' UTRs contributed more strongly than coding variants to risk for BD, both in pedigrees and in the case-control cohort. The genes and pathways identified in this study regulate diverse aspects of neuronal excitability. We conclude that rare variants in neuronal excitability genes contribute to risk for BD. C1 [Ament, Seth A.; Glusman, Gustavo; Ashworth, Justin; Brunkow, Mary E.; Mauldin, Denise E.; Stittrich, Anna-Barbara; Rouleau, Katherine; Price, Nathan D.; Gelinas, Richard; Hood, Leroy; Roach, Jared C.] Inst Syst Biol, Seattle, WA 98109 USA. [Szelinger, Szabolcs; Craig, David] Translat Genom Res Inst, Neurogen Div, Phoenix, AZ 85004 USA. [Hou, Liping; Akula, Nirmala; Detera-Wadleigh, Sevilla D.; McMahon, Francis J.] NIMH, Mood & Anxiety Disorders Sect, Human Genet Branch, Intramural Res Program,NIH,US Dept Hlth & Human S, Bethesda, MD 20892 USA. [Shekhtman, Tatyana; Kelsoe, John R.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Badner, Judith A.; Gershon, Elliot S.] Univ Chicago, Dept Psychiat, Chicago, IL 60637 USA. [Nurnberger, John I., Jr.] Indiana Univ Sch Med, Dept Psychiat, Indianapolis, IN 46202 USA. [Nurnberger, John I., Jr.; Edenberg, Howard J.] Indiana Univ Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46202 USA. [Edenberg, Howard J.] Indiana Univ Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA. [Schork, Nicholas] J Craig Venter Inst, La Jolla, CA 92037 USA. RP Hood, L (reprint author), Inst Syst Biol, Seattle, WA 98109 USA. EM lhood@systemsbiology.org; mcmahonf@intra.nimh.nih.gov; jkelsoe@ucsd.edu; jroach@systemsbiology.org RI Hou, Liping/G-1648-2011; OI Hou, Liping/0000-0003-3972-245X; Ashworth, Justin/0000-0003-4835-6551; McMahon, Francis/0000-0002-9469-305X; Glusman, Gustavo/0000-0001-8060-5955; Nurnberger, John/0000-0002-7674-1767; Edenberg, Howard/0000-0003-0344-9690 FU NIMH Bipolar Disorder Genetics Initiative [MH59545, MH059534, MH59533, MH59553, MH60068, MH059548, MH59535, MH59567, MH059556, 1Z01MH002810-01]; NIH from the National Cancer Institute [P50CA89392]; NIH from the National Institute of Drug Abuse [5K02DA021237]; University of Luxembourg Institute for Systems Biology Strategic Partnership; National Institute of General Medical Sciences Center for Systems Biology [P50 GM076547]; NIMH [R01 MH094483]; Intramural Research Program of the NIMH FX Most importantly, we thank the families who have participated in and contributed to these studies. We also thank the Rutgers University Cell and DNA Repository for transforming cell lines and providing DNA samples. Biomaterials and phenotypic data were obtained for control subjects from the National Institute of Mental Health (NIMH) Schizophrenia Genetics Initiative, which were collected by the "Molecular Genetics of Schizophrenia II" collaboration. Data and biomaterials were collected as part of 11 projects (Study 40) that participated in the NIMH Bipolar Disorder Genetics Initiative (MH59545, MH059534, MH59533, MH59553, MH60068, MH059548, MH59535, MH59567, MH059556, and 1Z01MH002810-01), which was also supported by NIH Grants P50CA89392, from the National Cancer Institute, and 5K02DA021237, from the National Institute of Drug Abuse. This work was supported by the University of Luxembourg Institute for Systems Biology Strategic Partnership, National Institute of General Medical Sciences Center for Systems Biology Grant P50 GM076547, NIMH Grant R01 MH094483, and the Intramural Research Program of the NIMH (F.J.M., principal investigator). J.A. is a Gordon and Betty Moore Foundation Fellow of the Life Sciences Research Foundation. NR 46 TC 27 Z9 28 U1 2 U2 12 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 MAR 17 PY 2015 VL 112 IS 11 BP 3576 EP 3581 DI 10.1073/pnas.1424958112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CD4NM UT WOS:000351060000102 PM 25730879 ER PT J AU Wang, WY Gao, Q Yang, MM Zhang, XL Yu, L Lawas, M Li, XR Bryant-Genevier, M Southall, NT Marugan, J Ferrer, M Xu, HX AF Wang, Wuyang Gao, Qiong Yang, Meimei Zhang, Xiaoli Yu, Lu Lawas, Maria Li, Xinran Bryant-Genevier, Marthe Southall, Noel T. Marugan, Juan Ferrer, Marc Xu, Haoxing TI Up-regulation of lysosomal TRPML1 channels is essential for lysosomal adaptation to nutrient starvation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE lysosome; starvation; TRPML1; TFEB; mTOR ID LIPID STORAGE DISORDERS; CELLULAR CLEARANCE; AUTOPHAGY; MTOR; TFEB; BIOGENESIS; ACTIVATION; TRAFFICKING; EXOCYTOSIS; PIKFYVE AB Upon nutrient starvation, autophagy digests unwanted cellular components to generate catabolites that are required for housekeeping biosynthesis processes. A complete execution of autophagy demands an enhancement in lysosome function and biogenesis to match the increase in autophagosome formation. Here, we report that mucolipin-1 (also known as TRPML1 or ML1), a Ca2+ channel in the lysosome that regulates many aspects of lysosomal trafficking, plays a central role in this quality-control process. By using Ca2+ imaging and whole-lysosome patch clamping, lysosomal Ca2+ release and ML1 currents were detected within hours of nutrient starvation and were potently up-regulated. In contrast, lysosomal Na+-selective currents were not upregulated. Inhibition of mammalian target of rapamycin (mTOR) or activation of transcription factor EB (TFEB) mimicked a starvation effect in fed cells. The starvation effect also included an increase in lysosomal proteostasis and enhanced clearance of lysosomal storage, including cholesterol accumulation in Niemann-Pick disease type C (NPC) cells. However, this effect was not observed when ML1 was pharmacologically inhibited or genetically deleted. Furthermore, overexpression of ML1 mimicked the starvation effect. Hence, lysosomal adaptation to environmental cues such as nutrient levels requires mTOR/TFEB-dependent, lysosome-to-nucleus regulation of lysosomal ML1 channels and Ca2+ signaling. C1 [Wang, Wuyang; Gao, Qiong; Yang, Meimei; Zhang, Xiaoli; Yu, Lu; Lawas, Maria; Li, Xinran; Xu, Haoxing] Univ Michigan, Dept Mol Cellular & Dev Biol, Ann Arbor, MI 48109 USA. [Bryant-Genevier, Marthe; Southall, Noel T.; Marugan, Juan; Ferrer, Marc] NIH, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. RP Xu, HX (reprint author), Univ Michigan, Dept Mol Cellular & Dev Biol, Ann Arbor, MI 48109 USA. EM haoxingx@umich.edu RI Southall, Noel/H-8991-2012; di Ronza, Alberto/H-7674-2016 OI Southall, Noel/0000-0003-4500-880X; di Ronza, Alberto/0000-0002-9813-5143 FU NIH [NS062792, MH096595, AR060837] FX WT control and NPC CHO cells were a gift from Dr. T.Y. Chang (Dartmouth Medical School). We thank Drs. Rosa Puertollano (NIH) and Andrea Ballabio (Telethon Institute of Genetics and Medicine, TIGEM) for the human TFEB plasmid, Dr. Johnny Fares (University of Arizona) for the ML1-overexpressing RAW macrophage, and Dr. Susan Slaugenhaupt (Harvard Medical School) for the ML1 KO mice, as well as H.X. laboratory members for encouragement and helpful comments. This work was supported by NIH Grants NS062792, MH096595, and AR060837 (to H.X.). NR 48 TC 19 Z9 19 U1 6 U2 14 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 MAR 17 PY 2015 VL 112 IS 11 BP E1373 EP E1381 DI 10.1073/pnas.1419669112 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CD4NM UT WOS:000351060000027 PM 25733853 ER PT J AU Nan, HM Hutter, CM Lin, Y Jacobs, EJ Ulrich, CM White, E Baron, JA Berndt, SI Brenner, H Butterbach, K Caan, BJ Campbell, PT Carlson, CS Casey, G Chang-Claude, J Chanock, SJ Cotterchio, M Duggan, D Figueiredo, JC Fuchs, CS Giovannucci, EL Gong, J Haile, RW Harrison, TA Hayes, RB Hoffmeister, M Hopper, JL Hudson, TJ Jenkins, MA Jiao, S Lindor, NM Lemire, M Le Marchand, L Newcomb, PA Ogino, S Pflugeisen, BM Potter, JD Qu, CH Rosse, SA Rudolph, A Schoen, RE Schumacher, FR Seminara, D Slattery, ML Thibodeau, SN Thomas, F Thornquist, M Warnick, GS Zanke, BW Gauderman, WJ Peters, U Hsu, L Chan, AT AF Nan, Hongmei Hutter, Carolyn M. Lin, Yi Jacobs, Eric J. Ulrich, Cornelia M. White, Emily Baron, John A. Berndt, Sonja I. Brenner, Hermann Butterbach, Katja Caan, Bette J. Campbell, Peter T. Carlson, Christopher S. Casey, Graham Chang-Claude, Jenny Chanock, Stephen J. Cotterchio, Michelle Duggan, David Figueiredo, Jane C. Fuchs, Charles S. Giovannucci, Edward L. Gong, Jian Haile, Robert W. Harrison, Tabitha A. Hayes, Richard B. Hoffmeister, Michael Hopper, John L. Hudson, Thomas J. Jenkins, Mark A. Jiao, Shuo Lindor, Noralane M. Lemire, Mathieu Le Marchand, Loic Newcomb, Polly A. Ogino, Shuji Pflugeisen, Bethann M. Potter, John D. Qu, Conghui Rosse, Stephanie A. Rudolph, Anja Schoen, Robert E. Schumacher, Fredrick R. Seminara, Daniela Slattery, Martha L. Thibodeau, Stephen N. Thomas, Fridtjof Thornquist, Mark Warnick, Greg S. Zanke, Brent W. Gauderman, W. James Peters, Ulrike Hsu, Li Chan, Andrew T. CA CCFR GECCO TI Association of Aspirin and NSAID Use With Risk of Colorectal Cancer According to Genetic Variants SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID GENOME-WIDE ASSOCIATION; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; PROSTAGLANDIN E-2 BIOSYNTHESIS; COLON-CANCER; PIK3CA MUTATION; METAANALYSIS; CYCLOOXYGENASE-2; CHEMOPREVENTION; INTERLEUKIN-16; POLYMORPHISMS AB IMPORTANCE Use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with lower risk of colorectal cancer. OBJECTIVE To identify common genetic markers that may confer differential benefit from aspirin or NSAID chemoprevention, we tested gene x environment interactions between regular use of aspirin and/or NSAIDs and single-nucleotide polymorphisms (SNPs) in relation to risk of colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS Case-control study using data from 5 case-control and 5 cohort studies initiated between 1976 and 2003 across the United States, Canada, Australia, and Germany and including colorectal cancer cases (n=8634) and matched controls (n=8553) ascertained between 1976 and 2011. Participants were all of European descent. EXPOSURES Genome-wide SNP data and information on regular use of aspirin and/or NSAIDs and other risk factors. MAIN OUTCOMES AND MEASURES Colorectal cancer. RESULTS Regular use of aspirin and/or NSAIDs was associated with lower risk of colorectal cancer (prevalence, 28% vs 38%; odds ratio [OR], 0.69 [95% Cl, 0.64-0.74]; P = 6.2 x 10(-28)) compared with nonregular use. In the conventional logistic regression analysis, the SNP rs2965667 at chromosome 12p12.3 near the MGST1 gene showed a genome-wide significant interaction with aspirin and/or NSAID use (P = 4.6 x 10(-9) for interaction). Aspirin and/or NSAID use was associated with a lower risk of colorectal cancer among individuals with rs2965667-TT genotype (prevalence, 28% vs 38%; OR, 0.66 [95% CI, 0.61-0.70]; P =7.7 x 10(-33)) but with a higher risk among those with rare (4%) TA or AA genotypes (prevalence, 35% vs 29%; OR, 1.89 [95% Cl, 1.27-2.81]; P = .002). In case-only interaction analysis, the SNP rs16973225 at chromosome 15q25.2 near the IL16 gene showed a genome-wide significant interaction with use of aspirin and/or NSAIDs (P = 8.2 x 10(-9) for interaction). Regular use was associated with a lower risk of colorectal cancer among individuals with rs16973225-AA genotype (prevalence, 28% vs 38%; OR, 0.66 [95% CI, 0.62-0.71]; P = 1.9 x 10(-30)) but was not associated with risk of colorectal cancer among those with less common (9%) AC or CC genotypes (prevalence, 36% vs 39%; OR, 0.97 [95% Cl, 0.78-1.20]; P = .76). CONCLUSIONS AND RELEVANCE In this genome-wide investigation of gene x environment interactions, use of aspirin and/or NSAIDs was associated with lower risk of colorectal cancer, and this association differed according to genetic variation at 2 SNPs at chromosomes 12 and 15. Validation of these findings in additional populations may facilitate targeted colorectal cancer prevention strategies. C1 [Nan, Hongmei] Indiana Univ, Richard M Fairbanks Sch Publ Hlth, Dept Epidemiol, Indianapolis, IN 46204 USA. [Nan, Hongmei] Indiana Univ, Melvin & Bren Simon Canc Ctr, Indianapolis, IN 46204 USA. [Hutter, Carolyn M.; Seminara, Daniela] NHGRI, NIH, Bethesda, MD 20892 USA. [Lin, Yi; Ulrich, Cornelia M.; White, Emily; Carlson, Christopher S.; Gong, Jian; Harrison, Tabitha A.; Jiao, Shuo; Newcomb, Polly A.; Pflugeisen, Bethann M.; Potter, John D.; Qu, Conghui; Rosse, Stephanie A.; Thornquist, Mark; Warnick, Greg S.; Peters, Ulrike; Hsu, Li] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Jacobs, Eric J.; Campbell, Peter T.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Ulrich, Cornelia M.] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA. [White, Emily; Peters, Ulrike] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Baron, John A.] Univ N Carolina, Sch Med, Div Gastroenterol & Hepatol, Chapel Hill, NC USA. [Berndt, Sonja I.; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Brenner, Hermann; Butterbach, Katja; Hoffmeister, Michael] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Brenner, Hermann] German Canc Consortium DKTK, Heidelberg, Germany. [Caan, Bette J.] Kaiser Permanente Med Care Program No Calif, Div Res, Oakland, CA USA. [Casey, Graham; Figueiredo, Jane C.; Haile, Robert W.; Schumacher, Fredrick R.; Gauderman, W. James] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Chang-Claude, Jenny; Rudolph, Anja] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Cotterchio, Michelle] Canc Care Ontario, Prevent & Canc Control, Toronto, ON, Canada. [Duggan, David] Translat Genom Res Inst TGen, Genet Basis Human Dis Div, Phoenix, AZ USA. [Fuchs, Charles S.; Ogino, Shuji] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Giovannucci, Edward L.; Chan, Andrew T.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Channing Div Network Med, Boston, MA 02115 USA. [Hayes, Richard B.] NYU, Sch Med, Dept Populat Hlth, Div Epidemiol, New York, NY USA. [Hopper, John L.; Jenkins, Mark A.] Univ Melbourne, Melbourne Sch Populat Hlth, Melbourne, Vic 3010, Australia. [Hudson, Thomas J.] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada. [Hudson, Thomas J.; Lemire, Mathieu] Ontario Inst Canc Res, Toronto, ON, Canada. [Lindor, Noralane M.] Mayo Clin, Dept Hlth Sci Res, Scottsdale, AZ USA. [Le Marchand, Loic] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96822 USA. [Ogino, Shuji] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Ogino, Shuji] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Potter, John D.] Massey Univ, Ctr Publ Hlth Res, Wellington, New Zealand. [Schoen, Robert E.] Univ Pittsburgh, Med Ctr, Dept Med & Epidemiol, Pittsburgh, PA USA. [Slattery, Martha L.] Univ Utah, Hlth Sci Ctr, Dept Internal Med, Salt Lake City, UT USA. [Thibodeau, Stephen N.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Thibodeau, Stephen N.] Mayo Clin, Dept Med Genet, Rochester, MN USA. [Thomas, Fridtjof] Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Div Biostat & Epidemiol, Memphis, TN 38163 USA. [Zanke, Brent W.] Ottawa Hosp, Res Inst, Clin Epidemiol Program, Ottawa, ON, Canada. [Hsu, Li] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Chan, Andrew T.] Harvard Univ, Sch Med, Boston, MA USA. RP Hsu, L (reprint author), Fred Hutchinson Canc Res Ctr, 1100 Fairview Ave North,M2-B500, Seattle, WA 98109 USA. EM lih@fredhutch.org; achan@mgh.harvard.edu RI Hoffmeister, Michael/B-5745-2012; Jenkins, Mark/P-7803-2015; Brenner, Hermann/B-4627-2017; OI Hoffmeister, Michael/0000-0002-8307-3197; Jenkins, Mark/0000-0002-8964-6160; Brenner, Hermann/0000-0002-6129-1572; Potter, John/0000-0001-5439-1500; Hayes, Richard/0000-0002-0918-661X FU National Cancer Institute (NCI), National Institutes of Health (NIH), US Department of Health and Human Services [U01 CA137088, RO1 CA059045]; NIH [RFA CA-95-011, R01 CA48998, P01 CA 055075, UM1 CA167552, R01137178, R01 CA137178, P01 CA 087969, RO1 CA151993, P50 CA 127003, U01 CA074783, R01 CA076366, K05 CA154337]; NCI, NIH [U01 CA122839]; NIH: Australasian Colorectal Cancer Family Registry [U01 CA097735]; Ontario Registry for Studies of Familial Colorectal Cancer [U01 CA074783]; Seattle Colorectal Cancer Family Registry [U01 CA074794]; German Research Council (Deutsche Forschungsgemeinschaft) [BR 1704/6-1, BR 1704163, BR 1704/6-4, CH 117/1-1]; German Federal Ministry of Education and Research [01KH0404, 01ER0814]; Ontario Research Fund [GL2]; Canadian Institutes of Health Research; Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society Research Institute; Ontario Institute for Cancer Research through Ontario Ministry of Research and Innovation; Division of Cancer Epidemiology and Genetics; Division of Cancer Prevention, NCI, NIH, Department of Health and Human Services; National Heart, Lung, and Blood Institute, NIH, US Department of Health and Human Services [HHSN268201100046C, HH5N268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C]; [K24 DK098311] FX GECCO (Genetics and Epidemiology of Colorectal Cancer Consortium) was supported by the National Cancer Institute (NCI), National Institutes of Health (NIH), US Department of Health and Human Services (U01 CA137088; RO1 CA059045). CCFR (Colon Cancer Family Registry) was supported by the NIH (RFA CA-95-011) and through cooperative agreements with members of the Colon Cancer Family Registry and prinicipal investigators. This genome wide scan was supported by the NCI, NIH, by U01 CA122839. The following Colon CFR centers contributed data to this manuscript and were supported by NIH: Australasian Colorectal Cancer Family Registry (U01 CA097735), Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783), and Seattle Colorectal Cancer Family Registry (U01 CA074794). DACHS (Darmkrebs: Chancen der Verhutung durch Screening Study) is supported by the German Research Council (Deutsche Forschungsgemeinschaft, BR 1704/6-1, BR 1704163, BR 1704/6-4 and CH 117/1-1) and the German Federal Ministry of Education and Research (01KH0404 and 01ER0814). DALS (Diet, Activity and Lifestyle Study) is suported by the NIH (R01 CA48998 to Dr Slattery). HPFS (Health Professionals Follow-up Study) is supported by the NIH (P01 CA 055075, UM1 CA167552, R01137178, RO1 CA151993, and P50 CA 127003) and the NHS (Nurses Health Study) by the NIH (R01 CA137178, P01 CA 087969, RO1 CA151993, and P50 CA 127003). Dr Chan is also supported by K24 DK098311 and is a Damon Runyon Clinical Investigator. OFCCR (Ontario Familial Colorectal Cancer Registry) is supported by the NIH through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783) (see CCFR section above). As subset of ARCTIC, OFCCR is supported by a GL2 grant from the Ontario Research Fund, the Canadian Institutes of Health Research, and the Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society Research Institute. Dr Hudson and Dr Zanke are recipients of Senior Investigator Awards from the Ontario Institute for Cancer Research, through generous support from the Ontario Ministry of Research and Innovation. PLCO (Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial) is supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and by contracts from the Division of Cancer Prevention, NCI, NIH, Department of Health and Human Services. PMH-CCFR (Postmenopausal Hormone Study-Colon Cancer Family Registry) is suported by the NIH (R01 CA076366 to Dr Newcomb). VITAL (VITamins And Lifestyle) is supported by the NIH (K05 CA154337). WHI (Women's Health Initiative) is supported by the National Heart, Lung, and Blood Institute, NIH, US Department of Health and Human Services, through contracts HHSN268201100046C, HH5N268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. NR 40 TC 42 Z9 43 U1 8 U2 30 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 MAR 17 PY 2015 VL 313 IS 11 BP 1133 EP 1142 DI 10.1001/jama.2015.1815 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA CD5BP UT WOS:000351102500015 PM 25781442 ER PT J AU Jarvik, JG Gold, LS Comstock, BA Heagerty, PJ Rundell, SD Turner, JA Avins, AL Bauer, Z Bresnahan, BW Friedly, JL James, K Kessler, L Nedeljkovic, SS Nerenz, DR Shi, X Sullivan, SD Chan, L Schwalb, JM Deyo, RA AF Jarvik, Jeffrey G. Gold, Laura S. Comstock, Bryan A. Heagerty, Patrick J. Rundell, Sean D. Turner, Judith A. Avins, Andrew L. Bauer, Zoya Bresnahan, Brian W. Friedly, Janna L. James, Kathryn Kessler, Larry Nedeljkovic, Srdjan S. Nerenz, David R. Shi, Xu Sullivan, Sean D. Chan, Leighton Schwalb, Jason M. Deyo, Richard A. TI Associaion of Early Imaging for Back Pain With Clinical Outcomes in Older Adults SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID BASE-LINE DATA; COMORBIDITY INDEX; LONGITUDINAL DATA; AMERICAN-COLLEGE; DISABILITY; PHYSICIANS; METAANALYSIS; PREVALENCE; MANAGEMENT; SCIATICA AB IMPORTANCE In contrast to the recommendations for younger adults, many guidelines allow for older adults with back pain to undergo imaging without waiting 4 to 6 weeks. However, early imaging may precipitate interventions that do not improve outcomes. OBJECTIVE To compare function and pain at the 12-month follow-up visit among older adults who received early imaging with those who did not receive early imaging after a new primary care visit for back pain without radiculopathy. DESIGN, SETTING, AND PARTICIPANTS Prospective cohort of 5239 patients 65 years or older with a new primary care visit for back pain (2011-2013) in 3 US health care systems. We matched controls 1:1 using propensity score matching of demographic and clinical characteristics, including diagnosis, pain severity, pain duration, functional status, and prior resource use. EXPOSURES Diagnostic imaging (plain films, computed tomography [CT], magnetic resonance imaging [MRI]) of the lumbar or thoracic spine within 6 weeks of the index visit. MAIN OUTCOME AND MEASURES Primary outcome: back or leg pain-related disability measured by the modified Roland-Morris Disability Questionnaire (score range, 0-24; higher scores indicate greater disability) 12 months after enrollment. RESULTS Among the 5239 patients, 1174 had early radiographs and 349 had early MRI/CT. At 12 months, neither the early radiograph group nor the early MRI/CT group differed significantly from controls on the disability questionnaire. The mean score for patients who underwent early radiography was 8.54 vs 8.74 among the control group (difference, -0.10 [95% Cl, -0.71 to 0.50]; mixed model, P = .36). The mean score for the early MRI/CT group was 9.81 vs 10.50 for the control group (difference,-0.51[-1.62 to 0.60]; mixed model, P=.18). CONCLUSIONS AND RELEVANCE Among older adults with a new primary care visit for back pain, early imaging was not associated with better 1-year outcomes. The value of early diagnostic imaging in older adults for back pain without radiculopathy is uncertain. C1 [Jarvik, Jeffrey G.; Gold, Laura S.; Bauer, Zoya; Bresnahan, Brian W.; James, Kathryn] Univ Washington, Dept Radiol, Seattle, WA 98104 USA. [Jarvik, Jeffrey G.] Univ Washington, Dept Neurol Surg, Seattle, WA 98104 USA. [Jarvik, Jeffrey G.; Kessler, Larry] Univ Washington, Dept Hlth Serv, Seattle, WA 98104 USA. [Jarvik, Jeffrey G.; Gold, Laura S.; Comstock, Bryan A.; Heagerty, Patrick J.; Rundell, Sean D.; Turner, Judith A.; Bauer, Zoya; Bresnahan, Brian W.; Friedly, Janna L.] Univ Washington, Comparat Effectiveness Cost & Outcomes Res Ctr, Seattle, WA 98104 USA. [Comstock, Bryan A.; Heagerty, Patrick J.; Shi, Xu] Univ Washington, Dept Biostat, Seattle, WA 98104 USA. [Turner, Judith A.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98104 USA. [Rundell, Sean D.; Friedly, Janna L.] Univ Washington, Dept Rehabil Med, Seattle, WA 98104 USA. [Nedeljkovic, Srdjan S.] Brigham & Womens Hosp, Dept Anesthesiol Perioperat & Pain Med, Boston, MA 02115 USA. [Nedeljkovic, Srdjan S.] Harvard Vanguard Med Associates, Spine Unit, Boston, MA USA. [Nerenz, David R.] Henry Ford Hosp, Neurosci Inst, Detroit, MI 48202 USA. [Avins, Andrew L.] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Jarvik, Jeffrey G.; Gold, Laura S.; Sullivan, Sean D.] Univ Washington, Dept Pharm, Seattle, WA 98104 USA. [Chan, Leighton] NIH, Dept Rehabil Med, Mark O Hatfield Clin Res Ctr, Bethesda, MD 20892 USA. [Schwalb, Jason M.] Henry Ford Hlth Syst, Dept Neurosurg, Detroit, MI USA. [Schwalb, Jason M.] Henry Ford Hlth Syst, Ctr Hlth Policy & Hlth Serv Res, Detroit, MI USA. [Deyo, Richard A.] Oregon Hlth & Sci Univ, Dept Family Med Internal Med & Publ Hlth & Preven, Portland, OR 97201 USA. [Deyo, Richard A.] Oregon Hlth & Sci Univ, Oregon Inst Occupat Hlth Sci, Portland, OR 97201 USA. RP Jarvik, JG (reprint author), Univ Washington, CECORC, Dept Radiol, POB 359728,325 Ninth Ave, Seattle, WA 98104 USA. EM jarvikj@uw.edu OI Rundell, Sean/0000-0003-0782-5999 FU Agency for Healthcare Research and Quality (AHRQ) [1R01HS01922201, 1R01HS022972-01]; NIH Intramural Research Program FX This work was supported by grants 1R01HS01922201 and 1R01HS022972-01 from the Agency for Healthcare Research and Quality (AHRQ) and from the NIH Intramural Research Program (Dr Chan's time). NR 43 TC 13 Z9 14 U1 2 U2 5 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 MAR 17 PY 2015 VL 313 IS 11 BP 1143 EP 1153 DI 10.1001/jama.2015.1871 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA CD5BP UT WOS:000351102500016 PM 25781443 ER PT J AU Gopal, AD Desai, NR Tse, T Ross, JS AF Gopal, Anand D. Desai, Nihar R. Tse, Tony Ross, Joseph S. TI Reporting of Noninferiority Trials in ClinicalTrials.gov and Corresponding Publications SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID EQUIVALENCE RANDOMIZED-TRIALS C1 [Gopal, Anand D.] Yale Univ, Sch Med, New Haven, CT 06520 USA. [Desai, Nihar R.; Ross, Joseph S.] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06520 USA. [Tse, Tony] NIH, Natl Lib Med, Bethesda, MD 20892 USA. RP Ross, JS (reprint author), Yale Univ, Sch Med, Gen Internal Med Sect, POB 208093, New Haven, CT 06520 USA. EM joseph.ross@yale.edu FU Intramural NIH HHS; NIA NIH HHS [K08 AG032886] NR 6 TC 3 Z9 3 U1 0 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 MAR 17 PY 2015 VL 313 IS 11 BP 1163 EP 1165 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA CD5BP UT WOS:000351102500020 PM 25781447 ER PT J AU Choi, A Shanbhag, S Bronson, K Saba, S LaRocca, G Ertel, A Rao, A Yu, J Parikh, K Leifer, E Arai, A Chen, M AF Choi, Andrew Shanbhag, Sujata Bronson, Kathie Saba, Shahryar LaRocca, Gina Ertel, Andrew Rao, Anu Yu, Jeannie Parikh, Kalindi Leifer, Eric Arai, Andrew Chen, Marcus TI CLINICALLY EQUIVALENT CORONARY ARTERY CALCIFICATION SCORING AT 70% LOWER DOSE RADIATION WITH ITERATIVE RECONSTRUCTION VERSUS STANDARD DOSE RADIATION SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT Scientific Session of the American-College-of-Cardiology (ACC) CY MAR 14-16, 2015 CL San Diego, CA SP Amer Coll Cardiol C1 NHLBI, NIH, Bethesda, MD 20892 USA. Medstar Washington Hosp Ctr, Div Cardiol, Washington, DC 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 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 17 PY 2015 VL 65 IS 10 SU S BP A1165 EP A1165 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DL0ND UT WOS:000375328801485 ER PT J AU Greve, AM Schelbert, E Launer, L Harris, T Thorgeirsson, G Eiriksdottir, G LaRocca, G Aspelund, T Gudnason, V Arai, A AF Greve, Anders M. Schelbert, Erik Launer, Lenore Harris, Tamara Thorgeirsson, Gudmundur Eiriksdottir, Gudny LaRocca, Gina Aspelund, Thor Gudnason, Vilmundur Arai, Andrew TI INFLUENCE OF AGE ON THE PROGNOSTIC PERFORMANCE OF BRAIN NATRIURETIC PEPTIDES: THE AGES REYKJAVIK STUDY SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT Scientific Session of the American-College-of-Cardiology (ACC) CY MAR 14-16, 2015 CL San Diego, CA SP Amer Coll Cardiol C1 [Greve, Anders M.; Schelbert, Erik; Launer, Lenore; Harris, Tamara; Thorgeirsson, Gudmundur; Eiriksdottir, Gudny; LaRocca, Gina; Aspelund, Thor; Gudnason, Vilmundur; Arai, Andrew] NHLBI, 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 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 17 PY 2015 VL 65 IS 10 SU S MA 1128M-03 BP A770 EP A770 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DL0ND UT WOS:000375328801090 ER PT J AU Hammer-Hansen, S Bandettini, WP Hsu, LY Leung, S Shanbhag, S Mancini, C Greve, A Kober, L Thune, JJ Kellman, P Arai, A AF Hammer-Hansen, Sophia Bandettini, W. Patricia Hsu, Li-Yueh Leung, Steve Shanbhag, Sujata Mancini, Christine Greve, Anders Kober, Lars Thune, Jens Jakob Kellman, Peter Arai, Andrew TI EARLY GADOLINIUM ENHANCEMENT OVERESTIMATES HUMAN INFARCT SIZE IN ACUTE MYOCARDIAL INFARCTION: A QUANTITATIVE AND KINETIC STUDY SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT Scientific Session of the American-College-of-Cardiology (ACC) CY MAR 14-16, 2015 CL San Diego, CA SP Amer Coll Cardiol C1 [Hammer-Hansen, Sophia; Bandettini, W. Patricia; Hsu, Li-Yueh; Leung, Steve; Shanbhag, Sujata; Mancini, Christine; Greve, Anders; Kober, Lars; Thune, Jens Jakob; Kellman, Peter; Arai, Andrew] NIH, Bethesda, MD 20892 USA. RI Leung, Steve/E-5624-2011 OI Leung, Steve/0000-0003-2832-2258 NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 17 PY 2015 VL 65 IS 10 SU S MA 1172-009 BP A1196 EP A1196 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DL0ND UT WOS:000375328801516 ER PT J AU Lewis, EF Claggett, B Liu, JK Boineau, R Desai, A Solomon, S Anand, I Sweitzer, N Rouleau, JL Fang, J Thaik, C O'Meara, E Retta, TM Clausell, N McKinlay, S Pitt, B Pfeffer, M AF Lewis, Eldrin F. Claggett, Brian Liu, JianKang Boineau, Robin Desai, Akshay Solomon, Scott Anand, Inderjit Sweitzer, Nancy Rouleau, Jean L. Fang, James Thaik, Cynthia O'Meara, Eileen Retta, Tamrat M. Clausell, Nadine McKinlay, Sonja Pitt, Bertram Pfeffer, Marc TI BLACK RACE ASSOCIATED WITH WORSE OUTCOMES IN AMBULATORY HEART FAILURE PRESERVED EJECTION FRACTION PATIENTS SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT Scientific Session of the American-College-of-Cardiology (ACC) CY MAR 14-16, 2015 CL San Diego, CA SP Amer Coll Cardiol C1 Brigham & Womens Hosp, Boston, MA 02115 USA. NHLBI, 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 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 17 PY 2015 VL 65 IS 10 SU S MA 1113-220 BP A837 EP A837 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DL0ND UT WOS:000375328801157 ER PT J AU Natarajan, B Salahuddin, T Sadek, H Playford, M Doveikis, J Reddy, A Naik, H Herschovitch, P Mehta, N AF Natarajan, Balaji Salahuddin, Taufiq Sadek, Hadeel Playford, Martin Doveikis, Julia Reddy, Aarthi Naik, Haley Herschovitch, Peter Mehta, Nehal TI DETERMINANTS OF VASCULAR INFLAMMATION USING [18F]-FLUORODEOXYGLUCOSE PET/CT: FINDINGS FROM THE PSORIASIS, ATHEROSCLEROSIS AND CARDIOMETABOLIC DISEASE INITIATIVE (PACI) SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT Scientific Session of the American-College-of-Cardiology (ACC) CY MAR 14-16, 2015 CL San Diego, CA SP Amer Coll Cardiol C1 [Natarajan, Balaji; Salahuddin, Taufiq; Sadek, Hadeel; Playford, Martin; Doveikis, Julia; Reddy, Aarthi; Naik, Haley; Herschovitch, Peter; Mehta, Nehal] NHLBI, 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 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 17 PY 2015 VL 65 IS 10 SU S MA 1101-016 BP A1101 EP A1101 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DL0ND UT WOS:000375328801421 ER PT J AU Salahuddin, T Natarajan, B Selwaness, M Sadek, A Playford, M Doveikis, J Nanda, N Bluemke, D Mehta, N AF Salahuddin, Taufiq Natarajan, Balaji Selwaness, Mariana Sadek, Ahmed Playford, Martin Doveikis, Julia Nanda, Navya Bluemke, David Mehta, Nehal TI VASCULAR INFLAMMATION IN THE AORTA IS RELATED TO CORONARY PLAQUE BURDEN IN PSORIASIS SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT Scientific Session of the American-College-of-Cardiology (ACC) CY MAR 14-16, 2015 CL San Diego, CA SP Amer Coll Cardiol C1 [Salahuddin, Taufiq; Natarajan, Balaji; Selwaness, Mariana; Sadek, Ahmed; Playford, Martin; Doveikis, Julia; Nanda, Navya; Bluemke, David; Mehta, Nehal] NHLBI, 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 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 17 PY 2015 VL 65 IS 10 SU S MA 1207-035 BP A1272 EP A1272 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DL0ND UT WOS:000375328801592 ER PT J AU Sandeep, N Kanter, J Leatherbury, L Mukouyama, YS AF Sandeep, Nefthi Kanter, Joshua Leatherbury, Linda Mukouyama, Yoh-suke TI CHARACTERIZING THE ANGIOGENIC ACTIVITY OF SINGLE VENTRICLE PATIENTS WITH AORTOPULMONARY COLLATERAL VESSELS SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT Scientific Session of the American-College-of-Cardiology (ACC) CY MAR 14-16, 2015 CL San Diego, CA SP Amer Coll Cardiol C1 Childrens Natl Hlth Syst, Washington, DC USA. 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 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 17 PY 2015 VL 65 IS 10 SU S MA 1168M-05 BP A491 EP A491 DI 10.1016/S0735-1097(15)60491-0 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DL0ND UT WOS:000375328800492 ER PT J AU Vargas, JD Manichaikul, AW Chen, M Arai, A Mullikin, J Bluemke, D Biesecker, L AF Vargas, Jose D. Manichaikul, Ani W. Chen, Marcus Arai, Andrew Mullikin, James Bluemke, David Biesecker, Leslie TI RARE VARIANTS IN SORT1 ASSOCIATE WITH CORONARY ARTERY CALCIUM IN THE CLINSEQ STUDY SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT Scientific Session of the American-College-of-Cardiology (ACC) CY MAR 14-16, 2015 CL San Diego, CA SP Amer Coll Cardiol C1 MedStar Georgetown Univ Hosp, Washington, DC USA. 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 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 17 PY 2015 VL 65 IS 10 SU S MA 1124M-09 BP A1064 EP A1064 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DL0ND UT WOS:000375328801384 ER PT J AU Krumm, BE Grisshammer, R AF Krumm, Brian E. Grisshammer, Reinhard TI Peptide ligand recognition by G protein-coupled receptors SO FRONTIERS IN PHARMACOLOGY LA English DT Article DE neurotensin receptor; peptide agonist; peptide GPCRs; GPCR structure; chemokine receptors; opioid receptors; protease activated receptors ID RESOLUTION CRYSTAL-STRUCTURE; OPIOID RECEPTOR; NEUROTENSIN RECEPTOR; THROMBIN RECEPTOR; COMPLEX; AGONIST; CHEMOKINE; ADRENOCEPTOR; ANTAGONISTS; CXCR4 AB The past few years have seen spectacular progress in the structure determination of G protein-coupled receptors (GPCRs). We now have structural representatives from classes A, B, C, and F. Within the rhodopsin-like class A, most structures belong to the a group, whereas fewer GPCR structures are available from the beta, gamma, and groups, which include peptide GPCRs such as the receptors for neurotensin (beta group), opioids, chemokines (gamma group), and protease-activated receptors (F, group). Structural information on peptide GPCRs is restricted to complexes with non-peptidic drug-like antagonists with the exception of the chemokine receptor CXCR4 that has been crystallized in the presence of a cyclic peptide antagonist. Notably, the neurotensin receptor 1 is to date the only peptide GPCR whose structure has been solved in the presence of a peptide agonist. Although limited in number, the current peptide GPCR structures reveal great diversity in shape and electrostatic properties of the ligand binding pockets, features that play key roles in the discrimination of ligands. Here, we review these aspects of peptide GPCRs in view of possible models for peptide agonist binding. C1 [Krumm, Brian E.; Grisshammer, Reinhard] NINDS, Membrane Prot Struct Funct Unit, NIH, Rockville, MD 20852 USA. RP Grisshammer, R (reprint author), NINDS, Membrane Prot Struct Funct Unit, NIH, 5625 Fishers Lane,Room 4S12, Rockville, MD 20852 USA. EM rkgriss@helix.nih.gov FU National Institute of Neurological Disorders and Stroke; National Institutes of Health, USA FX The research of BK and RG is supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, the National Institutes of Health, USA. NR 36 TC 4 Z9 4 U1 1 U2 15 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1663-9812 J9 FRONT PHARMACOL JI Front. Pharmacol. PD MAR 16 PY 2015 VL 6 AR 48 DI 10.3389/fphar.2015.00048 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CF9PK UT WOS:000352897300001 PM 25852552 ER PT J AU Dyer, KD Rosenberg, HF AF Dyer, Kimberly D. Rosenberg, Helene F. TI Physiologic Concentrations of HMGB1 Have No Impact on Cytokine-Mediated Eosinophil Survival or Chemotaxis in Response to Eotaxin-2 (CCL24) SO PLOS ONE LA English DT Article ID MOBILITY GROUP BOX-1; MOLECULAR-PATTERN MOLECULES; GROUP PROTEIN B1; SERUM-LEVELS; CHRONIC RHINOSINUSITIS; EXPRESSION; DISEASE; INFLAMMATION; MICE; ACTIVATION AB HMGB1 is an alarmin that can stimulate the innate immune system alone or in a complex with other inflammatory mediators. Given the recent interest in HMGB1 with respect to the pathogenesis of eosinophil-associated disorders, including asthmatic inflammation and chronic rhinosinusitis, we have explored the role of this mediator and in promoting eosinophil activation. HMGB1 receptors RAGE and TLR4 but not TLR2 were detected on freshly isolated human eosinophils from healthy donors. Physiologic and relevant pathophysiologic levels of biologically-active HMGB1 had no effect on survival of human eosinophils alone or in combination with pro-survival cytokines IL-5, IL-3, or GM-CSF, and increasing concentrations of HMGB1 had no impact on surface expression of RAGE, TLR2 or TLR4. Similarly, HMGB1 did not elicit chemotaxis of human eosinophils alone and had no effect in combination with the eosinophil chemotactic agent, eotaxin-2 (CCL24). However, surface expression of TLR2 and TLR4 increased in response to cell stress, notably on eosinophils that remain viable after 48 hours without IL-5. As such, HMGB1 signaling on eosinophils may be substantially more detailed, and may involve complex immunostimulatory pathways other than or in addition to those evaluated here. C1 [Dyer, Kimberly D.; Rosenberg, Helene F.] NIAID, Inflammat Immunobiol Sect, NIH, Bethesda, MD 20892 USA. RP Dyer, KD (reprint author), NIAID, Inflammat Immunobiol Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM kdyer@niaid.nih.gov FU NIAID Division of Intramural Research [AI000941] FX This work is supported by the NIAID Division of Intramural Research #AI000941 to HFR. Funding supported the design, execution and interpretation of the results. Source of funding did not play a role in the performance, decision to publish or preparation of the manuscript. NR 40 TC 0 Z9 0 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 MAR 16 PY 2015 VL 10 IS 3 AR UNSP e0118887 DI 10.1371/journal.pone.0118887 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CD6EY UT WOS:000351183500049 PM 25774667 ER PT J AU Tao-Cheng, JH Yang, YJ Reese, TS Dosemeci, A AF Tao-Cheng, Jung-Hwa Yang, Yijung Reese, Thomas S. Dosemeci, Ayse TI Differential Distribution of Shank and GKAP at the Postsynaptic Density SO PLOS ONE LA English DT Article ID EXCITATORY SYNAPSES; PROTEINS; HOMER; COMPLEX; FAMILY AB Shank and GKAP are scaffold proteins and binding partners at the postsynaptic density (PSD). The distribution and dynamics of Shank and GKAP were studied in dissociated hippocampal cultures by pre-embedding immunogold electron microscopy. Antibodies against epitopes containing their respective mutual binding sites were used to verify the expected juxtapositioning of Shank and GKAP. If all Shank and GKAP molecules at the PSD were bound to each other, the distribution of label for the two proteins should coincide. However, labels for the mutual binding sites showed significant differences in distribution, with a narrow distribution for GKAP located close to the postsynaptic membrane, and a wider distribution for Shank extending deeper into the cytoplasm. Upon depolarization with high K+, neither the intensity nor distribution of label for GKAP changed, but labeling intensity for Shank at the PSD increased to similar to 150% of controls while the median distance of label from postsynaptic membrane increased by 7.5 nm. These results indicate a preferential recruitment of Shank to more distal parts of the PSD complex. Conversely, upon incubation in Ca2+-free medium containing EGTA, the labeling intensity of Shank at the PSD decreased to similar to 70% of controls and the median distance of label from postsynaptic membrane decreased by 9 nm, indicating a preferential loss of Shank molecules in more distal parts of the PSD complex. These observations identify two pools of Shank at the PSD complex, one relatively stable pool, closer to the postsynaptic membrane that can bind to GKAP, and another more dynamic pool at a location too far away to bind to GKAP. C1 [Tao-Cheng, Jung-Hwa] NINDS, EM Facil, NIH, Bethesda, MD 20892 USA. [Yang, Yijung; Reese, Thomas S.; Dosemeci, Ayse] NINDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Tao-Cheng, JH (reprint author), NINDS, EM Facil, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM chengs@ninds.nih.gov FU Intramural Research Program of the National Institute of Neurological Disorders and Stroke; National Institutes of Health, United States of America FX The work was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health, United States of America. NR 25 TC 6 Z9 6 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 MAR 16 PY 2015 VL 10 IS 3 AR e0118750 DI 10.1371/journal.pone.0118750 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CD6EY UT WOS:000351183500038 PM 25775468 ER PT J AU Donninger, H Calvisi, DF Barnoud, T Clark, J Schmidt, ML Vos, MD Clark, GJ AF Donninger, Howard Calvisi, Diego F. Barnoud, Thibaut Clark, Jennifer Schmidt, M. Lee Vos, Michele D. Clark, Geoffrey J. TI NORE1A is a Ras senescence effector that controls the apoptotic/senescent balance of p53 via HIPK2 SO JOURNAL OF CELL BIOLOGY LA English DT Article ID INTERACTING PROTEIN KINASE-2; ONCOGENE-INDUCED SENESCENCE; TUMOR-SUPPRESSOR; CELLULAR SENESCENCE; ACTIVATED RAS; CANCER-CELLS; IN-VIVO; PATHWAY; APOPTOSIS; GROWTH AB The Ras oncoprotein is a key driver of cancer. However, Ras also provokes senescence, which serves as a major barrier to Ras-driven transformation. Ras senescence pathways remain poorly characterized. NORE1A is a novel Ras effector that serves as a tumor suppressor. It is frequently inactivated in tumors. We show that NORE1A is a powerful Ras senescence effector and that down-regulation of NORE1A suppresses senescence induction by Ras and enhances Ras transformation. We show that Ras induces the formation of a complex between NORE1A and the kinase HIPK2, enhancing HIPK2 association with p53. HIPK2 is a tumor suppressor that can induce either proapoptotic or prosenescent posttranslational modifications of p53. NORE1A acts to suppress its proapoptotic phosphorylation of p53 but enhance its prosenescent acetylation of p53. Thus, we identify a major new Ras signaling pathway that links Ras to the control of specific protein acetylation and show how NORE1A allows Ras to qualitatively modify p53 function to promote senescence. C1 [Donninger, Howard; Clark, Jennifer] Univ Louisville, James Graham Brown Canc Ctr, Mol Targets Grp, Dept Med, Louisville, KY 40202 USA. [Barnoud, Thibaut; Schmidt, M. Lee] Univ Louisville, James Graham Brown Canc Ctr, Mol Targets Grp, Dept Biochem & Mol Biol, Louisville, KY 40202 USA. [Clark, Geoffrey J.] Univ Louisville, James Graham Brown Canc Ctr, Mol Targets Grp, Dept Pharmacol & Toxicol, Louisville, KY 40202 USA. [Calvisi, Diego F.] Ernst Moritz Arndt Univ Greifswald, D-17489 Greifswald, Germany. [Vos, Michele D.] NCI, Res Anal & Evaluat Branch, Rockville, MD 20850 USA. RP Clark, GJ (reprint author), Univ Louisville, James Graham Brown Canc Ctr, Mol Targets Grp, Dept Pharmacol & Toxicol, Louisville, KY 40202 USA. EM gjclar01@louisville.edu FU National Institutes of Health [RR18733, CA133171-01]; NCI intramural funds FX This work was funded in part by National Institutes of Health grants RR18733 and CA133171-01 and NCI intramural funds (G.J. Clark). NR 60 TC 8 Z9 9 U1 0 U2 8 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0021-9525 EI 1540-8140 J9 J CELL BIOL JI J. Cell Biol. PD MAR 16 PY 2015 VL 208 IS 6 BP 777 EP 789 DI 10.1083/jcb.201408087 PG 13 WC Cell Biology SC Cell Biology GA CD6UO UT WOS:000351225300014 PM 25778922 ER PT J AU Indaram, M Ma, WX Zhao, L Fariss, RN Rodriguez, IR Wong, WT AF Indaram, Maanasa Ma, Wenxin Zhao, Lian Fariss, Robert N. Rodriguez, Ignacio R. Wong, Wai T. TI 7-Ketocholesterol Increases Retinal Microglial Migration, Activation, and Angiogenicity: A Potential Pathogenic Mechanism Underlying Age-related Macular Degeneration SO SCIENTIFIC REPORTS LA English DT Article ID QUICK-FREEZE/DEEP-ETCH; SMOOTH-MUSCLE-CELLS; NF-KAPPA-B; CHOROIDAL NEOVASCULARIZATION; BRUCHS MEMBRANE; IN-VITRO; NLRP3 INFLAMMASOME; ENDOTHELIAL-CELLS; PHOTORECEPTOR DEGENERATION; SUBRETINAL MICROGLIA AB Age-related macular degeneration (AMD) has been associated with both accumulation of lipid and lipid oxidative products, as well as increased neuroinflammatory changes and microglial activation in the outer retina. However, the relationships between these factors are incompletely understood. 7-Ketocholesterol (7KCh) is a cholesterol oxidation product localized to the outer retina with prominent pro-inflammatory effects. To explore the potential relationship between 7KCh and microglial activation, we localized 7KCh and microglia to the outer retina of aged mice and investigated 7KCh effects on retinal microglia in both in vitro and in vivo systems. We found that retinal microglia demonstrated a prominent chemotropism to 7KCh and readily internalized 7KCh. Sublethal concentrations of 7KCh resulted in microglial activation and polarization to a pro-inflammatory M1 state via NLRP3 inflammasome activation. Microglia exposed to 7KCh reduced expression of neurotrophic growth factors but increased expression of angiogenic factors, transitioning to a more neurotoxic and pro-angiogenic phenotype. Finally, subretinal transplantation of 7KCh-exposed microglia promoted choroidal neovascularization (CNV) relative to control microglia in a Matrigel-CNV model. The interaction of retinal microglia with 7KCh in the aged retina may thus underlie how outer retinal lipid accumulation in intermediate AMD results in neuroinflammation that ultimately drives progression towards advanced AMD. C1 [Indaram, Maanasa; Ma, Wenxin; Zhao, Lian; Wong, Wai T.] NEI, Retinal Cell & Mol Biol Lab, Unit Neuron Glia Interact Retinal Dis, NIH, Bethesda, MD 20892 USA. [Fariss, Robert N.] NEI, Retinal Cell & Mol Biol Lab, Biol Imaging Core, NIH, Bethesda, MD 20892 USA. [Rodriguez, Ignacio R.] NEI, Retinal Cell & Mol Biol Lab, Mech Retinal Dis Sect, Bethesda, MD 20892 USA. RP Wong, WT (reprint author), NEI, Retinal Cell & Mol Biol Lab, Unit Neuron Glia Interact Retinal Dis, NIH, Bethesda, MD 20892 USA. EM wongw@nei.nih.gov RI Wong, Wai/B-6118-2017 OI Wong, Wai/0000-0003-0681-4016 NR 79 TC 16 Z9 16 U1 0 U2 13 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 MAR 16 PY 2015 VL 5 AR UNSP 9144 DI 10.1038/srep09144 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CD6DZ UT WOS:000351181000008 PM 25775051 ER PT J AU Zong, XF Hu, ML Li, ZC Cao, HB He, Y Liao, YH Zhou, J Sang, DE Zhao, HZ Tang, JS Lv, LX Chen, XG AF Zong, Xiaofen Hu, Maolin Li, Zongchang Cao, Hongbao He, Ying Liao, Yanhui Zhou, Jun Sang, Deen Zhao, Hongzeng Tang, Jinsong Lv, Luxian Chen, Xiaogang TI N-Acetylaspartate Reduction in the Medial Prefrontal Cortex Following 8 weeks of Risperidone Treatment in First-Episode Drug-Naive Schizophrenia Patients SO SCIENTIFIC REPORTS LA English DT Article ID PROTON-MAGNETIC-RESONANCE; ELECTRON-TRANSPORT CHAIN; MITOCHONDRIAL COMPLEX-I; ANTIPSYCHOTIC-DRUGS; ATYPICAL ANTIPSYCHOTICS; THIOL OXIDATION; BRAIN-INJURY; SPECTROSCOPY; HALOPERIDOL; D1 AB It is unclear whether N-acetylaspartate (NAA) depletions documented in schizophrenia patients might be due to the disease progression or medications. Here we investigated longitudinal NAA changes in drug-naive first-episode patients (FEP) who are relatively free from chronicity. Forty-two drug-naive FEP and 38 controls were enrolled in this study to explore the effect of 8-week risperidone monotherapy on NAA. All spectra were obtained from the medial prefrontal cortex (MPFC) on a 3.0 T MRI and analyzed with LCModel. At baseline, patients presented no significant differences inNAA(P=0.084) or NAA/Cr1Pcr ( P = 0.500) compared to controls; NAA levels were negatively correlated with PANSS total scores (P = 0.001) and WCST-PE (P = 0.041). After treatment, patients demonstrated significant reductions of NAA (P<0.001) and NAA/Cr1Pcr (P<0.001), and significant improvement in PANSS-P (P<0.001) and PANSS-G (P<0.001) symptoms. We detected no significant correlations between NAA alterations and PANSS-P (P = 0.679) or PANSS-G ( P = 0.668) symptom changes; nor did NAA/Cr1Pcr changes with alterations in PANSS-P (P = 0.677) and PANSS-G (P = 0.616). This is the first evidence that short- term risperidone treatment induces an acute reduction of MPFC NAA during the early phase of schizophrenia, which may be a previously unavailable biomarker to indicate risperidone with a similar pharmacological mechanism, although the functional significance is still unclear. C1 [Zong, Xiaofen; Hu, Maolin; Li, Zongchang; He, Ying; Liao, Yanhui; Zhou, Jun; Tang, Jinsong; Chen, Xiaogang] Cent S Univ, Xiangya Hosp 2, Inst Mental Hlth, Changsha, Hunan, Peoples R China. [Cao, Hongbao] NIMH, Unit Stat Genom, NIH, Bethesda, MD 20892 USA. [Sang, Deen; Zhao, Hongzeng] Xinxiang Med Univ, Affiliated Hosp 2, Dept Radiol, Xinxiang, Henan, Peoples R China. [Lv, Luxian] Xinxiang Med Univ, Henan Key Lab Biol Psychiat, Xinxiang, Henan, Peoples R China. [Lv, Luxian] Xinxiang Med Univ, Dept Psychiat, Affiliated Hosp 2, Xinxiang, Henan, Peoples R China. [Chen, Xiaogang] Cent S Univ, Key Lab Psychiat & Mental Hlth Hunan Prov, Changsha, Hunan, Peoples R China. [Chen, Xiaogang] Cent S Univ, Natl Technol Inst Psychiat, Changsha, Hunan, Peoples R China. RP Chen, XG (reprint author), Cent S Univ, Xiangya Hosp 2, Inst Mental Hlth, Changsha, Hunan, Peoples R China. EM tangjinsonghn@gmail.com; lvluxian@126.com; chenxghn@gmail.com RI Liao, Yanhui/L-1590-2016 OI Liao, Yanhui/0000-0003-4735-3252 FU National Natural Science Foundation of China [81271484, 81471361, 30900486, 81371480]; National Key Basic Research and Development Program (973) [2012CB517904] FX This study was supported by the National Natural Science Foundation of China (Grant No. 81271484 and 81471361 to X.C., Grant No. 30900486 and 81371480 to J.T.) and the National Key Basic Research and Development Program (973) (Grant No. 2012CB517904 to X.C.). NR 35 TC 5 Z9 6 U1 0 U2 7 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 MAR 16 PY 2015 VL 5 AR 9109 DI 10.1038/srep09109 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CD6DT UT WOS:000351180400001 PM 25778460 ER PT J AU Liang, ZJ Li, B Liang, Y Su, YP Ito, Y AF Liang, Zhenjie Li, Bin Liang, Yong Su, Yaping Ito, Yoichiro TI Separation and Purification of Two Minor Compounds from Radix isatidis by Integrative MPLC and HSCCC with Preparative HPLC SO JOURNAL OF LIQUID CHROMATOGRAPHY & RELATED TECHNOLOGIES LA English DT Article DE pre-HPLP; macroporous resin; HPLC; Radix isatidis; MPLC; HSCCC ID PERFORMANCE LIQUID-CHROMATOGRAPHY; COUNTER-CURRENT CHROMATOGRAPHY; FLAVONE C-GLYCOSIDES; EXTRACT; LEAVES; IDENTIFICATION; MAE; MS AB Radix isatidis has been widely used as a Chinese traditional medicine for its antivirus and anticancer activities where the minor components may contribute to these beneficial pharmaceutical effects. In order to enrich the target minor compounds effectively and rapidly, extraction, medium-pressure liquid chromatography (MPLC), high-speed countercurrent chromatography (HSCCC), and preparative high-performance liquid chromatography (pre-HPLC) were integratively used for separation and purification of two target minor compounds indole-3-acetonitrile-6-O-beta-D-glucopyranoside (target 1) and clemastanin B (target 2) in the present study. Radix isatidis was dried, pulverized, and extracted with 50% methanol at room temperature, then concentrated, and subjected to pretreatment with D-101 macroporous resin chromatography and extraction by MPLC. The first target compound was separated by MPLC at the purity raised to 70-80%, but without the second minor compounds which were irreversibly adsorbed by C18 solid support. Therefore, the second target compound in the crude extract was directly separated by HSCCC at a purity of 80-90%. Finally, these refined samples were further separated by pre-HPLC to obtain a high purity at 98-99%. The chemical structure identification of each target compound was carried out by infrared radiation (IR), electrospray ionization mass spectrometry (ESI-MS), and H-1-NMR. C1 [Liang, Zhenjie; Liang, Yong; Su, Yaping] S China Normal Univ, Inst Analyt Chem, Sch Chem & Environm, Guangzhou, Guangdong, Peoples R China. [Li, Bin] Shenzhen Entry Exit Inspect & Quarantine Bur, Shenzhen, Peoples R China. [Ito, Yoichiro] NHLBI, Lab Bioseparat Technol, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. RP Ito, Y (reprint author), NHLBI, Lab Bioseparat Technol, Biochem & Biophys Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM itoy@nhlbi.nih.gov FU Intramural NIH HHS [Z99 HL999999] NR 22 TC 3 Z9 3 U1 1 U2 37 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1082-6076 EI 1520-572X J9 J LIQ CHROMATOGR R T JI J. Liq. Chromatogr. Relat. Technol. PD MAR 16 PY 2015 VL 38 IS 5 BP 647 EP 653 DI 10.1080/10826076.2014.936606 PG 7 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA AY8FH UT WOS:000347789300015 PM 25745338 ER PT J AU Richmond, J Carol, H Evans, K High, L Mendomo, A Robbins, A Meyer, C Venn, NC Marschalek, R Henderson, M Sutton, R Kurmasheva, RT Kees, UR Houghton, PJ Smith, MA Lock, RB AF Richmond, Jennifer Carol, Hernan Evans, Kathryn High, Laura Mendomo, Agnes Robbins, Alissa Meyer, Claus Venn, Nicola C. Marschalek, Rolf Henderson, Michelle Sutton, Rosemary Kurmasheva, Raushan T. Kees, Ursula R. Houghton, Peter J. Smith, Malcolm A. Lock, Richard B. TI Effective Targeting of the P53-MDM2 Axis in Preclinical Models of Infant MLL-Rearranged Acute Lymphoblastic Leukemia SO CLINICAL CANCER RESEARCH LA English DT Article ID CHILDRENS ONCOLOGY GROUP; PROGNOSTIC-SIGNIFICANCE; ANTAGONIST RG7112; TESTING PROGRAM; MDM-2 ONCOGENE; P53 PATHWAY; DNA-DAMAGE; CELL-CYCLE; CHILDHOOD; GENE AB Purpose: Although the overall cure rate for pediatric acute lymphoblastic leukemia (ALL) approaches 90%, infants with ALL harboring translocations in the mixed-lineage leukemia (MLL) oncogene (infant MLL-ALL) experience shorter remission duration and lower survival rates (similar to 50%). Mutations in the p53 tumor-suppressor gene are uncommon in infant MLL-ALL, and drugs that release p53 from inhibitory mechanisms may be beneficial. The purpose of this study was to assess the efficacy of the orally available nutlin, RG7112, against patient-derived MLL-ALL xenografts. Experimental Design: Eight MLL-ALL patient-derived xenografts were established in immune-deficient mice, and their molecular features compared with B-lineage ALL and T-ALL xenografts. The sensitivity of MLL-ALL xenografts to RG7112 was assessed in vitro and in vivo, and the ability of RG7112 to induce p53, cell-cycle arrest, and apoptosis in vivo was evaluated. Results: Gene-expression analysis revealed that MLL-ALL, B-lineage ALL, and T-ALL xenografts clustered according to subtype. Moreover, genes previously reported to be overexpressed in MLL-ALL, including MEIS1, CCNA1, and members of the HOXA family, were significantly upregulated in MLL-ALL xenografts, confirming their ability to recapitulate the clinical disease. Exposure of MLL-ALL xenografts to RG7112 in vivo caused p53 upregulation, cell-cycle arrest, and apoptosis. RG7112 as a single agent induced significant regressions in infant MLL-ALL xenografts. Therapeutic enhancement was observed when RG7112 was assessed using combination treatment with an induction-type regimen (vincristine/dexamethasone/L-asparaginase) against an MLL-ALL xenograft. Conclusions: The utility of targeting the p53-MDM2 axis in combination with established drugs for the management of infant MLL-ALL warrants further investigation. (C) 2015 AACR. C1 [Richmond, Jennifer; Carol, Hernan; Evans, Kathryn; High, Laura; Mendomo, Agnes; Robbins, Alissa; Venn, Nicola C.; Henderson, Michelle; Sutton, Rosemary; Lock, Richard B.] UNSW, Lowy Canc Res Ctr, Childrens Canc Inst, Sydney, NSW, Australia. [Meyer, Claus; Marschalek, Rolf] Goethe Univ Frankfurt, Inst Pharmaceut Biol, Diagnost Ctr Acute Leukemia, D-60054 Frankfurt, Germany. [Kurmasheva, Raushan T.; Houghton, Peter J.] Nationwide Childrens Hosp, Ctr Childhood Canc, Columbus, OH USA. [Kees, Ursula R.] Univ Western Australia, Telethon Kids Inst, Perth, WA 6009, Australia. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Lock, RB (reprint author), UNSW, Lowy Canc Res Ctr, Childrens Canc Inst, Randwick, NSW 2031, Australia. EM rlock@ccia.unsw.edu.au RI Sutton, Rosemary /J-3784-2014; Lock, Richard/G-4253-2013; henderson, Michelle/G-6657-2012; Fachbereich14, Dekanat/C-8553-2015; OI Marschalek, Rolf/0000-0003-4870-3445 FU National Cancer Institute [NOI-CM-42216, NOI-CM-91001-03]; German Children Cancer Aid [DKS 2011.09]; National Health and Medical Research Council FX This research was funded by grants from the National Cancer Institute (NOI-CM-42216 and NOI-CM-91001-03), and by grant DKS 2011.09 from the German Children Cancer Aid (to R. Marschalek). R.B. Lock is supported by a Fellowship from the National Health and Medical Research Council. NR 50 TC 10 Z9 10 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 MAR 15 PY 2015 VL 21 IS 6 BP 1395 EP 1405 DI 10.1158/1078-0432.CCR-14-2300 PG 11 WC Oncology SC Oncology GA CE8DJ UT WOS:000352071200021 PM 25573381 ER PT J AU Wang, SS Vajdic, CM Linet, MS Slager, SL Voutsinas, J Nieters, A de Sanjose, S Cozen, W Alarcon, GS Martinez-Maza, O Brown, EE Bracci, PM Lightfoot, T Turner, J Hjalgrim, H Spinelli, JJ Zheng, TZ Morton, LM Birmann, BM Flowers, CR Paltiel, O Becker, N Holly, EA Kane, E Weisenburger, D Maynadie, M Cocco, P Foretova, L Staines, A Davis, S Severson, R Cerhan, JR Breen, EC Lan, Q Brooks-Wilson, A De Roos, AJ Smith, MT Roman, E Boffetta, P Kricker, A Zhang, YW Skibola, C Chanock, SJ Rothman, N Benavente, Y Hartge, P Smedby, KE AF Wang, Sophia S. Vajdic, Claire M. Linet, Martha S. Slager, Susan L. Voutsinas, Jenna Nieters, Alexandra de Sanjose, Silvia Cozen, Wendy Alarcon, Graciela S. Martinez-Maza, Otoniel Brown, Elizabeth E. Bracci, Paige M. Lightfoot, Tracy Turner, Jennifer Hjalgrim, Henrik Spinelli, John J. Zheng, Tongzhang Morton, Lindsay M. Birmann, Brenda M. Flowers, Christopher R. Paltiel, Ora Becker, Nikolaus Holly, Elizabeth A. Kane, Eleanor Weisenburger, Dennis Maynadie, Marc Cocco, Pierluigi Foretova, Lenka Staines, Anthony Davis, Scott Severson, Richard Cerhan, James R. Breen, Elizabeth C. Lan, Qing Brooks-Wilson, Angela De Roos, Anneclaire J. Smith, Martyn T. Roman, Eve Boffetta, Paolo Kricker, Anne Zhang, Yawei Skibola, Christine Chanock, Stephen J. Rothman, Nathaniel Benavente, Yolanda Hartge, Patricia Smedby, Karin E. TI Associations of Non-Hodgkin Lymphoma (NHL) Risk With Autoimmune Conditions According to Putative NHL Loci SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE autoimmune conditions; environment; genetics; interaction; human leukocyte antigen; lymphoma; non-Hodgkin; tumor necrosis factor ID CHRONIC LYMPHOCYTIC-LEUKEMIA; GENOME-WIDE ASSOCIATION; RHEUMATOID-ARTHRITIS; FOLLICULAR LYMPHOMA; MEDICAL HISTORY; INFLAMMATORY DISORDERS; INTERLYMPH-CONSORTIUM; GENETIC-VARIATION; EPIDEMIOLOGIC RESEARCH; MALIGNANT-LYMPHOMAS AB Autoimmune conditions and immune system-related genetic variations are associated with risk of non-Hodgkin lymphoma (NHL). In a pooled analysis of 8,692 NHL cases and 9,260 controls from 14 studies (1988-2007) within the International Lymphoma Epidemiology Consortium, we evaluated the interaction between immune system genetic variants and autoimmune conditions in NHL risk. We evaluated the immunity-related single nucleotide polymorphisms rs1800629 (tumor necrosis factor gene (TNF) G308A), rs1800890 (interleukin-10 gene (IL10) T3575A), rs6457327 (human leukocyte antigen gene (HLA) class I), rs10484561 (HLA class II), and rs2647012 (HLA class II)) and categorized autoimmune conditions as primarily mediated by B-cell or T-cell responses. We constructed unconditional logistic regressionmodels tomeasure associations between autoimmune conditions and NHL with stratification by genotype. Autoimmune conditions mediated by B-cell responses were associated with increased NHL risk, specifically diffuse large B-cell lymphoma (odds ratio (OR) = 3.11, 95% confidence interval (CI): 2.25, 4.30) and marginal zone lymphoma (OR = 5.80, 95% CI: 3.82, 8.80); those mediated by T-cell responses were associated with peripheral T-cell lymphoma (OR = 2.14, 95% CI: 1.35, 3.38). In the presence of the rs1800629 AG/AA genotype, B-cell-mediated autoimmune conditions increasedNHLrisk (OR = 3.27,95% CI: 2.07, 5.16; P-interaction = 0.03) in comparison with the GG genotype (OR = 1.82, 95% CI: 1.31, 2.53). This interaction was consistent across major B-cell NHL subtypes, including marginal zone lymphoma (P-interaction = 0.02) and follicular lymphoma (P-interaction = 0.04). C1 [Wang, Sophia S.; Voutsinas, Jenna] City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Duarte, CA 91010 USA. [Vajdic, Claire M.] Univ New S Wales, Prince Wales Clin Sch, Lowy Canc Res Ctr, Adult Canc Program, Sydney, NSW, Australia. [Linet, Martha S.; Morton, Lindsay M.; Lan, Qing; Chanock, Stephen J.; Rothman, Nathaniel; Hartge, Patricia] NCI, Div Canc Epidemiol & Genet, NIH, Gaithersburg, MD USA. [Slager, Susan L.; Cerhan, James R.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Nieters, Alexandra] Univ Med Ctr Freiburg, Ctr Chron Immunodeficiency, Freiburg, Germany. [de Sanjose, Silvia; Benavente, Yolanda] Inst Catala Oncol, Canc Epidemiol Res Programme, Unit Infect & Canc, Barcelona, Spain. [de Sanjose, Silvia; Benavente, Yolanda] Biomed Res Ctr Network Epidemiol & Publ Hlth CIBE, Barcelona, Spain. [Cozen, Wendy] Univ So Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Dept Prevent Med, Los Angeles, CA 90033 USA. [Alarcon, Graciela S.; Brown, Elizabeth E.] Univ Alabama Birmingham, Sch Med, Dept Med, Div Rheumatol & Clin Immunol, Birmingham, AL USA. [Alarcon, Graciela S.; Brown, Elizabeth E.] Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA. [Martinez-Maza, Otoniel] Univ Calif Los Angeles, David Geffen Sch Med, Dept Microbiol, Los Angeles, CA 90095 USA. [Martinez-Maza, Otoniel] Univ Calif Los Angeles, David Geffen Sch Med, Dept Immunol & Mol Genet, Los Angeles, CA 90095 USA. [Martinez-Maza, Otoniel] Univ Calif Los Angeles, David Geffen Sch Med, Dept Obstet & Gynecol, Los Angeles, CA 90095 USA. [Martinez-Maza, Otoniel] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Dept Epidemiol, Los Angeles, CA USA. [Bracci, Paige M.; Holly, Elizabeth A.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Lightfoot, Tracy; Kane, Eleanor; Roman, Eve] Univ York, Epidemiol & Canc Stat Grp, York YO10 5DD, N Yorkshire, England. [Turner, Jennifer] Macquarie Univ, Fac Med & Hlth Sci, Australian Sch Adv Med, Sydney, NSW 2109, Australia. [Turner, Jennifer] Macquarie Univ Hosp, Dept Histopathol, Douglass Hanly Moir Pathol, Sydney, NSW, Australia. [Hjalgrim, Henrik] Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark. [Spinelli, John J.] British Columbia Canc Res Ctr, Vancouver, BC V5Z 1L3, Canada. [Zheng, Tongzhang; Zhang, Yawei] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. [Birmann, Brenda M.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Birmann, Brenda M.] Harvard Univ, Sch Med, Boston, MA USA. [Flowers, Christopher R.] Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. [Paltiel, Ora] Hebrew Univ Jerusalem, Hadassah Med Ctr, Dept Hematol, Braun Sch Publ Hlth & Community Med, Jerusalem, Israel. [Becker, Nikolaus] German Canc Res Ctr, Div Clin Epidemiol, Heidelberg, Germany. [Weisenburger, Dennis] City Hope Natl Med Ctr, Dept Pathol, Duarte, CA USA. [Maynadie, Marc] Burgundy Univ, Registry Hematol Malignancies Cote dOr, Dijon, France. [Maynadie, Marc] Univ Hosp, Dijon, France. [Cocco, Pierluigi] Univ Cagliari, Dept Publ Hlth, Occupat Hlth Sect, Cagliari, Italy. [Foretova, Lenka] Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Brno, Czech Republic. [Staines, Anthony] Dublin City Univ, Sch Nursing & Human Sci, Dublin 9, Ireland. [Davis, Scott] Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle, WA 98195 USA. [Davis, Scott] Univ Washington, Sch Publ Hlth & Community Med, Seattle, WA 98195 USA. [Severson, Richard] Wayne State Univ, Dept Family Med, Detroit, MI USA. [Severson, Richard] Wayne State Univ, Sch Med, Karmanos Canc Inst, Detroit, MI USA. [Breen, Elizabeth C.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Brooks-Wilson, Angela] Simon Fraser Univ, Fac Sci, Dept Biomed Physiol & Kinesiol, Vancouver, BC, Canada. [De Roos, Anneclaire J.] Drexel Univ, Sch Publ Hlth, Dept Environm & Occupat Hlth, Philadelphia, PA 19104 USA. [Smith, Martyn T.] Univ Calif Berkeley, Sch Publ Hlth, Div Environm Hlth Sci, Berkeley, CA 94720 USA. [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. [Kricker, Anne] Univ Sydney, Sydney Sch Publ Hlth, Sydney, NSW 2006, Australia. [Brown, Elizabeth E.; Skibola, Christine] Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA. [Smedby, Karin E.] Karolinska Inst, Clin Epidemiol Unit, Dept Med Solna, Stockholm, Sweden. [Smedby, Karin E.] Karolinska Univ Hosp, Stockholm, Sweden. RP Wang, SS (reprint author), City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Div Canc Etiol, 1500 E Duarte Rd, Duarte, CA 91010 USA. EM sowang@coh.org RI Flowers, Christopher/F-1953-2010; Martinez-Maza, Otoniel/B-2667-2009; Brooks-Wilson, Angela/E-9399-2012; de Sanjose Llongueras, Silvia/H-6339-2014; OI Flowers, Christopher/0000-0002-9524-3990; Martinez-Maza, Otoniel/0000-0003-1364-0675; Brooks-Wilson, Angela/0000-0003-1009-6408; Staines, Anthony/0000-0001-9161-1357 FU National Institutes of Health (NIH) [CA17955801, CA033572]; NIH [CA45614, CA89745, CA87014, NO1-CO-12400, CA92153]; National Cancer Institute of Canada; Canadian Institutes of Health Research; Michael Smith Foundation for Health Research (British Columbia study); Intramural Research Program of the NIH; European Commission [QLK4-CT-2000-00422]; Fondazione Cariverona; Compagnia di San Paolo-Programma Oncologia; Jose Carreras Leukemia Foundation [DJCLS-R04/08]; Federal Office for Radiation Protection [StSch4261, StSch4420]; Fondo Investigaciones Sanitarias [PI040091, PI041467]; Network for Research in Epidemiology and Public Health [03/09]; Leukaemia Research Fund; National Health and Medical Research Council of Australia; Cancer Council New South Wales; University of Sydney Medical Foundation Program; National Cancer Institute [CA62006]; Health Research Board, Ireland (EpiLymph); Cancer Research, Ireland (InterLymph) FX This work was supported by National Institutes of Health (NIH) grants CA17955801 (S. S. Wang, Principal Investigator (PI), City of Hope) and CA033572 (M. Friedman, PI, City of Hope); NIH grants CA45614, CA89745, and CA87014 (E. A. Holly, PI, University of California, San Francisco/University of California, Berkeley studies); the National Cancer Institute of Canada, the Canadian Institutes of Health Research, and the Michael Smith Foundation for Health Research (British Columbia study); the Intramural Research Program of the NIH (P. Hartge, PI, National Cancer Institute-Surveillance, Epidemiology, and End Results study); the European Commission (grant QLK4-CT-2000-00422, EpiLymph study); NIH contract NO1-CO-12400 (EpiLymph Italy study); the Fondazione Cariverona (2004: A. Scarpa, PI, EpiLymph Italy study; 2005: P. S. Moore, PI, EpiLymph Italy study); the Compagnia di San Paolo-Programma Oncologia (P. Cocco, PI, EpiLymph Italy study); Jose Carreras Leukemia Foundation grant DJCLS-R04/08 (A. Nieters, PI, EpiLymph Germany study); Federal Office for Radiation Protection grants StSch4261 and StSch4420 (N. Becker, PI, EpiLymph Germany study); Fondo Investigaciones Sanitarias grant PI040091 (S. de Sanjose, PI, EpiLymph Spain study); Network for Research in Epidemiology and Public Health grant 03/09 and Fondo Investigaciones Sanitarias grant PI041467 (R. Bosch, PI, EpiLymph Spain study); the Leukaemia Research Fund (E. Roman, PI, United Kingdom study); the National Health and Medical Research Council of Australia, Cancer Council New South Wales, and the University of Sydney Medical Foundation Program (B. Armstrong, PI, New South Wales study); National Cancer Institute grant CA62006 (T. Zheng, PI, Yale University study); NIH grant CA92153 (J. Cerhan, PI, Mayo Clinic study); the Health Research Board, Ireland (EpiLymph); and Cancer Research, Ireland (InterLymph) (A. Staines, PI, EpiLymph Ireland study). NR 59 TC 13 Z9 14 U1 0 U2 8 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD MAR 15 PY 2015 VL 181 IS 6 BP 406 EP 421 DI 10.1093/aje/kwu290 PG 16 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CE0QA UT WOS:000351508200007 PM 25713336 ER PT J AU Kember, RL Georgi, B Bailey-Wilson, JE Stambolian, D Paul, SM Bucan, M AF Kember, Rachel L. Georgi, Benjamin Bailey-Wilson, Joan E. Stambolian, Dwight Paul, Steven M. Bucan, Maja TI Copy number variants encompassing Mendelian disease genes in a large multigenerational family segregating bipolar disorder SO BMC GENETICS LA English DT Article DE CNV; Bipolar disorder; Family based studies; Mendelian disease genes; Genetics loci ID GENOME-WIDE ASSOCIATION; DE-NOVO CNVS; PSYCHIATRIC-DISORDERS; DELETION MUTATION; SPECTRUM DISORDER; COMPLEX DISEASE; PLAIN PEOPLE; TUSC3 GENE; RISK; SCHIZOPHRENIA AB Background: Bipolar affective disorder (BP) is a common, highly heritable psychiatric disorder characterized by periods of depression and mania. Using dense SNP genotype data, we characterized CNVs in 388 members of an Old Order Amish Pedigree with bipolar disorder. We identified CNV regions arising from common ancestral mutations by utilizing the pedigree information. By combining this analysis with whole genome sequence data in the same individuals, we also explored the role of compound heterozygosity. Results: Here we describe 541 inherited CNV regions, of which 268 are rare in a control population of European origin but present in a large number of Amish individuals. In addition, we highlight a set of CNVs found at higher frequencies in BP individuals, and within genes known to play a role in human development and disease. As in prior reports, we find no evidence for an increased burden of CNVs in BP individuals, but we report a trend towards a higher burden of CNVs in known Mendelian disease loci in bipolar individuals (BPI and BPII, p = 0.06). Conclusions: We conclude that CNVs may be contributing factors in the phenotypic presentation of mood disorders and co-morbid medical conditions in this family. These results reinforce the hypothesis of a complex genetic architecture underlying BP disorder, and suggest that the role of CNVs should continue to be investigated in BP data sets. C1 [Kember, Rachel L.; Georgi, Benjamin; Bucan, Maja] Univ Penn, Dept Genet, Philadelphia, PA 19104 USA. [Stambolian, Dwight] Univ Penn, Dept Ophthalmol, Philadelphia, PA 19104 USA. [Bucan, Maja] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Paul, Steven M.] Weill Cornell Med Coll, Mind & Brain Inst, Appel Alzheimers Dis Res Inst, New York, NY USA. [Bailey-Wilson, Joan E.] NHGRI, Computat & Stat Genom Branch, NIH, Baltimore, MD USA. RP Bucan, M (reprint author), Univ Penn, Dept Genet, Philadelphia, PA 19104 USA. EM bucan@upenn.edu OI Bailey-Wilson, Joan/0000-0002-9153-2920 FU NIH [R01MH093415]; National Institutes of Health [HHSN268200782096C]; Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health; [RO1EY020483] FX This study was supported by the NIH grant R01MH093415. Genotyping of AREDS data was provided through CIDR, which is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. DS is supported by RO1EY020483. JEBW is supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. The authors would like to acknowledge Xiao Ji, Philip Ginsbach, Dusanka Lalic and Emma Greger for help with quality control of the Amish data. In addition, they would like to thank Erik Puffenberger and Laura Conlin for their discussion, and Ingrid Lindquist for her contribution to the Amish project. The authors are especially indebted to the members of the Old Order Amish settlements who participated in The Amish Study of Major Affective Disorder and Dr. Egeland who designed and directed this study since 1976. NR 84 TC 3 Z9 3 U1 0 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2156 J9 BMC GENET JI BMC Genet. PD MAR 15 PY 2015 VL 16 AR 27 DI 10.1186/s12863-015-0184-1 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA CE6ZK UT WOS:000351986500001 PM 25887117 ER PT J AU Josyula, S Lin, J Xue, XN Rothman, N Lan, Q Rohan, TE Hosgood, HD AF Josyula, Sowmya Lin, Juan Xue, Xiaonan Rothman, Nathaniel Lan, Qing Rohan, Thomas E. Hosgood, H. Dean, III TI Household air pollution and cancers other than lung: a meta-analysis SO ENVIRONMENTAL HEALTH LA English DT Review DE Solid fuels; Cervical cancer; Upper aero-digestive cancer; Meta-analysis; Risk factor ID HIGH-RISK POPULATION; COOKING OIL FUMES; NASOPHARYNGEAL CARCINOMA; PRECURSOR LESIONS; CERVICAL-CANCER; UTERINE CERVIX; SOLID FUELS; SALTED FISH; CHINA; STOVES AB Household air pollution (HAP) from solid fuel combustion contributes to 2.6% of the global burden of disease. HAP emissions are an established lung carcinogen; however, associations with other cancer sites have not been fully explored. We conducted a meta-analysis of 18 case-control studies. Using fixed-effects models, utilizing the adjusted odds ratios (OR) and 95% confidence intervals (95% CI) from each study, we evaluated the association between HAP and cervical neoplasia (663 cases and 1747 controls) and upper aero-digestive tract cancers (6022 cases and 15 325 controls). We found that HAP was associated with cervical neoplasia (OR = 6.46; 95% CI = 3.12-13.36; 4 studies); oral (OR = 2.44; 95% CI = 1.87-3.19; 4 studies; 1000 cases/3450 controls); nasopharyngeal (OR = 1.80; 95% CI = 1.42-2.29; 6 studies; 2231 cases/2160 controls); pharyngeal (OR = 3.56; 95% CI = 2.22-5.70; 4 studies; 1036 cases/3746 controls); and laryngeal (OR = 2.35; 95% CI = 1.72-3.21; 5 studies; 1416 cases/4514 controls) cancers. The elevated risk for esophageal cancer (OR = 1.92; 95% CI = 0.82-4.49; 2 studies; 339 cases/1455 controls) was non-significant. HAP was associated with cervical neoplasia among studies that accounted for HPV infection (OR = 9.60; 95% CI = 3.79-24.32) and smoking (OR = 4.72; 95% CI = 1.84-12.07). Similarly, our observed associations between HAP and upper aero-digestive tract cancers remained significantly elevated when analyses were restricted to studies that controlled for smoking. No significant publication bias was detected. Our results suggest that the carcinogenic effect of HAP observed for lung cancer may extend to other cancers, including those of the cervix and the upper aero-digestive tract. Further research is needed to confirm these associations in prospective studies. C1 [Josyula, Sowmya; Lin, Juan; Xue, Xiaonan; Rohan, Thomas E.; Hosgood, H. Dean, III] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Rothman, Nathaniel; Lan, Qing] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Josyula, S (reprint author), Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. EM sowmya.josyula@einstein.yu.edu FU NCATS NIH HHS [UL1 TR001073]; NCI NIH HHS [P30 CA013330, P30 CA016672] NR 35 TC 5 Z9 5 U1 2 U2 14 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-069X J9 ENVIRON HEALTH-GLOB JI Environ. Health PD MAR 15 PY 2015 VL 14 AR 24 DI 10.1186/s12940-015-0001-3 PG 11 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA CE8OG UT WOS:000352102000001 PM 25890249 ER PT J AU Morrison, VA Johnson, GR Schmader, KE Levin, MJ Zhang, JH Looney, DJ Betts, R Gelb, L Guatelli, JC Harbecke, R Pachucki, C Keay, S Menzies, B Griffin, MR Kauffman, CA Marques, A Toney, J Boardman, K Su, SC Li, XM Chan, ISF Parrino, J Annunziato, P Oxman, MN AF Morrison, Vicki A. Johnson, Gary R. Schmader, Kenneth E. Levin, Myron J. Zhang, Jane H. Looney, David J. Betts, Robert Gelb, Larry Guatelli, John C. Harbecke, Ruth Pachucki, Connie Keay, Susan Menzies, Barbara Griffin, Marie R. Kauffman, Carol A. Marques, Adriana Toney, John Boardman, Kathy Su, Shu-Chih Li, Xiaoming Chan, Ivan S. F. Parrino, Janie Annunziato, Paula Oxman, Michael N. CA Shingles Prevention Study Grp TI Long-term Persistence of Zoster Vaccine Efficacy SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE herpes zoster; herpes zoster vaccine; herpes zoster burden of illness; postherpetic neuralgia; persistence of vaccine efficacy ID HERPES-ZOSTER; POSTHERPETIC NEURALGIA; VARICELLA-VACCINATION; SHINGLES PREVENTION; OLDER-ADULTS; TRIALS; SAFETY; BURDEN; IMPACT; RISK AB Background. The Shingles Prevention Study (SPS) demonstrated zoster vaccine efficacy through 4 years postvaccination. A Short-Term Persistence Substudy (STPS) demonstrated persistence of vaccine efficacy for at least 5 years. A Long-Term Persistence Substudy (LTPS) was undertaken to further assess vaccine efficacy in SPS vaccine recipients followed for up to 11 years postvaccination. Study outcomes were assessed for the entire LTPS period and for each year from 7 to 11 years postvaccination. Methods. Surveillance, case determination, and follow-up were comparable to those in SPS and STPS. Because SPS placebo recipients were offered zoster vaccine before the LTPS began, there were no unvaccinated controls. Instead, SPS and STPS placebo results were used to model reference placebo groups. Results. The LTPS enrolled 6867 SPS vaccine recipients. Compared to SPS, estimated vaccine efficacy in LTPS decreased from 61.1% to 37.3% for the herpes zoster (HZ) burden of illness (BOI), from 66.5% to 35.4% for incidence of postherpetic neuralgia, and from 51.3% to 21.1% for incidence of HZ, and declined for all 3 outcome measures from 7 through 11 years postvaccination. Vaccine efficacy for the HZ BOI was significantly greater than zero through year 10 postvaccination, whereas vaccine efficacy for incidence of HZ was significantly greater than zero only through year 8. Conclusions. Estimates of vaccine efficacy decreased over time in the LTPS population compared with modeled control estimates. Statistically significant vaccine efficacy for HZ BOI persisted into year 10 postvaccination, whereas statistically significant vaccine efficacy for incidence of HZ persisted only through year 8. C1 [Johnson, Gary R.] VAMC, Minneapolis, MN 55417 USA. [Morrison, Vicki A.] Univ Minnesota, Minneapolis, MN USA. [Johnson, Gary R.; Zhang, Jane H.] Vet Affairs Connecticut Healthcare Syst, Cooperat Studies Program, Coordinating Ctr, West Haven, CT USA. [Schmader, Kenneth E.] Durham Vet Affairs Med Ctr, GRECC, Durham, NC USA. [Schmader, Kenneth E.] Duke Univ, Durham, NC 27706 USA. [Levin, Myron J.] Univ Colorado Denver, Aurora, CO USA. [Looney, David J.; Guatelli, John C.; Harbecke, Ruth; Oxman, Michael N.] Vet Affairs San Diego Healthcare Syst, San Diego, CA USA. [Looney, David J.; Guatelli, John C.; Harbecke, Ruth; Oxman, Michael N.] Univ Calif San Diego, San Diego, CA 92103 USA. [Betts, Robert] Univ Rochester, New York, NY USA. [Gelb, Larry] Vet Affairs Med Ctr, St Louis, MO USA. [Pachucki, Connie] Hines Vet Affairs Med Ctr, Chicago, IL USA. [Keay, Susan] Vet Affairs Maryland Hlth Care Syst, Baltimore, MD USA. [Keay, Susan] Univ Maryland, Baltimore, MD 21201 USA. [Menzies, Barbara] Vet Affairs Med Ctr, Seattle, WA 98108 USA. [Griffin, Marie R.] Vanderbilt Univ, Nashville, TN 37235 USA. [Griffin, Marie R.] Vet Affairs Tennessee Valley Healthcare Syst, Midsouth GRECC, Nashville, TN USA. [Kauffman, Carol A.] Vet Affairs Ann Arbor Hlth Care Syst, Ann Arbor, MI USA. [Kauffman, Carol A.] Univ Michigan, Ann Arbor, MI 48109 USA. [Marques, Adriana] NIAID, Bethesda, MD 20892 USA. [Toney, John] Vet Affairs Med Ctr, Tampa, FL USA. [Boardman, Kathy] Cent Res Pharm Coordinating Ctr, Cooperat Studies Program, Albuquerque, NM USA. [Su, Shu-Chih; Li, Xiaoming; Chan, Ivan S. F.; Parrino, Janie; Annunziato, Paula] Merck & Co Inc, Whitehouse Stn, NJ USA. RP Morrison, VA (reprint author), VAMC, Sect Hematol Oncol, 111E,One Vet Dr, Minneapolis, MN 55417 USA. EM morri002@umn.edu FU Merck Co.; James R. and Jesse V. Scott Fund for Shingles Research; Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX The study was conducted by the Cooperative Studies Program, Department of Veterans Affairs, Office of Research and Development through an agreement between Merck & Co, Inc, and the VA Connecticut Research and Education Foundation (VACREF) under which funding was provided to VACREF by Merck & Co. Additional support was provided by the James R. and Jesse V. Scott Fund for Shingles Research, and by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 24 TC 44 Z9 46 U1 0 U2 4 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 MAR 15 PY 2015 VL 60 IS 6 BP 900 EP 909 DI 10.1093/cid/ciu918 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CD4KP UT WOS:000351051600013 PM 25416754 ER PT J AU Bianco, P Robey, PG AF Bianco, Paolo Robey, Pamela G. TI Skeletal stem cells SO DEVELOPMENT LA English DT Article DE Bone marrow stromal cell; Bone; Cartilage; Hematopoiesis; In vivo transplantation; Skeletal stem cells ID HUMAN-BONE-MARROW; IN-VIVO; HEMATOPOIETIC MICROENVIRONMENT; MESENCHYMAL PROGENITORS; ALKALINE-PHOSPHATASE; OSTEOGENIC CELLS; STROMAL CELLS; DIFFERENTIATION; CARTILAGE; OSTEOBLASTS AB Skeletal stem cells (SSCs) reside in the postnatal bone marrow and give rise to cartilage, bone, hematopoiesis-supportive stroma and marrow adipocytes in defined in vivo assays. These lineages emerge in a specific sequence during embryonic development and post natal growth, and together comprise a continuous anatomical system, the bone-bone marrow organ. SSCs conjoin skeletal and hematopoietic physiology, and are a tool for understanding and ameliorating skeletal and hematopoietic disorders. Here and in the accompanying poster, we concisely discuss the biology of SSCs in the context of the development and postnatal physiology of skeletal lineages, to which their use in medicine must remain anchored. C1 [Bianco, Paolo] Univ Roma La Sapienza, Dept Mol Med, I-00161 Rome, Italy. [Robey, Pamela G.] Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Bianco, P (reprint author), Univ Roma La Sapienza, Dept Mol Med, I-00161 Rome, Italy. EM paolo.bianco@uniroma1.it; probey@dir.nidcr.nih.gov RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 FU Telethon [GGP09227]; Italian Ministry of Education, Universities and Research (MIUR); Fondazione Roma; Fondazione Institut Pasteur-Cenci Bolognetti; Italian Ministry of HealthEuropean Union; DIR; National Institute of Dental and Craniofacial Research (NIDCR); Intramural Research Program (IRP); National Institutes of Health (NIH); Department of Health and Human Services (DHHS) FX This work was supported by Telethon [GGP09227], the Italian Ministry of Education, Universities and Research (MIUR); Fondazione Roma; Fondazione Institut Pasteur-Cenci Bolognetti; the Italian Ministry of Health; the European Union (PluriMes consortium) and Sapienza University of Rome, Italy (to P.B.); and by the DIR, the National Institute of Dental and Craniofacial Research (NIDCR), a part of the Intramural Research Program (IRP), National Institutes of Health (NIH), Department of Health and Human Services (DHHS) (to P.G.R.). Deposited in PMC for release after 12 months. NR 57 TC 28 Z9 28 U1 2 U2 25 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 EI 1477-9129 J9 DEVELOPMENT JI Development PD MAR 15 PY 2015 VL 142 IS 6 BP 1023 EP 1027 DI 10.1242/dev.102210 PG 5 WC Developmental Biology SC Developmental Biology GA CE3AY UT WOS:000351697700001 PM 25758217 ER PT J AU Walentin, K Hinze, C Werth, M Haase, N Varma, S Morell, R Aue, A Potschke, E Warburton, D Qiu, AD Barasch, J Purfurst, B Dieterich, C Popova, E Bader, M Dechend, R Staff, AC Yurtdas, ZY Kilic, E Schmidt-Ott, KM AF Walentin, Katharina Hinze, Christian Werth, Max Haase, Nadine Varma, Saaket Morell, Robert Aue, Annekatrin Poetschke, Elisabeth Warburton, David Qiu, Andong Barasch, Jonathan Purfuerst, Bettina Dieterich, Christoph Popova, Elena Bader, Michael Dechend, Ralf Staff, Anne Cathrine Yurtdas, Zeliha Yesim Kilic, Ergin Schmidt-Ott, Kai M. TI A Grhl2-dependent gene network controls trophoblast branching morphogenesis SO DEVELOPMENT LA English DT Article DE Placenta defects; Epithelial differentiation; Epithelial morphogenesis; Spint1; Basement membrane defects ID FACTOR ACTIVATOR INHIBITOR; SERINE-PROTEASE INHIBITOR; GRAINYHEAD-LIKE 2; TRANSCRIPTION FACTOR AP-2; EPITHELIAL MORPHOGENESIS; EPIDERMAL DIFFERENTIATION; CHORIOALLANTOIC PLACENTA; EMBRYONIC-DEVELOPMENT; NEURAL-TUBE; EXPRESSION AB Healthy placental development is essential for reproductive success; failure of the feto-maternal interface results in pre-eclampsia and intrauterine growth retardation. We found that grainyhead-like 2 (GRHL2), a CP2-type transcription factor, is highly expressed in chorionic trophoblast cells, including basal chorionic trophoblast (BCT) cells located at the chorioallantoic interface in murine placentas. Placentas from Grhl2-deficient mouse embryos displayed defects in BCT cell polarity and basement membrane integrity at the chorioallantoic interface, as well as a severe disruption of labyrinth branching morphogenesis. Selective Grhl2 inactivation only in ep cells rescued all placental defects but phenocopied intraembryonic defects observed in global Grhl2 deficiency, implying the importance of Grhl2 activity in trophectoderm-derived cells. ChIP-seq identified 5282 GRHL2 binding sites in placental tissue. By integrating these data with placental gene expression profiles, we identified direct and indirect Grhl2 targets and found a marked enrichment of GRHL2 binding adjacent to genes downregulated in Grhl2(-/-) placentas, which encoded known regulators of placental development and epithelial morphogenesis. These genes included that encoding the serine protease inhibitor Kunitz type 1 (Spint1), which regulates BCT cell integrity and labyrinth formation. In human placenta, we found that human orthologs of murine GRHL2 and its targets displayed co-regulation and were expressed in trophoblast cells in a similar domain as in mouse placenta. Our data indicate that a conserved Grhl2-coordinated gene network controls trophoblast branching morphogenesis, thereby facilitating development of the site of feto-maternal exchange. This might have implications for syndromes related to placental dysfunction. C1 [Walentin, Katharina; Hinze, Christian; Werth, Max; Aue, Annekatrin; Poetschke, Elisabeth; Purfuerst, Bettina; Popova, Elena; Bader, Michael; Yurtdas, Zeliha Yesim; Schmidt-Ott, Kai M.] Max Delbruck Ctr Mol Med, D-13125 Berlin, Germany. [Walentin, Katharina; Hinze, Christian; Werth, Max; Haase, Nadine; Aue, Annekatrin; Dechend, Ralf; Schmidt-Ott, Kai M.] Expt & Clin Res Ctr, D-13125 Berlin, Germany. [Werth, Max; Qiu, Andong; Barasch, Jonathan] Columbia Univ Coll Phys & Surg, Dept Med, New York, NY 10032 USA. [Varma, Saaket; Warburton, David] Childrens Hosp Los Angeles, Saban Res Inst, Dept Dev Biol, Los Angeles, CA 90027 USA. [Varma, Saaket; Warburton, David] Childrens Hosp Los Angeles, Saban Res Inst, Regenerat Med Program, Los Angeles, CA 90027 USA. [Morell, Robert] NIDCD, Mol Genet Lab, NIH, Rockville, MD 20850 USA. [Dieterich, Christoph] Max Planck Inst Biol Ageing, Bioinformat, D-50931 Cologne, Germany. [Staff, Anne Cathrine] Oslo Univ Hosp, Inst Clin Med, Dept Gynecol & Obstet, N-0450 Oslo, Norway. [Staff, Anne Cathrine] Univ Oslo, N-0450 Oslo, Norway. [Yurtdas, Zeliha Yesim] Charite, Dept Urol, D-10117 Berlin, Germany. [Yurtdas, Zeliha Yesim] Berlin Inst Urol Res, D-10117 Berlin, Germany. [Kilic, Ergin] Charite, Dept Pathol, D-10117 Berlin, Germany. [Schmidt-Ott, Kai M.] Charite, Dept Nephrol, D-10117 Berlin, Germany. RP Schmidt-Ott, KM (reprint author), Max Delbruck Ctr Mol Med, Robert Rossle Str 10, D-13125 Berlin, Germany. EM kai.schmidt-ott@mdc-berlin.de OI Morell, Robert/0000-0003-1537-7356 FU German Research Foundation [DE 631/9-1]; Urological Research Foundation (Stiftung Urologische Forschung); National Institute on Deafness and Other Communication Disorders, National Institutes of Health (NIDCD/NIH) [1Z01DC000039-14] FX This work was funded by the German Research Foundation [Emmy-Noether grant; Research Unit 667 grant and Research Unit 1368 grant (all to K.M.S.-O.); Research grant DE 631/9-1 (to R.D.)]; and by the Urological Research Foundation (Stiftung Urologische Forschung). R.J.M. was supported by intramural funds [1Z01DC000039-14] from the National Institute on Deafness and Other Communication Disorders, National Institutes of Health (NIDCD/NIH) to Thomas B. Friedman. Deposited in PMC for release after 12 months. NR 64 TC 12 Z9 12 U1 0 U2 6 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 EI 1477-9129 J9 DEVELOPMENT JI Development PD MAR 15 PY 2015 VL 142 IS 6 BP 1125 EP 1136 DI 10.1242/dev.113829 PG 12 WC Developmental Biology SC Developmental Biology GA CE3AY UT WOS:000351697700012 PM 25758223 ER PT J AU Chen-Izu, Y Shaw, RM Pitt, GS Yarov-Yarovoy, V Sack, JT Abriel, H Aldrich, RW Belardinelli, L Cannell, MB Catterall, WA Chazin, WJ Chiamvimonvat, N Deschenes, I Grandi, E Hund, TJ Izu, LT Maier, LS Maltsev, VA Marionneau, C Mohler, PJ Rajamani, S Rasmusson, RL Sobie, EA Clancy, CE Bers, DM AF Chen-Izu, Ye Shaw, Robin M. Pitt, Geoffrey S. Yarov-Yarovoy, Vladimir Sack, Jon T. Abriel, Hugues Aldrich, Richard W. Belardinelli, Luiz Cannell, Mark B. Catterall, William A. Chazin, Walter J. Chiamvimonvat, Nipavan Deschenes, Isabelle Grandi, Eleonora Hund, Thomas J. Izu, Leighton T. Maier, Lars S. Maltsev, Victor A. Marionneau, Celine Mohler, Peter J. Rajamani, Sridharan Rasmusson, Randall L. Sobie, Eric A. Clancy, Colleen E. Bers, Donald M. TI Na+ channel function, regulation, structure, trafficking and sequestration SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Review ID LATE SODIUM CURRENT; PROTEIN-KINASE-II; HUMAN VENTRICULAR CARDIOMYOCYTES; CHRONIC HEART-FAILURE; CARDIAC MYOCYTES; VOLTAGE-SENSOR; ION-CHANNEL; CRYSTAL-STRUCTURE; MOLECULAR DETERMINANTS; DOG CARDIOMYOCYTES AB This paper is the second of a series of three reviews published in this issue resulting from the University of California Davis Cardiovascular Symposium 2014: Systems approach to understanding cardiac excitation-contraction coupling and arrhythmias: Na+ channel and Na+ transport. The goal of the symposium was to bring together experts in the field to discuss points of consensus and controversy on the topic of sodium in the heart. The present review focuses on Na+ channel function and regulation, Na+ channel structure and function, and Na+ channel trafficking, sequestration and complexing. C1 [Chen-Izu, Ye; Grandi, Eleonora; Izu, Leighton T.; Clancy, Colleen E.; Bers, Donald M.] Univ Calif Davis, Dept Pharmacol, Davis, CA 95616 USA. [Chen-Izu, Ye] Univ Calif Davis, Dept Biomed Engn, Davis, CA 95616 USA. [Chen-Izu, Ye; Chiamvimonvat, Nipavan] Univ Calif Davis, Dept Internal Med Cardiol, Davis, CA 95616 USA. [Shaw, Robin M.] Cedars Sinai, Dept Cardiol, Los Angeles, CA USA. [Pitt, Geoffrey S.] Duke Univ, Dept Med, Durham, NC USA. [Pitt, Geoffrey S.] Duke Univ, Dept Neurobiol, Durham, NC USA. [Pitt, Geoffrey S.] Duke Univ, Dept Pharmacol, Durham, NC USA. [Pitt, Geoffrey S.] Duke Univ, Dept Canc Biol, Durham, NC USA. [Yarov-Yarovoy, Vladimir; Sack, Jon T.] Univ Calif Davis, Dept Physiol & Membrane Biol, Davis, CA 95616 USA. [Abriel, Hugues] Univ Bern, Dept Clin Res, Bern, Switzerland. [Aldrich, Richard W.] Univ Texas Austin, Interdisciplinary Biomed Res 2, Austin, TX 78712 USA. [Belardinelli, Luiz; Rajamani, Sridharan] Gilead Sci, Fremont, CA USA. [Cannell, Mark B.] Univ Bristol, Dept Physiol & Pharmacol, Bristol, Avon, England. [Catterall, William A.] Univ Washington, Dept Pharmacol, Seattle, WA 98195 USA. [Chazin, Walter J.] Vanderbilt Univ Sch Med, Dept Biochem, Nashville, TN USA. [Deschenes, Isabelle] Case Western Reserve Univ, Dept Physiol & Biophys, Cleveland, OH 44106 USA. [Hund, Thomas J.] Ohio State Univ, Dept Biomed Engn, Columbus, OH 43210 USA. [Maier, Lars S.] Univ Klinikum Regensburg, Klin & Poliklin Innere Med 2, Regensburg, Germany. [Maltsev, Victor A.] NIH, Baltimore, MD USA. [Marionneau, Celine] Univ Nantes, Inst Thorax, Nantes, France. [Mohler, Peter J.] Ohio State Univ, Coll Med, Columbus, OH 43210 USA. [Rasmusson, Randall L.] SUNY Buffalo, Dept Physiol & Biophys, Buffalo, NY 14260 USA. [Sobie, Eric A.] Mt Sinai Sch Med, Dept Pharmacol, New York, NY USA. RP Chen-Izu, Y (reprint author), Univ Calif Davis, Dept Pharmacol, 451 Hlth Sci Dr,Tupper Hall,Rm 2221, Davis, CA 95616 USA. EM ychenizu@ucdavis.edu RI Marionneau, Celine/D-4011-2015; Hund, Thomas/C-9222-2012; Abriel, Hugues/B-9800-2009; OI Abriel, Hugues/0000-0003-0465-5138; Shaw, Robin/0000-0001-7429-6092; Bers, Donald/0000-0002-2237-9483 FU National Institutes of Health [R13HL110618, P01-HL080101] FX The authors acknowledge grant support from the National Institutes of Health (R13HL110618 to Y.C. and D.M.B. and P01-HL080101 to D.M.B.) and additional grants to other authors that allowed them to participate. Sponsors who subsidized conference costs can be found on the conference website. NR 114 TC 10 Z9 10 U1 3 U2 21 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3751 EI 1469-7793 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD MAR 15 PY 2015 VL 593 IS 6 BP 1347 EP 1360 DI 10.1113/jphysiol.2014.281428 PG 14 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA CD9DU UT WOS:000351398500004 PM 25772290 ER PT J AU Mishra, S Reznikov, V Maltsev, VA Undrovinas, NA Sabbah, HN Undrovinas, A AF Mishra, Sudhish Reznikov, Vitaliy Maltsev, Victor A. Undrovinas, Nidas A. Sabbah, Hani N. Undrovinas, Albertas TI Contribution of sodium channel neuronal isoform Na(v)1.1 to late sodium current in ventricular myocytes from failing hearts SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID LATE NA+ CURRENT; CARDIAC MYOCYTES; DOG CARDIOMYOCYTES; HUMAN MYOCARDIUM; BETA-SUBUNITS; FAILURE MODEL; CANINE MODEL; MOUSE HEART; EXPRESSION; CA2+ AB Late Na+ current (I-NaL) contributes to action potential (AP) duration and Ca2+ handling in cardiac cells. Augmented I-NaL was implicated in delayed repolarization and impaired Ca2+ handling in heart failure (HF). We tested if Na+ channel (Na-v) neuronal isoforms contribute to I-NaL and Ca2+ cycling defects in HF in 17 dogs in which HF was achieved via sequential coronary artery embolizations. Six normal dogs served as control. Transient Na+ current (I-NaT) and I-NaL in left ventricular cardiomyocytes (VCMs) were recorded by patch clamp while Ca2+ dynamics was monitored using Fluo-4. Virally delivered short interfering RNA (siRNA) ensured Na(v)1.1 and Na(v)1.5 post-transcriptional silencing. The expression of six Na(v)s was observed in failing VCMs as follows: Na(v)1.5 (57.3%) > Na(v)1.2 (15.3%) > Na(v)1.1 (11.6%) > Na(v)2.1 (10.7%) >Na(v)1.3 (4.6%) > Na(v)1.6 (0.5%). Failing VCMs showed up-regulation of Na(v)1.1 expression, but reduction of Na(v)1.6 mRNA. A similar Na-v expression pattern was found in samples from human hearts with ischaemic HF. VCMs with silenced Na(v)1.5 exhibited residual I-NaT and I-NaL (approximate to 30% of control) with rightwardly shifted steady-state activation and inactivation. These currents were tetrodotoxin sensitive but resistant to MTSEA, a specific Na(v)1.5 blocker. The amplitude of the tetrodotoxin-sensitive I-NaL was 0.1709 +/- 0.0299pApF(-1) (n=7 cells) and the decay time constant was =790 +/- 76ms (n=5). This I-NaL component was lacking in VCMs with a silenced Na(v)1.1 gene, indicating that, among neuronal isoforms, Na(v)1.1 provides the largest contribution to I-NaL. At -10mV this contribution is approximate to 60% of total I-NaL. Our further experimental and in silico examinations showed that this new Na(v)1.1 I-NaL component contributes to Ca(2+)accumulation in failing VCMs and modulates AP shape and duration. In conclusion, we have discovered an Na(v)1.1-originated I-NaL component in dog heart ventricular cells. This component is physiologically relevant to controlling AP shape and duration, as well as to cell Ca2+ dynamics. C1 [Mishra, Sudhish; Reznikov, Vitaliy; Undrovinas, Nidas A.; Sabbah, Hani N.; Undrovinas, Albertas] Henry Ford Hosp, Dept Internal Med, Detroit, MI 48202 USA. [Maltsev, Victor A.] Natl Inst Aging, Intramural Res Program, Baltimore, MD USA. RP Undrovinas, NA (reprint author), Henry Ford Hosp, Cardiovasc Res, Educ & Res Bldg,Room 4015,2799 West Grand Blvd, Detroit, MI 48202 USA. EM adas7247@yahoo.com FU National Heart, Lung, and Blood Institute [HL-53819, HL-074238]; American Heart Association [0350472Z]; Intramural Research Program of the National Institute on Aging FX This study was supported by National Heart, Lung, and Blood Institute Grants HL-53819 and HL-074238, by a grant-in-aid from the American Heart Association (0350472Z; to A. Undrovinas), and, in part, by the Intramural Research Program of the National Institute on Aging (to V. A. Maltsev; the numerical modelling part). NR 47 TC 9 Z9 10 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3751 EI 1469-7793 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD MAR 15 PY 2015 VL 593 IS 6 BP 1409 EP 1427 DI 10.1113/jphysiol.2014.278259 PG 19 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA CD9DU UT WOS:000351398500010 PM 25772296 ER PT J AU Chason, RJ Kang, JH Gerkowicz, SA Dufau, ML Catt, KJ Segars, JH AF Chason, Rebecca J. Kang, Jung-Hoon Gerkowicz, Sabrina A. Dufau, Maria L. Catt, Kevin J. Segars, James H. TI GnRH agonist reduces estrogen receptor dimerization in GT1-7 cells: Evidence for cross-talk between membrane-initiated estrogen and GnRH signaling SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article DE GT1-7 cells; Estradiol; Non-classical estrogen signaling; Estrogen receptor alpha; Estrogen receptor beta; GnRH receptor ID RESONANCE ENERGY-TRANSFER; BREAST-CANCER CELLS; ELEMENT-BINDING PROTEIN; LHRH MESSENGER-RNA; PLASMA-MEMBRANE; HORMONE NEURONS; RAPID ACTION; ER ALPHA; ESTRADIOL; BETA AB 17 beta-estradiol (E-2), a key participant on the initiation of the LH surge, exerts both positive and negative feedback on GnRH neurons. We sought to investigate potential interactions between estrogen receptors alpha (ER alpha) and beta (ER beta) and gonadotropin releasing hormone receptor (GnRH-R) in GT1-7 cells. Radioligand binding studies demonstrated a significant decrease in saturation E-2 binding in cells treated with GnRH agonist. Conversely, there was a significant reduction in GnRH binding in GT1-7 cells treated with E-2. In BRET1 experiments, ER alpha-ER alpha dimerization was suppressed in GT1-7 cells treated with GnRH agonist (p < 0.05). There was no evidence of direct interaction between ERs and GnRH-R. This study provides the first evidence of reduced ERa homodimerization by GnRH agonist. Collectively, these findings demonstrate significant cross-talk between membrane-initiated GnRH and E-2 signaling in GT1-7 cells. Published by Elsevier Ireland Ltd. C1 [Chason, Rebecca J.; Segars, James H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Kang, Jung-Hoon; Dufau, Maria L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, Sect Mol Endocrinol, NIH, Bethesda, MD 20892 USA. [Gerkowicz, Sabrina A.] Univ Miami, Dept Obstet & Gynecol, Miami, FL 33136 USA. [Catt, Kevin J.] NICHD, Sect Hormonal Regulat, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD USA. RP Segars, JH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, 10 CRC,Room 1E-3140,10 Ctr Dr,MSC 1109, Bethesda, MD 20892 USA. EM segarsj@mail.nih.gov FU National Institutes of Health (Intramural Research Program of the NICHD) [Z01-HD 008737, Z01-HD 00184, ZIA-HD 000150-39] FX The authors thank Dr. Alan DeCherney for his support of the project, and Dr. Carlos Medina for approving and facilitating Dr. Gerkowicz's time at the NIH. This work was supported by the National Institutes of Health (Intramural Research Program of the NICHD), Grants Z01-HD 008737 (Dr. James Segars), Z01-HD 00184 (Dr. Kevin Cat) and ZIA-HD 000150-39 (Dr. Maria Dufau). NR 53 TC 3 Z9 3 U1 2 U2 6 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 MAR 15 PY 2015 VL 404 IS C BP 67 EP 74 DI 10.1016/j.mce.2015.01.023 PG 8 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA CE2KY UT WOS:000351645700008 PM 25619861 ER PT J AU Spruill, TM Williams, O Teresi, JA Lehrer, S Pezzin, L Waddy, SP Lazar, RM Williams, SK Jean-Louis, G Ravenell, J Penesetti, S Favate, A Flores, J Henry, KA Kleiman, A Levine, SR Sinert, R Smith, TY Stern, M Valsamis, H Ogedegbe, G AF Spruill, Tanya M. Williams, Olajide Teresi, Jeanne A. Lehrer, Susan Pezzin, Liliana Waddy, Salina P. Lazar, Ronald M. Williams, Stephen K. Jean-Louis, Girardin Ravenell, Joseph Penesetti, Sunil Favate, Albert Flores, Judith Henry, Katherine A. Kleiman, Anne Levine, Steven R. Sinert, Richard Smith, Teresa Y. Stern, Michelle Valsamis, Helen Ogedegbe, Gbenga TI Comparative effectiveness of home blood pressure telemonitoring (HBPTM) plus nurse case management versus HBPTM alone among Black and Hispanic stroke survivors: study protocol for a randomized controlled trial SO TRIALS LA English DT Article DE stroke; hypertension; blood pressure; disparities; telehealth; comparative effectiveness research ID EVALUATION INTERVIEW SCHEDULE; HEALTH-CARE PROFESSIONALS; HYPERTENSION CONTROL; UNITED-STATES; COMPREHENSIVE ASSESSMENT; COST-EFFECTIVENESS; RACIAL-DIFFERENCES; INDICATOR-SCALES; RISK-FACTORS; MEDICATION ADHERENCE AB Background: Black and Hispanic stroke survivors experience higher rates of recurrent stroke than whites. This disparity is partly explained by disproportionately higher rates of uncontrolled hypertension in these populations. Home blood pressure telemonitoring (HBPTM) and nurse case management (NCM) have proven efficacy in addressing the multilevel barriers to blood pressure (BP) control and reducing BP. However, the effectiveness of these interventions has not been evaluated in stroke patients. This study is designed to evaluate the comparative effectiveness, cost-effectiveness and sustainability of these two telehealth interventions in reducing BP and recurrent stroke among high-risk Black and Hispanic stroke survivors with uncontrolled hypertension. Methods/Design: A total of 450 Black and Hispanic patients with recent nondisabling stroke and uncontrolled hypertension are randomly assigned to one of two 12-month interventions: 1) HBPTM with wireless feedback to primary care providers or 2) HBPTM plus individualized, culturally-tailored, telephone-based NCM. Patients are recruited from stroke centers and primary care practices within the Health and Hospital Corporations (HHC) Network in New York City. Study visits occur at baseline, 6, 12 and 24 months. The primary outcomes are within-patient change in systolic BP at 12 months, and the rate of stroke recurrence at 24 months. The secondary outcome is the comparative cost-effectiveness of the interventions at 12 and 24 months; and exploratory outcomes include changes in stroke risk factors, health behaviors and treatment intensification. Recruitment for the stroke telemonitoring hypertension trial is currently ongoing. Discussion: The combination of two established and effective interventions along with the utilization of health information technology supports the sustainability of the HBPTM+ NCM intervention and feasibility of its widespread implementation. Results of this trial will provide strong empirical evidence to inform clinical guidelines for management of stroke in minority stroke survivors with uncontrolled hypertension. If effective among Black and Hispanic stroke survivors, these interventions have the potential to substantially mitigate racial and ethnic disparities in stroke recurrence. C1 [Spruill, Tanya M.; Williams, Stephen K.; Jean-Louis, Girardin; Ravenell, Joseph; Penesetti, Sunil; Ogedegbe, Gbenga] NYU, Sch Med, New York, NY 10016 USA. [Williams, Olajide; Lazar, Ronald M.] Columbia Univ, Dept Neurol, Sch Med, New York, NY USA. [Teresi, Jeanne A.] Hebrew Home Riverdale, Div Res, Bronx, NY USA. [Teresi, Jeanne A.] Columbia Univ, Stroud Ctr, New York, NY USA. [Teresi, Jeanne A.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Lehrer, Susan] Hlth & Hosp Corp, New York, NY USA. [Pezzin, Liliana] Med Coll Wisconsin, Dept Med, Milwaukee, WI 53226 USA. [Waddy, Salina P.] NINDS, Off Clin Res, NIH, Bethesda, MD 20892 USA. [Favate, Albert; Henry, Katherine A.] NYU, Sch Med, Dept Neurol, New York, NY 10016 USA. [Flores, Judith] Woodhull Med Ctr, New York, NY USA. [Henry, Katherine A.] Bellevue Hosp Ctr, New York, NY 10016 USA. [Kleiman, Anne] Harlem Hosp Med Ctr, New York, NY USA. [Levine, Steven R.; Valsamis, Helen] Suny Downstate Med Ctr, Dept Neurol, Brooklyn, NY 11203 USA. [Levine, Steven R.] Suny Downstate Med Ctr, Dept Emergency Med, Brooklyn, NY 11203 USA. [Levine, Steven R.] Kings Cty Hosp Ctr, Dept Neurol, Brooklyn, NY USA. [Sinert, Richard; Smith, Teresa Y.] Kings Cty Hosp Ctr, Dept Emergency Med, Brooklyn, NY USA. [Stern, Michelle] Jacobi Med Ctr, New York, NY USA. [Valsamis, Helen] Kings Cty Hosp, Neurol Serv, Brooklyn, NY USA. RP Spruill, TM (reprint author), NYU, Sch Med, 227 East 30th St,Room 640, New York, NY 10016 USA. EM Tanya.Spruill@nyumc.org RI Williams, Stephen/L-2032-2016; OI Williams, Stephen/0000-0003-2004-2526; Spruill, Tanya/0000-0003-2998-3007; Jean-Louis, Girardin/0000-0001-6777-2724 FU National Institute of Neurological Disorders and Stroke [U54 NS081765] FX This study is supported by the National Institute of Neurological Disorders and Stroke (U54 NS081765). The authors thank Leanne Leurassi, MPH, Stephanie Silver, MPH, Sueann Godfrey, MPH, and Amy Zarrow, RN for their support and assistance with this trial. NR 79 TC 1 Z9 1 U1 3 U2 9 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 MAR 15 PY 2015 VL 16 AR 97 DI 10.1186/s13063-015-0605-5 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CD9OL UT WOS:000351427600001 PM 25873044 ER PT J AU Kobayashi, N Ueno, T Ohashi, K Yamashita, H Takahashi, Y Sakamoto, K Manabe, S Hara, S Takashima, Y Dan, T Pastan, I Miyata, T Kurihara, H Matsusaka, T Reiser, J Nagata, M AF Kobayashi, Namiko Ueno, Toshiharu Ohashi, Kumi Yamashita, Hanako Takahashi, Yukina Sakamoto, Kazuo Manabe, Shun Hara, Satoshi Takashima, Yasutoshi Dan, Takashi Pastan, Ira Miyata, Toshio Kurihara, Hidetake Matsusaka, Taiji Reiser, Jochen Nagata, Michio TI Podocyte injury-driven intracapillary plasminogen activator inhibitor type 1 accelerates podocyte loss via uPAR-mediated beta(1)-integrin endocytosis SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE podocyte; plasminogen activator inhibitor type 1; endocytosis; integrin; kidney; pathology ID FOCAL SEGMENTAL GLOMERULOSCLEROSIS; RENAL THROMBOTIC MICROANGIOPATHY; UROKINASE RECEPTOR; EPITHELIAL-CELLS; KIDNEY-DISEASE; EXPRESSION; STRESS; GROWTH; GLOMERULONEPHRITIS; MECHANISM AB Podocyte-endothelial cell cross-talk is paramount for maintaining the filtration barrier. The present study investigated the endothelial response to podocyte injury and its subsequent role in glomerulosclerosis using the podocyte-specific injury model of NEP25/LMB2 mice. NEP25/LMB2 mice showed proteinuria and local podocyte loss accompanied by thrombotic microangiopathy on day 8. Mice showed an increase of glomerular plasminogen activator inhibitor type 1 (PAI-1) mRNA and aberrant endothelial PAI-1 protein already on day 1, before thrombosis and proteinuria. A PAI-1-specific inhibitor reduced proteinuria and thrombosis and preserved podocyte numbers in NEP25/LMB2 mice by stabilization of beta(1)-integrin translocation. Heparin loading significantly reduced thrombotic formation, whereas proteinuria and podocyte numbers were unchanged. Immortalized podocytes treated with PAI-1 and the urokinase plasminogen activator (uPA) complex caused significant cell detachment, whereas podocytes treated with PAI-1 or uPA alone or with the PAI-1/uPA complex pretreated with an anti-uPA receptor (uPAR) antibody failed to cause detachment. Confocal microscopy and cell surface biotinylation experiments showed that internalized beta(1)-integrin was found together with uPAR in endocytotic vesicles. The administration of PAI-1 inhibitor or uPAR-blocking antibody protected cultured podocytes from cell detachment. In conclusion, PAI-1/uPA complex-mediated uPAR-dependent podocyte beta(1)-integrin endocytosis represents a novel mechanism of glomerular injury leading to progressive podocytopenia. This aberrant cross-talk between podocytes and endothelial cells represents a feedforward injury response driving podocyte loss and progressive glomerulosclerosis. C1 [Kobayashi, Namiko; Ueno, Toshiharu; Ohashi, Kumi; Yamashita, Hanako; Takahashi, Yukina; Sakamoto, Kazuo; Manabe, Shun; Hara, Satoshi; Takashima, Yasutoshi; Nagata, Michio] Univ Tsukuba, Grad Sch Comprehens Human Sci, Dept Pathol, Ibaraki, Japan. [Dan, Takashi; Miyata, Toshio] Tohoku Univ, Grad Sch Med, Ctr Translat & Adv Res, Sendai, Miyagi 980, Japan. [Pastan, Ira] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Kurihara, Hidetake] Juntendo Univ, Sch Med, Dept Anat, Bunkyo Ku, Tokyo 113, Japan. [Matsusaka, Taiji] Tokai Univ, Sch Med, Dept Internal Med, Inst Med Sci, Isehara, Kanagawa 25911, Japan. [Reiser, Jochen] Rush Univ, Dept Med, Chicago, IL 60612 USA. RP Nagata, M (reprint author), Univ Tsukuba, Fac Med, Kidney & Vasc Pathol, 1-1-1 Ten Nodai, Tsukuba, Ibaraki 3058577, Japan. EM nagatam@md.tsukuba.ac.jp RI Miyata, Toshio/A-4872-2010 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; Japan Society for the Promotion of Science (KAKEN) [22590877, 26461210]; Progressive Renal Disease Research of the Ministry of Health, Labor and Welfare of Japan; Astellas Pharma in Japan FX This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, Grants-In-Aid for Scientific Research from the Japan Society for the Promotion of Science (KAKEN; Research Project nos. 22590877 and 26461210), Progressive Renal Disease Research of the Ministry of Health, Labor and Welfare of Japan, and Astellas Pharma in Japan. NR 46 TC 4 Z9 5 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X EI 1522-1466 J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD MAR 15 PY 2015 VL 308 IS 6 BP F614 EP F626 DI 10.1152/ajprenal.00616.2014 PG 13 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA CD4NT UT WOS:000351060800011 PM 25587125 ER PT J AU Rikhy, R Mavrakis, M Lippincott-Schwartz, J AF Rikhy, Richa Mavrakis, Manos Lippincott-Schwartz, Jennifer TI Dynamin regulates metaphase furrow formation and plasma membrane compartmentalization in the syncytial Drosophila embryo SO BIOLOGY OPEN LA English DT Article DE Dynamin; Endocytosis; Drosophila; Polarity; Actin; Compartmentalization; Syncytium ID COATED VESICLE FORMATION; MEDIATED ENDOCYTOSIS; APICAL CONSTRICTION; NUCLEAR-FALLOUT; E-CADHERIN; PROTEIN; POLARITY; CELLULARIZATION; CYCLES; DOMAIN AB The successive nuclear division cycles in the syncytial Drosophila embryo are accompanied by ingression and regression of plasma membrane furrows, which surround individual nuclei at the embryo periphery, playing a central role in embryo compartmentalization prior to cellularization. Here, we demonstrate that cell cycle changes in dynamin localization and activity at the plasma membrane (PM) regulate metaphase furrow formation and PM organization in the syncytial embryo. Dynamin was localized on short PM furrows during interphase, mediating endocytosis of PM components. Dynamin redistributed off ingressed PM furrows in metaphase, correlating with stabilized PM components and the associated actin regulatory machinery on long furrows. Acute inhibition of dynamin in the temperature sensitive shibire mutant embryo resulted in morphogenetic consequences in the syncytial division cycle. These included inhibition of metaphase furrow ingression, randomization of proteins normally polarized to intercap PM and disruption of the diffusion barrier separating PM domains above nuclei. Based on these findings, we propose that cell cycle changes in dynamin orchestrate recruitment of actin regulatory machinery for PM furrow dynamics during the early mitotic cycles in the Drosophila embryo. C1 [Rikhy, Richa; Lippincott-Schwartz, Jennifer] NICHD, Cell Biol & Metab Program, NIH, Bethesda, MD USA. [Mavrakis, Manos] Aix Marseille Univ, Inst Biol Dev Marseille, CNRS UMR7288, F-13288 Marseille, France. RP Rikhy, R (reprint author), Indian Inst Sci Educ & Res, Homi Bhabha Rd, Pune 411008, Maharashtra, India. EM richa@iiserpune.ac.in; lippincj@mail.nih.gov OI Rikhy, Richa/0000-0002-4262-0238 FU Indian Institute of Science Education and Research (IISER; Pune, India); Department of Biotechnology (DBT; India); National Institutes of Health (USA) FX We thank grants from Indian Institute of Science Education and Research (IISER; Pune, India), Department of Biotechnology (DBT; India) and National Institutes of Health (USA) for funding this work. NR 55 TC 5 Z9 5 U1 0 U2 6 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 2046-6390 J9 BIOL OPEN JI Biol. Open PD MAR 15 PY 2015 VL 4 IS 3 BP 301 EP 311 DI 10.1242/bio.20149936 PG 11 WC Biology SC Life Sciences & Biomedicine - Other Topics GA CD3SL UT WOS:000351000900006 PM 25661871 ER PT J AU Sohl, SJ Borowski, LA Kent, EE Smith, AW Oakley-Girvan, I Rothman, RL Arora, NK AF Sohl, Stephanie J. Borowski, Laurel A. Kent, Erin E. Smith, Ashley Wilder Oakley-Girvan, Ingrid Rothman, Russell L. Arora, Neeraj K. TI Cancer Survivors' Disclosure of Complementary Health Approaches to Physicians: The Role of Patient-Centered Communication SO CANCER LA English DT Article; Proceedings Paper CT 1st Palliative Care in Oncology Symposium CY OCT, 2014 CL Boston, MA DE communication; complementary medicine; complementary therapies; neoplasms; patient-centered care; survivors ID ALTERNATIVE MEDICINE USE; BREAST-CANCER; CAM USE; CARE; PERSPECTIVES AB BACKGROUNDCancer survivors' disclosure of complementary health approaches (CHAs) to their follow-up care physicians is necessary to ensure the safe and optimal use of such approaches. Rates of disclosure of CHAs are variable and may be facilitated by patient-centered communication. METHODSThis cross-sectional study conducted in 2003-2004 examined a population-based sample of leukemia, colorectal, and bladder cancer survivors (n=623) who were 2 to 5 years after their diagnosis. A subset of participants who reported using CHAs (n=196) was analyzed with multivariate logistic regression to examine the association between patients' perceptions of their physician's patient-centered communication (ie, information exchange, affective behavior, knowledge of patients as persons) and patients' disclosure of CHA use to their physician with adjustments for physician, patient, and patient-physician relationship factors. RESULTSThirty-one percent of the full sample used CHAs, and 47.6% of CHA users disclosed their use to their physicians. Disclosure was significantly associated with patient-centered communication even with adjustments for hypothesized covariates (odds ratio [OR], 1.37; 95% confidence interval [CI], 1.09-1.71). Perceived physician knowledge of the patient as a person (OR, 1.28; 95% CI, 1.10-1.48) and information exchange (OR, 1.27; 95% CI, 1.02-1.60) were the aspects of patient-centered communication that contributed to this association. The main reason for nondisclosure assessed in the survey was that survivors did not think that it was important to discuss CHAs (67.0%). A majority of physicians encouraged continued use of CHAs when they were disclosed (64.8%). CONCLUSIONSResults support the idea that improving the overall patient centeredness of cancer follow-up care and improving the disclosure of CHA use are potentially synergistic clinical goals. Cancer 2015;121:900-907. (c) 2014 American Cancer Society. Analyses of a population-based sample of cancer survivors support the idea that improving the overall patient centeredness of cancer follow-up care and improving the disclosure of complementary health approaches to physicians are potentially synergistic clinical goals. C1 [Sohl, Stephanie J.; Rothman, Russell L.] Vanderbilt Univ, Dept Med, Med Ctr, Nashville, TN 37203 USA. [Borowski, Laurel A.] Truven Hlth Analyt, Franklin, TN USA. [Kent, Erin E.; Smith, Ashley Wilder; Arora, Neeraj K.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Oakley-Girvan, Ingrid] Canc Prevent Inst Calif, Fremont, CA USA. EM stephanie.sohl@vanderbilt.edu FU National Institutes of Health (NIH HHS/United States) [N01-PC-35136/PC/NCI]; National Institutes of Health through a Building Interdisciplinary Research Careers in Women's Health Scholar Program [2K12HD043483-11] FX This study was supported by the National Institutes of Health through a contract (N01-PC-35136/PC/NCI NIH HHS/United States) and through a grant from the Building Interdisciplinary Research Careers in Women's Health Scholar Program (2K12HD043483-11). NR 39 TC 2 Z9 2 U1 2 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD MAR 15 PY 2015 VL 121 IS 6 BP 900 EP 907 DI 10.1002/cncr.29138 PG 8 WC Oncology SC Oncology GA CD0HF UT WOS:000350750700015 PM 25387799 ER PT J AU Nundel, K Green, NM Shaffer, AL Moody, KL Busto, P Eilat, D Miyake, K Oropallo, MA Cancro, MP Marshak-Rothstein, A AF Nuendel, Kerstin Green, Nathaniel M. Shaffer, Arthur L. Moody, Krishna L. Busto, Patricia Eilat, Dan Miyake, Kensuke Oropallo, Michael A. Cancro, Michael P. Marshak-Rothstein, Ann TI Cell-Intrinsic Expression of TLR9 in Autoreactive B Cells Constrains BCR/TLR7-Dependent Responses SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MURINE LUPUS; AUTOANTIBODY PRODUCTION; INDUCED AUTOIMMUNITY; DENDRITIC CELLS; PLASMA-CELLS; MOUSE MODEL; RECEPTOR 7; IN-VIVO; ACTIVATION; MICE AB Endosomal TLRs play an important role in systemic autoimmune diseases, such as systemic erythematosus lupus, in which DNA-and RNA-associated autoantigens activate autoreactive B cells through TLR9- and TLR7-dependent pathways. Nevertheless, TLR9-deficient autoimmune-prone mice develop more severe clinical disease, whereas TLR7-deficient and TLR7/9-double deficient autoimmune-prone mice develop less severe disease. To determine whether the regulatory activity of TLR9 is B cell intrinsic, we directly compared the functional properties of autoantigen-activated wild-type, TLR9-deficient, and TLR7-deficient B cells in an experimental system in which proliferation depends on BCR/TLR coengagement. In vitro, TLR9-deficient cells are less dependent on survival factors for a sustained proliferative response than are either wild-type or TLR7-deficient cells. The TLR9-deficient cells also preferentially differentiate toward the plasma cell lineage, as indicated by expression of CD138, sustained expression of IRF4, and other molecular markers of plasma cells. In vivo, autoantigen-activated TLR9-deficient cells give rise to greater numbers of autoantibody-producing cells. Our results identify distinct roles for TLR7 and TLR9 in the differentiation of autoreactive B cells that explain the capacity of TLR9 to limit, as well as TLR7 to promote, the clinical features of systemic erythematosus lupus. C1 [Nuendel, Kerstin; Green, Nathaniel M.; Moody, Krishna L.; Busto, Patricia; Marshak-Rothstein, Ann] Univ Massachusetts, Sch Med, Dept Med, Div Rheumatol, Worcester, MA 01605 USA. [Shaffer, Arthur L.] NCI, Lymphoid Malignancies Branch, NIH, Bethesda, MD 20892 USA. [Eilat, Dan] Hadassah Univ Hosp, IL-91322 Jerusalem, Israel. [Miyake, Kensuke] Univ Tokyo, Dept Microbiol & Immunol, Tokyo 1088639, Japan. [Oropallo, Michael A.; Cancro, Michael P.] Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Marshak-Rothstein, A (reprint author), Univ Massachusetts, Sch Med, Dept Med, Div Rheumatol, 364 Plantat St, Worcester, MA 01605 USA. EM ann.rothstein@umassmed.edu FU National Institute of Arthritis and Musculoskeletal and Skin Diseases/National Institutes of Health (NIH) Grant [AR050256]; Department of the Army Grant [PR120610]; NIH Training Grant [T32 AI-055428]; NIH intramural program FX This work was supported by National Institute of Arthritis and Musculoskeletal and Skin Diseases/National Institutes of Health (NIH) Grant AR050256 (to A.M.-R.) and Department of the Army Grant PR120610 (to M.P.C.). M.A.O. was supported in part by NIH Training Grant T32 AI-055428, and A.L.S. was supported by the NIH intramural program. NR 49 TC 15 Z9 15 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 MAR 15 PY 2015 VL 194 IS 6 BP 2504 EP 2512 DI 10.4049/jimmunol.1402425 PG 9 WC Immunology SC Immunology GA CD0IS UT WOS:000350755200009 PM 25681333 ER PT J AU Montezuma-Rusca, JM Moir, S Kardava, L Buckner, CM Louie, A Kim, LJY Santich, BH Wang, W Fankuchen, OR Diaz, G Daub, JR Rosenzweig, SD Chun, TW Li, YX Braylan, RC Calvo, KR Fauci, AS AF Montezuma-Rusca, Jairo M. Moir, Susan Kardava, Lela Buckner, Clarisa M. Louie, Aaron Kim, Leo J. Y. Santich, Brian H. Wang, Wei Fankuchen, Olivia R. Diaz, Gabriella Daub, Janine R. Rosenzweig, Sergio D. Chun, Tae-Wook Li, Yuxing Braylan, Raul C. Calvo, Katherine R. Fauci, Anthony S. TI Bone Marrow Plasma Cells Are a Primary Source of Serum HIV-1-Specific Antibodies in Chronically Infected Individuals SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HUMAN MONOCLONAL-ANTIBODIES; MEMORY B-CELLS; NEUTRALIZING ANTIBODIES; ANTIRETROVIRAL THERAPY; VIREMIC INDIVIDUALS; HIV-1 INFECTION; VACCINE; BROAD; RESPONSES AB Several potent and broadly neutralizing Abs to HIV-1 have been isolated recently from peripheral blood B cells of infected individuals, based on prescreening of Ab activity in the serum. However, little is known regarding the cells that make the Abs that circulate in the blood. Accordingly, we investigated the most likely source, the bone marrow, of chronically HIV-1-infected individuals who were not receiving antiretroviral therapy. Increased frequencies of plasma cells, as well as B cell precursors, namely preB-I and preB-II, and decreased frequencies of mature B cells were observed in bone marrow aspirates of these individuals compared with HIV-negative counterparts. Increased frequencies of bone marrow plasma cells are consistent with known hallmarks of HIV-1 infection, namely hypergammaglobulinemia and increased frequencies of peripheral blood plasmablasts. Levels of HIV-1 envelope (Env)-binding and HIV-1-neutralizing Abs were measured in serum, and corresponding frequencies of Ab-secreting or Env-binding cells were measured in the blood (plasmablasts and memory B cells) and in the bone marrow (plasma cells). A strong correlation was observed between serum HIV-1-specific Abs and Env-specific bone marrow-derived plasma cells, but not circulating plasmablasts or memory B cells. These findings demonstrate that, despite HIV-1-induced phenotypic and functional B cell dysregulation in the peripheral blood and secondary lymphoid tissues, bone marrow plasma cells remain a primary source for circulating HIV-1-specific Abs in HIV-1-infected individuals. C1 [Montezuma-Rusca, Jairo M.; Moir, Susan; Kardava, Lela; Buckner, Clarisa M.; Louie, Aaron; Kim, Leo J. Y.; Santich, Brian H.; Wang, Wei; Fankuchen, Olivia R.; Chun, Tae-Wook; Fauci, Anthony S.] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Diaz, Gabriella] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Clin Res Directorate, Clin Monitoring Res Program, Frederick, MD 21702 USA. [Daub, Janine R.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Rosenzweig, Sergio D.; Braylan, Raul C.; Calvo, Katherine R.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Li, Yuxing] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Li, Yuxing] Scripps Res Inst, Int AIDS Vaccine Initiat Neutralizing Antibody Ct, La Jolla, CA 92037 USA. [Li, Yuxing] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. RP Moir, S (reprint author), NIH, 9000 Rockville Pike,Bldg 10,Room 6A02, Bethesda, MD 20892 USA. EM smoir@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health; National Institutes of Health/NIAID Grant [R01AI102766]; NIAID from the Center for AIDS Research, University of California, San Diego [P30AI36214] FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health. Y.L. was supported by National Institutes of Health/NIAID Grant R01AI102766 and by a development grant (a sub-award from NIAID P30AI36214) from the Center for AIDS Research, University of California, San Diego. NR 48 TC 6 Z9 6 U1 1 U2 7 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 MAR 15 PY 2015 VL 194 IS 6 BP 2561 EP 2568 DI 10.4049/jimmunol.1402424 PG 8 WC Immunology SC Immunology GA CD0IS UT WOS:000350755200015 PM 25681347 ER PT J AU Chatterjee, S Clark, CE Lugli, E Roederer, M Nutman, TB AF Chatterjee, Soumya Clark, Carolyn E. Lugli, Enrico Roederer, Mario Nutman, Thomas B. TI Filarial Infection Modulates the Immune Response to Mycobacterium tuberculosis through Expansion of CD4(+) IL-4 Memory T Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID EXPERIMENTAL PULMONARY TUBERCULOSIS; HUMAN LYMPHATIC FILARIASIS; PROLIFERATIVE RESPONSES; LYMPHOCYTE POPULATIONS; SCHISTOSOMA-MANSONI; CYTOKINE RESPONSES; PARASITE ANTIGEN; SOUTH-INDIA; PERSISTENCE; TH2 AB Exaggerated CD4(+) T helper 2-specific cytokine producing memory T cell responses developing concomitantly with a T helper 1 response might have a detrimental role in immunity to infection caused by Mycobacterium tuberculosis. To assess the dynamics of Ag-specific memory T cell compartments in the context of filarial infection, we used multiparameter flow cytometry on PBMCs from 25 microfilaremic filarial-infected (Inf) and 14 filarial-uninfected (Uninf) subjects following stimulation with filarial Ag (BmA) or with the M. tuberculosis-specific Ag culture filtrate protein-10 (CFP-10). Our data demonstrated that the Inf group had a marked increase in BmA-specific CD4(+)IL-4(+) cells (median net frequency compared with baseline [Fo] = 0.09% versus 0.01%; p = 0.038) but also to CFP-10 (Fo = 0.16% versus 0.007%; p = 0.04) and staphylococcal enterotoxin B (Fo = 0.49% versus 0.26%; p = 0.04). The Inf subjects showed a BmA-specific expansion of CD4(+)CD45RO(+)IL-4(+) producing central memory (TCM, CD45RO(+)CCR7(+)CD27(+); Fo = 1.1% versus 0.5%; p = 0.04) as well as effector memory (TEM, CD45RO(+)CCR7(-)CD27(-); Fo = 1.5% versus 0.2%; p = 0.03) with a similar but nonsignificant response to CFP-10. In addition, there was expansion of CD4(+)IL-4(+)CD45RA(+)CCR7(+)CD27(+) (naive-like) in Inf individuals compared with Uninf subjects. Among Inf subjects with definitive latent tuberculosis, there were no differences in frequencies of IL-4-producing cells within any of the memory compartments compared with the Uninf group. Our data suggest that filarial infection induces Ag-specific, exaggerated IL-4 responses in distinct T cell memory compartments to M. tuberculosis-specific Ags, which are attenuated in subjects who are able to mount a delayed type hypersensitivity reaction to M. tuberculosis. C1 [Chatterjee, Soumya; Clark, Carolyn E.; Nutman, Thomas B.] NIAID, NIH, Parasit Dis Lab, Bethesda, MD 20892 USA. [Lugli, Enrico; Roederer, Mario] NIAID, Immunotechnol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Chatterjee, S (reprint author), NIAID, NIH, 4 Ctr Dr,Room B1-09, Bethesda, MD 20892 USA. EM chatterjees3@mail.nih.gov FU Division of Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases FX This work was supported in part by the Division of Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 48 TC 5 Z9 5 U1 1 U2 3 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 MAR 15 PY 2015 VL 194 IS 6 BP 2706 EP 2714 DI 10.4049/jimmunol.1402718 PG 9 WC Immunology SC Immunology GA CD0IS UT WOS:000350755200030 PM 25667413 ER PT J AU Maier, NK Leppla, SH Moayeri, M AF Maier, Nolan K. Leppla, Stephen H. Moayeri, Mahtab TI The Cyclopentenone Prostaglandin 15d-PGJ(2) Inhibits the NLRP1 and NLRP3 Inflammasomes SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ANTHRAX LETHAL TOXIN; PROLIFERATOR-ACTIVATED RECEPTOR; ANTIOXIDANT RESPONSE ELEMENT; TRANSCRIPTION FACTOR NRF2; 15-DEOXY-DELTA(12,14)-PROSTAGLANDIN J(2); PPAR-GAMMA; ANTIPROLIFERATIVE ACTIVITY; ACUTE-INFLAMMATION; LIPID MEDIATORS; GENE-EXPRESSION AB Inflammasomes are cytosolic protein complexes that respond to diverse danger signals by activating caspase-1. The sensor components of the inflammasome, often proteins of the nucleotide-binding oligomerization domain-like receptor (NLR) family, detect stress, danger stimuli, and pathogen-associated molecular patterns. We report that the eicosanoid 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)) and related cyclopentenone PGs inhibit caspase-1 activation by the NLR family leucine-rich repeat protein (NLRP)1 and NLRP3 inflammasomes. This inhibition was independent of the well-characterized role of 15d-PGJ(2) as a peroxisome proliferator receptor-gamma agonist, its activation of NF erythroid 2-related factor 2, or its anti-inflammatory function as an inhibitor of NF-kappa B. Instead, 15d-PGJ(2) prevents the autoproteolytic activation of caspase-1 and the maturation of IL-1 beta through induction of a cellular state inhibitory to caspase-1 proteolytic function. The eicosanoid does not directly modify or inactivate the caspase-1 enzyme. Rather, inhibition is dependent on de novo protein synthesis. In a mouse peritonitis model of gout, using monosodium urate crystals to activate NLRP3, 15d-PGJ(2) caused a significant inhibition of cell recruitment and associated IL-1 beta release. Furthermore, in a murine anthrax infection model, 15d-PGJ(2) reversed anthrax lethal toxin-mediated NLRP1-dependent resistance. The findings reported in this study suggest a novel mechanism for the anti-inflammatory properties of the cyclopentenone PGs through inhibition of caspase-1 and the inflammasome. C1 [Maier, Nolan K.; Leppla, Stephen H.; Moayeri, Mahtab] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Moayeri, M (reprint author), NIH, Bldg 33,Room 1W20B, Bethesda, MD 20892 USA. EM mmoayeri@niaid.nih.gov OI , /0000-0001-6103-6726 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 69 TC 7 Z9 8 U1 0 U2 8 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 MAR 15 PY 2015 VL 194 IS 6 BP 2776 EP 2785 DI 10.4049/jimmunol.1401611 PG 10 WC Immunology SC Immunology GA CD0IS UT WOS:000350755200037 PM 25681332 ER PT J AU Yasuda, M Hikosaka, O AF Yasuda, Masaharu Hikosaka, Okihide TI Functional territories in primate substantia nigra pars reticulata separately signaling stable and flexible values SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article DE saccade; reward; caudate nucleus; superior colliculus; monkey ID SACCADIC EYE-MOVEMENTS; BASAL GANGLIA; CAUDATE-NUCLEUS; OCULOMOTOR FUNCTIONS; SUPERIOR COLLICULUS; NEURONAL-ACTIVITY; STRIATAL NEURONS; BEHAVING MONKEY; HABIT FORMATION; MOTOR PROGRAMS AB Gaze is strongly attracted to visual objects that have been associated with rewards. Key to this function is a basal ganglia circuit originating from the caudate nucleus (CD), mediated by the substantia nigra pars reticulata (SNr), and aiming at the superior colliculus (SC). Notably, subregions of CD encode values of visual objects differently: stably by CD tail [CD(T)] vs. flexibly by CD head [CD(H)]. Are the stable and flexible value signals processed separately throughout the CD-SNr-SC circuit? To answer this question, we identified SNr neurons by their inputs from CD and outputs to SC and examined their sensitivity to object values. The direct input from CD was identified by SNr neuron's inhibitory response to electrical stimulation of CD. We found that SNr neurons were separated into two groups: 1) neurons inhibited by CD(T) stimulation, located in the caudal-dorsal-lateral SNr (cdlSNr), and 2) neurons inhibited by CD(H) stimulation, located in the rostral-ventral-medial SNr (rvmSNr). Most of CD(T)-recipient SNr neurons encoded stable values, whereas CD(H)-recipient SNr neurons tended to encode flexible values. The output to SC was identified by SNr neuron's antidromic response to SC stimulation. Among the antidromically activated neurons, many encoded only stable values, while some encoded only flexible values. These results suggest that CD(T)cdlSNr-SC circuit and CD(H)-rvmSNr-SC circuit transmit stable and flexible value signals, largely separately, to SC. The speed of signal transmission was faster through CD(T)-cdlSNr-SC circuit than through CD(H)-rvmSNr-SC circuit, which may reflect automatic and controlled gaze orienting guided by these circuits. C1 [Yasuda, Masaharu; Hikosaka, Okihide] NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RP Yasuda, M (reprint author), Kansai Med Univ, Dept Physiol, 2-5-1 Shin Machi, Hirakata, Osaka 5730101, Japan. EM yasudama@hirakata.kmu.ac.jp FU Intramural Research Program at the National Institutes of Health, National Eye Institute FX This research was supported by the Intramural Research Program at the National Institutes of Health, National Eye Institute. NR 72 TC 2 Z9 2 U1 2 U2 12 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 EI 1522-1598 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD MAR 15 PY 2015 VL 113 IS 6 BP 1681 EP 1696 DI 10.1152/jn.00674.2014 PG 16 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA CD3QQ UT WOS:000350994900001 PM 25540224 ER PT J AU Zhou, ZQ Ota, S Deng, CX Akiyama, H Hurlin, PJ AF Zhou, Zi-Qiang Ota, Sara Deng, Chuxia Akiyama, Haruhiko Hurlin, Peter J. TI Mutant activated FGFR3 impairs endochondral bone growth by preventing SOX9 downregulation in differentiating chondrocytes SO HUMAN MOLECULAR GENETICS LA English DT Article ID AUTOSOMAL SEX REVERSAL; SRY-RELATED GENE; FACTOR RECEPTOR-3; THANATOPHORIC DYSPLASIA; NEGATIVE REGULATOR; TRANSGENIC MICE; HYPERTROPHIC CHONDROCYTES; CONSTITUTIVE ACTIVATION; CAMPOMELIC DYSPLASIA; SKELETAL DEVELOPMENT AB Fibroblast growth factor receptor 3 (FGFR3) plays a critical role in the control of endochondral ossification, and bone growth and mutations that cause hyperactivation of FGFR3 are responsible for a collection of developmental disorders that feature poor endochondral bone growth. FGFR3 is expressed in proliferating chondrocytes of the cartilaginous growth plate but also in chondrocytes that have exited the cell cycle and entered the prehypertrophic phase of chondrocyte differentiation. Achondroplasia disorders feature defects in chondrocyte proliferation and differentiation, and the defects in differentiation have generally been considered to be a secondary manifestation of altered proliferation. By initiating a mutant activated knockin allele of FGFR3 (FGFR3K650E) that causes Thanatophoric Dysplasia Type II (TDII) specifically in prehypertrophic chondrocytes, we show that mutant FGFR3 induces a differentiation block at this stage independent of any changes in proliferation. The differentiation block coincided with persistent expression of SOX9, the master regulator of chondrogenesis, and reducing SOX9 dosage allowed chondrocyte differentiation to proceed and significantly improved endochondral bone growth in TDII. These findings suggest that a proliferation-independent and SOX9-dependent differentiation block is a key driving mechanism responsible for poor endochondral bone growth in achondroplasia disorders caused by mutations in FGFR3. C1 [Zhou, Zi-Qiang; Ota, Sara; Hurlin, Peter J.] Shriners Hosp Children, Portland, OR 97239 USA. [Deng, Chuxia] NIDDK, Genet Dev & Dis Branch, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Akiyama, Haruhiko] Gifu Univ, Dept Orthoped, Gifu 5011194, Japan. [Hurlin, Peter J.] Oregon Hlth & Sci Univ, Dept Cell & Dev Biol, Portland, OR 97239 USA. [Hurlin, Peter J.] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97239 USA. RP Hurlin, PJ (reprint author), Shriners Hosp Children, 3101 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM pjh@shcc.org RI deng, chuxia/N-6713-2016 FU Shriners Hospitals for Children FX This work was supported by a grant from Shriners Hospitals for Children to P.J.H. NR 56 TC 5 Z9 5 U1 2 U2 20 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 MAR 15 PY 2015 VL 24 IS 6 BP 1764 EP 1773 DI 10.1093/hmg/ddu594 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA CC1ZO UT WOS:000350144200021 PM 25432534 ER PT J AU He, MA Xu, M Zhang, B Liang, J Chen, P Lee, JY Johnson, TA Li, HX Yang, XB Dai, JC Liang, LM Gui, LX Qi, QB Huang, JY Li, YP Adair, LS Aung, T Cai, QY Cheng, CY Cho, MC Cho, YS Chu, MJ Cui, B Gao, YT Go, MJ Gu, DF Gu, WQ Guo, H Hao, YC Hong, J Hu, ZB Hu, YL Huang, JF Hwang, JY Ikram, MK Jin, GF Kang, DH Khor, CC Kim, BJ Kim, HT Kubo, M Lee, J Lee, J Lee, NR Li, RY Li, J Liu, JJ Longe, JR Lu, W Lu, XF Miao, XP Okada, Y Ong, RTH Qiu, GK Seielstad, M Sim, XL Song, HD Takeuchi, F Tanaka, T Taylor, PR Wang, LY Wang, WQ Wang, YQ Wu, C Wu, Y Xiang, YB Yamamoto, K Yang, HD Liao, M Yokota, M Young, T Zhang, XM Kato, N Wang, QK Zheng, W Hu, FB Lin, DX Shen, HB Teo, YY Mo, ZN Wong, TY Lin, X Mohlke, KL Ning, G Tsunoda, T Han, BG Shu, XO Tai, ES Wu, TC Qi, L AF He, Meian Xu, Min Zhang, Ben Liang, Jun Chen, Peng Lee, Jong-Young Johnson, Todd A. Li, Huaixing Yang, Xiaobo Dai, Juncheng Liang, Liming Gui, Lixuan Qi, Qibin Huang, Jinyan Li, Yanping Adair, Linda S. Aung, Tin Cai, Qiuyin Cheng, Ching-Yu Cho, Myeong-Chan Cho, Yoon Shin Chu, Minjie Cui, Bin Gao, Yu-Tang Go, Min Jin Gu, Dongfeng Gu, Weiqiong Guo, Huan Hao, Yongchen Hong, Jie Hu, Zhibin Hu, Yanling Huang, Jianfeng Hwang, Joo-Yeon Ikram, Mohammad Kamran Jin, Guangfu Kang, Dae-Hee Khor, Chiea Chuen Kim, Bong-Jo Kim, Hung Tae Kubo, Michiaki Lee, Jeannette Lee, Juyoung Lee, Nanette R. Li, Ruoying Li, Jun Liu, JianJun Longe, Jirong Lu, Wei Lu, Xiangfeng Miao, Xiaoping Okada, Yukinori Ong, Rick Twee-Hee Qiu, Gaokun Seielstad, Mark Sim, Xueling Song, Huaidong Takeuchi, Fumihiko Tanaka, Toshihiro Taylor, Phil R. Wang, Laiyuan Wang, Weiqing Wang, Yiqin Wu, Chen Wu, Ying Xiang, Yong-Bing Yamamoto, Ken Yang, Handong Liao, Ming Yokota, Mitsuhiro Young, Terri Zhang, Xiaomin Kato, Norihiro Wang, Qing K. Zheng, Wei Hu, Frank B. Lin, Dongxin Shen, Hongbing Teo, Yik Ying Mo, Zengnan Wong, Tien Yin Lin, Xu Mohlke, Karen L. Ning, Guang Tsunoda, Tatsuhiko Han, Bok-Ghee Shu, Xiao-Ou Tai, E. Shyong Wu, Tangchun Qi, Lu TI Meta-analysis of genome-wide association studies of adult height in East Asians identifies 17 novel loci SO HUMAN MOLECULAR GENETICS LA English DT Article ID CORONARY-ARTERY-DISEASE; GENOTYPE IMPUTATION; BIOLOGICAL PATHWAYS; GENETIC-VARIANTS; CANCER; RISK; PHOSPHOLIPIDS; MUTATIONS; PTPN11; GROWTH AB Human height is associated with risk of multiple diseases and is profoundly determined by an individual's genetic makeup and shows a high degree of ethnic heterogeneity. Large-scale genome-wide association (GWA) analyses of adult height in Europeans have identified nearly 180 genetic loci. A recent study showed high replicability of results from Europeans-based GWA studies in Asians; however, population-specific loci may exist due to distinct linkage disequilibrium patterns. We carried out a GWA meta-analysis in 93 926 individuals from East Asia. We identified 98 loci, including 17 novel and 81 previously reported loci, associated with height at P<5x10(-8), together explaining 8.89% of phenotypic variance. Among the newly identified variants, 10 are commonly distributed (minor allele frequency, MAF > 5%) in Europeans, with comparable frequencies with in Asians, and 7single-nucleotide polymorphisms are with low frequency (MAF <5%) in Europeans. In addition, our data suggest that novel biological pathway such as the protein tyrosine phosphatase family is involved in regulation of height. The findings from this study considerably expand our knowledge of the genetic architecture of human height in Asians. C1 [He, Meian; Gui, Lixuan; Guo, Huan; Li, Jun; Miao, Xiaoping; Qiu, Gaokun; Zhang, Xiaomin; Wu, Tangchun] Huazhong Univ Sci & Technol, Tongji Med Coll, Sch Publ Hlth, MOE Key Lab Environm & Hlth, Wuhan 430030, Hubei, Peoples R China. [Xu, Min; Liang, Liming; Qi, Qibin; Huang, Jinyan; Li, Yanping; Hu, Frank B.; Qi, Lu] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Xu, Min; Cui, Bin; Gu, Weiqiong; Hong, Jie; Wang, Weiqing; Ning, Guang] Shanghai Jiao Tong Univ, Shanghai Inst Endocrine & Metab Dis,Minist Hlth, Shanghai Clin Ctr Endocrine & Metab Dis,Sch Med,R, Key Lab Endocrine & Metab Dis,Dept Endocrinol & M, Shanghai 200025, Peoples R China. [Song, Huaidong] Shanghai Jiao Tong Univ, State Key Lab Med Genom, Shanghai Inst Endocrine & Metab Dis, Mol Med Ctr,Ruijin Hosp,Sch Med, Shanghai 200025, Peoples R China. [Zhang, Ben; Cai, Qiuyin; Longe, Jirong; Zheng, Wei; Shu, Xiao-Ou] Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, Div Epidemiol,Dept Med, Nashville, TN 37232 USA. [Liang, Jun] Southeast Univ, Affiliated Hosp, Cent Hosp Xuzhou, Dept Endocrinol, Xuzhou 221009, Jiangsu, Peoples R China. [Chen, Peng; Cheng, Ching-Yu; Ikram, Mohammad Kamran; Khor, Chiea Chuen; Lee, Jeannette; Liu, JianJun; Ong, Rick Twee-Hee; Sim, Xueling; Teo, Yik Ying; Tai, E. Shyong] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 119077, Singapore. [Cheng, Ching-Yu; Ikram, Mohammad Kamran; Khor, Chiea Chuen; Wong, Tien Yin] Natl Univ Singapore, Dept Ophthalmol, Singapore 119077, Singapore. [Khor, Chiea Chuen; Seielstad, Mark] Natl Univ Singapore, Dept Paediat, Natl Univ Hlth Syst, Singapore 119077, Singapore. [Li, Ruoying; Tai, E. Shyong] Natl Univ Singapore, Dept Med, Yong Loo Lin Sch Med, Singapore 119077, Singapore. [Teo, Yik Ying] Natl Univ Singapore, NUS Grad Sch Integrat Sci & Engn, Singapore 119077, Singapore. [Teo, Yik Ying] Natl Univ Singapore, Inst Life Sci, Singapore 119077, Singapore. [Teo, Yik Ying] Natl Univ Singapore, Dept Stat & Appl Probabil, Singapore 119077, Singapore. [Lee, Jong-Young; Cho, Myeong-Chan; Cho, Yoon Shin; Go, Min Jin; Hwang, Joo-Yeon; Kim, Bong-Jo; Kim, Hung Tae; Lee, Juyoung; Han, Bok-Ghee] Osong Hlth Technol Adm Complex, Natl Inst Hlth, Ctr Genome Sci, Chungcheongbuk Do 363700, South Korea. [Johnson, Todd A.; Tsunoda, Tatsuhiko] RIKEN Ctr Genom Med, Lab Med Informat, Yokohama, Kanagawa 2300045, Japan. [Kubo, Michiaki] RIKEN Ctr Genom Med, Lab Genotyping Dev, Yokohama, Kanagawa 2300045, Japan. [Okada, Yukinori] RIKEN Ctr Genom Med, Lab Stat Anal, Yokohama, Kanagawa 2300045, Japan. [Tanaka, Toshihiro] RIKEN Ctr Genom Med, Lab Cardiovasc Dis, Yokohama, Kanagawa 2300045, Japan. [Li, Huaixing; Wang, Yiqin; Lin, Xu] Chinese Acad Sci, Shanghai Inst Biol Sci, Key Lab Nutr & Metab, Inst Nutr Sci, Shanghai 200031, Peoples R China. [Yang, Xiaobo; Liao, Ming; Mo, Zengnan] Guangxi Med Univ, Inst Urol & Nephrol, Affiliated Hosp 1, Nanning 530021, Guangxi, Peoples R China. [Yang, Xiaobo; Liao, Ming; Mo, Zengnan] Guangxi Med Univ, Ctr Genom & Personalized Med, Nanning 530021, Guangxi, Peoples R China. [Hu, Yanling] Guangxi Med Univ, Med Sci Res Ctr, Nanning 530021, Guangxi, Peoples R China. [Yang, Xiaobo] Guangxi Med Univ, Dept Environm & Occupat Hlth, Sch Publ Hlth, Nanning 530021, Guangxi, Peoples R China. [Dai, Juncheng; Chu, Minjie; Hu, Zhibin; Jin, Guangfu; Shen, Hongbing] Nanjing Med Univ, Dept Epidemiol & Biostat, Sch Publ Hlth, Nanjing 210029, Jiangsu, Peoples R China. [Adair, Linda S.] Univ N Carolina, Dept Nutr, Chapel Hill, NC 27599 USA. [Wu, Ying; Mohlke, Karen L.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Aung, Tin; Cheng, Ching-Yu; Ikram, Mohammad Kamran; Wong, Tien Yin] Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore 168751, Singapore. [Cheng, Ching-Yu; Young, Terri; Tai, E. Shyong] Duke Natl Univ Singapore, Grad Sch Med, Singapore 169857, Singapore. [Gao, Yu-Tang; Xiang, Yong-Bing] Shanghai Jiao Tong Univ, Sch Med, Shanghai Canc Inst, Dept Epidemiol, Shanghai 200025, Peoples R China. [Gu, Dongfeng; Hao, Yongchen; Huang, Jianfeng; Lu, Xiangfeng; Wang, Laiyuan] Chinese Acad Med Sci, State Key Lab Cardiovasc Dis, Dept Evidence Based Med, Fuwai Hosp,Natl Ctr Cardiovasc Dis, Beijing 100730, Peoples R China. [Wu, Chen; Lin, Dongxin] Chinese Acad Med Sci, State Key Lab Mol Oncol, Canc Inst & Hosp, Beijing 100730, Peoples R China. [Wu, Chen; Lin, Dongxin] Peking Union Med Coll, Beijing 100730, Peoples R China. [Ikram, Mohammad Kamran] Erasmus MC, Dept Ophthalmol, NL-3015 Rotterdam, Netherlands. [Ikram, Mohammad Kamran] Natl Univ Hlth Syst, Memory Aging & Cognit Ctr, Singapore 119228, Singapore. [Kang, Dae-Hee] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul 110799, South Korea. [Khor, Chiea Chuen; Liu, JianJun; Teo, Yik Ying] Agcy Sci Technol & Res, Genome Inst Singapore, Singapore 138672, Singapore. [Lee, Nanette R.] Univ San Carlos, Off Populat Studies Fdn, Cebu 6000, Philippines. [Lu, Wei] Shanghai Municipal Ctr Dis Control & Prevent, Shanghai 200336, Peoples R China. [Sim, Xueling] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Sim, Xueling] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Takeuchi, Fumihiko; Kato, Norihiro] Natl Ctr Global Hlth & Med, Res Inst, Dept Gene Diagnost & Therapeut, Tokyo 1628655, Japan. [Taylor, Phil R.] NCI, Div Canc Epidemiol & Genet, Genet Epidemiol Branch, Bethesda, MD 20892 USA. [Yamamoto, Ken] Kyushu Univ, Dept Mol Genet, Med Inst Bioregulat, Fukuoka 8128582, Japan. [Yang, Handong] Dongfeng Motor Corp, Dongfeng Cent Hosp, Dept Cardiol, Shiyan 442008, Hubei, Peoples R China. [Yang, Handong] Hubei Univ Med, Shiyan 442008, Hubei, Peoples R China. [Yokota, Mitsuhiro] Aichi Gakuin Univ, Sch Dent, Dept Genome Sci, Nagoya, Aichi 4648650, Japan. [Young, Terri] Duke Univ, Med Ctr, Duke Eye Ctr, Durham, NC 27710 USA. [Wang, Qing K.] Huazhong Univ Sci & Technol, Key Lab Mol Biophys, Minist Educ, Coll Life Sci & Technol,Cardio X Inst, Wuhan 430074, Hubei, Peoples R China. [Wang, Qing K.] Huazhong Univ Sci & Technol, Ctr Human Genome Res, Wuhan 430074, Hubei, Peoples R China. RP He, MA (reprint author), Huazhong Univ Sci & Technol, Tongji Med Coll, Sch Publ Hlth, MOE Key Lab Environm & Hlth, Wuhan 430030, Hubei, Peoples R China. EM hemeian@hotmail.com RI miao, xiaoping/C-4336-2011; Chen, Peng/E-5546-2015; Tsunoda, Tatsuhiko/K-2061-2014; Tanaka, Toshihiro/J-9310-2014; U-ID, Kyushu/C-5291-2016; Yang, Xiaobo/G-3854-2016; Kubo, Michiaki/N-7947-2015 OI miao, xiaoping/0000-0002-6818-9722; Johnson, Todd Andrew/0000-0003-3377-6692; Khor, Chiea Chuen/0000-0002-1128-4729; Ikram, Mohammad Kamran/0000-0003-0173-9571; Chen, Peng/0000-0002-1422-4641; Tai, E Shyong/0000-0003-2929-8966; Tanaka, Toshihiro/0000-0001-6201-9784; FU National Basic Research Program of China (973 Plan) [2011CB503901]; High-Tech Research and Development Program of China (863 Plan) [2012AA02A516]; Ministry of Science and Technology of China [2011BAI11B03, 2011BAI09B03]; National Institutes of Health [DK078150, TW05596, HL085144]; National Heart, Lung, and Blood Institute [HL071981]; National Institute of Diabetes and Digestive and Kidney Diseases [DK091718, DK078616]; Boston Obesity Nutrition Research Center [DK46200]; United States-Israel Binational Science Foundation [2011036]; Guangxi Provincial Department of Finance and Education [2009GJCJ150]; Fudan-VARI Center for Genetic Epidemiology and Fudan University Institute of Urology; Korea Center for Disease Control and Prevention [4845-301, 4851-302, 4851307]; Korea National Institute of Health [2012-N73002-00]; National High Technology Research and Development Program [2009AA022704]; Knowledge Innovation Program [KSCX2-EW-R-10]; National Natural Science Foundation of China [30930081, 81021002, 81170734, 30730080, 30972541, 30901233, 30872178, 81270877]; National Key Basic Research Program of China [2012CB524900]; China National High-Tech Research and Development Program [2009AA022705]; National Key Basic Research Program Grant [2011CB503805]; Key Laboratory for Endocrine and Metabolic Diseases of Ministry of Health [1994DP131044]; Ministry of Health [201002002]; National Key New Drug Creation and Manufacturing Program of Ministry of Science and Technology [2012ZX09303006-001]; U.S. National Institutes of Health [R37CA070867, R01CA082729, R01CA124558, R01CA148667, R01CA122364]; Vanderbilt University School of Medicine; ShanghaiWomen's Health Study [R37CA070867]; Shanghai Men's Health Study [R01CA82729]; Shanghai Breast and Endometrial Cancer Studies [R01CA064277, R01CA092585]; Singapore Ministry of Health's National Medical Research Council under its Individual Research Grant funding scheme; Singapore National Research Foundation under its Clinician Scientist Award; Singapore Translational Research Investigator Award funding schemes; National Basic Research Program [2011CB503800]; Programme of Introducing Talents of Discipline to Universities; Program for New Century Excellent Talents in University; General Program of the National Natural Science Foundation of China [81172751]; [RR20649]; [ES10126]; [DK56350] FX BGWAS (Beijing Genome-wide Association Studies): This work was supported by the National Basic Research Program of China (973 Plan) (2011CB503901), the High-Tech Research and Development Program of China (863 Plan) (2012AA02A516), grants (2011BAI11B03, 2011BAI09B03) from the Ministry of Science and Technology of China. CLHNS (the Cebu Longitudinal Health and Nutrition Survey): The study was supported by National Institutes of Health grants DK078150, TW05596 and HL085144 and pilot funds from RR20649, ES10126 and DK56350. We thank the Office of Population Studies Foundation research and data collection teams and the study participants who generously provided their time for this study. CRC (the Cardiometabolic Risk in Chinese study): This study was supported by grants from the National Heart, Lung, and Blood Institute (HL071981), the National Institute of Diabetes and Digestive and Kidney Diseases (DK091718 and DK078616), the Boston Obesity Nutrition Research Center (DK46200) and United States-Israel Binational Science Foundation Grant 2011036. FAMHES (Fangchenggang Area Male Health and Examination Survey): This study was supported by the Guangxi Provincial Department of Finance and Education (2009GJCJ150); intramural funding from the Fudan-VARI Center for Genetic Epidemiology and Fudan University Institute of Urology to Z. Mo. HEXA (Health Examinee) shared control study, KARE (the Korea Association Resource study): The work was supported by a grant from the Korea Center for Disease Control and Prevention (4845-301, 4851-302, 4851307), and intramural grant from the Korea National Institute of Health (2012-N73002-00). NHAPC (Nutrition and Health of Aging Population in China study): This study is supported by research grants including the National High Technology Research and Development Program (2009AA022704), Knowledge Innovation Program (KSCX2-EW-R-10), the National Natural Science Foundation of China (30930081, 81021002, 81170734) and the and National Key Basic Research Program of China (2012CB524900). NJ study (Nanjing GWA study): This work is funded by the China National High-Tech Research and Development Program Grant (2009AA022705), the National Key Basic Research Program Grant (2011CB503805), the National Natural Science Foundation of China (30730080, 30972541, 30901233 and 30872178). RJ study (RuiJin T2D study): the Key Laboratory for Endocrine and Metabolic Diseases of Ministry of Health (No. 1994DP131044), the Sector Funds of Ministry of Health (No. 201002002), the National Key New Drug Creation and Manufacturing Program of Ministry of Science and Technology (No. 2012ZX09303006-001) and the National Natural Science Foundation of China (No. 81270877). SGWAS (Shanghai Genome-Wide Association Studies): The content of this paper is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies. The authors thank the study participants and research staff for their contributions and commitment to this project, Regina Courtney for DNA preparation, Jing He for data processing and analyses and Bethanie Rammer for editing and preparing the manuscript. This research was supported in part by U.S. National Institutes of Health grants R37CA070867, R01CA082729, R01CA124558, R01CA148667, and R01CA122364, as well as Ingram Professorship and Research Reward funds from the Vanderbilt University School of Medicine.; Participating studies (grant support) in the Shanghai Genome Wide Association Studies are as follows: ShanghaiWomen's Health Study (R37CA070867), Shanghai Men's Health Study (R01CA82729) and Shanghai Breast and Endometrial Cancer Studies (R01CA064277 and R01CA092585). SP2 (Singapore Prospective Study Program), SCES (Singapore Chinese Eye Study) and SiMES (Singapore Malay Eye Study): the studies were supported by the Singapore Ministry of Health's National Medical Research Council under its Individual Research Grant funding scheme, the Singapore National Research Foundation under its Clinician Scientist Award and Singapore Translational Research Investigator Award funding schemes which are administered by the Singapore Ministry of Health's National Medical Research Council and the Singapore Biomedical Research Council (BMRC) individual research grant funding scheme. WHBJ (Wuhan-Beijing GWA study): This work was supported by grants from the National Basic Research Program grant (2011CB503800) and the Programme of Introducing Talents of Discipline to Universities to T. Wu and the Program for New Century Excellent Talents in University and the General Program of the National Natural Science Foundation of China (81172751) to M.H. NR 43 TC 9 Z9 9 U1 4 U2 20 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 MAR 15 PY 2015 VL 24 IS 6 BP 1791 EP 1800 DI 10.1093/hmg/ddu583 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA CC1ZO UT WOS:000350144200023 PM 25429064 ER PT J AU Anticevic, A Corlett, PR Cole, MW Savic, A Gancsos, M Tang, YQ Repovs, G Murray, JD Driesen, NR Morgan, PT Xu, K Wang, F Krystal, JH AF Anticevic, Alan Corlett, Philip R. Cole, Michael W. Savic, Aleksandar Gancsos, Mark Tang, Yanqing Repovs, Grega Murray, John D. Driesen, Naomi R. Morgan, Peter T. Xu, Ke Wang, Fei Krystal, John H. TI N-Methyl-D-Aspartate Receptor Antagonist Effects on Prefrontal Cortical Connectivity Better Model Early Than Chronic Schizophrenia SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Chronic schizophrenia; Disinhibition; First episode; Glutamate; High-risk; Ketamine; NMDA receptor; Prefrontal connectivity ID WORKING-MEMORY; HEALTHY-VOLUNTEERS; BRAIN ACTIVITY; BLOOD-FLOW; PSYCHOSIS; KETAMINE; COGNITION; DOPAMINE; CORTEX; DISORDER AB BACKGROUND: Prefrontal cortex (PFC) function contributes to schizophrenia onset and progression. However, little is known about neural mechanisms behind PFC functional alterations along illness stages. Recent pharmacologic studies indicate that glutamate dysfunction may produce increased functional connectivity. However, pharmacologic models of schizophrenia overlook effects of illness progression on PFC function. This study compared N-methyl-D-aspartate glutamate receptor (NMDAR) antagonist effects in healthy volunteers with stages of schizophrenia with respect to PFC functional connectivity. METHODS: First, we tested ketamine effects on PFC functional connectivity in healthy volunteers in a data-driven way (n = 19). Next, we compared healthy subjects (n = 96) with three clinical groups: individuals at high risk for schizophrenia (n = 21), people early in their course of schizophrenia (EC-SCZ) (n = 28), and patients with chronic illness (n = 20). Across independent analyses, we used data-driven global brain connectivity techniques restricted to PFC to identify functional dysconnectivity. RESULTS: Results revealed robust PFC hyperconnectivity in healthy volunteers administered ketamine (Cohen's d = 1.46), resembling individuals at high risk for schizophrenia and EC-SCZ. Hyperconnectivity was not found in patients with chronic illness relative to EC-SCZ patients. Results provide the first evidence that ketamine effects on PFC functional connectivity resemble early course but not chronic schizophrenia. CONCLUSIONS: Results suggest an illness phase-specific relevance of NMDAR antagonist administration for prefrontal dysconnectivity associated with schizophrenia. This finding has implications for the neurobiology of illness progression and for the widespread use of NMDAR antagonists in the development of therapeutics for schizophrenia. C1 [Anticevic, Alan; Corlett, Philip R.; Savic, Aleksandar; Gancsos, Mark; Driesen, Naomi R.; Morgan, Peter T.; Wang, Fei; Krystal, John H.] Yale Univ, Sch Med, Connecticut Mental Hlth Ctr, Dept Psychiat, New Haven, CT 06508 USA. [Anticevic, Alan; Krystal, John H.] NIAAA, Ctr Translat Neurosci Alcoholism, Connecticut Mental Hlth Ctr, New Haven, CT USA. [Anticevic, Alan; Corlett, Philip R.; Savic, Aleksandar; Gancsos, Mark; Morgan, Peter T.; Krystal, John H.] Connecticut Mental Hlth Ctr, Abraham Ribicoff Res Facil, New Haven, CT USA. [Cole, Michael W.] Rutgers State Univ, Ctr Mol & Behav Neurosci, Newark, NJ 07102 USA. [Tang, Yanqing] China Med Univ, Affiliated Hosp 1, Dept Psychiat, Shenyang 110001, Liaoning, Peoples R China. [Repovs, Grega] Univ Ljubljana, Dept Psychol, Ljubljana, Slovenia. [Murray, John D.] Yale Univ, Dept Neurobiol, New Haven, CT 06508 USA. [Murray, John D.] Yale Univ, Dept Phys, New Haven, CT 06508 USA. [Savic, Aleksandar] Univ Zagreb, Univ Psychiat Hosp Vrapce, Zagreb 41000, Croatia. [Xu, Ke; Wang, Fei] China Med Univ, Affiliated Hosp 1, Dept Radiol, Shenyang 110001, Liaoning, Peoples R China. [Krystal, John H.] Yale New Haven Med Ctr, Dept Psychiat, New Haven, CT 06504 USA. RP Wang, F (reprint author), China Med Univ, Affiliated Hosp 1, Dept Radiol & Psychiat, 155 Nanjing North St, Shenyang 110001, Liaoning, Peoples R China. EM fei.wang@yale.edu RI Murray, John/B-2835-2009; Cole, Michael/G-1056-2010; OI Murray, John/0000-0003-4115-8181; Cole, Michael/0000-0003-4329-438X; Corlett, Philip/0000-0002-5368-1992 FU National Institutes of Health [DP5OD012109-01, MH096801]; National Institute on Alcohol Abuse and Alcoholism [2P50AA012870-11]; Brain and Behavior Research Foundation Young Investigator Award; Fulbright Foundation; AstraZeneca Pharmaceuticals FX Financial support for this study was provided by National Institutes of Health Grant DP5OD012109-01 (principal investigator [PI]: AA), National Institute on Alcohol Abuse and Alcoholism Grant 2P50AA012870-11 (PI: JHK), National Institutes of Health Grant MH096801 (PI: MWC), Brain and Behavior Research Foundation Young Investigator Award (PI: AA), and the Fulbright Foundation (AS), as well as AstraZeneca Pharmaceuticals. NR 65 TC 30 Z9 31 U1 3 U2 27 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 MAR 15 PY 2015 VL 77 IS 6 BP 569 EP 580 DI 10.1016/j.biopsych.2014.07.022 PG 12 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA CB6ZQ UT WOS:000349776000010 PM 25281999 ER PT J AU Zhang, L Evans, DS Raheja, UK Stephens, SH Stiller, JW Reeves, GM Johnson, M Ryan, KA Weizel, N Vaswani, D McLain, H Shuldiner, AR Mitchell, BD Hsueh, WC Snitker, S Postolache, TT AF Zhang, Layan Evans, Daniel S. Raheja, Uttam K. Stephens, Sarah H. Stiller, John W. Reeves, Gloria M. Johnson, Mary Ryan, Kathleen A. Weizel, Nancy Vaswani, Dipika McLain, Hassan Shuldiner, Alan R. Mitchell, Braxton D. Hsueh, Wen-Chi Snitker, Soren Postolache, Teodor T. TI Chronotype and seasonality: Morningness is associated with lower seasonal mood and behavior changes in the Old Order Amish SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Seasonal Affective Disorder; Amish; Seasonal Pattern Assessment Questionnaire (SPAQ); Global Seasonality Score (GSS); Morningness-Eveningness Questionnaire (MEQ) ID SLEEP PHASE SYNDROME; DUAL VULNERABILITY HYPOTHESIS; PLACEBO-CONTROLLED TRIAL; HUMAN DIURNAL PREFERENCE; HUMAN CIRCADIAN CLOCK; AFFECTIVE-DISORDER; WINTER DEPRESSION; LIGHT TREATMENT; BRIGHT LIGHT; MELATONIN TREATMENT AB Background: Several studies documented that lower scores On the Momingness-Eveningness Questionnaire (MEQ) are associated with a higher global seasonality of mood (GSS). As for the Modern Man artificial lighting predominantly extends evening activity and exposure to light, and as evening bright light phase is known to delay circadian rhythms, this chronic exposure could potentially lead to both lower Momingness as well as higher GSS. The aim of the study was to investigate if the MEQ-GSS relationship holds in the Old Order Amish of Lancaster County, PA, a population that does not use network electrical light. Methods: 489 Old Order Amish adults (47.6% women), with average (SD) age of 49.7 (14.2) years, completed both the Seasonal Pattern Assessment Questionnaire (SPAQ) for the assessment of GSS, and MEQ. Associations between GSS scores and MEQ scores were analyzed using linear models, accounting for age, gender and relatedness by including the relationship matrix in the model as a random effect. Results: GSS was inversely associated with MEQ scores (p=0.006, adjusted). Limitations include a potential recall bias associated with self-report questionnaires and no actual light exposure measurements. Conclusion: We confirmed the previously reported inverse association between MEQ scores and lower seasonality of mood, for the first time in a population that does not use home network electrical lighting. This result suggests that the association is not a byproduct of exposure to network electric light, and calls for additional research to investigate mechanisms by which Momingness is negatively associated with seasonality. Published by Elsevier B.V. C1 [Zhang, Layan; Raheja, Uttam K.; Stiller, John W.; Vaswani, Dipika; McLain, Hassan; Postolache, Teodor T.] Univ Maryland, Sch Med, Mood & Anxiety Program, Baltimore, MD 21201 USA. [Zhang, Layan; Raheja, Uttam K.; Stiller, John W.] St Elizabeth Hosp, Psychiat Residency Training Program, Washington, DC USA. [Evans, Daniel S.] Calif Pacific Med Ctr, Inst Res, San Francisco, CA USA. [Stephens, Sarah H.; Ryan, Kathleen A.; Shuldiner, Alan R.; Mitchell, Braxton D.; Snitker, Soren] Univ Maryland, Sch Med, Dept Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. [Reeves, Gloria M.; Weizel, Nancy] Univ Maryland, Div Child & Adolescent Psychiat, Baltimore, MD 21201 USA. [Reeves, Gloria M.; Weizel, Nancy] Univ Maryland, Univ Maryland Child & Adolescent Mental Hlth Inno, Baltimore, MD 21201 USA. [Johnson, Mary] Univ Maryland, Sch Med, Dept Ophthalmol & Visual Sci, Baltimore, MD 21201 USA. [Hsueh, Wen-Chi] NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ USA. [Postolache, Teodor T.] VISN 5 Capitol Hlth Care Network Mental Illness R, Baltimore, MD USA. [Postolache, Teodor T.] VISN 19 MIRECC, Denver, CO USA. RP Postolache, TT (reprint author), Univ Maryland, Sch Med, Dept Psychiat, Mood & Anxiety Program, 685 West Baltimore St,MSTF Bldg Room 930, Baltimore, MD 21201 USA. EM teopostolache@gmail.com OI Mitchell, Braxton/0000-0003-4920-4744 FU National Institutes of Health [K18MH093940-01]; Mid-Atlantic Nutrition and Obesity Research Center (NORC) [P30DK072438]; VISN 5 Capitol Health Care Network Mental Illness Research Education and Clinical Center (MIRECC), Baltimore, MD, USA; VISN 19 MIRECC, Denver, CO-department of Veterans Affairs FX Main support: K18MH093940-01 from the National Institutes of Health (PI Postolache). Partial funding was also provided by the Mid-Atlantic Nutrition and Obesity Research Center (NORC) (P30DK072438), and by the VISN 5 Capitol Health Care Network Mental Illness Research Education and Clinical Center (MIRECC), Baltimore, MD, USA and VISN 19 MIRECC, Denver, CO-department of Veterans Affairs. The views, opinions and findings contained in this article are those of the authors and should not be construed as an official NIH or Department of Veterans Affairs position. NR 84 TC 5 Z9 5 U1 0 U2 12 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 MAR 15 PY 2015 VL 174 BP 209 EP 214 DI 10.1016/j.jad.2014.11.039 PG 6 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA CC0CY UT WOS:000350003800030 PM 25527990 ER PT J AU Tighe, SK Ritchey, M Schweizer, B Goes, FS MacKinnon, D Mondimore, F DePaulo, JR McMahon, FJ Schulze, TG Zandi, PP Potash, JB AF Tighe, Sarah K. Ritchey, Megan Schweizer, Barbara Goes, Fernando S. MacKinnon, Dean Mondimore, Francis DePaulo, J. Raymond McMahon, Francis J. Schulze, Thomas G. Zandi, Peter P. Potash, James B. TI Test-retest reliability of a new questionnaire for the retrospective assessment of long-term lithium use in bipolar disorder SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Bipolar disorder; Lithium; Retrospective assessment; Long-term therapy; Predictors of treatment response; The Alda Scale ID PROPHYLAXIS AB Background: The identification of predictors of treatment response holds tremendous potential for the improvement of clinical outcomes in bipolar disorder (BP). The goal of this project is to evaluate the test-retest reliability of a new clinical tool, the Lithium Questionnaire (LQ), for the retrospective assessment of long-term lithium use in research participants with BP. Methods: Twenty-nine individuals with BP-I (n=27), major depression (n=1), or schizoaffective disorder (n=1) were recruited for participation. The LQ was administered to all participants at two time-points, spaced 17 months apart on average, and used to determine each subject's score on the Retrospective Criteria of Long Term Treatment Response in Research Subjects with Bipolar Disorder Scale, or the Alda Scale. Scores were confirmed through a best estimate procedure, and test-retest reliability (intra-class correlation coefficient [ICC]) of the LQ was calculated. Results: The correlation between the total Alda Scale scores at the two time points was in the moderate range (ICC=0.60). Relevant clinical factors such as age or presence of Axis I psychiatric comorbidity did not influence the reliability. Limitations: The validity of the LQ was not examined. Inclusion of two participants with non BP diagnoses may have affected the LQ's reliability, but re-analysis of our data after exclusion of these participants did not influence the reliability. The absence of measures of mood and cognition at time of LQ may be a limitation of this work. Conclusions: The LQ holds promise for the standardization of the retrospective assessment of long-term treatment in BP. (C) 2014 Elsevier B.V. All rights reserved. C1 [Tighe, Sarah K.; Potash, James B.] Univ Iowa, Carver Coll Med, Dept Psychiat, Iowa City, IA 52242 USA. [Ritchey, Megan; Schweizer, Barbara; Goes, Fernando S.; MacKinnon, Dean; Mondimore, Francis; DePaulo, J. Raymond; Schulze, Thomas G.; Zandi, Peter P.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD USA. [McMahon, Francis J.] Natl Inst Hlth, NIMH, Human Genet Branch, Bethesda, MD USA. [Schulze, Thomas G.] Univ Med Ctr Gottingen, Dept Psychiat Pscyhotherapy, Gottingen, Germany. [Schulze, Thomas G.] Univ Munich, Inst Psychiat Phenom Gen, Munich, Germany. [Zandi, Peter P.] Johns Hopkins Univ, Bloomberg Sch Public Hlth, Dept Mental Hlth, Baltimore, MD USA. RP Tighe, SK (reprint author), Univ Iowa, Carver Coll Med, Dept Psychiat, W278 GH,200 Hawkins Dr, Iowa City, IA 52242 USA. EM sarah-k-tighe@uiowa.edu OI McMahon, Francis/0000-0002-9469-305X FU James Wah Fund; Project MATCH; National Institute of Mental Health Intramural Research Program; NIH/NIA Grant [T32 AG027668]; Deutsche Forschungsgemeinschaft Grant [RI 908/7-1] FX Supported by the James Wah Fund (SKI), Project MATCH (BS, DM, PZ), the National Institute of Mental Health Intramural Research Program (FJM), NIH/NIA Grant T32 AG027668 (SKI), and Deutsche Forschungsgemeinschaft Grant RI 908/7-1 (TGS). The remaining authors have no biomedical financial interests or potential conflicts of interest to report. NR 15 TC 2 Z9 2 U1 1 U2 3 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 MAR 15 PY 2015 VL 174 BP 589 EP 593 DI 10.1016/j.jad.2014.11.021 PG 5 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA CC0CY UT WOS:000350003800081 PM 25562671 ER PT J AU Neuner, SM Wilmott, LA Hope, KA Hoffmann, B Chong, JA Abramowitz, J Birnbaumer, L O'Connell, KM Tryba, AK Greene, AS Chan, CS Kaczorowski, CC AF Neuner, Sarah M. Wilmott, Lynda A. Hope, Kevin A. Hoffmann, Brian Chong, Jayhong A. Abramowitz, Joel Birnbaumer, Lutz O'Connell, Kristen M. Tryba, Andrew K. Greene, Andrew S. Chan, C. Savio Kaczorowski, Catherine C. TI TRPC3 channels critically regulate hippocampal excitability and contextual fear memory SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE Hippocampus; Memory; Transient receptor potential cation channel; Afterhyperpoloarization; Aging; Proteomics ID CA1 PYRAMIDAL NEURONS; LONG-TERM POTENTIATION; INBRED MOUSE STRAINS; SLOW AFTERHYPERPOLARIZATION; PROTEIN-SYNTHESIS; INTRINSIC EXCITABILITY; SYNAPTIC-TRANSMISSION; LEARNING-ABILITY; RNA INTERFERENCE; SIRNA SEQUENCES AB Memory formation requires de nova protein synthesis, and memory disorders may result from misregulated synthesis of critical proteins that remain largely unidentified. Plasma membrane ion channels and receptors are likely candidates given their role in regulating neuron excitability, a candidate memory mechanism. Here we conduct targeted molecular monitoring and quantitation of hippocampal plasma membrane proteins from mice with intact or impaired contextual fear memory to identify putative candidates. Here we report contextual fear memory deficits correspond to increased Trpc3 gene and protein expression, and demonstrate TRPC3 regulates hippocampal neuron excitability associated with memory function. These data provide a mechanistic explanation for enhanced contextual fear memory reported herein following knockdown of TRPC3 in hippocampus. Collectively, TRPC3 modulates memory and may be a feasible target to enhance memory and treat memory disorders. (C) 2014 The Authors. Published by Elsevier B.V. C1 [Neuner, Sarah M.; Wilmott, Lynda A.; Hope, Kevin A.; Kaczorowski, Catherine C.] Univ Tennessee, Hlth Sci Ctr, Dept Anat & Neurobiol, Memphis, TN 38163 USA. [Hoffmann, Brian; Greene, Andrew S.] Med Coll Wisconsin, Dept Biotechnol & Bioengn, Milwaukee, WI 53226 USA. [Chong, Jayhong A.] Hydra Biosci, Cambridge, MA USA. [Abramowitz, Joel; Birnbaumer, Lutz] NIEHS, Neurobiol Lab, Res Triangle Pk, NC 27709 USA. [O'Connell, Kristen M.] Univ Tennessee, Hlth Sci Ctr, Dept Physiol, Memphis, TN USA. [Tryba, Andrew K.] Univ Chicago, Dept Pediat, Chicago, IL 60637 USA. [Greene, Andrew S.] Med Coll Wisconsin, Dept Physiol, Milwaukee, WI 53226 USA. [Chan, C. Savio] Northwestern Fienberg Sch Med, Dept Physiol, Chicago, IL USA. RP Kaczorowski, CC (reprint author), Univ Tennessee, Hlth Sci Ctr, Dept Anat & Neurobiol, Memphis, TN 38163 USA. EM ckaczoro@tennessee.edu RI Abramowitz, Joel/A-2620-2015; OI Tryba, Andrew/0000-0002-9610-9259 FU Intramural Research Program of the National Institutes of Health [ZO1-ES-101684]; University of Tennessee Health Science Center, Neuroscience Institute; Biotechnology Training Grant [T32-HL-094273]; Robert and Patricia Kern Foundation; [P01-HL-082798]; [R01-NS-069777]; [DoD W81XWH-13-1-0243]; [K99/R00-AG-039511] FX This work was supported in part by the Intramural Research Program of the National Institutes of Health (ZO1-ES-101684 to L.B.). S.M.N. and K.A.H. were supported by the University of Tennessee Health Science Center, Neuroscience Institute. B.H. was supported by the Biotechnology Training Grant (T32-HL-094273) and generous support from the Robert and Patricia Kern Foundation. A.S.G. was supported by P01-HL-082798 (PI: Greene). C.S.C. was supported by R01-NS-069777 and DoD W81XWH-13-1-0243 (PI: Chan). C.C.K. and L.A.W. were supported by K99/R00-AG-039511 (PI: Kaczorowski). NR 74 TC 5 Z9 5 U1 0 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 EI 1872-7549 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD MAR 15 PY 2015 VL 281 BP 69 EP 77 DI 10.1016/j.bbr.2014.12.018 PG 9 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA CB3CA UT WOS:000349504600009 PM 25513972 ER PT J AU Barrett, JH Taylor, JC Bright, C Harland, M Dunning, AM Akslen, LA Andresen, PA Avril, MF Azizi, E Scarra, GB Brossard, M Brown, KM Debniak, T Elder, DE Friedman, E Ghiorzo, P Gillanders, EM Gruis, NA Hansson, J Helsing, P Hocevar, M Hoiom, V Ingvar, C Landi, MT Lang, J Lathrop, GM Lubinski, J Mackie, RM Molven, A Novakovic, S Olsson, H Puig, S Puig-Butille, JA van der Stoep, N van Doorn, R van Workum, W Goldstein, AM Kanetsky, PA Pharoah, PDP Demenais, F Hayward, NK Newton Bishop, JA Bishop, DT Iles, MM AF Barrett, Jennifer H. Taylor, John C. Bright, Chloe Harland, Mark Dunning, Alison M. Akslen, Lars A. Andresen, Per A. Avril, Marie-Francoise Azizi, Esther Scarra, Giovanna Bianchi Brossard, Myriam Brown, Kevin M. Debniak, Tadeusz Elder, David E. Friedman, Eitan Ghiorzo, Paola Gillanders, Elizabeth M. Gruis, Nelleke A. Hansson, Johan Helsing, Per Hocevar, Marko Hoiom, Veronica Ingvar, Christian Landi, Maria Teresa Lang, Julie Lathrop, G. Mark Lubinski, Jan Mackie, Rona M. Molven, Anders Novakovic, Srdjan Olsson, Hakan Puig, Susana Anton Puig-Butille, Joan van der Stoep, Nienke van Doorn, Remco van Workum, Wilbert Goldstein, Alisa M. Kanetsky, Peter A. Pharoah, Paul D. P. Demenais, Florence Hayward, Nicholas K. Newton Bishop, Julia A. Bishop, D. Timothy Iles, Mark M. CA GenoMEL Consortium TI Fine mapping of genetic susceptibility loci for melanoma reveals a mixture of single variant and multiple variant regions SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE melanoma; fine mapping; penalized regression; heritability; genome-wide signal ID GENOME-WIDE ASSOCIATION; CORONARY-ARTERY-DISEASE; SEQUENCE VARIANTS; TELOMERE LENGTH; IDENTIFIES 3; RISK; CANCER; POPULATION; LINKAGE; BREAST AB At least 17 genomic regions are established as harboring melanoma susceptibility variants, in most instances with genome-wide levels of significance and replication in independent samples. Based on genome-wide single nucleotide polymorphism (SNP) data augmented by imputation to the 1,000 Genomes reference panel, we have fine mapped these regions in over 5,000 individuals with melanoma (mainly from the GenoMEL consortium) and over 7,000 ethnically matched controls. A penalized regression approach was used to discover those SNP markers that most parsimoniously explain the observed association in each genomic region. For the majority of the regions, the signal is best explained by a single SNP, which sometimes, as in the tyrosinase region, is a known functional variant. However in five regions the explanation is more complex. At the CDKN2A locus, for example, there is strong evidence that not only multiple SNPs but also multiple genes are involved. Our results illustrate the variability in the biology underlying genome-wide susceptibility loci and make steps toward accounting for some of the missing heritability. What's new? In genome-wide association studies, researchers identify genetic variants that frequently associate with a particular disease, though the variants identified may not contribute to the molecular cause of the disease. This study took a closer look at 17 regions associated with melanoma, fine mapping the regions both in people with melanoma and in healthy controls. Though single SNPs account for the association in some regions, they found that in a few regions, several SNPs - and possibly multiple genes - contributed to the association signal. These findings illustrate the importance of not overlooking the interaction between multiple genetic markers when conducting such studies. C1 [Barrett, Jennifer H.; Taylor, John C.; Bright, Chloe; Harland, Mark; Newton Bishop, Julia A.; Bishop, D. Timothy; Iles, Mark M.] Univ Leeds, Sect Epidemiol & Biostat, Leeds Inst Canc & Pathol, Leeds, W Yorkshire, England. [Dunning, Alison M.; Pharoah, Paul D. P.] Univ Cambridge, Dept Oncol, Cambridge, England. [Akslen, Lars A.] Univ Bergen, Ctr Canc Biomarkers CCBIO, Dept Clin Med, Bergen, Norway. [Akslen, Lars A.; Molven, Anders] Haukeland Hosp, Dept Pathol, N-5021 Bergen, Norway. [Andresen, Per A.] Univ Oslo, Rikshosp, Oslo Univ Hosp, Dept Pathol, N-0027 Oslo, Norway. [Avril, Marie-Francoise] Univ Paris 05, Hop Cochin, AP HP, Serv Dermatol, Paris, France. [Azizi, Esther] Chaim Sheba Med Ctr, Dept Dermatol, IL-52621 Tel Hashomer, Israel. [Azizi, Esther; Friedman, Eitan] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. [Azizi, Esther; Friedman, Eitan] Chaim Sheba Med Ctr, Oncogenet Unit, IL-52621 Tel Hashomer, Israel. [Scarra, Giovanna Bianchi; Ghiorzo, Paola] Univ Genoa, Dept Internal Med & Med Specialties, Genoa, Italy. [Scarra, Giovanna Bianchi; Ghiorzo, Paola] IRCCS AOU San Martino IST, Lab Genet Rare Hereditary Canc, Genoa, Italy. [Brossard, Myriam; Demenais, Florence] INSERM, UMR 946, Genet Variat & Human Dis Unit, Paris, France. [Brossard, Myriam; Demenais, Florence] Univ Paris Diderot, Sorbonne Paris Cite, Inst Univ Hematol, Paris, France. [Brown, Kevin M.; Landi, Maria Teresa; Goldstein, Alisa M.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Debniak, Tadeusz; Lubinski, Jan] Pomeranian Med Univ, Int Hereditary Canc Ctr, Szczecin, Poland. [Elder, David E.] Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA USA. [Gillanders, Elizabeth M.] NHGRI, Epidemiol & Genom Res Program, Div Canc Control & Populat Sci, NIH, Baltimore, MD USA. [Gruis, Nelleke A.; van Doorn, Remco] Leiden Univ, Med Ctr, Dept Dermatol, Leiden, Netherlands. [Hansson, Johan; Hoiom, Veronica] Karolinska Inst, Karolinska Univ Hosp, Dept Oncol Pathol, S-17176 Stockholm, Sweden. [Helsing, Per] Univ Oslo, Rikshosp, Oslo Univ Hosp, Dept Dermatol, N-0027 Oslo, Norway. [Hocevar, Marko] Inst Oncol Ljubljana, Dept Surg Oncol, Ljubljana 1000, Slovenia. [Ingvar, Christian] Lund Univ, Dept Surg, Lund, Sweden. [Lang, Julie] Univ Glasgow, Dept Med Genet, Glasgow, Lanark, Scotland. [Lathrop, G. Mark] McGill Univ, Montreal, PQ, Canada. [Lathrop, G. Mark] Genome Quebec Innovat Ctr, Montreal, PQ, Canada. [Lathrop, G. Mark] CEA, Inst Genom, Ctr Natl Genotypage, Evry, France. [Mackie, Rona M.] Univ Glasgow, Dept Publ Hlth, Glasgow, Lanark, Scotland. [Mackie, Rona M.] Dept Med Genet, Glasgow, Lanark, Scotland. [Molven, Anders] Univ Bergen, Dept Clin Med, Gade Lab Pathol, Bergen, Norway. [Novakovic, Srdjan] Inst Oncol Ljubljana, Dept Mol Diagnost, Ljubljana 1000, Slovenia. [Olsson, Hakan] Lund Univ, Dept Oncol, Lund, Sweden. [Olsson, Hakan] Lund Univ, Dept Canc Epidemiol, Lund, Sweden. [Puig, Susana; Anton Puig-Butille, Joan] Univ Barcelona, Melanoma Unit, Dept Dermatol, Hosp Clin,Inst Invest Biomed August Pi Sune, Barcelona, Spain. [Puig, Susana; Anton Puig-Butille, Joan] Inst Salud Carlos III, CIBER Enfermedades Raras, Barcelona, Spain. [van der Stoep, Nienke] Leiden Univ, Med Ctr, Ctr Human & Clin Genet, Dept Clin Genet, Leiden, Netherlands. [van Workum, Wilbert] ServiceXS BV, Leiden, Netherlands. [Kanetsky, Peter A.] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Canc Epidemiol, Tampa, FL 33682 USA. [Pharoah, Paul D. P.] Strangeways Res Lab, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge CB1 4RN, England. [Hayward, Nicholas K.] QIMR Berghofer Med Res Inst, Brisbane, Qld 4029, Australia. RP Barrett, JH (reprint author), St James Univ Hosp, Canc Genet Bldg,Beckett St, Leeds LS9 7TF, W Yorkshire, England. EM j.h.barrett@leeds.ac.uk RI hayward, nicholas/C-1367-2015; Hoiom, Veronica/F-4153-2012; Akslen, Lars /C-1202-2017; Demenais, Florence/G-3298-2013; OI Puig, Susana/0000-0003-1337-9745; hayward, nicholas/0000-0003-4760-1033; , Srdjan/0000-0002-8888-4810; Akslen, Lars /0000-0003-2710-9543; Demenais, Florence/0000-0001-8361-0936; Gruis, Nelleke/0000-0002-5210-9150; Barrett, Jenny/0000-0002-1720-7724; Dunning, Alison Margaret/0000-0001-6651-7166; Bishop, Tim/0000-0002-8752-8785; Newton Bishop, Julia/0000-0001-9147-6802 FU European Commission [LSHC-CT-2006-018702]; Cancer Research UK Programme Awards [C588/A4994, C588/A10589]; Cancer Research UK Project Grant [C8216/A6129]; US National Institutes of Health [CA83115]; CIDR [HHSN268201100011I]; Wellcome Trust [076113]; SEARCH: Cancer Research UK "Genetic Epidemiology of Cancer" [C8197/A10123, C490/A11021, C1287/A10122, C1287/A10118, C490/A10119]; Genetic Factors in Telomere Length [C1287/A9540]; European Research Council Advanced Grant [ERC-2011-294576]; Universita degli Studi di Genova Progetti di Ricerca di Ateneo [PRA 2012-2013]; Institut National du Cancer [INCa_5982/PLBIO-2012]; Catalan Government, Spain [AGAUR 2009 SGR 1337]; Ligue Nationale Contre Le Cancer [PRE05/FD, PRE 09/FD]; Programme Hospitalier de Recherche Clinique [AOM-07-195]; European Biobanking and Biomolecular Resources Research Infrastructure (BBMRI)-Netherlands Hub [CO18]; Fondo de Investigaciones Sanitarias [P.I. 09/01393]; Comprehensive Cancer Center, Oslo University Hospital [SE0728]; Norwegian Cancer Society [71512-PR-2006-0356]; Intramural Research Program of the NIH; National Cancer Institute (NCI); Ministere de l'Enseignement Superieur et de la Recherche; Institut National du Cancer (INCa); Swedish Cancer Society; Karolinska Institutet's Research Funds; Gunnar Nilsson Foundation; IRCCS Azienda Ospedaliera Universitaria San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, 5 per 1000 per la Ricerca Corrente; Intramural Research Program of National Institutes of Health; National Cancer Institute, Division of Cancer Epidemiology and Genetics; Ligue Nationale Contre Le Cancer Doctoral Fellowship; CIBER de Enfermedades Raras of the Instituto de Salud Carlos III, Spain FX Grant sponsor: European Commission; Grant number: LSHC-CT-2006-018702; Grant sponsor: Cancer Research UK Programme Awards; Grant numbers: C588/A4994, C588/A10589; Grant sponsor: Cancer Research UK Project Grant; Grant number: C8216/A6129; Grant sponsor: US National Institutes of Health; Grant number: CA83115; Grant sponsor: CIDR; Grant number: HHSN268201100011I; Grant sponsor: Wellcome Trust; Grant number: 076113; Grant sponsor: SEARCH: Cancer Research UK "Genetic Epidemiology of Cancer"; Grant numbers: C8197/A10123, C490/A11021, C1287/A10122, C1287/A10118, C490/A10119; Grant sponsor: Genetic Factors in Telomere Length; Grant number: C1287/A9540; Grant sponsor: European Research Council Advanced Grant; Grant number: ERC-2011-294576; Grant sponsor: Universita degli Studi di Genova Progetti di Ricerca di Ateneo; Grant number: PRA 2012-2013; Grant sponsor: Institut National du Cancer; Grant number: INCa_5982/PLBIO-2012; Grant sponsor: Catalan Government, Spain; Grant number: AGAUR 2009 SGR 1337; Grant sponsor: Ligue Nationale Contre Le Cancer; Grant numbers: PRE05/FD, PRE 09/FD; Grant sponsor: Programme Hospitalier de Recherche Clinique; Grant number: AOM-07-195; Grant sponsor: European Biobanking and Biomolecular Resources Research Infrastructure (BBMRI)-Netherlands Hub; Grant number: CO18; Grant sponsor: Fondo de Investigaciones Sanitarias; Grant number: P.I. 09/01393; Grant sponsor: Comprehensive Cancer Center, Oslo University Hospital; Grant number: SE0728; Grant sponsor: Norwegian Cancer Society; Grant number: 71512-PR-2006-0356; Grant sponsor: Intramural Research Program of the NIH; National Cancer Institute (NCI); Ministere de l'Enseignement Superieur et de la Recherche; Institut National du Cancer (INCa); Swedish Cancer Society; Karolinska Institutet's Research Funds; Swedish Cancer Society; Gunnar Nilsson Foundation; IRCCS Azienda Ospedaliera Universitaria San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, 5 per 1000 per la Ricerca Corrente; Intramural Research Program of National Institutes of Health; National Cancer Institute, Division of Cancer Epidemiology and Genetics; Ligue Nationale Contre Le Cancer Doctoral Fellowship; CIBER de Enfermedades Raras of the Instituto de Salud Carlos III, Spain NR 30 TC 11 Z9 11 U1 1 U2 13 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 MAR 15 PY 2015 VL 136 IS 6 BP 1351 EP 1360 DI 10.1002/ijc.29099 PG 10 WC Oncology SC Oncology GA AY6XD UT WOS:000347705200041 PM 25077817 ER PT J AU Nasrollahzadeh, D Ye, WM Shakeri, R Sotoudeh, M Merat, S Kamangar, F Abnet, CC Islami, F Boffetta, P Dawsey, SM Brennan, P Malekzadeh, R AF Nasrollahzadeh, Dariush Ye, Weimin Shakeri, Ramin Sotoudeh, Masoud Merat, Shahin Kamangar, Farin Abnet, Christian C. Islami, Farhad Boffetta, Paolo Dawsey, Sanford M. Brennan, Paul Malekzadeh, Reza TI Contact with ruminants is associated with esophageal squamous cell carcinoma risk SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE esophageal neoplasm; risk factors; ruminants; animal contact; relative risk ID CANCER-RISK; IRAN; AREA; EUPHORBIACEAE; MORTALITY; ALCOHOL; TOBACCO; CATTLE; PLANTS AB The etiology of esophageal squamous cell carcinoma (ESCC) in the high risk area of northern Iran is only partially known. We aimed to investigate prolonged animal contact as a risk factor for ESCC in this population. From 2003 to 2007, we administered a validated questionnaire to 300 ESCC cases and 571 randomly selected controls matched for neighborhood of residence, age (2 years) and sex. Questions on lifelong exposure to equines, ruminants, canines, and poultry, including duration and level of contact, were asked in a face-to-face interviews. Conditional logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs) adjusted for potential confounders. A total of 94.7% of cases and 68.7% of controls reported lifelong history of contact with ruminants. After controlling for potential confounders, contact with ruminants was associated with an eightfold increase (95% CI: 3.92-14.86) in risk of ESCC, and increments in duration of contact raised the risk estimates in a dose-dependent manner. Contact with equines and poultry did not significantly change associated OR for ESCC risk and contact with ruminants. OR (95% CI) for contact with canines was 1.99 (1.35-2.93) which after exclusion of contact with ruminants was not significant (OR for contact only with canine: 3.18, 95% CI: 0.73-13.17). These results add to the evidence that contact with ruminants may increase the risk of ESCC. What's new? People across a particular part of Central Asia have an elevated risk of esophageal cancer, but no one has yet discovered quite why. This study asks how contact with animals influences risk. The authors gave a questionnaire to people in northern Iran with and without esophageal squamous cell cancer, inquiring about their contact with various animals, including horses, dogs, poultry, and ruminants, such as sheep and cattle. It turned out that contact with ruminants was associated with an 8-fold increase in risk of esophageal squamous cell carcinoma, and the longer the exposure over a lifetime, the greater the risk. C1 [Nasrollahzadeh, Dariush; Ye, Weimin] Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden. [Nasrollahzadeh, Dariush; Shakeri, Ramin; Sotoudeh, Masoud; Merat, Shahin; Islami, Farhad; Malekzadeh, Reza] Univ Tehran Med Sci, Digest Dis Res Inst, Digest Oncol Res Ctr, Tehran 14117, Iran. [Kamangar, Farin] Morgan State Univ, Dept Publ Hlth Anal, Sch Community Hlth & Policy, Baltimore, MD 21239 USA. [Abnet, Christian C.; Dawsey, Sanford M.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Islami, Farhad; Boffetta, Paolo] Icahn Sch Med Mt Sinai, Inst Translat Epidemiol, New York, NY 10029 USA. [Islami, Farhad; Boffetta, Paolo] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA. [Brennan, Paul] Int Agcy Res Canc, Genet Epidemiol Grp, F-69372 Lyon, France. RP Malekzadeh, R (reprint author), Univ Tehran Med Sci, Digest Dis Res Inst, Digest Oncol Res Ctr, Tehran 14117, Iran. EM malek@ams.ac.ir RI Abnet, Christian/C-4111-2015; OI Abnet, Christian/0000-0002-3008-7843; , Ramin/0000-0003-0487-3629; Malekzadeh, Reza/0000-0003-1043-3814 FU Digestive Disease Research Center of Tehran University of Medical Sciences [82-603]; National Cancer Institute at the National Institutes of Health; KID scholarship from Karolinska Institute FX Grant sponsor: Digestive Disease Research Center of Tehran University of Medical Sciences; Grant number: 82-603; Grant sponsor: National Cancer Institute at the National Institutes of Health. Grant sponsor: KID scholarship from Karolinska Institute (Supporting D.N.) NR 27 TC 3 Z9 3 U1 0 U2 9 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 MAR 15 PY 2015 VL 136 IS 6 BP 1468 EP 1474 DI 10.1002/ijc.29109 PG 7 WC Oncology SC Oncology GA AY6XD UT WOS:000347705200052 PM 25082448 ER PT J AU Rudolph, A Milne, RL Truong, T Knight, JA Seibold, P Flesch-Janys, D Behrens, S Eilber, U Bolla, MK Wang, Q Dennis, J Dunning, AM Shah, M Munday, HR Darabi, H Eriksson, M Brand, JS Olson, J Vachon, CM Hallberg, E Castelao, JE Carracedo, A Torres, M Li, JM Humphreys, K Cordina-Duverger, E Menegaux, F Flyger, H Nordestgaard, BG Nielsen, SF Yesilyurt, BT Floris, G Leunen, K Engelhardt, EG Broeks, A Rutgers, EJ Glendon, G Mulligan, AM Cross, S Reed, M Gonzalez-Neira, A Perez, JIA Provenzano, E Apicella, C Southey, MC Spurdle, A Haberle, L Beckmann, MW Ekici, AB Dieffenbach, AK Arndt, V Stegmaier, C McLean, C Baglietto, L Chanock, SJ Lissowska, J Sherman, ME Bruning, T Hamann, U Ko, YD Orr, N Schoemaker, M Ashworth, A Kosma, VM Kataja, V Hartikainen, JM Mannermaa, A Swerdlow, A Giles, GG Brenner, H Fasching, PA Chenevix-Trench, G Hopper, J Benitez, J Cox, A Andrulis, IL Lambrechts, D Gago-Dominguez, M Couch, F Czene, K Bojesen, SE Easton, DF Schmidt, MK Guenel, P Hall, P Pharoah, PDP Garcia-Closas, M Chang-Claude, J AF Rudolph, Anja Milne, Roger L. Truong, Therese Knight, Julia A. Seibold, Petra Flesch-Janys, Dieter Behrens, Sabine Eilber, Ursula Bolla, Manjeet K. Wang, Qin Dennis, Joe Dunning, Alison M. Shah, Mitul Munday, Hannah R. Darabi, Hatef Eriksson, Mikael Brand, Judith S. Olson, Janet Vachon, Celine M. Hallberg, Emily Esteban Castelao, J. Carracedo, Angel Torres, Maria Li, Jingmei Humphreys, Keith Cordina-Duverger, Emilie Menegaux, Florence Flyger, Henrik Nordestgaard, Borge G. Nielsen, Sune F. Yesilyurt, Betul T. Floris, Giuseppe Leunen, Karin Engelhardt, Ellen G. Broeks, Annegien Rutgers, Emiel J. Glendon, Gord Mulligan, Anna Marie Cross, Simon Reed, Malcolm Gonzalez-Neira, Anna Arias Perez, Jose Ignacio Provenzano, Elena Apicella, Carmel Southey, Melissa C. Spurdle, Amanda Haeberle, Lothar Beckmann, Matthias W. Ekici, Arif B. Dieffenbach, Aida Karina Arndt, Volker Stegmaier, Christa McLean, Catriona Baglietto, Laura Chanock, Stephen J. Lissowska, Jolanta Sherman, Mark E. Bruening, Thomas Hamann, Ute Ko, Yon-Dschun Orr, Nick Schoemaker, Minouk Ashworth, Alan Kosma, Veli-Matti Kataja, Vesa Hartikainen, Jaana M. Mannermaa, Arto Swerdlow, Anthony Giles, Graham G. Brenner, Hermann Fasching, Peter A. Chenevix-Trench, Georgia Hopper, John Benitez, Javier Cox, Angela Andrulis, Irene L. Lambrechts, Diether Gago-Dominguez, Manuela Couch, Fergus Czene, Kamila Bojesen, Stig E. Easton, Doug F. Schmidt, Marjanka K. Guenel, Pascal Hall, Per Pharoah, Paul D. P. Garcia-Closas, Montserrat Chang-Claude, Jenny CA KConFab Investigators AOCS Grp GENICA-Network TI Investigation of gene-environment interactions between 47 newly identified breast cancer susceptibility loci and environmental risk factors SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE gene-environment interaction; breast cancer; risk factor; genetic susceptibility ID PROGESTERONE-RECEPTOR STATUS; GENOME-WIDE ASSOCIATION; INOSITOL POLYPHOSPHATES; METAANALYSIS; COHORT; VARIANTS; ESTROGEN; HEIGHT; WOMEN; BIAS AB A large genotyping project within the Breast Cancer Association Consortium (BCAC) recently identified 41 associations between single nucleotide polymorphisms (SNPs) and overall breast cancer (BC) risk. We investigated whether the effects of these 41 SNPs, as well as six SNPs associated with estrogen receptor (ER) negative BC risk are modified by 13 environmental risk factors for BC. Data from 22 studies participating in BCAC were pooled, comprising up to 26,633 cases and 30,119 controls. Interactions between SNPs and environmental factors were evaluated using an empirical Bayes-type shrinkage estimator. Six SNPs showed interactions with associated p-values (p(int)) <1.1 x 10(-3). None of the observed interactions was significant after accounting for multiple testing. The Bayesian False Discovery Probability was used to rank the findings, which indicated three interactions as being noteworthy at 1% prior probability of interaction. SNP rs6828523 was associated with increased ER-negative BC risk in women 170 cm (OR = 1.22, p = 0.017), but inversely associated with ER-negative BC risk in women <160 cm (OR = 0.83, p = 0.039, p(int) = 1.9 x 10(-4)). The inverse association between rs4808801 and overall BC risk was stronger for women who had had four or more pregnancies (OR = 0.85, p = 2.0 x 10(-4)), and absent in women who had had just one (OR = 0.96, p = 0.19, p(int) = 6.1 x 10(-4)). SNP rs11242675 was inversely associated with overall BC risk in never/former smokers (OR = 0.93, p = 2.8 x 10(-5)), but no association was observed in current smokers (OR = 1.07, p = 0.14, p(int) = 3.4 x 10(-4)). In conclusion, recently identified BC susceptibility loci are not strongly modified by established risk factors and the observed potential interactions require confirmation in independent studies. What's new? The recent discovery of 47 susceptibility loci associated with all or estrogen receptor-negative breast cancer provided new opportunities for genetic risk prediction but it remained unclear how exposure levels of environmental (non-genetic) risk factors influenced the risk assessment. In this gene-environment study, the international team examined interactions between the single nucleotide polymorphisms and 13 established environmental risk factors including parity, height and alcohol consumption. Notably, relative risks of breast cancer associated with the susceptibility loci were not strongly modified by environmental risk factors, a finding that, if confirmed, has important implications for the risk assessment in breast cancer. C1 [Rudolph, Anja; Seibold, Petra; Behrens, Sabine; Eilber, Ursula; Chang-Claude, Jenny] German Canc Res Ctr, Div Canc Epidemiol, D-69120 Heidelberg, Germany. [Milne, Roger L.; Baglietto, Laura; Giles, Graham G.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Milne, Roger L.; Baglietto, Laura; Giles, Graham G.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic 3010, Australia. [Truong, Therese; Cordina-Duverger, Emilie; Menegaux, Florence; Guenel, Pascal] Inserm Natl Inst Hlth & Med Res, CESP Ctr Res Epidemiol & Populat Hlth, U1018, Villejuif, France. [Truong, Therese; Cordina-Duverger, Emilie; Menegaux, Florence; Guenel, Pascal] Univ Paris Sud, UMRS 1018, Villejuif, France. [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 1A1, Canada. [Flesch-Janys, Dieter] Univ Clin Hamburg Eppendorf, Clin Canc Registry, Dept Canc Epidemiol, Hamburg, Germany. [Flesch-Janys, Dieter] Univ Clin Hamburg Eppendorf, Inst Med Biometr & Epidemiol, Hamburg, Germany. [Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Easton, Doug F.; Pharoah, Paul D. P.] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge CB2 1TN, England. [Dunning, Alison M.; Shah, Mitul; Munday, Hannah R.; Easton, Doug F.; Pharoah, Paul D. P.] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Oncol, Cambridge CB2 1TN, England. [Darabi, Hatef; Eriksson, Mikael; Brand, Judith S.; Humphreys, Keith; Czene, Kamila; Hall, Per] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Olson, Janet; Vachon, Celine M.; Hallberg, Emily] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Esteban Castelao, J.] Univ Vigo, Oncol & Genet Unit, Biomed Res Inst Vigo IBIV, Complejo Hosp,Serv Galego Saude SERGAS, Vigo 36310, Spain. [Carracedo, Angel; Gago-Dominguez, Manuela] Inst Invest Sanitaria Santiago IDIS, Serv Galego Saude SERGAS, Galician Fdn Genom Med, Genom Med Grp, Santiago De Compostela, Spain. [Carracedo, Angel; Torres, Maria] Univ Santiago de Compostela, Natl Genotyping Ctr, CIBERER, Galicia, Spain. [Carracedo, Angel] King Abdulaziz Univ, Ctr Excellence Genom Med Res, Jeddah 21413, Saudi Arabia. [Li, Jingmei] Genome Inst Singapore, Div Human Genet, Singapore, Singapore. [Flyger, Henrik] Copenhagen Univ Hosp, Herlev Hosp, Dept Breast Surg, Copenhagen, Denmark. [Nordestgaard, Borge G.; Nielsen, Sune F.; Bojesen, Stig E.] Univ Copenhagen, Copenhagen Univ Hosp, Herlev Hosp, Copenhagen Gen Populat Study, DK-1168 Copenhagen, Denmark. [Nordestgaard, Borge G.; Nielsen, Sune F.; Bojesen, Stig E.] Univ Copenhagen, Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, DK-1168 Copenhagen, Denmark. [Yesilyurt, Betul T.; Lambrechts, Diether] VIB, VRC, Leuven, Belgium. [Floris, Giuseppe; Leunen, Karin] Univ Hosp Gasthuisberg, Multidisciplinary Breast Ctr, Leuven, Belgium. [Engelhardt, Ellen G.] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Div Psychosocial Res & Epidemiol, Amsterdam, Netherlands. [Broeks, Annegien] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Div Mol Pathol, Amsterdam, Netherlands. [Rutgers, Emiel J.] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Dept Surg, Amsterdam, Netherlands. [Glendon, Gord; Andrulis, Irene L.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Ontario Canc Genet Network, Toronto, ON M5G 1X5, Canada. [Mulligan, Anna Marie] Univ Hlth Network, Lab Med Program, Toronto, ON, Canada. [Mulligan, Anna Marie] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5S 1A1, Canada. [Cross, Simon] Univ Sheffield, Acad Unit Pathol, Dept Neurosci, Sheffield S10 2TN, S Yorkshire, England. [Reed, Malcolm; Cox, Angela] Univ Sheffield, Dept Oncol, Sheffield Canc Res Ctr, Sheffield S10 2TN, S Yorkshire, England. [Gonzalez-Neira, Anna] Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Program, Human Genotyping Unit CEGEN, Madrid, Spain. [Arias Perez, Jose Ignacio] Hosp Monte Naranco, Serv Cirugia Gen & Especialidades, Oviedo, Spain. [Provenzano, Elena] Canc Res UK Cambridge Inst, Cambridge, England. [Provenzano, Elena] Cambridge Univ Hosp NHS Fdn Trust, Addenbrookes Hosp, Cambridge Breast Unit, Cambridge, England. [Provenzano, Elena] NIHR Cambridge Biomed Res Ctr, Cambridge, England. [Apicella, Carmel; Hopper, John] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic 3010, Australia. [Southey, Melissa C.] Univ Melbourne, Dept Pathol, Melbourne, Vic 3010, Australia. [Spurdle, Amanda; Chenevix-Trench, Georgia] QIMR Berghofer Med Res Inst, Dept Genet, Brisbane, Qld, Australia. [KConFab Investigators] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [AOCS Grp] QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia. [Haeberle, Lothar; Beckmann, Matthias W.; Fasching, Peter A.] Univ Erlangen Nurnberg, Comprehens Canc Ctr Erlangen EMN, Univ Hosp Erlangen, Dept Gynecol & Obstet, D-91054 Erlangen, Germany. [Ekici, Arif B.] Univ Erlangen Nurnberg, Comprehens Canc Ctr Erlangen EMN, Univ Hosp Erlangen, Inst Human Genet, D-91054 Erlangen, Germany. [Dieffenbach, Aida Karina; Arndt, Volker; Brenner, Hermann] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, D-69120 Heidelberg, Germany. [Dieffenbach, Aida Karina; Brenner, Hermann] German Canc Consortium DKTK, Heidelberg, Germany. [Stegmaier, Christa] Saarland Canc Registry, Saarbrucken, Germany. [McLean, Catriona] Alfred Hosp, Melbourne, Vic, Australia. [Chanock, Stephen J.; Sherman, Mark E.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Lissowska, Jolanta] M Sklodowska Curie Mem Canc Ctr, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. [Sherman, Mark E.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Bruening, Thomas] Inst Ruhr Univ Bochum IPA, Inst Prevent & Occupat Med, German Social Accid Insurance, Bochum, Germany. [Hamann, Ute] German Canc Res Ctr, D-69120 Heidelberg, Germany. [Ko, Yon-Dschun] Evangel Kliniken Bonn gGmbH, Johanniter Krankenhaus, Dept Internal Med, Bonn, Germany. [Orr, Nick; Ashworth, Alan] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England. [Schoemaker, Minouk; Swerdlow, Anthony; Garcia-Closas, Montserrat] Inst Canc Res, Div Genet & Epidemiol, Sutton, Surrey, England. [Kosma, Veli-Matti; Hartikainen, Jaana M.; Mannermaa, Arto] Univ Eastern Finland, Sch Med, Inst Clin Med Pathol & Forens Med, Kuopio, Finland. [Kosma, Veli-Matti; Hartikainen, Jaana M.; Mannermaa, Arto] Univ Eastern Finland, Canc Ctr Eastern Finland, Kuopio, Finland. [Kosma, Veli-Matti; Hartikainen, Jaana M.; Mannermaa, Arto] Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, SF-70210 Kuopio, Finland. [Kataja, Vesa] Univ Eastern Finland, Sch Med, Inst Clin Med, Oncol & Canc Ctr Eastern Finland, Kuopio, Finland. [Kataja, Vesa] Kuopio Univ Hosp, Ctr Canc, SF-70210 Kuopio, Finland. [Kataja, Vesa] Jyvaskyla Cent Hosp, Jyvaskyla, Finland. [Swerdlow, Anthony] Inst Canc Res, Div Breast Canc Res, Sutton, Surrey, England. GENICA Network Dr Margarete Fischer Bosch Inst Cl, Stuttgart, Germany. Univ Tubingen, Baden Wurttemberg, Germany. Univ Bonn, Inst Pathol, Bonn, Germany. [GENICA-Network] Univ Med Ctr Hamburg Eppendorf, Inst Occupat Med & Maritime Med, Hamburg, Germany. [Fasching, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematology Oncol, Los Angeles, CA 90095 USA. [Benitez, Javier] Spanish Natl Canc Res, Ctr CNIO, Human Canc Genet Program, Human Genet Grp, Madrid, Spain. [Andrulis, Irene L.] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A1, Canada. [Couch, Fergus] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Schmidt, Marjanka K.] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands. [Garcia-Closas, Montserrat] Inst Canc Res, Breakthrough Breast Canc Res Ctr, Div Breast Canc Res, London SW3 6JB, England. RP Rudolph, A (reprint author), German Canc Res Ctr, Div Canc Epidemiol, Neuenheimer Feld 581, D-69120 Heidelberg, Germany. EM a.rudolph@dkfz.de RI Hartikainen, Jaana/E-6256-2015; Li, Jingmei/I-2904-2012; Garcia-Closas, Montserrat /F-3871-2015; Knight, Julia/A-6843-2012; Bowtell, David/H-1007-2016; Bruning, Thomas/G-8120-2015; Brenner, Hermann/B-4627-2017; Gonzalez-Neira, Anna/C-5791-2015; OI Li, Jingmei/0000-0001-8587-7511; Garcia-Closas, Montserrat /0000-0003-1033-2650; Bowtell, David/0000-0001-9089-7525; Bruning, Thomas/0000-0001-9560-5464; Brenner, Hermann/0000-0002-6129-1572; Schoemaker, Minouk/0000-0001-8403-2234; Torres, Maria/0000-0002-2658-0133; Czene, Kamila/0000-0002-3233-5695; Carracedo, Angel/0000-0003-1085-8986; Dunning, Alison Margaret/0000-0001-6651-7166; Cox, Angela/0000-0002-5138-1099; Giles, Graham/0000-0003-4946-9099 FU European Community's Seventh Framework Programme [HEALTH-F2-2009-223175]; Cancer Research UK [C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692]; National Institutes of Health (NIH) [CA128978, RFA-CA-06-503]; Post-Cancer GWAS initiative [1U19 CA148537, 1U19 CA148065, 1U19 CA148112]; Department of Defence [W81XWH-10-1-0341]; Canadian Institutes of Health Research (CIHR); Komen Foundation for the Cure; Breast Cancer Research Foundation; Ovarian Cancer Research Fund; United States National Cancer Institute; Breast Cancer Family Registry (BCFR); Cancer Care Ontario [U01 CA69467]; Cancer Prevention Institute of California [U01 CA69417]; University of Melbourne [U01 CA69638]; 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 [NKI2007-3839, NKI2009-4363]; Dutch government [NWO 184.021.007]; ELAN-Program of the University Hospital of Erlangen; FIS, Accion Estrategica de Salud del Instituto de Salud Carlos III [PI12/02125, PI13/01136]; KAU [1-117-1434-HiCi]; Botin Foundation's Fund; Programa Grupos Emergentes; Cancer Genetics Unit, CHUVI Vigo Hospital, Instituto de Salud Carlos III, Spain; Conselleria de Industria Programa Sectorial de Investigacion Aplicada; PEME I+D e I+D Suma del Plan Gallego de Investigacion; Desarrollo e Innovacion Tecnologica de la Conselleria de Industria de la Xunta de Galicia, Spain [10CSA012E]; Fomento de la Investigacion Clinica Independiente, Ministerio de Sanidad, Servicios Sociales e Igualdad, Spain [EC11-192]; Grant FEDER-Innterconecta. Ministerio de Economia y Competitividad, Xunta de Galicia, Spain; Fondation de France; French National Institute of Cancer (INCa); National League against Cancer; National Agency for Environmental and Occupational Health and Food Safety (ANSES); National Agency for Research (ANR); Association for Research against Cancer (ARC); 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; Baden-Wurttemberg State Ministry of Science, Research and Arts; German Federal Ministry of Education and Research; German Cancer Aid (Deutsche Krebshilfe); Federal Ministry of Education and Research (BMBF) Germany [01KW9975/5, 01KW9976/8, 01KW9977/0, 01KW0114, 01KH0401, 01KH0410, 01KH0411]; 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 (IPA), Bochum; Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany; EVO, Kuopio University Hospital grants; Cancer Fund of North Savo; Finnish Cancer Organizations; Academy of Finland; University of Eastern Finland; National Breast Cancer Foundation; National Health and Medical Research Council (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; US Army Medical Research and Materiel Command [DAMD 170110729, W81XWH0610220]; Stichting tegen Kanker [232-2008, 196-2010]; NCI [P50 CA116201, NIH R01 CA128978]; Deutsche Krebshilfe e.V. [70-2892-BR I]; Hamburg Cancer Society; German Cancer Research Center; Federal Ministry of Education and Research (BMBF), Germany [01KH0402]; VicHealth; Cancer Council Victoria; Australian NHMRC [209057, 251553, 504711]; National Cancer Institute [UM1 CA164920]; 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); Linnaeus Centre [70867902]; Agency for Science, Technology and Research of Singapore (AstarSTAR); US National Institute of Health (NIH); Susan G. Komen Breast Cancer Foundation; Swedish Cancer Society [5128-B07-01PAF]; Yorkshire Cancer Research [S305PA]; Cancer Research, UK [C490/A10124]; UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge; Breakthrough Breast Cancer and the Institute of Cancer Research (ICR); NHS; NIHR Biomedical Research Centre FX Grant sponsor: European Community's Seventh Framework Programme; Grant numbers: HEALTH-F2-2009-223175; Grant sponsor: Cancer Research UK; Grant numbers: C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007 and C5047/A10692; Grant sponsor: National Institutes of Health (NIH); Grant numbers: CA128978; Grant sponsor: Post-Cancer GWAS initiative; Grant numbers: 1U19 CA148537, 1U19 CA148065 and 1U19 CA148112; Grant sponsor: the Department of Defence; Grant numbers: W81XWH-10-1-0341; Grant sponsor: Canadian Institutes of Health Research (CIHR); Grant sponsor: Komen Foundation for the Cure; Grant sponsor: the Breast Cancer Research Foundation; Grant sponsor: Ovarian Cancer Research Fund; Grant sponsor: United States National Cancer Institute; Grant sponsor: National Institutes of Health (NIH); Grant numbers: RFA-CA-06-503; Grant sponsor: Breast Cancer Family Registry (BCFR); Grant sponsor: Cancer Care Ontario; Grant numbers: U01 CA69467; Grant sponsor: Cancer Prevention Institute of California; Grant numbers: U01 CA69417; Grant sponsor: University of Melbourne; Grant numbers: U01 CA69638; Grant sponsor: National Health and Medical Research Council of Australia; Grant sponsor: New South Wales Cancer Council; Grant sponsor: Victorian Health Promotion Foundation (Australia); Grant sponsor: Victorian Breast Cancer Research Consortium; Grant sponsor: Dutch Cancer Society; Grant numbers: NKI2007-3839; Grant sponsor: Dutch government (NWO 184.021.007); Grant sponsor: Dutch Cancer Society; Grant numbers: NKI2009-4363; Grant sponsor: ELAN-Program of the University Hospital of Erlangen; Grant sponsor: FIS, Accion Estrategica de Salud del Instituto de Salud Carlos III; Grant numbers: PI12/02125 and PI13/01136; Grant sponsor: KAU; Grant numbers: 1-117-1434-HiCi; Grant sponsor: Botin Foundation's Fund; Grant sponsor: Programa Grupos Emergentes; Cancer Genetics Unit, CHUVI Vigo Hospital, Instituto de Salud Carlos III, Spain; Grant sponsor: Conselleria de Industria Programa Sectorial de Investigacion Aplicada; Grant sponsor: PEME I+D e I+D Suma del Plan Gallego de Investigacion; Grant sponsor: Desarrollo e Innovacion Tecnologica de la Conselleria de Industria de la Xunta de Galicia, Spain; Grant numbers: 10CSA012E; Grant sponsor: Fomento de la Investigacion Clinica Independiente, Ministerio de Sanidad, Servicios Sociales e Igualdad, Spain; Grant numbers: EC11-192; Grant sponsor: Grant FEDER-Innterconecta.; Ministerio de Economia y Competitividad, Xunta de Galicia, Spain; Grant sponsor: Fondation de France; Grant sponsor: French National Institute of Cancer (INCa); Grant sponsor: The National League against Cancer; Grant sponsor: National Agency for Environmental and Occupational Health and Food Safety (ANSES); Grant sponsor: National Agency for Research (ANR); Grant sponsor: Association for Research against Cancer (ARC); Grant sponsor: Chief Physician Johan Boserup and Lise Boserup Fund; Grant sponsor: the Danish Medical Research Council; Grant sponsor: Herlev Hospital; Grant sponsor: Genome Spain Foundation; Grant sponsor: Red Tematica de Investigacion Cooperativa en Cancer; Grant sponsor: Asociacion Espanola Contra el Cancer; Grant sponsor: Fondo de Investigacion Sanitario; Grant numbers: PI11/00923 and PI081120; Grant sponsor: Instituto de Salud Carlos III; Grant sponsor: Baden-Wurttemberg State Ministry of Science, Research and Arts; Grant sponsor: German Federal Ministry of Education and Research; Grant sponsor: German Cancer Aid (Deutsche Krebshilfe); Grant sponsor: Federal Ministry of Education and Research (BMBF) Germany; Grant numbers: 01KW9975/5, 01KW9976/8, 01KW9977/0, 01KW0114, 01KH0401, 01KH0410 and 01KH0411; Grant sponsor: Robert Bosch Foundation, Stuttgart; Grant sponsor: Deutsches Krebsforschungszentrum (DKFZ), Heidelberg; Grant sponsor: Institute for Prevention and Occupational Medicine of the German Social Accident Insurance; Institute of the Ruhr University (IPA), Bochum; Grant sponsor: Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany; Grant sponsor: EVO, Kuopio University Hospital grants; Grant sponsor: Cancer Fund of North Savo; Grant sponsor: Finnish Cancer Organizations; Grant sponsor: Academy of Finland; Grant sponsor: University of Eastern Finland; Grant sponsor: National Breast Cancer Foundation; Grant sponsor: National Health and Medical Research Council (NHMRC); Grant sponsor: Queensland Cancer Fund; Grant sponsor: Cancer Councils of New South Wales, Victoria, Tasmania and South Australia; Grant sponsor: Cancer Foundation of Western Australia; Grant sponsor: US Army Medical Research and Materiel Command; Grant numbers: DAMD 170110729 and W81XWH0610220; Grant sponsor: Stichting tegen Kanker; Grant numbers: 232-2008 and 196-2010; Grant sponsor: NCI; Grant numbers: P50 CA116201 and NIH R01 CA128978; Grant sponsor: Breast Cancer Research Foundation; Grant sponsor: Deutsche Krebshilfe e.V.; Grant numbers: 70-2892-BR I; Grant sponsor: Hamburg Cancer Society; Grant sponsor: German Cancer Research Center; Grant sponsor: Federal Ministry of Education and Research (BMBF), Germany; Grant numbers: 01KH0402; Grant sponsor: VicHealth; Grant sponsor: Cancer Council Victoria; Grant sponsor: Australian NHMRC; Grant numbers: 209057, 251553 and 504711; Grant sponsor: National Cancer Institute; Grant numbers: UM1 CA164920; Grant sponsor: Intramural Research Funds of the National Cancer Institute; Department of Health and Human Services, USA; Grant sponsor: Marit and Hans Rausings Initiative Against Breast Cancer; Grant sponsor: Cancer Risk Prediction Center (CRisP); Grant sponsor: Linnaeus Centre; Grant numbers: 70867902; Grant sponsor: Agency for Science, Technology and Research of Singapore (AstarSTAR); Grant sponsor: US National Institute of Health (NIH); Grant sponsor: Susan G.; Komen Breast Cancer Foundation; Grant sponsor: Swedish Cancer Society; Grant numbers: 5128-B07-01PAF; Grant sponsor: Yorkshire Cancer Research; Grant numbers: S305PA; Grant sponsor: Cancer Research, UK; Grant numbers: C490/A10124; Grant sponsor: UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge; Grant sponsor: Breakthrough Breast Cancer and the Institute of Cancer Research (ICR); Grant sponsor: NHS; Grant sponsor: NIHR Biomedical Research Centre. NR 44 TC 9 Z9 9 U1 1 U2 29 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 MAR 15 PY 2015 VL 136 IS 6 BP E685 EP E696 DI 10.1002/ijc.29188 PG 12 WC Oncology SC Oncology GA AY6XD UT WOS:000347705200021 PM 25227710 ER PT J AU Weinstein, SJ Purdue, MP Smith-Warner, SA Mondul, AM Black, A Ahn, J Huang, WY Horst, RL Kopp, W Rager, H Ziegler, RG Albanes, D AF Weinstein, Stephanie J. Purdue, Mark P. Smith-Warner, Stephanie A. Mondul, Alison M. Black, Amanda Ahn, Jiyoung Huang, Wen-Yi Horst, Ronald L. Kopp, William Rager, Helen Ziegler, Regina G. Albanes, Demetrius TI Serum 25-hydroxyvitamin D, vitamin D binding protein and risk of colorectal cancer in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE 25-hydroxyvitamin D; vitamin D binding protein; colorectal cancer; serum biomarkers; prospective study ID PANCREATIC-CANCER; PLASMA 1,25-DIHYDROXYVITAMIN-D; PROSPECTIVE COHORT; D SUPPLEMENTATION; RECTAL-CANCER; D-RECEPTOR; CALCIUM; ASSOCIATION; HEALTH; REPRODUCIBILITY AB The potential role of vitamin D in cancer prevention has generated substantial interest, and laboratory experiments indicate several anti-cancer properties for vitamin D compounds. Prospective studies of circulating 25-hydroxyvitamin D [25(OH)D], the accepted biomarker of vitamin D status, suggest an inverse association with colorectal cancer risk, but with some inconsistencies. Furthermore, the direct or indirect impact of the key transport protein, vitamin D binding protein (DBP), has not been examined. We conducted a prospective study of serum 25(OH)D and DBP concentrations and colorectal cancer risk in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, based on 476 colorectal cancer cases and 476 controls, matched on age, sex, race and date of serum collection. All subjects underwent sigmoidoscopic screening at baseline and once during follow-up. Conditional logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs). Circulating 25(OH)D was inversely associated with colorectal cancer (OR=0.60, 95% CI 0.38-0.94 for highest versus lowest quintile, p trend 0.01). Adjusting for recognized colorectal cancer risk factors and accounting for seasonal vitamin D variation did not alter the findings. Neither circulating DBP nor the 25(OH)D:DBP molar ratio, a proxy for free circulating 25(OH)D, was associated with risk (OR=0.82, 95% CI 0.54-1.26, and OR=0.79, 95% CI 0.52-1.21, respectively), and DBP did not modify the 25(OH)D association. The current study eliminated confounding by colorectal cancer screening behavior, and supports an association between higher vitamin D status and substantially lower colorectal cancer risk, but does not indicate a direct or modifying role for DBP. What's new? Vitamin D possesses anticancer properties, such as an ability to inhibit cell proliferation and angiogenesis and to promote cell differentiation and apoptosis. In particular, vitamin D status may be inversely linked with colorectal cancer risk, though studies have yielded inconsistent results. The present investigation suggests that increased levels of circulating 25-hydroxyvitamin D (25[OH]D), a biomarker for vitamin D status, are associated with a substantially reduced risk of colorectal cancer. No association or modifying role was detected for circulating levels of vitamin D binding protein, the primary carrier of 25(OH)D. C1 [Weinstein, Stephanie J.; Purdue, Mark P.; Mondul, Alison M.; Black, Amanda; Huang, Wen-Yi; Ziegler, Regina G.; Albanes, Demetrius] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Smith-Warner, Stephanie A.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Smith-Warner, Stephanie A.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Ahn, Jiyoung] NYU, Sch Med, Dept Populat Hlth, New York, NY USA. [Horst, Ronald L.] Heartland Assays LLC, Ames, IA USA. [Kopp, William; Rager, Helen] Leidos Biomed Res Inc, Clin Support Lab, Appl Dev Res Directorate, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Weinstein, SJ (reprint author), NCI, Nutr Epidemiol Branch, DCEG, 9609 Med Ctr Dr MSC 9768, Bethesda, MD 20892 USA. EM weinstes@mail.nih.gov RI Albanes, Demetrius/B-9749-2015; Purdue, Mark/C-9228-2016; OI Purdue, Mark/0000-0003-1177-3108; Mondul, Alison/0000-0002-8843-1416 FU R01 [R01CA152071]; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Intramural Research Program of the Division of Cancer Epidemiology and Genetics; Division of Cancer Prevention, National Cancer Institute, NIH, DHHS FX Grant sponsor: R01; Grant number: R01CA152071; Grant sponsor: National Cancer Institute, National Institutes of Health; Grant number: HHSN261200800001E; Grant sponsors: Intramural Research Program of the Division of Cancer Epidemiology and Genetics; Division of Cancer Prevention, National Cancer Institute, NIH, DHHS NR 52 TC 17 Z9 18 U1 1 U2 32 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 MAR 15 PY 2015 VL 136 IS 6 BP E654 EP E664 DI 10.1002/ijc.29157 PG 11 WC Oncology SC Oncology GA AY6XD UT WOS:000347705200018 PM 25156182 ER PT J AU Harlan, LC Warren, JL AF Harlan, Linda C. Warren, Joan L. TI Global survival patterns: potential for cancer control SO LANCET LA English DT Editorial Material ID PREVENTION C1 [Harlan, Linda C.; Warren, Joan L.] NCI, Bethesda, MD 20892 USA. RP Harlan, LC (reprint author), NCI, Bethesda, MD 20892 USA. EM harlanl@mail.nih.gov NR 8 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 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD MAR 14 PY 2015 VL 385 IS 9972 BP 926 EP 928 DI 10.1016/S0140-6736(14)62251-0 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA CD2EK UT WOS:000350886900010 PM 25467589 ER PT J AU Neuschwander-Tetri, BA Loomba, R Sanyal, AJ Lavine, JE Van Natta, ML Abdelmalek, MF Chalasani, N Dasarathy, S Diehl, AM Hameed, B Kowdley, KV McCullough, A Terrault, N Clark, JM Tonascia, J Brunt, EM Kleiner, DE Doo, E AF Neuschwander-Tetri, Brent A. Loomba, Rohit Sanyal, Arun J. Lavine, Joel E. Van Natta, Mark L. Abdelmalek, Manal F. Chalasani, Naga Dasarathy, Srinivasan Diehl, Anna Mae Hameed, Bilal Kowdley, Kris V. McCullough, Arthur Terrault, Norah Clark, Jeanne M. Tonascia, James Brunt, Elizabeth M. Kleiner, David E. Doo, Edward CA Nash Clin Res Network TI Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial SO LANCET LA English DT Article ID FATTY LIVER-DISEASE; BILE-ACIDS; GLUCOSE-METABOLISM; INSULIN-RESISTANCE; FXR; AGONIST; THERAPY; NAFLD; NASH; RATS AB Background The bile acid derivative 6-ethylchenodeoxycholic acid (obeticholic acid) is a potent activator of the farnesoid X nuclear receptor that reduces liver fat and fibrosis in animal models of fatty liver disease. We assessed the efficacy of obeticholic acid in adult patients with non-alcoholic steatohepatitis. Methods We did a multicentre, double-blind, placebo-controlled, parallel group, randomised clinical trial at medical centres in the USA in patients with non-cirrhotic, non-alcoholic steatohepatitis to assess treatment with obeticholic acid given orally (25 mg daily) or placebo for 72 weeks. Patients were randomly assigned 1: 1 using a computer-generated, centrally administered procedure, stratified by clinical centre and diabetes status. The primary outcome measure was improvement in centrally scored liver histology defined as a decrease in non-alcoholic fatty liver disease activity score by at least 2 points without worsening of fibrosis from baseline to the end of treatment. A planned interim analysis of change in alanine aminotransferase at 24 weeks undertaken before end-of-treatment (72 weeks) biopsies supported the decision to continue the trial (relative change in alanine aminotransferase -24%, 95% CI -45 to -3). A planned interim analysis of the primary outcome showed improved efficacy of obeticholic acid (p=0 . 0024) and supported a decision not to do end-of- treatment biopsies and end treatment early in 64 patients, but to continue the trial to obtain the 24-week post-treatment measures. Analyses were done by intention-to-treat. This trial was registered with ClinicalTrials.gov, number NCT01265498. Findings Between March 16, 2011, and Dec 3, 2012, 141 patients were randomly assigned to receive obeticholic acid and 142 to placebo. 50 (45%) of 110 patients in the obeticholic acid group who were meant to have biopsies at baseline and 72 weeks had improved liver histology compared with 23 (21%) of 109 such patients in the placebo group (relative risk 1 . 9, 95% CI 1 . 3 to 2 . 8; p=0 . 0002). 33 (23%) of 141 patients in the obeticholic acid developed pruritus compared with nine (6%) of 142 in the placebo group. Interpretation Obeticholic acid improved the histological features of non-alcoholic steatohepatitis, but its long-term benefits and safety need further clarifi cation. C1 [Neuschwander-Tetri, Brent A.] St Louis Univ, St Louis, MO 63110 USA. [Loomba, Rohit] Univ Calif San Diego, La Jolla, CA 92093 USA. [Sanyal, Arun J.] Virginia Commonwealth Univ, Richmond, VA USA. [Lavine, Joel E.] Columbia Univ, New York, NY USA. [Van Natta, Mark L.; Clark, Jeanne M.; Tonascia, James] Johns Hopkins Univ, Baltimore, MD USA. [Abdelmalek, Manal F.; Diehl, Anna Mae] Duke Univ, Durham, NC USA. [Chalasani, Naga] Indiana Univ, Indianapolis, IN 46204 USA. [McCullough, Arthur] Cleveland Clin, Cleveland, OH 44106 USA. [Hameed, Bilal; Terrault, Norah] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Kowdley, Kris V.] Virginia Mason Med Ctr, Seattle, WA 98101 USA. [Dasarathy, Srinivasan] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Brunt, Elizabeth M.] Washington Univ, St Louis, MO USA. [Kleiner, David E.] NCI, Bethesda, MD 20892 USA. [Doo, Edward] NIDDK, Bethesda, MD 20892 USA. RP Neuschwander-Tetri, BA (reprint author), St Louis Univ, Div Gastroenterol & Hepatol, St Louis, MO 63110 USA. EM tetriba@slu.edu RI Vaughn, Ivana/B-6138-2016; Bashir, Mustafa/P-3428-2015 OI Vaughn, Ivana/0000-0002-7201-0289; FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [U01DK061718, U01DK061728, U01DK061731, U01DK061732, U01DK061734, U01DK061737, U01DK061738, U01DK061730, U01DK061713]; National Center for Advancing Translational Sciences (NCATS) for NASH CRN Studies [UL1TR000439, UL1TR000436, UL1TR000006, UL1TR000448, UL1TR000100, UL1TR000004, UL1TR000423, UL1TR000058]; Laboratory of Pathology, Intramural Division of the National Cancer Institute FX The Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (grants U01DK061718, U01DK061728, U01DK061731, U01DK061732, U01DK061734, U01DK061737, U01DK061738, U01DK061730, U01DK061713). Several clinical centres had support from the National Center for Advancing Translational Sciences (NCATS) for NASH CRN Studies (grants UL1TR000439, UL1TR000436, UL1TR000006, UL1TR000448, UL1TR000100, UL1TR000004, UL1TR000423, and UL1TR000058). Additional support was provided by the Laboratory of Pathology, Intramural Division of the National Cancer Institute. The NASH CRN expresses its gratitude to the patients enrolled in this study, Patricia Robuck for her guidance in trial design, Jay Hoofnagle for his guidance in trial design and data analysis, and Averell Sherker for his assistance in coordinating communications among the NIDDK, the industry sponsor, and the NASH CRN steering committee. NR 30 TC 252 Z9 260 U1 12 U2 47 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 MAR 14 PY 2015 VL 385 IS 9972 BP 956 EP 965 DI 10.1016/S0140-6736(14)61933-4 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA CD2EK UT WOS:000350886900030 PM 25468160 ER PT J AU Iranzo, J Lobkovsky, AE Wolf, YI Koonin, EV AF Iranzo, Jaime Lobkovsky, Alexander E. Wolf, Yuri I. Koonin, Eugene V. TI Immunity, suicide or both? Ecological determinants for the combined evolution of anti-pathogen defense systems SO BMC EVOLUTIONARY BIOLOGY LA English DT Article ID CRISPR-CAS SYSTEMS; RESTRICTION-MODIFICATION SYSTEMS; PROGRAMMED CELL-DEATH; HOST ARMS-RACE; ADAPTIVE IMMUNITY; PROMOTES COOPERATION; LOCAL ADAPTATION; RESISTANCE; BACTERIA; DYNAMICS AB Background: Parasite-host arms race is one of the key factors in the evolution of life. Most cellular life forms, in particular prokaryotes, possess diverse forms of defense against pathogens including innate immunity, adaptive immunity and programmed cell death (altruistic suicide). Coevolution of these different but interacting defense strategies yields complex evolutionary regimes. Results: We develop and extensively analyze a computational model of coevolution of different defense strategies to show that suicide as a defense mechanism can evolve only in structured populations and when the attainable degree of immunity against pathogens is limited. The general principle of defense evolution seems to be that hosts do not evolve two costly defense mechanisms when one is sufficient. Thus, the evolutionary interplay of innate immunity, adaptive immunity and suicide, leads to an equilibrium state where the combination of all three defense strategies is limited to a distinct, small region of the parameter space. The three strategies can stably coexist only if none of them are highly effective. Coupled adaptive immunity-suicide systems, the existence of which is implied by the colocalization of genes for the two types of defense in prokaryotic genomes, can evolve either when immunity-associated suicide is more efficacious than other suicide systems or when adaptive immunity functionally depends on the associated suicide system. Conclusions: Computational modeling reveals a broad range of outcomes of coevolution of anti-pathogen defense strategies depending on the relative efficacy of different mechanisms and population structure. Some of the predictions of the model appear compatible with recent experimental evolution results and call for additional experiments. C1 [Iranzo, Jaime; Lobkovsky, Alexander E.; Wolf, Yuri I.; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov OI Iranzo, Jaime/0000-0002-4538-7726 FU intramural funds of the US Department of Health and Human Services FX We thank Michael Galperin for helpful discussions on prokaryotic sociality. The authors are supported by intramural funds of the US Department of Health and Human Services (to the National Library of Medicine). NR 72 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 1471-2148 J9 BMC EVOL BIOL JI BMC Evol. Biol. PD MAR 13 PY 2015 VL 15 AR 43 DI 10.1186/s12862-015-0324-2 PG 14 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA CE0OS UT WOS:000351504300001 PM 25881094 ER PT J AU Ahmad, F Shen, WX Vandeput, F Szabo-Fresnais, N Krall, J Degerman, E Goetz, F Klussmann, E Movsesian, M Manganiello, V AF Ahmad, Faiyaz Shen, Weixing Vandeput, Fabrice Szabo-Fresnais, Nicolas Krall, Judith Degerman, Eva Goetz, Frank Klussmann, Enno Movsesian, Matthew Manganiello, Vincent TI Regulation of Sarcoplasmic Reticulum Ca2+ ATPase 2 (SERCA2) Activity by Phosphodiesterase 3A (PDE3A) in Human Myocardium PHOSPHORYLATION-DEPENDENT INTERACTION OF PDE3A1 WITH SERCA2 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CARDIAC MYOCYTES; CALCIUM-ATPASE; 3B PDE3B; PROTEIN; HEART; PHOSPHOLAMBAN; INSULIN; ISOFORMS; CONTRACTILITY; ACTIVATION AB Cyclic nucleotide phosphodiesterase 3A (PDE3) regulates cAMP-mediated signaling in the heart, and PDE3 inhibitors augment contractility in patients with heart failure. Studies in mice showed that PDE3A, not PDE3B, is the subfamily responsible for these inotropic effects and that murine PDE3A1 associates with sarcoplasmic reticulum Ca2+ ATPase 2 (SERCA2), phospholamban (PLB), and AKAP18 in a multiprotein signalosome in human sarcoplasmic reticulum (SR). Immunohistochemical staining demonstrated that PDE3A co-localizes in Z-bands of human cardiac myocytes with desmin, SERCA2, PLB, and AKAP18. In human SR fractions, cAMPincreased PLB phosphorylation and SERCA2 activity; this was potentiated by PDE3 inhibition but not by PDE4 inhibition. During gel filtration chromatography of solubilized SR membranes, PDE3 activity was recovered in distinct high molecular weight (HMW) and low molecular weight (LMW) peaks. HMW peaks contained PDE3A1 and PDE3A2, whereas LMW peaks contained PDE3A1, PDE3A2, and PDE3A3. Western blotting showed that endogenous HMW PDE3A1 was the principal PKA-phosphorylated isoform. Phosphorylation of endogenous PDE3A by rPKAc increased cAMP-hydrolytic activity, correlated with shift of PDE3A from LMW to HMW peaks, and increased co-immunoprecipitation of SERCA2, cav3, PKAregulatory subunit (PKARII), PP2A, and AKAP18 with PDE3A. In experiments with recombinant proteins, phosphorylation of recombinant human PDE3A isoforms by recombinant PKA catalytic subunit increased co-immunoprecipitation with rSERCA2 and rat rAKAP18 (recombinant AKAP18). Deletion of the recombinant human PDE3A1/PDE3A2 N terminus blocked interactions with recombinant SERCA2. Serine-to-alanine substitutions identified Ser-292/Ser-293, a site unique to human PDE3A1, as the principal site regulating its interaction with SERCA2. These results indicate that phosphorylation of human PDE3A1 at a PKA site in its unique N-terminal extension promotes its incorporation into SERCA2/AKAP18 signalosomes, where it regulates a discrete cAMP pool that controls contractility by modulating phosphorylation-dependent protein-protein interactions, PLB phosphorylation, and SERCA2 activity. C1 [Ahmad, Faiyaz; Shen, Weixing; Manganiello, Vincent] NHLBI, Cardiovasc Pulm Branch, NIH, Bethesda, MD 20892 USA. [Vandeput, Fabrice; Szabo-Fresnais, Nicolas; Krall, Judith; Movsesian, Matthew] VA Salt Lake City Hlth Care Syst, Salt Lake City, UT USA. [Vandeput, Fabrice; Szabo-Fresnais, Nicolas; Krall, Judith; Movsesian, Matthew] Univ Utah, Salt Lake City, UT USA. [Degerman, Eva] Lund Univ, Dept Expt Med Sci, Div Diabet Metab & Endocrinol, Lund, Sweden. [Klussmann, Enno] Max Delbrueck Ctr Mol Med Berlin Buch MDC, D-13125 Berlin, Germany. [Klussmann, Enno] German Ctr Cardiovasc Res, DZHK, D-13347 Berlin, Germany. RP Ahmad, F (reprint author), NHLBI, Cardiovasc Pulm Branch, NIH, Bldg 10,Rm 5N311,9000 Rockville Pike, Bethesda, MD 20892 USA. EM Ahmadf@nhlbi.nih.gov FU National Institutes of Health NHLBI Intramural program; Foundation Leducq Grant [06CVD02 cAMP]; American Heart Association; Swedish Research Council [3362]; Deutsche Forschungsgemeinschaft [KL1415-4/2]; Else Kroner-Fresenius-Stiftung [2013_A145]; German-Israeli Foundation [I-1210-286.13/2012]; United States Department of Veterans Affairs FX This work was supported, in whole or in part, by National Institutes of Health NHLBI Intramural program. This work was also supported by medical research funds from the United States Department of Veterans Affairs and Foundation Leducq Grant 06CVD02 cAMP and an American Heart Association grant-in-aid (to M. M.); by Swedish Research Council Project 3362 (to E.D.); and by Deutsche Forschungsgemeinschaft Grant KL1415-4/2, the Else Kroner-Fresenius-Stiftung (2013_A145), and the German-Israeli Foundation (I-1210-286.13/2012) (to E. K. and F. G.). NR 39 TC 11 Z9 12 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 MAR 13 PY 2015 VL 290 IS 11 BP 6763 EP 6776 DI 10.1074/jbc.M115.638585 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CD3PP UT WOS:000350991500013 PM 25593322 ER PT J AU Dijksterhuis, JP Baljinnyam, B Stanger, K Sercan, HO Ji, Y Andres, O Rubin, JS Hannoush, RN Schulte, G AF Dijksterhuis, Jacomijn P. Baljinnyam, Bolormaa Stanger, Karen Sercan, Hakki O. Ji, Yun Andres, Osler Rubin, Jeffrey S. Hannoush, Rami N. Schulte, Gunnar TI Systematic Mapping of WNT-FZD Protein Interactions Reveals Functional Selectivity by Distinct WNT-FZD Pairs SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MOUSE PRIMARY MICROGLIA; FRIZZLED RECEPTORS; WNT/BETA-CATENIN; INTERNATIONAL UNION; PHOSPHORYLATION; PATHWAY; LRP6; MEMBRANE; ACTIVATION; MIDBRAIN AB The seven-transmembrane-spanning receptors of the FZD1-10 class are bound and activated by the WNT family of lipoglycoproteins, thereby inducing a complex network of signaling pathways. However, the specificity of the interaction between mammalian WNT and FZD proteins and the subsequent signaling cascade downstream of the different WNT-FZD pairs have not been systematically addressed to date. In this study, we determined the binding affinities of various WNTs for different members of the FZD family by using bio-layer interferometry and characterized their functional selectivity in a cell system. Using purified WNTs, we show that different FZD cysteine-rich domains prefer to bind to distinct WNTs with fast on-rates and slow off-rates. In a 32D cell-based system engineered to overexpress FZD(2), FZD(4), or FZD(5), we found that WNT-3A (but not WNT-4, -5A, or -9B) activated the WNT-beta-catenin pathway through FZD(2/4/5) as measured by phosphorylation of LRP6 and beta-catenin stabilization. Surprisingly, different WNT-FZD pairs showed differential effects on phosphorylation of DVL2 and DVL3, revealing a previously unappreciated DVL isoform selectivity by different WNT-FZD pairs in 32D cells. In summary, we present extensive mapping of WNT-FZD cysteine-rich domain interactions complemented by analysis of WNT-FZD pair functionality in a unique cell system expressing individual FZD isoforms. Differential WNT-FZD binding and selective functional readouts suggest that endogenous WNT ligands evolved with an intrinsic natural bias toward different downstream signaling pathways, a phenomenon that could be of great importance in the design of FZD-targeting drugs. C1 [Dijksterhuis, Jacomijn P.; Schulte, Gunnar] Karolinska Inst, Dept Physiol & Pharmacol, Sect Receptor Biol & Signaling, S-17177 Stockholm, Sweden. [Dijksterhuis, Jacomijn P.; Sercan, Hakki O.; Ji, Yun; Andres, Osler; Rubin, Jeffrey S.] NCI, Cellular & Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Stanger, Karen; Hannoush, Rami N.] Genentech Inc, Dept Early Discovery Biochem, San Francisco, CA 94080 USA. [Schulte, Gunnar] Masaryk Univ, Fac Sci, Inst Expt Biol, CS-61137 Brno, Czech Republic. RP Hannoush, RN (reprint author), Genentech Inc, Dept Early Discovery Biochem, 1 DNA Way, San Francisco, CA 94080 USA. EM hannoush.rami@gene.com; gunnar.schulte@ki.se OI Dijksterhuis, Jacomijn/0000-0002-9214-6255 FU National Institutes of Health NCI Intramural Research Program; Karolinska Institutet; Swedish Research Council [K2008-68P-20810-01-4, K2008-68X-20805-01-4, K2011-67X-20805-05-3]; Swedish Cancer Society [CAN 2008/539, 2011/690]; KI-NIH Joint PhD Program; Signhild Engkvist Foundations; KI-MU Project [CZ.1.07/2.3.00/20.0180]; Czech Research Council [GACR 13-32990S] FX The work was supported, in whole or in part, by the National Institutes of Health NCI Intramural Research Program. The work also was also supported by the Karolinska Institutet; Swedish Research Council Grants K2008-68P-20810-01-4, K2008-68X-20805-01-4, and K2011-67X-20805-05-3; Swedish Cancer Society Grants CAN 2008/539 and 2011/690; The KI-NIH Joint PhD Program; the Signhild Engkvist Foundations; KI-MU Project Grant CZ.1.07/2.3.00/20.0180; and Czech Research Council (GACR 13-32990S). NR 50 TC 8 Z9 9 U1 3 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 MAR 13 PY 2015 VL 290 IS 11 BP 6789 EP 6798 DI 10.1074/jbc.M114.612648 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CD3PP UT WOS:000350991500015 PM 25605717 ER PT J AU Keembiyehetty, C Love, DC Harwood, KR Gavrilova, O Comly, ME Hanover, JA AF Keembiyehetty, Chithra Love, Dona C. Harwood, Katryn R. Gavrilova, Oksana Comly, Marcella E. Hanover, John A. TI Conditional Knock-out Reveals a Requirement for O-Linked N-Acetylglucosaminase (O-GlcNAcase) in Metabolic Homeostasis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INDUCE INSULIN-RESISTANCE; TYPE-2 DIABETES-MELLITUS; CAENORHABDITIS-ELEGANS; GLYCOGEN-SYNTHASE; 3T3-L1 ADIPOCYTES; TRANSGENIC MICE; ADIPOSE-TISSUE; NUCLEOCYTOPLASMIC GLYCOSYLATION; PROTEIN GLYCOSYLATION; DYNAMIC INTERPLAY AB O-GlcNAc cycling is maintained by the reciprocal activities of the O-GlcNAc transferase and the O-GlcNAcase (OGA) enzymes. O-GlcNAc transferase is responsible forO-GlcNAc addition to serine and threonine (Ser/Thr) residues and OGA for its removal. Although the Oga gene (MGEA5) is a documented human diabetes susceptibility locus, its role in maintaining insulin-glucose homeostasis is unclear. Here, we report a conditional disruption of the Oga gene in the mouse. The resulting homozygous Oga null (KO) animals lack OGA enzymatic activity and exhibit elevated levels of the O-GlcNAc modification. The Oga KO animals showed nearly complete perinatal lethality associated with low circulating glucose and low liver glycogen stores. Defective insulin-responsive GSK3 beta phosphorylation was observed in both heterozygous (HET) and KO Oga animals. Although Oga HET animals were viable, they exhibited alterations in both transcription and metabolism. Transcriptome analysis using mouse embryonic fibroblasts revealed deregulation in the transcripts of both HET and KO animals specifically in genes associated with metabolism and growth. Additionally, metabolic profiling showed increased fat accumulation in HET and KO animals compared with WT, which was increased by a high fat diet. Reduced insulin sensitivity, glucose tolerance, and hyperleptinemia were also observed in HET and KO female mice. Notably, the respiratory exchange ratio of the HET animals was higher than that observed in WT animals, indicating the preferential utilization of glucose as an energy source. These results suggest that the loss of mouse OGA leads to defects in metabolic homeostasis culminating in obesity and insulin resistance. C1 [Keembiyehetty, Chithra; Love, Dona C.; Harwood, Katryn R.; Comly, Marcella E.; Hanover, John A.] NIDDK, LCBB, NIH, Bethesda, MD 20892 USA. [Gavrilova, Oksana] NIDDK, Mouse Metab Core Lab, NIH, Bethesda, MD 20892 USA. RP Hanover, JA (reprint author), NIDDK, LCBB, NIH, 8 Ctr Dr, Bethesda, MD 20892 USA. EM jah@helix.nih.gov FU National Institutes of Health FX This work was supported, in whole or in part, by a National Institutes of Health Intramural Grant. NR 84 TC 17 Z9 17 U1 2 U2 12 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 MAR 13 PY 2015 VL 290 IS 11 BP 7097 EP 7113 DI 10.1074/jbc.M114.617779 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CD3PP UT WOS:000350991500041 PM 25596529 ER PT J AU Lizunov, VA Stenkula, KG Blank, PS Troy, A Lee, JP Skarulis, MC Cushman, SW Zimmerberg, J AF Lizunov, Vladimir A. Stenkula, Karin G. Blank, Paul S. Troy, Aaron Lee, Jo-Ping Skarulis, Monica C. Cushman, Samuel W. Zimmerberg, Joshua TI Human Adipose Cells In Vitro Are Either Refractory or Responsive to Insulin, Reflecting Host Metabolic State SO PLOS ONE LA English DT Article ID GLUCOSE-METABOLISM; GLUT4 VESICLES; FAT-CELLS; RESISTANCE; SENSITIVITY; OBESITY; FUSION; TISSUE; HETEROGENEITY; EXPRESSION AB While intercellular communication processes are frequently characterized by switch-like transitions, the endocrine system, including the adipose tissue response to insulin, has been characterized by graded responses. Yet here individual cells from adipose tissue biopsies are best described by a switch-like transition between the basal and insulin-stimulated states for the trafficking of the glucose transporter GLUT4. Two statistically-defined populations best describe the observed cellular heterogeneity, representing the fractions of refractive and responsive adipose cells. Furthermore, subjects exhibiting high systemic insulin sensitivity indices (SI) have high fractions of responsive adipose cells in vitro, while subjects exhibiting decreasing SI have increasing fractions of refractory cells in vitro. Thus, a two-component model best describes the relationship between cellular refractory fraction and subject SI. Since isolated cells exhibit these different response characteristics in the presence of constant culture conditions and milieu, we suggest that a physiological switching mechanism at the adipose cellular level ultimately drives systemic SI. C1 [Lizunov, Vladimir A.; Blank, Paul S.; Troy, Aaron; Zimmerberg, Joshua] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD USA. [Stenkula, Karin G.; Lee, Jo-Ping; Cushman, Samuel W.] NIDDK, Expt Diabet Metab & Nutr Sect, NIH, Bethesda, MD 20892 USA. [Skarulis, Monica C.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Stenkula, Karin G.] Lund Univ, Expt Med Sci, Lund, Sweden. RP Zimmerberg, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD USA. EM joshz@mail.nih.gov FU Intramural Research Programs of Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX This work was supported by the Intramural Research Programs of Eunice Kennedy Shriver National Institute of Child Health and Human Development and National Institute of Diabetes and Digestive and Kidney Diseases, 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 30 TC 0 Z9 0 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 13 PY 2015 VL 10 IS 3 AR e0119291 DI 10.1371/journal.pone.0119291 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CD7NO UT WOS:000351277500074 PM 25768970 ER PT J AU Kotsyfakis, M Schwarz, A Erhart, J Ribeiro, JMC AF Kotsyfakis, Michalis Schwarz, Alexandra Erhart, Jan Ribeiro, Jose M. C. TI Tissue- and time-dependent transcription in Ixodes ricinus salivary glands and midguts when blood feeding on the vertebrate host SO SCIENTIFIC REPORTS LA English DT Article ID RHIPICEPHALUS BOOPHILUS MICROPLUS; SERINE-PROTEASE INHIBITOR; DERMACENTOR-VARIABILIS; HARD TICK; HAEMAPHYSALIS-LONGICORNIS; ANNOTATED CATALOG; BABESIA-BOVIS; GENOME SIZE; SCAPULARIS; IXODIDAE AB Ixodes ricinus is a tick that transmits the pathogens of Lyme and several arboviral diseases. Pathogens invade the tick midgut, disseminate through the hemolymph, and are transmitted to the vertebrate host via the salivary glands; subverting these processes could be used to interrupt pathogen transfer. Here, we use massive de novo sequencing to characterize the transcriptional dynamics of the salivary and midgut tissues of nymphal and adult Ixodes ricinus at various time points after attachment on the vertebrate host. Members of a number of gene families show stage- and time-specific expression. We hypothesize that gene expression switching may be under epigenetic control and, in support of this, identify 34 candidate proteins that modify histones. Ixodes ricinus-secreted proteins are encoded by genes that have a non-synonymous to synonymous mutation rate even greater than immune-related genes. Midgut transcriptome (mialome) analysis reveals several enzymes associated with protein, carbohydrate, and lipid digestion, transporters and channels that might be associated with nutrient uptake, and immune-related transcripts including antimicrobial peptides. This publicly available dataset supports the identification of protein and gene targets for biochemical and physiological studies that exploit the transmission lifecycle of this disease vector for preventative and therapeutic purposes. C1 [Kotsyfakis, Michalis; Schwarz, Alexandra; Erhart, Jan] Acad Sci Czech Republic, Ctr Biol, Inst Parasitol, Budweis 37005, Czech Republic. [Ribeiro, Jose M. C.] NIAID, Sect Vector Biol, Lab Malaria & Vector Res, Rockville, MD 20852 USA. RP Kotsyfakis, M (reprint author), Acad Sci Czech Republic, Ctr Biol, Inst Parasitol, Branisovska 31, Budweis 37005, Czech Republic. EM mich_kotsyfakis@yahoo.com RI Kotsyfakis, Michail/G-9525-2014; OI Kotsyfakis, Michail/0000-0002-7526-1876; Ribeiro, Jose/0000-0002-9107-0818 FU Grant Agency of the Czech Republic (GACR grant) [P502/12/2409]; Czech Academy of Sciences [RVO 60077344]; 7th Framework Program of the European Union (EU FP7; Marie Curie Reintegration grant) [PIRG07-GA-2010-268177]; European Union, 7th Framework Program, project TRANSVAC [FP7-INFRASTRUCTURES-2008-228403]; Alexander von Humboldt Foundation (Feodor Lynen Research Fellowship); Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH; USA); Czech Academy of Sciences (Jan Evangelista Purkyne Fellowship); European Molecular Biology Organization [EMBO; Application Short Term Fellowship (ASTF)] [482-2012] FX This work was supported by the Grant Agency of the Czech Republic (GACR grant P502/12/2409 to M.K.), the Czech Academy of Sciences (grant no. RVO 60077344 to the Institute of Parasitology), and the 7th Framework Program of the European Union (EU FP7; Marie Curie Reintegration grant PIRG07-GA-2010-268177 to M. K.). Library construction and Illumina sequencing of all the samples was supported by the European Union, 7th Framework Program, project TRANSVAC (FP7-INFRASTRUCTURES-2008-228403 to M.K.). This publication reflects only the authors' views and the European Union is not liable for any use that may be made of the information contained herein. A.S. was funded by the Alexander von Humboldt Foundation (Feodor Lynen Research Fellowship). J.M.C.R. was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH; USA). M.K. received support from the Czech Academy of Sciences (Jan Evangelista Purkyne Fellowship) and the European Molecular Biology Organization [EMBO; Application Short Term Fellowship (ASTF) 482-2012]. The authors are also grateful to Andrea Gocke (National Center for Biotechnology Information, USA) for helping with sequence submission. The NIH reserves the right to provide the work to PubMedCentral for display and use by the public, and PubMedCentral may tag or modify the work consistent with its customary practices. Rights can be established outside of the United States subject to a government use license. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 23 Z9 23 U1 3 U2 15 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAR 13 PY 2015 VL 5 AR 9103 DI 10.1038/srep09103 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CD5UE UT WOS:000351152800001 PM 25765539 ER PT J AU Takahashi, S Metcalf, CJE Ferrari, MJ Moss, WJ Truelove, SA Tatem, AJ Grenfell, BT Lessler, J AF Takahashi, Saki Metcalf, C. Jessica E. Ferrari, Matthew J. Moss, William J. Truelove, Shaun A. Tatem, Andrew J. Grenfell, Bryan T. Lessler, Justin TI Reduced vaccination and the risk of measles and other childhood infections post-Ebola SO SCIENCE LA English DT Article ID MORTALITY AB The Ebola epidemic in West Africa has caused substantial morbidity and mortality. The outbreak has also disrupted health care services, including childhood vaccinations, creating a second public health crisis. We project that after 6 to 18 months of disruptions, a large connected cluster of children unvaccinated for measles will accumulate across Guinea, Liberia, and Sierra Leone. This pool of susceptibility increases the expected size of a regional measles outbreak from 127,000 to 227,000 cases after 18 months, resulting in 2000 to 16,000 additional deaths (comparable to the numbers of Ebola deaths reported thus far). There is a clear path to avoiding outbreaks of childhood vaccine-preventable diseases once the threat of Ebola begins to recede: an aggressive regional vaccination campaign aimed at age groups left unprotected because of health care disruptions. C1 [Takahashi, Saki; Metcalf, C. Jessica E.; Grenfell, Bryan T.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Metcalf, C. Jessica E.] Princeton Univ, Woodrow Wilson Sch, Princeton, NJ 08544 USA. [Ferrari, Matthew J.] Penn State Univ, Ctr Infect Dis Dynam, State Coll, PA 16801 USA. [Moss, William J.; Truelove, Shaun A.; Lessler, Justin] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Tatem, Andrew J.] Univ Southampton, Dept Geog & Environm, Southampton SO17 1BJ, Hants, England. [Tatem, Andrew J.; Grenfell, Bryan T.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Tatem, Andrew J.] Flowminder Fdn, S-17177 Stockholm, Sweden. RP Lessler, J (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. EM justin@jhu.edu OI Lessler, Justin/0000-0002-9741-8109 FU Bill & Melinda Gates Foundation [OPP1094793, OPP1106427, 1032350]; U.S. Department of Homeland Security Science & Technology Directorate [HSHQDC-12-C-00058]; RAPIDD program of the Department of Homeland Security Science & Technology Directorate; NIH Fogarty International Center; National Institute of Allergy and Infectious Diseases (NIAID) [R01 AI102939, U19AI089674] FX Supported by Bill & Melinda Gates Foundation grant OPP1094793 and U.S. Department of Homeland Security Science & Technology Directorate contract HSHQDC-12-C-00058 (B.T.G., C.J.E.M.); the RAPIDD program of the Department of Homeland Security Science & Technology Directorate and the NIH Fogarty International Center (C.J.E.M., B.T.G., A.J.T.); National Institute of Allergy and Infectious Diseases (NIAID) grant R01 AI102939 (J.L.); and NIAID grant U19AI089674 and Bill & Melinda Gates Foundation grants OPP1106427 and 1032350 (A.J.T.). We thank M. Hanson for helping to organize the assessment of the impact of Ebola on measles vaccination and for motivating this work, and W. Hao for helpful discussion in preparation of the manuscript. Demographic and Health Surveys data are made freely available to those filing a request (22). WorldPop project demographic data may be obtained from www.worldpop.org.uk. Data on measles incidence, routine vaccination coverage, and SIAs are available at www.who.int/immunization/monitoring_surveillance/data/en/. Ebola incidence data were extracted from publicly available situation reports (23-25). NR 25 TC 37 Z9 37 U1 3 U2 72 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 MAR 13 PY 2015 VL 347 IS 6227 BP 1240 EP 1242 DI 10.1126/science.aaa3438 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CD1GZ UT WOS:000350824300035 PM 25766232 ER PT J AU Heesterbeek, H Anderson, RM Andreasen, V Bansal, S De Angelis, D Dye, C Eames, KTD Edmunds, WJ Frost, SDW Funk, S Hollingsworth, TD House, T Isham, V Klepac, P Lessler, J Lloyd-Smith, JO Metcalf, CJE Mollison, D Pellis, L Pulliam, JRC Roberts, MG Viboud, C AF Heesterbeek, Hans Anderson, Roy M. Andreasen, Viggo Bansal, Shweta De Angelis, Daniela Dye, Chris Eames, Ken T. D. Edmunds, W. John Frost, Simon D. W. Funk, Sebastian Hollingsworth, T. Deirdre House, Thomas Isham, Valerie Klepac, Petra Lessler, Justin Lloyd-Smith, James O. Metcalf, C. Jessica E. Mollison, Denis Pellis, Lorenzo Pulliam, Juliet R. C. Roberts, Mick G. Viboud, Cecile CA Isaac Newton Inst IDD Collaboratio TI Modeling infectious disease dynamics in the complex landscape of global health SO SCIENCE LA English DT Review ID EBOLA-VIRUS DISEASE; SUB-SAHARAN AFRICA; ANTIRETROVIRAL THERAPY; ANTIMICROBIAL RESISTANCE; EPIDEMIOLOGIC DYNAMICS; MATHEMATICAL-MODELS; HIV TRANSMISSION; DECISION-MAKING; SOUTH-AFRICA; WEST-AFRICA AB Despite some notable successes in the control of infectious diseases, transmissible pathogens still pose an enormous threat to human and animal health. The ecological and evolutionary dynamics of infections play out on a wide range of interconnected temporal, organizational, and spatial scales, which span hours to months, cells to ecosystems, and local to global spread. Moreover, some pathogens are directly transmitted between individuals of a single species, whereas others circulate among multiple hosts, need arthropod vectors, or can survive in environmental reservoirs. Many factors, including increasing antimicrobial resistance, increased human connectivity and changeable human behavior, elevate prevention and control from matters of national policy to international challenge. In the face of this complexity, mathematical models offer valuable tools for synthesizing information to understand epidemiological patterns, and for developing quantitative evidence for decision-making in global health. C1 [Heesterbeek, Hans] Univ Utrecht, Fac Vet Med, Utrecht, Netherlands. [Anderson, Roy M.] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, London, England. [Andreasen, Viggo] Roskilde Univ, Roskilde, Denmark. [Bansal, Shweta; Funk, Sebastian] Georgetown Univ, Washington, DC USA. [De Angelis, Daniela] MRC, Biostat Unit, Cambridge CB2 2BW, England. [Dye, Chris] WHO, CH-1211 Geneva, Switzerland. [Eames, Ken T. D.; Edmunds, W. John] London Sch Hyg Trop Med, Ctr Math Modelling Infect Dis, London, England. [Frost, Simon D. W.; Klepac, Petra] Univ Cambridge, Cambridge, England. [Hollingsworth, T. Deirdre] Univ Warwick, Sch Life Sci, Coventry CV4 7AL, W Midlands, England. [Hollingsworth, T. Deirdre] Univ Liverpool, Sch Trop Med, Liverpool L69 3BX, Merseyside, England. [House, Thomas; Pellis, Lorenzo] Univ Warwick, Warwick Math Inst, Coventry CV4 7AL, W Midlands, England. [Isham, Valerie] UCL, Dept Stat Sci, London, England. [Lessler, Justin] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Lloyd-Smith, James O.] Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA USA. [Metcalf, C. Jessica E.] Univ Oxford, Dept Zool, Oxford, England. [Metcalf, C. Jessica E.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Mollison, Denis] Heriot Watt Univ, Edinburgh, Midlothian, Scotland. [Pulliam, Juliet R. C.] Univ Florida, Dept Biol, Emerging Pathogens Inst, Gainesville, FL USA. [Pulliam, Juliet R. C.; Viboud, Cecile] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Roberts, Mick G.] Massey Univ, Inst Nat & Math Sci, Auckland, New Zealand. RP Heesterbeek, H (reprint author), Univ Utrecht, Fac Vet Med, Utrecht, Netherlands. EM j.a.p.heesterbeek@uu.nl RI Hollingsworth, Deirdre/D-2421-2009; Lloyd-Smith, James/K-4080-2012; OI Hollingsworth, Deirdre/0000-0001-5962-4238; Lloyd-Smith, James/0000-0001-7941-502X; Bogich, Tiffany/0000-0002-8143-5289; Pulliam, Juliet/0000-0003-3314-8223; Lessler, Justin/0000-0002-9741-8109; Bansal, Shweta/0000-0002-1740-5421 FU Isaac Newton Institute for Mathematical Sciences; Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, U.S. Department of Homeland Security; Fogarty International Center, NIH FX H.H. conceived and wrote the paper; R.M.A., V.A., S.B., D.D.A., C.D., K.T.D.E., W.J.E., S.D.W.F., S.F., T.D.H., T.H., V.I., P.K., J.L., J.O.L.-S., C.J.E.M., D.M., J.R.C.P., L.P., M.G.R., and C.V. provided text and edited the manuscript; J.L., C.J.E.M. and T.D.H. produced figures; the Isaac Newton Institute IDD Collaboration jointly produced and discussed ideas for the outline and content (all of the above plus N.A., F.B., T.B., J.G., B.G., A.L.L., A.M., P.O.N., C.P., S.R., G.S.T., P.T., and J.W.). We gratefully acknowledge help by K. Koelle and D. Fisman in producing adapted versions of their figures for Fig. 2 (panels C, D, and E). This paper was conceived and developed at a program on Infectious Disease Dynamics at the Isaac Newton Institute for Mathematical Sciences, Cambridge, UK, 19 August to 13 September 2013 and 19 May to 6 June 2014 (www.newton.ac.uk). We gratefully acknowledge financial and infrastructural support from the Isaac Newton Institute for Mathematical Sciences which is fundamental to the success of this program. We are also grateful for the financial support the program received from 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, NIH. R.M.A. is a non-executive director of GlaxoSmithKline. C.D. acts as an advisor for the Wellcome Trust, for which he receives financial remuneration. NR 132 TC 35 Z9 36 U1 8 U2 67 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 MAR 13 PY 2015 VL 347 IS 6227 BP 1216 EP U29 AR aaa4339 DI 10.1126/science.aaa4339 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DE9NH UT WOS:000370964100002 PM 25766240 ER PT J AU Derbyshire, MK Gonzales, NR Lu, SN He, J Marchler, GH Wang, ZX Marchler-Bauer, A AF Derbyshire, Myra K. Gonzales, Noreen R. Lu, Shennan He, Jane Marchler, Gabriele H. Wang, Zhouxi Marchler-Bauer, Aron TI Improving the consistency of domain annotation within the Conserved Domain Database SO DATABASE-THE JOURNAL OF BIOLOGICAL DATABASES AND CURATION LA English DT Article AB When annotating protein sequences with the footprints of evolutionarily conserved domains, conservative score or E-value thresholds need to be applied for RPS-BLAST hits, to avoid many false positives. We notice that manual inspection and classification of hits gathered at a higher threshold can add a significant amount of valuable domain annotation. We report an automated algorithm that 'rescues' valuable borderline-scoring domain hits that are well-supported by domain architecture (DA, the sequential order of conserved domains in a protein query), including tandem repeats of domain hits reported at a more conservative threshold. This algorithm is now available as a selectable option on the public conserved domain search (CD-Search) pages. We also report on the possibility to 'suppress' domain hits close to the threshold based on a lack of well-supported DA and to implement this conservatively as an option in live conserved domain searches and for pre-computed results. Improving domain annotation consistency will in turn reduce the fraction of NR sequences with incomplete DAs. C1 [Derbyshire, Myra K.; Gonzales, Noreen R.; Lu, Shennan; He, Jane; Marchler, Gabriele H.; Wang, Zhouxi; Marchler-Bauer, Aron] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Marchler-Bauer, A (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 38 A,Room 5S508,8600 Rockville Pike, Bethesda, MD 20894 USA. EM bauer@ncbi.nlm.nih.gov FU Intramural Research Program of National Library of Medicine at the National Institutes of Health/DHHS FX Intramural Research Program of the National Library of Medicine at National Institutes of Health/DHHS. Funding for open access charge: Intramural Research Program of the National Library of Medicine at the National Institutes of Health/DHHS. NR 12 TC 2 Z9 2 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1758-0463 J9 DATABASE-OXFORD JI Database PD MAR 12 PY 2015 AR bav012 DI 10.1093/database/bav012 PG 8 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA CR0WS UT WOS:000361044900001 ER PT J AU Nakagawa-Goto, K Oda, A Hamel, E Ohkoshi, E Lee, KH Goto, M AF Nakagawa-Goto, Kyoko Oda, Akifumi Hamel, Ernest Ohkoshi, Emika Lee, Kuo-Hsiung Goto, Masuo TI Development of a Novel Class of Tubulin Inhibitor from Desmosdumotin B with a Hydroxylated Bicyclic B-Ring SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID POLAR MOLECULAR-SURFACE; COLCHICINE; RESISTANCE; ANALOGS; AGENTS; ABSORPTION; CANCER; DRUGS; EXPRESSION; PREDICTION AB A series of newly synthesized hydroxylated analogues of triethyldesmosdumotin B (TEDB) with a bicyclic B-ring exhibited a significantly different mode of action for affecting microtubule dynamics and spindle formation but had the same antiproliferative activity spectrum, including activity against multidrug-resistant tumors. These analogues efficiently induced cell cycle arrest at prometaphase and caused formation of immature multipolar spindles. 6'-Hydroxyl TEDB-TB (8) disrupted bipolar spindle formation but had a negligible effect on interphase microtubules. On the basis of the predicted binding modes of the new compounds with tubulin dimer, compound 4 forms three hydrogen bonds (H-bonds) only with alpha-tubulin at the colchicine site; in contrast, 8 forms H-bonds with both alpha- and beta-tubulin. We predict that, when a compound/ligand, such as 8, forms H-bonds to both alpha- and beta-tubulins, spindle formation is disrupted more than the dynamics of interphase microtubules. This result may reflect the well-known greater dynamicity of spindle microtubules as compared with interphase microtubules. C1 [Nakagawa-Goto, Kyoko; Oda, Akifumi] Kanazawa Univ, Coll Med Pharmaceut & Hlth Sci, Sch Pharmaceut Sci, Kanazawa, Ishikawa 9201192, Japan. [Nakagawa-Goto, Kyoko; Ohkoshi, Emika; Lee, Kuo-Hsiung; Goto, Masuo] Univ N Carolina, UNC Eshelman Sch Pharm, Chem Biol & Med Chem, Nat Prod Res Labs, Chapel Hill, NC 27599 USA. [Lee, Kuo-Hsiung] Univ N Carolina, UNC Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,Frederick Natl Lab Canc, Frederick, MD 21702 USA. [Lee, Kuo-Hsiung] China Med Univ & Hosp, Chinese Med Res & Dev Ctr, Taichung 40447, Taiwan. RP Nakagawa-Goto, K (reprint author), Kanazawa Univ, Coll Med Pharmaceut & Hlth Sci, Sch Pharmaceut Sci, Kanazawa, Ishikawa 9201192, Japan. EM kngoto@p.kanazawa-u.ac.jp; goto@med.unc.edu RI GOTO, Kyoko/D-8389-2015 OI GOTO, Kyoko/0000-0002-1642-6538 FU Ministry of Education, Culture, Sports, Science and Technology (MEXT KAKENHI, Japan) [25293024, 25670054, 23790137]; Terumo Life Science Foundation; NIH from the National Cancer Institute [CA177584]; University Research Council (UNC) FX We wish to thank the Microscopy Service Laboratory (UNC-CH) for their expertise in fluorescence microscopy and confocal microscopy as well as Dr. Leaf Huang (UNC-CH) for use of his flow cytometer. In addition, we appreciate critical comments, suggestions, and editing of the manuscript by Dr. Susan L. Morris-Natschke (UNC-CH). This study was supported by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology (MEXT KAKENHI, Japan) awarded to K.N.G. (Grant Number 25293024 & 25670054) and A.O. (Grant Number 23790137), by a grant from Terumo Life Science Foundation awarded to K.N.G, by NIH grant CA177584 from the National Cancer Institute awarded to K.H.L., and by a grant from the Junior Faculty Development Awards (UNC) as well as the University Research Council (UNC) awarded to M.G. NR 28 TC 11 Z9 11 U1 2 U2 15 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 MAR 12 PY 2015 VL 58 IS 5 BP 2378 EP 2389 DI 10.1021/jm501859j PG 12 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA CD6GB UT WOS:000351186500025 PM 25695315 ER PT J AU Yang, XR Killian, JK Hammond, S Burke, LS Bennett, H Wang, Y Davis, SR Strong, LC Neglia, J Stovall, M Weathers, RE Robison, LL Bhatia, S Mabuchi, K Inskip, PD Meltzer, P AF Yang, Xiaohong R. Killian, J. Keith Hammond, Sue Burke, Laura S. Bennett, Hunter Wang, Yonghong Davis, Sean R. Strong, Louise C. Neglia, Joseph Stovall, Marilyn Weathers, Rita E. Robison, Leslie L. Bhatia, Smita Mabuchi, Kiyohiko Inskip, Peter D. Meltzer, Paul TI Characterization of Genomic Alterations in Radiation-Associated Breast Cancer among Childhood Cancer Survivors, Using Comparative Genomic Hybridization (CGH) Arrays SO PLOS ONE LA English DT Article ID ATOMIC-BOMB SURVIVORS; SUBTYPES; TUMORS; INSTABILITY; RISK AB Ionizing radiation is an established risk factor for breast cancer. Epidemiologic studies of radiation- exposed cohorts have been primarily descriptive; molecular events responsible for the development of radiation-associated breast cancer have not been elucidated. In this study, we used array comparative genomic hybridization (array-CGH) to characterize genome- wide copy number changes in breast tumors collected in the Childhood Cancer Survivor Study (CCSS). Array-CGH data were obtained from 32 cases who developed a second primary breast cancer following chest irradiation at early ages for the treatment of their first cancers, mostly Hodgkin lymphoma. The majority of these cases developed breast cancer before age 45 (91%, n = 29), had invasive ductal tumors (81%, n = 26), estrogen receptor (ER)-positive staining (68%, n = 19 out of 28), and high proliferation as indicated by high Ki67 staining (77%, n = 17 out of 22). Genomic regions with low-copy number gains and losses and high-level amplifications were similar to what has been reported in sporadic breast tumors, however, the frequency of amplifications of the 17q12 region containing human epidermal growth factor receptor 2 (HER2) was much higher among CCSS cases (38%, n = 12). Our findings suggest that second primary breast cancers in CCSS were enriched for an "amplifier" genomic subgroup with highly proliferative breast tumors. Future investigation in a larger irradiated cohort will be needed to confirm our findings. C1 [Yang, Xiaohong R.; Burke, Laura S.; Bennett, Hunter; Mabuchi, Kiyohiko; Inskip, Peter D.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Killian, J. Keith; Wang, Yonghong; Davis, Sean R.; Meltzer, Paul] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Hammond, Sue] Childrens Hosp, Dept Lab Med & Pathol, Columbus, OH 43205 USA. [Hammond, Sue] Ohio State Univ, Coll Med, Columbus, OH 43210 USA. [Strong, Louise C.] Univ Texas MD Anderson Canc Ctr, Dept Genet, Houston, TX 77030 USA. [Neglia, Joseph] Univ Minnesota, Sch Med, Dept Pediat, Minneapolis, MN 55455 USA. [Stovall, Marilyn; Weathers, Rita E.] Univ Texas MD Anderson Canc Ctr, Dept Radiat Phys, Houston, TX 77030 USA. [Robison, Leslie L.] St Jude Childrens Res Hosp, Epidemiol & Canc Control, Memphis, TN 38105 USA. [Bhatia, Smita] Univ Alabama Birmingham, Dept Pediat, Birmingham, AL USA. RP Yang, XR (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM royang@mail.nih.gov FU Intramural Research Program of the NIH, NCI, Division of Cancer Epidemiology Genetics [U24 CA55727] FX This research was supported in part by the Intramural Research Program of the NIH, NCI, Division of Cancer Epidemiology & Genetics and grant for the CCSS (U24 CA55727). NR 27 TC 4 Z9 4 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 MAR 12 PY 2015 VL 10 IS 3 AR e0116078 DI 10.1371/journal.pone.0116078 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CD7ND UT WOS:000351276300004 PM 25764003 ER PT J AU Hall, D Kardos, J Edskes, H Carver, JA Goto, YJ AF Hall, Damien Kardos, Jozsef Edskes, Herman Carver, John A. Goto, Yuji TI A multi-pathway perspective on protein aggregation: Implications for control of the rate and extent of amyloid formation SO FEBS LETTERS LA English DT Article DE Amyloid; Amorphous aggregation; Competition; Anti-amyloid ligand screen; Kinetic model; Regulation ID VOLUME-EXCLUDING MACROMOLECULES; ALZHEIMERS-DISEASE; ALPHA-SYNUCLEIN; FIBRIL FORMATION; KINETIC-ANALYSIS; FIBER FORMATION; RATE CONSTANTS; BETA; PEPTIDE; MODEL AB The nucleation-growth model has been used extensively for characterizing in vitro amyloid fibril formation kinetics and for simulating the relationship between amyloid and disease. In the majority of studies amyloid has been considered as the dominant, or sole, aggregation end product, with the presence of other competing non-amyloid aggregation processes, for example amorphous aggregate formation, being largely ignored. Here, we examine possible regulatory effects that off-pathway processes might exert on the rate and extent of amyloid formation - in particular their potential for providing false positives and negatives in the evaluation of anti-amyloidogenic agents. Furthermore, we investigate how such competing reactions might influence the standard interpretation of amyloid aggregation as a two-state system. We conclude by discussing our findings in terms of the general concepts of supersaturation and system metastability - providing some mechanistic insight as to how these empirical phenomena may manifest themselves in the amyloid arena. Crown Copyright (C) 2015 Published by Elsevier B.V. on behalf of Federation of European Biochemical society. All rights reserved. C1 [Hall, Damien; Carver, John A.] Australian Natl Univ, Res Sch Chem, Canberra, ACT 0200, Australia. [Hall, Damien; Goto, Yuji] Osaka Univ, Inst Prot Res, Suita, Osaka 5650871, Japan. [Kardos, Jozsef] Eotvos Lorand Univ, Inst Biol, MTA ELTE NAP B Neuroimmunol Res Grp, H-1117 Budapest, Hungary. [Kardos, Jozsef] Eotvos Lorand Univ, Inst Biol, Dept Biochem, H-1117 Budapest, Hungary. [Edskes, Herman] NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Hall, D (reprint author), Australian Natl Univ, Res Sch Chem, Canberra, ACT 0200, Australia. EM damien.hall@anu.edu.au RI Carver, John/J-3825-2014; Hall, Damien/D-9927-2012 OI Carver, John/0000-0002-2441-8108; Hall, Damien/0000-0003-1538-7618 FU A.N.U. Senior Research Fellowship; Hungarian Academy of Sciences; National Health and Medical Research Council of Australia; Japanese Ministry of Education, Culture, Sports, Science and Technology; Intramural Research Program of the NIH, National Institute of Diabetes Digestive and Kidney Diseases FX The research of D.H. is supported by an A.N.U. Senior Research Fellowship. The research of J.K. is supported by a Bolyai Janos fellowship from the Hungarian Academy of Sciences. The research of J.A.C. is supported by a Project Grant from the National Health and Medical Research Council of Australia. The research of Y.G. is supported by the Japanese Ministry of Education, Culture, Sports, Science and Technology. The research of H.E. was supported in part by the Intramural Research Program of the NIH, National Institute of Diabetes Digestive and Kidney Diseases. NR 60 TC 11 Z9 11 U1 3 U2 26 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 EI 1873-3468 J9 FEBS LETT JI FEBS Lett. PD MAR 12 PY 2015 VL 589 IS 6 BP 672 EP 679 DI 10.1016/j.febslet.2015.01.032 PG 8 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA CC6BR UT WOS:000350450100002 PM 25647034 ER PT J AU Esposito, G Setoh, P Bornstein, MH AF Esposito, Gianluca Setoh, Peipei Bornstein, Marc H. TI Beyond practices and values: toward a physio-bioecological analysis of sleeping arrangements in early infancy SO FRONTIERS IN PSYCHOLOGY LA English DT Editorial Material DE sleeping arrangement; mother-infant interaction; cross-cultural research; co-sleeping; physio-bioecological C1 [Esposito, Gianluca] Univ Trento, Dept Psychol & Cognit Sci, Affiliat Behav & Physiol Lab, Trento, Italy. [Esposito, Gianluca; Setoh, Peipei] Nanyang Technol Univ, Div Psychol, Singapore 639798, Singapore. [Bornstein, Marc H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Esposito, G (reprint author), Univ Trento, Dept Psychol & Cognit Sci, Affiliat Behav & Physiol Lab, Trento, Italy. EM gianluca.esposito@unitn.it NR 11 TC 0 Z9 0 U1 1 U2 4 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-1078 J9 FRONT PSYCHOL JI Front. Psychol. PD MAR 12 PY 2015 VL 6 AR 264 DI 10.3389/fpsyg.2015.00264 PG 3 WC Psychology, Multidisciplinary SC Psychology GA CD0WJ UT WOS:000350794500001 PM 25814970 ER PT J AU Martinez, P Sundling, C O'Dell, S Mascola, JR Wyatt, RT Hedestam, GBK AF Martinez, Paola Sundling, Christopher O'Dell, Sijy Mascola, John R. Wyatt, Richard T. Hedestam, Gunilla B. Karlsson TI Primate immune responses to HIV-1 Env formulated in the saponin-based adjuvant AbISCO-100 in the presence or absence of TLR9 co-stimulation SO SCIENTIFIC REPORTS LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; B-CELL RESPONSES; PLASMACYTOID DENDRITIC CELLS; RANDOMIZED CONTROLLED-TRIAL; ANTIBODY-RESPONSES; NEUTRALIZING ANTIBODIES; RHESUS MACAQUES; CPG OLIGODEOXYNUCLEOTIDES; NONHUMAN-PRIMATES; INFLUENZA VACCINE AB Protein-based vaccines require adjuvants to achieve optimal responses. Toll-like receptor (TLR) 9 agonists were previously shown to improve responses to protein-based vaccines, such as the Hepatitis B virus vaccine formulated in alum. Here, we used CpG-C together with the clinically relevant saponin-based adjuvant AbISCO-100/Matrix-M (AbISCO), to assess if TLR9 co-stimulation would quantitatively or qualitatively modulate HIV-1 envelope glycoprotein (Env)-specific B and T cell responses in rhesus macaques. The macaques were inoculated with soluble Env trimers in AbISCO, with or without the addition of CpG-C, using an interval similar to the Hepatitis B virus vaccine. Following a comprehensive evaluation of antigen-specific responses in multiple immune compartments, we show that the Env-specific circulating IgG, memory B cells and plasma cells displayed similar kinetics and magnitude in the presence or absence of CpG-C and that there was no apparent difference between the two groups in the elicited HIV-1 neutralizing antibody titers or antigen-specific CD4+ T cell responses. Importantly, the control of SHIV viremia was significantly improved in animals from both Env-immunized groups relative to adjuvant alone controls, demonstrating the potential of AbISCO to act as a stand-alone adjuvant for Env-based vaccines. C1 [Martinez, Paola; Sundling, Christopher; Hedestam, Gunilla B. Karlsson] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden. [O'Dell, Sijy; Mascola, John R.] NIAID, NIH, Bethesda, MD 20892 USA. [Wyatt, Richard T.] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, Dept Immunol & Microbiol Sci, La Jolla, CA 92037 USA. RP Hedestam, GBK (reprint author), Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden. EM Gunilla.Karlsson.Hedestam@ki.se OI Sundling, Christopher/0000-0002-6138-690X FU Karolinska Institutet funds and foundations; Swedish Research Council; NIH/NIAID grant [AI100663]; NIH intramural research program; International AIDS Vaccine Initiative (IAVI) FX We thank Mats Spangberg, Helene Fredlund and the personnel at Astrid Fagraeus laboratory at Karolinska Institutet for expert assistance with rhesus macaques. We also thank Linda Stertman and Karin Lovgren Bengtsson at Novavax (previously Isconova) for sharing AbISCO-100 and Gabriel Pedersen for constructive comments on the manuscript. This work was supported by grants from Karolinska Institutet funds and foundations (PM and CS), the Swedish Research Council (GKH), NIH/NIAID grant AI100663 (RTW), the NIH intramural research program (JM), and the International AIDS Vaccine Initiative (IAVI) (RTW and GKH). IAVI's funding is made possible by generous support from many donors with the full list of IAVI donors available at www.iavi.org. NR 57 TC 4 Z9 4 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 MAR 12 PY 2015 VL 5 AR 8925 DI 10.1038/srep08925 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CD5QI UT WOS:000351142500001 PM 25762407 ER PT J AU Cassano, PA Guertin, KA Kristal, AR Ritchie, KE Bertoia, ML Arnold, KB Crowley, JJ Hartline, J Goodman, PJ Tangen, CM Minasian, LM Lippman, SM Klein, E AF Cassano, Patricia A. Guertin, Kristin A. Kristal, Alan R. Ritchie, Kathryn E. Bertoia, Monica L. Arnold, Kathryn B. Crowley, John J. Hartline, Joann Goodman, Phyllis J. Tangen, Catherine M. Minasian, Lori M. Lippman, Scott M. Klein, Eric TI A randomized controlled trial of vitamin E and selenium on rate of decline in lung function SO RESPIRATORY RESEARCH LA English DT Article DE Spirometry; Vitamin E; Selenium; Forced expiratory volume; Forced expiratory flow rate ID PULMONARY-FUNCTION; CANCER PREVENTION; PROSTATE-CANCER; HEALTH; COPD; SUPPLEMENTATION; SMOKING; RISK; FEV1; DIET AB Background: The intake of nutrients with antioxidant properties is hypothesized to augment antioxidant defenses, decrease oxidant damage to tissues, and attenuate age-related rate of decline in lung function. The objective was to determine whether long-term intervention with selenium and/or vitamin E supplements attenuates the annual rate of decline in lung function, particularly in cigarette smokers. Methods: The Respiratory Ancillary Study (RAS) tested the single and joint effects of selenium (200 mu g/d L-selenomethionine) and vitamin E (400 IU/day all rac-a-tocopheryl acetate) in a randomized double-blind placebo-controlled trial. At the end of the intervention, 1,641 men had repeated pulmonary function tests separated by an average of 3 years. Linear mixed-effects regression models estimated the effect of intervention on annual rate of decline in lung function. Results: Compared to placebo, intervention had no main effect on either forced expiratory volume in the first second (FEV1) or forced expiratory flow (FEF25-75). There was no evidence for a smoking by treatment interaction for FEV1, but selenium attenuated rate of decline in FEF25-75 in current smokers (P = 0.0219). For current smokers randomized to selenium, annual rate of decline in FEF25-75 was similar to the annual decline experienced by never smokers randomized to placebo, with consistent effects for selenium alone and combined with vitamin E. Conclusions: Among all men, there was no effect of selenium and/or vitamin E supplementation on rate of lung function decline. However, current smokers randomized to selenium had an attenuated rate of decline in FEF25-75, a marker of airflow. C1 [Cassano, Patricia A.; Guertin, Kristin A.; Ritchie, Kathryn E.; Bertoia, Monica L.] Cornell Univ, Div Nutr Sci, Ithaca, NY 14853 USA. [Cassano, Patricia A.] Weill Cornell Med Coll, Div Biostat & Epidemiol, Dept Healthcare Policy & Res, New York, NY USA. [Kristal, Alan R.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Kristal, Alan R.; Tangen, Catherine M.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Arnold, Kathryn B.; Crowley, John J.; Hartline, Joann; Goodman, Phyllis J.] SWOG Stat Ctr, Seattle, WA USA. [Minasian, Lori M.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Lippman, Scott M.] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. [Klein, Eric] Cleveland Clin, Cleveland, OH 44106 USA. RP Cassano, PA (reprint author), Cornell Univ, Div Nutr Sci, 209 Savage Hall, Ithaca, NY 14853 USA. EM pac6@cornell.edu FU NHLBI [R01HL071022]; Public Health Service from the National Cancer Institute [CA37429, 5UM1CA182883] FX Supported by the NHLBI (R01HL071022), and SELECT was funded by Public Health Service grants CA37429 and 5UM1CA182883 from the National Cancer Institute. NR 29 TC 5 Z9 5 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-993X EI 1465-9921 J9 RESP RES JI Respir. Res. PD MAR 11 PY 2015 VL 16 AR 35 DI 10.1186/s12931-015-0195-5 PG 9 WC Respiratory System SC Respiratory System GA CG4MI UT WOS:000353259500001 PM 25889509 ER PT J AU Schwentner, R Papamarkou, T Kauer, MO Stathopoulos, V Yang, F Bilke, S Meltzer, PS Girolami, M Kovar, H AF Schwentner, Raphaela Papamarkou, Theodore Kauer, Maximilian O. Stathopoulos, Vassilios Yang, Fan Bilke, Sven Meltzer, Paul S. Girolami, Mark Kovar, Heinrich TI EWS-FLI1 employs an E2F switch to drive target gene expression SO NUCLEIC ACIDS RESEARCH LA English DT Article ID EWINGS-SARCOMA; CELL-PROLIFERATION; IN-VIVO; FAMILY; REPRESSION; PROTEIN; GROWTH; CANCER; TUMORS; ROLES AB Cell cycle progression is orchestrated by E2F factors. We previously reported that in ETS-driven cancers of the bone and prostate, activating E2F3 cooperates with ETS on target promoters. The mechanism of target co-regulation remained unknown. Using RNAi and time-resolved chromatin-immunoprecipitation in Ewing sarcoma we report replacement of E2F3/pRB by constitutively expressed repressive E2F4/p130 complexes on target genes upon EWS-FLI1 modulation. Using mathematical modeling we interrogated four alternative explanatory models for the observed EWS-FLI1/E2F3 cooperation based on longitudinal E2F target and regulating transcription factor expression analysis. Bayesian model selection revealed the formation of a synergistic complex between EWS-FLI1 and E2F3 as the by far most likely mechanism explaining the observed kinetics of E2F target induction. Consequently we propose that aberrant cell cycle activation in Ewing sarcoma is due to the de-repression of E2F targets as a consequence of transcriptional induction and physical recruitment of E2F3 by EWS-FLI1 replacing E2F4 on their target promoters. C1 [Schwentner, Raphaela; Kauer, Maximilian O.; Kovar, Heinrich] St Anna Kinderkrebsforsch, Childrens Canc Res Inst, A-1090 Vienna, Austria. [Papamarkou, Theodore; Stathopoulos, Vassilios; Girolami, Mark] Univ Warwick, Dept Stat, Coventry CV4 7AL, W Midlands, England. [Yang, Fan; Bilke, Sven; Meltzer, Paul S.] NCI, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Kovar, Heinrich] Med Univ, Dept Pediat, A-1090 Vienna, Austria. RP Kovar, H (reprint author), St Anna Kinderkrebsforsch, Childrens Canc Res Inst, A-1090 Vienna, Austria. EM heinrich.kovar@ccri.at RI Papamarkou, Theodore/A-2958-2012; OI Papamarkou, Theodore/0000-0002-9689-543X; Kovar, Heinrich/0000-0001-6873-9109 FU Austrian Science Fund (FWF) [22328-B09]; 7th framework program of the European Commission [259348]; DOC-fFORTE fellowship of the Austrian Academy of Sciences FX Austrian Science Fund (FWF) [22328-B09]; 7th framework program of the European Commission [259348] (ASSET). DOC-fFORTE fellowship of the Austrian Academy of Sciences [to R.S.]. Funding for open access charge: 7th framework program of the European Commission [259348] (ASSET). NR 37 TC 11 Z9 11 U1 2 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD MAR 11 PY 2015 VL 43 IS 5 BP 2780 EP 2789 DI 10.1093/nar/gkv123 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CF3ZG UT WOS:000352487100031 PM 25712098 ER PT J AU Zheng, WW De Sancho, D Hoppe, T Best, RB AF Zheng, Wenwei De Sancho, David Hoppe, Travis Best, Robert B. TI Dependence of Internal Friction on Folding Mechanism SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID MOLECULAR-DYNAMICS METHOD; BETA-HAIRPIN FORMATION; TRANSITION PATH TIMES; SOLVENT VISCOSITY; ENERGY LANDSCAPE; ALPHA-HELIX; DISORDERED PROTEINS; SECONDARY STRUCTURE; GLOBULAR-PROTEINS; CHAIN DYNAMICS AB An outstanding challenge in protein folding is understanding the origin of internal friction in folding dynamics, experimentally identified from the dependence of folding rates on solvent viscosity. A possible origin suggested by simulation is the crossing of local torsion barriers. However, it was unclear why internal friction varied from protein to protein or for different folding barriers of the same protein. Using all-atom simulations with variable solvent viscosity, in conjunction with transition-path sampling to obtain reaction rates and analysis via Markov state models, we are able to determine the internal friction in the folding of several peptides and miniproteins. In agreement with experiment, we find that the folding events with greatest internal friction are those that mainly involve helix formation, while hairpin formation exhibits little or no evidence of friction. Via a careful analysis of folding transition paths, we show that internal friction arises when torsion angle changes are an important part of the folding mechanism near the folding free energy barrier. These results suggest an explanation for the variation of internal friction effects from protein to protein and across the energy landscape of the same protein. C1 [Zheng, Wenwei; Hoppe, Travis; Best, Robert B.] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [De Sancho, David] Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England. [De Sancho, David] CIC NanoGUNE, Donostia San Sebastian 20018, Spain. [De Sancho, David] Ikerbasque, Basque Fdn Sci, Bilbao 48013, Spain. RP Best, RB (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM robertbe@helix.nih.gov RI nanoGUNE, CIC/A-2623-2015; Zheng, Wenwei/M-5031-2015; De Sancho, David/C-4995-2009; Best, Robert/H-7588-2016; OI Zheng, Wenwei/0000-0002-9603-009X; De Sancho, David/0000-0002-8985-2685; Best, Robert/0000-0002-7893-3543; Hoppe, Travis/0000-0002-4694-3050 FU Intramural Research Programme of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health; Engineering and Physical Sciences Research Council FX We thank William Eaton for helpful comments on the manuscript. This work was supported by the Intramural Research Programme of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (R.B.B., T.H. and W.Z) and a grant from the Engineering and Physical Sciences Research Council (D.d.S.). 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 67 TC 8 Z9 8 U1 5 U2 38 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 MAR 11 PY 2015 VL 137 IS 9 BP 3283 EP 3290 DI 10.1021/ja511609u PG 8 WC Chemistry, Multidisciplinary SC Chemistry GA CD6GI UT WOS:000351187200029 PM 25721133 ER PT J AU Cohen, AA Milot, E Li, Q Bergeron, P Poirier, R Dusseault-Belanger, F Fulop, T Leroux, M Legault, V Metter, EJ Fried, LP Ferrucci, L AF Cohen, Alan A. Milot, Emmanuel Li, Qing Bergeron, Patrick Poirier, Roxane Dusseault-Belanger, Francis Fueloep, Tamas Leroux, Maxime Legault, Veronique Metter, E. Jeffrey Fried, Linda P. Ferrucci, Luigi TI Detection of a Novel, Integrative Aging Process Suggests Complex Physiological Integration SO PLOS ONE LA English DT Article ID PRINCIPAL COMPONENT ANALYSIS; BIOLOGICAL AGE; SYSTEMS BIOLOGY; INFLAMMATORY MARKERS; OLDER-ADULTS; HEPCIDIN; ANEMIA; DYSREGULATION; DECLINE; COMPUTATION AB Many studies of aging examine biomarkers one at a time, but complex systems theory and network theory suggest that interpretations of individual markers may be context-dependent. Here, we attempted to detect underlying processes governing the levels of many biomarkers simultaneously by applying principal components analysis to 43 common clinical biomarkers measured longitudinally in 3694 humans from three longitudinal cohort studies on two continents (Women's Health and Aging I & II, InCHIANTI, and the Baltimore Longitudinal Study on Aging). The first axis was associated with anemia, inflammation, and low levels of calcium and albumin. The axis structure was precisely reproduced in all three populations and in all demographic sub-populations (by sex, race, etc.); we call the process represented by the axis "integrated albunemia." Integrated albunemia increases and accelerates with age in all populations, and predicts mortality and frailty - but not chronic disease - even after controlling for age. This suggests a role in the aging process, though causality is not yet clear. Integrated albunemia behaves more stably across populations than its component biomarkers, and thus appears to represent a higher-order physiological process emerging from the structure of underlying regulatory networks. If this is correct, detection of this process has substantial implications for physiological organization more generally. C1 [Cohen, Alan A.; Li, Qing; Bergeron, Patrick; Legault, Veronique] Univ Sherbrooke, Dept Family Med, Grp Rech PRIMUS, Sherbrooke, PQ J1H 5N4, Canada. [Milot, Emmanuel] Univ Quebec Trois Rivieres, Dept Chem Biochem & Phys, Trois Rivieres, PQ G9A 5H7, Canada. [Poirier, Roxane] Univ Sherbrooke, Dept Biol, Sherbrooke, PQ J1K 2R1, Canada. [Dusseault-Belanger, Francis] Univ Sherbrooke, Dept Math, Sherbrooke, PQ J1K 2R1, Canada. [Fueloep, Tamas] Univ Sherbrooke, Dept Geriatr, Sherbrooke, PQ J1H 5N4, Canada. [Leroux, Maxime] Univ Quebec, ESG, Dept Econ, Montreal, PQ H2X 3X2, Canada. [Metter, E. Jeffrey; Ferrucci, Luigi] NIA, MedStar Harbor Hosp, Longitudinal Studies Sect, Translat Gerontol Branch,NIH, Baltimore, MD 21225 USA. [Fried, Linda P.] Columbia Univ, Mailman Sch Publ Hlth, New York, NY 10032 USA. RP Cohen, AA (reprint author), Univ Sherbrooke, Dept Family Med, Grp Rech PRIMUS, 3001 12e Ave N, Sherbrooke, PQ J1H 5N4, Canada. EM Alan.Cohen@USherbrooke.ca FU FRQ-S; Canadian Institutes of Health Research grant [110789, 120305, 119485]; National Science and Engineering Research Council Discovery Grant [402079-2011]; Intramural Research Program of the National Institute on Aging FX AAC is a member of the Fonds de recherche du Quebec - Sante (FRQ-S)-supported Centre de recherche sur le vieillissement and Centre de recherche du CHUS, and is a funded Research Scholar of the FRQ-S. This research was supported by Canadian Institutes of Health Research grant #s 110789, 120305, 119485 and by National Science and Engineering Research Council Discovery Grant # 402079-2011 (all for AAC and TF), as well as by the Intramural Research Program of the National Institute on Aging (EJM and LF). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 11 Z9 11 U1 2 U2 15 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 MAR 11 PY 2015 VL 10 IS 3 AR e0116489 DI 10.1371/journal.pone.0116489 PG 26 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CD7MQ UT WOS:000351275000005 PM 25761112 ER PT J AU Houser, K Subbarao, K AF Houser, Katherine Subbarao, Kanta TI Influenza Vaccines: Challenges and Solutions SO CELL HOST & MICROBE LA English DT Review ID COMPUTATIONALLY OPTIMIZED HEMAGGLUTININ; SEASONAL INFLUENZA; PANDEMIC INFLUENZA; ANTIBODY-RESPONSE; SYSTEMS BIOLOGY; H5N1 INFLUENZA; DOUBLE-BLIND; VIRUS; VACCINATION; IMMUNOGENICITY C1 [Houser, Katherine; Subbarao, Kanta] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Subbarao, K (reprint author), NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. EM ksubbarao@niaid.nih.gov FU Intramural Research Program of the NIH; NIAID FX The authors are supported by the Intramural Research Program of the NIH and NIAID. NR 47 TC 17 Z9 18 U1 4 U2 20 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 MAR 11 PY 2015 VL 17 IS 3 BP 295 EP 300 DI 10.1016/j.chom.2015.02.012 PG 6 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA CD3LL UT WOS:000350979800008 PM 25766291 ER PT J AU Liu, SW Katsafanas, GC Liu, RK Wyatt, LS Moss, B AF Liu, Shin-Wu Katsafanas, George C. Liu, Ruikang Wyatt, Linda S. Moss, Bernard TI Poxvirus Decapping Enzymes Enhance Virulence by Preventing the Accumulation of dsRNA and the Induction of Innate Antiviral Responses SO CELL HOST & MICROBE LA English DT Article ID DOUBLE-STRANDED-RNA; VIRUS-INFECTED CELLS; VACCINIA VIRUS; MESSENGER-RNA; PROTEIN-KINASE; GENE-PRODUCT; VIRAL TRANSCRIPTION; DNA-BINDING; HOST-RANGE; E3L GENE AB Poxvirus replication involves synthesis of double-stranded RNA (dsRNA), which can trigger antiviral responses by inducing phosphorylation-mediated activation of protein kinase R (PKR) and stimulating 2'5'-oligoadenylate synthetase (OAS). PKR inactivates the translation initiation factor eIF2 alpha via phosphorylation, while OAS induces the endonuclease RNase L to degrade RNA. We show that poxvirus decapping enzymes D9 and D10, which remove caps from mRNAs, inhibit these antiviral responses by preventing dsRNA accumulation. Catalytic site mutations of D9 and D10, but not of either enzyme alone, halt vaccinia virus late protein synthesis and inhibit virus replication. Infection with the D9-D10 mutant was accompanied by massive mRNA reduction, cleavage of ribosomal RNA, and phosphorylation of PKR and eIF2 alpha that correlated with a similar to 15-fold increase in dsRNA compared to wild-type virus. Additionally, mouse studies show extreme attenuation of the mutant virus. Thus, vaccinia virus decapping, in addition to targeting mRNAs for degradation, prevents dsRNA accumulation and anti-viral responses. C1 [Liu, Shin-Wu; Katsafanas, George C.; Liu, Ruikang; Wyatt, Linda S.; Moss, Bernard] NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. EM bmoss@nih.gov FU Division of Intramural Research, NIAID, NIH FX We thank Catherine Cotter, Wei Xao, and Andrea Weisberg in the Laboratory of Viral Diseases for help with cell cultures, determination of antibody titers and transmission electron microscopy, respectively; Sundar Ganesan in the Biological Imaging Section for quantification of fluorescence microscopy; and members of the Comparative Medicine Branch for maintaining and weighing mice. David Evans provided the MAb to I3, and Robert Silverman generously provided shRNase L A543 cells prior to publication. During the course of this study, Hannah Burgess and Ian Mohr kindly shared with us their data on the effects of Xrn1 on vaccinia virus infection. The research was supported by the Division of Intramural Research, NIAID, NIH. NR 56 TC 13 Z9 13 U1 1 U2 10 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 MAR 11 PY 2015 VL 17 IS 3 BP 320 EP 331 DI 10.1016/j.chom.2015.02.002 PG 12 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA CD3LL UT WOS:000350979800011 PM 25766293 ER PT J AU Chen, X Bi, Y Wang, TY Li, PF Yan, X Hou, SS Bammert, CE Ju, JF Gibson, KM Pavan, WJ Bi, LR AF Chen, Xin Bi, Yue Wang, Tianyang Li, Pengfei Yan, Xin Hou, Shanshan Bammert, Catherine E. Ju, Jingfang Gibson, K. Michael Pavan, William J. Bi, Lanrong TI Lysosomal Targeting with Stable and Sensitive Fluorescent Probes (Superior LysoProbes): Applications for Lysosome Labeling and Tracking during Apoptosis SO SCIENTIFIC REPORTS LA English DT Article ID POTENTIAL THERAPEUTIC TARGET; CANCER-THERAPY; PH CHANGES; AUTOPHAGY; CELLS; DRUG; VISUALIZATION; MITOCHONDRIA; MECHANISMS; ORGANELLES AB Intracellular pH plays an important role in the response to cancer invasion. We have designed and synthesized a series of new fluorescent probes (Superior LysoProbes) with the capacity to label acidic organelles and monitor lysosomal pH. Unlike commercially available fluorescent dyes, Superior LysoProbes are lysosome- specific and are highly stable. The use of Superior LysoProbes facilitates the direct visualization of the lysosomal response to lobaplatin elicited in human chloangiocarcinoma (CCA) RBE cells, using confocal laser scanning microscopy. Additionally, we have characterized the role of lysosomes in autophagy, the correlation between lysosome function and microtubule strength, and the alteration of lysosomal morphology during apoptosis. Our findings indicate that Superior LysoProbes offer numerous advantages over previous reagents to examine the intracellular activities of lysosomes. C1 [Chen, Xin; Yan, Xin; Hou, Shanshan; Bammert, Catherine E.; Bi, Lanrong] Michigan Technol Univ, Dept Chem, Houghton, MI 49931 USA. [Bi, Yue; Wang, Tianyang; Li, Pengfei] HeBei Med Univ, Hosp 2, Shijiazhuang 050000, Peoples R China. [Ju, Jingfang] Stony Brook Med, Translat Res Lab, Stony Brook, NY 11794 USA. [Gibson, K. Michael] Washington State Univ, Coll Pharm, Expt & Syst pharmacol, Spokane, WA 99202 USA. [Pavan, William J.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Bi, LR (reprint author), Michigan Technol Univ, Dept Chem, Houghton, MI 49931 USA. EM jingfang.ju@stonybrookmedicine.edu; mike.gibson@wsu.edu; lanrong@mtu.edu OI Ju, Jingfang/0000-0002-4821-7458 FU NIH [GM088795-01]; NSF [1048655]; NASA [MSGC R85197]; MIIE [1204010]; Research Excellence Fund [R01121, R01323]; VPR-SI fund [R01386] FX The authors gratefully acknowledge the support of NIH (GM088795-01), NSF (No. 1048655), NASA (# MSGC R85197), MIIE (# 1204010) and Research Excellence Fund (# R01121 and # R01323), and VPR-SI fund (# R01386). The authors are particularly thankful to Dr. Bruce Seely for his ongoing support of our work. NR 39 TC 7 Z9 7 U1 13 U2 81 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 MAR 11 PY 2015 VL 5 AR 9004 DI 10.1038/srep09004 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CD5OS UT WOS:000351138300019 PM 25758662 ER PT J AU Kreimer, AR Brennan, P Kuhs, KAL Waterboer, T Clifford, G Franceschi, S Michel, A Willhauck-Fleckenstein, M Riboli, E Castellsague, X Hildesheim, A Fortner, RT Kaaks, R Palli, D Ljuslinder, I Panico, S Clavel-Chapelon, F Boutron-Ruault, MC Mesrine, S Trichopoulou, A Lagiou, P Trichopoulos, D Peeters, PH Cross, AJ Bueno-de-Mesquita, HB Vineis, P Larranaga, N Pala, V Sanchez, MJ Navarro, C Barricarte, A Tumino, R Khaw, KT Wareham, N Boeing, H Steffen, A Travis, RC Quiros, JR Weiderpass, E Pawlita, M Johansson, M AF Kreimer, Aimee R. Brennan, Paul Kuhs, Krystle A. Lang Waterboer, Tim Clifford, Gary Franceschi, Silvia Michel, Angelika Willhauck-Fleckenstein, Martina Riboli, Elio Castellsague, Xavier Hildesheim, Allan Fortner, Renee Turzanski Kaaks, Rudolf Palli, Domenico Ljuslinder, Ingrid Panico, Salvatore Clavel-Chapelon, Francoise Boutron-Ruault, Marie-Christine Mesrine, Sylvie Trichopoulou, Antonia Lagiou, Pagona Trichopoulos, Dimitrios Peeters, Petra H. Cross, Amanda J. Bueno-de-Mesquita, H. Bas Vineis, Paolo Larranaga, Nerea Pala, Valeria Sanchez, Maria-Jose Navarro, Carmen Barricarte, Aurelio Tumino, Rosario Khaw, Kay-Tee Wareham, Nicholas Boeing, Heiner Steffen, Annika Travis, Ruth C. Ramon Quiros, J. Weiderpass, Elisabete Pawlita, Michael Johansson, Mattias TI Human Papillomavirus Antibodies and Future Risk of Anogenital Cancer: A Nested Case-Control Study in the European Prospective Investigation Into Cancer and Nutrition Study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID INVASIVE CERVICAL-CANCER; OROPHARYNGEAL CANCER; GENOTYPE ATTRIBUTION; EARLY PROTEINS; NECK-CANCER; CARCINOMA; MARKERS; PREVALENCE; WORLDWIDE; COHORT AB Purpose Human papillomavirus (HPV) type 16 (HPV16) causes cancer at several anatomic sites. In the European Prospective Investigation Into Cancer and Nutrition study, HPV16 E6 seropositivity was present more than 10 years before oropharyngeal cancer diagnosis and was nearly absent in controls. The current study sought to evaluate the extent to which HPV16 E6 antibodies are present before diagnosis of anogenital cancers within the same cohort. Methods Four hundred incident anogenital cancers (273 cervical, 24 anal, 67 vulvar, 12 vaginal, and 24 penile cancers) with prediagnostic blood samples (collected on average 3 and 8 years before diagnosis for cervix and noncervix cancers, respectively) and 718 matched controls were included. Plasma was analyzed for antibodies against HPV16 E6 and multiple other HPV proteins and genotypes and evaluated in relation to risk using unconditional logistic regression. Results HPV16 E6 seropositivity was present in 29.2% of individuals (seven of 24 individuals) who later developed anal cancer compared with 0.6% of controls (four of 718 controls) who remained cancer free (odds ratio [OR], 75.9; 95% CI, 17.9 to 321). HPV16 E6 seropositivity was less common for cancers of the cervix (3.3%), vagina (8.3%), vulva (1.5%), and penis (8.3%). No associations were seen for non-type 16 HPV E6 antibodies, apart from anti-HPV58 E6 and anal cancer (OR, 6.8; 95% CI, 1.4 to 33.1). HPV16 E6 seropositivity tended to increase in blood samples drawn closer in time to cancer diagnosis. Conclusion HPV16 E6 seropositivity is relatively common before diagnosis of anal cancer but rare for other HPV-related anogenital cancers. (C) 2015 by American Society of Clinical Oncology C1 [Kreimer, Aimee R.; Kuhs, Krystle A. Lang; Hildesheim, Allan] NCI, NIH, Bethesda, MD 20892 USA. [Lagiou, Pagona; Trichopoulos, Dimitrios] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Brennan, Paul; Clifford, Gary; Franceschi, Silvia; Johansson, Mattias] Int Agcy Res Canc, F-69372 Lyon, France. [Clavel-Chapelon, Francoise; Boutron-Ruault, Marie-Christine; Mesrine, Sylvie] INSERM, Ctr Res Epidemiol & Populat Hlth, Villejuif, France. [Clavel-Chapelon, Francoise; Boutron-Ruault, Marie-Christine; Mesrine, Sylvie] Univ Paris 11, Villejuif, France. [Clavel-Chapelon, Francoise; Boutron-Ruault, Marie-Christine; Mesrine, Sylvie] Inst Gustave Roussy, Villejuif, France. [Waterboer, Tim; Michel, Angelika; Willhauck-Fleckenstein, Martina; Fortner, Renee Turzanski; Kaaks, Rudolf; Pawlita, Michael] German Canc Res Ctr, Heidelberg, Germany. [Boeing, Heiner; Steffen, Annika] German Inst Human Nutr Potsdam Rehbrucke, Nuthetal, Germany. [Riboli, Elio; Cross, Amanda J.; Bueno-de-Mesquita, H. Bas; Vineis, Paolo] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, London, England. [Khaw, Kay-Tee; Wareham, Nicholas] Univ Cambridge, Cambridge, England. [Travis, Ruth C.] Univ Oxford, Nuffield Dept Populat Hlth, Oxford, England. [Castellsague, Xavier] CIBERESP, Inst Catala Oncol, Inst Invest Biomed Bellvitge IDIBELL, Lhospitalet De Llobregat, Spain. [Larranaga, Nerea; Sanchez, Maria-Jose; Navarro, Carmen; Barricarte, Aurelio] CIBERESP, Madrid, Spain. [Sanchez, Maria-Jose] Univ Granada, Hosp Univ Granada, Inst Invest Biosanitaria, Escuela Andaluza Salud Publ, Granada, Spain. [Navarro, Carmen] Murcia Reg Hlth Council, Murcia, Spain. [Navarro, Carmen] Univ Murcia, Murcia, Spain. [Barricarte, Aurelio] Navarre Publ Hlth Inst, Pamplona, Spain. [Ramon Quiros, J.] Publ Hlth Directorate, Asturias, Spain. [Larranaga, Nerea] Basque Reg Hlth Dept, San Sebastian, Spain. [Palli, Domenico] Canc Res & Prevent Inst ISPO, Florence, Italy. [Panico, Salvatore] Univ Naples Federico II, Naples, Italy. [Vineis, Paolo] Human Genet Fdn, Turin, Italy. [Pala, Valeria] Ist Nazl Tumori, Fdn Ist Ricovero & Cura Carattere Sci, I-20133 Milan, Italy. [Tumino, Rosario] Civ MP Arezzo Hosp, Ragusa, Italy. [Ljuslinder, Ingrid] Umea Univ, Umea, Sweden. [Weiderpass, Elisabete] Karolinska Inst, Stockholm, Sweden. [Trichopoulou, Antonia; Lagiou, Pagona] Univ Athens, Sch Med, WHO Collaborating Ctr Food & Nutr Policies, GR-11527 Athens, Greece. [Trichopoulou, Antonia; Trichopoulos, Dimitrios] Hellen Hlth Fdn, Athens, Greece. [Lagiou, Pagona; Trichopoulos, Dimitrios] Acad Athens, Athens, Greece. [Peeters, Petra H.] Univ Med Ctr, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Bueno-de-Mesquita, H. Bas] Univ Med Ctr, Utrecht, Netherlands. [Bueno-de-Mesquita, H. Bas] Natl Inst Publ Hlth & Environm, NL-3720 BA Bilthoven, Netherlands. [Bueno-de-Mesquita, H. Bas] Univ Malaya, Kuala Lumpur, Malaysia. [Weiderpass, Elisabete] Arctic Univ Norway, Univ Tromso, Tromso, Norway. [Weiderpass, Elisabete] Canc Registry Norway, Oslo, Norway. [Weiderpass, Elisabete] Folkhalsan Res Ctr, Helsinki, Finland. RP Kreimer, AR (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,RM 6-E104, Bethesda, MD 20892 USA. EM kreimera@mail.nih.gov RI Weiderpass, Elisabete/M-4029-2016; Waterboer, Tim/G-1252-2010; Hildesheim, Allan/B-9760-2015; Kreimer, Aimee/H-1687-2015; Castellsague Pique, Xavier/N-5795-2014; Steffen, Annika/E-8540-2016; Panico, Salvatore/K-6506-2016 OI PALLI, Domenico/0000-0002-5558-2437; Fortner, Renee/0000-0002-1426-8505; Pawlita, Michael/0000-0002-4720-8306; Weiderpass, Elisabete/0000-0003-2237-0128; Hildesheim, Allan/0000-0003-0257-2363; Castellsague Pique, Xavier/0000-0002-0802-3595; Steffen, Annika/0000-0003-4072-9245; Panico, Salvatore/0000-0002-5498-8312 FU National Cancer Institute Intramural Research Program; International Agency for Research on Cancer; Associazione Italiana per la Ricerca sul Cancro, Italy; Regional Government of Asturias; Europe Against Cancer Program of the European Commission; Deutsche Krebshilfe; Deutsches Krebsforschungszentrum; German Federal Ministry of Education and Research; Danish Cancer Society; Health Research Fund of the Spanish Ministry of Health; 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; Italian National Research Council; Fondazione-Istituto Banco Napoli, Italy; Associazione Italiana per la Ricerca sul Cancro, 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, France; National Institute for Health and Medical Research, France; Mutuelle Generale de l'Education Nationale, France; 3M Co, France; Gustave Roussy Institute, France; General Councils of France; Spanish Regional Government of Andalucia; Spanish Regional Government of Asturias; Spanish Regional Government of Basque Country; Spanish Regional Government of Murcia; Spanish Regional Government of Navarra FX Supported by the National Cancer Institute Intramural Research Program (A.R.K.) and International Agency for Research on Cancer (P.B.). D.P. is supported by a grant from Associazione Italiana per la Ricerca sul Cancro, Italy. J.R.Q. receives funds from the Regional Government of Asturias. The European Prospective Investigation Into Cancer and Nutrition study has been supported by the Europe Against Cancer Program of the European Commission; Deutsche Krebshilfe, Deutsches Krebsforschungszentrum, German Federal Ministry of Education and Research; Danish Cancer Society; Health Research Fund 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; Italian National Research Council, Fondazione-Istituto Banco Napoli, Italy; Associazione Italiana per la Ricerca sul Cancro, 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, France; National Institute for Health and Medical Research, France; Mutuelle Generale de l'Education Nationale, France; 3M Co, France; Gustave Roussy Institute, France; and General Councils of France. NR 28 TC 7 Z9 7 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 MAR 10 PY 2015 VL 33 IS 8 BP 877 EP + DI 10.1200/JCO.2014.57.8435 PG 10 WC Oncology SC Oncology GA CK2QI UT WOS:000356055600014 PM 25667279 ER PT J AU Dalgard, CL Jacobowitz, DM Singh, VK Saleem, KS Ursano, RJ Starr, JM Pollard, HB AF Dalgard, Clifton L. Jacobowitz, David M. Singh, Vijay K. Saleem, Kadharbatcha S. Ursano, Robert J. Starr, Joshua M. Pollard, Harvey B. TI A novel analytical brain block tool to enable functional annotation of discriminatory transcript biomarkers among discrete regions of the fronto-limbic circuit in primate brain SO BRAIN RESEARCH LA English DT Article DE Systems; RNA-seq; Area 25; Hippocampus; Anterior cingulate cortex; Amygdala ID FACTOR-KAPPA-B; TREATMENT-RESISTANT DEPRESSION; MESSENGER-RNA EXPRESSION; HUMAN PREFRONTAL CORTEX; GENE-EXPRESSION; TEMPORAL-LOBE; ALZHEIMERS-DISEASE; SIGNALING PATHWAYS; NONHUMAN-PRIMATES; BIPOLAR DISORDER AB Fronto-limbic circuits in the primate brain are responsible for executive function, learning and memory, and emotions, including fear. Consequently, changes in gene expression in cortical and subcortical brain regions housing these circuits are associated with many important psychiatric and neurological disorders. While high quality gene expression profiles can be identified in brains from model organisms, primate brains have unique features such as Brodmann Area 25, which is absent in rodents, yet profoundly important in primates, including humans. The potential insights to be gained from studying the human brain are complicated by the fact that the post-mortem interval (PMI) is variable, and most repositories keep solid tissue in the deep frozen state. Consequently, sampling the important medial and internal regions of these brains is difficult. Here we describe a novel method for obtaining discrete regions from the fronto-limbic circuits of a 4 year old and a 5 year old, male, intact, frozen non-human primate (NHP) brain, for which the PMI is exactly known. The method also preserves high quality RNA, from which we use transcriptional profiling and a new algorithm to identify region-exclusive RNA signatures for Area 25 (NF kappa B and dopamine receptor signaling), the anterior cingulate cortex (LXR/RXR signaling), the amygdala (semaphorin signaling), and the hippocampus (Ca++ and retinoic acid signaling). The RNA signatures not only reflect function of the different regions, but also include highly expressed RNAs for which function is either poorly understood, or which generate proteins presently lacking annotated functions. We suggest that this new approach will provide a useful strategy for identifying changes in fronto-limbic system biology underlying normal development, aging and disease in the human brain. Published by Elsevier B.V. C1 [Dalgard, Clifton L.; Jacobowitz, David M.; Starr, Joshua M.; Pollard, Harvey B.] Uniformed Serv Univ Hlth Sci, Uniformed Serv Univ Sch Med, Dept Anat Physiol & Genet, Bethesda, MD 20814 USA. [Dalgard, Clifton L.; Jacobowitz, David M.; Starr, Joshua M.; Pollard, Harvey B.] Uniformed Serv Univ Hlth Sci, Uniformed Serv Univ Sch Med, Ctr Med Prote, Bethesda, MD 20814 USA. [Singh, Vijay K.] Uniformed Serv Univ Hlth Sci, Armed Forces Radiobiol Inst AFRRI, Dept Radiat Biol, Bethesda, MD 20814 USA. [Saleem, Kadharbatcha S.] NIMH, NIH, Bethesda, MD 20892 USA. [Ursano, Robert J.] Uniformed Serv Univ Hlth Sci, Uniformed Serv Univ Sch Med, Dept Psychiat, Bethesda, MD 20814 USA. [Ursano, Robert J.] Uniformed Serv Univ Hlth Sci, Uniformed Serv Univ Sch Med, Ctr Study Traumat Stress, Bethesda, MD 20814 USA. RP Pollard, HB (reprint author), Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, Bldg B,Room B2100,4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM Harvey.pollard@usuhs.edu FU AFRRI [CBM.RAD.01.10, AR.005(G3B2EO)]; CDMRP-PTSD [PTO74415] FX This work was supported by in part by AFRRI grant no. CBM.RAD.01.10. AR.005(G3B2EO) to VKS; and by CDMRP-PTSD (PTO74415) to HBP. Additionally, the authors would like to thank Ms. Xiuying Zhang for her expert help in preparing the manuscript, and the excellent technical assistance from Ms. Tinghua Chen. Gene expression data are deposited in the Gene Expression Omnibus (GEO) database: http://www.ncbi.nlm.nih.gov/geo (accession number GSE64797). NR 109 TC 4 Z9 4 U1 6 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 EI 1872-6240 J9 BRAIN RES JI Brain Res. PD MAR 10 PY 2015 VL 1600 BP 42 EP 58 DI 10.1016/j.brainres.2014.12.031 PG 17 WC Neurosciences SC Neurosciences & Neurology GA CF7OR UT WOS:000352746700004 PM 25529630 ER PT J AU Hamilton, DH Fernando, RI Schlom, J Palena, C AF Hamilton, Duane H. Fernando, Romaine I. Schlom, Jeffrey Palena, Claudia TI Aberrant expression of the embryonic transcription factor brachyury in human tumors detected with a novel rabbit monoclonal antibody SO ONCOTARGET LA English DT Article DE Brachyury; EMT; prognosis marker; tumor antigen; monoclonal antibody ID EPITHELIAL-MESENCHYMAL TRANSITION; HUMAN CARCINOMA-CELLS; PROSTATE-CANCER; PHENOTYPE; GENE; TISSUE; IDENTIFICATION; PROGRESSION; METASTASIS; RESISTANCE AB The embryonic transcription factor brachyury is overexpressed in a variety of human tumors, including lung, breast, colon and prostate carcinomas, chordomas and hemangioblastomas. In human carcinoma cells, overexpression of brachyury associates with the occurrence of the phenomenon of epithelial-mesenchymal transition (EMT), acquisition of metastatic propensity and resistance to a variety of anti-cancer therapeutics. Brachyury is preferentially expressed in human tumors vs. normal adult tissues, and high levels of this molecule associate with poor prognosis in patients with lung, colon and prostate carcinomas, and in breast cancer patients treated with adjuvant tamoxifen. Brachyury is immunogenic in humans and vaccines against this novel oncotarget are currently undergoing clinical investigation. While our group and others have employed various anti-brachyury antibodies to interrogate the above findings, we report here on the development and thorough characterization of a novel rabbit monoclonal antibody (MAb 54-1) that reacts with distinct high affinity and specificity with human brachyury. MAb 54-1 was successfully used in ELISA, western blot, immunofluorescence and immunohistochemistry assays to evaluate expression of brachyury in various human tumor cell lines and tissues. We propose the use of this antibody to assist in research studies of EMT and in prognostic studies for a range of human tumors. C1 [Hamilton, Duane H.; Fernando, Romaine I.; Schlom, Jeffrey; Palena, Claudia] NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Schlom, J (reprint author), NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM js141c@nih.gov FU Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 39 TC 7 Z9 7 U1 1 U2 5 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAR 10 PY 2015 VL 6 IS 7 BP 4853 EP 4862 PG 10 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CF8FR UT WOS:000352792000024 PM 25605015 ER PT J AU Soubias, O Teague, WE Hines, KG Gawrisch, K AF Soubias, Olivier Teague, Walter E., Jr. Hines, Kirk G. Gawrisch, Klaus TI Rhodopsin/Lipid Hydrophobic Matching-Rhodopsin Oligomerization and Function SO BIOPHYSICAL JOURNAL LA English DT Article ID LIPID-PROTEIN INTERACTIONS; ROD OUTER SEGMENTS; COUPLED RECEPTORS; CRYSTAL-STRUCTURE; BOUNDARY LIPIDS; MODEL BILAYERS; DISK MEMBRANES; SPIN-LABEL; BOVINE; MODULATION AB Lipid composition of the membrane and rhodopsin packing density strongly modulate the early steps of the visual response of photoreceptor membranes. In this study, lipid-order and bovine rhodopsin function in proteoliposomes composed of the sn-1 chain perdeuterated lipids 14:0(d27)-14:1-PC, 16:0(d31)-16:1-PC, 18:0(d35)-18:1-PC, or 20:0(d39)-20:1-PC at rhodopsin/lipid molar ratios from 1:70 to 1:1000 (mol/mol) were investigated. Clear evidence for matching of hydrophobic regions on rhodopsin transmembrane helices and hydrophobic thickness of lipid bilayers was observed from H-2 nuclear magnetic resonance order parameter measurements at low rhodopsin concentrations. Thin bilayers stretched to match the length of transmembrane helices observed as increase of sn-1 chain order, while thicker bilayers were compressed near the protein. A quantitative analysis of lipid-order parameter changes suggested that the protein adjusts its conformation to bilayer hydrophobic thickness as well, which confirmed our earlier circular-dichroism measurements. Changes in lipid order parameters upon rhodopsin incorporation vanished for bilayers with a hydrophobic thickness of 27 +/- 1 angstrom, suggesting that this is the bilayer thickness at which rhodopsin packs in bilayers at the lowest membrane perturbation. The lipid-order parameter studies also indicated that a hydrophobic mismatch between rhodopsin and lipids triggers rhodopsin oligomerization with increasing rhodopsin concentrations. Both hydrophobic mismatch and rhodopsin oligomerization result in substantial shifts of the equilibrium between the photointermediates metarhodopsin I and metarhodopsin II; increasing bilayer thickness favors formation of metarhodopsin II while oligomerization favors metarhodopsin I. The results highlight the importance of hydrophobic matching for rhodopsin structure, oligomerization, and function. C1 [Soubias, Olivier; Teague, Walter E., Jr.; Hines, Kirk G.; Gawrisch, Klaus] NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20892 USA. RP Gawrisch, K (reprint author), NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20892 USA. EM gawrisch@helix.nih.gov NR 39 TC 6 Z9 6 U1 0 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD MAR 10 PY 2015 VL 108 IS 5 BP 1125 EP 1132 DI 10.1016/j.bpj.2015.01.006 PG 8 WC Biophysics SC Biophysics GA CD3HM UT WOS:000350969000014 PM 25762324 ER PT J AU Bolland, S Pierce, SK AF Bolland, Silvia Pierce, Susan K. TI Ups and downs in the search for a Herpes simplex virus vaccine SO ELIFE LA English DT Editorial Material ID GENITAL HERPES C1 [Bolland, Silvia; Pierce, Susan K.] NIAID, Immunogenet Lab, Rockville, MD 20852 USA. RP Bolland, S (reprint author), NIAID, Immunogenet Lab, Rockville, MD 20852 USA. EM spierce@niaid.nih.gov NR 6 TC 0 Z9 0 U1 3 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 MAR 10 PY 2015 VL 4 AR e06883 DI 10.7554/eLife.06883 PG 3 WC Biology SC Life Sciences & Biomedicine - Other Topics GA CE5II UT WOS:000351864600001 ER PT J AU Bann, CM Abresch, RT Biesecker, B Conway, KC Heatwole, C Peay, H Scal, P Strober, J Uzark, K Wolff, J Margolis, M Blackwell, A Street, N Montesanti, A Bolen, J AF Bann, Carla M. Abresch, Richard T. Biesecker, Barbara Conway, Kristin Caspers Heatwole, Chad Peay, Holly Scal, Peter Strober, Jonathan Uzark, Karen Wolff, Jodi Margolis, Marjorie Blackwell, Angela Street, Natalie Montesanti, Angela Bolen, Julie TI Measuring quality of life in muscular dystrophy SO NEUROLOGY LA English DT Article ID PARENT PROXY-REPORTS; CONCEPTUAL-MODEL; NEURO-QOL; CHILDREN; ADOLESCENTS; IMPAIRMENT; DISABILITY; AGREEMENT; TYPE-1; IMPACT AB Objectives: The objectives of this study were to develop a conceptual model of quality of life (QOL) in muscular dystrophies (MDs) and review existing QOL measures for use in the MD population. Methods: Our model for QOL among individuals with MD was developed based on a modified Delphi process, literature review, and input from patients and patient advocacy organizations. Scales that have been used to measure QOL among patients with MD were identified through a literature review and evaluated using the COSMIN (Consensus-Based Standards for the Selection of Health Measurement Instruments) checklist. Results: The Comprehensive Model of QOL in MD (CMQM) captures 3 broad domains of QOL (physical, psychological, and social), includes factors influencing self-reported QOL (disease-related factors, support/resources, and expectations/aspirations), and places these concepts within the context of the life course. The literature review identified 15 QOL scales (9 adult and 6 pediatric) that have been applied to patients with MD. Very few studies reported reliability data, and none included data on responsiveness of the measures to change in disease progression, a necessary psychometric property for measures included in treatment and intervention studies. No scales captured all QOL domains identified in the CMQM model. Conclusions: Additional scale development research is needed to enhance assessment of QOL for individuals with MD. Item banking and computerized adaptive assessment would be particularly beneficial by allowing the scale to be tailored to each individual, thereby minimizing respondent burden. C1 [Bann, Carla M.] RTI Int, Res Triangle Pk, NC 27709 USA. [Abresch, Richard T.] Univ Calif Davis, Davis, CA 95616 USA. [Biesecker, Barbara] NHGRI, Bethesda, MD 20892 USA. [Conway, Kristin Caspers] Univ Iowa, Iowa City, IA USA. [Heatwole, Chad] Univ Rochester, Rochester, NY 14627 USA. [Peay, Holly] Parent Project Muscular Dystrophy, Hackensack, NJ USA. [Scal, Peter] Univ Minnesota, Minneapolis, MN USA. [Strober, Jonathan] UCSF Benioff Childrens Hosp, San Francisco, CA USA. [Uzark, Karen] Univ Michigan, Ann Arbor, MI 48109 USA. [Wolff, Jodi] Muscular Dystrophy Assoc, Chicago, IL USA. [Margolis, Marjorie] Univ N Carolina, Chapel Hill, NC USA. [Blackwell, Angela] RTI Int, Atlanta, GA USA. [Street, Natalie; Montesanti, Angela; Bolen, Julie] Ctr Dis Control & Prevent, Atlanta, GA USA. RP Bann, CM (reprint author), RTI Int, Res Triangle Pk, NC 27709 USA. EM cmb@rti.org FU Centers for Disease Control and Prevention [200-2007-22644/0016] FX Supported by the Centers for Disease Control and Prevention (contract 200-2007-22644/0016). The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. NR 39 TC 3 Z9 3 U1 1 U2 4 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 MAR 10 PY 2015 VL 84 IS 10 BP 1034 EP 1042 DI 10.1212/WNL.0000000000001336 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA CD9YR UT WOS:000351458100018 PM 25663223 ER PT J AU Tse, LA Li, MJ Chan, WC Kwok, CH Leung, SL Wu, C Yu, ITS Yu, WC Lao, XQ Wang, XR Wong, CKM Lee, PMY Wang, F Yang, XR AF Tse, Lap Ah Li, Mengjie Chan, Wing-cheong Kwok, Chi-hei Leung, Siu-lan Wu, Cherry Yu, Ignatius Tak-sun Yu, Wai-cho Lao, Xiangqian Wang, Xiaorong Wong, Carmen Ka-man Lee, Priscilla Ming-yi Wang, Feng Yang, Xiaohong Rose TI Familial Risks and Estrogen Receptor-Positive Breast Cancer in Hong Kong Chinese Women SO PLOS ONE LA English DT Article ID CONFER SUSCEPTIBILITY; COMMON VARIANTS; METAANALYSIS; POPULATION; SHANGHAI; HISTORY; DISEASE; TWINS AB Purpose The role of family history to the risk of breast cancer was analyzed by incorporating menopausal status in Hong Kong Chinese women, with a particular respect to the estrogen receptor-positive (ER+) type. Methods Seven hundred and forty seven breast cancer incident cases and 781 hospital controls who had completed information on family cancer history in first-degree relatives (nature father, mother, and siblings) were recruited. Odds ratio for breast cancer were calculated by unconditional multiple logistic regression, stratified by menopausal status (a surrogate of endogenous female sex hormone level and age) and type of relative affected with the disease. Further subgroup analysis by tumor type according to ER status was investigated. Results Altogether 52 (6.96%) breast cancer cases and 23 (2.95%) controls was found that the patients' one or more first-degree relatives had a history of breast cancer, showing an adjusted odds ratio (OR) of 2.41 (95% CI: 1.45-4.02). An excess risk of breast cancer was restricted to the ER+ tumor (OR = 2.43, 95% CI: 1.38-4.28), with a relatively higher risk associated with an affected mother (OR = 3.97, 95% CI: 1.46-10.79) than an affected sister (OR = 2.06, 95% CI: 1.07-3.97), while the relative risk was more prominent in the subgroup of pre-menopausal women. Compared with the breast cancer overall, the familial risks to the ER+ tumor increased progressively with the number of affected first-degree relatives. Conclusions This study provides new insights on a relationship between family breast cancer history, menopausal status, and the ER+ breast cancer. A separate risk prediction model for ER+ tumor in Asian population is desired. C1 [Tse, Lap Ah; Li, Mengjie; Yu, Ignatius Tak-sun; Lao, Xiangqian; Wang, Xiaorong; Wong, Carmen Ka-man; Lee, Priscilla Ming-yi; Wang, Feng] Chinese Univ Hong Kong, JC Sch Publ Hlth & Primary Care, Hong Kong, Hong Kong, Peoples R China. [Chan, Wing-cheong] North Dist Hosp, Dept Surg, Hong Kong, Hong Kong, Peoples R China. [Kwok, Chi-hei] Princess Margaret Hosp, Dept Oncol, Hong Kong, Hong Kong, Peoples R China. [Leung, Siu-lan] Pamela Youde Nethersole Eastern Hosp, Dept Surg, Hong Kong, Hong Kong, Peoples R China. [Wu, Cherry] North Dist Hosp, Dept Pathol, Hong Kong, Hong Kong, Peoples R China. [Yu, Wai-cho] Princess Margaret Hosp, Dept Med, Hong Kong, Hong Kong, Peoples R China. [Yang, Xiaohong Rose] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Tse, LA (reprint author), Chinese Univ Hong Kong, JC Sch Publ Hlth & Primary Care, Hong Kong, Hong Kong, Peoples R China. EM shelly@cuhk.edu.hk; fwang@cuhk.edu.hk RI Yu, Ignatius Tak Sun/A-9936-2008; OI , Xiang Qian/0000-0002-2645-0128 FU Research Grants Council of Hong Kong [474811] FX This work was supported by Research Grants Council of Hong Kong [Grant number 474811]. The funding source had no role in the study design, data collection, data analysis, or interpretation of the findings. NR 25 TC 3 Z9 3 U1 0 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 MAR 10 PY 2015 VL 10 IS 3 AR e0120741 DI 10.1371/journal.pone.0120741 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CD7MX UT WOS:000351275700074 PM 25756203 ER PT J AU Micklitsch, CM Medina, SH Yucel, T Nagy-Smith, KJ Pochan, DJ Schneider, JP AF Micklitsch, Christopher M. Medina, Scott H. Yucel, Tuna Nagy-Smith, Katelyn J. Pochan, Darrin J. Schneider, Joel P. TI Influence of Hydrophobic Face Amino Acids on the Hydrogelation of beta-Hairpin Peptide Amphiphiles SO MACROMOLECULES LA English DT Article ID AIR-WATER-INTERFACE; DE-NOVO DESIGN; SECONDARY STRUCTURE; ASSEMBLIES; NANOFIBERS; FILAMENTS; PROTEINS; FIBRIL; SHEETS AB Hydrophobic residues provide much of the thermodynamic driving force for the folding, self-assembly, and consequent hydrogelation of amphiphilic beta-hairpin peptides. We investigate how the identity of hydrophobic side chains displayed from the hydrophobic face of these amphiphilic peptides influences their behavior to expound on the design criteria important to gel formation: Six peptides Were designed that globally incorporate valine, aminobutyric acid, norvaline, norleucine, phenylalanine, or isoleucine on the hydrophobic face of the hairpin to study how systematic changes in hydrophobic content, beta-sheet propensity, and aromaticity affect gelation. Circular dichroism (CD) spectroscopy indicates that hydrophobic content, rather than beta-sheet propensity, dictates the temperature- and pH-dependent folding and assembly behavior of these peptides. Transmission electron microscopy (TEM) and small-angle neutron scattering (SANS) show that the local morphology of the fibrils formed via self-assembly is little affected by amino acid type. However, residue type does influence the propensity of peptide fibrils to undergo higher order assembly events. Oscillatory rheology Shows that the mechanical rigidity of the peptide gels is highly influenced by residue type, but there is no apparent correlation between rigidity and residue hydrophobicity nor beta-sheet propensity. Lastly, the large planar aromatic side chain of phenylalanine supports hairpin folding and assembly, affording a gel characterized by a rate of formation and storage modulus similar to the parent valine-containing peptide. C1 [Micklitsch, Christopher M.; Nagy-Smith, Katelyn J.] Univ Delaware, Dept Chem & Biochem, Newark, DE 19716 USA. [Yucel, Tuna; Pochan, Darrin J.] Univ Delaware, Dept Mat Sci & Engn, Newark, DE 19716 USA. [Medina, Scott H.; Nagy-Smith, Katelyn J.; Schneider, Joel P.] NCI, Biol Chem Lab, Ctr Canc Res, Frederick, MD 21701 USA. RP Schneider, JP (reprint author), NCI, Biol Chem Lab, Ctr Canc Res, Frederick, MD 21701 USA. EM Joel.Schneider@nih.gov RI Schneider, Joel/N-2610-2014 FU Intramural Research Program of the National Cancer Institute of the National Institutes of Health; NIST, U.S. Department of Commerce [70NANB12H239]; UD-NIST Center for Neutron Science FX This work was supported in part by funding from the Intramural Research Program of the National Cancer Institute of the National Institutes of Health and also by the cooperative agreement 70NANB12H239 from NIST, U.S. Department of Commerce, and the UD-NIST Center for Neutron Science. The statements, findings, conclusions, and recommendations are those of the authors and do not necessarily reflect the view of NIST or the Department of Commerce. NR 47 TC 5 Z9 5 U1 9 U2 56 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0024-9297 EI 1520-5835 J9 MACROMOLECULES JI Macromolecules PD MAR 10 PY 2015 VL 48 IS 5 BP 1281 EP 1288 DI 10.1021/ma5024796 PG 8 WC Polymer Science SC Polymer Science GA CD2OK UT WOS:000350918700002 ER PT J AU Kucka, M Tomic, M Bjelobaba, I Stojilkovic, SS Budimirovic, DB AF Kucka, Marek Tomic, Melanija Bjelobaba, Ivana Stojilkovic, Stanko S. Budimirovic, Dejan B. TI Paliperidone and aripiprazole differentially affect the strength of calcium-secretion coupling in female pituitary lactotrophs SO SCIENTIFIC REPORTS LA English DT Article ID PROLACTIN-RELEASE; EXTENDED-RELEASE; ANTIPSYCHOTIC ARIPIPRAZOLE; PARTIAL AGONIST; OPEN-LABEL; INDUCED HYPERPROLACTINEMIA; ATYPICAL ANTIPSYCHOTICS; 9-HYDROXY METABOLITE; ADJUNCTIVE TREATMENT; ELECTRICAL-ACTIVITY AB Hyperprolactinemia is a common adverse in vivo effect of antipsychotic medications that are used in the treatment of patients with schizophrenia. Here, we compared the effects of two atypical antipsychotics, paliperidone and aripiprazole, on cAMP/calcium signaling and prolactin release in female rat pituitary lactotrophs in vitro. Dopamine inhibited spontaneous cAMP/calcium signaling and prolactin release. In the presence of dopamine, paliperidone rescued cAMP/calcium signaling and prolactin release in a concentration-dependent manner, whereas aripiprazole was only partially effective. In the absence of dopamine, paliperidone stimulated cAMP/calcium signaling and prolactin release, whereas aripiprazole inhibited signaling and secretion more potently but less effectively than dopamine. Forskolin-stimulated cAMP production was facilitated by paliperidone and inhibited by aripiprazole, although the latter was not as effective as dopamine. None of the compounds affected prolactin transcript activity, intracellular prolactin accumulation, or growth hormone secretion. These data indicate that paliperidone has dual hyperprolactinemic actions in lactotrophs i) by preserving the coupling of spontaneous electrical activity and prolactin secretion in the presence of dopamine and ii) by inhibiting intrinsic dopamine receptor activity in the absence of dopamine, leading to enhanced calcium signaling and secretion. In contrast, aripiprazole acts on prolactin secretion by attenuating, but not abolishing, calcium-secretion coupling. C1 [Kucka, Marek; Tomic, Melanija; Bjelobaba, Ivana; Stojilkovic, Stanko S.] NICHHD, Sect Cellular Signaling, NIH, Bethesda, MD 20892 USA. [Budimirovic, Dejan B.] Johns Hopkins Sch Med, Kennedy Krieger Inst, Clin Trials Unit, Baltimore, MD 21205 USA. RP Kucka, M (reprint author), NICHHD, Sect Cellular Signaling, NIH, Bethesda, MD 20892 USA. EM mkucka@gmail.com RI Tomic, Melanija/C-3371-2016 FU Intramural Research Program of the NICHD, NIH FX We are thankful to Marija Janjic for help with cell preparation. This study was supported by the Intramural Research Program of the NICHD, NIH. NR 60 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAR 10 PY 2015 VL 5 AR 8902 DI 10.1038/srep08902 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CD4YF UT WOS:000351091800006 PM 25754735 ER PT J AU Krishnaswamy, JK Singh, A Gowthaman, U Wu, RN Gorrepati, P Nascimento, MS Gallman, A Liu, D Rhebergen, AM Calabro, S Xu, L Ranney, P Srivastava, A Ranson, M Gorham, JD McCaw, Z Kleeberger, SR Heinz, LX Muller, AC Bennett, KL Superti-Furga, G Henao-Mejia, J Sutterwala, FS Williams, A Flavell, RA Eisenbarth, SC AF Krishnaswamy, Jayendra Kumar Singh, Arpita Gowthaman, Uthaman Wu, Renee Gorrepati, Pavane Nascimento, Manuela Sales Gallman, Antonia Liu, Dong Rhebergen, Anne Marie Calabro, Samuele Xu, Lan Ranney, Patricia Srivastava, Anuj Ranson, Matthew Gorham, James D. McCaw, Zachary Kleeberger, Steven R. Heinz, Leonhard X. Mueller, Andre C. Bennett, Keiryn L. Superti-Furga, Giulio Henao-Mejia, Jorge Sutterwala, Fayyaz S. Williams, Adam Flavell, Richard A. Eisenbarth, Stephanie C. TI Coincidental loss of DOCK8 function in NLRP10-deficient and C3H/HeJ mice results in defective dendritic cell migration SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE dendritic cell; NLRP10; DOCK8; C3H/HeJ; CDC42 ID LEUKOCYTE MIGRATION; ADAPTIVE IMMUNITY; NLRP10; INFLAMMASOME; RESPONSES; MOUSE; ACTIVATION; EXPRESSION; RECEPTORS; MUTATION AB Dendritic cells (DCs) are the primary leukocytes responsible for priming T cells. To find and activate naive T cells, DCs must migrate to lymph nodes, yet the cellular programs responsible for this key step remain unclear. DC migration to lymph nodes and the subsequent T-cell response are disrupted in a mouse we recently described lacking the NOD-like receptor NLRP10 (NLR family, pyrin domain containing 10); however, the mechanism by which this pattern recognition receptor governs DC migration remained unknown. Using a proteomic approach, we discovered that DCs from Nlrp10 knockout mice lack the guanine nucleotide exchange factor DOCK8 (dedicator of cytokinesis 8), which regulates cytoskeleton dynamics in multiple leukocyte populations; in humans, loss-of-function mutations in Dock8 result in severe immunodeficiency. Surprisingly, Nlrp10 knockout mice crossed to other backgrounds had normal DOCK8 expression. This suggested that the original Nlrp10 knockout strain harbored an unexpected mutation in Dock8, which was confirmed using whole-exome sequencing. Consistent with our original report, NLRP3 inflammasome activation remained unaltered in NLRP10-deficient DCs even after restoring DOCK8 function; however, these DCs recovered the ability to migrate. Isolated loss of DOCK8 via targeted deletion confirmed its absolute requirement for DC migration. Because mutations in Dock genes have been discovered in other mouse lines, we analyzed the diversity of Dock8 across different murine strains and found that C3H/HeJ mice also harbor a Dock8 mutation that partially impairs DC migration. We conclude that DOCK8 is an important regulator of DC migration during an immune response and is prone to mutations that disrupt its crucial function. C1 [Krishnaswamy, Jayendra Kumar; Singh, Arpita; Gowthaman, Uthaman; Wu, Renee; Gorrepati, Pavane; Nascimento, Manuela Sales; Gallman, Antonia; Liu, Dong; Calabro, Samuele; Xu, Lan; Ranney, Patricia; Eisenbarth, Stephanie C.] Yale Univ, Sch Med, Dept Lab Med, New Haven, CT 06520 USA. [Krishnaswamy, Jayendra Kumar; Singh, Arpita; Gowthaman, Uthaman; Wu, Renee; Gorrepati, Pavane; Nascimento, Manuela Sales; Gallman, Antonia; Liu, Dong; Rhebergen, Anne Marie; Calabro, Samuele; Xu, Lan; Ranney, Patricia; Flavell, Richard A.; Eisenbarth, Stephanie C.] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT 06520 USA. [Flavell, Richard A.] Yale Univ, Sch Med, Howard Hughes Med Inst, New Haven, CT 06520 USA. [Srivastava, Anuj] Jackson Lab, Bar Harbor, ME 04609 USA. [Ranson, Matthew; Gorham, James D.] Geisel Sch Med Dartmouth, Dept Pathol, Hanover, NH 03755 USA. [McCaw, Zachary; Kleeberger, Steven R.] NIEHS, Res Triangle Pk, NC 27709 USA. [Heinz, Leonhard X.; Mueller, Andre C.; Bennett, Keiryn L.; Superti-Furga, Giulio] Austrian Acad Sci, CeMM Res Ctr Mol Med, A-1090 Vienna, Austria. [Henao-Mejia, Jorge] Univ Penn, Perelman Sch Med, Dept Pathol, Inst Immunol, Philadelphia, PA 19104 USA. [Henao-Mejia, Jorge] Univ Penn, Perelman Sch Med, Dept Lab Med, Inst Immunol, Philadelphia, PA 19104 USA. [Sutterwala, Fayyaz S.] Univ Iowa, Dept Internal Med, Inflammat Program, Iowa City, IA 52241 USA. [Williams, Adam] Univ Connecticut, Ctr Hlth, Jackson Lab Genom Med, Dept Genet & Genome Sci, Farmington, CT 06032 USA. RP Flavell, RA (reprint author), Yale Univ, Sch Med, Dept Immunobiol, 333 Cedar St, New Haven, CT 06520 USA. EM richard.flavell@yale.edu; stephanie.eisenbarth@yale.edu RI Superti-Furga, Giulio/F-4755-2015; OI Superti-Furga, Giulio/0000-0002-0570-1768; Eisenbarth, Stephanie/0000-0002-1244-208X FU NIH National Institute of Allergy and Infectious Diseases (NIAID) [K08 AI085038]; Hartwell Foundation Individual Biomedical Research Award; NIH NIAID [R01 AI108829, R01 AI087630]; Austrian Academy of Sciences; European Research Council [i-FIVE 250179] FX We thank Mark Firla, Lucy Rowe, Mary Barter, and Katja Parapatics for technical assistance, Jennifer A. Doudna and Stephen Floor for guidance with establishing the CRISPR/Cas9 system, and Krishna Karuturi, Florian P. Breitwieser, and Jacques Colinges for support with bio-informatics analysis. This work was supported by NIH National Institute of Allergy and Infectious Diseases (NIAID) Grant K08 AI085038 (to S.C.E.), a Hartwell Foundation Individual Biomedical Research Award (to S.C.E.), NIH NIAID Grant R01 AI108829 (to S.C.E.), Austrian Academy of Sciences and European Research Council Advanced Grant i-FIVE 250179 (to G.S.-F.), and NIH NIAID Grant R01 AI087630 (to F.S.S.). NR 34 TC 14 Z9 14 U1 4 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 MAR 10 PY 2015 VL 112 IS 10 BP 3056 EP 3061 DI 10.1073/pnas.1501554112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CC8VK UT WOS:000350646500047 PM 25713392 ER PT J AU Huys, QJM Lally, N Faulkner, P Eshel, N Seifritz, E Gershman, SJ Dayan, P Roiser, JP AF Huys, Quentin J. M. Lally, Niall Faulkner, Paul Eshel, Neir Seifritz, Erich Gershman, Samuel J. Dayan, Peter Roiser, Jonathan P. TI Interplay of approximate planning strategies SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE planning; hierarchical reinforcement learning; memoization; pruning ID INTERNATIONAL NEUROPSYCHIATRIC INTERVIEW; PREFRONTAL CORTEX; NEURAL REPRESENTATIONS; COGNITIVE CONTROL; DSM-IV; BEHAVIOR; CHUNKING; CHOICES; HABITS; MINI AB Humans routinely formulate plans in domains so complex that even the most powerful computers are taxed. To do so, they seem to avail themselves of many strategies and heuristics that efficiently simplify, approximate, and hierarchically decompose hard tasks into simpler subtasks. Theoretical and cognitive research has revealed several such strategies; however, little is known about their establishment, interaction, and efficiency. Here, we use model-based behavioral analysis to provide a detailed examination of the performance of human subjects in a moderately deep planning task. We find that subjects exploit the structure of the domain to establish subgoals in a way that achieves a nearly maximal reduction in the cost of computing values of choices, but then combine partial searches with greedy local steps to solve subtasks, and maladaptively prune the decision trees of subtasks in a reflexive manner upon encountering salient losses. Subjects come idiosyncratically to favor particular sequences of actions to achieve subgoals, creating novel complex actions or "options." C1 [Huys, Quentin J. M.] Univ Zurich, Inst Biomed Engn, Translat Neuromodeling Unit, CH-8032 Zurich, Switzerland. [Huys, Quentin J. M.] Swiss Fed Inst Technol, CH-8032 Zurich, Switzerland. [Huys, Quentin J. M.; Seifritz, Erich] Univ Zurich, Hosp Psychiat, Dept Psychiat Psychotherapy & Psychosomat, CH-8032 Zurich, Switzerland. [Lally, Niall; Roiser, Jonathan P.] UCL, Inst Cognit Neurosci, London WC1N 3AR, England. [Lally, Niall] NIMH, Expt Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Faulkner, Paul] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90095 USA. [Eshel, Neir] Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02115 USA. [Eshel, Neir] Harvard Univ, Sch Med, MD PhD Program, Boston, MA 02115 USA. [Gershman, Samuel J.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Dayan, Peter] UCL, Gatsby Computat Neurosci Unit, London WC1N 3AR, England. RP Huys, QJM (reprint author), Univ Zurich, Inst Biomed Engn, Translat Neuromodeling Unit, CH-8032 Zurich, Switzerland. EM qhuys@cantab.net OI Eshel, Neir/0000-0002-5976-2013 FU British Academy; German Research Foundation; Wellcome Trust-National Institutes of Health (NIH); Sackler Fellowship in Psychobiology; NIH [T32GM007753, F30MH100729]; Swiss National Science Foundation; University of Zurich; Neuroscience Centre Zurich; Gatsby Charitable Foundation FX This study has appeared in abstract form and was funded by a British Academy grant to J.P.R. Q.J.M.H. received funds from the German Research Foundation and N.L. from a Wellcome Trust-National Institutes of Health (NIH) studentship. N.E. is supported by a Sackler Fellowship in Psychobiology and NIH Grants T32GM007753 and F30MH100729. E.S. is supported by the Swiss National Science Foundation, the University of Zurich, and the Neuroscience Centre Zurich and P.D. by the Gatsby Charitable Foundation. NR 37 TC 19 Z9 19 U1 2 U2 18 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 MAR 10 PY 2015 VL 112 IS 10 BP 3098 EP 3103 DI 10.1073/pnas.1414219112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CC8VK UT WOS:000350646500054 PM 25675480 ER PT J AU Leone, V Pogoryelov, D Meier, T Faraldo-Gomez, JD AF Leone, Vanessa Pogoryelov, Denys Meier, Thomas Faraldo-Gomez, Jose D. TI On the principle of ion selectivity in Na+/H+-coupled membrane proteins: Experimental and theoretical studies of an ATP synthase rotor SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE molecular motor; ion-coupled transport; binding thermodynamics; energy transduction; membrane bioenergetics ID ISOTHERMAL TITRATION CALORIMETRY; MATE MULTIDRUG TRANSPORTER; HIGH-RESOLUTION STRUCTURE; ESCHERICHIA-COLI; ILYOBACTER-TARTARICUS; PROPIONIGENIUM-MODESTUM; MOLECULAR-DYNAMICS; ENTEROCOCCUS-HIRAE; MELIBIOSE CARRIER; SUBSTRATE-BINDING AB Numerous membrane transporters and enzymes couple their mechanisms to the permeation of Na+ or H+, thereby harnessing the energy stored in the form of transmembrane electrochemical potential gradients to sustain their activities. The molecular and environmental factors that control and modulate the ion specificity of most of these systems are, however, poorly understood. Here, we use isothermal titration calorimetry to determine the Na+/H+ selectivity of the ion-driven membrane rotor of an F-type ATP synthase. Consistent with earlier theoretical predictions, we find that this rotor is significantly H+ selective, although not sufficiently to be functionally coupled to H+, owing to the large excess of Na+ in physiological settings. The functional Na+ specificity of this ATP synthase thus results from two opposing factors, namely its inherent chemical selectivity and the relative availability of the coupling ion. Further theoretical studies of this membrane rotor, and of two others with a much stronger and a slightly weaker H+ selectivity, indicate that, although the inherent selectivity of their ion-binding sites is largely set by the balance of polar and hydrophobic groups flanking a conserved carboxylic side chain, subtle variations in their structure and conformational dynamics, for a similar chemical makeup, can also have a significant contribution. We propose that the principle of ion selectivity outlined here may provide a rationale for the differentiation of Na+ and H+-coupled systems in other families of membrane transporters and enzymes. C1 [Leone, Vanessa; Faraldo-Gomez, Jose D.] NHLBI, Theoret Mol Biophys Sect, NIH, Bethesda, MD 20892 USA. [Leone, Vanessa; Faraldo-Gomez, Jose D.] Max Planck Inst Biophys, Theoret Mol Biophys Grp, D-60438 Frankfurt, Germany. [Pogoryelov, Denys; Meier, Thomas] Max Planck Inst Biophys, Dept Biol Struct, D-60438 Frankfurt, Germany. [Pogoryelov, Denys; Meier, Thomas] Goethe Univ, Cluster Excellence Macromol Complexes, D-60438 Frankfurt, Germany. RP Leone, V (reprint author), NHLBI, Theoret Mol Biophys Sect, NIH, Bldg 10, Bethesda, MD 20892 USA. EM vanessa.leonealvarez@nih.gov; jose.faraldo@nih.gov RI Faraldo-Gomez, Jose/H-7127-2016 FU National Heart, Lung, and Blood Institute at the National Institutes of Heath; Max Planck Institute of Biophysics; Cluster of Excellence [EXC115]; Collaborative Research Center of the German Research Foundation [SFB807] FX We are greatly indebted to Dr. Ernst Grell from the Max Planck Institute of Biophysics for suggesting the use of ITC to investigate Na+ binding to the I. tartaricus c-ring, for contributing to the design of this experimental study, and for guiding the measurements and evaluations of the data carried out in Frankfurt, Germany. This research was supported in part by the Intramural Research Program of the National Heart, Lung, and Blood Institute at the National Institutes of Heath (J.D.F.-G.), by the Max Planck Institute of Biophysics (V.L., D.P., T.M., and J.D.F.-G.), and by the Cluster of Excellence EXC115 (T.M. and J.D.F.-G.) and the Collaborative Research Center SFB807 (T.M.) of the German Research Foundation. NR 67 TC 7 Z9 7 U1 1 U2 21 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 MAR 10 PY 2015 VL 112 IS 10 BP E1057 EP E1066 DI 10.1073/pnas.1421202112 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CC8VK UT WOS:000350646500005 PM 25713346 ER PT J AU Pasetto, M Antignani, A Ormanoglu, P Buehler, E Guha, R Pastan, I Martin, SE FitzGerald, DJ AF Pasetto, Matteo Antignani, Antonella Ormanoglu, Pinar Buehler, Eugen Guha, Rajarshi Pastan, Ira Martin, Scott E. FitzGerald, David J. TI Whole-genome RNAi screen highlights components of the endoplasmic reticulum/Golgi as a source of resistance to immunotoxin-mediated cytotoxicity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE RNAi; toxin; immunotoxin; screen; genome ID DIAMOND-BLACKFAN ANEMIA; PSEUDOMONAS-EXOTOXIN; DIPHTHERIA-TOXIN; HEMATOLOGIC MALIGNANCIES; DUCTAL ADENOCARCINOMAS; MONOCLONAL-ANTIBODIES; PROTEIN-DEGRADATION; BREAST-CANCER; MESOTHELIN; TARGET AB Immunotoxins (antibody-toxin fusion proteins) target surface antigens on cancer cells and kill these cells via toxin-mediated inhibition of protein synthesis. To identify genes controlling this process, an RNAi whole-genome screen (similar to 22,000 genes at three siRNAs per gene) was conducted via monitoring the cytotoxicity of the mesothelin-directed immunotoxin SS1P. SS1P, a Pseudomonas exotoxin-based immunotoxin, was chosen because it is now in clinical trials and has produced objective tumor regressions in patients. High and low concentrations of SS1P were chosen to allow for the identification of both mitigators and sensitizers. As expected, silencing known essential genes in the immunotoxin pathway, such as mesothelin, furin, KDEL receptor 2, or members of the diphthamide pathway, protected cells. Of greater interest was the observation that many RNAi targets increased immunotoxin sensitivity, indicating that these gene products normally contribute to inefficiencies in the killing pathway. Of the top sensitizers, many genes encode proteins that locate to either the endoplasmic reticulum (ER) or Golgi and are annotated as part of the secretory system. Genes related to the ER-associated degradation system were not among high-ranking mitigator or sensitizer candidates. However, the p97 inhibitor eeyarestatin 1 enhanced immunotoxin killing. Our results highlight potential targets for chemical intervention that could increase immunotoxin killing of cancer cells and enhance our understanding of toxin trafficking. C1 [Pasetto, Matteo; Antignani, Antonella; Pastan, Ira; FitzGerald, David J.] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Ormanoglu, Pinar; Buehler, Eugen; Guha, Rajarshi; Martin, Scott E.] Natl Ctr Adv Translat Sci, Div Preclin Innovat, NIH, Rockville, MD 20850 USA. RP Pasetto, M (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM pastani@mail.nih.gov; fitzgerd@helix.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; NIH Director's Challenge Innovation Award FX This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and via the NIH Director's Challenge Innovation Award. NR 70 TC 7 Z9 7 U1 0 U2 8 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 MAR 10 PY 2015 VL 112 IS 10 BP E1135 EP E1142 DI 10.1073/pnas.1501958112 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CC8VK UT WOS:000350646500013 PM 25713356 ER PT J AU Rothenberger, MK Keele, BF Wietgrefe, SW Fletcher, CV Beilman, GJ Chipman, JG Khoruts, A Estes, JD Anderson, J Callisto, SP Schmidt, TE Thorkelson, A Reilly, C Perkey, K Reimann, TG Utay, NS Makamdop, KN Stevenson, M Douek, DC Haase, AT Schacker, TW AF Rothenberger, Meghan K. Keele, Brandon F. Wietgrefe, Stephen W. Fletcher, Courtney V. Beilman, Gregory J. Chipman, Jeffrey G. Khoruts, Alexander Estes, Jacob D. Anderson, Jodi Callisto, Samuel P. Schmidt, Thomas E. Thorkelson, Ann Reilly, Cavan Perkey, Katherine Reimann, Thomas G. Utay, Netanya S. Makamdop, Krystelle Nganou Stevenson, Mario Douek, Daniel C. Haase, Ashley T. Schacker, Timothy W. TI Large number of rebounding/founder HIV variants emerge from multifocal infection in lymphatic tissues after treatment interruption SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE HIV/AIDS; founder population; treatment interruption; viral recrudescence ID CD4(+) T-CELLS; ANTIRETROVIRAL TREATMENT INTERRUPTION; LYMPHOID-TISSUES; COMBINATION THERAPY; LATENT RESERVOIR; PLASMA VIREMIA; REPLICATION; KINETICS; REDISTRIBUTION; IDENTIFICATION AB Antiretroviral therapy (ART) suppresses HIV replication in most individuals but cannot eradicate latently infected cells established before ART was initiated. Thus, infection rebounds when treatment is interrupted by reactivation of virus production from this reservoir. Currently, one or a few latently infected resting memory CD4 T cells are thought be the principal source of recrudescent infection, but this estimate is based on peripheral blood rather than lymphoid tissues (LTs), the principal sites of virus production and persistence before initiating ART. We, therefore, examined lymph node (LN) and gut-associated lymphoid tissue (GALT) biopsies from fully suppressed subjects, interrupted therapy, monitored plasma viral load (pVL), and repeated biopsies on 12 individuals as soon as pVL became detectable. Isolated HIV RNA-positive (vRNA+) cells were detected by in situ hybridization in LTs obtained before interruption in several patients. After interruption, multiple foci of vRNA+ cells were detected in 6 of 12 individuals as soon as pVL was measureable and in some subjects, in more than one anatomic site. Minimal estimates of the number of rebounding/founder (R/F) variants were determined by single-gene amplification and sequencing of viral RNA or DNA from peripheral blood mononuclear cells and plasma obtained at or just before viral recrudescence. Sequence analysis revealed a large number of R/F viruses representing recrudescent viremia from multiple sources. Together, these findings are consistent with the origins of recrudescent infection by reactivation from many latently infected cells at multiple sites. The inferred large pool of cells and sites to rekindle recrudescent infection highlights the challenges in eradicating HIV. C1 [Rothenberger, Meghan K.; Khoruts, Alexander; Anderson, Jodi; Callisto, Samuel P.; Schmidt, Thomas E.; Thorkelson, Ann; Reimann, Thomas G.; Schacker, Timothy W.] Univ Minnesota, Dept Med, Minneapolis, MN 55455 USA. [Keele, Brandon F.; Estes, Jacob D.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, AIDS & Canc Virus Program, Frederick, MD 21702 USA. [Wietgrefe, Stephen W.; Perkey, Katherine; Haase, Ashley T.] Univ Minnesota, Dept Microbiol, Minneapolis, MN 55455 USA. [Fletcher, Courtney V.] Univ Nebraska, Med Ctr, Coll Pharm, Omaha, NE 68198 USA. [Beilman, Gregory J.; Chipman, Jeffrey G.] Univ Minnesota, Dept Surg, Minneapolis, MN 55455 USA. [Reilly, Cavan] Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA. [Utay, Netanya S.] Univ Texas Med Branch, Dept Med, Galveston, TX 77555 USA. [Makamdop, Krystelle Nganou; Douek, Daniel C.] NIH, Vaccine Res Ctr, Bethesda, MD 20814 USA. [Stevenson, Mario] Univ Miami, Miller Sch Med, Dept Med, Miami, FL 33136 USA. RP Schacker, TW (reprint author), Univ Minnesota, Dept Med, Box 736 UMHC, Minneapolis, MN 55455 USA. EM schacker@umn.edu OI Utay, Netanya/0000-0002-6407-8670; Chipman, Jeffrey/0000-0002-0759-3705; Beilman, Gregory/0000-0001-5036-3027 FU NIH [P01AI074340]; National Cancer Institute (NIH) [HHSN261200800001E] FX This work was supported by NIH Grant P01AI074340 and in part with federal funds from the National Cancer Institute (NIH Contract HHSN261200800001E). NR 30 TC 37 Z9 37 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 MAR 10 PY 2015 VL 112 IS 10 BP E1126 EP E1134 DI 10.1073/pnas.1414926112 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CC8VK UT WOS:000350646500012 PM 25713386 ER PT J AU Harlid, S Xu, ZL Panduri, V D'Aloisio, AA DeRoo, LA Sandler, DP Taylor, JA AF Harlid, Sophia Xu, Zongli Panduri, Vijayalakshmi D'Aloisio, Aimee A. DeRoo, Lisa A. Sandler, Dale P. Taylor, Jack A. TI In Utero Exposure to Diethylstilbestrol and Blood DNA Methylation in Women Ages 40-59 Years from the Sister Study SO PLOS ONE LA English DT Article ID GENE-EXPRESSION; DEVELOPMENTAL EXPOSURE; ESTROGEN-RECEPTOR; BREAST-CANCER; MOUSE UTERUS; YOUNG-WOMEN; VAGINA; RISK; MICE AB In utero exposure to diethylstilbestrol (DES) has been associated with increased risk of adverse health outcomes such as fertility problems and vaginal as well as breast cancer. Animal studies have linked prenatal DES exposure to lasting DNA methylation changes. We investigated genome-wide DNA methylation and in utero DES exposure in a sample of non-Hispanic white women aged 40-59 years from the Sister Study, a large United States cohort study of women with a family history of breast cancer. Using questionnaire information from women and their mothers, we selected 100 women whose mothers reported taking DES while pregnant and 100 control women whose mothers had not taken DES. DNA methylation in blood was measured at 485,577 CpG sites using the Illumina HumanMethylation450 BeadChip. Associations between CpG methylation and DES exposure status were analyzed using robust linear regression with adjustment for blood cell composition and multiple comparisons. Although four CpGs had p<10(5), after accounting for multiple comparisons using the false discovery rate (FDR), none reached genome-wide significance. In conclusion, adult women exposed to DES in utero had no evidence of large persistent changes in blood DNA methylation. C1 [Harlid, Sophia; Xu, Zongli; D'Aloisio, Aimee A.; DeRoo, Lisa A.; Sandler, Dale P.; Taylor, Jack A.] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. [Harlid, Sophia; Panduri, Vijayalakshmi; Taylor, Jack A.] NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. [DeRoo, Lisa A.] Univ Bergen, Dept Global Publ Hlth & Primary Hlth Care, Bergen, Norway. RP Taylor, JA (reprint author), NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. EM taylor@niehs.nih.gov OI Harlid, Sophia/0000-0001-8540-6891; xu, zongli/0000-0002-9034-8902; taylor, jack/0000-0001-5303-6398; Sandler, Dale/0000-0002-6776-0018 FU NIH, National Institute of Environmental Health Sciences FX This study was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 27 TC 3 Z9 3 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 MAR 9 PY 2015 VL 10 IS 3 AR e0118757 DI 10.1371/journal.pone.0118757 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CC9LT UT WOS:000350692700009 PM 25751399 ER PT J AU Moses, MA Neckers, L AF Moses, Michael A. Neckers, Len TI The GLU that Holds Cancer Together: Targeting GLUtamine Transporters in Breast Cancer SO CANCER CELL LA English DT Editorial Material C1 [Moses, Michael A.; Neckers, Len] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Neckers, L (reprint author), NCI, Urol Oncol Branch, Ctr Canc Res, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM neckersl@mail.nih.gov NR 10 TC 2 Z9 2 U1 0 U2 8 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 MAR 9 PY 2015 VL 27 IS 3 BP 317 EP 319 DI 10.1016/j.ccell.2015.02.010 PG 3 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CD3KL UT WOS:000350977200002 PM 25759015 ER PT J AU Chernomordik, LV Kozlov, MM AF Chernomordik, Leonid V. Kozlov, Michael M. TI Myoblast Fusion: Playing Hard to Get SO DEVELOPMENTAL CELL LA English DT Editorial Material ID MEMBRANE-FUSION C1 [Chernomordik, Leonid V.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Membrane Biol, Program Phys Biol, NIH, Bethesda, MD 20892 USA. [Kozlov, Michael M.] Tel Aviv Univ, Dept Physiol & Pharmacol, Sackler Fac Med, IL-69978 Tel Aviv, Israel. RP Chernomordik, LV (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Membrane Biol, Program Phys Biol, NIH, Bethesda, MD 20892 USA. EM chernoml@mail.nih.gov; michk@post.tau.ac.il FU Intramural NIH HHS [ZIA HD001501-18] NR 10 TC 2 Z9 2 U1 1 U2 9 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 MAR 9 PY 2015 VL 32 IS 5 BP 529 EP 530 DI 10.1016/j.devcel.2015.02.018 PG 2 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA CD3OY UT WOS:000350989300001 PM 25758859 ER PT J AU Kim, JH Ren, YX Ng, WP Li, S Son, SM Kee, YS Zhang, SL Zhang, GF Fletcher, DA Robinson, DN Chen, EH AF Kim, Ji Hoon Ren, Yixin Ng, Win Pin Li, Shuo Son, Sungmin Kee, Yee-Seir Zhang, Shiliang Zhang, Guofeng Fletcher, Daniel A. Robinson, Douglas N. Chen, Elizabeth H. TI Mechanical Tension Drives Cell Membrane Fusion SO DEVELOPMENTAL CELL LA English DT Article ID MYOBLAST FUSION; IMMUNOGLOBULIN SUPERFAMILY; ACTIN NETWORKS; RHO-KINASE; MYOSIN-II; IN-VIVO; DROSOPHILA; MORPHOGENESIS; EXOCYTOSIS; PROTEINS AB Membrane fusion is an energy-consuming process that requires tight juxtaposition of two lipid bilayers. Little is known about how cells overcome energy barriers to bring their membranes together for fusion. Previously, we have shown that cell-cell fusion is an asymmetric process in which an "attacking" cell drills finger-like protrusions into the "receiving" cell to promote cell fusion. Here, we show that the receiving cell mounts a Myosin II (MyoII)-mediated mechanosensory response to its invasive fusion partner. MyoII acts as a mechanosensor, which directs its force-induced recruitment to the fusion site, and the mechanosensory response of MyoII is amplified by chemical signaling initiated by cell adhesion molecules. The accumulated MyoII, in turn, increases cortical tension and promotes fusion pore formation. We propose that the protrusive and resisting forces from fusion partners put the fusogenic synapse under high mechanical tension, which helps to overcome energy barriers for membrane apposition and drives cell membrane fusion. C1 [Kim, Ji Hoon; Li, Shuo; Zhang, Shiliang; Chen, Elizabeth H.] Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA. [Ren, Yixin; Kee, Yee-Seir; Robinson, Douglas N.] Johns Hopkins Univ, Sch Med, Dept Cell Biol, Baltimore, MD 21205 USA. [Ng, Win Pin; Son, Sungmin; Fletcher, Daniel A.] Univ Calif Berkeley, Dept Bioengn, Berkeley, CA 94720 USA. [Zhang, Guofeng] Natl Inst Biomed Imaging & Bioengn, Lab Bioengn & Phys Sci, NIH, Bethesda, MD 20892 USA. RP Chen, EH (reprint author), Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA. EM echen@jhmi.edu FU NIH [R01AR053173, R01GM098816, R01GM66817]; National Science Foundation; Muscular Dystrophy Association FX We thank Drs. S. Abmayr, K. Jagla, D. Kiehart, S. Menon, B. Paterson, M. Ruiz-Gomez, R. Ward, J. Zallen, and the Bloomington Stock Center for antibodies and fly stocks; Dr. J. Nathans for access to LSM 700; Dr. J. S. Kim and members of the E.H.C. laboratory for helpful discussions; and Drs. J. Nathans, D. Pan, and G. Seydoux for comments on the manuscript. This work was supported by grants from the NIH (R01AR053173 and R01GM098816 to E.H.C.; R01GM66817 to D.N.R.), the National Science Foundation (D.A.F.), and the Muscular Dystrophy Association (E.H.C.). NR 61 TC 25 Z9 25 U1 2 U2 16 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 MAR 9 PY 2015 VL 32 IS 5 BP 561 EP 573 DI 10.1016/j.devcel.2015.01.005 PG 13 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA CD3OY UT WOS:000350989300006 PM 25684354 ER PT J AU Kumar, A Shiloach, J Betenbaugh, MJ Gallagher, EJ AF Kumar, Amit Shiloach, Joseph Betenbaugh, Michael J. Gallagher, Emily J. TI The beta-3 adrenergic agonist (CL-316,243) restores the expression of down-regulated fatty acid oxidation genes in type 2 diabetic mice SO NUTRITION & METABOLISM LA English DT Article DE Type 2 diabetes; Fatty acid oxidation; Microarray analysis ID HUMAN SKELETAL-MUSCLE; WHITE ADIPOSE-TISSUE; ACYL-COA OXIDASE; INSULIN-RESISTANCE; RAT-LIVER; WEIGHT-LOSS; MKR MICE; SUBSTRATE SPECIFICITIES; CELL DYSFUNCTION; TRANSGENIC MODEL AB Background: The hallmark of Type 2 diabetes (T2D) is hyperglycemia, although there are multiple other metabolic abnormalities that occur with T2D, including insulin resistance and dyslipidemia. To advance T2D prevention and develop targeted therapies for its treatment, a greater understanding of the alterations in metabolic tissues associated with T2D is necessary. The aim of this study was to use microarray analysis of gene expression in metabolic tissues from a mouse model of pre-diabetes and T2D to further understand the metabolic abnormalities that may contribute to T2D. We also aimed to uncover the novel genes and pathways regulated by the insulin sensitizing agent (CL-316,243) to identify key pathways and target genes in metabolic tissues that can reverse the diabetic phenotype. Methods: Male MKR mice on an FVB/n background and age matched wild-type (WT) FVB/n mice were used in all experiments. Skeletal muscle, liver and fat were isolated from prediabetic (3 week old) and diabetic (8 week old) MKR mice. Male MKR mice were treated with CL-316,243. Skeletal muscle, liver and fat were isolated after the treatment period. RNA was isolated from the metabolic tissues and subjected to microarray and KEGG database analysis. Results: Significant decreases in the expression of mitochondrial and peroxisomal fatty acid oxidation genes were found in the skeletal muscle and adipose tissue of adult MKR mice, and the liver of pre-diabetic MKR mice, compared to WT controls. After treatment with CL-316,243, the circulating glucose and insulin concentrations in the MKR mice improved, an increase in the expression of peroxisomal fatty acid oxidation genes was observed in addition to a decrease in the expression of retinaldehyde dehydrogenases. These genes were not previously known to be regulated by CL-316,243 treatment. Conclusions: This study uncovers novel genes that may contribute to pharmacological reversal of insulin resistance and T2D and may be targets for treatment. In addition, it explains the lower free fatty acid levels in MKR mice after treatment with CL-316,243 and furthermore, it provides biomarker genes such as ACAA1 and HSD17b4 which could be further probed in a future study. C1 [Kumar, Amit; Shiloach, Joseph] NIDDK, Biotechnol Core Lab, NIH, Bethesda, MD 20892 USA. [Kumar, Amit; Betenbaugh, Michael J.] Johns Hopkins Univ, Dept Chem & Biomol Engn, Baltimore, MD 21218 USA. [Gallagher, Emily J.] Icahn Sch Med Mt Sinai, Div Endocrinol Diabet & Bone Dis, New York, NY 10029 USA. RP Gallagher, EJ (reprint author), Icahn Sch Med Mt Sinai, Div Endocrinol Diabet & Bone Dis, One Gustave L Levy Pl,Box 1055, New York, NY 10029 USA. EM Emily.Gallagher@mssm.edu FU Intramural program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; National Cancer Institute [1K08CA190770-01] FX Funding for the study was provided by the Intramural program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. This work was also funded in part by the National Cancer Institute grant 1K08CA190770-01 to EJG. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 70 TC 1 Z9 1 U1 4 U2 12 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1743-7075 J9 NUTR METAB JI Nutr. Metab. PD MAR 8 PY 2015 VL 12 AR 8 DI 10.1186/s12986-015-0003-8 PG 14 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CD5IZ UT WOS:000351122500001 PM 25784953 ER PT J AU Albert, JS Bhattacharyya, N Wolfe, LA Bone, WP Maduro, V Accardi, J Adams, DR Schwartz, CE Norris, J Wood, T Gafni, RI Collins, MT Tosi, LL Markello, TC Gahl, WA Boerkoel, CF AF Albert, Jessica S. Bhattacharyya, Nisan Wolfe, Lynne A. Bone, William P. Maduro, Valerie Accardi, John Adams, David R. Schwartz, Charles E. Norris, Joy Wood, Tim Gafni, Rachel I. Collins, Michael T. Tosi, Laura L. Markello, Thomas C. Gahl, William A. Boerkoel, Cornelius F. TI Impaired osteoblast and osteoclast function characterize the osteoporosis of Snyder - Robinson syndrome SO ORPHANET JOURNAL OF RARE DISEASES LA English DT Article DE Spermine; Snyder-Robinson syndrome; Osteoblast; Osteoclast; Osteoporosis ID SYMPATHETIC-NERVOUS-SYSTEM; LINKED MENTAL-RETARDATION; AMINO-ACID SUBSTITUTIONS; AFFECT PROTEIN FUNCTION; SPERMINE SYNTHASE; BONE MASS; MISSENSE MUTATION; POLYAMINES; DENSITY; CELLS AB Background: Snyder-Robinson Syndrome (SRS) is an X-linked intellectual disability disorder also characterized by osteoporosis, scoliosis, and dysmorphic facial features. It is caused by mutations in SMS, a ubiquitously expressed gene encoding the polyamine biosynthetic enzyme spermine synthase. We hypothesized that the tissue specificity of SRS arises from differential sensitivity to spermidine toxicity or spermine deficiency. Methods: We performed detailed clinical, endocrine, histopathologic, and morphometric studies on two affected brothers with a spermine synthase loss of function mutation (NM_004595.4:c.443A > G, p.Gln148Arg). We also measured spermine and spermidine levels in cultured human bone marrow stromal cells (hBMSCs) and fibroblasts using the Biochrom 30 polyamine protocol and assessed the osteogenic potential of hBMSCs. Results: In addition to the known tissue-specific features of SRS, the propositi manifested retinal pigmentary changes, recurrent episodes of hyper-and hypoglycemia, nephrocalcinosis, renal cysts, and frequent respiratory infections. Bone histopathology and morphometry identified a profound depletion of osteoblasts and osteoclasts, absence of a trabecular meshwork, a low bone volume and a thin cortex. Comparison of cultured fibroblasts from affected and unaffected individuals showed relatively small changes in polyamine content, whereas comparison of cultured osteoblasts identified marked differences in spermidine and spermine content. Osteogenic differentiation of the SRS-derived hBMSCs identified a severe deficiency of calcium phosphate mineralization. Conclusions: Our findings support the hypothesis that cell specific alterations in polyamine metabolism contribute to the tissue specificity of SRS features, and that the low bone density arises from a failure of mineralization. C1 [Albert, Jessica S.; Wolfe, Lynne A.; Bone, William P.; Maduro, Valerie; Accardi, John; Adams, David R.; Markello, Thomas C.; Gahl, William A.; Boerkoel, Cornelius F.] NIH, Undiagnosed Dis Program, Common Fund, Off Director, Bethesda, MD 20814 USA. [Albert, Jessica S.; Wolfe, Lynne A.; Adams, David R.; Markello, Thomas C.; Gahl, William A.] NHGRI, Med Genet Branch, Bethesda, MD 20892 USA. [Bhattacharyya, Nisan; Norris, Joy; Gafni, Rachel I.; Collins, Michael T.] Natl Inst Dent & Craniofacial Res, Skeletal Clin Studies Unit, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. [Schwartz, Charles E.; Wood, Tim] Greenwood Genet Ctr, JC Self Res Inst, Greenwood, SC 29646 USA. [Tosi, Laura L.] George Washington Univ, Sch Med, Washington, DC USA. [Tosi, Laura L.] Childrens Natl Med Ctr, Washington, DC 20010 USA. RP Gahl, WA (reprint author), NIH, Undiagnosed Dis Program, Common Fund, Off Director, Bethesda, MD 20814 USA. EM gahlw@helix.nih.gov FU Intramural Research Programs of the National Human Genome Research Institute; National Institute of Dental and Craniofacial Research; Common Fund of the NIH Office of the Director, National Institutes of Health; NINDS [NS073854]; South Carolina Department of Disabilities and Special Needs (SCDDSN) FX We thank Drs. Paul Lee, May Christine Malicdan and Grace Zhai for critical review of the manuscript. We would like to thank Dr. Edward McCarthy at The Johns Hopkins School of Medicine for performing the bone histomorphometry, Dr. Camilo Toro for imaging interpretations and Shira Ziegler for technical guidance for the alkaline phosphatase assay. This work was supported by the Intramural Research Programs of the National Human Genome Research Institute and National Institute of Dental and Craniofacial Research and the Common Fund of the NIH Office of the Director, National Institutes of Health. This work as also supported by extramural funding from NINDS (NS073854) and South Carolina Department of Disabilities and Special Needs (SCDDSN). NR 57 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 1750-1172 J9 ORPHANET J RARE DIS JI Orphanet J. Rare Dis. PD MAR 7 PY 2015 VL 10 AR 27 DI 10.1186/s13023-015-0235-8 PG 13 WC Genetics & Heredity; Medicine, Research & Experimental SC Genetics & Heredity; Research & Experimental Medicine GA DD3QR UT WOS:000369838200001 PM 25888122 ER PT J AU Baratz, R Tweedie, D Wang, JY Rubovitch, V Luo, WM Hoffer, BJ Greig, NH Pick, CG AF Baratz, Renana Tweedie, David Wang, Jia-Yi Rubovitch, Vardit Luo, Weiming Hoffer, Barry J. Greig, Nigel H. Pick, Chaim G. TI Transiently lowering tumor necrosis factor-alpha synthesis ameliorates neuronal cell loss and cognitive impairments induced by minimal traumatic brain injury in mice SO JOURNAL OF NEUROINFLAMMATION LA English DT Article ID CLOSED-HEAD INJURY; SIGNAL-TRANSDUCTION PATHWAYS; CONTROLLED CORTICAL IMPACT; TNF-ALPHA; SYNTHESIS INHIBITOR; ALZHEIMERS-DISEASE; FACTOR RECEPTORS; DENTATE GYRUS; NEURODEGENERATIVE DISEASE; HIPPOCAMPAL NEUROGENESIS AB Background: The treatment of traumatic brain injury (TBI) represents an unmet medical need, as no effective pharmacological treatment currently exists. The development of such a treatment requires a fundamental understanding of the pathophysiological mechanisms that underpin the sequelae resulting from TBI, particularly the ensuing neuronal cell death and cognitive impairments. Tumor necrosis factor-alpha (TNF-alpha) is a cytokine that is a master regulator of systemic and neuroinflammatory processes. TNF-alpha levels are reported to become rapidly elevated post TBI and, potentially, can lead to secondary neuronal damage. Methods: To elucidate the role of TNF-alpha in TBI, particularly as a drug target, the present study evaluated (i) time-dependent TNF-alpha levels and (ii) markers of apoptosis and gliosis within the brain and related these to behavioral measures of 'well being' and cognition in a mouse closed head 50 g weight drop mild TBI (mTBI) model in the presence and absence of post-treatment with an experimental TNF-alpha synthesis inhibitor, 3,6'-dithiothalidomide. Results: mTBI elevated brain TNF-alpha levels, which peaked at 12 h post injury and returned to baseline by 18 h. This was accompanied by a neuronal loss and an increase in astrocyte number (evaluated by neuronal nuclei (NeuN) and glial fibrillary acidic protein (GFAP) immunostaining), as well as an elevation in the apoptotic death marker BH3-interacting domain death agonist (BID) at 72 h. Selective impairments in measures of cognition, evaluated by novel object recognition and passive avoidance paradigms - without changes in well being, were evident at 7 days after injury. A single systemic treatment with the TNF-alpha synthesis inhibitor 3,6'-dithiothalidomide 1 h post injury prevented the mTBI-induced TNF-alpha elevation and fully ameliorated the neuronal loss (NeuN), elevations in astrocyte number (GFAP) and BID, and cognitive impairments. Cognitive impairments evident at 7 days after injury were prevented by treatment as late as 12 h post mTBI but were not reversed when treatment was delayed until 18 h. Conclusions: These results implicate that TNF-alpha in mTBI induced secondary brain damage and indicate that pharmacologically limiting the generation of TNF-alpha post mTBI may mitigate such damage, defining a time-dependent window of up to 12 h to achieve this reversal. C1 [Baratz, Renana; Rubovitch, Vardit; Pick, Chaim G.] Tel Aviv Univ, Sackler Sch Med, Dept Anat & Anthropol, IL-69978 Tel Aviv, Israel. [Tweedie, David; Luo, Weiming; Greig, Nigel H.] NIA, Drug Design & Dev Sect, Translat Gerontol Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Wang, Jia-Yi] Taipei Med Univ, Coll Med, Grad Inst Med Sci, Taipei, Taiwan. [Hoffer, Barry J.] Case Western Reserve Univ, Sch Med, Dept Neurosurg, Cleveland, OH USA. RP Greig, NH (reprint author), NIA, Drug Design & Dev Sect, Translat Gerontol Branch, Intramural Res Program,NIH, BRC Room 05C220,251 Bayview Blvd, Baltimore, MD 21224 USA. EM greign@grc.nia.nih.gov FU Intramural Research Program, National Institute on Aging, NIH, Baltimore, USA; Tel-Aviv University, Tel-Aviv, Israel; Ministry of Science and Technology, Taiwan [MOST103-2321-B-038-002] FX This study was supported in part by the Intramural Research Program, National Institute on Aging, NIH, Baltimore, USA; by Tel-Aviv University, Tel-Aviv, Israel; and by a grant from the Ministry of Science and Technology, Taiwan (MOST103-2321-B-038-002 to JY Wang). None of the authors have any competing interests in the manuscript. NR 103 TC 22 Z9 22 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-2094 J9 J NEUROINFLAMM JI J. Neuroinflamm. PD MAR 7 PY 2015 VL 12 AR 45 DI 10.1186/s12974-015-0237-4 PG 14 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA CD3FQ UT WOS:000350963800001 PM 25879458 ER PT J AU Ghitza, UE AF Ghitza, Udi E. TI Needed relapse-prevention research on novel framework (ASPIRE model) for substance use disorders treatment SO FRONTIERS IN PSYCHIATRY LA English DT Editorial Material DE addictive disorders; drug abuse; substance abuse; addiction; addiction treatment; drug abuse treatment; precision medicine ID COCAINE-DEPENDENT INDIVIDUALS; SHARED DECISION-MAKING; N-ACETYLCYSTEINE; CLINICAL-PRACTICE; DOUBLE-BLIND; CANNABIS USE; GUANFACINE; ABSTINENCE; WITHDRAWAL; DISEASE C1 NIDA, Ctr Clin Trials Network, NIH, Bethesda, MD 20892 USA. RP Ghitza, UE (reprint author), NIDA, Ctr Clin Trials Network, NIH, Bethesda, MD 20892 USA. EM ghitzau@nida.nih.gov NR 30 TC 5 Z9 5 U1 0 U2 0 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-0640 J9 FRONT PSYCHIATRY JI Front. Psychiatry PD MAR 6 PY 2015 VL 6 AR 37 DI 10.3389/fpsyt.2015.00037 PG 4 WC Psychiatry SC Psychiatry GA CV4AO UT WOS:000364208000001 PM 25798112 ER PT J AU Morris, SE Pitzer, VE Viboud, C Metcalf, CJE Bjornstad, ON Grenfell, BT AF Morris, Sinead E. Pitzer, Virginia E. Viboud, Cecile Metcalf, C. Jessica E. Bjornstad, Ottar N. Grenfell, Bryan T. TI Demographic buffering: titrating the effects of birth rate and imperfect immunity on epidemic dynamics SO JOURNAL OF THE ROYAL SOCIETY INTERFACE LA English DT Article DE partial immunity; susceptible-infected-recovered-susceptible; acute infection; demography; birth rate; epidemiology ID RESPIRATORY-SYNCYTIAL-VIRUS; INFECTIOUS-DISEASES; ROTAVIRUS INFECTION; YOUNG-CHILDREN; TIME-SERIES; TRANSMISSION DYNAMICS; DEVELOPING-COUNTRIES; POPULATION BIOLOGY; MEASLES EPIDEMICS; ANTIGENIC DRIFT AB Host demography can alter the dynamics of infectious disease. In the case of perfectly immunizing infections, observations of strong sensitivity to demographic variation have been mechanistically explained through analysis of the susceptible-infected-recovered (SIR) model that assumes lifelong immunity following recovery from infection. When imperfect immunity is incorporated into this framework via the susceptible-infected-recovered-susceptible (SIRS) model, with individuals regaining full susceptibility following recovery, we show that rapid loss of immunity is predicted to buffer populations against the effects of demographic change. However, this buffering is contrary to the dependence on demography recently observed for partially immunizing infections such as rotavirus and respiratory syncytial virus. We show that this discrepancy arises from a key simplification embedded in the SIR(S) framework, namely that the potential for differential immune responses to repeat exposures is ignored. We explore the minimum additional immunological information that must be included to reflect the range of observed dependencies on demography. We show that including partial protection and lower transmission following primary infection is sufficient to capture more realistic reduced levels of buffering, in addition to changes in epidemic timing, across a range of partially and fully immunizing infections. Furthermore, our results identify key variables in this relationship, including R-0. C1 [Morris, Sinead E.; Metcalf, C. Jessica E.; Grenfell, Bryan T.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Pitzer, Virginia E.] Yale Univ, Sch Publ Hlth, Dept Epidemiol Microbial Dis, New Haven, CT USA. [Pitzer, Virginia E.; Viboud, Cecile; Metcalf, C. Jessica E.; Bjornstad, Ottar N.; Grenfell, Bryan T.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Bjornstad, Ottar N.] Penn State Univ, Dept Entomol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Bjornstad, Ottar N.] Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. RP Morris, SE (reprint author), Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. EM semorris@princeton.edu OI Pitzer, Virginia/0000-0003-1015-2289 FU US Department of Homeland Security [HSHQDC-12-C-00058]; Bill and Melinda Gates Foundation FX C.J.E.M. and B.T.G. were supported by funding from the US Department of Homeland Security contract HSHQDC-12-C-00058. V.E.P., C.J.E.M., O.N.B. and B.T.G. were funded by the Bill and Melinda Gates Foundation. NR 67 TC 4 Z9 4 U1 1 U2 10 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 MAR 6 PY 2015 VL 12 IS 104 AR 20141245 DI 10.1098/rsif.2014.1245 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CD6VC UT WOS:000351227000024 PM 25589567 ER PT J AU Iyer, MR Rothman, RB Dersch, CM Jacobson, AE Rice, KC AF Iyer, Malliga R. Rothman, Richard B. Dersch, Christina M. Jacobson, Arthur E. Rice, Kenner C. TI Probes for narcotic receptor mediated phenomena 49. N-substituted rac-cis-4a-arylalkyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ol s SO EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article DE Synthesis; cis-4a-arylalkyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ols; Opioid receptors; [S-35]GTP-gamma-S efficacy assays; mu-and delta-receptor antagonists ID OXIDE-BRIDGED PHENYLMORPHANS; AFFINITY; DEPENDENCE; TOLERANCE; EFFICACY; LIGANDS AB Racemic N-substituted -1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ols containing cis-4a-aralkyl groups were explored as probes for opioid receptors. Specifically cis-4a-phenylpropyl, -phenylbutyl, and -phenylpentyl groups coupled with widely varied substituents on the nitrogen atom were synthesized and their pharmacological profiles at opioid receptors examined. The study yielded compounds with good affinity and moderate to potent antagonist activity at the mu- and delta-opioid receptors, and agonist activity at the kappa-opioid receptor. An N-allyl substituent in the C4a phenylpropyl series induced 6-fold higher affinity at delta-than mu-receptors, while an N-CPM substituent in the C4a (CH2)(3)Ph series led to a compound with high delta-affinity and potent delta-antagonist activity. Published by Elsevier Masson SAS. C1 [Iyer, Malliga R.; Jacobson, Arthur E.; Rice, Kenner C.] NIDA, Drug Design & Synth Sect, Mol Targets & Medicat Discovery Branch, Intramural Res Program,Dept Hlth & Human Serv,NIH, Bethesda, MD 20892 USA. [Iyer, Malliga R.; Jacobson, Arthur E.; Rice, Kenner C.] NIAAA, Intramural Res Program, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. [Rothman, Richard B.; Dersch, Christina M.] NIDA, Med Chem Sect, Intramural Res Program, Dept Hlth & Human Serv,NIH, Baltimore, MD 21224 USA. RP Rice, KC (reprint author), NIDA, Drug Design & Synth Sect, Mol Targets & Medicat Discovery Branch, Intramural Res Program,Dept Hlth & Human Serv,NIH, 9800 Med Ctr Dr, Bethesda, MD 20892 USA. EM kennerr@mail.nih.gov FU NIH Intramural Research Program of the National Institute on Drug Abuse (NIDA); NIH Intramural Research Program of the National Institute of Alcohol Abuse and Alcoholism FX The work of the Drug Design and Synthesis Section, was supported by the NIH Intramural Research Programs of the National Institute on Drug Abuse (NIDA) and the National Institute of Alcohol Abuse and Alcoholism. The Clinical Psychopharmacology Section, CBRB, NIDA, was supported by the NIH Intramural Research Program of the National Institute on Drug Abuse (NIDA). We also thank Dr. Klaus Gawrisch and Dr. Walter Teague (Laboratory of Membrane Biochemistry and Biophysics, NIAAA, for NMR spectral data. The authors express their thanks to Noel Whittaker, Mass Spectrometry Facility, NIDDK, for mass spectral data. NR 17 TC 1 Z9 1 U1 0 U2 3 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 MAR 6 PY 2015 VL 92 BP 531 EP 539 DI 10.1016/j.ejmech.2015.01.025 PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA CD2OO UT WOS:000350919100043 PM 25599950 ER PT J AU Ueyama, T Sakuma, M Ninoyu, Y Hamada, T Dupuy, C Geiszt, M Leto, TL Saito, N AF Ueyama, Takehiko Sakuma, Megumi Ninoyu, Yuzuru Hamada, Takeshi Dupuy, Corinne Geiszt, Miklos Leto, Thomas L. Saito, Naoaki TI The Extracellular A-loop of Dual Oxidases Affects the Specificity of Reactive Oxygen Species Release SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FAMILY NADPH OXIDASES; HYDROGEN-PEROXIDE; CONGENITAL HYPOTHYROIDISM; HOST-DEFENSE; CLONING; GENE; EVOLUTION; ACTIVATION; EXPRESSION; DOMAIN AB NADPH oxidase (Nox) family proteins produce superoxide (W) directly by transferring an electron to molecular oxygen. Dual oxidases (Duoxes) also produce an W intermediate, although the final species secreted by mature Duoxes is H2O2, suggesting that intramolecular O-2(center dot)-, dismutation or other mechanisms contribute to H2O2 release. We explored the structural determinants affecting reactive oxygen species formation by Duox enzymes. Duox2 showed O-2(center dot)-, leakage when mismatched with Duox activator 1 (DuoxA1). Duox2 released O-2(center dot)- even in correctly matched combinations, including Duox2 + DuoxA2 and Duox2 + N-terminally tagged DuoxA2 regardless of the type or number of tags. Conversely, Duox1 did not release O-2(center dot)-, in any combination. Chimeric Duox2 possessing the A-loop of Duoxl showed no W. leakage; chimeric Duoxl possessing the A-loop of Duox2 released W. Moreover, Duox2 proteins possessing the A-loops of Noxl or Nox5 co-expressed with DuoxA2 showed enhanced W release, and D uox1 proteins possessing the A-loops of Noxl or Nox5 co-expressed with DuoxAl acquired W leakage. Although we identified Duoxl A-loop residues His(1071), His(1072), and Gly(1074)) important for reducing O-2(center dot)- release, mutations of these residues to those of Duox2 failed to convert Duoxl to an O-2(center dot)--releasing enzyme. Using immunoprecipitation and endoglycosidase H sensitivity assays, we found that the A-loop of Duoxes binds to DuoxA N termini, creating more stable, mature Duox-DuoxA complexes. In conclusion, the A-loops of both Duoxes support H2O2 production through interaction with corresponding activators, but complex formation between the Duoxl A-loop and DuoxAl results in tighter control of H2O2 release by the enzyme complex. C1 [Ueyama, Takehiko; Sakuma, Megumi; Ninoyu, Yuzuru; Hamada, Takeshi; Saito, Naoaki] Kobe Univ, Biosignal Res Ctr, Lab Mol Pharmacol, Kobe, Hyogo 6578501, Japan. [Dupuy, Corinne] Univ Paris 11, CNRS, Inst Gustave Roussy, Lab Stabilite Genet & Oncogenese,UMR8200, F-94805 Villejuif, France. [Geiszt, Miklos] Semmelweis Univ, Dept Physiol, Fac Med, H-1444 Budapest, Hungary. [Geiszt, Miklos] Semmelweis Univ, Lendulet Peroxidase Enzyme Res Grp, H-1444 Budapest, Hungary. [Geiszt, Miklos] Hungarian Acad Sci, H-1444 Budapest, Hungary. [Leto, Thomas L.] NIAID, Mol Def Sect, Lab Host Def, NIH, Rockville, MD 20852 USA. RP Ueyama, T (reprint author), Kobe Univ, Biosignal Res Ctr, Lab Mol Pharmacol, Nada Ku, 1-1 Rokkodai Cho, Kobe, Hyogo 6578501, Japan. EM tueyama@kobe-u.ac.jp; naosaito@kobe-u.ac.jp FU Intramural Research Program of the NIAID, National Institutes of Health; Ministry of Education, Culture, Sports, Science and Technology, Japan; Japan Society for the Promotion of Science; Hungarian Academy of Sciences; Uehara Memorial Foundation; Hyogo Science and Technology Association FX This work was supported, in whole or in part, by the Intramural Research Program of the NIAID, National Institutes of Health. This work was also supported in part by a grant-in-aid for Scientific Research (C) of the Ministry of Education, Culture, Sports, Science and Technology, Japan, by a grant "Japan-Hungary Research Cooperative Program" from the Japan Society for the Promotion of Science and the Hungarian Academy of Sciences, by the Uehara Memorial Foundation, and by the Hyogo Science and Technology Association. NR 33 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 MAR 6 PY 2015 VL 290 IS 10 BP 6495 EP 6506 DI 10.1074/jbc.M114.592717 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CD0AO UT WOS:000350732500052 PM 25586178 ER PT J AU Williams, AS Kang, L Zheng, J Grueter, C Bracy, DP James, FD Pozzi, A Wasserman, DH AF Williams, Ashley S. Kang, Li Zheng, Jenny Grueter, Carrie Bracy, Deanna P. James, Freyja D. Pozzi, Ambra Wasserman, David H. TI Integrin alpha 1-null Mice Exhibit Improved Fatty Liver When Fed a High Fat Diet Despite Severe Hepatic Insulin Resistance SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FOCAL ADHESION KINASE; ENDOGENOUS GLUCOSE-PRODUCTION; TYROSINE-PHOSPHATASE; GENE-EXPRESSION; NONALCOHOLIC STEATOHEPATITIS; EXTRACELLULAR-MATRIX; RECEPTOR SUBSTRATE-1; DIABETES-MELLITUS; CROSS-TALK; DISEASE AB Hepatic insulin resistance is associated with increased collagen. Integrin alpha 1 beta 1 is a collagen-binding receptor expressed on hepatocytes. Here, we show that expression of the alpha 1 subunit is increased in hepatocytes isolated from high fat (HF)-fed mice. To determine whether the integrin al subunit protects against impairments in hepatic glucose metabolism, we analyzed glucose tolerance and insulin sensitivity in Ft-F.-fed integrin alpha 1-null (itgal(-/-)) and wild-type (itga1(+/+)) littermates. Using the insulin clamp, we found that insulin-stimulated hepatic glucose production was suppressed by similar to 50% in HF-fed itgal(+/+) mice. In contrast, it was not suppressed in HF-fed itga1(-/-) mice, indicating severe hepatic insulin resistance. This was associated with decreased hepatic insulin signaling in FIF-fed itgal(-/-) mice. Interestingly, hepatic triglyceride and diglyceride contents were normalized to chow-fed levels in FIF-fed itgal(-/-) mice. This indicates that hepatic steatosis is dissociated from insulin resistance in FIF-fed itgal(-/-) mice. The decrease in hepatic lipid accumulation in HF-fed itgal-1- mice was associated with altered free fatty acid metabolism. These studies establish a role for integrin signaling in facilitating hepatic insulin action while promoting lipid accumulation in mice challenged with a HF diet. C1 [Williams, Ashley S.; Kang, Li; Zheng, Jenny; Bracy, Deanna P.; James, Freyja D.; Pozzi, Ambra; Wasserman, David H.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. [Grueter, Carrie] Vanderbilt Univ, Dept Anesthesiol, Nashville, TN 37232 USA. [Pozzi, Ambra] Vanderbilt Univ, Div Nephrol, Dept Med, Nashville, TN 37232 USA. [Wasserman, David H.] Vanderbilt Univ, Mouse Metab Phenotyping Ctr, Nashville, TN 37232 USA. [Pozzi, Ambra] Dept Vet Affairs, Dept Med, Nashville, TN 37212 USA. RP Williams, AS (reprint author), Vanderbilt Univ, Dept Mol Physiol & Biophys, 823 Light Hall,2215 Garland Ave, Nashville, TN 37232 USA. EM ashley.s.williams@vanderbilt.edu OI Grueter, Carrie/0000-0002-1913-2527 FU National Institutes of Health [R37 DK050277, R01 DK054902, U24 DK059637, R01 DK095761, DK20593]; Veterans Affairs Merit Review [1I01BX002025-01]; Vanderbilt Molecular Endocrinology Training Program FX This work was supported, in whole or in part, by National Institutes of Health Grants R37 DK050277, R01 DK054902, and U24 DK059637 (to D. H. W.); Grant R01 DK095761 (to A. P.); and Grant DK20593 (to the Vanderbilt Diabetes Research and Training Center). This work was also supported by Veterans Affairs Merit Review 1I01BX002025-01 (to A. P.) and the Vanderbilt Molecular Endocrinology Training Program. NR 55 TC 6 Z9 7 U1 1 U2 2 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 MAR 6 PY 2015 VL 290 IS 10 BP 6546 EP 6557 DI 10.1074/jbc.M114.615716 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CD0AO UT WOS:000350732500057 PM 25593319 ER PT J AU Moayeri, M Leysath, CE Tremblay, JM Vrentas, C Crown, D Leppla, SH Shoemaker, CB AF Moayeri, Mahtab Leysath, Clinton E. Tremblay, Jacqueline M. Vrentas, Catherine Crown, Devorah Leppla, Stephen H. Shoemaker, Charles B. TI A Heterodimer of a VHH (Variable Domains of Camelid Heavy Chain-only) Antibody That Inhibits Anthrax Toxin Cell Binding Linked to a VHH Antibody That Blocks Oligomer Formation Is Highly Protective in an Anthrax Spore Challenge Model SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID LETHAL FACTOR; MONOCLONAL-ANTIBODIES; ANTIGEN; MICE; NANOBODIES; CLEARANCE; LIBRARIES; AFFINITY; RECEPTOR; AGENTS AB Anthrax disease is caused by a toxin consisting of protective antigen (PA), lethal factor, and edema factor. Antibodies against PA have been shown to be protective against the disease. Variable domains of camelid heavy chain-only antibodies (VHHs) with affinity for PA were obtained from immunized alpacas and screened for anthrax neutralizing activity in macrophage toxicity assays. Two classes of neutralizing VHHs were identified recognizing distinct, non-overlapping epitopes. One class recognizes domain 4 of PA at a well characterized neutralizing site through which PA binds to its cellular receptor. A second neutralizing VHH (JKH-C7) recognizes a novel epitope. This antibody inhibits conversion of the PA oligomer from "pre-pore" to its SDS and heat-resistant "pore" conformation while not preventing cleavage of full-length 83-kDa PA (PA83) by cell surface proteases to its oligomer-competent 63-kDa form (PA63). The antibody prevents endocytosis of the cell surface-generated PA63 subunit but not preformed PA63 oligomers formed in solution. JKH-C7 and the receptor-blocking VHH class (JIK-B8) were expressed as a heterodimeric VHH-based neutralizing agent (VNA2-PA). This VNA displayed improved neutralizing potency in cell assays and protected mice from anthrax toxin challenge with much better efficacy than the separate component VHHs. The VNA protected virtually all mice when separately administered at a 1:1 ratio to toxin and protected mice against Bacillus anthracis spore infection. Thus, our studies show the potential of VNAs as anthrax therapeutics. Due to their simple and stable nature, VNAs should be amenable to genetic delivery or administration via respiratory routes. C1 [Moayeri, Mahtab; Leysath, Clinton E.; Vrentas, Catherine; Crown, Devorah; Leppla, Stephen H.] Tufts Univ, Dept Infect Dis & Global Hlth, Cummings Sch Vet Med, North Grafton, MA 01536 USA. [Tremblay, Jacqueline M.; Shoemaker, Charles B.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Shoemaker, CB (reprint author), Tufts Univ, Dept Infect Dis & Global Hlth, Cummings Sch Vet Med, 200 Westboro Rd, North Grafton, MA 01536 USA. EM charles.shoemaker@tufts.edu FU National Institutes of Health [U54 AI057159]; Intramural Research Program of the National Institutes of Health (NIAID) FX This work was supported, in whole or in part, by National Institutes of Health Grant U54 AI057159 (NIAID) and by the Intramural Research Program of the National Institutes of Health (NIAID). NR 42 TC 6 Z9 6 U1 2 U2 16 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 MAR 6 PY 2015 VL 290 IS 10 BP 6584 EP 6595 DI 10.1074/jbc.M114.627943 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CD0AO UT WOS:000350732500060 PM 25564615 ER PT J AU Nasrollahzadeh, D Malekzadeh, R Ploner, A Shakeri, R Sotoudeh, M Fahimi, S Nasseri-Moghaddam, S Kamangar, F Abnet, CC Winckler, B Islami, F Boffetta, P Brennan, P Dawsey, SM Ye, WM AF Nasrollahzadeh, Dariush Malekzadeh, Reza Ploner, Alexander Shakeri, Ramin Sotoudeh, Masoud Fahimi, Saman Nasseri-Moghaddam, Siavosh Kamangar, Farin Abnet, Christian C. Winckler, Bjoern Islami, Farhad Boffetta, Paolo Brennan, Paul Dawsey, Sanford M. Ye, Weimin TI Variations of gastric corpus microbiota are associated with early esophageal squamous cell carcinoma and squamous dysplasia SO SCIENTIFIC REPORTS LA English DT Article ID HELICOBACTER-PYLORI INFECTION; 16S RIBOSOMAL-RNA; INCREASED RISK; BACTERIAL MICROBIOTA; GUT MICROBIOME; ORAL HYGIENE; CANCER; STOMACH; ATROPHY; IRAN AB Observational studies revealed a relationship between changes in gastric mucosa and risk of esophageal squamous cell carcinoma (ESCC) which suggested a possible role for gastric microbiota in ESCC carcinogenesis. In this study we aimed to compare pattern of gastric corpus microbiota in ESCC with normal esophagus. Cases were included subjects with early ESCC (stage I-II) and esophageal squamous dysplasia (ESD) as the cancer precursor. Control groups included age and sex-matched subjects with mid-esophagus esophagitis (diseased-control), and histologically normal esophagus (healthy-control). DNA was extracted from snap-frozen gastric corpus tissues and 16S rRNA was sequenced on GS-FLX Titanium. After noise removal, an average of 3004 reads per sample was obtained from 93 subjects. We applied principal coordinate analysis to ordinate distances from beta diversity data. Pattern of gastric microbiota using Unifrac (p = 0.004) and weighted Unifrac distances (p = 0.018) statistically varied between cases and healthy controls. Sequences were aligned to SILVA database and Clostridiales and Erysipelotrichales orders were more abundant among cases after controling for multiple testing (p = 0.011). No such difference was observed between mid-esophagitis and healthy controls. This study is the first to show that composition of gastric corpus mucosal microbiota differs in early ESCC and ESD from healthy esophagus. C1 [Nasrollahzadeh, Dariush; Ploner, Alexander; Winckler, Bjoern; Ye, Weimin] Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden. [Nasrollahzadeh, Dariush; Malekzadeh, Reza; Shakeri, Ramin; Sotoudeh, Masoud; Fahimi, Saman; Nasseri-Moghaddam, Siavosh; Islami, Farhad] Univ Tehran Med Sci, Digest Dis Res Inst, Digest Oncol Res Ctr, Tehran, Iran. [Kamangar, Farin] Morgan State Univ, Sch Community Hlth & Policy, Dept Publ Hlth Anal, Baltimore, MD 21239 USA. [Abnet, Christian C.; Dawsey, Sanford M.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Islami, Farhad; Boffetta, Paolo] Icahn Sch Med Mt Sinai, Inst Translat Epidemiol, New York, NY 10029 USA. [Islami, Farhad; Boffetta, Paolo] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA. [Brennan, Paul] Int Agcy Res Canc, F-69372 Lyon, France. RP Malekzadeh, R (reprint author), Univ Tehran Med Sci, Digest Dis Res Inst, Digest Oncol Res Ctr, Tehran, Iran. EM malek@ams.ac.ir; Weimin.Ye@ki.se RI Abnet, Christian/C-4111-2015; OI Abnet, Christian/0000-0002-3008-7843; , Ramin/0000-0003-0487-3629; Ploner, Alexander/0000-0002-5042-8326 FU Science for Life Laboratory; national infrastructure SNISS (Uppmax); Swedish Research Council [2008-3027]; Digestive Disease Research Center of Tehran University of Medical Sciences [82-603]; National Cancer Institute at the National Institutes of Health; Karolinska Institutet FX The authors would like to acknowledge support from Science for Life Laboratory, the national infrastructure SNISS (Uppmax), Daniel Lundin from BILS (Bioinformatics Infrastructure for Life Sciences) for providing assistance in massively parallel sequencing and computational infrastructure. This study was supported by a grant from Swedish Research Council (2008-3027). Field work and subject recruitment were supported by a grant from Digestive Disease Research Center of Tehran University of Medical Sciences (grant 82-603). Case-Control study received support from Intramural funds of the National Cancer Institute at the National Institutes of Health. D.N. was partially supported by KID-funding (Faculty funds for partial financing of doctoral student) from Karolinska Institutet. NR 44 TC 6 Z9 6 U1 3 U2 18 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 MAR 6 PY 2015 VL 5 AR 8820 DI 10.1038/srep08820 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CC6KL UT WOS:000350473700014 PM 25743945 ER PT J AU Andrecka, J Arroyo, JO Takagi, Y de Wit, G Fineberg, A MacKinnon, L Young, GV Sellers, JR Kukura, P AF Andrecka, Joanna Arroyo, Jaime Ortega Takagi, Yasuharu de Wit, Gabrielle Fineberg, Adam MacKinnon, Lachlan Young, Gavin Sellers, James R. Kukura, Philipp TI Structural dynamics of myosin 5 during processive motion revealed by interferometric scattering microscopy SO ELIFE LA English DT Article AB Myosin 5a is a dual-headed molecular motor that transports cargo along actin filaments. By following the motion of individual heads with interferometric scattering microscopy at nm spatial and ms temporal precision we found that the detached head occupies a loosely fixed position to one side of actin from which it rebinds actin in a controlled manner while executing a step. Improving the spatial precision to the sub-nm regime provided evidence for an angstrom-level structural transition in the motor domain associated with the power stroke. Simultaneous tracking of both heads revealed that consecutive steps follow identical paths to the same side of actin in a compass-like spinning motion demonstrating a symmetrical walking pattern. These results visualize many of the critical unknown aspects of the stepping mechanism of myosin 5 including head-head coordination, the origin of lever-arm motion and the spatiotemporal dynamics of the translocating head during individual steps. C1 [Andrecka, Joanna; Arroyo, Jaime Ortega; de Wit, Gabrielle; Fineberg, Adam; MacKinnon, Lachlan; Young, Gavin; Kukura, Philipp] NHLBI, Phys & Theoret Chem Lab, Dept Chem, NIH, Bethesda, MD 20892 USA. [Takagi, Yasuharu; Young, Gavin] NHLBI, Lab Mol Physiol, NIH, Bethesda, MD 20892 USA. RP Kukura, P (reprint author), NHLBI, Phys & Theoret Chem Lab, Dept Chem, NIH, Bldg 10, Bethesda, MD 20892 USA. EM philipp.kukura@chem.ox.ac.uk OI Kukura, Philipp/0000-0003-0136-7704 FU CONACyT [213546]; Marie Curie Fellowship [330215]; National Heart, Lung, and Blood Institute, National Institutes of Health [ZIA HL004229]; John Fell Fund, a career acceleration fellowship; EPSRC [EP/H003541]; ERC starting grant (Nano Scope) FX We would like to thank Dr. Attila Nagy for assistance on the myosin 5a construct design, Dr. Katelyn Spillane for initial assistance with the myosin construce and Dr. Christof Gebhardt for helpful discussions. J.O.A was supported by a scholarship from CONACyT (scholar: 213546), J.A. by a Marie Curie Fellowship (330215), J.R.S. by the intramural funds from the National Heart, Lung, and Blood Institute, National Institutes of Health (ZIA HL004229), and P.K. by the John Fell Fund, a career acceleration fellowship by the EPSRC (EP/H003541) and an ERC starting grant (Nano Scope). NR 1 TC 9 Z9 9 U1 2 U2 2 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD MAR 6 PY 2015 VL 4 AR e05413 DI 10.7554/eLife.05413 PG 43 WC Biology SC Life Sciences & Biomedicine - Other Topics GA CE5IE UT WOS:000351864100004 ER PT J AU Kathawala, RJ Wang, YJ Shukla, S Zhang, YK Alqahtani, S Kaddoumi, A Ambudkar, SV Ashby, CR Chen, ZS AF Kathawala, Rishil J. Wang, Yi-Jun Shukla, Suneet Zhang, Yun-Kai Alqahtani, Saeed Kaddoumi, Amal Ambudkar, Suresh V. Ashby, Charles R., Jr. Chen, Zhe-Sheng TI ATP-binding cassette subfamily B member 1 (ABCB1) and subfamily C member 10 (ABCC10) are not primary resistance factors for cabazitaxel SO CHINESE JOURNAL OF CANCER LA English DT Article DE ATP-binding cassette (ABC) transporters; ATP-binding cassette subfamily B member 1 (ABCB1); ATP-binding cassette subfamily C member 10 (ABCC10); Taxane; Paclitaxel; Cabazitaxel ID MULTIDRUG-RESISTANCE; P-GLYCOPROTEIN; PACLITAXEL RESISTANCE; MECHANISMS; TRANSPORT; EFFLUX; CANCER; DRUGS; MRP7 AB Introduction: ATP-binding cassette subfamily B member 1 (ABCB1) and subfamily C member 10 (ABCC10) proteins are efflux transporters that couple the energy derived from ATP hydrolysis to the translocation of toxic substances and chemotherapeutic drugs out of cells. Cabazitaxel is a novel taxane that differs from paclitaxel by its lower affinity for ATP-binding cassette (ABC) transporters. Methods: We determined the effects of cabazitaxel, a novel tubulin-binding taxane, and paclitaxel on paclitaxel-resistant, ABCB1-overexpressing KB-C2 and LLC-MDR1-WT cells and paclitaxel-resistant, ABCC10-overexpressing HEK293/ABCC10 cells by calculating the degree of drug resistance and measuring ATPase activity of the ABCB1 transporter. Results: Decreased resistance to cabazitaxel compared with paclitaxel was observed in KB-C2, LLC-MDR1-WT, and HEK293/ABCC10 cells. Moreover, cabazitaxel had low efficacy, whereas paclitaxel had high efficacy in stimulating the ATPase activity of ABCB1, indicating a direct interaction of both drugs with the transporter. Conclusion: ABCB1 and ABCC10 are not primary resistance factors for cabazitaxel compared with paclitaxel, suggesting that cabazitaxel may have a low affinity for these efflux transporters. C1 [Kathawala, Rishil J.; Wang, Yi-Jun; Zhang, Yun-Kai; Ashby, Charles R., Jr.; 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. [Alqahtani, Saeed; Kaddoumi, Amal] Univ Louisiana, Coll Pharm, Dept Basic Pharmaceut Sci, Monroe, LA 71209 USA. RP Ashby, CR (reprint author), St Johns Univ, Coll Pharm & Hlth Sci, Dept Pharmaceut Sci, Queens, NY 11439 USA. EM ashbyc@stjohns.edu; chenz@stjohns.edu RI Wang, Yi-Jun/K-3218-2016 FU National Institutes of Health [1R15CA143701]; St. John's University Research Seed Grant [579-1110-7002]; Intramural Research Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This work was supported by funds from the National Institutes of Health (1R15CA143701) and St. John's University Research Seed Grant (579-1110-7002) to Dr. Zhe-Sheng Chen. Drs. Suneet Shukla and Suresh V. Ambudkar were supported by the Intramural Research Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 26 TC 1 Z9 1 U1 1 U2 4 PU SUN YAT SEN UNIV MED SCI WHO PI GUANGZHOU PA 651 DONGFENG RD E, GUANGZHOU, GUANGDONG 510060, PEOPLES R CHINA SN 1000-467X EI 1944-446X J9 CHIN J CANCER JI Chin. J. Cancer PD MAR 5 PY 2015 VL 34 AR 5 DI 10.1186/s40880-015-0003-0 PG 6 WC Oncology SC Oncology GA CP9OQ UT WOS:000360224500005 ER PT J AU Iacovelli, S Hug, E Bennardo, S Duehren-von Minden, M Gobessi, S Rinaldi, A Suljagic, M Bilbao, D Bolasco, G Eckl-Dorna, J Niederberger, V Autore, F Sica, S Laurenti, L Wang, HS Cornall, RJ Clarke, SH Croce, CM Bertoni, F Jumaa, H Efremov, DG AF Iacovelli, Stefano Hug, Eva Bennardo, Sara Duehren-von Minden, Marcus Gobessi, Stefania Rinaldi, Andrea Suljagic, Mirza Bilbao, Daniel Bolasco, Giulia Eckl-Dorna, Julia Niederberger, Verena Autore, Francesco Sica, Simona Laurenti, Luca Wang, Hongsheng Cornall, Richard J. Clarke, Stephen H. Croce, Carlo M. Bertoni, Francesco Jumaa, Hassan Efremov, Dimitar G. TI Two types of BCR interactions are positively selected during leukemia development in the E mu-TCL1 transgenic mouse model of CLL SO BLOOD LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; B-CELL RECEPTOR; GENE MUTATION STATUS; HEAVY-CHAIN IIA; TYROSINE KINASE; APOPTOTIC CELLS; FOSTAMATINIB DISODIUM; DISEASE PROGRESSION; SIGNALING PATHWAYS; CD38 EXPRESSION AB Chronic lymphocytic leukemia (CLL) is a common B-cell malignancy characterized by a highly variable course and outcome. The disease is believed to be driven by B-cell receptor (BCR) signals generated by external antigens and/or cell-autonomous BCR interactions, but direct in vivo evidence for this is still lacking. To further define the role of the BCR pathway in the development and progression of CLL, we evaluated the capacity of different types of antigen/BCR interactions to induce leukemia in the E mu-TCL1 transgenic mouse model. We show that cell autonomous signaling capacity is a uniform characteristic of the leukemia-derived BCRs and represents a prerequisite for CLL development. Low-affinity BCR interactions with autoantigens generated during apoptosis are also positively selected, suggesting that they contribute to the pathogenesis of the disease. In contrast, high-affinity BCR interactions are not selected, regardless of antigen form or presentation. We also show that the capacity of the leukemic cells to respond to cognate antigen correlates inversely with time to leukemia development, suggesting that signals induced by external antigen increase the aggressiveness of the disease. Collectively, these findings provide in vivo evidence that the BCR pathway drives the development and can influence the clinical course of CLL. C1 [Iacovelli, Stefano; Bennardo, Sara; Gobessi, Stefania; Suljagic, Mirza; Efremov, Dimitar G.] Int Ctr Genet Engn & Biotechnol, Mol Hematol, Rome, Italy. [Hug, Eva; Duehren-von Minden, Marcus; Jumaa, Hassan] Max Planck Inst Immunobiol & Epigenet, Freiburg, Germany. [Rinaldi, Andrea; Bertoni, Francesco] IOR Inst Oncol Res, Lymphoma & Genom Res Program, Bellinzona, Switzerland. [Bilbao, Daniel; Bolasco, Giulia] European Mol Biol Lab, Rome, Italy. [Eckl-Dorna, Julia; Niederberger, Verena] Med Univ Vienna, Dept Otorhinolaryngol, Vienna, Austria. [Autore, Francesco; Sica, Simona; Laurenti, Luca] Catholic Univ Hosp A Gemelli, Dept Hematol, Rome, Italy. [Wang, Hongsheng] NIAID, Immunopathol Lab, NIH, Rockville, MD USA. [Cornall, Richard J.] Univ Oxford, Nuffield Dept Clin Med, Oxford, England. [Clarke, Stephen H.] Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill, NC USA. [Croce, Carlo M.] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Bertoni, Francesco] IOSI Oncol Inst Southern Switzerland, Bellinzona, Switzerland. [Jumaa, Hassan] Univ Clin Ulm, Inst Immunol, Ulm, Germany. RP Efremov, DG (reprint author), ICGEB, Mol Hematol Unit, CNR Campus Adriano Buzzati Traverso,Via E, I-00016 Rome, Italy. EM efremov@icgeb.org FU Italian Association for Cancer Research [AIRC IG_12939]; Leukemia & Lymphoma Society [R6170-10]; Nelia et Amadeo Barletta Foundation; Deutsche Krebshilfe [108935] FX This work was supported by grants from the Italian Association for Cancer Research (project AIRC IG_12939), the Leukemia & Lymphoma Society (project R6170-10), the Nelia et Amadeo Barletta Foundation, and the Deutsche Krebshilfe (project 108935). NR 60 TC 11 Z9 12 U1 0 U2 4 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 MAR 5 PY 2015 VL 125 IS 10 BP 1578 EP 1588 DI 10.1182/blood-2014-07-587790 PG 11 WC Hematology SC Hematology GA CI3AM UT WOS:000354619800016 PM 25564405 ER PT J AU Chen, X Walters, KJ AF Chen, Xiang Walters, Kylie J. TI Structural Plasticity Allows UCH37 to Be Primed by RPN13 or Locked Down by INO80G SO MOLECULAR CELL LA English DT Editorial Material ID PROTEASOME; UBIQUITIN; SPECIFICITY; ACTIVATION; MECHANISM; THERAPY; CANCER; DOMAIN C1 [Chen, Xiang; Walters, Kylie J.] NCI, Prot Proc Sect, Struct Biophys Lab, Ctr Canc Res, Ft Detrick, MD 21702 USA. RP Walters, KJ (reprint author), NCI, Prot Proc Sect, Struct Biophys Lab, Ctr Canc Res, Ft Detrick, MD 21702 USA. EM kylie.walters@nih.gov NR 11 TC 5 Z9 5 U1 1 U2 3 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 MAR 5 PY 2015 VL 57 IS 5 BP 767 EP 768 DI 10.1016/j.molcel.2015.02.025 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CE3GO UT WOS:000351714900003 PM 25747657 ER PT J AU Sodt, AJ Mei, Y Konig, G Tao, P Steele, RP Brooks, BR Shao, YH AF Sodt, Alexander J. Mei, Ye Koenig, Gerhard Tao, Peng Steele, Ryan P. Brooks, Bernard R. Shao, Yihan TI Multiple Environment Single System Quantum Mechanical/Molecular Mechanical (MESS-QM/MM) Calculations. 1. Estimation of Polarization Energies SO JOURNAL OF PHYSICAL CHEMISTRY A LA English DT Article; Proceedings Paper CT 25th Austin Symposium on Molecular Structure and Dynamics CY MAR, 2014 CL Dallas, TX ID DENSITY-FUNCTIONAL THEORY; MOLECULAR-ORBITAL METHODS; LINEAR-RESPONSE KERNEL; CHEMICAL-REACTIONS; ELECTRONIC RESPONSES; REACTIVITY INDEXES; ENZYME-REACTIONS; EXCITED-STATES; HARTREE-FOCK; BASIS-SETS AB In combined quantum mechanical/molecular mechanical (QM/MM) free energy calculations, it is often advantageous to have a frozen geometry for the quantum mechanical (QM) region. For such multiple-environment single-system (MESS) cases, two schemes are proposed here for estimating the polarization energy: the first scheme, termed MESS-E, involves a Roothaan step extrapolation of the self-consistent field (SCF) energy; whereas the other scheme, termed MESS-H, employs a Newton-Raphson correction using an approximate inverse electronic Hessian of the QM region (which is constructed only once). Both schemes are extremely efficient, because the expensive Fock updates and SCF iterations in standard QM/MM calculations are completely avoided at each configuration. They produce reasonably accurate QM/MM polarization energies: MESS-E can predict the polarization energy within 0.25 kcal/mol in terms of the mean signed error for two of our test cases, solvated methanol and solvated beta-alanine, using the M06-2X or omega B97X-D functionals; MESS-H can reproduce the polarization energy within 0.2 kcal/mol for these two cases and for the oxyluciferin-luciferase complex, if the approximate inverse electronic Hessians are constructed with sufficient accuracy. C1 [Sodt, Alexander J.; Mei, Ye; Koenig, Gerhard; Brooks, Bernard R.] NHLBI, Lab Computat Biol, NIH, Rockville, MD 20852 USA. [Mei, Ye] E China Normal Univ, Ctr Laser & Computat Biophys, State Key Lab Precis Spect, Dept Phys, Shanghai 200062, Peoples R China. [Mei, Ye] E China Normal Univ, Inst Theoret & Computat Sci, Shanghai 200062, Peoples R China. [Mei, Ye] NYU Shanghai, NYU ECNU Ctr Computat Chem, Shanghai 200062, Peoples R China. [Tao, Peng] So Methodist Univ, Dept Chem, Dallas, TX 75275 USA. [Steele, Ryan P.] Univ Utah, Dept Chem, Salt Lake City, UT 84112 USA. [Shao, Yihan] Q Chem Inc, Pleasanton, CA 94588 USA. RP Shao, YH (reprint author), Q Chem Inc, 6601 Owens Dr,Suite 105, Pleasanton, CA 94588 USA. EM yihan@q-chem.com RI MEI, Ye/C-5843-2009; OI MEI, Ye/0000-0002-3953-8508; Tao, Peng/0000-0002-2488-0239 FU DOE [DE-SC0011297]; NIH [GM096678-02]; Intramural Research Program of the NIH, NHLBI; China Scholarship Council [201208310344] FX This research is partially supported by DOE grant No. DE-SC0011297 and NIH grant No. GM096678-02 (is.), by the Intramural Research Program of the NIH, NHLBI (A.J.S., G.K., B.R.B.), and by the China Scholarship Council Grant No. 201208310344 (Y.M.). Y.S. thanks Drs. Andres Cisneros, Scott Perrin, Frank Pickard, Andy Simmonnet, Rick Veneble, and Lee Woodcock for helpful discussions. Y.S. also thanks Drs. Shushu Zhang, Chungen Liu and Shawn Chen for sharing their work on luciferase. Y.S. is very grateful to Prof. Peter Pulay for helpful discussions, especially some of their earlier work on the computation of MESS QM/MM polarization energies using generalized multipolar polarizabilities.81,82 Computational resources and services used in this work were provided by the LoBoS cluster of the National Institutes of Health. NR 82 TC 8 Z9 8 U1 2 U2 17 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1089-5639 J9 J PHYS CHEM A JI J. Phys. Chem. A PD MAR 5 PY 2015 VL 119 IS 9 BP 1511 EP 1523 DI 10.1021/jp5072296 PG 13 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA CD1NE UT WOS:000350840800010 PM 25321186 ER PT J AU Machiela, MJ Zhou, WY Sampson, JN Dean, MC Jacobs, KB Black, A Brinton, LA Chang, IS Chen, C Chen, C Chen, KX Cook, LS Bou, MC De Vivo, I Doherty, J Friedenreich, CM Gaudet, MM Haiman, CA Hankinson, SE Hartge, P Henderson, BE Hong, YC Hosgood, HD Hsiung, CA Hu, W Hunter, DJ Jessop, L Kim, HN Kim, YH Kim, YT Klein, R Kraft, P Lan, Q Lin, DX Liu, JJ Le Marchand, L Liang, XL Lissowska, J Lu, LG Magliocco, AM Matsuo, K Olson, SH Orlow, I Park, JY Pooler, L Prescott, J Rastogi, R Risch, HA Schumacher, F Seow, A Setiawan, VW Shen, HB Sheng, X Shin, MH Shu, XO VanDen Berg, D Wang, JC Wentzensen, N Wong, MP Wu, C Wu, TC Wu, YL Xia, L Yang, HP Yang, PC Zheng, W Zhou, BS Abnet, CC Albanes, D Aldrich, MC Amos, C Amundadottir, LT Berndt, SI Blot, WJ Bock, CH Bracci, PM Burdett, L Buring, JE Butler, MA Carreon, T Chatterjee, N Chung, CC Cook, MB Cullen, M Davis, FG Ding, T Duell, EJ Epstein, CG Fan, JH Figueroa, JD Fraumeni, JF Freedman, ND Fuchs, CS Gao, YT Gapstur, SM Patino-Garcia, A Garcia-Closas, M Gaziano, JM Giles, GG Gillanders, EM Giovannucci, EL Goldin, L Goldstein, AM Greene, MH Hallmans, G Harris, CC Henriksson, R Holly, EA Hoover, RN Hu, N Hutchinson, A Jenab, M Johansen, C Khaw, KT Koh, WP Kolonel, LN Kooperberg, C Krogh, V Kurtz, RC LaCroix, A Landgren, A Landi, MT Li, DH Liao, LM Malats, N McGlynn, KA McNeill, LH McWilliams, RR Melin, BS Mirabello, L Peplonska, B Peters, U Petersen, GM Prokunina-Olsson, L Purdue, M Qiao, YL Rabe, KG Rajaraman, P Real, FX Riboli, E Rodriguez-Santiago, B Rothman, N Ruder, AM Savage, SA Schwartz, AG Schwartz, KL Sesso, HD Severi, G Silverman, DT Spitz, MR Stevens, VL Stolzenberg-Solomon, R Stram, D Tang, ZZ Taylor, PR Teras, LR Tobias, GS Viswanathan, K Wacholder, S Wang, ZM Weinstein, SJ Wheeler, W White, E Wiencke, JK Wolpin, BM Wu, XF Wunder, JS Yu, K Zanetti, KA Zeleniuch-Jacquotte, A Ziegler, RG De Andrade, M Barnes, KC Beaty, TH Bierut, LJ Desch, KC Doheny, KF Feenstra, B Ginsburg, D Heit, JA Kang, JH Laurie, CA Li, JZ Lowe, WL Marazita, ML Melbye, M Mirel, DB Murray, JC Nelson, SC Pasquale, LR Rice, K Wiggs, JL Wise, A Tucker, M Perez-Jurado, LA Laurie, CC Caporaso, NE Yeager, M Chanock, SJ AF Machiela, Mitchell J. Zhou, Weiyin Sampson, Joshua N. Dean, Michael C. Jacobs, Kevin B. Black, Amanda Brinton, Louise A. Chang, I-Shou Chen, Chu Chen, Constance Chen, Kexin Cook, Linda S. Bou, Marta Crous De Vivo, Immaculata Doherty, Jennifer Friedenreich, Christine M. Gaudet, Mia M. Haiman, Christopher A. Hankinson, Susan E. Hartge, Patricia Henderson, Brian E. Hong, Yun-Chul Hosgood, H. Dean, III Hsiung, Chao A. Hu, Wei Hunter, David J. Jessop, Lea Kim, Hee Nam Kim, Yeul Hong Kim, Young Tae Klein, Robert Kraft, Peter Lan, Qing Lin, Dongxin Liu, Jianjun Le Marchand, Loic Liang, Xiaolin Lissowska, Jolanta Lu, Lingeng Magliocco, Anthony M. Matsuo, Keitaro Olson, Sara H. Orlow, Irene Park, Jae Yong Pooler, Loreall Prescott, Jennifer Rastogi, Radhai Risch, Harvey A. Schumacher, Fredrick Seow, Adeline Setiawan, Veronica Wendy Shen, Hongbing Sheng, Xin Shin, Min-Ho Shu, Xiao-Ou VanDen Berg, David Wang, Jiu-Cun Wentzensen, Nicolas Wong, Maria Pik Wu, Chen Wu, Tangchun Wu, Yi-Long Xia, Lucy Yang, Hannah P. Yang, Pan-Chyr Zheng, Wei Zhou, Baosen Abnet, Christian C. Albanes, Demetrius Aldrich, Melinda C. Amos, Christopher Amundadottir, Laufey T. Berndt, Sonja I. Blot, William J. Bock, Cathryn H. Bracci, Paige M. Burdett, Laurie Buring, Julie E. Butler, Mary A. Carreon, Tania Chatterjee, Nilanjan Chung, Charles C. Cook, Michael B. Cullen, Michael Davis, Faith G. Ding, Ti Duell, Eric J. Epstein, Caroline G. Fan, Jin-Hu Figueroa, Jonine D. Fraumeni, Joseph F., Jr. Freedman, Neal D. Fuchs, Charles S. Gao, Yu-Tang Gapstur, Susan M. Patino-Garcia, Ana Garcia-Closas, Montserrat Gaziano, J. Michael Giles, Graham G. Gillanders, Elizabeth M. Giovannucci, Edward L. Goldin, Lynn Goldstein, Alisa M. Greene, Mark H. Hallmans, Goran Harris, Curtis C. Henriksson, Roger Holly, Elizabeth A. Hoover, Robert N. Hu, Nan Hutchinson, Amy Jenab, Mazda Johansen, Christoffer Khaw, Kay-Tee Koh, Woon-Puay Kolonel, Laurence N. Kooperberg, Charles Krogh, Vittorio Kurtz, Robert C. LaCroix, Andrea Landgren, Annelie Landi, Maria Teresa Li, Donghui Liao, Linda M. Malats, Nuria McGlynn, Katherine A. McNeill, Lorna H. McWilliams, Robert R. Melin, Beatrice S. Mirabello, Lisa Peplonska, Beata Peters, Ulrike Petersen, Gloria M. Prokunina-Olsson, Ludmila Purdue, Mark Qiao, You-Lin Rabe, Kari G. Rajaraman, Preetha Real, Francisco X. Riboli, Elio Rodriguez-Santiago, Benjamin Rothman, Nathaniel Ruder, Avima M. Savage, Sharon A. Schwartz, Ann G. Schwartz, Kendra L. Sesso, Howard D. Severi, Gianluca Silverman, Debra T. Spitz, Margaret R. Stevens, Victoria L. Stolzenberg-Solomon, Rachael Stram, Daniel Tang, Ze-Zhong Taylor, Philip R. Teras, Lauren R. Tobias, Geoffrey S. Viswanathan, Kala Wacholder, Sholom Wang, Zhaoming Weinstein, Stephanie J. Wheeler, William White, Emily Wiencke, John K. Wolpin, Brian M. Wu, Xifeng Wunder, Jay S. Yu, Kai Zanetti, Krista A. Zeleniuch-Jacquotte, Anne Ziegler, Regina G. De Andrade, Mariza Barnes, Kathleen C. Beaty, Terri H. Bierut, Laura J. Desch, Karl C. Doheny, Kimberly F. Feenstra, Bjarke Ginsburg, David Heit, John A. Kang, Jae H. Laurie, Cecilia A. Li, Jun Z. Lowe, William L. Marazita, Mary L. Melbye, Mads Mirel, Daniel B. Murray, Jeffrey C. Nelson, Sarah C. Pasquale, Louis R. Rice, Kenneth Wiggs, Janey L. Wise, Anastasia Tucker, Margaret Perez-Jurado, Luis A. Laurie, Cathy C. Caporaso, Neil E. Yeager, Meredith Chanock, Stephen J. TI Characterization of Large Structural Genetic Mosaicism in Human Autosomes SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID DETECTABLE CLONAL MOSAICISM; COPY-NUMBER-VARIATION; SOMATIC MOSAICISM; MAFFUCCI SYNDROME; OLLIER DISEASE; HUMAN GENOME; MUTATIONS; CANCER; CELLS; IDENTIFICATION AB Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 x 3 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population. C1 [Machiela, Mitchell J.; Zhou, Weiyin; Sampson, Joshua N.; Black, Amanda; Brinton, Louise A.; Hartge, Patricia; Hosgood, H. Dean, III; Hu, Wei; Jessop, Lea; Lan, Qing; Wentzensen, Nicolas; Yang, Hannah P.; Abnet, Christian C.; Albanes, Demetrius; Amundadottir, Laufey T.; Berndt, Sonja I.; Burdett, Laurie; Chatterjee, Nilanjan; Chung, Charles C.; Cook, Michael B.; Cullen, Michael; Epstein, Caroline G.; Figueroa, Jonine D.; Fraumeni, Joseph F., Jr.; Freedman, Neal D.; Goldin, Lynn; Goldstein, Alisa M.; Greene, Mark H.; Hoover, Robert N.; Hu, Nan; Hutchinson, Amy; Landgren, Annelie; Landi, Maria Teresa; Liao, Linda M.; McGlynn, Katherine A.; Mirabello, Lisa; Prokunina-Olsson, Ludmila; Purdue, Mark; Rajaraman, Preetha; Rothman, Nathaniel; Savage, Sharon A.; Silverman, Debra T.; Stolzenberg-Solomon, Rachael; Taylor, Philip R.; Tobias, Geoffrey S.; Wacholder, Sholom; Wang, Zhaoming; Weinstein, Stephanie J.; Yu, Kai; Ziegler, Regina G.; Tucker, Margaret; Caporaso, Neil E.; Yeager, Meredith; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Zhou, Weiyin; Jacobs, Kevin B.; Burdett, Laurie; Chung, Charles C.; Cullen, Michael; Hutchinson, Amy; Wang, Zhaoming; Yeager, Meredith] NCI, Canc Genom Res Lab, Div Canc Epidemiol & Genet, NIH,Leidos Biomed Res Inc, Bethesda, MD 20892 USA. [Dean, Michael C.] NCI, Expt Immunol Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Jacobs, Kevin B.] BioInformed LLC, Gaithersburg, MD 20877 USA. [Chang, I-Shou] Natl Inst Canc Res, Natl Hlth Res Inst, Zhunan 35053, Taiwan. [Chen, Chu; Kooperberg, Charles; LaCroix, Andrea; Peters, Ulrike; White, Emily] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Chen, Constance; Bou, Marta Crous; De Vivo, Immaculata; Hunter, David J.; Kraft, Peter; Prescott, Jennifer] Harvard Univ, Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA 02115 USA. [Chen, Kexin] Tianjin Med Univ, Canc Inst & Hosp, Dept Epidemiol & Biostat, Tianjin 300040, Peoples R China. [Cook, Linda S.] Univ New Mexico, Albuquerque, NM 87131 USA. [Bou, Marta Crous; De Vivo, Immaculata; Hankinson, Susan E.; Hunter, David J.; Prescott, Jennifer; Fuchs, Charles S.; Giovannucci, Edward L.; Wolpin, Brian M.; Kang, Jae H.; Pasquale, Louis R.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Bou, Marta Crous; De Vivo, Immaculata; Hankinson, Susan E.; Hunter, David J.; Prescott, Jennifer; Fuchs, Charles S.; Gaziano, J. Michael; Giovannucci, Edward L.; Wolpin, Brian M.; Kang, Jae H.; Pasquale, Louis R.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Doherty, Jennifer] Dartmouth Coll, Geisel Sch Med, Hanover, NH 03755 USA. [Friedenreich, Christine M.] Alberta Hlth Serv, CancerControl Alberta, Dept Populat Hlth Res, Calgary, AB T2N 2T9, Canada. [Gaudet, Mia M.; Gapstur, Susan M.; Stevens, Victoria L.; Teras, Lauren R.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30303 USA. [Haiman, Christopher A.; Henderson, Brian E.; Schumacher, Fredrick; Setiawan, Veronica Wendy; VanDen Berg, David; Stram, Daniel] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Hankinson, Susan E.] Univ Massachusetts, Sch Publ Hlth & Hlth Sci, Div Biostat & Epidemiol, Amherst, MA 01003 USA. [Hong, Yun-Chul] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul 151742, South Korea. [Hosgood, H. Dean, III] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10461 USA. [Hsiung, Chao A.] Inst Populat Hlth Sci, Natl Hlth Res Inst, Zhunan 35053, Taiwan. [Hunter, David J.; Mirel, Daniel B.] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. [Kim, Hee Nam] Chonnam Natl Univ, Ctr Creat Biomed Scientists, Kwangju 500757, South Korea. [Kim, Yeul Hong] Korea Univ, Anam Hosp, Coll Med, Div Oncol Hematol,Dept Internal Med, Seoul 151742, South Korea. [Kim, Young Tae] Seoul Natl Univ, Coll Med, Dept Thorac & Cardiovasc Surg, Canc Res Inst, Seoul 151742, South Korea. [Klein, Robert] Mem Sloan Kettering Canc Ctr, Program Canc Biol & Genet, New York, NY 10065 USA. [Lin, Dongxin; Wu, Chen] Chinese Acad Med Sci, Canc Inst & Hosp, Dept Etiol & Carcinogenesis, Beijing 100730, Peoples R China. [Lin, Dongxin; Wu, Chen] Peking Union Med Coll, Beijing 100730, Peoples R China. [Lin, Dongxin; Wu, Chen] Chinese Acad Med Sci, Canc Inst & Hosp, State Key Lab Mol Oncol, Beijing 100730, Peoples R China. [Liu, Jianjun] Genome Inst Singapore, Dept Human Genet, Singapore 138672, Singapore. [Liu, Jianjun] Anhui Med Univ, Sch Life Sci, Hefei 230032, Peoples R China. [Le Marchand, Loic; Kolonel, Laurence N.] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96813 USA. [Liang, Xiaolin; Olson, Sara H.; Orlow, Irene; Rastogi, Radhai] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10065 USA. [Lissowska, Jolanta] Maria Sklodowska Curie Canc Ctr, Dept Canc Epidemiol & Prevent, PL-02781 Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, PL-02781 Warsaw, Poland. [Lu, Lingeng; Risch, Harvey A.] Yale Univ, Sch Publ Hlth, New Haven, CT 06510 USA. [Magliocco, Anthony M.] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. [Matsuo, Keitaro] Kyushu Univ, Fac Med Sci, Dept Prevent Med, Fukuoka 8190395, Japan. [Park, Jae Yong] Kyungpook Natl Univ, Med Ctr, Lung Canc Ctr, Daegu 101, South Korea. [Pooler, Loreall; Sheng, Xin; Xia, Lucy] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90007 USA. [Seow, Adeline; Koh, Woon-Puay] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 119077, Singapore. [Shen, Hongbing] Nanjing Med Univ, Jiangsu Key Lab Canc Biomarkers Prevent & Treatme, Nanjing 210029, Jiangsu, Peoples R China. [Shen, Hongbing] Nanjing Med Univ, Minist Educ, Key Lab Modern Toxicol, Nanjing 210029, Jiangsu, Peoples R China. [Shin, Min-Ho] Chonnam Natl Univ, Sch Med, Dept Prevent Med, Gwanju 501746, South Korea. [Shu, Xiao-Ou] Vanderbilt Univ, Med Ctr, Vanderbilt Ingram Canc Ctr, Dept Med,Vanderbilt Epidemiol Ctr, Nashville, TN 37232 USA. [Wang, Jiu-Cun] Fudan Univ, Sch Life Sci, Key Lab Contemporary Anthropol, Minist Educ, Shanghai 200433, Peoples R China. [Wang, Jiu-Cun] Fudan Univ, Sch Life Sci, State Key Lab Genet Engn, Shanghai 200433, Peoples R China. [Wong, Maria Pik] Univ Hong Kong, Li Ka Shing Fac Med, Dept Pathol, Hong Kong, Hong Kong, Peoples R China. [Wu, Tangchun] Huazhong Univ Sci & Technol, Sch Publ Hlth, Inst Occupat Med, Wuhan 430400, Peoples R China. [Wu, Tangchun] Huazhong Univ Sci & Technol, Sch Publ Hlth, Minist Educ, Key Lab Environm & Hlth, Wuhan 430400, Peoples R China. [Wu, Yi-Long] Guangdong Gen Hosp, Guangdong Lung Canc Inst, Guangzhou 515200, Guangdong, Peoples R China. [Wu, Yi-Long] Guangdong Acad Med Sci, Guangzhou 515200, Guangdong, Peoples R China. [Yang, Pan-Chyr] Natl Taiwan Univ, Dept Internal Med, Coll Med, Taipei 10617, Taiwan. [Zheng, Wei; Aldrich, Melinda C.; Blot, William J.] Vanderbilt Univ, Med Ctr, Vanderbilt Epidemiol Ctr, Div Epidemiol,Dept Med, Nashville, TN 37232 USA. [Zhou, Baosen] China Med Univ, Sch Publ Hlth, Dept Epidemiol, Shenyang 110001, Peoples R China. [Aldrich, Melinda C.] Vanderbilt Univ, Sch Med, Dept Thorac Surg, Nashville, TN 37232 USA. [Amos, Christopher] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Div Canc Prevent & Populat Sci, Houston, TX 77030 USA. [Blot, William J.] Int Epidemiol Inst, Rockville, MD 20850 USA. [Bock, Cathryn H.; Schwartz, Ann G.] Wayne State Univ, Sch Med, Karmanos Canc Inst, Detroit, MI 48201 USA. [Bock, Cathryn H.; Schwartz, Ann G.] Wayne State Univ, Sch Med, Dept Oncol, Detroit, MI 48201 USA. [Bracci, Paige M.; Holly, Elizabeth A.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Buring, Julie E.; Sesso, Howard D.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Butler, Mary A.; Carreon, Tania; Ruder, Avima M.] NIOSH, Ctr Dis Control & Prevent, Cincinnati, OH 45226 USA. [Davis, Faith G.] Univ Alberta, Sch Publ Hlth, Dept Publ Hlth Sci, Edmonton, AB T6G 2R3, Canada. [Ding, Ti; Tang, Ze-Zhong] Shanxi Canc Hosp, Taiyuan 030013, Shanxi, Peoples R China. [Duell, Eric J.] Catalan Inst Oncol, Bellvitge Biomed Res Inst, Canc Epidemiol Res Program, Unit Nutr Environm & Canc, Barcelona 08908, Spain. [Fan, Jin-Hu] Shanghai Canc Inst, Shanghai 200032, Peoples R China. [Fuchs, Charles S.; Wolpin, Brian M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Gao, Yu-Tang] Shanghai Jiao Tong Univ, Sch Med, Renji Hosp, Dept Epidemiol,Shanghai Canc Inst, Shanghai 200032, Peoples R China. [Patino-Garcia, Ana] Univ Navarra, Univ Navarra Clin, Dept Pediat, E-31080 Pamplona, Spain. [Garcia-Closas, Montserrat] Inst Canc Res, Div Genet & Epidemiol, London SM2 5NG, Surrey, England. [Garcia-Closas, Montserrat] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London SM2 5NG, Surrey, England. [Gaziano, J. Michael] Brigham & Womens Hosp, Dept Med, Div Prevent Med, Boston, MA 02115 USA. [Gaziano, J. Michael] Brigham & Womens Hosp, Dept Med, Div Aging, Boston, MA 02115 USA. [Gaziano, J. Michael] Vet Affairs Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr, Boston, MA 02130 USA. [Gaziano, J. Michael] Vet Affairs Boston Healthcare Syst, Cooperat Studies Programs, Boston, MA 02130 USA. [Giles, Graham G.; Severi, Gianluca] Univ Melbourne, Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic 3010, Australia. [Giles, Graham G.; Severi, Gianluca] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic 3010, Australia. [Gillanders, Elizabeth M.; Zanetti, Krista A.] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Hallmans, Goran] Umea Univ, Dept Publ Hlth & Clin Med, Nutr Res Unit, S-90187 Umea, Sweden. [Harris, Curtis C.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Henriksson, Roger; Melin, Beatrice S.] Umea Univ, Dept Radiat Sci, Dept Oncol, S-90187 Umea, Sweden. [Jenab, Mazda] Int Agcy Res Canc, F-69372 Lyon, France. [Johansen, Christoffer] Rigshosp, Finsen Ctr, Dept Oncol, DK-2100 Copenhagen, Denmark. [Johansen, Christoffer] Danish Canc Soc, Res Ctr, Unit Survivorship Res, DK-2100 Copenhagen, Denmark. [Khaw, Kay-Tee] Univ Cambridge, Sch Clin Med, Cambridge CB2 1TN, England. [Koh, Woon-Puay] Duke NUS Grad Med Sch, Singapore 169857, Singapore. [Krogh, Vittorio] Fdn IRCCS Ist Nazl Tumori, I-20133 Milan, Italy. [Kurtz, Robert C.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA. [Li, Donghui] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX 77030 USA. [Malats, Nuria; Real, Francisco X.] Spanish Natl Canc Res Ctr, Madrid 28029, Spain. [McNeill, Lorna H.] Univ Texas MD Anderson Canc Ctr, Dept Hlth Dispar Res, Div OVP Canc Prevent & Populat Sci, Houston, TX 77030 USA. [McNeill, Lorna H.] Univ Texas MD Anderson Canc Ctr, Ctr Community Engaged Translat Res, Duncan Family Inst, Houston, TX 77030 USA. [McWilliams, Robert R.] Mayo Clin, Dept Oncol, Rochester, MN 55905 USA. [Peplonska, Beata] Nofer Inst Occupat Med, PL-91348 Lodz, Poland. [Petersen, Gloria M.; Rabe, Kari G.; De Andrade, Mariza] Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA. [Qiao, You-Lin] Chinese Acad Med Sci, Inst Canc, Dept Epidemiol, Beijing 100730, Peoples R China. [Real, Francisco X.; Rodriguez-Santiago, Benjamin; Perez-Jurado, Luis A.] Univ Pompeu Fabra, Dept Ciencies Expt & Salut, Barcelona 08003, Spain. [Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Div Epidemiol & Biostat, London SW7 2AZ, England. [Rodriguez-Santiago, Benjamin; Perez-Jurado, Luis A.] Ctr Invest Biomed Red Enfermedades Raras, Barcelona 08003, Spain. [Rodriguez-Santiago, Benjamin] QGenomics, Quantitat Genom Med Lab, Barcelona 08003, Spain. [Schwartz, Kendra L.] Wayne State Univ, Sch Med, Karmanos Canc Inst, Detroit, MI 48201 USA. [Schwartz, Kendra L.] Wayne State Univ, Sch Med, Dept Family Med & Publ Hlth Sci, Detroit, MI 48201 USA. [Severi, Gianluca] Human Genet Fdn, I-10126 Turin, Italy. [Spitz, Margaret R.] Baylor Coll Med, Houston, TX 77030 USA. [Viswanathan, Kala; Beaty, Terri H.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21218 USA. [Wheeler, William] Informat Management Serv Inc, Calverton, MD 20904 USA. [Wiencke, John K.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Wu, Xifeng] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Wunder, Jay S.] Washington Univ, Sch Med, Div Urol Surg, St Louis, MO 63110 USA. [Zeleniuch-Jacquotte, Anne] NYU, Sch Med, Dept Populat Hlth, New York, NY 10016 USA. [Zeleniuch-Jacquotte, Anne] NYU, Perlmutter Canc Inst, New York, NY 10016 USA. [Barnes, Kathleen C.] Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. [Bierut, Laura J.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. [Desch, Karl C.] Univ Michigan, Dept Pediat & Communicable Dis, CS Mott Childrens Hosp, Ann Arbor, MI 48109 USA. [Doheny, Kimberly F.] Johns Hopkins Univ, Inst Med Genet, Sch Med, Ctr Inherited Dis Res, Baltimore, MD 21218 USA. [Feenstra, Bjarke; Melbye, Mads] Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark. [Ginsburg, David] Univ Michigan, Howard Hughes Med Inst, Ann Arbor, MI 48109 USA. [Ginsburg, David] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Heit, John A.] Mayo Clin, Dept Internal Med, Rochester, MN 55905 USA. [Laurie, Cecilia A.; Nelson, Sarah C.; Rice, Kenneth; Laurie, Cathy C.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Li, Jun Z.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Lowe, William L.] Northwestern Univ, Feinberg Sch Med, Div Endocrinol Metab & Mol Med, Evanston, IL 60208 USA. [Marazita, Mary L.] Univ Pittsburgh, Sch Dent Med, Dept Oral Biol, Ctr Craniofacial & Dent Genet, Pittsburgh, PA 15260 USA. [Marazita, Mary L.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15260 USA. [Melbye, Mads] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. [Murray, Jeffrey C.] Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA. [Pasquale, Louis R.; Wiggs, Janey L.] Harvard Univ, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Wise, Anastasia] NHGRI, Off Populat Genom, NIH, Bethesda, MD 20892 USA. [Perez-Jurado, Luis A.] Hosp del Mar, Res Inst, Barcelona 08003, Spain. RP Chanock, SJ (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM chanocks@mail.nih.gov RI Savage, Sharon/B-9747-2015; Krogh, Vittorio/K-2628-2016; Tobias, Geoffrey/M-4135-2016; Qiao, You-Lin/B-4139-2012; Perez Jurado, Luis Alberto/M-7706-2015; Hsiung, Chao Agnes/E-3994-2010; Garcia-Closas, Montserrat /F-3871-2015; Chang, I-Shou/D-2084-2010; Brinton, Louise/G-7486-2015; Freedman, Neal/B-9741-2015; Real Arribas, Francisco/H-5275-2015; Cook, Michael/A-5641-2009; U-ID, Kyushu/C-5291-2016; Abnet, Christian/C-4111-2015; Malats, Nuria/H-7041-2015; Patino-Garcia, Ana/I-4299-2012 OI Orlow, Irene/0000-0001-6234-6961; Giles, Graham/0000-0003-4946-9099; Matsuo, Keitaro/0000-0003-1761-6314; Zeleniuch-Jacquotte, Anne/0000-0001-9350-1303; Savage, Sharon/0000-0001-6006-0740; Krogh, Vittorio/0000-0003-0122-8624; Tobias, Geoffrey/0000-0002-2878-8253; Qiao, You-Lin/0000-0001-6380-0871; Nelson, Sarah/0000-0002-2109-6465; Rodriguez-Santiago, Benjamin/0000-0003-1167-3852; YANG, PAN-CHYR/0000-0001-6330-6048; Prokunina-Olsson, Ludmila/0000-0002-9622-2091; Liao, Linda/0000-0002-1923-5294; Machiela, Mitchell/0000-0001-6538-9705; Garcia-Closas, Montserrat /0000-0003-1033-2650; Brinton, Louise/0000-0003-3853-8562; Freedman, Neal/0000-0003-0074-1098; Real Arribas, Francisco/0000-0001-9501-498X; Cook, Michael/0000-0002-0533-7302; Abnet, Christian/0000-0002-3008-7843; Malats, Nuria/0000-0003-2538-3784; FU Medical Research Council [G0401527, G1000143]; NCI NIH HHS [P01 CA087969, K05 CA154337, K07 CA172294, P30 CA008748, P30 CA016672, P30 CA023108, R01 CA092447, R01 CA124908, R25 CA174664, UM1 CA182934]; NEI NIH HHS [P30 EY014104, R01 EY015473, R01 EY022305]; NHLBI NIH HHS [R01 HL039693, R01 HL112642]; NIDCR NIH HHS [R01 DE014899, R01 DE016148] NR 35 TC 14 Z9 14 U1 2 U2 17 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 MAR 5 PY 2015 VL 96 IS 3 BP 487 EP 497 DI 10.1016/j.ajhg.2015.01.011 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA CD0GD UT WOS:000350747800022 PM 25748358 ER PT J AU Krivega, I Dean, A AF Krivega, Ivan Dean, Ann TI Chromosome Togetherness at the Onset of ESC Differentiation SO CELL STEM CELL LA English DT Editorial Material ID TRANSCRIPTIONAL REGULATION; X-INACTIVATION; CELLS AB Pairing of homologous alleles is a phenomenon generally associated with imprinted and mono-allelically expressed loci. In this issue, Hogan et al. (2015) examine the earliest steps between pluripotency and lineage commitment in ESCs and find a critical role for transient pairing of Oct4 alleles in exiting the pluripotent state. C1 [Krivega, Ivan; Dean, Ann] NIDDK, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. RP Dean, A (reprint author), NIDDK, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. EM anndean@helix.nih.gov RI Krivega, Ivan/G-9247-2015 OI Krivega, Ivan/0000-0002-3473-4198 FU Intramural NIH HHS [Z01 DK015508-20] NR 10 TC 0 Z9 0 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 EI 1875-9777 J9 CELL STEM CELL JI Cell Stem Cell PD MAR 5 PY 2015 VL 16 IS 3 BP 213 EP 214 DI 10.1016/j.stem.2015.02.009 PG 2 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA CD0GC UT WOS:000350747700001 PM 25748925 ER PT J AU Li, N Chen, TW Guo, ZV Gerfen, CR Svoboda, K AF Li, Nuo Chen, Tsai-Wen Guo, Zengcai V. Gerfen, Charles R. Svoboda, Karel TI A motor cortex circuit for motor planning and movement SO NATURE LA English DT Article ID FUNCTIONAL-ORGANIZATION; SENSORIMOTOR CORTEX; INTENDED MOVEMENT; CORTICAL ACTIVITY; NEURONAL-ACTIVITY; TRANSGENIC MICE; SINGLE NEURONS; MONKEY; MOUSE; DIRECTION AB Activity in motor cortex predicts specific movements seconds before they occur, but how this preparatory activity relates to upcoming movements is obscure. We dissected the conversion of preparatory activity to movement within a structured motor cortex circuit. An anterior lateral region of the mouse cortex (a possible homologue of prernotor cortex in primates) contains equal proportions of intermingled neurons predicting ipsi- or contralateral movements, yet unilateral inactivation of this cortical region during movement planning disrupts contralateral movements. Using cell-type-specific electrophysiology, cellular imaging and optogenetic perturbation, we show that layer 5 neurons projecting within the cortex have unbiased laterality. Activity with a contralateral population bias arises specifically in layer 5 neurons projecting to the brairtstern, and only late during movement planning. These results reveal the transformation of distributed preparatory activity into movement commands within hierarchically organized cortical circuits. C1 [Li, Nuo; Chen, Tsai-Wen; Guo, Zengcai V.; Svoboda, Karel] Howard Hughes Med Inst, Ashburn, VA 20147 USA. [Gerfen, Charles R.] NIMH, Lab Syst Neurosci, Bethesda, MD 20892 USA. RP Svoboda, K (reprint author), Howard Hughes Med Inst, Janelia Res Campus, Ashburn, VA 20147 USA. EM svobodak@janelia.hhmi.org FU Howard Hughes Medical Institute FX We thank B. Dickson, S. Druckmann, J. Dudman, D. Gutnisky, H. Inagaki, V. Jayaraman, D. O'Connor, S. Peron, T. Sato and G. Shepherd for comments on the manuscript and discussion, L. Walendy and E. Ophir for animal training, S. Michael and A. Hu for histology, T. Harris and B. Barbarits for the silicon probe recording system. This work was funded by the Howard Hughes Medical Institute. N.L. is a Helen Hay Whitney Foundation postdoctoral fellow. NR 54 TC 39 Z9 39 U1 9 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 MAR 5 PY 2015 VL 519 IS 7541 BP 51 EP U88 DI 10.1038/nature14178 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CC4EQ UT WOS:000350304000033 PM 25731172 ER PT J AU Gardner, MR Kattenhorn, LM Kondur, HR von Schaewen, M Dorfman, T Chiang, JJ Haworth, KG Decker, JM Alpert, MD Bailey, CC Neale, ES Fellinger, CH Joshi, VR Fuchs, SP Martinez-Navio, JM Quinlan, BD Yao, AY Mouquet, H Gorman, J Zhang, BS Poignard, P Nussenzweig, MC Burton, DR Kwong, PD Piatak, M Lifson, JD Gao, GP Desrosiers, RC Evans, DT Hahn, BH Ploss, A Cannon, PM Seaman, MS Farzan, M AF Gardner, Matthew R. Kattenhorn, Lisa M. Kondur, Hema R. von Schaewen, Markus Dorfman, Tatyana Chiang, Jessica J. Haworth, Kevin G. Decker, Julie M. Alpert, Michael D. Bailey, Charles C. Neale, Ernest S., Jr. Fellinger, Christoph H. Joshi, Vinita R. Fuchs, Sebastian P. Martinez-Navio, Jose M. Quinlan, Brian D. Yao, Annie Y. Mouquet, Hugo Gorman, Jason Zhang, Baoshan Poignard, Pascal Nussenzweig, Michel C. Burton, Dennis R. Kwong, Peter D. Piatak, Michael, Jr. Lifson, Jeffrey D. Gao, Guangping Desrosiers, Ronald C. Evans, David T. Hahn, Beatrice H. Ploss, Alexander Cannon, Paula M. Seaman, Michael S. Farzan, Michael TI AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges SO NATURE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; FUSION INHIBITOR T-20; ENVELOPE GLYCOPROTEIN; TYROSINE SULFATION; HIV-1 GP120; N-TERMINUS; NEUTRALIZING ANTIBODIES; POTENT NEUTRALIZATION; MONOCLONAL-ANTIBODIES; PEPTIDE VARIANTS AB Long-term in vivo expression of a broad and potent entry inhibitor could circumvent the need for a conventional vaccine for HIV-1. Adeno-associated virus (AAV) vectors can stably express HIV-1 broadly neutralizing antibodies (bNAbs)(1,2). However, even the best bNAbs neutralize 10-50% of HIV-1 isolates inefficiently (80% inhibitory concentration (IC80) > 5 mu g ml(-1)), suggesting that high concentrations of these antibodies would be necessary to achieve general protection(3-6). Here we show that eCD4-Ig, a fusion ofCD4-Ig with a small CCR5-mimetic sulfopeptide, binds avidly and cooperatively to the HIV-1 envelope glycoprotein (Env) and is more potent than the best bNAbs (geometric mean half-maximum inhibitory concentration (IC50), 0.05 mu g ml(-1)). Because eCD4-Ig binds only conserved regions of Env, it is also much broader than any bNAb. For example, eCD4-Ig efficiently neutralized 100% of a diverse panel of neutralization-resistant HIV-1, HIV-2 and simian immunodeficiency virus isolates, including a comprehensive set of isolates resistant to the CD4-binding site bNAbs VRC01, NIH45-46 and 3BNC117. Rhesus macaques inoculated with an AAV vector stably expressed 17-77 mu g ml(-1) of fully functional rhesuseCD4-Ig for more than 40 weeks, and these macaques were protected from several infectious challenges with SHIV-AD8. Rhesus eCD4-Ig was also markedly less immunogenic than rhesus forms of four well-characterized bNAbs. Our data suggest that AAV-delivered eCD4-Ig can function like an effective HIV-1 vaccine. C1 [Gardner, Matthew R.; Kondur, Hema R.; Dorfman, Tatyana; Bailey, Charles C.; Fellinger, Christoph H.; Joshi, Vinita R.; Quinlan, Brian D.; Farzan, Michael] Scripps Res Inst, Dept Infect Dis, Jupiter, FL 33458 USA. [Kattenhorn, Lisa M.; Chiang, Jessica J.; Alpert, Michael D.; Neale, Ernest S., Jr.; Yao, Annie Y.; Desrosiers, Ronald C.] Harvard Univ, Sch Med, New England Primate Res Ctr, Dept Comparat Pathol, Southborough, MA 01772 USA. [von Schaewen, Markus; Ploss, Alexander] Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA. [Haworth, Kevin G.; Cannon, Paula M.] Univ So Calif, Keck Sch Med, Dept Mol Microbiol & Immunol, Los Angeles, CA 90033 USA. [Decker, Julie M.; Hahn, Beatrice H.] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Decker, Julie M.; Hahn, Beatrice H.] Univ Penn, Perelman Sch Med, Dept Microbiol, Philadelphia, PA 19104 USA. [Alpert, Michael D.] Immunathon Inc, Cambridge, MA 02141 USA. [Fuchs, Sebastian P.; Martinez-Navio, Jose M.; Desrosiers, Ronald C.] Univ Miami, Miller Sch Med, Dept Pathol, Miami, FL 33136 USA. [Mouquet, Hugo; Nussenzweig, Michel C.] Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. [Mouquet, Hugo] Inst Pasteur, Dept Immunol, F-75015 Paris, France. [Gorman, Jason; Zhang, Baoshan; Kwong, Peter D.] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Poignard, Pascal; Burton, Dennis R.] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Poignard, Pascal; Burton, Dennis R.] Scripps Res Inst, Ctr HIV AIDS Vaccine Immunol & Immunogen Discover, La Jolla, CA 92037 USA. [Nussenzweig, Michel C.] Howard Hughes Med Inst, New York, NY 10065 USA. [Burton, Dennis R.] Ragon Inst MGH MIT & Harvard, Cambridge, MA 02139 USA. [Piatak, Michael, Jr.; Lifson, Jeffrey D.] Frederick Natl Lab Canc Res, AIDS & Canc Virus Program, Leidos Biomed Res Inc, Frederick, MD 21702 USA. [Gao, Guangping] Univ Massachusetts, Sch Med, Gene Therapy Ctr, Worcester, MA 01655 USA. [Evans, David T.] Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI 53711 USA. [Seaman, Michael S.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. RP Farzan, M (reprint author), Scripps Res Inst, Dept Infect Dis, Jupiter, FL 33458 USA. EM mfarzan@scripps.edu RI Mouquet, Hugo/M-2750-2014; poignard, pascal/N-6678-2013 FU National Institutes of Health (NIH) [R01 AI091476, R01 AI080324, P01 AI100263, RR000168, RO1 AI058715]; Vaccine Research Center, NIAID, NIH; National Cancer Institute, NIH [HHSN261200800001E] FX This project was supported by National Institutes of Health (NIH) grants R01 AI091476 and RO1 AI080324 (M.F.), P01 AI100263 (G.G., R.C.D., M.F.), RR000168 (M.R.G., L.M.K., D.T.E., R.C.D., M.F.), R01 AI058715 (B.H.H.), by the Intramural Research program of the Vaccine Research Center, NIAID, NIH (J.G., B.Z., P.D.K.), and by federal funds from the National Cancer Institute, NIH under contract no. HHSN261200800001E. The authors would like to thank H. Choe and M. Martin for critical advice. NR 50 TC 74 Z9 75 U1 7 U2 53 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 MAR 5 PY 2015 VL 519 IS 7541 BP 87 EP U173 DI 10.1038/nature14264 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CC4EQ UT WOS:000350304000041 PM 25707797 ER PT J AU Moore, HCF Unger, JM Phillips, KA Boyle, F Hitre, E Porter, D Francis, PA Goldstein, LJ Gomez, HL Vallejos, CS Partridge, AH Dakhil, SR Garcia, AA Gralow, J Lombard, JM Forbes, JF Martino, S Barlow, WE Fabian, CJ Minasian, L Meyskens, FL Gelber, RD Hortobagyi, GN Albain, KS AF Moore, Halle C. F. Unger, Joseph M. Phillips, Kelly-Anne Boyle, Frances Hitre, Erika Porter, David Francis, Prudence A. Goldstein, Lori J. Gomez, Henry L. Vallejos, Carlos S. Partridge, Ann H. Dakhil, Shaker R. Garcia, Agustin A. Gralow, Julie Lombard, Janine M. Forbes, John F. Martino, Silvana Barlow, William E. Fabian, Carol J. Minasian, Lori Meyskens, Frank L., Jr. Gelber, Richard D. Hortobagyi, Gabriel N. Albain, Kathy S. CA POEMS S0230 Investigators TI Goserelin for Ovarian Protection during Breast-Cancer Adjuvant Chemotherapy SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID RANDOMIZED-CONTROLLED-TRIAL; FERTILITY PRESERVATION; HORMONE AGONISTS; SUPPRESSION; AMENORRHEA; WOMEN; TRIPTORELIN; PREVENTION AB BACKGROUND Ovarian failure is a common toxic effect of chemotherapy. Studies of the use of gonadotropin-releasing hormone (GnRH) agonists to protect ovarian function have shown mixed results and lack data on pregnancy outcomes. METHODS We randomly assigned 257 premenopausal women with operable hormone-receptor-negative breast cancer to receive standard chemotherapy with the GnRH agonist goserelin (goserelin group) or standard chemotherapy without goserelin (chemotherapy-alone group). The primary study end point was the rate of ovarian failure at 2 years, with ovarian failure defined as the absence of menses in the preceding 6 months and levels of follicle-stimulating hormone (FSH) in the postmenopausal range. Rates were compared with the use of conditional logistic regression. Secondary end points included pregnancy outcomes and disease-free and overall survival. RESULTS At baseline, 218 patients were eligible and could be evaluated. Among 135 with complete primary end-point data, the ovarian failure rate was 8% in the goserelin group and 22% in the chemotherapy-alone group (odds ratio, 0.30; 95% confidence interval, 0.09 to 0.97; two-sided P = 0.04). Owing to missing primary end-point data, sensitivity analyses were performed, and the results were consistent with the main findings. Missing data did not differ according to treatment group or according to the stratification factors of age and planned chemotherapy regimen. Among the 218 patients who could be evaluated, pregnancy occurred in more women in the goserelin group than in the chemotherapy-alone group (21% vs. 11%, P = 0.03); women in the goserelin group also had improved disease-free survival (P = 0.04) and overall survival (P = 0.05). CONCLUSIONS Although missing data weaken interpretation of the findings, administration of goserelin with chemotherapy appeared to protect against ovarian failure, reducing the risk of early menopause and improving prospects for fertility. (Funded by the National Cancer Institute and others; POEMS/S0230 ClinicalTrials.gov number, NCT00068601.) C1 [Moore, Halle C. F.] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Unger, Joseph M.; Barlow, William E.] Fred Hutchinson Canc Res Ctr, SWOG Canc Res Grp Stat Ctr, Seattle, WA 98104 USA. [Gralow, Julie] Seattle Canc Care Alliance, Seattle, WA USA. [Gralow, Julie] Univ Washington, Seattle, WA 98195 USA. [Phillips, Kelly-Anne; Francis, Prudence A.] Univ Melbourne, Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [Phillips, Kelly-Anne; Francis, Prudence A.; Forbes, John F.] New Zealand Breast Canc Trials Grp ANZBCTG, Newcastle, NSW, Australia. [Boyle, Frances; Lombard, Janine M.; Forbes, John F.] Calvary Mater Hosp, Newcastle, NSW, Australia. [Boyle, Frances] Univ Sydney, Sydney, NSW 2006, Australia. [Phillips, Kelly-Anne; Francis, Prudence A.] IBCSG, Bern, Switzerland. [Hitre, Erika] Natl Inst Oncol, Budapest, Hungary. [Porter, David] Auckland Reg Canc & Blood Serv, Auckland, New Zealand. [Goldstein, Lori J.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Gomez, Henry L.] Inst Enfermedades Neoplas, Lima, Peru. [Vallejos, Carlos S.] Oncosalud SAC, Lima, Peru. [Partridge, Ann H.; Gelber, Richard D.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Gelber, Richard D.] IBCSG Stat Ctr, Boston, MA USA. [Dakhil, Shaker R.] Wichita Community Clin Oncol Program, Wichita, KS USA. [Fabian, Carol J.] Univ Kansas, Westwood, KS USA. [Garcia, Agustin A.] Univ So Calif, Norris Canc Ctr, Los Angeles, CA USA. [Martino, Silvana] Angeles Clin, Santa Monica, CA USA. [Martino, Silvana] Res Inst, Santa Monica, CA USA. [Meyskens, Frank L., Jr.] Univ Calif Irvine, Chao Family Comprehens Canc Ctr, Orange, CA 92668 USA. [Minasian, Lori] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Hortobagyi, Gabriel N.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Albain, Kathy S.] Loyola Univ, Med Ctr, Cardinal Bernardin Canc Ctr, Maywood, IL 60153 USA. RP Moore, HCF (reprint author), Cleveland Clin Fdn, Taussig Canc Inst, R35,9500 Euclid Ave, Cleveland, OH 44195 USA. EM mooreh1@ccf.org OI Gomez, Henry/0000-0003-2660-1843; Phillips, Kelly-Anne/0000-0002-0475-1771 FU National Cancer Institute FX Funded by the National Cancer Institute and others; POEMS/S0230 ClinicalTrials.gov number, NCT00068601. NR 23 TC 102 Z9 108 U1 3 U2 30 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 MAR 5 PY 2015 VL 372 IS 10 BP 923 EP 932 DI 10.1056/NEJMoa1413204 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA CC4EU UT WOS:000350304500008 PM 25738668 ER PT J AU Esposito, G Nakazawa, J Ogawa, S Stival, R Putnick, DL Bornstein, MH AF Esposito, Gianluca Nakazawa, Jun Ogawa, Shota Stival, Rita Putnick, Diane L. Bornstein, Marc H. TI Using infrared thermography to assess emotional responses to infants SO EARLY CHILD DEVELOPMENT AND CARE LA English DT Article DE emotional valence; baby schema; automatic response; baby faces; emotional representation; attitude towards infants; infrared thermography ID SKIN TEMPERATURE; BABY SCHEMA; FACES; REWARD; FEAR AB Adult-infant interactions operate simultaneously across multiple domains and at multiple levels - from physiology to behaviour. Unpackaging and understanding them, therefore, involve analysis of multiple data streams. In this study, we tested physiological responses and cognitive preferences for infant and adult faces in adult females and males. Infrared thermography was used to assess facial temperature changes as a measure of emotional valence, and we used a behavioural rating system to assess adults' expressed preferences. We found greater physiological activation in response to infant stimuli in females than males. As for cognitive preferences, we found greater responses to adult stimuli than to infant stimuli, both in males and females. The results are discussed in light of the Life History Theory. Finally, we discuss the importance of integrating the two data streams on our conclusions. C1 [Esposito, Gianluca; Stival, Rita] Univ Trent, Dept Psychol & Cognit Sci, Trento, Italy. [Esposito, Gianluca] RIKEN Brain Sci Inst, Unit Affiliat Social Behav, Wako, Saitama, Japan. [Nakazawa, Jun] Chiba Univ, Fac Educ, Dept Dev Sci, Chiba, Japan. [Ogawa, Shota] Tokyo Gakugei Univ, United Grad Sch Educ, Chiba, Japan. [Putnick, Diane L.; Bornstein, Marc H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Esposito, G (reprint author), Univ Trent, Dept Psychol & Cognit Sci, Trento, Italy. EM gianluca.esposito@unitn.it OI Putnick, Diane/0000-0002-6323-749X NR 35 TC 2 Z9 2 U1 2 U2 9 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0300-4430 EI 1476-8275 J9 EARLY CHILD DEV CARE JI Early Child Dev. Care PD MAR 4 PY 2015 VL 185 IS 3 BP 438 EP 447 DI 10.1080/03004430.2014.932153 PG 10 WC Psychology, Developmental SC Psychology GA CH8DR UT WOS:000354266900007 ER PT J AU Caprioli, D Jupp, B Hong, YT Sawiak, SJ Ferrari, V Wharton, L Williamson, DJ McNabb, C Berry, D Aigbirhio, FI Robbins, TW Fryer, TD Dalley, JW AF Caprioli, Daniele Jupp, Bianca Hong, Young T. Sawiak, Stephen J. Ferrari, Valentina Wharton, Laura Williamson, David J. McNabb, Carolyn Berry, David Aigbirhio, Franklin I. Robbins, Trevor W. Fryer, Tim D. Dalley, Jeffrey W. TI Dissociable Rate-Dependent Effects of Oral Methylphenidate on Impulsivity and D-2/3 Receptor Availability in the Striatum SO JOURNAL OF NEUROSCIENCE LA English DT Article DE addiction; attention-deficit hyperactivity disorder; dopamine; methylphenidate; nucleus accumbens; positron emission tomography ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; REACTION-TIME-TASK; DEFICIT HYPERACTIVITY DISORDER; PSYCHOMOTOR STIMULANT-DRUGS; PREFRONTAL CORTEX; NUCLEUS-ACCUMBENS; BEHAVIORAL PHARMACOLOGY; VENTRAL STRIATUM; ADOLESCENT RATS; WORKING-MEMORY AB We have previously shown that impulsivity in rats is linked to decreased dopamineD(2/3) receptor availability in the ventral striatum. In the present study, we investigated, using longitudinal positron emission tomography (PET), the effects of orally administered methylphenidate (MPH), a first-line treatment for attention deficit hyperactivity disorder, on D-2/3 receptor availability in the dorsal and ventral striatum and related these changes to impulsivity. Rats were screened for impulsive behavior on a five-choice serial reaction time task. After a baseline PET scan with the D-2/3 ligand [F-18] fallypride, rats received 6 mg/kg MPH, orally, twice each day for 28 d. Rats were then reassessed for impulsivity and underwent a second [F-18] fallypride PET scan. Before MPH treatment, we found that D-2/3 receptor availability was significantly decreased in the left but not the right ventral striatum of high-impulse (HI) rats compared with low-impulse (LI) rats. MPH treatment increased impulsivity in LI rats, and modulated impulsivity and D-2/3 receptor availability in the dorsal and ventral striatum of HI rats through inverse relationships with baseline levels of impulsivity and D-2/3 receptor availability, respectively. However, we found no relationship between the effects of MPH on impulsivity and D-2/3 receptor availability in any of the striatal subregions investigated. These findings indicate that trait-like impulsivity is associated with decreased D-2/3 receptor availability in the left ventral striatum, and that stimulant drugs modulate impulsivity and striatal D-2/3 receptor availability through independent mechanisms. C1 [Caprioli, Daniele] NIDA, Dept Hlth & Human Serv, Behav Neurosci Res Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Jupp, Bianca; Sawiak, Stephen J.; Wharton, Laura; Aigbirhio, Franklin I.; Robbins, Trevor W.; Fryer, Tim D.; Dalley, Jeffrey W.] Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England. [Jupp, Bianca; Wharton, Laura; Robbins, Trevor W.; Dalley, Jeffrey W.] Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England. [Hong, Young T.; Sawiak, Stephen J.; Ferrari, Valentina; Williamson, David J.; Aigbirhio, Franklin I.; Fryer, Tim D.] Univ Cambridge, Wolfson Brain Imaging Ctr, Dept Clin Neurosci, Cambridge CB2 0QQ, England. [McNabb, Carolyn] Univ Auckland, Sch Pharm, Auckland 1142, New Zealand. [Berry, David] Epilepsy Soc, Gerrards Cross SL9 0RJ, England. [Dalley, Jeffrey W.] Univ Cambridge, Dept Psychiat, Cambridge CB2 2QQ, England. RP Dalley, JW (reprint author), Univ Cambridge, Dept Psychol, Downing St, Cambridge CB2 3EB, England. EM jwd20@cam.ac.uk RI Sawiak, Stephen/I-8944-2012 OI Sawiak, Stephen/0000-0003-4210-9816 FU Medical Research Council Grant [G0701500]; Medical Research Council [G1000183]; Wellcome Trust of the Behavioural and Clinical Neuroscience Institute at the University of Cambridge [093875/Z/10/Z]; Medical Research Council of the ICCAM addiction cluster in the United Kingdom [G1000018]; AXA Research Fund; Australian National Health and Medical Research Council [1016313] FX This work was funded by Medical Research Council Grant G0701500, and by a joint award from the Medical Research Council (Grant G1000183) and the Wellcome Trust (Grant 093875/Z/10/Z) in support of the Behavioural and Clinical Neuroscience Institute at the University of Cambridge. We also acknowledge funding from the Medical Research Council in support of the ICCAM addiction cluster in the United Kingdom (G1000018). B.J. is supported by grants from the AXA Research Fund and the Australian National Health and Medical Research Council (Grant 1016313). NR 59 TC 10 Z9 10 U1 0 U2 14 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAR 4 PY 2015 VL 35 IS 9 BP 3747 EP 3755 DI 10.1523/JNEUROSCI.3890-14.2015 PG 9 WC Neurosciences SC Neurosciences & Neurology GA CD0DP UT WOS:000350740900003 PM 25740505 ER PT J AU Bouret, S Richmond, BJ AF Bouret, Sebastien Richmond, Barry J. TI Sensitivity of Locus Ceruleus Neurons to Reward Value for Goal-Directed Actions SO JOURNAL OF NEUROSCIENCE LA English DT Article DE decision-making; locus ceruleus; motivation; neuromodulation; noradrenaline; reward ID COERULEUS NEURONS; PHASIC ACTIVATION; NORADRENERGIC NEURONS; MOTIVATIONAL SALIENCE; PREFRONTAL CORTEX; MONKEYS; MODULATION; ATTENTION; STIMULI; SYSTEM AB The noradrenergic nucleus locus ceruleus (LC) is associated classically with arousal and attention. Recent data suggest that it might also play a role in motivation. To study how LC neuronal responses are related to motivational intensity, we recorded 121 single neurons from two monkeys while reward size (one, two, or four drops) and the manner of obtaining reward (passive vs active) were both manipulated. The monkeys received reward under three conditions: (1) releasing a bar when a visual target changed color; (2) passively holding a bar; or (3) touching and releasing a bar. In the first two conditions, a visual cue indicated the size of the upcoming reward, and, in the third, the reward was constant through each block of 25 trials. Performance levels and lipping intensity (an appetitive behavior) both showed that the monkeys' motivation in the task was related to the predicted reward size. In conditions 1 and 2, LC neurons were activated phasically in relation to cue onset, and this activation strengthened with increasing expected reward size. In conditions 1 and 3, LC neurons were activated before the bar-release action, and the activation weakened with increasing expected reward size but only in task 1. These effects evolved as monkeys progressed through behavioral sessions, because increasing fatigue and satiety presumably progressively decreased the value of the upcoming reward. These data indicate that LC neurons integrate motivationally relevant information: both external cues and internal drives. The LC might provide the impetus to act when the predicted outcome value is low. C1 [Bouret, Sebastien; Richmond, Barry J.] NIMH, Lab Neuropsychol, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. [Bouret, Sebastien] Grp Hosp Pitie Salpetriere, Inst Cerveau & Moelle Epiniere ICM, Brain Behav MBB Team, Motivat, F-75013 Paris, France. RP Bouret, S (reprint author), Grp Hosp Pitie Salpetriere, Inst Cerveau & Moelle Epiniere, Motivat Brain Behav Team, 47 Bd Hop, F-75013 Paris, France. EM sebastien.bouret@icm-institute.org OI Bouret, Sebastien/0000-0003-2279-6161 FU Intramural Research Program of the National Institute of Mental Health; European Research Council Starting Grant BIOMOTIV FX This work was supported by the Intramural Research Program of the National Institute of Mental Health. S.B. is supported by European Research Council Starting Grant BIOMOTIV. NR 38 TC 21 Z9 21 U1 1 U2 13 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAR 4 PY 2015 VL 35 IS 9 BP 4005 EP 4014 DI 10.1523/JNEUROSCI.4553-14.2015 PG 10 WC Neurosciences SC Neurosciences & Neurology GA CD0DP UT WOS:000350740900026 PM 25740528 ER PT J AU Kwak, JT Kajdacsy-Balla, A Macias, V Walsh, M Sinha, S Bhargava, R AF Kwak, Jin Tae Kajdacsy-Balla, Andre Macias, Virgilia Walsh, Michael Sinha, Saurabh Bhargava, Rohit TI Improving Prediction of Prostate Cancer Recurrence using Chemical Imaging SO SCIENTIFIC REPORTS LA English DT Article ID RAMAN-SCATTERING MICROSCOPY; RADICAL PROSTATECTOMY; POSTOPERATIVE NOMOGRAM; DISEASE RECURRENCE; BREAST-CANCER; PROGRESSION; STATISTICS; DIAGNOSIS; BIOPSY; RISK AB Precise Outcome prediction is crucial to providing optimal cancer care across the spectrum of solid cancers. Clinically-useful tools to predict risk of adverse events (metastases, recurrence), however, remain deficient. Here, we report an approach to predict the risk of prostate cancer recurrence, at the time of initial diagnosis, using a combination of emerging chemical imaging, a diagnostic protocol that focuses simultaneously on the tumor and its microenvironment, and data analysis of frequent patterns in molecular expression. Fourier transform infrared (FT-IR) spectroscopic imaging was employed to record the structure and molecular content from tumors prostatectomy. We analyzed data from a patient cohort that is mid-grade dominant - which is the largest cohort of patients in the modern era and in whom prognostic methods are largely ineffective. Our approach outperforms the two widely used tools, Kattan nomogram and CAPRA-S score in a head-to-head comparison for predicting risk of recurrence. Importantly, the approach provides a histologic basis to the prediction that identifies chemical and morphologic features in the tumor microenvironment that is independent of conventional clinical information, opening the door to similar advances in other solid tumors. C1 [Kwak, Jin Tae] NIH, Ctr Intervent Oncol, Bethesda, MD 20892 USA. [Kwak, Jin Tae; Sinha, Saurabh] Univ Illinois, Dept Comp Sci, Urbana, IL 61801 USA. [Kwak, Jin Tae; Walsh, Michael; Bhargava, Rohit] Univ Illinois, Beckman Inst Adv Sci & Technol, Urbana, IL 61801 USA. [Kajdacsy-Balla, Andre; Macias, Virgilia; Walsh, Michael] Univ Illinois, Dept Pathol, Chicago, IL 60612 USA. [Bhargava, Rohit] Univ Illinois, Dept Bioengn Mech Sci & Engn, Elect & Comp Engn, Chem & Biomol Engn, Urbana, IL 61801 USA. [Bhargava, Rohit] Univ Illinois, Univ Illinois Canc Ctr, Urbana, IL 61801 USA. RP Sinha, S (reprint author), Univ Illinois, Dept Comp Sci, Urbana, IL 61801 USA. EM sinhas@illinois.edu; rxb@illinois.edu OI Bhargava, Rohit/0000-0001-7360-994X FU National Institutes of Health [1R01CA138882] FX Support from the National Institutes of Health via grant 1R01CA138882 is gratefully acknowledged. We would like to thank Prof. Peter Gann of University of Illinois at Chicago for fruitful discussions and several valuable suggestions. NR 63 TC 17 Z9 18 U1 3 U2 16 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 MAR 4 PY 2015 VL 5 AR 8758 DI 10.1038/srep08758 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CC5CO UT WOS:000350375900031 PM 25737022 ER PT J AU Valapala, M Edwards, M Hose, S Hu, JF Wawrousek, E Lutty, GA Zigler, JS Qian, J Sinha, D AF Valapala, Mallika Edwards, Malia Hose, Stacey Hu, Jianfei Wawrousek, Eric Lutty, Gerard A. Zigler, J. Samuel, Jr. Qian, Jiang Sinha, Debasish TI beta A3/A1-crystallin is a critical mediator of STAT3 signaling in optic nerve astrocytes SO SCIENTIFIC REPORTS LA English DT Article ID VASCULAR DEVELOPMENT; NOTCH; CELLS; ANGIOGENESIS; RETINA; GROWTH; VEGF; ACTIVATION; FILOPODIA; TEMPLATE AB We have previously reported that in the Nuc1 rat, which has a spontaneous mutation in Cryba1 (the gene encoding beta A3/A1-crystallin), astrocytes exhibit decreased Notch signaling, leading to reduced promoter activity for glial fibrillary acidic protein (GFAP). Interestingly, in both Nuc1 astrocytes and in wild type astrocytes following knockdown of Cryba1, vascular endothelial growth factor (VEGF) secretion is decreased. This has led us to explore signaling mediators that could be regulated by beta A3/A1-crystallin to modulate both GFAP and VEGF. Several studies have shown that the signal transducer and activator of transcription 3 (STAT3) is involved in the co-regulation of GFAP and VEGF. We show that STAT3 and beta A3/A1-crystallin may co-regulate each other in astrocytes. Such co-regulation would create a positive feedback circuit; i.e., in the cytosol of astrocytes, beta A3/A1-crystallin is necessary for the phosphorylation of STAT3, which then dimerizes and translocates to the nucleus to form DNA-binding complexes, activating transcription of Cryba1. This stoichiometric co-regulation of STAT3 and Cryba1 could potentiate expression of GFAP and secretion of VEGF, both of which are essential for maintaining astrocyte and blood vessel homeostasis in the retina. Consistent with this idea, Cryba1 knockout mice exhibit an abnormal astrocyte pattern and defective remodeling of retinal vessels. C1 [Valapala, Mallika; Edwards, Malia; Hose, Stacey; Hu, Jianfei; Lutty, Gerard A.; Zigler, J. Samuel, Jr.; Qian, Jiang; Sinha, Debasish] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21287 USA. [Wawrousek, Eric] NEI, NIH, Bethesda, MD 20892 USA. RP Sinha, D (reprint author), Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21287 USA. EM Debasish@jhmi.edu FU National Institutes of Health [EY019037, EY019037-S, EY009357]; Research to Prevent Blindness FX We thank Dr. Morton F. Goldberg for critical reading and discussion of the manuscript and Dr. Celine Gongora for her help during the course of this study. This research was supported by National Institutes of Health: EY019037 (D.S.), EY019037-S (D.S.), EY009357 (G.L.) and Research to Prevent Blindness (an unrestricted grant to The Wilmer Eye Institute). NR 35 TC 4 Z9 4 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAR 4 PY 2015 VL 5 AR 8755 DI 10.1038/srep08755 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CC5CO UT WOS:000350375900028 PM 25736717 ER PT J AU Roberts, ME Gibbons, FX Gerrard, M Klein, WMP AF Roberts, Megan E. Gibbons, Frederick X. Gerrard, Meg Klein, William M. P. TI Individual Differences in Situation Awareness: Validation of the Situationism Scale SO JOURNAL OF SOCIAL PSYCHOLOGY LA English DT Article DE self control; self-regulation; alcohol use; scale validation; eating behavior ID SELF-CONTROL; EXTERNAL CONTROL; LAY THEORIES; DEPLETION; STRATEGIES; ADOLESCENTS; PERSONALITY; CONSUMPTION; PSYCHOLOGY; MOTIVATION AB ABSTRACT. This article concerns the construct of lay situationism-an individual's belief in the importance of a behavior's context. Study 1 identified a 13-item Situationism Scale, which demonstrated good reliability and validity. In particular, higher situationism was associated with greater situation-control (strategies to manipulate the environment in order to avoid temptation). Subsequent laboratory studies indicated that people higher on the situationism subscales used greater situation-control by sitting farther from junk food (Study 2) and choosing to drink non-alcoholic beverages before a cognitive task (Study 3). Overall, findings provide preliminary support for the psychometric validity and predictive utility of the Situationism Scale and offer this individual difference construct as a means to expand self-regulation theory. C1 [Roberts, Megan E.; Gibbons, Frederick X.] Dartmouth Coll, Hanover, NH 03755 USA. [Gerrard, Meg] Dartmouth Med Sch, Hanover, NH USA. [Klein, William M. P.] NCI, Bethesda, MD 20892 USA. RP Roberts, ME (reprint author), Ohio State Univ, Coll Publ Hlth, Columbus, OH 43210 USA. EM roberts.1558@osu.edu FU NIDA NIH HHS [R01 DA021898, T32 DA016184] NR 57 TC 0 Z9 0 U1 1 U2 10 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0022-4545 EI 1940-1183 J9 J SOC PSYCHOL JI J. Soc. Psychol. PD MAR 4 PY 2015 VL 155 IS 2 BP 143 EP 162 DI 10.1080/00224545.2014.977762 PG 20 WC Psychology, Social SC Psychology GA CB0PG UT WOS:000349328100005 PM 25329242 ER PT J AU Nguyen, AB Oh, A Moser, RP Patrick, H AF Nguyen, Anh B. Oh, April Moser, Richard P. Patrick, Heather TI Perceptions of the roles of behaviour and genetics in disease risk: Are they associated with behaviour change attempts SO PSYCHOLOGY & HEALTH LA English DT Article DE behaviour change; causal beliefs; chronic conditions ID STYLE CAUSAL BELIEFS; HEALTH INFORMATION; PHYSICAL-ACTIVITY; FAMILIAL HYPERCHOLESTEROLEMIA; PLANNED BEHAVIOR; PUBLIC-OPINION; ADOLESCENTS; OBESITY; METAANALYSIS; CHILDRENS AB The aims of the present study were to (i) examine the prevalence of perceived behavioural and genetic causal beliefs for four chronic conditions (i.e. obesity, heart disease, diabetes and cancer); (ii) to examine the association between these causal beliefs and attempts at behaviour change (i.e. physical activity, weight management, fruit intake, vegetable intake and soda intake). The data come from the Health Information National Trends Survey, a nationally representative population-based survey of adults (N=3407). Results indicated that participants held both behavioural and genetic causal beliefs for all four chronic conditions. Multivariate analyses indicated that behavioural causal beliefs were significantly associated with attempts to increase physical activity and vegetable intake and to decrease weight. Genetic causal beliefs for cancer were significantly associated with reported attempts to maintain weight. Behaviour and genetic causal beliefs were not associated with changes in either fruit or soda intake. In conclusion, while behavioural causal beliefs are associated with behavioural change, measurement must capture disease-specific behavioural causal beliefs as they are associated with different health behaviours. C1 [Nguyen, Anh B.; Oh, April; Moser, Richard P.; Patrick, Heather] NCI, Div Canc Control & Populat Sci, Rockville, MD 20852 USA. RP Nguyen, AB (reprint author), NCI, Div Canc Control & Populat Sci, Rockville, MD 20852 USA. EM Anh.Nguyen3@nih.gov NR 44 TC 1 Z9 1 U1 3 U2 25 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0887-0446 EI 1476-8321 J9 PSYCHOL HEALTH JI Psychol. Health PD MAR 4 PY 2015 VL 30 IS 3 BP 336 EP 353 DI 10.1080/08870446.2014.972958 PG 18 WC Public, Environmental & Occupational Health; Psychology, Multidisciplinary SC Public, Environmental & Occupational Health; Psychology GA AY4KO UT WOS:000347547000006 PM 25369236 ER PT J AU Beydoun, MA Beydoun, HA Dore, GA Fanelli-Kuczmarski, MT Evans, MK Zonderman, AB AF Beydoun, M. A. Beydoun, H. A. Dore, G. A. Fanelli-Kuczmarski, M. T. Evans, M. K. Zonderman, A. B. TI Total serum cholesterol, atherogenic indices and their longitudinal association with depressive symptoms among US adults SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID CARDIOVASCULAR RISK-FACTORS; LATE-LIFE DEPRESSION; MIDDLE-AGED MEN; CORONARY-HEART-DISEASE; PROSPECTIVE FOLLOW-UP; VITAMIN-E LEVELS; MAJOR DEPRESSION; PSYCHIATRIC-DISORDERS; COMMUNITY SAMPLE; LIPID PROFILE AB Serum cholesterol, both total and lipoprotein fractions, has been associated with mid-and late-life depression. Using longitudinal data on a large and ethnically diverse sample of urban adults, the associations of serum lipid profile measured by high or low total cholesterol (TC; >4200 mg dl(-1); <160 mg dl(-1)) and by atherogenic indices, namely high total cholesterol and low-density lipoprotein cholesterol relative to high-density lipoprotein cholesterol, with change in total and domain-specific depressive symptoms over time were examined. Findings were compared by sex. (Hypothesis 1) In addition, baseline depressive symptoms as predictors for longitudinal change in lipid profile trajectory were tested. (Hypothesis 2) Mixed-effects regression analyses stratified by sex was used. Sample sizes of participants (n) and repeated observations (n') were: Hypothesis 1 (Men: n = 826; n' = 1319; Women: n = 1099; n' = 1817); Hypothesis 2 (Men: n = 738; n' = 1230; Women: n = 964; n' = 1678). As hypothesized, a higher level of atherogenic indices was linked to faster increase in depressive symptom scores, particularly depressed affect and interpersonal problems, though this relationship was found only among women. Among men a U-shaped relationship between baseline TC and longitudinal increase in somatic complaints and a direct link between low TC and longitudinal putative improvement in positive affect was found. On excluding statin users among women, low TC was associated with slower increase in depressed affect over time, whereas high TC was associated with faster increase in interpersonal problems. In summary, atherogenic indices were directly linked to faster increase in depressive symptoms among women only. More studies are needed to explain these sex-specific associations. C1 [Beydoun, M. A.; Dore, G. A.; Evans, M. K.; Zonderman, A. B.] NIA, Biomed Res Ctr, NIH, IRP, Baltimore, MD 21224 USA. [Beydoun, H. A.] Eastern Virginia Med Sch, Grad Program Publ Hlth, Norfolk, VA 23501 USA. [Fanelli-Kuczmarski, M. T.] Univ Delaware, Dept Hlth Nutr & Exercise Sci, Newark, DE USA. RP Beydoun, MA (reprint author), NIA, Biomed Res Ctr, NIH, IRP, 251 Bayview Blvd,Suite 100,Room 04B118, Baltimore, MD 21224 USA. EM baydounm@mail.nih.gov FU Intramural Reasearch Program of the National Institutes of Health, National Insitute on Aging, NIA/NIH/IRP FX This work was fully supported by the Intramural Reasearch Program of the National Institutes of Health, National Insitute on Aging, NIA/NIH/IRP. NR 84 TC 6 Z9 6 U1 0 U2 0 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 MAR 3 PY 2015 VL 5 AR e518 DI 10.1038/tp.2015.4 PG 14 WC Psychiatry SC Psychiatry GA DA2VC UT WOS:000367653900002 PM 25734511 ER PT J AU Japee, S Holiday, K Satyshur, MD Mukai, I Ungerleider, LG AF Japee, Shruti Holiday, Kelsey Satyshur, Maureen D. Mukai, Ikuko Ungerleider, Leslie G. TI A role of right middle frontal gyrus in reorienting of attention: a case study SO FRONTIERS IN SYSTEMS NEUROSCIENCE LA English DT Article DE right middle frontal gyrus; dorsal attention network; ventral attention network; resting state fMRI; endogenous attention; exogenous attention; reorienting of attention; frontal lobe tumor resection ID STATE FUNCTIONAL CONNECTIVITY; POSTERIOR PARIETAL CORTEX; STIMULUS-DRIVEN ATTENTION; VISUAL-ATTENTION; SPATIAL ATTENTION; WORKING-MEMORY; SELECTIVE ATTENTION; CORTICAL MECHANISMS; PARKINSONS-DISEASE; NEURAL MECHANISMS AB The right middle fontal gyrus (MFG) has been proposed to be a site of convergence of the dorsal and ventral attention networks, by serving as a circuit-breaker to interrupt ongoing endogenous attentional processes in the dorsal network and reorient attention to an exogenous stimulus. Here, we probed the contribution of the right MFG to both endogenous and exogenous attention by comparing performance on an orientation discrimination task of a patient with a right MFG resection and a group of healthy controls. On endogenously cued trials, participants were shown a central cue that predicted with 90% accuracy the location of a subsequent peri-threshold Gabor patch stimulus. On exogenously cued trials, a cue appeared briefly at one of two peripheral locations, followed by a variable inter-stimulus interval (ISI; range 0-700 ms) and a Gabor patch in the same or opposite location as the cue. Behavioral data showed that for endogenous, and short ISI exogenous trials, valid cues facilitated responses compared to invalid cues, for both the patient and controls. However, at long ISIs, the patient exhibited difficulty in reverting to top-down attentional control, once the facilitatory effect of the exogenous cue had dissipated. When explicitly cued during long ISIs to attend to both stimulus locations, the patient was able to engage successfully in top-down control. This result indicates that the right MFG may play an important role in reorienting attention from exogenous to endogenous attentional control. Resting state fMRI data revealed that the right superior parietal lobule and right orbitofrontal cortex, showed significantly higher correlations with a left MFG seed region (a region tightly coupled with the right MFG in controls) in the patient relative to controls. We hypothesize that this paradoxical increase in cortical coupling represents a compensatory mechanism in the patient to offset the loss of function of the resected tissue in right prefrontal cortex. C1 [Japee, Shruti; Holiday, Kelsey; Ungerleider, Leslie G.] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Satyshur, Maureen D.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Mukai, Ikuko] Laureate Inst Brain Res, Tulsa, OK USA. RP Japee, S (reprint author), NIMH, Lab Brain & Cognit, NIH, 10 Ctr Dr,Room 10-4C104, Bethesda, MD 20892 USA. EM japees@mail.nih.gov NR 84 TC 8 Z9 9 U1 2 U2 4 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5137 J9 FRONT SYST NEUROSCI JI Front. Syst. Neurosci. PD MAR 3 PY 2015 VL 9 AR UNSP 23 DI 10.3389/fnsys.2015.00023 PG 16 WC Neurosciences SC Neurosciences & Neurology GA CU6VG UT WOS:000363672000001 PM 25784862 ER PT J AU Ghitza, UE Gore-Langton, RE Lindblad, R Tai, B AF Ghitza, Udi E. Gore-Langton, Robert E. Lindblad, Robert Tai, Betty TI NIDA clinical trials network common data elements initiative: advancing big-data addictive-disorders research SO FRONTIERS IN PSYCHIATRY LA English DT Editorial Material DE substance use disorders; addiction; addiction treatment; drug abuse treatment; health information technology; electronic health record; electronic medical record; medical informatics ID SUBSTANCE USE DISORDERS; INFORMATION C1 [Ghitza, Udi E.; Tai, Betty] NIDA, Ctr Clin Trials Network, NIH, Bethesda, MD 20892 USA. [Gore-Langton, Robert E.; Lindblad, Robert] EMMES Corp, Rockville, MD USA. RP Ghitza, UE (reprint author), NIDA, Ctr Clin Trials Network, NIH, Bethesda, MD 20892 USA. EM ghitzau@nida.nih.gov NR 13 TC 2 Z9 2 U1 2 U2 4 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-0640 J9 FRONT PSYCHIATRY JI Front. Psychiatry PD MAR 3 PY 2015 VL 6 AR 33 DI 10.3389/fpsyt.2015.00033 PG 3 WC Psychiatry SC Psychiatry GA CV4AL UT WOS:000364207700001 PM 25784882 ER PT J AU Yang, HP Cook, LS Weiderpass, E Adami, HO Anderson, KE Cai, H Cerhan, JR Clendenen, TV Felix, AS Friedenreich, CM Garcia-Closas, M Goodman, MT Liang, X Lissowska, J Lu, L Magliocco, AM McCann, SE Moysich, KB Olson, SH Petruzella, S Pike, MC Polidoro, S Ricceri, F Risch, HA Sacerdote, C Setiawan, VW Shu, XO Spurdle, AB Trabert, B Webb, PM Wentzensen, N Xiang, YB Xu, Y Yu, H Zeleniuch-Jacquotte, A Brinton, LA AF Yang, H. P. Cook, L. S. Weiderpass, E. Adami, H-O Anderson, K. E. Cai, H. Cerhan, J. R. Clendenen, T. V. Felix, A. S. Friedenreich, C. M. Garcia-Closas, M. Goodman, M. T. Liang, X. Lissowska, J. Lu, L. Magliocco, A. M. McCann, S. E. Moysich, K. B. Olson, S. H. Petruzella, S. Pike, M. C. Polidoro, S. Ricceri, F. Risch, H. A. Sacerdote, C. Setiawan, V. W. Shu, X. O. Spurdle, A. B. Trabert, B. Webb, P. M. Wentzensen, N. Xiang, Y-B Xu, Y. Yu, H. Zeleniuch-Jacquotte, A. Brinton, L. A. TI Infertility and incident endometrial cancer risk: a pooled analysis from the epidemiology of endometrial cancer consortium (E2C2) SO BRITISH JOURNAL OF CANCER LA English DT Article DE endometrial cancer; infertility; nulliparity; pooled analysis ID POLYCYSTIC-OVARY-SYNDROME; IN-VITRO FERTILIZATION; HOSPITAL DISCHARGE DIAGNOSIS; IOWA WOMENS HEALTH; REPRODUCTIVE FACTORS; GYNECOLOGICAL CONDITIONS; FERTILITY DRUGS; COHORT; BREAST; OVULATION AB Background: Nulliparity is an endometrial cancer risk factor, but whether or not this association is due to infertility is unclear. Although there are many underlying infertility causes, few studies have assessed risk relations by specific causes. Methods: We conducted a pooled analysis of 8153 cases and 11 713 controls from 2 cohort and 12 case-control studies. All studies provided selfreported infertility and its causes, except for one study that relied on data from national registries. Logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI). Results: Nulliparous women had an elevated endometrial cancer risk compared with parous women, even after adjusting for infertility (OR = 1.76; 95% CI: 1.59-1.94). Women who reported infertility had an increased risk compared with those without infertility concerns, even after adjusting for nulliparity (OR = 1.22; 95% CI: 1.13-1.33). Among women who reported infertility, none of the individual infertility causes were substantially related to endometrial cancer. Conclusions: Based on mainly self-reported infertility data that used study-specific definitions of infertility, nulliparity and infertility appeared to independently contribute to endometrial cancer risk. Understanding residual endometrial cancer risk related to infertility, its causes and its treatments may benefit from large studies involving detailed data on various infertility parameters. C1 [Yang, H. P.; Felix, A. S.; Trabert, B.; Wentzensen, N.; Brinton, L. A.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Cook, L. S.] Univ New Mexico, Albuquerque, NM 87131 USA. [Weiderpass, E.; Adami, H-O] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden. [Weiderpass, E.] Folkhalsan Res Ctr, Dept Genet Epidemiol, Helsinki 00014, Finland. [Weiderpass, E.] Canc Registry Norway, Dept Res, N-0304 Oslo, Norway. [Weiderpass, E.] Arctic Univ Norway, Univ Tromso, Dept Community Med, N-90109 Tromso, Norway. [Adami, H-O] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Anderson, K. E.] Univ Minnesota, Sch Publ Hlth, Minneapolis, MN 55454 USA. [Cai, H.; Shu, X. O.] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Dept Med,Div Epidemiol, Nashville, TN 37232 USA. [Cerhan, J. R.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA. [Clendenen, T. V.; Zeleniuch-Jacquotte, A.] NYU, Sch Med, Dept Populat Hlth, New York, NY 10016 USA. [Clendenen, T. V.; Zeleniuch-Jacquotte, A.] NYU, Sch Med, NYU Perimutter Canc Ctr, New York, NY 10016 USA. [Friedenreich, C. M.] Alberta Hlth Serv, Calgary, AB T2T 5C7, Canada. [Garcia-Closas, M.] Inst Canc Res, Sutton SM2 5NG, Surrey, England. [Goodman, M. T.] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 USA. [Liang, X.; Olson, S. H.; Petruzella, S.; Pike, M. C.; Xu, Y.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10065 USA. [Lissowska, J.] M Sklodowska Curie Mem Canc Ctr, PL-02781 Warsaw, Poland. [Lissowska, J.] Inst Oncol, PL-02781 Warsaw, Poland. [Lu, L.; Risch, H. A.] Yale Univ, Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT 06510 USA. [Magliocco, A. M.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. [Magliocco, A. M.] Res Inst, Tampa, FL 33612 USA. [McCann, S. E.; Moysich, K. B.] Roswell Pk Canc Inst, Buffalo, NY 14203 USA. [Pike, M. C.; Setiawan, V. W.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90089 USA. [Polidoro, S.; Ricceri, F.; Sacerdote, C.] Human Genet Fdn, I-10126 Turin, Italy. [Sacerdote, C.] Univ Turin, Canc Epidemiol Unit, I-10124 Turin, Italy. [Sacerdote, C.] Ctr Canc Prevent, I-10124 Turin, Italy. [Spurdle, A. B.; Webb, P. M.] QIMR Berghofer Med Res Inst, Herston, Qld 4029, Australia. [Xiang, Y-B] Shanghai Jiao Tong Univ, Sch Med, Renji Hosp, Shanghai Canc Inst, Shanghai 200030, Peoples R China. [Yu, H.] Univ Hawaii, Ctr Canc, Honolulu, HI 96813 USA. RP Yang, HP (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM yanghan@mail.nih.gov RI Garcia-Closas, Montserrat /F-3871-2015; Brinton, Louise/G-7486-2015; Trabert, Britton/F-8051-2015; Felix, Ashley/A-3240-2016; Weiderpass, Elisabete/M-4029-2016; Spurdle, Amanda/A-4978-2011; OI Garcia-Closas, Montserrat /0000-0003-1033-2650; Brinton, Louise/0000-0003-3853-8562; Weiderpass, Elisabete/0000-0003-2237-0128; Spurdle, Amanda/0000-0003-1337-7897; Sacerdote, Carlotta/0000-0002-8008-5096; Zeleniuch-Jacquotte, Anne/0000-0001-9350-1303 FU ALBERTA (Cancer Institute of Canada) [NIH R01 CA082838]; ALBERTA (Canadian Cancer Society) [NIH R01 CA082838]; ALBERTA (Canadian Institute for Health Research) [NIH R01 CA082838]; Alberta Innovates-Health Solutions; Alberta Cancer Foundation through the Weekend to End Women's Cancers Breast Cancer Chair; Canada Research Chairs program; ANECS (National Health and Medical Research Council (NHMRC) of Australia and the Cancer Council of Queensland) [339435]; ANECS (National Health and Medical Research Council (NHMRC) of Australia and the Cancer Council of Tasmania ) [339435]; NHMRC; CECS [NIH R01 CA098346]; EDGE [NIH R01 CA83918, P30CA008748]; HAW [NIH P01 CA33619, R01 CA58598, N01 CN67001, N01 PC35137]; IWHS [NIH R01 CA39742]; NYU (NIH/NCI) [R01 CA098661, R01 CA08121, P30 CA016087]; PECS (Intramural Research Funds of the NCI, NIH, Department of Health and Human Services); PEDS; SECS (NIH) [R01 CA092585]; TURIN (Italian Association for Research on Cancer and Ricerca Finalizzata Regione Piemonte); US (Intramural Research Funds of the NCI, NIH, the Department of Health and Human Services); USC [NIH R01 CA48774, P30 CA14089]; WLHS (the Swedish Research Council); WLHS (Swedish Cancer Society); WLHS (Hans-Olov Distinguished Professor Award at Karolinska Institutet) [2368-10-221]; Associazione Italiana per la Ricerca sul Cancro FX We thank many individuals who participated and the numerous institutions and their staff who supported the individual studies. We also thank Dr Leah Mechanic at NCI's Division of Cancer Control and Population Sciences for her support in the E2C2 activities. Individual studies were funded by the following grants and agencies: ALBERTA (Cancer Institute of Canada with funds from the Canadian Cancer Society and the Canadian Institute for Health Research, NIH R01 CA082838, CMF is supported by career awards from Alberta Innovates-Health Solutions and the Alberta Cancer Foundation through the Weekend to End Women's Cancers Breast Cancer Chair, LSC was supported through the Canada Research Chairs program); ANECS (National Health and Medical Research Council (NHMRC, grant # 339435) of Australia and the Cancer Councils of Queensland and Tasmania; PMW and ABS are supported by Fellowships from the NHMRC); CECS (NIH R01 CA098346); EDGE (NIH R01 CA83918; P30CA008748); HAW (NIH P01 CA33619, R01 CA58598, N01 CN67001, N01 PC35137); IWHS (NIH R01 CA39742); NYU (NIH/NCI grants R01 CA098661 and R01 CA08121, and Center grant P30 CA016087); PECS (Intramural Research Funds of the NCI, NIH, Department of Health and Human Services); PEDS; SECS (NIH Grant No. R01 CA092585); TURIN (Italian Association for Research on Cancer and Ricerca Finalizzata Regione Piemonte); US (Intramural Research Funds of the NCI, NIH, the Department of Health and Human Services); USC (NIH R01 CA48774 and P30 CA14089); WLHS (the Swedish Research Council, Swedish Cancer Society and the Hans-Olov Distinguished Professor Award at Karolinska Institutet (Dnr: 2368-10-221). NR 43 TC 5 Z9 6 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD MAR 3 PY 2015 VL 112 IS 5 BP 925 EP 933 DI 10.1038/bjc.2015.24 PG 9 WC Oncology SC Oncology GA CD8ZH UT WOS:000351384800019 PM 25688738 ER PT J AU Lee, C Zeng, J Drew, BG Sallam, T Martin-Montalvo, A Wan, JX Kim, SJ Mehta, H Hevener, AL de Cabo, R Cohen, P AF Lee, Changhan Zeng, Jennifer Drew, Brian G. Sallam, Tamer Martin-Montalvo, Alejandro Wan, Junxiang Kim, Su-Jeong Mehta, Hemal Hevener, Andrea L. de Cabo, Rafael Cohen, Pinchas TI The Mitochondrial-Derived Peptide MOTS-c Promotes Metabolic Homeostasis and Reduces Obesity and Insulin Resistance SO CELL METABOLISM LA English DT Article ID SMALL RIBOSOMAL-RNA; GERM PLASM; DROSOPHILA-MELANOGASTER; OXYGEN-CONSUMPTION; XENOPUS EMBRYOS; POLAR GRANULES; LIFE-SPAN; CELL; METFORMIN; HUMANIN AB Mitochondria are known to be functional organelles, but their role as a signaling unit is increasingly being appreciated. The identification of a short open reading frame (sORF) in the mitochondrial DNA (mtDNA) that encodes a signaling peptide, humanin, suggests the possible existence of additional sORFs in the mtDNA. Here we report a sORF within the mitochondrial 12S rRNA encoding a 16-amino-acid peptide named MOTS-c (mitochondrial open reading frame of the 12S rRNA-c) that regulates insulin sensitivity and metabolic homeostasis. Its primary target organ appears to be the skeletal muscle, and its cellular actions inhibit the folate cycle and its tethered de novo purine biosynthesis, leading to AMPK activation. MOTS-c treatment in mice prevented age-dependent and high-fat-diet-induced insulin resistance, as well as diet-induced obesity. These results suggest that mitochondria may actively regulate metabolic homeostasis at the cellular and organismal level via peptides encoded within their genome. C1 [Lee, Changhan; Zeng, Jennifer; Wan, Junxiang; Kim, Su-Jeong; Mehta, Hemal; Cohen, Pinchas] Univ So Calif, Leonard Davis Sch Gerontol, Los Angeles, CA 90089 USA. [Drew, Brian G.; Hevener, Andrea L.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Endocrinol Diabet & Hypertens, Los Angeles, CA 90095 USA. [Martin-Montalvo, Alejandro; de Cabo, Rafael] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. [Sallam, Tamer] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Cardiol, Los Angeles, CA 90095 USA. RP Lee, C (reprint author), Univ So Calif, Leonard Davis Sch Gerontol, Los Angeles, CA 90089 USA. EM changhan.lee@usc.edu; hassy@usc.edu RI de Cabo, Rafael/J-5230-2016; Martin-Montalvo, Alejandro/C-2031-2017; OI de Cabo, Rafael/0000-0002-3354-2442; Martin-Montalvo, Alejandro/0000-0002-3886-5355; Sallam, Tamer/0000-0001-7144-7393; , rafael/0000-0003-2830-5693 FU UCSD-UCLA Diabetes Research Center grant [NIH DK063491]; Glenn Foundation Award; NIH [1R01AG 034430, 1R01GM 090311, 1R01ES 020812]; Ellison Medical Foundation New Scholar Award; SC-CTSI grant; Hanson Thorell Family Research Award; Zumberge award FX We would like to thank Y. Zhang, E. Lehrmann, W. Wood, and K. Becker for microarray assistance, as well as Brianna Manes for graphical abstract assistance. P.C. is a stockholder of and consultant for, and C.L. is a consultant for, CohBar, Inc. This research was supported by a UCSD-UCLA Diabetes Research Center grant (NIH DK063491), a Glenn Foundation Award and NIH grants to P.C. (1R01AG 034430, 1R01GM 090311, 1R01ES 020812), and an Ellison Medical Foundation New Scholar Award, a SC-CTSI grant, a Hanson Thorell Family Research Award, and a Zumberge award to C.L. NR 62 TC 51 Z9 54 U1 8 U2 39 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 MAR 3 PY 2015 VL 21 IS 3 BP 443 EP 454 DI 10.1016/j.cmet.2015.02.009 PG 12 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA CD1ZI UT WOS:000350872800012 PM 25738459 ER PT J AU Li, P Ruan, XB Yang, L Kiesewetter, K Zhao, Y Luo, HT Chen, Y Gucek, M Zhu, J Cao, HM AF Li, Ping Ruan, Xiangbo Yang, Ling Kiesewetter, Kurtis Zhao, Yi Luo, Haitao Chen, Yong Gucek, Marjan Zhu, Jun Cao, Haiming TI A Liver-Enriched Long Non-Coding RNA, lncLSTR, Regulates Systemic Lipid Metabolism in Mice SO CELL METABOLISM LA English DT Article ID C-II DEFICIENCY; TRANSCRIPTION; HYPERTRIGLYCERIDEMIA; LIPOPROTEIN; ANNOTATION; MECHANISMS; EXPRESSION; PREDICTION; EVOLUTION; DISEASES AB Long non-coding RNAs (lncRNAs) constitute a significant portion of mammalian genome, yet the physiological importance of lncRNAs is largely unknown. Here, we identify a liver-enriched lncRNA in mouse that we term liver-specific triglyceride regulator (lncLSTR). Mice with a liver-specific depletion of lncLSTR exhibit a marked reduction in plasma triglyceride levels. We show that lncLSTR depletion enhances apoC2 expression, leading to robust lipoprotein lipase activation and increased plasma triglyceride clearance. We further demonstrate that the regulation of apoC2 expression occurs through an FXR-mediated pathway. LncLSTR forms a molecular complex with TDP-43 to regulate expression of Cyp8b1, a key enzyme in the bile acid synthesis pathway, and engenders an in vivo bile pool that induces apoC2 expression through FXR. Finally, we demonstrate that lncLSTR depletion can reduce triglyceride levels in a hyperlipidemia mouse model. Taken together, these data support a model in which lncLSTR regulates a TDP-43/FXR/apoC2-dependent pathway to maintain systemic lipid homeostasis. C1 [Li, Ping; Ruan, Xiangbo; Yang, Ling; Kiesewetter, Kurtis; Cao, Haiming] NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. [Zhao, Yi; Luo, Haitao] Chinese Acad Sci, Inst Comp Technol, Key Lab Intelligent Informat Proc, Beijing, Peoples R China. [Chen, Yong; Gucek, Marjan] NHLBI, Prote Core, NIH, Bethesda, MD 20892 USA. [Zhu, Jun] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. RP Cao, HM (reprint author), NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. EM haiming.cao@nih.gov RI Yang, Ling/F-4404-2016; Zhao, Yi/A-2962-2011; Cao, Haiming/P-4634-2016; Ruan, Xiangbo/P-9265-2016 OI Zhao, Yi/0000-0001-6046-8420; FU Division of Intramural Research of the National Heart Lung and Blood Institute of the NIH, USA [HL006103, HL006159]; National Natural Science Foundation of China [31371320] FX This work was supported by the Division of Intramural Research of the National Heart Lung and Blood Institute (HL006103 and HL006159) of the NIH, USA. Y.Z. and H.L. were supported by a grant from National Natural Science Foundation of China (No. 31371320). NR 39 TC 36 Z9 45 U1 2 U2 29 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 MAR 3 PY 2015 VL 21 IS 3 BP 455 EP 467 DI 10.1016/j.cmet.2015.02.004 PG 13 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA CD1ZI UT WOS:000350872800013 PM 25738460 ER PT J AU Scholz, SW Jeon, BS AF Scholz, Sonja W. Jeon, Beom S. TI GBA mutations and Parkinson disease When genotype meets phenotype SO NEUROLOGY LA English DT Editorial Material ID GAUCHER-DISEASE; GLUCOCEREBROSIDASE MUTATIONS; GENE AB The last 2 decades have seen remarkable advances in our understanding of genetic risk factors underlying the pathogenesis of Parkinson disease (PD). One of the most surprising discoveries was that mutations in GBA (glucosidase, beta, acid), coding for the lysosomal enzyme glucocerebrosidase, have a substantial role in PD. While homozygous GBA mutations were known for some time as the cause of Gaucher disease, subsequent clinical, neuropathologic, and genetic studies established that heterozygous and occasional homozygous mutations in this gene are also common risk factors for PD, particularly in the Ashkenazi-Jewish population.(1-790% of SIVcpz and SIVgor strains with low-nanomolar (0.13 to 8.4 nM) potency. Importantly, the latter antibodies blocked virus entry not only in TZM-bl cells but also in Cf2Th cells expressing chimpanzee CD4 and CCR5 and neutralized SIVcpz in chimpanzee CD4(+) T cells, with 50% inhibitory concentrations (IC(50)s) ranging from 3.6 to 40.5 nM. These findings provide new insight into the protective capacity of anti-HIV-1 bNabs and identify candidates for further development to combat SIVcpz infection. IMPORTANCE SIVcpz is widespread in wild-living chimpanzees and can cause AIDS-like immunopathology and clinical disease. HIV-1 infection of humans can be controlled by antiretroviral therapy; however, treatment of wild-living African apes with current drug regimens is not feasible. Nonetheless, it may be possible to curb the spread of SIVcpz in select ape communities using vectored immunoprophylaxis and/or therapy. Here, we show that antibodies and antibody-like inhibitors developed to combat HIV-1 infection in humans are capable of neutralizing genetically diverse SIVcpz and SIVgor strains with considerable breadth and potency, including in primary chimpanzee CD4(+) T cells. These reagents provide an important first step toward translating intervention strategies currently developed to treat and prevent AIDS in humans to SIV-infected apes. C1 [Barbian, Hannah J.; Bibollet-Ruche, Frederic; Learn, Gerald H.; Parrish, Nicholas F.; Iyer, Shilpa S.; Li, Yingying; Shaw, George M.; Hahn, Beatrice H.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Barbian, Hannah J.; Bibollet-Ruche, Frederic; Learn, Gerald H.; Parrish, Nicholas F.; Iyer, Shilpa S.; Li, Yingying; Shaw, George M.; Hahn, Beatrice H.] Univ Penn, Dept Microbiol, Philadelphia, PA 19104 USA. [Decker, Julie M.] Univ Alabama Birmingham, Dept Microbiol, Birmingham, AL 35294 USA. [Galimidi, Rachel P.; West, Anthony P., Jr.; Bjorkman, Pamela J.] CALTECH, Div Biol & Biol Engn, Pasadena, CA 91125 USA. [Galimidi, Rachel P.; West, Anthony P., Jr.; Bjorkman, Pamela J.] CALTECH, Howard Hughes Med Inst, Pasadena, CA 91125 USA. [Pace, Craig S.] Gilead Sci Inc, Foster City, CA 94404 USA. [Song, Ruijiang; Huang, Yaoxing; Ho, David D.] Rockefeller Univ, Aaron Diamond AIDS Res Ctr, New York, NY 10021 USA. [Denny, Thomas N.] Duke Univ, Sch Med, Duke Human Vaccine Inst, Durham, NC USA. [Mouquet, Hugo; Nussenzweig, Michel C.] Rockefeller Univ, Lab Mol Immunol, New York, NY 10021 USA. [Mouquet, Hugo; Nussenzweig, Michel C.] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10021 USA. [Mouquet, Hugo] Inst Pasteur, Dept Immunol, Lab Humoral Response Pathogens, F-75724 Paris, France. [Martin, Loic] CEA, IBiTecS, Serv Ingn Mol Prot, Gif Sur Yvette, France. [Acharya, Priyamvada; Zhang, Baoshan; Kwong, Peter D.; Mascola, John R.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Verrips, C. Theo] QVQ BV, Utrecht, Netherlands. [Strokappe, Nika M.; Rutten, Lucy] Univ Utrecht, Fac Sci, Biomol Imaging BMI, Utrecht, Netherlands. [McCoy, Laura E.; Weiss, Robin A.] UCL, Div Infect & Immun, London, England. [Brown, Corrine S.; Jackson, Raven] Chimp Haven Inc, Keithville, LA USA. [Silvestri, Guido] Emory Univ, Yerkes Reg Primate Res Ctr, Atlanta, GA 30322 USA. [Connors, Mark] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Burton, Dennis R.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Farzan, Michael] Scripps Res Inst, Dept Immunol & Microbial Sci, Jupiter, FL USA. RP Hahn, BH (reprint author), Univ Penn, Dept Med, Philadelphia, PA 19104 USA. EM bhahn@upenn.edu FU National Institutes of Health [R37 AI 50529, R01 AI 58715, R37 AI 066998, P01 AI 088564, P51 RR 000165, P30 AI 045008]; Federal Government; National Institutes of Health FX This work was supported by grants from the National Institutes of Health (R37 AI 50529, R01 AI 58715, R37 AI 066998, P01 AI 088564, P51 RR 000165, and P30 AI 045008).; The views and opinions expressed in this publication represent the authors' views alone and do not express or imply the views, endorsement, or financial support of the Federal Government or any of its agencies, including the National Institutes of Health, unless otherwise stated by an authorized representative thereof. NR 137 TC 2 Z9 2 U1 3 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD MAR-APR PY 2015 VL 6 IS 2 AR e00296-15 DI 10.1128/mBio.00296-15 PG 22 WC Microbiology SC Microbiology GA CJ2KE UT WOS:000355312400007 ER PT J AU Noriea, NF Clark, TR Hackstadt, T AF Noriea, Nicholas F. Clark, Tina R. Hackstadt, Ted TI Targeted Knockout of the Rickettsia rickettsii OmpA Surface Antigen Does Not Diminish Virulence in a Mammalian Model System SO MBIO LA English DT Article ID MOUNTAIN-SPOTTED-FEVER; OUTER-MEMBRANE PROTEIN; ACTIN-BASED MOTILITY; MONOCLONAL-ANTIBODIES; TRANSPOSON MUTAGENESIS; DERMACENTOR-ANDERSONI; PLAQUE-ASSAY; PROWAZEKII; GENE; CELLS AB Strains of Rickettsia rickettsii, the causative agent of Rocky Mountain spotted fever (RMSF), differ dramatically in virulence despite >99% genetic homology. Spotted fever group (SFG) rickettsiae produce two immunodominant outer membrane proteins, rickettsial OmpA (rOmpA) and rOmpB, which are conserved throughout the SFG and thought to be fundamental to pathogenesis. rOmpA is present in all virulent strains of R. rickettsii but is not produced in the only documented avirulent strain, Iowa, due to a premature stop codon. Here we report the creation of an isogenic ompA mutant in the highly virulent strain Sheila Smith by insertion of intronic RNA to create a premature stop codon 312 bp downstream of the 6,747-bp open reading frame initiation site (int312). Targeted insertion was accomplished using an LtrA group II intron retrohoming system. Growth and entry rates of Sheila Smith ompA:: int312 in Vero cells remained comparable to those of the wild type. Virulence was assessed in a guinea pig model by challenge with 100 PFU of either ompA:: int312 Sheila Smith or the wild type, but no significant difference in either fever peak (40.5 degrees C) or duration (8 days) were shown between the wild type and the knockout. The ability to disrupt genes in a site-specific manner using an LtrA group II intron system provides an important new tool for evaluation of potential virulence determinants in rickettsial disease research. IMPORTANCE R. rickettsii rOmpA is an immunodominant outer membrane autotransporter conserved in the spotted fever group. Previous studies and genomic comparisons suggest that rOmpA is involved in adhesion and may be critical for virulence. Little information is available for rickettsial virulence factors in an isogenic background, as limited systems for targeted gene disruption are currently available. Here we describe the creation of an rOmpA knockout by insertion of a premature stop codon into the 5' end of the open reading frame using a group II intron system. An isogenic rOmpA knockout mutation in the highly virulent Sheila Smith strain did not cause attenuation in a guinea pig model of infection, and no altered phenotype was observed in cell culture. We conclude that rOmpA is not critical for virulence in a guinea pig model but may play a role in survival or transmission from the tick vector. C1 [Noriea, Nicholas F.; Clark, Tina R.; Hackstadt, Ted] NIAID, Host Parasite Interact Sect, Intracellular Parasites Lab, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. RP Hackstadt, T (reprint author), NIAID, Host Parasite Interact Sect, Intracellular Parasites Lab, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. EM Ted_Hackstadt@NIH.gov FU NIAID, NIH FX This work was supported by the Intramural Research Program of the NIAID, NIH. NR 58 TC 5 Z9 5 U1 1 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD MAR-APR PY 2015 VL 6 IS 2 AR e00323-15 DI 10.1128/mBio.00323-15 PG 9 WC Microbiology SC Microbiology GA CJ2KE UT WOS:000355312400071 ER PT J AU Qi, YW Zhu, F Eastman, RT Fu, Y Zilversmit, M Pattaradilokrat, S Hong, LX Liu, SF McCutchan, TF Pan, WQ Xu, WY Li, J Huang, FS Su, XZ AF Qi, Yanwei Zhu, Feng Eastman, Richard T. Fu, Young Zilversmit, Martine Pattaradilokrat, Sittiporn Hong, Lingxian Liu, Shengfa McCutchan, Thomas F. Pan, Weiqing Xu, Wenyue Li, Jian Huang, Fusheng Su, Xin-Zhuan TI Regulation of Plasmodium yoelii Oocyst Development by Strain- and Stage-Specific Small-Subunit rRNA SO MBIO LA English DT Article ID STRUCTURALLY DISTINCT; MALARIA PARASITE; GENETIC CROSSES; RODENT MALARIA; LIFE-CYCLE; BERGHEI; FALCIPARUM; MICROSATELLITES; LEVEL; GFP AB One unique feature of malaria parasites is the differential transcription of structurally distinct rRNA (rRNA) genes at different developmental stages: the A-type genes are transcribed mainly in asexual stages, whereas the S-type genes are expressed mostly in sexual or mosquito stages. Conclusive functional evidence of different rRNAs in regulating stage-specific parasite development, however, is still absent. Here we performed genetic crosses of Plasmodium yoelii parasites with one parent having an oocyst development defect (ODD) phenotype and another producing normal oocysts to identify the gene(s) contributing to the ODD. The parent with ODD-characterized as having small oocysts and lacking infective sporozoites-was obtained after introduction of a plasmid with a green fluorescent protein gene into the parasite genome and subsequent passages in mice. Quantitative trait locus analysis of genome-wide microsatellite genotypes of 48 progeny from the crosses linked an similar to 200-kb segment on chromosome 6 containing one of the S-type genes (D-type small subunit rRNA gene [D-ssu]) to the ODD. Fine mapping of the plasmid integration site, gene expression pattern, and gene knockout experiments demonstrated that disruption of the D-ssu gene caused the ODD phenotype. Interestingly, introduction of the D-ssu gene into the same parasite strain (self), but not into a different subspecies, significantly affected or completely ablated oocyst development, suggesting a stage-and subspecies (strain)-specific regulation of oocyst development by D-ssu. This study demonstrates that P. yoelii D-ssu is essential for normal oocyst and sporozoite development and that variation in the D-ssu sequence can have dramatic effects on parasite development. IMPORTANCE Malaria parasites are the only known organisms that express structurally distinct rRNA genes at different developmental stages. The differential expression of these genes suggests that they play unique roles during the complex life cycle of the parasites. Conclusive functional proof of different rRNAs in regulating parasite development, however, is still absent or controversial. Here we functionally demonstrate for the first time that a stage-specifically expressed D-type small-subunit rRNA gene (D-ssu) is essential for oocyst development of the malaria parasite Plasmodium yoelii in the mosquito. This study also shows that variations in D-ssu sequence and/or the timing of transcription may have profound effects on parasite oocyst development. The results show that in addition to protein translation, rRNAs of malaria parasites also regulate parasite development and differentiation in a strain-specific manner, which can be explored for controlling parasite transmission. C1 [Qi, Yanwei; Zhu, Feng; Hong, Lingxian; Liu, Shengfa; Li, Jian; Su, Xin-Zhuan] Xiamen Univ, State Key Lab Cellular Stress Biol, Innovat Ctr Cell Signaling Network, Sch Life Sci, Xiamen, Fujian, Peoples R China. [Qi, Yanwei; Eastman, Richard T.; Zilversmit, Martine; Pattaradilokrat, Sittiporn; Su, Xin-Zhuan] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Zhu, Feng; Fu, Young; Xu, Wenyue; Huang, Fusheng] Third Mil Med Univ, Dept Pathogen Biol, Chongqing, Peoples R China. [Pattaradilokrat, Sittiporn] Chulalongkorn Univ, Fac Sci, Dept Biol, Bangkok, Thailand. [McCutchan, Thomas F.; Pan, Weiqing] Second Mil Med Univ, Dept Pathogen Biol, Shanghai, Peoples R China. RP Huang, FS (reprint author), Third Mil Med Univ, Dept Pathogen Biol, Chongqing, Peoples R China. EM jianli_204@xmu.edu.cn; fushenghster@gmail.com; xsu@niaid.nih.gov OI Xu, Wenyue/0000-0003-3681-5052; Su, Xinzhuan/0000-0003-3246-3248 FU National Natural Science Foundation of China [81271858, 81220108019, 81201324]; Project 111 of the State Bureau of Foreign Experts; Ministry of Education of China [B06016]; Fundamental Research Funds for the Central Universities [2011121031]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the National Natural Science Foundation of China no. 81271858, 81220108019, and no. 81201324, by Project 111 of the State Bureau of Foreign Experts and Ministry of Education of China (B06016), by the Fundamental Research Funds for the Central Universities (2011121031), and by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 32 TC 0 Z9 0 U1 0 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD MAR-APR PY 2015 VL 6 IS 2 AR e00117-15 DI 10.1128/mBio.00117-15 PG 12 WC Microbiology SC Microbiology GA CJ2KE UT WOS:000355312400080 PM 25759501 ER PT J AU Schellenberg, MJ Tumbale, PP Williams, RS AF Schellenberg, Matthew J. Tumbale, Percy P. Williams, R. Scott TI Molecular underpinnings of Aprataxin RNA/DNA deadenylase function and dysfunction in neurological disease SO PROGRESS IN BIOPHYSICS & MOLECULAR BIOLOGY LA English DT Review DE Aptx; Aprataxin; AOA1; DNA damage response; DNA ligase; Neurodegenerative disease ID STRAND-BREAK REPAIR; HISTIDINE TRIAD SUPERFAMILY; ATAXIA-OCULOMOTOR APRAXIA-1; OCULAR MOTOR APRAXIA; DNA-DAMAGE RESPONSE; HIT PROTEIN FAMILY; NEURODEGENERATIVE DISEASE; RIBONUCLEOTIDE INCORPORATION; POLYNUCLEOTIDE KINASE; CEREBELLAR-ATAXIA AB Eukaryotic DNA ligases seal DNA breaks in the final step of DNA replication and repair transactions via a three-step reaction mechanism that can abort if DNA ligases encounter modified DNA termini, such as the products and repair intermediates of DNA oxidation, alkylation, or the aberrant incorporation of ribonucleotides into genomic DNA. Such abortive DNA ligation reactions act as molecular checkpoint for DNA damage and create 5'-adenylated nucleic acid termini in the context of DNA and RNA-DNA substrates in DNA single strand break repair (SSBR) and ribonucleotide excision repair (RER). Aprataxin (APTX), a protein altered in the heritable neurological disorder Ataxia with Oculomotor Apraxia 1 (AOA1), acts as a DNA ligase "proofreader" to directly reverse AMP-modified nucleic acid termini in DNA- and RNA-DNA damage responses. Herein, we survey APTX function and the emerging cell biological, structural and biochemical data that has established a molecular foundation for understanding the APTX mediated deadenylation reaction, and is providing insights into the molecular bases of APTX deficiency in AOA1. Published by Elsevier Ltd. C1 [Schellenberg, Matthew J.; Tumbale, Percy P.; Williams, R. Scott] NIEHS, Genome Integr & Struct Biol Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Williams, RS (reprint author), NIEHS, Genome Integr & Struct Biol Lab, NIH, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. EM williamsrs@niehs.nih.gov RI Williams, Robert/A-6059-2015 FU NIH Intramural Program: National Institute of Environmental Health Sciences [1Z01ES102765] FX Our studies are supported by the NIH Intramural Program: National Institute of Environmental Health Sciences, 1Z01ES102765 to R.S.W. We thank J Williams, S Andres and B Wallace for comments. NR 68 TC 5 Z9 5 U1 1 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0079-6107 J9 PROG BIOPHYS MOL BIO JI Prog. Biophys. Mol. Biol. PD MAR PY 2015 VL 117 IS 2-3 BP 157 EP 165 DI 10.1016/j.pbiomolbio.2015.01.007 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA CI8MH UT WOS:000355025900005 PM 25637650 ER PT J AU Pommier, Y Murai, J AF Pommier, Y. Murai, J. TI CLASSIFICATION OF PARP INHIBITORS BASED ON PARP TRAPPING AND CATALYTIC INHIBITION, AND RATIONALE FOR COMBINATIONS SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 13th International Congress on Targeted Anticancer Therapies (TAT) CY MAR 02-04, 2015 CL Paris, FRANCE C1 [Pommier, Y.] NCI, Bethesda, MD 20892 USA. [Murai, J.] Kyoto Univ, Kyoto, Japan. NR 0 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD MAR PY 2015 VL 26 SU 2 MA O6.1 BP 8 EP 8 DI 10.1093/annonc/mdv084.1 PG 1 WC Oncology SC Oncology GA CI4OC UT WOS:000354729300008 ER PT J AU Bates, S Lindenberg, M Bryla, C Patronas, N Amiri-Kordestani, L Fojo, T Balasubramaniam, S Choyke, P AF Bates, S. Lindenberg, M. Bryla, C. Patronas, N. Amiri-Kordestani, L. Fojo, T. Balasubramaniam, S. Choyke, P. TI ANG-1005 IN PATIENTS WITH BRAIN METASTASES FROM BREAST CANCER: CORRELATIVE IMAGING WITH 18F-FLT-PET/CT SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 13th International Congress on Targeted Anticancer Therapies (TAT) CY MAR 02-04, 2015 CL Paris, FRANCE C1 [Bates, S.; Lindenberg, M.; Bryla, C.; Amiri-Kordestani, L.; Fojo, T.; Balasubramaniam, S.; Choyke, P.] NCI, Bethesda, MD 20892 USA. [Patronas, N.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD MAR PY 2015 VL 26 SU 2 MA P2.01 BP 20 EP 20 DI 10.1093/annonc/mdv091.1 PG 1 WC Oncology SC Oncology GA CI4OC UT WOS:000354729300020 ER PT J AU Stratula, OR Kalendar, RN Sivolap, YM AF Stratula, O. R. Kalendar, R. N. Sivolap, Yu M. TI Allelic Variants of the Gene bamy1 Barley in Eastern European and Central Asian Areas SO CYTOLOGY AND GENETICS LA English DT Article DE beta-amylase; intron; genetic diversity ID INVERTED-REPEAT ELEMENTS; HORDEUM-VULGARE L.; BETA-AMYLASE; THERMOSTABILITY; FERMENTABILITY; POLYMORPHISMS; REVEALS; FAMILY AB Collections of varieties of spring barley cultivars from Eastern European and Central Asian areas were analyzed by exon-specific PCR (EPIC) for beta-amylase genes. The endosperm beta-amylase gene (bamy1) was differentiated by the presence of 126 bp MITE insertion into intron 3, which is associated with low activity beta-amylase. The findings suggest that a low level of genetic variation for bamy1 gene within climatic zones is associated with individual breeding program for each climatic zone. C1 [Stratula, O. R.; Sivolap, Yu M.] Natl Ctr Seed & Cultivar Investigat, Plant Breeding & Genet Inst, UA-65036 Odessa, Ukraine. [Kalendar, R. N.] Natl Ctr Biotechnol, Astana 010000, Kazakhstan. RP Stratula, OR (reprint author), Natl Ctr Seed & Cultivar Investigat, Plant Breeding & Genet Inst, Ovidopolskaya Doroga 3-13, UA-65036 Odessa, Ukraine. EM olgastratula@rambler.ru RI Kalendar, Ruslan/D-9751-2012 OI Kalendar, Ruslan/0000-0003-3986-2460 FU Gene Isolation and Search of New Alleles of Wheat Genome; National Center of Biotechnology of the Scientific Committee of the Ministry of Education and Science of the Republic of Kazakhstan FX This work was supported by the Gene Isolation and Search of New Alleles of Wheat Genome grant of the National Center of Biotechnology of the Scientific Committee of the Ministry of Education and Science of the Republic of Kazakhstan. We thank A.A. Pomortsev (Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia); the Head of the Department of Selection and Barley Seed Farming of SGI, A.A. Linchevsky; and the Deputy Director of the Yuryev Plant Production Institute (National Academy of Agrarian Sciences, Ukraine), V.K. Ryabchun for their kind help and for providing barley seeds. NR 25 TC 0 Z9 0 U1 1 U2 3 PU ALLERTON PRESS INC PI NEW YORK PA 18 WEST 27TH ST, NEW YORK, NY 10001 USA SN 0095-4527 EI 1934-9440 J9 CYTOL GENET+ JI Cytol. Genet. PD MAR PY 2015 VL 49 IS 2 BP 80 EP 89 DI 10.3103/S0095452715020103 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA CI2XU UT WOS:000354612300002 ER PT J AU Han, B Compton, WM Gfroerer, J McKeon, R AF Han, Beth Compton, Wilson M. Gfroerer, Joseph McKeon, Richard TI Prevalence and Correlates of Past 12-Month Suicide Attempt Among Adults With Past-Year Suicidal Ideation in the United States SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID NATIONAL COMORBIDITY SURVEY; MAJOR DEPRESSIVE DISORDER; SUBSTANCE USE; RISK-FACTORS; BEHAVIOR; HEALTH; PREDICTORS; PLANS; DEATH AB Objective: To examine the prevalence and correlates of attempting suicide in the past 12 months among adults with past-year suicidal ideation in the United States. Method: Data were from 229,600 persons aged 18 years or older who participated in the 2008-2012 National Survey on Drug Use and Health. Among them, 12,300 reported having past-year suicidal ideation, and over 2,000 of those reported attempting suicide within the past 12 months prior to survey interview. Descriptive analyses and pooled and stratified (by suicide plan and major depressive episode [MDE]) multivariate logistic regression models were applied. Major depressive episode was based on assessments of individual diagnostic criteria from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). Results: Among persons aged 18 years or older in the United States, 3.8% reported having suicidal ideation in the past 12 months. Among past-year suicidal ideators, 13.2% attempted suicide in the past 12 months. The prevalence of past 12-month suicide attempt among past-year ideators with MDE was higher than among those without MDE (14.1% vs 12.0%). Past 12-month suicide attempt was more common among ideators with a suicide plan than among ideators without a plan (37.0% vs 3.7%). However, the prevalence of suicide attempt was higher among ideators with a plan but without MDE than among ideators with a plan and MDE (42.1% vs 32.9%). Compared with ideators without a plan, ideators with a plan had a higher (adjusted odds ratio [AOR] = 2.2; 95% confidence interval [CI], 1.47-3.45) suicide attempt risk among those without MDE (AOR = 22.4; 95% CI, 16.55-30.27) than among those with MDE (AOR = 10.7; 95% CI, 7.91-14.49). Conclusions: Among adult suicidal ideators, factors associated with their progression from ideation to suicide attempt may vary by their suicide plan and major depression status. Focusing attention on high-risk subgroups may be warranted. (C) Copyright 2015 Physicians Postgraduate Press, Inc. C1 [Han, Beth; Gfroerer, Joseph; McKeon, Richard] Subst Abuse & Mental Hlth Serv Adm, Rockville, MD USA. [Compton, Wilson M.] NIDA, NIH, Bethesda, MD 20892 USA. RP Han, B (reprint author), 1 Choke Cherry Rd,Room 7-1010, Rockville, MD 20857 USA. EM Beth.Han@SAMHSA.HHS.GOV FU Pfizer FX All individuals in a position to influence the content of this activity were asked to complete a statement regarding all relevant personal financial relationships between themselves or their spouse/partner and any commercial interest. The CME Institute has resolved any conflicts of interest that were identified. In the past year, Alan J. Gelenberg, MD, Editor in Chief, has been a consultant for Zynx Health and Bloom Burton, has received grant/research support from Pfizer, and has been a stock shareholder of Healthcare Technology Systems. No member of the CME Institute staff reported any relevant personal financial relationships. Faculty financial disclosure appears at the end of the article. NR 34 TC 9 Z9 9 U1 0 U2 4 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 MAR PY 2015 VL 76 IS 3 BP 295 EP 302 DI 10.4088/JCP.14m09287 PG 8 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA CI7PD UT WOS:000354955400024 PM 25830449 ER PT J AU Smith, MD Adeniji, A Wahed, AS Patterson, E Chapman, W Courcoulas, AP Dakin, G Flum, D McCloskey, C Mitchell, JE Pomp, A Staten, M Wolfe, B AF Smith, Mark D. Adeniji, Abidemi Wahed, Abdus S. Patterson, Emma Chapman, William Courcoulas, Anita P. Dakin, Gregory Flum, David McCloskey, Carol Mitchell, James E. Pomp, Alfons Staten, Myrlene Wolfe, Bruce TI Technical factors associated with anastomotic leak after Roux-en-Y gastric bypass SO SURGERY FOR OBESITY AND RELATED DISEASES LA English DT Article DE Roux-en-Y gastric bypass; Anastomotic leak; Technical factors ID BARIATRIC SURGERY; INTRAOPERATIVE ENDOSCOPY; LONGITUDINAL ASSESSMENT; RANDOMIZED-TRIAL; COMPLICATIONS; MORTALITY; OUTCOMES; TRENDS; OBESITY; SAFETY AB Background: Anastomotic leak is one of the most serious complications after Roux-en-Y gastric bypass (RYGB). Our objective was to examine the relationship between technical factors and incidence of clinically relevant anastomotic leak after RYGB in longitudinal assessment of bariatric surgery (LABS). The setting of the study was 11 bariatric centers in the United States, university, and private practice. Methods: Patient characteristics, technical factors of surgery, and postoperative outcomes were assessed by trained researchers using standardized protocols. Correlation of surgical factors of patients undergoing RYGB (n = 4444) with the incidence of postoperative anastomotic leak was assessed by univariate chi(2) analysis. Results: Forty-four participants (1.0%, 95% CI .7%-1.3%) experienced a clinically relevant anastomotic leak. Of these, 39 (89%) underwent abdominal reoperation and 3 (7%) died. Technical factors associated with anastomotic leak were open surgery (P < .0001), revision surgery (P < .0001), and use of an abdominal drain (P = .02). Provocative leak testing, method of gastrojejunostomy, and use of fibrin sealant were not associated with anastomotic leak. Conclusions: Anastomotic leak after RYGB was rare (1.0%). Most cases required reintervention; however, the majority (93%) recovered from this event. Open surgery, revision surgery, and routine drain placement were associated with increased leak rate. Some of these findings may be due to differences in preoperative patient risk. (C) 2015 American Society for Metabolic and Bariatric Surgery. Published by Elsevier Inc. All rights reserved. C1 [Smith, Mark D.; Patterson, Emma] Legacy Good Samaritan Med Ctr, Portland, OR USA. [Adeniji, Abidemi] Boehringer Ingelheim GmbH & Co KG, Ridgefield, CT USA. [Wahed, Abdus S.] Univ Pittsburgh, Pittsburgh, PA USA. [Chapman, William] E Carolina Univ, Sch Med, Dept Surg, Greenville, NC 27858 USA. [Courcoulas, Anita P.; McCloskey, Carol] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Dakin, Gregory; Pomp, Alfons] Cornell Univ, New York, NY 10021 USA. [Flum, David] Univ Washington, Dept Surg, Seattle, WA 98195 USA. [Mitchell, James E.] Neuropsychiat Res Inst, Fargo, ND USA. [Staten, Myrlene] Natl Inst Diabet & Digest & Kidney Dis, Bethesda, MD USA. [Wolfe, Bruce] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. RP Smith, MD (reprint author), 37 Duke St, Invercargill 9810, New Zealand. EM mdsmith2@mac.com OI Wahed, Abdus/0000-0001-6911-7221 FU NCATS NIH HHS [UL1 TR000005]; NIDDK NIH HHS [U01 DK066526, U01 DK066568, U01 DK066667, U01 DK066557, U01 DK066585, P30 DK017047, U01 DK066555] NR 28 TC 7 Z9 7 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1550-7289 EI 1878-7533 J9 SURG OBES RELAT DIS JI Surg. Obes. Relat. Dis. PD MAR-APR PY 2015 VL 11 IS 2 BP 313 EP 320 DI 10.1016/j.soard.2014.05.036 PG 8 WC Surgery SC Surgery GA CI0HU UT WOS:000354418500012 PM 25595919 ER PT J AU Nalls, MA Bras, J Hernandez, DG Keller, MF Majounie, E Renton, AE Saad, M Jansen, I Guerreiro, R Lubbe, S Plagnol, V Gibbs, JR Schulte, C Pankratz, N Sutherland, M Bertram, L Lill, CM DeStefano, AL Faroud, T Eriksson, N Tung, JY Edsall, C Nichols, N Brooks, J Arepalli, S Pliner, H Letson, C Heutink, P Martinez, M Gasser, T Traynor, BJ Wood, N Hardy, J Singleton, AB AF Nalls, Mike A. Bras, Jose Hernandez, Dena G. Keller, Margaux F. Majounie, Elisa Renton, Alan E. Saad, Mohamad Jansen, Iris Guerreiro, Rita Lubbe, Steven Plagnol, Vincent Gibbs, J. Raphael Schulte, Claudia Pankratz, Nathan Sutherland, Margaret Bertram, Lars Lill, Christina M. DeStefano, Anita L. Faroud, Tatiana Eriksson, Nicholas Tung, Joyce Y. Edsall, Connor Nichols, Noah Brooks, Janet Arepalli, Sampath Pliner, Hannah Letson, Chris Heutink, Peter Martinez, Maria Gasser, Thomas Traynor, Bryan J. Wood, Nick Hardy, John Singleton, Andrew B. CA Int Parkinson's Dis Genomics Conso Parkinson's Dis Meta-Anal Consorti TI NeuroX, a fast and efficient genotyping platform for investigation of neurodegenerative diseases SO NEUROBIOLOGY OF AGING LA English DT Article DE Genotyping; Methods; Genetics; Neurodegeneration; Parkinson's; Meta-analysis; Imputation ID GENOME-WIDE ASSOCIATION; PARKINSONS-DISEASE; ALZHEIMERS-DISEASE; COMMON VARIANTS; IDENTIFICATION; IMPUTATION AB Our objective was to design a genotyping platform that would allow rapid genetic characterization of samples in the context of genetic mutations and risk factors associated with common neurodegenerative diseases. The platform needed to be relatively affordable, rapid to deploy, and use a common and accessible technology. Central to this project, we wanted to make the content of the platform open to any investigator without restriction. In designing this array we prioritized a number of types of genetic variability for inclusion, such as known risk alleles, disease-causing mutations, putative risk alleles, and other functionally important variants. The array was primarily designed to allow rapid screening of samples for disease-causing mutations and large population studies of risk factors. Notably, an explicit aim was to make this array widely available to facilitate data sharing across and within diseases. The resulting array, NeuroX, is a remarkably cost and time effective solution for high-quality genotyping. NeuroX comprises a backbone of standard Illumina exome content of approximately 240,000 variants, and over 24,000 custom content variants focusing on neurologic diseases. Data are generated at approximately $50-$60 per sample using a 12-sample format chip and regular Infinium infrastructure; thus, genotyping is rapid and accessible to many investigators. Here, we describe the design of NeuroX, discuss the utility of NeuroX in the analyses of rare and common risk variants, and present quality control metrics and a brief primer for the analysis of NeuroX derived data. Published by Elsevier Inc. RP Singleton, AB (reprint author), NIA, Neurogenet Lab, 35 Lincoln Dr, Bethesda, MD 20892 USA. EM singleta@mail.nih.gov RI Martinez, Maria/B-3111-2013; Deloukas, Panos/B-2922-2013; Singleton, Andrew/C-3010-2009; Hardy, John/C-2451-2009; Lubbe, Steven/L-8261-2013; Schapira, Anthony/A-1245-2010; Lill, Christina/J-9449-2015; Pliner, Hannah/F-3608-2015; Lunnon, Katie/C-4638-2012; Scheffer, Hans/E-4644-2012; Bertram, Lars/K-3889-2015; Morris, Huw/B-8527-2008; Houlden, Henry/C-1532-2008; corvol, jean-christophe/I-6387-2012; OI Martinez, Maria/0000-0003-2180-4537; Deloukas, Panos/0000-0001-9251-070X; Schapira, Anthony/0000-0002-3018-3966; Lill, Christina/0000-0002-2805-1307; Pliner, Hannah/0000-0003-1484-6501; Lunnon, Katie/0000-0001-7570-6065; Scheffer, Hans/0000-0002-2986-0915; Bertram, Lars/0000-0002-0108-124X; Chen, Honglei/0000-0003-3446-7779; Morris, Huw/0000-0002-5473-3774; Houlden, Henry/0000-0002-2866-7777; corvol, jean-christophe/0000-0001-7325-0199; Bras, Jose/0000-0001-8186-0333; Seshadri, Sudha/0000-0001-6135-2622; Plagnol, Vincent/0000-0002-5597-9215; Wood, Nicholas/0000-0002-9500-3348 FU Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services [Z01-AG000949-02, 2003077]; Wellcome Trust and/or MRC Joint Call in Neurodegeneration award [WT089698] FX This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services (project numbers Z01-AG000949-02, under human subjects protocol 2003077), and by the Wellcome Trust and/or MRC Joint Call in Neurodegeneration award (WT089698) to the UK Parkinson's Disease Consortium (UKPDC) whose members are from the UCL/Institute of Neurology, the University of Sheffield, and the MRC Protein Phosphorylation Unit at the University of Dundee. Additional funding information is provided in the consortium information section included as a Supplementary online appendix. Special thanks to Megan L. Grove-Gaona, Jerome Rotter, Eric Boerwinkle, and Christopher O'Donnell on behalf of the CHARGE consortium for the their helpful advice on aspects of this project. The authors thank the NHLBI GO Exome Sequencing Project and its ongoing studies which produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the WHI Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926), and the Heart GO Sequencing Project (HL-103010). They thank and acknowledge all who made this research possible. 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), and DNA panels, samples, and clinical data from the National Institute of Neurological Disorders and Stroke Human Genetics Resource Center DNA and Cell Line Repository. People who contributed samples are acknowledged in descriptions of every panel on the repository website. They thank the French Parkinson's Disease Genetics Study Group: Y Agid, M Anheim, A-M Bonnet, M Borg, A Brice, E Broussolle, J-C Corvol, P Damier, A Destee, A Durr, F Durif, S Klebe, E Lohmann, M Martinez, P Pollak, O Rascol, F Tison, C Tranchant, M Verin, F Viallet, and M Vidailhet. They also thank the members of the French 3C Consortium: A Alperovitch, C Berr, C Tzourio, and P Amouyel for allowing us to use part of the 3C cohort, and D Zelenika for support in generating the genome-wide molecular data. They thank P Tienari (Molecular Neurology Programme, Biomedicum, University of Helsinki), T Peuralinna (Department of Neurology, Helsinki University Central Hospital), L Myllykangas (Folkhalsan Institute of Genetics and Department of Pathology, University of Helsinki), and R Sulkava (Department of Public Health and General Practice Division of Geriatrics, University of Eastern Finland) for the Finnish controls (Vantaa85+ GWAS data). NR 24 TC 12 Z9 12 U1 2 U2 17 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD MAR PY 2015 VL 36 IS 3 AR 1605.e7 DI 10.1016/j.neurobiolaging.2014.07.028 PG 6 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA CI1XJ UT WOS:000354538100057 PM 25444595 ER PT J AU Rollinson, S Callister, JB Young, K Ryan, SJ Druyeh, R Rohrer, JD Snowden, J Richardson, A Jones, M Harris, J Davidson, Y Robinson, A Ealing, J Johnson, JO Traynor, B Mead, S Mann, D Pickering-Brown, SM AF Rollinson, Sara Callister, Janis Bennion Young, Kate Ryan, Sarah J. Druyeh, Ronald Rohrer, Jonathan D. Snowden, Julie Richardson, Anna Jones, Matt Harris, Jenny Davidson, Yvonne Robinson, Andrew Ealing, John Johnson, Janel O. Traynor, Bryan Mead, Simon Mann, David Pickering-Brown, Stuart M. TI A small deletion in C9orf72 hides a proportion of expansion carriers in FTLD SO NEUROBIOLOGY OF AGING LA English DT Article DE Frontotemporal lobar degeneration; FTLD; C9orf72; Repeat expansion; ALS ID HEXANUCLEOTIDE REPEAT; GGGGCC-REPEAT; MUTATIONS; TAU; FTD; ALS AB Frontotemporal lobar degeneration is a highly familial disease and the most common known genetic cause is the repeat expansion mutation in the gene C9orf72. We have identified 2 brothers with an expansion mutation in C9orf72 using Southern blotting that is undetectable using repeat-primed polymerase chain reaction. Sequencing using high concentrations of DNA denaturants of a bacterial artificial chromosome clone obtained from one of the brothers identified a 10-base pair deletion adjacent to the expansion that presumably confers strong secondary structure that interferes with the genotyping. Using an alternative method, we have identified missed expansion carriers in our cohort, and this number has increased by approximately 25%. This observation has important implications for patients undergoing genetic testing for C9orf72. (C) 2015 The Authors. Published by Elsevier Inc. C1 [Rollinson, Sara; Callister, Janis Bennion; Young, Kate; Ryan, Sarah J.; Pickering-Brown, Stuart M.] Univ Manchester, Inst Brain Behav & Mental Hlth, Fac Human & Med Sci, Manchester M13 9PT, Lancs, England. [Druyeh, Ronald; Rohrer, Jonathan D.] UCL Inst Neurol, Dept Neurodegenerat Dis, Dementia Res Ctr, London, England. [Snowden, Julie; Richardson, Anna; Jones, Matt; Harris, Jenny; Davidson, Yvonne; Robinson, Andrew; Mann, David] Univ Manchester, Fac Human & Med Sci, Salford Royal Hosp, Mental Hlth & Neurodegenerat Res Grp, Salford, Lancs, England. [Ealing, John] Salford Royal NHS Fdn Trust, Greater Manchester Neurosci Ctr, MND Care Ctr, Salford, Lancs, England. [Johnson, Janel O.; Traynor, Bryan] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Mead, Simon] UCL Inst Neurol, Dept Neurodegenerat Dis, London, England. RP Pickering-Brown, SM (reprint author), Univ Manchester, Inst Brain Behav & Mental Hlth, AV Hill Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England. EM SPB@Manchester.ac.uk RI Pickering-Brown, Stuart/D-4008-2009; OI Pickering-Brown, Stuart/0000-0003-1561-6054; Snowden, Julie/0000-0002-3976-4310; Rohrer, Jonathan/0000-0002-6155-8417 FU Medical Research Council [G0701441] FX This work was supported by the Medical Research Council (G0701441). NR 16 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD MAR PY 2015 VL 36 IS 3 AR 1601.e5 DI 10.1016/j.neurobiolaging.2014.12.009 PG 5 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA CI1XJ UT WOS:000354538100042 ER PT J AU Piercy, KL Dorn, JM Fulton, JE Janz, KF Lee, SM McKinnon, RA Pate, RR Pfeiffer, KA Young, DR Troiano, RP Lavizzo-Mourey, R AF Piercy, Katrina L. Dorn, Joan M. Fulton, Janet E. Janz, Kathleen F. Lee, Sarah M. McKinnon, Robin A. Pate, Russell R. Pfeiffer, Karin A. Young, Deborah Rohm Troiano, Richard P. Lavizzo-Mourey, Risa TI Opportunities for Public Health to Increase Physical Activity Among Youths SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material ID CHILD-CARE; INTERVENTIONS; ENVIRONMENT; PRESCHOOL; PROGRAM AB Despite the well-known benefits of youths engaging in 60 or more minutes of daily physical activity, physical inactivity remains a significant public health concern. The 2008 Physical Activity Guidelines for Americans (PAG) provides recommendations on the amount of physical activity needed for overall health; the PAG Midcourse Report (2013) describes effective strategies to help youths meet these recommendations. Public health professionals can be dynamic change agents where youths live, learn, and play by changing environments and policies to empower youths to develop regular physical activity habits to maintain throughout life. We have summarized key findings from the PAG Midcourse Report and outlined actions that public health professionals can take to ensure that all youths regularly engage in health-enhancing physical activity. C1 [Piercy, Katrina L.] US Dept HHS, Off Dis Prevent & Hlth Promot, Rockville, MD USA. [Dorn, Joan M.; Fulton, Janet E.; Lee, Sarah M.] US Dept HHS, Ctr Dis Control & Prevent, Atlanta, GA USA. [Janz, Kathleen F.] Univ Iowa, Dept Hlth & Human Physiol, Iowa City, IA USA. [McKinnon, Robin A.; Troiano, Richard P.] US Dept HHS, NIH, Bethesda, MD USA. [Pate, Russell R.] Univ S Carolina, Dept Exercise Sci, Columbia, SC 29208 USA. [Pfeiffer, Karin A.] Michigan State Univ, Dept Kinesiol, E Lansing, MI 48824 USA. [Young, Deborah Rohm] Kaiser Permanente So Calif, Dept Res & Evaluat, Pasadena, CA 91101 USA. [Lavizzo-Mourey, Risa] Robert Wood Johnson Fdn, Princeton, NJ 08540 USA. RP Piercy, KL (reprint author), 1101Wootton Pkwy,Suite LL100, Rockville, MD 20852 USA. EM Katrina.Piercy@hhs.gov OI Troiano, Richard/0000-0002-6807-989X NR 32 TC 7 Z9 7 U1 0 U2 5 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 MAR PY 2015 VL 105 IS 3 BP 421 EP 426 DI 10.2105/AJPH.2014.302325 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CH5DP UT WOS:000354055100019 PM 25602864 ER PT J AU Rosenthal, J AF Rosenthal, Joshua TI The Real Challenge for Cookstoves and Health: More Evidence SO ECOHEALTH LA English DT Editorial Material ID HOUSEHOLD AIR-POLLUTION; RISK-FACTOR; DISEASE C1 NIH, Div Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Rosenthal, J (reprint author), NIH, Div Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. EM joshua_rosenthal@nih.gov NR 17 TC 2 Z9 2 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1612-9202 EI 1612-9210 J9 ECOHEALTH JI EcoHealth PD MAR PY 2015 VL 12 IS 1 BP 8 EP 11 DI 10.1007/s10393-014-0997-9 PG 4 WC Biodiversity Conservation; Ecology; Environmental Sciences SC Biodiversity & Conservation; Environmental Sciences & Ecology GA CH3EK UT WOS:000353910000002 PM 25691140 ER PT J AU Capannolo, M Fasciani, I Romeo, S Aloisi, G Rossi, M Bellio, P Celenza, G Cinque, B Cifone, MG Scarselli, M Maggio, R AF Capannolo, Marta Fasciani, Irene Romeo, Stefania Aloisi, Gabriella Rossi, Mario Bellio, Pierangelo Celenza, Giuseppe Cinque, Benedetta Cifone, Maria Grazia Scarselli, Marco Maggio, Roberto TI The atypical antipsychotic clozapine selectively inhibits interleukin 8 (IL-8)-induced neutrophil chemotaxis SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Article DE Clozapine; Neutrophil chemotaxis; Agranulocytosis; Multi-drug resistance proteins; Leukotriene B4 ID CANCER RESISTANCE PROTEIN; HEMATOLOGICAL TOXICITY; HEMATOPOIETIC-CELLS; LEUKOTRIENE B-4; RECEPTOR; DRUGS; TRANSPORTER; ACTIVATION; AGONIST; 5-LIPOXYGENASE AB Clozapine is the most effective antipsychotic to date, but its benefits are counterbalanced by the risk of severe hematological effects. In this study, we analyzed whether clozapine inhibits polymorphonuclear (PMN) leukocyte chemotaxis. We found that clozapine, within the therapeutic concentration range, potently and selectively inhibits PMN chemotaxis induced by interleukin 8 (IL-8), a chemokine inducing neutrophil migration. The effect was not due to its action at dopamine, serotonin and nnuscarinic receptors, or to a direct antagonism to IL-8 receptors. Furthermore, clozapine did not inhibit PMN chemotaxis by its presumed toxic mechanism. In fact, after an overnight incubation in cell culture, the drug did not increase the physiological PMN apoptosis. An interference of clozapine with the autocrine release of leukotriene B4 (LTB4), a secondary chemoattractant secreted by neutrophils in response to the primary chemoattractant IL-8, was hypothesized. In agreement with this hypothesis, clozapine attenuated the IL-8-induced release of LTB4 in PMNs. A series of experiments with an antagonist of the LTB4 receptor, U75302, and an inhibitor of LTB4 synthesis, zileuton, provided support to this conjecture. Intriguingly MK-571, an inhibitor of the multi-drug resistance protein MRP4, playing a pivotal role in effluxing LTB4, completely blocked PMN chemotaxis induced by IL-8, but gave conflicting results when tested for its ability to reduce LTB4 release, increasing LTB4 efflux by itself but reducing the release when in combination with IL-8. The reduction of PMN chemotaxis due to clozapine could predispose patients to infections. Whether this effect is a prelude to clozapine agranulocytosis requires further investigation. (C) 2014 Elsevier B.V. and ECNP. All rights reserved. C1 [Capannolo, Marta; Fasciani, Irene; Romeo, Stefania; Aloisi, Gabriella; Bellio, Pierangelo; Celenza, Giuseppe; Maggio, Roberto] Univ Aquila, Biotechnol & Appl Clin Sci Dept, I-67100 Laquila, Italy. [Rossi, Mario] NIDDK, Mol Signaling Sect, Bethesda, MD 20892 USA. [Cinque, Benedetta; Cifone, Maria Grazia] Univ Aquila, Dept Life Hlth & Environm Sci, I-67100 Laquila, Italy. [Scarselli, Marco] Univ Pisa, Dept Translat Res & New Technol Med, I-56126 Pisa, Italy. RP Maggio, R (reprint author), Univ Aquila, Biotechnol & Appl Clin Sci Dept, Via Vetoio Coppito 2, I-67100 Laquila, Italy. EM roberto.maggio@univaq.it RI Celenza, Giuseppe/A-4940-2016; OI Scarselli, Marco/0000-0001-5087-3182; Capannolo, Marta/0000-0001-9485-1276; Bellio, Pierangelo/0000-0001-6488-8027; Celenza, Giuseppe/0000-0003-2796-9228; Maggio, Roberto/0000-0003-4436-2356; Cinque, Benedetta/0000-0003-4510-9416; CIFONE, Maria Grazia/0000-0002-9923-5445 FU Biotechnological and Applied Clinical Sciences Department (University of L'Aquila, Italy) FX Funding for this study was provided by the Biotechnological and Applied Clinical Sciences Department (University of L'Aquila, Italy). The Department had no further role in study design, in the collection, analysis and interpretation of data, and in the decision to submit the paper for publication. NR 49 TC 1 Z9 1 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X EI 1873-7862 J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD MAR PY 2015 VL 25 IS 3 BP 413 EP 424 DI 10.1016/j.euroneuro.2014.12.002 PG 12 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CH0VL UT WOS:000353740400014 PM 25554564 ER PT J AU Legrand, F Klion, AD AF Legrand, Fanny Klion, Amy D. TI Biologic Therapies Targeting Eosinophils: Current Status and Future Prospects SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE LA English DT Review DE Hypereosinophilic syndrome; Eosinophilic gastrointestinal disorders; Asthma; mAb; Mepolizumab; Reslizumab; Benralizumab ID CHURG-STRAUSS-SYNDROME; HUMANIZED MONOCLONAL-ANTIBODY; PLACEBO-CONTROLLED TRIAL; RECEPTOR-ALPHA; SEVERE ASTHMA; MEPOLIZUMAB THERAPY; SPUTUM EOSINOPHILIA; PERSISTENT ASTHMA; ATOPIC-DERMATITIS; DOUBLE-BLIND AB The recent explosion in the number of biologic therapies in clinical development for the treatment of eosinophilic disorders is unprecedented. As these agents become available for clinical use, the selection of the most appropriate agent for a given patient will become increasingly complicated. The aims of this review were 2-fold: (1) to present the lessons learned from clinical trials using the first generation of eosinophil-targeted biologics (antieIL-5 antibodies) and (2) to discuss the advantages and potential limitations of currently available and novel targeted therapies to treat eosinophilic disorders. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology C1 [Legrand, Fanny; Klion, Amy D.] NIAID, Parasit Dis Lab, Human Eosinophil Sect, NIH, Bethesda, MD 20892 USA. RP Klion, AD (reprint author), NIH, Bldg 4,Rm B1-28, Bethesda, MD 20892 USA. EM a.klion@nih.gov OI Klion, Amy/0000-0002-4986-5326 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 86 TC 9 Z9 9 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2213-2198 EI 2213-2201 J9 J ALLER CL IMM-PRACT JI J. Allergy Clin. Immunol.-Pract. PD MAR-APR PY 2015 VL 3 IS 2 BP 167 EP 174 DI 10.1016/j.jaip.2015.01.013 PG 8 WC Allergy; Immunology SC Allergy; Immunology GA CH7JI UT WOS:000354211800003 PM 25754717 ER PT J AU Ogbogu, PU Klion, AD AF Ogbogu, Princess U. Klion, Amy D. TI Hypereosinophilic Disorders SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE LA English DT Editorial Material DE Eosinophil; Hypereosinophilic syndrome; FIP1L1-PDGFRA ID IMATINIB C1 [Ogbogu, Princess U.] Ohio State Univ, Wexner Med Ctr, Div Pulm Allergy Crit Care & Sleep Med, Columbus, OH 43210 USA. [Klion, Amy D.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Ogbogu, PU (reprint author), Ohio State Univ, Wexner Med Ctr, 473 W 12th Ave,201 DHLRI, Columbus, OH 43210 USA. EM princess.ogbogu@osumc.edu OI Klion, Amy/0000-0002-4986-5326 FU Intramural NIH HHS [ZIA AI001130-04] NR 5 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2213-2198 EI 2213-2201 J9 J ALLER CL IMM-PRACT JI J. Allergy Clin. Immunol.-Pract. PD MAR-APR PY 2015 VL 3 IS 2 BP 304 EP 305 DI 10.1016/j.jaip.2014.09.024 PG 2 WC Allergy; Immunology SC Allergy; Immunology GA CH7JI UT WOS:000354211800029 PM 25754721 ER PT J AU Besschetnova, TY Ichimura, T Katebi, N St Croix, B Bonventre, JV Olsen, BR AF Besschetnova, Tatiana Y. Ichimura, Takaharu Katebi, Negin St Croix, Brad Bonventre, Joseph V. Olsen, Bjorn R. TI Regulatory mechanisms of anthrax toxin receptor 1-dependent vascular and connective tissue homeostasis SO MATRIX BIOLOGY LA English DT Review DE Hemangioma; Angiogenesis; Fibrosis; GAPO syndrome; MMP2 ID OF-THE-LITERATURE; GAPO SYNDROME; INFANTILE HEMANGIOMA; WINCHESTER-SYNDROME; ACTIN CYTOSKELETON; FIBROTIC RESPONSE; TGF-BETA; IN-VIVO; CELL; MATRIX-METALLOPROTEINASE-2 AB It is well known that angiogenesis is linked to fibrotic processes in fibroproliferative diseases, but insights into pathophysiological processes are limited, due to lack of understanding of molecular mechanisms controlling endothelial and fibroblastic homeostasis. We demonstrate here that the matrix receptor anthrax toxin receptor 1 (ANTXR1), also known as tumor endothelial marker 8 (TEM8), is an essential component of these mechanisms. Loss of TEM8 function in mice causes reduced synthesis of endothelial basement membrane components and hyperproliferative and leaky blood vessels in skin. In addition, endothelial cell alterations in mutants are almost identical to those of endothelial cells in infantile hemangioma lesions, including activated VEGF receptor signaling in endothelial cells, increased expression of the downstream targets VEGF and CXCL12, and increased numbers of macrophages and mast cells. In contrast, loss of TEM8 in fibroblasts leads to increased rates of synthesis of fiber-forming collagens, resulting in progressive fibrosis in skin and other organs. Compromised interactions between TEM8-deficient endothelial and fibroblastic cells cause dramatic reduction in the activity of the matrix-degrading enzyme MMP2. In addition to insights into mechanisms of connective tissue homeostasis, our data provide molecular explanations for vascular and connective tissue abnormalities in GAPO syndrome, caused by loss-of-function mutations in ANTXR1. Furthermore, the loss of MMP2 activity suggests that fibrotic skin abnormalities in GAPO syndrome are, in part, the consequence of pathophysiological mechanisms underlying syndromes (NAO, Torg and Winchester) with multicentric skin nodulosis and osteolysis caused by homozygous loss-of-function mutations in MMP2. (C) 2015 Elsevier B.V. C1 [Besschetnova, Tatiana Y.; Katebi, Negin; Olsen, Bjorn R.] Harvard Univ, Sch Dent Med, Dept Dev Biol, Boston, MA 02115 USA. [Ichimura, Takaharu; Bonventre, Joseph V.] Brigham & Womens Hosp, Dept Med, Div Renal, Boston, MA 02115 USA. [St Croix, Brad] NCI, Tumor Angiogenesis Sect, Mouse Canc Genet Program, NIH, Frederick, MD 21701 USA. [Bonventre, Joseph V.] Harvard MIT Div Hlth Sci & Technol, Cambridge, MA USA. [Olsen, Bjorn R.] Harvard Univ, Sch Med, Dept Cell Biol, Cambridge, MA 02138 USA. RP Besschetnova, TY (reprint author), Harvard Univ, Sch Dent Med, 188 Longwood Ave,REB 409-406, Boston, MA 02115 USA. EM Tatiana_Besschetnova@hms.harvard.edu; Bjorn_Olsen@hms.harvard.edu FU Program Project grant "Molecular and Cellular Mechanisms of Vascular Anomalies" [P01 AR48564]; NIH [R37DK39773] FX We thank Nikon Imaging Center, Electron Microscopy facility, Mass Spectrometry and Isotope Counting centers at Harvard Medical School for providing equipment and technical assistance when needed. Authors also thank Sofiya Plotkina for the technical assistance in mouse husbandry and genotyping analysis. We also thank the members of the Olsen laboratory and members of the Program Project for helpful discussions. We are grateful for the service (generation of Antxr1 null and Antxr1 KI mouse strains) provided by the trans-NIH Knock-Out Mouse Project (KOMP) and Applied StemCell, Inc. The work was supported by Program Project grant P01 AR48564 "Molecular and Cellular Mechanisms of Vascular Anomalies" (B.R.O.), a Dean's Scholar Fellowship 2011-2013 (T.Y.B.) and NIH R37DK39773 (J.V.B). NR 50 TC 4 Z9 4 U1 0 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0945-053X EI 1569-1802 J9 MATRIX BIOL JI Matrix Biol. PD MAR PY 2015 VL 42 BP 56 EP 73 DI 10.1016/j.matbio.2014.12.002 PG 18 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CH9FD UT WOS:000354340500003 PM 25572963 ER PT J AU Addington, J Buchy, L Cadenhead, K Cannon, T Cornblatt, B McGlashan, T Perkins, D Seidman, L Tsuang, M Walker, E Woods, S Heinssen, R Bearden, C Mathalon, D AF Addington, Jean Buchy, Lisa Cadenhead, K. Cannon, Tyrone Cornblatt, B. McGlashan, T. Perkins, D. Seidman, L. Tsuang, M. Walker, E. Woods, S. Heinssen, R. Bearden, C. Mathalon, D. TI SUBSTANCE USE IN INDIVIDUALS AT CLINICAL HIGH RISK OF PSYCHOSIS SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 15th International Congress on Schizophrenia Research (ICOSR) CY MAR 28-APR 01, 2015 CL Colorado Springs, CO C1 [Addington, Jean; Buchy, Lisa] Univ Calgary, Psychiat, Calgary, AB, Canada. [Cadenhead, K.; Tsuang, M.] Univ Calif San Diego, Psychiat, San Diego, CA USA. [Cannon, Tyrone] Yale Univ, Psychol, New Haven, CT USA. [Cornblatt, B.] Zucker Hillside Hosptial, Psychiat, Long Isl City, NY USA. [McGlashan, T.; Woods, S.] Yale Univ, Psychiat, New Haven, CT USA. [Perkins, D.] UNC, Psychiat, Chapel Hill, NC USA. [Seidman, L.] Harvard, Psychiat, Boston, MA USA. [Walker, E.] Emory, Psychol, Atlanta, GA USA. [Heinssen, R.] NIMH, Div Adult Translat Res, Bethesda, MD 20892 USA. [Bearden, C.] Univ Calif Los Angeles, Psychiat, Los Angeles, CA USA. [Mathalon, D.] UCSF, Psychiat, San Francisco, CA USA. NR 0 TC 1 Z9 1 U1 2 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2015 VL 41 SU 1 MA 2084311 BP S104 EP S104 PG 1 WC Psychiatry SC Psychiatry GA CG8HO UT WOS:000353548200277 ER PT J AU Cella, M Stahl, D Morris, S Keefe, R Bell, MD Heinssen, R Wykes, T AF Cella, Matteo Stahl, Daniel Morris, Sarah Keefe, Richard Bell, Morris David Heinssen, Robea Wykes, Til TI EFFECTS OF COGNITIVE REMEDIATION ON NEGATIVE SYMPTOMS DIMENSIONS: EXPLORING THE ROLE OF WORKING MEMORY SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 15th International Congress on Schizophrenia Research (ICOSR) CY MAR 28-APR 01, 2015 CL Colorado Springs, CO C1 [Cella, Matteo; Wykes, Til] Kings Coll London, IoPPN, Psychol, London WC2R 2LS, England. [Stahl, Daniel] Kings Coll London, IoPPN, Biostat, London WC2R 2LS, England. [Morris, Sarah; Heinssen, Robea] NIMH, Div Adult Translat Res & Treatment Dev, Bethesda, MD 20892 USA. [Keefe, Richard] Duke Univ, Med Ctr, Psychiat, Durham, NC USA. [Keefe, Richard] Duke Univ, Med Ctr, Dept Behav Sci, Durham, NC USA. [Bell, Morris David] Yale Univ, Sch Med, Psychiat, West Haven, CT 06516 USA. RI Stahl, Daniel/B-9713-2011; Wykes, Til/B-3812-2011 OI Stahl, Daniel/0000-0001-7987-6619; Wykes, Til/0000-0002-5881-8003 NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2015 VL 41 SU 1 MA 2114279 BP S40 EP S41 PG 2 WC Psychiatry SC Psychiatry GA CG8HO UT WOS:000353548200109 ER PT J AU Chung, Y Jacobson, A He, G van Erp, T McEwen, S Addington, J Bearden, C Cadenhead, K Cornblatt, B Mathalon, D McGlashan, T Perkins, D Seidman, LJ Tsuang, M Walker, E Woods, S Heinssen, R Cannon, T AF Chung, Yoonho Jacobson, Aims He, George van Erp, T. McEwen, Sarah Addington, Jean Bearden, Carrie Cadenhead, Kristin Cornblatt, Barbara Mathalon, Daniel McGlashan, Thomas Perkins, Diana Seidman, Larry J. Tsuang, Ming Walker, Elaine Woods, Scott Heinssen, Robert Cannon, Tyrone TI PRODROMAL SYMPTOM SEVERITY PREDICTS ACCELERATED GRAY MATTER REDUCTION AND THIRD VENTRICLE EXPANSION AMONG CLINICALLY HIGH RISK YOUTH DEVELOPING PSYCHOTIC DISORDERS SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 15th International Congress on Schizophrenia Research (ICOSR) CY MAR 28-APR 01, 2015 CL Colorado Springs, CO C1 [Chung, Yoonho; Jacobson, Aims; He, George; Cannon, Tyrone] Yale Univ, Psychol, New Haven, CT USA. [van Erp, T.] UC Irvine, Psychiat & Human Behav, Irvine, CA USA. [McEwen, Sarah; Bearden, Carrie] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90024 USA. [McEwen, Sarah; Bearden, Carrie] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90024 USA. [Addington, Jean] Univ Calgary, Psychiat, Calgary, AB, Canada. [Cadenhead, Kristin; Tsuang, Ming] UCSD San Diego, Psychiat, La Jolla, CA USA. [Cornblatt, Barbara] Zucker Hillside, Psychiat, Glen Oaks, NY USA. [Mathalon, Daniel] UCSF, Psychiany, San Francisco, CA USA. [McGlashan, Thomas; Woods, Scott] Yale Univ, Psychiat, New Haven, CT USA. [Perkins, Diana] Univ N Carolina, Psychiat, Chapel Hill, NC USA. [Perkins, Diana] Univ N Carolina, Renaissance Comp Inst, Chapel Hill, NC USA. [Seidman, Larry J.] Beth Israel Deaconess Med Ctr, Psychiat, Cambridge, MA USA. [Seidman, Larry J.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Seidman, Larry J.] Massachusetts Gen Hosp, Psychiat, Cambridge, MA USA. [Walker, Elaine] Emory Univ, Psychol, Atlanta, GA 30322 USA. [Heinssen, Robert] NIMH, Div Treatment & Prevent Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2015 VL 41 SU 1 BP S249 EP S249 PG 1 WC Psychiatry SC Psychiatry GA CG8HO UT WOS:000353548200658 ER PT J AU Cortes, CR Fisher, JE Griego, JA Gullapalli, RP Tagamets, MA AF Cortes, Carlos R. Fisher, Joscelyn E. Griego, Jacqueline A. Gullapalli, Rao P. Tagamets, Malle A. TI GABA INTERNEURON FUNCTION AND WORKING MEMORY INTERFERENCE AS A PREFRONTAL MECHANISM IN SCHIZOPHRENIA SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 15th International Congress on Schizophrenia Research (ICOSR) CY MAR 28-APR 01, 2015 CL Colorado Springs, CO C1 [Cortes, Carlos R.] NIAAA, Lab Clin & Translat Studies, Bethesda, MD USA. [Cortes, Carlos R.; Fisher, Joscelyn E.; Griego, Jacqueline A.; Tagamets, Malle A.] Univ Maryland, Sch Med, Dept Psychiat, MPRC, Baltimore, MD 21201 USA. [Fisher, Joscelyn E.] Uniformed Serv Univ Hlth Sci, Psychiat Ctr Study Traumat Stress, Bethesda, MD 20814 USA. [Gullapalli, Rao P.] Univ Maryland, Sch Med, Diagnost Radiol & Nucl Med, Baltimore, MD 21201 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2015 VL 41 SU 1 MA 2086243 BP S220 EP S220 PG 1 WC Psychiatry SC Psychiatry GA CG8HO UT WOS:000353548200583 ER PT J AU Demyanovich, H Feldman, S Jackson, J Eaton, W Cascella, NG Fasano, A Santora, D Sullivan, KM Raley, H McMahon, R Carpenter, WT Kelly, D AF Demyanovich, Haley Feldman, Stephanie Jackson, Jessica Eaton, William Cascella, Nicola G. Fasano, Alessio Santora, Debby Sullivan, Kelli Marie Raley, Heather McMahon, Robert Carpenter, William T. Kelly, Deanna TI THE RELATIONSHIP BETWEEN GLUTEN SENSITIVITY AND PSYCHIATRIC SYMPTOMS IN PEOPLE WITH SCHIZOPHRENIA SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 15th International Congress on Schizophrenia Research (ICOSR) CY MAR 28-APR 01, 2015 CL Colorado Springs, CO C1 [Demyanovich, Haley; Feldman, Stephanie; Sullivan, Kelli Marie; McMahon, Robert; Carpenter, William T.; Kelly, Deanna] Univ Maryland, Maryland Psychiat Res Ctr, Baltimore, MD 21201 USA. [Jackson, Jessica] Temple Univ, Sch Med, Philadelphia, PA 19122 USA. [Eaton, William] Johns Hopkins Univ, Sch Publ Hlth, Baltimore, MD USA. [Cascella, Nicola G.] Sheppard Pratt Hosp, Neuropsychiat, Baltimore, MD USA. [Fasano, Alessio] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Santora, Debby] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Raley, Heather] NIDA, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2015 VL 41 SU 1 MA 2092944 BP S17 EP S17 PG 1 WC Psychiatry SC Psychiatry GA CG8HO UT WOS:000353548200043 ER PT J AU Dickinson, D AF Dickinson, Dwight TI THE CENTRAL NATURE OF 'LOWER-ORDER' COGNITIVE IMPAIRMENT IN SCHIZOPHRENIA SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 15th International Congress on Schizophrenia Research (ICOSR) CY MAR 28-APR 01, 2015 CL Colorado Springs, CO C1 [Dickinson, Dwight] NIMH, Clin & Translat Neurosci Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2015 VL 41 SU 1 MA 2119235 BP S42 EP S42 PG 1 WC Psychiatry SC Psychiatry GA CG8HO UT WOS:000353548200114 ER PT J AU Dickinson, D Giangrande, E Weinberger, DR Berman, K AF Dickinson, Dwight Giangrande, Evan Weinberger, Daniel R. Berman, Karen TI COGNITIVE SUBGROUPING IN PEOPLE WITH SCHIZOPHRENIA AND THEIR SIBLINGS: A FOCUS ON COGNITIVELY "PRESERVED" SCHIZOPHRENIA SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 15th International Congress on Schizophrenia Research (ICOSR) CY MAR 28-APR 01, 2015 CL Colorado Springs, CO C1 [Dickinson, Dwight; Giangrande, Evan; Berman, Karen] NIMH, Clin & Translat Neurosci Branch, NIH, Bethesda, MD 20892 USA. [Weinberger, Daniel R.] Lieber Inst Brain Dev, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2015 VL 41 SU 1 MA 2083622 BP S42 EP S42 PG 1 WC Psychiatry SC Psychiatry GA CG8HO UT WOS:000353548200113 ER PT J AU Giangrande, EJ Berman, KF Weinberger, DR Dickinson, D AF Giangrande, Evan J. Berman, Karen F. Weinberger, Daniel R. Dickinson, Dwight TI COGNITIVE SUBGROUPS IN SCHIZOPHRENIA: CONTRASTING HIGH COGNITIVE PERFORMANCE CASES WITH THEIR OWN UNAFFECTED SIBLINGS ON COGNITIVE, CLINICAL, AND FUNCTIONAL VARIABLES SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 15th International Congress on Schizophrenia Research (ICOSR) CY MAR 28-APR 01, 2015 CL Colorado Springs, CO C1 [Giangrande, Evan J.; Berman, Karen F.; Dickinson, Dwight] NIMH, Clin & Translat Neurosci Branch, IRP, NIH, Bethesda, MD 20892 USA. [Weinberger, Daniel R.] Johns Hopkins Univ, Sch Med, Lieber Inst Brain Dev, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2015 VL 41 SU 1 MA 2087468 BP S44 EP S44 PG 1 WC Psychiatry SC Psychiatry GA CG8HO UT WOS:000353548200119 ER PT J AU Gogtay, N AF Gogtay, Nitin TI PUBLICATION IMPACT FROM NIMH FUNDED CLINICAL TRIALS SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 15th International Congress on Schizophrenia Research (ICOSR) CY MAR 28-APR 01, 2015 CL Colorado Springs, CO C1 [Gogtay, Nitin] NIMH, Rockville, MD 20857 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2015 VL 41 SU 1 MA 2119056 BP S313 EP S313 PG 1 WC Psychiatry SC Psychiatry GA CG8HO UT WOS:000353548200824 ER PT J AU Hahn, B Harvey, AN Gold, JM Fischer, BA Keller, WR Ross, TJ Stein, EA AF Hahn, Britta Harvey, Alexander N. Gold, James M. Fischer, Bernard A. Keller, William R. Ross, Thomas J. Stein, Elliot A. TI HYPERDEACTIVATION OF THE DEFAULT NETWORK IN PEOPLE WITH SCHIZOPHRENIA WHEN ENGAGING IN COGNITIVE FUNCTIONS IMPAIRED IN SCHIZOPHRENIA SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 15th International Congress on Schizophrenia Research (ICOSR) CY MAR 28-APR 01, 2015 CL Colorado Springs, CO C1 [Hahn, Britta; Harvey, Alexander N.; Gold, James M.; Fischer, Bernard A.; Keller, William R.] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Catonsville, MD 21228 USA. [Ross, Thomas J.; Stein, Elliot A.] NIDA, Neuroimaging Res Branch, Intramural Res Program, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2015 VL 41 SU 1 MA 2118081 BP S225 EP S226 PG 2 WC Psychiatry SC Psychiatry GA CG8HO UT WOS:000353548200597 ER PT J AU Haut, KM Addington, J Bearden, CE Cadenhead, K Cornblatt, B Mathalon, D McGlashan, TH Perkins, DO Seidman, LJ Tsuang, M Walker, E Woods, S Heinssen, R Cannon, T AF Haut, Kristen M. Addington, Jean Bearden, Carrie E. Cadenhead, Kristin Cornblatt, Barbara Mathalon, Daniel McGlashan, Thomas H. Perkins, Diana O. Seidman, Larry J. Tsuang, Ming Walker, Elaine Woods, Scott Heinssen, Robert Cannon, Tyrone TI REDUCED WHITE MATTER INTEGRITY IN A MULTISITE LONGITUDINAL STUDY OF YOUTH AT RISK FOR PSYCHOSIS SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 15th International Congress on Schizophrenia Research (ICOSR) CY MAR 28-APR 01, 2015 CL Colorado Springs, CO C1 [Haut, Kristen M.; Cannon, Tyrone] Yale Univ, Psychol, New Haven, CT USA. [Addington, Jean] Univ Calgary, Hotchkiss Brain Inst, Psychiat, Calgary, AB T2N 1N4, Canada. [Bearden, Carrie E.] Univ Calif Los Angeles, Psychiat & Biobehav Sci & Psychol, Los Angeles, CA USA. [Cadenhead, Kristin] Univ Calif San Diego, Psychiat, San Diego, CA 92103 USA. [McGlashan, Thomas H.; Woods, Scott; Cannon, Tyrone] Yale Univ, Psychiat, New Haven, CT USA. [Cornblatt, Barbara] Zucker Hillside Hosp, Psychiat, Long Isl City, NY USA. [Mathalon, Daniel] Univ Calif San Francisco, Psychiat, San Francisco, CA 94143 USA. [Perkins, Diana O.] Univ N Carolina, Psychiat, Chapel Hill, NC USA. [Seidman, Larry J.] Beth Israel Deaconess Med Ctr, Harvard Med Sch, Psychiat, Boston, MA 02215 USA. [Seidman, Larry J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Tsuang, Ming] Univ Calif San Diego, Ctr Behav Genom, Inst Genom Med, Psychiat, La Jolla, CA 92093 USA. [Walker, Elaine] Emory Univ, Psychol & Psychiat, Atlanta, GA 30322 USA. [Heinssen, Robert] NIMH, Div Adulta Translat Res & Treatment Dev, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2015 VL 41 SU 1 MA 2083088 BP S257 EP S257 PG 1 WC Psychiatry SC Psychiatry GA CG8HO UT WOS:000353548200679 ER PT J AU Meyer, CT Kuo, S Zhang, Y Barnett, AS Shen, J Weinberger, DR Apud, JA Berman, KF Mareno, S AF Meyer, Christian T. Kuo, Susan Zhang, Yan Barnett, Alan S. Shen, Jun Weinberger, Daniel R. Apud, Jose A. Berman, Karen F. Mareno, Stefano TI PREDICTING RESPONSE TO ANTIPSYCHOTICS WITH GLUTAMATE PROTON MAGNETIC RESONANCE SPECTROSCOPY (MRS) SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 15th International Congress on Schizophrenia Research (ICOSR) CY MAR 28-APR 01, 2015 CL Colorado Springs, CO C1 [Meyer, Christian T.; Kuo, Susan; Barnett, Alan S.; Apud, Jose A.; Berman, Karen F.; Mareno, Stefano] NIMH, Clin Translat Neurosci Branch, Bethesda, MD 20892 USA. [Zhang, Yan; Shen, Jun] NIMH, Magnet Resonance Spect Unit, Bethesda, MD 20892 USA. [Weinberger, Daniel R.] Lieber Inst Brain Dev, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2015 VL 41 SU 1 MA 2094478 BP S265 EP S266 PG 2 WC Psychiatry SC Psychiatry GA CG8HO UT WOS:000353548200700 ER PT J AU Paksarian, D Merikangas, KR Calkins, ME Gur, RE AF Paksarian, Diana Merikangas, Kathleen R. Calkins, Monica E. Gur, Raquel E. TI RACIAL-ETHNIC DISPARITIES IN SPECIFICITY AND OVERLAP OF SUBCLINICAL PSYCHOSIS AND MANIA SYMPTOMS IN A US SAMPLE OF YOUTH SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 15th International Congress on Schizophrenia Research (ICOSR) CY MAR 28-APR 01, 2015 CL Colorado Springs, CO C1 [Paksarian, Diana; Merikangas, Kathleen R.] NIMH, Genet Epidemiol Res Branch, Bethesda, MD 20892 USA. [Calkins, Monica E.; Gur, Raquel E.] Univ Penn, Psychiat, Philadelphia, PA 19104 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2015 VL 41 SU 1 MA 2105686 BP S149 EP S150 PG 2 WC Psychiatry SC Psychiatry GA CG8HO UT WOS:000353548200395 ER PT J AU Perkins, D Jeffries, C Addington, J Bearden, CE Cadenhead, K Cannon, T Cornblatt, BA Heinssen, R Mathalon, D McGlashan, T Seidman, LJ Walker, E Woods, SW Chandler, S Glatt, S Stark, T Yee, E Tsuang, M AF Perkins, Diana Jeffries, Clark Addington, Jean Bearden, Carrie E. Cadenhead, Kristin Cannon, Tyrone Cornblatt, Barbara A. Heinssen, Robert Mathalon, Daniel McGlashan, Thomas Seidman, Larry J. Walker, Elaine Woods, Scott W. Chandler, Sharon Glatt, Stephen Stark, Thomas Yee, Eugene Tsuang, Ming TI DISCERNING RISK PATHWAYS FOR PSYCHOSIS IN THE NAPLS2 COHORT SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 15th International Congress on Schizophrenia Research (ICOSR) CY MAR 28-APR 01, 2015 CL Colorado Springs, CO C1 [Perkins, Diana] Univ N Carolina, Psychiat, Chapel Hill, NC USA. [Jeffries, Clark] Univ N Carolina, Renaissance Comp Inst, Chapel Hill, NC USA. [Addington, Jean] Univ Calgary, Hotchkiss Brain Inst, Calgary, AB T2N 1N4, Canada. [Bearden, Carrie E.] Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA USA. [Bearden, Carrie E.] Univ Calif Los Angeles, Dept Biobehav Sci, Los Angeles, CA USA. [Cadenhead, Kristin; Chandler, Sharon] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Cannon, Tyrone; McGlashan, Thomas; Woods, Scott W.] Yale Univ, Dept Psychiat & Psychol, New Haven, CT USA. [Cornblatt, Barbara A.] Zucker Hillside Hosp, Dept Psychiat, Long Isl City, NY USA. [Heinssen, Robert] NIMH, Rockville, MD 20857 USA. [Mathalon, Daniel] Univ Calif San Francisco, Dept Psychiat, San Francisoco, CA USA. [Seidman, Larry J.] Harvard Univ, Sch Med, Dept Psychiat, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. [Seidman, Larry J.] Massachusetts Gen Hsopital, Boston, MA USA. [Walker, Elaine] Emory Univ, Dept Psychol, Atlanta, GA 30322 USA. [Walker, Elaine] Emory Univ, Dept Psychiat, Atlanta, GA 30322 USA. [Chandler, Sharon] Univ Calif San Diego, Ctr Behav Genom, San Diego, CA 92103 USA. [Glatt, Stephen] SUNY Upstate Med Univ, Psychiat Genet Epidemiol & Neurobiol Lab, Dept Psychiat, Syracuse, NY 13210 USA. [Stark, Thomas; Yee, Eugene] Univ Calif San Diego, Cellular & Mol Med, San Diego, CA 92103 USA. [Tsuang, Ming] Univ Calif San Diego, Dept Psychiat, Ctr Behav Genom, San Diego, CA 92103 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2015 VL 41 SU 1 MA 2142211 BP S24 EP S25 PG 2 WC Psychiatry SC Psychiatry GA CG8HO UT WOS:000353548200065 ER PT J AU Pratt, DN Weinberger, DR Berman, KF Dickinson, D AF Pratt, Danielle N. Weinberger, Daniel R. Berman, Karen F. Dickinson, Dwight TI SUBGROUPING SCHIZOPHRENIA BASED ON SYMPTOM DIMENSIONS: THE DEFICIT SYNDROME AND MORE? SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 15th International Congress on Schizophrenia Research (ICOSR) CY MAR 28-APR 01, 2015 CL Colorado Springs, CO C1 [Pratt, Danielle N.; Berman, Karen F.; Dickinson, Dwight] NIMH, Clin & Translat Neurosci Branch, IRP, NIH, Bethesda, MD 20892 USA. [Weinberger, Daniel R.] Lieber Inst Brain Dev, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2015 VL 41 SU 1 MA 2089358 BP S115 EP S116 PG 2 WC Psychiatry SC Psychiatry GA CG8HO UT WOS:000353548200309 ER PT J AU Rubinstein, D Eisenberg, DP Carver, FW Holroyd, T Weinberger, DR Apud, J Coppola, R Berman, KF AF Rubinstein, Dani Eisenberg, Daniel P. Carver, Frederick W. Holroyd, Tom Weinberger, Daniel R. Apud, Jose Coppola, Richard Berman, Karen F. TI TIME-SPECIFIC ALTERATIONS IN WORKING MEMORY-RELATED BETA BAND ACTIVITY IN PATIENTS WITH SCHIZOPHRENIA STUDIED WITH MEG WHILE ON AND OFF ANTIPSYCHOTIC MEDICATION SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 15th International Congress on Schizophrenia Research (ICOSR) CY MAR 28-APR 01, 2015 CL Colorado Springs, CO C1 [Rubinstein, Dani; Eisenberg, Daniel P.; Apud, Jose; Coppola, Richard; Berman, Karen F.] NIMH, CTNB, Bethesda, MD 20892 USA. [Rubinstein, Dani] Brown Univ, Neurosci, Providence, RI 02912 USA. [Carver, Frederick W.; Holroyd, Tom; Coppola, Richard] NIH, MEG Core Facil, Bethesda, MD 20892 USA. [Weinberger, Daniel R.] Lieber Inst Brain Dev, Clin Sci, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2015 VL 41 SU 1 BP S238 EP S238 PG 1 WC Psychiatry SC Psychiatry GA CG8HO UT WOS:000353548200630 ER PT J AU Seidman, LJ Meyer, EC Carrion, RE Cornblatt, BA Addington, J Cadenhead, KS Cannon, T McGlashan, TH Perkins, DO Tsuang, MT Walker, EF Woods, SW Heinssen, R AF Seidman, Larry J. Meyer, Eric C. Carrion, Ricardo E. Cornblatt, Barbara A. Addington, Jean Cadenhead, Kristin S. Cannon, Tyrone McGlashan, Thomas H. Perkins, Diana O. Tsuang, Ming T. Walker, Elaine F. Woods, Scott W. Heinssen, Robert TI THE RELATIONSHIP OF NEUROCOGNITION AND NEGATIVE SYMPTOMS TO SOCIAL AND ROLE FUNCTIONING OVER TIME IN INDIVIDUALS AT CLINICAL HIGH RISK SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 15th International Congress on Schizophrenia Research (ICOSR) CY MAR 28-APR 01, 2015 CL Colorado Springs, CO C1 [Meyer, Eric C.] VA VISN 17 Ctr Excellence Res Returning War Vet, Waco, TX USA. [Meyer, Eric C.] Texas A&M Hlth Sci Ctr, Psychiat & Behav Sci, Coll Med, College Stn, TX USA. [Carrion, Ricardo E.; Cornblatt, Barbara A.] NS LIJHS, Zucker Hillside Hosp, Div Psychiat Res, Glen Oaks, NY USA. [Addington, Jean] Univ Calgary, Psychiat, Calgary, AB, Canada. [Cadenhead, Kristin S.; Tsuang, Ming T.] Univ Calif San Diego, Psychiat, San Diego, CA USA. [Cannon, Tyrone] Univ Calif Los Angeles, Psychol & Psychiat & Biobehav Sci, Los Angeles, CA USA. [Cannon, Tyrone; McGlashan, Thomas H.; Woods, Scott W.] Yale Univ, Psychiat, New Haven, CT USA. [Perkins, Diana O.] Univ N Carolina, Psychiat, Chapel Hill, NC USA. [Tsuang, Ming T.] UCSD, Ctr Behav Genom, La Jolla, CA USA. [Tsuang, Ming T.] UCSD, Inst Genom Med, La Jolla, CA USA. [Walker, Elaine F.] Emory Univ, Psychol & Psychiat, Atlanta, GA 30322 USA. [Heinssen, Robert] NIMH, Schizophrenia Spectrum Res Program, Div Adult Translat Res, Bethesda, MD 20892 USA. [Seidman, Larry J.] Harvard Univ, Sch Med, Psychiat, Boston, MA USA. [Seidman, Larry J.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Seidman, Larry J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2015 VL 41 SU 1 BP S61 EP S61 PG 1 WC Psychiatry SC Psychiatry GA CG8HO UT WOS:000353548200165 ER PT J AU Stone, WS Mesholam-Gately, RI Giuliano, AJ Woodbury, KA Addington, J Bearden, CE Cadenhead, KS Cannon, TD Cornblatt, BA Mathalon, DH McGlashan, TA Perkins, DO Tsuang, MT Walker, EF Woods, SW Heinssen, R Seidman, LJ AF Stone, William S. Mesholam-Gately, Raquelle I. Giuliano, Anthony J. Woodbury, Kristen A. Addington, Jean Bearden, Carrie E. Cadenhead, Kristin S. Cannon, Tyrone D. Cornblatt, Barbara A. Mathalon, Daniel H. McGlashan, Thomas A. Perkins, Diana O. Tsuang, Ming T. Walker, Elaine F. Woods, Scott W. Heinssen, Robert Seidman, Larry J. TI HEALTHY NORTH AMERICAN ADOLESCENT PERFORMANCE ON THE MATRICS COGNITIVE CONSENSUS BATTERY (MCB): DEVELOPMENTAL AND NORMATIVE DATA FROM THE NAPLS AND CIDAR STUDIES SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 15th International Congress on Schizophrenia Research (ICOSR) CY MAR 28-APR 01, 2015 CL Colorado Springs, CO C1 [Stone, William S.; Mesholam-Gately, Raquelle I.; Giuliano, Anthony J.; Woodbury, Kristen A.; Seidman, Larry J.] Harvard Univ, Sch Med, Psychiat, Boston, MA USA. [Stone, William S.; Mesholam-Gately, Raquelle I.; Giuliano, Anthony J.; Woodbury, Kristen A.; Seidman, Larry J.] Beth Israel Deaconess Med Ctr, Psychiat, Boston, MA 02215 USA. [Addington, Jean] Univ Calgary, Hotchkiss Brain Inst, Psychiat, Calgary, AB, Canada. [Bearden, Carrie E.] Univ Calif Los Angeles, Psychiat & Biobehav Sci & Psychol, Los Angeles, CA USA. [Cadenhead, Kristin S.] Univ Calif San Diego, Psychiat, San Diego, CA 92103 USA. [Cannon, Tyrone D.] Yale Univ, Psychiat, Psychol, New Haven, CT USA. [Cornblatt, Barbara A.] Zucker Hillside Hosp, Psychiat, Long Isl City, NY USA. [Mathalon, Daniel H.] Univ Calif San Francisco, Psychiat, San Francisco, CA 94143 USA. [McGlashan, Thomas A.; Woods, Scott W.] Yale Univ, Psychiat, New Haven, CT USA. [Perkins, Diana O.] Univ N Carolina, Psychiat, Chapel Hill, NC USA. [Tsuang, Ming T.] Univ Calif San Diego, Psychiat, Ctr Behav Gen, Inst Gen Med, La Jolla, CA 92093 USA. [Walker, Elaine F.] Emory Univ, Psychol & Psychiat, Atlanta, GA 30322 USA. [Heinssen, Robert] NIMH, Div Adult Translat Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2015 VL 41 SU 1 BP S62 EP S63 PG 2 WC Psychiatry SC Psychiatry GA CG8HO UT WOS:000353548200168 ER PT J AU Waltz, JA Brown, JK Gold, JM Ross, TJ Salmeron, BJ Stein, EA AF Waltz, James A. Brown, Jaime K. Gold, James M. Ross, Thomas J. Salmeron, Betty J. Stein, Elliot A. TI MOTIVATIONAL DEFICITS IN SCHIZOPHRENIA AND THE REPRESENTATION OF VALUE: IMPLICATIONS FOR FUNCTIONAL OUTCOME SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 15th International Congress on Schizophrenia Research (ICOSR) CY MAR 28-APR 01, 2015 CL Colorado Springs, CO C1 [Waltz, James A.; Brown, Jaime K.; Gold, James M.] Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21201 USA. [Ross, Thomas J.; Salmeron, Betty J.; Stein, Elliot A.] NIDA, Neuroimaging Res Branch, Intramural Res Program, Baltimore, MD USA. RI Salmeron, Betty Jo/M-1793-2016 OI Salmeron, Betty Jo/0000-0003-1699-9333 NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2015 VL 41 SU 1 MA 2084092 BP S99 EP S100 PG 2 WC Psychiatry SC Psychiatry GA CG8HO UT WOS:000353548200267 ER PT J AU Wehring, H Sullivan, KM McMahon, RP Kearns, AM Heishman, SJ Liu, F Richardson, CM Vyas, G Feldman, S Kelly, DL AF Wehring, Heidi Sullivan, Kelli Marie McMahon, Robert P. Kearns, Ann Marie Heishman, Stephen J. Liu, Fang Richardson, Charles M. Vyas, Gopal Feldman, Stephanie Kelly, Deanna L. TI MINOCYCLINE AND TOBACCO CRAVING IN SCHIZOPHRENIA SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 15th International Congress on Schizophrenia Research (ICOSR) CY MAR 28-APR 01, 2015 CL Colorado Springs, CO C1 [Wehring, Heidi; Sullivan, Kelli Marie; McMahon, Robert P.; Kearns, Ann Marie; Liu, Fang; Richardson, Charles M.; Vyas, Gopal; Feldman, Stephanie; Kelly, Deanna L.] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Baltimore, MD 21201 USA. [Heishman, Stephen J.] NIDA, Intramural Res Program, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2015 VL 41 SU 1 BP S131 EP S131 PG 1 WC Psychiatry SC Psychiatry GA CG8HO UT WOS:000353548200346 ER PT J AU Wigton, R Johns, M Averbeck, B Shergill, SS AF Wigton, Rebekah Johns, Michaela Averbeck, Bruno Shergill, Sukhi S. TI IMAGING OXYTOCIN IN SCHIZOPHRENIA: OXYTOCIN ATTENUATES NEURAL ACTIVITY IN THE AMYGDALA AND TEMPOROPARIETAL JUNCTION DURING A DECISION-MAKING TASK INCORPORATING IMPLICIT FACIAL PROCESSING SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 15th International Congress on Schizophrenia Research (ICOSR) CY MAR 28-APR 01, 2015 CL Colorado Springs, CO C1 [Wigton, Rebekah; Johns, Michaela; Shergill, Sukhi S.] Kings Coll London, Inst Psychiat, Cognit Schizophrenia & Imaging Lab, London WC2R 2LS, England. [Averbeck, Bruno] NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2015 VL 41 SU 1 BP S242 EP S242 PG 1 WC Psychiatry SC Psychiatry GA CG8HO UT WOS:000353548200642 ER PT J AU Yang, LH Link, B Wonpat-Borja, A Gill, K Ben-David, S Philippova, T Singh, T Corcoran, C AF Yang, Lawrence Hsin Link, Bruce Wonpat-Borja, Ahtoy Gill, Kelly Ben-David, Shelly Philippova, Tatiana Singh, Tanya Corcoran, Cheryl TI STIGMA OF THE HIGH RISK STATE FOR PSYCHOSIS AND ITS RELATIONSHIP WITH ANXIETY AND DEPRESSION SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 15th International Congress on Schizophrenia Research (ICOSR) CY MAR 28-APR 01, 2015 CL Colorado Springs, CO C1 [Yang, Lawrence Hsin; Link, Bruce; Wonpat-Borja, Ahtoy] Columbia Univ, Epidemiol, New York, NY USA. [Ben-David, Shelly] NYU, Social Work, New York, NY USA. [Gill, Kelly] NIH, Neurosci, Bethesda, MD 20892 USA. [Singh, Tanya] Columbia Univ, Psychol, New York, NY USA. [Philippova, Tatiana] Univ Chicago, Publ Policy, Chicago, IL 60637 USA. [Corcoran, Cheryl] Columbia Univ, New York State Psychiat Inst, Psychiat, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2015 VL 41 SU 1 MA 2116759 BP S121 EP S122 PG 2 WC Psychiatry SC Psychiatry GA CG8HO UT WOS:000353548200325 ER PT J AU Yao, Y Zhang, FQ AF Yao, Yin Zhang, FuQuan TI MIRNA BIOGENESIS IN SCHIZOPHRENIA, A CHINESE STUDY SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 15th International Congress on Schizophrenia Research (ICOSR) CY MAR 28-APR 01, 2015 CL Colorado Springs, CO C1 [Yao, Yin; Zhang, FuQuan] NIMH, Intramural Res Program, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2015 VL 41 SU 1 MA 2093240 BP S27 EP S27 PG 1 WC Psychiatry SC Psychiatry GA CG8HO UT WOS:000353548200073 ER PT J AU Usdin, K House, NCM Freudenreich, CH AF Usdin, Karen House, Nealia C. M. Freudenreich, Catherine H. TI Repeat instability during DNA repair: Insights from model systems SO CRITICAL REVIEWS IN BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Review DE Chromosome fragility; DNA damage checkpoint; DNA structure; recombination; repair; replication; structure-specific helicases; trinucleotide repeat expansion ID FRAGILE-X-SYNDROME; DOUBLE-STRAND BREAKS; BASE EXCISION-REPAIR; S-PHASE CHECKPOINT; SISTER-CHROMATID RECOMBINATION; MYOTONIC-DYSTROPHY TYPE-1; MACHADO-JOSEPH-DISEASE; GROUP-B PROTEIN; ATAXIA (GAA)(N)CENTER-DOT(TTC)(N) REPEATS; EUKARYOTIC MISMATCH REPAIR AB The expansion of repeated sequences is the cause of over 30 inherited genetic diseases, including Huntington disease, myotonic dystrophy (types 1 and 2), fragile X syndrome, many spinocerebellar ataxias, and some cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Repeat expansions are dynamic, and disease inheritance and progression are influenced by the size and the rate of expansion. Thus, an understanding of the various cellular mechanisms that cooperate to control or promote repeat expansions is of interest to human health. In addition, the study of repeat expansion and contraction mechanisms has provided insight into how repair pathways operate in the context of structure-forming DNA, as well as insights into non-canonical roles for repair proteins. Here we review the mechanisms of repeat instability, with a special emphasis on the knowledge gained from the various model systems that have been developed to study this topic. We cover the repair pathways and proteins that operate to maintain genome stability, or in some cases cause instability, and the cross-talk and interactions between them. C1 [Usdin, Karen] NIDDK, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. [House, Nealia C. M.; Freudenreich, Catherine H.] Tufts Univ, Dept Biol, Medford, MA 02155 USA. [Freudenreich, Catherine H.] Tufts Univ, Genet Program, Boston, MA 02111 USA. RP Freudenreich, CH (reprint author), Tufts Univ, Dept Biol, Medford, MA 02155 USA. EM catherine.freudenreich@tufts.edu OI House, Nealia/0000-0003-1264-7699 FU National Institutes of Health [P01GM105473]; National Science Foundation [MCB1330743]; Tufts University; National Institute of Diabetes, Kidney and Digestive Diseases [DK057808] FX Research in CHF's laboratory is supported by the National Institutes of Health (Award P01GM105473), National Science Foundation (MCB1330743), and Tufts University. Research in KU's laboratory is supported by the Intramural Program of the National Institute of Diabetes, Kidney and Digestive Diseases (DK057808). The authors report no declarations of interest. NR 306 TC 15 Z9 15 U1 2 U2 21 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1040-9238 EI 1549-7798 J9 CRIT REV BIOCHEM MOL JI Crit. Rev. Biochem. Mol. Biol. PD MAR-APR PY 2015 VL 50 IS 2 BP 142 EP 167 DI 10.3109/10409238.2014.999192 PG 26 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CH3IE UT WOS:000353923000003 PM 25608779 ER PT J AU Petryk, A Shankar, RK Giri, N Hollenberg, AN Rutter, MM Nathan, B Lodish, M Alter, BP Stratakis, CA Rose, SR AF Petryk, Anna Shankar, Roopa Kanakatti Giri, Neelam Hollenberg, Anthony N. Rutter, Meilan M. Nathan, Brandon Lodish, Maya Alter, Blanche P. Stratakis, Constantine A. Rose, Susan R. TI Endocrine Disorders in Fanconi Anemia: Recommendations for Screening and Treatment SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Review ID GROWTH-HORMONE DEFICIENCY; HEMATOPOIETIC-CELL TRANSPLANTATION; PITUITARY-STALK INTERRUPTION; CHILDHOOD-CANCER SURVIVOR; IDIOPATHIC SHORT STATURE; BONE-MINERAL DENSITY; LONG-TERM MORTALITY; GLUCOSE-TOLERANCE; CLINICAL-PRACTICE; 2ND NEOPLASMS AB Context: Endocrine problems are common in patients with Fanconi anemia (FA). About 80% of children and adults with FA have at least one endocrine abnormality, including short stature, GH deficiency, abnormal glucose or insulin metabolism, dyslipidemia, hypothyroidism, pubertal delay, hypogonadism, or impaired fertility. The goal of this report is to provide an overview of endocrine abnormalities and guidelines for routine screening and treatment to allow early diagnosis and timely intervention. Evidence Acquisition: This work is based on a comprehensive literature review, including relevant articles published between 1971 and 2014, and proceedings of a Consensus Conference held by the Fanconi Anemia Research Fund in 2013. Evidence Synthesis: The panel of experts collected published evidence and discussed its relevance to reflect current information about the endocrine care of children and adults with FA before the Consensus Conference and through subsequent deliberations that led to the consensus. Conclusions: Individuals with FA should be routinely screened for endocrine abnormalities, including evaluation of growth; glucose, insulin, and lipid metabolism; thyroid function; puberty; gonadal function; and bone mineral metabolism. Inclusion of an endocrinologist as part of the multidisciplinary patient care team is key to providing comprehensive care for patients with FA. C1 [Petryk, Anna; Nathan, Brandon] Univ Minnesota, Mason Childrens Hosp, Div Pediat Endocrinol, Minneapolis, MN 55454 USA. [Shankar, Roopa Kanakatti] Virginia Commonwealth Univ, Childrens Hosp Richmond, Dept Pediat, Richmond, VA 23229 USA. [Giri, Neelam; Alter, Blanche P.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA. [Hollenberg, Anthony N.] Beth Israel Deaconess Med Ctr, Div Endocrinol Diabet & Metab, Boston, MA 02215 USA. [Hollenberg, Anthony N.] Harvard Univ, Sch Med, Boston, MA 02215 USA. [Rutter, Meilan M.; Rose, Susan R.] Univ Cincinnati, Cincinnati Childrens Hosp Med Ctr, Coll Med, Div Endocrinol, Cincinnati, OH 45229 USA. [Lodish, Maya] NIH, Pediat Endocrinol Interinst Training Program, Bethesda, MD 20892 USA. [Lodish, Maya; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, Bethesda, MD 20892 USA. RP Petryk, A (reprint author), Univ Minnesota, Mason Childrens Hosp, East Bldg Room MB671,2450 Riverside Ave, Minneapolis, MN 55454 USA. EM petry005@umn.edu; susan.rose@cchmc.org FU National Institutes of Health [R01 CA181024]; Intramural Research Program of the National Institute of Child Health and Human Development; Intramural Program of the National Institutes of Health; National Cancer Institute; Fanconi Anemia Research Fund FX This work was supported in part by the National Institutes of Health (Grant R01 CA181024, to A.P.), the Intramural Research Program of the National Institute of Child Health and Human Development (to R.K.S., M.L., and C.A.S.), the Intramural Program of the National Institutes of Health, and the National Cancer Institute (to B.P.A. and N.G.). The Fanconi Anemia Research Fund supported costs associated with the 2013 Consensus Conference. NR 83 TC 9 Z9 9 U1 1 U2 4 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD MAR PY 2015 VL 100 IS 3 BP 803 EP 811 DI 10.1210/jc.2014-4357 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CG5TR UT WOS:000353358900027 PM 25575015 ER PT J AU Krieger, CC Neumann, S Place, RF Marcus-Samuels, B Gershengorn, MC AF Krieger, Christine C. Neumann, Susanne Place, Robert F. Marcus-Samuels, Bernice Gershengorn, Marvin C. TI Bidirectional TSH and IGF-1 Receptor Cross Talk Mediates Stimulation of Hyaluronan Secretion by Graves' Disease Immunoglobins SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID GROWTH-FACTOR-I; RAT-THYROID CELLS; ORBITAL FIBROBLASTS; ACID SYNTHESIS; DNA-SYNTHESIS; OPHTHALMOPATHY; ANTIBODY; ORBITOPATHY; ACTIVATION; HORMONE AB Context: There is no pathogenetically linked medical therapy for Graves' ophthalmopathy (GO). Lack of animal models and conflicting in vitro studies have hindered the development of such therapy. Recent reports propose that Graves' Igs bind to and activate thyrotropin receptors (TSHRs) and IGF-1 receptors (IGF-1Rs) on cells in orbital fat, stimulating hyaluronan (HA) secretion, a component of GO. Objective: The objective of the study was to investigate potential cross talk between TSHRs and IGF-1Rs in the pathogenesis of GO using a sensitive HA assay. Design/Setting/Participants: Orbital fibroblasts from GO patients were collected in an academic clinical practice and cultured in a research laboratory. Cells were treated with TSH, IGF-1, and a monoclonal Graves' Ig M22. Main Outcome Measures: HA was measured by a modified ELISA. Results: Simultaneous activation by TSH and IGF-1 synergistically increased HA secretion from 320 +/- 52 for TSH and 430 +/- 65 mu g/mL for IGF-1 alone, to 1300 +/- 95 mu g/mL. IGF-1 shifted the TSH EC50 19-fold to higher potency. The dose response to M22 was biphasic. An IGF-1R antagonist inhibited the higher potency phase but had no effect on the lower potency phase. M22 did not cause IGF-1R autophosphorylation. A TSHR antagonist abolished both phases of M22-stimulated HA secretion. Conclusions: M22 stimulation of HA secretion by GO fibroblasts/preadipocytes involves cross talk between TSHR and IGF-1R. This cross talk relies on TSHR activation rather than direct activation of IGF-1R and leads to synergistic stimulation of HA secretion. These data propose a model for GO pathogenesis that explains previous contradictory results and argues for TSHR as the primary therapeutic target for GO. C1 [Krieger, Christine C.; Neumann, Susanne; Place, Robert F.; Marcus-Samuels, Bernice; Gershengorn, Marvin C.] NIDDK, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20892 USA. RP Gershengorn, MC (reprint author), 50 South Dr,Bldg 50,Room 4134, Bethesda, MD 20892 USA. EM marving@intra.niddk.nih.gov OI Krieger, Christine/0000-0002-1856-415X FU NIH [DK011006] FX This work was supported by NIH funding DK011006. NR 27 TC 13 Z9 14 U1 0 U2 9 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD MAR PY 2015 VL 100 IS 3 BP 1071 EP 1077 DI 10.1210/jc.2014-3566 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CG5TR UT WOS:000353358900057 PM 25485727 ER PT J AU Piaggi, P Thearle, MS Bogardus, C Krakoff, J AF Piaggi, Paolo Thearle, Marie S. Bogardus, Clifton Krakoff, Jonathan TI Fasting Hyperglycemia Predicts Lower Rates of Weight Gain by Increased Energy Expenditure and Fat Oxidation Rate SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID RESTING METABOLIC-RATE; DEPENDENT DIABETES-MELLITUS; IMPAIRED GLUCOSE-TOLERANCE; INSULIN-RESISTANCE; PIMA-INDIANS; INDUCED THERMOGENESIS; LIPID-METABOLISM; OBESE SUBJECTS; BODY-WEIGHT; ADIPOSITY AB Context: Increased adiposity and insulin resistance are associated with hyperglycemia and previous studies have reported that higher glucoses are associated with lower rates of weight gain. One possible mechanism is via increased energy expenditure (EE). Objective: To assess the relationships between changes in EE during spontaneous weight gain and concomitant changes in glucose levels. Design and Participants: Body composition, metabolic, and glycemic data were available from nondiabetic Native Americans who underwent two measurements of 24-h EE during eucaloric feeding in a metabolic chamber (N = 144; time between measurements: 5.0 +/- 3.3 years) or resting EE by ventilated hood system during the euglycemic-hyperinsulinemic clamp (N = 261; 4.5 +/- 3.2 years). Long-term follow-up data (8.3 +/- 4.3 years) for weight and body composition were available in 131 and 122 subjects, respectively. Main Outcome Measures: Twenty four hour EE and respiratory quotient (RQ), resting (RMR), and sleeping (SMR) metabolic rates, glucose, and insulin levels, basal glucose output (BGO). Results: Weight gain-associated increase in fasting plasma glucose (FPG) levels was accompanied with decreased 24-h RQ (partial R = -0.24, P = .002) and increased 24-h EE, RMR, SMR, and fat oxidation after accounting for changes in body composition (partial R: 0.12 to 0.19, all P <= .05). Upon weight gain, BGO tended to increase (P = .07), while insulin infusion induced a decrease in EE (P = .04). Higher baseline FPG predicted lower rates of future weight gain (partial R = -0.18, P = .04). Conclusions: Higher FPG after weight gain was associated with greater-than-expected increase in EE. The rise in BGO and the insulin-induced EE suppression at follow-up indicate that increased hepatic gluconeogenesismaybeanimportant mediator of EE changes associated with weight gain. C1 [Piaggi, Paolo; Thearle, Marie S.; Bogardus, Clifton; Krakoff, Jonathan] NIDDK, Obes & Diabet Clin Res Sect, NIH, Phoenix, AZ 85016 USA. [Piaggi, Paolo] Univ Hosp, Obes Res Ctr, Endocrinol Unit, I-56124 Pisa, Italy. RP Piaggi, P (reprint author), NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, 4212 N 16th St, Phoenix, AZ 85016 USA. EM paolo.piaggi@gmail.com OI Piaggi, Paolo/0000-0003-2774-9161 FU Intramural Research Program of the National Institutes of Health (NIH); National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) FX This work was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). NR 40 TC 4 Z9 4 U1 0 U2 2 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD MAR PY 2015 VL 100 IS 3 BP 1078 EP 1087 DI 10.1210/jc.2014-3582 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CG5TR UT WOS:000353358900058 PM 25559400 ER PT J AU Mallappa, A Sinaii, N Kumar, P Whitaker, MJ Daley, LA Digweed, D Eckland, DJA Van Ryzin, C Nieman, LK Arlt, W Ross, RJ Merke, DP AF Mallappa, Ashwini Sinaii, Ninet Kumar, Parag Whitaker, Martin J. Daley, Lori-Ann Digweed, Dena Eckland, David J. A. Van Ryzin, Carol Nieman, Lynnette K. Arlt, Wiebke Ross, Richard J. Merke, Deborah P. TI A Phase 2 Study of Chronocort, a Modified-Release Formulation of Hydrocortisone, in the Treatment of Adults With Classic Congenital Adrenal Hyperplasia SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID GLUCOCORTICOID REPLACEMENT THERAPY; 21-HYDROXYLASE DEFICIENCY; CORTISOL EXPOSURE; CIRCADIAN THERAPY; HPA AXIS; INSUFFICIENCY; 17-HYDROXYPROGESTERONE; MANAGEMENT; INFUSION; PROFILE AB Context: Treatment of congenital adrenal hyperplasia (CAH) is suboptimal. Inadequate suppression of androgens and glucocorticoid excess are common and current glucocorticoid formulations cannot replace the cortisol circadian rhythm. Objectives: The primary objective was to characterize the pharmacokinetic profile of Chronocort, a modified-release hydrocortisone formulation, in adults with CAH. Secondary objectives included examining disease control following 6 months of Chronocort with dose titration. Design, Setting, and Patients: Sixteen adults (eight females) with classic CAH participated in an open-label, nonrandomized, Phase 2 study at the National Institutes of Health Clinical Center. Twenty-four-hour blood sampling was performed on conventional glucocorticoids and following 6 months of Chronocort. Chronocort was initiated at 10 mg (0700 h) and 20 mg (2300 h). Dose titration was performed based on androstenedione and 17-hydroxyprogresterone (17-OHP) levels and clinical symptomatology. Main Outcome Measures: The primary outcome was cortisol pharmacokinetics of Chronocort and secondary outcomes included biomarkers of CAH control (androstenedione and 17-OHP). Results: In patients with CAH, Chronocort cortisol profiles were similar to physiologic cortisol secretion. Compared with conventional therapy, 6 months of Chronocort resulted in a decrease in hydrocortisone dose equivalent (28 +/- 11.8 vs 25.9 +/- 7.1 mg/d), with lower 24-hour (P = .004), morning (0700-1500 h; P = .002), and afternoon (1500-2300 h; P = .011) androstenedione area under the curve (AUC) and lower 24-hour (P = .023) and morning (0700-1500 h; P = .02) 17-OHP AUC. Conclusions: Twice-daily Chronocort approximates physiologic cortisol secretion, and was well tolerated and effective in controlling androgen excess in adults with CAH. This novel hydrocortisone formulation represents a new treatment approach for patients with CAH. C1 [Mallappa, Ashwini; Sinaii, Ninet; Kumar, Parag; Daley, Lori-Ann; Van Ryzin, Carol; Merke, Deborah P.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Whitaker, Martin J.; Digweed, Dena; Eckland, David J. A.; Arlt, Wiebke; Ross, Richard J.] Diurnal Ltd, Cardiff CF14 4UJ, S Glam, Wales. [Nieman, Lynnette K.; Merke, Deborah P.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. [Arlt, Wiebke] Univ Birmingham, Sch Clin & Expt Med, Ctr Endocrinol Diabet & Metab, Birmingham B15 2TT, W Midlands, England. [Ross, Richard J.] Univ Sheffield, Sheffield S10 2RX, S Yorkshire, England. RP Mallappa, A (reprint author), NIH, Ctr Clin, Clin Res Ctr, 10 Ctr Dr,Bldg 10,Room 1-2610, Bethesda, MD 20892 USA. EM ashwini.mallappa@nih.gov; r.j.ross@sheffield.ac.uk OI Arlt, Wiebke/0000-0001-5106-9719 FU Intramural Research Program of the National Institutes of Health; Diurnal Ltd UK FX This work was supported in part by the Intramural Research Program of the National Institutes of Health and in part by Diurnal Ltd UK. NR 36 TC 15 Z9 16 U1 2 U2 8 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD MAR PY 2015 VL 100 IS 3 BP 1137 EP 1145 DI 10.1210/jc.2014-3809 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CG5TR UT WOS:000353358900065 PM 25494662 ER PT J AU Cunningham, GR Stephens-Shields, AJ Rosen, RC Wang, C Ellenberg, SS Matsumoto, AM Bhasin, S Molitch, ME Farrar, JT Cella, D Barrett-Connor, E Cauley, JA Cifelli, D Crandall, JP Ensrud, KE Fluharty, L Gill, TM Lewis, CE Pahor, M Resnick, SM Storer, TW Swerdloff, RS Anton, S Basaria, S Diem, S Tabatabaie, V Hou, XL Snyder, PJ AF Cunningham, Glenn R. Stephens-Shields, Alisa J. Rosen, Raymond C. Wang, Christina Ellenberg, Susan S. Matsumoto, Alvin M. Bhasin, Shalender Molitch, Mark E. Farrar, John T. Cella, David Barrett-Connor, Elizabeth Cauley, Jane A. Cifelli, Denise Crandall, Jill P. Ensrud, Kristine E. Fluharty, Laura Gill, Thomas M. Lewis, Cora E. Pahor, Marco Resnick, Susan M. Storer, Thomas W. Swerdloff, Ronald S. Anton, Stephen Basaria, Shehzad Diem, Susan Tabatabaie, Vafa Hou, Xiaoling Snyder, Peter J. TI Association of Sex Hormones With Sexual Function, Vitality, and Physical Function of Symptomatic Older Men With Low Testosterone Levels at Baseline in the Testosterone Trials SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID SERUM TESTOSTERONE; ELDERLY-MEN; ERECTILE FUNCTION; INTERNATIONAL INDEX; BODY-COMPOSITION; HYPOGONADAL MEN; YOUNG MEN; HEALTHY; DYSFUNCTION; AGE AB Context: The prevalence of sexual dysfunction, low vitality, and poor physical function increases with aging, as does the prevalence of low total and free testosterone (TT and FT) levels. However, the relationship between sex hormones and age-related alterations in older men is not clear. Objective: To test the hypotheses that baseline serum TT, FT, estradiol (E2), and sex hormonebinding globulin (SHBG) levels are independently associated with sexual function, vitality, and physical function in older symptomatic men with low testosterone levels participating in the Testosterone Trials (TTrials). Design: Cross-sectional study of baseline measures in the TTrials. Setting: The study was conducted at 12 sites in the United States. Participants: The 788 TTrials participants were >= 65 years and had evidence of sexual dysfunction, diminished vitality, and/or mobility disability, and an average of two TT < 275 ng/dL. Interventions: None. Main Outcome Measures: Question 4 of Psychosocial Daily Questionnaire (PDQ-Q4), the FACIT-Fatigue Scale, and the 6-minute walk test. Results: Baseline serum TT and FT, but not E2 or SHBG levels had small, but statistically significant associations with validated measures of sexual desire, erectile function, and sexual activity. None of these hormones was significantly associated within or across trials with FACIT-Fatigue, PHQ-9 Depression or Physical Function-10 scores, or gait speed. Conclusions: FT and TT levels were consistently, independently, and positively associated, albeit to a small degree, with measures of sexual desire, erectile function, and sexual activity, but not with measures of vitality or physical function in symptomatic older men with low T who qualified for the TTrials. C1 [Cunningham, Glenn R.] Baylor Coll Med, Div Endocrinol Diabet & Metab, Houston, TX 77030 USA. Baylor St Lukes Med Ctr, Houston, TX 77030 USA. [Stephens-Shields, Alisa J.; Farrar, John T.; Cella, David; Fluharty, Laura] Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Rosen, Raymond C.] New England Res Inst Inc, Watertown, MA 02472 USA. [Wang, Christina; Swerdloff, Ronald S.] Harbor Univ Los Calif Angeles Med Ctr, Div Endocrinol, Torrance, CA 90502 USA. Los Angeles Biomed Res Inst, Torrance, CA 90502 USA. [Ellenberg, Susan S.; Hou, Xiaoling] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Matsumoto, Alvin M.] Univ Washington, Sch Med, Dept Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA 98108 USA. Univ Washington, Sch Med, Dept Internal Med, Div Gerontol & Geriatr Med, Seattle, WA 98108 USA. [Bhasin, Shalender; Basaria, Shehzad] Harvard Univ, Sch Med, Brigham & Womens Hosp, Res Program Mens Hlth Aging & Metab, Boston, MA 02115 USA. [Molitch, Mark E.] Northwestern Univ, Feinberg Sch Med, Div Endocrinol Metab & Mol Med, Chicago, IL 60611 USA. [Cifelli, Denise] Northwestern Univ, Feinberg Sch Med, Dept Med Social Sci, Chicago, IL 60611 USA. [Barrett-Connor, Elizabeth] Univ Calif San Diego, Sch Med, Dept Family & Preventat Med, Div Epidemiol, La Jolla, CA 92093 USA. [Cauley, Jane A.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Crandall, Jill P.; Tabatabaie, Vafa] Albert Einstein Coll Med, Div Endocrinol, Bronx, NY 10461 USA. [Crandall, Jill P.; Tabatabaie, Vafa] Albert Einstein Coll Med, Div Geriatr, Bronx, NY 10461 USA. [Ensrud, Kristine E.; Diem, Susan] Univ Minnesota, Div Epidemiol & Community Hlth, Dept Med, Minneapolis, MN 55415 USA. [Ensrud, Kristine E.] Minneapolis VA Hlth Care Syst, Minneapolis, MN 55417 USA. [Gill, Thomas M.] Yale Univ, Sch Med, Div Geriatr Med, New Haven, CT 06511 USA. [Lewis, Cora E.] Univ Alabama Birmingham, Div Prevent Med, Birmingham, AL 35205 USA. [Pahor, Marco; Anton, Stephen] Univ Florida, Dept Aging & Geriatr Res, Gainesville, FL 32611 USA. [Resnick, Susan M.] NIA, Lab Behav Neurosci, NIH, Baltimore, MD 20817 USA. [Storer, Thomas W.] Boston Med Ctr, Sect Endocrinol Diabet & Nutr, Boston, MA 02115 USA. [Snyder, Peter J.] Univ Penn, Perelman Sch Med, Div Endocrinol Diabet & Metab, Philadelphia, PA 19104 USA. RP Snyder, PJ (reprint author), Univ Penn, Div Endocrinol Diabet & Metab, Med, Philadelphia, PA 19104 USA. EM pjs@mail.med.upenn.edu RI Cauley, Jane/N-4836-2015 OI Cauley, Jane/0000-0003-0752-4408 FU National Institute of Aging [U01 AG030644]; National Institutes of Health National Heart, Lung and Blood Institute; National Institute of Neurologic Diseases and Stroke; National Institute of Child Health and Human Development; AbbVie Inc.; Academic Leadership Award National Institute on Aging [K07AG043587]; Claude D. Pepper Older Americans Independence Center [P30 AG021342]; Boston Claude D. Pepper Older Americans Independence Center: Mechanism-Based Discovery of Function Promoting Anabolic Therapies, NIH/NIA [5P30AG013679]; Harvard Catalyst The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award) [UL1 TR001102]; Claude D. Pepper Older Americans Independence Center (NIH/NIA) [P30 AG028740]; Intramural Research Program, National Institute on Aging, NIH; [Yale CTSAUL1 TR000142] FX The TTrials were funded by a grant from the National Institute of Aging (U01 AG030644), supplemented by funds from the National Institutes of Health National Heart, Lung and Blood Institute, National Institute of Neurologic Diseases and Stroke, and National Institute of Child Health and Human Development and also by a grant from AbbVie Inc.; Dr. Gill is the recipient of an Academic Leadership Award (K07AG043587) from the National Institute on Aging. The Yale Field Center was partially supported by the Claude D. Pepper Older Americans Independence Center (P30 AG021342) and Yale CTSAUL1 TR000142). The Boston Site was supported partly by the Boston Claude D. Pepper Older Americans Independence Center: Mechanism-Based Discovery of Function Promoting Anabolic Therapies, NIH/NIA 5P30AG013679 and by the Harvard Catalyst The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award No. UL1 TR001102. The University of Florida site was supported partly by the Claude D. Pepper Older Americans Independence Center (NIH/NIA P30 AG028740). Susan Resnick is supported by the Intramural Research Program, National Institute on Aging, NIH. NR 40 TC 13 Z9 13 U1 0 U2 8 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD MAR PY 2015 VL 100 IS 3 BP 1146 EP 1155 DI 10.1210/jc.2014-3818 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CG5TR UT WOS:000353358900066 PM 25548978 ER PT J AU Denes, J Swords, F Rattenberry, E Stals, K Owens, M Cranston, T Xekouki, P Moran, L Kumar, A Wassif, C Fersht, N Baldeweg, SE Morris, D Lightman, S Agha, A Rees, A Grieve, J Powell, M Boguszewski, CL Dutta, P Thakker, RV Srirangalingam, U Thompson, CJ Druce, M Higham, C Davis, J Eeles, R Stevenson, M O'Sullivan, B Taniere, P Skordilis, K Gabrovska, P Barlier, A Webb, SM Aulinas, A Drake, WM Bevan, JS Preda, C Dalantaeva, N Ribeiro-Oliveira, A Garcia, IT Yordanova, G Iotova, V Evanson, J Grossman, AB Trouillas, J Ellard, S Stratakis, CA Maher, ER Roncaroli, F Korbonits, M AF Denes, Judit Swords, Francesca Rattenberry, Eleanor Stals, Karen Owens, Martina Cranston, Treena Xekouki, Paraskevi Moran, Linda Kumar, Ajith Wassif, Christopher Fersht, Naomi Baldeweg, Stephanie E. Morris, Damian Lightman, Stafford Agha, Amar Rees, Aled Grieve, Joan Powell, Michael Boguszewski, Cesar Luiz Dutta, Pinaki Thakker, Rajesh V. Srirangalingam, Umasuthan Thompson, Chris J. Druce, Maralyn Higham, Claire Davis, Julian Eeles, Rosalind Stevenson, Mark O'Sullivan, Brendan Taniere, Phillipe Skordilis, Kassiani Gabrovska, Plamena Barlier, Anne Webb, Susan M. Aulinas, Anna Drake, William M. Bevan, John S. Preda, Cristina Dalantaeva, Nadezhda Ribeiro-Oliveira, Antonio, Jr. Garcia, Isabel Tena Yordanova, Galina Iotova, Violeta Evanson, Jane Grossman, Ashley B. Trouillas, Jacqueline Ellard, Sian Stratakis, Constantine A. Maher, Eamonn R. Roncaroli, Federico Korbonits, Marta TI Heterogeneous Genetic Background of the Association of Pheochromocytoma/Paraganglioma and Pituitary Adenoma: Results From a Large Patient Cohort SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID ENDOCRINE NEOPLASIA TYPE-1; HORMONE-RELEASING FACTOR; HIPPEL-LINDAU-DISEASE; B GENE; MUTATIONS; PARAGANGLIOMA; TUMORS; MITOCHONDRIA; PREVALENCE; DIAGNOSIS AB Context: Pituitary adenomas and pheochromocytomas/paragangliomas (pheo/PGL) can occur in the same patient or in the same family. Coexistence of the two diseases could be due to either a common pathogenic mechanism or a coincidence. Objective: The objective of the investigation was to study the possible coexistence of pituitary adenoma and pheo/PGL. Design: Thirty-nine cases of sporadic or familial pheo/PGL and pituitary adenomas were investigated. Known pheo/PGL genes (SDHA-D, SDHAF2, RET, VHL, TMEM127, MAX, FH) and pituitary adenoma genes (MEN1, AIP, CDKN1B) were sequenced using next generation or Sanger sequencing. Loss of heterozygosity study and pathological studies were performed on the available tumor samples. Setting: The study was conducted at university hospitals. Patients: Thirty-nine patients with sporadic of familial pituitary adenoma and pheo/PGL participated in the study. Outcome: Outcomes included genetic screening and clinical characteristics. Results: Eleven germline mutations (five SDHB, one SDHC, one SDHD, two VHL, and two MEN1) and four variants of unknown significance (two SDHA, one SDHB, and one SDHAF2) were identified in the studied genes in our patient cohort. Tumor tissue analysis identified LOH at the SDHB locus in three pituitary adenomas and loss of heterozygosity at the MEN1 locus in two pheochromocytomas. All the pituitary adenomas of patients affected by SDHX alterations have a unique histological feature not previously described in this context. Conclusions: Mutations in the genes known to cause pheo/PGL can rarely be associated with pituitary adenomas, where as mutation in a gene predisposing to pituitary adenomas(MEN1) can be associated with pheo/PGL. Our findings suggest that genetic testing should be considered in all patients or families with the constellation of pheo/PGL and a pituitary adenoma. C1 [Denes, Judit; Srirangalingam, Umasuthan; Druce, Maralyn; Gabrovska, Plamena; Drake, William M.; Korbonits, Marta] Queen Mary Univ London, Barts, Dept Endocrinol, London EC1M 6BQ, England. [Denes, Judit; Srirangalingam, Umasuthan; Druce, Maralyn; Gabrovska, Plamena; Drake, William M.; Korbonits, Marta] Queen Mary Univ London, London Sch Med, London EC1M 6BQ, England. [Denes, Judit] Semmelweis Univ, Sch PhD Studies, Sch Clin Med, H-1085 Budapest, Hungary. [Swords, Francesca] Norfolk & Norwich Univ Hosp, Endocrinol Directorate, Norwich NR4 7UZ, Norfolk, England. [Maher, Eamonn R.; Roncaroli, Federico] Univ Birmingham, Dept Med & Mol Genet, Birmingham B15 2TT, W Midlands, England. [Stals, Karen; Owens, Martina; Ellard, Sian] Royal Devon, Dept Mol Genet, Exeter EX2 5DW, Devon, England. Exeter Natl Hlth Serv Fdn Trust, Exeter EX2 5DW, Devon, England. [Ellard, Sian] Univ Exeter, Sch Med, Exeter EX4 4PY, Devon, England. [Cranston, Treena] Univ Oxford, Churchill Hosp, Hosp Natl Hlth Serv Trust, Oxford Med Genet Labs, Oxford OX3 7LJ, England. [Xekouki, Paraskevi; Stratakis, Constantine A.] Eunice Kennedy Shriver Inst Child Hlth & Human De, Sect Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Wassif, Christopher] Eunice Kennedy Shriver Inst Child Hlth & Human De, Sect Mol Dysmorphol, NIH, Bethesda, MD 20892 USA. [Moran, Linda] Imperial Coll Healthcare Natl Hlth Serv Trust, Charing Cross Hosp, Dept Histopathol, Elect Microscopy Unit, London W6 8RF, England. [Kumar, Ajith] Great Ormond St Hosp Sick Children, Dept Clin Genet, London WC1N 1LE, England. [Fersht, Naomi] UCL, Dept Oncol, London WC1E 6BT, England. [Baldeweg, Stephanie E.] UCL, Dept Endocrinol, London WC1E 6BT, England. [Morris, Damian] Ipswich Hosp Natl Hlth Serv Trust, Dept Endocrinol & Diabet, Ipswich IP4 5PD, Suffolk, England. [Lightman, Stafford] Univ Bristol, Henry Wellcome Labs Integrat Neurosci & Endocrino, Bristol BS1 3NY, Avon, England. [Agha, Amar; Thompson, Chris J.] Beaumont Hosp, Dept Endocrinol, Dublin 9, Ireland. [Rees, Aled] Cardiff Univ, Inst Mol & Expt Med, Cardiff CF10 3US, S Glam, Wales. [Grieve, Joan; Powell, Michael] Natl Hosp Neurol & Neurosurg, Dept Neurosurg, London WC1N 3BG, England. [Boguszewski, Cesar Luiz] Univ Fed Parana, Hosp Clin, Serv Endocrinol & Metabol, BR-80210 Curitiba, Parana, Brazil. [Dutta, Pinaki] Post Grad Inst Med Educ & Res, Dept Endocrinol, Chandigarh 160012, India. [Thakker, Rajesh V.; Stevenson, Mark] Univ Oxford, Acad Endocrine Unit, Oxford OX1 3QX, England. [Higham, Claire] Christie Hosp Natl Hlth Serv Fdn Trust, Manchester M20 4BX, Lancs, England. [Davis, Julian] Univ Manchester, Fac Med & Human Sci, Ctr Endocrinol & Diabet, Inst Human Dev, Manchester M13 9PT, Lancs, England. [Davis, Julian] Manchester Acad, Hlth Sci Ctr, Cent Manchester Univ Hosp Natl Hlth Fdn Trust, Manchester Royal Infirm,Dept Endocrinol, Manchester M13 9WL, Lancs, England. [Eeles, Rosalind] Inst Canc Res, Div Genet & Epidemiol, London SW7 3RP, England. [O'Sullivan, Brendan; Taniere, Phillipe; Skordilis, Kassiani] Univ Hosp Birmingham Natl Hlth Serv Fdn Trust, Dept Histopathol, Birmingham B29 6JD, W Midlands, England. [Barlier, Anne] APHM Concept, Mol Biol Lab, F-7286 Marseille, France. Aix Marseille Univ, CNRS, CRN2M, Unite Mixte Rech, F-7286 Marseille, France. [Webb, Susan M.; Aulinas, Anna] Hosp Sant Pau, Inst Salud Carlos III, Centro Invest Biomed Red Enfermedades Rara, Dept Endocrinol & Med,St Pau IIB, Madrid 28029, Spain. Univ Autonoma Barcelona, Barcelona 08035, Spain. [Bevan, John S.] Aberdeen Royal Infirm, JJR Macleod Ctr Diabet Endocrinol & Metab, Aberdeen AB25 2ZB, Scotland. [Preda, Cristina] GrT Popa Univ Med & Pharm, Dept Endocrinol, Iasi 700115, Romania. [Dalantaeva, Nadezhda] Lomonosov Moscow State Univ, Endocrinol Res Ctr, Moscow 115478, Russia. [Ribeiro-Oliveira, Antonio, Jr.] Univ Fed Minas Gerais, Dept Internal Med, BR-30330120 Belo Horizonte, MG, Brazil. [Garcia, Isabel Tena] Castellon Prov Hosp, Dept Med Oncol & Canc Genet, Castellon de La Plana 12002, Spain. [Yordanova, Galina; Iotova, Violeta] Univ Multiprofile Hosp Active Treatment St Marina, Dept Pediat & Med Genet, Varna, Bulgaria. [Evanson, Jane] St Bartholomews Hosp, Dept Radiol, London E1 4NS, England. [Grossman, Ashley B.] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX3 7LJ, England. [Trouillas, Jacqueline] Univ Lyon, Hosp Civils Lyon, Ctr Pathol Est, INSERM Unite 1028, F-69622 Lyon, France. [Maher, Eamonn R.] Univ Cambridge, Dept Med Genet, Cambridge CB2 1TN, England. [Roncaroli, Federico] Univ London Imperial Coll Sci Technol & Med, Div Brain Sci, London SW7 2AZ, England. RP Denes, J (reprint author), Queen Mary Univ London, Barts, Dept Endocrinol, London EC1M 6BQ, England. RI BOGUSZEWSKI, CESAR /D-4603-2013; MAHER, EAMONN/A-9507-2008; Higham, Claire/L-4136-2015; Khoo, Bernard/B-1247-2009; OI MAHER, EAMONN/0000-0002-6226-6918; Higham, Claire/0000-0002-0917-9743; Khoo, Bernard/0000-0002-4223-9736; Thakker, Rajesh/0000-0002-1438-3220; Eeles, Rosalind/0000-0002-3698-6241; Barlier, Anne/0000-0002-3740-6173; Rees, Aled/0000-0002-1165-9092; Wassif, Christopher/0000-0002-2524-1420; Korbonits, Marta/0000-0002-4101-9432 FU Royal Society FX N.D. was supported by a grant from the Royal Society. NR 52 TC 24 Z9 25 U1 2 U2 9 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD MAR PY 2015 VL 100 IS 3 BP E531 EP E541 DI 10.1210/jc.2014-3399 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CG5TR UT WOS:000353358900023 PM 25494863 ER PT J AU Sepanlou, SG Newson, RB Poustchi, H Malekzadeh, MM Asl, PR Etemadi, A Khademi, H Islami, F Pourshams, A Pharoah, PD Abnet, CC Brennan, P Bofetta, P Dawsey, SM Kamangar, F Malekzadeh, R AF Sepanlou, Sadaf G. Newson, Roger B. Poustchi, Hossein Malekzadeh, Masoud M. Asl, Parisa Rezanejad Etemadi, Arash Khademi, Hooman Islami, Farhad Pourshams, Akram Pharoah, Paul D. Abnet, Christian C. Brennan, Paul Bofetta, Paolo Dawsey, Sanford M. Kamangar, Farin Malekzadeh, Reza TI Cardiovascular Disease Mortality and Years of Life Lost Attributable to Non-optimal Systolic Blood Pressure and Hypertension in Northeastern Iran SO ARCHIVES OF IRANIAN MEDICINE LA English DT Article DE Blood pressure; hypertension; Iran; mortality; years of life lost ID COMPARATIVE RISK-ASSESSMENT; GLOBAL BURDEN; ESOPHAGEAL CANCER; POLYPILL POLYCAP; RANDOMIZED-TRIAL; DIETARY SALT; FOLLOW-UP; POPULATION; HEALTH; STROKE AB Background: High blood pressure is the second Most important risk factor of cardiovasoular diseases (CVDs) in Iran. It is imperative to estimate the burden of CVDs that den be averted if high blood pressure is controlled at the population level: The aim Of the current study was to:estimate the avertable CVD mortality in the setting of Golestan Cohort Study (GCS). Methods: Over 50,000 participants were recruited and followed for a median of 7 years. The exposures of interest in this study were non-optimal systolic blood pressure (SBP) and hypertension measured at baseline. Deaths by cause have been precisely recorded. The Population Attributable Fraction (PAF) of deaths and Years of Life Lost (YLLs) due to CVDs attributable to exposures of interest were calculated. Results: Overall, 223 deaths due to ischemic head disease (IHD), 207 deaths due to cerebrovascular accidents (CVA), and 460 deaths due to all CVDs could be averted if the SBP of all subjects in the study Were optimal. Similarly, 5,560 YLLs due to IHD, 4,771 YLLs due CVA, and 11,135 YLLs due to CVDs could be prevented if SBP were optimal. In all age groups, the avertable deaths and YLLs were higher due to IHD compared with CVA. Deaths and YLLs attributable to non-Optimal SBP in women were less than-men Conclusions: A very large proportion of CVD deaths can be averted if blood pressure is controlled in Iran. Effective interventions in primary and secondary health care-setting are mandatory to be implemented as early as possible. C1 [Sepanlou, Sadaf G.; Poustchi, Hossein; Malekzadeh, Masoud M.; Asl, Parisa Rezanejad; Etemadi, Arash; Khademi, Hooman; Islami, Farhad; Pourshams, Akram; Kamangar, Farin; Malekzadeh, Reza] Univ Tehran Med Sci, Digest Dis Res Inst, Shariati Hosp, Tehran 1411713135, Iran. [Newson, Roger B.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London SW7 2AZ, England. [Etemadi, Arash; Abnet, Christian C.; Dawsey, Sanford M.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Khademi, Hooman; Brennan, Paul] Int Agcy Res Canc, F-69372 Lyon, France. [Islami, Farhad] Amer Canc Soc, Surveillance & Hlth Serv Res, Atlanta, GA 30329 USA. [Pharoah, Paul D.] Univ Cambridge, Dept Oncol, Cambridge, England. [Pharoah, Paul D.] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Bofetta, Paolo] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA. [Bofetta, Paolo] Icahn Sch Med Mt Sinai, Inst Translat Epidemiol, New York, NY 10029 USA. [Kamangar, Farin] Morgan State Univ, Sch Community Hlth & Policy, Dept Publ Hlth Anal, Baltimore, MD 21239 USA. RP Malekzadeh, R (reprint author), Univ Tehran Med Sci, Digest Dis Res Ctr, Shariati Hosp, Tehran 1411713135, Iran. EM dr.reza.malekzadeh@gmail.com RI Abnet, Christian/C-4111-2015; Etemadi, Arash/C-1386-2016; Sepanlou, Sadaf/H-9343-2016 OI Abnet, Christian/0000-0002-3008-7843; Etemadi, Arash/0000-0002-3458-1072; Sepanlou, Sadaf/0000-0002-3669-5129 FU Division of Cancer Epidemiology and Genetics of the National Cancer Institute, NIH; Digestive Disease Research Center of Tehran University of Medical Sciences [82-603]; Cancer Research UK (CRUK); International Agency for Research on Cancer FX This study was supported in part by the intramural research program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute, NIH, by the Digestive Disease Research Center of Tehran University of Medical Sciences (grant No 82-603), by Cancer Research UK (CRUK), and by the International Agency for Research on Cancer. NR 41 TC 3 Z9 3 U1 0 U2 6 PU ACAD MEDICAL SCIENCES I R IRAN PI TEHRAN PA PO BOX 19395-5655, TEHRAN, 00000, IRAN SN 1029-2977 J9 ARCH IRAN MED JI Arch. Iran. Med. PD MAR PY 2015 VL 18 IS 3 BP 144 EP 152 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA CG3KS UT WOS:000353179700001 PM 25773687 ER PT J AU Pursnani, A Chou, ET Zakroysky, P Deano, RC Mamuya, WS Woodard, PK Nagurney, JT Fleg, JL Lee, H Schoenfeld, D Udelson, JE Hoffmann, U Truong, QA AF Pursnani, Amit Chou, Eric T. Zakroysky, Pearl Deano, Roderick C. Mamuya, Wilfred S. Woodard, Pamela K. Nagurney, John T. Fleg, Jerome L. Lee, Hang Schoenfeld, David Udelson, James E. Hoffmann, Udo Truong, Quynh A. TI Use of Coronary Artery Calcium Scanning Beyond Coronary Computed Tomographic Angiography in the Emergency Department Evaluation for Acute Chest Pain The ROMICAT II Trial SO Circulation-Cardiovascular Imaging LA English DT Article DE acute coronary syndrome; hospital emergency service; multidetector-row computed tomography ID AMERICAN-HEART-ASSOCIATION; ELECTRON-BEAM TOMOGRAPHY; CT ANGIOGRAPHY; TUBE-VOLTAGE; ASSISTED TOMOGRAPHY; RADIATION-EXPOSURE; IMAGE QUALITY; FOLLOW-UP; CALCIFICATION; RISK AB Background-Whether a coronary artery calcium (CAC) scan provides added value to coronary computed tomographic angiography (CCTA) in emergency department patients with acute chest pain remains unsettled. We sought to determine the value of CAC scan in patients with acute chest pain undergoing CCTA. Methods and Results-In the multicenter Rule Out Myocardial Infarction using Computer-Assisted Tomography (ROMICAT) II trial, we enrolled low-intermediate risk emergency department patients with symptoms suggesting acute coronary syndrome (ACS). In this prespecified subanalysis of 473 patients (54 +/- 8 years, 53% men) who underwent both CAC scanning and CCTA, the ACS rate was 8%. Overall, 53% of patients had CAC=0 of whom 2 (0.8%) developed ACS, whereas 7% had CAC>400 with 49% whom developed ACS. C-statistic of CAC>0 was 0.76, whereas that using the optimal cut point of CAC >= 22 was 0.81. Continuous CAC score had lower discriminatory capacity than CCTA (c-statistic, 0.86 versus 0.92; P=0.03). Compared with CCTA alone, there was no benefit combining CAC score with CCTA (c-statistic, 0.93; P=0.88) or with selective CCTA strategies after initial CAC>0 or optimal cut point CAC >= 22 (P >= 0.09). Mean radiation dose from CAC acquisition was 1.4 +/- 0.7 mSv. Higher CAC scores resulted in more nondiagnostic CCTA studies although the majority remained interpretable. Conclusions-In emergency department patients with acute chest pain, CAC score does not provide incremental value beyond CCTA for ACS diagnosis. CAC=0 does not exclude ACS, nor a high CAC score preclude interpretation of CCTA in most patients. Thus, CAC results should not influence the decision to proceed with CCTA, and the decision to perform a CAC scan should be balanced with the additional radiation exposure required. C1 [Pursnani, Amit; Mamuya, Wilfred S.; Hoffmann, Udo] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol,Div Cardiol,Cardiac MR PET CT Program, Boston, MA USA. [Nagurney, John T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Emergency Dept, Boston, MA USA. [Zakroysky, Pearl; Lee, Hang; Schoenfeld, David] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Biostat Ctr, Boston, MA USA. [Chou, Eric T.] Kaiser Permanente Fontana Med Ctr, Div Cardiol, Fontana, CA USA. [Deano, Roderick C.; Truong, Quynh A.] New York Presbyterian Hosp, Weill Cornell Med Coll, Dalio Inst Cardiovasc Imaging, New York, NY 10021 USA. [Woodard, Pamela K.] Washington Univ, Sch Med, Mallinckrodt Inst Radiol, St Louis, MO USA. [Fleg, Jerome L.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Udelson, James E.] Tufts Med Ctr, Div Cardiol, Boston, MA USA. [Udelson, James E.] Tufts Med Ctr, Ctr Cardiovasc, Boston, MA USA. RP Truong, QA (reprint author), New York Presbyterian Hosp, Weill Cornell Med Coll, Dalio Inst Cardiovasc Imaging, 413 E 69th St,Suite 108, New York, NY 10021 USA. EM qat9001@med.cornell.edu FU National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute [U01HL092040, U01HL092022]; NIH [K23HL098370, L30HL093896]; [NIHT32 HL076136] FX The study was supported by the National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (U01HL092040 and U01HL092022). Dr Truong was supported by the NIH (K23HL098370 and L30HL093896). Dr Pursnani was supported by NIHT32 HL076136. NR 35 TC 5 Z9 5 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1941-9651 EI 1942-0080 J9 CIRC-CARDIOVASC IMAG JI Circ.-Cardiovasc. Imaging PD MAR PY 2015 VL 8 IS 3 AR e002225 DI 10.1161/CIRCIMAGING.114.002225 PG 11 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA CG5CW UT WOS:000353309700003 ER PT J AU Tanami, Y Jinzaki, M Kishi, S Matheson, M Vavere, AL Rochitte, CE Dewey, M Chen, MY Clouse, ME Cox, C Kuribayashi, S Lima, JAC Arbab-Zadeh, A AF Tanami, Yutaka Jinzaki, Masahiro Kishi, Satoru Matheson, Matthew Vavere, Andrea L. Rochitte, Carlos E. Dewey, Marc Chen, Marcus Y. Clouse, Melvin E. Cox, Christopher Kuribayashi, Sachio Lima, Joao A. C. Arbab-Zadeh, Armin TI Lack of Association Between Epicardial Fat Volume and Extent of Coronary Artery Calcification, Severity of Coronary Artery Disease, or Presence of Myocardial Perfusion Abnormalities in a Diverse, Symptomatic Patient Population Results From the CORE320 Multicenter Study SO Circulation-Cardiovascular Imaging LA English DT Article DE coronary artery disease; coronary stenosis; myocardial ischemia ID MULTISLICE COMPUTED-TOMOGRAPHY; CARDIOVASCULAR RISK-FACTORS; VISCERAL ABDOMINAL FAT; ADIPOSE-TISSUE VOLUME; BODY-MASS INDEX; PERICARDIAL FAT; DIAGNOSTIC PERFORMANCE; METABOLIC SYNDROME; CT ANGIOGRAPHY; ATHEROSCLEROSIS AB Background-Epicardial fat may play a role in the pathogenesis of coronary artery disease (CAD). We explored the relationship of epicardial fat volume (EFV) with the presence and severity of CAD or myocardial perfusion abnormalities in a diverse, symptomatic patient population. Methods and Results-Patients (n=380) with known or suspected CAD who underwent 320-detector row computed tomographic angiography, nuclear stress perfusion imaging, and clinically driven invasive coronary angiography for the CORE320 international study were included. EFV was defined as adipose tissue within the pericardial borders as assessed by computed tomography using semiautomatic software. We used linear and logistic regression models to assess the relationship of EFV with coronary calcium score, stenosis severity by quantitative coronary angiography, and myocardial perfusion abnormalities by single photon emission computed tomography (SPECT). Median EFV among patients (median age, 62.6 years) was 102 cm(3) (interquartile range: 53). A coronary calcium score of >= 1 was present in 83% of patients. Fifty-nine percent of patients had >= 1 coronary artery stenosis of >= 50% by quantitative coronary angiography, and 49% had abnormal myocardial perfusion results by SPECT. There were no significant associations between EFV and coronary artery calcium scanning, presence severity of >= 50% stenosis by quantitative coronary angiography, or abnormal myocardial perfusion by SPECT. Conclusions-In a diverse population of symptomatic patients referred for invasive coronary angiography, we did not find associations of EFV with the presence and severity of CAD or with myocardial perfusion abnormalities. The clinical significance of quantifying EFV remains uncertain but may relate to the pathophysiology of acute coronary events rather than the presence of atherosclerotic disease. C1 [Tanami, Yutaka; Jinzaki, Masahiro; Kuribayashi, Sachio] Keio Univ, Dept Radiol, Tokyo, Japan. [Kishi, Satoru; Vavere, Andrea L.; Lima, Joao A. C.; Arbab-Zadeh, Armin] Johns Hopkins Univ, Dept Med Cardiol, Baltimore, MD 21287 USA. [Matheson, Matthew; Cox, Christopher] Johns Hopkins Univ, Dept Epidemiol, Bloomberg Sch Publ Hlth, Baltimore, MD 21287 USA. [Rochitte, Carlos E.] InCor Heart Inst, Dept Med Cardiol, Sao Paulo, Brazil. [Dewey, Marc] Charite, Dept Radiol, Berlin, Germany. [Chen, Marcus Y.] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. [Clouse, Melvin E.] Beth Israel Deaconess Med Ctr, Dept Radiol, Boston, MA 02215 USA. RP Arbab-Zadeh, A (reprint author), Johns Hopkins Univ, Div Cardiol, 600 N Wolfe St,Blalock 524, Baltimore, MD 21287 USA. EM azadeh1@jhmi.edu FU Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, United States; National Institutes of Health [K23HL098368]; Toshiba Medical Systems FX This work was funded, in part, by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, United States. Dr Arbab-Zadeh was funded by grant K23HL098368 from the National Institutes of Health. The parent study for this research, the CORE320 multicenter study, was sponsored by Toshiba Medical Systems. NR 44 TC 13 Z9 13 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1941-9651 EI 1942-0080 J9 CIRC-CARDIOVASC IMAG JI Circ.-Cardiovasc. Imaging PD MAR PY 2015 VL 8 IS 3 AR e002676 DI 10.1161/CIRCIMAGING.114.002676 PG 9 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA CG5CW UT WOS:000353309700006 PM 25752899 ER PT J AU Berger, VW Mickenautsch, S AF Berger, Vance W. Mickenautsch, Steffen TI On the need for objective measures of risk of bias SO CONTEMPORARY CLINICAL TRIALS LA English DT Letter DE Objective measures; Randomized trials; Risk of bias ID CLINICAL-TRIALS; SELECTION BIAS C1 [Berger, Vance W.] NCI, Biometry Res Grp, UMBC, Bethesda, MD 20892 USA. [Mickenautsch, Steffen] Univ Witwatersrand, Fac Hlth Sci, Syst Initiat, Dept Community Dent, ZA-2193 Johannesburg, South Africa. RP Berger, VW (reprint author), NCI, Biometry Res Grp, UMBC, Execut Plaza North,Suite 3131,6130 Execut Blvd, Bethesda, MD 20892 USA. EM vb78c@nih.gov; neem@global.co.za OI Mickenautsch, Steffen/0000-0002-4994-2328 NR 9 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 1551-7144 EI 1559-2030 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD MAR PY 2015 VL 41 BP 202 EP 203 DI 10.1016/j.cct.2015.02.001 PG 2 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA CG0YQ UT WOS:000353000500024 PM 25666855 ER PT J AU Matsuda, K Fujishima, Y Maeda, N Mori, T Hirata, A Sekimoto, R Tsushima, Y Masuda, S Yamaoka, M Inoue, K Nishizawa, H Kita, S Ranscht, B Funahashi, T Shimomura, I AF Matsuda, Keisuke Fujishima, Yuya Maeda, Norikazu Mori, Takuya Hirata, Ayumu Sekimoto, Ryohei Tsushima, Yu Masuda, Shigeki Yamaoka, Masaya Inoue, Kana Nishizawa, Hitoshi Kita, Shunbun Ranscht, Barbara Funahashi, Tohru Shimomura, Iichiro TI Positive Feedback Regulation Between Adiponectin and T-Cadherin Impacts Adiponectin Levels in Tissue and Plasma of Male Mice SO ENDOCRINOLOGY LA English DT Article ID GENOME-WIDE ASSOCIATION; ADIPOSE-SPECIFIC PROTEIN; INSULIN-RESISTANCE; METABOLIC SYNDROME; PHOSPHOLIPASE-D; ENDOTHELIAL-CELLS; HUMAN-SERUM; CDH13; GENE; RECEPTOR AB Adiponectin (Adipo), a multimeric adipocyte-secreted protein abundant in the circulation, is implicated in cardiovascular protective functions. Recent work documented that Adipo locally associates with responsive tissues through interactions with T-cadherin (Tcad), an atypical, glycosylphosphatidylinositol (GPI)-anchored cadherin cell surface glycoprotein. Mice deficient for Tcad lack tissue-associated Adipo, accumulate Adipo in the circulation, and mimic the Adipo knockout (KO) cardiovascular phenotype. In reverse, Tcad protein is visibly reduced from cardiac tissue in Adipo-KO mice, suggesting interdependent regulation of the 2 proteins. Here, we evaluate the effect of Adipo on Tcad protein expression. Adipo and Tcad proteins were colocalized in aorta, heart, and skeletal muscle. Adipo positively regulated levels of Tcad protein in vivo and in endothelial cell (EC) cultures. In Tcad-KO mice, binding of endogenous and exogenously administered Adipo to cardiovascular tissues was dramatically reduced. Consistently, knockdown of Tcad in cultured murine vascular ECs significantly diminished Adipo binding. In search for a possible mechanism, we found that enzymatic cleavage of Tcad with phosphatidylinositol-specific phospholipase C increases plasma Adipo while decreasing tissue-bound levels. Similarly, pretreatment of cultured ECs with serum containing Adipo attenuated phosphatidylinositol-specific phospholipase C-mediated Tcad cleavage. In vivo administration of adenovirus producing Adipo suppressed plasma levels of GPI phospholipase D, the endogenous cleavage enzyme for GPI-anchored proteins. In conclusion, our data show that both circulating and tissue-bound Adipo levels are dependent on Tcad and, in reverse, regulate tissue Tcad levels through a positive feedback loop that operates by suppressing phospholipase-mediated Tcad release from the cell surface. C1 [Matsuda, Keisuke; Fujishima, Yuya; Maeda, Norikazu; Mori, Takuya; Hirata, Ayumu; Tsushima, Yu; Masuda, Shigeki; Yamaoka, Masaya; Inoue, Kana; Nishizawa, Hitoshi; Kita, Shunbun; Funahashi, Tohru; Shimomura, Iichiro] Osaka Univ, Grad Sch Med, Dept Metab Med, Suita, Osaka 5650871, Japan. [Hirata, Ayumu; Kita, Shunbun; Funahashi, Tohru] Osaka Univ, Grad Sch Med, Dept Metab & Atherosclerosis, Suita, Osaka 5650871, Japan. [Ranscht, Barbara] NIH, Sanford Burnham Med Res Inst, Designated Canc Ctr, Dev Aging & Regenerat Program, La Jolla, CA 92037 USA. RP Maeda, N (reprint author), Osaka Univ, Grad Sch Med, Dept Metab Med, 2-2 Yamada Oka, Suita, Osaka 5650871, Japan. EM norikazu_maeda@endmet.med.osaka-u.ac.jp FU Japan Society for the Promotion of Science [22590979, 24390238, 22126008]; National Institutes of Health [MH103861]; Takeda Science Foundation FX This work was supported in part by the Japan Society for the Promotion of Science Grant-in-Aid for Scientific Research (C) 22590979 (to N.M.), a Grant-in-Aid for Scientific Research (B) 24390238 (to I.S.), and a Grant-in-Aid for Scientific Research on Innovative Areas 22126008 (to T.F.); the National Institutes of Health Grant MH103861 (to B.R.); and the Takeda Science Foundation (to N.M.). NR 49 TC 7 Z9 8 U1 1 U2 6 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 MAR PY 2015 VL 156 IS 3 BP 934 EP 946 DI 10.1210/en.2014-1618 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CG4QS UT WOS:000353272000016 PM 25514086 ER PT J AU Lee, MH Lee, JU Joung, KH Kim, YK Ryu, MJ Lee, SE Kim, SJ Chung, HK Choi, MJ Chang, JY Lee, SH Kweon, GR Kim, HJ Kim, KS Kim, SM Jo, YS Park, J Cheng, SY Shong, M AF Lee, Min Hee Lee, Jung Uee Joung, Kyong Hye Kim, Yong Kyung Ryu, Min Jeong Lee, Seong Eun Kim, Soung Jung Chung, Hyo Kyun Choi, Min Jeong Chang, Joon Young Lee, Sang-Hee Kweon, Gi Ryang Kim, Hyun Jin Kim, Koon Soon Kim, Seong-Min Jo, Young Suk Park, Jeongwon Cheng, Sheue-Yann Shong, Minho TI Thyroid Dysfunction Associated With Follicular Cell Steatosis in Obese Male Mice and Humans SO ENDOCRINOLOGY LA English DT Article ID ENDOPLASMIC-RETICULUM; HEPATIC STEATOSIS; CONGENITAL GOITER; BODY-WEIGHT; ER STRESS; THYROGLOBULIN; MODEL; LIVER; HYPOTHYROIDISM; ROSIGLITAZONE AB Adult thyroid dysfunction is a common endocrine disorder associated with an increased risk of cardiovascular disease and mortality. Arecent epidemiologic study revealed a link between obesity and increased prevalence of hypothyroidism. It is conceivable that excessive adiposity in obesity might lead to expansion of the interfollicular adipose (IFA) depot or steatosis in thyroid follicular cells (thyroid steatosis, TS). In this study, weinvestigated the morphological and functional changes in thyroid glands of obese humans and animal models, diet-induced obese (DIO), ob/ob, and db/db mice. Expanded IFA depot and TS were observed in obese patients. Furthermore, DIO mice showed increased expression of lipogenesis-regulation genes, such as sterol regulatory element binding protein 1 (SREBP-1), peroxisome proliferator-activated receptor gamma (PPAR gamma), acetyl coenzyme A carboxylase (ACC), and fatty acid synthetase (FASN) in the thyroid gland. Steatosis and ultrastructural changes, including distension of the endoplasmic reticulum (ER) and mitochondrial distortion in thyroid follicular cells, were uniformly observed in DIO mice and genetically obese mouse models, ob/ob and db/db mice. Obese mice displayed a variable degree of primary thyroid hypofunction, which was not corrected by PPAR gamma agonist administration. We propose that systemically increased adiposity is associated with characteristic IFA depots and TS and may cause or influence the development of primary thyroid failure. C1 [Lee, Min Hee; Joung, Kyong Hye; Kim, Yong Kyung; Ryu, Min Jeong; Lee, Seong Eun; Kim, Soung Jung; Chung, Hyo Kyun; Choi, Min Jeong; Chang, Joon Young; Kim, Hyun Jin; Kim, Koon Soon; Jo, Young Suk] Chungnam Natl Univ, Sch Med, Res Ctr Endocrine & Metab Dis, Taejon 301721, South Korea. [Lee, Jung Uee] Catholic Univ Korea, Daejeon St Marys Hosp, Coll Med, Dept Pathol, Taejon 301723, South Korea. [Lee, Sang-Hee] Korea Adv Inst Biol Sci, Dept Biomed Sci, Taejon 305701, South Korea. [Kweon, Gi Ryang] Chungnam Natl Univ, Sch Med, Dept Biochem, Taejon 301721, South Korea. [Kim, Seong-Min] Chungnam Natl Univ & Hosp, Dept Nucl Med, Daejeon 301721, South Korea. [Park, Jeongwon; Cheng, Sheue-Yann] NCI, Mol Biol Lab, Bethesda, MD 20892 USA. RP Shong, M (reprint author), Chungnam Natl Univ, Sch Med, Res Ctr Endocrine & Metab Dis, 33 Munhwa Ro, Taejon 301721, South Korea. EM minhos@cnu.ac.kr FU Basic Science Research Program of the National Research Foundation of Korea - Ministry of Education, Science and Technology, Sejong, Korea [2012R1A2A1A03002833] FX This work was supported by the Basic Science Research Program of the National Research Foundation of Korea, funded by the Ministry of Education, Science and Technology (2012R1A2A1A03002833), Sejong, Korea. NR 44 TC 5 Z9 5 U1 1 U2 3 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 MAR PY 2015 VL 156 IS 3 BP 1181 EP 1193 DI 10.1210/en.2014-1670 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CG4QS UT WOS:000353272000037 PM 25555091 ER PT J AU Dossey, L AF Dossey, Larry TI NONLOCAL MIND: A (FAIRLY) BRIEF HISTORY OF THE TERM SO EXPLORE-THE JOURNAL OF SCIENCE AND HEALING LA English DT Article ID CORONARY-CARE UNIT; RANDOMIZED CONTROLLED TRIAL; BRAIN ELECTRICAL-ACTIVITIES; LARGE SOCIAL NETWORK; INTERCESSORY PRAYER; IN-VITRO; CONSCIOUSNESS; POPULATION; OUTCOMES; SCIENCE C1 [Dossey, Larry] Med City Dallas Hosp, Dallas, TX USA. [Dossey, Larry] NIH, Natl Ctr Complementary & Alternat Med, Panel Mind Body Intervent, Bethesda, MD USA. NR 172 TC 0 Z9 0 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1550-8307 EI 1878-7541 J9 EXPLORE-NY JI Explore-J Sci. Heal. PD MAR-APR PY 2015 VL 11 IS 2 BP 89 EP 101 DI 10.1016/j.explore.2014.12.001 PG 13 WC Integrative & Complementary Medicine SC Integrative & Complementary Medicine GA CG2DR UT WOS:000353085600004 PM 25812781 ER PT J AU Patterson, AR Mo, XK Shapiro, A Wernke, KE Archer, TK Burd, CJ AF Patterson, Andrea R. Mo, Xiaokui Shapiro, Ali Wernke, Karen E. Archer, Trevor K. Burd, Craig J. TI Sustained Reprogramming of the Estrogen Response After Chronic Exposure to Endocrine Disruptors SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID BISPHENOL-A BPA; BREAST-CANCER; CHEMICALS; MECHANISMS; RECEPTOR; EXPRESSION; GENES; RATS AB The pervasive nature of estrogenic industrial and dietary compounds is a growing health concern linked to cancer, obesity, and neurological disorders. Prior analyses of endocrine disruptor action have focused primarily on the short-term consequences of exposure. However, these studies are unlikely to reflect the consequences of constant exposures common to industrialized countries. Here we examined the global effects of long-term endocrine disruption on gene transcription and estrogen signaling. Estrogen-dependent breast cancer cell lines were chronically treated with physiologically relevant levels of bisphenol A or genistein for more than 70 passages. Microarray analysis demonstrated global reprogramming of the transcriptome when compared with a similarly cultured control cell line. Estrogen-responsive targets showed diminished expression in both the presence and absence of estrogen. Estrogen receptor recruitment, H3K4 monomethylation, and deoxyribonuclease accessibility were reduced at nearby response elements. Based on these observations, we investigated the potential of long-term endocrine disruptor exposure to initiate persistent transcriptional reprogramming. Culture of chronically exposed cell lines in the absence of the endocrine disruptors did not reverse many of the signaling defects that accumulated during treatment. Taken together, these data demonstrate that chronic exposure to endocrine disrupting compounds can permanently alter physiological hormone signaling. C1 [Patterson, Andrea R.; Shapiro, Ali; Wernke, Karen E.; Burd, Craig J.] Ohio State Univ, Dept Mol Genet, Columbus, OH 43210 USA. [Mo, Xiaokui] Ohio State Univ, Wexner Med Ctr, Ctr Biostat, Columbus, OH 43210 USA. [Patterson, Andrea R.; Shapiro, Ali; Burd, Craig J.] Arthur G James Comprehens Canc Ctr, Columbus, OH 43210 USA. [Archer, Trevor K.] NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. RP Burd, CJ (reprint author), Ohio State Univ, Dept Mol Genet, 590 Biomed Res Tower,460 West 12th Ave, Columbus, OH 43210 USA. EM craig.burd@osumc.edu RI Burd, Craig/D-9500-2017; OI Burd, Craig/0000-0002-6899-6751 FU National Institute of Environmental Health Sciences of the National Institutes of Health [R00ES019918] FX This work was supported by the National Institute of Environmental Health Sciences of the National Institutes of Health under Award R00ES019918. NR 19 TC 4 Z9 4 U1 3 U2 16 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD MAR PY 2015 VL 29 IS 3 BP 384 EP 395 DI 10.1210/me.2014-1237 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CG4XH UT WOS:000353291900006 PM 25594248 ER PT J AU Gwinn, WM Qu, W Bousquet, RW Price, H Shines, CJ Taylor, GJ Waalkes, MP Morgan, DL AF Gwinn, William M. Qu, Wei Bousquet, Ronald W. Price, Herman Shines, Cassandra J. Taylor, Genie J. Waalkes, Michael P. Morgan, Daniel L. TI Macrophage Solubilization and Cytotoxicity of Indium-Containing Particles as in vitro Correlates to Pulmonary Toxicity in vivo SO TOXICOLOGICAL SCIENCES LA English DT Article DE indium; InP; sintered ITO; solubilization; macrophage cytotoxicity; pulmonary toxicity ID TIN-OXIDE; INTRATRACHEAL INSTILLATIONS; ALVEOLAR PROTEINOSIS; CELL-LINE; LUNG; INHALATION; PHOSPHIDE; WORKERS; HAMSTERS; MICE AB Macrophage-solubilized indium-containing particles (ICPs) were previously shown in vitro to be cytotoxic. In this study, we compared macrophage solubilization and cytotoxicity of indium phosphide (InP) and indium-tin oxide (ITO) with similar particle diameters (similar to 1.5 mu m) and then determined if relative differences in these in vitro parameters correlated with pulmonary toxicity in vivo. RAW 264.7 macrophages were treated with InP or ITO particles and cytotoxicity was assayed at 24 h. Ionic indium was measured in 24h culture supernatants. Macrophage cytotoxicity and particle solubilization in vitro were much greater for InP compared with ITO. To correlate changes in vivo, B6C3F1 mice were treated with InP or ITO by oropharyngeal aspiration. On Days 14 and 28, bronchoalveolar lavage (BAL) and pleural lavage (PL) fluids were collected and assayed for total leukocytes. Cell differentials, lactate dehydrogenase activity, and protein levels were also measured in BAL. All lavage parameters were greatly increased in mice treated with InP compared with ITO. These data suggest that macrophage solubilization and cytotoxicity of some ICPs in vitro are capable of predicting pulmonary toxicity in vivo. In addition, these differences in toxicity were observed despite the two particulate compounds containing similar amounts of indium suggesting that solubilization, not total indium content, better reflects the toxic potential of some ICPs. Soluble InCl3 was shown to be more cytotoxic than InP to macrophages and lung epithelial cells in vitro further suggesting that ionic indium is the primary cytotoxic component of InP. C1 [Gwinn, William M.; Qu, Wei; Shines, Cassandra J.; Waalkes, Michael P.; Morgan, Daniel L.] NIEHS, NTP Lab, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Bousquet, Ronald W.; Price, Herman; Taylor, Genie J.] Alion Sci & Technol Corp, Res Triangle Pk, NC 27709 USA. RP Gwinn, WM (reprint author), NIEHS, Resp Toxicol, DNTP, MD IF-00,POB 12233, Res Triangle Pk, NC 27709 USA. EM gwinnwm@niehs.nih.gov FU National Toxicology Program, National Institute of Environmental Health Sciences (NIEHS); National Institutes of Health (NIH) FX National Toxicology Program, National Institute of Environmental Health Sciences (NIEHS), and National Institutes of Health (NIH). NR 30 TC 2 Z9 2 U1 3 U2 13 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 EI 1096-0929 J9 TOXICOL SCI JI Toxicol. Sci. PD MAR PY 2015 VL 144 IS 1 BP 17 EP 26 DI 10.1093/toxsci/kfu273 PG 10 WC Toxicology SC Toxicology GA CG8FP UT WOS:000353543000006 PM 25527823 ER PT J AU Tanaka, TQ Guiguemde, WA Barnett, DS Maron, MI Min, J Connelly, MC Suryadevara, PK Guy, RK Williamson, KC AF Tanaka, Takeshi Q. Guiguemde, W. Armand Barnett, David S. Maron, Maxim I. Min, Jaeki Connelly, Michele C. Suryadevara, Praveen Kumar Guy, R. Kiplin Williamson, Kim C. TI Potent Plasmodium falciparum Gametocytocidal Activity of Diaminonaphthoquinones, Lead Antimalarial Chemotypes Identified in an Antimalarial Compound Screen SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID SURFACE ANION CHANNEL; SEXUAL DEVELOPMENT; MALARIA PARASITES; LIFE-CYCLE; TRANSMISSION; STAGE; INHIBITORS; ERYTHROCYTES; ARTEMISININ; ARTESUNATE AB Forty percent of the world's population is threatened by malaria, which is caused by Plasmodium parasites and results in an estimated 200 million clinical cases and 650,000 deaths each year. Drug resistance has been reported for all commonly used antimalarials and has prompted screens to identify new drug candidates. However, many of these new candidates have not been evaluated against the parasite stage responsible for transmission, gametocytes. If Plasmodium falciparum gametocytes are not eliminated, patients continue to spread malaria for weeks after asexual parasite clearance. Asymptomatic individuals can also harbor gametocyte burdens sufficient for transmission, and a safe, effective gametocytocidal agent could also be used in community-wide malaria control programs. Here, we identify 15 small molecules with nanomolar activity against late-stage gametocytes. Fourteen are diaminonaphthoquinones (DANQs), and one is a 2-imino-benzo[d] imidazole (IBI). One of the DANQs identified, SJ000030570, is a lead antimalarial candidate. In contrast, 94% of the 650 compounds tested are inactive against late-stage gametocytes. Consistent with the ineffectiveness of most approved antimalarials against gametocytes, of the 19 novel compounds with activity against known anti-asexual-stage targets, only 3 had any strong effect on gametocyte viability. These data demonstrate the distinct biology of the transmission stages and emphasize the importance of screening for gametocytocidal activity. The potent gametocytocidal activity of DANQ and IBI coupled with their efficacy against asexual parasites provides leads for the development of antimalarials with the potential to prevent both the symptoms and the spread of malaria. C1 [Tanaka, Takeshi Q.; Williamson, Kim C.] NIAID, Lab Malaria & Vector Res, Bethesda, MD 20892 USA. [Guiguemde, W. Armand; Barnett, David S.; Min, Jaeki; Connelly, Michele C.; Suryadevara, Praveen Kumar; Guy, R. Kiplin] St Jude Childrens Res Hosp, Dept Chem Biol & Therapeut, Memphis, TN 38105 USA. [Maron, Maxim I.; Williamson, Kim C.] Loyola Univ Chicago, Dept Biol, Chicago, IL USA. RP Williamson, KC (reprint author), NIAID, Lab Malaria & Vector Res, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM kwilli4@luc.edu RI Guy, Rodney/J-7107-2013 OI Guy, Rodney/0000-0002-9638-2060 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health; American Lebanese Syrian Associated Charities (ALSAC); St. Jude Children's Research Hospital (SJCRH); Public Health Service grant from the National Institute of Allergy and Infectious Diseases [AI101396] FX This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, the American Lebanese Syrian Associated Charities (ALSAC), St. Jude Children's Research Hospital (SJCRH), and Public Health Service grant AI101396 from the National Institute of Allergy and Infectious Diseases. T.Q.T. is a JSPS Research Fellow in Biomedical and Behavioral Research at NIH. NR 43 TC 4 Z9 4 U1 0 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD MAR PY 2015 VL 59 IS 3 BP 1389 EP 1397 DI 10.1128/AAC.01930-13 PG 9 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA CF4VF UT WOS:000352550000001 PM 25512421 ER PT J AU Allem, JP Ayers, JW Unger, JB Vollinger, RE Latkin, C Juon, HS Park, HR Paik, HY Hofstetter, CR Hovell, MF AF Allem, Jon-Patrick Ayers, John W. Unger, Jennifer B. Vollinger, Robert E., Jr. Latkin, Carl Juon, Hee-Soon Park, Hae-Ryun Paik, Hee-Young Hofstetter, C. Richard Hovell, Melbourne F. TI The Environment Modifies the Relationship Between Social Networks and Secondhand Smoke Exposure Among Korean Nonsmokers in Seoul and California SO ASIA-PACIFIC JOURNAL OF PUBLIC HEALTH LA English DT Article DE cross-cultural communication; smoke exposure; global health; population health; smoking/tobacco/drug abuse ID INTERNATIONAL TOBACCO CONTROL; CIGARETTE-SMOKING; FREE POLICIES; CANCER-RISK; WOMEN; IMPLEMENTATION; ACCULTURATION; COUNTRIES; DESCENT; SUPPORT AB This study compared risks of secondhand smoke exposure (SHSe) among Korean nonsmokers in Seoul, South Korea and California, United States. Social networks were hypothesized to contain more smokers in Seoul than in California, and smokers were hypothesized to produce more secondhand smoke in Seoul than California, as Seoul's policies and norms are less restrictive. Telephone interviews were conducted with Korean adults in Seoul (N = 500) and California (N = 2830). In all, 69% (95% confidence interval [CI] = 64-74) of Koreans and 31% (95% CI = 29-33) of Korean Americans reported any SHSe. A total of 44% (95% CI = 40-47) of Korean family members smoked versus 29% (95% CI = 28-30) of Korean American family members (t = 7.84, P <.01). A 25% to 75% increase in the proportion of family members that smoked corresponded with a 13% (95% CI = 5-21) higher probability of any SHSe among Koreans compared with 6% (95% CI = 2-10) among Korean Americans. Network interventions in combination with policies and/or health campaigns may help reduce SHSe globally. C1 [Allem, Jon-Patrick; Unger, Jennifer B.] Univ So Calif, Keck Sch Med, Los Angeles, CA 90032 USA. [Ayers, John W.] Harvard Mit Div Hlth Sci & Technol, Childrens Hosp, Informat Program, Boston, MA USA. [Vollinger, Robert E., Jr.; Latkin, Carl; Juon, Hee-Soon] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Vollinger, Robert E., Jr.] NCI, NIH, Bethesda, MD 20892 USA. [Park, Hae-Ryun] Myongji Univ, Seoul, South Korea. [Paik, Hee-Young] Seoul Natl Univ, Seoul, South Korea. [Hofstetter, C. Richard; Hovell, Melbourne F.] San Diego State Univ, San Diego, CA 92182 USA. RP Allem, JP (reprint author), Univ So Calif, Keck Sch Med, 2001 N Soto St,3rd Floor, Los Angeles, CA 90032 USA. EM allem@usc.edu OI Unger, Jennifer/0000-0001-9064-6603 FU National Cancer Institute [R01CA105199] FX Data collection was supported by funds provided by the National Cancer Institute, Grant Number R01CA105199, to CRH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. The authors volunteered their time for the analysis and drafting of the report. NR 30 TC 3 Z9 3 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1010-5395 EI 1941-2479 J9 ASIA-PAC J PUBLIC HE JI Asia-Pac. J. Public Health PD MAR PY 2015 VL 27 IS 2 BP NP437 EP NP447 DI 10.1177/1010539512459750 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CF5GT UT WOS:000352586200042 PM 23000798 ER PT J AU Fay, MP Proschan, MA Brittain, E AF Fay, Michael P. Proschan, Michael A. Brittain, Erica TI Combining One-Sample Confidence Procedures for Inference in the Two-Sample Case SO BIOMETRICS LA English DT Article DE Behrens-Fisher problem; Confidence distributions; Difference in medians; Exact confidence interval; Fisher's exact test; Kaplan-Meier estimator ID BINOMIAL PROPORTIONS; FIDUCIAL-INFERENCE; TESTS; INTERVALS; DIFFERENCE; TABLES; LIMITS; TIME AB We present a simple general method for combining two one-sample confidence procedures to obtain inferences in the two-sample problem. Some applications give striking connections to established methods; for example, combining exact binomial confidence procedures gives new confidence intervals on the difference or ratio of proportions that match inferences using Fisher's exact test, and numeric studies show the associated confidence intervals bound the type I error rate. Combining exact one-sample Poisson confidence procedures recreates standard confidence intervals on the ratio, and introduces new ones for the difference. Combining confidence procedures associated with one-sample t-tests recreates the Behrens-Fisher intervals. Other applications provide new confidence intervals with fewer assumptions than previously needed. For example, the method creates new confidence intervals on the difference in medians that do not require shift and continuity assumptions. We create a new confidence interval for the difference between two survival distributions at a fixed time point when there is independent censoring by combining the recently developed beta product confidence procedure for each single sample. The resulting interval is designed to guarantee coverage regardless of sample size or censoring distribution, and produces equivalent inferences to Fisher's exact test when there is no censoring. We show theoretically that when combining intervals asymptotically equivalent to normal intervals, our method has asymptotically accurate coverage. Importantly, all situations studied suggest guaranteed nominal coverage for our new interval whenever the original confidence procedures themselves guarantee coverage. C1 [Fay, Michael P.; Proschan, Michael A.; Brittain, Erica] NIAID, Bethesda, MD 20892 USA. RP Fay, MP (reprint author), NIAID, 6700B Rockledge Dr MSC 7630, Bethesda, MD 20892 USA. EM mfay@niaid.nih.gov FU Intramural NIH HHS [Z99 AI999999] NR 30 TC 2 Z9 2 U1 2 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-341X EI 1541-0420 J9 BIOMETRICS JI Biometrics PD MAR PY 2015 VL 71 IS 1 BP 146 EP 156 DI 10.1111/biom.12231 PG 11 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA CF5GO UT WOS:000352585700017 PM 25274182 ER PT J AU Li, ZJ Zhang, Y Tong, YX Tong, JN Thiele, CJ AF Li, Zhijie Zhang, Yi Tong, Yuxin Tong, Jenna Thiele, Carol J. TI Trk inhibitor attenuates the BDNF/TrkB-induced protection of neuroblastoma cells from etoposide in vitro and in vivo SO CANCER BIOLOGY & THERAPY LA English DT Article DE AZD6918; etoposide; neuroblastoma; Trk inhibitor; BDNF; brain-derived neurotrophic factor; NB; neuroblastoma; TET; tetracycline; Trk; tropomyosin-related kinase ID NEUROTROPHIC FACTOR; KINASE INHIBITOR; CEP-701; LESTAURTINIB; EXPRESSION; PROLIFERATION; APOPTOSIS; SURVIVAL; MODELS AB TrkB activation by brain-derived neurotrophic factor (BDNF) contributes to chemo-resistance in neuroblastoma (NB). AZD6918 is a novel potent and selective inhibitor of the Trk tyrosine kinases. In this study we evaluated the effect of AZD6918 on the sensitivity of TrkB-expressing NB cells or tumors to etoposide, a topoisomerase II inhibitor. TrkB-expressing NB cells were treated with AZD6918 and etoposide in the presence or absence of BDNF in vitro and cell survival was determined. NB xenograft tumors were treated with AZD6918 and etoposide, either alone or in combination in vivo, and the anti-tumor growth effect or mice survival advantage was evaluated. Our study showed that AZD6918 induced cell death as a single agent and attenuated BDNF/TrkB-induced protection from etoposide in vitro. Although AZD6918 alone didn't show anti-tumor growth effect or survival advantage in vivo, a combination of AZD6918 and etoposide had a statistically significant stronger anti-tumor growth effect and survival advantage compared to treatment with either agent alone. Our data indicate that as a Trk inhibitor AZD6918 increased the sensitivity of NB to etoposide. These results extend the spectrum of cytotoxic drugs whose efficacy is increased in combination with Trk inhibitors and support the combination of Trk inhibitors and cytotoxic drugs for NB treatment. C1 [Li, Zhijie; Tong, Jenna; Thiele, Carol J.] NCI, Cell & Mol Biol Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Li, Zhijie; Zhang, Yi; Tong, Yuxin] China Med Univ, Shengjing Hosp, Med Res Ctr, Shenyang 110001, Peoples R China. RP Li, ZJ (reprint author), NCI, Cell & Mol Biol Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. EM lizhijie68@hotmail.com FU NCI Intramural Research Program at National Cancer Institute in National Institute of Health; National Natural Science Foundation of China [81272538, 81472359]; Society Development Foundation of Liaoning Province [2012225016]; Liaoning Climbing Scholar Foundation FX This work was supported by NCI Intramural Research Program at National Cancer Institute in National Institute of Health, National Natural Science Foundation of China (No. 81272538, No. 81472359), Society Development Foundation of Liaoning Province (No. 2012225016), 2013 Liaoning Climbing Scholar Foundation. NR 22 TC 3 Z9 3 U1 4 U2 9 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1538-4047 EI 1555-8576 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD MAR PY 2015 VL 16 IS 3 BP 477 EP 483 DI 10.1080/15384047.2015.1016659 PG 7 WC Oncology SC Oncology GA CF5OQ UT WOS:000352607000015 PM 25700942 ER PT J AU Rougeron, V Feldmann, H Grard, G Becker, S Leroy, EM AF Rougeron, V. Feldmann, H. Grard, G. Becker, S. Leroy, E. M. TI Ebola and Marburg haemorrhagic fever SO JOURNAL OF CLINICAL VIROLOGY LA English DT Article ID PROTECTS NONHUMAN-PRIMATES; REVERSE TRANSCRIPTION-PCR; VIRUS-INFECTION; VP35 PROTEIN; CYNOMOLGUS MACAQUES; IMMUNE-RESPONSES; IMMUNOELECTRON MICROSCOPY; POSTEXPOSURE TREATMENT; PASSIVE TRANSFER; IMMUNOGLOBULIN-G AB Ebolaviruses and Marburgviruses (family Filoviridae) are among the most virulent pathogens for humans and great apes causing severe haemorrhagic fever and death within a matter of days. This group of viruses is characterized by a linear, non-segmented, single-stranded RNA genome of negative polarity. The overall burden of filovirus infections is minimal and negligible compared to the devastation caused by malnutrition and other infectious diseases prevalent in Africa such as malaria, dengue or tuberculosis. In this paper, we review the knowledge gained on the eco/epidemiology, the pathogenesis and the disease control measures for Marburg and Ebola viruses developed over the last 15 years. The overall progress is promising given the little attention that these pathogen have achieved in the past; however, more is to come over the next decade given the more recent interest in these pathogens as potential public and animal health concerns. Licensing of therapeutic and prophylactic options may be achievable over the next 5-10 years. (C) 2015 Elsevier B.V. All rights reserved. C1 [Rougeron, V.; Leroy, E. M.] UMR IRD 224 CNRS 5290 UMI, Lab MiVEGEC, F-34394 Montpellier 5, France. [Rougeron, V.; Grard, G.; Leroy, E. M.] Int Ctr Med Res Franceville, Franceville, Gabon. [Feldmann, H.] NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. [Becker, S.] Univ Marburg, Inst Virol, D-35037 Marburg, Germany. RP Rougeron, V (reprint author), UMR IRD 224 CNRS 5290 UMI, Lab MiVEGEC, 911 Av Agropolis, F-34394 Montpellier 5, France. EM rougeron.virginie@gmail.com RI LEROY, Eric/I-4347-2016 OI Rougeron, Virginie/0000-0001-5873-5681; LEROY, Eric/0000-0003-0022-0890 FU Gabonese Government; Total Gabon; Deutsche Forschungsgemeinschaft (Germany) [Sonderforschungsbereich 593, Sonderforschungsbereich 1021]; NIAID, NIH (U.S.A) FX We thank the Gabonese Government, Total Gabon, the Deutsche Forschungsgemeinschaft, Sonderforschungsbereich 593 and 1021 (Germany) and the Intramural Research Program of NIAID, NIH (U.S.A) for financial support. NR 112 TC 24 Z9 25 U1 4 U2 46 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1386-6532 EI 1873-5967 J9 J CLIN VIROL JI J. Clin. Virol. PD MAR PY 2015 VL 64 BP 111 EP 119 DI 10.1016/j.jcv.2015.01.014 PG 9 WC Virology SC Virology GA CF0ZP UT WOS:000352273600021 PM 25660265 ER PT J AU Papa, A Mirazimi, A Koksal, I Estrada-Pena, A Feldmann, H AF Papa, Anna Mirazimi, Ali Koksal, Iftihar Estrada-Pena, Augustin Feldmann, Heinz TI Recent advances in research on Crimean-Congo hemorrhagic fever SO JOURNAL OF CLINICAL VIROLOGY LA English DT Article DE Crimean-Congo hemorrhagic fever; Ecology; Epidemiology ID TICK-BORNE ENCEPHALITIS; REVERSE TRANSCRIPTASE-PCR; RECEPTOR-KNOCKOUT MICE; NECROSIS-FACTOR-ALPHA; VIRAL LOAD; VIRUS-INFECTION; I INTERFERON; CIRCLE AMPLIFICATION; HYALOMMA-MARGINATUM; MOLECULAR-DETECTION AB Crimean-Congo hemorrhagic fever (CCHF) is an expanding tick-borne hemorrhagic disease with increasing human and animal health impact. Immense knowledge was gained over the past 10 years mainly due to advances in molecular biology, but also driven by an increased global interest in CCHFV as an emerging/re-emerging zoonotic pathogen. In the present article, we discuss the advances in research with focus on CCHF ecology, epidemiology, pathogenesis, diagnostics, prophylaxis and treatment. Despite tremendous achievements, future activities have to concentrate on the development of vaccines and antivirals/therapeutics to combat CCHF. Vector studies need to continue for better public and animal health preparedness and response. We conclude with a roadmap for future research priorities. (C) 2014 Elsevier B.V. All rights reserved. C1 [Papa, Anna] Aristotle Univ Thessaloniki, Dept Microbiol, Thessaloniki 54124, Greece. [Mirazimi, Ali] Swedish Inst Communicable Dis Control, SE-17182 Solna, Sweden. [Mirazimi, Ali] Natl Vet Inst, SE-75651 Uppsala, Sweden. [Mirazimi, Ali] Linkopings Univ, Dept Clin & Expt Med, SE-58183 Linkoping, Sweden. [Koksal, Iftihar] Karadeniz Tech Univ, Fac Med, Dept Infect Dis, Trabzon, Turkey. [Estrada-Pena, Augustin] Univ Zaragoza, Dept Anim Pathol, Zaragoza, Spain. [Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT USA. RP Papa, A (reprint author), Aristotle Univ Thessaloniki, Dept Microbiol, Sch Med, Thessaloniki 54124, Greece. EM annap@med.auth.gr RI Koksal, Iftihar/B-7518-2016 FU European Commission [260427]; Swedish Research Council; NIAID, NIH FX Anna Papa and Ali Mirazimi are partners of the CCH Fever Network (Collaborative Project) supported by the European Commission under the Health Cooperation Work Program of the 7th Framework Program (Grant agreement no. 260427). Ali Mirazimi is also supported by the Swedish Research Council. Heinz Feldmann is supported by the Intramural Research Program of the NIAID, NIH. NR 88 TC 8 Z9 8 U1 1 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1386-6532 EI 1873-5967 J9 J CLIN VIROL JI J. Clin. Virol. PD MAR PY 2015 VL 64 BP 137 EP 143 DI 10.1016/j.jcv.2014.08.029 PG 7 WC Virology SC Virology GA CF0ZP UT WOS:000352273600024 PM 25453328 ER PT J AU Larkin, ME AF Larkin, Megan E. TI Acoustic Separation and Biomedical Research: Lessons from Indian Regulation of Compensation for Research Injury SO JOURNAL OF LAW MEDICINE & ETHICS LA English DT Article ID RESEARCH PARTICIPANTS; CLINICAL-RESEARCH; RESPONSIBILITIES; STANDARD; POLICY AB In early 2013, the Indian government introduced new rules governing the conduct of clinical trials involving human participants. Among other provisions, the law requires that sponsors of research compensate participants who are injured during the course of their research participation. This article examines the effects of India's compensation law and the efforts that policymakers in India have made to tailor the law since its passage. I use the legal concept of acoustic separation as a framework to explain and justify the approach that India has taken in refining its regulation of research related injuries. I conclude that India's example may provide useful lessons for research sponsors and lawmakers in other regulatory states seeking to promote a well-regulated biomedical research industry. C1 Natl Inst Hlth, Dept Bioeth, Clin Ctr, Bethesda, MD 20814 USA. RP Larkin, ME (reprint author), Natl Inst Hlth, Dept Bioeth, Clin Ctr, Bethesda, MD 20814 USA. FU NIH, in the Warren G. Magnuson Clinical Center FX This research was supported by the Intramural Research Program of the NIH, in the Warren G. Magnuson Clinical Center. The opinions expressed here are the views of the author. They do not represent any position or policy of the U.S. National Institutes of Health, the Public Health Service, or the Department of Health and Human Services. The author would like to thank Seema Shah, Alan Wertheimer, Ben Berkman, Joe Millum, Dave Wendler and Ron Ghatan for their helpful comments and suggestions. NR 38 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1073-1105 EI 1748-720X J9 J LAW MED ETHICS JI J. Law Med. Ethics PD SPR PY 2015 VL 43 IS 1 SI SI BP 105 EP 115 DI 10.1111/jlme.12199 PG 11 WC Ethics; Law; Medical Ethics; Medicine, Legal SC Social Sciences - Other Topics; Government & Law; Medical Ethics; Legal Medicine GA CF5CN UT WOS:000352573100009 PM 25846042 ER PT J AU Marcum, CS Butts, CT AF Marcum, Christopher Steven Butts, Carter T. TI Constructing and Modifying Sequence Statistics for relevent Using informR in R SO JOURNAL OF STATISTICAL SOFTWARE LA English DT Article DE relational events; sequence statistics; relevent ID NOCTURIA AB The informR package greatly simplifies the analysis of complex event histories in R by providing user friendly tools to build sufficient statistics for the relevent package. Historically, building sufficient statistics to model event sequences (of the form a -> b) using the egocentric generalization of Butts' (2008) relational event framework for modeling social action has been cumbersome. The informR package simplifies the construction of the complex list of arrays needed by the rem() model fitting for a variety of cases involving egocentric event data, multiple event types, and/or support constraints. This paper introduces these tools using examples from real data extracted from the American Time Use Survey. C1 [Marcum, Christopher Steven] Natl Human Genome Res Inst, NIH, Bethesda, MD 20892 USA. [Butts, Carter T.] Univ Calif Irvine, Dept Sociol, Dept Stat, Irvine, CA USA. [Butts, Carter T.] Univ Calif Irvine, EECS, Irvine, CA USA. [Butts, Carter T.] Univ Calif Irvine, Inst Math Behav Sci, Irvine, CA USA. RP Marcum, CS (reprint author), Natl Human Genome Res Inst, NIH, Bethesda, MD 20892 USA. EM chris.marcum@nih.gov; buttsc@uci.edu OI Marcum, Christopher/0000-0002-0899-6143 FU National Science Foundation [CMS-0624257]; Office of Naval Research [N00014-08-1-1015]; National Institutes of Health Intramural Research Program [Z01HG200335] FX We would like to thank the anonymous reviewers for their useful comments and suggestions. Funding for the development of this project was supported by grants from the National Science Foundation (CMS-0624257) and the Office of Naval Research (N00014-08-1-1015), and revisions were supported by funding from the National Institutes of Health Intramural Research Program (Z01HG200335 to L. Koehly). NR 18 TC 2 Z9 2 U1 0 U2 0 PU JOURNAL STATISTICAL SOFTWARE PI LOS ANGELES PA UCLA DEPT STATISTICS, 8130 MATH SCIENCES BLDG, BOX 951554, LOS ANGELES, CA 90095-1554 USA SN 1548-7660 J9 J STAT SOFTW JI J. Stat. Softw. PD MAR PY 2015 VL 64 IS 5 BP 1 EP 36 PG 36 WC Computer Science, Interdisciplinary Applications; Statistics & Probability SC Computer Science; Mathematics GA CF9UD UT WOS:000352911400001 PM 26185488 ER PT J AU Sarris, J Logan, AC Akbaraly, TN Amminger, GP Balanza-Martinez, V Freeman, MP Hibbeln, J Matsuoka, Y Mischoulon, D Mizoue, T Nanri, A Nishi, D Ramsey, D Rucklidge, JJ Sanchez-Villegas, A Scholey, A Su, KP Jacka, FN AF Sarris, Jerome Logan, Alan C. Akbaraly, Tasnime N. Amminger, G. Paul Balanza-Martinez, Vicent Freeman, Marlene P. Hibbeln, Joseph Matsuoka, Yutaka Mischoulon, David Mizoue, Tetsuya Nanri, Akiko Nishi, Daisuke Ramsey, Drew Rucklidge, Julia J. Sanchez-Villegas, Almudena Scholey, Andrew Su, Kuan-Pin Jacka, Felice N. CA Int Soc Nutr Psychiat Res TI Nutritional medicine as mainstream in psychiatry SO LANCET PSYCHIATRY LA English DT Editorial Material ID S-ADENOSYL METHIONINE; DUTCH-HUNGER-WINTER; DIETARY PATTERNS; MENTAL-HEALTH; PRENATAL EXPOSURE; MAJOR DEPRESSION; ADULTS; EFFICACY; TRIAL; METAANALYSIS AB Psychiatry is at an important juncture, with the current pharmacologically focused model having achieved modest benefits in addressing the burden of poor mental health worldwide. Although the determinants of mental health are complex, the emerging and compelling evidence for nutrition as a crucial factor in the high prevalence and incidence of mental disorders suggests that diet is as important to psychiatry as it is to cardiology, endocrinology, and gastroenterology. Evidence is steadily growing for the relation between dietary quality (and potential nutritional deficiencies) and mental health, and for the select use of nutrient-based supplements to address deficiencies, or as monotherapies or augmentation therapies. We present a viewpoint from an international collaboration of academics (members of the International Society for Nutritional Psychiatry Research), in which we provide a context and overview of the current evidence in this emerging field of research, and discuss the future direction. We advocate recognition of diet and nutrition as central determinants of both physical and mental health. C1 [Sarris, Jerome] Univ Melbourne, Melbourne Clin, Melbourne, Vic, Australia. [Jacka, Felice N.] Univ Melbourne, Royal Melbourne Hosp, Dept Psychiat, Melbourne, Vic 3050, Australia. [Sarris, Jerome; Scholey, Andrew] Swinburne Univ Technol, Ctr Human Psychopharmacol, Hawthorn, Vic 3122, Australia. [Logan, Alan C.] CAMNR, Calabasas, CA USA. [Akbaraly, Tasnime N.] Univ Montpellier, INSERM, U710, F-34059 Montpellier, France. [Akbaraly, Tasnime N.] UCL, Dept Epidemiol & Publ Hlth, London, England. [Amminger, G. Paul] Orygen Youth Hlth Res Ctr, Parkville, Vic, Australia. [Balanza-Martinez, Vicent] La Fe Univ, Teaching Unit Psychiat & Psychol Med, Valencia, Spain. [Balanza-Martinez, Vicent] Univ Valencia, Polytech Hosp, Sch Med, Ctr Invest Biomed Red Salud Mental CIBERSAM, Valencia, Spain. [Freeman, Marlene P.] Massachusetts Gen Hosp, Perinatal & Reprod Psychiat, Boston, MA 02114 USA. [Mischoulon, David] Massachusetts Gen Hosp, Depress & Clincal Res Program, Boston, MA 02114 USA. [Hibbeln, Joseph] NIAAA, NIH, Bethesda, MD USA. [Matsuoka, Yutaka] Natl Ctr Neurol & Psychiat, Dept Clin Epidemiol, Translat Med Ctr, Kodaira, Tokyo, Japan. [Nishi, Daisuke] Natl Ctr Neurol & Psychiat, Natl Inst Mental Hlth, Dept Mental Hlth Policy & Evaluat, Kodaira, Tokyo, Japan. [Mizoue, Tetsuya; Nanri, Akiko] Natl Ctr Global Hlth & Med, Dept Epidemiol & Prevent, Ctr Clin Sci, Shijuku Ku, Tokyo, Japan. [Ramsey, Drew] Columbia Univ Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. [Rucklidge, Julia J.] Univ Canterbury, Dept Psychol, Christchurch 1, New Zealand. [Sanchez-Villegas, Almudena] Univ Las Palmas Gran Canaria, Dept Clin Sci, Las Palmas Gran Canaria, Spain. [Su, Kuan-Pin] China Med Univ, Dept Psychiat, Taichung, Taiwan. [Su, Kuan-Pin] China Med Univ, Mind Body Interface Lab MBI Lab, China Med Univ Hosp, Taichung, Taiwan. [Su, Kuan-Pin] China Med Univ, Grad Inst Neural & Cognit Sci, Taichung, Taiwan. [Jacka, Felice N.] Deakin Univ, Sch Med, IMPACT Strateg Res Ctr, Geelong, Vic 3217, Australia. [Jacka, Felice N.] Murdoch Childrens Res Ctr, Parkville, Vic, Australia. [Jacka, Felice N.] Hosp Rd Prince Wales Hosp, Black Dog Inst, Randwick, NSW, Australia. RP Sarris, J (reprint author), Melbourne Clin, 2 Salisbury St, Melbourne, Vic 3121, Australia. EM jsarris@unimelb.edu.au FU Integria Health; Blackmores; Bioceuticals; Taki Mai; Pepsico; HealthEd; Soho-Flordis; Pfizer; Elsevier; Society for Medicinal Plant and Natural Product Research; CR Roper Fellowship; National Health and Medical Research Council (NHMRC); Genuine Health (Toronto, Canada); Angelini; AstraZeneca; Bristol-Myers-Squibb; Janssen; Juste; Lilly; Lundbeck; Otsuka; Spanish Ministry of Science and Innovation; Fundacion Alicia Koplowitz; Takeda; Genentech; Johnson Johnson; JDS Therapeutics; Japan Science and Technology Agency; National Center of Neurology and Psychiatry (Japan); Ministry of Health, Labour, and Welfare of Japan; Mochida Pharmaceutical Co; Takeda Pharmaceutical Company; Suntory Wellness; Eli Lilly Japan KK; Otsuka Pharmaceutical Co; DHA & EPA Association; Bowman Family Foundation; FisherWallace; Nordic Naturals; Methylation Sciences; PharmoRx Therapeutics; Japan Society for the Promotion of Science; National Center for Global Health and Medicine (Japan); National Cancer Center (Japan); Industrial Health Foundation; Uehara Memorial Foundation; Otsuka Pharmaceutical Co.; Foundation for Total Health Promotion; Qol Co; NTT DoCoMo; Emotional Quotient Academy; Biotechnology and Biological Sciences Research Council (UK); Australian Research Council; NHMRC; British Psychological Society; Australian Wine Research Institute; Abbott Nutrition; Arla Foods; Bayer Healthcare; Cognis; Cyvex; GlaxoSmithKline Nutrition; Masterfoods; Martek; Naturex; Nestle; Neurobrands; Sanofi; Verdure Sciences; Wrigley; Barilla; Danone; Flordis; GlaxoSmithKline Healthcare; Kraft; Novartis; Unilever; National Science Council; National Health Research Institute; China Medical University in Taiwan; Royal Society (UK); National Centre for Research and Development (Poland); Brain and Behaviour Research Institute (USA); Australian Rotary Health; Geelong Medical Research Foundation; Ian Potter Foundation; Eli Lilly; Meat and Livestock Board Australia; University of Melbourne; Sanofi -Synthelabo; Janssen Cilag; Servier; Health Ed; Network Nutrition; Angelini Farmaceutica FX JS has received honoraria, research support, royalties, consultancy, or travel grant funding from Integria Health, Blackmores, Bioceuticals, Taki Mai, Pepsico, HealthEd, Soho-Flordis, Pfizer, Elsevier,the Society for Medicinal Plant and Natural Product Research, CR Roper Fellowship, and the National Health and Medical Research Council (NHMRC). ACL has received consulting fees from Genuine Health (Toronto, Canada). VB-M has received grants, and served as consultant, adviser, or continuing medical education (CME) speaker during the past 3 years for the following entities: Angelini, AstraZeneca, Bristol-Myers-Squibb, Janssen, Juste, Lilly, Lundbeck, Otsuka, the Spanish Ministry of Science and Innovation, and Fundacion Alicia Koplowitz. MPF has received funding for advisory board positions, or consulting, from: Takeda, Otsuka, Lundbeck, Genentech, Johnson & Johnson, and JDS Therapeutics; pending research support from Takeda; and for medical editing for DSM Nutritionals and GOED Omega-3. YM has received research support from the Japan Science and Technology Agency, National Center of Neurology and Psychiatry (Japan), the Ministry of Health, Labour, and Welfare of Japan, and has been a paid speaker for Mochida Pharmaceutical Co, Takeda Pharmaceutical Company, Suntory Wellness, Eli Lilly Japan KK, Otsuka Pharmaceutical Co, and DHA & EPA Association. DM has received research support from the Bowman Family Foundation, FisherWallace, Nordic Naturals, Methylation Sciences, and PharmoRx Therapeutics. He has received honoraria for consulting, speaking, and writing from Pamlab, and the Massachusetts General Hospital Psychiatry Academy. He has received royalties from Lippincott Williams & Wilkins for the published book Natural medications for psychiatric disorders: considering the alternatives. TM has received research grants from the Japan Society for the Promotion of Science, the National Center for Global Health and Medicine (Japan), the National Cancer Center (Japan), the Ministry of Health, Labour, and Welfare of Japan, the Industrial Health Foundation, the Uehara Memorial Foundation, and Otsuka Pharmaceutical Co. DN has received research support from the Japan Society for the Promotion of Science and the Foundation for Total Health Promotion, and lecture fees from Qol Co, DHA & EPA Association, NTT DoCoMo, and Emotional Quotient Academy. AS has received funding from the Biotechnology and Biological Sciences Research Council (UK), The Australian Research Council, the NHMRC, the British Psychological Society, the Australian Wine Research Institute, Abbott Nutrition, Arla Foods, Bayer Healthcare, Cognis, Cyvex, GlaxoSmithKline Nutrition, Masterfoods, Martek, Naturex, Nestle, Neurobrands, Sanofi, Verdure Sciences, and Wrigley, and received speaker fees from Abbott Nutrition, Barilla, Bayer Healthcare, Danone, Flordis, GlaxoSmithKline Healthcare, Kraft, Masterfoods, Martek, Novartis, Unilever, and Wrigley. K-PS has received research grants from the National Science Council, National Health Research Institute, and China Medical University in Taiwan, and joint research grants from the Royal Society (UK) and National Centre for Research and Development (Poland).; FNJ has received grants and research support from the Brain and Behaviour Research Institute (USA), the NHMRC, Australian Rotary Health, the Geelong Medical Research Foundation, the Ian Potter Foundation, Eli Lilly, the Meat and Livestock Board Australia, and The University of Melbourne, and has been a paid speaker for Sanofi -Synthelabo, Janssen Cilag, Servier, Pfizer, Health Ed, Network Nutrition, Angelini Farmaceutica, and Eli Lilly. NR 31 TC 38 Z9 38 U1 8 U2 51 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2215-0374 J9 LANCET PSYCHIAT JI Lancet Psychiatry PD MAR PY 2015 VL 2 IS 3 BP 271 EP 274 DI 10.1016/S2215-0366(14)00051-0 PG 4 WC Psychiatry SC Psychiatry GA CF6ZX UT WOS:000352706800025 PM 26359904 ER PT J AU Yoshimura, Y Kobayashi, S Kaneko, H Suzuki, T Imamichi, T AF Yoshimura, Yuichi Kobayashi, Satoshi Kaneko, Hitomi Suzuki, Takeshi Imamichi, Tomozumi TI Construction of an Isonucleoside on a 2,6-Dioxobicyclo[3.2.0]-heptane Skeleton SO MOLECULES LA English DT Article ID REVERSE-TRANSCRIPTASE INHIBITORS; ANTI-HIV AGENTS; CARBOCYCLIC NUCLEOSIDES; ASYMMETRIC-SYNTHESIS; HYPERVALENT IODINE; HUMAN-LYMPHOCYTES; IN-VITRO; DESIGN; INFECTIVITY; DERIVATIVES AB We have built a new isonucleoside derivative on a 2,6-dioxobicyclo[3.2.0]heptane skeleton as a potential anti-HIV agent. To synthesize the target compound, an acetal-protected dihydroxyacetone was first converted to a 2,3-epoxy-tetrahydrofuran derivative. Introduction of an azide group, followed by the formation of an oxetane ring, gave a pseudosugar derivative with a 2,6-dioxobicyclo[3.2.0]heptane skeleton. The desired isonucleoside was obtained by constructing a purine base moiety on the scaffold, followed by amination. C1 [Yoshimura, Yuichi; Kobayashi, Satoshi; Kaneko, Hitomi; Suzuki, Takeshi] Tohoku Pharmaceut Univ, Fac Pharmaceut Sci, Aoba Ku, Sendai, Miyagi 9818558, Japan. [Imamichi, Tomozumi] Leidos Biochem Res Inc, Frederick Natl Lab Canc Res, Lab Human Retrovirol, Frederick, MD 21702 USA. RP Yoshimura, Y (reprint author), Tohoku Pharmaceut Univ, Fac Pharmaceut Sci, Aoba Ku, 4-4-1 Komatsushima, Sendai, Miyagi 9818558, Japan. EM yoshimura@tohoku-pharm.ac.jp; s-kobayashi@fujichemical.co.jp; hitomi.f528@gmail.com; suzutake19851109@coral.plala.or.jp; timamichi@mail.nih.gov FU JSPS [24590143]; Ministry of Education, Culture, Sport, Science, and Technology, Japan (MEXT) FX This work was supported in part by a Grant-in-Aid for Scientific Research (No. 24590143, Y.Y.) from JSPS and by a grant of Strategic Research Foundation Grant-aided Project for Private Universities from Ministry of Education, Culture, Sport, Science, and Technology, Japan (MEXT), 2010-2014. NR 25 TC 0 Z9 0 U1 0 U2 1 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1420-3049 J9 MOLECULES JI Molecules PD MAR PY 2015 VL 20 IS 3 BP 4623 EP 4634 DI 10.3390/molecules20034623 PG 12 WC Chemistry, Organic SC Chemistry GA CF3TS UT WOS:000352472000030 PM 25774493 ER PT J AU Huan, TX Rong, J Liu, CY Zhang, XL Tanriverdi, K Joehanes, R Chen, BH Murabito, JM Yao, C Courchesne, P Munson, PJ O'Donnell, CJ Cox, N Johnson, AD Larson, MG Levy, D Freedman, JE AF Huan, Tianxiao Rong, Jian Liu, Chunyu Zhang, Xiaoling Tanriverdi, Kahraman Joehanes, Roby Chen, Brian H. Murabito, Joanne M. Yao, Chen Courchesne, Paul Munson, Peter J. O'Donnell, Christopher J. Cox, Nancy Johnson, Andrew D. Larson, Martin G. Levy, Daniel Freedman, Jane E. TI Genome-wide identification of microRNA expression quantitative trait loci SO NATURE COMMUNICATIONS LA English DT Article ID GENETIC ARCHITECTURE; HEART-FAILURE; ASSOCIATION; DISEASE; RNA; TRANSCRIPTOME; ANNOTATION; RESOURCE; DATABASE; DESIGN AB Identification of microRNA expression quantitative trait loci (miR-eQTL) can yield insights into regulatory mechanisms of microRNA transcription, and can help elucidate the role of microRNA as mediators of complex traits. Here we present a miR-eQTL mapping study of whole blood from 5,239 individuals, and identify 5,269 cis-miR-eQTLs for 76 mature microRNAs. Forty-nine per cent of cis-miR-eQTLs are located 300-500 kb upstream of their associated intergenic microRNAs, suggesting that distal regulatory elements may affect the interindividual variability in microRNA expression levels. We find that cis-miR-eQTLs are highly enriched for cis-mRNA-eQTLs and regulatory single nucleotide polymorphisms. Among 243 cis-miR-eQTLs that were reported to be associated with complex traits in prior genomewide association studies, many cis-miR-eQTLs miRNAs display differential expression in relation to the corresponding trait (for example, rs7115089, miR-125b-5p and high-density lipoprotein cholesterol). Our study provides a roadmap for understanding the genetic basis of miRNA expression, and sheds light on miRNA involvement in a variety of complex traits. C1 [Huan, Tianxiao; Liu, Chunyu; Zhang, Xiaoling; Joehanes, Roby; Chen, Brian H.; Murabito, Joanne M.; Yao, Chen; Courchesne, Paul; O'Donnell, Christopher J.; Johnson, Andrew D.; Larson, Martin G.; Levy, Daniel] Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA. [Huan, Tianxiao; Liu, Chunyu; Joehanes, Roby; Chen, Brian H.; Yao, Chen; Courchesne, Paul; Levy, Daniel] NHLBI, Populat Sci Branch, Div Intramural Res, Bethesda, MD 20824 USA. [Rong, Jian; Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02118 USA. [Zhang, Xiaoling; O'Donnell, Christopher J.; Johnson, Andrew D.] NHLBI, Cardiovasc Epidemiol & Human Genom Branch, Div Intramural Res, Bethesda, MD 20824 USA. [Tanriverdi, Kahraman; Freedman, Jane E.] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA 01655 USA. [Joehanes, Roby; Munson, Peter J.] NIH, Math & Stat Comp Lab, Ctr Informat Technol, Bethesda, MD 20824 USA. [Joehanes, Roby] Harvard Univ, Harvard Med Sch, Boston, MA 02115 USA. [Joehanes, Roby] Hebrew SeniorLife, Boston, MA 02131 USA. [Murabito, Joanne M.] Boston Univ, Gen Internal Med Sect, Dept Med, Sch Med, Boston, MA 02118 USA. [Cox, Nancy] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. RP Levy, D (reprint author), Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA. EM Levyd@nih.gov; jane.freedman@umassmed.edu RI Johnson, Andrew/G-6520-2013 FU National Institutes of Health [N01-HC-25195]; Division of Intramural Research, National Heart, Lung, and Blood Institute; National Institutes of Health; Center for Information Technology, the National Institutes of Health, Bethesda, MD, USA FX The Framingham Heart Study is funded by the National Institutes of Health contract N01-HC-25195. The laboratory work for this investigation was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, the National Institutes of Health. The analytical component of this project was funded by the Division of Intramural Research, the National Heart, Lung, and Blood Institute, and the Center for Information Technology, the National Institutes of Health, Bethesda, MD, USA. 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). NR 50 TC 20 Z9 20 U1 81 U2 89 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 MAR PY 2015 VL 6 AR 6601 DI 10.1038/ncomms7601 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CG1NR UT WOS:000353040300014 PM 25791433 ER PT J AU Ma, XT Edmonson, M Yergeau, D Muzny, DM Hampton, OA Rusch, M Song, GC Easton, J Harvey, RC Wheeler, DA Ma, J Doddapaneni, H Vadodaria, B Wu, G Nagahawatte, P Carroll, WL Chen, IM Gastier-Foster, JM Relling, MV Smith, MA Devidas, M Auvil, JMG Downing, JR Loh, ML Willman, CL Gerhard, DS Mullighan, CG Hunger, SP Zhang, JH AF Ma, Xiaotu Edmonson, Michael Yergeau, Donald Muzny, Donna M. Hampton, Oliver A. Rusch, Michael Song, Guangchun Easton, John Harvey, Richard C. Wheeler, David A. Ma, Jing Doddapaneni, HarshaVardhan Vadodaria, Bhavin Wu, Gang Nagahawatte, Panduka Carroll, William L. Chen, I-Ming Gastier-Foster, Julie M. Relling, Mary V. Smith, Malcolm A. Devidas, Meenakshi Auvil, Jaime M. Guidry Downing, James R. Loh, Mignon L. Willman, Cheryl L. Gerhard, Daniela S. Mullighan, Charles G. Hunger, Stephen P. Zhang, Jinghui TI Rise and fall of subclones from diagnosis to relapse in pediatric B-acute lymphoblastic leukaemia SO NATURE COMMUNICATIONS LA English DT Article ID ACUTE MYELOID-LEUKEMIA; YOUNG-ADULTS; MUTATIONS; ORIGINS; NT5C2 AB There is incomplete understanding of genetic heterogeneity and clonal evolution during cancer progression. Here we use deep whole-exome sequencing to describe the clonal architecture and evolution of 20 pediatric B-acute lymphoblastic leukaemias from diagnosis to relapse. We show that clonal diversity is comparable at diagnosis and relapse and clonal survival from diagnosis to relapse is not associated with mutation burden. Six pathways were frequently mutated, with NT5C2, CREBBP, WHSC1, TP53, USH2A, NRAS and IKZF1 mutations enriched at relapse. Half of the leukaemias had multiple subclonal mutations in a pathway or gene at diagnosis, but mostly with only one, usually minor clone, surviving therapy to acquire additional mutations and become the relapse founder clone. Relapse-specific mutations in NT5C2 were found in nine cases, with mutations in four cases being in descendants of the relapse founder clone. These results provide important insights into the genetic basis of treatment failure in ALL and have implications for the early detection of mutations driving relapse. C1 [Ma, Xiaotu; Edmonson, Michael; Rusch, Michael; Wu, Gang; Nagahawatte, Panduka; Zhang, Jinghui] St Jude Childrens Res Hosp, Computat Biol, Memphis, TN 38105 USA. [Yergeau, Donald; Easton, John; Vadodaria, Bhavin] St Jude Childrens Res Hosp, Pediat Canc Genome Project, Validat Lab, Memphis, TN 38105 USA. [Muzny, Donna M.; Hampton, Oliver A.; Wheeler, David A.; Doddapaneni, HarshaVardhan] Baylor Coll Med, Human Genome Sequencing Ctr, Canc Genom, Houston, TX 77030 USA. [Song, Guangchun; Ma, Jing; Downing, James R.; Mullighan, Charles G.] St Jude Childrens Res Hosp, Pathol, Memphis, TN 38105 USA. [Harvey, Richard C.; Chen, I-Ming; Willman, Cheryl L.] Univ New Mexico, Ctr Canc, Albuquerque, NM 87131 USA. [Carroll, William L.] NYU, Langone Med Ctr, Perlmutter Canc Ctr, New York, NY 10016 USA. [Gastier-Foster, Julie M.] Nationwide Childrens Hosp, Dept Pathol & Lab Med, Columbus, OH 43205 USA. [Gastier-Foster, Julie M.] Ohio State Univ, Dept Pathol, Columbus, OH 43210 USA. [Gastier-Foster, Julie M.] Ohio State Univ, Dept Pediat, Columbus, OH 43210 USA. [Relling, Mary V.] St Jude Childrens Res Hosp, Dept Pharmaceut Sci, Memphis, TN 38105 USA. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Devidas, Meenakshi] Univ Florida, Coll Med, Dept Biostat, Gainesville, FL 32607 USA. [Devidas, Meenakshi] Univ Florida, Coll Publ Hlth, Dept Biostat, Gainesville, FL 32607 USA. [Devidas, Meenakshi] Univ Florida, Coll Hlth Profess, Dept Biostat, Gainesville, FL 32607 USA. [Auvil, Jaime M. Guidry; Gerhard, Daniela S.] NCI, Off Canc Genom, Bethesda, MD 20892 USA. [Loh, Mignon L.] Univ Calif San Francisco, Benioff Childrens Hosp, Dept Pediat, San Francisco, CA 94143 USA. [Loh, Mignon L.] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Hunger, Stephen P.] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. [Hunger, Stephen P.] Childrens Hosp Philadelphia, Ctr Childhood Canc Res, Philadelphia, PA 19104 USA. RP Mullighan, CG (reprint author), St Jude Childrens Res Hosp, Pathol, 332 N Lauderdale St, Memphis, TN 38105 USA. EM charles.mullighan@stjude.org; hungers@email.chop.edu; Jinghui.zhang@stjude.org OI Mullighan, Charles/0000-0002-1871-1850 FU Acute Lymphoblastic Leukemia (ALL) [U10 CA98543]; American Lebanese Syrian Associated Charities; National Institutes of Health [CA21765, GM92666]; Federal ARRA funds from the National Cancer Institute, National Institutes of Health [HHSN261200800001E]; [U10 CA98413]; [U24 CA114766] FX The Acute Lymphoblastic Leukemia (ALL) data set is part of the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative, supported by a supplement to NCI Grant U10 CA98543 to the Children's Oncology Group (COG). This is a collaborative project of the COG, the University of New Mexico Cancer Center, the St Jude's Children's Research Hospital Pediatric Cancer Genome Project and the National Cancer Institute. This work was supported in part by the American Lebanese Syrian Associated Charities and National Institutes of Health Grants CA21765 and GM92666 to St Jude Children's Research Hospital and a St Baldrick's Foundation Scholar Award (to C.G.M.), and by grants to the Children's Oncology Group U10 CA98543 (Chair's grant and supplement to support the COG High-Risk ALL TARGET project), U10 CA98413 (Statistical Center) and U24 CA114766 (Specimen Banking). This project has been funded in part by the Federal ARRA funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views of 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 24 TC 52 Z9 52 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD MAR PY 2015 VL 6 AR 6604 DI 10.1038/ncomms7604 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CG1NR UT WOS:000353040300017 PM 25790293 ER PT J AU Miyake, M Yamashiro, K Tabara, Y Suda, K Morooka, S Nakanishi, H Khor, CC Chen, P Qiao, F Nakata, I Akagi-Kurashige, Y Gotoh, N Tsujikawa, A Meguro, A Kusuhara, S Polasek, O Hayward, C Wright, AF Campbell, H Richardson, AJ Schache, M Takeuchi, M Mackey, DA Hewitt, AW Cuellar, G Shi, Y Huang, L Yang, Z Leung, KH Kao, PYP Yap, MKH Yip, SP Moriyama, M Ohno-Matsui, K Mizuki, N MacGregor, S Vitart, V Aung, T Saw, SM Tai, ES Wong, TY Cheng, CY Baird, PN Yamada, R Matsuda, F Yoshimura, N AF Miyake, Masahiro Yamashiro, Kenji Tabara, Yasuharu Suda, Kenji Morooka, Satoshi Nakanishi, Hideo Khor, Chiea-Chuen Chen, Peng Qiao, Fan Nakata, Isao Akagi-Kurashige, Yumiko Gotoh, Norimoto Tsujikawa, Akitaka Meguro, Akira Kusuhara, Sentaro Polasek, Ozen Hayward, Caroline Wright, Alan F. Campbell, Harry Richardson, Andrea J. Schache, Maria Takeuchi, Masaki Mackey, David A. Hewitt, Alex W. Cuellar, Gabriel Shi, Yi Huang, Luling Yang, Zhenglin Leung, Kim Hung Kao, Patrick Y. P. Yap, Maurice K. H. Yip, Shea Ping Moriyama, Muka Ohno-Matsui, Kyoko Mizuki, Nobuhisa MacGregor, Stuart Vitart, Veronique Aung, Tin Saw, Seang-Mei Tai, E-Shyong Wong, Tien Yin Cheng, Ching-Yu Baird, Paul N. Yamada, Ryo Matsuda, Fumihiko Yoshimura, Nagahisa CA Nagahama Study Grp TI Identification of myopia-associated WNT7B polymorphisms provides insights into the mechanism underlying the development of myopia SO NATURE COMMUNICATIONS LA English DT Article ID GENOME-WIDE ASSOCIATION; PARASOL GANGLION-CELLS; CONE BIPOLAR CELLS; MOUSE RETINA; REFRACTIVE ERRORS; SUSCEPTIBILITY LOCUS; MAMMALIAN RETINA; CHOROIDAL NEOVASCULARIZATION; JAPANESE POPULATION; CORNEAL CURVATURE AB Myopia can cause severe visual impairment. Here, we report a two-stage genome-wide association study for three myopia-related traits in 9,804 Japanese individuals, which was extended with trans-ethnic replication in 2,674 Chinese and 2,690 Caucasian individuals. We identify WNT7B as a novel susceptibility gene for axial length (rs10453441, P-meta = 3.9 x 10(-13)) and corneal curvature (P-meta = 2.9 x 10(-40)) and confirm the previously reported association between GJD2 and myopia. WNT7B significantly associates with extreme myopia in a case-control study with 1,478 Asian patients and 4,689 controls (odds ratio (OR)(meta) = 1.13, P-meta = 0.011). We also find in a mouse model of myopia downregulation of WNT7B expression in the cornea and upregulation in the retina, suggesting its possible role in the development of myopia. C1 [Miyake, Masahiro; Yamashiro, Kenji; Suda, Kenji; Morooka, Satoshi; Nakanishi, Hideo; Nakata, Isao; Akagi-Kurashige, Yumiko; Tsujikawa, Akitaka; Yoshimura, Nagahisa] Kyoto Univ, Grad Sch Med, Dept Ophthalmol & Visual Sci, Kyoto 6068507, Japan. [Miyake, Masahiro; Tabara, Yasuharu; Nakata, Isao; Akagi-Kurashige, Yumiko; Gotoh, Norimoto; Yamada, Ryo; Matsuda, Fumihiko] Kyoto Univ, Grad Sch Med, Ctr Genom Med, Kyoto 6068503, Japan. [Khor, Chiea-Chuen; Chen, Peng; Qiao, Fan; Saw, Seang-Mei; Tai, E-Shyong] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117597, Singapore. [Khor, Chiea-Chuen; Chen, Peng; Qiao, Fan; Saw, Seang-Mei; Tai, E-Shyong] Natl Univ Hlth Syst, Singapore 117597, Singapore. [Khor, Chiea-Chuen; Aung, Tin; Wong, Tien Yin; Cheng, Ching-Yu] Natl Univ Singapore, Dept Ophthalmol, Singapore 119228, Singapore. [Khor, Chiea-Chuen; Aung, Tin; Tai, E-Shyong; Wong, Tien Yin; Cheng, Ching-Yu] Natl Univ Hlth Syst, Singapore 119228, Singapore. [Khor, Chiea-Chuen] Natl Univ Singapore, Dept Pediat, Singapore 119077, Singapore. [Khor, Chiea-Chuen] Genome Inst Singapore, Div Human Genet, Singapore 138672, Singapore. [Meguro, Akira; Mizuki, Nobuhisa] Yokohama City Univ, Grad Sch Med, Dept Ophthalmol & Visual Sci, Yokohama, Kanagawa 2360027, Japan. [Kusuhara, Sentaro] Kobe Univ, Grad Sch Med, Dept Surg, Div Ophthalmol, Kobe, Hyogo 6570013, Japan. [Polasek, Ozen] Univ Split, Fac Med, Split 21000, Croatia. [Hayward, Caroline; Wright, Alan F.; Vitart, Veronique] Univ Edinburgh, Inst Genet & Mol Med, Human Genet Unit, MRC, Edinburgh EH8 9YL, Midlothian, Scotland. [Campbell, Harry] Univ Edinburgh Sch Med, Ctr Populat Hlth Sci, Edinburgh EH8 9AG, Midlothian, Scotland. [Richardson, Andrea J.; Schache, Maria; Mackey, David A.; Hewitt, Alex W.] Univ Melbourne, Royal Victorian Eye & Ear Hosp, Ctr Eye Res Australia, Melbourne, Vic 3002, Australia. [Takeuchi, Masaki] NHGRI, Inflammatory Dis Sect, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Mackey, David A.] Univ Western Australia, Lions Eye Inst, Ctr Ophthalmol & Visual Sci, Perth, WA 6009, Australia. [Cuellar, Gabriel; MacGregor, Stuart] Queensland Inst Med Res, Berghofer Med Res Inst, Stat Genet, Brisbane, Qld 4006, Australia. [Shi, Yi; Huang, Luling; Yang, Zhenglin] Hosp Univ Elect Sci & Technol, Sichuan Prov Key Lab Human Dis Gene Study, Chengdu 610072, Sichuan, Peoples R China. [Shi, Yi; Huang, Luling; Yang, Zhenglin] Sichuan Prov Peoples Hosp, Chengdu 610072, Sichuan, Peoples R China. [Yang, Zhenglin] Univ Elect Sci & Technol China, Sch Med, Chengdu 610072, Sichuan, Peoples R China. [Yang, Zhenglin] Chinese Acad Sci, Sichuan Translat Med Hosp, Chengdu 610072, Sichuan, Peoples R China. [Leung, Kim Hung; Yip, Shea Ping] Hong Kong Polytech Univ, Dept Hlth Technol & Informat, Hong Kong 99907, Hong Kong, Peoples R China. [Kao, Patrick Y. P.; Yap, Maurice K. H.] Hong Kong Polytech Univ, Sch Optometry, Ctr Myopia Res, Hong Kong 99907, Hong Kong, Peoples R China. [Moriyama, Muka; Ohno-Matsui, Kyoko; Wong, Tien Yin] Tokyo Med & Dent Univ, Dept Ophthalmol & Visual Sci, Tokyo 1130034, Japan. [Aung, Tin; Saw, Seang-Mei; Wong, Tien Yin; Cheng, Ching-Yu] Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore 168751, Singapore. [Tai, E-Shyong] Natl Univ Singapore, Dept Med, Singapore 119228, Singapore. [Tai, E-Shyong; Cheng, Ching-Yu] Duke NUS Grad Med Sch, Singapore 169857, Singapore. RP Yamashiro, K (reprint author), Kyoto Univ, Grad Sch Med, Dept Ophthalmol & Visual Sci, Kyoto 6068507, Japan. EM yamashro@kuhp.kyoto-u.ac.jp RI Macgregor, Stuart/C-6442-2009; Polasek, Ozren/B-6002-2011; Yip, Shea Ping/A-1185-2016; Hewitt, Alex/D-1936-2013; Yap, Maurice/K-4927-2016; Kao, Yu Ping Patrick/K-9986-2016; Mackey, David/H-5340-2014; Cuellar Partida, Gabriel/C-6686-2017; OI Tai, E Shyong/0000-0003-2929-8966; Macgregor, Stuart/0000-0001-6731-8142; Polasek, Ozren/0000-0002-5765-1862; Yip, Shea Ping/0000-0002-2170-8185; Hewitt, Alex/0000-0002-5123-5999; Yap, Maurice/0000-0003-4687-4101; Kao, Yu Ping Patrick/0000-0001-7368-4595; Mackey, David/0000-0001-7914-4709; Cuellar Partida, Gabriel/0000-0001-7648-4097; Khor, Chiea Chuen/0000-0002-1128-4729 FU Japan Eye Bank Association FX We thank Ms Kaori Misono, Ms Hatsue Hamanaka and Ms Miwa Fukami for their assistance in animal experiments, IHC and genotyping. We also thank Japan Eye Bank Association for its financial support. NR 70 TC 12 Z9 12 U1 3 U2 15 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 MAR PY 2015 VL 6 AR 6689 DI 10.1038/ncomms7689 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CG1OQ UT WOS:000353043000001 PM 25823570 ER PT J AU Nelson, MI Viboud, C Vincent, AL Culhane, MR Detmer, SE Wentworth, DE Rambaut, A Suchard, MA Holmes, EC Lemey, P AF Nelson, Martha I. Viboud, Cecile Vincent, Amy L. Culhane, Marie R. Detmer, Susan E. Wentworth, David E. Rambaut, Andrew Suchard, Marc A. Holmes, Edward C. Lemey, Philippe TI Global migration of influenza A viruses in swine SO NATURE COMMUNICATIONS LA English DT Article ID PANDEMIC H1N1 INFLUENZA; NORTH-AMERICAN SWINE; PIG-POPULATION; UNITED-STATES; ORIGIN; REASSORTMENT; EVOLUTION; HUMANS; TRANSMISSION; SEQUENCE AB The complex and unresolved evolutionary origins of the 2009 H1N1 influenza pandemic exposed major gaps in our knowledge of the global spatial ecology and evolution of influenza A viruses in swine (swIAVs). Here we undertake an expansive phylogenetic analysis of swIAV sequence data and demonstrate that the global live swine trade strongly predicts the spatial dissemination of swIAVs, with Europe and North America acting as sources of viruses in Asian countries. In contrast, China has the world's largest swine population but is not a major exporter of live swine, and is not an important source of swIAVs in neighbouring Asian countries or globally. A meta-population simulation model incorporating trade data predicts that the global ecology of swIAVs is more complex than previously thought, and the United States and China's large swine populations are unlikely to be representative of swIAV diversity in their respective geographic regions, requiring independent surveillance efforts throughout Latin America and Asia. C1 [Nelson, Martha I.; Viboud, Cecile; Rambaut, Andrew] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Vincent, Amy L.] ARS, Virus & Prion Dis Livestock Res Unit, Natl Anim Dis Ctr, USDA, Ames, IA 50010 USA. [Culhane, Marie R.] Univ Minnesota, Vet Diagnost Lab, St Paul, MN 55108 USA. [Detmer, Susan E.] Univ Saskatchewan, Western Coll Vet Med, Saskatoon, SK S7N 5A8, Canada. [Wentworth, David E.] J Craig Venter Inst, Rockville, MD 20850 USA. [Rambaut, Andrew] Univ Edinburgh, Inst Evolutionary Biol, Ashworth Labs, Edinburgh EH9 FLT, Midlothian, Scotland. [Rambaut, Andrew] Univ Edinburgh, Ctr Immunol Infect & Evolut, Ashworth Labs, Edinburgh EH9 FLT, Midlothian, Scotland. [Suchard, Marc A.] Univ Calif Los Angeles, Dept Biomath, Los Angeles, CA 90095 USA. [Suchard, Marc A.] Univ Calif Los Angeles, Dept Biostat, Los Angeles, CA 90095 USA. [Suchard, Marc A.] Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA 90095 USA. [Holmes, Edward C.] Univ Sydney, Charles Perkins Ctr, Sch Biol Sci, Marie Bashir Inst Infect Dis & Biosecur, Sydney, NSW 2006, Australia. [Holmes, Edward C.] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. [Lemey, Philippe] Univ Leuven, KU Leuven, Dept Microbiol & Immunol, Rega Inst, Leuven, Belgium. RP Nelson, MI (reprint author), NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. EM nelsonma@mail.nih.gov OI Rambaut, Andrew/0000-0003-4337-3707; Wentworth, David/0000-0002-5190-980X; Holmes, Edward/0000-0001-9596-3552 FU Saskatchewan Ministry of Agriculture [C70077]; Multinational Influenza Seasonal Mortality Study (MISMS); Office of Pandemics and Emerging Threats at the U.S. Department of Health and Human Services; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN272200900007C]; European Union Seventh Framework Programme (FP7) [278433-PREDEMICS]; ERC [260864]; NHMRC Australia Fellowship [AF30] FX We thank Drs Sagar Goyal and Devi Patnayak, along with Wendy Wiese, Becca Wheeldon and Lotus Smasal at UMVDL for their virology work, and Rebecca Halpin, Nadia Fedorova, Xudong Lin and Timothy B. Stockwell at the J. Craig Venter Institute for their assistance in viral sequencing. Aaron Schwartzbard was greatly helpful in producing figures using R. This manuscript was prepared while D.E.W. was employed at the J. Craig Venter Institute. Partial support for this work was provided by a grant from the Saskatchewan Ministry of Agriculture contract number C70077. This work was supported in part by the Multinational Influenza Seasonal Mortality Study (MISMS), an on-going international collaborative effort to understand influenza epidemiology and evolution, led by the Fogarty International Center, National Institutes of Health, with funding from Office of Pandemics and Emerging Threats at the U.S. Department of Health and Human Services (A.R., M.I.N., C.V.). This project has also been funded 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 the (contract number HHSN272200900007C). P.L., M.A.S. and A. R. acknowledge the funding from the European Union Seventh Framework Programme (FP7/2007-2013) under Grant Agreement no. 278433-PREDEMICS and ERC Grant agreement no. 260864. E.C.H. is supported by an NHMRC Australia Fellowship (AF30). NR 50 TC 16 Z9 17 U1 3 U2 26 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 MAR PY 2015 VL 6 AR 6696 DI 10.1038/ncomms7696 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CG1OY UT WOS:000353043900001 PM 25813399 ER PT J AU Pratama, A Srivastava, M Williams, NJ Papa, I Lee, SK Dinh, XT Hutloff, A Jordan, MA Zhao, JL Casellas, R Athanasopoulos, V Vinuesa, CG AF Pratama, Alvin Srivastava, Monika Williams, Naomi J. Papa, Ilenia Lee, Sau K. Dinh, Xuyen T. Hutloff, Andreas Jordan, Margaret A. Zhao, Jimmy L. Casellas, Rafael Athanasopoulos, Vicki Vinuesa, Carola G. TI MicroRNA-146a regulates ICOS-ICOSL signalling to limit accumulation of T follicular helper cells and germinal centres SO NATURE COMMUNICATIONS LA English DT Article ID NF-KAPPA-B; SYSTEMIC-LUPUS-ERYTHEMATOSUS; RHEUMATOID-ARTHRITIS; C-REL; SYNOVIAL TISSUE; EXPRESSION; DIFFERENTIATION; MIR-146A; AUTOIMMUNITY; GENE AB Tight control of T follicular helper (Tfh) cells is required for optimal maturation of the germinal centre (GC) response. The molecular mechanisms controlling Tfh-cell differentiation remain incompletely understood. Here we show that microRNA-146a (miR-146a) is highly expressed in Tfh cells and peak miR-146a expression marks the decline of the Tfh response after immunization. Loss of miR-146a causes cell-intrinsic accumulation of Tfh and GC B cells. MiR-146a represses several Tfh-cell-expressed messenger RNAs, and of these, ICOS is the most strongly cell autonomously upregulated target in miR-146a-deficient T cells. In addition, miR-146a deficiency leads to increased ICOSL expression on GC B cells and antigen-presenting cells. Partial blockade of ICOS signalling, either by injections of low dose of ICOSL blocking antibody or by halving the gene dose of Icos in miR-146a-deficient T cells, prevents the Tfh and GC B-cell accumulation. Collectively, miR-146a emerges as a post-transcriptional brake to limit Tfh cells and GC responses. C1 [Pratama, Alvin; Srivastava, Monika; Williams, Naomi J.; Papa, Ilenia; Lee, Sau K.; Athanasopoulos, Vicki; Vinuesa, Carola G.] Australian Natl Univ, John Curtin Sch Med Res, Dept Pathogens & Immun, Canberra, ACT 0200, Australia. [Dinh, Xuyen T.; Jordan, Margaret A.] James Cook Univ, Comparat Genom Ctr, Townsville, Qld 4811, Australia. [Hutloff, Andreas] German Rheumatism Res Ctr Berlin DRFZ, Chron Immune React Grp, Leibniz Inst, D-10117 Berlin, Germany. [Zhao, Jimmy L.] CALTECH, Div Biol & Biol Engn, Pasadena, CA 91125 USA. [Casellas, Rafael] NIAMSD, Genom & Immun Sect, NIH, Bethesda, MD 20892 USA. RP Vinuesa, CG (reprint author), Australian Natl Univ, John Curtin Sch Med Res, Dept Pathogens & Immun, Bldg 131,Garran Rd, Canberra, ACT 0200, Australia. EM carola.vinuesa@anu.edu.au RI Hutloff, Andreas/D-1781-2014 OI Hutloff, Andreas/0000-0002-0572-8151 FU National Health and Medical Research Council (NHMRC) program; Elizabeth Blackburn Fellowship; International Postgraduate Research Scholarship; NHMRC/MSRA Betty Cuthbert Fellowship; National Research Service Award [F30HL110691]; UCLA/Caltech Medical Scientist Training Program FX We thank M. Devoy and H. Vohra (ANU) for technical assistance on fluorescence-activated cell sorting, R.A. Sweet, R.J. Rigby, P. Gonzalez and I.A. Parish (ANU) for technical assistance in several experiments, H. Qi and D. Liu (Tsinghua University, China) for helpful discussions and for providing the stimulation protocols to induce ICOSL expression, and C. C. Goodnow and A. Yates (ANU) for kind provision and initial characterization of the Stat1fae mice. This work was funded by the National Health and Medical Research Council (NHMRC) program and project grants and Elizabeth Blackburn Fellowship to C.G.V., International Postgraduate Research Scholarship to A.P., NHMRC/MSRA Betty Cuthbert Fellowship to M.A.J., National Research Service Award F30HL110691 and UCLA/Caltech Medical Scientist Training Program to J.L.Z. NR 69 TC 22 Z9 22 U1 7 U2 20 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 MAR PY 2015 VL 6 AR 6436 DI 10.1038/ncomms7436 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CF5YS UT WOS:000352633900020 PM 25743066 ER PT J AU Salvucci, O Ohnuki, H Maric, D Hou, X Li, XR Yoon, SO Segarra, M Eberhart, CG Acker-Palmer, A Tosato, G AF Salvucci, Ombretta Ohnuki, Hidetaka Maric, Dragan Hou, Xu Li, Xuri Yoon, Sung Ok Segarra, Marta Eberhart, Charles G. Acker-Palmer, Amparo Tosato, Giovanna TI EphrinB2 controls vessel pruning through STAT1-JNK3 signalling SO NATURE COMMUNICATIONS LA English DT Article ID ENDOTHELIAL-CELL APOPTOSIS; CARDIOVASCULAR DEVELOPMENT; SPROUTING ANGIOGENESIS; VASCULAR MORPHOGENESIS; EPHB RECEPTORS; VE-CADHERIN; SRC KINASES; MOUSE EYE; REGRESSION; MICE AB Angiogenesis produces primitive vascular networks that need pruning to yield hierarchically organized and functional vessels. Despite the critical importance of vessel pruning to vessel patterning and function, the mechanisms regulating this process are not clear. Here we show that EphrinB2, a well-known player in angiogenesis, is an essential regulator of endothelial cell death and vessel pruning. This regulation depends upon phosphotyrosine-EphrinB2 signalling repressing c-jun N-terminal kinase 3 activity via STAT1. JNK3 activation causes endothelial cell death. In the absence of JNK3, hyaloid vessel physiological pruning is impaired, associated with abnormal persistence of hyaloid vessels, defective retinal vasculature and microphthalmia. This syndrome closely resembles human persistent hyperplastic primary vitreus (PHPV), attributed to failed involution of hyaloid vessels. Our results provide evidence that EphrinB2/STAT1/JNK3 signalling is essential for vessel pruning, and that defects in this pathway may contribute to PHPV. C1 [Salvucci, Ombretta; Ohnuki, Hidetaka; Tosato, Giovanna] NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Maric, Dragan] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD 20892 USA. [Hou, Xu; Li, Xuri] NEI, NIH, Rockville, MD 20852 USA. [Yoon, Sung Ok] Ohio State Univ, Dept Mol & Cellular Biochem, Columbus, OH 43210 USA. [Segarra, Marta; Acker-Palmer, Amparo] Goethe Univ Frankfurt, Inst Cell Biol & Neurosci, D-60438 Frankfurt, Germany. [Segarra, Marta; Acker-Palmer, Amparo] Goethe Univ Frankfurt, BMLS, D-60438 Frankfurt, Germany. [Eberhart, Charles G.] Johns Hopkins Univ, Dept Pathol Ophthalmol & Oncol, Baltimore, MD 21287 USA. [Acker-Palmer, Amparo] Johannes Gutenberg Univ Mainz, Focus Program Translat Neurosci, D-55122 Mainz, Germany. RP Ohnuki, H (reprint author), NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM ohnukih@mail.nih.gov; Tosatog@mail.nih.gov RI Ohnuki, Hidetaka/E-1877-2012; Yoon, Sung Ok/C-5992-2012 OI Ohnuki, Hidetaka/0000-0001-8951-3264; FU JSPS: Japan Society for the Promotion of Science; Deutsche Forschungsgemeinschaft [CRC834, EXC 115, EXC147]; Gutenberg Research College; Intramural Research Program at NCI, CCR FX We thank T. Makinen, R. Davis, M. Henkemeyer, I. Daar, A. Follenzi, S. Sakakibara, I. Bethani, R. Yarchoan and D. Lowy for reagents, mice and discussions. The Intramural Research Program at NCI, CCR; Grant-in-Aid for Scientific Research and Strategic Young Researcher Overseas Visiting Program, JSPS: Japan Society for the Promotion of Science; and Deutsche Forschungsgemeinschaft CRC834, Clusters of Excellence EXC 115 and EXC147 and Gutenberg Research College to A. A-P provided funding. NR 66 TC 9 Z9 9 U1 1 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD MAR PY 2015 VL 6 AR 6576 DI 10.1038/ncomms7576 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CF7FD UT WOS:000352720700011 PM 25807892 ER PT J AU Taylor, PN Porcu, E Chew, S Campbell, PJ Traglia, M Brown, SJ Mullin, BH Shihab, HA Min, J Walter, K Memari, Y Huang, J Barnes, MR Beilby, JP Charoen, P Danecek, P Dudbridge, F Forgetta, V Greenwood, C Grundberg, E Johnson, AD Hui, JN Lim, EM McCarthy, S Muddyman, D Panicker, V Perry, JRB Bell, JT Yuan, W Relton, C Gaunt, T Schlessinger, D Abecasis, G Cucca, F Surdulescu, GL Woltersdorf, W Zeggini, E Zheng, HF Toniolo, D Dayan, CM Naitza, S Walsh, JP Spector, T Smith, GD Durbin, R Richards, JB Sanna, S Soranzo, N Timpson, NJ Wilson, SG AF Taylor, Peter N. Porcu, Eleonora Chew, Shelby Campbell, Purdey J. Traglia, Michela Brown, Suzanne J. Mullin, Benjamin H. Shihab, Hashem A. Min, Josine Walter, Klaudia Memari, Yasin Huang, Jie Barnes, Michael R. Beilby, John P. Charoen, Pimphen Danecek, Petr Dudbridge, Frank Forgetta, Vincenzo Greenwood, Celia Grundberg, Elin Johnson, Andrew D. Hui, Jennie Lim, Ee M. McCarthy, Shane Muddyman, Dawn Panicker, Vijay Perry, John R. B. Bell, Jordana T. Yuan, Wei Relton, Caroline Gaunt, Tom Schlessinger, David Abecasis, Goncalo Cucca, Francesco Surdulescu, Gabriela L. Woltersdorf, Wolfram Zeggini, Eleftheria Zheng, Hou-Feng Toniolo, Daniela Dayan, Colin M. Naitza, Silvia Walsh, John P. Spector, Tim Smith, George Davey Durbin, Richard Richards, J. Brent Sanna, Serena Soranzo, Nicole Timpson, Nicholas J. Wilson, Scott G. CA UK10K Consortium TI Whole-genome sequence-based analysis of thyroid function SO NATURE COMMUNICATIONS LA English DT Article ID WIDE ASSOCIATION; GENE-EXPRESSION; SERUM TSH; THYROXINE-BINDING; VARIANTS; TRANSTHYRETIN; DISEASE; IMPUTATION; RESOLUTION; MUTATIONS AB Normal thyroid function is essential for health, but its genetic architecture remains poorly understood. Here, for the heritable thyroid traits thyrotropin (TSH) and free thyroxine (FT4), we analyse whole-genome sequence data from the UK10K project (N = 2,287). Using additional whole-genome sequence and deeply imputed data sets, we report meta-analysis results for common variants (MAF >= 1%) associated with TSH and FT4 (N = 16,335). For TSH, we identify a novel variant in SYN2 (MAF = 23.5%, P = 6.15 x 10(-9)) and a new independent variant in PDE8B (MAF = 10.4%, P = 5.94 x 10(-14)). For FT4, we report a low-frequency variant near B4GALT6/ SLC25A52 (MAF = 3.2%, P = 1.27 x 10(-9)) tagging a rare TTR variant (MAF = 0.4%, P = 2.14 x 10(-11)). All common variants explain >= 20% of the variance in TSH and FT4. Analysis of rare variants (MAF<1%) using sequence kernel association testing reveals a novel association with FT4 in NRG1. Our results demonstrate that increased coverage in whole-genome sequence association studies identifies novel variants associated with thyroid function. C1 [Taylor, Peter N.; Dayan, Colin M.] Cardiff Univ, Sch Med, Inst Mol & Expt Med, Thyroid Res Grp, Cardiff CF14 4XN, S Glam, Wales. [Porcu, Eleonora; Cucca, Francesco; Naitza, Silvia; Sanna, Serena] Cittadella Univ Monserrato, IRGB, CNR, I-09042 Cagliari, CA, Italy. [Porcu, Eleonora; Cucca, Francesco] Univ Sassari, Dipartimento Sci Biomed, I-07100 Sassari, Italy. [Porcu, Eleonora] Univ Michigan, Biostat Dept, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Chew, Shelby; Campbell, Purdey J.; Brown, Suzanne J.; Mullin, Benjamin H.; Panicker, Vijay; Walsh, John P.; Wilson, Scott G.] Sir Charles Gairdner Hosp, Dept Endocrinol & Diabet, Nedlands, WA 6009, Australia. [Traglia, Michela; Toniolo, Daniela] San Raffaele Res Inst, Div Genet & Cell Biol, I-20132 Milan, Italy. [Mullin, Benjamin H.; Walsh, John P.; Wilson, Scott G.] Univ Western Australia, Sch Med & Pharmacol, Crawley, WA 6009, Australia. [Shihab, Hashem A.; Min, Josine; Relton, Caroline; Gaunt, Tom; Smith, George Davey; Timpson, Nicholas J.] Univ Bristol, Sch Social & Community Med, MRC Integrat Epidemiol Unit, Bristol BS8 2BN, Avon, England. [Walter, Klaudia; Memari, Yasin; Huang, Jie; Muddyman, Dawn; Zeggini, Eleftheria; Durbin, Richard; Soranzo, Nicole] Wellcome Trust Sanger Inst, Cambridge CB10 1HH, England. [Barnes, Michael R.] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London EC1M 6BQ, England. [Beilby, John P.; Hui, Jennie; Lim, Ee M.] Pathwest Lab Med WA, Nedlands, WA 6009, Australia. [Beilby, John P.; Hui, Jennie] Univ Western Australia, Sch Pathol & Lab Med, Crawley, WA 6009, Australia. [Charoen, Pimphen; Dudbridge, Frank] Univ London London Sch Hyg & Trop Med, Fac Epidemiol & Populat Hlth, London WC1E 7HT, England. [Charoen, Pimphen] Mahidol Univ, Fac Trop Med, Dept Trop Hyg, Bangkok 73170, Thailand. [Forgetta, Vincenzo; Greenwood, Celia; Richards, J. Brent] McGill Univ, Jewish Gen Hosp, Lady Davis Inst, Montreal, PQ H3T 1E2, Canada. [Forgetta, Vincenzo; Greenwood, Celia; Zheng, Hou-Feng; Richards, J. Brent] McGill Univ, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ H3T 1E2, Canada. [Greenwood, Celia] McGill Univ, Dept Oncol, Montreal, PQ H3A 1A5, Canada. [Greenwood, Celia; Grundberg, Elin; Zheng, Hou-Feng; Richards, J. Brent] McGill Univ, Dept Human Genet, Montreal, PQ H3A 1A5, Canada. [Grundberg, Elin] McGill Univ, Montreal, PQ H3A 1A5, Canada. [Grundberg, Elin] Genome Quebec Innovat Ctr, Montreal, PQ H3A 1A5, Canada. [Johnson, Andrew D.] NHLBI, Cardiovasc Epidemiol & Human Genom Branch, Bethesda, MD 20892 USA. [Perry, John R. B.] Addenbrookes Hosp, Inst Metab Sci, MRC Epidemiol Unit, Cambridge CB2 0QQ, England. [Perry, John R. B.; Bell, Jordana T.; Yuan, Wei; Surdulescu, Gabriela L.; Richards, J. Brent; Wilson, Scott G.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England. [Schlessinger, David] NIA, Genet Lab, Baltimore, MD 21224 USA. [Woltersdorf, Wolfram] Halle Leipzig GmbH, Facharzt Labs Med, Geschaftsfuhrer Amedes Ost, D-06112 Halle, Saale, Germany. [Zheng, Hou-Feng; Richards, J. Brent] McGill Univ, Dept Med, Montreal, PQ H3A 1A5, Canada. [Toniolo, Daniela] CNR, Inst Mol Genet, I-27100 Pavia, Italy. RP Taylor, PN (reprint author), Cardiff Univ, Sch Med, Inst Mol & Expt Med, Thyroid Res Grp, Cardiff CF14 4XN, S Glam, Wales. EM taylorpn@cardiff.ac.uk; scott.wilson@uwa.edu.au RI Schmidts, Miriam/A-3777-2012; Fox, Laura /C-6249-2016; Mullin, Benjamin/H-5493-2014; McQuillin, Andrew/C-1623-2008; Davey Smith, George/A-7407-2013; Naitza, Silvia/D-5620-2017; OI Walters, James/0000-0002-6980-4053; Iotchkova, Valentina/0000-0001-5057-0210; Plagnol, Vincent/0000-0002-5597-9215; Humphries, Stephen E/0000-0002-8221-6547; McKechanie, Andrew/0000-0003-4273-9906; Zeggini, Eleftheria/0000-0003-4238-659X; Semple, Robert/0000-0001-6539-3069; Dunham, Ian/0000-0003-2525-5598; Birney, Ewan/0000-0001-8314-8497; Anney, Richard/0000-0002-6083-407X; Timpson, Nicholas/0000-0002-7141-9189; Schmidts, Miriam/0000-0002-1714-6749; McQuillin, Andrew/0000-0003-1567-2240; Davey Smith, George/0000-0002-1407-8314; Soranzo, Nicole/0000-0003-1095-3852; Moayyeri, Alireza/0000-0002-9143-2161; Gallagher, Louise/0000-0001-9462-2836; Taylor, Peter/0000-0002-3436-422X; Forgetta, Vincenzo/0000-0002-6061-4720; Dayan, Colin/0000-0002-6557-3462; Coates, Guy/0000-0002-8055-4796; Small, Kerrin/0000-0003-4566-0005; Yang, Jian/0000-0003-2001-2474; McCarthy, Shane/0000-0002-2715-4187; Visscher, Peter/0000-0002-2143-8760; FitzPatrick, David R./0000-0003-4861-969X; Bochukova, Elena/0000-0003-0275-1548; Relton, Caroline/0000-0003-2052-4840; Gaunt, Tom/0000-0003-0924-3247; McIntosh, Andrew/0000-0002-0198-4588; Wain, Louise/0000-0003-4951-1867 FU Wellcome Trust [WT091310] FX We are grateful to all the participants in the cohort studies and the staff involved including interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. This study makes use of the data generated by the UK10K Consortium. Funding for UK10K was provided by the Wellcome Trust under award WT091310. A full list of the investigators who contributed to the generation of the data is available at www.UK10K.org. Further acknowledgements from all the cohorts and details on cohort and investigator funding can be found in the Supplementary Methods. NR 42 TC 17 Z9 18 U1 1 U2 22 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 MAR PY 2015 VL 6 AR 5681 DI 10.1038/ncomms6681 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CF5ZC UT WOS:000352635000001 PM 25743335 ER PT J AU Luke, JJ Triozzi, PL McKenna, KC Van Meir, EG Gershenwald, JE Bastian, BC Gutkind, JS Bowcock, AM Streicher, HZ Patel, PM Sato, T Sossman, JA Sznol, M Welch, J Thurin, M Selig, S Flaherty, KT Carvajal, RD AF Luke, Jason J. Triozzi, Pierre L. McKenna, Kyle C. Van Meir, Erwin G. Gershenwald, Jeffrey E. Bastian, Boris C. Gutkind, J. Silvio Bowcock, Anne M. Streicher, Howard Z. Patel, Poulam M. Sato, Takami Sossman, Jeffery A. Sznol, Mario Welch, Jack Thurin, Magdalena Selig, Sara Flaherty, Keith T. Carvajal, Richard D. TI Biology of advanced uveal melanoma and next steps for clinical therapeutics SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Review DE Ocular; Uveal; Melanoma; MEK; GNAQ; GNA11; metastasis; cancer ID INDUCIBLE FACTOR PATHWAY; PROTEIN-KINASE-C; PHASE-II TRIAL; GROWTH-FACTOR RECEPTOR; IMMUNE PRIVILEGE; OCULAR MELANOMA; METASTATIC MELANOMA; ANTERIOR-CHAMBER; TUMOR-CELLS; LYMPHOCYTIC INFILTRATION AB Uveal melanoma is the most common intraocular malignancy although it is a rare subset of all melanomas. Uveal melanoma has distinct biology relative to cutaneous melanoma, with widely divergent patient outcomes. Patients diagnosed with a primary uveal melanoma can be stratified for risk of metastasis by cytogenetics or gene expression profiling, with approximately half of patients developing metastatic disease, predominately hepatic in location, over a 15-yr period. Historically, no systemic therapy has been associated with a clear clinical benefit for patients with advanced disease, and median survival remains poor. Here, as a joint effort between the Melanoma Research Foundation's ocular melanoma initiative, CURE OM and the National Cancer Institute, the current understanding of the molecular and immunobiology of uveal melanoma is reviewed, and on-going laboratory research into the disease is highlighted. Finally, recent investigations relevant to clinical management via targeted and immunotherpies are reviewed, and next steps in the development of clinical therapeutics are discussed. C1 [Luke, Jason J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Triozzi, Pierre L.] Wake Forest Univ, Ctr Canc, Winston Salem, NC 27109 USA. [McKenna, Kyle C.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Van Meir, Erwin G.] Emory Univ, Sch Med, Winship Canc Inst, Atlanta, GA USA. [Gershenwald, Jeffrey E.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Bastian, Boris C.] Univ Calif San Francisco, Helen Diller Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, Bethesda, MD USA. [Bowcock, Anne M.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England. [Streicher, Howard Z.; Welch, Jack; Thurin, Magdalena] NCI, Bethesda, MD 20892 USA. [Patel, Poulam M.] Univ Nottingham, Nottingham NG7 2RD, England. [Sato, Takami] Thomas Jefferson Univ, Vanderbilt Ingram Canc Ctr, Ctr Canc, Philadelphia, PA 19107 USA. [Sossman, Jeffery A.] Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Nashville, TN 37235 USA. [Sznol, Mario] Yale Univ, Yale Canc Ctr, New Haven, CT USA. [Selig, Sara] Brigham & Womans Hosp, Washington, DC USA. [Selig, Sara] Melanoma Res Fdn, CURE OM, Washington, DC USA. [Flaherty, Keith T.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02115 USA. [Carvajal, Richard D.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Luke, JJ (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM Jason_Luke@dfci.harvard.edu OI Bowcock, Anne/0000-0001-8691-9090 FU NIH [R01 CA16187001, R01 CA142873, CA116804, CA176001, CA180805]; Samuel Waxman Cancer Research Foundation FX We thank Elisha Roberson for helpful comments in review of the manuscript. Anne Bowcock acknowledges funding via NIH R01 CA16187001. Boris Bastian acknowledges funding via NIH R01 CA142873. Erwin G. Van Meir acknowledges funding NIH CA116804, CA176001, and CA180805 and the Samuel Waxman Cancer Research Foundation. NR 118 TC 16 Z9 16 U1 1 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1755-1471 EI 1755-148X J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD MAR PY 2015 VL 28 IS 2 BP 135 EP 147 DI 10.1111/pcmr.12304 PG 13 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA CF8OJ UT WOS:000352821100007 PM 25113308 ER PT J AU Webster, MR Xu, M Kinzler, KA Kaur, A Appleton, J O'Connell, MP Marchbank, K Valiga, A Dang, VM Perego, M Zhang, G Slipicevic, A Keeney, F Lehrmann, E Wood, W Becker, KG Kossenkov, AV Frederick, DT Flaherty, KT Xu, XW Herlyn, M Murphy, ME Weeraratna, AT AF Webster, Marie R. Xu, Mai Kinzler, Kathryn A. Kaur, Amanpreet Appleton, Jessica O'Connell, Michael P. Marchbank, Katie Valiga, Alexander Dang, Vanessa M. Perego, Michela Zhang, Gao Slipicevic, Ana Keeney, Frederick Lehrmann, Elin Wood, William, III Becker, Kevin G. Kossenkov, Andrew V. Frederick, Dennie T. Flaherty, Keith T. Xu, Xiaowei Herlyn, Meenhard Murphy, Maureen E. Weeraratna, Ashani T. TI Wnt5A promotes an adaptive, senescent-like stress response, while continuing to drive invasion in melanoma cells SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Article DE Wnt5A; BRAF; senescence; metastasis; therapy resistance ID CANCER-THERAPY; CELLULAR SENESCENCE; INHIBITION; VEMURAFENIB; RESISTANCE; PHOSPHORYLATION; BRAF(V600E); SUPPRESSION; EXPRESSION; PHENOTYPE AB We have previously shown that Wnt5A drives invasion in melanoma. We have also shown that Wnt5A promotes resistance to therapy designed to target the BRAF(V600E) mutation in melanoma. Here, we show that melanomas characterized by high levels of Wnt5A respond to therapeutic stress by increasing p21 and expressing classical markers of senescence, including positivity for senescence-associated beta-galactosidase (SA-beta-gal), senescence-associated heterochromatic foci (SAHF), H3K9Me chromatin marks, and PML bodies. We find that despite this, these cells retain their ability to migrate and invade. Further, despite the expression of classic markers of senescence such as SA-beta-gal and SAHF, these Wnt5A-high cells are able to colonize the lungs in in vivo tail vein colony-forming assays. This clearly underscores the fact that these markers do not indicate true senescence in these cells, but instead an adaptive stress response that allows the cells to evade therapy and invade. Notably, silencing Wnt5A reduces expression of these markers and decreases invasiveness. The combined data point to Wnt5A as a master regulator of an adaptive stress response in melanoma, which may contribute to therapy resistance. C1 [Webster, Marie R.; Kaur, Amanpreet; Appleton, Jessica; O'Connell, Michael P.; Marchbank, Katie; Valiga, Alexander; Dang, Vanessa M.; Perego, Michela; Zhang, Gao; Slipicevic, Ana; Keeney, Frederick; Kossenkov, Andrew V.; Herlyn, Meenhard; Murphy, Maureen E.; Weeraratna, Ashani T.] Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA. [Xu, Mai; Kinzler, Kathryn A.; Lehrmann, Elin; Wood, William, III; Becker, Kevin G.] NIA, NIH, Baltimore, MD 21224 USA. [Frederick, Dennie T.; Flaherty, Keith T.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Xu, Xiaowei] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. RP Weeraratna, AT (reprint author), Wistar Inst Anat & Biol, 3601 Spruce St, Philadelphia, PA 19104 USA. EM aweeraratna@wistar.org RI Zhang, Gao/D-3471-2017 FU National Institute on Aging, Baltimore, MD; PA Department of Health (CURE); CCSG [P30 CA010815]; [P01 CA 114046-06]; [T32 CA 9171-36]; [RO1 CA174746-01] FX We thank Drs Chi V. Dang (Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA), Kenneth Kinzler (Sidney Kimmel Cancer Center, Johns Hopkins University), Mina Bissell (Lawrence Berkeley Laboratories, CA, USA), Daniel Peeper (Netherlands Cancer Institute), Andrew Aplin (Thomas Jefferson University, PA, USA), and Rugang Zhang, Dmitry Gabrilovich and Dario Altieri (The Wistar Institute) for critical reading of the manuscript. We thank Dr. Jessie Villanueva (The Wistar Institute) for the use of the WM983B-resistant cells. We thank Dr. Kate Nathanson for assistance with sequencing of the cell lines. We also thank Dr. Qin Liu for assistance with statistics. This work was supported in part by funds from the Intramural Program of the National Institute on Aging, Baltimore, MD, The PA Department of Health (CURE funding) to ATW, MPO, MRW and P01 CA 114046-06 (MH, ATW, GZ, KM, MEM), T32 CA 9171-36 (MRW) and RO1 CA174746-01 (ATW, AK, QL). Core facilities at the Wistar are supported by the CCSG grant P30 CA010815. NR 34 TC 8 Z9 8 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1755-1471 EI 1755-148X J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD MAR PY 2015 VL 28 IS 2 BP 184 EP 195 DI 10.1111/pcmr.12330 PG 12 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA CF8OJ UT WOS:000352821100011 PM 25407936 ER PT J AU Coelho, SG Yin, LL Smuda, C Mahns, A Kolbe, L Hearing, VJ AF Coelho, Sergio G. Yin, Lanlan Smuda, Christoph Mahns, Andre Kolbe, Ludger Hearing, Vincent J. TI Photobiological implications of melanin photoprotection after UVB-induced tanning of human skin but not UVA-induced tanning SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Article DE ultraviolet; skin; pigmentation; DNA damage; photoprotection ID CUTANEOUS MALIGNANT-MELANOMA; PYRIMIDINE DIMERS; IN-VIVO; DNA; ULTRAVIOLET; RADIATION; DAMAGE; RISK; IRRADIATION; PREVENTION AB Repetitive suberythemal UVA and/or UVB exposures were used to generate comparable UV-induced tans in human skin over the course of 2 weeks. To evaluate the potential photoprotective values of those UVA-and/or UVB-induced tans and to avoid the confounding issue of residual UV-induced DNA damage, we waited 1 week before challenging those areas with a 1.5 MED of UVA+ UVB after which we measure DNA damage. The results show that the type of UV used to induce skin pigmentation affects the redistribution of melanin in the skin and/ or de novo melanin synthesis. The UVA-induced tans failed to even provide a minimal SPF of 1.5, which suggests that producing a tan with UVA-rich sunlamps prior to a holiday or vacation is completely counterproductive. C1 [Coelho, Sergio G.; Yin, Lanlan; Hearing, Vincent J.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Smuda, Christoph; Mahns, Andre; Kolbe, Ludger] Beiersdorf AG, R&D Skin Res, Hamburg, Germany. RP Coelho, SG (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. EM coelhos@mail.nih.gov FU National Cancer Institute at NIH FX This research was supported in part by the Intramural Research Program of the National Cancer Institute at NIH. NR 39 TC 4 Z9 4 U1 1 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1755-1471 EI 1755-148X J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD MAR PY 2015 VL 28 IS 2 BP 210 EP 216 DI 10.1111/pcmr.12331 PG 7 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA CF8OJ UT WOS:000352821100013 PM 25417821 ER PT J AU Harris, ML Levy, DJ Watkins-Chow, DE Pavan, WJ AF Harris, Melissa L. Levy, Denise J. Watkins-Chow, Dawn E. Pavan, William J. TI Ectopic differentiation of melanocyte stem cells is influenced by genetic background SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Article DE melanocyte stem cell; genetic variation; hair graying; mouse; strain ID HUMAN HAIR FOLLICLE; PIGMENTATION; MAINTENANCE; NICHE; MELANOBLASTS; TISSUE; CYCLE AB Hair graying in mouse is attributed to the loss of melanocyte stem cell function and the progressive depletion of the follicular melanocyte population. Single-gene, hair graying mouse models have pointed to a number of critical pathways involved in melanocyte stem cell biology; however, the broad range of phenotypic variation observed in human hair graying suggests that additional genetic variants involved in this process may yet be discovered. Using a sensitized approach, we ask here whether natural genetic variation influences a predominant cellular mechanism of hair graying in mouse, melanocyte stem cell differentiation. We developed an innovative method to quantify melanocyte stem cell differentiation by measuring ectopically pigmented melanocyte stem cells in response to the melanocyte-specific transgene Tg(Dct-Sox10). We make the novel observation that the production of ectopically pigmented melanocyte stem cells varies considerably across strains. The success of sensitizing for melanocyte stem cell differentiation by Tg(Dct-Sox10) sets the stage for future investigations into the genetic basis of strain-specific contributions to melanocyte stem cell biology. C1 [Harris, Melissa L.; Levy, Denise J.; Watkins-Chow, Dawn E.; Pavan, William J.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Pavan, WJ (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM bpavan@mail.nih.gov OI Watkins-Chow, Dawn/0000-0002-4355-0868 FU NIH/NHGRI; NIH [K99/R00] FX For advice, we thank the Pavan laboratory members and give special mention to L. Baxter for editing the manuscript. For technical and mouse husbandry assistance, we thank A. Incao. This research was funded by the Intramural Research program of NIH/NHGRI (to DL, DW, WP) and by a NIH K99/R00 Pathway to Independence Award (to MH). NR 35 TC 0 Z9 1 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1755-1471 EI 1755-148X J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD MAR PY 2015 VL 28 IS 2 BP 223 EP 228 DI 10.1111/pcmr.12344 PG 6 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA CF8OJ UT WOS:000352821100015 PM 25495036 ER PT J AU Chen, L Shern, JF Wei, JS Yohe, ME Song, YK Hurd, L Liao, HL Catchpoole, D Skapek, SX Barr, FG Hawkins, DS Khan, J AF Chen, Li Shern, Jack F. Wei, Jun S. Yohe, Marielle E. Song, Young K. Hurd, Laura Liao, Hongling Catchpoole, Daniel Skapek, Stephen X. Barr, Frederic G. Hawkins, Douglas S. Khan, Javed TI Clonality and Evolutionary History of Rhabdomyosarcoma SO PLOS GENETICS LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; ACUTE MYELOID-LEUKEMIA; EMBRYONAL RHABDOMYOSARCOMA; INTERGROUP RHABDOMYOSARCOMA; PROTEIN-KINASE; CHILDHOOD RHABDOMYOSARCOMA; ALVEOLAR RHABDOMYOSARCOMA; PANCREATIC-CANCER; GENOMIC ANALYSIS; POINT MUTATIONS AB To infer the subclonality of rhabdomyosarcoma (RMS) and predict the temporal order of genetic events for the tumorigenic process, and to identify novel drivers, we applied a systematic method that takes into account germline and somatic alterations in 44 tumor-normal RMS pairs using deep whole-genome sequencing. Intriguingly, we find that loss of heterozygosity of 11p15.5 and mutations in RAS pathway genes occur early in the evolutionary history of the PAX-fusion-negative-RMS (PFN-RMS) subtype. We discover several early mutations in non-RAS mutated samples and predict them to be drivers in PFN-RMS including recurrent mutation of PKN1. In contrast, we find that PAX-fusion-positive (PFP) subtype tumors have undergone whole-genome duplication in the late stage of cancer evolutionary history and have acquired fewer mutations and subclones than PFN-RMS. Moreover we predict that the PAX3-FOXO1 fusion event occurs earlier than the whole genome duplication. Our findings provide information critical to the understanding of tumorigenesis of RMS. C1 [Chen, Li; Shern, Jack F.; Wei, Jun S.; Yohe, Marielle E.; Song, Young K.; Hurd, Laura; Liao, Hongling; Khan, Javed] NCI, Genet Branch, Oncogen Sect, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Shern, Jack F.; Yohe, Marielle E.; Khan, Javed] NIH, Pediat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Catchpoole, Daniel] Childrens Hosp Westmead, Biospecimens Res & Tumour Bank, Kids Res Inst, Westmead, NSW, Australia. [Skapek, Stephen X.] UT Southwestern Med Ctr, Dept Pediat, Div Pediat Hematol Oncol, Dallas, TX USA. [Barr, Frederic G.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Hawkins, Douglas S.] Seattle Childrens Hosp, Fred Hutchinson Canc Res Ctr, Dept Pediat, Seattle, WA USA. RP Chen, L (reprint author), NCI, Genet Branch, Oncogen Sect, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM khanjav@mail.nih.gov RI Khan, Javed/P-9157-2014 OI Khan, Javed/0000-0002-5858-0488 FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This work was supported by the Intramural Research Program of the National Institutes of Health, 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. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 62 TC 10 Z9 10 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7390 EI 1553-7404 J9 PLOS GENET JI PLoS Genet. PD MAR PY 2015 VL 11 IS 3 AR e1005075 DI 10.1371/journal.pgen.1005075 PG 25 WC Genetics & Heredity SC Genetics & Heredity GA CE9XO UT WOS:000352197100054 PM 25768946 ER PT J AU Gruber, AJ Erdem, AL Sabat, G Karata, K Jaszczur, MM Vo, DD Olsen, TM Woodgate, R Goodman, MF Cox, MM AF Gruber, Angela J. Erdem, Aysen L. Sabat, Grzegorz Karata, Kiyonobu Jaszczur, Malgorzata M. Vo, Dan D. Olsen, Tayla M. Woodgate, Roger Goodman, Myron F. Cox, Michael M. TI A RecA Protein Surface Required for Activation of DNA Polymerase V SO PLOS GENETICS LA English DT Article ID SINGLE-STRANDED-DNA; BETA-PROCESSIVITY CLAMP; SOS-INDUCED MUTAGENESIS; COLI POL-V; ESCHERICHIA-COLI; ERROR-PRONE; AMINO-ACID; HOMOLOGOUS RECOMBINATION; TRANSLESION SYNTHESIS; LESION-BYPASS AB DNA polymerase V (pol V) of Escherichia coli is a translesion DNA polymerase responsible for most of the mutagenesis observed during the SOS response. Pol V is activated by transfer of a RecA subunit from the 3'-proximal end of a RecA nucleoprotein filament to form a functional complex called DNA polymerase V Mutasome (pol V Mut). We identify a RecA surface, defined by residues 112-117, that either directly interacts with or is in very close proximity to amino acid residues on two distinct surfaces of the UmuC subunit of pol V. One of these surfaces is uniquely prominent in the active pol V Mut. Several conformational states are populated in the inactive and active complexes of RecA with pol V. The RecA D112R and RecA D112R N113R double mutant proteins exhibit successively reduced capacity for pol V activation. The double mutant RecA is specifically defective in the ATP binding step of the activation pathway. Unlike the classic non-mutable RecA S117F (recA1730), the RecA D112R N113R variant exhibits no defect in filament formation on DNA and promotes all other RecA activities efficiently. An important pol V activation surface of RecA protein is thus centered in a region encompassing amino acid residues 112, 113, and 117, a surface exposed at the 3'-proximal end of a RecA filament. The same RecA surface is not utilized in the RecA activation of the homologous and highly mutagenic RumA'B-2 polymerase encoded by the integrating-conjugative element (ICE) R391, indicating a lack of structural conservation between the two systems. The RecA D112R N113R protein represents a new separation of function mutant, proficient in all RecA functions except SOS mutagenesis. C1 [Gruber, Angela J.; Olsen, Tayla M.; Cox, Michael M.] Univ Wisconsin, Dept Biochem, Madison, WI 53705 USA. [Erdem, Aysen L.; Jaszczur, Malgorzata M.; Vo, Dan D.; Goodman, Myron F.] Univ So Calif, Dept Biol Sci, Los Angeles, CA 90089 USA. [Erdem, Aysen L.; Jaszczur, Malgorzata M.; Vo, Dan D.; Goodman, Myron F.] Univ So Calif, Dept Chem, Los Angeles, CA 90089 USA. [Sabat, Grzegorz] Univ Wisconsin, Ctr Biotechnol, Madison, WI 53705 USA. [Karata, Kiyonobu; Woodgate, Roger] NICHHD, Lab Genom Integr, NIH, Bethesda, MD 20892 USA. RP Gruber, AJ (reprint author), Univ Wisconsin, Dept Biochem, 420 Henry Mall, Madison, WI 53705 USA. FU National Institute of Health [GM32335, ES012259, GM21422]; NICHD/NIH Intramural Research Program; Molecular Biosciences Training Grant [T32 GM07215]; Burris Predoctoral Fellowship; Hilldale Undergraduate Research Fellowship FX This work was supported by National Institute of Health grants to MMC (GM32335) and to MFG (ES012259; GM21422) and funds from the NICHD/NIH Intramural Research Program to RW. AJG was supported by Molecular Biosciences Training Grant T32 GM07215, Science and Medicine Research Scholars, and Burris Predoctoral Fellowship. TMO is a recipient of the Hilldale Undergraduate Research Fellowship. The sponsors or funders of this work played no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 96 TC 10 Z9 10 U1 0 U2 8 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 MAR PY 2015 VL 11 IS 3 AR e1005066 DI 10.1371/journal.pgen.1005066 PG 37 WC Genetics & Heredity SC Genetics & Heredity GA CE9XO UT WOS:000352197100048 PM 25811184 ER PT J AU Huan, TX Esko, T Peters, MJ Pilling, LC Schramm, K Schurmann, C Chen, BH Liu, CY Joehanes, R Johnson, AD Yao, C Ying, SX Courchesne, P Milani, L Raghavachari, N Wang, R Liu, PC Reinmaa, E Dehghan, A Hofman, A Uitterlinden, AG Hernandez, DG Bandinelli, S Singleton, A Melzer, D Metspalu, A Carstensen, M Grallert, H Herder, C Meitinger, T Peters, A Roden, M Waldenberger, M Dorr, M Felix, SB Zeller, T Vasan, R O'Donnell, CJ Munson, PJ Yang, X Prokisch, H Volker, U van Meurs, JBJ Ferrucci, L Levy, D AF Huan, Tianxiao Esko, Tonu Peters, Marjolein J. Pilling, Luke C. Schramm, Katharina Schurmann, Claudia Chen, Brian H. Liu, Chunyu Joehanes, Roby Johnson, Andrew D. Yao, Chen Ying, Sai-xia Courchesne, Paul Milani, Lili Raghavachari, Nalini Wang, Richard Liu, Poching Reinmaa, Eva Dehghan, Abbas Hofman, Albert Uitterlinden, Andre G. Hernandez, Dena G. Bandinelli, Stefania Singleton, Andrew Melzer, David Metspalu, Andres Carstensen, Maren Grallert, Harald Herder, Christian Meitinger, Thomas Peters, Annette Roden, Michael Waldenberger, Melanie Doerr, Marcus Felix, Stephan B. Zeller, Tanja Vasan, Ramachandran O'Donnell, Christopher J. Munson, Peter J. Yang, Xia Prokisch, Holger Voelker, Uwe van Meurs, Joyce B. J. Ferrucci, Luigi Levy, Daniel CA Int Consortium Blood Pressure TI A Meta-analysis of Gene Expression Signatures of Blood Pressure and Hypertension SO PLOS GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; PERIPHERAL-BLOOD; MICROARRAY ANALYSIS; POTASSIUM; CELLS; PREVENTION; PROFILE; SODIUM; TRIALS; MICE AB Genome-wide association studies (GWAS) have uncovered numerous genetic variants (SNPs) that are associated with blood pressure (BP). Genetic variants may lead to BP changes by acting on intermediate molecular phenotypes such as coded protein sequence or gene expression, which in turn affect BP variability. Therefore, characterizing genes whose expression is associated with BP may reveal cellular processes involved in BP regulation and uncover how transcripts mediate genetic and environmental effects on BP variability. A meta-analysis of results from six studies of global gene expression profiles of BP and hypertension in whole blood was performed in 7017 individuals who were not receiving antihypertensive drug treatment. We identified 34 genes that were differentially expressed in relation to BP (Bonferroni-corrected p<0.05). Among these genes, FOS and PTGS2 have been previously reported to be involved in BP-related processes; the others are novel. The top BP signature genes in aggregate explain 5%-9% of inter-individual variance in BP. Of note, rs3184504 in SH2B3, which was also reported in GWAS to be associated with BP, was found to be a trans regulator of the expression of 6 of the transcripts we found to be associated with BP (FOS, MYADM, PP1R15A, TAGAP, S100A10, and FGBP2). Gene set enrichment analysis suggested that the BP-related global gene expression changes include genes involved in inflammatory response and apoptosis pathways. Our study provides new insights into molecular mechanisms underlying BP regulation, and suggests novel transcriptomic markers for the treatment and prevention of hypertension. C1 [Huan, Tianxiao; Chen, Brian H.; Liu, Chunyu; Joehanes, Roby; Johnson, Andrew D.; Yao, Chen; Courchesne, Paul; Vasan, Ramachandran; O'Donnell, Christopher J.; Levy, Daniel] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Huan, Tianxiao; Chen, Brian H.; Liu, Chunyu; Joehanes, Roby; Yao, Chen; Courchesne, Paul; O'Donnell, Christopher J.; Levy, Daniel] NHLBI, Populat Sci Branch, Div Intramural Res, Bethesda, MD 20892 USA. [Esko, Tonu; Milani, Lili; Reinmaa, Eva; Metspalu, Andres] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia. [Esko, Tonu] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Esko, Tonu] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Esko, Tonu] Broad Inst Harvard & MIT, Cambridge, MA USA. [Peters, Marjolein J.; Uitterlinden, Andre G.; van Meurs, Joyce B. J.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Peters, Marjolein J.; Dehghan, Abbas; Hofman, Albert; Uitterlinden, Andre G.; van Meurs, Joyce B. J.] NCHA, NGI, Leiden, Netherlands. [Peters, Marjolein J.; Dehghan, Abbas; Hofman, Albert; Uitterlinden, Andre G.; van Meurs, Joyce B. J.] NCHA, NGI, Rotterdam, Netherlands. [Pilling, Luke C.; Melzer, David] Univ Exeter, Sch Med, Epidemiol & Publ Hlth Grp, Exeter, Devon, England. [Schramm, Katharina; Meitinger, Thomas; Prokisch, Holger] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany. [Schramm, Katharina; Meitinger, Thomas; Prokisch, Holger] Tech Univ Munich, Inst Human Genet, D-80290 Munich, Germany. [Schurmann, Claudia; Voelker, Uwe] Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Dept Funct Genom, Greifswald, Germany. [Schurmann, Claudia] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA. [Joehanes, Roby; Ying, Sai-xia; Munson, Peter J.] NIH, Math & Stat Comp Lab, Ctr Informat Technol, Bethesda, MD 20892 USA. [Joehanes, Roby] Harvard Univ, Sch Med, Boston, MA USA. [Joehanes, Roby] Hebrew SeniorLife, Boston, MA USA. [Johnson, Andrew D.] NHLBI, Cardiovasc Epidemiol & Human Genom Branch, Div Intramural Res, Bethesda, MD 20892 USA. [Raghavachari, Nalini] NIA, Div Geriatr & Clin Gerontol, Bethesda, MD 20892 USA. [Wang, Richard; Liu, Poching] NHLBI, Genom Core Facil Genet & Dev Biol Ctr, Bethesda, MD 20892 USA. [Dehghan, Abbas; Hofman, Albert; Uitterlinden, Andre G.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Hernandez, Dena G.; Singleton, Andrew] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. [Bandinelli, Stefania] Azienda Sanitaria Firenze, Geriatr Unit, Florence, Italy. [Carstensen, Maren; Herder, Christian; Roden, Michael] Univ Dusseldorf, Leibniz Ctr Diabet Res, German Diabet Ctr, Inst Clin Diabetol, Dusseldorf, Germany. [Carstensen, Maren; Herder, Christian; Roden, Michael] German Ctr Diabet Res DZD eV, Partner Dusseldorf, Dusseldorf, Germany. [Grallert, Harald; Waldenberger, Melanie] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany. [Grallert, Harald; Peters, Annette; Waldenberger, Melanie] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany. [Grallert, Harald; Peters, Annette] German Ctr Diabet Res DZD eV, Partner Munich, Munich, Germany. [Meitinger, Thomas; Peters, Annette] DZHK German Ctr Cardiovasc Res, Partner Site Munich Heart Alliance, Munich, Germany. [Roden, Michael] Univ Dusseldorf, Fac Med, Div Endocrinol & Diabetol, Dusseldorf, Germany. [Doerr, Marcus; Felix, Stephan B.] Univ Med Greifswald, Dept Internal Med B Cardiol, Greifswald, Germany. [Doerr, Marcus; Felix, Stephan B.; Voelker, Uwe] DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, Greifswald, Germany. [Zeller, Tanja] Univ Herzzentrum Hamburg, Hamburg, Germany. [Zeller, Tanja] DZHK German Ctr Cardiovasc Res, Partner Site Hamburg Kiel Lubeck, Hamburg, Germany. [Yang, Xia] Univ Calif Los Angeles, Dept Integrat Biol & Physiol, Los Angeles, CA USA. [Ferrucci, Luigi] NIA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Huan, TX (reprint author), NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. EM xyang123@ucla.edu; prokisch@helmholtz-muenchen.de; voelker@uni-greifswald.de; j.vanmeurs@erasmusmc.nl; ferruccilu@mail.nih.gov; Levyd@nih.gov RI Wong, Andrew/M-8899-2016; Singleton, Andrew/C-3010-2009; Grallert, Harald/B-3424-2013; Waldenberger, Melanie/B-5355-2014; Meitinger, Thomas/O-1318-2015; Peters, Annette/A-6117-2011; Schurmann, Claudia/L-1204-2016; Johnson, Andrew/G-6520-2013 OI Tai, E Shyong/0000-0003-2929-8966; Dehghan, Abbas/0000-0001-6403-016X; Peters, Annette/0000-0001-6645-0985; Wurtz, Peter/0000-0002-5832-0221; Wong, Andrew/0000-0003-2079-4779; Pilling, Luke/0000-0002-3332-8454; Melzer, David/0000-0002-0170-3838; Esko, Tonu/0000-0003-1982-6569; Waldenberger, Melanie/0000-0003-0583-5093; Schurmann, Claudia/0000-0003-4158-9192; FU National Institutes of Health [N01-HC-25195]; Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health; Division of Intramural Research, National Heart, Lung, and Blood Institute; Center for Information Technology, National Institutes of Health, Bethesda, MD; Estonian Ministry of Science and Education [SF0180142s08]; Development Fund of the University of Tartu [SP1GVARENG]; European Regional Development Fund [3.2.0304.11-0312]; FP7 grant [313010]; NWO [916.12.154]; EUR Fellowship; Erasmus Medical Center; Erasmus University, Rotterdam; Netherlands Organization for the Health Research and Development (ZonMw); Netherlands Organisation of Scientific Research NWO Investments [175.010.2005.011, 911-03-012]; Research Institute for Diseases in the Elderly [014-93-015]; Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; European Commission (DG XII); Municipality of Rotterdam; Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Netherlands; Intramural Research Program, National Institute on Aging; Wellcome Trust [WT097835MF]; Helmholtz Zentrum Munchen, German Research Center for Environmental Health - BMBF; State of Bavaria; Munich Center of Health Sciences (MC Health), Ludwig Maximilians-Universitat; BMBF [01ZZ9603, 01ZZ0103, 01ZZ0403, 03ZIK012]; German Federal Ministry of Health; Ministry of School, Science and Research of the State of North-Rhine-Westphalia; BMBF (National Genome Research Network NGFN plus Atherogenomics) [01GS0834]; DZHK (Deutsches Zentrum fur Herz-Kreislauf-Forschung - German Centre for Cardiovascular Research); European Commission's Seventh Framework Programme [277984, 603288]; BMBF (German Ministry of Education and Research); DZHK (German Centre for Cardiovascular Research) within the framework of the MetaXpress consortium; Ministry of Cultural Affairs; Social Ministry of the Federal State of Mecklenburg-West Pomerania; network 'Greifswald Approach to Individualized Medicine (GANI_MED)' - BMBF [03IS2061A] FX The Framingham Heart Study is funded by National Institutes of Health contract N01-HC-25195. The laboratory work for this investigation was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health. The analytical component of this project was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, and the Center for Information Technology, National Institutes of Health, Bethesda, MD. EGCUT is supported by targeted financing from the Estonian Ministry of Science and Education [SF0180142s08]; the Development Fund of the University of Tartu (grant SP1GVARENG); the European Regional Development Fund to the Centre of Excellence in Genomics (EXCEGEN; grant 3.2.0304.11-0312); and through FP7 grant 313010. AD is supported by NWO grant (veni, 916.12.154) and the EUR Fellowship. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012), the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The generation and management of RNA-expression array data for the Rotterdam Study was executed and funded by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Netherlands. The InCHIANTI study was supported in part by the Intramural Research Program, National Institute on Aging. DM was generously supported by a Wellcome Trust Institutional Strategic Support Award (WT097835MF). The KORA research platform and the KORA Augsburg studies are financed by the Helmholtz Zentrum Munchen, German Research Center for Environmental Health, which is funded by the BMBF and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC Health), Ludwig Maximilians-Universitat, as part of the LMU innovative and in part by a grant from the BMBF to the German Center for Diabetes Research (DZD). The German Diabetes Center is funded by the German Federal Ministry of Health and the Ministry of School, Science and Research of the State of North-Rhine-Westphalia. Additional support was obtained from the BMBF (National Genome Research Network NGFN plus Atherogenomics, 01GS0834), by the DZHK (Deutsches Zentrum fur Herz-Kreislauf-Forschung - German Centre for Cardiovascular Research) and from the European Commission's Seventh Framework Programme (FP7/2007-2013, HEALTH-F2-2011, grant agreement No. 277984, TIRCON and HEALTH-F2-2013, grant agreement No. 603288, SysVasc). SHIP is supported by the BMBF (German Ministry of Education and Research) and by the DZHK (German Centre for Cardiovascular Research) within the framework of the MetaXpress consortium. SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by BMBF (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania, and the network 'Greifswald Approach to Individualized Medicine (GANI_MED)' funded by the BMBF (grant 03IS2061A). Generation of genome-wide data has been supported by the BMBF (grant no. 03ZIK012).; The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 32 TC 20 Z9 20 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7390 EI 1553-7404 J9 PLOS GENET JI PLoS Genet. PD MAR PY 2015 VL 11 IS 3 AR e1005035 DI 10.1371/journal.pgen.1005035 PG 29 WC Genetics & Heredity SC Genetics & Heredity GA CE9XO UT WOS:000352197100027 PM 25785607 ER PT J AU Martin, JE Waters, LS Storz, G Imlay, JA AF Martin, Julia E. Waters, Lauren S. Storz, Gisela Imlay, James A. TI The Escherichia coli Small Protein MntS and Exporter MntP Optimize the Intracellular Concentration of Manganese SO PLOS GENETICS LA English DT Article ID ENTERICA SEROVAR TYPHIMURIUM; BACTERIAL IRON HOMEOSTASIS; LACTIC-ACID BACTERIA; P-TYPE ATPASE; HYDROGEN-PEROXIDE; SUPEROXIDE-DISMUTASE; SALMONELLA-TYPHIMURIUM; DNA-DAMAGE; METABOLISM; STRESS AB Escherichia coli does not routinely import manganese, but it will do so when iron is unavailable, so that manganese can substitute for iron as an enzyme cofactor. When intracellular manganese levels are low, the cell induces the MntH manganese importer plus MntS, a small protein of unknown function; when manganese levels are high, the cell induces the MntP manganese exporter and reduces expression of MntH and MntS. The role of MntS has not been clear. Previous work showed that forced MntS synthesis under manganese-rich conditions caused bacteriostasis. Here we find that when manganese is scarce, MntS helps manganese to activate a variety of enzymes. Its overproduction under manganese-rich conditions caused manganese to accumulate to very high levels inside the cell; simultaneously, iron levels dropped precipitously, apparently because manganese-bound Fur blocked the production of iron importers. Under these conditions, heme synthesis stopped, ultimately depleting cytochrome oxidase activity and causing the failure of aerobic metabolism. Protoporphyrin IX accumulated, indicating that the combination of excess manganese and iron deficiency had stalled ferrochelatase. The same chain of events occurred when mutants lacking MntP, the manganese exporter, were exposed to manganese. Genetic analysis suggested the possibility that MntS exerts this effect by inhibiting MntP. We discuss a model wherein during transitions between low-and high-manganese environments E. coli uses MntP to compensate for MntH overactivity, and MntS to compensate for MntP overactivity. C1 [Martin, Julia E.; Imlay, James A.] Univ Illinois, Dept Microbiol, Urbana, IL 61801 USA. [Waters, Lauren S.] Univ Wisconsin, Dept Chem, Oshkosh, WI 54901 USA. [Storz, Gisela] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, Bethesda, MD USA. RP Martin, JE (reprint author), Univ Illinois, Dept Microbiol, 131 Burrill Hall, Urbana, IL 61801 USA. EM watersl@uwosh.edu; jimlay@illinois.edu OI Storz, Gisela/0000-0001-6698-1241 FU National Institutes of Health [GM101012, 5T32-GM070421]; Intramural Research Program of the National Institutes of Health FX This work was funded by grants GM101012 from the National Institutes of Health (www.nih.gov) (JAI JEM); 5T32-GM070421 from the National Institutes of Health (JEM); and The Intramural Research Program of the National Institutes of Health (LSW GS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 77 TC 17 Z9 17 U1 1 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7390 EI 1553-7404 J9 PLOS GENET JI PLoS Genet. PD MAR PY 2015 VL 11 IS 3 AR e1004977 DI 10.1371/journal.pgen.1004977 PG 31 WC Genetics & Heredity SC Genetics & Heredity GA CE9XO UT WOS:000352197100004 PM 25774656 ER PT J AU Simon, M Richard, EM Wang, XJ Shahzad, M Huang, VH Qaiser, TA Potluri, P Mahl, SE Davila, A Nazli, S Hancock, S Yu, M Gargus, J Chang, R Al-sheqaih, N Newman, WG Abdenur, J Starr, A Hegde, R Dorn, T Busch, A Park, E Wu, J Schwenzer, H Flierl, A Florentz, C Sissler, M Khan, SN Li, RH Guan, MX Friedman, TB Wu, DK Procaccio, V Riazuddin, S Wallace, DC Ahmed, ZM Huang, TS Riazuddin, S AF Simon, Mariella Richard, Elodie M. Wang, Xinjian Shahzad, Mohsin Huang, Vincent H. Qaiser, Tanveer A. Potluri, Prasanth Mahl, Sarah E. Davila, Antonio Nazli, Sabiha Hancock, Saege Yu, Margret Gargus, Jay Chang, Richard Al-sheqaih, Nada Newman, William G. Abdenur, Jose Starr, Arnold Hegde, Rashmi Dorn, Thomas Busch, Anke Park, Eddie Wu, Jie Schwenzer, Hagen Flierl, Adrian Florentz, Catherine Sissler, Marie Khan, Shaheen N. Li, Ronghua Guan, Min-Xin Friedman, Thomas B. Wu, Doris K. Procaccio, Vincent Riazuddin, Sheikh Wallace, Douglas C. Ahmed, Zubair M. Huang, Taosheng Riazuddin, Saima TI Mutations of Human NARS2, Encoding the Mitochondrial Asparaginyl-tRNA Synthetase, Cause Nonsyndromic Deafness and Leigh Syndrome SO PLOS GENETICS LA English DT Article ID C-OXIDASE DEFICIENCY; HEARING-LOSS; PROTEIN-STRUCTURE; PERRAULT SYNDROME; GENETIC-VARIANTS; SEQUENCING DATA; MOLECULAR-BASIS; HUMAN-DISEASE; BRAIN-STEM; TRANSLATION AB Here we demonstrate association of variants in the mitochondrial asparaginyl-tRNA synthetase NARS2 with human hearing loss and Leigh syndrome. A homozygous missense mutation ([c.637G> T; p.Val213Phe]) is the underlying cause of nonsyndromic hearing loss (DFNB94) and compound heterozygous mutations ([c.969T> A; p.Tyr323*] + [c.1142A> G; p.Asn381Ser]) result in mitochondrial respiratory chain deficiency and Leigh syndrome, which is a neurodegenerative disease characterized by symmetric, bilateral lesions in the basal ganglia, thalamus, and brain stem. The severity of the genetic lesions and their effects on NARS2 protein structure cosegregate with the phenotype. A hypothetical truncated NARS2 protein, secondary to the Leigh syndrome mutation p.Tyr323* is not detectable and p. Asn381Ser further decreases NARS2 protein levels in patient fibroblasts. p. Asn381Ser also disrupts dimerization of NARS2, while the hearing loss p.Val213Phe variant has no effect on NARS2 oligomerization. Additionally we demonstrate decreased steady-state levels of mt-tRNA(Asn) in fibroblasts from the Leigh syndrome patients. In these cells we show that a decrease in oxygen consumption rates (OCR) and electron transport chain (ETC) activity can be rescued by overexpression of wild type NARS2. However, overexpression of the hearing loss associated p.Val213Phe mutant protein in these fibroblasts cannot complement the OCR and ETC defects. Our findings establish lesions in NARS2 as a new cause for nonsyndromic hearing loss and Leigh syndrome. C1 [Simon, Mariella; Park, Eddie] Univ Calif Irvine, Sch Biol Sci, Dept Dev & Cellular Biol, Irvine, CA 92717 USA. [Simon, Mariella; Chang, Richard; Abdenur, Jose] CHOC Childrens, Div Metab, Orange, CA USA. [Richard, Elodie M.; Shahzad, Mohsin; Ahmed, Zubair M.; Riazuddin, Saima] Univ Maryland, Sch Med, Dept Otorhinolaryngol Head & Neck Surg, Baltimore, MD 21201 USA. [Wang, Xinjian; Huang, Vincent H.; Li, Ronghua; Guan, Min-Xin; Huang, Taosheng] Cincinnati Childrens Hosp Med Ctr, Div Human Genet, Cincinnati, OH 45229 USA. [Qaiser, Tanveer A.; Nazli, Sabiha; Khan, Shaheen N.] Univ Punjab, Natl Ctr Excellence Mol Biol, Lahore, Pakistan. [Potluri, Prasanth; Wallace, Douglas C.] Univ Penn, Childrens Hosp Philadelphia, Ctr Mitochondrial & Epigen Med, Philadelphia, PA 19104 USA. [Potluri, Prasanth; Wallace, Douglas C.] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA USA. [Mahl, Sarah E.] Cincinnati Childrens Hosp Med Ctr, Div Pediat Otolaryngol Head & Neck Surg, Cincinnati, OH 45229 USA. [Davila, Antonio] Univ Penn, Smilow Ctr Translat Res, Philadelphia, PA 19104 USA. [Hancock, Saege] Trovagene, San Diego, CA USA. [Yu, Margret] Marshall B Ketchum Univ, Fullerton, CA USA. [Gargus, Jay] Univ Calif Irvine, Dept Physiol & Biophys, Irvine, CA 92717 USA. [Al-sheqaih, Nada; Newman, William G.] Univ Manchester, Manchester Ctr Genom Med, Manchester, Lancs, England. [Al-sheqaih, Nada; Newman, William G.] Cent Manchester Univ Hosp NHS Fdn Trust, Manchester Acad Hlth Sci Ctr MAHSC, Manchester, Lancs, England. [Starr, Arnold] Univ Calif Irvine, Dept Neurol & Neurobiol, Irvine, CA 92717 USA. [Hegde, Rashmi] Cincinnati Childrens Hosp Med Ctr, Div Dev Biol, Cincinnati, OH 45229 USA. [Dorn, Thomas] Swiss Epilepsy Ctr, Zurich, Switzerland. [Busch, Anke] Inst Mol Biol, Mainz, Germany. [Wu, Jie] Univ Calif Irvine, Inst Genom & Bioinformat, Irvine, CA 92717 USA. [Schwenzer, Hagen; Florentz, Catherine; Sissler, Marie] Univ Strasbourg, Architecture & Reactivite ARN, CNRS, IBMC, Strasbourg, France. [Flierl, Adrian] Parkinsons Inst & Clin Ctr, Sunnyvale, CA USA. [Friedman, Thomas B.] NIDOCD, Mol Genet Lab, NIH, Bethesda, MD USA. [Wu, Doris K.] NIDOCD, Sect Sensory Cell Regenerat & Dev, NIH, Bethesda, MD USA. [Procaccio, Vincent] CHU Angers, Dept Biochem & Genet, CNRS, UMR 6214,INSERM,U1083, Angers, France. [Riazuddin, Sheikh] Univ Hlth Sci, Allama Iqbal Med Coll, Lahore, Pakistan. [Riazuddin, Sheikh] Univ Lahore, Lahore, Pakistan. [Riazuddin, Sheikh] Shaheed Zulfiqar Ali Bhutto Med Univ, Islamabad, Pakistan. RP Simon, M (reprint author), Univ Calif Irvine, Sch Biol Sci, Dept Dev & Cellular Biol, Irvine, CA 92717 USA. EM taosheng.huang@cchmc.org; sriazuddin@smail.umaryland.edu RI Nasim Khan, Shaheen/F-2135-2015; Procaccio, Vincent/M-2596-2015; OI Simon, Mariella/0000-0002-8200-3277; Newman, William/0000-0002-6382-4678 FU NIDCD [DC000039-17]; Action on Hearing Loss grant; National Institute on Deafness and Other Communication Disorders (NIDCD/NIH) [R01DC011803, R01DC011748, R01DC012564]; UC Irvine Foundation; S. Family Foundation; Cincinnati Children's Hospital Research Foundation; NIH [NS21328]; Doris Duke Foundation [2005057]; Simons Foundation [205844]; Centre National de la Recherche Scientifique (CNRS), Universite de Strasbourg (UdS); French National Program "Investissement d'Avenir" [ANR-11-LABX-0057_MITOCROSS]; National Center for Research Resources; National Center for Advancing Translational Sciences, National Institutes of Health [UL1 TR000153] FX This study was supported by intramural funds from the NIDCD DC000039-17 to TBF, by an Action on Hearing Loss grant and by National Institute on Deafness and Other Communication Disorders (NIDCD/NIH) research grants R01DC011803 and R01DC011748 to SR and R01DC012564 to ZMA. This work is supported in part by the UC Irvine Foundation, the S. Family Foundation and Cincinnati Children's Hospital Research Foundation to TH, NIH grant NS21328, Doris Duke Foundation grant 2005057, and Simons Foundation grant 205844 to DCW. This work was also partially supported by Centre National de la Recherche Scientifique (CNRS), Universite de Strasbourg (UdS), and by the French National Program "Investissement d'Avenir" [ANR-11-LABX-0057_MITOCROSS] to MSis. The project described was also supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant UL1 TR000153. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 70 TC 15 Z9 17 U1 3 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7390 EI 1553-7404 J9 PLOS GENET JI PLoS Genet. PD MAR PY 2015 VL 11 IS 3 AR e1005097 DI 10.1371/journal.pgen.1005097 PG 26 WC Genetics & Heredity SC Genetics & Heredity GA CE9XO UT WOS:000352197100065 PM 25807530 ER PT J AU Baniecki, ML Faust, AL Schaffner, SF Park, DJ Galinsky, K Daniels, RF Hamilton, E Ferreira, MU Karunaweera, ND Serre, D Zimmerman, PA Sa, JM Wellems, TE Musset, L Legrand, E Melnikov, A Neafsey, DE Volkman, SK Wirth, DF Sabeti, PC AF Baniecki, Mary Lynn Faust, Aubrey L. Schaffner, Stephen F. Park, Daniel J. Galinsky, Kevin Daniels, Rachel F. Hamilton, Elizabeth Ferreira, Marcelo U. Karunaweera, Nadira D. Serre, David Zimmerman, Peter A. Sa, Juliana M. Wellems, Thomas E. Musset, Lise Legrand, Eric Melnikov, Alexandre Neafsey, Daniel E. Volkman, Sarah K. Wirth, Dyann F. Sabeti, Pardis C. TI Development of a Single Nucleotide Polymorphism Barcode to Genotype Plasmodium vivax Infections SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID POPULATION-STRUCTURE; DRUG-RESISTANCE; MICROSATELLITE MARKER; GEOGRAPHIC STRUCTURE; GENETIC DIVERSITY; MELTING ANALYSIS; RURAL AMAZONIA; SRI-LANKA; MALARIA; FALCIPARUM AB Plasmodium vivax, one of the five species of Plasmodium parasites that cause human malaria, is responsible for 25-40% of malaria cases worldwide. Malaria global elimination efforts will benefit from accurate and effective genotyping tools that will provide insight into the population genetics and diversity of this parasite. The recent sequencing of P. vivax isolates from South America, Africa, and Asia presents a new opportunity by uncovering thousands of novel single nucleotide polymorphisms (SNPs). Genotyping a selection of these SNPs provides a robust, low-cost method of identifying parasite infections through their unique genetic signature or barcode. Based on our experience in generating a SNP barcode for P. falciparum using High Resolution Melting (HRM), we have developed a similar tool for P. vivax. We selected globally polymorphic SNPs from available P. vivax genome sequence data that were located in putatively selectively neutral sites (i.e., intergenic, intronic, or 4fold degenerate coding). From these candidate SNPs we defined a barcode consisting of 42 SNPs. We analyzed the performance of the 42-SNP barcode on 87 P. vivax clinical samples from parasite populations in South America (Brazil, French Guiana), Africa (Ethiopia) and Asia (Sri Lanka). We found that the P. vivax barcode is robust, as it requires only a small quantity of DNA (limit of detection 0.3 ng/mu l) to yield reproducible genotype calls, and detects polymorphic genotypes with high sensitivity. The markers are informative across all clinical samples evaluated (average minor allele frequency > 0.1). Population genetic and statistical analyses show the barcode captures high degrees of population diversity and differentiates geographically distinct populations. Our 42-SNP barcode provides a robust, informative, and standardized genetic marker set that accurately identifies a genomic signature for P. vivax infections. C1 [Baniecki, Mary Lynn; Schaffner, Stephen F.; Park, Daniel J.; Melnikov, Alexandre; Neafsey, Daniel E.; Volkman, Sarah K.; Wirth, Dyann F.; Sabeti, Pardis C.] Broad Inst, Cambridge, MA 02142 USA. [Faust, Aubrey L.; Daniels, Rachel F.; Sabeti, Pardis C.] Harvard Univ, Dept Organism & Evolutionary Biol, Cambridge, MA 02138 USA. [Galinsky, Kevin; Hamilton, Elizabeth; Volkman, Sarah K.; Wirth, Dyann F.; Sabeti, Pardis C.] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Ferreira, Marcelo U.] Univ Sao Paulo, Dept Parasitol, Sao Paulo, Brazil. [Karunaweera, Nadira D.] Univ Colombo, Fac Med, Dept Parasitol, Colombo, Sri Lanka. [Serre, David] Cleveland Clin Lerner Res Inst, Dept Genom Med Inst, Cleveland, OH USA. [Zimmerman, Peter A.] Case Western Reserve Univ, Dept Int Hlth Biol & Genet, Cleveland, OH 44106 USA. [Sa, Juliana M.; Wellems, Thomas E.] Natl Inst Allergy & Infect Dis, Malaria Genet Sect, Lab Malaria & Vector Res, Rockville, MD USA. [Musset, Lise; Legrand, Eric] Inst Pasteur, Dept Parasitol, Cayenne, French Guiana. [Volkman, Sarah K.] Simmons Coll, Sch Nursing & Hlth Sci, Boston, MA 02115 USA. RP Baniecki, ML (reprint author), Broad Inst, Cambridge, MA 02142 USA. EM baniecki@broadinstitute.org RI Schaffner, Stephen/D-1189-2011; Ferreira, Marcelo/G-8289-2011; OI Ferreira, Marcelo/0000-0002-5293-9090; Zimmerman, Peter/0000-0002-5349-4513; Galinsky, Kevin/0000-0003-0311-4938; Daniels, Rachel/0000-0002-9712-4581; Legrand, Eric/0000-0003-4725-0712 FU Bill and Melinda Gates Foundation; Common Fund of the National Institute of Allergy and Infectious Diseases, National Institutes of Health [NIH 1DP2OD006514-01]; Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This study is supported by the Bill and Melinda Gates Foundation. Additional support was provided by the Common Fund (NIH 1DP2OD006514-01) and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, 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 44 TC 16 Z9 17 U1 0 U2 12 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 MAR PY 2015 VL 9 IS 3 AR e0003539 DI 10.1371/journal.pntd.0003539 PG 18 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA CE9YK UT WOS:000352199400022 PM 25781890 ER PT J AU Horton, DL McElhinney, LM Freuling, CM Marston, DA Banyard, AC Goharrriz, H Wise, E Breed, AC Saturday, G Kolodziejek, J Zilahi, E Al-Kobaisi, MF Nowotny, N Mueller, T Fooks, AR AF Horton, Daniel L. McElhinney, Lorraine M. Freuling, Conrad M. Marston, Denise A. Banyard, Ashley C. Goharrriz, Hooman Wise, Emma Breed, Andrew C. Saturday, Greg Kolodziejek, Jolanta Zilahi, Erika Al-Kobaisi, Muhannad F. Nowotny, Norbert Mueller, Thomas Fooks, Anthony R. TI Complex Epidemiology of a Zoonotic Disease in a Culturally Diverse Region: Phylogeography of Rabies Virus in the Middle East SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID CANINE RABIES; PUBLIC-HEALTH; MOLECULAR EPIDEMIOLOGY; RECENT EMERGENCE; DOG RABIES; MERS-COV; ELIMINATION; GENE; POPULATIONS; HISTORY AB The Middle East is a culturally and politically diverse region at the gateway between Europe, Africa and Asia. Spatial dynamics of the fatal zoonotic disease rabies among countries of the Middle East and surrounding regions is poorly understood. An improved understanding of virus distribution is necessary to direct control methods. Previous studies have suggested regular trans-boundary movement, but have been unable to infer direction. Here we address these issues, by investigating the evolution of 183 rabies virus isolates collected from over 20 countries between 1972 and 2014. We have undertaken a discrete phylogeographic analysis on a subset of 139 samples to infer where and when movements of rabies have occurred. We provide evidence for four genetically distinct clades with separate origins currently circulating in the Middle East and surrounding countries. Introductions of these viruses have been followed by regular and multidirectional trans-boundary movements in some parts of the region, but relative isolation in others. There is evidence for minimal regular incursion of rabies from Central and Eastern Asia. These data support current initiatives for regional collaboration that are essential for rabies elimination. C1 [Horton, Daniel L.; McElhinney, Lorraine M.; Marston, Denise A.; Banyard, Ashley C.; Goharrriz, Hooman; Wise, Emma; Breed, Andrew C.; Fooks, Anthony R.] Anim & Plant Hlth Agcy, Addlestone, Surrey, England. [Horton, Daniel L.] Univ Surrey, Sch Vet Med, Guildford GU2 5XH, Surrey, England. [McElhinney, Lorraine M.; Fooks, Anthony R.] Univ Liverpool, Inst Infect & Global Hlth, Liverpool L69 3BX, Merseyside, England. [Freuling, Conrad M.; Mueller, Thomas] Friedrich Loeffler Inst, Inst Mol Virol & Cell Biol, Greifswald, Germany. [Saturday, Greg] NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Saturday, Greg] USAPHCR Europe Lab Sci, Vet Pathol, Landstuhl, Germany. [Kolodziejek, Jolanta; Nowotny, Norbert] Univ Vet Med Vienna, Inst Virol, Vienna, Austria. [Zilahi, Erika] United Arab Emirates Univ, Dept Med Microbiol & Immunol, Coll Med & Hlth Sci, Al Ain, U Arab Emirates. [Al-Kobaisi, Muhannad F.; Nowotny, Norbert] Sultan Qaboos Univ, Dept Microbiol & Immunol, Coll Med & Hlth Sci, Muscat, Oman. RP Fooks, AR (reprint author), Anim & Plant Hlth Agcy, Addlestone, Surrey, England. EM Tony.Fooks@apha.gsi.gov.uk RI Horton, Daniel/D-9909-2011; APHA, Staff publications/E-6082-2010; Banyard, Ashley/C-7998-2011; Wise, Emma/D-7998-2011; Breed, Andrew/A-5682-2011; Fooks, Anthony/F-5418-2010; Marston, Denise/D-7993-2011 OI Horton, Daniel/0000-0002-9126-2756; Banyard, Ashley/0000-0002-1286-9825; Marston, Denise/0000-0001-9215-088X FU UK Department for Environment and Rural Affairs (Defra ROAME) [SE0427]; UK Biological Engagement Program; EU [228292]; BMBF [01KI1016A]; United Arab Emirates University - Sultan Qaboos University Research FX This work was partially supported by the UK Department for Environment and Rural Affairs (Defra ROAME SE0427), the UK Biological Engagement Program, the EU FP7-funded Research Infrastructure Grant 'European Virus Archive (EVA)' (grant number 228292), BMBF grant 01KI1016A "Lyssaviruses - a potential re-emerging public health threat" and by a joint United Arab Emirates University - Sultan Qaboos University Research grant entitled "Molecular characterization of selected zoonotic and emerging viruses isolated in the U.A.E. and in Oman. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 76 TC 0 Z9 0 U1 1 U2 12 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 MAR PY 2015 VL 9 IS 3 AR e0003569 DI 10.1371/journal.pntd.0003569 PG 17 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA CE9YK UT WOS:000352199400041 PM 25811659 ER PT J AU Mahanty, S Orrego, MA Mayta, H Marzal, M Cangalaya, C Paredes, A Gonzales-Gustavson, E Arroyo, G Gonzalez, AE Guerra-Giraldez, C Garcia, HH Nash, TE AF Mahanty, Siddhartha Angel Orrego, Miguel Mayta, Holger Marzal, Miguel Cangalaya, Carla Paredes, Adriana Gonzales-Gustavson, Eloy Arroyo, Gianfranco Gonzalez, Armando E. Guerra-Giraldez, Cristina Garcia, Hector H. Nash, Theodore E. CA Cysticercosis Working Grp Peru TI Post-treatment Vascular Leakage and Inflammatory Responses around Brain Cysts in Porcine Neurocysticercosis SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID TAENIA-SOLIUM CYSTICERCOSIS; ALTERNATIVELY ACTIVATED MACROPHAGES; NATURALLY INFECTED-PIGS; IMMUNE-RESPONSE; CLINICAL HETEROGENEITY; PERILESIONAL EDEMA; PROGRAMMED DEATH-1; PARASITE; HOST; HISTOPATHOLOGY AB Cysticidal treatment of neurocysticercosis, an infection of humans and pig brains with Taenia solium, results in an early inflammatory response directed to cysts causing seizures and focal neurological manifestations. Treatment-induced pericystic inflammation and its association with blood brain barrier (BBB) dysfunction, as determined by Evans blue (EB) extravasation, was studied in infected untreated and anthelmintic-treated pigs. We compared the magnitude and extent of the pericystic inflammation, presence of EB-stained capsules, the level of damage to the parasite, expression of genes for proinflammatory and regulatory cytokines, chemokines, and tissue remodeling by quantitative PCR assays between treated and untreated infected pigs and between EB-stained (blue) and non stained (clear) cysts. Inflammatory scores were higher in pericystic tissues from EB-stained cysts compared to clear cysts from untreated pigs and also from anthelmintic-treated pigs 48 hr and 120 hr after treatment. The degree of inflammation correlated with the severity of cyst wall damage and both increased significantly at 120 hours. Expression levels of the proinflammatory genes for IL-6, IFN-gamma, TNF-alpha were higher in EB-stained cysts compared to clear cysts and unaffected brain tissues, and were generally highest at 120 hr. Additionally, expression of some markers of immunoregulatory activity (IL-10, IL-2R alpha) were decreased in EB-stained capsules. An increase in other markers for regulatory T cells (CTLA4, FoxP3) was found, as well as significant increases in expression of two metalloproteases, MMP1 and MMP2 at 48 hr and 120 hr post-treatment. We conclude that the increase in severity of the inflammation caused by treatment is accompanied by both a proinflammatory and a complex regulatory response, largely limited to pericystic tissues with compromised vascular integrity. Because treatment induced inflammation occurs in porcine NCC similar to that in human cases, this model can be used to investigate mechanisms involved in host damaging inflammatory responses and agents or modalities that may control damaging post treatment inflammation. C1 [Mahanty, Siddhartha; Nash, Theodore E.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Mahanty, Siddhartha; Angel Orrego, Miguel; Marzal, Miguel; Cangalaya, Carla; Paredes, Adriana; Guerra-Giraldez, Cristina; Garcia, Hector H.; Nash, Theodore E.] Univ Peruana Cayetano Heredia, Immunopathol Lab, Lima, Peru. [Mayta, Holger; Guerra-Giraldez, Cristina; Garcia, Hector H.] Univ Peruana Cayetano Heredia, Fac Ciencias & Filosofia, Lima, Peru. [Gonzales-Gustavson, Eloy; Arroyo, Gianfranco; Gonzalez, Armando E.] Univ Nacl Mayor San Marcos, Fac Vet Sci, Lima, Peru. [Garcia, Hector H.] Inst Nacl Ciencias Neurol, Cysticercosis Unit, Lima, Peru. RP Mahanty, S (reprint author), NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. EM smahanty@niaid.nih.gov OI Guerra-Giraldez, Cristina/0000-0002-9287-9838; Cangalaya, Carla/0000-0002-3525-8445; Gonzales-Gustavson, Eloy/0000-0001-7328-2983; Mahanty, Siddhartha/0000-0003-1068-0524 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH; Fogarty International Center-NIH Training grant [D43 TW001140]; Wellcome Trust Senior International Research Fellowship in Public Health and Tropical Medicine FX This research was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH. Partial support from Fogarty International Center-NIH Training grant D43 TW001140 is also acknowledged. HHG is supported by a Wellcome Trust Senior International Research Fellowship in Public Health and Tropical Medicine. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 7 Z9 7 U1 1 U2 8 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 MAR PY 2015 VL 9 IS 3 AR e0003577 DI 10.1371/journal.pntd.0003577 PG 18 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA CE9YK UT WOS:000352199400046 PM 25774662 ER PT J AU Talaat, KR Babu, S Menon, P Kumarasamy, N Sharma, J Arumugam, J Dhakshinamurthy, K Srinivasan, R Poongulali, S Gu, WJ Fay, MP Swaminathan, S Nutman, TB AF Talaat, Kawsar R. Babu, Subash Menon, Pradeep Kumarasamy, N. Sharma, Jabin Arumugam, Jeeva Dhakshinamurthy, Kalaivani Srinivasan, Ramalingam Poongulali, S. Gu, Wenjuan Fay, Michael P. Swaminathan, Soumya Nutman, Thomas B. TI Treatment of W. bancrofti (Wb) in HIV/Wb Coinfections in South India SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID PLACEBO-CONTROLLED TRIAL; PLASMA VIRAL LOAD; ANTIRETROVIRAL THERAPY; HELMINTH INFECTION; DOUBLE-BLIND; IMMUNODEFICIENCY-VIRUS; INTESTINAL HELMINTHS; LYMPHATIC FILARIASIS; CYTOKINE RESPONSES; ADULT TANZANIANS AB Background The disease course of human immunodeficiency virus (HIV) is often altered by existing or newly acquired coincident infections. Methodology/Principal Findings To assess the influence of pre-existing Wuchereria bancrofti infection on HIV progression, we performed a case-controlled treatment study of HIV positive individuals with (FIL+) or without (FIL-) W. bancrofti infection. Twenty-eight HIV+/FIL+ and 51 matched HIV+/FIL-subjects were treated with a single dose of diethylcarbamazine and albendazole (DEC/Alb) and followed for a year at regular intervals. Sixteen of the HIV+/FIL+ subjects (54%) and 28 of the HIV+/FIL-controls (57%) were on antiretroviral therapy (ART) during the study. Following treatment, no differences were noted in clinical outcomes between the 2 groups. There also was no significant difference between the groups in the HIV viral load at 12 months as a percentage of baseline viral load (HIV+/FIL+ group had on average 0.97 times the response of the HIV+/FIL-group, 95% CI 0.88, 1.07) between the groups. Furthermore, there were no significant differences found in either the change in viral load at 1, 3, or 6 months or in the change in CD4 count at 3, 6, or 12 months between the 2 groups. Conclusions/Significance We were unable to find a significant effect of W. bancrofti infection or its treatment on HIV clinical course or surrogate markers of HIV disease progression though we recognized that our study was limited by the smaller than predicted sample size and by the use of ART in half of the patients. Treatment ofW. bancrofti coinfection in HIV positive subjects (as is usual in mass drug administration campaigns) did not represent an increased risk to the subjects, and should therefore be considered for PLWHA living in W. bancrofti endemic areas. C1 [Talaat, Kawsar R.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Talaat, Kawsar R.; Babu, Subash; Nutman, Thomas B.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD USA. [Menon, Pradeep; Dhakshinamurthy, Kalaivani; Srinivasan, Ramalingam; Swaminathan, Soumya] Indian Council Med Res, Natl Inst Res TB, Madras, Tamil Nadu, India. [Kumarasamy, N.; Sharma, Jabin; Arumugam, Jeeva; Poongulali, S.] YRG CARE, Madras, Tamil Nadu, India. [Gu, Wenjuan; Fay, Michael P.] NIAID, Div Clin Res, Bethesda, MD 20892 USA. RP Talaat, KR (reprint author), NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. EM ktalaat@jhu.edu OI Fay, Michael P./0000-0002-8643-9625 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA. At the time of this work, 3 of the authors (KT, SB, TN) were employees of the National Institute of Allergy and Infectious Disease. Other than that, the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 31 TC 3 Z9 3 U1 0 U2 6 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 MAR PY 2015 VL 9 IS 3 AR e0003622 DI 10.1371/journal.pntd.0003622 PG 13 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA CE9YK UT WOS:000352199400080 PM 25793933 ER PT J AU Tian, HY Yu, PB Luis, AD Bi, P Cazelles, B Laine, M Huang, SQ Ma, CF Zhou, S Wei, J Li, S Lu, XL Qu, JH Dong, JH Tong, SL Wang, JJ Grenfell, B Xu, B AF Tian, Huai-Yu Yu, Peng-Bo Luis, Angela D. Bi, Peng Cazelles, Bernard Laine, Marko Huang, Shan-Qian Ma, Chao-Feng Zhou, Sen Wei, Jing Li, Shen Lu, Xiao-Ling Qu, Jian-Hui Dong, Jian-Hua Tong, Shi-Lu Wang, Jing-Jun Grenfell, Bryan Xu, Bing TI Changes in Rodent Abundance and Weather Conditions Potentially Drive Hemorrhagic Fever with Renal Syndrome Outbreaks in Xi'an, China, 2005-2012 SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID HANTAVIRUS PULMONARY SYNDROME; REPUBLIC-OF-CHINA; SEED PRODUCTION; SEOUL VIRUS; TRANSMISSION; DISEASE; RISK; VARIABILITY; RESERVOIR; CLIMATE AB Background Increased risks for hemorrhagic fever with renal syndrome (HFRS) caused by Hantaan virus have been observed since 2005, in Xi'an, China. Despite increased vigilance and preparedness, HFRS outbreaks in 2010, 2011, and 2012 were larger than ever, with a total of 3,938 confirmed HFRS cases and 88 deaths in 2010 and 2011. Methods and Findings Data on HFRS cases and weather were collected monthly from 2005 to 2012, along with active rodent monitoring. Wavelet analyses were performed to assess the temporal relationship between HFRS incidence, rodent density and climatic factors over the study period. Results showed that HFRS cases correlated to rodent density, rainfall, and temperature with 2, 3 and 4-month lags, respectively. Using a Bayesian time-series Poisson adjusted model, we fitted the HFRS outbreaks among humans for risk assessment in Xi'an. The best models included seasonality, autocorrelation, rodent density 2 months previously, and rainfall 2 to 3 months previously. Our models well reflected the epidemic characteristics by one step ahead prediction, out-of-sample. Conclusions In addition to a strong seasonal pattern, HFRS incidence was correlated with rodent density and rainfall, indicating that they potentially drive the HFRS outbreaks. Future work should aim to determine the mechanism underlying the seasonal pattern and autocorrelation. However, this model can be useful in risk management to provide early warning of potential outbreaks of this disease. C1 [Tian, Huai-Yu; Huang, Shan-Qian; Xu, Bing] Beijing Normal Univ, Coll Global Change & Earth Syst Sci, State Key Lab Remote Sensing Sci, Beijing 100875, Peoples R China. [Yu, Peng-Bo; Wei, Jing; Li, Shen; Dong, Jian-Hua; Wang, Jing-Jun] Shaanxi Prov Ctr Dis Control & Prevent, Xian, Shaanxi, Peoples R China. [Luis, Angela D.] Univ Montana, Dept Ecosyst & Conservat Sci, Missoula, MT 59812 USA. [Luis, Angela D.; Grenfell, Bryan] Princeton Univ, Dept Ecol & Evolut Biol, Princeton, NJ 08544 USA. [Luis, Angela D.; Grenfell, Bryan] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Bi, Peng] Univ Adelaide, Discipline Publ Hlth, Adelaide, SA, Australia. [Cazelles, Bernard] UPMC, IRD, UMI 209, UMMISCO, F-93142 Bondy, France. [Cazelles, Bernard] ENS, IBENS,UMR 8197, Ecoevolutionary Math, F-75230 Paris 05, France. [Laine, Marko] Finnish Meteorol Inst, FIN-00101 Helsinki, Finland. [Ma, Chao-Feng] Xian Ctr Dis Control & Prevent, Xian, Shaanxi, Peoples R China. [Zhou, Sen; Xu, Bing] Tsinghua Univ, Ctr Earth Syst Sci, Minist Educ, Key Lab Earth Syst Modelling, Beijing 100084, Peoples R China. [Lu, Xiao-Ling; Qu, Jian-Hui] Hu Cty Ctr Dis Control & Prevent Shaanxi Prov, Xian, Shaanxi, Peoples R China. [Tong, Shi-Lu] Queensland Univ Technol, Sch Publ Hlth, Brisbane, Qld 4001, Australia. [Tong, Shi-Lu] Queensland Univ Technol, Inst Hlth & Biomed Innovat, Brisbane, Qld 4001, Australia. RP Tian, HY (reprint author), Beijing Normal Univ, Coll Global Change & Earth Syst Sci, State Key Lab Remote Sensing Sci, Beijing 100875, Peoples R China. EM jingjunwang@china.com; bingxu@tsinghua.edu.cn RI Cazelles, Bernard/B-1572-2013; Tian, Huaiyu/G-1934-2016; OI Cazelles, Bernard/0000-0002-7972-361X; Yu, Paul/0000-0003-2145-4944 FU Ministry of Science and Technology, China, National Research Program [2012CB955501, 2012AA12A407]; National Natural Science Foundation of China [41271099]; European Commission [282-378]; Science and Technology Directorate, Department of Homeland Security [HSHQDC-12-C-00058]; Bill and Melinda Gates Foundation; RAPIDD program of the Science and Technology Directorate, U.S. Department of Homeland Security; Fogarty International Center, NIH FX This research was supported by Ministry of Science and Technology, China, National Research Program (2012CB955501, 2012AA12A407), the National Natural Science Foundation of China (41271099). BC was partially supported by the European Commission Seventh Framework Programme (FP7/2007-2013) for the DENFREE project under grant agreement no. 282-378. BG is supported by the Science and Technology Directorate, Department of Homeland Security contract HSHQDC-12-C-00058, the Bill and Melinda Gates Foundation. Luis and Grenfell are supported by the RAPIDD program of the Science and Technology Directorate, U.S. Department of Homeland Security, and the Fogarty International Center, NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 38 TC 4 Z9 4 U1 4 U2 19 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 MAR PY 2015 VL 9 IS 3 AR e0003530 DI 10.1371/journal.pntd.0003530 PG 13 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA CE9YK UT WOS:000352199400020 PM 25822936 ER PT J AU Knable, MB AF Knable, Michael B. TI This issue: Long-Term Residential Treatment and Its Alternatives SO PSYCHIATRIC ANNALS LA English DT Editorial Material C1 [Knable, Michael B.] Sylvan C Herman Fdn, Washington, DC USA. [Knable, Michael B.] Clearview Communities LLC, Frederick, MD 21701 USA. [Knable, Michael B.] NIMH, Rockville, MD USA. [Knable, Michael B.] Stanley Med Res Inst, Chevy Chase, MD USA. [Knable, Michael B.] Amer Psychiat Assoc, Washington, DC 20005 USA. RP Knable, MB (reprint author), Johns Hopkins Med, Suburban Hosp, Dept Psychiat, Baltimore, MD 21287 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 MAR PY 2015 VL 45 IS 3 BP 104 EP 105 DI 10.3928/00485713-20150304-03 PG 2 WC Psychiatry SC Psychiatry GA CF5GL UT WOS:000352585300003 ER PT J AU Meterko, M Restuccia, JD Stolzmann, K Mohr, D Brennan, C Glasgow, J Kaboli, P AF Meterko, Mark Restuccia, Joseph D. Stolzmann, Kelly Mohr, David Brennan, Caitlin Glasgow, Justin Kaboli, Peter TI RESPONSE RATES, NONRESPONSE BIAS, AND DATA QUALITY RESULTS FROM A NATIONAL SURVEY OF SENIOR HEALTHCARE LEADERS SO PUBLIC OPINION QUARTERLY LA English DT Article AB Survey response rate is regarded as a key data-quality indicator, yet response rate is not necessarily predictive of nonresponse bias. Our study objective was to use a high-response-rate survey to assess nonresponse bias across successive waves. This survey of healthcare leaders utilized a web-based, self-report format with an initial invitation and four nonrespondent follow-ups. Across five waves, comparisons were made for demographic and facility characteristics, proportion of items completed, and distribution of three question types: factual reports of customized categorical responses; single-item evaluations using five-point Likert scales; and multi-item scales, across four-or five-point Likert scales. The overall response rate was 95 percent (118/124); waves did not differ by demographic and facility characteristics or missing data. Across waves, there were no significant differences between responses to two factual report questions or the single-or multi-item scale measures of attitudes. According to a "what-if" analysis of cumulative results by wave, the same conclusions would have been reached if data collection had been halted at earlier points in time. Precision and statistical power increased as number of respondents accumulated by wave. The high response rate facilitated studying the impact of nonresponse bias by wave. Although high response rates are desirable because of precision and power, as survey fatigue increases, absolute thresholds representing "adequate" response rates may be less realistic. Results from "low" response-rate surveys should be considered on their merits, as they may accurately represent attitudes of the population. Therefore, low response rates should not be cited as reasons to dismiss results as uninformative. C1 [Meterko, Mark; Restuccia, Joseph D.; Stolzmann, Kelly; Mohr, David] Boston VA Healthcare Syst, CHOIR, Boston, MA USA. [Meterko, Mark; Mohr, David] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Restuccia, Joseph D.] Boston Univ, Sch Management, Boston, MA 02215 USA. [Brennan, Caitlin] NIH, Outcomes Management, Dept Nursing Res & Practice Dev, Ctr Clin, Bethesda, MD 20892 USA. [Glasgow, Justin] Christiana Care Hlth Syst, Wilmington, DE USA. [Kaboli, Peter] Iowa City VAMC, CADRE Ctr, Iowa City, IA 52246 USA. [Kaboli, Peter] Univ Iowa, Carver Coll Med, Internal Med, Iowa City, IA USA. RP Kaboli, P (reprint author), Iowa City VAMC, CADRE Ctr, Mailstop 152,601 Highway West, Iowa City, IA 52246 USA. EM peter.kaboli@va.gov FU Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development (HSRD) Service [REA 09-220]; Comprehensive Access & Delivery Research and Evaluation (CADRE) Center at the Iowa City VAMC [CIN 13-412]; HSR&D Center for Healthcare Organization and Implementation Research (CHOIR) at the Boston VA Healthcare System [HFP 04-145] FX MARK METERKO is an investigator at the Center for Healthcare Organization and Implementation Research (CHOIR) at the Boston VA Healthcare System, Boston, MA, USA, and research associate professor at the Boston University School of Public Health, Boston, MA, USA. JOSEPH D. RESTUCCIA is an investigator at the Center for Healthcare Organization and Implementation Research (CHOIR) at the Boston VA Healthcare System, Boston, MA, USA, and professor at the Boston University School of Management, Boston, MA, USA. KELLY STOLZMANN is a research analyst at the Center for Healthcare Organization and Implementation Research (CHOIR) at the Boston VA Healthcare System, Boston, MA, USA. DAVID MOHR is an investigator at the Center for Healthcare Organization and Implementation Research (CHOIR) at the Boston VA Healthcare System, Boston, MA, USA, and research assistant professor at the Boston University School of Public Health, Boston, MA, US. CAITLIN BRENNAN is Program Director for Outcomes Management, Department of Nursing Research and Practice Development, National Institutes of Health Clinical Center, Bethesda, MD, USA. JUSTIN GLASGOW is an internal medicine resident at Christiana Care Health System, Wilmington, DE, USA. PETER KABOLI is an investigator at the Comprehensive Access and Delivery Research and Evaluation (CADRE) Center at the Iowa City VA Healthcare System, Iowa City, IA, USA, and professor of internal medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA. The work reported here was supported by the Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development (HSR&D) Service [REA 09-220 to M.M., J.D.R., K.S., D.M., and P.K.], the Comprehensive Access & Delivery Research and Evaluation (CADRE) Center at the Iowa City VAMC [CIN 13-412 to P.K. and J.G.], and the HSR&D Center for Healthcare Organization and Implementation Research (CHOIR) at the Boston VA Healthcare System [HFP 04-145 to M.M., J.D.R., K.S., D.M., and C.B.]. The authors wish to thank Errol Baker, Erol Pekoz, and Michael Shwartz for their thoughtful advice regarding sampling, population, and power analysis issues associated with this study. All three individuals are affiliated with the Center for Healthcare Organization and Implementation Research (CHOIR), VA Boston Healthcare System. Views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. *Address correspondence to Peter J. Kaboli, MD, MS, Iowa City VAMC, Comprehensive Access & Delivery Research and Evaluation (CADRE) Center, Mailstop 152, 601 Highway West, Iowa City, IA 52246, USA; e-mail: peter.kaboli@va.gov. NR 17 TC 1 Z9 1 U1 3 U2 15 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0033-362X EI 1537-5331 J9 PUBLIC OPIN QUART JI Public Opin. Q. PD SPR PY 2015 VL 79 IS 1 BP 130 EP 144 DI 10.1093/poq/nfu052 PG 15 WC Communication; Political Science; Social Sciences, Interdisciplinary SC Communication; Government & Law; Social Sciences - Other Topics GA CF4RE UT WOS:000352537500006 ER PT J AU Jefferson, AL Beiser, AS Seshadri, S Wolf, PA Au, R AF Jefferson, Angela L. Beiser, Alexa S. Seshadri, Sudha Wolf, Philip A. Au, Rhoda TI APOE and mild cognitive impairment: the Framingham Heart Study SO AGE AND AGEING LA English DT Article DE Alzheimer's disease; APOE; genetic risk; mild cognitive impairment; older people; risk factors ID ETHNICALLY DIVERSE ELDERS; ALZHEIMERS-DISEASE; APOLIPOPROTEIN-E; RISK-FACTORS; DECLINE; EDUCATION; BRAIN; NORMS; LIFE; EPSILON-4 AB Background: the risk apolipoprotein E-4 (APOE4) poses for mild cognitive impairment (MCI) may vary based on the neuropsychological definition of MCI. Setting: a community-based cohort study. Methods: using two psychometric neuropsychological impairment definitions, we examined APOE4 and prevalent MCI among older adults or pre-MCI among middle-aged adults. Neuropsychological, clinical and genetic data were collected on 2,239 Framingham Offspring Cohort participants free from clinical stroke or dementia (62 +/- 9 years; 54% women). Prevalent amnestic MCI was defined from neuropsychological performances a parts per thousand yen1.5 SD below the mean based on (i) age and education or (ii) age and Wide Range Achievement Test-3 Reading (WRAT-3 Reading) performance adjustment. Results: in the entire sample, multivariable-adjusted logistic regressions found that APOE4 was associated with amnestic MCI when using the age and WRAT Reading definition (odds ratio [OR] = 1.7, P = 0.002) but not the age and education definition (OR = 1.0, P = 0.90). Results were modified by age, such that APOE4 was associated with amnestic MCI in participants a parts per thousand yen65 years using both the age and WRAT Reading definition (OR = 2.4, P < 0.001) and the age and education definition (OR = 1.7, P = 0.04). Conclusion: APOE4 risk for prevalent amnestic MCI varies depending on the definition of objective neuropsychological impairment for MCI. Our findings support existing literature emphasising the need to refine MCI neuropsychological profiling methods. C1 [Jefferson, Angela L.] Vanderbilt Univ, Med Ctr, Dept Neurol, Vanderbilt Memory & Alzheimers Ctr, Nashville, TN 37203 USA. [Beiser, Alexa S.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Beiser, Alexa S.; Seshadri, Sudha; Wolf, Philip A.; Au, Rhoda] NHLBI, Framingham Heart Study, Framingham, MA USA. [Beiser, Alexa S.; Seshadri, Sudha; Wolf, Philip A.; Au, Rhoda] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. RP Jefferson, AL (reprint author), Vanderbilt Univ, Med Ctr, Dept Neurol, Vanderbilt Memory & Alzheimers Ctr, 2525 West End Ave,Suite 1200, Nashville, TN 37203 USA. EM angela.jefferson@vanderbilt.edu OI Seshadri, Sudha/0000-0001-6135-2622; Beiser, Alexa/0000-0001-8551-7778 FU National Heart Lung Blood Institute's Framingham Heart Study [HC25195, AG030962, AG046373, HL11516, AG034962, AG027480, AG08122, NS017950, AG16495, AG033193, AG031287] FX Research supported by the National Heart Lung Blood Institute's Framingham Heart Study HC25195; AG030962, AG046373, HL11516, AG034962, AG027480; AG08122, NS017950, AG16495; and AG033193, AG031287. NR 30 TC 2 Z9 3 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0002-0729 EI 1468-2834 J9 AGE AGEING JI Age Ageing PD MAR PY 2015 VL 44 IS 2 BP 307 EP 311 DI 10.1093/ageing/afu183 PG 5 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA CE9JF UT WOS:000352159500023 PM 25497326 ER PT J AU Kapogiannis, D AF Kapogiannis, Dimitrios TI Energy metabolism and the brain: A bidirectional relationship SO AGEING RESEARCH REVIEWS LA English DT Editorial Material C1 NIA, Human Neurosci Unit, Lab Neurosci, NIH, Baltimore, MD 21225 USA. RP Kapogiannis, D (reprint author), NIA, Human Neurosci Unit, Lab Neurosci, NIH, 3001 South Hanover St,NM531, Baltimore, MD 21225 USA. EM Kapogiannisd@mail.nih.gov NR 5 TC 0 Z9 0 U1 1 U2 2 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 MAR PY 2015 VL 20 BP 35 EP 36 DI 10.1016/j.arr.2015.02.002 PG 2 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA CF0QS UT WOS:000352249900004 PM 25728594 ER PT J AU Mattson, MP AF Mattson, Mark P. TI Lifelong brain health is a lifelong challenge: From evolutionary principles to empirical evidence SO AGEING RESEARCH REVIEWS LA English DT Review DE Alzheimer's disease; Exercise; Intermittent fasting; Ketone bodies; Parkinson's disease; Synaptic plasticity ID TRANSGENIC MOUSE MODEL; AMYLOID-BETA-PEPTIDE; MILD COGNITIVE IMPAIRMENT; NEUROTROPHIC FACTOR; ALZHEIMERS-DISEASE; ENVIRONMENTAL ENRICHMENT; DIETARY RESTRICTION; HIPPOCAMPAL NEUROGENESIS; CALORIC RESTRICTION; VOLUNTARY EXERCISE AB Although the human brain is exceptional in size and information processing capabilities, it is similar to other mammals with regard to the factors that promote its optimal performance. Three such factors are the challenges of physical exercise, food deprivation/fasting, and social/intellectual engagement. Because it evolved, in part, for success in seeking and acquiring food, the brain functions best when the individual is hungry and physically active, as typified by the hungry lion stalking and chasing its prey. Indeed, studies of animal models and human subjects demonstrate robust beneficial effects of regular exercise and intermittent energy restriction/fasting on cognitive function and mood, particularly in the contexts of aging and associated neurodegenerative disorders. Unfortunately, the agricultural revolution and the invention of effort-sparing technologies have resulted in a dramatic reduction or elimination of vigorous exercise and fasting, leaving only intellectual challenges to bolster brain function. In addition to disengaging beneficial adaptive responses in the brain, sedentary overindulgent lifestyles promote obesity, diabetes and cardiovascular disease, all of which may increase the risk of cognitive impairment and Alzheimer's disease. It is therefore important to embrace the reality of the requirements for exercise, intermittent fasting and critical thinking for optimal brain health throughout life, and to recognize the dire consequences for our aging population of failing to implement such brain-healthy lifestyles. Published by Elsevier B.V. C1 NIA, Lab Neurosci, Intramural Res Program, Baltimore, MD 21224 USA. RP Mattson, MP (reprint author), NIA, Lab Neurosci, Intramural Res Program, Baltimore, MD 21224 USA. EM mark.mattson@nih.gov 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 the Glenn Foundation for Medical Research. NR 124 TC 24 Z9 24 U1 9 U2 52 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 MAR PY 2015 VL 20 BP 37 EP 45 DI 10.1016/j.arr.2014.12.011 PG 9 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA CF0QS UT WOS:000352249900005 PM 25576651 ER PT J AU Willette, AA Kapogiannis, D AF Willette, Auriel A. Kapogiannis, Dimitrios TI Does the brain shrink as the waist expands? SO AGEING RESEARCH REVIEWS LA English DT Review DE Obesity; Adiposity; Brain atrophy; Gray matter; White matter; Body mass index; MRI; MRS; Frontal lobe; Cognition ID BODY-MASS INDEX; MIDDLE-AGED ADULTS; WHITE-MATTER INTEGRITY; CARDIOVASCULAR-DISEASE RISK; EARLY ALZHEIMER-DISEASE; PRADER-WILLI-SYNDROME; COGNITIVE FUNCTION; OLDER-ADULTS; CALORIE RESTRICTION; RHESUS-MONKEYS AB Recent studies suggest that being overweight or obese is related to worse cognitive performance, particularly executive function. Obesity may also increase the risk of Alzheimer's disease. Consequently, there has been increasing interest in whether adiposity is related to gray or white matter (GM, WM) atrophy. In this review, we identified and critically evaluated studies assessing obesity and GM or WM volumes either globally or in specific regions of interest (ROIs). Across all ages, higher adiposity was consistently associated with frontal GM atrophy, particularly in prefrontal cortex. In children and adults <40 years of age, most studies found no relationship between adiposity and occipital or parietal GM volumes, whereas findings for temporal lobe were mixed. In middle-aged and aged adults, a majority of studies found that higher adiposity is associated with parietal and temporal GM atrophy, whereas results for precuneus, posterior cingulate, and hippocampus were mixed. Higher adiposity had no clear association with global or regional WM in any age group. We conclude that higher adiposity may be associated with frontal GM atrophy across all ages and parietal and temporal GM atrophy in middle and old age. Published by Elsevier B.V. C1 [Willette, Auriel A.; Kapogiannis, Dimitrios] NIA, Lab Neurosci, Baltimore, MD 21225 USA. RP Kapogiannis, D (reprint author), NIA, Lab Neurosci, 3001 S Hanover St,NM531, Baltimore, MD 21225 USA. EM kapogiannisd@mail.nih.gov FU Intramural NIH HHS [ZIA AG000975-05] NR 140 TC 15 Z9 15 U1 5 U2 21 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 MAR PY 2015 VL 20 BP 86 EP 97 DI 10.1016/j.arr.2014.03.007 PG 12 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA CF0QS UT WOS:000352249900010 PM 24768742 ER PT J AU Chouraki, V Beiser, A Younkin, L Preis, SR Weinstein, G Hansson, O Skoog, I Lambert, JC Au, R Launer, L Wolf, PA Younkin, S Seshadri, S AF Chouraki, Vincent Beiser, Alexa Younkin, Linda Preis, Sarah Rosner Weinstein, Galit Hansson, Oskar Skoog, Ingmar Lambert, Jean-Charles Au, Rhoda Launer, Lenore Wolf, Philip A. Younkin, Steven Seshadri, Sudha TI Plasma amyloid-beta and risk of Alzheimer's disease in the Framingham Heart Study SO ALZHEIMERS & DEMENTIA LA English DT Article DE A beta peptides; Plasma biomarker; Incident Alzheimer's disease; Incident dementia; Framingham Heart Study; Epidemiology; Meta-analysis ID MILD COGNITIVE IMPAIRMENT; ASSOCIATION WORKGROUPS; DIAGNOSTIC GUIDELINES; NATIONAL INSTITUTE; A-BETA; DEMENTIA; BIOMARKERS; RECOMMENDATIONS; HEALTH; COHORT AB Background: Plasma amyloid-P (A beta) peptide levels have been examined as a low-cost accessible marker for risk of incident Alzheimer's disease (AD) and dementia, but results have varied between studies. We reassessed these associations in one of the largest, prospective, community-based studies to date. Methods: A total of 2189 dementia-free, Framingham Study participants aged >60 years (mean age, 72 +/- 8 years; 56% women) had plasma A beta(1-42) and A beta(1-40) measured and were followed prospectively (mean, 7.6 +/- 3.0 years) for dementia/AD. Results: Increased plasma A beta(1-42) levels were associated with lower risk of dementia (A beta(1-42) hazard ratio [HR] = 0.80 [0.71-0.90], P < .001; A beta(1-42)-to-A beta(1-40) ratio: HR = 0.86 [0.76-0.98], P = .027) and AD (A beta(1-42): HR = 0.79 [0.69-0.90], P < .001; A beta(1-42)-to-A beta(1-40) ratio: HR = 0.83 [0.72-0.96], P = .012). Conclusion: Our results suggest that lower plasma A beta levels are associated with risk of incident AD and dementia. They encourage further evaluation of plasma All levels as a biomarker for risk of developing clinical AD and dementia. (C) 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved. C1 [Chouraki, Vincent; Beiser, Alexa; Preis, Sarah Rosner; Weinstein, Galit; Au, Rhoda; Wolf, Philip A.; Seshadri, Sudha] Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA. [Chouraki, Vincent; Beiser, Alexa; Weinstein, Galit; Au, Rhoda; Wolf, Philip A.; Seshadri, Sudha] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02215 USA. [Beiser, Alexa; Preis, Sarah Rosner] Boston Univ, Sch Med, Dept Biostat, Boston, MA 02215 USA. [Younkin, Linda; Younkin, Steven] Mayo Clin, Jacksonville, FL 32224 USA. [Hansson, Oskar] Lund Univ, Dept Clin Sci, Clin Memory Res Unit, Malmo, Sweden. [Skoog, Ingmar] Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Neuropsychiat Epidemiol Res Unit, Gothenburg, Sweden. [Lambert, Jean-Charles] INSERM UMR 744, Lille, France. [Lambert, Jean-Charles] Univ Lille Nord de France, Lille, France. [Lambert, Jean-Charles] Inst Pasteur, Lille, France. [Launer, Lenore] NIA, Lab Epidemiol & Populat Sci, Intramural Res Program, Bethesda, MD 20892 USA. RP Chouraki, V (reprint author), Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA. EM vchourak@bu.edu RI lambert, jean-charles/F-8787-2013; Hansson, Oskar/A-7134-2013; Lambert, jean-charles/A-9553-2014; OI Hansson, Oskar/0000-0001-8467-7286; Lambert, jean-charles/0000-0003-0829-7817; Chouraki, Vincent/0000-0002-4698-1794; Seshadri, Sudha/0000-0001-6135-2622 FU National Heart, Lung and Blood Institute [N01-HC-25195]; National Institute of Neurological Disorders and Stroke [NS17950]; National Institute on Aging [AG08122, AG16495, AG033193]; National Institutes of Health (National Institute on Aging) [NO1-AG-4-2149, 5U01AG017155-09, 5U01AG019349-08]; National Institutes of Health; Fondation pour la Recherche Medicale; Caisse Nationale Maladie des Travailleurs Salaries; Direction Generale de la Sante; MGEN; Institut de la Longevite; Agence Francaise de Securite Sanitaire des Produits de Sante; Aquitaine and Bourgogne Regional Councils; Fondation de France; French Ministry of Research/National Institute of Health and Medical Research "Cohortes et collections de donnees biologiques" program; Eisai; CNRS; Nord Pas-de-Calais Regional Council; European Regional Development Fund; INSERM-DHOS-INCA [A08037ECS]; European Community's cNEUPRO programme [LSHM-CT-2007-037950]; Swedish Research Council; Swedish Brain Power; ALF; Torsten and Ragnar Soderberg Foundation; Hans-Gabriel & Alice Trolle-Wachtmeisters Foundation for Medical Research; State University of New York Research Foundation FX Funding support:; Framingham Heart Study: This work received support from the National Heart, Lung and Blood Institute's Framingham Heart Study (contract no. N01-HC-25195) and grants from the National Institute of Neurological Disorders and Stroke (NS17950) and the National Institute on Aging (AG08122, AG16495, and AG033193).; Honolulu Asia Aging Study: This work was supported by the National Institutes of Health (National Institute on Aging contract NO1-AG-4-2149, cooperative agreements 5U01AG017155-09 and 5U01AG019349-08, and the Intramural Research Program of the National Institutes of Health and with resources at the Veterans Affairs Pacific Islands Health Care System).; Three-City Study: The Three-City (3C) Study was performed as part of a collaboration among the Institut National de la Sante et de la Recherche Medicale (INSERM), the Victor Segalen-Bordeaux II University, and Sanofi-Synthelabo. The Fondation pour la Recherche Medicale funded the preparation and initiation of the study. The 3C Study was also funded by the Caisse Nationale Maladie des Travailleurs Salaries, Direction Generale de la Sante, MGEN, Institut de la Longevite, Agence Francaise de Securite Sanitaire des Produits de Sante, the Aquitaine and Bourgogne Regional Councils, Fondation de France, and the joint French Ministry of Research/National Institute of Health and Medical Research "Cohortes et collections de donnees biologiques" program. Lille Genopole received an unconditional grant from Eisai.; This work was additionally funded by the CNRS, the Nord Pas-de-Calais Regional Council, and the European Regional Development Fund, and grants from INSERM-DHOS-INCA (Project A08037ECS) and the European Community's cNEUPRO programme (contract LSHM-CT-2007-037950). Prospective Population Study of Women and Gerontological (PPSW) and Geriatric Population (H70) Studies: This work was supported by the Swedish Research Council, Swedish Brain Power, ALF funding for medical training and research, the Torsten and Ragnar Soderberg Foundation, Hans-Gabriel & Alice Trolle-Wachtmeisters Foundation for Medical Research, and State University of New York Research Foundation. NR 44 TC 13 Z9 14 U1 1 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1552-5260 EI 1552-5279 J9 ALZHEIMERS DEMENT JI Alzheimers. Dement. PD MAR PY 2015 VL 11 IS 3 BP 249 EP 257 DI 10.1016/j.jalz.2014.07.001 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA CF3RB UT WOS:000352465100002 PM 25217292 ER PT J AU Rosano, C Abebe, KZ Aizenstein, HJ Boudreau, R Jennings, JR Venkatraman, V Harris, TB Yaffe, K Satterfield, S Newman, AB AF Rosano, Caterina Abebe, Kaleab Z. Aizenstein, Howard J. Boudreau, Robert Jennings, J. Richard Venkatraman, Vijay Harris, Tamara B. Yaffe, Kristine Satterfield, Suzanne Newman, Anne B. CA Hlth ABC Study TI Longitudinal Systolic Blood Pressure Characteristics and Integrity of White Matter Tracts in a Cohort of Very Old Black and White Adults SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Article DE blood pressure; diffusion tensor imaging; hypertension; systolic blood pressure; white matter ID COGNITIVE FUNCTION; LATE-LIFE; RISK-FACTORS; FOLLOW-UP; BRAIN; LESIONS; HYPERINTENSITIES; HYPERTENSION; DISEASE; DEMENTIA AB BACKGROUND We sought to determine which systolic blood pressure (SBP) characteristics are associated with reduced brain integrity and whether these associations are stronger for white or gray matter. We hypothesized that exposure to higher and variable SBP will be associated with lower structural integrity of both gray and white matter. METHODS Neuroimaging, SBP, and cognition were obtained in 311 community-dwelling adults in 2006-2008 (average age = 83 years; 58% women; 40% black). Antihypertensive medications, SBP, and health-related factors were collected from 1997 to 1998 to time of neuroimaging. SBP values obtained from 1997 to 1998 to time of neuroimaging were used to compute mean; pulse pressure; coefficient of variation; and peak, load, and group-based trajectories. RESULTS Higher mean SBP was associated with lower white matter integrity in uncinate and superior lateral fasciculi bilaterally, independent of age, stroke history, antihypertensive medication use (odds ratio of having white matter hyperintensities greater than or equal to the median for 10 mm Hg of SBP = 10.4, 95% confidence interval = 10.2-10.6, P = 0.0001; standardized beta for fractional anisotropy = -13.54, SE = 4.58, P = 0.003). These neuroimaging markers attenuated the association between higher SBP and lower digit symbol substitution test. Results were similar for trajectories of SBP and stronger for those with previously higher and variable SBP even if SBP was normal at neuroimaging. Results were similar for those without stroke. Associations with gray matter measures were not significant. CONCLUSIONS If confirmed, these data suggest a history of higher and variable SBP for very old adults may be useful to alert clinicians to potential lower integrity in selected tracts, whereas cross-sectional SBP measurements may obscure the risk of underlying white matter hyperintensities. Whether lowering and/or stabilizing SBP levels in very old adults without a remarkable cardiovascular history would have neuroprotective effects and reduce dementia risk needs further study. C1 [Rosano, Caterina; Boudreau, Robert; Newman, Anne B.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Abebe, Kaleab Z.] Univ Pittsburgh, Div Gen Internal Med, Pittsburgh, PA 15261 USA. [Aizenstein, Howard J.; Jennings, J. Richard] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15261 USA. [Venkatraman, Vijay] Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA 15261 USA. [Harris, Tamara B.] NIA, NIH, Bethesda, MD 20892 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Satterfield, Suzanne] Univ Tennessee, Hlth Sci Ctr, Dept Prevent Med, Memphis, TN USA. RP Rosano, C (reprint author), Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. EM rosanoc@edc.pitt.edu RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 FU National Institute on Aging (NIA) [N01 AG62101, N01 AG62103, N01 AG62106]; NIA [R01 AG29232, R01 AG037451, R01 AG028050]; National Institute of Nursing Research [NR012459]; Intramural Research Program of the NIA, National Institutes of Health FX We would like to acknowledge Lewis Lipsitz for his expert advice, Zachary Marcum with assistance with the medication inventory, and Amy J. Markowitz, JD, for her assistance in editing of the manuscript. This work was supported by National Institute on Aging (NIA) contracts N01 AG62101, N01 AG62103, and N01 AG62106; NIA grants R01 AG29232, R01 AG037451, and R01 AG028050; and National Institute of Nursing Research grant NR012459; and in part by the Intramural Research Program of the NIA, National Institutes of Health. NR 38 TC 5 Z9 5 U1 4 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0895-7061 EI 1941-7225 J9 AM J HYPERTENS JI Am. J. Hypertens. PD MAR PY 2015 VL 28 IS 3 BP 326 EP 334 DI 10.1093/ajh/hpu134 PG 9 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA CE9ZZ UT WOS:000352203600006 PM 25159083 ER PT J AU Chetty, A Bennett, M Dang, L Nakamura, D Cao, GJ Mujahid, S Volpe, M Herman, I Becerra, SP Nielsen, HC AF Chetty, Anne Bennett, Michelle Dang, Linh Nakamura, Daisy Cao, Gong-jie Mujahid, Sana Volpe, MaryAnn Herman, Ira Becerra, S. Patricia Nielsen, Heber C. TI Pigment Epithelium-Derived Factor Mediates Impaired Lung Vascular Development in Neonatal Hyperoxia SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article DE angiogenesis; pigment epithelium-derived factor; bronchopulmonary dysplasia; vascular endothelial growth factor ID ENDOTHELIAL GROWTH-FACTOR; DEVELOPING RAT LUNG; BRONCHOPULMONARY DYSPLASIA; PREMATURE BABOONS; PRETERM LAMBS; MURINE LUNG; II CELLS; PEDF; INJURY; ALVEOLARIZATION AB Bronchopulmonary dysplasia is a chronic lung disease of preterm infants characterized by arrested microvascularization and alveolarization. Studies show the importance of proangiogenic factors for alveolarization, but the importance of antiangiogenic factors is unknown. We proposed that hyperoxia increases the potent angiostatin, pigment epithelium-derived factor (PEDF), in neonatal lungs, inhibiting alveolarization and microvascularization. Wild-type (WT) and PEDF-/- mice were exposed to room air (RA) or 0.9 fraction of inspired oxygen from Postnatal Day 5 to 13. PEDF protein was increased in hyperoxic lungs compared with RA-exposed lungs (P < 0.05). In situ hybridization and immunofluorescence identified PEDF production primarily in alveolar epithelium. Hyperoxia reduced alveolarization in WT mice (P < 0.05) but not in PEDF-/- mice. WT hyperoxic mice had fewer platelet endothelial cell adhesion molecule (PECAM)-positive cells per alveolus (1.4 +/- 0.4) than RA-exposed mice (4.3 +/- 0.3; P < 0.05); this reduction was absent in hyperoxic PEDF(-/-)mice. The interactive regulation of lung microvascularization by vascular endothelial growth factor and PEDF was studied in vitro using MFLM-91U cells, a fetal mouse lung endothelial cell line. Vascular endothelial growth factor stimulation of proliferation, migration, and capillary tube formation was inhibited by PEDF. MFLM-91U cells exposed to conditioned medium (CM) from E17 fetal mouse lung type II (T2) cells cultured in 0.9 fraction of inspired oxygen formed fewer capillary tubes than CM from T2 cells cultured in RA (hyperoxia CM, 51 +/- 10% of RACM, P < 0.05), an effect abolished by PEDF antibody. We conclude that PEDF mediates reduced vasculogenesis and alveolarization in neonatal hyperoxia. Bronchopulmonary dysplasia likely results from an altered balance between pro-and antiangiogenic factors. C1 [Chetty, Anne; Bennett, Michelle; Dang, Linh; Cao, Gong-jie; Volpe, MaryAnn; Nielsen, Heber C.] Tufts Med Ctr, Dept Pediat, Boston, MA 02111 USA. [Nakamura, Daisy; Mujahid, Sana; Herman, Ira; Nielsen, Heber C.] Tufts Med Ctr, Sackler Sch Grad Biomed Sci, Boston, MA 02111 USA. [Becerra, S. Patricia] NEI, NIH, Bethesda, MD 20892 USA. RP Nielsen, HC (reprint author), Tufts Med Ctr, Dept Pediat, 800 Washington St, Boston, MA 02111 USA. EM heber.nielsen@tufts.edu OI Nielsen, Heber/0000-0002-9382-0539 FU National Institutes of Health [RO1 HL037930, RO1 HL085648, R21 HL 097231]; Peabody Foundation FX This work was supported by National Institutes of Health grants RO1 HL037930, RO1 HL085648, and R21 HL 097231, and by a grant from the Peabody Foundation. NR 40 TC 4 Z9 4 U1 0 U2 1 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1044-1549 EI 1535-4989 J9 AM J RESP CELL MOL JI Am. J. Respir. Cell Mol. Biol. PD MAR PY 2015 VL 52 IS 3 BP 295 EP 303 DI 10.1165/rcmb.2013-0229OC PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA CF0BS UT WOS:000352208100003 PM 25054647 ER PT J AU Alves, G Yu, YK AF Alves, Gelio Yu, Yi-Kuo TI Mass spectrometry-based protein identification with accurate statistical significance assignment SO BIOINFORMATICS LA English DT Article ID PEPTIDE IDENTIFICATION; SHOTGUN PROTEOMICS; DATABASE SEARCHES; SCORING SCHEMES; PROBABILITY; CONFIDENCE; INFERENCE; SPECTRA; VALUES; TESTS AB Motivation: Assigning statistical significance accurately has become increasingly important as metadata of many types, often assembled in hierarchies, are constructed and combined for further biological analyses. Statistical inaccuracy of metadata at any level may propagate to downstream analyses, undermining the validity of scientific conclusions thus drawn. From the perspective of mass spectrometry-based proteomics, even though accurate statistics for peptide identification can now be achieved, accurate protein level statistics remain challenging. Results: We have constructed a protein ID method that combines peptide evidences of a candidate protein based on a rigorous formula derived earlier; in this formula the database P-value of every peptide is weighted, prior to the final combination, according to the number of proteins it maps to. We have also shown that this protein ID method provides accurate protein level E-value, eliminating the need of using empirical post-processing methods for type-I error control. Using a known protein mixture, we find that this protein ID method, when combined with the Soric formula, yields accurate values for the proportion of false discoveries. In terms of retrieval efficacy, the results from our method are comparable with other methods tested. C1 [Alves, Gelio; Yu, Yi-Kuo] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Yu, YK (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM yyu@ncbi.nlm.nih.gov FU Intramural Research Program of the National Library of Medicine at the National Institutes of Health FX This work was supported by the Intramural Research Program of the National Library of Medicine at the National Institutes of Health. NR 39 TC 4 Z9 4 U1 2 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 EI 1460-2059 J9 BIOINFORMATICS JI Bioinformatics PD MAR 1 PY 2015 VL 31 IS 5 BP 699 EP 706 DI 10.1093/bioinformatics/btu717 PG 8 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA CF0XT UT WOS:000352268500011 PM 25362092 ER PT J AU Waldmann, TA AF Waldmann, Thomas A. TI The Shared and Contrasting Roles of IL2 and IL15 in the Life and Death of Normal and Neoplastic Lymphocytes: Implications for Cancer Therapy SO CANCER IMMUNOLOGY RESEARCH LA English DT Article ID CD8(+) T-CELLS; INTERLEUKIN-2-RECEPTOR GAMMA-CHAIN; IL-15 TRANS-PRESENTATION; LOW-DOSE INTERLEUKIN-2; HUMANIZED ANTI-TAC; ANTITUMOR-ACTIVITY; IN-VIVO; MONOCLONAL-ANTIBODY; NK CELLS; ADOPTIVE IMMUNOTHERAPY AB IL2 and IL15, members of the 4 alpha-helix bundle family of cytokines, play pivotal roles in the control of the life and death of lymphocytes. Although their heterotrimeric receptors have two receptor subunits in common, these two cytokines have contrasting roles in adaptive immune responses. The unique role of IL2 through maintenance of fitness of regulatory T cells and activation-induced cell death is the elimination of self-reactive T cells to prevent autoimmunity. In contrast with IL2, IL15 is dedicated to the prolonged maintenance of memory T-cell responses to invading pathogens. Blockade of IL2 and IL15 using monoclonal antibodies has been reported to be of value in the treatment of patients with leukemia, autoimmune disorders, and in the prevention of allograft rejection. IL2 has been approved by the FDA for the treatment of patients with malignant renal cell cancer and metastatic malignant melanoma. Clinical trials involving recombinant human IL15 given by bolus infusions have been completed, and studies assessing subcutaneous and continuous intravenous infusions are under way in patients with metastatic malignancy. Furthermore, clinical trials are being initiated that employ the combination of IL15 with IL15R alpha(+/-) IgFc. (C) 2015 AACR. C1 [Waldmann, Thomas A.] NCI, Lymphoid Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Waldmann, TA (reprint author), NCI, NIH, 10 Ctr Dr,Bldg 10,Room 4N115, Bethesda, MD 20892 USA. EM tawald@helix.nih.gov FU Intramural Research Program of the Center for Cancer Research, NCI, NIH FX This research was supported by the Intramural Research Program of the Center for Cancer Research, NCI, NIH. NR 108 TC 17 Z9 18 U1 1 U2 8 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 MAR PY 2015 VL 3 IS 3 BP 219 EP 227 DI 10.1158/2326-6066.CIR-15-0009 PG 9 WC Oncology; Immunology SC Oncology; Immunology GA CF2LP UT WOS:000352379100001 PM 25736261 ER PT J AU Lewis-Morrarty, E Degnan, KA Chronis-Tuscano, A Pine, DS Henderson, HA Fox, NA AF Lewis-Morrarty, Erin Degnan, Kathryn A. Chronis-Tuscano, Andrea Pine, Daniel S. Henderson, Heather A. Fox, Nathan A. TI Infant Attachment Security and Early Childhood Behavioral Inhibition Interact to Predict Adolescent Social Anxiety Symptoms SO CHILD DEVELOPMENT LA English DT Article ID INTERNALIZING SYMPTOMS; INSECURE ATTACHMENT; TEMPERAMENT; DISORDERS; CHILDREN; PRESCHOOL; RISK; LIFE; CLASSIFICATION; ORGANIZATION AB Insecure attachment and behavioral inhibition (BI) increase risk for internalizing problems, but few longitudinal studies have examined their interaction in predicting adolescent anxiety. This study included 165 adolescents (ages 14-17years) selected based on their reactivity to novelty at 4months. Infant attachment was assessed with the Strange Situation. Multimethod BI assessments were conducted across childhood. Adolescents and their parents independently reported on anxiety. The interaction of attachment and BI significantly predicted adolescent anxiety symptoms, such that BI and anxiety were only associated among adolescents with histories of insecure attachment. Exploratory analyses revealed that this effect was driven by insecure-resistant attachment and that the association between BI and social anxiety was significant only for insecure males. Clinical implications are discussed. C1 [Lewis-Morrarty, Erin; Degnan, Kathryn A.; Chronis-Tuscano, Andrea; Fox, Nathan A.] Univ Maryland, College Pk, MD 20742 USA. [Pine, Daniel S.] NIMH, Bethesda, MD USA. [Henderson, Heather A.] Univ Waterloo, Waterloo, ON N2L 3G1, Canada. RP Lewis-Morrarty, E (reprint author), Univ Maryland, Dept Psychol, 2109H Biol Psychol Bldg, College Pk, MD 20742 USA. EM morrarty@umd.edu FU National Institute of Mental Health [R01MH07454]; National Institute of Child Health and Human Development [R37HD17899] FX This research was supported by National Institute of Mental Health Grant R01MH07454 and National Institute of Child Health and Human Development Grant R37HD17899 awarded to Nathan A. Fox. NR 71 TC 6 Z9 6 U1 10 U2 37 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-3920 EI 1467-8624 J9 CHILD DEV JI Child Dev. PD MAR-APR PY 2015 VL 86 IS 2 BP 598 EP 613 DI 10.1111/cdev.12336 PG 16 WC Psychology, Educational; Psychology, Developmental SC Psychology GA CE8OX UT WOS:000352104000017 PM 25522059 ER PT J AU Hamo, CE Heitner, JF Pfeffer, MA Kim, HY Kenwood, CT Assmann, SF Solomon, SD Boineau, R Fleg, JL Spertus, JA Lewis, EF AF Hamo, Carine E. Heitner, John F. Pfeffer, Marc A. Kim, Hae-Young Kenwood, Christopher T. Assmann, Susan F. Solomon, Scott D. Boineau, Robin Fleg, Jerome L. Spertus, John A. Lewis, Eldrin F. TI Baseline Distribution of Participants With Depression and Impaired Quality of Life in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial SO CIRCULATION-HEART FAILURE LA English DT Article DE depression; heart failure; quality of life ID EJECTION FRACTION; HEALTH-STATUS; GENDER-DIFFERENCES; CLINICAL-OUTCOMES; MAJOR DEPRESSION; ADULT-POPULATION; RISK; QUESTIONNAIRE; PREVALENCE; DISEASE AB Background-Previous studies have demonstrated the psychosocial effect of heart failure in patients with reduced ejection fraction. However, the effects on patients with preserved ejection fraction have not yet been elucidated. This study aimed to determine the baseline characteristics of participants with heart failure with preserved ejection fraction as it relates to impaired quality of life (QOL) and depression, identify predictors of poor QOL and depression, and determine the correlation between QOL and depression. Methods and Results-Among patients enrolled in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial (TOPCAT), 3400 patients completed the Kansas City Cardiomyopathy Questionnaire, 3395 patients completed European QOL 5D Visual Analog Scale, and 1431 patients in United States and Canada completed the Patient Health Questionnaire-9. The mean summary score on the Kansas City Cardiomyopathy Questionnaire was 54.8, and on European QOL 5D Visual Analog Scale, it was 60.3; 27% of patients had moderate to severe depression. Factors associated with better Kansas City Cardiomyopathy Questionnaire and European QOL 5D Visual Analog Scale via multiple logistic regression analysis were American region, older age, no history of angina pectoris or asthma, no use of hypoglycemic agent, more activity level, and lower New York Heart Association class. Factors associated with depression via multiple logistic regression analysis included younger age, female sex, comorbid angina, chronic obstructive pulmonary disease, use of a hypoglycemic agent, lower activity level, higher New York Heart Association class, and selective serotonin reuptake inhibitor use. There were significant correlations between each of the QOL scores and depression. Conclusions-Patients with heart failure with preserved ejection fraction, who were younger had higher New York Heart Association class or comorbid angina pectoris, had lower activity levels, lived in Eastern Europe or were taking hypoglycemic agents, were more likely to have impaired QOL and depression. C1 [Hamo, Carine E.] Stony Brook Univ Hosp, Dept Med, Stony Brook, NY USA. [Heitner, John F.] New York Methodist Hosp, Div Cardiol, Brooklyn, NY 11215 USA. [Pfeffer, Marc A.; Solomon, Scott D.; Lewis, Eldrin F.] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. [Kim, Hae-Young; Kenwood, Christopher T.; Assmann, Susan F.] New England Res Inst, Watertown, MA 02172 USA. [Boineau, Robin; Fleg, Jerome L.] NHLBI, Div Cardiol, Bethesda, MD 20892 USA. [Spertus, John A.] Univ Missouri Kansas City, St Lukes Mid Amer Heart Inst, Kansas City, MO USA. RP Heitner, JF (reprint author), New York Methodist Hosp, 506 6th St, Brooklyn, NY 11215 USA. EM jfh9003@nyp.org FU Aastrom; Abbott Vascular; Amgen; Cerenis; Concert; Daiichi Sankyo; Fibrogen; Genzyme; GlaxoSmithKline; Hamilton Health Sciences; Medtronic; Merck; Novo Nordisk; Roche; Salix; Sanderling; Sanofi Aventis; Serono; Servier; Teva; New England Research Institute via National Institutes of Health; Celladon; Novartis; Sanofi-Aventis; National Heart, Lung, and Blood Institute; Bayer FX Dr Pfeffer has received consulting fees from Aastrom, Abbott Vascular, Amgen, Cerenis, Concert, Daiichi Sankyo, Fibrogen, Genzyme, GlaxoSmithKline, Hamilton Health Sciences, Medtronic, Merck, Novo Nordisk, Roche, Salix, Sanderling, Sanofi Aventis, Serono, Servier, and Teva, as well as research grants from New England Research Institute via subcontract from the National Institutes of Health, Amgen, Celladon, Novartis, and Sanofi-Aventis. The Brigham and Women's Hospital has patents for the use of inhibitors of the renin-angiotensin system in selected survivors of myocardial infarction with Novartis Pharmaceuticals on which Dr Pfeffer is a co-inventor. His share of the licensing agreement is irrevocably transferred to charity. Dr Assmann reports a contract between the National Heart, Lung, and Blood Institute and her employer, New England Research Institutes. Dr Lewis has received research grants from the National Heart, Lung, and Blood Institute, Novartis, and Sanofi Aventis. Dr Solomon has received consulting fees from Novartis and Bayer and research grants from the National Heart, Lung, and Blood Institute. The other authors report no conflicts. NR 39 TC 4 Z9 4 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1941-3289 EI 1941-3297 J9 CIRC-HEART FAIL JI Circ.-Heart Fail. PD MAR PY 2015 VL 8 IS 2 BP 268 EP + DI 10.1161/CIRCHEARTFAILURE.114.001838 PG 22 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CF0JL UT WOS:000352229500007 PM 25648577 ER PT J AU Teicher, BA Anderson, KC AF Teicher, Beverly A. Anderson, Kenneth C. TI CCR 20th Anniversary Commentary: In the Beginning, There Was PS-341 SO CLINICAL CANCER RESEARCH LA English DT Editorial Material ID PROTEASOME INHIBITOR PS-341; HEMATOLOGIC MALIGNANCIES; KAPPA-B; MYELOMA; ACTIVATION; MLN9708; CELLS AB Proteasome inhibitors have a 20-year history in cancer therapy. The first proteasome inhibitor, bortezomib, a breakthrough treatment for multiple myeloma, moved rapidly through development from the bench in 1994 to first FDA approval in 2003. Clinical Cancer Research has chronicled the development of proteasome inhibitors with publication of reports on bortezo (MLN9708). (C) 2015 AACR. C1 [Teicher, Beverly A.] NCI, Div Canc Treatment & Diag, Rockville, MD USA. [Anderson, Kenneth C.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Teicher, BA (reprint author), NCI, NIH, 9609 Med Ctr Dr,RM 4-W602,MSC 9735, Bethesda, MD 20892 USA. EM Beverly.Teicher@nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 11 TC 6 Z9 6 U1 0 U2 1 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 MAR PY 2015 VL 21 IS 5 BP 939 EP 941 DI 10.1158/1078-0432.CCR-14-2549 PG 3 WC Oncology SC Oncology GA CE6XZ UT WOS:000351982800001 PM 25733705 ER PT J AU Allen, CT Conley, B Sunwoo, JB Van Waes, C AF Allen, Clint T. Conley, Barbara Sunwoo, John B. Van Waes, Carter TI CCR 20th Anniversary Commentary: Preclinical Study of Proteasome Inhibitor Bortezomib in Head and Neck Cancer SO CLINICAL CANCER RESEARCH LA English DT Editorial Material ID FACTOR-KAPPA-B; SQUAMOUS-CELL CARCINOMA; TARGET AB In a study published in the May 1, 2001, issue of Clinical Cancer Research, Sunwoo and colleagues provided evidence for proteasome inhibition of NF-kappa B and tumorigenesis, supporting early-phase clinical trials in solid malignancies of the upper aerodigestive tract. Subsequent clinical studies uncovered a dichotomy of responses in patients with hematopoietic and solid malignancies, and the mechanisms of resistance. (C) 2015 AACR. C1 [Allen, Clint T.; Van Waes, Carter] NIDCD, Head & Neck Surg Branch, NIH, Bethesda, MD 20892 USA. [Conley, Barbara] NCI, Canc Diag Program, NIH, Bethesda, MD 20892 USA. [Sunwoo, John B.] Stanford Univ, Sch Med, Dept Otolaryngol, Div Head & Neck Surg, Stanford, CA 94305 USA. RP Van Waes, C (reprint author), NIDCD, NIH, CRC 4732,10 Ctr Dr, Bethesda, MD 20892 USA. EM vanwaesc@nidcd.nih.gov FU Intramural NIH HHS [ZIA DC000016-21] NR 10 TC 2 Z9 2 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 MAR PY 2015 VL 21 IS 5 BP 942 EP 943 DI 10.1158/1078-0432.CCR-14-2550 PG 2 WC Oncology SC Oncology GA CE6XZ UT WOS:000351982800002 PM 25733706 ER PT J AU Robbins, PF Kassim, SH Tran, TLN Crystal, JS Morgan, RA Feldman, SA Yang, JC Dudley, ME Wunderlich, JR Sherry, RM Kammula, US Hughes, MS Restifo, NP Raffeld, M Lee, CCR Li, YF El-Gamil, M Rosenberg, SA AF Robbins, Paul F. Kassim, Sadik H. Tran, Thai L. N. Crystal, Jessica S. Morgan, Richard A. Feldman, Steven A. Yang, James C. Dudley, Mark E. Wunderlich, John R. Sherry, Richard M. Kammula, Udai S. Hughes, Marybeth S. Restifo, Nicholas P. Raffeld, Mark Lee, Chyi-Chia R. Li, Yong F. El-Gamil, Mona Rosenberg, Steven A. TI A Pilot Trial Using Lymphocytes Genetically Engineered with an NY-ESO-1-Reactive T-cell Receptor: Long-term Follow-up and Correlates with Response SO CLINICAL CANCER RESEARCH LA English DT Article ID METASTATIC MELANOMA; CANCER REGRESSION; AUTOLOGOUS TUMOR; GENE-THERAPY; CD4+T CELLS; ANTIGEN; IMMUNOTHERAPY; NY-ESO-1; EXPRESSION; ANTIBODY AB Purpose: Although adoptive cell therapy can be highly effective for the treatment of patients with melanoma, the application of this approach to the treatment of other solid tumors has been limited. The observation that the cancer germline (CG) antigen NY-ESO-1 is expressed in 70% to 80% and in approximately 25% of patients with synovial cell sarcoma and melanoma, respectively, prompted us to perform this first-in-man clinical trial using the adoptive transfer of autologous peripheral blood mononuclear cells that were retrovirally transduced with an NY-ESO-1-reactive T-cell receptor (TCR) to heavily pretreated patients bearing these metastatic cancers. Experimental Design: HLA-*0201 patients with metastatic synovial cell sarcoma or melanoma refractory to standard treatments and whose cancers expressed NY-ESO-1 received autologous TCR-transduced T cells following a lymphodepleting preparative chemotherapy. Response rates using Response Evaluation Criteria in Solid Tumors (RECIST), as well as immunologic correlates of response, are presented in this report. Results: Eleven of 18 patients with NY-ESO-1(+) synovial cell sarcomas (61%) and 11 of 20 patients with NY-ESO-1(+) melanomas (55%) who received autologous T cells transduced with an NY-ESO-1-reactive TCR demonstrated objective clinical responses. The estimated overall 3- and 5-year survival rates for patients with synovial cell sarcoma were 38% and 14%, respectively, whereas the corresponding estimated survival rates for patients with melanoma were both 33%. Conclusions: The adoptive transfer of autologous T cells transduced with a retrovirus encoding a TCR against an HLA-A*0201 restricted NY-ESO-1 epitope can be an effective therapy for some patients bearing synovial cell sarcomas and melanomas that are refractory to other treatments. C1 [Robbins, Paul F.; Kassim, Sadik H.; Crystal, Jessica S.; Morgan, Richard A.; Feldman, Steven A.; Yang, James C.; Dudley, Mark E.; Wunderlich, John R.; Sherry, Richard M.; Kammula, Udai S.; Hughes, Marybeth S.; Restifo, Nicholas P.; Li, Yong F.; El-Gamil, Mona; Rosenberg, Steven A.] NCI, NIH, Surg Branch, Bethesda, MD 20892 USA. [Tran, Thai L. N.] Univ Calif Irvine, Irvine, CA USA. [Raffeld, Mark; Lee, Chyi-Chia R.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Robbins, PF (reprint author), NCI, NIH, Surg Branch, CRC 3-5744, Bethesda, MD 20892 USA. EM Paul_Robbins@nih.gov RI Lee, Chyi-Chia/I-1938-2013; OI Lee, Chyi-Chia/0000-0002-5306-7781; Restifo, Nicholas P./0000-0003-4229-4580 FU NIH; Kite Pharma; Milstein Family Foundation FX This work was supported by NIH intramural funds along with funds from Kite Pharma and the Milstein Family Foundation. NR 28 TC 81 Z9 83 U1 2 U2 9 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 MAR PY 2015 VL 21 IS 5 BP 1019 EP 1027 DI 10.1158/1078-0432.CCR-14-2708 PG 9 WC Oncology SC Oncology GA CE6XZ UT WOS:000351982800014 PM 25538264 ER PT J AU Himes, SK Dukes, KA Tripp, T Petersen, JM Raffo, C Burd, L Odendaal, H Elliott, AJ Hereld, D Signore, C Willinger, M Huestis, MA AF Himes, Sarah K. Dukes, Kimberly A. Tripp, Tara Petersen, Julie M. Raffo, Cheri Burd, Larry Odendaal, Hein Elliott, Amy J. Hereld, Dale Signore, Caroline Willinger, Marian Huestis, Marilyn A. CA Prenatal Alcohol SIDS Stillbirth TI Clinical Sensitivity and Specificity of Meconium Fatty Acid Ethyl Ester, Ethyl Glucuronide, and Ethyl Sulfate for Detecting Maternal Drinking during Pregnancy SO CLINICAL CHEMISTRY LA English DT Article ID FETAL ALCOHOL SYNDROME; PRENATAL EXPOSURE; RISK-FACTORS; NEUROBEHAVIORAL PROFILE; LIQUID-CHROMATOGRAPHY; ETHANOL EXPOSURE; BIOMARKERS; CONSUMPTION; VALIDATION; OUTCOMES AB BACKGROUND: We investigated agreement between self-reported prenatal alcohol exposure (PAE) and objective meconium alcohol markers to determine the optimal meconium marker and threshold for identifying PAE. METHODS: Meconium fatty acid ethyl esters (FAEE), ethyl glucuronide (EtG), and ethyl sulfate (EtS) were quantified by LC-MS/MS in 0.1 g meconium from infants of Safe Passage Study participants. Detailed PAE information was collected from women with a validated timeline follow-back interview. Because meconium formation begins during weeks 12-20, maternal self-reported drinking at or beyond 19 weeks was our exposure variable. RESULTS: Of 107 women, 33 reported no alcohol consumption in pregnancy, 16 stopped drinking by week 19, and 58 drank beyond 19 weeks (including 45 third-trimester drinkers). There was moderate to substantial agreement between self-reported PAE at >= 19 weeks and meconium EtG >= 30 ng/g (kappa = 0.57, 95% CI 0.41-0.73). This biomarker and associated cutoff was superior to a 7 FAEE sum >= 2 nmol/g and all other individual and combination marker cutoffs. With meconium EtG >= 30 ng/g as the gold standard condition and maternal self-report at >= 19 weeks' gestation as the test condition, 82% clinical sensitivity (95% CI 71.6-92.0) and 75% specificity (95% CI 63.2-86.8) were observed. A significant dose-concentration relationship between self-reported drinks per drinking day and meconium EtG >= 30 ng/g also was observed (all P < 0.01). CONCLUSIONS: Maternal alcohol consumption at >= 19 weeks was better represented by meconium EtG >= 30 ng/g than currently used FAEE cutoffs. (C) 2014 American Association for Clinical Chemistry C1 [Himes, Sarah K.; Huestis, Marilyn A.] NIDA, Chem & Drug Metab Sect, IRP, NIH, Baltimore, MD 21224 USA. [Dukes, Kimberly A.; Tripp, Tara; Petersen, Julie M.; Raffo, Cheri] DM STAT Inc, Malden, MA USA. [Burd, Larry] Univ N Dakota, Sch Med, Dept Pediat, Grand Forks, ND 58202 USA. [Odendaal, Hein] Univ Stellenbosch, Dept Obstet & Gynecol, Fac Med & Hlth Sci, ZA-7505 Tygerberg, South Africa. [Elliott, Amy J.] Ctr Hlth Outcomes & Prevent Res, Sanford Res, Sioux Falls, SD USA. [Hereld, Dale] NIAAA, Div Metab & Hlth Effects, NIH, Rockville, MD 20852 USA. [Signore, Caroline; Willinger, Marian] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Huestis, MA (reprint author), NIDA, Chem & Drug Metab Sect, IRP, NIH, 251 Bayview Blvd,Suite 200,Rm 05A721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU National Institute on Alcohol Abuse and Alcoholism; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute on Deafness and Other Communication Disorders [U01 HD055154, U01 HD045935, U01 HD055155, U01 HD045991, U01 AA016501]; Intramural Research Program, National Institute on Drug Abuse, NIH FX The PASS Research Network is supported by the National Institute on Alcohol Abuse and Alcoholism, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and National Institute on Deafness and Other Communication Disorders through the Cooperative Agreements (U01 HD055154, U01 HD045935, U01 HD055155, U01 HD045991 and U01 AA016501). Funding also was provided by the Intramural Research Program, National Institute on Drug Abuse, NIH. L. Burd, North Dakota Department of Health. NR 39 TC 17 Z9 17 U1 2 U2 10 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 EI 1530-8561 J9 CLIN CHEM JI Clin. Chem. PD MAR PY 2015 VL 61 IS 3 BP 523 EP 532 DI 10.1373/clinchem.2014.233718 PG 10 WC Medical Laboratory Technology SC Medical Laboratory Technology GA CE9JX UT WOS:000352161300014 PM 25595440 ER PT J AU Stolze, BR Gounden, V Gu, JG Abel, BS Merke, DP Skarulis, MC Soldin, SJ AF Stolze, Brian R. Gounden, Verena Gu, Jianghong Abel, Brent S. Merke, Deborah P. Skarulis, Monica C. Soldin, Steven J. TI Use of Micro-HPLC-MS/MS Method to Assess Diurnal Effects on Steroid Hormones SO CLINICAL CHEMISTRY LA English DT Letter ID REFERENCE INTERVALS; CALIPER C1 [Stolze, Brian R.; Gounden, Verena; Gu, Jianghong; Soldin, Steven J.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Abel, Brent S.; Skarulis, Monica C.] NIDDK, NIH, Bethesda, MD 20892 USA. [Merke, Deborah P.] Ctr Clin, Bethesda, MD USA. [Merke, Deborah P.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Soldin, Steven J.] Georgetown Univ, Dept Med, Washington, DC USA. RP Soldin, SJ (reprint author), Dept Lab Med, Room 2C306 NIH Bldg 10 9000 Rockville Pike, Bethesda, MD 20892 USA. EM steven.soldin@nih.gov NR 5 TC 2 Z9 2 U1 2 U2 4 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 EI 1530-8561 J9 CLIN CHEM JI Clin. Chem. PD MAR PY 2015 VL 61 IS 3 BP 556 EP 558 DI 10.1373/clinchem.2014.232546 PG 4 WC Medical Laboratory Technology SC Medical Laboratory Technology GA CE9JX UT WOS:000352161300018 PM 25518857 ER PT J AU Shockley, KR AF Shockley, Keith R. TI Quantitative high-throughput screening data analysis: challenges and recent advances SO DRUG DISCOVERY TODAY LA English DT Review ID NONLINEAR-REGRESSION MODELS; HILL EQUATION; TOXICOLOGICAL KNOWLEDGE; PREDICTIVE MODELS; DRUG-SENSITIVITY; PARAMETERS; CHEMICALS; DISCOVERY; TOXICITY; HTS AB In vitro HTS holds much potential to advance drug discovery and provide cell-based alternatives for toxicity testing. In quantitative HTS, concentration-response data can be generated simultaneously for thousands of different compounds and mixtures. However, nonlinear modeling in these multiple-concentration assays presents important statistical challenges that are not problematic for linear models. The uncertainty of parameter estimates obtained from the widely used Hill equation model can be extremely large when using standard designs. Failure to properly consider standard errors of these parameter estimates would greatly hinder chemical genomics and toxicity testing efforts. In this light, optimal study designs should be developed to improve nonlinear parameter estimation; or alternative approaches with reliable performance characteristics should be used to describe concentration-response profiles. C1 NIEHS, Biostat & Computat Biol Branch, NIH, Res Triangle Pk, NC 27709 USA. RP Shockley, KR (reprint author), NIEHS, Biostat & Computat Biol Branch, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM shockleykr@niehs.nih.gov FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [ZIA E5102865] FX The author thanks Dr Grace Kissling (Biostatistics Branch, NIEHS), Dr Shyamal Peddada (Biostatistics Branch, NIEHS), Dr Raymond Tice (Biomolecular Screening Branch, NIEHS), Dr David Umbach (Biostatistics Branch, NIEHS) and Dr Clare Weinberg (Biostatistics Branch, NIEHS) for helpful comments. This work was supported (in part) by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (ZIA E5102865). NR 30 TC 3 Z9 4 U1 6 U2 15 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1359-6446 EI 1878-5832 J9 DRUG DISCOV TODAY JI Drug Discov. Today PD MAR PY 2015 VL 20 IS 3 BP 296 EP 300 DI 10.1016/j.drudis.2014.10.005 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CF1TV UT WOS:000352331700003 PM 25449657 ER PT J AU Fan, XM Chen, P Jiang, YM Wang, Y Tan, HS Zeng, H Wang, YT Qu, AJ Gonzalez, FJ Huang, M Bi, HC AF Fan, Xiaomei Chen, Pan Jiang, Yiming Wang, Ying Tan, Huasen Zeng, Hang Wang, Yongtao Qu, Aijuan Gonzalez, Frank J. Huang, Min Bi, Huichang TI Therapeutic Efficacy of Wuzhi Tablet (Schisandra sphenanthera Extract) on Acetaminophen-Induced Hepatotoxicity through a Mechanism Distinct from N-Acetylcysteine SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID INDUCED LIVER-INJURY; OXIDATIVE STRESS; TISSUE-REPAIR; REGENERATION; MICE; FAILURE; INHIBITION; PROTECTION; CHINENSIS; TOXICITY AB Acetaminophen (APAP) hepatotoxicity is the most common cause of drug-induced liver injury and N-acetylcysteine (NAC) is the primary antidote of APAP poisoning. Wuzhi tablet (WZ), the active constituents well identified and quantified, is a preparation of an ethanol extract of Schisandra sphenanthera and exerts a protective effect toward APAP-induced hepatotoxicity in mice. However, the clinical use of WZ to rescue APAP-induced acute liver injury and the mechanisms involved in the therapeutic effect of WZ remain unclear. Therefore, the effect of WZ on APAP hepatotoxicity was compared with NAC in mice, and molecular pathways contributing to its therapeutic action were investigated. Administration ofWZ 4 hours after APAP treatment significantly attenuated APAP hepatotoxicity and exerted much better therapeutic effect than NAC, as revealed by morphologic, histologic, and biochemical assessments. Both WZ and NAC prevented APAP-induced c-Jun N-terminal protein kinase activation and mitochondrial glutathione depletion in livers. The protein expression of nuclear factor erythroid 2-related factor 2 target genes including Gclc, Gclm, Ho-1, and Nqo1 was increased by WZ administration. Furthermore, p53 and p21 levels were upregulated upon APAP exposure, which were completely reversed by postdosing of WZ 4 hours after APAP treatment over 48 hours. In comparison with NAC, WZ significantly increased the expression of cyclin D1, cyclin D-dependent kinase 4, proliferating cell nuclear antigen, and augmenter of liver regeneration in APAP-injured livers. This study demonstrated that WZ possessed a therapeutic efficacy against APAP-induced liver injury by inhibiting oxidative stress and stimulating a regenerative response after liver injury. ThusWZ may represent a new therapy for APAP-induced acute liver injury. C1 [Fan, Xiaomei; Jiang, Yiming; Wang, Ying; Tan, Huasen; Zeng, Hang; Wang, Yongtao; Huang, Min; Bi, Huichang] Sun Yat Sen Univ, Sch Pharmaceut Sci, Guangzhou 510006, Guangdong, Peoples R China. [Chen, Pan] Sun Yat Sen Univ, Affiliated Hosp 1, Guangzhou 510006, Guangdong, Peoples R China. [Qu, Aijuan; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Bi, HC (reprint author), Sun Yat Sen Univ, Sch Pharmaceut Sci, 132 Waihuandong Rd, Guangzhou 510006, Guangdong, Peoples R China. EM bihchang@mail.sysu.edu.cn OI chen, pan/0000-0003-0271-2725 FU Natural Science Foundation of China [81373470, 81320108027]; Science and Technology Ministry of China [2012ZX09506001-004]; Fundamental Research Fund for the Central Universities [13ykpy08] FX This work was supported by the Natural Science Foundation of China [Grants 81373470, 81320108027]; the Science and Technology Ministry of China [Grant: 2012ZX09506001-004]; and the Fundamental Research Fund for the Central Universities [No. 13ykpy08]. NR 36 TC 6 Z9 6 U1 4 U2 15 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0090-9556 EI 1521-009X J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD MAR PY 2015 VL 43 IS 3 BP 317 EP 324 DI 10.1124/dmd.114.062067 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CE7FA UT WOS:000352002200003 PM 25534769 ER PT J AU Laborde, A Tomasina, F Bianchi, F Brune, MN Buka, I Comba, P Corra, L Cori, L Duffert, CM Harari, R Iavarone, I McDiarmid, MA Gray, KA Sly, PD Soares, A Suk, WA Landrigan, PJ AF Laborde, Amalia Tomasina, Fernando Bianchi, Fabrizio Brune, Marie-Noel Buka, Irena Comba, Pietro Corra, Lilian Cori, Liliana Duffert, Christin Maria Harari, Raul Iavarone, Ivano McDiarmid, Melissa A. Gray, Kimberly A. Sly, Peter D. Soares, Agnes Suk, William A. Landrigan, Philip J. TI Children's Health in Latin America: The Influence of Environmental Exposures SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Review ID BLOOD-LEAD LEVELS; CHRONIC ARSENIC EXPOSURE; WASTE RECYCLING TOWN; ELECTRONIC WASTE; DRINKING-WATER; AIR-POLLUTION; DEVELOPING-COUNTRIES; RISK-ASSESSMENT; INTELLECTUAL FUNCTION; MERCURY POLLUTION AB Background: Chronic diseases are increasing among children in Latin America. Objective and Methods: To examine environmental risk factors for chronic disease in Latin American children and to develop a strategic initiative for control of these exposures, the World Health Organization (WHO) including the Pan American Health Organization (PAHO), the Collegium Ramazzini, and Latin American scientists reviewed regional and relevant global data. Results: Industrial development and urbanization are proceeding rapidly in Latin America, and environmental pollution has become widespread. Environmental threats to children's health include traditional hazards such as indoor air pollution and drinking-water contamination; the newer hazards of urban air pollution; toxic chemicals such as lead, asbestos, mercury, arsenic, and pesticides; hazardous and electronic waste; and climate change. The mix of traditional and modern hazards varies greatly across and within countries reflecting industrialization, urbanization, and socioeconomic forces. Conclusions: To control environmental threats to children's health in Latin America, WHO, including PAHO, will focus on the most highly prevalent and serious hazards- indoor and outdoor air pollution, water pollution, and toxic chemicals. Strategies for controlling these hazards include developing tracking data on regional trends in children's environmental health (CEH), building a network of Collaborating Centres, promoting biomedical research in CEH, building regional capacity, supporting development of evidence-based prevention policies, studying the economic costs of chronic diseases in children, and developing platforms for dialogue with relevant stakeholders. Citation: Laborde A, Tomasina F, Bianchi F, Brune MN, Buka I, Comba P, Corra L, Cori L, Duffert CM, Harari R, Iavarone I, McDiarmid MA, Gray KA, Sly PD, Soares A, Suk WA, Landrigan PJ. 2015. Children's health in Latin America: the influence of environmental exposures. Environ Health Perspect 123: 201-209 C1 [Laborde, Amalia; Tomasina, Fernando] Univ Republ Uruguay, Fac Med, Montevideo, Uruguay. [Bianchi, Fabrizio; Cori, Liliana] CNR, Inst Clin Physiol, Environm Epidemiol Unit, Pisa, Italy. [Brune, Marie-Noel; Duffert, Christin Maria] WHO, Environm & Social Determinants Hlth Dept, Dept Publ Hlth, CH-1211 Geneva, Switzerland. [Buka, Irena] Univ Alberta, Childrens Environm Hlth Ctr, Dept Paediat, Edmonton, AB, Canada. [Comba, Pietro; Iavarone, Ivano] Ist Super Sanita, Dept Environm & Primary Prevent, Environm Epidemiol Unit, I-00161 Rome, Italy. [Corra, Lilian] Univ Buenos Aires, Publ Hlth Program, Buenos Aires, DF, Argentina. [Corra, Lilian] Blacksmith Inst, Buenos Aires, DF, Argentina. [Harari, Raul] IFA Inst Dev Prod & Work Environm, Quito, Ecuador. [McDiarmid, Melissa A.] Univ Maryland, Dept Med, Div Occupat Med, Baltimore, MD 21201 USA. [Gray, Kimberly A.; Suk, William A.] NIEHS, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. [Sly, Peter D.] Univ Queensland, Queensland Childrens Med Res Inst, Brisbane, Qld, Australia. [Soares, Agnes] Pan Amer Hlth Org, Washington, DC USA. [Landrigan, Philip J.] Icahn Sch Med Mt Sinai, Dept Prevent Med, New York, NY 10029 USA. [Landrigan, Philip J.] Icahn Sch Med Mt Sinai, Arnhold Global Hlth Inst, New York, NY 10029 USA. RP Landrigan, PJ (reprint author), Icahn Sch Med Mt Sinai, Dept Prevent Med, 17 East 102nd St, New York, NY 10029 USA. EM phil.landrigan@mssm.edu RI Bianchi, Fabrizio/F-7900-2015; Cori, Liliana/K-6027-2014; Soares da Silva, Agnes/H-8070-2012 OI Bianchi, Fabrizio/0000-0002-3459-9301; Cori, Liliana/0000-0002-3070-2535; Soares da Silva, Agnes/0000-0003-2618-6061 FU World Health Organization [001] NR 154 TC 17 Z9 20 U1 6 U2 76 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 MAR PY 2015 VL 123 IS 3 BP 201 EP 209 DI 10.1289/ehp.1408292 PG 9 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA CE9MK UT WOS:000352167900009 PM 25499717 ER PT J AU French, JE Gatti, DM Morgan, DL Kissling, GE Shockley, KR Knudsen, GA Shepard, KG Price, HC King, D Witt, KL Pedersen, LC Munger, SC Svenson, KL Churchill, GA AF French, John E. Gatti, Daniel M. Morgan, Daniel L. Kissling, Grace E. Shockley, Keith R. Knudsen, Gabriel A. Shepard, Kim G. Price, Herman C. King, Deborah Witt, Kristine L. Pedersen, Lars C. Munger, Steven C. Svenson, Karen L. Churchill, Gary A. TI Diversity Outbred Mice Identify Population-Based Exposure Thresholds and Genetic Factors that Influence Benzene-Induced Genotoxicity SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID GENOME-WIDE ASSOCIATION; HUMAN VARIABILITY; HUMAN SULFOTRANSFERASES; COLLABORATIVE CROSS; RISK-ASSESSMENT; ANIMAL-MODELS; MOUSE; HEMATOTOXICITY; WORKERS; SUSCEPTIBILITY AB BACKGROUND: Inhalation of benzene at levels below the current exposure limit values leads to hematotoxicity in occupationally exposed workers. OBJECTIVE: We sought to evaluate Diversity Outbred (DO) mice as a tool for exposure threshold assessment and to identify genetic factors that influence benzene-induced genotoxicity. METHODS: We exposed male DO mice to benzene (0, 1, 10, or 100 ppm; 75 mice/exposure group) via inhalation for 28 days (6 hr/day for 5 days/week). The study was repeated using two independent cohorts of 300 animals each. We measured micronuclei frequency in reticulocytes from peripheral blood and bone marrow and applied benchmark concentration modeling to estimate exposure thresholds. We genotyped the mice and performed linkage analysis. RESULTS: We observed a dose-dependent increase in benzene-induced chromosomal damage and estimated a benchmark concentration limit of 0.205 ppm benzene using DO mice. This estimate is an order of magnitude below the value estimated using B6C3F1 mice. We identified a locus on Chr 10 (31.87 Mb) that contained a pair of overexpressed sulfotransferases that were inversely correlated with genotoxicity. CONCLUSIONS: The genetically diverse DO mice provided a reproducible response to benzene exposure. The DO mice display interindividual variation in toxicity response and, as such, may more accurately reflect the range of response that is observed in human populations. Studies using DO mice can localize genetic associations with high precision. The identification of sulfotransferases as candidate genes suggests that DO mice may provide additional insight into benzene-induced genotoxicity. C1 [French, John E.; Morgan, Daniel L.; King, Deborah; Witt, Kristine L.] NIEHS, Div Natl Toxicol Program, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. [Gatti, Daniel M.; Munger, Steven C.; Svenson, Karen L.; Churchill, Gary A.] Jackson Lab, Bar Harbor, ME 04609 USA. [Kissling, Grace E.; Shockley, Keith R.; Pedersen, Lars C.] NIEHS, Div Intramural Res, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Knudsen, Gabriel A.] NIEHS, NCI, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Shepard, Kim G.] Integrated Lab Syst Inc, Res Triangle Pk, NC USA. [Price, Herman C.] Alion Sci & Technol, Res Triangle Pk, NC USA. RP French, JE (reprint author), NIEHS, Div Natl Toxicol Program, Keystone Bldg,Room 2050,530 Davis Dr, Morrisville, NC 27560 USA. EM french@niehs.nih.gov RI Knudsen, Gabriel/G-3706-2013 OI Knudsen, Gabriel/0000-0002-7208-6451 FU NIEHS/NTP; NIEHS; NCI Intramural Research Programs; Jackson Laboratory; NIH [GM076468, GM070683, R01DA021336, R21DA024845, R01MH079103] FX This research was supported by funds from the NIEHS/NTP, NIEHS, and NCI Intramural Research Programs, The Jackson Laboratory, and the NIH (grants GM076468 and GM070683 awarded to G.A.C.) and by NIH grants R01DA021336, R21DA024845, and R01MH079103. NR 58 TC 15 Z9 16 U1 4 U2 15 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 MAR PY 2015 VL 123 IS 3 BP 237 EP 245 DI 10.1289/ehp.1408202 PG 9 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA CE9MK UT WOS:000352167900014 PM 25376053 ER PT J AU Freeman, KS AF Freeman, Kris S. TI Continental Reference Point Harmonized Human Biomonitoring across Europe SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT News Item C1 [Freeman, Kris S.] NIH, Bethesda, MD 20892 USA. [Freeman, Kris S.] Natl Pk Serv, Washington, DC USA. RP Freeman, KS (reprint author), NIH, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 1 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 MAR PY 2015 VL 123 IS 3 BP A71 EP A71 DI 10.1289/ehp.123-A71 PG 1 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA CE9MK UT WOS:000352167900008 PM 25730104 ER PT J AU Landrigan, PJ Suk, WA AF Landrigan, Philip J. Suk, William A. TI Jenny Pronczuk de Garbino: A Global Champion for Children's Health SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material ID EXPOSURE; DISEASE; BURDEN C1 [Landrigan, Philip J.] Icahn Sch Med Mt Sinai, Dept Prevent Med, New York, NY 10029 USA. [Landrigan, Philip J.] Icahn Sch Med Mt Sinai, Arnhold Global Hlth Inst, New York, NY 10029 USA. [Suk, William A.] NIEHS, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Landrigan, PJ (reprint author), Icahn Sch Med Mt Sinai, Dept Prevent Med, New York, NY 10029 USA. EM phil.landrigan@mssm.edu NR 13 TC 1 Z9 1 U1 0 U2 1 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 MAR PY 2015 VL 123 IS 3 BP A52 EP A53 DI 10.1289/ehp.1408293 PG 2 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA CE9MK UT WOS:000352167900001 PM 25730408 ER PT J AU Metcalf, CJE Andreasen, V Bjornstad, ON Eames, K Edmunds, WJ Funk, S Hollingsworth, TD Lessler, J Viboud, C Grenfell, BT AF Metcalf, C. J. E. Andreasen, V. Bjornstad, O. N. Eames, K. Edmunds, W. J. Funk, S. Hollingsworth, T. D. Lessler, J. Viboud, C. Grenfell, B. T. TI Seven challenges in modeling vaccine preventable diseases SO EPIDEMICS LA English DT Article DE Vaccination; Modeling; Coverage; Immunity; Elimination ID INFECTIOUS-DISEASES; MEASLES EPIDEMICS; DYNAMICS; PERTUSSIS; SPREAD; DENGUE; IMPACT AB Vaccination has been one of the most successful public health measures since the introduction of basic sanitation. Substantial mortality and morbidity reductions have been achieved via vaccination against many infections, and the list of diseases that are potentially controllable by vaccines is growing steadily. We introduce key challenges for modeling in shaping our understanding and guiding policy decisions related to vaccine preventable diseases. (C) 2014 The Authors. Published by Elsevier B.V. C1 [Metcalf, C. J. E.; Grenfell, B. T.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Metcalf, C. J. E.; Grenfell, B. T.] Princeton Univ, Woodrow Wilson Sch, Princeton, NJ 08544 USA. [Andreasen, V.] Dept Sci Syst & Models, DK-4000 Roskilde, Denmark. [Bjornstad, O. N.] Penn State Univ, Ctr Infect Dis Dynam, State Coll, PA USA. [Eames, K.; Edmunds, W. J.; Funk, S.] London Sch Hyg & Trop Med, Ctr Math Modelling Infect Dis, London WC1, England. [Hollingsworth, T. D.] Univ Warwick, Warwick Math Inst, Coventry CV4 7AL, W Midlands, England. [Hollingsworth, T. D.] Univ Warwick, Sch Life Sci, Coventry CV4 7AL, W Midlands, England. [Hollingsworth, T. D.] Univ Liverpool, Liverpool Sch Trop Med, Dept Clin Sci, Liverpool L3 5QA, Merseyside, England. [Lessler, J.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Viboud, C.; Grenfell, B. T.] NIH, Div Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Metcalf, CJE (reprint author), Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. EM cmetcalf@princeton.edu RI Hollingsworth, Deirdre/D-2421-2009; OI Hollingsworth, Deirdre/0000-0001-5962-4238; Lessler, Justin/0000-0002-9741-8109 FU Bill and Melinda Gates Foundation; Science and Technology Directorate, Department of Homeland Security [HSHQDC-12-C-00058]; National Institute for Health Research [NIHR-CDF-2011-04019]; RAPIDD program of the Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; Wellcome Trust Institutional Strategic [097830/Z/11/A-C]; UK Medical Research Council Career Development Fellowship in Biostatistics FX This work is funded by the Bill and Melinda Gates Foundation, the Science and Technology Directorate, Department of Homeland Security contract HSHQDC-12-C-00058 (B.T.G., C.J.E.M., J.L., O.N.B.), the National Institute for Health Research NIHR-CDF-2011-04019 (K.E.), the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security and the Fogarty International Center, National Institutes of Health (C.J.E.M., B.T.G., O.N.B., C.V.). The funding sources played no role in developingthis paper and preparing it for submission. This work emerged from discussion at the Isaac Newton Institute, Cambridge. TDH is a member of the Centre for Applied Health Research & Delivery(http:// www. lstmliverpool. ac. uk/research/cross-cutting-themes/cahrd/) which is supported by a Wellcome Trust Institutional Strategic Support Award (no. 097830/Z/11/A-C) to LSTM. SF was funded by a UK Medical Research Council Career Development Fellowship in Biostatistics. NR 40 TC 6 Z9 6 U1 1 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1755-4365 J9 EPIDEMICS-NETH JI Epidemics PD MAR PY 2015 VL 10 BP 11 EP 15 DI 10.1016/j.epidem.2014.08.004 PG 5 WC Infectious Diseases SC Infectious Diseases GA CF0IO UT WOS:000352226900004 PM 25843375 ER PT J AU Hollingsworth, TD Pulliam, JRC Funk, S Truscott, JE Isham, V Lloyd, AL AF Hollingsworth, T. Deirdre Pulliam, Juliet R. C. Funk, Sebastian Truscott, James E. Isham, Valerie Lloyd, Alun L. TI Seven challenges for modelling indirect transmission: Vector-borne diseases, macroparasites and neglected tropical diseases SO EPIDEMICS LA English DT Article DE Vector-borne disease; Macroparasites; Neglected tropical diseases; Helminths; Vectors ID PARASITE POPULATION INTERACTIONS; INFECTIOUS-DISEASE; LYME-DISEASE; DYNAMICS; STABILITY; AGGREGATION; COMPETITION; COMMUNITY; ECOLOGY; RISK AB Many of the challenges which face modellers of directly transmitted pathogens also arise when modelling the epidemiology of pathogens with indirect transmission -whether through environmental stages, vectors, intermediate hosts or multiple hosts. In particular, understanding the roles of different hosts, how to measure contact and infection patterns, heterogeneities in contact rates, and the dynamics close to elimination are all relevant challenges, regardless of the mode of transmission. However, there remain a number of challenges that are specific and unique to modelling vector-borne diseases and macroparasites. Moreover, many of the neglected tropical diseases which are currently targeted for control and elimination are vector-borne, macroparasitic, or both, and so this article includes challenges which will assist in accelerating the control of these high-burden diseases. Here, we discuss the challenges of indirect measures of infection in humans, whether through vectors or transmission life stages and in estimating the contribution of different host groups to transmission. We also discuss the issues of "evolution-proof" interventions against vector-borne disease. (C) 2014 The Authors. Published by Elsevier B.V. C1 [Hollingsworth, T. Deirdre] Univ Warwick, Math Inst, Coventry CV4 7AL, W Midlands, England. [Hollingsworth, T. Deirdre] Univ Warwick, Sch Life Sci, Coventry CV4 7AL, W Midlands, England. [Hollingsworth, T. Deirdre] Univ Liverpool, Liverpool Sch Trop Med, Dept Clin Sci, Liverpool L3 5QA, Merseyside, England. [Pulliam, Juliet R. C.] Univ Florida, Dept Biol, Gainesville, FL 32611 USA. [Pulliam, Juliet R. C.] Univ Florida, Emerging Pathogens Inst, Gainesville, FL 32610 USA. [Pulliam, Juliet R. C.; Lloyd, Alun L.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Funk, Sebastian] London Sch Hyg & Trop Med, Ctr Math Modelling Infect Dis, London WC1E 7HT, England. [Truscott, James E.] Univ London Imperial Coll Sci Technol & Med, Fac Med, London Ctr Neglected Trop Dis Res, Sch Publ Hlth,Dept Infect Dis Epidemiol, London W2 1PG, England. [Isham, Valerie] UCL, Dept Stat Sci, London WC1E 6BT, England. [Lloyd, Alun L.] N Carolina State Univ, Dept Math, Raleigh, NC 27695 USA. [Lloyd, Alun L.] N Carolina State Univ, Biomath Grad Program, Raleigh, NC 27695 USA. RP Hollingsworth, TD (reprint author), Univ Warwick, Warwick Math Inst, Coventry CV4 7AL, W Midlands, England. EM deirdre.hollingsworth@warwick.ac.uk RI Hollingsworth, Deirdre/D-2421-2009; Pulliam, Juliet/A-6516-2008 OI Hollingsworth, Deirdre/0000-0001-5962-4238; Pulliam, Juliet/0000-0003-3314-8223 FU Newton Institute; Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directory; Department of Homeland Security, and Fogarty International Center; National Institutes of Health; National Institutes of Health [R01-AI091980, P01-AI098670]; National Science Foundation [RTG/DMS - 1246991]; Bill and Melinda Gates Foundation; Wellcome Trust Institutional Strategic Support [097830/Z/11/A-C]; UK Medical Research Council Career Development Award in Biostatistics FX This work was initiated during the 2013 Infectious Disease Dynamics meeting at the Isaac Newton Institute for Mathematical Sciences, Cambridge, UK. All authors warmly acknowledge the support of the Newton Institute and the organizers of a stimulating meeting. JRCP and ALL are supported by the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directory, Department of Homeland Security, and Fogarty International Center, National Institutes of Health. ALL is supported by grants from the National Institutes of Health(R01-AI091980 and P01-AI098670) and the National Science Foundation (RTG/DMS - 1246991). TDH and JET gratefully acknowledge funding from the Bill and Melinda Gates Foundation. TDH is a member of the Centre for Applied Health Research and Delivery(http://www. lstmliverpool. ac. uk/research/cross-cutting-themes/cahrd/) and her position is partly supported by a Wellcome Trust Institutional Strategic Support Award (no. 097830/Z/11/A-C) to LSTM. SF was supported by a UK Medical Research Council Career Development Award in Biostatistics. NR 47 TC 6 Z9 7 U1 9 U2 24 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1755-4365 J9 EPIDEMICS-NETH JI Epidemics PD MAR PY 2015 VL 10 BP 16 EP 20 DI 10.1016/j.epidem.2014.08.007 PG 5 WC Infectious Diseases SC Infectious Diseases GA CF0IO UT WOS:000352226900005 PM 25843376 ER PT J AU Funk, S Bansal, S Bauch, CT Eames, KTD Edmunds, WJ Galvani, AP Klepac, P AF Funk, Sebastian Bansal, Shweta Bauch, Chris T. Eames, Ken T. D. Edmunds, W. John Galvani, Alison P. Klepac, Petra TI Nine challenges in incorporating the dynamics of behaviour in infectious diseases models SO EPIDEMICS LA English DT Article DE Behaviour; Model; Infectious disease dynamics; Movement and travel; Real-time data collection; Reporting ID INFLUENZA; PATTERNS; TRANSMISSION; ERADICATION; EPIDEMIC; NETWORKS; MOBILITY; ILLNESS; SPREAD AB Traditionally, the spread of infectious diseases in human populations has been modelled with static parameters. These parameters, however, can change when individuals change their behaviour. If these changes are themselves influenced by the disease dynamics, there is scope for mechanistic models of behaviour to improve our understanding of this interaction. Here, we present challenges in modelling changes in behaviour relating to disease dynamics, specifically: how to incorporate behavioural changes in models of infectious disease dynamics, how to inform measurement of relevant behaviour to parameterise such models, and how to determine the impact of behavioural changes on observed disease dynamics. (C) 2014 The Authors. Published by Elsevier B.V. C1 [Funk, Sebastian; Eames, Ken T. D.; Edmunds, W. John] London Sch Hyg & Trop Med, Ctr Math Modelling Infect Dis, London WC1E 7HT, England. [Bansal, Shweta] Georgetown Univ, Dept Biol, Washington, DC 20057 USA. [Bansal, Shweta] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Bauch, Chris T.] Univ Waterloo, Dept Appl Math, Waterloo, ON N2L 3G1, Canada. [Galvani, Alison P.] Yale Univ, Sch Publ Hlth, New Haven, CT 06520 USA. [Klepac, Petra] Univ Cambridge, Dept Appl Math & Theoret Phys, Cambridge CB3 OWA, England. RP Funk, S (reprint author), London Sch Hyg & Trop Med, Ctr Math Modelling Infect Dis, London WC1E 7HT, England. EM sebastian.funk@lshtm.ac.uk OI Funk, Sebastian/0000-0002-2842-3406; Bansal, Shweta/0000-0002-1740-5421 FU UK Medical Research Council Career Development Award in Biostatistics; RAPIDD Program of the Science & Technology Directorate; Department of Homeland Security; Fogarty International Center, National Institutes of Health; National Institute for Health Research [NIHR-CDF-2011-04-019]; NSERC FX All authors are grateful to the Isaac Newton Institute. SF is supported by a UK Medical Research Council Career Development Award in Biostatistics. SB is supported by the RAPIDD Program of the Science & Technology Directorate, Department of Homeland Security and the Fogarty International Center, National Institutes of Health. KE is supported by the National Institute for Health Research (grant NIHR-CDF-2011-04-019). CB is supported by a Discovery Grant from NSERC. NR 31 TC 17 Z9 17 U1 1 U2 12 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1755-4365 J9 EPIDEMICS-NETH JI Epidemics PD MAR PY 2015 VL 10 BP 21 EP 25 DI 10.1016/j.epidem.2014.09.005 PG 5 WC Infectious Diseases SC Infectious Diseases GA CF0IO UT WOS:000352226900006 PM 25843377 ER PT J AU Buhnerkempe, MG Roberts, MG Dobson, AP Heesterbeek, H Hudson, PJ Lloyd-Smith, JO AF Buhnerkempe, Michael G. Roberts, Mick G. Dobson, Andrew P. Heesterbeek, Hans Hudson, Peter J. Lloyd-Smith, James O. TI Eight challenges in modelling disease ecology in multi-host, multi-agent systems SO EPIDEMICS LA English DT Article DE Multiple hosts; Multiple pathogens; Community ecology; Maintenance; Food webs ID IDENTIFYING RESERVOIRS; TRANSMISSION DYNAMICS; COINFECTION; POPULATION; INFECTION; COMMUNITY; PARASITES; PLAGUE; BIODIVERSITY; PERSISTENCE AB Many disease systems exhibit complexities not captured by current theoretical and empirical work. In particular, systems with multiple host species and multiple infectious agents (i.e., multi-host, multi-agent systems) require novel methods to extend the wealth of knowledge acquired studying primarily single-host, single-agent systems. We outline eight challenges in multi-host, multi-agent systems that could substantively increase our knowledge of the drivers and broader ecosystem effects of infectious disease dynamics. (C) 2014 The Authors. Published by Elsevier B.V. C1 [Buhnerkempe, Michael G.; Lloyd-Smith, James O.] Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA 90095 USA. [Buhnerkempe, Michael G.; Hudson, Peter J.; Lloyd-Smith, James O.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Roberts, Mick G.] Massey Univ, New Zealand Inst Adv Study, Inst Nat & Math Sci, Auckland, New Zealand. [Roberts, Mick G.] Massey Univ, Infect Dis Res Ctr, Auckland, New Zealand. [Dobson, Andrew P.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Dobson, Andrew P.] Santa Fe Inst, Santa Fe, NM 87501 USA. [Heesterbeek, Hans] Univ Utrecht, Fac Vet Med, Utrecht, Netherlands. [Hudson, Peter J.] Penn State Univ, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Hudson, Peter J.] Penn State Univ, Huck Inst Life Sci, University Pk, PA 16802 USA. RP Buhnerkempe, MG (reprint author), Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA 90095 USA. EM michael.buhnerkempe@ucla.edu RI Lloyd-Smith, James/K-4080-2012 OI Lloyd-Smith, James/0000-0001-7941-502X FU Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directory; Department of Homeland Security; Fogarty International Center, National Institutes of Health; National Science Foundation [OCE-1335657]; Marsden Fund [MAU1106]; James S. McDonnell Foundation; NSF-NIH Ecology of Infectious Diseases program FX Ideas for this paper were conceived at the Isaac Newton Institute for Mathematical Sciences programme on Infectious Disease Dynamics. M.G.B., J.O.L.-S., and PJ.H. are supported by the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directory, Department of Homeland Security, and Fogarty International Center, National Institutes of Health. M.G.B. and J.O.L.-S. are also supported by the National Science Foundation (OCE-1335657). M.G.R is supported by the Marsden Fund under contract MAU1106. A.P.D. is supported by the James S. McDonnell Foundation and the NSF-NIH Ecology of Infectious Diseases program. NR 38 TC 6 Z9 6 U1 4 U2 42 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1755-4365 J9 EPIDEMICS-NETH JI Epidemics PD MAR PY 2015 VL 10 BP 26 EP 30 DI 10.1016/j.epidem.2014.10.001 PG 5 WC Infectious Diseases SC Infectious Diseases GA CF0IO UT WOS:000352226900007 PM 25843378 ER PT J AU Wikramaratna, PS Kucharski, A Gupta, S Andreasen, V McLean, AR Gog, JR AF Wikramaratna, Paul S. Kucharski, Adam Gupta, Sunetra Andreasen, Viggo McLean, Angela R. Gog, Julia R. TI Five challenges in modelling interacting strain dynamics SO EPIDEMICS LA English DT Article DE Multiple strains; Cross immunity; Adaptive immunity; Pathogen evolution; Mathematical modelling ID ANTIGENICALLY DIVERSE PATHOGENS; INFLUENZA-A DRIFT; POPULATION-STRUCTURE; HOST HETEROGENEITY; BRIDGING SCALES; EVOLUTION; IMMUNITY; SELECTION; DETERMINANTS; NETWORK AB Population epidemiological models where hosts can be infected sequentially by different strains have the potential to help us understand many important diseases. Researchers have in recent years started to develop and use such models, but the extra layer of complexity from multiple strains brings with it many technical challenges. It is therefore hard to build models which have realistic assumptions yet are tractable. Here we outline some of the main challenges in this area. First we begin with the fundamental question of how to translate from complex small-scale dynamics within a host to useful population models. Next we consider the nature of so-called "strain space". We describe two key types of host heterogeneities, and explain how models could help generate a better understanding of their effects. Finally, for diseases with many strains, we consider the challenge of modelling how immunity accumulates over multiple exposures. (C) 2014 The Authors. Published by Elsevier B.V. C1 [Wikramaratna, Paul S.] Univ Edinburgh, Inst Evolutionary Biol, Edinburgh EH9 3JT, Midlothian, Scotland. [Wikramaratna, Paul S.; Gupta, Sunetra; McLean, Angela R.] Univ Oxford, Dept Zool, Oxford OX1 3P5, England. [Kucharski, Adam] London Sch Hyg & Trop Med, Dept Infect Dis Epidemiol, London WC1E 7HT, England. [Andreasen, Viggo] Roskilde Univ, Dept Math & Phys, DK-4000 Roskilde, Denmark. [Gog, Julia R.] Univ Cambridge, Dept Appl Math & Theoret Phys, Cambridge CB3 OWA, England. [Gog, Julia R.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Gog, JR (reprint author), Univ Cambridge, Dept Appl Math & Theoret Phys, Cambridge CB3 OWA, England. EM jrg20@cam.ac.uk NR 34 TC 4 Z9 4 U1 1 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1755-4365 J9 EPIDEMICS-NETH JI Epidemics PD MAR PY 2015 VL 10 BP 31 EP 34 DI 10.1016/j.epidem.2014.07.005 PG 4 WC Infectious Diseases SC Infectious Diseases GA CF0IO UT WOS:000352226900008 PM 25843379 ER PT J AU Lloyd-Smith, JO Funk, S McLean, AR Riley, S Wood, JLN AF Lloyd-Smith, James O. Funk, Sebastian McLean, Angela R. Riley, Steven Wood, James L. N. TI Nine challenges in modelling the emergence of novel pathogens SO EPIDEMICS LA English DT Article DE Emerging infectious diseases; Zoonosis; Infectious disease dynamics; Host jump; Cross-species spillover transmission ID INFECTIOUS-DISEASES; INFLUENZA-VIRUS; NIPAH VIRUS; UNITED-STATES; DYNAMICS; SURVEILLANCE; HOST; TRANSMISSION; SEVERITY; OUTBREAK AB Studying the emergence of novel infectious agents involves many processes spanning host species, spatial scales, and scientific disciplines. Mathematical models play an essential role in combining insights from these investigations and drawing robust inferences from field and experimental data. We describe nine challenges in modelling the emergence of novel pathogens, emphasizing the interface between models and data. (C) 2014 The Authors. Published by Elsevier B.V. C1 [Lloyd-Smith, James O.] Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA 90089 USA. [Lloyd-Smith, James O.; Riley, Steven; Wood, James L. N.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Funk, Sebastian] London Sch Hyg & Trop Med, Ctr Math Modelling Infect Dis, London WC1, England. [McLean, Angela R.] Univ Oxford, Dept Zool, Oxford Martin Sch, Oxford, England. [Riley, Steven] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Infect Dis Epidemiol, MRC Ctr Outbreak Anal & Dis Modelling, London SW7 2AZ, England. [Wood, James L. N.] Univ Cambridge, Dept Vet Med, Dis Dynam Unit, Cambridge, England. RP Lloyd-Smith, JO (reprint author), Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA 90089 USA. EM jlloydsmith@ucla.edu RI Wood, James/A-1626-2008; Lloyd-Smith, James/K-4080-2012; OI Wood, James/0000-0002-0258-3188; Lloyd-Smith, James/0000-0001-7941-502X; Funk, Sebastian/0000-0002-2842-3406 FU Policy for Infectious Disease Dynamics (RAPIDD) programme of the Science and Technology Directory, Department of Homeland Security; Fogarty International Center, National Institutes of Health; National Science Foundation [EF-0928987, OCE-1335657]; De Logi Chair in Biological Sciences; UK Medical Research Council Career Development Award in Biostatistics; Wellcome Trust Project Award [093488/Z/10/Z]; Fogarty International Centre [R01 TW008246-01]; Medical Research Council (UK) [MR/J008761/1]; Alborada Trust; European Union FP7 project ANTIGONE [278976] FX The authors are grateful to the Isaac Newton Institute for Mathematical Sciences, for providing the setting for discussions leading to this paper. We acknowledge support from the Research and Policy for Infectious Disease Dynamics (RAPIDD) programme of the Science and Technology Directory, Department of Homeland Security, and Fogarty International Center, National Institutes of Health. JLS was also supported by the National Science Foundation (EF-0928987 and OCE-1335657) and the De Logi Chair in Biological Sciences. SF was supported by a UK Medical Research Council Career Development Award in Biostatistics. SR was supported by: Wellcome Trust Project Award 093488/Z/10/Z; R01 TW008246-01 from Fogarty International Centre; and The Medical Research Council (UK, Project Grant MR/J008761/1). JLNW was also supported by the Alborada Trust and the European Union FP7 project ANTIGONE (contract number 278976). NR 32 TC 4 Z9 4 U1 1 U2 19 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1755-4365 J9 EPIDEMICS-NETH JI Epidemics PD MAR PY 2015 VL 10 BP 35 EP 39 DI 10.1016/j.epidem.2014.09.002 PG 5 WC Infectious Diseases SC Infectious Diseases GA CF0IO UT WOS:000352226900009 PM 25843380 ER PT J AU Metcalf, CJE Birger, RB Funk, S Kouyos, RD Lloyd-Smith, JO Jansen, VAA AF Metcalf, C. J. E. Birger, R. B. Funk, S. Kouyos, R. D. Lloyd-Smith, J. O. Jansen, V. A. A. TI Five challenges in evolution and infectious diseases SO EPIDEMICS LA English DT Article DE Fitness; Genetic systems; Diversity; RO; Coinfection ID RNA VIRUSES; DYNAMICS; REPLICATION; VIRULENCE; RESISTANCE; MECHANISMS; PATHOGENS AB Evolution is a key aspect of the biology of many pathogens, driving processes ranging from immune escape to changes in virulence. Because evolution is inherently subject to feedbacks, and because pathogen evolution plays out at scales ranging from within-host to between-host and beyond, evolutionary questions provide special challenges to the modelling community. In this article, we provide an overview of five challenges in modelling the evolution of pathogens and their hosts, and point to areas for development, focussing in particular on the issue of linking theory and data. (C) 2014 The Authors. Published by Elsevier B.V. C1 [Metcalf, C. J. E.; Birger, R. B.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Metcalf, C. J. E.; Lloyd-Smith, J. O.] NIH, Div Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Funk, S.] London Sch Hyg & Trop Med, Ctr Math Modelling Infect Dis, London WC1, England. [Kouyos, R. D.] Univ Zurich Hosp, Div Infect Dis & Hosp Epidemiol, CH-8091 Zurich, Switzerland. [Lloyd-Smith, J. O.] Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA USA. [Jansen, V. A. A.] Royal Holloway Univ London, Sch Biol Sci, Egham, Surrey, England. RP Metcalf, CJE (reprint author), Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. EM cmetcalf@princeton.edu RI Birger, Ruthie/F-2416-2014; Kouyos, Roger/G-6226-2014; Infektiologie, USZ/A-6921-2011; Lloyd-Smith, James/K-4080-2012; OI Birger, Ruthie/0000-0002-2960-5084; Kouyos, Roger/0000-0002-9220-8348; Lloyd-Smith, James/0000-0001-7941-502X; Jansen, Vincent A.A./0000-0002-6518-2090 FU Bill and Melinda Gates Foundation; National Science Foundation [EF-0928690]; Medical Research Council; RAPIDD program of the Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX This work emerged from discussion at the Isaac Newton Institute, Cambridge; and was funded by the Bill and Melinda Gates Foundation (CJEM), the National Science Foundation (EF-0928690; JLS), the Medical Research Council (SF), and the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security and the Fogarty International Center, National Institutes of Health (CJEM, JLS). NR 45 TC 5 Z9 5 U1 1 U2 23 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1755-4365 J9 EPIDEMICS-NETH JI Epidemics PD MAR PY 2015 VL 10 BP 40 EP 44 DI 10.1016/j.epidem.2014.12.003 PG 5 WC Infectious Diseases SC Infectious Diseases GA CF0IO UT WOS:000352226900010 PM 25843381 ER PT J AU Gog, JR Pellis, L Wood, JLN McLean, AR Arinaminpathy, N Lloyd-Smith, JO AF Gog, Julia R. Pellis, Lorenzo Wood, James L. N. McLean, Angela R. Arinaminpathy, Nimalan Lloyd-Smith, James O. TI Seven challenges in modeling pathogen dynamics within-host and across scales SO EPIDEMICS LA English DT Article DE Within-host; Multiple scales; Superinfection; Transmission bottlenecks; Deep-sequencing ID INFLUENZA-VIRUS; EVOLUTIONARY DYNAMICS; HIV-1 INFECTION; IMMUNITY; TRANSMISSION; ADAPTATION; MECHANISMS; EPIDEMICS; REGION AB The population dynamics of infectious disease is a mature field in terms of theory and to some extent, application. However for microparasites, the theory and application of models of the dynamics within a single infected host is still an open field. Further, connecting across the scales - from cellular to host level, to population level - has potential to vastly improve our understanding of pathogen dynamics and evolution. Here, we highlight seven challenges in the following areas: transmission bottlenecks, heterogeneity within host, dynamic fitness landscapes within hosts, making use of next-generation sequencing data, capturing superinfection and when and how to model more than two scales. (C) 2014 The Authors. Published by Elsevier B.V. C1 [Gog, Julia R.; Wood, James L. N.; Lloyd-Smith, James O.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Gog, Julia R.] Univ Cambridge, Dept Appl Math & Theoret Phys, Ctr Math Sci, Cambridge CB3 OWA, England. [Pellis, Lorenzo] Univ Warwick, Warwick Infect Dis Epidemiol Res Ctr WIDER, Coventry CV4 7AL, W Midlands, England. [Pellis, Lorenzo] Univ Warwick, Warwick Math Inst, Coventry CV4 7AL, W Midlands, England. [Wood, James L. N.] Univ Cambridge, Dept Vet Med, Dis Dynam Unit, Cambridge CB3 0ES, England. [McLean, Angela R.] Univ Oxford, Oxford Martin Sch, Dept Zool, Oxford OX1 3P5, England. [Arinaminpathy, Nimalan] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Infect Dis Epidemiol, London SW7 2AZ, England. [Lloyd-Smith, James O.] Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA 90095 USA. RP Gog, JR (reprint author), Univ Cambridge, Dept Appl Math & Theoret Phys, Ctr Math Sci, Cambridge CB3 OWA, England. EM jrg20@cam.ac.uk RI Wood, James/A-1626-2008; Lloyd-Smith, James/K-4080-2012 OI Wood, James/0000-0002-0258-3188; Lloyd-Smith, James/0000-0001-7941-502X FU RAPIDD program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; Alborada Trust; Engineering and Physical Sciences Research Council; National Science Foundation [EF-0928690]; De Logi Chair in Biological Sciences FX We wish to thank Nicole Mideo for helpful comments on this manuscript. JLS, JRG and JLNW are supported by the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security and the Fogarty International Center, National Institutes of Health. JLNW is also supported by the Alborada Trust. LP is supported by the Engineering and Physical Sciences Research Council and JLS by the National Science Foundation (EF-0928690) and the De Logi Chair in Biological Sciences. NR 37 TC 8 Z9 8 U1 0 U2 12 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1755-4365 J9 EPIDEMICS-NETH JI Epidemics PD MAR PY 2015 VL 10 BP 45 EP 48 DI 10.1016/j.epidem.2014.09.009 PG 4 WC Infectious Diseases SC Infectious Diseases GA CF0IO UT WOS:000352226900011 PM 25843382 ER PT J AU Roberts, M Andreasen, V Lloyd, A Pellis, L AF Roberts, Mick Andreasen, Viggo Lloyd, Alun Pellis, Lorenzo TI Nine challenges for deterministic epidemic models SO EPIDEMICS LA English DT Article DE Deterministic models; Endemic equilibrium; Multi-strain systems; Spatial models; Non-communicable diseases ID JUMP MARKOV PROCESSES; RECURRENT EPIDEMICS; DYNAMICS; DISEASE; CANCER; VARIABILITY; PATTERNS AB Deterministic models have a long history of being applied to the study of infectious disease epidemiology. We highlight and discuss nine challenges in this area. The first two concern the endemic equilibrium and its stability. We indicate the need for models that describe multi-strain infections, infections with time-varying infectivity, and those where superinfection is possible. We then consider the need for advances in spatial epidemic models, and draw attention to the lack of models that explore the relationship between communicable and non-communicable diseases. The final two challenges concern the uses and limitations of deterministic models as approximations to stochastic systems. (C) 2014 The Authors. Published by Elsevier B.V. C1 [Roberts, Mick] Massey Univ, Inst Nat & Math Sci, Infect Dis Res Ctr, Auckland, New Zealand. [Roberts, Mick] Massey Univ, New Zealand Inst Adv Study, Auckland, New Zealand. [Andreasen, Viggo] Roskilde Univ, Dept Sci, DK-4000 Roskilde, Denmark. [Lloyd, Alun] N Carolina State Univ, Dept Math, Raleigh, NC 27695 USA. [Lloyd, Alun] N Carolina State Univ, Biomath Grad Program, Raleigh, NC 27695 USA. [Lloyd, Alun] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Pellis, Lorenzo] Univ Warwick, Warwick Infect Dis Epidemiol Res Ctr WIDER, Coventry CV4 7AL, W Midlands, England. [Pellis, Lorenzo] Univ Warwick, Warwick Math Inst, Coventry CV4 7AL, W Midlands, England. RP Roberts, M (reprint author), Massey Univ, Inst Nat & Math Sci, Infect Dis Res Ctr, Private Bag 102 904,North Shore Mail Ctr, Auckland, New Zealand. EM m.g.roberts@massey.ac.nz OI Roberts, Mick/0000-0003-2693-5093 FU Marsden Fund [MAU1106]; Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directory, Department of Homeland Security; Fogarty International Center, National Institutes of Health; National Institutes of Health [R01-AI091980]; National Science Foundation [RTG/DMS-1246991]; Engineering and Physical Sciences Research Council FX This paper was conceived while the authors took part in the Isaac Newton Institute for Mathematical Sciences programme on Infectious Disease Dynamics. The authors are grateful to the Institute, and the programme organisers, for their support. MGR is supported by the Marsden Fund under contract MAU1106. ALL is supported by the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directory, Department of Homeland Security, and Fogarty International Center, National Institutes of Health, and by grants from the National Institutes of Health (R01-AI091980) and the National Science Foundation (RTG/DMS-1246991). LP is supported by the Engineering and Physical Sciences Research Council. NR 36 TC 6 Z9 6 U1 0 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1755-4365 J9 EPIDEMICS-NETH JI Epidemics PD MAR PY 2015 VL 10 BP 49 EP 53 DI 10.1016/j.epidem.2014.09.006 PG 5 WC Infectious Diseases SC Infectious Diseases GA CF0IO UT WOS:000352226900012 PM 25843383 ER PT J AU Britton, T House, T Lloyd, AL Mollison, D Riley, S Trapman, P AF Britton, Tom House, Thomas Lloyd, Alun L. Mollison, Denis Riley, Steven Trapman, Pieter TI Five challenges for stochastic epidemic models involving global transmission SO EPIDEMICS LA English DT Article DE Stochastic epidemics; Global transmission; Extinction; Genetic evolution; Endemicity ID EVOLUTION; EXTINCTION; DYNAMICS AB The most basic stochastic epidemic models are those involving global transmission, meaning that infection rates depend only on the type and state of the individuals involved, and not on their location in the population. Simple as they are, there are still several open problems for such models. For example, when will such an epidemic go extinct and with what probability (questions depending on the population being fixed, changing or growing)? How can a model be defined explaining the sometimes observed scenario of frequent mid-sized epidemic outbreaks? How can evolution of the infectious agent transmission rates be modelled and fitted to data in a robust way? (C) 2014 The Authors. Published by Elsevier B.V. C1 [Britton, Tom; Trapman, Pieter] Stockholm Univ, Dept Math, S-10691 Stockholm, Sweden. [House, Thomas] Univ Warwick, Warwick Infect Dis Epidemiol Res Ctr WIDER, Coventry CV4 7AL, W Midlands, England. [House, Thomas] Univ Warwick, Warwick Math Inst, Coventry CV4 7AL, W Midlands, England. [Lloyd, Alun L.] N Carolina State Univ, Dept Math, Raleigh, NC 27695 USA. [Lloyd, Alun L.] N Carolina State Univ, Biomath Grad Program, Raleigh, NC 27695 USA. [Lloyd, Alun L.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Mollison, Denis] Heriot Watt Univ, Dept Actuarial Math & Stat, Edinburgh EH14 4AS, Midlothian, Scotland. [Riley, Steven] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Infect Dis Epidemiol, Ctr Outbreak Anal & Modelling, London, England. [Riley, Steven] Univ Hong Kong, Dept Community Med, Pokfulam, Hong Kong, Peoples R China. [Riley, Steven] Univ Hong Kong, Sch Publ Hlth, Pokfulam, Hong Kong, Peoples R China. RP Britton, T (reprint author), Stockholm Univ, Dept Math, S-10691 Stockholm, Sweden. EM tom.britton@math.su.se FU Swedish Research Council; Engineering and Physical Sciences Research Council; Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directory, Department of Homeland Security; Fogarty International Center, National Institutes of Health; National Institutes of Health [R01-AI091980]; National Science Foundation [RTG/DMS-1246991]; Wellcome Trust from Fogarty International Centre [093488/Z/10/Z, R01 TW008246-01]; Medical Research Council (UK) [MR/J008761/1]; RAPIDD program from Fogarty International Centre with the Science & Technology Directorate, Department of Homeland Security; Vetenskapsradet (Swedish Research Council) [20105873] FX All authors are grateful to the Isaac Newton Institute. TB is supported by the Swedish Research Council. TH is supported by the Engineering and Physical Sciences Research Council. ALL is supported by the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directory, Department of Homeland Security, and Fogarty International Center, National Institutes of Health, and by grants from the National Institutes of Health (R01-AI091980) and the National Science Foundation (RTG/DMS-1246991). SR is supported by Wellcome Trust Project Award 093488/Z/10/Z, R01 TW008246-01 from Fogarty International Centre, The Medical Research Council (UK, Project Grant MR/J008761/1) and the RAPIDD program from Fogarty International Centre with the Science & Technology Directorate, Department of Homeland Security. PT is supported by Vetenskapsradet (Swedish Research Council) project no. 20105873. NR 25 TC 5 Z9 5 U1 1 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1755-4365 J9 EPIDEMICS-NETH JI Epidemics PD MAR PY 2015 VL 10 BP 54 EP 57 DI 10.1016/j.epidem.2014.05.002 PG 4 WC Infectious Diseases SC Infectious Diseases GA CF0IO UT WOS:000352226900013 PM 25843384 ER PT J AU Pellis, L Ball, F Bansal, S Eames, K House, T Isham, V Trapman, P AF Pellis, Lorenzo Ball, Frank Bansal, Shweta Eames, Ken House, Thomas Isham, Valerie Trapman, Pieter TI Eight challenges for network epidemic models SO EPIDEMICS LA English DT Article DE Infectious disease models; Transmission dynamics; Contact networks; Random graphs; Dynamic networks; Control measures ID INFECTIOUS-DISEASE; CONTACT NETWORKS; SOCIAL NETWORKS; TRANSMISSION; INFLUENZA; SPREAD; IMPACT; H1N1 AB Networks offer a fertile framework for studying the spread of infection in human and animal populations. However, owing to the inherent high-dimensionality of networks themselves, modelling transmission through networks is mathematically and computationally challenging. Even the simplest network epidemic models present unanswered questions. Attempts to improve the practical usefulness of network models by including realistic features of contact networks and of host pathogen biology (e.g. waning immunity) have made some progress, but robust analytical results remain scarce. A more general theory is needed to understand the impact of network structure on the dynamics and control of infection. Here we identify a set of challenges that provide scope for active research in the field of network epidemic models. (C) 2014 The Authors. Published by Elsevier B.V. C1 [Pellis, Lorenzo; House, Thomas] Univ Warwick, Warwick Infect Dis Epidemiol Res Ctr WIDER, Coventry CV4 7AL, W Midlands, England. [Pellis, Lorenzo; House, Thomas] Univ Warwick, Warwick Math Inst, Coventry CV4 7AL, W Midlands, England. [Ball, Frank] Univ Nottingham, Sch Math Sci, Nottingham NG7 2RD, England. [Bansal, Shweta] Georgetown Univ, Dept Biol, Washington, DC 20057 USA. [Bansal, Shweta] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Eames, Ken] London Sch Hyg & Trop Med, Ctr Math Modelling Infect Dis, London WC1E 7HT, England. [Isham, Valerie] UCL, Dept Stat Sci, London WC1E 6BT, England. [Trapman, Pieter] Stockholm Univ, Dept Math, S-10691 Stockholm, Sweden. RP Pellis, L (reprint author), Univ Warwick, Warwick Infect Dis Epidemiol Res Ctr WIDER, Coventry CV4 7AL, W Midlands, England. EM l.pellis@warwick.ac.uk OI Bansal, Shweta/0000-0002-1740-5421 FU Engineering and Physical Sciences Research Council; Vetenskapsradet (Swedish Research Council) [2010-5873]; National Institute for Health Research [NIHR-CDF-2001-04-019]; RAPIDD Program of the Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX The authors want to acknowledge the Isaac Newton Institute for Mathematical Sciences, Cambridge, UK, for hosting the Infectious Disease Dynamics programme that resulted in this collaboration, and its follow-up programme where the collaborations continued. TH and LP are supported by the Engineering and Physical Sciences Research Council; PT by Vetenskapsradet (Swedish Research Council) project nr. 2010-5873; KE by a Career Development Fellowship award from the National Institute for Health Research (Grant NIHR-CDF-2001-04-019); and SB by the RAPIDD Program of the Science & Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. We would also like to thank the anonymous referee for helpful comments and improvements. NR 40 TC 16 Z9 16 U1 1 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1755-4365 J9 EPIDEMICS-NETH JI Epidemics PD MAR PY 2015 VL 10 BP 58 EP 62 DI 10.1016/j.epidem.2014.07.003 PG 5 WC Infectious Diseases SC Infectious Diseases GA CF0IO UT WOS:000352226900014 PM 25843385 ER PT J AU Eames, K Bansal, S Frost, S Riley, S AF Eames, K. Bansal, S. Frost, S. Riley, S. TI Six challenges in measuring contact networks for use in modelling SO EPIDEMICS LA English DT Article DE Networks; Contact patterns; Disease transmission; Mathematical modelling; Network measurement; Model-driven data collection ID INFECTIOUS-DISEASE; SOCIAL NETWORKS; MIXING PATTERNS; GREAT-BRITAIN; TRANSMISSION; SPREAD; OUTBREAK; INFLUENZA; DYNAMICS AB Contact networks are playing an increasingly important role in epidemiology. A contact network represents individuals in a host population as nodes and the interactions among them that may lead to the transmission of infection as edges. New avenues for data collection in recent years have afforded us the opportunity to collect individual- and population-scale information to empirically describe the patterns of contact within host populations. Here, we present some of the current challenges in measuring empirical contact networks. We address fundamental questions such as defining contact; measurement of non-trivial contact properties; practical issues of bounding measurement of contact networks in space, time and scope; exploiting proxy information about contacts; dealing with missing data. Finally, we consider the privacy and ethical issues surrounding the collection of contact network data. (C) 2014 The Authors. Published by Elsevier B.V. C1 [Eames, K.] London Sch Hyg & Trop Med, Ctr Math Modelling Infect Dis, London WC1E 7HT, England. [Bansal, S.] Georgetown Univ, Dept Biol, Washington, DC 20057 USA. [Bansal, S.] NIH, Fogarty Int Ctr, Bethesda, MD 20893 USA. [Frost, S.] Univ Cambridge, Dept Vet Med, Cambridge CB3 0ES, England. [Riley, S.] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Infect Dis Epidemiol, Ctr Outbreak Anal & Modelling, London W2 1PG, England. RP Eames, K (reprint author), London Sch Hyg & Trop Med, Ctr Math Modelling Infect Dis, Keppel St, London WC1E 7HT, England. EM ken.eames@ishtm.ac.uk; shweta@sbansal.com; sdf22@cam.ac.uk; s.riley@imperial.ac.uk OI Bansal, Shweta/0000-0002-1740-5421 FU National Institute for Health Research [NIHR-CDF-2001-04-019]; RAPIDD Program of the Science & Technology Directorate, Department of Homland Security; Fogarty International Center, National Institutes of Health, USA; Royal Society; ESRC [ES/J011266/1]; Wellcome Trust from Fogarty International Centre [093488/Z/10/Z, R01TW008246-01]; Medical Research Council (UK) [MR/J008761/1]; RAPIDD program from Fogarty International Centre; Science & Technology Directorate, Department of Homeland Security FX All authors are grateful to The Isaac Newton Institute. KE is supported by a Career Development Fellowship award from the National Institute for Health Research (grant NIHR-CDF-2001-04-019). SB is supported by the RAPIDD Program of the Science & Technology Directorate, Department of Homland Security, and the Fogarty International Center, National Institutes of Health, USA. SF is supported in part by the Royal Society and by the ESRC (grant no ES/J011266/1). SR is supported by Wellcome Trust Project Award 093488/Z/10/Z, R01TW008246-01 from Fogarty International Centre, The Medical Research Council (UK, Project Grant MR/J008761/1) and the RAPIDD program from Fogarty International Centre with the Science & Technology Directorate, Department of Homeland Security. NR 36 TC 16 Z9 16 U1 1 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1755-4365 J9 EPIDEMICS-NETH JI Epidemics PD MAR PY 2015 VL 10 BP 72 EP 77 DI 10.1016/j.epidem.2014.08.006 PG 6 WC Infectious Diseases SC Infectious Diseases GA CF0IO UT WOS:000352226900017 PM 25843388 ER PT J AU Lessler, J Edmunds, WJ Halloran, ME Hollingsworth, TD Lloyd, AL AF Lessler, J. Edmunds, W. J. Halloran, M. E. Hollingsworth, T. D. Lloyd, A. L. TI Seven challenges for model-driven data collection in experimental and observational studies SO EPIDEMICS LA English DT Article DE Modeling; Data collection; Observational studies; Experimental studies ID SENSITIVITY-ANALYSIS; DYNAMICS; TRANSMISSION; DESIGN; IMPACT; COHORT; TRIAL AB Infectious disease models are both concise statements of hypotheses and powerful techniques for creating tools from hypotheses and theories. As such, they have tremendous potential for guiding data collection in experimental and observational studies, leading to more efficient testing of hypotheses and more robust study designs. In numerous instances, infectious disease models have played a key role in informing data collection, including the Garki project studying malaria, the response to the 2009 pandemic of H1N1 influenza in the United Kingdom and studies of T-cell immunodynamics in mammals. However, such synergies remain the exception rather than the rule; and a close marriage of dynamic modeling and empirical data collection is far from the norm in infectious disease research. Overcoming the challenges to using models to inform data collection has the potential to accelerate innovation and to improve practice in how we deal with infectious disease threats. (C) 2014 The Authors. Published by Elsevier B.V. C1 [Lessler, J.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21224 USA. [Edmunds, W. J.] London Sch Hyg & Trop Med, London WC1E 7HT, England. [Halloran, M. E.] Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA. [Halloran, M. E.] Fred Hutchinson Canc Res Ctr, Ctr Stat & Quantitat Infect Dis, Seattle, WA 98109 USA. [Hollingsworth, T. D.] Univ Warwick, Math Inst, Coventry CV4 7AL, W Midlands, England. [Hollingsworth, T. D.] Univ Warwick, Sch Life Sci, Coventry CV4 7AL, W Midlands, England. [Hollingsworth, T. D.] Univ Liverpool, Liverpool Sch Trop Med, Liverpool L3 5QA, Merseyside, England. [Lloyd, A. L.] N Carolina State Univ, Dept Math, Raleigh, NC 27695 USA. [Lloyd, A. L.] N Carolina State Univ, Biomath Grad Program, Raleigh, NC 27695 USA. [Lloyd, A. L.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Lessler, J (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21224 USA. EM justin@jhu.edu RI Hollingsworth, Deirdre/D-2421-2009; OI Hollingsworth, Deirdre/0000-0001-5962-4238; Lessler, Justin/0000-0002-9741-8109 FU Newton Institute; National Institute of Allergy and Infectious Disease [K22-AI092150-01]; National Institutes of Health [U54-GM111274, R37-AI032042, P01-AI098670, R01-AI091980]; Wellcome Trust Institutional Strategic Support Award [097830/Z/11/A-C]; Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directory, Department of Homeland Security; Fogarty International Center, National Institutes of Health; National Science Foundation [RTG/DMS-1246991] FX This work was initiated during the 2013 Infectious Disease Dynamics meeting at the Isaac Newton Institute, Cambridge, UK. All authors warmly acknowledge the support of the Newton Institute. JL is a recipient of a K22 award from the National Institute of Allergy and Infectious Disease (K22-AI092150-01). MEH was supported by National Institutes of Health Grants Nos. U54-GM111274 and R37-AI032042. TDH is a member of the Center for Applied Health Research & Delivery (http://www.lstmliverpool.ac.uk/research/cross-cutting-themes/cahrd/) which is supported by a Wellcome Trust Institutional Strategic Support Award (No. 097830/Z/11/A-C) to LSTM. ALL is supported by the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directory, Department of Homeland Security, and Fogarty International Center, National Institutes of Health, and by grants from the National Institutes of Health (P01-AI098670, R01-AI091980) and the National Science Foundation (RTG/DMS-1246991). NR 34 TC 9 Z9 9 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1755-4365 J9 EPIDEMICS-NETH JI Epidemics PD MAR PY 2015 VL 10 BP 78 EP 82 DI 10.1016/j.epidem.2014.12.002 PG 5 WC Infectious Diseases SC Infectious Diseases GA CF0IO UT WOS:000352226900018 PM 25843389 ER PT J AU Frost, SDW Pybus, OG Gog, JR Viboud, C Bonhoeffer, S Bedford, T AF Frost, Simon D. W. Pybus, Oliver G. Gog, Julia R. Viboud, Cecile Bonhoeffer, Sebastian Bedford, Trevor TI Eight challenges in phylodynamic inference SO EPIDEMICS LA English DT Article DE Phylodynamics; Coalescent models; Selection; Recombination ID STATISTICAL PHYLOGENETICS; EVOLUTIONARY DYNAMICS; INFECTIOUS-DISEASE; INFLUENZA-VIRUS; POPULATION; HIV; RECOMBINATION; EPIDEMIOLOGY; TRANSMISSION; GENEALOGIES AB The field of phylodynamics, which attempts to enhance our understanding of infectious disease dynamics using pathogen phylogenies, has made great strides in the past decade. Basic epidemiological and evolutionary models are now well characterized with inferential frameworks in place. However, significant challenges remain in extending phylodynamic inference to more complex systems. These challenges include accounting for evolutionary complexities such as changing mutation rates, selection, reassortment, and recombination, as well as epidemiological complexities such as stochastic population dynamics, host population structure, and different patterns at the within-host and between-host scales. An additional challenge exists in making efficient inferences from an ever increasing corpus of sequence data. (C) 2014 The Authors. Published by Elsevier B.V. C1 [Frost, Simon D. W.] Univ Cambridge, Dept Vet Med, Cambridge, England. [Frost, Simon D. W.] Univ Cambridge, Inst Publ Hlth, Cambridge, England. [Pybus, Oliver G.] Univ Oxford, Dept Zool, Oxford, England. [Gog, Julia R.] Univ Cambridge, Dept Appl Math & Theoret Phys, Cambridge CB3 9EW, England. [Viboud, Cecile] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Bonhoeffer, Sebastian] ETH, Inst Integrat Biol, Zurich, Switzerland. [Bedford, Trevor] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98104 USA. RP Frost, SDW (reprint author), Univ Cambridge, Dept Vet Med, Cambridge, England. EM sdf22@cam.ac.uk RI Bonhoeffer, Sebastian/A-2735-2008; Frost, Simon/F-3648-2010; OI Bonhoeffer, Sebastian/0000-0001-8052-3925; Frost, Simon/0000-0002-5207-9879; Bedford, Trevor/0000-0002-4039-5794; Pybus, Oliver/0000-0002-8797-2667 FU Royal Society Wolfson Research Merit award; MRC Methodology Research Programme grant [MR/J013862/1]; ERC [268540-PBDR]; RAPIDD program of the Science and Technology Directorate, Department of Homeland Security FX S.D.W.F. was supported in part by a Royal Society Wolfson Research Merit award and by an MRC Methodology Research Programme grant (MR/J013862/1). S.B. was supported in part by the ERC advanced grant 268540-PBDR. J.R.G. was supported by the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security. NR 58 TC 22 Z9 22 U1 1 U2 25 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1755-4365 J9 EPIDEMICS-NETH JI Epidemics PD MAR PY 2015 VL 10 BP 88 EP 92 DI 10.1016/j.epidem.2014.09.001 PG 5 WC Infectious Diseases SC Infectious Diseases GA CF0IO UT WOS:000352226900020 PM 25843391 ER PT J AU Sinha, A Singh, VK Cruise, M Afghani, E Matsukuma, K Ali, S Andersen, DK Makary, MA Raman, SP Fishman, EK Zaheer, A AF Sinha, Amitasha Singh, Vikesh K. Cruise, Michael Afghani, Elham Matsukuma, Karen Ali, Sumera Andersen, Dana K. Makary, Martin A. Raman, Siva P. Fishman, Elliot K. Zaheer, Atif TI Abdominal CT predictors of fibrosis in patients with chronic pancreatitis undergoing surgery SO EUROPEAN RADIOLOGY LA English DT Article DE Chronic Pancreatitis; Surgical procedures; Post-operative pain management; Fibrosis; Calcification ID LONG-TERM; COMPUTED-TOMOGRAPHY; DUCT MORPHOLOGY; FREY PROCEDURE; RESECTION; PAIN; AGE; MANAGEMENT; DISEASE; PATTERN AB To determine which abdominal CT findings predict severe fibrosis and post-operative pain relief in chronic pancreatitis (CP). Pre-operative abdominal CTs of 66 patients (mean age 52 +/- 12 years, 53 % males) with painful CP who underwent the Whipple procedure (n = 32), Frey procedure (n = 32) or pancreatic head biopsy (n = 2), between 1/2003-3/2014, were evaluated. CT was evaluated for parenchymal calcifications, intraductal calculi, main pancreatic duct dilation (> 5 mm), main pancreatic duct stricture, and abnormal side branch(es). The surgical histopathology was graded for fibrosis. CT findings were evaluated as predictors of severe fibrosis and post-operative pain relief using regression and area under receiver operating curve (AUC) analysis. Thirty-eight (58 %) patients had severe fibrosis. Parenchymal calcification(s) were an independent predictor of severe fibrosis (p = 0.03), and post-operative pain relief over a mean follow-up of 1-year (p = 0.04). Presence of > 10 parenchymal calcifications had higher predictive accuracy for severe fibrosis than 1-10 parenchymal calcification(s) (AUC 0.88 vs. 0.59, p = 0.003). The predictive accuracy of > 10 versus 1-10 parenchymal calcifications increased after adjusting for all other CT findings (AUC 0.89 vs. 0.63, p = 0.01). Parenchymal calcification(s) independently predict severe fibrosis and are significantly associated with post-operative pain relief in CP. The presence of > 10 parenchymal calcifications is a better predictor of severe fibrosis than 1-10 parenchymal calcification(s). aEuro cent Parenchymal calcifications in chronic pancreatitis independently predict post-operative pain relief aEuro cent Intraductal calculi and MPD dilation are not associated with post-operative pain relief aEuro cent Better patient selection for pancreatic resection surgery in painful chronic pancreatitis. C1 [Ali, Sumera; Raman, Siva P.; Fishman, Elliot K.; Zaheer, Atif] Johns Hopkins Med Inst, Russel H Morgan Dept Radiol & Radiol Sci, Baltimore, MD 21287 USA. [Sinha, Amitasha; Singh, Vikesh K.; Afghani, Elham] Johns Hopkins Med Inst, Div Gastroenterol, Baltimore, MD 21287 USA. [Cruise, Michael; Matsukuma, Karen] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21287 USA. [Makary, Martin A.] Johns Hopkins Med Inst, Dept Surg, Baltimore, MD 21287 USA. [Singh, Vikesh K.; Makary, Martin A.; Zaheer, Atif] Johns Hopkins Med Inst, Pancreatitis Ctr, Baltimore, MD 21287 USA. [Andersen, Dana K.] Natl Inst Diabet & Digest & Kidney Dis, NIH, Bethesda, MD USA. [Zaheer, Atif] Johns Hopkins Med Inst, Baltimore, MD 21287 USA. RP Zaheer, A (reprint author), Johns Hopkins Med Inst, 601 North Caroline St,JHOC 3235 A, Baltimore, MD 21287 USA. EM amitashasinha@gmail.com; vsingh1@jhmi.edu; mwcruise@gmail.com; ellie.afghani@gmail.com; kmatsuku@gmail.com; sumerabhojani@hotmail.com; andersendk@mail.nih.gov; mmakary1@jhmi.edu; sraman3@jhmi.edu; efishman@jhmi.edu; azaheer1@jhmi.edu OI fishman, elliot/0000-0002-2567-1658; Cruise, Michael/0000-0001-6544-732X FU Pancreatitis Research Fund at the Johns Hopkins Medical Institutions FX The scientific guarantor of this publication is Atif Zaheer. The authors of this manuscript declare relationships with the following companies: Vikesh K. Singh is a consultant for Abbvie, Santarus, Boston Scientific, Enteromedics, and Novo Nordisk. The authors of this manuscript declare no relationships with any companies whose products or services may be related to the subject matter of the article. This study has received funding by the Pancreatitis Research Fund at the Johns Hopkins Medical Institutions (VKS). One of the authors has significant statistical expertise. No complex statistical methods were necessary for this paper. Institutional Review Board approval was obtained. Written informed consent was not required for this study because it is an anonymous retrospective chart review. Written informed consent was waived by the Institutional Review Board. Methodology: retrospective, diagnostic or prognostic study, performed at one institution. NR 33 TC 3 Z9 3 U1 0 U2 0 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 MAR PY 2015 VL 25 IS 5 BP 1339 EP 1346 DI 10.1007/s00330-014-3526-x PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CF6EK UT WOS:000352649400014 PM 25471477 ER PT J AU Batycka-Baran, A Hattinger, E Zwicker, S Summer, B Szepietowski, JC Howard, ZO Ruzicka, T Prinz, J Wolf, R AF Batycka-Baran, A. Hattinger, E. Zwicker, S. Summer, B. Szepietowski, J. C. Howard, Z. O. Ruzicka, T. Prinz, J. Wolf, R. TI Leukocyte-derived S100-'alarmins' are UVB-dependent therapeutic markers in psoriasis SO EXPERIMENTAL DERMATOLOGY LA English DT Meeting Abstract CT 42nd Annual Meeting of the Arbeitsgemeinschaft-Dermatologische-Forschung (ADF) CY MAR 05-07, 2015 CL Ulm, GERMANY SP Arbeitsgemeinschaft Dermatologische Forsch C1 [Batycka-Baran, A.; Szepietowski, J. C.] Wroclaw Med Univ, Dept Dermatol Venerol & Allergol, Wroclaw, Poland. [Hattinger, E.; Zwicker, S.; Summer, B.; Ruzicka, T.; Prinz, J.; Wolf, R.] Univ Munich, Dept Dermatol & Allergol, Munich, Germany. [Howard, Z. O.] NCI, Mol Immunoregulat Lab, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0906-6705 EI 1600-0625 J9 EXP DERMATOL JI Exp. Dermatol. PD MAR PY 2015 VL 24 IS 3 MA P170 BP E30 EP E30 PG 1 WC Dermatology SC Dermatology GA CE6IB UT WOS:000351939000171 ER PT J AU Scheffel, J Maurer, M Rivera, J AF Scheffel, J. Maurer, M. Rivera, J. TI Transcriptome analysis of FceRI-stimulated mast cells reveals Syk-independent regulation of gene expression SO EXPERIMENTAL DERMATOLOGY LA English DT Meeting Abstract CT 42nd Annual Meeting of the Arbeitsgemeinschaft-Dermatologische-Forschung (ADF) CY MAR 05-07, 2015 CL Ulm, GERMANY SP Arbeitsgemeinschaft Dermatologische Forsch C1 [Scheffel, J.; Rivera, J.] NIAMS, Immunogenet Mol Lab, NIH, Bethesda, MD 20892 USA. [Scheffel, J.; Maurer, M.] Charite, Dept Dermatol & Allergy, D-10117 Berlin, Germany. 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 0906-6705 EI 1600-0625 J9 EXP DERMATOL JI Exp. Dermatol. PD MAR PY 2015 VL 24 IS 3 MA P037 BP E7 EP E7 PG 1 WC Dermatology SC Dermatology GA CE6IB UT WOS:000351939000038 ER PT J AU Ferguson, GM Bornstein, MH AF Ferguson, Gail M. Bornstein, Marc H. TI Remote acculturation of early adolescents in Jamaica towards European American culture: A replication and extension SO INTERNATIONAL JOURNAL OF INTERCULTURAL RELATIONS LA English DT Article DE Globalization; Tridimensional acculturation; Immigration; Caribbean/West Indian; Media; Fast food ID IMMIGRANT FAMILIES; UNITED-STATES; IDENTITY; ADAPTATION; SCALE AB Remote acculturation is a modern form of non-immigrant acculturation identified among early adolescents in Jamaica as "Americanization". This study aimed to replicate the original remote acculturation findings in a new cohort of early adolescents in Jamaica (n = 222; M= 12.08 years) and to extend our understanding of remote acculturation by investigating potential vehicles of indirect and intermittent intercultural contact. Cluster analyses replicated prior findings: relative to Traditional Jamaican adolescents (62%), Americanized Jamaican adolescents (38%) reported stronger European American cultural orientation, lower Jamaican orientation, lower family obligations, and greater conflict with parents. More U.S. media (girls) and less local media and local sports (all) were the primary vehicles of intercultural contact predicting higher odds of Americanization. U.S. food, U.S. tourism, and transnational communication were also linked to U.S. orientation. Findings have implications for acculturation research and for practice and policy targeting Caribbean youth and families. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Ferguson, Gail M.] Univ Illinois, Dept Human & Community Dev, Urbana, IL 61801 USA. [Ferguson, Gail M.] Knox Coll, Dept Psychol, Galesburg, IL 61401 USA. [Bornstein, Marc H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Child & Family Res Sect, NIH, Bethesda, MD 20892 USA. RP Ferguson, GM (reprint author), Univ Illinois, Dept Human & Community Dev, Doris Kelley Christopher Hall,MC-081,904 West Nev, Urbana, IL 61801 USA. EM gmfergus@illinois.edu FU Intramural NIH HHS [ZIA HD001119-23] NR 48 TC 5 Z9 5 U1 4 U2 12 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0147-1767 EI 1873-7552 J9 INT J INTERCULT REL JI Int. J. Intercult. Relat. PD MAR PY 2015 VL 45 BP 24 EP 35 DI 10.1016/j.ijintrel.2014.12.007 PG 12 WC Psychology, Social; Social Sciences, Interdisciplinary; Sociology SC Psychology; Social Sciences - Other Topics; Sociology GA CF0OQ UT WOS:000352244400003 PM 25709142 ER PT J AU Shi, GP Chen, SQ Wandu, WS Ogbeifun, O Nugent, LF Maminishkis, A Hinshaw, SJH Rodriguez, IR Gery, I AF Shi, Guangpu Chen, Siqi Wandu, Wambui S. Ogbeifun, Osato Nugent, Lindsey F. Maminishkis, Arvydas Hinshaw, Samuel J. H. Rodriguez, Ignacio R. Gery, Igal TI Inflammasomes Induced by 7-Ketocholesterol and Other Stimuli in RPE and in Bone Marrow-Derived Cells Differ Markedly in Their Production of IL-1 beta and IL-18 SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article DE bone marrow-derived cells; IL-1; IL-18; inflammasomes; RPE cells ID RETINAL-PIGMENT EPITHELIUM; MACULAR DEGENERATION; NLRP3 INFLAMMASOME; ACTIVATION; INDUCTION; ATHEROSCLEROSIS; INTERLEUKIN-18; OXYSTEROLS; DRUSEN; VEGF AB PURPOSE. The inflammatory process plays a major role in the pathogenesis of AMD, and recent data indicate the involvement of inflammasomes. Inflammasomes are intracellular structures that trigger inflammation by producing mature interleukin-(IL)-1 beta and IL-18. This study examined the capacity of 7-ketocholesterol (7KCh), an oxysterol that accumulates in the retinal pigmented epithelium (RPE) and choroid, to initiate inflammasome formation in RPE and bone marrow-derived cells. METHODS. Tested cells included fetal human RPE (fhRPE), human ARPE-19 cells, primary human brain microglia cells, and human THP-1 monocyte cells. 7-Ketocholesterol and other compounds were added to the cell cultures, and their stimulatory effects were determined by quantitative PCR and release of cytokines, measured by ELISA and Western blotting. RESULTS. 7-Ketocholesterol efficiently induced inflammasome formation by all primed cell populations, but secreted cytokine levels were higher in cultures of bone marrow-derived cells (microglia and THP-1 cells) than in RPE cultures. Interestingly, inflammasomes formed in cells of the two populations differed strikingly in their preferential production of the two cytokines. Thus, whereas bone marrow-derived cells produced levels of IL-1 beta that were higher than those of IL-18, the opposite was found with RPE cells, which secreted higher levels of IL-18. Importantly, Western blot analysis showed that IL-18, but not IL-1 beta, was expressed constitutively by RPE cells. CONCLUSIONS. 7-Ketocholesterol efficiently stimulates inflammasome formation and is conceivably involved in the pathogenesis of AMD. In contrast to bone marrow-derived cells, RPE cells produced higher levels of IL-18 than IL-1 beta. Further, IL-18, a multifunctional cytokine, was expressed constitutively by RPE cells. These observations provide new information about stimuli and cells and their products assumed to be involved in the pathogenesis of AMD. C1 [Shi, Guangpu; Chen, Siqi; Wandu, Wambui S.; Ogbeifun, Osato; Nugent, Lindsey F.; Hinshaw, Samuel J. H.; Gery, Igal] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Maminishkis, Arvydas] NEI, Sect Epithelial & Retinal Physiol & Dis, NIH, Bethesda, MD USA. [Rodriguez, Ignacio R.] NEI, Lab Retinal Cell & Mol Biol, NIH, Bethesda, MD USA. RP Gery, I (reprint author), NEI, Immunol Lab, NIH, Bldg 10,Room 10N208, Bethesda, MD 20892 USA. EM geryi@nei.nih.gov FU Intramural Research Program of the National Eye Institute, National Institutes of Health FX Supported by the Intramural Research Program of the National Eye Institute, National Institutes of Health. NR 32 TC 3 Z9 3 U1 0 U2 2 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 MAR PY 2015 VL 56 IS 3 BP 1658 EP 1664 DI 10.1167/iovs.14-14557 PG 7 WC Ophthalmology SC Ophthalmology GA CE9BF UT WOS:000352137600035 PM 25678688 ER PT J AU Kaup, AR Nettiksimmons, J Harris, TB Sink, KM Satterfield, S Metti, AL Ayonayon, HN Yaffe, K AF Kaup, Allison R. Nettiksimmons, Jasmine Harris, Tamara B. Sink, Kaycee M. Satterfield, Suzanne Metti, Andrea L. Ayonayon, Hilsa N. Yaffe, Kristine CA Hlth Aging Body Composition Hlth TI Cognitive Resilience to Apolipoprotein E epsilon 4 Contributing Factors in Black and White Older Adults SO JAMA NEUROLOGY LA English DT Article ID ALZHEIMER-DISEASE; AFRICAN-AMERICANS; BODY-COMPOSITION; VARIABLE IMPORTANCE; METABOLIC SYNDROME; RANDOM FORESTS; APOE GENOTYPE; RISK-FACTORS; DEMENTIA; COMMUNITY AB IMPORTANCE Apolipoprotein E (APOE) epsilon 4 is an established risk factor for cognitive decline and the development of dementia, but other factors may help to minimize its effects. OBJECTIVE Using APOE epsilon 4 as an indicator of high risk, we investigated factors associated with cognitive resilience among black and white older adults who are APOE epsilon 4 carriers. DESIGN, SETTING, AND PARTICIPANTS Participants included 2487 community-dwelling older (aged 69-80 years at baseline) black and white adults examined at 2 community clinics in the prospective cohort Health, Aging, and Body Composition (Health ABC) study. The baseline visits occurred from May 1997 through June 1998. Our primary analytic cohort consisted of 670 APOE epsilon 4 carriers (329 black and 341 white participants) who were free of cognitive impairment at baseline and underwent repeated cognitive testing during an 11-year follow-up (through 2008) using the Modified Mini-Mental State Examination. MAIN OUTCOMES AND MEASURES We stratified all analyses by race. Using the Modified Mini-Mental State Examination scores, we assessed normative cognitive change in the entire cohort (n = 2487) and classified the APOE epsilon 4 carriers as being cognitively resilient vs nonresilient by comparing their cognitive trajectories with those of the entire cohort. We then conducted bivariate analyses and multivariable random forest and logistic regression analyses to explore factors predictive of cognitive resilience in APOE epsilon 4 carriers. RESULTS Among white APOE epsilon 4 carriers, the strongest predictors of cognitive resilience were, in relative order of importance, no recent negative life events, a higher literacy level, advanced age, a higher educational level, and more time spent reading. Among black APOE epsilon 4 carriers, the strongest predictors of cognitive resilience were, in relative order of importance, a higher literacy level, a higher educational level, female sex, and the absence of diabetes mellitus. In follow-up logistic regression models, higher literacy level (adjusted odds ratio [OR], 9.50 [95% CI, 2.67-60.89]), a higher educational level (adjusted OR for college graduate vs less than high school, 3.81 [95% CI, 1.13-17.56]), and age (adjusted OR for 73-76 vs 69-72 years, 2.01 [95% CI, 1.13-3.63]) had significant independent effects in predicting cognitive resilience among white APOE epsilon 4 carriers. Among black APOE epsilon 4 carriers, a higher literacy level (adjusted OR, 2.27 [95% CI, 1.29-4.06]) and a higher educational level (adjusted OR for high school graduate/some college vs less than high school, 2.86 [95% CI, 1.54-5.49]; adjusted OR for college graduate vs less than high school, 2.52 [95% CI, 1.14-5.62]) had significant independent effects in predicting cognitive resilience. CONCLUSIONS AND RELEVANCE Although APOE epsilon 4 carriers are at high risk for cognitive decline, our findings suggest possible intervention targets, including the enhancement of cognitive reserve and improvement of other psychosocial and health factors, to promote cognitive resilience among black and white APOE epsilon 4 carriers. C1 [Kaup, Allison R.; Yaffe, Kristine] San Francisco VA Med Ctr, Sierra Pacific Mental Illness Res Educ & Clin Ctr, San Francisco, CA 94121 USA. [Kaup, Allison R.; Nettiksimmons, Jasmine; Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Harris, Tamara B.] NIA, Lab Epidemiol & Populat Sci, Intramural Res Program, Bethesda, MD 20892 USA. [Sink, Kaycee M.] Wake Forest Sch Med, Dept Med, Sect Gerontol & Geriatr Med, Winston Salem, NC USA. [Satterfield, Suzanne] Univ Tennessee Hlth Sci Ctr, Dept Prevent Med, Memphis, TN USA. [Metti, Andrea L.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Ayonayon, Hilsa N.; Yaffe, Kristine] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. RP Kaup, AR (reprint author), San Francisco VA Med Ctr, Sierra Pacific Mental Illness Res Educ & Clin Ctr, 4150 Clement St,Mail Code T16H, San Francisco, CA 94121 USA. EM allison.kaup@ucsf.edu FU NIA [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050, K24AG031155]; National Institute on Nursing Research [R01-NR012459]; NIA/NIH; Department of Veterans Affairs Office of Academic Affiliations Advanced Fellowship Program in Mental Illness Research and Treatment; Medical Research Service of the San Francisco Veterans Affairs Medical Center; Sierra Pacific Mental Illness Research, Education, and Clinical Center FX This study was supported by contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106 and grant R01-AG028050 from the NIA; by grant R01-NR012459 from the National Institute on Nursing Research; and in part by the Intramural Research Program of the NIA/NIH, all of which supported the design and conduct of the study; collection, management, analysis, and interpretation of the data; and review and approval of the manuscript. This study was also supported by grant K24AG031155 from the NIA (Dr Yaffe), which supported the design and conduct of the study, analysis and interpretation of the data, preparation and review of the manuscript, and decision to submit the manuscript for publication. Preparation of the manuscript was supported by the Department of Veterans Affairs Office of Academic Affiliations Advanced Fellowship Program in Mental Illness Research and Treatment, the Medical Research Service of the San Francisco Veterans Affairs Medical Center, and the Sierra Pacific Mental Illness Research, Education, and Clinical Center. NR 38 TC 5 Z9 5 U1 1 U2 5 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6149 EI 2168-6157 J9 JAMA NEUROL JI JAMA Neurol. PD MAR PY 2015 VL 72 IS 3 BP 340 EP 348 DI 10.1001/jamaneurol.2014.3978 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA CE9IJ UT WOS:000352157200015 PM 25599330 ER PT J AU Corps, KN Roth, TL McGavern, DB AF Corps, Kara N. Roth, Theodore L. McGavern, Dorian B. TI Inflammation and Neuroprotection in Traumatic Brain Injury SO JAMA NEUROLOGY LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; SPINAL-CORD-INJURY; NADPH OXIDASE; IN-VIVO; RECRUITMENT; MICROGLIA; NEUTROPHILS; ACTIVATION; EXPRESSION; BARRIER AB IMPORTANCE Traumatic brain injury (TBI) is a significant public health concern that affects individuals in all demographics. With increasing interest in the medical and public communities, understanding the inflammatory mechanisms that drive the pathologic and consequent cognitive outcomes can inform future research and clinical decisions for patients with TBI. OBJECTIVES To review known inflammatory mechanisms in TBI and to highlight clinical trials and neuroprotective therapeutic manipulations of pathologic and inflammatory mechanisms of TBI. EVIDENCE REVIEW We searched articles in PubMed published between 1960 and August 1, 2014, using the following keywords: traumatic brain injury, sterile injury, inflammation, astrocytes, microglia, monocytes, macrophages, neutrophils, T cells, reactive oxygen species, alarmins, danger-associated molecular patterns, purinergic receptors, neuroprotection, and clinical trials. Previous clinical trials or therapeutic studies that involved manipulation of the discussed mechanisms were considered for inclusion. The final list of selected studies was assembled based on novelty and direct relevance to the primary focus of this review. FINDINGS Traumatic brain injury is a diverse group of sterile injuries induced by primary and secondary mechanisms that give rise to cell death, inflammation, and neurologic dysfunction in patients of all demographics. Pathogenesis is driven by complex, interacting mechanisms that include reactive oxygen species, ion channel and gap junction signaling, purinergic receptor signaling, excitotoxic neurotransmitter signaling, perturbations in calcium homeostasis, and damage-associated molecular pattern molecules, among others. Central nervous system resident and peripherally derived inflammatory cells respond to TBI and can provide neuroprotection or participate in maladaptive secondary injury reactions. The exact contribution of inflammatory cells to a TBI lesion is dictated by their anatomical positioning as well as the local cues to which they are exposed. CONCLUSIONS AND RELEVANCE The mechanisms that drive TBI lesion development as well as those that promote repair are exceedingly complex and often superimposed. Because pathogenic mechanisms can diversify over time or even differ based on the injury type, it is important that neuroprotective therapeutics be developed and administered with these variables in mind. Due to its complexity, TBI has proven particularly challenging to treat; however, a number of promising therapeutic approaches are now under pre-clinical development, and recent clinical trials have even yielded a few successes. Given the worldwide impact of TBI on the human population, it is imperative that research remains active in this area and that we continue to develop therapeutics to improve outcome in afflicted patients. C1 [Corps, Kara N.; Roth, Theodore L.; McGavern, Dorian B.] NINDS, Viral Immunol & Intravital Imaging Sect, NIH, Bethesda, MD 20892 USA. RP McGavern, DB (reprint author), NINDS, Viral Immunol & Intravital Imaging Sect, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM mcgavernd@mail.nih.gov OI McGavern, Dorian/0000-0001-9568-545X; Roth, Theodore/0000-0002-3970-9573 FU National Institutes of Health FX This work was supported by the National Institutes of Health intramural program. NR 59 TC 71 Z9 73 U1 12 U2 30 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6149 EI 2168-6157 J9 JAMA NEUROL JI JAMA Neurol. PD MAR PY 2015 VL 72 IS 3 BP 355 EP 362 DI 10.1001/jamaneurol.2014.3558 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA CE9IJ UT WOS:000352157200017 PM 25599342 ER PT J AU Barros, FC Papageorghiou, AT Victora, CG Noble, JA Pang, RY Lams, J Ismail, LC Goldenberg, RL Lambert, A Kramer, MS Carvalho, M Conde-Agudelo, A Jaffer, YA Bertino, E Gravett, MG Altman, DG Ohuma, EO Purwar, M Frederick, LO Bhutta, ZA Kennedy, SH Villar, J AF Barros, Fernando C. Papageorghiou, Aris T. Victora, Cesar G. Noble, Julia A. Pang, Ruyan Lams, Jay Ismail, Leila Cheikh Goldenberg, Robert L. Lambert, Ann Kramer, Michael S. Carvalho, Maria Conde-Agudelo, Agustin Jaffer, Yasmin A. Bertino, Enrico Gravett, Michael G. Altman, Doug G. Ohuma, Eric O. Purwar, Manorama Frederick, Lhunnaya O. Bhutta, Zulfigar A. Kennedy, Stephen H. Villar, Jose CA Int Fetal & Newborn Growth Consort TI The Distribution of Clinical Phenotypes of Preterm Birth Syndrome Implications for Prevention SO JAMA PEDIATRICS LA English DT Article ID TIME TRENDS; INTERGROWTH-21ST PROJECT; SYSTEMATIC ANALYSIS; CLUSTER-ANALYSIS; COUNTRIES; OUTCOMES; WEIGHT; HEALTH AB IMPORTANCE Preterm birth has been difficult to study and Prevent because of its complex syndromic nature. OBJECTIVE To identify phenotypes of preterm delivery syndrome in the Newborn Cross-Sectional Study of the INTERGROWTH-21st Project. DESIGN, SETTING, AND PARTICIPANTS A population-based, multiethnic, cross-sectional study conducted at 8 geographically demarcated sites in Brazil, China, India, Italy, Kenya, Oman, the United Kingdom, and the United States. A total of 60 058 births over a 12-month fixed period between April 27, 2009, and March 2, 2014. Of these, 53 871 had an ultrasonography estimate of gestational age, among which 5828 were preterm births (10.8%). Pregnancies were prospectively studied using a standardized data collection and online data management system. Newborns had anthroponietric and clinical examinations using standardized methods and identical equipment and were followed up until hospital discharge. MAIN OUTCOMES AND MEASURES The main study outcomes were clusters of preterm phenotypes and for each cluster, we analyzed signs of presentation at hospital admission, admission rates for neonatal intensive care for 7 days or more, and neonatal mortality rates. RESULTS Twelve Preterm birth clusters were identified using our conceptual framework. Eleven consisted of combinations of conditions known to be associated with preterm birth, 10 of which were dominated by a single condition. However, the most common single cluster (30.0% of the total preterm cases; n = 1747) was not associated with any severe maternal, fetal, or placental condition that was clinically detectable based on the information available; within this cluster, many cases were caregiver initiated. Only 22% (n = 1284) of all the preterm births occurred spontaneously without any of these severe conditions. Maternal presentation on hospital admission, newborn anthropometry, and risk for death before hospital discharge or admission for 7 or more days to a neonatal intensive care unit, none of which were used to construct the clusters, also differed according to the identified phenotypes. The prevalence of preterm birth ranged from 8.2% in Muscat, Oman, and Oxford, England, to 16.6% in Seattle, Washington. CONCLUSIONS AND RELEVANCE We identified 12 preterm birth phenotypes associated with different patterns of neonatal outcomes. In 22% of all Preterm births, Parturition started spontaneously and was not associated with any of the phenotypic conditions considered. We believe these results contribute to an improved understanding of this complex syndrome and provide an empirical basis to focus research on a more homogenous set of phenotypes. C1 [Barros, Fernando C.] Univ Catolica Pelotas, Programa Posgrad Saude & Comportamento, Pelotas, RS, Brazil. [Barros, Fernando C.; Victora, Cesar G.] Univ Fed Pelotas, Programa Posgradu Epidemiol, Pelotas, RS, Brazil. [Papageorghiou, Aris T.; Ismail, Leila Cheikh; Lambert, Ann; Ohuma, Eric O.; Kennedy, Stephen H.; Villar, Jose] Univ Oxford, Green Templeton Coll, Nuffield Dept Obstet & Gynaecol, Oxford, England. [Papageorghiou, Aris T.; Ismail, Leila Cheikh; Lambert, Ann; Ohuma, Eric O.; Kennedy, Stephen H.; Villar, Jose] Univ Oxford, Green Templeton Coll, Oxford Maternal & Perinatal Hlth Inst, Oxford, England. [Noble, Julia A.] Univ Oxford, Dept Engn Sci, Oxford OX1 3PJ, England. [Pang, Ruyan] Peking Univ, Sch Publ Hlth, Beijing 100871, Peoples R China. [Lams, Jay] Ohio State Univ, Dept Obstet & Gynecol, Columbus, OH 43210 USA. [Goldenberg, Robert L.] Columbia Univ, Dept Obstet & Gynecol, New York, NY USA. [Kramer, Michael S.] McGill Univ, Fac Med, Dept Pediat & Epidemiol Biostat & Occupat Hlth, Montreal, PQ, Canada. [Carvalho, Maria] Aga Khan Univ, Fac Hlth Sci, Nairobi, Kenya. [Conde-Agudelo, Agustin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Dept Hlth & Human Serv, NIH, Bethesda, MD USA. [Conde-Agudelo, Agustin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Dept Hlth & Human Serv, NIH, Detroit, MI USA. [Jaffer, Yasmin A.] Minist Hlth, Dept Family & Community Hlth, Muscat, Oman. [Bertino, Enrico] Univ Turin, Dipartimento Sci Pediatr & Adolescenza, Cattedradi Neonatol, Turin, Italy. [Gravett, Michael G.] Univ Washington, Sch Med, Seattle, WA USA. [Altman, Doug G.; Ohuma, Eric O.] Univ Oxford, Botnar Res Ctr, Ctr Stat Med, Oxford, England. [Purwar, Manorama] Ketkar Hosp, Nagpur INTERGROWTH Res Ctr 21, Nagpur, Maharashtra, India. [Frederick, Lhunnaya O.] Swedish Med Ctr, Ctr Perinatal Studies, Seattle, WA USA. [Bhutta, Zulfigar A.] Aga Khan Univ, Ctr Excellence Women & Child Hlth, Karachi, Pakistan. [Bhutta, Zulfigar A.] Hosp Sick Children, Ctr Global Child Hlth, Toronto, ON M5G 1X8, Canada. RP Villar, J (reprint author), Univ Oxford, Womens Ctr, John Radcliffe Hosp, Nuffield Dept Obstet & Gynaecol, Level 3, Oxford OX3 9DU, England. EM jose.villar@obs-gyn.ox.ac.uk RI Epidemiologicas, Centro de pesquisas /D-4561-2013; Sanchez Luna, Manuel/H-2165-2014; Victora, Cesar/D-4476-2013; OI Sanchez Luna, Manuel/0000-0001-9543-7392; Todros, Tullia/0000-0003-3016-1510; Victora, Cesar/0000-0002-2465-2180; Matijasevich, Alicia/0000-0003-0060-1589; Giuliani, Francesca/0000-0002-4265-207X FU Bill and Melinda Gates Foundation [49038] FX This study was supported by INTERGROWTH-21st grant 49038 from the Bill and Melinda Gates Foundation to the University of Oxford. NR 36 TC 14 Z9 15 U1 2 U2 7 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6203 EI 2168-6211 J9 JAMA PEDIATR JI JAMA Pediatr. PD MAR PY 2015 VL 169 IS 3 BP 220 EP 229 DI 10.1001/jamapediatrics.2014.3040 PG 10 WC Pediatrics SC Pediatrics GA CF3KR UT WOS:000352447900010 PM 25561016 ER PT J AU Ellen, JM Greenberg, L Willard, N Korelitz, J Kapogiannis, BG Monte, D Boyer, CB Harper, GW Henry-Reid, LM Friedman, LB Gonin, R AF Ellen, Jonathan M. Greenberg, Lauren Willard, Nancy Korelitz, James Kapogiannis, Bill G. Monte, Dina Boyer, Cherrie B. Harper, Gary W. Henry-Reid, Lisa M. Friedman, Lawrence B. Gonin, Rene TI Evaluation of the Effect of Human Immunodeficiency Virus-Related Structural Interventions The Connect to Protect Project SO JAMA PEDIATRICS LA English DT Article ID HIV PREVENTION; HEALTH AB IMPORTANCE With the emphasis on structural-level interventions that target social determinants of human immunodeficiency virus (HIV) transmission to curb the HIV epidemic, there is a need to develop evaluation models that can detect changes in individual factors associated with HIV-related structural changes. OBJECTIVE To describe whether structural changes developed and achieved by community coalitions are associated with an effect on individual factors associated with the risk of contracting HIV. DESIGN, SETTING, AND PARTICIPANTS In this serial cross-sectional survey design, data were collected from 8 cities during 4 rounds of annual surveys from March 13, 2007, through July 29, 2010. Study recruitment took place at venues where the population of focus was known to congregate, such as clubs, bars, community centers, and low-income housing. The convenience sample of at-risk youth (persons aged 12-24 years) included 5337 individuals approached about the survey and 3142 (58.9%) who were screened for eligibility. Of the 2607 eligible participants, 2559 (98.2%) ultimately agreed to participate. INTERVENTIONS Achievement of locally identified structural changes that targeted public and private entities (eg, federal agencies, homeless shelters, and school systems) with the goal of fostering changes in policy and practice to ultimately facilitate positive behavioral changes aimed at preventing HIV. MAIN OUTCOMES AND MEASURES Number of sexual partners, partner characteristics, condom use, and history of sexually transmitted infections and HIV testing. RESULTS Exposure to structural changes was not statistically significantly associated with any of the outcome measures, although some results were in the direction of a positive structural change effect (eg, a 10-unit increase in a structural change score had an odds ratio of 0.88 [95% Cl, 0.76-1.03; P = .11] for having an older sexual partner and an odds ratio of 0.91[95% Cl, 0.60-1.39; P = .39] for using a condom half the time or less with a casual partner). CONCLUSIONS AND RELEVANCE This study evaluated a broad representation of at-risk individuals and assessed the effect of numerous structural changes related to various HIV risk factors. No structural changes as measured in this study were associated with a statistically significant reduction in risk behaviors. These null findings underscore the need for a long-term approach in evaluating structural interventions and the development of more nuanced methods of quantifying and comparing structural-change initiatives and determining the appropriate strategies for evaluating effect. C1 [Ellen, Jonathan M.] Johns Hopkins Med, All Childrens Hosp, Sch Med, Dept Pediat, St Petersburg, FL 33701 USA. [Greenberg, Lauren; Korelitz, James; Monte, Dina; Gonin, Rene] Westat Corp, Hlth Studies Sect, Rockville, MD USA. [Willard, Nancy] Johns Hopkins Univ, Dept Pediat, Sch Med, Baltimore, MD 21218 USA. [Kapogiannis, Bill G.] NICHHD, NIH, Bethesda, MD 20892 USA. [Boyer, Cherrie B.] Univ Calif San Francisco, Dept Pediat, Div Adolescent Med, San Francisco, CA 94143 USA. [Harper, Gary W.] Univ Michigan, Sch Publ Hlth, Dept Hlth Behav & Hlth Educ, Ann Arbor, MI 48109 USA. [Henry-Reid, Lisa M.] John H Stroger Jr Hosp Cook Cty, Dept Pediat, Chicago, IL USA. [Friedman, Lawrence B.] Univ Miami, Miller Sch Med, Dept Pediat, Div Adolescent Med, Miami, FL 33136 USA. RP Ellen, JM (reprint author), Johns Hopkins Med, All Childrens Hosp, Sch Med, Dept Pediat, 5016th Ave, St Petersburg, FL 33701 USA. EM jellen@jhmi.edu FU Adolescent Medicine Trials Network for HIV/AIDS Interventions from the National Institutes of Health through the National Institute of Child Health and Human Development [U01 HD 040533, U01 HD 040474]; National Institutes on Drug Abuse and Mental Health FX This work was supported by grants U01 HD 040533 and U01 HD 040474 from The Adolescent Medicine Trials Network for HIV/AIDS Interventions from the National Institutes of Health through the National Institute of Child Health and Human Development (Dr Kapogiannis), with supplemental funding from the National Institutes on Drug Abuse and Mental Health. NR 14 TC 2 Z9 2 U1 0 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6203 EI 2168-6211 J9 JAMA PEDIATR JI JAMA Pediatr. PD MAR PY 2015 VL 169 IS 3 BP 256 EP 263 DI 10.1001/jamapediatrics.2014.3010 PG 8 WC Pediatrics SC Pediatrics GA CF3KR UT WOS:000352447900014 PM 25580593 ER PT J AU Casey, W Jacobs, A Maull, E Matheson, J Clarke, C Lowit, A AF Casey, Warren Jacobs, Abigail Maull, Elizabeth Matheson, Joanna Clarke, Carol Lowit, Anna TI A New Path Forward: The Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) and National Toxicology Program's Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM) SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Article AB In 2000, the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) was congressionally established, with representatives from Federal regulatory and research agencies that require, use, generate, or disseminate toxicologic and safety testing information. For over 15 y, ICCVAM and the National Toxicology Program's Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM) have worked together to promote the development, validation, and regulatory acceptance of test methods that replace, reduce, or refine the use of animals in regulatory testing. In 2013, both NICEATM and ICCVAM underwent major changes to their operating paradigms, to increase the speed and efficiency of regulatory approval and industry adoption of 3Rs testing methods within the United States and internationally. Accordingly, increased emphasis has been placed on international activities, primarily through interaction with the Organization for Economic Cooperation and Development and participation in the International Cooperation on Alternative Test Methods. In addition, ICCVAM has committed to increasing public awareness of and transparency about federal agencies' 3R activities and to fostering interactions with stakeholders. Finally, although it continues to support ICCVAM, NICEATM's work now includes validation support for Tox21, a collaboration aimed at identifying in vitro methods and computational approaches for testing chemicals to better understand and predict hazards to humans and the environment. The combination of more efficient operating paradigms, increased international collaboration, improved communication and interaction with stakeholders, and active participation in Tox21 likely will substantially increase the number of 3Rs methods developed and used in the United States and internationally. C1 [Casey, Warren; Maull, Elizabeth] NIEHS, NIH, DNTP, NICEATM, Res Triangle Pk, NC 27709 USA. [Jacobs, Abigail] FDA, CDER, Silver Spring, MD USA. [Matheson, Joanna; Lowit, Anna] US Consumer Prod Safety Commiss, Bethesda, MD USA. [Clarke, Carol] USDA, Riverdale, MD USA. US EPA, Washington, DC 20460 USA. RP Casey, W (reprint author), NIEHS, NIH, DNTP, NICEATM, POB 12233, Res Triangle Pk, NC 27709 USA. EM warren.casey@nih.gov NR 3 TC 4 Z9 4 U1 0 U2 5 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD MAR PY 2015 VL 54 IS 2 BP 170 EP 173 PG 4 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA CE8UJ UT WOS:000352119300008 PM 25836963 ER PT J AU Duverger, O AF Duverger, Olivier TI Hair keratins in tooth enamel: the link between hair disorders and dental caries SO M S-MEDECINE SCIENCES LA French DT News Item ID PROTEIN; MATRIX C1 NIAMSD, Skin Biol Lab, NIH, Bethesda, MD 20892 USA. RP Duverger, O (reprint author), NIAMSD, Skin Biol Lab, NIH, 50 South Dr, Bethesda, MD 20892 USA. EM duvergero@mail.nih.gov NR 10 TC 0 Z9 0 U1 3 U2 7 PU EDP SCIENCES S A PI LES ULIS CEDEX A PA 17, AVE DU HOGGAR, PA COURTABOEUF, BP 112, F-91944 LES ULIS CEDEX A, FRANCE SN 0767-0974 J9 M S-MED SCI JI M S-Med. Sci. PD MAR PY 2015 VL 31 IS 3 BP 239 EP 241 DI 10.1051/medsci/20153103004 PG 4 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CF4FK UT WOS:000352504000004 PM 25855272 ER PT J AU Carpentier, A Liang, TJ AF Carpentier, Arnaud Liang, T. Jake TI Transplantation of human hepatocytes derived from stem cells in the liver of mouse A new murine model of infection by the virus of hepatitis C SO M S-MEDECINE SCIENCES LA French DT News Item ID DIFFERENTIATION C1 [Carpentier, Arnaud; Liang, T. Jake] NIDDK, Liver Dis Branch, Bethesda, MD 20892 USA. RP Carpentier, A (reprint author), NIDDK, Liver Dis Branch, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM arnaud.carpentier@nih.gov NR 11 TC 2 Z9 2 U1 0 U2 1 PU EDP SCIENCES S A PI LES ULIS CEDEX A PA 17, AVE DU HOGGAR, PA COURTABOEUF, BP 112, F-91944 LES ULIS CEDEX A, FRANCE SN 0767-0974 J9 M S-MED SCI JI M S-Med. Sci. PD MAR PY 2015 VL 31 IS 3 BP 256 EP 259 DI 10.1051/medsci/20153103010 PG 4 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CF4FK UT WOS:000352504000010 PM 25855278 ER PT J AU Asanuma, D Sakabe, M Kamiya, M Yamamoto, K Hiratake, J Ogawa, M Kosaka, N Choyke, PL Nagano, T Kobayashi, H Urano, Y AF Asanuma, Daisuke Sakabe, Masayo Kamiya, Mako Yamamoto, Kyoko Hiratake, Jun Ogawa, Mikako Kosaka, Nobuyuki Choyke, Peter L. Nagano, Tetsuo Kobayashi, Hisataka Urano, Yasuteru TI Sensitive beta-galactosidase-targeting fluorescence probe for visualizing small peritoneal metastatic tumours in vivo SO NATURE COMMUNICATIONS LA English DT Article ID GYNECOLOGIC-ONCOLOGY-GROUP; EPITHELIAL OVARIAN-CANCER; 5-AMINOLEVULINIC ACID; GLYCOSIDASE ACTIVITIES; PROTOPORPHYRIN-IX; CELL-LINE; CARCINOMA; RESECTION; BLADDER; PREDICTION AB Fluorescence-guided diagnostics is one of the most promising approaches for facile detection of cancer in situ. Here we focus on beta-galactosidase, which is overexpressed in primary ovarian cancers, as a molecular target for visualizing peritoneal metastases from ovarian cancers. As existing fluorescence probes are unsuitable, we have designed membrane-permeable HMRef-beta Gal, in which the optimized intramolecular spirocyclic function affords > 1,400-fold fluorescence enhancement on activation. We confirm that HMRef-bGal sensitively detects intracellular beta-galactosidase activity in several ovarian cancer lines. In vivo, this probe visualizes metastases as small as < 1 mm in diameter in seven mouse models of disseminated human peritoneal ovarian cancer (SHIN3, SKOV3, OVK18, OVCAR3, OVCAR4, OVCAR5 and OVCAR8). Because of its high brightness, real-time detection of metastases with the naked eye is possible. Endoscopic fluorescence detection of metastases is also demonstrated. The results clearly indicate preclinical potential value of the probe for fluorescence-guided diagnosis of peritoneal metastases from ovarian cancers. C1 [Asanuma, Daisuke; Kamiya, Mako; Yamamoto, Kyoko; Urano, Yasuteru] Univ Tokyo, Grad Sch Med, Bunkyo Ku, Tokyo 1130033, Japan. [Asanuma, Daisuke; Sakabe, Masayo; Urano, Yasuteru] Univ Tokyo, Grad Sch Pharmaceut Sci, Bunkyo Ku, Tokyo 1130033, Japan. [Kamiya, Mako] Japan Sci & Technol Agcy, PRESTO, Kawaguchi, Saitama 3320012, Japan. [Hiratake, Jun] Kyoto Univ, Inst Chem Res, Uji, Kyoto 6110011, Japan. [Ogawa, Mikako; Kosaka, Nobuyuki; Choyke, Peter L.; Kobayashi, Hisataka] NCI, Mol Imaging Program, Ctr Canc Res, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Nagano, Tetsuo] Univ Tokyo, Open Innovat Ctr Drug Discovery, Bunkyo Ku, Tokyo 1130033, Japan. [Urano, Yasuteru] Japan Sci & Technol Agcy, CREST, Kawaguchi, Saitama 3320012, Japan. [Urano, Yasuteru] Japan Sci & Technol Agcy, Basic Res Program, Kawaguchi, Saitama 3320012, Japan. RP Urano, Y (reprint author), Univ Tokyo, Grad Sch Med, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan. EM uranokun@m.u-tokyo.ac.jp FU Ministry of Education, Culture, Sports, Science and Technology of Japan [26560441, 23249004, 26111012, 23113504, 25113707, 25870180]; Specially Promoted Research Grant [22000006]; Research Foundation for Opto-Science and Technology; Japan Science and Technology Agency; JSPS Core-to-Core Program; Daiichi-Sankyo Foundation of Life Science; Mochida Memorial Foundation for Medical and Pharmaceutical Research; Tokyo Society of Medical Sciences; A. Advanced Research Networks FX This research was supported in part by the Ministry of Education, Culture, Sports, Science and Technology of Japan (Grant-in-Aid for Scientific Research (KAKENHI), grant 26560441 to D.A., grants 23249004 and 26111012 to Y.U., and grants 23113504, 25113707 and 25870180 to M.K.), by Specially Promoted Research Grant (22000006 to T.N.), by a Basic Research Program from the Japan Science and Technology Agency (to Y.U.), by Research Foundation for Opto-Science and Technology (to D.A.), by JSPS Core-to-Core Program, A. Advanced Research Networks, by The Daiichi-Sankyo Foundation of Life Science (grant to Y.U.), by The Mochida Memorial Foundation for Medical and Pharmaceutical Research (grants to D.A. and M.K.) and by the Tokyo Society of Medical Sciences (grant to M.K.). We also thank R.T. for support for probe synthesis. NR 38 TC 25 Z9 27 U1 22 U2 87 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 MAR PY 2015 VL 6 AR 6463 DI 10.1038/ncomms7463 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CF6WJ UT WOS:000352697100004 PM 25765713 ER PT J AU Gao, W Tang, ZW Zhang, YF Feng, MQ Qian, M Dimitrov, DS Ho, M AF Gao, Wei Tang, Zhewei Zhang, Yi-Fan Feng, Mingqian Qian, Min Dimitrov, Dimiter S. Ho, Mitchell TI Immunotoxin targeting glypican-3 regresses liver cancer via dual inhibition of Wnt signalling and protein synthesis SO NATURE COMMUNICATIONS LA English DT Article ID ADVANCED HEPATOCELLULAR-CARCINOMA; PHASE-II; RECOMBINANT IMMUNOTOXIN; ANTITUMOR-ACTIVITY; HUMAN-ANTIBODY; IN-VITRO; EXPRESSION; IRINOTECAN; EFFICACY; GROWTH AB Glypican-3 is a cell surface glycoprotein that associates with Wnt in liver cancer. We develop two antibodies targeting glypican-3, HN3 and YP7. The first antibody recognizes a functional epitope and inhibits Wnt signalling, whereas the second antibody recognizes a C-terminal epitope but does not inhibit Wnt signalling. Both are fused to a fragment of Pseudomonas exotoxin A (PE38) to create immunotoxins. Interestingly, the immunotoxin based on HN3 (HN3-PE38) has superior antitumor activity as compared with YP7 (YP7-PE38) both in vitro and in vivo. Intravenous administration of HN3-PE38 alone, or in combination with chemotherapy, induces regression of Hep3B and HepG2 liver tumour xenografts in mice. This study establishes glypican-3 as a promising candidate for immunotoxin-based liver cancer therapy. Our results demonstrate immunotoxin-induced tumour regression via dual mechanisms: inactivation of cancer signalling via the antibody and inhibition of protein synthesis via the toxin. C1 [Gao, Wei; Tang, Zhewei; Zhang, Yi-Fan; Feng, Mingqian; Ho, Mitchell] NCI, Antibody Therapy Sect, Mol Biol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Tang, Zhewei; Qian, Min] E China Normal Univ, Sch Life Sci, Inst Biomed Sci, Shanghai 200062, Peoples R China. [Dimitrov, Dimiter S.] NCI, Prot Interact Grp, Expt Immunol Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Ho, M (reprint author), NCI, Antibody Therapy Sect, Mol Biol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM homi@mail.nih.gov RI Ho, Mitchell/F-5059-2015; Zhang, Yifan/O-9621-2015 OI Zhang, Yifan/0000-0002-0629-0200 FU Intramural Research Program of NIH, NCI, Center for Cancer Research FX This research was supported by the Intramural Research Program of NIH, NCI, Center for Cancer Research. We thank Ira Pastan (NCI) for helpful comments throughout this study; David FitzGerald (NCI) and Jeffrey S. Rubin (NCI) for critically reading the manuscript. We thank Chunling Yi (Georgetown University) for providing the Yap/TEAD reporter plasmid; Jeremy Nathans (Johns Hopkins Medical School) for providing the HEK293 SuperTopFlash stable cell line; Yingzi Yang (NHGRI) for the kind gift of L-cell and L-Wnt3a cell lines; Hong Zhou (NCI) for the assistance in [ 3H] leucine incorporation assay; Helen Michael (NCI) for the assistance in immunohistochemistry analysis. We also thank the NIH Fellows Editorial Board and Yen Phung (NCI) for editorial assistance. NR 52 TC 9 Z9 11 U1 5 U2 20 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 MAR PY 2015 VL 6 AR 6536 DI 10.1038/ncomms7536 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CF7EW UT WOS:000352720000026 PM 25758784 ER PT J AU Gupta, M Shin, DM Ramakrishna, L Goussetis, DJ Platanias, LC Xiong, HB Morse, HC Ozato, K AF Gupta, Monica Shin, Dong-Mi Ramakrishna, Lakshmi Goussetis, Dennis J. Platanias, Leonidas C. Xiong, Huabao Morse, Herbert C., III Ozato, Keiko TI IRF8 directs stress-induced autophagy in macrophages and promotes clearance of Listeria monocytogenes SO NATURE COMMUNICATIONS LA English DT Article ID IFN REGULATORY FACTOR-8; CELL SUBSET DEVELOPMENT; ACTIVATED MACROPHAGES; FLOW-CYTOMETRY; IMMUNITY; DIFFERENTIATION; PROTEINS; PATHWAYS; GENES; P62 AB Autophagy, activated by many stresses, plays a critical role in innate immune responses. Here we show that interferon regulatory factor 8 (IRF8) is required for the expression of autophagy-related genes in dendritic cells. Furthermore in macrophages, IRF8 is induced by multiple autophagy-inducing stresses, including IFN gamma and Toll-like receptor stimulation, bacterial infection, starvation and by macrophage colony-stimulating factor. IRF8 directly activates many genes involved in various steps of autophagy, promoting autophagosome formation and lysosomal fusion. Consequently, Irf8(-/-) macrophages are deficient in autophagic activity, and excessively accumulate SQSTM1 and ubiquitin-bound proteins. We show that clearance of Listeria monocytogenes in macrophages requires IRF8-dependent activation of autophagy genes and subsequent autophagic capturing and degradation of Listeria antigens. These processes are defective in Irf8(-/-) macrophages where uninhibited bacterial growth ensues. Together these data suggest that IRF8 is a major autophagy regulator in macrophages, essential for macrophage maturation, survival and innate immune responses. C1 [Gupta, Monica; Ramakrishna, Lakshmi; Ozato, Keiko] NICHD, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [Shin, Dong-Mi; Morse, Herbert C., III] NIAID, Immunopathol Lab, NIH, Rockville, MD 20852 USA. [Shin, Dong-Mi] Seoul Natl Univ, Dept Food & Nutr, Seoul 151742, South Korea. [Goussetis, Dennis J.; Platanias, Leonidas C.] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. [Platanias, Leonidas C.] Jesse Brown VA Med Ctr, Div Hematol Oncol, Chicago, IL 60612 USA. [Xiong, Huabao] Mt Sinai Sch Med, Inst Immunol, New York, NY 10029 USA. RP Ozato, K (reprint author), NICHD, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. EM ozatok@nih.gov FU Intramural Program of NICHD and NIAID; National Institutes of Health [CA77816, CA121192] FX We thank K.-T. Jeang, H.-S. Wang, S. Bradfute, V. Nagarajan, K.-A. McDonough and H. Yoshii for advice and critical reading of the manuscript. This work was supported by the Intramural Program of NICHD and NIAID, National Institutes of Health and NIH grants CA77816 and CA121192. NR 47 TC 6 Z9 6 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 MAR PY 2015 VL 6 AR 6379 DI 10.1038/ncomms7379 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CF5YK UT WOS:000352633100004 PM 25775030 ER PT J AU Lu, GM Zhang, RH Geng, S Peng, L Jayaraman, P Chen, C Xu, FF Yang, JJ Li, Q Zheng, H Shen, K Wang, J Liu, XY Wang, WD Zheng, ZH Qi, CF Si, CP He, JC Liu, KB Lira, SA Sikora, AG Li, LW Xiong, HB AF Lu, Geming Zhang, Ruihua Geng, Shuo Peng, Liang Jayaraman, Padmini Chen, Chun Xu, Feifong Yang, Jianjun Li, Qin Zheng, Hao Shen, Kimberly Wang, Juan Liu, Xiyu Wang, Weidong Zheng, Zihan Qi, Chen-Feng Si, Chuanping He, John Cijiang Liu, Kebin Lira, Sergio A. Sikora, Andrew G. Li, Liwu Xiong, Huabao TI Myeloid cell-derived inducible nitric oxide synthase suppresses M1 macrophage polarization SO NATURE COMMUNICATIONS LA English DT Article ID BREAST-CANCER CELLS; KAPPA-B ACTIVATION; ALTERNATIVE ACTIVATION; LISTERIA-MONOCYTOGENES; TRANSCRIPTION FACTORS; MURINE MACROPHAGES; TYROSINE NITRATION; IMMUNE-RESPONSE; IRF FAMILY; T-CELLS AB Here we show that iNOS-deficient mice display enhanced classically activated M1 macrophage polarization without major effects on alternatively activated M2 macrophages. eNOS and nNOS mutant mice show comparable M1 macrophage polarization compared with wild-type control mice. Addition of N6-(1-iminoethyl)-L-lysine dihydrochloride, an iNOS inhibitor, significantly enhances M1 macrophage polarization while S-nitroso-N-acetylpenicillamine, a NO donor, suppresses M1 macrophage polarization. NO derived from iNOS mediates nitration of tyrosine residues in IRF5 protein, leading to the suppression of IRF5-targeted M1 macrophage signature gene activation. Computational analyses corroborate a circuit that fine-tunes the expression of IL-12 by iNOS in macrophages, potentially enabling versatile responses based on changing microenvironments. Finally, studies of an experimental model of endotoxin shock show that iNOS deficiency results in more severe inflammation with an enhanced M1 macrophage activation phenotype. These results suggest that NO derived from iNOS in activated macrophages suppresses M1 macrophage polarization. C1 [Lu, Geming; Zhang, Ruihua; Peng, Liang; Jayaraman, Padmini; Xu, Feifong; Yang, Jianjun; Li, Qin; Zheng, Hao; Shen, Kimberly; Wang, Juan; Liu, Xiyu; Zheng, Zihan; He, John Cijiang; Lira, Sergio A.; Sikora, Andrew G.; Xiong, Huabao] Icahn Sch Med Mt Sinai, Inst Immunol, Dept Med, New York, NY 10029 USA. [Geng, Shuo; Chen, Chun; Li, Liwu] Virginia Tech, Ctr Inflammat, Dept Biol Sci, Blacksburg, VA 24061 USA. [Wang, Weidong] Cornell Univ, Weill Med Coll, Ronald O Perelman & Claudia Cohen Ctr Reprod Med, New York, NY 10021 USA. [Qi, Chen-Feng] NIAID, Immunogenet Lab, NIH, Bethesda, MD 20892 USA. [Si, Chuanping; Xiong, Huabao] Jining Med Coll, Inst Immunol & Mol Med, Jining 272067, Shandong, Peoples R China. [Liu, Kebin] Georgia Regents Univ, Med Coll Georgia, Dept Biochem & Mol Biol, Augusta, GA 30912 USA. RP Li, LW (reprint author), Virginia Tech, Ctr Inflammat, Dept Biol Sci, Blacksburg, VA 24061 USA. EM lwli@vt.edu; Huabao.Xiong@mssm.edu RI Geng, Shuo/J-3735-2013; OI Zheng, Zihan/0000-0003-1486-9586; Liu, Kebin/0000-0003-1965-7240; Li, Liwu/0000-0001-8870-5299 FU NIH [R01HL115835, R56AI108264, P01DK072201, R56AI091871, RO1AI104688] FX We express our thanks to Drs Adrian Ting and Feng Hong for technical support. L.L. was supported by NIH grants (R01HL115835, R56AI108264). H.X. was supported by the NIH funding (P01DK072201, R56AI091871 and RO1AI104688). NR 53 TC 18 Z9 18 U1 2 U2 8 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 MAR PY 2015 VL 6 AR 6676 DI 10.1038/ncomms7676 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CF5ZA UT WOS:000352634800005 PM 25813085 ER PT J AU Schuetze, P Lessard, J Colder, CR Maiorana, N Shisler, S Eiden, RD Huestis, MA Henrie, J AF Schuetze, Pamela Lessard, Jared Colder, Craig R. Maiorana, Nicole Shisler, Shannon Eiden, Rina D. Huestis, Marilyn A. Henrie, James TI Physiological reactivity during object manipulation among cigarette-exposed infants at 9 months of age SO NEUROTOXICOLOGY AND TERATOLOGY LA English DT Article DE Prenatal cigarette exposure; Object manipulation; Heart rate; Physiological arousal; Attention ID MATERNAL SMOKING; HEART-RATE; PRENATAL EXPOSURE; ALLOSTATIC LOAD; PREGNANCY RISK; YOUNG INFANTS; ATTENTION; CHILDREN; ALCOHOL; GROWTH AB The purpose of this study was to examine the association between prenatal exposure to cigarettes and heart rate during an object manipulation task at 9 months of age. Second-by-second heart rate was recorded for 181 infants who were prenatally exposed to cigarettes and 77 nonexposed infants during the manipulation of four standardized toys. A series of longitudinal multilevel models were run to examine the association of prenatal smoking on the intercept and slope of heart rate during four 90-second object manipulation tasks. After controlling for maternal age, prenatal marijuana and alcohol use, duration of focused attention and activity level, results indicated that the heart rates of exposed infants significantly increased during the object manipulation task. These findings suggest casual rather than focused attention and a possible increase in physiological arousal during object manipulation. (C) 2015 Elsevier Inc. All rights reserved. C1 [Schuetze, Pamela] State Univ New York Buffalo State, Dept Psychol, Buffalo, NY 14222 USA. [Lessard, Jared; Maiorana, Nicole; Shisler, Shannon; Eiden, Rina D.; Henrie, James] SUNY Buffalo, Res Inst Addict, Buffalo, NY 14203 USA. [Colder, Craig R.] SUNY Buffalo, Dept Psychol, Buffalo, NY 14260 USA. [Huestis, Marilyn A.] NIDA, Chem & Drug Metab, IRP, NIH, Bethesda, ND USA. RP Schuetze, P (reprint author), State Univ New York Buffalo State, Dept Psychol, 1300 Elmwood Ave, Buffalo, NY 14222 USA. EM schuetp@buffalostate.edu OI Schuetze, Pamela/0000-0001-9348-5788 FU National Institute on Drug Abuse, National Institutes on Health [R01DA019632] FX The authors report no conflict of interest The authors thank parents and infants who participated in this study and the research staff who were responsible for conducting numerous assessments with these families. Special thanks to Dr. Amol tale for collaboration on data collection and Dr. Gerard Connors for collaboration on the larger study. The study was made possible by a grant from the National Institute on Drug Abuse, National Institutes on Health (R01DA019632). NR 26 TC 0 Z9 0 U1 1 U2 3 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 MAR-APR PY 2015 VL 48 BP 64 EP 68 DI 10.1016/j.ntt.2015.02.001 PG 5 WC Neurosciences; Toxicology SC Neurosciences & Neurology; Toxicology GA CE9MZ UT WOS:000352169400009 PM 25681531 ER PT J AU Schweitzer, JB Riggins, T Liang, X Gallen, C Kurup, PK Ross, TJ Black, MM Nair, P Salmeron, BJ AF Schweitzer, Julie B. Riggins, Tracy Liang, Xia Gallen, Courtney Kurup, Pradeep K. Ross, Thomas J. Black, Maureen M. Nair, Prasanna Salmeron, Betty Jo TI Prenatal drug exposure to illicit drugs alters working memory-related brain activity and underlying network properties in adolescence SO NEUROTOXICOLOGY AND TERATOLOGY LA English DT Article DE Prenatal drug exposure; Illicit drugs; Working memory; Graph theory; fMRI; Adolescence; Cocaine ID GESTATIONAL COCAINE EXPOSURE; FUNCTIONAL CONNECTIVITY MRI; SCHOOL-AGED CHILDREN; SMALL-WORLD NETWORKS; IN-UTERO; PREFRONTAL CORTEX; HEAD MOTION; BEHAVIOR; ADHD; FMRI AB The persistence of effects of prenatal drug exposure (PDE) on brain functioning during adolescence is poorly understood. We explored neural activation to a visuospatial working memory (VSWM) versus a control task using functional magnetic resonance imaging (fMRI) in adolescents with PDE and a community comparison group (CC) of non-exposed adolescents. We applied graph theory metrics to resting state data using a network of nodes derived from the VSWM task activation map to further explore connectivity underlying WM functioning. Participants (ages 12-15 years) included 47 adolescents (27 POE and 20 CC). All analyses controlled for potentially confounding differences in birth characteristics and postnatal environment. Significant group by task differences in brain activation emerged in the left middle frontal gyrus (BA 6) with the CC group, but not the PDE group, activating this region during VSWM. The PDE group deactivated the culmen, whereas the CC group activated it during the VSWM task. The CC group demonstrated a significant relation between reaction time and culmen activation, not present in the POE group. The network analysis underlying VSWM performance showed that POE group had lower global efficiency than the CC group and a trend level reduction in local efficiency. The network node corresponding to the BA 6 group by task interaction showed reduced nodal efficiency and fewer direct connections to other nodes in the network. These results suggest that adolescence reveals altered neural functioning related to response planning that may reflect less efficient network functioning in youth with PDE. (C) 2015 Elsevier Inc. All rights reserved. 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 20742 USA. [Liang, Xia; Gallen, Courtney; Kurup, Pradeep K.; Ross, Thomas J.; Salmeron, Betty Jo] NIDA, Neuroimaging Res Branch, Intramural Res Program, Bethesda, MD USA. [Black, Maureen M.; Nair, Prasanna] Univ Maryland, Sch Med, Dept Pediat, Baltimore, MD USA. RP Schweitzer, JB (reprint author), Univ Calif Davis, MIND Inst, 2825 50th St, Sacramento, CA 95817 USA. EM Julie.schwetizer@ucdmc.ucdavis.edu RI Salmeron, Betty Jo/M-1793-2016; OI Salmeron, Betty Jo/0000-0003-1699-9333; Ross, Thomas/0000-0002-7745-3572 FU National Institutes of Health [R01 DA07432, R01 DA021059]; NIH, NIDA FX This research was funded by the National Institutes of Health grants R01 DA07432 (Nair) and R01 DA021059 (Black) and the Intramural Research Program of the NIH, NIDA. The funders had no involvement in the collection, analysis or interpretation of data; in the writing of the report; or in the decision to submit the manuscript for publication. The authors have no competing financial interests in relation to the work described. NR 78 TC 3 Z9 3 U1 1 U2 12 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 MAR-APR PY 2015 VL 48 BP 69 EP 77 DI 10.1016/j.ntt.2015.02.002 PG 9 WC Neurosciences; Toxicology SC Neurosciences & Neurology; Toxicology GA CE9MZ UT WOS:000352169400010 PM 25683798 ER PT J AU Hsu, P Xie, ZH Frith, K Wong, M Kakakios, A Stone, KD Druey, KM AF Hsu, Peter Xie, Zhihui Frith, Katie Wong, Melanie Kakakios, Alyson Stone, Kelly D. Druey, Kirk M. TI Idiopathic Systemic Capillary Leak Syndrome in Children SO PEDIATRICS LA English DT Article ID CLARKSON DISEASE; SHOCK; GIRL AB Adult subjects with systemic capillary leak syndrome (SCLS) present with acute and recurrent episodes of vascular leak manifesting as severe hypotension, hypoalbuminemia, hemoconcentration, and generalized edema. We studied clinical disease characteristics, serum cytokine profiles, and treatment modalities in a cohort of children with documented SCLS. Six children with SCLS were recruited from the United States, Australia, Canada, and Italy. Serum cytokines from SCLS subjects and a group of 10 healthy children were analyzed. Children with SCLS (aged 5-11 years old) presented with at least 1 acute, severe episode of hypotension, hypoalbuminemia, and hemoconcentration in the absence of underlying causes for these abnormalities. In contrast to what is observed in adult SCLS, identifiable infectious triggers precipitated most episodes in these children, and none of them had a monoclonal gammopathy. We found elevated levels of chemokine (C-C motif) ligand 2 (CCL2), interleukin-8, and tumor necrosis factor a in baseline SCLS sera compared with the control group. All patients are alive and well on prophylactic therapy, with 4 patients receiving intravenous or subcutaneous immunoglobulins at regular intervals. The clinical manifestations of pediatric and adult SCLS are similar, with the notable exceptions of frequent association with infections and the lack of monoclonal gammopathy. Prophylactic medication, including high dose immunoglobulins or theophylline plus verapamil, appears to be safe and efficacious therapy for SCLS in children. C1 [Hsu, Peter; Wong, Melanie; Kakakios, Alyson] Childrens Hosp Westmead, Dept Allergy & Immunol, Sydney, NSW, Australia. [Xie, Zhihui; Stone, Kelly D.; Druey, Kirk M.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Frith, Katie] Sydney Childrens Hosp, Dept Immunol & Infect Dis, Sydney, NSW, Australia. RP Druey, KM (reprint author), 50 South Dr,Room 4154, Bethesda, MD 20892 USA. EM kdruey@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases, National Institutes of Health [AI001830]; National Institutes of Health (NIH) FX Supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (project number AI001830, to Dr Druey). Funded by the National Institutes of Health (NIH). NR 21 TC 4 Z9 4 U1 0 U2 1 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD MAR PY 2015 VL 135 IS 3 BP E730 EP E735 DI 10.1542/peds.2014-2268 PG 6 WC Pediatrics SC Pediatrics GA CF0BD UT WOS:000352206600024 PM 25713284 ER PT J AU Pappas, A Shankaran, S McDonald, SA Vohr, BR Hintz, SR Ehrenkranz, RA Tyson, JE Yolton, K Das, A Bara, R Hammond, J Higgins, RD AF Pappas, Athina Shankaran, Seetha McDonald, Scott A. Vohr, Betty R. Hintz, Susan R. Ehrenkranz, Richard A. Tyson, Jon E. Yolton, Kimberly Das, Abhik Bara, Rebecca Hammond, Jane Higgins, Rosemary D. CA Hypothermia Extended Follow-Up Sub TI Cognitive Outcomes After Neonatal Encephalopathy SO PEDIATRICS LA English DT Article ID HYPOXIC-ISCHEMIC ENCEPHALOPATHY; WHOLE-BODY HYPOTHERMIA; GROSS MOTOR FUNCTION; SCHOOL-AGE; DEVELOPMENTAL-DISABILITY; SYSTEMIC HYPOTHERMIA; CHILDHOOD OUTCOMES; CEREBRAL-PALSY; BIRTH ASPHYXIA; TERM INFANTS AB OBJECTIVES: To describe the spectrum of cognitive outcomes of children with and without cerebral palsy (CP) after neonatal encephalopathy, evaluate the prognostic value of early developmental testing and report on school services and additional therapies. METHODS: The participants of this study are the school-aged survivors of the National Institute of Child Health and Human Development Neonatal Research Network randomized controlled trial of whole-body hypothermia. Children underwent neurologic examinations and neurodevelopmental and cognitive testing with the Bayley Scales of Infant Development-II at 18 to 22 months and the Wechsler intelligence scales and the Neuropsychological Assessment-Developmental Neuropsychological Assessment at 6 to 7 years. Parents were interviewed about functional status and receipt of school and support services. We explored predictors of cognitive outcome by using multiple regression models. RESULTS: Subnormal IQ scores were identified in more than a quarter of the children: 96% of survivors with CP had an IQ <70, 9% of children without CP had an IQ <70, and 31% had an IQ of 70 to 84. Children with a mental developmental index <70 at 18 months had, on average, an adjusted IQ at 6 to 7 years that was 42 points lower than that of those with a mental developmental index >84 (95% confidence interval, -49.3 to -35.0; P < .001). Twenty percent of children with normal IQ and 28% of those with IQ scores of 70 to 84 received special educational support services or were held back >= 1 grade level. CONCLUSIONS: Cognitive impairment remains an important concern for all children with neonatal encephalopathy. C1 [Pappas, Athina; Shankaran, Seetha; Bara, Rebecca] Wayne State Univ, Dept Pediat, Detroit, MI 48202 USA. [McDonald, Scott A.] RTI Int, Social Stat & Environm Sci Unit, Res Triangle Pk, NC USA. [Vohr, Betty R.] Brown Univ, Women & Infants Hosp, Dept Pediat, Providence, RI 02908 USA. [Hintz, Susan R.] Stanford Univ, Sch Med, Dept Pediat, Palo Alto, CA 94304 USA. [Ehrenkranz, Richard A.] Yale Univ, Dept Pediat, New Haven, CT 06520 USA. [Tyson, Jon E.] Univ Texas Houston, Sch Med, Dept Pediat, Houston, TX USA. [Yolton, Kimberly] Univ Cincinnati, Dept Pediat, Cincinnati, OH USA. [Das, Abhik; Hammond, Jane] RTI Int, Social Stat & Environm Sci Unit, Rockville, MD USA. [Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. RP Pappas, A (reprint author), Childrens Hosp Michigan, Div Neonatal Perinatal Med, 3901 Beaubien Blvd, Detroit, MI 48201 USA. EM apappas@med.wayne.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Center for Research Resources; National Center for Advancing Translational Sciences; National Institutes of Health (NIH); National Institutes of Health FX The National Institutes of Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Center for Research Resources, and the National Center for Advancing Translational Sciences provided grant support for the Neonatal Research Network's Whole-Body Hypothermia Trial and its 6-7 Year School-age Follow-up through cooperative agreements. Although NICHD staff did have input into the study design, conduct, analysis, and manuscript drafting, the comments and views of the authors do not necessarily represent the views of the NICHD. Funded by the National Institutes of Health (NIH). NR 40 TC 15 Z9 15 U1 1 U2 7 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD MAR PY 2015 VL 135 IS 3 BP E624 EP E634 DI 10.1542/peds.2014-1566 PG 11 WC Pediatrics SC Pediatrics GA CF0BD UT WOS:000352206600010 PM 25713280 ER PT J AU Averbeck, BB AF Averbeck, Bruno B. TI Theory of Choice in Bandit, Information Sampling and Foraging Tasks SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID PARKINSONS-DISEASE; DECISION-MAKING; PREDICTION ERRORS; SEEKING BEHAVIOR; IMPULSIVITY; HUMANS; CORTEX; CONCLUSIONS; UNCERTAINTY AB Decision making has been studied with a wide array of tasks. Here we examine the theoretical structure of bandit, information sampling and foraging tasks. These tasks move beyond tasks where the choice in the current trial does not affect future expected rewards. We have modeled these tasks using Markov decision processes (MDPs). MDPs provide a general framework for modeling tasks in which decisions affect the information on which future choices will be made. Under the assumption that agents are maximizing expected rewards, MDPs provide normative solutions. We find that all three classes of tasks pose choices among actions which trade-off immediate and future expected rewards. The tasks drive these trade-offs in unique ways, however. For bandit and information sampling tasks, increasing uncertainty or the time horizon shifts value to actions that pay-off in the future. Correspondingly, decreasing uncertainty increases the relative value of actions that pay-off immediately. For foraging tasks the time-horizon plays the dominant role, as choices do not affect future uncertainty in these tasks. C1 NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. RP Averbeck, BB (reprint author), NIMH, Neuropsychol Lab, NIH, Bldg 9, Bethesda, MD 20892 USA. EM bruno.averbeck@nih.gov FU NIH [ZIA MH002928-01] FX BBA was the recipient of an NIH grant: ZIA MH002928-01. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 5 Z9 5 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-734X EI 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD MAR PY 2015 VL 11 IS 3 AR e1004164 DI 10.1371/journal.pcbi.1004164 PG 28 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA CE9XB UT WOS:000352195700046 PM 25815510 ER PT J AU Chow, CC Finn, KK Storchan, GB Lu, XP Sheng, XY Simons, SS AF Chow, Carson C. Finn, Kelsey K. Storchan, Geoffery B. Lu, Xinping Sheng, Xiaoyan Simons, S. Stoney, Jr. TI Kinetically-Defined Component Actions in Gene Repression SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID GLUCOCORTICOID-RECEPTOR ACTION; DOSE-RESPONSE CURVES; RNA-POLYMERASE-II; TRANSCRIPTIONAL REPRESSION; HORMONE-RECEPTOR; INDUCTION; PROMOTER; PROTEIN; BINDING; COACTIVATORS AB Gene repression by transcription factors, and glucocorticoid receptors (GR) in particular, is a critical, but poorly understood, physiological response. Among the many unresolved questions is the difference between GR regulated induction and repression, and whether transcription cofactor action is the same in both. Because activity classifications based on changes in gene product level are mechanistically uninformative, we present a theory for gene repression in which the mechanisms of factor action are defined kinetically and are consistent for both gene repression and induction. The theory is generally applicable and amenable to predictions if the dose-response curve for gene repression is non-cooperative with a unit Hill coefficient, which is observed for GR-regulated repression of AP1LUC reporter induction by phorbol myristate acetate. The theory predicts the mechanism of GR and co-factors, and where they act with respect to each other, based on how each cofactor alters the plots of various kinetic parameters vs. cofactor. We show that the kinetically-defined mechanism of action of each of four factors (reporter gene, p160 coactivator TIF2, and two pharmaceuticals [NU6027 and phenanthroline]) is the same in GR-regulated repression and induction. What differs is the position of GR action. This insight should simplify clinical efforts to differentially modulate factor actions in gene induction vs. gene repression. C1 [Chow, Carson C.] NIDDK, Math Biol Sect, LBM, NIH, Bethesda, MD 20892 USA. [Finn, Kelsey K.; Storchan, Geoffery B.; Lu, Xinping; Sheng, Xiaoyan; Simons, S. Stoney, Jr.] NIDDK, Steroid Hormones Sect, LERB, NIH, Bethesda, MD 20892 USA. RP Chow, CC (reprint author), NIDDK, Math Biol Sect, LBM, NIH, Bethesda, MD 20892 USA. EM carsonc@mail.nih.gov; stoneys@helix.nih.gov FU Intramural Research Program of the NIH, NIDDK FX This work is funded by the Intramural Research Program of the NIH, NIDDK. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 55 TC 2 Z9 2 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-734X EI 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD MAR PY 2015 VL 11 IS 3 AR UNSP e1004122 DI 10.1371/journal.pcbi.1004122 PG 28 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA CE9XB UT WOS:000352195700027 PM 25816223 ER PT J AU Derking, R Ozorowski, G Sliepen, K Yasmeen, A Cupo, A Torres, JL Julien, JP Lee, JH van Montfort, T de Taeye, SW Connors, M Burton, DR Wilson, IA Klasse, PJ Ward, AB Moore, JP Sanders, RW AF Derking, Ronald Ozorowski, Gabriel Sliepen, Kwinten Yasmeen, Anila Cupo, Albert Torres, Jonathan L. Julien, Jean-Philippe Lee, Jeong Hyun van Montfort, Thijs de Taeye, Steven W. Connors, Mark Burton, Dennis R. Wilson, Ian A. Klasse, Per-Johan Ward, Andrew B. Moore, John P. Sanders, Rogier W. TI Comprehensive Antigenic Map of a Cleaved Soluble HIV-1 Envelope Trimer SO PLOS PATHOGENS LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; BROADLY NEUTRALIZING ANTIBODIES; MONOCLONAL-ANTIBODIES; GP41-GP120 INTERFACE; GLYCOPROTEIN COMPLEX; DEPENDENT EPITOPE; BINDING-SITE; ENV TRIMERS; CD4 BINDING; POTENT AB The trimeric envelope (Env) spike is the focus of vaccine design efforts aimed at generating broadly neutralizing antibodies (bNAbs) to protect against HIV-1 infection. Three recent developments have facilitated a thorough investigation of the antigenic structure of the Env trimer: 1) the isolation of many bNAbs against multiple different epitopes; 2) the generation of a soluble trimer mimic, BG505 SOSIP. 664 gp140, that expresses most bNAb epitopes; 3) facile binding assays involving the oriented immobilization of tagged trimers. Using these tools, we generated an antigenic map of the trimer by antibody cross-competition. Our analysis delineates three well-defined epitope clusters (CD4 binding site, quaternary V1V2 and Asn332-centered oligomannose patch) and new epitopes at the gp120-gp41 interface. It also identifies the relationships among these clusters. In addition to epitope overlap, we defined three more ways in which antibodies can cross-compete: steric competition from binding to proximal but non-overlapping epitopes (e.g., PGT151 inhibition of 8ANC195 binding); allosteric inhibition (e.g., PGT145 inhibition of 1NC9, 8ANC195, PGT151 and CD4 binding); and competition by reorientation of glycans (e.g., PGT135 inhibition of CD4bs bNAbs, and CD4bs bNAb inhibition of 8ANC195). We further demonstrate that bNAb binding can be complex, often affecting several other areas of the trimer surface beyond the epitope. This extensive analysis of the antigenic structure and the epitope interrelationships of the Env trimer should aid in design of both bNAb-based therapies and vaccines intended to induce bNAbs. C1 [Derking, Ronald; Sliepen, Kwinten; van Montfort, Thijs; de Taeye, Steven W.; Sanders, Rogier W.] Univ Amsterdam, Acad Med Ctr, Dept Med Microbiol, NL-1105 AZ Amsterdam, Netherlands. [Ozorowski, Gabriel; Torres, Jonathan L.; Julien, Jean-Philippe; Lee, Jeong Hyun; Wilson, Ian A.; Ward, Andrew B.] Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA. [Ozorowski, Gabriel; Torres, Jonathan L.; Julien, Jean-Philippe; Lee, Jeong Hyun; Burton, Dennis R.; Wilson, Ian A.; Ward, Andrew B.] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, Ctr HIV AIDS Vaccine Immunol & Immunogen Discover, La Jolla, CA 92037 USA. [Ozorowski, Gabriel; Torres, Jonathan L.; Julien, Jean-Philippe; Lee, Jeong Hyun; Burton, Dennis R.; Wilson, Ian A.; Ward, Andrew B.] Scripps Res Inst, Collaborat AIDS Vaccine Discovery CAVD, La Jolla, CA 92037 USA. [Yasmeen, Anila; Cupo, Albert; Klasse, Per-Johan; Moore, John P.; Sanders, Rogier W.] Cornell Univ, Dept Microbiol & Immunol, Weill Med Coll, New York, NY 10021 USA. [Julien, Jean-Philippe] Hosp Sick Children, Res Inst, Program Mol Struct & Funct, Toronto, ON M5G 1X8, Canada. [Julien, Jean-Philippe] Univ Toronto, Dept Biochem, Toronto, ON, Canada. [Julien, Jean-Philippe] Univ Toronto, Dept Immunol, Toronto, ON, Canada. [Connors, Mark] NIAID, HIV Specif Immun Sect, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Burton, Dennis R.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Burton, Dennis R.] Ragon Inst MGH MIT & Harvard, Cambridge, MA USA. [Wilson, Ian A.] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA. RP Derking, R (reprint author), Univ Amsterdam, Acad Med Ctr, Dept Med Microbiol, NL-1105 AZ Amsterdam, Netherlands. EM rws2002@med.cornell.edu RI Ward, Andrew/F-9203-2014 OI Ward, Andrew/0000-0001-7153-3769 FU National Institutes of Health [P01 AI82362, R37 AI36082]; International AIDS Vaccine Initiative (IAVI); Aids fonds Netherlands [2011032]; Vidi grant from the Netherlands Organization for Scientific Research (NWO); European Research Council [ERC-StG-2011-280829-SHEV]; National Institutes of Health through the National Center for Research Resources' P41 Program [RR017573] FX This study was sponsored by the National Institutes of Health Grants P01 AI82362 and R37 AI36082, by the International AIDS Vaccine Initiative (IAVI), and by the Aids fonds Netherlands, grant #2011032. RWS is a recipient of a Vidi grant from the Netherlands Organization for Scientific Research (NWO) and obtained a Starting Investigator Grant from the European Research Council (ERC-StG-2011-280829-SHEV). The electron microscopy data were collected at the National Resource for Automated Molecular Microscopy (NRAMM), which is supported by the National Institutes of Health through the National Center for Research Resources' P41 Program Grant RR017573. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 36 Z9 36 U1 0 U2 22 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 MAR PY 2015 VL 11 IS 3 AR UNSP e1004767 DI 10.1371/journal.ppat.1004767 PG 22 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA CE9ZI UT WOS:000352201900074 PM 25807248 ER PT J AU Moreira, D Rodrigues, V Abengozar, M Rivas, L Rial, E Laforge, M Li, XL Foretz, M Viollet, B Estaquier, J da Silva, AC Silvestre, R AF Moreira, Diana Rodrigues, Vasco Abengozar, Maria Rivas, Luis Rial, Eduardo Laforge, Mireille Li, Xiaoling Foretz, Marc Viollet, Benoit Estaquier, Jerome da Silva, Anabela Cordeiro Silvestre, Ricardo TI Leishmania infantum Modulates Host Macrophage Mitochondrial Metabolism by Hijacking the SIRT1-AMPK Axis SO PLOS PATHOGENS LA English DT Article ID ACTIVATED PROTEIN-KINASE; INFECTED MACROPHAGES; ENERGY-EXPENDITURE; UPSTREAM KINASE; DENDRITIC CELLS; AMPK; MICE; HYPOXIA; PGC-1-ALPHA; HOMEOSTASIS AB Metabolic manipulation of host cells by intracellular pathogens is currently recognized to play an important role in the pathology of infection. Nevertheless, little information is available regarding mitochondrial energy metabolism in Leishmania infected macrophages. Here, we demonstrate that during L. infantum infection, macrophages switch from an early glycolytic metabolism to an oxidative phosphorylation, and this metabolic deviation requires SIRT1 and LKB1/AMPK. SIRT1 or LBK1 deficient macrophages infected with L. infantum failed to activate AMPK and up-regulate its targets such as Slc2a4 and Ppargc1a, which are essential for parasite growth. As a result, impairment of metabolic switch caused by SIRT1 or AMPK deficiency reduces parasite load in vitro and in vivo. Overall, our work demonstrates the importance of SIRT1 and AMPK energetic sensors for parasite intracellular survival and proliferation, highlighting the modulation of these proteins as potential therapeutic targets for the treatment of leishmaniasis. C1 [Moreira, Diana; Rodrigues, Vasco; da Silva, Anabela Cordeiro; Silvestre, Ricardo] Univ Porto, IBMC, Parasite Dis Grp, P-4100 Oporto, Portugal. [Moreira, Diana; Rodrigues, Vasco; da Silva, Anabela Cordeiro; Silvestre, Ricardo] Univ Porto, Inst Invest & Inovacao Saude, P-4100 Oporto, Portugal. [Rodrigues, Vasco; Laforge, Mireille; Estaquier, Jerome] Univ Paris 05, CNRS, FRE 3636, Paris, France. [Abengozar, Maria; Rivas, Luis] CSIC, Ctr Invest Biol, UMIB, Madrid, Spain. [Rial, Eduardo] CSIC, Ctr Invest Biol, Dept Cellular & Mol Med, Madrid, Spain. [Li, Xiaoling] NIEHS, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. [Foretz, Marc; Viollet, Benoit] Inst Cochin, INSERM, U1016, Paris, France. [Foretz, Marc; Viollet, Benoit] CNRS, UMR 8104, Paris, France. [Foretz, Marc; Viollet, Benoit] Univ Paris 05, Sorbonne Paris Cite, Paris, France. [Estaquier, Jerome] Univ Laval, Ctr Rech, CHU Quebec, Quebec City, PQ, Canada. [da Silva, Anabela Cordeiro] Univ Porto, Fac Farm, Dept Ciencias Biol, P-4100 Oporto, Portugal. RP Moreira, D (reprint author), Univ Porto, IBMC, Parasite Dis Grp, Rua Campo Alegre 823, P-4100 Oporto, Portugal. EM cordeiro@ibmc.up.pt; rleal@ibmc.up.pt RI Rial, Eduardo/A-4242-2008; Cordeiro-da-Silva, Anabela/J-7807-2013; Silvestre, Ricardo/C-7243-2011; OI Rial, Eduardo/0000-0001-8634-8902; Cordeiro-da-Silva, Anabela/0000-0003-2392-6087; Silvestre, Ricardo/0000-0002-9270-2717; Estaquier, Jerome/0000-0002-9432-8044; Abengozar Infantes, Maria de los Angeles/0000-0002-2432-3512 FU FEDER funds through the Operational Competitiveness Programme - COMPETE; National Funds through FCT - Fundacao para a Ciencia e a Tecnologia [FCOMP-01-0124-FEDER-011054 (PTDC/SAU-FCF/100749/2008), PTDC/BIA-MIC/118644/2010]; European Community [602773]; ISCIII-Subdireccion General de Redes y Centros de Investigacion Cooperativa-FEDER [RICET RD12/0018/0007]; Spanish Ministerio de Economia y Competitividad [SAF2010-20256]; ANR grant (LEISH-APO, France); Partenariat Hubert Curien (PHC) (program Volubilis) [MA/11/262]; Canada Research Chair programme; ANR; Programa Ciencia - Programa Operacional Potencial Humano POPH - QREN - Tipologia 4.2 - Promocao do Emprego Cientifico; Fundo Social Europeu and National funding from Ministry of Science, Technology and Higher Education (MCTES); [SFRH/BD/91543/2012]; [SFRH/BD/64064/2009]; [PN de I+D+I 2008-2011]; [PI12-02706]; [VI PN de I+D+I 2008-2011] FX This work was funded by FEDER funds through the Operational Competitiveness Programme - COMPETE and by National Funds through FCT - Fundacao para a Ciencia e a Tecnologia under the project FCOMP-01-0124-FEDER-011054 (PTDC/SAU-FCF/100749/2008) and PTDC/BIA-MIC/118644/2010. The research leading to these results has also received funding from the European Community's Seventh Framework Programme under grant agreement No. 602773 (Project KINDRED). DM and VR were supported by SFRH/BD/91543/2012 and SFRH/BD/64064/2009, respectively. LR was supported by PN de I+D+I 2008-2011, PI12-02706 and VI PN de I+D+I 2008-2011, ISCIII-Subdireccion General de Redes y Centros de Investigacion Cooperativa-FEDER (RICET RD12/0018/0007). ER was supported by a project grant of the Spanish Ministerio de Economia y Competitividad (SAF2010-20256). JE was supported by an ANR grant (LEISH-APO, France) and a Partenariat Hubert Curien (PHC) (program Volubilis, MA/11/262). JE is also supported by the Canada Research Chair programme. ML was supported by a fellowship from ANR. RS was supported by Programa Ciencia financed by Programa Operacional Potencial Humano POPH - QREN - Tipologia 4.2 - Promocao do Emprego Cientifico, co-funded by Fundo Social Europeu and National funding from Ministry of Science, Technology and Higher Education (MCTES). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 7 Z9 7 U1 0 U2 10 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 MAR PY 2015 VL 11 IS 3 AR e1004684 DI 10.1371/journal.ppat.1004684 PG 24 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA CE9ZI UT WOS:000352201900016 PM 25738568 ER PT J AU Moutsopoulos, NM Chalmers, NI Barb, JJ Abusleme, L Greenwell-Wild, T Dutzan, N Paster, BJ Munson, PJ Fine, DH Uzel, G Holland, SM AF Moutsopoulos, Niki M. Chalmers, Natalia I. Barb, Jennifer J. Abusleme, Loreto Greenwell-Wild, Teresa Dutzan, Nicolas Paster, Bruce J. Munson, Peter J. Fine, Daniel H. Uzel, Gulbu Holland, Steven M. TI Subgingival Microbial Communities in Leukocyte Adhesion Deficiency and Their Relationship with Local Immunopathology SO PLOS PATHOGENS LA English DT Article ID AGGRESSIVE PERIODONTITIS; AGGREGATIBACTER-ACTINOMYCETEMCOMITANS; IDENTIFICATION MICROARRAY; PORPHYROMONAS-GINGIVALIS; REFRACTORY PERIODONTITIS; INFECTION; INFLAMMATION; RESPONSES; CHILDREN; HEALTH AB Leukocyte Adhesion Deficiency I (LAD-I) is a primary immunodeficiency caused by single gene mutations in the CD18 subunit of beta 2 integrins which result in defective transmigration of neutrophils into the tissues. Affected patients suffer from recurrent life threatening infections and severe oral disease (periodontitis). Microbial communities in the local environment (subgingival plaque) are thought to be the triggers for inflammatory periodontitis, yet little is known regarding the microbial communities associated with LAD-I periodontitis. Here we present the first comprehensive characterization of the subgingival communities in LAD-I, using a 16S rRNA gene-based microarray, and investigate the relationship of this tooth adherent microbiome to the local immunopathology of periodontitis. We show that the LAD subgingival microbiome is distinct from that of health and Localized Aggressive Periodontitits. Select periodontitis-associated species in the LAD microbiome included Parvimonas micra, Porphyromonas endodontalis, Eubacterium brachy and Treponema species. Pseudomonas aeruginosa, a bacterium not typically found in subgingival plaque is detected in LAD-I. We suggest that microbial products from LAD-associated communities may have a role in stimulating the local inflammatory response. We demonstrate that bacterial LPS translocates into the lesions of LAD-periodontitis potentially triggering immunopathology. We also show in in vitro assays with human macrophages and in vivo in animal models that microbial products from LAD-associated subgingival plaque trigger IL-23-related immune responses, which have been shown to dominate in patient lesions. In conclusion, our current study characterizes the subgingival microbial communities in LAD-periodontitis and supports their role as triggers of disease pathogenesis. C1 [Moutsopoulos, Niki M.; Abusleme, Loreto; Greenwell-Wild, Teresa; Dutzan, Nicolas] Natl Inst Dent & Craniofacial Res, Oral Immun & Inflammat Unit, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. [Chalmers, Natalia I.] Natl Inst Dent & Craniofacial Res, Clin Res Core, NIH, Bethesda, MD USA. [Barb, Jennifer J.; Munson, Peter J.] NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. [Paster, Bruce J.] Forsyth Inst, Cambridge, MA USA. [Paster, Bruce J.] Harvard Univ, Sch Dent Med, Boston, MA 02115 USA. [Fine, Daniel H.] Rutgers State Univ, Rutgers Sch Dent Med, Newark, NJ 07102 USA. [Uzel, Gulbu; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Moutsopoulos, NM (reprint author), Natl Inst Dent & Craniofacial Res, Oral Immun & Inflammat Unit, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. EM nmoutsop@mail.nih.gov FU Intramural Research Program of the NIH; National Institute of Dental and Craniofacial Research (NIDCR); National Institute of Allergy and Infectious Diseases (NIAID) FX This research was supported in part by the Intramural Research Program of the NIH, National Institute of Dental and Craniofacial Research (NIDCR) and National Institute of Allergy and Infectious Diseases (NIAID). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 47 TC 10 Z9 10 U1 0 U2 1 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 MAR PY 2015 VL 11 IS 3 AR e1004698 DI 10.1371/journal.ppat.1004698 PG 19 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA CE9ZI UT WOS:000352201900027 PM 25741691 ER PT J AU Shannon, JG Bosio, CF Hinnebusch, BJ AF Shannon, Jeffrey G. Bosio, Christopher F. Hinnebusch, B. Joseph TI Dermal Neutrophil, Macrophage and Dendritic Cell Responses to Yersinia pestis Transmitted by Fleas SO PLOS PATHOGENS LA English DT Article ID ORIENTAL RAT FLEA; IN-VIVO; XENOPSYLLA-CHEOPIS; PLAGUE BACILLUS; SYSTEM; TRANSMISSION; INFECTION; EVOLUTION AB Yersinia pestis, the causative agent of plague, is typically transmitted by the bite of an infected flea. Many aspects of mammalian innate immune response early after Y. pestis infection remain poorly understood. A previous study by our lab showed that neutrophils are the most prominent cell type recruited to the injection site after intradermal needle inoculation of Y. pestis, suggesting that neutrophil interactions with Y. pestis may be important in bubonic plague pathogenesis. In the present study, we developed new tools allowing for intravital microscopy of Y. pestis in the dermis of an infected mouse after transmission by its natural route of infection, the bite of an infected flea. We found that uninfected flea bites typically induced minimal neutrophil recruitment. The magnitude of neutrophil response to flea-transmitted Y. pestis varied considerably and appeared to correspond to the number of bacteria deposited at the bite site. Macrophages migrated towards flea bite sites and interacted with small numbers of flea-transmitted bacteria. Consistent with a previous study, we observed minimal interaction between Y. pestis and dendritic cells; however, dendritic cells did consistently migrate towards flea bite sites containing Y. pestis. Interestingly, we often recovered viable Y. pestis from the draining lymph node (dLN) 1 h after flea feeding, indicating that the migration of bacteria from the dermis to the dLN may be more rapid than previously reported. Overall, the innate cellular host responses to flea-transmitted Y. pestis differed from and were more variable than responses to needle-inoculated bacteria. This work highlights the importance of studying the interactions between fleas, Y. pestis and the mammalian host to gain a better understanding of the early events in plague pathogenesis. C1 [Shannon, Jeffrey G.; Bosio, Christopher F.; Hinnebusch, B. Joseph] NIAID, Plague Sect, Lab Zoonot Pathogens, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. RP Shannon, JG (reprint author), NIAID, Plague Sect, Lab Zoonot Pathogens, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. EM jshannon@niaid.nih.gov FU Division of Intramural Research, NIAID, NIH FX This work was supported by the Division of Intramural Research, NIAID, NIH. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 32 TC 10 Z9 10 U1 2 U2 11 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 MAR PY 2015 VL 11 IS 3 AR UNSP e1004734 DI 10.1371/journal.ppat.1004734 PG 19 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA CE9ZI UT WOS:000352201900052 PM 25781984 ER PT J AU de Cabo, R Liu, LJ Ali, A Price, N Zhang, J Wang, MY Lakatta, E Irusta, PM AF de Cabo, Rafael Liu, Lijuan Ali, Ahmed Price, Nathan Zhang, Jing Wang, Mingyi Lakatta, Edward Irusta, Pablo M. TI Serum from calorie-restricted animals delays senescence and extends the lifespan of normal human fibroblasts in vitro SO AGING-US LA English DT Article DE human diploid fibroblasts; senescence; caloric restriction; lifespan extension; SIRT1; aging ID HUMAN ENDOTHELIAL-CELLS; CELLULAR SENESCENCE; DIETARY RESTRICTION; OXIDATIVE STRESS; MATRIX METALLOPROTEINASES; TUMOR PROGRESSION; NICOTINAMIDE PHOSPHORIBOSYLTRANSFERASE; SIRT1 ACTIVATION; COLLAGEN MATRIX; CANCER-CELLS AB The cumulative effects of cellular senescence and cell loss over time in various tissues and organs are considered major contributing factors to the ageing process. In various organisms, caloric restriction (CR) slows ageing and increases lifespan, at least in part, by activating nicotinamide adenine dinucleotide (NAD(+))-dependent protein deacetylases of the sirtuin family. Here, we use an in vitro model of CR to study the effects of this dietary regime on replicative senescence, cellular lifespan and modulation of the SIRT1 signaling pathway in normal human diploid fibroblasts. We found that serum from calorie-restricted animals was able to delay senescence and significantly increase replicative lifespan in these cells, when compared to serum from ad libitum fed animals. These effects correlated with CR-mediated increases in SIRT1 and decreases in p53 expression levels. In addition, we show that manipulation of SIRT1 levels by either over-expression or siRNA-mediated knockdown resulted in delayed and accelerated cellular senescence, respectively. Our results demonstrate that CR can delay senescence and increase replicative lifespan of normal human diploid fibroblasts in vitro and suggest that SIRT1 plays an important role in these processes. (185 words). C1 [de Cabo, Rafael; Liu, Lijuan; Ali, Ahmed; Price, Nathan; Zhang, Jing; Wang, Mingyi; Irusta, Pablo M.] NIA, Expt Gerontol Sect, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. [Lakatta, Edward] NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. [Lakatta, Edward] NIA, Cardiovasc Funct Sect, NIH, Baltimore, MD 21224 USA. [Irusta, Pablo M.] Georgetown Univ, Med Ctr, Dept Human Sci, Washington, DC 20057 USA. RP de Cabo, R (reprint author), NIA, Expt Gerontol Sect, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. EM decabora@grc.nia.nih.gov; pmi2@georgetown.edu RI de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; , rafael/0000-0003-2830-5693 NR 121 TC 4 Z9 4 U1 0 U2 3 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 MAR PY 2015 VL 7 IS 3 BP 152 EP 166 PG 15 WC Cell Biology SC Cell Biology GA CE9JN UT WOS:000352160300005 PM 25855056 ER PT J AU Hernandez-Cadena, L Zeldin, DC Barraza-Villarreal, A Sever, ML Sly, PD London, SJ Escamilla-Nunez, MC Romieu, I AF Hernandez-Cadena, Leticia Zeldin, Darryl C. Barraza-Villarreal, Albino Sever, Michelle L. Sly, Peter D. London, Stephanie J. Consuelo Escamilla-Nunez, Maria Romieu, Isabelle TI Indoor determinants of dustborne allergens in Mexican homes SO ALLERGY AND ASTHMA PROCEEDINGS LA English DT Article ID HOUSE-DUST MITE; 1ST NATIONAL-SURVEY; INNER-CITY ASTHMA; PREVALENCE; CHILDHOOD; EXPOSURE; CHILDREN; SUPPLEMENTATION; SCHOOLCHILDREN; SENSITIZATION AB Exposure to indoor allergens represents a significant risk factor for allergies and asthma in several parts of the world. In Mexico, few studies have evaluated indoor allergens, including cat, dog, and mouse allergens and the factors that predict their presence. This study evaluates the main environmental and household predictors of high prenatal allergen levels and multiple allergen exposures in a birth cohort from Mexico City. A cross-sectional study was conducted as part of a birth cohort study of 1094 infants recruited during pregnancy and followed until delivery. We collected dust samples in a subset of 264 homes and assessed environmental factors. Der p 1, Der f 1, dust mite group 2, Fel d 1, Can f 1, Rat n 1, Mus m 1, and Bla g 2 concentrations in dust samples were measured using immunoassays. To define detectable allergen levels, the lowest limits of detection for each allergen were taken as cutoff points. Overall allergen exposure was considered high when four or more allergens exceeded detectable levels in the same household. Logistic regression was used for predictive models. Eighty-five percent of homes had at least one allergen in dust over the detection limit, 52.1% had high exposure (four or more allergens above detectable limits), and 11.7% of homes had detectable levels for more than eight allergens. Der p 1, Der p 2, Mus m 1, and Fel d 1 were the most frequent allergens detected. Each allergen had both common and distinct predictors. The main predictors of a high multiple allergen index were the size of the home, pesticide use, mother's age, mother as homemaker, and season. Increased indoor environmental allergen exposure is mainly related to sociodemographic factors and household cleaning. C1 [Hernandez-Cadena, Leticia; Barraza-Villarreal, Albino; Consuelo Escamilla-Nunez, Maria; Romieu, Isabelle] Inst Nacl Salud Publ, Cuernavaca 62100, Morelos, Mexico. [Zeldin, Darryl C.; Sever, Michelle L.; London, Stephanie J.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Sly, Peter D.] Univ Queensland, Queensland Childrens Med Res Inst, Brisbane, Qld, Australia. [Sly, Peter D.] Royal Childrens Hosp, Brisbane, Qld, Australia. RP Barraza-Villarreal, A (reprint author), Inst Nacl Salud Publ, Ave Univ 655, Cuernavaca 62100, Morelos, Mexico. EM abarraza@correo.insp.mx OI Sly, Peter/0000-0001-6305-2201; London, Stephanie/0000-0003-4911-5290 FU National Council of Sciences and Technology CONACYT [87121]; Kennedy Shriver National Institute of Child Health & Human Development [R01HD058818]; Intramural Research Division of the National Institutes of Health, National Institute of Environmental Health Sciences [Z01 ES025034] FX Funded by the National Council of Sciences and Technology CONACYT (Grant 87121). The project described was funded by Award Number R01HD058818 from the Eunice Kennedy Shriver National Institute of Child Health & Human Development and, in part, by the Intramural Research Division of the National Institutes of Health, National Institute of Environmental Health Sciences (Z01 ES025034) NR 32 TC 2 Z9 2 U1 0 U2 9 PU OCEAN SIDE PUBLICATIONS INC PI PROVIDENCE PA 95 PITMAN ST, PROVIDENCE, RI 02906 USA SN 1088-5412 EI 1539-6304 J9 ALLERGY ASTHMA PROC JI Allergy Asthma Proc. PD MAR-APR PY 2015 VL 36 IS 2 BP 130 EP 137 DI 10.2500/aap.2015.36.3801 PG 8 WC Allergy SC Allergy GA CE5RM UT WOS:000351893400010 PM 25715241 ER PT J AU Choung, RS Ditah, IC Nadeau, AM Rubio-Tapia, A Marietta, EV Brantner, TL Camilleri, MJ Rajkumar, SV Landgren, O Everhart, JE Murray, JA AF Choung, Rok Seon Ditah, Ivo C. Nadeau, Ashley M. Rubio-Tapia, Alberto Marietta, Eric V. Brantner, Tricia L. Camilleri, Michael J. Rajkumar, S. Vincent Landgren, Ola Everhart, James E. Murray, Joseph A. TI Trends and Racial/Ethnic Disparities in Gluten-Sensitive Problems in the United States: Findings from the National Health and Nutrition Examination Surveys From 1988 to 2012 SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Article ID UNDIAGNOSED CELIAC-DISEASE; INCREASING PREVALENCE; RISK; POPULATION; DIAGNOSIS; EPIDEMIOLOGY; INDIVIDUALS; MORTALITY; HAPLOTYPE; COMMUNITY AB OBJECTIVES: Racial disparities in the prevalence of celiac disease (CD) and the number of people without CD avoiding gluten (PWAG) in the United States are unknown. We aimed to describe racial differences in the prevalence of CD and PWAG, and evaluate the trends of CD in the noninstitutionalized civilian adult population of the US between 1988 and 2012. METHODS: A population-based cross-sectional study was conducted using data from the National Health and Nutrition Examination Surveys (NHANES) from 1988 to 1994, 1999 to 2004, and 2009 to 2012. Serum samples from the NHANES participants were tested for CD serology, which included IgA tissue transglutaminase (tTG IgA) and, if findings were abnormal, for IgA endomysial antibodies. Information about adherence to a gluten-free diet was obtained by means of an interviewer administered questionnaire. RESULTS: In NHANES 2009-2012, the adjusted prevalence of CD was significantly higher (P < 0.0001) among non-Hispanic whites (1.0%) than among non-Hispanic blacks (0.2%) and Hispanics (0.3%), whereas the adjusted prevalence of PWAG was signifi cantly higher (P = 0.01) in blacks (1.2%) as compared with Hispanics (0.5%) and whites (0.7%). The seroprevalence of CD in adults aged 50 years and older increased from 0.17% (95% confidence interval (CI) 0.03-0.33) in 1988-1994 to 0.44% (95% CI 0.24-0.81) in 2009-2012 (P < 0.05). CONCLUSIONS: The overall prevalence of CD increased between 1988 and 2012 and is signifi cantly more common in whites. In addition, a higher proportion of individuals maintaining a gluten-free diet in the absence of a diagnosis of CD are blacks. C1 [Choung, Rok Seon; Ditah, Ivo C.; Nadeau, Ashley M.; Rubio-Tapia, Alberto; Marietta, Eric V.; Brantner, Tricia L.; Murray, Joseph A.] Mayo Clin, Div Gastroenterol & Hepatol, Rochester, MN 55905 USA. [Camilleri, Michael J.] Mayo Clin, Dept Dermatol, Rochester, MN 55905 USA. [Rajkumar, S. Vincent] Mayo Clin, Div Hematol, Dept Med, Rochester, MN 55905 USA. [Landgren, Ola] Mem Sloan Kettering Canc Ctr, Dept Med, Myeloma Serv, New York, NY 10021 USA. [Everhart, James E.] NIDDK, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP Murray, JA (reprint author), Mayo Clin, Div Gastroenterol & Hepatol, 200 First St SW, Rochester, MN 55905 USA. EM murray.joseph@mayo.edu FU Centers for Disease Control [M26561] FX Financial support : This work was partly supported by the Centers for Disease Control Contract No. M26561. NR 35 TC 18 Z9 18 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 EI 1572-0241 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD MAR PY 2015 VL 110 IS 3 BP 455 EP 461 DI 10.1038/ajg.2015.8 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CE6AF UT WOS:000351917100013 PM 25665935 ER PT J AU Hunziker, R Lumelsky, N Wang, F AF Hunziker, Rosemarie Lumelsky, Nadya Wang, Fei TI Editorial: Scaffolds for Regenerative Medicine: A Special Issue of the Annals of Biomedical Engineering SO ANNALS OF BIOMEDICAL ENGINEERING LA English DT Editorial Material C1 [Hunziker, Rosemarie] NIBIB, Tissue Engn Regenerat Med & Biomat Programs, NIH, Bethesda, MD 20892 USA. [Lumelsky, Nadya] NIDCR, Tissue Engn & Regenerat Med Program, NIH, Bethesda, MD USA. [Wang, Fei] Natl Inst Arthrit & Musculoskeletal & Skin Dis NI, Regenerat Med Program, NIH, Bethesda, MD USA. RP Hunziker, R (reprint author), NIBIB, Tissue Engn Regenerat Med & Biomat Programs, NIH, Bethesda, MD 20892 USA. EM hunzikerr@mail.nih.gov NR 0 TC 0 Z9 0 U1 1 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0090-6964 EI 1573-9686 J9 ANN BIOMED ENG JI Ann. Biomed. Eng. PD MAR PY 2015 VL 43 IS 3 BP 487 EP 488 DI 10.1007/s10439-015-1296-5 PG 2 WC Engineering, Biomedical SC Engineering GA CE3QF UT WOS:000351742500001 PM 25773983 ER PT J AU Clarke, JH Giudici, ML Burke, JE Williams, RL Maloney, DJ Marugan, J Irvine, RF AF Clarke, Jonathan H. Giudici, Maria-Luisa Burke, John E. Williams, Roger L. Maloney, David J. Marugan, Juan Irvine, Robin F. TI The function of phosphatidylinositol 5-phosphate 4-kinase gamma (PI5P4K gamma) explored using a specific inhibitor that targets the PI5P-binding site SO BIOCHEMICAL JOURNAL LA English DT Article DE phosphatidylinositol 5-phosphate (PI5P); phosphatidylinositol 5-phosphate 4-kinase (PI5P4K); phosphatidylinositol 5-phosphate 4-kinase gamma (PI5P4K gamma) ID KINASE II-GAMMA; PHOSPHATE KINASE; NUCLEAR-LOCALIZATION; CELLS; ACTIVATION; BETA; VASOPRESSIN; EXPRESSION; P110-ALPHA; ISOFORM AB NIH-12848 (NCGC00012848-02), a putative phosphatidylinositol 5-phosphate 4-kinase gamma (PI5P4K gamma) inhibitor, was explored as a tool for investigating this enigmatic, low activity, lipid kinase. PI5P4K assays in vitro showed that NIH-12848 inhibited PI5P4K gamma with an IC50 of approximately 1 mu M but did not inhibit the alpha and beta PI5P4K isoforms at concentrations up to 100 mu M. A lack of inhibition of PI5P4K gamma ATPase activity suggested that NIH-12848 does not interact with the enzyme's ATP-binding site and direct exploration of binding using hydrogen-deuterium exchange (HDX)-MS (HDX-MS) revealed the putative PI5P-binding site of PI5P4K gamma to be the likely region of interaction. This was confirmed by a series of mutation experiments which led to the identification of a single PI5P4K gamma amino acid residue that can be mutated to its PI5P4Ks alpha and beta homologue to render PI5P4K gamma resistant NIH-12848 inhibition. NIH-12848 (10 mu M) was applied to cultured mouse principal kidney cortical collecting duct (mpkCCD) cells which, we show, express PI5P4K gamma that increases when the cells grow to confluence and polarize. NIH-12848 inhibited the translocation of Na+/K+-ATPase to the plasma membrane that occurs when mpkCCD cells grow to confluence and also prevented reversibly their forming of 'domes' on the culture dish. Both these NIH-12848-induced effects were mimicked by specific RNAi knockdown of PI5P4K gamma, but not that of PI5P4Ks alpha or beta. Overall, the data reveal a probable contribution of PI5P4K gamma to the development and maintenance of epithelial cell functional polarity and show that NIH-12848 is a potentially powerful tool for exploring the cell physiology of PI5P4Ks. C1 [Clarke, Jonathan H.; Giudici, Maria-Luisa; Irvine, Robin F.] Dept Pharmacol, Cambridge CB2 1PD, England. [Burke, John E.; Williams, Roger L.] MRC Lab Mol Biol, Cambridge CB2 0QH, England. [Maloney, David J.; Marugan, Juan] Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. RP Irvine, RF (reprint author), Dept Pharmacol, Tennis Court Rd, Cambridge CB2 1PD, England. EM rfi20@cam.ac.uk FU Medical Research Council [RG64071]; Biotechnology and Biological Sciences Research Council [RG65394]; British Heart Foundation [PG11/109/29247] FX This work was supported by the Medical Research Council [grant number RG64071 (to J.H.C.)]; the Biotechnology and Biological Sciences Research Council [grant number RG65394 (to M.-L.G.)]; and the British Heart Foundation [grant number PG11/109/29247 (to J.E.B.)]. NR 31 TC 2 Z9 3 U1 2 U2 8 PU PORTLAND PRESS LTD PI LONDON PA CHARLES DARWIN HOUSE, 12 ROGER STREET, LONDON WC1N 2JU, ENGLAND SN 0264-6021 EI 1470-8728 J9 BIOCHEM J JI Biochem. J. PD MAR 1 PY 2015 VL 466 BP 359 EP 367 DI 10.1042/BJ20141333 PN 2 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CE2YA UT WOS:000351686800015 PM 25495341 ER PT J AU Dusek, D Stipetic, MM Grce, M Pulanic, D Grkovic, L Seiwerth, RS Pulanic, TK Ceovic, R Bukovski, S Jelic, M Cindric, M Rajic, L Bilic, E Peric, Z Durakovic, N Vince, A Vrhovac, R Pavletic, SZ Nemet, D AF Dusek, D. Stipetic, M. Mravak Grce, M. Pulanic, D. Grkovic, L. Seiwerth, R. Serventi Pulanic, T. Klepac Ceovic, R. Bukovski, S. Jelic, M. Cindric, M. Rajic, L. Bilic, E. Peric, Z. Durakovic, N. Vince, A. Vrhovac, R. Pavletic, S. Z. Nemet, D. TI Oral Candida species colonization in chronic Graft-versus-Host Disease SO BONE MARROW TRANSPLANTATION LA English DT Meeting Abstract CT 41st Annual Meeting of the European-Society-for-Blood-and-Marrow-Transplantation CY MAR 22-25, 2015 CL Istanbul, TURKEY SP European Soc Blood & Marrow Transplantat C1 [Dusek, D.] Univ Hosp Infect Dis, Zagreb, Croatia. [Stipetic, M. Mravak] Univ Zagreb, Sch Dent Med, Zagreb 41000, Croatia. [Grce, M.; Cindric, M.] Rudjer Boskovic Inst, Div Mol Med, Zagreb, Croatia. [Pulanic, D.] Univ Hosp Ctr Zagreb, Dept Internal Med, Div Hematol, Zagreb, Croatia. [Pulanic, D.; Ceovic, R.; Bilic, E.; Peric, Z.; Durakovic, N.; Vince, A.; Vrhovac, R.; Nemet, D.] Univ Zagreb, Sch Med, Zagreb 41001, Croatia. [Grkovic, L.; Seiwerth, R. Serventi; Peric, Z.; Durakovic, N.; Vrhovac, R.; Nemet, D.] Univ Hosp Ctr Zagreb, Dept Internal Med, Div Hematol, Zagreb, Croatia. [Pulanic, T. Klepac] Community Hlth Ctr Zagreb East, Zagreb, Croatia. [Ceovic, R.] Univ Hosp Ctr Zagreb, Dept Dermatovenerol, Zagreb, Croatia. [Bukovski, S.; Jelic, M.] Univ Hosp Infect Dis, Dept Microbiol, Zagreb, Croatia. [Rajic, L.; Bilic, E.] Univ Hosp Ctr Zagreb, Dept Pediat, Zagreb, Croatia. [Pavletic, S. Z.] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 EI 1476-5365 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD MAR PY 2015 VL 50 SU 1 MA P102 BP S168 EP S168 PG 1 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA CE2GN UT WOS:000351632901098 ER PT J AU Grkovic, L Pulanic, D Peric, Z Batinic, D Seiwerth, RS Stipetic, MM Bilic, E Ceovic, R Rajic, L Durakovic, N Matic, N Pulanic, TK Petricek, I Vukic, T Ljubas, D Bilic, E Dusek, D Prenc, E Prah, I Bojanic, I Grce, M Zadro, R Vrhovac, R Pavletic, SZ Nemet, D AF Grkovic, L. Pulanic, D. Peric, Z. Batinic, D. Seiwerth, R. Serventi Stipetic, M. Mravak Bilic, E. Ceovic, R. Rajic, L. Durakovic, N. Matic, N. Pulanic, T. Klepac Petricek, I. Vukic, T. Ljubas, D. Bilic, E. Dusek, D. Prenc, E. Prah, I. Bojanic, I. Grce, M. Zadro, R. Vrhovac, R. Pavletic, S. Z. Nemet, D. TI Association of NIH organ cGVHD scores with blood lymphocyte subsets - a pilot study SO BONE MARROW TRANSPLANTATION LA English DT Meeting Abstract CT 41st Annual Meeting of the European-Society-for-Blood-and-Marrow-Transplantation CY MAR 22-25, 2015 CL Istanbul, TURKEY SP European Soc Blood & Marrow Transplantat C1 [Grkovic, L.; Pulanic, D.; Peric, Z.; Batinic, D.; Seiwerth, R. Serventi; Stipetic, M. Mravak; Bilic, E.; Ceovic, R.; Rajic, L.; Durakovic, N.; Matic, N.; Pulanic, T. Klepac; Petricek, I.; Vukic, T.; Ljubas, D.; Bilic, E.; Prenc, E.; Prah, I.; Bojanic, I.; Zadro, R.; Vrhovac, R.; Nemet, D.] UHC Zagreb, Zagreb, Croatia. [Dusek, D.] Univ Hosp Infect Dis, Infect Dis, Zagreb, Croatia. [Grce, M.] Rudjer Boskovic Inst, Zagreb, Croatia. [Pavletic, S. Z.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 EI 1476-5365 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD MAR PY 2015 VL 50 SU 1 MA P129 BP S183 EP S184 PG 2 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA CE2GN UT WOS:000351632901125 ER PT J AU Kralj, M Kuzmina, Z Weigl, R Rose, J Pavletic, SZ Rottal, A Kormoczi, U Pickl, WF Hakim, FT Greinix, HT AF Kralj, M. Kuzmina, Z. Weigl, R. Rose, J. Pavletic, S. Z. Rottal, A. Koermoeczi, U. Pickl, W. F. Hakim, F. T. Greinix, H. T. TI Elevation of CD19+CD21low B-cells in patients with chronic graft-versus-host-disease: A validation study in two independent patient cohorts SO BONE MARROW TRANSPLANTATION LA English DT Meeting Abstract CT 41st Annual Meeting of the European-Society-for-Blood-and-Marrow-Transplantation CY MAR 22-25, 2015 CL Istanbul, TURKEY SP European Soc Blood & Marrow Transplantat C1 [Kralj, M.; Kuzmina, Z.; Weigl, R.; Greinix, H. T.] Med Univ Vienna, Bone Marrow Transplant Unit, Dept Internal Med 1, Vienna, Austria. [Rose, J.; Pavletic, S. Z.; Hakim, F. T.] NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Rottal, A.; Koermoeczi, U.; Pickl, W. F.] Med Univ Vienna, Inst Immunol, Vienna, Austria. NR 0 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 0268-3369 EI 1476-5365 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD MAR PY 2015 VL 50 SU 1 MA P518 BP S380 EP S380 PG 1 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA CE2GN UT WOS:000351632902133 ER PT J AU Pulanic, D Grkovic, L Seiwerth, RS Stipetic, MM Bilic, E Ceovic, R Peric, Z Rajic, L Durakovic, N Matic, N Pulanic, TK Petricek, I Vukic, T Bilic, E Dusek, D Prenc, E Prah, IO Bojanic, I Grce, M Zadro, R Batinic, D Vrhovac, R Pavletic, SZ Nemet, D AF Pulanic, D. Grkovic, L. Seiwerth, R. Serventi Stipetic, M. Mravak Bilic, E. Ceovic, R. Peric, Z. Rajic, L. Durakovic, N. Matic, N. Pulanic, T. Klepac Petricek, I. Vukic, T. Bilic, E. Dusek, D. Prenc, E. Prah, I. O. Bojanic, I. Grce, M. Zadro, R. Batinic, D. Vrhovac, R. Pavletic, S. Z. Nemet, D. TI Von Willebrand Factor and Factor VIII as potential biomarkers of chronic Graft-versus-Host Disease SO BONE MARROW TRANSPLANTATION LA English DT Meeting Abstract CT 41st Annual Meeting of the European-Society-for-Blood-and-Marrow-Transplantation CY MAR 22-25, 2015 CL Istanbul, TURKEY SP European Soc Blood & Marrow Transplantat C1 [Pulanic, D.; Peric, Z.; Durakovic, N.; Vrhovac, R.; Nemet, D.] Univ Zagreb, Div Hematol, Dept Internal Med, Univ Hosp Ctr Zagreb, Zagreb 41000, Croatia. [Pulanic, D.; Peric, Z.; Durakovic, N.; Prenc, E.; Prah, I. O.; Vrhovac, R.; Nemet, D.] Univ Zagreb, Sch Med, Zagreb 41001, Croatia. [Grkovic, L.; Seiwerth, R. Serventi; Matic, N.] Univ Hosp Ctr Zagreb, Dept Internal Med, Div Hematol, Zagreb, Croatia. [Stipetic, M. Mravak; Pavletic, S. Z.] Univ Zagreb, Sch Dent Med, Zagreb 41000, Croatia. [Bilic, E.] Univ Hosp Ctr Zagreb, Dept Neurol, Zagreb, Croatia. [Ceovic, R.] Univ Hosp Ctr Zagreb, Dept Dermatol, Zagreb, Croatia. [Rajic, L.; Bilic, E.] Univ Hosp Ctr Zagreb, Dept Pediat, Zagreb, Croatia. [Rajic, L.; Bilic, E.] Univ Zagreb, Sch Med, Commun Hlth Ctr Zagreb East, Zagreb 41001, Croatia. [Petricek, I.] Univ Hosp Ctr Zagreb, Dept Pediat, Zagreb, Croatia. [Vukic, T.] Univ Hosp Ctr Zagreb, Dept Rheumatol & Rehabil, Zagreb, Croatia. [Dusek, D.] Univ Hosp Infect Dis, Zagreb, Croatia. [Bojanic, I.] Univ Hosp Ctr Zagreb, Dept Transfus Med, Zagreb, Croatia. [Grce, M.] Univ Zagreb, Div Mol Med, Rudjer Boskov Instute, Zagreb 41000, Croatia. [Zadro, R.; Batinic, D.] Univ Zagreb, Univ Hosp Ctr Zagreb, Dept Lab Med, Zagreb 41000, Croatia. [Pavletic, S. Z.] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 EI 1476-5365 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD MAR PY 2015 VL 50 SU 1 MA P105 BP S169 EP S170 PG 2 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA CE2GN UT WOS:000351632901101 ER PT J AU Pulanic, TK Stratton, P Grkovic, L Oreskovic, S Kasum, M Pulanic, D Nemet, D Pavletic, SZ AF Pulanic, T. Klepac Stratton, P. Grkovic, L. Oreskovic, S. Kasum, M. Pulanic, D. Nemet, D. Pavletic, S. Z. TI Demographic and clinical characteristic of female patients with genital cGVHD SO BONE MARROW TRANSPLANTATION LA English DT Meeting Abstract CT 41st Annual Meeting of the European-Society-for-Blood-and-Marrow-Transplantation CY MAR 22-25, 2015 CL Istanbul, TURKEY SP European Soc Blood & Marrow Transplantat C1 [Pulanic, T. Klepac] Community Hlth Ctr Zagreb East, Zagreb, Croatia. [Stratton, P.] NICHD, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Grkovic, L.] Univ Hosp Ctr Zagreb, Div Hematol, Zagreb, Croatia. [Oreskovic, S.] Univ Zagreb, Sch Med, Clin Hosp Ctr Zagreb, Dept Obstet & Gynecol 4, Zagreb 41001, Croatia. [Kasum, M.] Univ Zagreb, Sch Med, Clin Hosp Ctr Zagreb, Dept Obstet & Gynecol, Zagreb 41001, Croatia. [Pulanic, D.; Nemet, D.] Univ Hosp Ctr Zagreb, Div Hematol, Zagreb, Croatia. [Pavletic, S. Z.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NR 0 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 0268-3369 EI 1476-5365 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD MAR PY 2015 VL 50 SU 1 MA P544 BP S392 EP S393 PG 2 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA CE2GN UT WOS:000351632902159 ER PT J AU Pulanic, TK Stratton, P Grkovic, L Oreskovic, S Kasum, M Seiwert, RS Grce, M Dusek, D Pulanic, D Vrhovac, R Pavletic, SZ Nemet, D AF Pulanic, T. Klepac Stratton, P. Grkovic, L. Oreskovic, S. Kasum, M. Seiwert, R. Serventi Grce, M. Dusek, D. Pulanic, D. Vrhovac, R. Pavletic, S. Z. Nemet, D. TI Importance of gynecological examination in female patients with chronic graft versus host disease SO BONE MARROW TRANSPLANTATION LA English DT Meeting Abstract CT 41st Annual Meeting of the European-Society-for-Blood-and-Marrow-Transplantation CY MAR 22-25, 2015 CL Istanbul, TURKEY SP European Soc Blood & Marrow Transplantat C1 [Pulanic, T. Klepac] Community Hlth Ctr Zagreb East, Zagreb, Croatia. [Stratton, P.] NICHD, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Grkovic, L.] Univ Hosp Ctr Zagreb, Div Hematol, Zagreb, Croatia. [Oreskovic, S.] Univ Zagreb, Sch Med, Clin Hosp Ctr Zagreb, Dept Obstet & Gynecol, Zagreb 41001, Croatia. [Kasum, M.] Univ Zagreb, Sch Med, Clin Hosp Ctr Zagreb, Dept Obstet & Gynecol 4, Zagreb 41001, Croatia. [Seiwert, R. Serventi] Univ Hosp Ctr Zagreb, Div Hematol, Zagreb, Croatia. [Grce, M.] Rudjer Boskovic Inst, Div Mol Med, Zagreb, Croatia. [Dusek, D.] Univ Hosp Infect Dis, Zagreb, Croatia. [Pulanic, D.; Vrhovac, R.; Nemet, D.] Univ Zagreb, Sch Med, Univ Hosp Ctr Zagreb, Div Hematol, Zagreb 41001, Croatia. [Pavletic, S. Z.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NR 0 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 0268-3369 EI 1476-5365 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD MAR PY 2015 VL 50 SU 1 MA P545 BP S393 EP S393 PG 1 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA CE2GN UT WOS:000351632902160 ER PT J AU Marrone, M Schilsky, RL Liu, G Khoury, MJ Freedman, AN AF Marrone, Michael Schilsky, Richard L. Liu, Geoff Khoury, Muin J. Freedman, Andrew N. TI Opportunities for Translational Epidemiology: The Important Role of Observational Studies to Advance Precision Oncology SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID THIOPURINE METHYLTRANSFERASE ACTIVITY; METASTATIC COLORECTAL-CANCER; HUMAN-BREAST CANCER; CHILDHOOD LEUKEMIA; CLINICAL-TRIALS; NEU ONCOGENE; PHARMACOGENETICS; 6-MERCAPTOPURINE; CETUXIMAB; THERAPY AB Within current oncology practice, several genomic applications are being used to inform treatment decisions with molecularly targeted therapies in breast, lung, colorectal, melanoma, and other cancers. This commentary introduces a conceptual framework connecting the full spectrum of biomedical research disciplines, including fundamental laboratory research, clinical trials, and observational studies in the translation of genomic applications into clinical practice. The conceptual framework illustrates the contribution that well-designed observational epidemiologic studies provide to the successful translation of these applications, and characterizes the role observational epidemiology plays in driving the dynamic and iterative bench-to-bedside, and bedside-to-bench translation continuum. We also discuss how the principles of this conceptual model, emphasizing integration of multidisciplinary research, can be applied to the evolving paradigm in "precision oncology" focusing on multiplex tumor sequencing, and we identify opportunities for observational studies to contribute to the successful and efficient translation of this paradigm. (c) 2015 AACR. C1 [Marrone, Michael; Khoury, Muin J.; Freedman, Andrew N.] NCI, Epidemiol & Genom Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Schilsky, Richard L.] Amer Soc Clin Oncol, Alexandria, VA USA. [Liu, Geoff] Princess Margaret Hosp, Div Med Oncol, Univ Hlth Network, Toronto, ON M4X 1K9, Canada. [Khoury, Muin J.] Ctr Dis Control & Prevent, Off Publ Hlth Gen, Atlanta, GA USA. RP Freedman, AN (reprint author), NCI, Clin & Translat Epidemiol Branch, Epidemiol & Genom Res Program, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,Rm4E226 MSC 9762, Bethesda, MD 20892 USA. EM andrew_freedman@nih.gov RI Liu, Geoffrey/N-4421-2016 FU Intramural CDC HHS [CC999999]; Intramural NIH HHS [Z99 CA999999] NR 38 TC 3 Z9 3 U1 0 U2 4 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 MAR PY 2015 VL 24 IS 3 BP 484 EP 489 DI 10.1158/1055-9965.EPI-14-1086 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CE6NC UT WOS:000351953100002 PM 25750251 ER PT J AU Cook, MB Guenel, P Gapstur, SM van den Brandt, PA Michels, KB Casagrande, JT Cooke, R Van Den Eeden, SK Ewertz, M Falk, RT Gaudet, MM Gkiokas, G Habel, LA Hsing, AW Johnson, K Kolonel, LN La Vecchia, C Lynge, E Lubin, JH McCormack, VA Negri, E Olsson, H Parisi, D Petridou, ET Riboli, E Sesso, HD Swerdlow, A Thomas, DB Willett, WC Brinton, LA AF Cook, Michael B. Guenel, Pascal Gapstur, Susan M. van den Brandt, Piet A. Michels, Karin B. Casagrande, John T. Cooke, Rosie Van Den Eeden, Stephen K. Ewertz, Marianne Falk, Roni T. Gaudet, Mia M. Gkiokas, George Habel, Laurel A. Hsing, Ann W. Johnson, Kenneth Kolonel, Laurence N. La Vecchia, Carlo Lynge, Elsebeth Lubin, Jay H. McCormack, Valerie A. Negri, Eva Olsson, Hakan Parisi, Dominick Petridou, Eleni Th. Riboli, Elio Sesso, Howard D. Swerdlow, Anthony Thomas, David B. Willett, Walter C. Brinton, Louise A. TI Tobacco and Alcohol in Relation to Male Breast Cancer: An Analysis of the Male Breast Cancer Pooling Project Consortium SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID BASE-LINE CHARACTERISTICS; MODELING TOTAL EXPOSURE; BODY-MASS INDEX; RISK-FACTORS; CIGARETTE-SMOKING; UNITED-STATES; MENSTRUAL-CYCLE; ACTIVE SMOKING; FOLLOW-UP; MEN AB Background: The etiology of male breast cancer is poorly understood, partly due to its relative rarity. Although tobacco and alcohol exposures are known carcinogens, their association with male breast cancer risk remains ill-defined. Methods: The Male Breast Cancer Pooling Project consortium provided 2,378 cases and 51,959 controls for analysis from 10 case-control and 10 cohort studies. Individual participant data were harmonized and pooled. Unconditional logistic regression was used to estimate study design-specific (case-control/cohort) ORs and 95% confidence intervals (CI), which were then combined using fixed-effects meta-analysis. Results: Cigarette smoking status, smoking pack-years, duration, intensity, and age at initiation were not associated with male breast cancer risk. Relations with cigar and pipe smoking, tobacco chewing, and snuff use were also null. Recent alcohol consumption and average grams of alcohol consumed per day were also not associated with risk; only one subanalysis of very high recent alcohol consumption (> 60 g/day) was tentatively associated with male breast cancer (ORunexposed referent = 1.29; 95% CI, 0.97-1.71; OR>0-<7 g/day referent = 1.36; 95% CI, 1.04-1.77). Specific alcoholic beverage types were not associated with male breast cancer. Relations were not altered when stratified by age or body mass index. Conclusions: In this analysis of the Male Breast Cancer Pooling Project, we found little evidence that tobacco and alcohol exposures were associated with risk of male breast cancer. Impact: Tobacco and alcohol do not appear to be carcinogenic for male breast cancer. Future studies should aim to assess these exposures in relation to subtypes of male breast cancer. (c) 2014 AACR. C1 [Cook, Michael B.; Falk, Roni T.; Lubin, Jay H.; Brinton, Louise A.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Guenel, Pascal] INSERM, CESP Ctr Res Epidemiol & Populat Hlth, Environm Epidemiol Canc, Villejuif, France. [Guenel, Pascal] Univ Paris 11, UMRS 1018, Villejuif, France. [Gapstur, Susan M.; Gaudet, Mia M.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [van den Brandt, Piet A.] Maastricht Univ, Dept Epidemiol, NL-6200 MD Maastricht, Netherlands. [Michels, Karin B.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Obstetr & Gynecol Epidemiol Ctr,Dept Obstet Gynec, Boston, MA 02115 USA. [Casagrande, John T.] Univ So Calif, Dept Prevent Med, Los Angeles, CA USA. [Cooke, Rosie; Swerdlow, Anthony] Inst Canc Res, Div Genet & Epidemiol, Sutton, Surrey, England. [Van Den Eeden, Stephen K.] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Ewertz, Marianne] Univ Southern Denmark, Odense Univ Hosp, Inst Clin Res, Dept Oncol, Odense, Denmark. [Gkiokas, George] Aretaie Univ Hosp, Dept Surg, Athens, Greece. [Hsing, Ann W.] Canc Prevent Inst Calif, Fremont, CA USA. [Hsing, Ann W.] Stanford Canc Inst, Stanford, CA USA. [Johnson, Kenneth] Univ Ottawa, Dept Epidemiol & Community Med, Ottawa, ON, Canada. [Kolonel, Laurence N.] Univ Hawaii, Ctr Canc, Canc Epidemiol Program, Honolulu, HI 96822 USA. [La Vecchia, Carlo] Univ Milan, Dept Clin Sci & Community Hlth, Milan, Italy. [Lynge, Elsebeth] Univ Copenhagen, Inst Publ Hlth, DK-1168 Copenhagen, Denmark. [McCormack, Valerie A.] Int Agcy Res Canc, Sect Environm & Radiat, F-69372 Lyon, France. [Negri, Eva] Ist Richerche Farmacologiche Mario Negri, Milan, Italy. [Olsson, Hakan] Lund Univ, Dept Oncol, Lund, Sweden. [Parisi, Dominick] Informat Management Serv Inc, Rockville, MD USA. [Petridou, Eleni Th.] Univ Athens, Sch Med, Dept Hyg Epidemiol & Med Stat, GR-11527 Athens, Greece. [Sesso, Howard D.] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, London, England. [Sesso, Howard D.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Sesso, Howard D.] Brigham & Womens Hosp, Div Aging, Boston, MA 02115 USA. [Swerdlow, Anthony] Inst Canc Res, Div Breast Can Res, London SW3 6JB, England. [Thomas, David B.] Fred Hutchinson Canc Res Ctr, Program Epidemiol, Seattle, WA 98104 USA. [Willett, Walter C.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Willett, Walter C.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Div Prevent Med, Boston, MA 02115 USA. RP Cook, MB (reprint author), NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, 9609 Med Ctr Dr,Room 7-E106,MSC 9774, Bethesda, MD 20892 USA. EM cook.mich@mail.nih.gov RI Brinton, Louise/G-7486-2015; Cook, Michael/A-5641-2009; OI Brinton, Louise/0000-0003-3853-8562; Cook, Michael/0000-0002-0533-7302; Lynge, Elsebeth/0000-0003-4785-5236; La Vecchia, Carlo/0000-0003-1441-897X FU Intramural Program of the NCI, NIH, Department of Health andHuman Services; Intramural Program of the NCI, NIH, Department of Health and Human Services; Kaiser Foundation Research Institute; American Cancer Society; Breakthrough Breast Cancer [BBC066]; National Health Service; National Cancer Institute, National Institutes of Health [UM1CA167552, P01CA 55075, R37 CA54281]; Intramural Program of the National Cancer Institute, National Institutes of Health, Department of Health and Human Services; Dutch Cancer Society; NIH [CA 097193, CA 34944, CA 40360, HL 26490, HL 34595] FX This research was funded, in part, by the Intramural Program of the NCI, NIH, Department of Health andHuman Services. J.H. Lubin, L.A. Brinton, M.B. Cook, and R.T. Falk were supported by the Intramural Program of the NCI, NIH, Department of Health and Human Services. S. Van Den Eeden and L.A. Habel were supported by the Kaiser Foundation Research Institute. Follow-up and maintenance of the Cancer Prevention Study-II was supported by the American Cancer Society.; The England and Wales Male Breast Cancer Case-Control Study was funded by Breakthrough Breast Cancer grant BBC066 awarded to A. Swerdlow and A. Ashworth. In addition, the Institute of Cancer Research acknowledges National Health Service funding to the National Institute for Health Research Biomedical Research Centre. The Health Professionals' Follow-up Study was supported by grants UM1CA167552 and P01CA 55075 from the National Cancer Institute, National Institutes of Health awarded to K.B. Michels and W.C. Willett. The Multiethnic Cohort Study was supported by grant #R37 CA54281 from the National Cancer Institute, National Institutes of Health awarded to L.N. Kolonel. The National Mortality Follow-back Study was supported by the Intramural Program of the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. The Netherlands Cohort Study was supported by grants from the Dutch Cancer Society awarded to P.A. van den Brandt. The Physicians' Health Study was supported by grants CA 097193, CA 34944, CA 40360, HL 26490, and HL 34595 from the NIH. NR 69 TC 3 Z9 3 U1 0 U2 6 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 MAR PY 2015 VL 24 IS 3 BP 520 EP 531 DI 10.1158/1055-9965.EPI-14-1009 PG 12 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CE6NC UT WOS:000351953100007 PM 25515550 ER PT J AU Hofmann, JN Hoppin, JA Lynch, CF Poole, JA Purdue, MP Blair, A Alavanja, MC Freeman, LEB AF Hofmann, Jonathan N. Hoppin, Jane A. Lynch, Charles F. Poole, Jill A. Purdue, Mark P. Blair, Aaron Alavanja, Michael C. Freeman, Laura E. Beane TI Farm Characteristics, Allergy Symptoms, and Risk of Non-Hodgkin Lymphoid Neoplasms in the Agricultural Health Study SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID IMMUNOLOGICALLY ACTIVE AGENTS; OCCUPATIONAL-EXPOSURE; CANCER-MORTALITY; GROWING-UP; ASTHMA; ATOPY; COHORT; RHINITIS; WOMEN; MALIGNANCIES AB Background: Because of unique exposures, studies among farmers may yield insights into the relationship between allergies and non-Hodgkin lymphoid (NHL) neoplasms. We evaluated farm characteristics, allergic symptoms and conditions, and risk of NHL including specific subtypes in the Agricultural Health Study, a prospective cohort of farmers and spouses from North Carolina and Iowa. Methods: We identified 710 incident cases of NHL (including chronic lymphocytic leukemia and multiple myeloma) among 82,370 participants with baseline data on crop and animal exposures, including 454 cases among 52,850 participants with baseline data on recent allergy symptoms (rhinitis) and living on a farm during childhood. HR and 95% confidence intervals (CI) were calculated using multivariable-adjusted proportional hazards models. Results: We observed reduced risks of NHL among farmers and spouses with rhinitis at baseline (HR, 0.63; 95% CI, 0.51-0.79), related to growing soybeans (HR, 0.80; 95% CI, 0.67-0.96), and among farmers who handled stored grains or hay (HR, 0.66; 95% CI, 0.52-0.82). Growing up on a farm was associated with increased NHL risk (HR, 1.51; 95% CI, 1.15-1.98). Results did not differ significantly by NHL subtype. Conclusions: Both the reduced risk of NHL among those with allergy symptoms and specific farm exposures in adulthood, and the increased risk among those who grew up on a farm suggest that the host immune response to agricultural allergens may influence NHL development. Impact: This prospective study is, to our knowledge, the first to investigate the relationship between allergy symptoms and NHL risk in farmers; confirmation of these findings in other farming populations is warranted. (c) 2015 AACR. C1 [Hofmann, Jonathan N.; Purdue, Mark P.; Blair, Aaron; Alavanja, Michael C.; 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. [Lynch, Charles F.] Univ Iowa, Dept Epidemiol, Iowa City, IA USA. [Poole, Jill A.] Univ Nebraska Med Ctr, Dept Internal Med, Omaha, NE USA. [Purdue, Mark P.] Ontario Inst Canc Res, Toronto, ON, Canada. RP Hofmann, JN (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Room 6E132,MSC 9771, Bethesda, MD 20892 USA. EM hofmannjn@mail.nih.gov RI Purdue, Mark/C-9228-2016; Beane Freeman, Laura/C-4468-2015 OI Purdue, Mark/0000-0003-1177-3108; Beane Freeman, Laura/0000-0003-1294-4124 FU Intramural Research Program of the NIH, National Cancer Institute [Z01CP010119] FX This work was supported by the Intramural Research Program of the NIH, National Cancer Institute (Z01CP010119). NR 31 TC 2 Z9 2 U1 1 U2 3 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 MAR PY 2015 VL 24 IS 3 BP 587 EP 594 DI 10.1158/1055-9965.EPI-14-1246 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CE6NC UT WOS:000351953100015 PM 25583946 ER PT J AU Mondul, AM Shui, IM Yu, K Weinstein, SJ Tsilidis, KK Joshi, AD Agudo, A Berg, CD Black, A Buring, JE Chasman, DI Gaudet, MM Haiman, C Hankinson, SE Henderson, BE Hoover, RN Hunter, DJ Khaw, KT Kuhn, T Kvaskoff, M Le Marchand, L Lindstrom, S McCullough, ML Overvad, K Peeters, PH Riboli, E Ridker, PM Stram, DO Sund, M Trichopoulos, D Tumino, R Weiderpass, E Willett, W Kraft, P Ziegler, RG Albanes, D AF Mondul, Alison M. Shui, Irene M. Yu, Kai Weinstein, Stephanie J. Tsilidis, Konstantinos K. Joshi, Amit D. Agudo, Antonio Berg, Christine D. Black, Amanda Buring, Julie E. Chasman, Daniel I. Gaudet, Mia M. Haiman, Christopher Hankinson, Susan E. Henderson, Brian E. Hoover, Robert N. Hunter, David J. Khaw, Kay-Tee Kuehn, Tilman Kvaskoff, Marina Le Marchand, Loic Lindstroem, Sara McCullough, Marjorie L. Overvad, Kim Peeters, Petra H. Riboli, Elio Ridker, Paul M. Stram, Daniel O. Sund, Malin Trichopoulos, Dimitrios Tumino, Rosario Weiderpass, Elisabete Willett, Walter Kraft, Peter Ziegler, Regina G. Albanes, Demetrius TI Vitamin D-Associated Genetic Variation and Risk of Breast Cancer in the Breast and Prostate Cancer Cohort Consortium (BPC3) SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID GENOME-WIDE ASSOCIATION; 25-HYDROXYVITAMIN D AB Background: Two recent genome-wide association studies (GWAS) identified SNPs in or near four genes related to circulating 25-hydroxyvitamin D [25(OH) D] concentration. To examine the hypothesized inverse relationship between vitamin D status and breast cancer, we studied the associations between SNPs in these genes and breast cancer risk in a large pooled study of 9,456 cases and 10,816 controls from six cohorts. Methods: SNP markers localized to each of four genes (GC, CYP24A1, CYP2R1, and DHCR7) previously associated with 25 (OH) D were genotyped and examined both individually and as a 4-SNP polygenic score. Logistic regression was used to estimate the associations between the genetic variants and risk of breast cancer. Results: We found no association between any of the four SNPs or their polygenic score and breast cancer risk. Conclusions: Our findings do not support an association between vitamin D status, as reflected by 25(OH) D-related genotypes, and breast cancer risk. Impact: These findings may contribute to future meta-analyses and scientific review articles, and provide new data about the association between vitamin D-related genes and breast cancer. (c) 2014 AACR. C1 [Mondul, Alison M.; Yu, Kai; Weinstein, Stephanie J.; Black, Amanda; Hoover, Robert N.; Ziegler, Regina G.; Albanes, Demetrius] NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Shui, Irene M.; Joshi, Amit D.; Hankinson, Susan E.; Hunter, David J.; Lindstroem, Sara; Trichopoulos, Dimitrios; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Tsilidis, Konstantinos K.] Univ Oxford, Nuffield Dept Clin Med, Canc Epidemiol Unit, Oxford, England. [Tsilidis, Konstantinos K.] Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, GR-45110 Ioannina, Greece. [Agudo, Antonio] Catalan Inst Oncol IDIBELL, Canc Epidemiol Res Program, Unit Nutr Environm & Canc, Barcelona, Spain. [Berg, Christine D.] Johns Hopkins Med, Dept Radiat Oncol & Mol Radiat Sci, Baltimore, MD USA. [Buring, Julie E.; Chasman, Daniel I.; Ridker, Paul M.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Buring, Julie E.; Chasman, Daniel I.; Kvaskoff, Marina; Ridker, Paul M.] Harvard Univ, Sch Med, Boston, MA USA. [Gaudet, Mia M.; McCullough, Marjorie L.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Haiman, Christopher; Henderson, Brian E.; Stram, Daniel O.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Hankinson, Susan E.] Univ Massachusetts, Amherst Sch Publ Hlth & Hlth Sci, Dept Epidemiol, Amherst, MA 01003 USA. [Hankinson, Susan E.] Brigham & Womens Hosp, Canc Res Ctr, Boston, MA 02115 USA. [Khaw, Kay-Tee] Univ Cambridge, Sch Clin Med, Dept Publ Hlth & Primary Care, Cambridge, England. [Kuehn, Tilman] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Kvaskoff, Marina] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Le Marchand, Loic] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96822 USA. [Overvad, Kim] Aarhus Univ, Dept Publ Hlth, Epidemiol Sect, Aarhus, Denmark. [Peeters, Petra H.] Univ Med Ctr, Julius Ctr Hlth Sci & Primary Care, Dept Epidemiol, Utrecht, Netherlands. [Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. [Sund, Malin] Umea Univ, Dept Surg & Perioperat Sci, Umea, Sweden. [Trichopoulos, Dimitrios] Acad Athens, Bur Epidemiol Res, Athens, Greece. [Trichopoulos, Dimitrios] Hellen Hlth Fdn, Athens, Greece. [Tumino, Rosario] Civ MP Arezzo Hosp, Canc Registry, Asp Ragusa, Italy. [Tumino, Rosario] Civ MP Arezzo Hosp, Histopathol Unit, Asp Ragusa, Italy. [Weiderpass, Elisabete] Univ Tromso, Arctic Univ Norway, Fac Hlth Sci, Dept Community Med, Tromso, Norway. [Weiderpass, Elisabete] Canc Registry Norway, Oslo, Norway. [Weiderpass, Elisabete] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Weiderpass, Elisabete] Folkhalsan Res Ctr, Dept Genet Epidemiol, Helsinki, Finland. [Willett, Walter] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. RP Mondul, AM (reprint author), Univ Michigan, Sch Publ Hlth, Dept Epidemiol, 1415 Washington Hts, Ann Arbor, MI 48109 USA. EM amondul@umich.edu RI Agudo, Antonio/J-1805-2016; Weiderpass, Elisabete/M-4029-2016; KVASKOFF, Marina/E-7981-2017; OI Weiderpass, Elisabete/0000-0003-2237-0128; KVASKOFF, Marina/0000-0002-4557-3772; Mondul, Alison/0000-0002-8843-1416 FU NIH, National Cancer Institute [U01-CA98233-07, U01-CA98710-06, U01-CA98216-06, U01-CA98758-07]; Intramural Research Program of NIH/National Cancer Institute, Division of Cancer Epidemiology and Genetics; National Research Service Award from the National Cancer Institute, NIH [T32 CA09001] FX This work was supported by the NIH, National Cancer Institute cooperative agreements U01-CA98233-07 (to D.J. Hunter), U01-CA98710-06 (to M.J. Thun), U01-CA98216-06 (to E. Riboli and R. Kaaks), and U01-CA98758-07 (to B.E. Henderson), and the Intramural Research Program of NIH/National Cancer Institute, Division of Cancer Epidemiology and Genetics. I. M. Shui was supported by a National Research Service Award (T32 CA09001) from the National Cancer Institute, NIH. NR 8 TC 6 Z9 7 U1 1 U2 5 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 MAR PY 2015 VL 24 IS 3 BP 627 EP 630 DI 10.1158/1055-9965.EPI-14-1127 PG 4 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CE6NC UT WOS:000351953100020 PM 25542828 ER PT J AU Andreotti, G Birmann, BM Cozen, W De Roos, AJ Chiu, BCH Costas, L de Sanjose, S Moysich, K Camp, NJ Spinelli, JJ Pahwa, P Dosman, JA McLaughlin, JR Boffetta, P Staines, A Weisenburger, D Benhaim-Luzon, V Brennan, P Costantini, AS Miligi, L Campagna, M Nieters, A Becker, N Maynadie, M Foretova, L Zheng, TZ Tricot, G Milliken, K Krzystan, J Steplowski, E Baris, D Purdue, MP AF Andreotti, Gabriella Birmann, Brenda M. Cozen, Wendy De Roos, Anneclaire J. Chiu, Brian C. H. Costas, Laura de Sanjose, Silvia Moysich, Kirsten Camp, Nicola J. Spinelli, John J. Pahwa, Punam Dosman, James A. McLaughlin, John R. Boffetta, Paolo Staines, Anthony Weisenburger, Dennis Benhaim-Luzon, Veronique Brennan, Paul Costantini, Adele Seniori Miligi, Lucia Campagna, Marcello Nieters, Alexandra Becker, Nikolaus Maynadie, Marc Foretova, Lenka Zheng, Tongzhang Tricot, Guido Milliken, Kevin Krzystan, Joseph Steplowski, Emily Baris, Dalsu Purdue, Mark P. TI A Pooled Analysis of Cigarette Smoking and Risk of Multiple Myeloma from the International Multiple Myeloma Consortium SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID TOBACCO SMOKING; METAANALYSIS AB Background: Past investigations of cigarette smoking and multiple myeloma have been underpowered to detect moderate associations, particularly within subgroups. To clarify this association, we conducted a pooled analysis of nine case-control studies in the International Multiple Myeloma Consortium, with individual-level questionnaire data on cigarette smoking history and other covariates. Methods: Using a pooled population of 2,670 cases and 11,913 controls, we computed odds ratios (OR) and 95% confidence intervals (CI) relating smoking to multiple myeloma risk using unconditional logistic regression adjusting for gender, age group, race, education, body mass index, alcohol consumption, and study center. Results: Neither ever smokers (OR, 0.95; 95% CI, 0.87-1.05), current smokers (OR, 0.82; 95% CI, 0.73-0.93), nor former smokers (OR, 1.03; 95% CI, 0.92-1.14) had increased risks of multiple myeloma compared with never smokers. Analyses of smoking frequency, pack-years, and duration did not reveal significant or consistent patterns, and there was no significant effect modification by subgroups. Conclusion: Findings from this large pooled analysis do not support the hypothesis of cigarette smoking as a causal factor for multiple myeloma. Impact: Cigarette smoking is one of the most important risk factors for cancer, but the association with multiple myeloma was inconclusive. This study had excellent power to detect modest associations, and had individual-level data to evaluate confounding and effect modification by potentially important factors that were not evaluated in previous studies. Our findings confirm that smoking is not a risk factor for multiple myeloma. (c) 2014 AACR. C1 [Andreotti, Gabriella; Baris, Dalsu; Purdue, Mark P.] NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Rockville, MD 20850 USA. [Birmann, Brenda M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Div Network Med,Dept Med, Boston, MA 02115 USA. [Cozen, Wendy] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Cozen, Wendy] Univ So Calif, Norris Comprehens Canc Ctr, Los Angeles, CA USA. [De Roos, Anneclaire J.] Drexel Univ, Sch Publ Hlth, Dept Environm & Occupat Hlth, Philadelphia, PA 19104 USA. [Chiu, Brian C. H.] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. [Costas, Laura; de Sanjose, Silvia] Univ Barcelona, IDIBELL, Catalan Inst Oncol, Unit Infect & Canc, Barcelona, Spain. [Moysich, Kirsten] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Camp, Nicola J.] Univ Utah, Sch Med, Div Genet Epidemiol, Salt Lake City, UT USA. [Spinelli, John J.] British Columbia Canc Agcy, Canc Control Res, Vancouver, BC V5Z 4E6, Canada. [Spinelli, John J.] Univ British Columbia, Sch Populat & Publ Hlth, Vancouver, BC V5Z 1M9, Canada. [Pahwa, Punam; Dosman, James A.] Univ Saskatchewan, Canadian Ctr Hlth & Safety Agr, Saskatoon, SK, Canada. [Pahwa, Punam] Univ Saskatchewan, Community Hlth & Epidemiol, Saskatoon, SK, Canada. [McLaughlin, John R.] Publ Hlth Ontario, Toronto, ON, Canada. [McLaughlin, John R.] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Boffetta, Paolo] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA. [Boffetta, Paolo] Icahn Sch Med Mt Sinai, Inst Translat Epidemiol, New York, NY 10029 USA. [Staines, Anthony] Publ Hlth Univ Coll, Dept Publ Hlth, Dublin, Ireland. [Weisenburger, Dennis] City Hope Natl Med Ctr, Duarte, CA 91010 USA. [Benhaim-Luzon, Veronique; Brennan, Paul] Int Agcy Res Canc, F-69372 Lyon, France. [Costantini, Adele Seniori; Miligi, Lucia] Ctr Study & Prevent Canc, Unit Occupat & Environm Epidemiol, Florence, Italy. [Campagna, Marcello] Univ Cagliari, Occupat Hlth Sect, Dept Publ Hlth Clin & Mol Med, Monserrato, Italy. [Nieters, Alexandra] German Canc Res Ctr, Div Clin Epidemiol, Heidelberg, Germany. [Becker, Nikolaus] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Maynadie, Marc] Univ Burgundy, EA4184, Registry Hematol Malignancies Cote dOr, Dijon, France. [Foretova, Lenka] Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Brno, Czech Republic. [Zheng, Tongzhang] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. [Tricot, Guido] Univ Iowa, Dept Internal Med, Iowa City, IA 52242 USA. [Milliken, Kevin] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Krzystan, Joseph; Steplowski, Emily] Informat Management Serv Inc, Silver Spring, MD USA. RP Andreotti, G (reprint author), NCI, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM andreotg@mail.nih.gov RI Purdue, Mark/C-9228-2016; de Sanjose Llongueras, Silvia/H-6339-2014; Campagna, Marcello/L-1011-2016; OI Purdue, Mark/0000-0003-1177-3108; Campagna, Marcello/0000-0002-5277-8477; Staines, Anthony/0000-0001-9161-1357; Costas, Laura/0000-0003-2755-302X FU Leukemia and Lymphoma Society [6067-09]; NCI [CA152336, K07 CA115687, CA149445]; University of Utah Huntsman Cancer Institute (HCI); HCI Cancer Center Support grant from the NCI [P30 CA42014]; NCI SEER program [HHSN261201000026C]; Utah State Department of Health; University of Utah; European Regional Development Fund; State Budget of the Czech Republic (RECAMO) [CZ.1.05/2.1.00/03.0101]; American Cancer Society [RSG-11-020-01-CNE]; European Commission [QLK4-CT-2000-00422, FOOD-CT-2006-023103]; Spanish Ministry of Health (CIBERESP) [PI11/01810, PI14/01219, RCESP C03/09, RTICESP C03/10, RTIC RD06/0020/0095]; Rio Hortega [CM13/00232]; Agencia de Gestio d'Ajuts Universitaris i de Recerca-Generalitat de Catalunya (Catalonian Government) [2014SGR756-F]; NIH [NO1-CO-12400]; Italian Ministry of Education, University and Research (PRIN) [prot. 2007WEJLZB, prot. 20092ZELR2]; Italian Association for Cancer Research (IG) [11855/2011]; Federal Office for Radiation Protection [StSch4261, StSch4420]; Jose Carreras Leukemia Foundation [DJCLS-R04/08]; German Federal Ministry for Education and Research [BMBF-01-EO-1303]; Health Research Board, Ireland; Cancer Research Ireland [EpiLymph]; Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute FX Funding for the Utah study was, in part, from the Leukemia and Lymphoma Society 6067-09 (to N.J. Camp) and the NCI CA152336 (to N.J. Camp). Data collection for the Utah resource was made possible by the Utah Population Database (UPDB) and the Utah Cancer Registry (UCR). Partial support for all datasets within the UPDB was provided by the University of Utah Huntsman Cancer Institute (HCI) and the HCI Cancer Center Support grant, P30 CA42014 from the NCI. The UCR is funded by contract HHSN261201000026C from the NCI SEER program with additional support from the Utah State Department of Health and the University of Utah.; The work was supported by the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101). The work conducted by B.M. Birmann was supported, in part, by grants from the NCI (K07 CA115687, CA149445) and the American Cancer Society (RSG-11-020-01-CNE).; EPILYMPH was supported by European Commission (QLK4-CT-2000-00422 and FOOD-CT-2006-023103), Spanish Ministry of Health (CIBERESP, PI11/01810, PI14/01219, RCESP C03/09, RTICESP C03/10, and RTIC RD06/0020/0095), Rio Hortega (CM13/00232), Agencia de Gestio d'Ajuts Universitaris i de Recerca-Generalitat de Catalunya (Catalonian Government, 2014SGR756-F), NIH (contract NO1-CO-12400), Italian Ministry of Education, University and Research (PRIN 2007 prot. 2007WEJLZB, PRIN 2009 prot. 20092ZELR2), Italian Association for Cancer Research (IG grant 11855/2011); Federal Office for Radiation Protection (StSch4261 and StSch4420), Jose Carreras Leukemia Foundation (DJCLS-R04/08), German Federal Ministry for Education and Research (BMBF-01-EO-1303), Health Research Board, Ireland and Cancer Research Ireland [EpiLymph].; This work was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute. NR 7 TC 2 Z9 2 U1 0 U2 2 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 MAR PY 2015 VL 24 IS 3 BP 631 EP 634 DI 10.1158/1055-9965.EPI-14-1145 PG 4 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CE6NC UT WOS:000351953100021 PM 25538226 ER PT J AU Nicastro, HL Ross, SA Milner, JA AF Nicastro, Holly L. Ross, Sharon A. Milner, John A. TI Garlic and Onions: Their Cancer Prevention Properties SO CANCER PREVENTION RESEARCH LA English DT Review ID HELICOBACTER-PYLORI INFECTION; N-ACETYLTRANSFERASE ACTIVITY; FRIED BEEF PATTIES; ORGANOSULFUR COMPOUNDS; GASTRIC-CANCER; DIALLYL DISULFIDE; HETEROCYCLIC AMINES; CELL-PROLIFERATION; ALLIUM VEGETABLES; SULFUR-COMPOUNDS AB The Allium genus includes garlic, onions, shallots, leeks, and chives. These vegetables are popular in cuisines worldwide and are valued for their potential medicinal properties. Epidemiologic studies, while limited in their abilities to assess Allium consumption, indicate some associations of Allium vegetable consumption with decreased risk of cancer, particularly cancers of the gastrointestinal tract. Limited intervention studies have been conducted to support these associations. The majority of supportive evidence on Allium vegetables cancer-preventive effects comes from mechanistic studies. These studies highlight potential mechanisms of individual sulfur-containing compounds and of various preparations and extracts of these vegetables, including decreased bioactivation of carcinogens, antimicrobial activities, and redox modification. Allium vegetables and their components have effects at each stage of carcinogenesis and affect many biologic processes that modify cancer risk. This review discusses the cancer-preventive effects of Allium vegetables, particularly garlic and onions, and their bioactive sulfur compounds and highlights research gaps. (C)2015 AACR. C1 [Nicastro, Holly L.] NCI, Canc Prevent Fellowship Program, Nutr Sci Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. [Ross, Sharon A.] NCI, Nutr Sci Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. [Milner, John A.] USDA ARS, Beltsville Human Nutr Res Ctr, Beltsville, MD USA. RP Nicastro, HL (reprint author), NHLBI, 9609 Rockledge Dr 10110, Bethesda, MD 20892 USA. EM holly.nicastro@nih.gov FU Intramural NIH HHS [Z99 HL999999] NR 96 TC 9 Z9 9 U1 10 U2 58 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 EI 1940-6215 J9 CANCER PREV RES JI Cancer Prev. Res. PD MAR PY 2015 VL 8 IS 3 BP 181 EP 189 DI 10.1158/1940-6207.CAPR-14-0172 PG 9 WC Oncology SC Oncology GA CE8FM UT WOS:000352077100001 PM 25586902 ER PT J AU Campbell, CMP Kreimer, AR Lin, HY Fulp, W O'Keefe, MT Ingles, DJ Abrahamsen, M Villa, LL Lazcano-Ponce, E Giuliano, AR AF Pierce Campbell, Christine M. Kreimer, Aimee R. Lin, Hui-Yi Fulp, William O'Keefe, Michael T. Ingles, Donna J. Abrahamsen, Martha Villa, Luisa L. Lazcano-Ponce, Eduardo Giuliano, Anna R. TI Long-term Persistence of Oral Human Papillomavirus Type 16: The HPV Infection in Men (HIM) Study SO CANCER PREVENTION RESEARCH LA English DT Article ID SQUAMOUS-CELL CARCINOMAS; NATURAL-HISTORY; UNITED-STATES; OLDER WOMEN; PREVALENCE; CANCER; WORLDWIDE; TRENDS; COHORT; HEAD AB Persistent infection with oral HPV16 is believed to drive the development of most oropharyngeal cancers. However, patterns of oral HPV16 persistence remain understudied, particularly among HIV-negative individuals. Oral HPV16 persistence was evaluated among 1,626 participants of the HPV Infection in Men (HIM) Study. Twenty-three oral HPV16-positive men who provided an oral gargle sample on >= 2 study visits were included in the analysis. Archived oral samples from all follow-up visits were tested for HPV16 using Linear Array and INNO-LiPA detection methods. Persistence was evaluated using consecutive HPV16-positive visits held approximately 6 months apart and using the Kaplan-Meier method. Oral HPV16-positive men were aged 18 to 64 years [median, 36 years; interquartile range (IQR), 25-42] and were followed for a median of 44.4 months (IQR, 29.9-49.5). Of 13 incident infections, 4 (30.8%) persisted >= 12 months, 1 (10.0%) persisted >= 24 months, and none persisted >= 36 months [median infection duration, 7.3 months; 95% confidence interval (CI), 6.4-NA)]. Of 10 prevalent infections, 9 (90.0%) persisted >= 12 months, 8 (80.0%) persisted >= 24 months, 4 (57.1%) persisted >= 36 months, and 2 (40.0%) persisted >= 48 months (median infection duration, NA). Twelve-month persistence of incident infections increased significantly with age (P-trend = 0.028). Prevalent oral HPV16 infections in men persisted longer than newly acquired infections, and persistence appeared to increase with age. These findings may explain the high prevalence of oral HPV observed at older ages. Understanding oral HPV16 persistence will aid in the identification of men at high-risk of developing HPV-related oropharyngeal cancer. (C)2015 AACR. C1 [Pierce Campbell, Christine M.; O'Keefe, Michael T.; Ingles, Donna J.; Abrahamsen, Martha; Giuliano, Anna R.] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL 33612 USA. [Pierce Campbell, Christine M.; Ingles, Donna J.; Abrahamsen, Martha; Giuliano, Anna R.] H Lee Moffitt Canc Ctr & Res Inst, Ctr Infect Res Canc, Tampa, FL 33612 USA. [Kreimer, Aimee R.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Lin, Hui-Yi; Fulp, William] H Lee Moffitt Canc Ctr & Res Inst, Dept Biostat & Bioinformat, Tampa, FL 33612 USA. [Villa, Luisa L.] Inst Canc Estado Sao Paulo, Ctr Translat Oncol, Mol Biol Lab, Sao Paulo, Brazil. [Villa, Luisa L.] Univ Sao Paulo, Sch Med, Dept Radiol & Oncol, Sao Paulo, Brazil. [Villa, Luisa L.] Univ Sao Paulo, Sch Med, HPV Inst, Sao Paulo, Brazil. [Lazcano-Ponce, Eduardo] Inst Nacl Salud Publ, Ctr Invest Salud Poblac, Cuernavaca, Morelos, Mexico. RP Giuliano, AR (reprint author), H Lee Moffitt Canc Ctr & Res Inst, MRC CANCONT, 12902 Magnolia Dr, Tampa, FL 33612 USA. EM anna.giuliano@moffitt.org RI Kreimer, Aimee/H-1687-2015; OI Pierce Campbell, Christine/0000-0002-0233-4894 FU NCI, NIH [R01 CA098803]; NCI Intramural Program; Investigator-Initiated Studies Program of Merck Sharp Dohme; American Cancer Society [PF-13-222-01-MPC] FX The infrastructure of the HIM Study cohort was supported through a grant from the NCI, NIH, (R01 CA098803; to A. Giuliano). Funding for a subset of oral sample collection and HPV testing was provided by the NCI Intramural Program to A. Kreimer. Additional funding for testing of the remaining oral samples was provided through a research grant from the Investigator-Initiated Studies Program of Merck Sharp & Dohme (to A. Giuliano). C. M. Pierce Campbell was supported, in part, by a Postdoctoral Fellowship (PF-13-222-01-MPC) from the American Cancer Society. NR 33 TC 7 Z9 7 U1 0 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 EI 1940-6215 J9 CANCER PREV RES JI Cancer Prev. Res. PD MAR PY 2015 VL 8 IS 3 BP 190 EP 196 DI 10.1158/1940-6207.CAPR-14-0296 PG 7 WC Oncology SC Oncology GA CE8FM UT WOS:000352077100002 ER PT J AU Madera, D Vitale-Cross, L Martin, D Schneider, A Molinolo, AA Gangane, N Carey, TE McHugh, JB Komarck, CM Walline, HM William, WN Seethala, RR Ferris, RL Gutkind, JS AF Madera, Dmitri Vitale-Cross, Lynn Martin, Daniel Schneider, Abraham Molinolo, Alfredo A. Gangane, Nitin Carey, Thomas E. McHugh, Jonathan B. Komarck, Christine M. Walline, Heather M. William, William N., Jr. Seethala, Raja R. Ferris, Robert L. Gutkind, J. Silvio TI Prevention of Tumor Growth Driven by PIK3CA and HPV Oncogenes by Targeting mTOR Signaling with Metformin in Oral Squamous Carcinomas Expressing OCT3 SO CANCER PREVENTION RESEARCH LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; HUMAN-PAPILLOMAVIRUS; CELL CARCINOMA; NECK-CANCER; IN-VITRO; LIPODYSTROPHY SYNDROME; MOLECULAR TARGET; PROTEIN-KINASE; UNITED-STATES; HEAD AB Most squamous cell carcinomas of the head and neck (HNSCC) exhibit a persistent activation of the PI3K-mTOR signaling pathway. We have recently shown that metformin, an oral antidiabetic drug that is also used to treat lipodystrophy in HIV-infected (HIV+) individuals, diminishes mTOR activity and prevents the progression of chemically induced experimental HNSCC premalignant lesions. Here, we explored the preclinical activity of metformin in HNSCCs harboring PIK3CA mutations and HPV oncogenes, both representing frequent HNSCC alterations, aimed at developing effective targeted preventive strategies. The biochemical and biologic effects of metformin were evaluated in representative HNSCC cells expressing mutated PIK3CA or HPV oncogenes (HPV+). The oral delivery of metformin was optimized to achieve clinical relevant blood levels. Molecular determinants of metformin sensitivity were also investigated, and their expression levels were examined in a large collection of HNSCC cases. We found that metformin inhibits mTOR signaling and tumor growth in HNSCC cells expressing mutated PIK3CA and HPV oncogenes, and that these activities require the expression of organic cation transporter 3 (OCT3/SLC22A3), a metformin uptake transporter. Coexpression of OCT3 and the mTOR pathway activation marker pS6 were observed in most HNSCC cases, including those arising in HIV+ patients. Activation of the PI3K-mTOR pathway is a widespread event in HNSCC, including HPV- and HPV+ lesions arising in HIV+ patients, all of which coexpress OCT3. These observations may provide a rationale for the clinical evaluation of metformin to halt HNSCC development from precancerous lesions, including in HIV+ individuals at risk of developing HPV- associated cancers. (C)2015 AACR. C1 [Madera, Dmitri; Vitale-Cross, Lynn; Martin, Daniel; Molinolo, Alfredo A.; Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, Mol Carcinogenesis Sect, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. [Schneider, Abraham] Univ Maryland, Sch Dent, Dept Oncol & Diagnost Sci, Baltimore, MD 21201 USA. [Schneider, Abraham] Univ Maryland, Greenebaum Canc Ctr, Program Oncol, Baltimore, MD 21201 USA. [Gangane, Nitin] Mahatma Gandhi Inst Med Sci, Dept Pathol, Wardha, Maharashtra, India. [Carey, Thomas E.; McHugh, Jonathan B.; Komarck, Christine M.; Walline, Heather M.] Univ Michigan, Dept Otolaryngol Head & Neck Surg, Ann Arbor, MI 48109 USA. [Carey, Thomas E.; McHugh, Jonathan B.; Komarck, Christine M.; Walline, Heather M.] Univ Michigan, Head & Neck SPORE Tissue Core, Ann Arbor, MI 48109 USA. [William, William N., Jr.] Univ Texas MD Anderson Canc Ctr, Dept Thoracic Head & Neck Med Oncol, Houston, TX 77030 USA. [Seethala, Raja R.] Univ Pittsburgh, Sch Med, Pathol Program, Pittsburgh, PA USA. [Ferris, Robert L.] Univ Pittsburgh, Sch Med, Canc Immunol Program, Immunol,Otolaryngol, Pittsburgh, PA USA. RP Gutkind, JS (reprint author), Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, 30 Convent Dr,Bldg 30,Room 320, Bethesda, MD 20892 USA. EM sg39v@nih.gov OI Carey, Thomas/0000-0002-5202-7518 FU NIH, National Institute of Dental and Craniofacial Research [Z01DE00558]; Intramural AIDS Targeted Antiviral Program (IATAP); Head and Neck SPORE Consortium NCI supplement [P50 CA097248] FX This work was supported by the Intramural Research Program of the NIH, National Institute of Dental and Craniofacial Research (project Z01DE00558) and by the Intramural AIDS Targeted Antiviral Program (IATAP), (to D. Madera, L. Vitale-Cross, D. Martin, A.A. Molinolo and J.S. Gutkind) and by the Head and Neck SPORE Consortium NCI supplement # P50 CA097248 ( to T.E. Carey, J.B. McHugh, C.M. Komarck, H.M. Walline, W.N. William, R.R. Seethala and R.L. Ferris). NR 51 TC 7 Z9 7 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 EI 1940-6215 J9 CANCER PREV RES JI Cancer Prev. Res. PD MAR PY 2015 VL 8 IS 3 BP 197 EP 207 DI 10.1158/1940-6207.CAPR-14-0348 PG 11 WC Oncology SC Oncology GA CE8FM UT WOS:000352077100003 PM 25681087 ER PT J AU Gillen, DL Meyskens, FL Morgan, TR Zell, JA Carroll, R Benya, R Chen, WP Mo, A Tucker, C Bhattacharya, A Huang, ZL Arcilla, M Wong, V Chung, J Gonzalez, R Rodriguez, LM Szabo, E Rosenberg, DW Lipkin, SM AF Gillen, Daniel L. Meyskens, Frank L. Morgan, Timothy R. Zell, Jason A. Carroll, Robert Benya, Richard Chen, Wen-Pin Mo, Allen Tucker, Chris Bhattacharya, Asmita Huang, Zhiliang Arcilla, Myra Wong, Vanessa Chung, Jinah Gonzalez, Rachel Rodriguez, Luz Maria Szabo, Eva Rosenberg, Daniel W. Lipkin, Steven M. TI A Phase IIa Randomized, Double-Blind Trial of Erlotinib in Inhibiting Epidermal Growth Factor Receptor Signaling in Aberrant Crypt Foci of the Colorectum SO CANCER PREVENTION RESEARCH LA English DT Article ID CELL LUNG-CANCER; RAT AZOXYMETHANE MODEL; KRAS MUTATIONS; COLON-CANCER; COLONOSCOPIC POLYPECTOMY; KINASE INHIBITORS; SOMATIC MUTATIONS; PREVENTION; CELECOXIB; EGFR AB Colorectal cancer progresses through multiple distinct stages that are potentially amenable to chemopreventative intervention. Epidermal growth factor receptor (EGFR) inhibitors are efficacious in advanced tumors including colorectal cancer. There is significant evidence that EGFR also plays important roles in colorectal cancer initiation, and that EGFR inhibitors block tumorigenesis. We performed a double-blind randomized clinical trial to test whether the EGFR inhibitor erlotinib given for up to 30 days had an acceptable safety and efficacy profile to reduce EGFR signaling biomarkers in colorectal aberrant crypt foci (ACF), a subset of which progress to colorectal cancer, and normal rectal tissue. A total of 45 patients were randomized to one of three erlotinib doses (25, 50, and 100 mg) with randomization stratified by nonsteroidal anti-inflammatory drug (NSAID) use. There were no unanticipated adverse events with erlotinib therapy. Erlotinib was detected in both normal rectal mucosa and ACFs. Colorectal ACF phosphorylated ERK (pERK), phosphorylated EGFR (pEGFR), and total EGFR signaling changes from baseline were modest and there was no dose response. Overall, this trial did not meet is primary efficacy endpoint. Colorectal EGFR signaling inhibition by erlotinib is therefore likely insufficient to merit further studies without additional prescreening stratification or potentially longer duration of use. (C)2015 AACR. C1 [Gillen, Daniel L.] Univ Calif Irvine, Dept Stat, Irvine, CA USA. [Gillen, Daniel L.; Meyskens, Frank L.; Morgan, Timothy R.; Zell, Jason A.; Chen, Wen-Pin; Wong, Vanessa; Chung, Jinah] Univ Calif Irvine, Chao Family Comprehens Canc Ctr, Irvine, CA USA. [Morgan, Timothy R.; Gonzalez, Rachel] VA Long Beach Hlth Care Syst, Dept Med, Long Beach, CA USA. [Zell, Jason A.] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA. [Carroll, Robert; Benya, Richard] Univ Illinois, Dept Med, Med Ctr, Chicago, IL USA. [Mo, Allen; Rosenberg, Daniel W.] Univ Connecticut Hlth, Dept Mol Med, Farmington, CT USA. [Tucker, Chris] Astellas Pharmaceut, Long Isl City, NY USA. [Bhattacharya, Asmita; Huang, Zhiliang; Arcilla, Myra; Lipkin, Steven M.] Weill Cornell Med Coll, Div Gastroenterol & Hepatol, New York, NY USA. [Rodriguez, Luz Maria; Szabo, Eva] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Rodriguez, Luz Maria] Walter Reed Natl Mil Med Ctr, Dept Surg, Bethesda, MD USA. RP Lipkin, SM (reprint author), Weill Cornell Med Coll, 541 E 71 St,Rm 718, New York, NY 10021 USA. EM stl2012@med.cornell.edu FU NCI [N01-CN-35160, P30CA062203]; National Center for Research Resources; National Center for Advancing Translational Sciences, NIH [UL1 TR000153] FX The project described was supported by NCI N01-CN-35160 (to F.L. Meyskens), NCI P30CA062203, and the National Center for Research Resources and the National Center for Advancing Translational Sciences, NIH, through grant UL1 TR000153. NR 38 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 1940-6207 EI 1940-6215 J9 CANCER PREV RES JI Cancer Prev. Res. PD MAR PY 2015 VL 8 IS 3 BP 222 EP 230 DI 10.1158/1940-6207.CAPR-14-0148 PG 9 WC Oncology SC Oncology GA CE8FM UT WOS:000352077100005 PM 25604134 ER PT J AU Thompson, MD Grubbs, CJ Bode, AM Reid, JM McGovern, R Bernard, PS Stijleman, IJ Green, JE Bennett, C Juliana, MM Moeinpour, F Steele, VE Lubet, RA AF Thompson, Matthew D. Grubbs, Clinton J. Bode, Ann M. Reid, Joel M. McGovern, Renee Bernard, Philip S. Stijleman, Inge J. Green, Jeffrey E. Bennett, Christina Juliana, M. Margaret Moeinpour, Fariba Steele, Vernon E. Lubet, Ronald A. TI Lack of Effect of Metformin on Mammary Carcinogenesis in Nondiabetic Rat and Mouse Models SO CANCER PREVENTION RESEARCH LA English DT Article ID EARLY BREAST-CANCER; TOPOISOMERASE II-ALPHA; CELL-PROLIFERATION; POSTMENOPAUSAL WOMEN; TRANSGENIC MICE; TUMORS; GROWTH; TAMOXIFEN; PREVENTS; TUMORIGENESIS AB Epidemiologic studies have shown that diabetics receiving the biguanide metformin, as compared with sulfonylureas or insulin, have a lower incidence of breast cancer. Metformin increases levels of activated AMPK (AMP-activated protein kinase) and decreases circulating IGF-1; encouraging its potential use in both cancer prevention and therapeutic settings. In anticipation of clinical trials in nondiabetic women, the efficacy of metformin in nondiabetic rat and mouse mammary cancer models was evaluated. Metformin was administered by gavage or in the diet, at a human equivalent dose, in standard mammary cancer models: (i) methylnitrosourea (MNU)-induced estrogen receptor-positive (ER+) mammary cancers in rats, and (ii) MMTV-Neu/p53KO ER+ (estrogen receptor-negative) mammary cancers in mice. In the MNU rat model, metformin dosing (150 or 50 mg/kg BW/d, by gavage) was ineffective in decreasing mammary cancer multiplicity, latency, or weight. Pharmacokinetic studies of metformin (150 mg/kg BW/d, by gavage) yielded plasma levels (C-max and AUC) higher than humans taking 1.5 g/d. In rats bearing small palpable mammary cancers, short-term metformin (150 mg/kg BW/d) treatment increased levels of phospho-AMPK and phospho-p53 (Ser20), but failed to reduce Ki67 labeling or expression of proliferation-related genes. In the mouse model, dietary metformin (1,500 mg/kg diet) did not alter final cancer incidence, multiplicity, or weight. Metformin did not prevent mammary carcinogenesis in two mammary cancer models, raising questions about metformin efficacy in breast cancer in nondiabetic populations. (C) 2015 AACR. C1 [Thompson, Matthew D.] NCI, Bethesda, MD 20892 USA. [Grubbs, Clinton J.; Juliana, M. Margaret; Moeinpour, Fariba] Univ Alabama Birmingham, Birmingham, AL 35294 USA. [Bode, Ann M.] Univ Minnesota, Hormel Inst, Austin, MN 55912 USA. [Reid, Joel M.; McGovern, Renee] Mayo Clin, Ctr Canc, Rochester, MN USA. [Bernard, Philip S.; Stijleman, Inge J.] Huntsman Canc Inst, Salt Lake City, UT USA. [Green, Jeffrey E.; Bennett, Christina] NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. [Steele, Vernon E.; Lubet, Ronald A.] NCI, CARDG, Canc Prevent Div, Bethesda, MD 20892 USA. RP Grubbs, CJ (reprint author), Univ Alabama Birmingham, 1720 2nd Ave South,VH-G78D, Birmingham, AL 35294 USA. EM clintongrubbs@uabmc.edu FU NCI [HHSN261201200021I] FX NCI Contract Number HHSN261201200021I awarded to Dr. Clinton J. Grubbs, University of Alabama at Birmingham (Birmingham, AL). NR 42 TC 6 Z9 6 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 EI 1940-6215 J9 CANCER PREV RES JI Cancer Prev. Res. PD MAR PY 2015 VL 8 IS 3 BP 231 EP 239 DI 10.1158/1940-6207.CAPR-14-0181-T PG 9 WC Oncology SC Oncology GA CE8FM UT WOS:000352077100006 PM 25681088 ER PT J AU Lavi, O AF Lavi, Orit TI Redundancy: A Critical Obstacle to Improving Cancer Therapy SO CANCER RESEARCH LA English DT Article ID MULTIDRUG-RESISTANCE; GENETIC REDUNDANCY; DRUG-RESISTANCE; CTLA-4 BLOCKADE; BREAST-CANCER; NETWORK; MELANOMA; PERSPECTIVE; METABOLISM; MECHANISMS AB A system characterized by redundancy has various elements that are able to act in the same biologic or dynamic manner, where the inhibition of one of those elements has no significant effect on the global biologic outcome or on the system's dynamic behavior. Methods that aim to predict the effectiveness of cancer therapies must include evolutionary and dynamic features that would change the static view that is widely accepted. Here, we explore several important issues about mechanisms of redundancy, heterogeneity, biologic importance, and drug resistance and describe methodologic challenges that, if overcome, would significantly contribute to cancer research. C1 NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Lavi, O (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, 37 Convent Dr,Room 2112, Bethesda, MD 20892 USA. EM orit.lavi@nih.gov FU Intramural Research Program of the NIH, the National Cancer Institute FX Thiswork was supported by the Intramural Research Program of the NIH, the National Cancer Institute. NR 45 TC 8 Z9 8 U1 0 U2 2 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 MAR 1 PY 2015 VL 75 IS 5 BP 808 EP 812 DI 10.1158/0008-5472.CAN-14-3256 PG 5 WC Oncology SC Oncology GA CE6GG UT WOS:000351934100005 PM 25576083 ER PT J AU Pascual, B Masdeu, JC Hollenbeck, M Makris, N Insausti, R Ding, SL Dickerson, BC AF Pascual, Belen Masdeu, Joseph C. Hollenbeck, Mark Makris, Nikos Insausti, Ricardo Ding, Song-Lin Dickerson, Bradford C. TI Large-Scale Brain Networks of the Human Left Temporal Pole: A Functional Connectivity MRI Study SO CEREBRAL CORTEX LA English DT Article DE anterior temporal lobe; brain anatomy; cytoarchitecture; language; resting-state fMRI ID KLUVER-BUCY-SYNDROME; MEDIAL PREFRONTAL NETWORKS; COMPARATIVE CYTOARCHITECTONIC ANALYSIS; MONKEY MACACA-FASCICULARIS; DISTORTION-CORRECTED FMRI; MULTIPLE SYSTEM ATROPHY; HUMAN CEREBRAL-CORTEX; OLD-WORLD MONKEY; RHESUS-MONKEY; SEMANTIC MEMORY AB The most rostral portion of the human temporal cortex, the temporal pole (TP), has been described as "enigmatic" because its functional neuroanatomy remains unclear. Comparative anatomy studies are only partially helpful, because the human TP is larger and cytoarchitectonically more complex than in nonhuman primates. Considered by Brodmann as a single area (BA 38), the human TP has been recently parceled into an array of cytoarchitectonic subfields. In order to clarify the functional connectivity of subregions of the TP, we undertook a study of 172 healthy adults using resting-state functional connectivity MRI. Remarkably, a hierarchical cluster analysis performed to group the seeds into distinct subsystems according to their large-scale functional connectivity grouped 87.5% of the seeds according to the recently described cytoarchitectonic subregions of the TP. Based on large-scale functional connectivity, there appear to be 4 major subregions of the TP: 1) dorsal, with predominant connectivity to auditory/somatosensory and language networks; 2) ventromedial, predominantly connected to visual networks; 3) medial, connected to paralimbic structures; and 4) anterolateral, connected to the default-semantic network. The functional connectivity of the human TP, far more complex than its known anatomic connectivity in monkey, is concordant with its hypothesized role as a cortical convergence zone. C1 [Pascual, Belen; Hollenbeck, Mark; Dickerson, Bradford C.] Massachusetts Gen Hosp, MGH Frontotemporal Dementia Unit, Alzheimers Dis Res Ctr, Dept Neurol,Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Pascual, Belen; Hollenbeck, Mark; Makris, Nikos; Dickerson, Bradford C.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Masdeu, Joseph C.] NIH, Sect Integrat Neuroimaging, Bethesda, MD 20892 USA. [Makris, Nikos] Massachusetts Gen Hosp, Ctr Morphometr Anal, Dept Psychiat, Charlestown, MA 02129 USA. [Makris, Nikos] Massachusetts Gen Hosp, Ctr Morphometr Anal, Dept Neurol, Charlestown, MA 02129 USA. [Makris, Nikos] Massachusetts Gen Hosp, Ctr Morphometr Anal, Dept Radiol Serv, Charlestown, MA 02129 USA. [Makris, Nikos; Dickerson, Bradford C.] Massachusetts Gen Hosp, Ctr Neural Syst Invest, Dept Neurol, Charlestown, MA 02129 USA. [Makris, Nikos; Dickerson, Bradford C.] Massachusetts Gen Hosp, Ctr Neural Syst Invest, Dept Psychiat, Charlestown, MA 02129 USA. [Insausti, Ricardo] Univ Castilla La Mancha, Ctr Human Neuroanat Lab, Dept Hlth Sci, Sch Med, Albacete 02071, Spain. [Ding, Song-Lin] Allen Inst Brain Sci, Seattle, WA 98103 USA. RP Dickerson, BC (reprint author), MGH Frontotemporal Dementia Unit, 149 13th St,Suite 2691, Charlestown, MA 02129 USA. EM bradd@nmr.mgh.harvard.edu FU National Institute on Aging [P50-AG005134]; National Institute of Neurological Disorders and Stroke [R21-NS077059] FX Supported by grants from the National Institute on Aging (P50-AG005134) and National Institute of Neurological Disorders and Stroke (R21-NS077059). NR 151 TC 34 Z9 35 U1 8 U2 34 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 MAR PY 2015 VL 25 IS 3 BP 680 EP 702 DI 10.1093/cercor/bht260 PG 23 WC Neurosciences SC Neurosciences & Neurology GA CE6GW UT WOS:000351935800010 PM 24068551 ER PT J AU Pollitt, LC Sim, D Salathe, R Read, AF AF Pollitt, Laura C. Sim, Derek Salathe, Rahel Read, Andrew F. TI Understanding genetic variation in in vivo tolerance to artesunate: implications for treatment efficacy and resistance monitoring SO EVOLUTIONARY APPLICATIONS LA English DT Article DE artemisinin; clearance rates; drug resistance; genetic variation; malaria; Plasmodium chabaudi ID ANTIMALARIAL-DRUG RESISTANCE; MALARIA PLASMODIUM-CHABAUDI; ARTEMISININ RESISTANCE; PARASITE CLEARANCE; RODENT MALARIA; FALCIPARUM-MALARIA; ANTIBIOTIC-RESISTANCE; WESTERN CAMBODIA; VIRULENCE; TRANSMISSION AB Artemisinin-based drugs are the front-line weapon in the treatment of human malaria cases, but there is concern that recent reports of slow clearing infections may signal developing resistance to treatment. In the absence of molecular markers for resistance, current efforts to monitor drug efficacy are based on the rate at which parasites are cleared from infections. However, some knowledge of the standing variation in parasite susceptibility is needed to identify a meaningful increase in infection half-life. Here, we show that five previously unexposed genotypes of the rodent malaria parasite Plasmodium chabaudi differ substantially in their in vivo response to treatment. Slower clearance rates were not linked to parasite virulence or growth rate, going against the suggestion that drug treatment will drive the evolution of virulence in this system. The level of variation observed here in a relatively small number of genotypes suggests existing resistant' parasites could be present in the population and therefore, increased parasite clearance rates could represent selection on pre-existing variation rather than de novo resistance events. This has implications for resistance monitoring as susceptibility may depend on evolved traits unrelated to drug exposure. C1 [Pollitt, Laura C.; Sim, Derek; Salathe, Rahel; Read, Andrew F.] Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Pollitt, Laura C.] Univ Edinburgh, Ctr Immun Infect & Evolut, Edinburgh EH9 3JT, Midlothian, Scotland. [Read, Andrew F.] Penn State Univ, Dept Entomol, University Pk, PA 16802 USA. [Read, Andrew F.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Pollitt, LC (reprint author), Univ Edinburgh, Ctr Immun Infect & Evolut, Edinburgh EH9 3JT, Midlothian, Scotland. EM laura.pollitt@googlemail.com FU National Institutes of Health through the Institute of General Medical Science [R01 GM089932]; Institute of Allergy and Infectious Disease [R01 AI089819] FX For discussion, we thank D. Kennedy, W. Nelson and members of the Read-Thomas groups, as well as members of the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. This study was funded by the National Institutes of Health through the Institute of General Medical Science (R01 GM089932 to AFR) and the Institute of Allergy and Infectious Disease (R01 AI089819) to Jon Juliano, University of North Carolina. The funders had no role in study design, data collection and analysis or decision to publish, or the preparation of the manuscript. NR 48 TC 5 Z9 6 U1 2 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1752-4571 J9 EVOL APPL JI Evol. Appl. PD MAR PY 2015 VL 8 IS 3 SI SI BP 296 EP 304 DI 10.1111/eva.12194 PG 9 WC Evolutionary Biology SC Evolutionary Biology GA CE2WS UT WOS:000351682500008 PM 25861387 ER PT J AU Coronini-Cronberg, S Bixby, H Laverty, AA Wachter, RM Millett, C AF Coronini-Cronberg, Sophie Bixby, Honor Laverty, Anthony A. Wachter, Robert M. Millett, Christopher TI English National Health Service's Savings Plan May Have Helped Reduce The Use Of Three 'Low-Value' Procedures SO HEALTH AFFAIRS LA English DT Article ID CARE; COUNTRIES; MEDICARE; POLICY; DISINVESTMENT; NHS AB The pressure to contain health expenditures is unprecedented. In England a flattening of the health budget but increasing demand led the National Health Service (NHS) to seek reductions in health expenditures of 17 percent over four years. The spending cuts were to be achieved through improvements in service quality and efficiency, including reducing the use of ineffective, overused, or inappropriate procedures. However, the NHS left it to the local commissioning (or funding) organizations, known as primary care trusts, to determine what steps to take to reduce spending. To assess whether the initiative had an impact, we examined six low-value procedures: spinal surgery for lower back pain, myringotomy to relieve eardrum pressure, inguinal hernia repair, cataract removal, primary hip replacement, and hysterectomy for heavy menstrual bleeding. We found significant reductions in three of the six procedures-cataract removal, hysterectomy, and myringotomy-in the program's first year, compared to prior years' trends. However, changes in the rates of all examined procedures varied widely across commissioning organizations. Our findings highlight some of the challenges of making major budget cuts in health care. Reducing ineffective spending remains a significant opportunity for the US health care system, and the English experience may hold valuable lessons. C1 [Coronini-Cronberg, Sophie; Laverty, Anthony A.] Univ London Imperial Coll Sci Technol & Med, Dept Primary Care & Publ Hlth, London, England. [Bixby, Honor] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London, England. [Wachter, Robert M.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Millett, Christopher] Natl Inst Hlth, Bethesda, MD USA. [Millett, Christopher] Univ London Imperial Coll Sci Technol & Med, Dept Primary Care & Publ Hlth, London, England. RP Coronini-Cronberg, S (reprint author), Univ London Imperial Coll Sci Technol & Med, Dept Primary Care & Publ Hlth, London, England. EM coronini-cronberg@imperial.ac.uk OI Laverty, Anthony/0000-0003-1318-8439 FU American Board of Internal Medicine; IPC-The Hospitalist Company; Higher Education Funding Council for England; NIHR CLAHRC for North West London; NIHR Biomedical Research Centre; NIHR CLAHRC; Imperial Centre for Patient Safety and Service Quality FX This research was presented as a poster at the annual meeting of the Society for Social Medicine, Oxford, England, September 10-12, 2014. It was also presented as a paper at the European Public Health Conference, Glasgow, Scotland, November 20-22, 2014. This article presents independent research commissioned by the National Institute for Health Research (NIHR) under the Collaborations for Leadership in Applied Health Research and Care (CLAHRC) program for North West London. Robert Wachter serves as the immediate past chair of the American Board of Internal Medicine (for which he received a stipend) and a current member of the ABIM Foundation board; he received a stipend and stock options for serving on the board of directors of IPC-The Hospitalist Company; and he serves on the scientific advisory boards for Amino.com, PatientSafe Solutions, CRISI, QPID, and EarlySense (for which he receives stock options). Christopher Millett is funded by the Higher Education Funding Council for England and the NIHR CLAHRC for North West London. Imperial College London is grateful for support from the NIHR Biomedical Research Centre Funding scheme, the NIHR CLAHRC, and the Imperial Centre for Patient Safety and Service Quality. Sophie Coronini-Cronberg's role in this research formed part of her specialty training and was made possible by Health Education England-London (formerly London Deanery), the regional body responsible for providing higher specialty medical and dental training programs. At the time of this research, Honor Bixby was a research assistant in the Department of Public Health and Primary Care, Imperial College London. The views expressed in this article are those of the authors and not necessarily those of the National Health Service, the NIHR, Health Education England-London, Bupa, or the UK Department of Health. NR 47 TC 2 Z9 2 U1 1 U2 8 PU PROJECT HOPE PI BETHESDA PA 7500 OLD GEORGETOWN RD, STE 600, BETHESDA, MD 20814-6133 USA SN 0278-2715 J9 HEALTH AFFAIR JI Health Aff. PD MAR PY 2015 VL 34 IS 3 BP 381 EP 389 DI 10.1377/hlthaff.2014.0773 PG 9 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA CE3HB UT WOS:000351716200004 PM 25732487 ER PT J AU Ohyama, Y Ambale-Venkatesh, B Chamera, E Shehata, ML Corona-Villalobos, CP Zimmerman, SL Hassoun, PM Bluemke, DA Lima, JAC AF Ohyama, Yoshiaki Ambale-Venkatesh, Bharath Chamera, Elzbieta Shehata, Monda L. Corona-Villalobos, Celia P. Zimmerman, Stefan L. Hassoun, Paul M. Bluemke, David A. Lima, Joao A. C. TI Comparison of strain measurement from multimodality tissue tracking with strain-encoding MRI and harmonic phase MRI in pulmonary hypertension SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE Cardiac magnetic resonance; Myocardial strain; Pulmonary hypertension ID REGIONAL MYOCARDIAL-FUNCTION; CARDIOVASCULAR MAGNETIC-RESONANCE; ARTERIAL-HYPERTENSION; CIRCUMFERENTIAL STRAIN; HEART-FAILURE; ECHOCARDIOGRAPHY; ATHEROSCLEROSIS; REPRODUCIBILITY; HETEROGENEITY; ASSOCIATION AB Background: Pixel-based multimodality tissue tracking (MTT) is a new noninvasive method for the quantification of cardiac deformation from cine image of MRI. The aim of this study is to validate bi-ventricular strain measurement by MTT compared to strain-encoding (SENC) MRI and harmonic phase (HARP) MRI in pulmonary hypertension (PH) patients. Methods: In 45 subjects (30 PH patients and 15 normal subjects), RV and LV peak global longitudinal strains (Ell) were measured from long axis 4 chamber view using MTT. LV peak global circumferential strains (Ecc) by MTT were measured from short axis. For validation, RV and LV Ell by MTT were compared to measures by SENC-MRI from short axis, and LV Ecc by MTT was compared to measures by short axis tagged MRI analysis (HARP). Reproducibility of MTT was also determined. Results: MTT quantified RV Ell correlated closely to those of SENC (r=0.72, p < 0.001), with good limits of agreement. LV Ell quantified by MTT showed moderate correlation with SENC (r=0.57, p=0.001), and LV Ecc by MTT also showed moderate correlation with HARP (-16.9 +/- 4.1 vs -14.3 +/- 3.5, p < 0.001 for all, r=0.60, p < 0.001). RV Ell negatively correlated with RVEF (r=-0.53, p=0.001) and also positively correlated with mean PAP in PH patients (r=0.60, p=0.001). Strain measurement by MTT showed high reproducibility. Conclusions: We demonstrate that MTT is a reproducible tool for quantification of cardiac deformation using cine images in PH patients. Hence, it could serve as a new rapid and comprehensive technique for clinical assessment of regional cardiac function. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Ohyama, Yoshiaki; Ambale-Venkatesh, Bharath; Chamera, Elzbieta; Lima, Joao A. C.] Johns Hopkins Univ, Div Cardiol, Baltimore, MD USA. [Shehata, Monda L.] Mercy Cathol Med Ctr, Philadelphia, PA USA. [Corona-Villalobos, Celia P.; Zimmerman, Stefan L.] Johns Hopkins Univ, Div Radiol, Baltimore, MD USA. [Hassoun, Paul M.] Johns Hopkins Univ, Div Pulm, Baltimore, MD USA. [Hassoun, Paul M.] Johns Hopkins Univ, Div Pulm & Crit Care Med, Baltimore, MD USA. [Bluemke, David A.] NIH, Bethesda, MD USA. RP Lima, JAC (reprint author), 600N Wolf St Blalock 524, Baltimore, MD 21287 USA. EM yohyama1@jhmi.edu; bambale1@jhmi.edu; echamer1@jhmi.edu; mondashehata@gmail.com; ccorona1@jhmi.edu; stefan.zimmerman@jhmi.edu; phassou1@jhmi.edu; bluemked@cc.nih.gov; jlima@jhmi.edu RI Ambale Venkatesh, Bharath/F-4941-2016; OI Ambale Venkatesh, Bharath/0000-0002-2330-2373; Bluemke, David/0000-0002-8323-8086 FU National Institutes of Health [NIH1P50HL084946] FX This research was supported by grants NIH1P50HL084946 from National Institutes of Health. NR 30 TC 5 Z9 5 U1 1 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD MAR 1 PY 2015 VL 182 BP 342 EP 348 DI 10.1016/j.ijcard.2015.01.016 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CE6DU UT WOS:000351927600101 PM 25590963 ER PT J AU Torre, P Hoffman, HJ Springer, G Cox, C Young, MA Margolick, JB Plankey, M AF Torre, Peter, III Hoffman, Howard J. Springer, Gayle Cox, Christopher Young, Mary A. Margolick, Joseph B. Plankey, Michael TI Hearing Loss Among HIV-Seropositive and HIV-Seronegative Men and Women SO JAMA OTOLARYNGOLOGY-HEAD & NECK SURGERY LA English DT Article ID MULTICENTER AIDS COHORT; NUTRITION EXAMINATION SURVEY; ANTIRETROVIRAL THERAPY; ACOUSTIC CHARACTERISTICS; DIABETES-MELLITUS; NATIONAL-HEALTH; INTERAGENCY HIV; INFECTION; ADULTS; ASSOCIATION AB IMPORTANCE Age-related hearing loss affects quality of life. Data on hearing loss among aging human immunodeficiency virus-seropositive (HIV+) adults are limited. OBJECTIVE To evaluate pure-tone hearing thresholds among HIV+ and HIV-seronegative (HIV-) adults and to determine whether HIV disease variables and antiretroviral therapy are associated with pure-tone threshold levels. DESIGN, SETTING, AND PARTICIPANTS A total of 262 men (117 HIV+) from the Baltimore, Maryland/Washington, DC, site of the Multicenter AIDS Cohort Study and 134 women (105 HIV+) from the Washington, DC, site of the Women's Interagency HIV Study participated. Pure-tone air conduction thresholds were collected in a sound-treated room for each ear at frequencies from 250 through 8000 Hz. Linear mixed regression models tested the effect of HIV on hearing after adjustment for age, sex, race, and noise exposure history. MAIN OUTCOMES AND MEASURES Low-frequency pure-tone average (LPTA) at 250, 500, 1000, and 2000 Hz and high-frequency PTA (HPTA) at 3000, 4000, 6000, and 8000 Hz. Differential HIV effects for LPTA and HPTA and better/worse ear were also examined. CD4(+) and CD8(+) T-cell counts, log(10) plasma HIV RNA concentrations, receipt of AIDS diagnosis, and cumulative duration of antiretroviral therapy were included in the models for HIV+ participants only. RESULTS HPTA and LPTA were significantly higher (18%: estimated ratio, 1.18 [95% CI, 1.02-1.36]; P=.02; and 12%: estimated ratio, 1.12 [95% CI, 1.00-1.26]; P=.05, respectively) for HIV+ participants compared with HIV-participants for the better ear. The direction of the effect was consistent across both the better and worse ears. There were no significant associations between HIV disease variables or treatment variables and LPTA or HPTA. CONCLUSIONS AND RELEVANCE The HIV+ adults had significantly poorer lower-frequency and higher-frequency hearing than HIV-adults. High-frequency hearing loss is consistent with an accelerated aging (presbycusis); low-frequency hearing loss in middle age is unexpected. Because some vowels and consonants have predominantly low-frequency acoustic energy, poor low-frequency hearing may impair communication in HIV+ individuals. C1 [Torre, Peter, III] San Diego State Univ, Sch Speech Language & Hearing Sci, San Diego, CA 92182 USA. [Hoffman, Howard J.] NIDCD, Epidemiol & Stat Program, NIH, Bethesda, MD USA. [Springer, Gayle; Cox, Christopher] Johns Hopkins Univ, Dept Epidemiol, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Young, Mary A.; Plankey, Michael] Georgetown Univ, Med Ctr, Dept Med, Div Infect Dis, Washington, DC 20007 USA. [Margolick, Joseph B.] Johns Hopkins Univ, Dept Mol Microbiol & Immunol, Bloomberg Sch Publ Hlth, Baltimore, MD USA. RP Torre, P (reprint author), San Diego State Univ, Sch Speech Language & Hearing Sci, 5500 Campanile Dr, San Diego, CA 92182 USA. EM ptorre@mail.sdsu.edu FU National Institute on Deafness and Other Communication Disorders (NIDCD); National Institutes of Health (NIH), via interagency; National Institute of Allergy and Infectious Diseases (NIAID); NIH [U01 AI-035042-18, U01 AI-034994-17]; Baltimore-Washington; DC; MACS by the NIAID; National Cancer Institute [U01-AI-35042]; General Clinic Research Center [UL1-RR025005]; Metropolitan Washington; WIHS by the NIAID [U01-AI-34994]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH [U01-HD-32632] FX This research was supported by the National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health (NIH), via interagency agreement with the National Institute of Allergy and Infectious Diseases (NIAID), NIH, for Cooperative Agreements U01 AI-035042-18 (MACS) and U01 AI-034994-17 (WIHS). Support of the Baltimore-Washington, DC, MACS site was provided by the NIAID, with additional supplemental funding from the National Cancer Institute (U01-AI-35042) and General Clinic Research Center (UL1-RR025005). Support of the Metropolitan Washington, DC, WIHS site was provided by the NIAID (U01-AI-34994) and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH (U01-HD-32632). NR 35 TC 6 Z9 6 U1 1 U2 1 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 MAR PY 2015 VL 141 IS 3 BP 202 EP 210 DI 10.1001/jamaoto.2014.3302 PG 9 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA CE1PV UT WOS:000351585000002 PM 25541676 ER PT J AU Courcoulas, AP Yanovski, SZ Horlick, M AF Courcoulas, Anita P. Yanovski, Susan Z. Horlick, Mary TI Clarification of the Goals of the National Institutes of Health Symposium on Bariatric Surgery Outcomes SO JAMA SURGERY LA English DT Letter C1 [Courcoulas, Anita P.] Univ Pittsburgh, Med Ctr, Minimally Invas Bariatr & Gen Surg, Pittsburgh, PA 15213 USA. [Yanovski, Susan Z.] Natl Inst Diabet & Digest & Kidney Dis, Off Obes Res, Bethesda, MD USA. [Yanovski, Susan Z.] Natl Inst Diabet & Digest & Kidney Dis, Obes & Eating Disorders Program, Bethesda, MD USA. [Horlick, Mary] Natl Inst Diabet & Digest & Kidney Dis, Clin Bariatr Surg Program, Bethesda, MD USA. RP Courcoulas, AP (reprint author), Univ Pittsburgh, Med Ctr, Minimally Invas Bariatr & Gen Surg, 3380 Blvd Allies,Ste 390, Pittsburgh, PA 15213 USA. EM courcoulasap@upmc.edu NR 2 TC 1 Z9 1 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6254 EI 2168-6262 J9 JAMA SURG JI JAMA Surg. PD MAR PY 2015 VL 150 IS 3 BP 277 EP 277 DI 10.1001/jamasurg.2014.3515 PG 1 WC Surgery SC Surgery GA CE2HQ UT WOS:000351636800019 PM 25629293 ER PT J AU Rodriguez, D Gao, ZG Moss, SM Jacobson, KA Carlsson, J AF Rodriguez, David Gao, Zhang-Guo Moss, Steven M. Jacobson, Kenneth A. Carlsson, Jens TI Molecular Docking Screening Using Agonist-Bound GPCR Structures: Probing the A(2A) Adenosine Receptor SO JOURNAL OF CHEMICAL INFORMATION AND MODELING LA English DT Article ID PROTEIN-COUPLED RECEPTORS; STRUCTURE-BASED DISCOVERY; CRYSTAL-STRUCTURE; LIGAND RECOGNITION; NUCLEIC-ACIDS; DRUG TARGETS; FORCE-FIELD; ANTAGONISTS; DYNAMICS; COMPLEX AB Crystal structures of G protein-coupled receptors (GPCRs) have recently revealed the molecular basis of ligand binding and activation, which has provided exciting opportunities for structure-based drug design. The A(2A) adenosine receptor (A(2A)AR) is a promising therapeutic target for cardiovascular diseases, but progress in this area is limited by the lack of novel agonist scaffolds. We carried out docking screens of 6.7 million commercially available molecules against active-like conformations of the A(2A)AR to investigate whether these structures could guide the discovery of agonists. Nine out of the 20 predicted agonists were confirmed to be A(2A)AR ligands, but none of these activated the ARs. The difficulties in discovering AR agonists using structure-based methods originated from limited atomic-level understanding of the activation mechanism and a chemical bias toward antagonists in the screened library. In particular, the composition of the screened library was found to strongly reduce the likelihood of identifying AR agonists, which reflected the high ligand complexity required for receptor activation. Extension of this analysis to other pharmaceutically relevant GPCRs suggested that library screening may not be suitable for targets requiring a complex receptor-ligand interaction network. Our results provide specific directions for the future development of novel A(2A)AR agonists and general strategies for structure-based drug discovery. C1 [Rodriguez, David; Carlsson, Jens] Stockholm Univ, Sci Life Lab, SE-17121 Solna, Sweden. [Rodriguez, David; Carlsson, Jens] Swedish E Sci Res Ctr SeRC, SE-10044 Stockholm, Sweden. [Rodriguez, David; Carlsson, Jens] Stockholm Univ, Dept Biochem & Biophys, SE-10691 Stockholm, Sweden. [Rodriguez, David; Carlsson, Jens] Stockholm Univ, Ctr Biomembrane Res, SE-10691 Stockholm, Sweden. [Gao, Zhang-Guo; Moss, Steven M.; Jacobson, Kenneth A.] NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Jacobson, KA (reprint author), NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. EM kennethj@helix.nih.gov; jens.carlsson@dbb.su.se RI Jacobson, Kenneth/A-1530-2009; OI Jacobson, Kenneth/0000-0001-8104-1493; Carlsson, Jens/0000-0003-4623-2977 FU Knut and Alice Wallenberg Foundation; Center of Biomembrane Research; Swedish Foundation for Strategic Research; Swedish e-Science Research Center; NIDDK Intramural Research Program; Sven och Lilly Lawski Foundation FX This work was supported by grants from the Knut and Alice Wallenberg Foundation, the Center of Biomembrane Research, the Swedish Foundation for Strategic Research, and the Swedish e-Science Research Center to J.C. and by funding from the NIDDK Intramural Research Program to K.A.J. D.R. was funded by a postdoctoral fellowship from the Sven och Lilly Lawski Foundation. Computational resources were provided by the Swedish National Infrastructure for Computing and the National Supercomputer Centre in Linkoping. We thank OpenEye Scientific Software for the use of OEChem, OMEGA, and ROCS at no cost. J.C. and D.R. participated in the European COST Action CM1207 (GLISTEN). NR 66 TC 20 Z9 20 U1 5 U2 25 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1549-9596 EI 1549-960X J9 J CHEM INF MODEL JI J. Chem Inf. Model. PD MAR PY 2015 VL 55 IS 3 BP 550 EP 563 DI 10.1021/ci500639g PG 14 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications SC Pharmacology & Pharmacy; Chemistry; Computer Science GA CE2NS UT WOS:000351652900008 PM 25625646 ER PT J AU Feng, ZW Pearce, LV Xu, XM Yang, XL Yang, P Blumberg, PM Xie, XQ AF Feng, Zhiwei Pearce, Larry V. Xu, Xiaomeng Yang, Xiaole Yang, Peng Blumberg, Peter M. Xie, Xiang-Qun TI Structural Insight into Tetrameric hTRPV1 from Homology Modeling, Molecular Docking, Molecular Dynamics Simulation, Virtual Screening, and Bioassay Validations SO JOURNAL OF CHEMICAL INFORMATION AND MODELING LA English DT Article ID BETA(2) ADRENERGIC-RECEPTOR; DEPENDENT K+ CHANNEL; TRPV1 ION-CHANNEL; GS PROTEIN; C-REGION; ANTAGONIST; CAPSAICIN; PROGRAM; AGONIST; PAIN AB The transient receptor potential vanilloid type 1 (TRPV1) is a heat-activated cation channel protein, which contributes to inflammation, acute and persistent pain. Antagonists of human TRPV1 (hTRPV1) represent a novel therapeutic approach for the treatment of pain. Developing various antagonists of hTRPV1, however, has been hindered by the unavailability of a 3D structure of hTRPV1. Recently, the 3D structures of rat TRPV1 (rTRPV1) in the presence and absence of ligand have been reported as determined by cryo-EM. rTRPV1 shares 85.7% sequence identity with hTRPV1. In the present work, we constructed and reported the 3D homology tetramer model of hTRPV1 based on the cryo-EM structures of rTRPV1. Molecular dynamics (MD) simulations, energy minimizations, and prescreen were applied to select and validate the best model of hTRPV1. The predicted binding pocket of hTRPV1 consists of two adjacent monomers subunits, which were congruent with the experimental rTRPV1 data and the cyro-EM structures of rTRPV1. The detailed interactions between hTRPV1 and its antagonists or agonists were characterized by molecular docking, which helped us to identify the important residues. Conformational changes of hTRPV1 upon antagonist/agonist binding were also explored by MD simulation. The different movements of compounds led to the different conformational changes of monomers in hTRPV1, indicating that TRPV1 works in a concerted way, resembling some other channel proteins such as aquaporins. We observed that the selective filter was open when hTRPV1 bound with an agonist during MD simulation. For the lower gate of hTRPV1, we observed large similarities between hTRPV1 bound with antagonist and with agonist. A five-point pharmacophore model based on several antagonists was established, and the structural model was used to screen in silico for new antagonists for hTRPV1. By using the 3D TRPV1 structural model above, the pilot in silico screening has begun to yield promising hits with activity as hTRPV1 antagonists, several of which showed substantial potency. C1 [Feng, Zhiwei; Xu, Xiaomeng; Yang, Xiaole; Yang, Peng; Xie, Xiang-Qun] Univ Pittsburgh, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA. [Feng, Zhiwei; Xu, Xiaomeng; Yang, Xiaole; Yang, Peng; Xie, Xiang-Qun] Univ Pittsburgh, Sch Pharm, Computat Chem Genom Screening Ctr, Pittsburgh, PA 15261 USA. [Feng, Zhiwei; Xu, Xiaomeng; Yang, Xiaole; Yang, Peng; Xie, Xiang-Qun] Univ Pittsburgh, NIDA Natl Ctr Excellence Computat Drug Abuse Res, Pittsburgh, PA 15261 USA. [Feng, Zhiwei; Xu, Xiaomeng; Yang, Xiaole; Yang, Peng; Xie, Xiang-Qun] Univ Pittsburgh, Drug Discovery Inst, Pittsburgh, PA 15261 USA. [Xie, Xiang-Qun] Univ Pittsburgh, Dept Computat Biol, Pittsburgh, PA 15261 USA. [Xie, Xiang-Qun] Univ Pittsburgh, Dept Struct Biol, Pittsburgh, PA 15261 USA. [Pearce, Larry V.; Blumberg, Peter M.] NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. RP Blumberg, PM (reprint author), NCI, Lab Canc Biol & Genet, NIH, Bldg 37,Room 4048B,37 Convent Dr MSC 4255, Bethesda, MD 20892 USA. EM blumberp@dc37a.nci.nih.gov; xix15@pitt.edu FU NIH NIDA [P30 DA035778A1]; NIH [R01 DA025612]; Intramural Program of the Center for Cancer Research, National Cancer Institute, NIH [Z1A BC 005270] FX The project is supported by funding to the Xie laboratory from the NIH NIDA (P30 DA035778A1) and NIH (R01 DA025612) and in part by the Intramural Program of the Center for Cancer Research, National Cancer Institute, NIH (Project Z1A BC 005270). We also thank our lab member Ms. Guanxing Hu for collecting data on the compounds reported or marketed. NR 55 TC 13 Z9 13 U1 4 U2 26 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1549-9596 EI 1549-960X J9 J CHEM INF MODEL JI J. Chem Inf. Model. PD MAR PY 2015 VL 55 IS 3 BP 572 EP 588 DI 10.1021/ci5007189 PG 17 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications SC Pharmacology & Pharmacy; Chemistry; Computer Science GA CE2NS UT WOS:000351652900010 PM 25642729 ER PT J AU Anighoro, A Stumpfe, D Heikamp, K Beebe, K Neckers, LM Bajorath, J Rastelli, G AF Anighoro, Andrew Stumpfe, Dagmar Heikamp, Kathrin Beebe, Kristin Neckers, Leonard M. Bajorath, Jurgen Rastelli, Giulio TI Computational Polypharmacology Analysis of the Heat Shock Protein 90 Interactome SO JOURNAL OF CHEMICAL INFORMATION AND MODELING LA English DT Article ID ESTROGEN-RECEPTOR-BETA; HSP90 MOLECULAR CHAPERONE; STRUCTURE-BASED DESIGN; DRUG DISCOVERY; BREAST-CANCER; POTENT INHIBITORS; CRYSTAL-STRUCTURE; STRUCTURAL BASIS; BINDING-SITE; LIGANDS AB The design of a single drug molecule that is able to simultaneously and specifically interact with multiple biological targets is gaining major consideration in drug discovery. However, the rational design of drugs with a desired polypharmacology profile is still a challenging task, especially when these targets are distantly related or unrelated. In this work, we present a computational approach aimed at the identification of suitable target combinations for multitarget drug design within an ensemble of biologically relevant proteins. The target selection relies on the analysis of activity annotations present in molecular databases and on ligand-based virtual screening. A few target combinations were also inspected with structure-based methods to demonstrate that the identified dual-activity compounds are able to bind target combinations characterized by remote binding site similarities. Our approach was applied to the heat shock protein 90 (Hsp90) interactome, which contains several targets of key importance in cancer. Promising target combinations were identified, providing a basis for the computational design of compounds with dual activity. The approach may be used on any ensemble of proteins of interest for which known inhibitors are available. C1 [Anighoro, Andrew; Rastelli, Giulio] Univ Modena & Reggio Emilia, Dept Life Sci, I-41125 Modena, Italy. [Stumpfe, Dagmar; Heikamp, Kathrin; Bajorath, Jurgen] Univ Bonn, LIMES Program Unit Chem Biol & Med Chem, Dept Life Sci Informat, B IT, D-53113 Bonn, Germany. [Beebe, Kristin; Neckers, Leonard M.] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Bajorath, J (reprint author), Univ Bonn, LIMES Program Unit Chem Biol & Med Chem, Dept Life Sci Informat, B IT, Dahlmannstr 2, D-53113 Bonn, Germany. EM bajorath@bit.uni-bonn.de; giulio.rastelli@unimore.it OI Rastelli, Giulio/0000-0002-2474-0607 NR 64 TC 3 Z9 3 U1 0 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1549-9596 EI 1549-960X J9 J CHEM INF MODEL JI J. Chem Inf. Model. PD MAR PY 2015 VL 55 IS 3 BP 676 EP 686 DI 10.1021/ci5006959 PG 11 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications SC Pharmacology & Pharmacy; Chemistry; Computer Science GA CE2NS UT WOS:000351652900019 PM 25686391 ER PT J AU Fowler, JS Logan, J Shumay, E Alia-Klein, N Wang, GJ Volkow, ND AF Fowler, Joanna S. Logan, Jean Shumay, Elena Alia-Klein, Nelly Wang, Gene-Jack Volkow, Nora D. TI Monoamine oxidase: radiotracer chemistry and human studies SO JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS LA English DT Review DE monoamine oxidase; PET; radiotracer chemistry; human studies ID POSITRON-EMISSION-TOMOGRAPHY; B MAO-B; C-11 DEUTERIUM-DEPRENYL; HEALTHY-HUMAN SUBJECTS; HUMAN-BRAIN; IN-VIVO; PERIPHERAL ORGANS; BABOON BRAIN; SELECTIVE INHIBITORS; CIGARETTE-SMOKING AB Monoamine oxidase (MAO) oxidizes amines from both endogenous and exogenous sources thereby regulating the concentration of neurotransmitter amines such as serotonin, norepinephrine, and dopamine as well as many xenobiotics. MAO inhibitor drugs are used in the treatment of Parkinson's disease and in depression stimulating the development of radiotracer tools to probe the role of MAO in normal human biology and in disease. Over the past 30years since the first radiotracers were developed and the first positron emission tomography (PET) images of MAO in humans were carried out, PET studies of brain MAO in healthy volunteers and in patients have identified different variables that have contributed to different MAO levels in brain and in peripheral organs. MAO radiotracers and PET have also been used to study the current and developing MAO inhibitor drugs including the selection of doses for clinical trials. In this article, we describe the following: (1) the development of MAO radiotracers; (2) human studies including the relationship of brain MAO levels to genotype, personality, neurological, and psychiatric disorders; and (3) examples of the use of MAO radiotracers in drug research and development. We will conclude with outstanding needs to improve the radiotracers that are currently used and possible new applications. C1 [Fowler, Joanna S.] Brookhaven Natl Lab, Biol Environm & Climate Sci Dept, Upton, NY 11973 USA. [Logan, Jean] NYU, Langone Med Ctr, Dept Radiol, New York, NY USA. [Shumay, Elena; Wang, Gene-Jack; Volkow, Nora D.] NIAAA, NIH, Bethesda, MD USA. [Alia-Klein, Nelly] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Volkow, Nora D.] NIDA, NIH, Bethesda, MD 20892 USA. RP Fowler, JS (reprint author), Brookhaven Natl Lab, Biol Environm & Climate Sci Dept, Upton, NY 11973 USA. EM fowler@bnl.gov OI Logan, Jean/0000-0002-6993-9994 NR 114 TC 12 Z9 13 U1 0 U2 29 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0362-4803 EI 1099-1344 J9 J LABELLED COMPD RAD JI J. Label. Compd. Radiopharm. PD MAR PY 2015 VL 58 IS 3 SI SI BP 51 EP 64 DI 10.1002/jlcr.3247 PG 14 WC Biochemical Research Methods; Chemistry, Medicinal; Chemistry, Analytical SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA CE3XV UT WOS:000351764300003 PM 25678277 ER PT J AU de Sousa, RT Zanetti, MV Talib, LL Serpa, MH Chaim, TM Carvalho, AF Brunoni, AR Busatto, GF Gattaz, WE Machado-Vieira, R AF de Sousa, Rafael T. Zanetti, Marcus V. Talib, Leda L. Serpa, Mauricio H. Chaim, Tiffany M. Carvalho, Andre F. Brunoni, Andre R. Busatto, Geraldo F. Gattaz, Wagner E. Machado-Vieira, Rodrigo TI Lithium increases platelet serine-9 phosphorylated GSK-3 beta levels in drug-free bipolar disorder during depressive episodes SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Bipolar disorder; GSK3; Lithium; Treatment; Depression; Neurobiology ID GLYCOGEN-SYNTHASE KINASE-3; SINGLE NUCLEOTIDE POLYMORPHISM; ALZHEIMERS-DISEASE; PREFRONTAL CORTEX; OXIDATIVE STRESS; ELDERLY-PATIENTS; GLYCOGEN-SYNTHASE-KINASE-3-BETA; GSK3-BETA; RISK; HYPOTHESIS AB Background: Glycogen synthase kinase-3 beta (GSK3 beta) is an intracellular enzyme directly implicated in several neural processes relevant to bipolar disorder (BD) pathophysiology. GSK3 beta is also an important target for lithium and antidepressants. When phosphorylated at serine-9, GSK3 beta becomes inactive. Few studies evaluated serine-9 phosphorylated GSK3 beta(phospho-GSK3 beta) levels in BD subjects in vivo and no study has assessed it specifically in bipolar depression. Also, the effect of lithium monotherapy on GSK3 beta has never been studied in humans. Methods: In 27 patients with bipolar depression, total GSK3 beta and phospho-GSK3 beta were assessed in platelets by enzyme immunometric assay. Subjects were evaluated before and after 6 weeks of lithium treatment at therapeutic levels. Healthy subjects (n = 22) were used as a control group. Results: No differences in phospho-GSK3 beta or total GSK3 beta were observed when comparing drug-free BD subjects in depression and healthy controls. Baseline HAM-D scores were not correlated with phospho GSK3 beta and total GSK3 beta levels. From baseline to endpoint, lithium treatment inactivated GSK3 beta by significantly increasing phospho-GSK3 beta levels (p = 0.010). Clinical improvement (baseline HAM-D endpoint HAM-D) negatively correlated with the increase in phospho-GSK3 beta (p = 0.03). Conclusion: The present results show that lithium inactivates platelet GSK3 beta in BD during mood episodes. No direct association with pathophysiology of BD was observed. Further studies are needed to clarify the role of GSK3 beta as a key biomarker in BD and its association with treatment response as well as the relevance of GSK3 beta in other neuropsychiatric disorders and as a new therapeutic target per se. Published by Elsevier Ltd. C1 [de Sousa, Rafael T.; Zanetti, Marcus V.; Talib, Leda L.; Brunoni, Andre R.; Gattaz, Wagner E.; Machado-Vieira, Rodrigo] Univ Sao Paulo, Lab Neurosci, Inst & Dept Psychiat, LIM 27, BR-05508 Sao Paulo, Brazil. [Zanetti, Marcus V.; Busatto, Geraldo F.; Gattaz, Wagner E.; Machado-Vieira, Rodrigo] Univ Sao Paulo, Ctr Interdisciplinary Res Appl Neurosci NAPNA, BR-05508 Sao Paulo, Brazil. [Zanetti, Marcus V.; Serpa, Mauricio H.; Chaim, Tiffany M.; Busatto, Geraldo F.] Univ Sao Paulo, Lab Psychiat Neuroimaging, LIM 21, Dept & Inst Psychiat, BR-05508 Sao Paulo, Brazil. [Machado-Vieira, Rodrigo] NIMH, ETPB, NIH, Bethesda, MD 20892 USA. [Carvalho, Andre F.] Univ Fed Ceara, Translat Psychiat Res Grp, Fac Med, Fortaleza, Ceara, Brazil. [Carvalho, Andre F.] Univ Fed Ceara, Dept Clin Med, Fac Med, Fortaleza, Ceara, Brazil. RP Machado-Vieira, R (reprint author), Univ Sao Paulo, Lab Neurosci LIM27, Dept & Inst Psychiat, BR-05508 Sao Paulo, Brazil. EM machadovieirar@gmail.com RI Busatto, Geraldo/D-4431-2009; MACHADO-VIEIRA, RODRIGO/D-8293-2012 OI MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190 FU Sao Paulo Research Foundation (FAPESP, Brazil) [2009/14891-9] FX This study was sponsored by Sao Paulo Research Foundation (FAPESP, Brazil; Grant 2009/14891-9, RM-V), but FAPESP had no role in the design of the study, collection, analysis of data, and decision to publish. NR 48 TC 6 Z9 6 U1 2 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 EI 1879-1379 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD MAR PY 2015 VL 62 BP 78 EP 83 DI 10.1016/j.jpsychires.2015.01.016 PG 6 WC Psychiatry SC Psychiatry GA CE4GS UT WOS:000351789700010 PM 25691093 ER PT J AU Gould, L Abadir, P Brem, H Carter, M Conner-Kerr, T Davidson, J DiPietro, L Falanga, V Fife, C Gardner, S Grice, E Harmon, J Hazzard, WR High, KP Houghton, P Jacobson, N Kirsner, RS Kovacs, EJ Margolis, D McFarland Horne, F Reed, MJ Sullivan, DH Thom, S Tomic-Canic, M Walston, J Whitney, JA Williams, J Zieman, S Schmader, K AF Gould, Lisa Abadir, Peter Brem, Harold Carter, Marissa Conner-Kerr, Teresa Davidson, Jeff DiPietro, Luisa Falanga, Vincent Fife, Caroline Gardner, Sue Grice, Elizabeth Harmon, John Hazzard, William R. High, Kevin P. Houghton, Pamela Jacobson, Nasreen Kirsner, Robert S. Kovacs, Elizabeth J. Margolis, David McFarland Horne, Frances Reed, May J. Sullivan, Dennis H. Thom, Stephen Tomic-Canic, Marjana Walston, Jeremy Whitney, Jo Anne Williams, John Zieman, Susan Schmader, Kenneth TI Chronic Wound Repair and Healing in Older Adults: Current Status and Future Research SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Review DE chronic wound; pressure ulcer; diabetic foot ulcer; venous leg ulcer; wound repair; wound healing ID RANDOMIZED CONTROLLED-TRIAL; VENOUS LEG ULCERS; HUMAN ALLOGENEIC FIBROBLASTS; PERIPHERAL VASCULAR-DISEASE; HYPERBARIC-OXYGEN THERAPY; LOW-FREQUENCY ULTRASOUND; VACUUM-ASSISTED CLOSURE; NURSING-HOME RESIDENTS; MESENCHYMAL STEM-CELLS; DIABETIC FOOT ULCERS AB Older adults are more likely to have chronic wounds than younger people, and the effect of chronic wounds on quality of life is particularly profound in this population. Wound healing slows with age, but the basic biology underlying chronic wounds and the influence of age-associated changes on wound healing are poorly understood. Most studies have used in vitro approaches and various animal models, but observed changes translate poorly to human healing conditions. The effect of age and accompanying multimorbidity on the effectiveness of existing and emerging treatment approaches for chronic wounds is also unknown, and older adults tend to be excluded from randomized clinical trials. Poorly defined outcomes and variables; lack of standardization in data collection; and variations in the definition, measurement, and treatment of wounds also hamper clinical studies. The Association of Specialty Professors, in conjunction with the National Institute on Aging and the Wound Healing Society, held a workshop, summarized in this article, to explore the current state of knowledge and research challenges, engage investigators across disciplines, and identify research questions to guide future study of age-associated changes in chronic wound healing. C1 [Gould, Lisa] Kent Hosp, Wound Recovery & Hyperbar Med Ctr, Warwick, RI USA. [Abadir, Peter; Walston, Jeremy] Johns Hopkins Univ, Div Geriatr & Gerontol Med, Baltimore, MD USA. [Brem, Harold] Winthrop Univ Hosp, Dept Wound Healing & Regenerat Med, Mineola, NY 11501 USA. [Brem, Harold] SUNY Stony Brook, Sch Med, Mineola, NY USA. [Carter, Marissa] Strateg Solut Inc, Cody, WY USA. [Conner-Kerr, Teresa] Winston Salem State Univ, Dept Phys Therapy, Winston Salem, NC USA. [Davidson, Jeff] Vanderbilt Univ, Sch Med, Dept Pathol Microbiol & Immunol, Nashville, TN 37212 USA. [DiPietro, Luisa] Univ Illinois, Ctr Wound Healing & Tissue Regenerat, Chicago, IL USA. [Falanga, Vincent] Boston Univ, Sch Med, Dept Dermatol, Boston, MA 02118 USA. [Fife, Caroline] Baylor Coll Med, Dept Geriatr, Houston, TX 77030 USA. [Fife, Caroline] St Lukes Wound Ctr, The Woodlands, TX USA. [Gardner, Sue] Univ Iowa, Coll Nursing, Iowa City, IA 52242 USA. [Grice, Elizabeth] Univ Penn, Penn Inst Immunol, Philadelphia, PA 19104 USA. [Harmon, John] Johns Hopkins Univ, Dept Surg, Baltimore, MD USA. [Hazzard, William R.] Wake Forest Univ, Sch Med, Gerontol & Geriatr Med, Winston Salem, NC 27109 USA. [High, Kevin P.] Wake Forest Univ, Sch Med, Dept Internal Med, Winston Salem, NC 27109 USA. [High, Kevin P.] Wake Forest Univ, Sch Med, Infect Dis Sect, Winston Salem, NC 27109 USA. [Houghton, Pamela] Univ Western Ontario, Sch Phys Therapy, London, ON, Canada. [Jacobson, Nasreen] Smith & Nephew, Ft Worth, TX USA. [Kirsner, Robert S.] Univ Miami, Miller Sch Med, Dept Dermatol & Cutaneous Surg, Miami, FL 33136 USA. [Kovacs, Elizabeth J.] Loyola Univ, Burn & Shock Trauma Res Inst, Dept Surg, Chicago, IL 60611 USA. [Margolis, David] Univ Penn, Dept Dermatol, Philadelphia, PA 19104 USA. [McFarland Horne, Frances] Assoc Specialty Professors, Alexandria, VA USA. [Reed, May J.] Univ Washington, Div Gerontol & Geriatr Med, Seattle, WA 98195 USA. [Sullivan, Dennis H.] Univ Arkansas Med Sci, Dept Geriatr, Little Rock, AR 72205 USA. [Thom, Stephen] Univ Maryland, Dept Emergency Med, Baltimore, MD 21201 USA. [Tomic-Canic, Marjana] Univ Miami, Miller Sch Med, Wound Healing & Regenerat Med Res Program, Miami, FL 33136 USA. [Walston, Jeremy] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Whitney, Jo Anne] Univ Washington, Sch Nursing, Seattle, WA 98195 USA. [Williams, John; Zieman, Susan] NIA, Bethesda, MD 20892 USA. [Schmader, Kenneth] Durham Vet Affairs Med Ctr, Geriatr Res Educ & Clin Ctr, Durham, NC USA. [Schmader, Kenneth] Duke Univ, Med Ctr, Durham, NC USA. RP Gould, L (reprint author), Kent Mem Hosp, Wound Recovery & Hyperbar Med Ctr, 455 Tollgate Rd, Warwick, RI 02886 USA. EM lgould44@hotmail.com RI Abadir, Peter/A-2067-2017 OI Abadir, Peter/0000-0002-8186-0066 FU National Institute on Aging [1 U13 AG040938 01]; John A. Hartford Foundation FX This workshop was supported by generous grants to ASP from the National Institute on Aging (1 U13 AG040938 01) and the John A. Hartford Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of National Institute on Aging or the National Institutes of Health (NIH). In addition, the views expressed in written conference materials or publications and by speakers or moderators do not necessarily reflect the official policies of the Department of Health and Human Services; nor does mention by trade names, commercial practices, or organizations imply endorsement by the U.S. government. We are grateful to Nancy Woolard for her assistance with organizing the workshop. To see the agenda, a list of workshop moderators and attendees, and workshop presentations, please visit http://www.im.org/p/cm/ld/fid=599. NR 137 TC 12 Z9 13 U1 6 U2 25 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAR PY 2015 VL 63 IS 3 BP 427 EP 438 DI 10.1111/jgs.13332 PG 12 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA CE3PO UT WOS:000351740400002 PM 25753048 ER PT J AU Huh, JY Ross, GW Chen, RD Abbott, RD Bell, C Willcox, B Launer, L Petrovitch, H Kaya, B Masaki, K AF Huh, Ji Young Ross, George Webster Chen, Randi Abbott, Robert D. Bell, Christina Willcox, Bradley Launer, Lenore Petrovitch, Helen Kaya, Brock Masaki, Kamal TI Total and Differential White Blood Cell Counts in Late Life Predict 8-Year Incident Stroke: The Honolulu Heart Program SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE white blood cell count; differential WBC counts; incident stroke; Japanese-American men; longitudinal cohort study ID LEUKOCYTE COUNT; PROSPECTIVE COHORT; ISCHEMIC-STROKE; ATHEROSCLEROSIS; DISEASE; INFLAMMATION; MEN; MORTALITY; EVENTS; RISK AB ObjectivesTo study the association between total and differential white blood cell (WBC) count and incident stroke in an older Asian population. DesignProspective population-based study with 8years of follow-up. SettingThe Honolulu Heart Program, Oahu, Hawaii. ParticipantsJapanese-American men aged 71 to 93 who were free of stroke and had baseline WBC counts measured in 1991-93 (N=3,342). MeasurementsParticipants were divided into quartiles of total and differential WBC count for analysis and were followed for incident stroke (thromboembolic and hemorrhagic (hemorrhagic)) for 8years using data from a comprehensive hospital surveillance system. ResultsAge-adjusted incident stroke rates increased significantly with increasing WBC quartile (Q1, 7.68; Q2, 9.04; Q3, 9.26; Q4, 14.10 per 1,000 person-years of follow-up, P=.001). Hazard ratios (HRs) for stroke for each quartile of total and differential WBC count were obtained using Cox regression analysis, with the lowest quartile as the reference group. After full adjustment, including age; cardiovascular risk factors; fibrinogen; prevalent coronary heart disease, cancer, or chronic obstructive pulmonary disease, and nonsteroidal anti-inflammatory drug use, HRs were 1.62 (95% confidence interval (CI)=1.04-2.52, P=.03) in the highest quartile of total WBC and 2.19 (95% CI=1.41-3.39, P<.001) in the highest quartile of neutrophil counts. Significant associations were also seen for thromboembolic but not for hemorrhagic strokes. No significant associations were found between lymphocyte or monocyte counts and incident stroke or subtypes. ConclusionIn elderly Japanese-American men, higher total WBC and neutrophil counts were independent predictors of overall stroke, as well as thromboembolic stroke. C1 [Huh, Ji Young; Ross, George Webster; Abbott, Robert D.; Bell, Christina; Willcox, Bradley; Petrovitch, Helen; Masaki, Kamal] Univ Hawaii, John A Burns Sch Med, John A Hartford Fdn Ctr Excellence Geriatr, Dept Geriatr Med, Honolulu, HI 96822 USA. [Ross, George Webster; Petrovitch, Helen] Vet Affairs Pacific Isl Hlth Care Syst, Honolulu, HI USA. [Chen, Randi; Willcox, Bradley; Masaki, Kamal] Kuakini Med Ctr, Honolulu, HI USA. [Abbott, Robert D.] Shiga Univ Med Sci, Ctr Epidemiol Res Asia, Otsu, Shiga 52021, Japan. [Launer, Lenore] NIA, Bethesda, MD 20892 USA. [Kaya, Brock] Univ Hawaii, John A Burns Sch Med, Dept Pathol, Honolulu, HI 96822 USA. RP Huh, JY (reprint author), 347 N Kuakini St,HPM-9, Honolulu, HI 96817 USA. EM huhjfm@gmail.com FU John A. Hartford Center of Excellence in Geriatrics, Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii; Kuakini Medical Center; National Institutes of Health (NIH) from the National Institute on Aging [N01-AG-4-2149, U01 AG019349, R01AG027060, R01AG038707]; National Institutes of Health (NIH) from the National Heart, Lung, and Blood Institute [N01-HC-05102]; Hawaii Community Foundation [2004-0463]; Office for Research and Development, Department of Veterans Affairs FX This study was supported by the John A. Hartford Center of Excellence in Geriatrics, Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii; the Kuakini Medical Center; the National Institutes of Health (NIH) (Contract N01-AG-4-2149, Grants U01 AG019349, R01AG027060, and R01AG038707 from the National Institute on Aging, and Contract N01-HC-05102 from the National Heart, Lung, and Blood Institute); Hawaii Community Foundation grant 2004-0463; and the Office for Research and Development, Department of Veterans Affairs. The views expressed in this paper do not necessarily represent those of the federal government. NR 26 TC 0 Z9 0 U1 2 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAR PY 2015 VL 63 IS 3 BP 439 EP 446 DI 10.1111/jgs.13298 PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA CE3PO UT WOS:000351740400003 PM 25739422 ER PT J AU Wynne, JH Lunney, J Ives, D Newman, AB Satterfield, S Garcia, M Harris, T Ayonayon, HN Rubin, SM Albert, SM AF Wynne, Juliana Hoffelder Lunney, June Ives, Diane Newman, Anne B. Satterfield, Suzanne Garcia, Melissa Harris, Tamara Ayonayon, Hilsa N. Rubin, Susan M. Albert, Steven M. TI PERCEPTIONS OF VERY OLD ADULTS ABOUT INFORMED CARE IN MEDICAL ENCOUNTERS SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Letter C1 [Wynne, Juliana Hoffelder] Philadelphia Coll Osteopath Med, Philadelphia, PA 19131 USA. [Lunney, June] Univ Pittsburgh, Hosp & Palliat Nurses Assoc, Pittsburgh, PA USA. [Ives, Diane; Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Satterfield, Suzanne] Univ Tennessee, Hlth Sci Ctr Memphis, Dept Prevent Med, Memphis, TN USA. [Garcia, Melissa; Harris, Tamara] NIA, Lab Epidemiol Biometry & Demog, NIH, Bethesda, MD 20892 USA. [Ayonayon, Hilsa N.; Rubin, Susan M.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Albert, Steven M.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Behav & Community Hlth Sci, Pittsburgh, PA USA. RP Wynne, JH (reprint author), Philadelphia Coll Osteopath Med, Philadelphia, PA 19131 USA. RI Newman, Anne B./C-6408-2013; OI Newman, Anne B./0000-0002-0106-1150; Albert, Steven/0000-0001-6786-9956 FU National Institutes of Health (NIH), National Institute on Aging (NIA); American Federation for Aging Research Medical Student Training in Aging program; NIA [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050, R01-AG024827]; National Institute of Nursing [R01-NR012459] FX This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), National Institute on Aging (NIA).; Juliana Hoffelder-Wyne was supported by the American Federation for Aging Research Medical Student Training in Aging program. Health ABC efforts were supported by NIA Contracts N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050, and R01-AG024827 and National Institute of Nursing Research Contract R01-NR012459. NR 6 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAR PY 2015 VL 63 IS 3 BP 612 EP 614 DI 10.1111/jgs.13291 PG 3 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA CE3PO UT WOS:000351740400038 ER PT J AU Guyette, FX Meier, EN Newgard, C McKnight, B Daya, M Bulger, EM Powell, JL Brasel, KJ Kerby, JD Egan, D Sise, M Coimbra, R Fabian, TC Hoyt, DB AF Guyette, Francis X. Meier, Eric N. Newgard, Craig McKnight, Barbara Daya, Mohamud Bulger, Eileen M. Powell, Judy L. Brasel, Karen J. Kerby, Jeffery D. Egan, Debra Sise, Michael Coimbra, Raul Fabian, Timothy C. Hoyt, David B. CA ROC Investigators TI A comparison of prehospital lactate and systolic blood pressure for predicting the need for resuscitative care in trauma transported by ground SO JOURNAL OF TRAUMA AND ACUTE CARE SURGERY LA English DT Article DE Lactate; prehospital; trauma ID PERSISTENT OCCULT HYPOPERFUSION; 110 MM HG; SERUM LACTATE; REDEFINING HYPOTENSION; SIGNIFICANT INCREASE; INFECTION-RATE; BLUNT TRAUMA; VITAL SIGNS; MORTALITY; TRIAGE AB BACKGROUND: Reliance on prehospital trauma triage guidelines misses patients with serious injury. Lactate is a biomarker capable of identifying high-risk trauma patients. Our objective was to compare prehospital point-of-care lactate (P-LAC) with systolic blood pressure (SBP) for predicting the need for resuscitative care (RC) in trauma patients transported by ground emergency medical services. METHODS: This is a prospective observational study at nine sites within the Resuscitation Outcomes Consortium conducted from March 2011 to August 2012. Lactate was measured on patients with a prehospital SBP of 100 mm Hg or less who were transported by emergency medical services to a Level I or II trauma center. Patients were followed up for the need for RC, defined as any of the following within 6 hours of emergency department arrival: blood transfusion of 5 U or greater; intervention for hemorrhage including thoracotomy, laparotomy, pelvic fixation, or interventional radiology embolization; or death. RESULTS: A total of 387 patients had a lactate value and presented with SBP between 71 mm Hg and 100 mm Hg, and 70 (18%) required RC. With the use of a P-LAC decision rule (>= 2.5 mmol/L) that yielded the same specificity as that of SBP of 90 mm Hg or less (48%), the observed sensitivities for RC were 93% (95% confidence interval [CI], 84-98%) for P-LAC of 2.5 mmol/L or greater and 67% (95% CI, 55-78%) for SBP of 90 mm Hg or less (McNemar's test, p < 0.001). P-LAC has an estimated area under the curve of 0.78 (95% CI, 0.73-0.83), which is statistically superior to that of SBP (0.59; 95% CI, 0.53-0.66) and shock index (heart rate / SBP) (0.66; 95% CI, 0.60-0.74). CONCLUSION: P-LAC obtained at the scene is associated with the need for RC. P-LAC is superior to other early surrogates for hypoperfusion (SBP and shock index) in predicting the need for RC in trauma patients with 70 mm Hg < SBP <= 100 mm Hg. (Copyright (C) 2015 Wolters Kluwer Health, Inc. All rights reserved.) C1 [Guyette, Francis X.] Univ Pittsburgh, Dept Emergency Med, Pittsburgh, PA 15261 USA. [Bulger, Eileen M.] Univ Washington, Dept Surg, Seattle, WA 98195 USA. [Meier, Eric N.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Powell, Judy L.] Univ Washington, Clin Trials Ctr, Seattle, WA 98195 USA. [Brasel, Karen J.] Med Coll Wisconsin, Dept Surg, Milwaukee, WI 53226 USA. [Daya, Mohamud] Oregon Hlth & Sci Univ, Dept Emergency Med, Portland, OR 97201 USA. [Newgard, Craig] Oregon Hlth & Sci Univ, Emergency Med Surg & Publ Hlth & Prevent Med, Portland, OR 97201 USA. [Kerby, Jeffery D.] Univ Alabama Birmingham, Dept Surg, Birmingham, AL USA. [Sise, Michael; Coimbra, Raul] Univ Calif San Diego, Dept Surg, San Diego, CA 92103 USA. [Fabian, Timothy C.] Univ Tennessee, Dept Surg, Memphis, TN USA. [Egan, Debra] NHLBI, NIH, Bethesda, MD 20892 USA. [Hoyt, David B.] Amer Coll Surg, Chicago, IL USA. RP Guyette, FX (reprint author), Univ Pittsburgh, Sch Med, 3600 Forbes Ave,Suite 400A, Pittsburgh, PA 15261 USA. EM guyettef@upmc.edu FU National Heart, Lung and Blood Institute [5U01 HL077863, HL077866, HL077867, HL077871, HL077873, HL077881, HL077887, HL077908]; US Army Medical Research & Material Command; Canadian Institutes of Health Research (CIHR)-Institute of Circulatory and Respiratory Health, Defense Research and Development Canada; Heart, Stroke Foundation of Canada; American Heart Association FX The ROC is supported by a series of cooperative agreements to nine regional clinical centers and one Data Coordinating Center (5U01 HL077863-University of Washington Data Coordinating Center, HL077866-Medical College of Wisconsin, HL077867-University of Washington, HL077871-University of Pittsburgh, HL077873-Oregon Health and Science University, HL077881-University of Alabama at Birmingham, HL077887-University of Texas SW Medical Ctr/Dallas, HL077908-University of California San Diego) from the National Heart, Lung and Blood Institute in partnership with the US Army Medical Research & Material Command, The Canadian Institutes of Health Research (CIHR)-Institute of Circulatory and Respiratory Health, Defense Research and Development Canada, the Heart, Stroke Foundation of Canada and the American Heart Association. NR 36 TC 9 Z9 10 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 2163-0755 EI 2163-0763 J9 J TRAUMA ACUTE CARE JI J. Trauma Acute Care Surg. PD MAR PY 2015 VL 78 IS 3 BP 600 EP 606 DI 10.1097/TA.0000000000000549 PG 7 WC Critical Care Medicine; Surgery SC General & Internal Medicine; Surgery GA CE8DQ UT WOS:000352072000028 PM 25710433 ER PT J AU Khan, I Tang, E Arany, P AF Khan, Imran Tang, Elieza Arany, Praveen TI ER STRESS-MEDIATED BY ATF-4 ORCHESTRATES NEAR-INFRARED LASER PHOTOTOXICITY SO LASERS IN SURGERY AND MEDICINE LA English DT Meeting Abstract C1 [Khan, Imran; Tang, Elieza; Arany, Praveen] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0196-8092 EI 1096-9101 J9 LASER SURG MED JI Lasers Surg. Med. PD MAR PY 2015 VL 47 SU 26 MA 91 BP 31 EP 32 PG 2 WC Dermatology; Surgery SC Dermatology; Surgery GA CE8NN UT WOS:000352099900091 ER PT J AU Engel, K Khan, I Arany, P AF Engel, Karl Khan, Imran Arany, Praveen TI EFFECTS OF LASER PULSING ON CELL VIABILITY SO LASERS IN SURGERY AND MEDICINE LA English DT Meeting Abstract C1 [Engel, Karl; Khan, Imran; Arany, Praveen] NIDCR, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0196-8092 EI 1096-9101 J9 LASER SURG MED JI Lasers Surg. Med. PD MAR PY 2015 VL 47 SU 26 MA 123 BP 41 EP 42 PG 2 WC Dermatology; Surgery SC Dermatology; Surgery GA CE8NN UT WOS:000352099900123 ER PT J AU Xu, XH Gera, N Li, HY Yun, M Zhang, LY Wang, YH Wang, QJ Jin, T AF Xu, Xuehua Gera, Nidhi Li, Hongyan Yun, Michelle Zhang, Liyong Wang, Youhong Wang, Q. Jane Jin, Tian TI GPCR-mediated PLC beta gamma/PKC beta/PKD signaling pathway regulates the cofilin phosphatase slingshot 2 in neutrophil chemotaxis SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID ACTIN REORGANIZATION; LIM-KINASE; PHOSPHORYLATION; ACTIVATION; CELLS; ROLES; RECEPTOR; FAMILY; POLARIZATION; DOWNSTREAM AB Chemotaxis requires precisely coordinated polymerization and depolymerization of the actin cytoskeleton at leading fronts of migrating cells. However, GPCR activation-controlled F-actin depolymerization remains largely elusive. Here, we reveal a novel signaling pathway, including G alpha i, PLC, PKC beta, protein kinase D (PKD), and SSH2, in control of cofilin phosphorylation and actin cytoskeletal reorganization, which is essential for neutrophil chemotaxis. We show that PKD is essential for neutrophil chemotaxis and that GPCR-mediated PKD activation depends on PLC/PKC signaling. More importantly, we discover that GPCR activation recruits/activates PLC gamma 2 in a PI3K-dependent manner. We further verify that PKC beta specifically interacts with PKD1 and is required for chemotaxis. Finally, we identify slingshot 2 (SSH2), a phosphatase of cofilin (actin depolymerization factor), as a target of PKD1 that regulates cofilin phosphorylation and remodeling of the actin cytoskeleton during neutrophil chemotaxis. C1 [Xu, Xuehua; Gera, Nidhi; Li, Hongyan; Yun, Michelle; Wang, Youhong; Jin, Tian] NIAID, Chemotaxis Signaling Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Li, Hongyan] 302 Hosp PLA, Ctr Therapeut Res Hepatocellular Carcinoma, Beijing 100039, Peoples R China. [Zhang, Liyong; Wang, Q. Jane] Univ Pittsburgh, Sch Med, Dept Pharmacol & Chem Biol, Pittsburgh, PA 15213 USA. RP Xu, XH (reprint author), NIAID, Chemotaxis Signaling Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. EM xxu@niaid.nih.gov FU National Institutes of Health Intramural Fund from the National Institute of Allergy and Infectious Diseases, National Institutes of Health; National Institutes of Health [R01CA142580] FX This work was supported by the National Institutes of Health Intramural Fund from the National Institute of Allergy and Infectious Diseases, National Institutes of Health. Q. Jane Wang was supported in part by National Institutes of Health grant R01CA142580. We acknowledge Thomas Leto and Blazs Rada, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, for their help with the PMN experiments. We also thank Joseph Brzostowski, Laboratory of Immunogenetics Imaging Facility, for his help. NR 37 TC 6 Z9 6 U1 2 U2 5 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 MAR 1 PY 2015 VL 26 IS 5 BP 874 EP 886 DI 10.1091/mbc.E14-05-0982 PG 13 WC Cell Biology SC Cell Biology GA CE6KO UT WOS:000351945500005 PM 25568344 ER PT J AU Ferre, S AF Ferre, Sergi TI The GPCR heterotetramer: challenging classical pharmacology SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Review DE GPCR; oligomerization; signalosome; adenylyl cyclase ID ADENOSINE A(2A) RECEPTORS; PROTEIN-COUPLED RECEPTORS; BETA-ADRENERGIC-RECEPTOR; M-2 MUSCARINIC RECEPTOR; ADENYLATE-CYCLASE; FUNCTIONAL SELECTIVITY; ALLOSTERIC INTERACTIONS; DOPAMINE-D-2 RECEPTORS; SUBUNIT DISSOCIATION; PARKINSONS-DISEASE AB Two concepts are gaining increasing acceptance in G protein-coupled receptor (GPCR) pharmacology: (i) pre-coupling of GPCRs with their preferred signaling molecules, and (ii) GPCR oligomerization. This is begging for the introduction of new models such as GPCR oligomer-containing signaling complexes with GPCR homodimers as functional building blocks. This model favors the formation of GPCR heterotetramers - heteromers of homodimers coupled to their cognate G protein. The GPCR heterotetramer offers an optimal framework for a canonical antagonistic interaction between activated Gs and Gi proteins, which can simultaneously bind to their respective preferred receptors and to adenylyl cyclase (AC) catalytic units. This review addresses the current evidence for pre-coupling of the various specific components that provide the very elaborate signaling machinery exemplified by the Gs-Gi-AC-coupled GPCR heterotetramer. C1 NIDA, Integrat Neurobiol Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Ferre, S (reprint author), NIDA, Integrat Neurobiol Sect, Intramural Res Program, NIH, Triad Technol Bldg,333 Cassell Dr, Baltimore, MD 21224 USA. EM sferre@intra.nida.nih.gov RI Ferre, Sergi/K-6115-2014 OI Ferre, Sergi/0000-0002-1747-1779 FU National Institute on Drug Abuse FX S.F. is in debt to Prof. Carme Lluis for countless scientific discussions, and to whom this article is dedicated. Work supported by the intramural funds of the National Institute on Drug Abuse. NR 57 TC 18 Z9 19 U1 5 U2 14 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD MAR PY 2015 VL 36 IS 3 BP 145 EP 152 DI 10.1016/j.tips.2015.01.002 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CE7SW UT WOS:000352043100002 PM 25704194 ER PT J AU Hoque, A Yao, S Till, C Kristal, AR Goodman, PJ Hsing, AW Tangen, CM Platz, EA Stanczyk, FZ Reichardt, JKV vanBokhoven, A Neuhouser, ML Santella, RM Figg, WD Price, DK Parnes, HL Lippman, SM Ambrosone, CB Thompson, IM AF Hoque, Ashraful Yao, Song Till, Cathee Kristal, Alan R. Goodman, Phyllis J. Hsing, Ann W. Tangen, Catherine M. Platz, Elizabeth A. Stanczyk, Frank Z. Reichardt, Juergen K. V. vanBokhoven, Adrie Neuhouser, Marian L. Santella, Regina M. Figg, William D. Price, Douglas K. Parnes, Howard L. Lippman, Scott M. Ambrosone, Christine B. Thompson, Ian M. TI Effect of Finasteride on Serum Androstenedione and Risk of Prostate Cancer Within the Prostate Cancer Prevention Trial: Differential Effect on High- and Low-grade Disease SO UROLOGY LA English DT Article ID BINDING GLOBULIN CONCENTRATIONS; MALE PSEUDOHERMAPHRODITISM; TESTOSTERONE; HORMONES AB OBJECTIVE To evaluate the effect of finasteride on serum androst-4-ene-3,17-dione (androstenedione) and its association with prostate cancer risk among subjects who participated in the Prostate Cancer Prevention Trial. METHODS We analyzed serum androstenedione levels in 317 prostate cancer cases and 353 controls, nested in the Prostate Cancer Prevention Trial, a randomized placebo-controlled trial that found finasteride decreased prostate cancer risk. Androstenedione is the second most important circulating androgen in men besides testosterone and also a substrate for 5 alpha-reductase enzyme. RESULTS We observed a 22% increase in androstenedione levels compared with the baseline values in subjects who were treated with finasteride for 3 years. This significant increase did not vary by case-control status. Adjusted odds ratio and 95% confidence interval for the third tertile of absolute change in androstenedione levels compared with the first tertile were 0.42 (95% confidence interval, 0.19-0.94) for low-grade (Gleason score <7) cases. Similar results were observed when analyzed using percent change. There were no significant associations between serum androstenedione levels and the risk of high-grade disease. CONCLUSION The results of this nested case-control study confirm that finasteride blocks the conversion of testosterone to dihydrotestosterone (DHT) and of androstenedione to 5 alpha-androstanedione-3,17-dione, which also leads to the reduction of DHT formation. This decrease in DHT may help reduce the risk of low-grade prostate cancer in men. Our data on a differential effect of androstenedione also suggest that some high-grade prostate cancers may not require androgen for progression. (C) 2015 Elsevier Inc. C1 [Hoque, Ashraful] Univ Texas MD Anderson Canc Ctr, Dept Clin Canc Prevent, Houston, TX 77030 USA. Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. Fred Hutchinson Canc Res Ctr, Canc Prevent Program, Seattle, WA 98104 USA. Canc Prevent Inst Calif, Fremont, CA USA. Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. Univ So Calif, Dept Obstet & Gynecol, Los Angeles, CA 90089 USA. Univ So Calif, Dept Prevent Med, Los Angeles, CA 90089 USA. James Cook Univ, Sch Pharm & Mol Sci, Townsville, Qld 4811, Australia. Univ Colorado, Dept Pathol, Aurora, CO USA. Columbia Univ, Mailman Sch Publ Hlth, Dept Environm Hlth Sci, New York, NY USA. NCI, Genitourinary Malignancies Branch, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Prostate & Urol Canc Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. Univ Calif San Diego, Moores Canc Ctr, San Diego, CA 92103 USA. Univ Texas Hlth Sci Ctr San Antonio, Dept Urol, San Antonio, TX 78229 USA. RP Hoque, A (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Clin Canc Prevent, 1155 Herman P Pressler,CPB6 3494,Unit 1360, Houston, TX 77030 USA. EM ahoque@mdanderson.org RI Figg Sr, William/M-2411-2016; OI Reichardt, Juergen/0000-0001-6458-2773 FU National Cancer Institute [P01 CA108964, R03 CA117490, CA37429] FX This work is funded in part by grants P01 CA108964 (Ashraful Hoque, Alan R. Kristal, Phyllus J. Goodman, Ann W. Hsing, Catherine M. Tangen, Elizabeth A. Platz, Juergen K.V. Reichardt, Marian L. Neuhouser, Regina M. Santella, William D. Figg, Douglas K. Price, Scott M. Lippman, Christine B. Ambrosone, and Ian M. Thompson); R03 CA117490 (Ashraful Hoque); and CA37429 (Ian M. Thompson and Catherine M. Tangen) from the National Cancer Institute. NR 13 TC 2 Z9 2 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 EI 1527-9995 J9 UROLOGY JI Urology PD MAR PY 2015 VL 85 IS 3 BP 616 EP 620 DI 10.1016/j.urology.2014.11.024 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA CE6JJ UT WOS:000351942400034 PM 25733274 ER PT J AU Tofoleanu, F Brooks, BR Buchete, NV AF Tofoleanu, Florentina Brooks, Bernard R. Buchete, Nicolae-Viorel TI Modulation of Alzheimer's A beta Protofilament-Membrane Interactions by Lipid Headgroups SO ACS CHEMICAL NEUROSCIENCE LA English DT Article DE Alzheimer's disease; amyloid beta-peptide fibrils; A beta fibrillar oligomers; molecular dynamics simulations; toxic amyloid channels; amyloid peptide-lipid membrane interactions ID MOLECULAR-DYNAMICS SIMULATION; ISLET AMYLOID POLYPEPTIDE; EXPERIMENTAL CONSTRAINTS; PROTEIN OLIGOMERS; FIBRIL FORMATION; PEPTIDE; AGGREGATION; BINDING; MODEL; TOXICITY AB The molecular pathogenesis of Alzheimer's POPE disease (AD) is complex and sparsely understood. The relationship between AD's amyloid beta (A beta) peptides and neuronal membranes is central to A beta's cytotoxicity and is directly modulated by the composition of the lipid headgroups. Molecular studies of the insertion of model A beta(40) protofilaments in lipid bilayers revealed strong interactions that affect the structural integrity of both the membranes and the ordered amyloid aggregates. In particular, electrostatics plays a crucial role in the interaction between A beta protofilaments and palmytoil-oleoyl-phosphatidylethanolamine (POPE) lipids, a common component of neuronal plasma membranes. Here, we use all-atom molecular dynamics and steered molecular dynamics simulations to systematically compare the effects that POPE and palmytoil-oleoyl-phosphatidylcholine (POPC) headgroups have on the A beta-lipid interactions. We find that A beta protofilaments exhibit weaker electrostatic interactions with POPC headgroups and establish significantly shorter-lived contacts with the POPC bilayer. This illustrates the crucial yet complex role of electrostatic and hydrogen bonding interactions in modulating the anchoring and insertion of A beta peptides into lipid bilayers. Our study reveals the atomistic details behind the barrier created by the lipid headgroup region in impeding solution-aggregated fibrillar oligomers to spontaneously insert into POPC bilayers, in contrast to the POPE case. While the biological reality is notoriously more complex (e.g., including other factors such as cholesterol), our results evidence a simple experimentally and computationally testable case for probing the factors that control the insertion of A beta oligomeric aggregates in neuronal cell membranes-a process central to their neurotoxicity. C1 [Tofoleanu, Florentina; Brooks, Bernard R.] NHLBI, Lab Computat Biol, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. [Buchete, Nicolae-Viorel] Univ Coll Dublin, Sch Phys & Complex, Dublin 4, Ireland. [Buchete, Nicolae-Viorel] Univ Coll Dublin, Adapt Syst Lab, Dublin 4, Ireland. RP Buchete, NV (reprint author), Univ Coll Dublin, Sch Phys & Complex, Dublin 4, Ireland. EM buchete@ucd.ie FU Biowulf Linux cluster at the National Institutes of Health, USA; intramural research program of the National Heart, Lung and Blood Institute, National Institutes of Health; Irish Research Council FX The authors thank the DJEI/DES/SFI/HEA Irish Centre for High-End Computing (ICHEC) and the Biowulf Linux cluster at the National Institutes of Health, USA (http://biowulf.nih. gov), for the provision of computational facilities and support. F.T. and B.R.B. were supported by the intramural research program of the National Heart, Lung and Blood Institute, National Institutes of Health. F.T. and N.V.B are also grateful for financial support from the Irish Research Council. NR 64 TC 15 Z9 15 U1 1 U2 41 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-7193 J9 ACS CHEM NEUROSCI JI ACS Chem. Neurosci. PD MAR PY 2015 VL 6 IS 3 BP 446 EP 455 DI 10.1021/cn500277f PG 10 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Neurosciences SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Neurosciences & Neurology GA CD9LN UT WOS:000351419900013 PM 25581460 ER PT J AU Zou, HX Limpert, AS Zou, JW Dembo, A Lee, PS Grant, D Ardecky, R Pinkerton, AB Magnuson, GK Goldman, ME Rong, J Teriete, P Sheffler, DJ Reed, JC Cosford, NDP AF Zou, Haixia Limpert, Allison S. Zou, Jiwen Dembo, Anna Lee, Pooi-San Grant, Daniel Ardecky, Robert Pinkerton, Anthony B. Magnuson, Gavin K. Goldman, Mark E. Rong, Juan Teriete, Peter Sheffler, Douglas J. Reed, John C. Cosford, Nicholas D. P. TI Benzodiazepinone Derivatives Protect against Endoplasmic Reticulum Stress-Mediated Cell Death in Human Neuronal Cell Lines SO ACS CHEMICAL NEUROSCIENCE LA English DT Article DE Benzodiazepinone; ER stress; p38 MAPK; calcium homeostasis; neurodegeneration; thapsigargin ID AMYOTROPHIC-LATERAL-SCLEROSIS; MITOCHONDRIA CALCIUM CYCLE; ER STRESS; MOTOR-NEURONS; SPINAL-CORD; DISEASE; DYSREGULATION; DYNAMICS; KINASE; ALS AB Endoplasmic reticulum (ER) stress causes neuronal dysfunction followed by cell death and is recognized as a feature of many neurodegenerative diseases. Using a phenotypic screen, we recently identified benzodiazepinone derivatives that reduce ER stress-mediated apoptosis in a rat neuronal progenitor cell line (CSM14.1). Herein we describe how structure activity relationship (SAR) studies around these screening hits led to compounds that display robust cytoprotective activity against thapsigargin-induced ER stress in SH-SYSY and H4 human neuronal cell lines. We demonstrate that the most potent of these derivatives, compound 4hh, inhibits the activation of p38 MAP kinase (p38) and c-Jun N-terminal kinase (JNK), protein kinases that are downstream signal effectors of the unfolded protein response (UPR). Compound 4hh specifically protects against thapsigargin-induced cell death and displays no protection against other insults known to induce cellular stress or activate p38. However, compound 4lith provides moderate inhibition of p38 activity stimulated by compounds that disrupt calcium homeostasis. Our data indicate that probe compound 4hh is a valuable small molecule tool that can be used to investigate the effects of ER stress on human neurons. This approach may provide the basis for the future development of therapeutics for the treatment of neurodegenerative diseases. C1 [Zou, Haixia; Limpert, Allison S.; Dembo, Anna; Lee, Pooi-San; Grant, Daniel; Goldman, Mark E.; Rong, Juan; Teriete, Peter; Sheffler, Douglas J.; Reed, John C.; Cosford, Nicholas D. P.] Sanford Burnham Med Res Inst, NCI, Designated Canc Ctr, Cell Death & Survival Networks Res Program, La Jolla, CA 92037 USA. [Zou, Jiwen; Ardecky, Robert; Pinkerton, Anthony B.; Magnuson, Gavin K.; Cosford, Nicholas D. P.] Sanford Burnham Med Res Inst, Conrad Prebys Ctr Chem Gen, La Jolla, CA 92037 USA. RP Cosford, NDP (reprint author), Sanford Burnham Med Res Inst, NCI, Designated Canc Ctr, Cell Death & Survival Networks Res Program, 10901 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM ncosford@sanfordburnham.org OI Pinkerton, Anthony/0000-0003-4571-152X FU NIH [HG005033]; Department of Defense Amyotrophic Lateral Sclerosis Research Program [W81XWH-12-1-0373]; Janssen Research and Development LLC FX This work was supported by NIH Grant HG005033 (NIGMS/NIMH), the Department of Defense Amyotrophic Lateral Sclerosis Research Program under Award Number W81XWH-12-1-0373 (to N.D.P.C.), and Janssen Research and Development LLC. NR 30 TC 2 Z9 2 U1 1 U2 13 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-7193 J9 ACS CHEM NEUROSCI JI ACS Chem. Neurosci. PD MAR PY 2015 VL 6 IS 3 BP 464 EP 475 DI 10.1021/cn500297v PG 12 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Neurosciences SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Neurosciences & Neurology GA CD9LN UT WOS:000351419900015 PM 25544056 ER PT J AU Chen, X Choo, H Huang, XP Yang, XB Stone, O Roth, BL Jin, J AF Chen, Xin Choo, Hyunah Huang, Xi-Ping Yang, Xiaobao Stone, Orrin Roth, Bryan L. Jin, Jian TI The First Structure-Activity Relationship Studies for Designer Receptors Exclusively Activated by Designer Drugs SO ACS CHEMICAL NEUROSCIENCE LA English DT Article DE DREADD; CNO; hM3Dq; SAR; neuronal activation; perlapine ID CLOZAPINE-N-OXIDE; UBER SIEBENGLIEDRIGE HETEROCYCLEN; SEROTONERGIC NEURON INHIBITION; PROTEIN-COUPLED RECEPTORS; BODY-TEMPERATURE CONTROL; GENETIC IDENTIFICATION; ANTIPSYCHOTIC-DRUGS; CHEMOGENETIC TOOLS; NETWORK ACTIVITY; REMOTE-CONTROL AB Over the past decade, two independent technologies have emerged and been widely adopted by the neuroscience community for remotely controlling neuronal activity: optogenetics which utilize engineered channelrhodopsin and other opsins, and chemogenetics which utilize engineered G protein-coupled receptors (Designer Receptors Exclusively Activated by Designer Drugs (DREADDs)) and other orthologous ligand receptor pairs. Using directed molecular evolution, two types of DREADDs derived from human muscarinic acetylcholine receptors have been developed: hM3Dq which activates neuronal firing, and hM4Di which inhibits neuronal firing. Importantly, these DREADDs were not activated by the native ligand acetylcholine (ACh), but selectively activated by dozapine N-oxide (CNO), a pharmacologically inert ligand. CNO has been used extensively in rodent models to activate DREADDs, and although CNO is not subject to significant metabolic transformation in mice, a small fraction of CNO is apparently metabolized to clozapine in humans and guinea pigs, lessening the translational potential of DREADDs. To effectively translate the DREADD technology, the next generation of DREADD agonists are needed and a thorough understanding of structure activity relationships (SARs) of DREADDs is required for developing such ligands. We therefore conducted the first SAR studies of hM3Dq. We explored multiple regions of the scaffold represented by CNO, identified interesting SAR trends, and discovered several compounds that are very potent hM3Dq agonists but do not activate the native human M3 receptor (hM3). We also discovered that the approved drug perlapine is a novel hM3Dq agonist with >10 000-fold selectivity for hM3Dq over hM3. C1 [Chen, Xin; Yang, Xiaobao; Jin, Jian] Icahn Sch Med Mt Sinai, Dept Struct & Chem Biol, New York, NY 10029 USA. [Chen, Xin; Yang, Xiaobao; Jin, Jian] Icahn Sch Med Mt Sinai, Dept Oncol Sci, New York, NY 10029 USA. [Chen, Xin; Yang, Xiaobao; Jin, Jian] Icahn Sch Med Mt Sinai, Dept Pharmacol, New York, NY 10029 USA. [Chen, Xin; Yang, Xiaobao; Jin, Jian] Icahn Sch Med Mt Sinai, Dept Syst Therapeut, New York, NY 10029 USA. [Choo, Hyunah; Huang, Xi-Ping; Stone, Orrin] Univ N Carolina, Sch Med, Dept Pharmacol, NIMH,Psychoact Drug Screening Program, Chapel Hill, NC 27599 USA. [Choo, Hyunah] Korea Inst Sci & Technol, Ctr Neuromed, Seoul 136791, South Korea. RP Roth, BL (reprint author), Univ N Carolina, Sch Med, Dept Pharmacol, NIMH,Psychoact Drug Screening Program, Chapel Hill, NC 27599 USA. EM bryan_roth@med.unc.edu; jian.jin@mssm.edu RI Roth, Bryan/F-3928-2010 FU NIH [U01MH105892]; Korea NRF grant [NRF-2013-R1A1A2A10009907] FX This work was supported by the NIH Grant U01MH105892 (to B.L.R. and J.J.) and Korea NRF grant NRF-2013-R1A1A2A10009907 (to H.C.). NR 50 TC 10 Z9 10 U1 3 U2 21 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-7193 J9 ACS CHEM NEUROSCI JI ACS Chem. Neurosci. PD MAR PY 2015 VL 6 IS 3 BP 476 EP 484 DI 10.1021/cn500325v PG 9 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Neurosciences SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Neurosciences & Neurology GA CD9LN UT WOS:000351419900016 PM 25587888 ER PT J AU Kyle, TL Horigian, VE Tross, S Gruber, VA Pereyra, M Mandler, RN Feaster, DJ Metsch, LR AF Kyle, Tiffany L. Horigian, Viviana E. Tross, Susan Gruber, Valerie A. Pereyra, Margaret Mandler, Raul N. Feaster, Daniel J. Metsch, Lisa R. TI Uptake of HIV Testing in Substance Use Disorder Treatment Programs That Offer On-Site Testing SO AIDS AND BEHAVIOR LA English DT Article DE HIV testing; HIV screening; Substance use; Community treatment programs ID PREVENTION EFFORTS; UNITED-STATES; DRUG-USERS; INFECTION; ASSOCIATIONS; BEHAVIORS; UNAWARE; AWARE AB Increasing rates of HIV testing within substance use disorder (SUD) treatment clients is an important public health strategy for reducing HIV transmission rates. The present study examined uptake of HIV testing among 1,224 clients in five SUD treatment units that offered on-site testing in Florida, New York, and California. Nearly one-third (30 %) of the participants, who had not previously tested positive, reported not having been tested for HIV within the past 12 months. Women, African Americans, and injection drug users had a higher likelihood of having been tested within the past 12 months. The SUD treatment program was the most frequently identified location of participants' last HIV test. Despite the availability of free, on-site testing, a substantial proportion of clients were not tested, suggesting that strategies to increase uptake of testing should include addressing barriers not limited to location and cost. C1 [Kyle, Tiffany L.] Aspire Hlth Partners, Orlando, FL 32804 USA. [Horigian, Viviana E.; Pereyra, Margaret; Feaster, Daniel J.; Metsch, Lisa R.] Univ Miami, Miller Sch Med, Dept Publ Hlth Sci, Miami, FL 33136 USA. [Tross, Susan] Columbia Univ, Med Ctr, Dept Psychiat, HIV Ctr Clin & Behav Studies, New York, NY 10032 USA. [Tross, Susan] Columbia Univ, Med Ctr, Substance Use Res Ctr, New York, NY 10032 USA. [Gruber, Valerie A.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94110 USA. [Gruber, Valerie A.] San Francisco Gen Hosp, San Francisco, CA 94110 USA. [Pereyra, Margaret; Metsch, Lisa R.] Columbia Univ, Mailman Sch Publ Hlth, Dept Sociomed Sci, New York, NY USA. [Mandler, Raul N.] NIDA, Ctr Clin Trials Network, Bethesda, MD 20892 USA. RP Kyle, TL (reprint author), Aspire Hlth Partners, 5151 Adanson St, Orlando, FL 32804 USA. EM tiffany.kyle@aspirehp.org FU National Drug Abuse Treatment Clinical Trials Network (NIDA CTN) [U10 DA13720, U10 DA13035-09, 5U10DA015815-10] FX This research was supported by the National Drug Abuse Treatment Clinical Trials Network (NIDA CTN), (U10 DA13720, U10 DA13035-09, 5U10DA015815-10). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the views of the funding agencies or the U.S. government. The authors gratefully acknowledge Carmen Rosa from the Center for the Clinical Trials Network, National Institute of Drug Abuse for her support of this project; the staff at the participating programs and nodes, particularly Cheri Hansen, Sara Clingerman, Evie Perez, Remy Hammel, Alexandra Reyes, Janet Lerner, and Jennifer Lima; and the clients at the programs that participated in this study. NR 29 TC 2 Z9 2 U1 3 U2 3 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 EI 1573-3254 J9 AIDS BEHAV JI AIDS Behav. PD MAR PY 2015 VL 19 IS 3 BP 536 EP 542 DI 10.1007/s10461-014-0864-2 PG 7 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA CD5RZ UT WOS:000351146900014 PM 25074737 ER PT J AU Butler, J Fonarow, GC O'Connor, C Adams, K Bonow, RO Cody, RJ Collins, SP Dunnmon, P Dinh, W Fiuzat, M Georgiopoulou, VV Grant, S Kim, SY Kupfer, S Lefkowitz, M Mentz, RJ Misselwitz, F Pitt, B Roessig, L Schelbert, E Shah, M Solomon, S Stockbridge, N Yancy, C Gheorghiade, M AF Butler, Javed Fonarow, Gregg C. O'Connor, Christopher Adams, Kirkwood Bonow, Robert O. Cody, Robert J. Collins, Sean P. Dunnmon, Preston Dinh, Wiffried Fiuzat, Mona Georgiopoulou, Vasiliki V. Grant, Stephen Kim, So-Young Kupfer, Stuart Lefkowitz, Martin Mentz, Robert J. Misselwitz, Frank Pitt, Bertram Roessig, Lothar Schelbert, Erik Shah, Monica Solomon, Scott Stockbridge, Norman Yancy, Clyde Gheorghiade, Mihai TI Improving cardiovascular clinical trials conduct in the United States: Recommendation from clinicians, researchers, sponsors, and regulators SO AMERICAN HEART JOURNAL LA English DT Article ID HEART-FAILURE; BLOOD INSTITUTE; NATIONAL HEART; OUTCOMES; GUIDELINES; TOLVAPTAN; BARRIERS; REGION; LUNG AB Advances in medical therapies leading to improved patient outcomes are in large part related to successful conduct of clinical trials that offer critical information regarding the efficacy and safety of novel interventions. The conduct of clinical trials in the United States, however, continues to face increasing challenges with recruitment and retention. These trends are paralleled by an increasing shift toward more multinational trials where most participants are enrolled in countries outside the United States, bringing into question the generalizability of the results to the American population. This manuscript presents the perspectives and recommendations from clinicians, researchers, sponsors, and regulators who attended a meeting facilitated by the Food and Drug Administration to improve upon the current clinical trial trends in the United States. C1 [Butler, Javed] SUNY Stony Brook, Div Cardiol, Stony Brook, NY 11794 USA. [Fonarow, Gregg C.] Univ Calif Los Angeles, Los Angeles, CA USA. [O'Connor, Christopher; Fiuzat, Mona; Mentz, Robert J.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. [Adams, Kirkwood] Univ N Carolina, Chapel Hill, NC USA. [Bonow, Robert O.; Gheorghiade, Mihai] Northwestern Univ, Feinberg Sch Med, Ctr Cardiovasc Innovat, Chicago, IL 60611 USA. [Cody, Robert J.] Janssen Pharmaceut, Cardiovasc & Metab, Raritan, NJ USA. [Collins, Sean P.] Vanderbilt Univ, Nashville, TN 37235 USA. [Dunnmon, Preston; Grant, Stephen; Stockbridge, Norman] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Dinh, Wiffried] Witten Univ, Dept Cardiol, Witten, Germany. [Dinh, Wiffried] Bayer Pharma AG, Clin Sci, Global Drug Discovery, Berlin, Germany. [Georgiopoulou, Vasiliki V.] Emory Univ, Emory Cardiovasc Clin Res Inst, Atlanta, GA 30322 USA. [Kim, So-Young; Misselwitz, Frank; Roessig, Lothar] Bayer HealthCare, Global Clin Dev, Wuppertal, Germany. [Kupfer, Stuart] Takeda Pharmaceut Int, Deerfield, IL USA. [Lefkowitz, Martin] Novartis Pharmaceut Inc, E Hanover, NJ USA. [Pitt, Bertram] Univ Michigan, Div Cardiol, Sch Med, Ann Arbor, MI USA. [Schelbert, Erik] Univ Pittsburgh, Med Ctr, Inst Heart & Vasc, Pittsburgh, PA USA. [Shah, Monica] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Solomon, Scott] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. [Yancy, Clyde] Northwestern Univ, Dept Med, Div Cardiol, Feinberg Sch Med, Chicago, IL 60611 USA. RP Butler, J (reprint author), SUNY Stony Brook, Div Cardiol, Hlth Sci Ctr, T-16,Room 080, Stony Brook, NY 11794 USA. EM javed.butler@stonybrookmedicine.edu OI Schelbert, Erik/0000-0003-0356-4437 FU National Institutes of Health; European Union; Health Resources Service Administration; Agency for Healthcare research and Quality; ResMed corporation; Otsuka; Roche Diagnostics; Amgen; Novartis Critical Diagnostics; Cardiorentis; Cardioxyl; Sorbent; Covis Pharmaceuticals; Res Med corporation; Gilead Sciences; Bayer; Novartis FX Authors' Conflict of Interest: Javed Butler reports research support from National Institutes of Health, European Union, and Health Resources Service Administration and is consultant to Amgen, Bayer, BG Medicine, Cardiocell, Celladon, GE Healthcare, Medtronic, Novartis, Ono Phrama, Otsuka, Takeda, Trevena, and Zensun. Gregg C. Fonarow has received research funding by the National Institutes of Health, Agency for Healthcare research and Quality, and has served as a consultant for Amgen, Bayer, Gambro, Janssen, Novartis, Medtronic, and Medicines Company. Christopher O'Connor has received researcg funding by ResMed corporation, Otsuka, and Roche Diagnostics and has served as a consultant for ResMed corporation. Kirkwood Adams has received research funding by Amgen, Roche Diagnostics, Novartis Critical Diagnostics, Otsuka, Cardiorentis, Cardioxyl, Sorbent, and Covis Pharmaceuticals and has served as consultant for Covis Pharmaceuticals. Robert O. Bonow has no relevant relationships. Robert J. Cody is an employee of Janssen R&D. Sean P. Collins has served as a consultant for Novartis, Radiometer, Medtronic, The Medicines Company, Trevena, and Thermo-Fisher Scientific. Preston Dunnmon has no relationships elevant to the contents of this manuscript. Wilfried Dinh is an employee of Bayer HealthCare. Mona Firuzat has received research funding by Res Med corporation, Otsuka, and Roche Diagnostics and has served as a consultant for Res Med corporation, Novartis, and Roche Diagnostics. Vasiliki V. Georgiopoulou has no relationships relevant to the contents of this manuscript to disclose. Stephen Grant has no relationships relevant to this manuscript. So-Young Kim is an employee of Bayer HealthCare. Stuart Kupfer is an employee of Takeda. Martin Lefkowitz is an employee of Novartis. Robert J. Mentz has received honoraria from ResMed, Thoratec, Novartis, and BristolMyers Squibb and research support from Gilead Sciences. Frank Misselwitz is an employee of and owns stock for Bayer HealthCare. Bertram Pitt has served as a consultant for Pfizer, Bayer, Relypsa, Stealth Peptides, and Mesoblast. Lothar Roessig is an employee of Bayer HealthCare. Erik Schelbert has received a Prohance contrast as a gift from Bracco for research. Monica Shah has no relationships relevant to the contents of this manuscript. Scott Solomon has received research support from and has served as a consultant for Novartis and Bayer. Norman Stockbridge has no relationships relevant to this manuscript. Clyde Yancy has no relationships relevant to this manuscript. Mihai Gheorghiade reports relationships with Abbott Laboratories, Astellas, AstraZeneca, Bayer Schering Pharma AG, Cardiorentis Ltd, CorThera, Cytokinetics, CytoPherx, Inc, DebioPharm S.A., Errekappa. Terapeutici, GlaxoSmithKline, Ikaria, Intersection Medical Inc, Johnson & Johnson, Medtronic, Merck, Novartis Pharma AG, Ono Parmaceuticals USA, Otsuka Pharmaceuticals, Palatin Technologies, Pericor Therapeutics, Protein Design Laboratories, Sanofi-Aventis, Sigma Tau, Solvay Pharmaceuticals, Sticares InterACT, Takeda Pharmaceuticals North America, Inc and Trevena Therapeutics. NR 39 TC 10 Z9 10 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 EI 1097-5330 J9 AM HEART J JI Am. Heart J. PD MAR PY 2015 VL 169 IS 3 BP 305 EP 314 DI 10.1016/j.ahj.2014.12.001 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CE0ID UT WOS:000351486800001 PM 25728719 ER PT J AU Mohandas, R Segal, M Srinivas, TR Johnson, BD Wen, X Handberg, EM Petersen, JW Sopko, G Merz, CNB Pepine, CJ AF Mohandas, Rajesh Segal, Mark Srinivas, Titte R. Johnson, B. Delia Wen, Xuerong Handberg, Eileen M. Petersen, John W. Sopko, George Merz, C. Noel Bairey Pepine, Carl J. TI Mild renal dysfunction and long-term adverse outcomes in women with chest pain: Results from the National Heart, Lung, and Blood Institute-sponsored Women's Ischemia Syndrome Evaluation (WISE) SO AMERICAN HEART JOURNAL LA English DT Article ID CHRONIC KIDNEY-DISEASE; GLOMERULAR-FILTRATION-RATE; CORONARY-ARTERY-DISEASE; ATHEROSCLEROTIC VASCULAR-DISEASE; CARDIOVASCULAR OUTCOMES; MYOCARDIAL-INFARCTION; POSTMENOPAUSAL WOMEN; INSUFFICIENCY; EVENTS; RISK AB Background Chronic kidney disease (CKD) is associated with accelerated atherosclerosis and adverse cardiovascular outcomes, but mechanisms are unclear. We hypothesized that mild CKD independently predicts adverse outcomes in women with symptoms and signs of ischemia. Methods We categorized 876 women from the Women's lschemia Syndrome Evaluation cohort according to estimated glomerular filtration rate (eGFR) (eGFR >= 90 mL/min per 1.73 m(2) [normal], 60-89 mL/min per 1.73 m(2) [mild CKD], mL/min per 1.73 m(2) [severe CKD]). Time to death from all-cause and cardiovascular causes and major adverse outcomes were assessed by multivariate regression adjusted for baseline covariates. Results Obstructive coronary artery disease (CAD) was present only in few patients (39%). Even after adjusting for CAD severity, renal function remained a strong independent predictor of all-cause and cardiac mortality (P < .001). Every 10-unit decrease in eGFR was associated with a 14% increased risk of all-cause mortality (adjusted hazard ratio [AHR] 1.14 [1.08-1.20], P < .0001), 16% increased risk of cardiovascular mortality (AHR 1.16 [1.09-1.23], P < .0001), and 9% increased risk of adverse cardiovascular events (AHR 1.09 [1.03-1.15], P = .002). Conclusions Even mild CKD is a strong independent predictor of all-cause and cardiac mortality in women with symptoms/signs of ischemia, regardless of underlying obstructive CAD severity, underscoring the need to better understand the interactions between ischemic heart disease and CKD. C1 [Mohandas, Rajesh; Segal, Mark; Srinivas, Titte R.; Wen, Xuerong] Univ Florida, Div Nephrol Hypertens & Transplantat, Gainesville, FL 32610 USA. [Mohandas, Rajesh; Segal, Mark] North Florida South Georgia Vet Hlth Syst, Nephrol & Hypertens Sect, Gainesville, FL USA. [Srinivas, Titte R.] Med Univ S Carolina, Charleston, SC 29425 USA. [Johnson, B. Delia] Univ Pittsburgh, Pittsburgh, PA USA. [Handberg, Eileen M.; Petersen, John W.; Pepine, Carl J.] Univ Florida, Div Cardiovasc Med, Gainesville, FL 32610 USA. [Sopko, George] NIH, Bethesda, MD 20892 USA. [Merz, C. Noel Bairey] Cedars Sinai Med Ctr, Barbra Streisand Womens Heart Ctr, Los Angeles, CA 90048 USA. RP Pepine, CJ (reprint author), Univ Florida, Div Cardiovasc Med, 1600 SW Archer Rd,POB 100277, Gainesville, FL 32610 USA. EM Carl.Pepine@medicine.ufl.edu OI Mohandas, Rajesh/0000-0002-4430-8678 FU NCATS NIH HHS [UL1 TR000064, UL1 TR001427]; NHLBI NIH HHS [N01 HV068163, R01 HL090957, U01 HL064924] NR 25 TC 3 Z9 4 U1 0 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 EI 1097-5330 J9 AM HEART J JI Am. Heart J. PD MAR PY 2015 VL 169 IS 3 BP 412 EP 418 DI 10.1016/j.ahj.2014.12.010 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CE0ID UT WOS:000351486800014 PM 25728732 ER PT J AU Spitz, MR Lam, TK Schully, SD Khoury, MJ AF Spitz, Margaret R. Lam, Tram Kim Schully, Sheri D. Khoury, Muin J. TI RE: "THE NEXT GENERATION OF LARGE-SCALE EPIDEMIOLOGIC RESEARCH: IMPLICATIONS FOR TRAINING CANCER EPIDEMIOLOGISTS" REPLY SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Letter C1 [Spitz, Margaret R.] Baylor Coll Med, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. [Lam, Tram Kim; Schully, Sheri D.; Khoury, Muin J.] NCI, Epidemiol & Genom Res Program, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Khoury, Muin J.] Ctr Dis Control & Prevent, Off Publ Hlth Genom, Atlanta, GA USA. RP Spitz, MR (reprint author), Baylor Coll Med, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. EM spitz@bcm.edu NR 6 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 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD MAR 1 PY 2015 VL 181 IS 5 BP 361 EP 361 DI 10.1093/aje/kwv019 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CE0PR UT WOS:000351507100012 PM 25698647 ER PT J AU Horton, AL Lai, YL Rouse, DJ Spong, CY Leveno, KJ Varner, MW Mercer, BM Iams, JD Wapner, RJ Sorokin, Y Thorp, JM Ramin, SM Malone, FD O'Sullivan, MJ Hankins, GDV Caritis, SN AF Horton, Amanda L. Lai, Yinglei Rouse, Dwight J. Spong, Catherine Y. Leveno, Kenneth J. Varner, Michael W. Mercer, Brian M. Iams, Jay D. Wapner, Ronald J. Sorokin, Yoram Thorp, John M. Ramin, Susan M. Malone, Fergal D. O'Sullivan, Mary J. Hankins, Gary D. V. Caritis, Steve N. CA Eunice Kennedy Shriver Natl Inst TI Effect of Magnesium Sulfate Administration for Neuroprotection on Latency in Women with Preterm Premature Rupture of Membranes SO AMERICAN JOURNAL OF PERINATOLOGY LA English DT Article DE latency; magnesium sulfate; neuroprotection; preterm premature rupture of membranes ID RANDOMIZED CONTROLLED-TRIAL; MANAGEMENT; BIRTH; ANTIBIOTICS; THERAPY AB ObjectiveThis study aims to evaluate whether magnesium sulfate administration for neuroprotection prolongs latency in women with preterm premature rupture of membranes (PPROM) between 24 and 31(6/7) weeks' gestation. Study DesignThis is a secondary analysis of a randomized controlled trial of magnesium sulfate for prevention of cerebral palsy. Gravid women with a singleton pregnancy between 24 and 31(6/7) weeks' gestation with PPROM without evidence of labor were randomized to receive magnesium sulfate, administered intravenously as a 6-g bolus followed by a constant infusion of 2g per hour up to 12 hours, or placebo. Maternal outcomes for this analysis were delivery in less than 48 hours and in less than 7 days from randomization. Neonatal outcomes included a composite of respiratory distress syndrome, interventricular hemorrhage grades 3 or 4, periventricular leukomalacia, sepsis, necrotizing enterocolitis, retinopathy of prematurity, or death. ResultsA total of 1,259 women were included. The rate of delivery<48 hours was not different in the magnesium sulfate and the placebo groups (22.2 and 20.7%, p=0.51). Delivery<7 days was similar between groups (55.4 and 51.4%, p=0.16). Median latency was also similar between groups (median [interquartile range], 6.0 days [range, 2.4-13.8 days] and 6.6 days [range, 2.4-15.1 days], p=0.29). Composite neonatal outcomes did not differ between groups. ConclusionMagnesium sulfate administration given for neuroprotection in women with a singleton gestation with PPROM and without labor before 32 weeks does not impact latency. C1 [Horton, Amanda L.] NorthShore Univ Hlth Syst, Dept Obstet & Gynecol, Evanston, IL USA. [Lai, Yinglei] George Washington Univ, Ctr Biostat, Dept Obstet & Gynecol, Washington, DC USA. [Rouse, Dwight J.] Univ Alabama Birmingham, Dept Obstet & Gynecol, Birmingham, AL 35294 USA. [Spong, Catherine Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Leveno, Kenneth J.] Univ Texas SW Med Ctr Dallas, Dept Obstet & Gynecol, Dallas, TX 75390 USA. [Varner, Michael W.] Univ Utah, Dept Obstet & Gynecol, Salt Lake City, UT USA. [Mercer, Brian M.] Case Western Reserve Univ, MetroHlth Med Ctr, Dept Obstet & Gynecol, Cleveland, OH 44106 USA. [Iams, Jay D.] Ohio State Univ, Dept Obstet & Gynecol, Columbus, OH 43210 USA. [Wapner, Ronald J.] Thomas Jefferson Univ, Dept Obstet & Gynecol, Philadelphia, PA 19107 USA. [Wapner, Ronald J.] Drexel Univ, Philadelphia, PA 19104 USA. [Sorokin, Yoram] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. [Thorp, John M.] Univ N Carolina, Dept Obstet & Gynecol, Chapel Hill, NC USA. [Ramin, Susan M.] Univ Texas Hlth Sci Ctr Houston, Childrens Mem Hermann Hosp, Dept Obstet & Gynecol, Houston, TX 77030 USA. [Malone, Fergal D.] Columbia Univ, Dept Obstet & Gynecol, New York, NY USA. [O'Sullivan, Mary J.] Univ Miami, Dept Obstet & Gynecol, Miami, FL USA. [Hankins, Gary D. V.] Univ Texas Med Branch, Dept Obstet & Gynecol, Galveston, TX 77555 USA. [Caritis, Steve N.] Univ Pittsburgh, Dept Obstet & Gynecol, Pittsburgh, PA USA. RP Horton, AL (reprint author), 2650 Ridge Ave, Evanston, IL 60201 USA. EM horton.alm@gmail.com RI Varner, Michael/K-9890-2013 OI Varner, Michael/0000-0001-9455-3973 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [HD27869, HD34208, HD34116, HD40544, HD27915, HD34136, HD21414, HD27917, HD27860, HD40560, HD40545, HD40485, HD40500, HD27905, HD27861, HD34122, HD40512, HD53907, HD34210, HD21410, HD36801, HD19897, MO1-RR-000080]; National Institute of Neurological Disorders and Stroke (NINDS) FX The project described was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (HD27869, HD34208, HD34116, HD40544, HD27915, HD34136, HD21414, HD27917, HD27860, HD40560, HD40545, HD40485, HD40500, HD27905, HD27861, HD34122, HD40512, HD53907, HD34210, HD21410, HD36801, and HD19897), MO1-RR-000080, and by the National Institute of Neurological Disorders and Stroke (NINDS) and does not necessarily represent the official views of the NICHD, NINDS, or the National Institutes of Health. NR 18 TC 0 Z9 0 U1 1 U2 2 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0735-1631 EI 1098-8785 J9 AM J PERINAT JI Am. J. Perinatol. PD MAR PY 2015 VL 32 IS 4 BP 387 EP 392 DI 10.1055/s-0034-1387930 PG 6 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA CE2RR UT WOS:000351664400012 PM 25241107 ER PT J AU Kiley, J Mockrin, S Lauer, M Mensah, GA Hoots, K Patel, Y Cook, NL Patterson, AP Gibbons, GH AF Kiley, James Mockrin, Stephen Lauer, Michael Mensah, George A. Hoots, Keith Patel, Yasin Cook, Nakela L. Patterson, Amy P. Gibbons, Gary H. TI NHLBI Strategic Visioning: Setting an Agenda Together for the NHLBI of 2025 SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Editorial Material ID DISEASE C1 [Kiley, James; Mockrin, Stephen; Lauer, Michael; Mensah, George A.; Hoots, Keith; Patel, Yasin; Cook, Nakela L.; Gibbons, Gary H.] NHLBI, NIH, Bethesda, MD 20892 USA. [Patterson, Amy P.] NIH, Bethesda, MD 20892 USA. RP Kiley, J (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 14 TC 3 Z9 3 U1 0 U2 3 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 MAR 1 PY 2015 VL 191 IS 5 BP 489 EP 491 DI 10.1164/rccm.201501-0194ED PG 3 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA CD1KN UT WOS:000350833900001 PM 25706106 ER PT J AU Eum, KD Seals, RM Taylor, KM Grespin, M Umbach, DM Hu, H Sandler, DP Kamel, F Weisskopf, MG AF Eum, Ki-Do Seals, Ryan M. Taylor, Kathryn M. Grespin, Matthew Umbach, David M. Hu, Howard Sandler, Dale P. Kamel, Freya Weisskopf, Marc G. TI Modification of the association between lead exposure and amyotrophic lateral sclerosis by iron and oxidative stress related gene polymorphisms SO AMYOTROPHIC LATERAL SCLEROSIS AND FRONTOTEMPORAL DEGENERATION LA English DT Article DE Amyotrophic lateral sclerosis; epidemiology; hemochromatosis; iron metabolism; oxidative stress ID X-RAY-FLUORESCENCE; HEMOCHROMATOSIS GENE; H63D POLYMORPHISM; SPORADIC ALS; IN-VIVO; HFE; CONSEQUENCES; MUTATIONS; SYSTEMS; VARIANT AB Our objective was to examine whether functional polymorphisms in hemochromatosis (HFE; H63D and C282Y), transferrin (TfC2), and glutathione-s-transferase Pi1 (GSTP1; Ile 105Val) genes modify any lead-ALS association. We measured blood lead using atomic absorption spectroscopy and bone lead - a biomarker of cumulative lead exposure - using K-shell-X-ray fluorescence in 100 neurologist-confirmed ALS cases and 194 controls, the latter recruited as part of two separate studies; all subjects lived in New England. Participants were considered variant carriers or wildtype for each polymorphism. To assess effect modification, we included cross-product terms between lead biomarkers and each polymorphism in separate adjusted polytomous logistic regression models. Compared with wild-type, the odds ratio (OR) per 15.6 mu g/g patella lead (interquartile range; IQR) was 8.24 (95% CI 0.94-72.19) times greater among C282Y variant carriers, and 0.34 (95% CI 0.15-0.78) times smaller among H63D variant carriers. Results were weaker for tibia lead. Compared with wild-type the OR per 2 mu g/dl blood lead (IQR) was 0.36 (95% CI 0.19-0.68) times smaller among H63D variant carriers, and 1.96 (95% CI 0.98-3.92) times greater among GSTP1 variant carriers. In conclusion, we found that HFE and GSTP1 genotypes modified the association between lead biomarkers and ALS. Contrasting modifi cation by the HFE polymorphisms H63D and C282Y may suggest that the modifi cation is not simply the result of increased iron. C1 [Eum, Ki-Do; Taylor, Kathryn M.; Grespin, Matthew; Weisskopf, Marc G.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02215 USA. [Seals, Ryan M.; Weisskopf, Marc G.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02215 USA. [Umbach, David M.] NIEHS, Biostat Branch, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Sandler, Dale P.; Kamel, Freya] NIEHS, Epidemiol Branch, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Hu, Howard] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON M5S 1A1, Canada. RP Weisskopf, MG (reprint author), Harvard Univ, Sch Publ Hlth, Landmark Ctr, Dept Environm Hlth Environm & Occupat Med & Epide, 401 Pk Dr,POB 15677, Boston, MA 02215 USA. EM mweissko@hsph.harvard.edu OI Hu, Howard/0000-0002-3676-2707; Kamel, Freya/0000-0001-5052-6615; Sandler, Dale/0000-0002-6776-0018 FU National Institutes of Health, National Institute of Environmental Health Sciences; Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences FX This work was supported in part by grants from the National Institutes of Health, National Institute of Environmental Health Sciences, as well as by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. NR 36 TC 4 Z9 5 U1 1 U2 4 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 2167-8421 EI 2167-9223 J9 AMYOTROPH LAT SCL FR JI Amyotroph. Lateral Scher. Frontotemp. Degenerat. PD MAR PY 2015 VL 16 IS 1-2 BP 72 EP 79 DI 10.3109/21678421.2014.964259 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA CE0WV UT WOS:000351531900012 PM 25293352 ER PT J AU Shinomiya, K Yoshida, K Tokura, K Tsukidate, E Yanagidaira, K Ito, Y AF Shinomiya, Kazufusa Yoshida, Kazunori Tokura, Koji Tsukidate, Etsuhiro Yanagidaira, Kazuhiro Ito, Yoichiro TI Countercurrent Chromatographic Separation of Proteins Using an Eccentric Coiled Column with Synchronous and Nonsynchronous Type-J Planetary Motions SO ANALYTICAL SCIENCES LA English DT Article DE Countercurrent chromatography; universal high-speed countercurrent chromatograph; eccentric coil; toroidal coil; partition efficiency; protein separation with polymer phase system ID POLYMER PHASE SYSTEMS; AQUEOUS 2-PHASE SYSTEMS; CENTRIFUGE; PURIFICATION; DESIGN AB Protein separation was performed using the high-speed countercurrent chromatograph (HSCCC) at both synchronous and nonsynchronous type-J planetary motions. The partition efficiency was evaluated with two different column configurations, eccentric coil and toroidal coil, on the separation of a set of stable protein samples including cytochrome C, myoglobin and lysozyme with a polymer phase system composed of 12.5% (w/w) polyethylene glycol 1000 and 12.5% (w/w) dibasic potassium phosphate. Better peak resolution was obtained by the eccentric coil than by the toroidal coil using either lower or upper phase as the mobile phase. The peak resolution was further improved using the eccentric coil by the nonsynchronous type-J planetary motion with the combination of 1066 rpm of column rotation and 1000 rpm of revolution. C1 [Shinomiya, Kazufusa] Nihon Univ, Sch Pharm, Funabashi, Chiba 2748555, Japan. [Yoshida, Kazunori; Tokura, Koji; Tsukidate, Etsuhiro; Yanagidaira, Kazuhiro] Nihon Univ, Coll Sci & Technol, Funabashi, Chiba 2748501, Japan. [Ito, Yoichiro] NHLBI, Lab Bioseparat Technol, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. RP Shinomiya, K (reprint author), Nihon Univ, Sch Pharm, 7-7-1 Narashinodai, Funabashi, Chiba 2748555, Japan. EM shinomiya.kazufusa@nihon-u.ac.jp FU Ministry of Education, Culture, Sports, Science and Technology of Japan FX The present study was supported in part by a grant from the Ministry of Education, Culture, Sports, Science and Technology of Japan. NR 12 TC 2 Z9 2 U1 1 U2 32 PU JAPAN SOC ANALYTICAL CHEMISTRY PI TOKYO PA 26-2 NISHIGOTANDA 1 CHOME SHINAGAWA-KU, TOKYO, 141, JAPAN SN 0910-6340 EI 1348-2246 J9 ANAL SCI JI Anal. Sci. PD MAR PY 2015 VL 31 IS 3 BP 211 EP 218 PG 8 WC Chemistry, Analytical SC Chemistry GA CE1IW UT WOS:000351566300012 PM 25765276 ER PT J AU Tranmer, M Marcum, CS Morton, FB Croft, DP de Kort, SR AF Tranmer, Mark Marcum, Christopher Steven Morton, F. Blake Croft, Darren P. de Kort, Selvino R. TI Using the relational event model (REM) to investigate the temporal dynamics of animal social networks SO ANIMAL BEHAVIOUR LA English DT Article DE animal social behaviour; event data; food sharing; jackdaw; longitudinal network; reciprocity; social network analysis; temporal network analysis ID JACKDAWS CORVUS-MONEDULA; FRAMEWORK; RECIPROCITY; PATTERNS; BEHAVIOR AB Social dynamics are of fundamental importance in animal societies. Studies on nonhuman animal social systems often aggregate social interaction event data into a single network within a particular time frame. Analysis of the resulting network can provide a useful insight into the overall extent of interaction. However, through aggregation, information is lost about the order in which interactions occurred, and hence the sequences of actions over time. Many research hypotheses relate directly to the sequence of actions, such as the recency or rate of action, rather than to their overall volume or presence. Here, we demonstrate how the temporal structure of social interaction sequences can be quantified from disaggregated event data using the relational event model (REM). We first outline the REM, explaining why it is different from other models for longitudinal data, and how it can be used to model sequences of events unfolding in a network. We then discuss a case study on the European jackdaw, Corvus monedula, in which temporal patterns of persistence and reciprocity of action are of interest, and present and discuss the results of a REM analysis of these data. One of the strengths of a REM analysis is its ability to take into account different ways in which data are collected. Having explained how to take into account the way in which the data were collected for the jackdaw study, we briefly discuss the application of the model to other studies. We provide details of how the models may be fitted in the R statistical software environment and outline some recent extensions to the REM framework. (C) 2015 The Association for the Study of Animal Behaviour. Published by Elsevier Ltd. All rights reserved. C1 [Tranmer, Mark] Univ Manchester, Social Stat, Manchester M13 9PL, Lancs, England. [Marcum, Christopher Steven] NHGRI, NIH, Bethesda, MD 20892 USA. [Morton, F. Blake] Univ Stirling, Psychol, Stirling FK9 4LA, Scotland. [Croft, Darren P.] Univ Exeter, Psychol, Exeter, Devon, England. [de Kort, Selvino R.] Manchester Metropolitan Univ, Sch Sci & Environm, Manchester M15 6BH, Lancs, England. RP Tranmer, M (reprint author), Univ Manchester, Sch Social Sci, Social Stat, Manchester M13 9PL, Lancs, England. EM mark.tranmer@manchester.ac.uk RI Croft, Darren/B-5503-2009; OI Croft, Darren/0000-0001-6869-5097; Marcum, Christopher/0000-0002-0899-6143 FU National Institutes of Health Intramural Research Program [Z01HG200335]; University of Stirling; Primate Society of Great Britain; Leverhulme Trust [RPG-17] FX Work by C.S.M. was supported by the National Institutes of Health Intramural Research Program (Z01HG200335 Koehly, PI). F.B.M thanks Professors Phyllis C. Lee and Hannah M. Buchanan-Smith for supervising the research and the University of Stirling and Primate Society of Great Britain for funding. Work by D.P.C. was supported by funding from The Leverhulme Trust (RPG-17). M.T. thanks Professor Mark Handcock (UCLA) for his help at an early stage of this research, Katie Faust (UCI) for helpful comments, and the NimBios team for organizing the meeting in Knoxville on Social Networks in March 2014. S.d.K. thanks the regulars at the Fox & Goose (Hebden Bridge) for their support. Finally, we thank the journal editor and two anonymous referees for their helpful comments. NR 43 TC 2 Z9 2 U1 3 U2 24 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0003-3472 EI 1095-8282 J9 ANIM BEHAV JI Anim. Behav. PD MAR PY 2015 VL 101 BP 99 EP 105 DI 10.1016/j.anbehav.2014.12.005 PG 7 WC Behavioral Sciences; Zoology SC Behavioral Sciences; Zoology GA CD3YR UT WOS:000351020200013 PM 26190856 ER PT J AU Phillips, SJ AF Phillips, Steven J. TI Nuclear Powered Devices: Is it Time to Revisit the Use of Nuclear Energy? SO ARTIFICIAL ORGANS LA English DT Editorial Material ID VENTRICULAR ASSIST DEVICES C1 US Dept HHS, Natl Lib Med, NIH, Bethesda, MD 20892 USA. RP Phillips, SJ (reprint author), US Dept HHS, Natl Lib Med, NIH, 6707 Democracy Blvd,Suite 510, Bethesda, MD 20892 USA. EM steven_phillips@nlm.nih.gov NR 13 TC 2 Z9 2 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0160-564X EI 1525-1594 J9 ARTIF ORGANS JI Artif. Organs PD MAR PY 2015 VL 39 IS 3 BP 201 EP 202 DI 10.1111/aor.12493 PG 2 WC Engineering, Biomedical; Transplantation SC Engineering; Transplantation GA CE1ZW UT WOS:000351612900002 PM 25788210 ER PT J AU Deshapriya, IK Stromer, BS Pattammattel, A Kim, CS Iglesias-Bartolome, R Gonzalez-Fajardo, L Patel, V Gutkind, JS Lu, XL Kumar, CV AF Deshapriya, Inoka K. Stromer, Bobbi S. Pattammattel, Ajith Kim, Christina S. Iglesias-Bartolome, Ramiro Gonzalez-Fajardo, Laura Patel, Vyomesh Gutkind, J. Silvio Lu, Xiuling Kumar, Challa V. TI Fluorescent, Bioactive Protein Nanoparticles (Prodots) for Rapid, Improved Cellular Uptake SO BIOCONJUGATE CHEMISTRY LA English DT Article ID DRUG-DELIVERY; GOLD NANOPARTICLES; IN-VITRO; SILICA NANOPARTICLES; HYDROGEN-PEROXIDE; CARBON NANOTUBES; QUANTUM DOTS; CANCER-CELLS; TAT PEPTIDE; CYTOTOXICITY AB A simple and effective method for synthesizing highly fluorescent, protein-based nanoparticles (Prodots) and their facile uptake into the cytoplasm of cells is described here. Prodots made from bovine serum albumin (nBSA), glucose oxidase (nGO), horseradish peroxidase (nHRP), catalase (nCatalase), and lipase (nLipase) were found to be 15-50 nm wide and have been characterized by gel electrophoresis, transmission electron microscopy (TEM), circular dichroism (CD), fluorescence spectroscopy, dynamic light scattering (DLS), and optical microscopic methods. Data showed that the secondary structure of the protein in Prodots is retained to a significant extent and specific activities of nGO, nHRP, nCatalase, and nLipase were 80%, 70%, 65%, and 50% of their respective unmodified enzyme activities. Calorimetric studies indicated that the denaturation temperatures of nGO and nBSA increased while those of other Prodots remained nearly unchanged, and accelerated storage half-lives of Prodots at 60 degrees C increased by 4- to 8-fold. Exposure of nGO and nBSA+ nGO to cells indicated rapid uptake within 1-3 h, accompanied by significant blebbing of the plasma membrane, but no uptake has been noted in the absence of nGO. The presence of nGO/glucose in the media facilitated the uptake, and hydrogen peroxide induced membrane permeability could be responsible for this rapid uptake of Prodots. In control studies, FITC alone did not enter the cell, BSA-FITC was not internalized even in the presence of nGO, and there has been no uptake of nBSA-FITC in the absence of nGO. These are the very first examples of very rapid cellular uptake of fluorescent nanoparticles into cells, particularly nanoparticles made from pure proteins. The current approach is a simple and efficient method for the preparation of bioactive, fluorescent protein nanoparticles of controllable size for cellular imaging, and cell uptake is under the control of two separate chemical triggers. C1 [Deshapriya, Inoka K.; Stromer, Bobbi S.; Pattammattel, Ajith; Kim, Christina S.; Kumar, Challa V.] Univ Connecticut, Dept Chem, Storrs, CT 06269 USA. [Deshapriya, Inoka K.; Stromer, Bobbi S.; Pattammattel, Ajith; Kim, Christina S.; Kumar, Challa V.] Univ Connecticut, Dept Mol & Cell Biol, Storrs, CT 06269 USA. [Iglesias-Bartolome, Ramiro; Patel, Vyomesh; Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. [Gonzalez-Fajardo, Laura; Lu, Xiuling] Univ Connecticut, Sch Pharm, Dept Pharmaceut, Storrs, CT 06269 USA. RP Kumar, CV (reprint author), Univ Connecticut, Dept Chem, Storrs, CT 06269 USA. EM challa.kumar@uconn.edu FU NSF EAGER [DMR-1441879] FX This publication is in fond memory of late Professor Nicholas J. Turro of Columbia University. Authors (C.V.K. and I.K.D.) are grateful for the generous financial support of this work by the NSF EAGER award (DMR-1441879). NR 61 TC 4 Z9 4 U1 7 U2 64 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1043-1802 J9 BIOCONJUGATE CHEM JI Bioconjugate Chem. PD MAR PY 2015 VL 26 IS 3 BP 396 EP 404 DI 10.1021/bc500621h PG 9 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Multidisciplinary; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA CD9LY UT WOS:000351421000005 PM 25642999 ER PT J AU Qin, J Zhang, H Li, PF Albanes, D Yu, K AF Qin, Jing Zhang, Han Li, Pengfei Albanes, Demetrius Yu, Kai TI Using covariate-specific disease prevalence information to increase the power of case-control studies SO BIOMETRIKA LA English DT Article DE Auxiliary information; Biased sampling; Case and control studies; Empirical likelihood; Estimating equations; Meta-analysis ID GENOME-WIDE ASSOCIATION; LUNG-CANCER; SUSCEPTIBILITY LOCUS; EMPIRICAL LIKELIHOOD; MODELS; VARIANTS; 5P15.33 AB Public registration databases and large cohort studies provide vital information on disease prevalence at various levels of a risk factor. This auxiliary information can be helpful in conducting statistical inference in a new study. We aim to develop a statistical procedure that improves the efficiency of the logistic regression model for a case-control study by utilizing auxiliary information on covariate-specific disease prevalence via a series of unbiased estimating equations. We adopt empirical likelihood for statistical inference, and demonstrate its advantages through simulation and an application. C1 [Qin, Jing] NIAID, NIH, Bethesda, MD 20892 USA. [Zhang, Han; Albanes, Demetrius; Yu, Kai] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Li, Pengfei] Univ Waterloo, Dept Stat & Actuarial Sci, Waterloo, ON N2L 3G1, Canada. RP Qin, J (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jingqin@niaid.nih.gov; han.zhang2@nih.gov; pengfei.li@uwaterloo.ca; albanesd@mail.nih.gov; yuka@mail.nih.gov RI Zhang, Han/K-2118-2016 OI Zhang, Han/0000-0001-7977-9616 NR 18 TC 2 Z9 2 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-3444 EI 1464-3510 J9 BIOMETRIKA JI Biometrika PD MAR PY 2015 VL 102 IS 1 BP 169 EP 180 DI 10.1093/biomet/asu048 PG 12 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA CD3TJ UT WOS:000351004200012 ER PT J AU Hall, RP Fairley, J Woodley, D Werth, VP Hannah, D Streilein, RD McKillip, J Okawa, J Rose, M Keyes-Elstein, LL Pinckney, A Overington, A Wedgwood, J Ding, L Welch, B AF Hall, R. P., III Fairley, J. Woodley, D. Werth, V. P. Hannah, D. Streilein, R. D. McKillip, J. Okawa, J. Rose, M. Keyes-Elstein, L. L. Pinckney, A. Overington, A. Wedgwood, J. Ding, L. Welch, B. TI A multicentre randomized trial of the treatment of patients with pemphigus vulgaris with infliximab and prednisone compared with prednisone alone SO BRITISH JOURNAL OF DERMATOLOGY LA English DT Article ID NECROSIS-FACTOR-ALPHA; RHEUMATOID-ARTHRITIS; MESSENGER-RNA; IN-VITRO; THERAPY; ACANTHOLYSIS; ETANERCEPT; MORTALITY AB Background Pemphigus vulgaris (PV) is a blistering disease and tumour necrosis factor-alpha has a role in its pathogenesis. Objectives To evaluate the safety of infliximab (IFX) with prednisone compared with prednisone alone in the treatment of PV. In addition, treatment response was assessed and mechanistic studies were performed. Methods Subjects with PV who had ongoing disease activity while being maintained on prednisone were randomized to receive either IFX or placebo in addition to prednisone. Response status and immunoglobulin (Ig) G anti-desmoglein (Dsg) 1 and Dsg3 antibodies were assessed at 18 and 26 weeks. Results Ten subjects were randomized to each group. There were no safety signals during the course of the study. At week 18, one subject in each group had responded. At week 26, three IFX-treated subjects vs. none in the placebo group had responded (P = 0.21). At weeks 18 and 26, the median IgG anti-Dsg1 and anti-Dsg3 levels were lower in the IFX-treated patients [IgG anti-Dsg-1 (week 18, P = 0.035; week 26, P = 0.022); IgG anti-Dsg3 (week 18, P = 0.035; week, 26 P = 0.05)]. Conclusions This study is limited by the relatively small sample size. There was no significant difference between study arms in the proportion of subjects with treatment-related adverse events > grade 3. IFX therapy was not shown to be effective for the treatment of patients with PV in this randomized, placebo-controlled trial, although IFX treatment may be associated with a decrease in anti-Dsg1 and Dsg3 antibodies. C1 [Hall, R. P., III; Hannah, D.; Streilein, R. D.] Duke Univ, Med Ctr, Duke Hosp South, Dept Dermatol, Durham, NC 27710 USA. [Fairley, J.; McKillip, J.] Univ Iowa, Dept Dermatol, Iowa City, IA USA. [Woodley, D.] Univ So Calif, Dept Dermatol, Los Angeles, CA USA. [Werth, V. P.; Okawa, J.; Rose, M.] Univ Penn, Dept Dermatol, Philadelphia, PA 19104 USA. [Keyes-Elstein, L. L.; Pinckney, A.; Overington, A.] Rho Inc, Chapel Hill, NC USA. [Wedgwood, J.; Ding, L.; Welch, B.] NIAID, Clin Immunol Branch, Div Allergy Immunol & Transplantat, NIH, Bethesda, MD 20892 USA. RP Hall, RP (reprint author), Duke Univ, Med Ctr, Duke Hosp South, Dept Dermatol, Room 4044, Durham, NC 27710 USA. EM russell.hall@duke.edu FU Autoimmunity Centers of Excellence, NIAID [5U19AI056363-7] FX Supported by grants from: Autoimmunity Centers of Excellence, NIAID (Grant #5U19AI056363-7), with participation in study design, data analysis through Data and Safety Monitoring Board (DSMB), and manuscript review; no participation in data collection or publication decision; and Janssen Biologics (participation in design, data collection, data analysis, manuscript preparation, publication decision: None). NR 22 TC 10 Z9 11 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-0963 EI 1365-2133 J9 BRIT J DERMATOL JI Br. J. Dermatol. PD MAR PY 2015 VL 172 IS 3 BP 760 EP 768 DI 10.1111/bjd.13350 PG 9 WC Dermatology SC Dermatology GA CD9EM UT WOS:000351400500037 PM 25123295 ER PT J AU Newman, EM Morgan, RJ Kummar, S Beumer, JH Blanchard, MS Ruel, C El-Khoueiry, AB Carroll, MI Hou, JM Li, C Lenz, HJ Eiseman, JL Doroshow, JH AF Newman, Edward M. Morgan, Robert J. Kummar, Shivaani Beumer, Jan H. Blanchard, M. Suzette Ruel, Christopher El-Khoueiry, Anthony B. Carroll, Mary I. Hou, Jessie M. Li, Chun Lenz, Heinz J. Eiseman, Julie L. Doroshow, James H. TI A phase I, pharmacokinetic, and pharmacodynamic evaluation of the DNA methyltransferase inhibitor 5-fluoro-2'-deoxycytidine, administered with tetrahydrouridine SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE Fluorodeoxycytidine; DNA methylation; First-in-human; Phase I clinical trial; Pharmacokinetics; Pharmacodynamics ID MYELODYSPLASTIC SYNDROMES; CANCER; 5-FLUORO-2'-DEOXYCYTIDINE; METHYLATION; DEAMINATION; METABOLITES; THERAPY; CELLS AB Inhibitors of DNA (cytosine-5)-methyltransferases (DNMT) are active antineoplastic agents. We conducted the first-in-human phase I trial of 5-fluoro-2'-deoxycytidine (FdCyd), a DNMT inhibitor stable in aqueous solution, in patients with advanced solid tumors. Objectives were to establish the safety, maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of FdCyd + tetrahydrouridine (THU). FdCyd + THU were administered by 3 h IV infusion on days 1-5 every 3 weeks, or days 1-5 and 8-12 every 4 weeks. FdCyd was administered IV with a fixed 350 mg/m(2)/day dose of THU to inhibit deamination of FdCyd. Pharmacokinetics of FdCyd, downstream metabolites and THU were assessed by LC-MS/MS. RBC gamma-globin expression was evaluated as a pharmacodynamics biomarker. Patients were enrolled on the 3-week schedule at doses up to 80 mg/m(2)/day without dose-limiting toxicity (DLT) prior to transitioning to the 4-week schedule, which resulted in an MTD of 134 mg/m(2)/day; one of six patients had a first-cycle DLT (grade 3 colitis). FdCyd a parts per thousand yen40 mg/m(2)/day produced peak plasma concentrations > 1 A mu M. Although there was inter-patient variability, gamma-globin mRNA increased during the first two treatment cycles. One refractory breast cancer patient experienced a partial response (PR) of > 90 % decrease in tumor size, lasting over a year. The MTD was established at 134 mg/m(2) FdCyd + 350 mg/m(2) THU days 1-5 and 8-12 every 4 weeks. Based on toxicities observed over multiple cycles, good plasma exposures, and the sustained PR observed at 67 mg/m(2)/day, the phase II dose for our ongoing multi-histology trial is 100 mg/m(2)/day FdCyd with 350 mg/m(2)/day THU. C1 [Newman, Edward M.; Morgan, Robert J.; Blanchard, M. Suzette; Ruel, Christopher; Carroll, Mary I.; Hou, Jessie M.; Li, Chun] City Hope Beckman Res Inst, Dept Mol Pharmacol, Duarte, CA 91010 USA. [Kummar, Shivaani; Doroshow, James H.] NCI, Bethesda, MD 20892 USA. [Beumer, Jan H.; Eiseman, Julie L.] Univ Pittsburgh, Drug Discovery Program, Inst Canc, Mol Therapeut, Pittsburgh, PA USA. [El-Khoueiry, Anthony B.; Lenz, Heinz J.] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90033 USA. RP Newman, EM (reprint author), City Hope Beckman Res Inst, Dept Mol Pharmacol, 1500 East Duarte Rd, Duarte, CA 91010 USA. EM enewman@coh.org OI Beumer, Jan/0000-0002-8978-9401 FU [U01CA062505]; [UM1CA186717]; [P30CA033572]; [N01-CM-52202]; [U01CA099168]; [UM1CA186690]; [P30CA047904] FX A California Cancer Consortium Study. This manuscript is dedicated to the memory of Dr. Merrill J. Egorin, who would be a co-author if he were able to review the manuscript. Previous Presentation: Presented in part at the 38th Annual Meeting of the American Society of Clinical Oncology, May 18-May 21, 2002, Orlando, FL and the 102nd Annual Meeting of the American Association for Cancer Research, April 2-6, 2011 Orlando, FL. An interim pharmacokinetic analysis has been published [13]. Research Support: Supported in part by U01CA062505, UM1CA186717, P30CA033572, N01-CM-52202, U01CA099168, UM1CA186690, and P30CA047904. NR 17 TC 10 Z9 10 U1 1 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 EI 1432-0843 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD MAR PY 2015 VL 75 IS 3 BP 537 EP 546 DI 10.1007/s00280-014-2674-7 PG 10 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA CC4UZ UT WOS:000350350900012 PM 25567350 ER PT J AU Faupel-Badger, JM Raue, K Nelson, DE Tsakraklides, S AF Faupel-Badger, Jessica M. Raue, Kimberley Nelson, David E. Tsakraklides, Sophia TI Alumni Perspectives on Career Preparation during a Postdoctoral Training Program: A Qualitative Study SO CBE-LIFE SCIENCES EDUCATION LA English DT Article ID CANCER PREVENTION; EDUCATION; SCIENCE AB Published evaluations of career preparation of alumni from long-standing postdoctoral fellowship programs in the biomedical sciences are limited and often focus on quantitative analysis of data from extant publicly available sources. Qualitative methods provide the opportunity to gather robust information about specific program elements from structured postdoctoral training programs and the influence of this training on subsequent career paths of alumni. In-depth interviews with a subset of the National Cancer Institute's Cancer Prevention Fellowship Program (CPFP) alumni (n = 27), representing more than 25 years of the program's history and multiple career sectors, were conducted to assess alumni reflections on the training environment and career preparation during their time in the CPFP. NVivo software was used to analyze data and identify major themes. Four main themes emerged from these interviews, including: the value of structured training curriculum, mentorship, transdisciplinary environment, and professional identity. Even when reflecting on training that occurred one to two decades earlier, alumni were able to highlight specific components of a structured postdoctoral training program as influencing their research and career trajectories. These results may have relevance for those interested in assessing how postdoctoral training can influence fellows throughout their careers and understanding salient features of structured programs. C1 [Faupel-Badger, Jessica M.; Nelson, David E.] NCI, Canc Prevent Fellowship Program, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Raue, Kimberley; Tsakraklides, Sophia] Westat Corp, Rockville, MD 20850 USA. RP Faupel-Badger, JM (reprint author), NCI, Canc Prevent Fellowship Program, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. EM badgerje@mail.nih.gov FU National Cancer Institute Cancer Prevention Fellowship Program, Division of Cancer Prevention FX We thank the participants in this study for the time they dedicated to the interviews and the candid feedback they provided. This work was supported by the National Cancer Institute Cancer Prevention Fellowship Program, Division of Cancer Prevention, through a contract to Westat. NR 19 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1931-7913 J9 CBE-LIFE SCI EDUC JI CBE-Life Sci. Educ. PD MAR PY 2015 VL 14 IS 1 DI 10.1187/cbe.14-06-0102 PG 8 WC Education, Scientific Disciplines SC Education & Educational Research GA CD9MQ UT WOS:000351422800005 ER PT J AU Gril, B Palmieri, D Qian, YZ Hua, E Liewehr, DL Steinberg, SM Lockman, PR Smith, QR Steeg, PS AF Gril, Brunilde Palmieri, Diane Qian, Yongzhen Hua, Emily Liewehr, David L. Steinberg, Seth M. Lockman, Paul R. Smith, Quentin R. Steeg, Patricia S. TI Molecular and preclinical insights in brain metastasis of breast cancer SO CLINICAL & EXPERIMENTAL METASTASIS LA English DT Meeting Abstract C1 [Gril, Brunilde; Hua, Emily; Steeg, Patricia S.] NCI, Womens Malignancies Branch, CCR, Bethesda, MD 20892 USA. [Palmieri, Diane] NHLBI, Off Sci Director, Bethesda, MD USA. [Qian, Yongzhen] Frederick Natl Lab Canc Res, Frederick, MD USA. [Liewehr, David L.; Steinberg, Seth M.] NIH, Biostat & Data Management Sect, CCR, Natl Canc Res, Bethesda, MD 20892 USA. [Lockman, Paul R.] W Virginia Univ, Hlth Sci Ctr, Dept Basic Pharmaceut Sci, Morgantown, WV 26506 USA. [Smith, Quentin R.] Texas Tech Univ HSC, Dept Pharmaceut Sci, Amarillo, TX USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0262-0898 EI 1573-7276 J9 CLIN EXP METASTAS JI Clin. Exp. Metastasis PD MAR PY 2015 VL 32 IS 3 MA SA1 BP 181 EP 181 PG 1 WC Oncology SC Oncology GA CE1VX UT WOS:000351601900002 ER PT J AU Williams, K Lee, M Andreas, J Patel, S Yang, S Trivedi, N Cropp, S Bailey-Wilson, J Crawford, N AF Williams, K. Lee, M. Andreas, J. Patel, S. Yang, S. Trivedi, N. Cropp, S. Bailey-Wilson, J. Crawford, N. TI Germline variation modulates susceptibility to metastasis in a mouse model of prostate tumorigenesis SO CLINICAL & EXPERIMENTAL METASTASIS LA English DT Meeting Abstract C1 [Williams, K.; Lee, M.; Andreas, J.; Patel, S.; Yang, S.; Trivedi, N.; Cropp, S.; Bailey-Wilson, J.; Crawford, N.] NHGRI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0262-0898 EI 1573-7276 J9 CLIN EXP METASTAS JI Clin. Exp. Metastasis PD MAR PY 2015 VL 32 IS 3 MA 26 BP 199 EP 199 PG 1 WC Oncology SC Oncology GA CE1VX UT WOS:000351601900056 ER PT J AU Faraji, F Hu, Y Hunter, KW AF Faraji, Farhoud Hu, Ying Hunter, Kent W. TI Mechanistic dissection of the CCR4-NOT complex deadenylase, Cnot7, as a catalytic-activity dependent driver of tumor metastasis SO CLINICAL & EXPERIMENTAL METASTASIS LA English DT Meeting Abstract C1 [Faraji, Farhoud; Hu, Ying; Hunter, Kent W.] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0262-0898 EI 1573-7276 J9 CLIN EXP METASTAS JI Clin. Exp. Metastasis PD MAR PY 2015 VL 32 IS 3 MA 32 BP 201 EP 201 PG 1 WC Oncology SC Oncology GA CE1VX UT WOS:000351601900062 ER PT J AU Shukla, A Bai, L Geiger, T Hu, Y Yang, H Wong, K Lee, M Adams, D Hunter, K AF Shukla, Anjali Bai, Ling Geiger, Thomas Hu, Ying Yang, Howard Wong, Kim Lee, Maxwell Adams, David Hunter, Kent TI Integrating SNPs, epigenetics and transcriptomics to better understand the inherited predisposition to breast cancer metastasis SO CLINICAL & EXPERIMENTAL METASTASIS LA English DT Meeting Abstract C1 [Shukla, Anjali; Bai, Ling; Geiger, Thomas; Hunter, Kent] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Hu, Ying] NCI, Ctr Bioinformat, NIH, Bethesda, MD 20892 USA. [Yang, Howard; Wong, Kim; Lee, Maxwell; Adams, David] NCI, Basic Res Lab, NIH, Bethesda, MD 20892 USA. Welcome Trust Sanger Ctr, Hinxton, Cambs, England. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0262-0898 EI 1573-7276 J9 CLIN EXP METASTAS JI Clin. Exp. Metastasis PD MAR PY 2015 VL 32 IS 3 MA 62 BP 211 EP 211 PG 1 WC Oncology SC Oncology GA CE1VX UT WOS:000351601900092 ER PT J AU Lizardo, MM Morrow, JJ Scacheri, PC Helman, LJ Khanna, C AF Lizardo, Michael M. Morrow, James J. Scacheri, Peter C. Helman, Lee J. Khanna, Chand TI Metastatic osteosarcoma cell adaptation to proteotoxic stress in the lung microenvironment involves upregulation of the endoplasmic reticulum chaperone glucose-related protein 78 SO CLINICAL & EXPERIMENTAL METASTASIS LA English DT Meeting Abstract C1 [Lizardo, Michael M.; Morrow, James J.; Helman, Lee J.; Khanna, Chand] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Morrow, James J.; Scacheri, Peter C.] Case Western Reserve Univ, Sch Med, Dept Genet & Genome Sci, Cleveland, OH 44106 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0262-0898 EI 1573-7276 J9 CLIN EXP METASTAS JI Clin. Exp. Metastasis PD MAR PY 2015 VL 32 IS 3 MA 85 BP 219 EP 219 PG 1 WC Oncology SC Oncology GA CE1VX UT WOS:000351601900115 ER PT J AU Ren, L Mendoza, A Zhu, J Briggs, J Hong, ES Meltzer, P Khanna, C AF Ren, Ling Mendoza, Arnulfo Zhu, Jack Briggs, Joe Hong, Ellen S. Meltzer, Paul Khanna, Chand TI Functional characterization of high and low metastatic osteosarcoma cell lines provides representative models to study the human disease SO CLINICAL & EXPERIMENTAL METASTASIS LA English DT Meeting Abstract C1 [Ren, Ling; Mendoza, Arnulfo; Briggs, Joe; Hong, Ellen S.; Khanna, Chand] NCI, Mol Oncol Sect, Metastasis Biol Grp, Pediat Oncol Branch,NIH, Bethesda, MD 20892 USA. [Zhu, Jack; Meltzer, Paul] NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0262-0898 EI 1573-7276 J9 CLIN EXP METASTAS JI Clin. Exp. Metastasis PD MAR PY 2015 VL 32 IS 3 MA 124 BP 233 EP 233 PG 1 WC Oncology SC Oncology GA CE1VX UT WOS:000351601900154 ER PT J AU Wang, XM Walitt, B Saligan, L Tiwari, AFY Cheung, CW Zhang, ZJ AF Wang, Xiao-Min Walitt, Brian Saligan, Leorey Tiwari, Agnes F. Y. Cheung, Chi Wai Zhang, Zhang-Jin TI Chemobrain: A critical review and causal hypothesis of link between cytokines and epigenetic reprogramming associated with chemotherapy SO CYTOKINE LA English DT Review DE Cancer chemotherapy; Cognition dysfunction; Chemobrain; Cytokines and epigenetics ID BREAST-CANCER PATIENTS; INDUCED COGNITIVE IMPAIRMENT; QUALITY-OF-LIFE; CHRONIC-FATIGUE-SYNDROME; CENTRAL-NERVOUS-SYSTEM; ADJUVANT CHEMOTHERAPY; NEUROTROPHIC FACTOR; ALZHEIMERS-DISEASE; INFLAMMATORY CYTOKINES; SYNAPTIC PLASTICITY AB One consequence of modern cancer therapy is chemotherapy related cognitive dysfunction or "chemobrain", the subjective experience of cognitive deficits at any point during or following chemotherapy. Chemobrain, a well-established clinical syndrome, has become an increasing concern because the number of long-term cancer survivors is growing dramatically. There is strong evidence that correlates changes in peripheral cytokines with the development of chemobrain in commonly used chemotherapeutic drugs for different types of cancer. However, the mechanisms by which these cytokines elicit change in the central nervous system are still unclear. In this review, we hypothesize that the administration of chemotherapy agents initiates a cascade of biological changes, with short-lived alterations in the cytokine milieu inducing persistent epigenetic alterations. These epigenetic changes lead to changes in gene expression, alterations in metabolic activity and neuronal transmission that are responsible for generating the subjective experience of cognition. This speculative but testable hypothesis should help to gain a comprehensive understanding of the mechanism underlying cognitive dysfunction in cancer patients. Such knowledge is critical to identify pharmaceutical targets with the potential to prevent and treat cancer-treatment related cognitive dysfunction and similar disorders. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Wang, Xiao-Min; Tiwari, Agnes F. Y.] Univ Hong Kong, Sch Nursing, Hong Kong, Hong Kong, Peoples R China. [Wang, Xiao-Min; Cheung, Chi Wai] Univ Hong Kong, Dept Anaesthesiol, Hong Kong, Hong Kong, Peoples R China. [Walitt, Brian; Saligan, Leorey] NINR, NIH, Bethesda, MD 20892 USA. [Zhang, Zhang-Jin] Univ Hong Kong, Sch Chinese Med, Hong Kong, Hong Kong, Peoples R China. RP Wang, XM (reprint author), Univ Hong Kong, Sch Nursing, Hong Kong, Hong Kong, Peoples R China. EM xmwang1@hku.hk OI Tiwari, Agnes/0000-0002-3993-8552 FU NINR intramural program, NIH [1ZIANR000014-05]; NIH Bench-to-Bedside Program Awards FX The authors are gratefully acknowledge Alan Hoofring and Tyler Ethan from the NIH Medical Arts for their help with the illustrations. The authors are also gratefully acknowledge Steven E. Zhang from Stanford School of Medicine for his critical reading and grammar checking of the whole manuscript. This work was supported by Project Funding (1ZIANR000014-05) to XMW, NINR intramural program, NIH and 2008 NIH Bench-to-Bedside Program Awards to XMW. NR 133 TC 14 Z9 14 U1 5 U2 16 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 EI 1096-0023 J9 CYTOKINE JI Cytokine PD MAR PY 2015 VL 72 IS 1 BP 86 EP 96 DI 10.1016/j.cyto.2014.12.006 PG 11 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA CD8CI UT WOS:000351322400012 PM 25573802 ER PT J AU Gandhi, AS Wohlfarth, A Zhu, MS Pang, SK Castaneto, M Scheidweiler, KB Huestis, MA AF Gandhi, Adarsh S. Wohlfarth, Ariane Zhu, Mingshe Pang, Shaokun Castaneto, Marisol Scheidweiler, Karl B. Huestis, Marilyn A. TI High-resolution mass spectrometric metabolite profiling of a novel synthetic designer drug, N-(adamantan-1-yl)-1-(5-fluoropentyl)-1H-indole-3-carboxamide (STS-135), using cryopreserved human hepatocytes and assessment of metabolic stability with human liver microsomes SO DRUG TESTING AND ANALYSIS LA English DT Article DE STS-135; high resolution mass spectrometry; human hepatocytes; metabolism; synthetic cannabinoids ID URINARY METABOLITES; LC-MS/MS; QUANTITATIVE MEASUREMENT; CANNABINOIDS JWH-018; NEUTRAL ANTAGONIST; SMOKING MIXTURES; IDENTIFICATION; GAS; EXTRACTION; RECEPTORS AB N-(Adamantan-1-yl)-1-(5-fluoropentyl)-1H-indole-3-carboxamide (STS-135) is a new synthetic cannabinoid in herbal incense products discussed on Internet drug user forums and identified in police seizures. To date, there are no STS-135 clinical or in vitro studies identifying STS-135 metabolites. However, characterizing STS-135 metabolism is critical because synthetic cannabinoid metabolites can possess pharmacological activity and parent compounds are rarely detectable in urine. To characterize the metabolite profile, human hepatocytes were incubated with 10 mu mol/L STS-135 for up to 3 h. High-resolution mass spectrometry with software-assisted data mining identified 29 STS-135 metabolites. Less than 25% of STS-135 parent compound remained after 3 h incubation. Primary metabolites were generated by mono-, di- or trihydroxylation with and without ketone formation, dealkylation, and oxidative defluorination of N-fluoropentyl side chain or possible oxidation to carboxylic acid, some of them further glucuronidated. Hydroxylations occurred mainly on the aliphatic adamantane ring and less commonly on the N-pentyl side chain. At 1 h, phase I metabolites predominated, while at 3 h, phase II metabolites were present in higher amounts. The major metabolites were monohydroxy STS-135 (M25) and dihydroxy STS-135 (M21), both hydroxylated on the adamantane system. Moreover, metabolic stability of STS-135 (1 mu mol/L) was assessed in human liver microsomes experiments. The in vitro half-life of STS-135 was 3.10.2 min and intrinsic clearance (CLint) was 208.8 mL center dot min(-1)center dot kg(-1). This is the first report characterizing STS-135 hepatic metabolic pathways. These data provide potential urinary targets to document STS-135 intake in clinical and forensic settings and potential candidates for pharmacological testing. Copyright (c) 2014 John Wiley & Sons, Ltd. C1 [Gandhi, Adarsh S.; Wohlfarth, Ariane; Castaneto, Marisol; Scheidweiler, Karl B.; Huestis, Marilyn A.] NIDA, Chem & Drug Metab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Zhu, Mingshe] Bristol Myers Squibb Res & Dev, Dept Biotransformat, Princeton, NJ 08543 USA. [Pang, Shaokun] AB SCIEX, Redwood City, CA 94404 USA. RP Huestis, MA (reprint author), NIDA, Chem & Drug Metab, Intramural Res Program, 251 Bayview Blvd,Suite 200 Room 05A-721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health. NR 50 TC 12 Z9 12 U1 6 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1942-7603 EI 1942-7611 J9 DRUG TEST ANAL JI Drug Test. Anal. PD MAR PY 2015 VL 7 IS 3 BP 187 EP 198 DI 10.1002/dta.1662 PG 12 WC Biochemical Research Methods; Chemistry, Analytical; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Chemistry; Pharmacology & Pharmacy GA CD5NF UT WOS:000351134100003 PM 24827428 ER PT J AU Mirijello, A D'Angelo, C Ferrulli, A Vassallo, G Antonelli, M Caputo, F Leggio, L Gasbarrini, A Addolorato, G AF Mirijello, Antonio D'Angelo, Cristina Ferrulli, Anna Vassallo, Gabriele Antonelli, Mariangela Caputo, Fabio Leggio, Lorenzo Gasbarrini, Antonio Addolorato, Giovanni TI Identification and Management of Alcohol Withdrawal Syndrome SO DRUGS LA English DT Article ID GAMMA-HYDROXYBUTYRIC ACID; RANDOMIZED CONTROLLED-TRIAL; RAT HIPPOCAMPAL-NEURONS; BLIND CONTROLLED TRIAL; DEPENDENT PATIENTS; DELIRIUM-TREMENS; PRACTICE GUIDELINE; CLINICAL-TRIAL; PHARMACOLOGICAL-TREATMENT; GABAPENTIN TREATMENT AB Symptoms of alcohol withdrawal syndrome (AWS) may develop within 6-24 h after the abrupt discontinuation or decrease of alcohol consumption. Symptoms can vary from autonomic hyperactivity and agitation to delirium tremens. The gold-standard treatment for AWS is with benzodiazepines (BZDs). Among the BZDs, different agents (i.e., long-acting or short-acting) and different regimens (front-loading, fixed-dose or symptom-triggered) may be chosen on the basis of patient characteristics. Severe withdrawal could require ICU admission and the use of barbiturates or propofol. Other drugs, such as alpha(2)-agonists (clonidine and dexmetedomidine) and beta-blockers can be used as adjunctive treatments to control neuroautonomic hyperactivity. Furthermore, neuroleptic agents can help control hallucinations. Finally, other medications for the treatment for AWS have been investigated with promising results. These include carbamazepine, valproate, sodium oxybate, baclofen, gabapentin and topiramate. The usefulness of these agents are discussed. C1 [Mirijello, Antonio; D'Angelo, Cristina; Ferrulli, Anna; Vassallo, Gabriele; Antonelli, Mariangela; Gasbarrini, Antonio; Addolorato, Giovanni] Univ Cattolica Sacro Cuore, Gemelli Hosp, Inst Internal Med, Dept Internal Med,Alcohol Use Disorders Unit, I-00168 Rome, Italy. [Caputo, Fabio] SS Annunziata Hosp, Dept Internal Med, Cento, FE, Italy. [Caputo, Fabio] Univ Bologna, G Fontana Ctr Study & Multidisciplinary Treatment, Dept Clin Med, Bologna, Italy. [Leggio, Lorenzo] NIAAA, Sect Clin Psychoneuroendocrinol & Neuropsychophar, Lab Clin & Translat Studies, NIH, Bethesda, MD USA. [Leggio, Lorenzo] NIDA, Intramural Res Program, NIH, Baltimore, MD USA. [Leggio, Lorenzo] Brown Univ, Ctr Alcohol & Addict Studies, Dept Behav & Social Sci, Providence, RI 02912 USA. RP Addolorato, G (reprint author), Univ Cattolica Sacro Cuore, Gemelli Hosp, Inst Internal Med, Dept Internal Med,Alcohol Use Disorders Unit, Largo Gemelli 8, I-00168 Rome, Italy. EM g.addolorato@rm.unicatt.it RI Leggio, Lorenzo/M-2972-2016; Mirijello, Antonio/C-4103-2017; OI Mirijello, Antonio/0000-0003-3932-3803; Vassallo, Gabriele/0000-0002-9776-8870; Ferrulli, Anna/0000-0002-8518-5547 FU Italian Ministry for University, Scientific and Technological Research (MURST); Division of Intramural Clinical and Biological Research of the National Institute on Alcohol Abuse and Alcoholism (NIAAA); Intramural Research Program of the National Institute on Drug Abuse (NIDA) FX This study was supported by the Italian Ministry for University, Scientific and Technological Research (MURST) (AM, CDA, AF, GV, MA, FC, AG, GA). LL is a federal employee in the Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, which is supported by the Division of Intramural Clinical and Biological Research of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the Intramural Research Program of the National Institute on Drug Abuse (NIDA) (the content of this review is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health). We thank Ms. Caterina Mirijello for her expert revision of the English language. NR 120 TC 10 Z9 10 U1 1 U2 21 PU ADIS INT LTD PI NORTHCOTE PA 5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND SN 0012-6667 EI 1179-1950 J9 DRUGS JI Drugs PD MAR PY 2015 VL 75 IS 4 BP 353 EP 365 DI 10.1007/s40265-015-0358-1 PG 13 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA CE0VZ UT WOS:000351528700002 PM 25666543 ER PT J AU Singh, LK Dhasmana, N Sajid, A Kumar, P Bhaduri, A Bharadwaj, M Gandotra, S Kalia, VC Das, TK Goel, AK Pomerantsev, AP Misra, R Gerth, U Leppla, SH Singh, Y AF Singh, Lalit K. Dhasmana, Neha Sajid, Andaleeb Kumar, Prasun Bhaduri, Asani Bharadwaj, Mitasha Gandotra, Sheetal Kalia, Vipin C. Das, Taposh K. Goel, Ajay K. Pomerantsev, Andrei P. Misra, Richa Gerth, Ulf Leppla, Stephen H. Singh, Yogendra TI clpC operon regulates cell architecture and sporulation in Bacillus anthracis SO ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID GRAM-POSITIVE BACTERIA; GENE-EXPRESSION; COMPENSATORY MUTATIONS; STRESS INDUCTION; HIGH-TEMPERATURE; SIGMA-FACTOR; SUBTILIS; PROTEASES; PROTEIN; PROTEOLYSIS AB The clpC operon is known to regulate several processes such as genetic competence, protein degradation and stress survival in bacteria. Here, we describe the role of clpC operon in Bacillus anthracis. We generated knockout strains of the clpC operon genes to investigate the impact of CtsR, McsA, McsB and ClpC deletion on essential processes of B.anthracis. We observed that growth, cell division, sporulation and germination were severely affected in mcsB and clpC deleted strains, while none of deletions affected toxin secretion. Growth defect in these strains was pronounced at elevated temperature. The growth pattern gets restored on complementation of mcsB and clpC in respective mutants. Electron microscopic examination revealed that mcsB and clpC deletion also causes defect in septum formation leading to cell elongation. These vegetative cell deformities were accompanied by inability of mutant strains to generate morphologically intact spores. Higher levels of polyhydroxybutyrate granules accumulation were also observed in these deletion strains, indicating a defect in sporulation process. Our results demonstrate, for the first time, the vital role played by McsB and ClpC in physiology of B.anthracis and open up further interest on this operon, which might be of importance to success of B.anthracis as pathogen. C1 [Singh, Lalit K.; Dhasmana, Neha; Sajid, Andaleeb; Kumar, Prasun; Bhaduri, Asani; Bharadwaj, Mitasha; Gandotra, Sheetal; Kalia, Vipin C.; Misra, Richa; Singh, Yogendra] Inst Genom & Integrat Biol, CSIR, Delhi 110007, India. [Das, Taposh K.] All India Inst Med Sci, Dept Anat, New Delhi 110029, India. Def Res & Dev Estab, Gwalior 474002, India. [Pomerantsev, Andrei P.; Leppla, Stephen H.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Gerth, Ulf] Ernst Moritz Arndt Univ Greifswald, Inst Microbiol, Greifswald, Germany. RP Singh, Y (reprint author), Inst Genom & Integrat Biol, CSIR, Delhi 110007, India. EM ysingh@igib.res.in OI Sajid, Andaleeb/0000-0001-6248-4985 FU Council of Scientific and Industrial Research; University Grants Commission, India; National Institutes of Health, NIAID, Intramural Research Program, USA; Defence Research and Development Organisation, India [LSRB-268/BTB/2013] FX LS, ND, AS, PK and AB were supported by Council of Scientific and Industrial Research or University Grants Commission, India. This work was partly supported by the National Institutes of Health, NIAID, Intramural Research Program, USA. This work was also supported by Defence Research and Development Organisation, India (Grant No. LSRB-268/BTB/2013). We are thankful to Sandip Arya, Anurag Singh, Raj Girish Mishra and other technical staff from Electron Microscope facility AIIMS, Delhi, for their guidance and support. We thank to Dr. Ruchita Pal and SCP Sharma for technical guidance in scanning electron microscopy, AIRF, JNU, Delhi. We also thank Dr. Inka Sastalla for providing bacterial strains. The authors declare no conflict of interest. NR 46 TC 1 Z9 1 U1 3 U2 12 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 MAR PY 2015 VL 17 IS 3 BP 855 EP 865 DI 10.1111/1462-2920.12548 PG 11 WC Microbiology SC Microbiology GA CD9RK UT WOS:000351435600027 PM 24947607 ER PT J AU Schneider, A Mertes, CM Tatem, AJ Tan, B Sulla-Menashe, D Graves, SJ Patel, NN Horton, JA Gaughan, AE Rollo, JT Schelly, IH Stevens, FR Dastur, A AF Schneider, A. Mertes, C. M. Tatem, A. J. Tan, B. Sulla-Menashe, D. Graves, S. J. Patel, N. N. Horton, J. A. Gaughan, A. E. Rollo, J. T. Schelly, I. H. Stevens, F. R. Dastur, A. TI A new urban landscape in East-Southeast Asia, 2000-2010 SO ENVIRONMENTAL RESEARCH LETTERS LA English DT Article DE urbanization; urban sprawl; land cover change; remote sensing; change detection; urban density; population density ID LAND-USE CHANGE; CLIMATE-CHANGE; MEGA CITIES; MODIS DATA; URBANIZATION; GROWTH; METRICS; PATTERNS; CHINA; EXPANSION AB East-Southeast Asia is currently one of the fastest urbanizing regions in the world, with countries such as China climbing from 20 to 50% urbanized in just a few decades. By 2050, these countries are projected to add 1 billion people, with 90% of that growth occurring in cities. This population shift parallels an equally astounding amount of built-up land expansion. However, spatially-and temporally-detailed information on regional-scale changes in urban land or population distribution do not exist; previous efforts have been either sample-based, focused on one country, or drawn conclusions from datasets with substantial temporal/spatial mismatch and variability in urban definitions. Using consistent methodology, satellite imagery and census data for >1000 agglomerations in the East-Southeast Asian region, we show that urban land increased >22% between 2000 and 2010 (from 155 000 to 189 000 km(2)), an amount equivalent to the area of Taiwan, while urban populations climbed >31% (from 738 to 969 million). Although urban land expanded at unprecedented rates, urban populations grew more rapidly, resulting in increasing densities for the majority of urban agglomerations, including those in both more developed (Japan, South Korea) and industrializing nations (China, Vietnam, Indonesia). This result contrasts previous sample-based studies, which conclude that cities are universally declining in density. The patterns and rates of change uncovered by these datasets provide a unique record of the massive urban transition currently underway in East-Southeast Asia that is impacting local-regional climate, pollution levels, water quality/availability, arable land, as well as the livelihoods and vulnerability of populations in the region. C1 [Schneider, A.; Mertes, C. M.; Horton, J. A.; Rollo, J. T.; Schelly, I. H.] Univ Wisconsin, Nelson Inst Environm Studies, Ctr Sustainabil & Global Environm, Madison, WI 53706 USA. [Schneider, A.; Mertes, C. M.; Horton, J. A.; Rollo, J. T.; Schelly, I. H.] Univ Wisconsin, Dept Geog, Madison, WI 53706 USA. [Tatem, A. J.] Univ Southampton, Dept Geog & Environm, Southampton SO9 5NH, Hants, England. [Tatem, A. J.] Fogarty Int Ctr, NIH, Bethesda, MD USA. [Tan, B.] NASA, Goddard Space Flight Ctr, Sci Syst & Applicat Inc, Lanham, MD USA. [Sulla-Menashe, D.] Boston Univ, Dept Earth & Environm, Boston, MA 02215 USA. [Graves, S. J.] Univ Florida, Sch Forest Resources & Conservat, Gainesville, FL 32611 USA. [Patel, N. N.] George Mason Univ, Dept Geog & Geoinformat Sci, Fairfax, VA 22030 USA. [Gaughan, A. E.; Stevens, F. R.] Univ Louisville, Dept Geog & Geosci, Louisville, KY 40292 USA. [Dastur, A.] World Bank, Washington, DC 20433 USA. RP Schneider, A (reprint author), Univ Wisconsin, Nelson Inst Environm Studies, Ctr Sustainabil & Global Environm, Madison, WI 53706 USA. EM aschneider4@wisc.edu OI Stevens, Forrest/0000-0002-9328-3753 FU World Bank; RAPIDD program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; Bill and Melinda Gates Foundation [49446, 1032350] FX AS acknowledges funding support from the World Bank for preparation of datasets. AJT acknowledges funding support from the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health, and is also supported by grants from the Bill and Melinda Gates Foundation (#49446, #1032350). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors also wish to thank Caitlin Kontgis, Mutlu Ozdogan, and four anonymous reviewers for their helpful comments on an earlier draft of this manuscript. NR 44 TC 12 Z9 12 U1 15 U2 62 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 1748-9326 J9 ENVIRON RES LETT JI Environ. Res. Lett. PD MAR PY 2015 VL 10 IS 3 AR 034002 DI 10.1088/1748-9326/10/3/034002 PG 14 WC Environmental Sciences; Meteorology & Atmospheric Sciences SC Environmental Sciences & Ecology; Meteorology & Atmospheric Sciences GA CD9KB UT WOS:000351416100004 ER PT J AU Yamaguchi, T Qi, J Wang, HL Zhang, SL Morales, M AF Yamaguchi, Tsuyoshi Qi, Jia Wang, Hui-Ling Zhang, Shiliang Morales, Marisela TI Glutamatergic and dopaminergic neurons in the mouse ventral tegmental area SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE interpeduncular nucleus; lateral habenula; optogenetics reward; ventral tegmental area; VGluT2 ID NUCLEUS-ACCUMBENS; INTERFASCICULAR NUCLEUS; LATERAL HABENULA; RAT; MIDBRAIN; PROJECTIONS; SYSTEM; REWARD; VGLUT2; CONNECTIONS AB The ventral tegmental area (VTA) comprises dopamine (DA), -aminobutyric acid (GABA) and glutamate (Glu) neurons. Some rat VTA Glu neurons, expressing vesicular glutamate transporter 2 (VGluT2), co-express tyrosine hydroxylase (TH). While transgenic mice are now being used in attempts to determine the role of VGluT2/TH neurons in reward and neuronal signaling, such neurons have not been characterized in mouse tissue. By cellular detection of VGluT2 mRNA and TH immunoreactivity (TH-IR), we determined the cellular expression of VGluT2 mRNA within VTA TH-IR neurons in the mouse. We found that some mouse VGluT2 neurons coexpressed TH-IR, but their frequency was lower than in the rat. To determine whether low expression of TH mRNA or TH-IR accounts for this low frequency, we evaluated VTA cellular coexpression of TH transcripts and TH protein. Within the medial aspects of the VTA, some neurons expressed TH mRNA but lacked TH-IR; among them a subset coexpressed VGluT2 mRNA. To determine if lack of VTA TH-IR was due to TH trafficking, we tagged VTA TH neurons by Cre-inducible expression of mCherry in TH::Cre mice. By dual immunofluorescence, we detected axons containing mCherry, but lacking TH-IR, in the lateral habenula, indicating that low frequency of VGluT2 mRNA (+)/TH-IR (+) neurons in the mouse is due to lack of synthesis of TH protein, rather than TH protein trafficking. In conclusion, VGluT2 neurons are present in the rat and mouse VTA, but they differ in the populations of VGluT2/TH and TH neurons. Under normal conditions, the translation of TH protein is suppressed in the mouse mesohabenular TH neurons. C1 [Yamaguchi, Tsuyoshi; Qi, Jia; Wang, Hui-Ling; Zhang, Shiliang; Morales, Marisela] Natl Inst Drug Abuse, NIH, Intramural Res Program, Neuronal Networks Sect, Baltimore, MD 21224 USA. RP Morales, M (reprint author), Natl Inst Drug Abuse, NIH, Intramural Res Program, Neuronal Networks Sect, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM mmorales@intra.nida.nih.gov OI YAMAGUCHI, TSUYOSHI/0000-0002-0058-9244 FU National Institute on Drug Abuse FX This work was supported by the Intramural Research Program of the National Institute on Drug Abuse. Research was planned and carried by T.Y., J.Q. and M.M. T.Y., J.Q., H.-L.W., S.Z. and M.M. analysed the data. M.M. wrote the paper with the contribution of all the authors. The authors declare that they do not have any conflicts of interest related to the data presented in this manuscript. We thank Bing Liu for her help in processing brain tissue. NR 43 TC 23 Z9 23 U1 2 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0953-816X EI 1460-9568 J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD MAR PY 2015 VL 41 IS 6 BP 760 EP 772 DI 10.1111/ejn.12818 PG 13 WC Neurosciences SC Neurosciences & Neurology GA CD9SQ UT WOS:000351439000003 PM 25572002 ER PT J AU Zhang, HP Baldwin, DA Bukowski, RK Parry, S Xu, YJ Song, C Andrews, WW Saade, GR Esplin, MS Sadovsky, Y Reddy, UM Ilekis, J Varner, M Biggio, JR AF Zhang, Heping Baldwin, Don A. Bukowski, Radek K. Parry, Samuel Xu, Yaji Song, Chi Andrews, William W. Saade, George R. Esplin, M. Sean Sadovsky, Yoel Reddy, Uma M. Ilekis, John Varner, Michael Biggio, Joseph R., Jr. CA Eunice Kennedy Shriver Natl Inst TI A Genome-Wide Association Study of Early Spontaneous Preterm Delivery SO GENETIC EPIDEMIOLOGY LA English DT Article DE association analysis; obstetric; premature birth ID BIRTH AB Preterm birth is the leading cause of infant morbidity and mortality. Despite extensive research, the genetic contributions to spontaneous preterm birth (SPTB) are not well understood. Term controls were matched with cases by race/ethnicity, maternal age, and parity prior to recruitment. Genotyping was performed using Affymetrix SNP Array 6.0 assays. Statistical analyses utilized PLINK to compare allele occurrence rates between case and control groups, and incorporated quality control and multiple-testing adjustments. We analyzed DNA samples from mother-infant pairs from early SPTB cases (20(0/7)-33(6/7) weeks, 959 women and 979 neonates) and term delivery controls (39(0/7)-41(6/7) weeks, 960 women and 985 neonates). For validation purposes, we included an independent validation cohort consisting of early SPTB cases (293 mothers and 243 infants) and term controls (200 mothers and 149 infants). Clustering analysis revealed no population stratification. Multiple maternal SNPs were identified with association P-values between 10 x 10(-5) and 10 x 10(-6). The most significant maternal SNP was rs17053026 on chromosome 3 with an odds ratio (OR) 0.44 with a P-value of 1.0 x 10(-6). Two neonatal SNPs reached the genome-wide significance threshold, including rs17527054 on chromosome 6p22 with a P-value of 2.7 x 10(-12) and rs3777722 on chromosome 6q27 with a P-value of 1.4 x 10(-10). However, we could not replicate these findings after adjusting for multiple comparisons in a validation cohort. This is the first report of a genome-wide case-control study to identify single nucleotide polymorphisms (SNPs) that correlate with SPTB. C1 [Zhang, Heping; Xu, Yaji; Song, Chi] Yale Univ, Dept Biostat, Sch Publ Hlth, New Haven, CT 06520 USA. [Baldwin, Don A.] Pathonomics LLC, Philadelphia, PA USA. [Bukowski, Radek K.; Saade, George R.] Univ Texas Med Branch, Dept Obstet & Gynecol, Galveston, TX 77555 USA. [Parry, Samuel] Univ Penn, Sch Med, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA. [Andrews, William W.; Biggio, Joseph R., Jr.] Univ Alabama Birmingham, Dept Obstet & Gynecol, Birmingham, AL 35294 USA. [Esplin, M. Sean; Varner, Michael] Univ Utah, Sch Med, Dept Obstet & Gynecol, Salt Lake City, UT 84132 USA. [Esplin, M. Sean; Varner, Michael] Intermt Healthcare, Salt Lake City, UT USA. [Sadovsky, Yoel] Univ Pittsburgh, Sch Med, Magee Womens Res Inst, Pittsburgh, PA USA. [Reddy, Uma M.; Ilekis, John] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, Bethesda, MD USA. RP Zhang, HP (reprint author), Yale Univ, Dept Biostat, Sch Publ Hlth, 60 Coll St, New Haven, CT 06520 USA. EM heping.zhang@yale.edu RI Xu, Yaji/M-4985-2015; Song, Chi/B-1599-2016; Varner, Michael/K-9890-2013 OI Varner, Michael/0000-0001-9455-3973 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development Genomic and Proteomic Network for Preterm Birth Research [U01-HD-050062, U01-HD-050078, U01-HD-050080, U01-HD-050088, U01-HD-050094] FX This study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Genomic and Proteomic Network for Preterm Birth Research (U01-HD-050062; U01-HD-050078; U01-HD-050080; U01-HD-050088; U01-HD-050094). NR 15 TC 5 Z9 6 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD MAR PY 2015 VL 39 IS 3 BP 217 EP 226 DI 10.1002/gepi.21887 PG 10 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA CD9ZW UT WOS:000351462200009 PM 25599974 ER PT J AU Lee, AW Tyrer, JP Doherty, JA Stram, DA Kupryjanczyk, J Dansonka-Mieszkowska, A Plisiecka-Halasa, J Spiewankiewicz, B Myers, EJ Chenevix-Trench, G Fasching, PA Beckmann, MW Ekici, AB Hein, A Vergote, I Van Nieuwenhuysen, E Lambrechts, D Wicklund, KG Eilber, U Wang-Gohrke, S Chang-Claude, J Rudolph, A Sucheston-Campbell, L Odunsi, K Moysich, KB Shvetsov, YB Thompson, PJ Goodman, MT Wilkens, LR Dork, T Hillemanns, P Durst, M Runnebaum, IB Bogdanova, N Pelttari, LM Nevanlinna, H Leminen, A Edwards, RP Kelley, JL Harter, P Schwaab, I Heitz, F du Bois, A Orsulic, S Lester, J Walsh, C Karlan, BY Hogdall, E Kjaer, SK Jensen, A Vierkant, RA Cunningham, JM Goode, EL Fridley, BL Southey, MC Giles, GG Bruinsma, F Wu, XF Hildebrandt, MAT Lu, KR Liang, D Bisogna, M Levine, DA Weber, RP Schildkraut, JM Iversen, ES Berchuck, A Terry, KL Cramer, DW Tworoger, SS Poole, EM Olson, SH Orlow, I Bandera, EV Bjorge, L Tangen, IL Salvesen, HB Krakstad, C Massuger, LFAG Kiemeney, LA Aben, KKH van Altena, AM Bean, Y Pejovic, T Kellar, M Le, ND Cook, LS Kelemen, LE Brooks-Wilson, A Lubinski, J Gronwald, J Cybulski, C Jakubowska, A Wentzensen, N Brinton, LA Lissowska, J Yang, HN Nedergaard, L Lundvall, L Hogdall, C Song, HL Campbell, IG Eccles, D Glasspool, R Siddiqui, N Carty, K Paul, J McNeish, LA Sieh, W McGuire, V Rothstein, JH Whittemore, AS McLaughlin, JR Risch, HA Phelan, CM Anton-Culver, H Ziogas, A Menon, U Ramus, SJ Gentry-Maharaj, A Harrington, P Pike, MC Modugno, F Rossing, MA Ness, RB Pharoah, PDP Stram, DO Wu, AH Pearce, CL AF Lee, Alice W. Tyrer, Jonathan P. Doherty, Jennifer A. Stram, Douglas A. Kupryjanczyk, Jolanta Dansonka-Mieszkowska, Agnieszka Plisiecka-Halasa, Joanna Spiewankiewicz, Beata Myers, Emily J. Chenevix-Trench, Georgia Fasching, Peter A. Beckmann, Matthias W. Ekici, Arif B. Hein, Alexander Vergote, Ignace Van Nieuwenhuysen, Els Lambrechts, Diether Wicklund, Kristine G. Eilber, Ursula Wang-Gohrke, Shan Chang-Claude, Jenny Rudolph, Anja Sucheston-Campbell, Lara Odunsi, Kunle Moysich, Kirsten B. Shvetsov, Yurii B. Thompson, Pamela J. Goodman, Marc T. Wilkens, Lynne R. Doerk, Thilo Hillemanns, Peter Duerst, Matthias Runnebaum, Ingo B. Bogdanova, Natalia Pelttari, Liisa M. Nevanlinna, Heli Leminen, Arto Edwards, Robert P. Kelley, Joseph L. Harter, Philipp Schwaab, Ira Heitz, Florian du Bois, Andreas Orsulic, Sandra Lester, Jenny Walsh, Christine Karlan, Beth Y. Hogdall, Estrid Kjaer, Susanne K. Jensen, Allan Vierkant, Robert A. Cunningham, Julie M. Goode, Ellen L. Fridley, Brooke L. Southey, Melissa C. Giles, Graham G. Bruinsma, Fiona Wu, Xifeng Hildebrandt, Michelle A. T. Lu, Karen Liang, Dong Bisogna, Maria Levine, Douglas A. Weber, Rachel Palmieri Schildkraut, Joellen M. Iversen, Edwin S. Berchuck, Andrew Terry, Kathryn L. Cramer, Daniel W. Tworoger, Shelley S. Poole, Elizabeth M. Olson, Sara H. Orlow, Irene Bandera, Elisa V. Bjorge, Line Tangen, Ingvild L. Salvesen, Helga B. Krakstad, Camilla Massuger, Leon F. A. G. Kiemeney, Lambertus A. Aben, Katja K. H. van Altena, Anne M. Bean, Yukie Pejovic, Tanja Kellar, Melissa Le, Nhu D. Cook, Linda S. Kelemen, Linda E. Brooks-Wilson, Angela Lubinski, Jan Gronwald, Jacek Cybulski, Cezary Jakubowska, Anna Wentzensen, Nicolas Brinton, Louise A. Lissowska, Jolanta Yang, Hannah Nedergaard, Lotte Lundvall, Lene Hogdall, Claus Song, Honglin Campbell, Ian G. Eccles, Diana Glasspool, Rosalind Siddiqui, Nadeem Carty, Karen Paul, James McNeish, Lain A. Sieh, Weiva McGuire, Valerie Rothstein, Joseph H. Whittemore, Alice S. McLaughlin, John R. Risch, Harvey A. Phelan, Catherine M. Anton-Culver, Hoda Ziogas, Argyrios Menon, Usha Ramus, Susan J. Gentry-Maharaj, Aleksandra Harrington, Patricia Pike, Malcolm C. Modugno, Francesmary Rossing, Mary Anne Ness, Roberta B. Pharoah, Paul D. P. Stram, Daniel O. Wu, Anna H. Pearce, Celeste Leigh CA Australian Canc Study Ovarian Canc Australian Ovarian Canc Study Grp TI Evaluating the ovarian cancer gonadotropin hypothesis: A candidate gene study SO GYNECOLOGIC ONCOLOGY LA English DT Article DE Ovarian cancer; Gene; Gonadotropins; Genetics; Polymorphisms; Genetic variation ID GENOME-WIDE ASSOCIATION; GRANULOSA-CELL TUMOR; SUSCEPTIBILITY LOCUS; GENOTYPE IMPUTATION; RISK; POLYMORPHISMS; IDENTIFICATION; PROGESTERONE; VARIANTS; RECEPTOR AB Objective. Ovarian cancer is a hormone-related disease with a strong genetic basis. However, none of its high-penetrance susceptibility genes and GWAS-identified variants to date are known to be involved in hormonal pathways. Given the hypothesized etiologic role of gonadotropins, an assessment of how variability in genes involved in the gonadotropin signaling pathway impacts disease risk is warranted. Methods. Genetic data from 41 ovarian cancer study sites were pooled and unconditional logistic regression was used to evaluate whether any of the 2185 SNPs from 11 gonadotropin signaling pathway genes was associated with ovarian,cancer risk. A burden test using the admixture likelihood (AML) method was also used to evaluate gene-level associations. Results. We did not find any genome-wide significant associations between individual SNPs and ovarian cancer risk. However, there was some suggestion of gene-level associations for four gonadotropin signaling pathway genes: INHBB (p = 0.045, mucinous),LHCGR (p = 0.046, high-grade serous), GNRH (p = 0.041, high-grade serous), and FSHB (p = 0.036, overall invasive). There was also suggestive evidence for INHA (p = 0.060, overall invasive). Conclusions. Ovarian cancer studies have limited sample numbers, thus fewer genome-wide susceptibility alleles, with only modest associations, have been identified relative to breast and prostate cancers. We have evaluated the majority of ovarian cancer studies with biological samples, to our knowledge, leaving no opportunity for replication. Using both our understanding of biology and powerful gene-level tests, we have identified four putative ovarian cancer loci near INHBB, LHCGR, GNRH, and FSHB that warrant a second look if larger sample sizes and denser genotype chips become available. (C) 2014 Elsevier Inc. All rights reserved. C1 [Lee, Alice W.; Stram, Douglas A.; Myers, Emily J.; Ramus, Susan J.; Pike, Malcolm C.; Stram, Daniel O.; Wu, Anna H.; Pearce, Celeste Leigh] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Tyrer, Jonathan P.; Song, Honglin] Univ Cambridge, Strangeways Res Lab, Dept Oncol, Cambridge, England. [Doherty, Jennifer A.] Geisel Sch Med Dartmouth, Dept Epidemiol, Lebanon, NH USA. [Kupryjanczyk, Jolanta; Dansonka-Mieszkowska, Agnieszka; Plisiecka-Halasa, Joanna] Inst Oncol, Dept Pathol, Warsaw, Poland. [Spiewankiewicz, Beata] Inst Oncol, Dept Gynecol Oncol, Warsaw, Poland. [Chenevix-Trench, Georgia; Australian Canc Study Ovarian Canc] QIMR Berghofer Med Res Inst, Canc Div, Brisbane, Qld, Australia. [Australian Ovarian Canc Study Grp] Peter MacCallum Canc Inst, East Melbourne, Vic, Australia. [Fasching, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. [Fasching, Peter A.; Beckmann, Matthias W.; Hein, Alexander] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Dept Gynecol & Obstet, Comprehens Canc Ctr Erlangen EMN, D-91054 Erlangen, Germany. [Ekici, Arif B.] Univ Erlangen Nurnberg, Inst Human Genet, Univ Hosp Erlangen, D-91054 Erlangen, Germany. [Vergote, Ignace; Van Nieuwenhuysen, Els] Univ Hosp Leuven, Dept Oncol, Div Gynecol Oncol, Louvain, Belgium. [Lambrechts, Diether] VIB, Vesalius Res Ctr, Leuven, Belgium. [Lambrechts, Diether] VIB, Vesalius Res Ctr, Lab Translat Genet, Louvain, Belgium. [Lambrechts, Diether] Katholieke Univ Leuven, Louvain, Belgium. [Wicklund, Kristine G.; Rossing, Mary Anne] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Program Epidemiol, Seattle, WA 98104 USA. [Eilber, Ursula; Chang-Claude, Jenny; Rudolph, Anja] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Wang-Gohrke, Shan] Univ Ulm, Dept Obstet & Gynecol, D-89069 Ulm, Germany. [Sucheston-Campbell, Lara; Moysich, Kirsten B.] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Odunsi, Kunle] Roswell Pk Canc Inst, Dept Gynecol Oncol, Buffalo, NY 14263 USA. [Shvetsov, Yurii B.; Wilkens, Lynne R.] Univ Hawaii, Ctr Canc, Canc Epidemiol Program, Honolulu, HI 96822 USA. [Thompson, Pamela J.; Goodman, Marc T.] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Canc Prevent & Control, Los Angeles, CA 90048 USA. [Thompson, Pamela J.; Goodman, Marc T.] Cedars Sinai Med Ctr, Dept Biomed Sci, Community & Populat Hlth Res Inst, Los Angeles, CA 90048 USA. [Doerk, Thilo; Bogdanova, Natalia] Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany. [Hillemanns, Peter] Hannover Med Sch, Clin Obstet, Hannover, Germany. [Hillemanns, Peter] Hannover Med Sch, Clin Gynaecol, Hannover, Germany. [Duerst, Matthias; Runnebaum, Ingo B.] Univ Jena, Jena Univ Hosp, Dept Gynecol, Jena, Germany. [Pelttari, Liisa M.; Nevanlinna, Heli; Leminen, Arto] Univ Helsinki, Dept Obstet & Gynecol, Helsinki, Hus, Finland. [Pelttari, Liisa M.; Nevanlinna, Heli; Leminen, Arto] Univ Helsinki, Cent Hosp, Helsinki, Hus, Finland. [Edwards, Robert P.; Kelley, Joseph L.; Modugno, Francesmary] Univ Pittsburgh, Sch Med, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA. [Edwards, Robert P.] Univ Pittsburgh, Ovarian Canc Ctr Excellence, Pittsburgh, PA USA. [Harter, Philipp; Heitz, Florian; du Bois, Andreas] Kliniken Essen Mitte, Dept Gynecol & Gynecol Oncol, Essen, Germany. Dr Horst Schmidt Kliniken Wiesbaden, Dept Gynecol & Gynecol Oncol, Wiesbaden, Germany. [Schwaab, Ira] Inst Humangenet Wiesbaden, Wiesbaden, Germany. [Orsulic, Sandra; Lester, Jenny; Walsh, Christine; Karlan, Beth Y.] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Los Angeles, CA 90048 USA. [Hogdall, Estrid] Danish Canc Soc, Inst Canc Epidemiol, Copenhagen, Denmark. [Hogdall, Estrid] Univ Copenhagen, Herlev Hosp, Dept Pathol, Mol Unit, Copenhagen, Denmark. [Kjaer, Susanne K.; Jensen, Allan] Danish Canc Soc, Res Ctr, Dept Virus Lifestyle & Genes, Copenhagen, Denmark. [Kjaer, Susanne K.; Lundvall, Lene; Hogdall, Claus] Univ Copenhagen, Rigshosp, Dept Gynecol, DK-2100 Copenhagen, Denmark. [Vierkant, Robert A.; Goode, Ellen L.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Cunningham, Julie M.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Fridley, Brooke L.] Univ Kansas, Med Ctr, Biostat & Informat Shared Resource, Kansas City, KS 66103 USA. [Southey, Melissa C.; Campbell, Ian G.] Univ Melbourne, Dept Pathol, Parkville, Vic 3052, Australia. [Giles, Graham G.; Bruinsma, Fiona] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Giles, Graham G.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Biostat & Epidemiol, Melbourne, Vic 3010, Australia. [Wu, Xifeng; Hildebrandt, Michelle A. T.] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Lu, Karen] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA. [Liang, Dong] Texas So Univ, Coll Pharm & Hlth Sci, Houston, TX 77004 USA. [Bisogna, Maria; Levine, Douglas A.] Mem Sloan Kettering Canc Ctr, Dept Surg, Gynecol Serv, New York, NY 10021 USA. [Weber, Rachel Palmieri; Schildkraut, Joellen M.] Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC 27710 USA. [Schildkraut, Joellen M.] Duke Canc Inst, Canc Control & Populat Sci, Durham, NC USA. [Iversen, Edwin S.] Duke Univ, Dept Stat Sci, Durham, NC USA. [Berchuck, Andrew] Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC USA. [Terry, Kathryn L.; Cramer, Daniel W.] Brigham & Womens Hosp, Obstet & Gynecol Epidemiol Ctr, Boston, MA 02115 USA. [Terry, Kathryn L.; Cramer, Daniel W.; Tworoger, Shelley S.; Poole, Elizabeth M.] Harvard Univ, Sch Med, Boston, MA USA. [Terry, Kathryn L.; Cramer, Daniel W.; Tworoger, Shelley S.; Poole, Elizabeth M.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Tworoger, Shelley S.; Poole, Elizabeth M.] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Olson, Sara H.; Orlow, Irene; Pike, Malcolm C.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Bandera, Elisa V.] Rutgers Canc Inst New Jersey, Canc Prevent & Control, New Brunswick, NJ USA. [Bjorge, Line; Tangen, Ingvild L.; Salvesen, Helga B.; Krakstad, Camilla] Haukeland Hosp, Dept Gynecol & Obstet, N-5021 Bergen, Norway. [Bjorge, Line; Tangen, Ingvild L.; Salvesen, Helga B.; Krakstad, Camilla] Univ Bergen, Dept Clin Sci, Ctr Canc Biomarkers, Bergen, Norway. [Massuger, Leon F. A. G.; van Altena, Anne M.] Radboud Univ Nijmegen, Med Ctr, Dept Gynaecol, NL-6525 ED Nijmegen, Netherlands. [Kiemeney, Lambertus A.; Aben, Katja K. H.] Radboud Univ Nijmegen, Med Ctr, Dept Hlth Evidence, NL-6525 ED Nijmegen, Netherlands. [Kiemeney, Lambertus A.] Radboud Univ Nijmegen, Med Ctr, Dept Urol, NL-6525 ED Nijmegen, Netherlands. [Aben, Katja K. H.] Comprehens Canc Ctr Netherlands, Utrecht, Netherlands. [Bean, Yukie; Pejovic, Tanja; Kellar, Melissa] Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Portland, OR 97201 USA. [Bean, Yukie; Pejovic, Tanja; Kellar, Melissa] Knight Canc Inst, Portland, OR USA. [Le, Nhu D.] BC Canc Agcy, Canc Control Res, Vancouver, BC, Canada. [Cook, Linda S.] Univ New Mexico, Dept Internal Med, Div Epidemiol & Biostat, Albuquerque, NM 87131 USA. [Kelemen, Linda E.] Alberta Hlth Serv Canc Care, Dept Populat Hlth Res, Calgary, AB, Canada. [Kelemen, Linda E.] Univ Calgary, Dept Med Genet, Calgary, AB, Canada. [Kelemen, Linda E.] Univ Calgary, Dept Oncol, Calgary, AB, Canada. [Brooks-Wilson, Angela] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC, Canada. [Brooks-Wilson, Angela] Simon Fraser Univ, Dept Biomed Physiol & Kinesiol, Burnaby, BC V5A 1S6, Canada. [Lubinski, Jan; Gronwald, Jacek; Cybulski, Cezary; Jakubowska, Anna] Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland. [Wentzensen, Nicolas; Brinton, Louise A.; Yang, Hannah] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Lissowska, Jolanta] Maria Sklodowska Curie Mem Canc Ctr, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. [Nedergaard, Lotte] Univ Copenhagen, Rigshosp, Dept Pathol, DK-2100 Copenhagen, Denmark. [Campbell, Ian G.] Peter MacCallum Canc Ctr, Div Res, Canc Genet Lab, Melbourne, Vic, Australia. [Campbell, Ian G.] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Parkville, Vic 3052, Australia. [Eccles, Diana] Princess Anne Hosp, Wessex Clin Genet Serv, Southampton, Hants, England. [Glasspool, Rosalind; Carty, Karen; Paul, James] Univ Glasgow, Beatson West Scotland Canc Ctr, Canc Res UK Clin Trials Unit, Glasgow, Lanark, Scotland. [Siddiqui, Nadeem] Glasgow Royal Infirm, Dept Gynaecol Oncol, Glasgow G4 0SF, Lanark, Scotland. [McNeish, Lain A.] Univ Glasgow, Beatson Inst Canc Res, Wolfson Wohl Canc Res Ctr, Inst Canc Sci, Glasgow, Lanark, Scotland. [Sieh, Weiva; McGuire, Valerie; Rothstein, Joseph H.; 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. [Risch, Harvey A.] Yale Univ, Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT USA. [Phelan, Catherine M.] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL USA. [Anton-Culver, Hoda] Univ Calif Irvine, Sch Med, Genet Epidemiol Res Inst, Dept Epidemiol, Irvine, CA 92717 USA. [Ziogas, Argyrios] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA. [Menon, Usha; Gentry-Maharaj, Aleksandra] UCL, Inst Womens Hlth, Womens Canc, London, England. [Harrington, Patricia] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England. [Modugno, Francesmary] Magee Womens Res Inst, Womens Canc Res Program, Pittsburgh, PA USA. [Modugno, Francesmary] Univ Pittsburgh Canc Inst, Pittsburgh, PA USA. [Modugno, Francesmary] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Rossing, Mary Anne] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Ness, Roberta B.] Univ Texas Houston, Sch Publ Hlth, Houston, TX USA. [Pharoah, Paul D. P.] Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Dept Oncol, Cambridge, England. [Pearce, Celeste Leigh] Univ Michigan, Sch Med, Dept Epidemiol, Ann Arbor, MI USA. RP Pearce, CL (reprint author), 1415 Washington Hts,SPH Tower Off 4642, Ann Arbor, MI 48109 USA. EM lpearce@umich.edu RI salvesen, Helga/C-1187-2017; Bjorge, Line/C-1307-2017; Hein, Alexander/F-6999-2010; Brinton, Louise/G-7486-2015; Brooks-Wilson, Angela/E-9399-2012; Bandera, Elisa/M-4169-2014; Massuger, Leon/H-8072-2014; Kiemeney, Lambertus/D-3357-2009; van Altena, Anne/B-9824-2016; Dork, Thilo/J-8620-2012; Aben, Katja/G-9686-2016; Bowtell, David/H-1007-2016; Gronwald, Jacek/A-4576-2017 OI salvesen, Helga/0000-0002-4438-8831; Glasspool, Rosalind/0000-0002-5000-1680; Kjaer, Susanne/0000-0002-8347-1398; Ramus, Susan/0000-0003-0005-7798; Menon, Usha/0000-0003-3708-1732; McNeish, Iain/0000-0002-9387-7586; Orlow, Irene/0000-0001-6234-6961; Krakstad, Camilla/0000-0002-0174-8139; Giles, Graham/0000-0003-4946-9099; Bjorge, Line/0000-0002-0240-2770; Hein, Alexander/0000-0003-2601-3398; Brinton, Louise/0000-0003-3853-8562; Brooks-Wilson, Angela/0000-0003-1009-6408; Bandera, Elisa/0000-0002-8789-2755; Kiemeney, Lambertus/0000-0002-2368-1326; Aben, Katja/0000-0002-0214-2147; Bowtell, David/0000-0001-9089-7525; Gronwald, Jacek/0000-0002-3643-2871 FU US National Cancer Institute [R01-CA076016]; European Commission's Seventh Framework Programme grant [223175 HEALTH F2 2009-223175]; Genetic Associations and Mechanisms in Oncology (GAME-ON); NCI Cancer Post-GWAS Initiative [U19-CA148112]; Ovarian Cancer Association Consortium - Ovarian Cancer Research Fund [PPD/RPCI.07] FX The scientific development and funding for this project were funded by the following: the US National Cancer Institute (R01-CA076016); the COGS project is funded through a European Commission's Seventh Framework Programme grant (agreement number 223175 HEALTH F2 2009-223175); the Genetic Associations and Mechanisms in Oncology (GAME-ON): a NCI Cancer Post-GWAS Initiative (U19-CA148112); the Ovarian Cancer Association Consortium is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). NR 32 TC 6 Z9 6 U1 1 U2 14 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2015 VL 136 IS 3 BP 542 EP 548 DI 10.1016/j.ygyno.2014.12.017 PG 7 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA CD6GJ UT WOS:000351187300020 PM 25528498 ER PT J AU Khoury, P Herold, J Alpaugh, A Dinerman, E Holland-Thomas, N Stoddard, J Gurprasad, S Maric, I Simakova, O Schwartz, LB Fong, J Lee, CCR Xi, LQ Wang, ZF Raffeld, M Klion, AD AF Khoury, Paneez Herold, Jacqueline Alpaugh, Alexandra Dinerman, Ellen Holland-Thomas, Nicole Stoddard, Jennifer Gurprasad, Shakuntala Maric, Irina Simakova, Olga Schwartz, Lawrence B. Fong, Juelia Lee, Chyi-Chia Richard Xi, Liqiang Wang, Zengfeng Raffeld, Mark Klion, Amy D. TI Episodic angioedema with eosinophilia (Gleich syndrome) is a multilineage cell cycling disorder SO HAEMATOLOGICA LA English DT Article ID SEVERE CONGENITAL NEUTROPENIA; HISTAMINE-RELEASE; PERIPHERAL-BLOOD; PROLIFERATION; LYMPHOCYTES; ACTIVATION; MUTATIONS; ELASTASE; HYPEREOSINOPHILIA; THROMBOCYTOPENIA AB Episodic angioedema with eosinophilia (Gleich syndrome) is a rare disorder characterized by episodes of angioedema and eosinophilia that occur at monthly intervals and resolve spontaneously without therapy. Despite the striking periodicity of this disorder, its similarity to other cyclic hematopoietic disorders with multilineage involvement has not been assessed. To characterize the involvement of cell lineages in the etiology and pathogenesis of episodic angioedema with eosinophilia, four subjects were evaluated by blood counts and other analyses over the course of 1-2 months. Surface marker expression was assessed on T cells by flow cytometry and clonality by polymerase chain reaction. Intracellular cytokine evaluation, bone marrow and skin biopsies were performed during different parts of the cycle. Cycling of multiple cell lineages, including neutrophils, lymphocytes and eosinophils, was observed in the four subjects with the disorder with a periodicity of 25-35 days. An aberrant CD3(-)CD4(+) T-cell population was detected in all four subjects, and T-cell receptor rearrangement studies showed a clonal pattern in three subjects. A peak of type II cytokines was detected in the serum of subjects prior to the onset of symptoms and eosinophil cycling and corresponded to ex-vivo type II cytokines detected intracellularly in CD3(+)CD4(+)CD154(+) T cells. Although the etiology of episodic angioedema with eosinophilia is not yet known, multiple lineages, including lymphocytes, neutrophils and mast cells, are involved and may be related to disease pathogenesis. Whether these cells act directly or promote eosinophilia and eosinophil activation remains to be elucidated. All subjects gave informed consent and were evaluated under an Institutional Review Board-approved protocol (NCT00001406). C1 [Khoury, Paneez; Herold, Jacqueline; Alpaugh, Alexandra; Dinerman, Ellen; Fong, Juelia; Klion, Amy D.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Holland-Thomas, Nicole] Leidos Biomed Res Inc, Parasit Dis Lab, Clin Res Directorate CMRP, Frederick Natl Lab Canc Res, Frederick, MD USA. [Stoddard, Jennifer; Gurprasad, Shakuntala; Maric, Irina; Simakova, Olga] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Schwartz, Lawrence B.] Virginia Commonwealth Univ, Div Rheumatol Allergy & Immunol, Dept Internal Med, Richmond, VA USA. [Lee, Chyi-Chia Richard; Xi, Liqiang; Wang, Zengfeng; Raffeld, Mark] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Khoury, P (reprint author), NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. EM khouryp@niaid.nih.gov OI Klion, Amy/0000-0002-4986-5326 FU Division of Intramural Research; NIAID; National Institutes of Health; National Cancer Institute, National Institutes of Health [HHSN2610080001E]; National Institute of Allergy and Infectious Diseases FX Division of Intramural Research, NIAID, National Institutes of Health; Clinical Trials: NCT00001406. This project was funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract N. HHSN2610080001E. 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. This research was supported in part by the National Institute of Allergy and Infectious Diseases. NR 28 TC 7 Z9 7 U1 0 U2 3 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD MAR PY 2015 VL 100 IS 3 BP 300 EP 307 DI 10.3324/haematol.2013.091264 PG 8 WC Hematology SC Hematology GA CD7OK UT WOS:000351279900018 PM 25527564 ER PT J AU Rawson, RA Woody, G Kresina, TF Gust, S AF Rawson, Richard A. Woody, George Kresina, Thomas F. Gust, Steven TI The Globalization of Addiction Research: Capacity-Building Mechanisms and Selected Examples SO HARVARD REVIEW OF PSYCHIATRY LA English DT Article DE addiction; capacity building; drug abuse; drug-related disorders; health services research; international training fellowships; National Institute on Drug Abuse ID METHADONE-MAINTENANCE TREATMENT; PLACEBO-CONTROLLED TRIAL; INJECTION-DRUG USERS; DAR-ES-SALAAM; HIV RISK; HEROIN DEPENDENCE; RANDOMIZED-TRIAL; ST-PETERSBURG; HEPATITIS-C; RELEASE NALTREXONE AB Over the past decade, the amount and variety of addiction research around the world has increased substantially. Researchers in Australia, Canada, United Kingdom, United States, and western Europe have significantly contributed to knowledge about addiction and its treatment. However, the nature and context of substance use disorders and the populations using drugs are far more diverse than is reflected in studies done in Western cultures. To stimulate new research from a diverse set of cultural perspectives, the National Institute on Drug Abuse (NIDA) has promoted the development of addiction research capacity and skills around the world for over 25 years. This review will describe the programs NIDA has developed to sponsor international research and research fellows and will provide some examples of the work NIDA has supported. NIDA fellowships have allowed 496 individuals from 96 countries to be trained in addiction research. The United Arab Emirates and Saudi Arabia have recently developed funding to support addiction research to study, with advice from NIDA, the substance use disorder problems that affect their societies. Examples from Malaysia, Tanzania, Brazil, Russian Federation, Ukraine, Republic of Georgia, Iceland, China, and Vietnam are used to illustrate research being conducted with NIDA support. Health services research, collaboratively funded by the U.S. National Institutes of Health and Department of State, addresses a range of addiction service development questions in low- and middle-income countries. Findings have expanded the understanding of addiction and its treatment, and are enhancing the ability of practitioners and policy makers to address substance use disorders. C1 [Rawson, Richard A.] Univ Calif Los Angeles, David Geffen Sch Med, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90095 USA. [Rawson, Richard A.] Univ Calif Los Angeles, David Geffen Sch Med, UCLA Integrated Subst Abuse Programs, Los Angeles, CA 90095 USA. [Woody, George] Univ Penn, Perelman Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. [Kresina, Thomas F.] Subst Abuse & Mental Hlth Serv Adm, Ctr Subst Abuse Treatment, Div Pharmacol Therapies, Rockville, MD USA. [Gust, Steven] NIDA, Int Program, Rockville, MD USA. RP Rawson, RA (reprint author), 11075 Santa Monica Blvd,Suite 100, Los Angeles, CA 90025 USA. EM rrawson@mednet.ucla.edu FU NIDA [D43 TW009102, DA027633, UD1 TI023603, U10 DA-13043, KO5 DA-17009, DA032733] FX Supported by NIDA grant nos. D43 TW009102, DA027633, and UD1 TI023603 (Dr. Rawson) and NIDA grant nos. U10 DA-13043, KO5 DA-17009, and DA032733 (Dr. Woody). NR 66 TC 0 Z9 0 U1 5 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1067-3229 EI 1465-7309 J9 HARVARD REV PSYCHIAT JI Harv. Rev. Psychiatr. PD MAR-APR PY 2015 VL 23 IS 2 BP 147 EP 156 DI 10.1097/HRP.0000000000000067 PG 10 WC Psychiatry SC Psychiatry GA CD9TQ UT WOS:000351441700009 PM 25747927 ER PT J AU Lateef, TM Cui, LH Nakamura, E Dozier, J Merikangas, K AF Lateef, Tarannum M. Cui, Lihong Nakamura, Erin Dozier, Jaclyn Merikangas, Kathleen TI Accuracy of Family History Reports of Migraine in a Community-Based Family Study of Migraine SO HEADACHE LA English DT Article DE migraine; family studies; family history ID DISORDERS; TRANSMISSION; ADOLESCENTS; INFORMATION; AGREEMENT; VALIDITY; AURA AB BackgroundFamily history of migraine is the most potent and consistent risk factor for migraine. However, there has been limited systematic research on the reliability of family history information in detecting migraine based on valid diagnostic interviews. This study systematically evaluated the accuracy of migraine defined by the International Classification of Headache Disorders (ICHD-II) based on a direct structured interview compared to structured family history reports. The aim of the present study was to assess the validity of migraine diagnosis provided by family history compared with direct interview using a validated diagnostic interview of headache syndromes in the context of a family study of migraine comorbidity. MethodsThe sample included 921 study participants identified in a cross-sectional community-based controlled family study of comorbidity of migraine and affective disorders recruited from the greater Washington, DC community. Lifetime migraine and tension-type headache were ascertained by direct clinical interview using a validated interview that collects ICHD-II criteria for headache syndromes. A structured history of headache was also collected from all interviewed probands and relatives regarding their relatives. All family history reports were reviewed by the study neurologist according to ICHD-II criteria. Family history ratings and diagnoses were made by the neurologist, who was blinded to the headache diagnosis obtained by direct interview. ResultsThe sensitivity and specificity of family history reports of migraine compared with direct interview were 38.6% and 96.8%, respectively, indicating that the false positive rate was very low, whereas the false negative rate was substantial. The positive and negative predictive values of migraine diagnosis provided by family member report are 90.0% and 67.6%, respectively. ConclusionsOur results confirm that migraine assessed by family member report largely underestimates migraine in relatives. This demonstrates the value of direct interviews with relatives rather than reliance on family history report in both clinical practice and family and genetic studies. Potential steps to improve the reliability of family history report in clinical settings are described. C1 [Lateef, Tarannum M.] George Washington Univ, Sch Med, Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. [Lateef, Tarannum M.; Cui, Lihong; Nakamura, Erin; Dozier, Jaclyn; Merikangas, Kathleen] NIMH, Genet Epidemiol Res Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Lateef, TM (reprint author), George Washington Univ, Sch Med, Childrens Natl Med Ctr, Dept Neurol, 111 Michigan Ave, Washington, DC 20010 USA. EM tlateef@childrensnational.org FU National Institute of Mental Health, Intramural Research Program FX This study was supported by the National Institute of Mental Health, Intramural Research Program. NR 19 TC 6 Z9 6 U1 1 U2 3 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 MAR PY 2015 VL 55 IS 3 BP 407 EP 412 DI 10.1111/head.12501 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA CD6AS UT WOS:000351171200005 PM 25676478 ER PT J AU Ma, T Yu, MY Li, JW Munding, CE Chen, ZY Fei, CL Shung, KK Zhou, QF AF Ma, Teng Yu, Mingyue Li, Jiawen Munding, Chelsea E. Chen, Zeyu Fei, Chunlong Shung, K. Kirk Zhou, Qifa TI Multi-Frequency Intravascular Ultrasound (IVUS) Imaging (vol 62, pg 97, 2015) SO IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL LA English DT Correction C1 [Ma, Teng; Yu, Mingyue; Chen, Zeyu; Shung, K. Kirk; Zhou, Qifa] Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. [Ma, Teng; Yu, Mingyue; Chen, Zeyu; Shung, K. Kirk; Zhou, Qifa] Univ So Calif, NIH, Resource Ctr Med Ultrason Transducer Technol, Los Angeles, CA 90089 USA. [Li, Jiawen] Univ Calif Irvine, Dept Biomed Engn, Irvine, CA USA. [Munding, Chelsea E.] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada. [Fei, Chunlong] Wuhan Univ, Sch Phys & Technol, Wuhan 430072, Hubei, Peoples R China. RP Ma, T (reprint author), Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. EM qifazhou@usc.edu NR 5 TC 1 Z9 1 U1 4 U2 18 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0885-3010 EI 1525-8955 J9 IEEE T ULTRASON FERR JI IEEE Trans. Ultrason. Ferroelectr. Freq. Control PD MAR PY 2015 VL 62 IS 3 BP 604 EP 604 DI 10.1109/TUFFC.2015.007057 PG 1 WC Acoustics; Engineering, Electrical & Electronic SC Acoustics; Engineering GA CD9VH UT WOS:000351446800021 PM 25768827 ER PT J AU Break, TJ Jaeger, M Solis, NV Filler, SG Rodriguez, CA Lim, JK Lee, CCR Sobel, JD Netea, MG Lionakis, MS AF Break, Timothy J. Jaeger, Martin Solis, Norma V. Filler, Scott G. Rodriguez, Carlos A. Lim, Jean K. Lee, Chyi-Chia Richard Sobel, Jack D. Netea, Mihai G. Lionakis, Michail S. TI CX(3)CR1 Is Dispensable for Control of Mucosal Candida albicans Infections in Mice and Humans SO INFECTION AND IMMUNITY LA English DT Article ID CHRONIC MUCOCUTANEOUS CANDIDIASIS; INNATE LYMPHOID-CELLS; DELTA T-CELLS; INFLAMMATORY MONOCYTES; HOST-DEFENSE; OROPHARYNGEAL CANDIDIASIS; SYSTEMIC CANDIDIASIS; ORAL CANDIDIASIS; FUNGAL-INFECTION; TH17 CELLS AB Candida albicans is part of the normal commensal microbiota of mucosal surfaces in a large percentage of the human population. However, perturbations of the host's immune response or bacterial microbiota have been shown to predispose individuals to the development of opportunistic Candida infections. It was recently discovered that a defect in the chemokine receptor CX(3)CR1 increases susceptibility of mice and humans to systemic candidiasis. However, whether CX(3)CR1 confers protection against mucosal C. albicans infection has not been investigated. Using two different mouse models, we found that Cx(3)cr1 is dispensable for the induction of interleukin 17A (IL-17A), IL-22, and IL-23 in the tongue after infection, as well as for the clearance of mucosal candidiasis from the tongue or lower gastrointestinal (GI) tract colonization. Furthermore, the dysfunctional human CX(3)CR1 allele CX(3)CR1-M280 was not associated with development of recurrent vulvovaginal candidiasis (RVVC) in women. Taken together, these data indicate that CX(3)CR1 is not essential for protection of the host against mucosal candidiasis, underscoring the dependence on different mammalian immune factors for control of mucosal versus systemic Candida infections. C1 [Break, Timothy J.; Lionakis, Michail S.] NIAID, Fungal Pathogenesis Unt, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Jaeger, Martin; Netea, Mihai G.] Radboud Univ Nijmegen, Med Ctr, NL-6525 ED Nijmegen, Netherlands. [Jaeger, Martin; Netea, Mihai G.] Radboud Ctr Infect Dis RCI, Nijmegen, Netherlands. [Solis, Norma V.; Filler, Scott G.] Harbor UCLA Med Ctr, Div Infect Dis, Los Angeles Biomed Res Inst, Torrance, CA 90509 USA. [Filler, Scott G.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Rodriguez, Carlos A.; Lim, Jean K.] Icahn Sch Med Mt Sinai, Dept Microbiol, New York, NY 10029 USA. [Lee, Chyi-Chia Richard] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Sobel, Jack D.] Wayne State Univ, Sch Med, Dept Infect Dis, Detroit, MI USA. RP Lionakis, MS (reprint author), NIAID, Fungal Pathogenesis Unt, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM lionakism@niaid.nih.gov RI Netea, Mihai/N-5155-2014; Jaeger, Martin/H-3359-2015 FU Division of Intramural Research, NIAID, NIH; ERC Consolidator Grant [310372]; NIH [R01DE017088] FX This work was supported by the Division of Intramural Research, NIAID, NIH. M.G.N. was supported by an ERC Consolidator Grant ( no. 310372). S.G.F. was supported by NIH grant R01DE017088. NR 49 TC 8 Z9 8 U1 0 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 MAR PY 2015 VL 83 IS 3 BP 958 EP 965 DI 10.1128/IAI.02604-14 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CD6WG UT WOS:000351230200011 PM 25547797 ER PT J AU Zweifler, LE Patel, MK Nociti, FH Wimer, HF Millan, JL Somerman, MJ Foster, BL AF Zweifler, Laura E. Patel, Mudita K. Nociti, Francisco H., Jr. Wimer, Helen F. Millan, Jose L. Somerman, Martha J. Foster, Brian L. TI Counter-regulatory phosphatases TNAP and NPP1 temporally regulate tooth root cementogenesis SO INTERNATIONAL JOURNAL OF ORAL SCIENCE LA English DT Article DE cementum; bone; ectonucleotide pyrophosphatase phosphodiesterase 1; periodontal ligament; progressive ankylosis protein; tissue-nonspecific alkaline phosphatase ID NONSPECIFIC ALKALINE-PHOSPHATASE; CEMENTOBLASTS IN-VITRO; PERIODONTAL-LIGAMENT; ACELLULAR CEMENTUM; PYROPHOSPHATASE PHOSPHODIESTERASE-1; INFANTILE HYPOPHOSPHATASIA; DOMINANT HYPOPHOSPHATASIA; SKELETAL MINERALIZATION; DENTIN MINERALIZATION; DEVELOPMENTAL BIOLOGY AB Cementum is critical for anchoring the insertion of periodontal ligament fibers to the tooth root. Several aspects of cementogenesis remain unclear, including differences between acellular cementum and cellular cementum, and between cementum and bone. Biomineralization is regulated by the ratio of inorganic phosphate (P-i) to mineral inhibitor pyrophosphate (PPi), where local P-i and PPi concentrations are controlled by phosphatases including tissue-nonspecific alkaline phosphatase (TNAP) and ectonucleotide pyrophosphatase/phosphodiesterase 1 (NPP1). The focus of this study was to define the roles of these phosphatases in cementogenesis. TNAP was associated with earliest cementoblasts near forming acellular and cellular cementum. With loss of TNAP in the Alpl null mouse, acellular cementum was inhibited, while cellular cementum production increased, albeit as hypomineralized cementoid. In contrast, NPP1 was detected in cementoblasts after acellular cementum formation, and at low levels around cellular cementum. Loss of NPP1 in the Enpp1 null mouse increased acellular cementum, with little effect on cellular cementum. Developmental patterns were recapitulated in a mouse model for acellular cementum regeneration, with early TNAP expression and later NPP1 expression. In vitro, cementoblasts expressed Alpl gene/protein early, whereas Enpp1 gene/protein expression was significantly induced only under mineralization conditions. These patterns were confirmed in human teeth, including widespread TNAP, and NPP1 restricted to cementoblasts lining acellular cementum. These studies suggest that early TNAP expression creates a low PPi environment promoting acellular cementum initiation, while later NPP1 expression increases PPi, restricting acellular cementum apposition. Alterations in PPi have little effect on cellular cementum formation, though matrix mineralization is affected. C1 [Zweifler, Laura E.; Patel, Mudita K.; Nociti, Francisco H., Jr.; Somerman, Martha J.; Foster, Brian L.] NIAMSD, NIAMS, NIH, Bethesda, MD 20892 USA. [Nociti, Francisco H., Jr.] Univ Estadual Campinas, Sch Dent, Div Periodont, Dept Prosthodont & Periodont, Piracicaba, Brazil. [Wimer, Helen F.] Smithsonian Inst, Natl Museum Amer Hist, Dept Vertebrate Zool, Washington, DC 20560 USA. [Millan, Jose L.] Sanford Burnham Med Res Inst, Sanford Childrens Hlth Res Ctr, La Jolla, CA USA. RP Foster, BL (reprint author), NIAMSD, NIAMS, NIH, Bldg 50 Room 4120, Bethesda, MD 20892 USA. EM brian.foster@nih.gov RI Nociti, Francisco/G-4907-2015; Foster, Brian/H-8375-2015 OI Foster, Brian/0000-0003-3444-0576 FU Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the National Institutes of Health (NIH); NIH [JLM-DE12889, AR53102] FX This research was supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the National Institutes of Health (NIH) and extramural NIH funding (JLM-DE12889 and AR53102). The authors thank Dr Thaisangela Rodrigues for her role in development and execution of the mouse periodontal defect model featured here and in a previous publication. NR 85 TC 6 Z9 6 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1674-2818 EI 2049-3169 J9 INT J ORAL SCI JI Int. J. Oral Sci. PD MAR PY 2015 VL 7 IS 1 BP 27 EP 41 DI 10.1038/ijos.2014.62 PG 15 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA CD6HH UT WOS:000351189700006 PM 25504209 ER PT J AU Rogers, T Ratnayaka, K Sonmez, M Franson, DN Schenke, WH Mazal, JR Kocaturk, O Chen, MY Faranesh, AZ Lederman, RJ AF Rogers, Toby Ratnayaka, Kanishka Sonmez, Merdim Franson, Dominique N. Schenke, William H. Mazal, Jonathan R. Kocaturk, Ozgur Chen, Marcus Y. Faranesh, Anthony Z. Lederman, Robert J. TI Transatrial Intrapericardial Tricuspid Annuloplasty SO JACC-CARDIOVASCULAR INTERVENTIONS LA English DT Article DE annuloplasty; structural heart interventions; transcatheter repair; tricuspid regurgitation ID FUNCTIONAL MITRAL REGURGITATION; 3-DIMENSIONAL ECHOCARDIOGRAPHY; HEART-FAILURE; REPLACEMENT; PREDICTORS; MANAGEMENT; THERAPY; IMPACT; VALVES AB OBJECTIVES This study sought to demonstrate transcatheter deployment of a circumferential device within the pericardial space to modify tricuspid annular dimensions interactively and to reduce functional tricuspid regurgitation (TR) in swine. BACKGROUND Functional TR is common and is associated with increased morbidity and mortality. There are no reported transcatheter tricuspid valve repairs. We describe a transcatheter extracardiac tricuspid annuloplasty device positioned in the pericardial space and delivered by puncture through the right atrial appendage. We demonstrate acute and chronic feasibility in swine. METHODS Transatrial intrapericardial tricuspid annuloplasty (TRAIPTA) was performed in 16 Yorkshire swine, including 4 with functional TR. Invasive hemodynamics and cardiac magnetic resonance imaging (MRI) were performed at baseline, immediately after annuloplasty and at follow-up. RESULTS Pericardial access via a right atrial appendage puncture was uncomplicated. In 9 naive animals, tricuspid septal-lateral and anteroposterior dimensions, the annular area and perimeter, were reduced by 49%, 31%, 59%, and 24% (p < 0.001), respectively. Tricuspid leaflet coaptation length was increased by 53% (p < 0.001). Tricuspid geometric changes were maintained after 9.7 days (range, 7 to 14 days). Small effusions (mean, 46 ml) were observed immediately post-procedure but resolved completely at follow-up. In 4 animals with functional TR, severity of regurgitation by intracardiac echocardiography was reduced. CONCLUSIONS Transatrial intrapericardial tricuspid annuloplasty is a transcatheter extracardiac tricuspid valve repair performed by exiting the heart from within via a transatrial puncture. The geometry of the tricuspid annulus can interactively be modified to reduce severity of functional TR in an animal model. (C) 2015 by the American College of Cardiology Foundation. C1 [Rogers, Toby; Ratnayaka, Kanishka; Sonmez, Merdim; Franson, Dominique N.; Schenke, William H.; Mazal, Jonathan R.; Kocaturk, Ozgur; Chen, Marcus Y.; Faranesh, Anthony Z.; Lederman, Robert J.] NHLBI, Cardiovasc & Pulm Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Ratnayaka, Kanishka] Childrens Natl Med Ctr, Dept Cardiol, Washington, DC 20010 USA. [Kocaturk, Ozgur] Bogazici Univ, Inst Biomed Engn, Istanbul, Turkey. 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 Rogers, Toby/0000-0002-6043-3137; lederman, robert/0000-0003-1202-6673 FU Division of Intramural Research, NHLBI, NIH [Z01-HL006040] FX This work was supported by the Division of Intramural Research, NHLBI, NIH (Z01-HL006040). Dr. Rogers, Dr. Ratnayaka, Dr. Sonmez, Ms. Franson, Dr. Kocaturk, and Dr. Lederman are coinventors on patents, assigned to NIH, for TRAIPTA devices. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 23 TC 11 Z9 11 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-8798 EI 1876-7605 J9 JACC-CARDIOVASC INTE JI JACC-Cardiovasc. Interv. PD MAR PY 2015 VL 8 IS 3 BP 483 EP 491 DI 10.1016/j.jcin.2014.10.013 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CD6TC UT WOS:000351221300023 PM 25703872 ER PT J AU Sugar, A Gal, RL Kollman, C Raghinaru, D Dontchev, M Croasdale, CR Feder, RS Holland, EJ Lass, JH Macy, JI Mannis, MJ Smith, PW Soukiasian, SH Beck, RW Chow, CY Dunn, SP Heidemann, DG MacLeod, T Price, T Belin, MW Schultze, RL Semeiks, C Sutherland, C Oliva, MS Rotkis, WM Huddleston, C McDonald, R Taylor, J Verdier, DD Johnson, P Lass, JH Reinhart, WJ Singh, A Thomas, JM Trocme, SD Brown, L Mines, K Murray, M Norell, M Shaffer, S Washington, K Hamilton, SM Jayawant, GC Lee, WB Larson, J Simner, M Gross, RH Shaw, EL Blackburn, P Maskin, SL Eggers, E Lutzk, H Wagner, S Ayres, BD Ayres, BD Raber, IM DiCicco, J Spanelis-Diaz, I Sugar, J Tu, E Byrne, D Gorovoy, MS Glinos, D Lehet, R Nolan, B Manning, FJ Shelly, B Boland, TS Pascucci, SE Kunz, D Farjo, QA Meyer, RF Mian, SI Soong, HK Sugar, A Hussain, M Knowlton, J Pope, C Radenbaugh, P Kellogg, WK Galentine, PG Rosen, GB Ugland, DN Schafer, M Hannush, SB Bokosky, JE Riner, D Caudill, JW Coleman, L Feder, RS Kaminski, L Affeldt, JC Blanton, CL Cancino, M Holland, EJ Jost, A Meyer, A Bowman, RW Cavanagh, HD El-Agha, MSH McCulley, JP Molai, M Gillette, TE Buchan, I Corrigan, M Leahey, AB Malinowski, A Croasdale, CR Blaser, S DeBaufer, J Moudry, L Eiferman, RA Shields, S Soukiasian, SH Brown, K Morse, PA Sexton, P Dholakia, BK Randleman, JB Stulting, RD Brown, J Larson, P Loupe, D Stark, WJ Pratzer, K Kenyon, KR Rodman, RC Crompton, K Beebe, WE Gelender, H Heinle, S Ching, SS Plotnik, RD Anstey, J Fedick, N MacDowell, P Skrine, K Stoutenburg, A Goldberg, MA Owen, K Sumers, K Spentz, L Wykle, A Chem, KC Fynn-Thompson, NA McColgin, AZ Raizman, MB Healy, P Pereira, J Rosenfeld, SI Salvati, E Beach, D Davis, EA Hardten, DR Lindstrom, RL DeMarchi, J Jordan, A Lindstrom, R Mork, S Rockvam, A Mannis, MJ Imson, K Saya, M Sponzo, M Wallace, C Ford, JG Meisler, DM Holody, L Dobbins, K Price, FW Zeh, WG Quillin, C Berkowitz, PJ Zubik, L Lindquist, TD Sims, L Goodman, DF Ali, AM Beatty, RF Sutphin, JE Farjo, AA Goins, KM Mullinnix, C Burris, TE Johnson, S Kerns, D Powell, J Swenson, P Shriver, PA Williams, D Perry, K Wells, M Self, CA Wilbanks, GA Chute, C Hart, C Chuck, RS Gaster, RN Bradley, M Cohen, A Eghbali, K Farid, M Garg, S Grijalva, J Lomazow, W Kielty, DW Davis, GH Bourg, JM Van Meter, WS Webb, J Smith, PW Bradshaw, R Mewborn, T Sanchez, J Schaeffer, AR Owens, C Price, C Cohen, EJ Laibson, PR Rapuano, CJ Gardiner, A Baratz, KH Halpern, BL Pavilack, MA Gallagher, S Rosen, GB Doughman, DJ Kaufman, SC Cook, S Holleschau, A Perl, T Pak, SM Fornelos, A Cowden, JW Perlman, EM Cozzo, J Gallagher-Sylvia, M Olson, LE Skoog, ED Dobbs, E Gruzensky, WD Groos, EB Alexander, D Mifflin, MD Lundergan, MK Harrison, D Berger, ST Hyszczak, S Solomon, KD Bradham, C Dennis, RF Rubenstein, JB Levine, S Khan, H Sheth, N Voskull-Marre, D Kostick, AMP Santander, SH Roth, AS Bealer, LA Macy, JI O'Day, DG Maynard, L Terry, MA Sossi, NP Walter, KA Fish, J Johnston, FM Mavin, KL Mccoy, KE O'Keefe, MB Cole, GJ Johnston, DF Jones, MA Farazdaghi, SM Walunas, EN Montoya, MM Iliakis, B McDonald, RD Ostermiller, ML Saltwick, CE Woody, JK Weaver, MH Christ, MJ Gross, MB Engel, CR Dale, RA Hackl, SK Henriksen, EJ Kalmoe, KJ Larson, JM Malling, JV Philippy, BJ Hayes, SM Lytle, RE Rechtshaffen, DA Varnum, B Angel, EB Durell, MD Williams, TR Janssen, SV Kraus, BE McLain, MB Rossi, JA Heck, EL Hayes, MS Davis, GC Chavez, TL Oswald, LD Ruiz, NB Penta, JG Dietz, WE Nary, JL Sheriff, KR Driver, NC Faircloth, WJ Williams, PE Weber, K Barker, JW Bridges, DM Soper, M Allen, B Wright, SJ Martin, JR Watson, AJ McDonough, G Beilby, KD Fraser, LK Sharpe, TS Arffa, RC Tramber, MA Crow, BL Fisher, MM Stoeger, CG Jacobs, E Filbin, MP Mather, JI McGriff, CM Meinecke, EE Mason, PJ Locke, GD Reiter, JF Korroch, DE Thomas, PM Lange, WA Moore, RF Williams, LJ Friedhoff, YD Walkenbach, RJ Glover, JE Kafton, BA Lage, KJ Horn, BS Bottoms, HT Kerns, ER Jessen, R Dennis, WH Beck, RW Gal, RL Kollman, C Raghinaru, D Powe, A Ruedy, KJ Lester, LA Strayer, HJ Mares, ST Evans, A Parrimon, YA Gray, M Lass, JH Benetz, BA Burke, S Edwards, S Gentile, C Karpinecz, L Madere, M Redford, M Cotch, MF Fisher, M Bourne, W Redford, M Fishman, RS Foulks, G Musch, DC Holland, EJ Mannis, MJ Cotch, MF Dunn, S Heck, E Johnston, F Lass, JH Lindquist, T Montoya, MM Redford, M Sugar, A Sugar, J Woody, J AF Sugar, Alan Gal, Robin L. Kollman, Craig Raghinaru, Dan Dontchev, Mariya Croasdale, Christopher R. Feder, Robert S. Holland, Edward J. Lass, Jonathan H. Macy, Jonathan I. Mannis, Mark J. Smith, Patricia W. Soukiasian, Sarkis H. Beck, Roy W. Chow, Christopher Y. Dunn, Steven P. Heidemann, David G. MacLeod, Tina Price, Theresa Belin, Michael W. Schultze, Robert L. Semeiks, Cassandra Sutherland, Charity Oliva, Matthew S. Rotkis, Walter M. Huddleston, Cindy McDonald, Richard Taylor, Joy Verdier, David D. Johnson, Paula Lass, Jonathan H. Reinhart, William J. Singh, Annapurna Thomas, Joseph M. Trocme, Stefan D. Brown, Lauren Mines, Kristee Murray, Megin Norell, Marie Shaffer, Stephanie Washington, Kalisha Hamilton, Stephen M. Jayawant, Gina C. Lee, W. Barry Larson, Jacqueline Simner, Melanie Gross, Robert H. Shaw, Edward L. Blackburn, Pamela Maskin, Steven L. Eggers, Eloise Lutzk, Harriet Wagner, Sherry Ayres, Brandon D. Nagra, Parveen K. Raber, Irving M. DiCicco, Joy Spanelis-Diaz, Irene Sugar, Joel Tu, Elmer Byrne, Dolores Gorovoy, Mark S. Glinos, Deborah Lehet, Robert Nolan, Bernadette Manning, Francis J. Shelly, Brenda Boland, Thomas S. Pascucci, Stephen E. Kunz, Donna Farjo, Qais A. Meyer, Roger F. Mian, Shahzad I. Soong, H. Kaz Sugar, Alan Hussain, Munira Knowlton, Jessica Pope, Cindy Radenbaugh, Paulina Kellogg, W. K. Galentine, Paul G. Rosen, Gerald B. Ugland, David N. Schafer, Mara Hannush, Sadeer B. Bokosky, John E. Riner, Donna Caudill, James W. Coleman, Lea Feder, Robert S. Kaminski, Lori Affeldt, John C. Blanton, Christopher L. Cancino, Monica Holland, Edward J. Jost, Amy Meyer, Aimee Bowman, R. Wayne Cavanagh, H. Dwight El-Agha, Mohamed-Sameh H. McCulley, James P. Molai, Mike Gillette, Thomas E. Buchan, Isabel Corrigan, Michelle Leahey, Alan B. Malinowski, Ann Croasdale, Christopher R. Blaser, Stephanie DeBaufer, Jane Moudry, LuAnne Eiferman, Richard A. Shields, Shannon Soukiasian, Sarkis H. Brown, Ken Morse, Patti-Ann Sexton, Patricia Dholakia, Bhairavi K. Randleman, James B. Stulting, R. Doyle Brown, Jayne Larson, Paul Loupe, Donna Stark, Walter J. Pratzer, Kimberly Kenyon, Kenneth R. Rodman, Richard C. Crompton, Kari Beebe, Walter E. Gelender, Henry Heinle, Sidney Ching, Steven S. Plotnik, Ronald D. Anstey, Jennifer Fedick, Nancy MacDowell, Peter Skrine, Karen Stoutenburg, Ann Goldberg, Marc A. Owen, Kathy Sumers, Karen Spentz, Lisa Wykle, Amanda Chem, Kenneth C. Fynn-Thompson, Nicoletta A. McColgin, Ann Z. Raizman, Michael B. Healy, Patricia Pereira, Jacqueline Rosenfeld, Steven I. Salvati, Ellen Beach, Delray Davis, Elizabeth A. Hardten, David R. Lindstrom, Richard L. DeMarchi, Janet Jordan, Alexander Lindstrom, Richard Mork, Sara Rockvam, Allison Mannis, Mark J. Imson, Katrina Saya, Michael Sponzo, Marilyn Wallace, Cindy Ford, Jerry G. Meisler, David M. Holody, Laura Dobbins, Kendall Price, Francis W., Jr. Zeh, William G. Quillin, Clorissa Berkowitz, Peter J. Zubik, Lori Lindquist, Thomas D. Sims, Linda Goodman, Daniel F. Ali, Abdulfatah M. Beatty, Richard F. Sutphin, John E. Farjo, Ayad A. Goins, Kenneth M. Mullinnix, Connie Burris, Terry E. Johnson, Susan Kerns, Dawn Powell, Jenni Swenson, Portia Shriver, Peter A. Williams, Dennis Perry, Kelly Wells, Monica Self, Cynthia A. Wilbanks, Garth A. Chute, Courtney Hart, Cheryl Chuck, Roy S. Gaster, Ronald N. Bradley, Michael Cohen, Andre Eghbali, Kouroush Farid, Marjan Garg, Sumit Grijalva, Jeff Lomazow, Whitney Kielty, David W. Davis, Garvin H. Bourg, J. Mike Van Meter, Woodford S. webb, Jan Smith, Patricia W. Bradshaw, Robbin Mewborn, Tineta Sanchez, Jorge Schaeffer, Alan R. Owens, Chasity Price, Charlisha Cohen, Elisabeth J. Laibson, Peter R. Rapuano, Christopher J. Gardiner, Andrea Baratz, Keith H. Halpern, Barton L. Pavilack, Mark A. Gallagher, Shawn Rosen, Gerald B. Doughman, Donald J. Kaufman, Stephen C. Cook, Sally Holleschau, Ann Perl, Theodore Pak, Soo Mee Fornelos, Angelina Cowden, John W. Perlman, Elliot M. Cozzo, Joanie Gallagher-Sylvia, Margaret Olson, Lance E. Skoog, Erik D. Dobbs, Elaine Gruzensky, William D. Groos, Erich B., Jr. Alexander, Denise Mifflin, Mark D. Lundergan, Maureen K. Harrison, Deborah Berger, Steven T. Hyszczak, Sandy Solomon, Kerry D. Bradham, Carol Dennis, Richard F. Rubenstein, Jonathan B. Levine, Sarah Khan, Heena Sheth, Nisha Voskull-Marre, Denise Kostick, Alexandra M. P. Santander, Samuel H. Roth, Allen S. Bealer, Laura A. Macy, Jonathan I. O'Day, David G. Maynard, Linda Terry, Mark A. Sossi, Nunzio P. Walter, Keith A. Fish, Joan Johnston, Florence M. Mavin, Kyle L. McCoy, Kristen E. O'Keefe, Michael B. Cole, Gerald J. Johnston, Diane F. Jones, Mark A. Farazdaghi, Sameera M. Walunas, Elizabeth N. Montoya, Monty M. Iliakis, Bernie McDonald, Rick D. Ostermiller, Misty L. Saltwick, Cathy E. Woody, Jason K. Weaver, Mark H. Christ, Michael J. Gross, Mark B. Engel, Carol R. Dale, Raylene A. Hackl, Stephanie K. Henriksen, Elena J. Kalmoe, Kathryn J. Larson, Jennifer M. Malling, Jackie V. Philippy, Brian J. Hayes, Sue M. Lytle, Robert E. Rechtshaffen, David A. Varnum, Bruce Angel, Erin B. Durell, Matt D. Williams, Teresa R. Janssen, Susan V. Kraus, Brian E. McLain, Marcy B. Rossi, Jackie A. Heck, Ellen L. Hayes, Marilyn S. Davis, Gregory C. Chavez, Tara L. Oswald, Lori D. Ruiz, Noreen B. Penta, Jeffrey G. Dietz, Wayne E. Nary, Jennifer L. Sheriff, Kenneth R. Driver, Nancy C. Faircloth, William J. Williams, Paul E. Weber, Kurt Barker, Jerry W. Bridges, Donna M. Soper, Mark Allen, Betsy Wright, Samantha J. Martin, James R. Watson, Anne J. McDonough, Greg Beilby, Kristel D. Fraser, Linda K. Sharpe, Tammi S. Arffa, Robert C. Tramber, Michael A. Crow, Barbara L. Fisher, Matthew M. Stoeger, Chris G. Jacobs, Edmund Filbin, Michael P. Mather, James I. McGriff, Christopher M. Meinecke, Eric E. Mason, Patricia J. Locke, Garret D. Reiter, Janice F. Korroch, David E. Thomas, Penelope M. Lange, Wayne A. Moore, Rosemary F. Williams, Lee J. Friedhoff, Yvette D. Walkenbach, Ronald J. Glover, Jennifer E. Kafton, Brenda A. Lage, Kraig J. Horn, Brenda S. Bottoms, H. Tommy Kerns, Ellen R. Jessen, Raymond Dennis, William H. Beck, Roy W. Gal, Robin L. Kollman, Craig Raghinaru, Dan Powe, Alandra Ruedy, Katrina J. Lester, Lee Anne Strayer, Heidi J. Mares, Shelly T. Evans, Amber Parrimon, Yazandra A. Gray, Michael Lass, Jonathan H. Benetz, Beth Ann Burke, Stephanie Edwards, Shannon Gentile, Carmella Karpinecz, Lori Madere, Mark Redford, Maryann Cotch, Mary Frances Fisher, Marian Bourne, William Redford, Maryann Fishman, Rabbi Samuel Foulks, Gary Musch, David C. Holland, Edward J. Mannis, Mark J. Cotch, Mary Frances Dunn, Steven Heck, Ellen Johnston, Florence Lass, Jonathan H. Lindquist, Thomas Montoya, Monty M. Redford, Maryann Sugar, Alan Sugar, Joel Woody, Jason CA Writing Comm Cornea Donor Study Re TI Factors Associated With Corneal Graft Survival in the Cornea Donor Study SO JAMA OPHTHALMOLOGY LA English DT Article ID ENDOTHELIAL-CELL DENSITY; PENETRATING KERATOPLASTY; RISK-FACTORS; FAILURE; TRANSPLANTATION; AGE; THICKNESS; DYSTROPHY AB IMPORTANCE The Cornea Donor Study (CDS) showed that donor age is not a factor in survival of most penetrating keratoplasties for endothelial disease. Secondary analyses confirm the importance of surgical indication and presence of glaucoma in outcomes at 10 years. OBJECTIVE To assess the relationship between donor and recipient factors and corneal graft survival in the CDS. DESIGN, SETTING, AND PARTICIPANTS Multicenter prospective, double-masked, controlled clinical trial conducted at 80 clinical sites. One hundred five surgeons enrolled 1090 participants undergoing corneal transplant for a moderate-risk condition, principally Fuchs dystrophy or pseudophakic or aphakic corneal edema (PACE). Forty-three eye banks provided corneas. INTERVENTIONS Corneas from donors younger than 66 years and donors 66 years or older were assigned, masked to donor age. Surgery and postoperative care were performed according to the surgeons' usual routines. Participants were followed up for as long as 12 years. MAIN OUTCOMES AND MEASURES Graft failure, defined as a regrafting procedure or a cloudy cornea for 3 consecutive months. RESULTS The 10-year cumulative probability of graft failure was higher in participants with PACE than in those with Fuchs dystrophy (37% vs 20%; hazard ratio [HR], 2.1 [99% CI, 1.4-3.0]; P < .001) and in participants with a history of glaucoma before penetrating keratoplasty, particularly with prior glaucoma surgery (58% with prior glaucoma surgery and use of medications to lower intraocular pressure at the time of surgery vs 22% with no history of glaucoma surgery or medication use; HR, 4.1 [99% CI, 2.2-7.5]; P < .001). We found trends toward increased graft failure in recipients who were 70 years or older compared with those younger than 60 years (29% vs 19%; HR, 1.2 [99% CI, 0.7-2.1]; P = .04) or were African American (HR, 1.5; P = .11) or who had a history of smoking (35% vs 24%; HR, 1.6 [99% CI, 0.9-2.8]; P = .02). Lower endothelial cell density (ECD) and higher corneal thickness (CT) at 6 months (6% vs 41% for ECD >= 2700 vs < 1700 cells/mm(2) [P < .001]; 14% vs 36% for CT < 500 vs >= 600 mu m [P = .001]), 1 year (4% vs 39% for ECD >= 2700 vs < 1700 cells/mm(2) [P < .001]; 18% vs 28% for CT < 500 vs >= 600 mu m [P = .04]), and 5 years (2% vs 29% for ECD >= 1500 vs < 500 cells/mm(2) [P < .001]; 7% vs 34% for CT < 550 vs >= 650 mu m [P < .001]) were associated with subsequent graft failure. CONCLUSIONS AND RELEVANCE Most penetrating corneal grafts for Fuchs dystrophy or PACE remain clear at 10 years. The risk for failure is greater for graft recipients with PACE and those with a history of glaucoma. Measurements of ECD and CT during the course of postkeratoplasty follow-up are associated with a risk for failure. However, even with very low ECD and high CT at 5 years, most corneas remain clear at 10 years. C1 [Sugar, Alan] Jaeb Ctr Hlth Res, CDS Coordinating Ctr, Tampa, FL 33647 USA. [Sugar, Alan; Farjo, Qais A.; Meyer, Roger F.; Mian, Shahzad I.; Soong, H. Kaz; Sugar, Alan; Hussain, Munira; Knowlton, Jessica; Pope, Cindy; Radenbaugh, Paulina; Kellogg, W. K.] Univ Michigan, WK Kellogg Eye Ctr, Ann Arbor, MI 48109 USA. [Gal, Robin L.; Kollman, Craig; Raghinaru, Dan; Dontchev, Mariya; Beck, Roy W.] Jaeb Ctr Hlth Res, Tampa, FL USA. [Croasdale, Christopher R.] Davis Duehr Dean Clin, Madison, WI USA. [Feder, Robert S.] Northwestern Univ, Feinberg Sch Med, Dept Ophthalmol, Chicago, IL USA. [Holland, Edward J.] Univ Cincinnati, Cincinnati Eye Inst, Cincinnati, OH USA. [Holland, Edward J.] Univ Cincinnati, Dept Ophthalmol & Visual Sci, Cincinnati, OH USA. [Lass, Jonathan H.] Case Western Reserve Univ, Univ Hosp Eye Inst, Cleveland, OH 44106 USA. [Macy, Jonathan I.] Macy Eye Ctr, Los Angeles, CA USA. [Mannis, Mark J.] Univ Calif Davis, Ctr Eye, Davis, CA 95616 USA. [Smith, Patricia W.] Triangle Eye Physicians, Raleigh, NC USA. [Soukiasian, Sarkis H.] Lahey Clin Fdn, Dept Ophthalmol, Burlington, MA USA. Michigan Cornea Consultants PC, Southfield, MI USA. [Belin, Michael W.; Schultze, Robert L.; Semeiks, Cassandra; Sutherland, Charity] Cornea Consultants Albany, Albany, NY USA. [Lass, Jonathan H.; Reinhart, William J.; Trocme, Stefan D.; Brown, Lauren; Mines, Kristee; Murray, Megin; Norell, Marie; Shaffer, Stephanie; Washington, Kalisha] Case Western Reserve Univ, Univ Hosp Eye Inst, Cleveland, OH 44106 USA. [Hamilton, Stephen M.; Jayawant, Gina C.; Lee, W. Barry; Larson, Jacqueline; Simner, Melanie] Eye Consultants Atlanta PC, Atlanta, GA USA. [Gross, Robert H.; Shaw, Edward L.; Blackburn, Pamela] Cornea Consultants Arizona, Phoenix, AZ USA. [Maskin, Steven L.; Eggers, Eloise; Lutzk, Harriet; Wagner, Sherry] Cornea & Eye Surface Ctr, Tampa, FL USA. [Ayres, Brandon D.; Nagra, Parveen K.; Raber, Irving M.; DiCicco, Joy; Spanelis-Diaz, Irene] Ophthalm Subspecialty Consultants, Narberth, PA USA. [Sugar, Joel; Tu, Elmer; Byrne, Dolores] Univ Illinois, Chicago, IL 60680 USA. [Gorovoy, Mark S.; Glinos, Deborah; Lehet, Robert; Nolan, Bernadette] Eye Associates Ft Myers, Ft Myers, FL USA. [Manning, Francis J.; Shelly, Brenda] Eye Phys Lancaster, Lancaster, PA USA. [Boland, Thomas S.; Pascucci, Stephen E.; Kunz, Donna] Northeastern Eye Inst, Scranton, PA USA. [Galentine, Paul G.; Rosen, Gerald B.; Ugland, David N.; Schafer, Mara] Horizon Eye Care, Charlotte, NC USA. [Bokosky, John E.; Riner, Donna] Eye Care San Diego, San Diego, CA USA. [Caudill, James W.; Coleman, Lea] Charleston Eye Care PLLC, Charleston, WV USA. [Feder, Robert S.; Kaminski, Lori] Northwestern Univ, Chicago, IL 60611 USA. [Affeldt, John C.; Blanton, Christopher L.; Cancino, Monica] Inland Eye Inst, Colton, CA USA. [Holland, Edward J.; Jost, Amy; Meyer, Aimee] Cincinnati Eye Inst, Cincinnati, OH USA. [Bowman, R. Wayne; Cavanagh, H. Dwight; El-Agha, Mohamed-Sameh H.; McCulley, James P.; Molai, Mike] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Gillette, Thomas E.; Buchan, Isabel; Corrigan, Michelle] Eye Associates NW Inc PS, Seattle, WA USA. [Leahey, Alan B.; Malinowski, Ann] Lehigh Valley Eye Ctr PC, Allentown, PA USA. [Croasdale, Christopher R.; Blaser, Stephanie; DeBaufer, Jane; Moudry, LuAnne] Davis Duehr Dean Clin, Madison, WI USA. [Blackburn, Pamela; Eiferman, Richard A.; Shields, Shannon] Univ Louisville, Louisville, KY 40292 USA. [Soukiasian, Sarkis H.; Brown, Ken; Morse, Patti-Ann; Sexton, Patricia] Lahey Clin Fdn, Burlington, MA USA. [Dholakia, Bhairavi K.; Randleman, James B.; Stulting, R. Doyle; Loupe, Donna] Emory Univ, Atlanta, GA 30322 USA. [Pratzer, Kimberly] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Kenyon, Kenneth R.; Rodman, Richard C.; Crompton, Kari] Eye Hlth Vision Ctr, N Dartmouth, MA USA. [Beebe, Walter E.; Gelender, Henry; Heinle, Sidney] Cornea Associates Texas, Dallas, TX USA. [Ching, Steven S.; Plotnik, Ronald D.; Anstey, Jennifer; Fedick, Nancy; MacDowell, Peter; Skrine, Karen; Stoutenburg, Ann] Univ Rochester, Rochester, NY USA. [Goldberg, Marc A.; Owen, Kathy] Inst Eye, Tulsa, OK USA. [Chem, Kenneth C.; Fynn-Thompson, Nicoletta A.; McColgin, Ann Z.; Raizman, Michael B.; Healy, Patricia; Pereira, Jacqueline] Ctr Eye Res & Educ, Boston, MA USA. [Rosenfeld, Steven I.; Salvati, Ellen; Beach, Delray] Delray Eye Associates PA, Delray Beach, FL USA. [Davis, Elizabeth A.; Hardten, David R.; Lindstrom, Richard L.; DeMarchi, Janet; Jordan, Alexander; Lindstrom, Richard; Mork, Sara; Rockvam, Allison] Minnesota Eye Consultants PCA, Minneapolis, MN USA. [Mannis, Mark J.; Imson, Katrina; Saya, Michael; Sponzo, Marilyn; Wallace, Cindy] Univ Calif Davis, Davis, CA 95616 USA. [Ford, Jerry G.] Eye Associates Tallahassee, Tallahassee, FL USA. [Meisler, David M.; Holody, Laura] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Dobbins, Kendall; Price, Francis W., Jr.; Zeh, William G.; Quillin, Clorissa] Price Vision Grp, Indianapolis, IN USA. [Lindquist, Thomas D.; Sims, Linda] Grp Hlth Cooperat Puget Sound, Seattle, WA USA. [Ali, Abdulfatah M.; Beatty, Richard F.; Rossi, Jackie A.] Colorado Eye Physicians & Surg, Denver, CO USA. [Sutphin, John E.; Farjo, Ayad A.; Goins, Kenneth M.; Mullinnix, Connie] Univ Iowa, Iowa City, IA USA. [Burris, Terry E.; Johnson, Susan; Kerns, Dawn; Powell, Jenni; Swenson, Portia] Northwest Corneal Serv, Portland, OR USA. [Shriver, Peter A.; Williams, Dennis; Perry, Kelly; Wells, Monica] Southeast Eye Inst PA, Pinellas Pk, FL USA. [Self, Cynthia A.; Wilbanks, Garth A.; Chute, Courtney; Hart, Cheryl] Eastern Maine Eye Associates, Bangor, ME USA. [Chuck, Roy S.; Gaster, Ronald N.; Bradley, Michael; Cohen, Andre; Eghbali, Kouroush; Farid, Marjan; Garg, Sumit; Grijalva, Jeff; Lomazow, Whitney] Univ Calif Irvine, Irvine, CA USA. [Kielty, David W.] Southcoast Eye Care Inc, N Dartmouth, MA USA. [Davis, Garvin H.; Bourg, J. Mike] Univ Texas Med Branch, Galveston, TX 77555 USA. [Schaeffer, Alan R.; Owens, Chasity; Price, Charlisha] Associated Ophthalm Specialists, Memphis, TN USA. [Cohen, Elisabeth J.; Laibson, Peter R.; Rapuano, Christopher J.; Gardiner, Andrea] Corneal Associates PC, Philadelphia, PA USA. [Baratz, Keith H.] Mayo Clin, Coll Med, Rochester, MI USA. [Halpern, Barton L.; Pavilack, Mark A.] Eye Doctors Lancaster, Lancaster, PA USA. [Doughman, Donald J.; Kaufman, Stephen C.; Cook, Sally; Holleschau, Ann] Univ Minnesota, Minneapolis, MN USA. [Perl, Theodore; Pak, Soo Mee; Fornelos, Angelina] Corneal Associates New Jersey, Fairfield, CT USA. [Cowden, John W.; Hayes, Sue M.] Univ Missouri, Columbia, MO USA. [Gallagher-Sylvia, Margaret] Rhode Isl Eye Inst, Providence, RI USA. [Olson, Lance E.; Skoog, Erik D.; Dobbs, Elaine] Spokane Eye Clin, Spokane, WA USA. [Gruzensky, William D.] Pacific Cataract & Laser Inst, Tacoma, WA USA. [Groos, Erich B., Jr.; Alexander, Denise] Cornea Consultants Nashville PLLC, Nashville, TN USA. [Mifflin, Mark D.; Lundergan, Maureen K.; Harrison, Deborah] Univ Utah, Salt Lake City, UT USA. [Solomon, Kerry D.; Bradham, Carol] Med Univ S Carolina, Charleston, SC 29425 USA. [Dennis, Richard F.; Rubenstein, Jonathan B.; Levine, Sarah; Khan, Heena; Sheth, Nisha; Voskull-Marre, Denise] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Kostick, Alexandra M. P.] Atlantic Eye Ctr, Palm Coast, FL USA. [Roth, Allen S.] Cleveland Clin Fdn, Beachwood, OH USA. [Bealer, Laura A.] Eye Physicians & Surg PC, Decatur, GA USA. [O'Day, David G.; Maynard, Linda] Charleston Cornea & Refract Surg PA, Mt Pleasant, SC USA. [Terry, Mark A.] Devers Eye Inst, Portland, OR USA. [Sossi, Nunzio P.] Palm Beach Eye Clin, W Palm Beach, FL USA. [Walter, Keith A.; Fish, Joan] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC 27109 USA. [Gross, Mark B.] Eye Bank, Minneapolis, MN USA. [Engel, Carol R.; Dale, Raylene A.; Hackl, Stephanie K.; Henriksen, Elena J.; Kalmoe, Kathryn J.; Larson, Jennifer M.; Malling, Jackie V.; Philippy, Brian J.] Northeastern New York, Sight Soc, Albany, NY USA. [Hayes, Sue M.; Cotch, Mary Frances] Lions Eye Bank Delaware Valley, Philadelphia, PA USA. [Lytle, Robert E.; Rechtshaffen, David A.] Georgia Eye Bank Inc, Atlanta, GA USA. [Varnum, Bruce; Angel, Erin B.; Durell, Matt D.; Williams, Teresa R.] Cleveland Eye Bank, Cleveland, OH USA. [Janssen, Susan V.; Kraus, Brian E.; McLain, Marcy B.; Rossi, Jackie A.] Transplant Serv Ctr UT Southwestern, Dallas, TX USA. [Hayes, Marilyn S.] Donor Network Arizona, Phoenix, AZ USA. [Davis, Gregory C.; Chavez, Tara L.; Oswald, Lori D.; Ruiz, Noreen B.] San Diego Eye Bank, San Diego, CA USA. [Penta, Jeffrey G.; Dietz, Wayne E.; Nary, Jennifer L.] Med Eye Bank West Virginia, Charleston, WV USA. [Sheriff, Kenneth R.; Driver, Nancy C.] Lifeshare Carolinas, Charlotte, NC USA. [Faircloth, William J.; Williams, Paul E.] North Carolina Eye Bank Inc, Winston Salem, NC USA. [Weber, Kurt; Barker, Jerry W.; Bridges, Donna M.; Soper, Mark; Lester, Lee Anne] Inland Eye & Tissue Bank, Redlands, CA USA. [Allen, Betsy; Wright, Samantha J.] Univ Louisville, Lions Eye Bank, Louisville, KY 40292 USA. [Martin, James R.; Watson, Anne J.] Sierra Eye & Tissue Donor Serv DCI, Sacramento, CA USA. [McDonough, Greg; Beilby, Kristel D.] Rochester Eye & Human Parts Bank Inc, Rochester, MI USA. [Fraser, Linda K.; Sharpe, Tammi S.] Ctr Organ Recovery & Educ, Pittsburgh, PA USA. [Arffa, Robert C.; Tramber, Michael A.] Lions Eye Bank Oregon, Portland, OR USA. [Fisher, Matthew M.; Stoeger, Chris G.] Rocky Mt Lions Eye Bank, Aurora, CO USA. [Jacobs, Edmund; Filbin, Michael P.; Mather, James I.; McGriff, Christopher M.; Meinecke, Eric E.] Iowa Lions Eye Bank, Iowa City, IA USA. [Mason, Patricia J.; Locke, Garret D.; Reiter, Janice F.] Lions Med Eye Bank Eastern Virginia Inc, Norfolk, VA USA. [Korroch, David E.; Thomas, Penelope M.] Southeast Texas Lions Eye Bank Inc, Galveston, TX USA. [Lange, Wayne A.; Moore, Rosemary F.] Mid South Eye Bank Sight Restorat, Memphis, TN USA. [Williams, Lee J.; Friedhoff, Yvette D.] Heartland Lions Eye Bank, Columbia, MO USA. [Walkenbach, Ronald J.; Glover, Jennifer E.; Kafton, Brenda A.; Lage, Kraig J.] South Carolina Lions Eye Bank Inc, Charleston, SC USA. [Horn, Brenda S.; Bottoms, H. Tommy; Kerns, Ellen R.] Utah Lions Eye Bank, Salt Lake City, UT USA. [Gal, Robin L.; Kollman, Craig; Raghinaru, Dan; Dontchev, Mariya; Powe, Alandra; Ruedy, Katrina J.; Lester, Lee Anne; Strayer, Heidi J.; Mares, Shelly T.; Evans, Amber; Parrimon, Yazandra A.; Gray, Michael] Jaeb Ctr Hlth Res, Tampa, FL USA. [Lass, Jonathan H.; Benetz, Beth Ann; Burke, Stephanie; Edwards, Shannon; Gentile, Carmella; Karpinecz, Lori; Madere, Mark] Case Western Reserve Univ, Univ Hosp Eye Inst, Cleveland, OH 44106 USA. [Redford, Maryann; Cotch, Mary Frances] NEI, Bethesda, MD USA. RP Sugar, A (reprint author), Jaeb Ctr Hlth Res, CDS Coordinating Ctr, 15310 Amberly Dr,Ste 350, Tampa, FL 33647 USA. EM cds@jaeb.org FU National Eye Institute, National Institutes of Health, US Department of Health and Human Services [EY12728, EY12358]; Eye Bank Association of America; Bausch Lomb, Inc; Tissue Banks International; Vision Share, Inc; San Diego Eye Bank; Cornea Society; Katena Products, Inc; ViroMed Laboratories, Inc; Midwest Eye Bank; Konan Medical Corp; Eye Bank for Sight Restoration; SightLife; Sight Society of Northeastern New York (Lions Eye Bank of Albany); Lions Eye Bank of Oregon FX This study was supported by cooperative agreements EY12728 and EY12358 with the National Eye Institute, National Institutes of Health, US Department of Health and Human Services, and by the Eye Bank Association of America, Bausch & Lomb, Inc, Tissue Banks International, Vision Share, Inc, San Diego Eye Bank, The Cornea Society, Katena Products, Inc, ViroMed Laboratories, Inc, Midwest Eye Bank (Michigan Eye Bank, Illinois Eye Bank, Cleveland Eye Bank, and Lions Eye Bank of New Jersey), Konan Medical Corp, Eye Bank for Sight Restoration, SightLife, Sight Society of Northeastern New York (Lions Eye Bank of Albany), and Lions Eye Bank of Oregon. NR 23 TC 19 Z9 19 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6165 EI 2168-6173 J9 JAMA OPHTHALMOL JI JAMA Ophthalmol. PD MAR PY 2015 VL 133 IS 3 BP 246 EP 254 DI 10.1001/jamaophthalmol.2014.3923 PG 9 WC Ophthalmology SC Ophthalmology GA CD6UE UT WOS:000351224200003 ER PT J AU Dunn, BK Ghosh, S Kramer, BS AF Dunn, Barbara K. Ghosh, Sharmistha Kramer, Barnett S. TI JNCI and Cancer Prevention SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID INVASIVE BREAST-CANCER; RANDOMIZED CONTROLLED-TRIAL; SURGICAL ADJUVANT BREAST; TELEPHONE COUNSELING INTERVENTION; ADOLESCENT SMOKING-CESSATION; DISEASE-SPECIFIC MORTALITY; BASE-LINE CHARACTERISTICS; RETINOL EFFICACY TRIAL; RISK-ASSESSMENT MODELS; ORAL-CONTRACEPTIVE USE AB The Journal of the National Cancer Institute (JNCI), with its broad coverage of bench research, epidemiologic studies, and clinical trials, has a long history of publishing practice-changing studies in cancer prevention and public health. These include studies of tobacco cessation, chemoprevention, and nutrition. The landmark Breast Cancer Prevention Trial (BCPT)the first large trial to prove efficacy of a preventive medication for a major malignancy-was published in the Journal, as were key ancillary papers to the BCPT. Even when JNCI was not the publication venue for the main trial outcomes, conceptual and design discussions leading to the trial as well as critical follow-up analyses based on trial data from the Prostate Cancer Prevention Trial (PCPT) and the Selenium and Vitamin E Chemoprevention Trial (SELECT) were published in the Journal. The Journal has also published important evidence on very charged topics, such as the purported link between abortion and breast cancer risk. In summary, JNCI has been at the forefront of numerous major publications related to cancer prevention. C1 [Dunn, Barbara K.; Ghosh, Sharmistha; Kramer, Barnett S.] NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. RP Dunn, BK (reprint author), NCI, Canc Prevent Div, NIH, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM dunnb@mail.nih.gov NR 87 TC 0 Z9 0 U1 1 U2 4 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 MAR PY 2015 VL 107 IS 3 AR djv021 DI 10.1093/jnci/djv021 PG 7 WC Oncology SC Oncology GA CD7TZ UT WOS:000351297400021 ER PT J AU Gonzalez-Angulo, AM Krop, I Akcakanat, A Chen, HQ Liu, SY Li, YS Culotta, KS Tarco, E Piha-Paul, S Moulder-Thompson, S Velez-Bravo, V Sahin, AA Doyle, LA Do, KA Winer, EP Mills, GB Kurzrock, R Meric-Bernstam, F AF Gonzalez-Angulo, Ana M. Krop, Ian Akcakanat, Argun Chen, Huiqin Liu, Shuying Li, Yisheng Culotta, Kirk S. Tarco, Emily Piha-Paul, Sarina Moulder-Thompson, Stacy Velez-Bravo, Vivianne Sahin, Aysegul A. Doyle, Laurence A. Do, Kim-Anh Winer, Eric P. Mills, Gordon B. Kurzrock, Razelle Meric-Bernstam, Funda TI SU2C Phase Ib Study of Paclitaxel and MK-2206 in Advanced Solid Tumors and Metastatic Breast Cancer SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID AKT INHIBITOR MK-2206; TRASTUZUMAB RESISTANCE; PIK3CA MUTATIONS; CLINICAL-TRIAL; II TRIAL; COMBINATION; PATHWAY; PTEN; DISCOVERY; THERAPY AB Background: There is preclinical synergism between taxanes and MK-2206. We aim to determine the maximum tolerated dose, safety, and activity of combining MK-2206 and paclitaxel in metastatic cancer. Methods: Patients received weekly doses of paclitaxel at 80 mg/m2 on day 1, followed by MK-2206 orally on day 2 escalated at 90 mg, 135 mg, and 200 mg. Treatment continued until progression, excessive toxicity, or patient request. Blood and tissue were collected for pharmacokinetic and pharmacodynamics markers. A cycle consisted of three weeks of therapy. Dose-limiting toxicity (DLT) was defined as unacceptable toxicity during the first cycle. All statistical tests were two-sided. Results: Twenty-two patients were treated, nine in dose escalation and 13 in dose expansion. Median age was 55 years. Median number of cycles was four. Dose escalation was completed with no DLT. CTCAE Grade 3 or higher adverse events were fatigue (n = 2), rash (n = 2), hyperglycemia (n = 1), and neutropenia (n = 7). Four patients in the expansion phase required MK-2206 dose reduction. Phase II recommended dose was established as paclitaxel 80 mg/m2 weekly on day 1, and MK-2206 135 mg weekly on day 2. Paclitaxel systemic exposure was similar in the presence or absence of MK-2206. Plasma MK-2206 concentrations were similar to data from previous phase I monotherapy. There was a statistically significant decrease in expression of pAKT S473 (P = .01) and pAKT T308 (P = .002) after therapy. PI3K/AKT/mTOR downregulation in tumor tissues and circulating markers did not correlate with tumor response or clinical benefit. There were five objective responses, and nine patients had stable disease. Conclusion: MK-2206 was well tolerated with paclitaxel. Preliminary antitumor activity was documented. C1 [Gonzalez-Angulo, Ana M.; Liu, Shuying; Moulder-Thompson, Stacy] Univ Texas MD Anderson Canc Ctr, Dept Breast Med Oncol, Houston, TX 77030 USA. [Gonzalez-Angulo, Ana M.; Mills, Gordon B.] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA. [Chen, Huiqin; Li, Yisheng; Do, Kim-Anh] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA. [Culotta, Kirk S.] Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA. [Akcakanat, Argun; Tarco, Emily; Piha-Paul, Sarina; Velez-Bravo, Vivianne; Meric-Bernstam, Funda] Univ Texas MD Anderson Canc Ctr, Dept Invest Canc Therapeut, Houston, TX 77030 USA. [Sahin, Aysegul A.] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Meric-Bernstam, Funda] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA. [Krop, Ian; Winer, Eric P.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Hematol Oncol, Boston, MA 02115 USA. [Kurzrock, Razelle] Univ Calif San Diego, Div Hematol Oncol, San Diego, CA 92103 USA. [Doyle, Laurence A.] NCI, Canc Therapy Evaluat Program, NIH, Rockville, MD USA. RP Meric-Bernstam, F (reprint author), Univ Texas MD Anderson Canc Ctr, 1400 Holcombe Blvd,Unit 455, Houston, TX 77030 USA. EM fmeric@mdanderson.org OI LI, Yisheng/0000-0001-9847-8544 FU National Cancer Institute [1K23CA121994, U01 CA062461-18]; ASCO Career Development Award; Komen for the Cure Catalyst Award [KG090341]; American Cancer Society [121329-RSG-11-187-01-TBG, SUC2-AACR-DT0209 01]; Commonwealth Foundation for Cancer research FX This work was supported in part by National Cancer Institute 1K23CA121994 (AMG), ASCO Career Development Award (AMG), Komen for the Cure Catalyst Award KG090341 (AMG), American Cancer Society Research Scholar Grant 121329-RSG-11-187-01-TBG (AMG), SUC2-AACR-DT0209 01(AMG, GBM, FMB), National Cancer Institute U01 CA062461-18 (RK), and the Commonwealth Foundation for Cancer research (AMG). NR 27 TC 2 Z9 2 U1 1 U2 4 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 MAR PY 2015 VL 107 IS 3 AR dju493 DI 10.1093/jnci/dju493 PG 9 WC Oncology SC Oncology GA CD7TZ UT WOS:000351297400013 ER PT J AU Goodwin, PJ Parulekar, WR Gelmon, KA Shepherd, LE Ligibel, JA Hershman, DL Rastogi, P Mayer, IA Hobday, TJ Lemieux, J Thompson, AM Pritchard, KI Whelan, TJ Mukherjee, SD Chalchal, HI Oja, CD Tonkin, KS Bernstein, V Chen, BE Stambolic, V AF Goodwin, Pamela J. Parulekar, Wendy R. Gelmon, Karen A. Shepherd, Lois E. Ligibel, Jennifer A. Hershman, Dawn L. Rastogi, Priya Mayer, Ingrid A. Hobday, Timothy J. Lemieux, Julie Thompson, Alastair M. Pritchard, Kathleen I. Whelan, Timothy J. Mukherjee, Som D. Chalchal, Haji I. Oja, Conrad D. Tonkin, Katia S. Bernstein, Vanessa Chen, Bingshu E. Stambolic, Vuk TI Effect of Metformin vs Placebo on Weight and Metabolic Factors in NCIC CTG MA.32 SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID STAGE BREAST-CANCER; ACTIVATED PROTEIN-KINASE; INSULIN; OBESITY; TRIAL; WOMEN AB Background: Metformin may improve metabolic factors (insulin, glucose, leptin, highly sensitive C-reactive protein [hsCRP]) associated with poor breast cancer outcomes. The NCIC Clinical Trials Group (NCIC CTG) MA. 32 investigates effects of metformin vs placebo on invasive disease-free survival and other outcomes in early breast cancer. Maintaining blinding of investigators to outcomes, we conducted a planned, Data Safety Monitoring Committee-approved, analysis of the effect of metformin vs placebo on weight and metabolic factors at six months, including examination of interactions with baseline body mass index (BMI) and insulin, in the first 492 patients with paired blood samples. Methods: Eligible nondiabetic subjects with T1-3, N0-3, M0 breast cancer who had completed surgery and (neo) adjuvant chemotherapy (if given) provided fasting plasma samples at random assignment and at six months. Glucose was measured locally; blood was aliquoted, frozen, and stored at -80 degrees C. Paired plasma aliquots were analyzed for insulin, hs-CRP, and leptin. Spearman correlation coefficients were calculated and comparisons analyzed using Wilcoxon signed rank test. All statistical tests were two-sided. Results: Mean age was 52.1 +/- 9.5 years in the metformin group and 52.6 +/- 9.8 years in the placebo group. Arms were balanced for estrogen/progesterone receptor, BMI, prior (neo) adjuvant chemotherapy, and stage. At six months, decreases in weight and blood variables were statistically significantly greater in the metformin arm (vs placebo) in univariate analyses: weight -3.0%, glucose -3.8%, insulin -11.1%, homeostasis model assessment -17.1%, leptin -20.2%, hs-CRP -6.7%; all P values were less than or equal to .03. There was no statistically significant interaction of change in these variables with baseline BMI or insulin. Conclusions: Metformin statistically significantly improved weight, insulin, glucose, leptin, and CRP at six months. Effects did not vary by baseline BMI or fasting insulin. C1 [Goodwin, Pamela J.] Univ Toronto, Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada. [Parulekar, Wendy R.; Shepherd, Lois E.; Chen, Bingshu E.] Queens Univ, Canc Res Inst, NCIC Clin Trials Grp, Kingston, ON, Canada. [Gelmon, Karen A.] Univ British Columbia, British Columbia Canc Agcy, NCIC Clin Trials Grp, Vancouver, BC V5Z 1M9, Canada. [Ligibel, Jennifer A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Hershman, Dawn L.] Columbia Univ, Med Ctr, New York, NY USA. [Rastogi, Priya] Univ Pittsburgh, Inst Canc, Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. [Mayer, Ingrid A.] Vanderbilt Univ, Med Ctr, Vanderbilt Ingram Med Ctr, Nashville, TN USA. [Hobday, Timothy J.] Mayo Clin, Coll Med, Rochester, MN USA. [Lemieux, Julie] Hop St Sacrement, CHU Quebec, Ctr Rech, Unite Rech Sante Populat, Quebec City, PQ, Canada. [Thompson, Alastair M.] Natl Inst Canc Res, Breast Clin Studies Grp, London, England. [Pritchard, Kathleen I.] Univ Toronto, Sunnybrook Odette Canc Ctr, Toronto, ON, Canada. [Whelan, Timothy J.; Mukherjee, Som D.] McMaster Univ, Juravinski Canc Ctr, Hamilton Hlth Sci, Hamilton, ON, Canada. [Chalchal, Haji I.] Allan Blair Canc Ctr, Regina, SK, Canada. [Oja, Conrad D.] British Columbia Canc Agcy, Fraser Valley Ctr, Surrey, BC, Canada. [Tonkin, Katia S.] Univ Alberta, Cross Canc Inst, Edmonton, AB, Canada. [Bernstein, Vanessa] Univ British Columbia, British Columbia Canc Agcy, Vancouver Isl Ctr, Vancouver, BC V5Z 1M9, Canada. [Stambolic, Vuk] Univ Toronto, Ontario Canc Inst, Univ Hlth Network, Princess Margaret Hosp, Toronto, ON M5S 1A1, Canada. RP Goodwin, PJ (reprint author), Mt Sinai Hosp, 1284-600 Univ Ave, Toronto, ON M5G 1X4, Canada. EM pgoodwin@mtsinai.on.ca RI Goodwin, Pamela/K-1477-2013; Whelan, Timothy/D-3185-2017 FU Canadian Cancer Society Research Institute [021039]; National Cancer Institute (US) [CA077202]; Breast Cancer Research Foundation (New York); Canadian Breast Cancer Foundation - Ontario Region (Ontario Institute for Cancer Research) [10NOV-467] FX This work was supported by the Canadian Cancer Society Research Institute (#021039), the National Cancer Institute (US) (#CA077202), the Breast Cancer Research Foundation (New York), Canadian Breast Cancer Foundation - Ontario Region (Ontario Institute for Cancer Research) (#10NOV-467), and Apotex Canada (in kind donation of placebo and metformin). NR 20 TC 12 Z9 12 U1 0 U2 4 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 MAR PY 2015 VL 107 IS 3 AR djv006 DI 10.1093/jnci/djv006 PG 8 WC Oncology SC Oncology GA CD7TZ UT WOS:000351297400017 ER PT J AU Hur, K Toiyama, Y Schetter, AJ Okugawa, Y Harris, CC Boland, CR Goel, A AF Hur, Keun Toiyama, Yuji Schetter, Aaron J. Okugawa, Yoshinaga Harris, Curtis C. Boland, C. Richard Goel, Ajay TI Identification of a Metastasis-Specific MicroRNA Signature in Human Colorectal Cancer SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID TUMOR ANGIOGENESIS; HEPATIC RESECTION; LIVER METASTASES; RECTAL-CANCER; EXPRESSION; CELLS; MIR-21; COLON; CARCINOMA; PROFILES AB Background: Distant metastasis is the major cause of mortality in colorectal cancer (CRC). We performed a systemic, comprehensive discovery for expression patterns of metastasis-specific microRNAs (miRNAs) by directly comparing primary CRCs (pCRCs) and matched liver metastases (LMs) and evaluated the feasibility of their clinical application as metastasis-specific biomarkers. Methods: CRC metastasis-specific miRNA profiles were generated by analyzing nine pairs of pCRC and LM tissues, followed by quantitative validation in an independent cohort of 58 pairs of matched pCRC and LM tissues. We evaluated associations between miRNA expression and patient survival and ability to predict metastasis in another 84 patients with CRC. Subsequently, associations were quantitatively validated in 175 CRC tissues and 169 serum samples. Kaplan-Meier, Cox regression, and logistic regression analyses were used. All statistical tests were twosided. Results: Twenty-three miRNAs were identified that were differentially expressed between pCRC and LM (P < .001; FDR < .5). Four miRNAs downregulated in LM (let-7i, miR-10b, miR-221, and miR-320a) and one upregulated miR (miR-885-5p) were quantitatively validated in pCRC (P < .0001). Low let-7i expression in pCRC tissue predicted worsened prognosis (hazard ratio [HR] = 5.0, 95% confidence interval [CI] = 1.0 to 24.4, P = .0479) as well as distant metastasis (odds ratio [OR] = 5.5, 95% CI = 1.1 to 26.8, P = .0334). High miR-10b expression in pCRC tissue independently predicted distant metastasis (OR = 4.9, 95% CI = 1.2 to 19.7, P = .0248). High serum miR-885-5p expression independently predicted prognosis (HR = 2.9, 95% CI = 1.1 to 7.5, P = .0323), LN metastasis (OR = 3.0, 95% CI = 1.3 to 7.2, P = .0116), and distant metastasis (OR = 3.1, 95% CI = 1.0 to 10.0, P = .0456), whereas tissue miR-885-5p expression did not. Expression patterns of miRNAs were confirmed by in situ hybridization. Conclusions: We discovered a metastasis-specific miRNA signature in pCRCs and discovered novel tissue-and serum-based CRC metastasis-specific miRNA biomarkers through intensive validation. These unique miRNAs may be clinically applicable to predict prognosis and distant metastasis in CRC. C1 [Hur, Keun; Toiyama, Yuji; Okugawa, Yoshinaga; Boland, C. Richard; Goel, Ajay] Baylor Univ, Med Ctr, Ctr Gastrointestinal Res, Dallas, TX 75246 USA. [Hur, Keun; Toiyama, Yuji; Okugawa, Yoshinaga; Boland, C. Richard; Goel, Ajay] Baylor Univ, Med Ctr, Ctr Epigenet Canc Prevent & Canc Genom, Baylor Res Inst, Dallas, TX 75246 USA. [Hur, Keun; Toiyama, Yuji; Okugawa, Yoshinaga; Boland, C. Richard; Goel, Ajay] Baylor Univ, Med Ctr, Sammons Canc Ctr, Dallas, TX 75246 USA. [Schetter, Aaron J.; Harris, Curtis C.] NCI, NIH, Bethesda, MD 20892 USA. RP Goel, A (reprint author), Baylor Univ, Med Ctr, Gastrointestinal Canc Res Lab, 3500 Gaston Ave,Suite H-250, Dallas, TX 75246 USA. EM rickbo@baylorhealth.edu; ajay.goel@baylorhealth.edu FU National Cancer Institute, National Institutes of Health [R01 CA72851, CA181572]; Baylor Research Institute FX The present work was supported by grants R01 CA72851 and CA181572 from the National Cancer Institute, National Institutes of Health, and funds from the Baylor Research Institute. NR 32 TC 11 Z9 12 U1 3 U2 6 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 MAR PY 2015 VL 107 IS 3 AR dju492 DI 10.1093/jnci/dju492 PG 11 WC Oncology SC Oncology GA CD7TZ UT WOS:000351297400012 ER PT J AU Kreimer, AR Sherman, ME Sahasrabuddhe, VV Safaeian, M AF Kreimer, Aimee R. Sherman, Mark E. Sahasrabuddhe, Vikrant V. Safaeian, Mahboobeh TI The Case for Conducting a Randomized Clinical Trial to Assess the Efficacy of a Single Dose of Prophylactic HPV Vaccines Among Adolescents SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID HUMAN-PAPILLOMAVIRUS VACCINE; CERVICAL ABNORMALITIES; PARTICLE VACCINE; YOUNG-WOMEN; LONG-TERM; FOLLOW-UP; IMMUNOGENICITY; SAFETY; PROGRAM C1 [Kreimer, Aimee R.; Safaeian, Mahboobeh] NCI, Div Canc Epidemiol & Genet, Infect & Immunoepidemiol Branch, NIH, Bethesda, MD 20892 USA. [Sherman, Mark E.; Sahasrabuddhe, Vikrant V.] NCI, Canc Prevent Div, Breast & Gynecol Canc Res Grp, NIH, Bethesda, MD 20892 USA. [Sherman, Mark E.] NCI, Div Canc Epidemiol & Genet, Human Genet Program, NIH, Bethesda, MD 20892 USA. [Sahasrabuddhe, Vikrant V.] NCI, Div Canc Epidemiol & Genet, Hormonal & Reprod Epidemiol Branch, NIH, Bethesda, MD 20892 USA. [Sahasrabuddhe, Vikrant V.] Vanderbilt Univ, Dept Med, Sch Med, Nashville, TN USA. RP Kreimer, AR (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,RM 6-E104, Bethesda, MD 20892 USA. EM kreimera@mail.nih.gov RI Kreimer, Aimee/H-1687-2015 NR 27 TC 5 Z9 5 U1 0 U2 4 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 MAR PY 2015 VL 107 IS 3 AR dju436 DI 10.1093/jnci/dju436 PG 4 WC Oncology SC Oncology GA CD7TZ UT WOS:000351297400008 ER PT J AU Nyante, SJ Sherman, ME Pfeiffer, RM de Gonzalez, AB Brinton, LA Bowles, EJA Hoover, RN Glass, A Gierach, GL AF Nyante, Sarah J. Sherman, Mark E. Pfeiffer, Ruth M. de Gonzalez, Amy Berrington Brinton, Louise A. Bowles, Erin J. Aiello Hoover, Robert N. Glass, Andrew Gierach, Gretchen L. TI Prognostic Significance of Mammographic Density Change After Initiation of Tamoxifen for ER-Positive Breast Cancer SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID RISK; WOMEN; THERAPY; ASSOCIATION; REDUCTION; PATTERNS; CELLS; TRIAL AB Background: A prior analysis of postmenopausal breast cancer patients linked a decline in mammographic density (MD) following the initiation of tamoxifen treatment with improved survival, but excluded premenopausal women, for whom tamoxifen is the primary anti-endocrine therapy. Therefore, we evaluated change in MD after tamoxifen and breast cancer death among patients age 32 to 87 years. Methods: This case-control study included 349 estrogen receptor (ER)-positive breast cancer patients who were treated with tamoxifen at Kaiser Permanente Northwest (1990-2008): 97 who died from breast cancer (case patients) and 252 who did not (control patients), matched on age and year at diagnosis and disease stage. Percent MD in the unaffected breast was measured at baseline (mean six months before tamoxifen initiation) and follow-up (mean 12 months after initiation). Associations between change in MD and breast cancer death were estimated using conditional logistic regression. Results: Patients in the highest tertile of MD decline had a lower risk of breast cancer death when compared with women in the lowest tertile (odds ratio [OR] = 0.44, 95% confidence interval [CI] = 0.22 to 0.88); results were similar after adjustment for baseline MD (OR = 0.49, 95% CI = 0.23 to 1.02). Reductions in death were observed only among patients in the middle and upper tertiles of baseline MD. Associations did not differ by age, tamoxifen use duration, estrogen and/or progestin use, body mass index, or receipt of chemotherapy or radiotherapy. Conclusion: These data suggest that younger and older ER-positive breast cancer patients who experience large reductions in MD following tamoxifen initiation have an improved prognosis. C1 [Nyante, Sarah J.; Sherman, Mark E.; Pfeiffer, Ruth M.; de Gonzalez, Amy Berrington; Brinton, Louise A.; Hoover, Robert N.; Gierach, Gretchen L.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Sherman, Mark E.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Bowles, Erin J. Aiello] Grp Hlth Res Inst, Seattle, WA USA. [Glass, Andrew] Kaiser Permanente Northwest Ctr Hlth Res, Portland, OR USA. RP Gierach, GL (reprint author), 9609 Med Ctr Dr,Rm 7-E108, Bethesda, MD 20892 USA. EM gierachg@mail.nih.gov RI Brinton, Louise/G-7486-2015; Gierach, Gretchen/E-1817-2016 OI Brinton, Louise/0000-0003-3853-8562; Gierach, Gretchen/0000-0002-0165-5522 FU Intramural Research Program of the National Cancer Institute at the National Institutes of Health FX This work was supported by the Intramural Research Program of the National Cancer Institute at the National Institutes of Health. NR 28 TC 6 Z9 6 U1 0 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 MAR PY 2015 VL 107 IS 3 AR dju425 DI 10.1093/jnci/dju425 PG 11 WC Oncology SC Oncology GA CD7TZ UT WOS:000351297400003 ER PT J AU Robbins, HA Engels, EA Pfeiffer, RM Shiels, MS AF Robbins, Hilary A. Engels, Eric A. Pfeiffer, Ruth M. Shiels, Meredith S. TI Age at Cancer Diagnosis for Blacks Compared With Whites in the United States SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID NON-HODGKIN-LYMPHOMA; BREAST-CANCER; RACIAL DISPARITIES; EARLY-ONSET; SOCIOECONOMIC-STATUS; INCIDENCE PATTERNS; COLORECTAL-CANCER; AFRICAN-AMERICAN; CERVICAL-CANCER; INCIDENCE RATES AB Background: Younger ages at diagnosis for blacks compared with whites have been reported for several cancer types. However, the US black population is younger than the white population, which may bias age comparisons that do not account for the populations at risk. Methods: We analyzed Surveillance, Epidemiology, and End Results data for non-Hispanic blacks and non-Hispanic whites from 18 regions for the year 2010. We calculated crude mean ages at diagnosis among cases of 29 cancer types for whites and blacks. Separately, we calculated adjusted means that corrected for differences in population structure, which we obtained by fitting linear regression models to the ages at diagnosis with statistical weights specific to age and sex. Negative differences indicate younger ages in blacks, while positive differences indicate older ages in blacks. All statistical tests were two-sided. Results: Based on crude means, blacks were diagnosed at younger ages than whites for nearly every cancer type. However, adjustment for population structure shifted the comparisons toward older ages among blacks, and only six statistically significant differences of three or more years remained. Blacks were younger than whites at diagnosis for Kaposi sarcoma (-10.2 years), male soft tissue cancer (-5.6), male anal cancer (-5.5), and non-Hodgkin's lymphoma (-3.7), but older for cervical cancer (+4.7 years) and female thyroid cancer (+3.3). Smaller differences (<3 years) were present for female breast, female colon, lung, pancreas, prostate, and uterine corpus cancers (all P = .001). Conclusions: Most differences between blacks and whites in the age at cancer diagnosis are small. Large differences for a few cancer types may be driven by etiologic and subtype heterogeneity as well as disparities in access to care. C1 [Robbins, Hilary A.; Engels, Eric A.; Pfeiffer, Ruth M.; Shiels, Meredith S.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. RP Robbins, HA (reprint author), 9609 Med Ctr Dr,6-E228, Bethesda, MD 20892 USA. EM hilary.robbins@alumni.duke.edu FU Intramural Research Program of the National Cancer Institute at the National Institutes of Health FX This research was supported by the Intramural Research Program of the National Cancer Institute at the National Institutes of Health. NR 38 TC 0 Z9 0 U1 1 U2 4 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 MAR PY 2015 VL 107 IS 3 AR dju489 DI 10.1093/jnci/dju489 PG 8 WC Oncology SC Oncology GA CD7TZ UT WOS:000351297400010 ER PT J AU Hox, V Desai, A Bandara, G Gilfillan, AM Metcalfe, DD Olivera, A AF Hox, Valerie Desai, Avanti Bandara, Geethani Gilfillan, Alasdair M. Metcalfe, Dean D. Olivera, Ana TI Estrogen increases the severity of anaphylaxis in female mice through enhanced endothelial nitric oxide synthase expression and nitric oxide production SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Anaphylaxis; estrogen; nitric oxide synthase; vascular permeability; mast cells ID NO SYNTHASE; IDIOPATHIC ANAPHYLAXIS; CARDIOVASCULAR-SYSTEM; BODY-TEMPERATURE; UP-REGULATION; SEX-HORMONES; RELEASE; SHOCK; SENSITIVITY; ACTIVATION AB Background: Clinical observations suggest that anaphylaxis is more common in adult women compared with adult men, although the mechanistic basis for this sex bias is not well understood. Objectives: We sought to document sex-dependent differences in a mouse model of anaphylaxis and explore the role of female sex hormones and the mechanisms responsible. Methods: Passive systemic anaphylaxis was induced in female and male mice by using histamine, as well as IgE or IgG receptor aggregation. Anaphylaxis was assessed by monitoring body temperature, release of mast cell mediators and/or hematocrit, and lung weight as a measure of vascular permeability. A combination of ovariectomy, estrogen receptor antagonism, and estrogen administration techniques were used to establish estrogen involvement. Results: Anaphylactic responses were more pronounced in female than male mice. The enhanced severity of anaphylaxis in female mice was eliminated after pretreatment with an estrogen receptor antagonist or ovariectomy but restored after administration of estradiol in ovariectomized mice, demonstrating that the sex-specific differences are due to the female steroid estradiol. Estrogen did not affect mast cell responsiveness or anaphylaxis onset. Instead, it increased tissue expression of endothelial nitric oxide synthase (eNOS). Blockage of NOS activity with the inhibitor L-NG-nitroarginine methyl ester or genetic eNOS deficiency abolished the sex-related differences. Conclusion: Our study defines a contribution of estrogen through its regulation of eNOS expression and nitric oxide production to vascular hyperpermeability and intensified anaphylactic responses in female mice, providing additional mechanistic insights into risk factors and possible implications for clinical management in the further exploration of human anaphylaxis. C1 [Hox, Valerie; Desai, Avanti; Bandara, Geethani; Gilfillan, Alasdair M.; Metcalfe, Dean D.; Olivera, Ana] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Hox, V (reprint author), NIAID, Mast Cell Biol Sect, Lab Allerg Dis, NIH, Bldg 10,Rm 11C209,10 Ctr Dr MSC-1881, Bethesda, MD 20892 USA. EM valeriehox@gmail.com FU Division of Intramural Research Program within the National Institute of Allergy and Infectious Diseases/National Institutes of Health; Research Foundation Flanders (F.W.O.); F.W.O. as well as a Gustave Boel-Sofina-Belgian American Educational Foundation (B.A.E.F.) fellow FX Supported by the Division of Intramural Research Program within the National Institute of Allergy and Infectious Diseases/National Institutes of Health and by Research Foundation Flanders (F.W.O.). V.H. was a research fellow and the recipient of a Travel Grant from F.W.O. as well as a Gustave Boel-Sofina-Belgian American Educational Foundation (B.A.E.F.) fellow. NR 52 TC 16 Z9 17 U1 1 U2 9 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD MAR PY 2015 VL 135 IS 3 BP 729 EP U232 DI 10.1016/j.jaci.2014.11.003 PG 13 WC Allergy; Immunology SC Allergy; Immunology GA CD4PF UT WOS:000351065000020 PM 25553642 ER PT J AU Desai, AG Togias, A Schechter, C Fisher, B Parow, A Skloot, G AF Desai, Alpa G. Togias, Alkis Schechter, Clyde Fisher, Beth Parow, Aimee Skloot, Gwen TI Peripheral airways dysfunction in obesity reflects increased bronchomotor tone SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Letter ID ASTHMA; LEPTIN; TESTS C1 [Desai, Alpa G.] SUNY Stony Brook, Dept Med, Div Pulm Crit Care & Sleep Med, Stony Brook, NY 11794 USA. [Togias, Alkis] NIAID, NIH, Bethesda, MD 20892 USA. [Schechter, Clyde] Albert Einstein Coll Med, Dept Family & Social Med, Bronx, NY 10467 USA. [Fisher, Beth; Parow, Aimee; Skloot, Gwen] Icahn Sch Med Mt Sinai, Dept Med, Div Pulm Crit Care Sleep Med, New York, NY 10029 USA. RP Desai, AG (reprint author), SUNY Stony Brook, Dept Med, Div Pulm Crit Care & Sleep Med, Stony Brook, NY 11794 USA. EM Alpa.Desai@stonybrookmedicine.edu OI Togias, Alkis/0000-0001-9009-5717 NR 10 TC 1 Z9 1 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD MAR PY 2015 VL 135 IS 3 BP 820 EP 822 DI 10.1016/j.jaci.2014.09.016 PG 8 WC Allergy; Immunology SC Allergy; Immunology GA CD4PF UT WOS:000351065000033 PM 25441295 ER PT J AU Pacis, MM Fortin, CN Zarek, SM Mumford, SL Segars, JH AF Pacis, Michelle M. Fortin, Chelsea N. Zarek, Shvetha M. Mumford, Sunni L. Segars, James H. TI Vitamin D and assisted reproduction: should vitamin D be routinely screened and repleted prior to ART? A systematic review SO JOURNAL OF ASSISTED REPRODUCTION AND GENETICS LA English DT Review DE Vitamin D; Assisted reproductive technology; ART; In vitro fertilization; IVF ID POLYCYSTIC-OVARY-SYNDROME; GLYCATION END-PRODUCTS; PARATHYROID-HORMONE CONCENTRATIONS; D DEFICIENCY; INSULIN-RESISTANCE; D-RECEPTOR; 1,25-DIHYDROXYVITAMIN D-3; SPONTANEOUS-ABORTION; HUMAN SPERMATOZOA; FOLLICULAR-FLUID AB To review the current literature regarding the role of vitamin D status in pregnancy outcomes in women undergoing assisted reproductive technology (ART) and to assess cost-effectiveness of routine vitamin D deficiency screening and repletion prior to initiation of ART. A systematic literature review was conducted using PubMed. Relevant study outcomes were compared among the selected studies. A cost-benefit analysis was performed using a decision tree mathematical model with sensitivity analyses from the perspective of direct societal cost. Published data were used to estimate probabilities and costs in 2014 US dollars. Thirty-four articles were retrieved, of which eight met inclusion criteria. One study demonstrated a negative relationship between vitamin D status and ART outcomes, while two studies showed no association. The remaining five studies concluded that ART outcomes improved after vitamin D repletion. The majority of reviewed studies reported a decrement in ART outcomes in patients with vitamin D deficiency. Cost-benefit analyses suggested that screening and supplementing vitamin D prior to ART might be cost effective, but further evidence is needed. Given the absence of Level I evidence regarding vitamin D status and ART outcomes, full endorsement of routine vitamin D screening and supplementation prior to ART is premature. C1 [Pacis, Michelle M.] Dartmouth Hitchcock Med Ctr, Dept Obstet & Gynecol, Lebanon, NH 03756 USA. [Fortin, Chelsea N.] Wayne State Univ, Sch Med, Detroit, MI 48201 USA. [Zarek, Shvetha M.; Segars, James H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20882 USA. [Mumford, Sunni L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, Rockville, MD 20852 USA. RP Segars, JH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, 10 CRC Room 1E-3140,10 Ctr Dr, Bethesda, MD 20882 USA. EM segarsj@mail.nih.gov FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health; ZIA [HD-008737] FX This study was funded, 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, and ZIA HD-008737 to JHS. NR 84 TC 1 Z9 1 U1 0 U2 5 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1058-0468 EI 1573-7330 J9 J ASSIST REPROD GEN JI J. Assist. Reprod. Genet. PD MAR PY 2015 VL 32 IS 3 BP 323 EP 335 DI 10.1007/s10815-014-0407-9 PG 13 WC Genetics & Heredity; Obstetrics & Gynecology; Reproductive Biology SC Genetics & Heredity; Obstetrics & Gynecology; Reproductive Biology GA CE0QL UT WOS:000351509400002 PM 25547950 ER PT J AU Tanos, BE Bay, AEP Salvarezza, S Vivanco, I Mellinghoff, I Osman, M Sacks, DB Rodriguez-Boulan, E AF Tanos, Barbara E. Bay, Andres E. Perez Salvarezza, Susana Vivanco, Igor Mellinghoff, Ingo Osman, Mahasin Sacks, David B. Rodriguez-Boulan, Enrique TI IQGAP1 controls tight junction formation through differential regulation of claudin recruitment SO JOURNAL OF CELL SCIENCE LA English DT Article DE Claudin; IQGAP1; Paracellular permeability; Polarized epithelium; Tight junction ID EPITHELIAL POLARITY PROGRAM; CELL-CELL ADHESION; INTEGRATES CA2+/CALMODULIN; SMALL GTPASES; PROTEIN; CDC42; EXPRESSION; RAC1; PERMEABILITY; MEMBRANE AB IQGAP1 is a scaffolding protein previously implicated in adherens junction formation. However, its role in the establishment or maintenance of tight junctions (TJs) has not been explored. We hypothesized that IQGAP1 could regulate TJ formation by modulating the expression and/or localization of junctional proteins, and we systematically tested this hypothesis in the model Madin-Darby canine kidney (MDCK) cell line. We find that IQGAP1 silencing enhances a transient increase in transepithelial electrical resistance (TER) observed during the early stages of TJ formation (Cereijido et al., 1978). Quantitative microscopy and biochemical experiments suggest that this effect of IQGAP1 on TJ assembly is accounted for by reduced expression and TJ recruitment of claudin 2, and increased TJ recruitment of claudin 4. Furthermore, we show that IQGAP1 also regulates TJ formation through its interactor CDC42, because IQGAP1 knockdown increases the activity of the CDC42 effector JNK and dominant-negative CDC42 prevents the increase in TER caused by IQGAP1 silencing. Hence, we provide evidence that IQGAP1 modulates TJ formation by a twofold mechanism: (1) controlling the expression and recruitment of claudin 2 and recruitment of claudin 4 to the TJ, and (2) transient inhibition of the CDC42-JNK pathway. C1 [Tanos, Barbara E.; Bay, Andres E. Perez; Salvarezza, Susana; Rodriguez-Boulan, Enrique] Weill Cornell Med Coll, Margaret Dyson Vis Res Inst, Dept Ophthalmol, New York, NY 10065 USA. [Vivanco, Igor; Mellinghoff, Ingo] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, York, NY 10065 USA. [Mellinghoff, Ingo] Weill Cornell Med Coll, Dept Pharmacol, New York, NY 10065 USA. [Mellinghoff, Ingo] Mem Sloan Kettering Canc Ctr, Dept Neurol, New York, NY 10021 USA. [Osman, Mahasin] Brown Univ, Dept Mol Pharmacol Physiol & Biotechnol, Div Biol & Med, Alpert Sch Med, Providence, RI 02912 USA. [Sacks, David B.] NIH, Dept Lab Med, Bethesda, MD 20892 USA. [Rodriguez-Boulan, Enrique] Weill Cornell Med Coll, Dept Cell & Dev Biol, New York, NY 10065 USA. RP Tanos, BE (reprint author), Inst Canc Res, Div Canc Therapeut, London SM2 5NG, England. EM Barbara.tanos@icr.ac.uk; Boulan@med.cornell.edu OI Tanos, Barbara/0000-0002-7045-9496; Sacks, David/0000-0003-3100-0735 FU National Institutes of Health [GM-34107, EY-08538]; Dyson Foundation; Research to Prevent Blindness Foundation FX This work was supported by grants to E.R.B. from the National Institutes of Health [grant numbers GM-34107 and EY-08538]; by the Dyson Foundation; and by a departmental grant from the Research to Prevent Blindness Foundation. Deposited in PMC for release after 12 months. NR 55 TC 5 Z9 5 U1 0 U2 3 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 EI 1477-9137 J9 J CELL SCI JI J. Cell Sci. PD MAR 1 PY 2015 VL 128 IS 5 BP 853 EP 862 DI 10.1242/jcs.118703 PG 10 WC Cell Biology SC Cell Biology GA CC7SY UT WOS:000350569900004 PM 25588839 ER PT J AU Yesilkaya, E Bereket, A Darendeliler, F Bas, F Poyrazoglu, S Aydin, BK Darcan, S Dundar, B Buyukinan, M Kara, C Sari, E Adal, E Akinci, A Atabek, ME Demirel, F Celik, N Ozkan, B Ozhan, B Orbak, Z Ersoy, B Dogan, M Atas, A Turan, S Goksen, D Tarim, O Yuksel, B Ercan, O Hatun, S Simsek, E OOkten, A Abaci, A Doneray, H Ozbek, MN Keskin, M Onal, H Akyurek, N Bulan, K Tepe, D Emeksiz, HC Demir, K Kizilay, D Topaloglu, AK Eren, E Ozen, S Abali, S Akin, L Eklioglu, BS Kaba, S Anik, A Bas, S Unuvar, T Saglam, H Bolu, S Ozgen, T Dogan, D Cakir, ED Sen, Y Andiran, N Cizmecioglu, F Evliyaoglu, O Karaguzel, G Pirgon, O Catli, G Can, HD Gurbuz, F Binay, C Bas, VN Fidanci, K Polat, A Gul, D Acikel, C Demirbilek, H Cinaz, P Bondy, C AF Yesilkaya, Ediz Bereket, Abdullah Darendeliler, Feyza Bas, Firdevs Poyrazoglu, Sukran Aydin, Banu Kucukemre Darcan, Sukran Dundar, Bumin Buyukinan, Muammer Kara, Cengiz Sari, Erkan Adal, Erdal Akinci, Aysehan Atabek, Mehmet Emre Demirel, Fatma Celik, Nurullah Ozkan, Behzat Ozhan, Bayram Orbak, Zerrin Ersoy, Betul Dogan, Murat Atas, Ali Turan, Serap Goksen, Damla Tarim, Omer Yuksel, Bilgin Ercan, Oya Hatun, Sukru Simsek, Enver Okten, Aysenur Abaci, Ayhan Doneray, Hakan Ozbek, Mehmet Nuri Keskin, Mehmet Onal, Hasan Akyurek, Nesibe Bulan, Kezban Tepe, Derya Emeksiz, Hamdi Cihan Demir, Korcan Kizilay, Deniz Topaloglu, Ali Kemal Eren, Erdal Ozen, Samim Abali, Saygin Akin, Leyla Eklioglu, Beray Selver Kaba, Sultan Anik, Ahmet Bas, Serpil Unuvar, Tolga Saglam, Halil Bolu, Semih Ozgen, Tolga Dogan, Durmus Cakir, Esra Deniz Sen, Yasar Andiran, Nesibe Cizmecioglu, Filiz Evliyaoglu, Olcay Karaguzel, Gulay Pirgon, Ozgur Catli, Gonul Can, Hatice Dilek Gurbuz, Fatih Binay, Cigdem Bas, Veysel Nijat Fidanci, Kursat Polat, Adem Gul, Davut Acikel, Cengizhan Demirbilek, Huseyin Cinaz, Peyami Bondy, Carolyn TI Turner Syndrome and Associated Problems in Turkish Children: A Multicenter Study SO JOURNAL OF CLINICAL RESEARCH IN PEDIATRIC ENDOCRINOLOGY LA English DT Article DE Nationwide study; Turner syndrome; children; diagnostic features; associated problems ID CELIAC-DISEASE; CARDIOVASCULAR MALFORMATIONS; RENAL MALFORMATIONS; MELANOCYTIC NEVI; HEART-DISEASE; AORTIC-VALVE; RISK-FACTORS; ABNORMALITIES; PREVALENCE; GIRLS AB Objective: Turner syndrome (TS) is a chromosomal disorder caused by complete or partial X chromosome monosomy that manifests various clinical features depending on the karyotype and on the genetic background of affected girls. This study aimed to systematically investigate the key clinical features of TS in relationship to karyotype in a large pediatric Turkish patient population. Methods: Our retrospective study included 842 karyotype-proven TS patients aged 0-18 years who were evaluated in 35 different centers in Turkey in the years 2013-2014. Results: The most common karyotype was 45, X (50.7%), followed by 45, X/46, XX (10.8%), 46, X, i(Xq) (10.1%) and 45, X/46, X, i(Xq) (9.5%). Mean age at diagnosis was 10.2 +/- 4.4 years. The most common presenting complaints were short stature and delayed puberty. Among patients diagnosed before age one year, the ratio of karyotype 45, X was significantly higher than that of other karyotype groups. Cardiac defects (bicuspid aortic valve, coarctation of the aorta and aortic stenosis) were the most common congenital anomalies, occurring in 25% of the TS cases. This was followed by urinary system anomalies (horseshoe kidney, double collector duct system and renal rotation) detected in 16.3%. Hashimoto's thyroiditis was found in 11.1% of patients, gastrointestinal abnormalities in 8.9%, ear nose and throat problems in 22.6%, dermatologic problems in 21.8% and osteoporosis in 15.3%. Learning difficulties and/or psychosocial problems were encountered in 39.1%. Insulin resistance and impaired fasting glucose were detected in 3.4% and 2.2%, respectively. Dyslipidemia prevalence was 11.4%. Conclusion: This comprehensive study systematically evaluated the largest group of karyotype-proven TS girls to date. The karyotype distribution, congenital anomaly and comorbidity profile closely parallel that from other countries and support the need for close medical surveillance of these complex patients throughout their lifespan. C1 [Yesilkaya, Ediz; Sari, Erkan; Fidanci, Kursat; Polat, Adem; Gul, Davut; Acikel, Cengizhan] Gulhane Mil Med Acad, Dept Pediat Endocrinol, Ankara, Turkey. [Bereket, Abdullah; Turan, Serap; Abali, Saygin; Bas, Serpil] Marmara Univ, Dept Pediat Endocrinol, Fac Med, Istanbul, Turkey. [Darendeliler, Feyza; Bas, Firdevs; Poyrazoglu, Sukran; Aydin, Banu Kucukemre] Istanbul Univ, Istanbul Fac Med, Dept Pediat Endocrinol, Istanbul, Turkey. [Darcan, Sukran; Goksen, Damla; Ozen, Samim] Ege Univ, Fac Med, Dept Pediat Endocrinol, Izmir, Turkey. [Dundar, Bumin] Katip Celebi Univ, Fac Med, Dept Pediat Endocrinol, Izmir, Turkey. [Buyukinan, Muammer] Konya Training & Res Hosp, Clin Pediat Endocrinol, Konya, Turkey. [Kara, Cengiz] Ondokuz Mayis Univ, Fac Med, Dept Pediat Endocrinol, Samsun, Turkey. [Adal, Erdal; Onal, Hasan; Akin, Leyla; Unuvar, Tolga; Ozgen, Tolga] Kanuni Sultan Suleyman Training & Res Hosp, Clin Pediat Endocrinol, Istanbul, Turkey. [Akinci, Aysehan] Inonu Univ, Fac Med, Dept Pediat Endocrinol, Malatya, Turkey. [Atabek, Mehmet Emre; Akyurek, Nesibe; Eklioglu, Beray Selver] Necmettin Erbakan Univ, Fac Med, Dept Pediat Endocrinol, Konya, Turkey. [Demirel, Fatma; Tepe, Derya; Andiran, Nesibe] Yildirim Beyazit Univ, Dept Pediat Endocrinol, Fac Med, Ankara, Turkey. [Celik, Nurullah; Emeksiz, Hamdi Cihan; Cinaz, Peyami] Gazi Univ, Fac Med, Dept Pediat Endocrinol, Ankara, Turkey. [Ozkan, Behzat; Demir, Korcan] Dr Behcet Uz Children Hosp, Clin Pediat Endocrinol, Izmir, Turkey. [Ozhan, Bayram] Pamukkale Univ, Fac Med, Dept Pediat Endocrinol, Denizli, Turkey. [Orbak, Zerrin; Doneray, Hakan] Ataturk Univ, Fac Med, Dept Pediat Endocrinol, Erzurum, Turkey. [Ersoy, Betul; Kizilay, Deniz] Celal Bayar Univ, Fac Med, Dept Pediat Endocrinol, Manisa, Turkey. [Dogan, Murat; Bulan, Kezban; Kaba, Sultan] Yuzuncu Yil Univ, Fac Med, Dept Pediat Endocrinol, Van, Turkey. [Atas, Ali] Harran Univ, Fac Med, Dept Pediat Endocrinol, Sanliurfa, Turkey. [Tarim, Omer; Eren, Erdal; Saglam, Halil; Dogan, Durmus; Cakir, Esra Deniz; Can, Hatice Dilek] Uludag Univ, Fac Med, Dept Pediat Endocrinol, Bursa, Turkey. [Yuksel, Bilgin; Topaloglu, Ali Kemal; Gurbuz, Fatih] Cukurova Univ, Fac Med, Dept Pediat Endocrinol, Adana, Turkey. [Ercan, Oya; Evliyaoglu, Olcay] Istanbul Univ, Cerrahpasa Fac Med, Dept Pediat Endocrinol, Istanbul, Turkey. [Hatun, Sukru; Cizmecioglu, Filiz] Kocaeli Univ, Fac Med, Dept Pediat Endocrinol, Kocaeli, Turkey. [Simsek, Enver; Binay, Cigdem] Osmangazi Univ, Fac Med, Dept Pediat Endocrinol, Eskisehir, Turkey. [Okten, Aysenur; Karaguzel, Gulay] Karadeniz Tech Univ, Fac Med, Dept Pediat Endocrinol, Trabzon, Turkey. [Abaci, Ayhan; Anik, Ahmet; Catli, Gonul] Dokuz Eylul Univ, Fac Med, Dept Pediat Endocrinol, Izmir, Turkey. [Ozbek, Mehmet Nuri; Demirbilek, Huseyin] Diyarbakir Children State Hosp, Clin Pediat Endocrinol, Diyarbakir, Turkey. [Keskin, Mehmet] Gaziantep Univ, Fac Med, Dept Pediat Endocrinol, Gaziantep, Turkey. [Bolu, Semih] Duzce Univ, Fac Med, Dept Pediat Endocrinol, Duzce, Turkey. [Sen, Yasar] Selcuk Univ, Fac Med, Dept Pediat Endocrinol, Konya, Turkey. [Andiran, Nesibe] Kecioren Training & Res Hosp, Clin Pediat Endocrinol, Ankara, Turkey. [Pirgon, Ozgur] Suleyman Demirel Univ, Fac Med, Dept Pediat Endocrinol, TR-32200 Isparta, Turkey. [Bas, Veysel Nijat] Kayseri Training & Res Hosp, Clin Pediat Endocrinol, Kayseri, Turkey. [Bondy, Carolyn] NICHHD, Bethesda, MD 20892 USA. RP Yesilkaya, E (reprint author), Gulhane Mil Med Acad, Dept Pediat Endocrinol, Ankara, Turkey. EM dredizyesilkaya@gmail.com OI binay, cigdem/0000-0002-7749-8818 NR 62 TC 2 Z9 2 U1 9 U2 24 PU GALENOS YAYINCILIK PI FINDIKZADE PA ERKAN MOR, MOLLA GURANI CAD 21-1, FINDIKZADE, ISTANBUL 34093, TURKEY SN 1308-5727 EI 1308-5735 J9 J CLIN RES PEDIATR E JI J. Clin Res. Pediatr. Endocrinol. PD MAR PY 2015 VL 7 IS 1 BP 27 EP 36 DI 10.4274/jcrpe.1771 PG 10 WC Endocrinology & Metabolism; Pediatrics SC Endocrinology & Metabolism; Pediatrics GA CD7WZ UT WOS:000351307200005 PM 25800473 ER PT J AU Duchnowska, R Jassem, J Goswami, CP Dundar, M Gokmen-Polar, Y Li, L Woditschka, S Biernat, W Sosinska-Mielcarek, K Czartoryska-Arlukowicz, B Radecka, B Tomasevic, Z Stepniak, P Wojdan, K Sledge, GW Steeg, PS Badve, S AF Duchnowska, Renata Jassem, Jacek Goswami, Chirayu Pankaj Dundar, Murat Goekmen-Polar, Yesim Li, Lang Woditschka, Stephan Biernat, Wojciech Sosinska-Mielcarek, Katarzyna Czartoryska-Arlukowicz, Bogumila Radecka, Barbara Tomasevic, Zorica Stepniak, Piotr Wojdan, Konrad Sledge, George W., Jr. Steeg, Patricia S. Badve, Sunil TI Predicting early brain metastases based on clinicopathological factors and gene expression analysis in advanced HER2-positive breast cancer patients SO JOURNAL OF NEURO-ONCOLOGY LA English DT Article DE Breast cancer; Brain metastasis; HER2; RAD51; HDGF; TPR ID NERVOUS-SYSTEM METASTASES; ADJUVANT CHEMOTHERAPY; RECEPTOR STATUS; TRASTUZUMAB; PLUS; HER2; LAPATINIB; SURVIVAL; SUBTYPES; OUTCOMES AB The overexpression or amplification of the human epidermal growth factor receptor 2 gene (HER2/neu) is associated with high risk of brain metastasis (BM). The identification of patients at highest immediate risk of BM could optimize screening and facilitate interventional trials. We performed gene expression analysis using complementary deoxyribonucleic acid-mediated annealing, selection, extension and ligation and real-time quantitative reverse transcription PCR (qRT-PCR) in primary tumor samples from two independent cohorts of advanced HER2 positive breast cancer patients. Additionally, we analyzed predictive relevance of clinicopathological factors in this series. Study group included discovery Cohort A (84 patients) and validation Cohort B (75 patients). The only independent variables associated with the development of early BM in both cohorts were the visceral location of first distant relapse [ Cohort A: hazard ratio (HR) 7.4, 95 % CI 2.4-22.3; p < 0.001; Cohort B: HR 6.1, 95 % CI 1.5-25.6; p = 0.01] and the lack of trastuzumab administration in the metastatic setting (Cohort A: HR 5.0, 95 % CI 1.4-10.0; p = 0.009; Cohort B: HR 10.0, 95 % CI 2.0-100.0; p = 0.008). A profile including 13 genes was associated with early (<= 36 months) symptomatic BM in the discovery cohort. This was refined by qRT-PCR to a 3-gene classifier (RAD51, HDGF, TPR) highly predictive of early BM (HR 5.3, 95 % CI 1.6-16.7; p = 0.005; multivariate analysis). However, predictive value of the classifier was not confirmed in the independent validation Cohort B. The presence of visceral metastases and the lack of trastuzumab administration in the metastatic setting apparently increase the likelihood of early BM in advanced HER2-positive breast cancer. C1 [Duchnowska, Renata] Mil Inst Med, Dept Oncol, PL-04141 Warsaw, Poland. [Jassem, Jacek] Med Univ, Dept Radiotherapy & Oncol, Gdansk, Poland. [Goswami, Chirayu Pankaj; Dundar, Murat; Li, Lang] Indiana Univ Sch Med, Ctr Computat Biol & Bioinformat, Dept Med & Mol Genet, Indianapolis, IN 46202 USA. [Goekmen-Polar, Yesim; Badve, Sunil] Indiana Univ Sch Med, Dept Med, Indianapolis, IN 46202 USA. [Goekmen-Polar, Yesim; Badve, Sunil] Indiana Univ Sch Med, Dept Pathol, Indianapolis, IN 46202 USA. [Goekmen-Polar, Yesim; Badve, Sunil] Indiana Univ Sch Med, Dept Lab Med, Indianapolis, IN 46202 USA. [Woditschka, Stephan; Steeg, Patricia S.] NCI, Womens Cancers Sect, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Biernat, Wojciech] Med Univ, Dept Pathol & Oncol, Gdansk, Poland. [Sosinska-Mielcarek, Katarzyna] Reg Oncol Ctr, Gdansk, Poland. [Czartoryska-Arlukowicz, Bogumila] Ctr Oncol, Dept Oncol, Bialystok, Poland. [Radecka, Barbara] Ctr Oncol, Dept Oncol, Opole, Poland. [Tomasevic, Zorica] Inst Oncol & Radiol, Belgrade, Serbia. [Stepniak, Piotr] Transit Technol SA, Warsaw, Poland. [Wojdan, Konrad] Warsaw Univ Technol, Inst Heat Engn, Warsaw, Poland. [Sledge, George W., Jr.] Stanford Univ, Med Ctr, Div Oncol, Stanford, CA 94305 USA. RP Duchnowska, R (reprint author), Mil Inst Med, Dept Oncol, Szaserow St 128, PL-04141 Warsaw, Poland. EM rdtt@wp.pl OI Gokmen-Polar, Yesim/0000-0001-9927-4893 FU US Department of Defense Breast Cancer Research Program [W81 XWH-062-0033]; Intramural Research Programs of the National Cancer Institute in Bethesda, USA; Medical University of Gdansk, Poland FX This work was supported by the US Department of Defense Breast Cancer Research Program, Grant Number W81 XWH-062-0033. Additional support was from the Intramural Research Programs of the National Cancer Institute in Bethesda, USA and Medical University of Gdansk, Poland. NR 37 TC 5 Z9 5 U1 1 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X EI 1573-7373 J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD MAR PY 2015 VL 122 IS 1 BP 205 EP 216 DI 10.1007/s11060-014-1704-y PG 12 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA CD4YD UT WOS:000351091500023 PM 25559688 ER PT J AU Tovar-Moll, F Evangelou, IE Chiu, AW Auh, S Chen, C Ehrmantraut, M Ohayon, JM Richert, N Bagnato, F AF Tovar-Moll, Fernanda Evangelou, Iordanis E. Chiu, Annie W. Auh, Sungyoung Chen, Christina Ehrmantraut, Mary Ohayon, Joan M. Richert, Nancy Bagnato, Francesca TI Diffuse and Focal Corticospinal Tract Disease and Its Impact on Patient Disability in Multiple Sclerosis SO JOURNAL OF NEUROIMAGING LA English DT Article DE Multiple sclerosis; diffusion tensor imaging; black holes; white matter damage ID STATUS SCALE EDSS; WHITE-MATTER; DEMYELINATING DISEASE; CORPUS-CALLOSUM; PYRAMIDAL TRACT; OPTIC NEURITIS; BLACK-HOLES; TENSOR; BRAIN; MRI AB BACKGROUND AND PURPOSEWe investigated the impact of focal and diffuse corticospinal tracts damage on sensory-motor disability in multiple sclerosis (MS) patients. METHODSTwenty-five MS patients underwent 3.0 Tesla (3T) magnetic resonance imaging with diffusion tensor imaging (DTI). The Expanded Disability Status Scale (EDSS) and the Timed 25-Foot Walk test (T25FW) quantified patient physical disability. Fractional anisotropy (FA) and mean diffusivity (MD) of the corticospinal tracts, whole brain and corticospinal tracts lesion volume were also computed. Spearman rank correlation analyses measured the associations between DTI-derived metrics and other measures of disease. Partial correlation analyses between DTI and disability measures were performed and corrected for lesion volumes as appropriate. RESULTSSignificant associations were seen between FA of the corticospinal tracts and EDSS (r = -.500, P = .0011), motor-EDSS (r = -.519, P = .008), and T25WF (r = -.637, P = .001) scores and MD of the corticospinal tracts and motor-EDSS (r = .469, P = .018) and T25WF (r = .428, P = .033) scores. When correcting for lesion volumes, only the association between FA of the corticospinal tracts and EDSS (r -.516, p .01) or motor-EDSS score (r -.516, p .01) persisted. CONCLUSIONSDTI at 3T shows that the impact of diffuse corticospinal tracts disease on sensory-motor disability is greatly mediated by focal lesions in MS. C1 [Tovar-Moll, Fernanda; Evangelou, Iordanis E.; Chiu, Annie W.; Chen, Christina; Ehrmantraut, Mary; Ohayon, Joan M.; Richert, Nancy; Bagnato, Francesca] NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. [Auh, Sungyoung] NINDS, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Tovar-Moll, Fernanda] DOr Inst Res & Educ IDOR, Rio De Janeiro, Brazil. [Tovar-Moll, Fernanda] Univ Fed Rio de Janeiro, Inst Biomed Sci, Rio De Janeiro, Brazil. [Tovar-Moll, Fernanda] Univ Fed Rio de Janeiro, Natl Ctr Struct Biol & Bioimaging CENABIO, Rio De Janeiro, Brazil. RP Bagnato, F (reprint author), Univ Maryland, Dept Neurol, 110 S Paca St, Baltimore, MD 21201 USA. EM fbagnato@umm.edu FU NINDS-NIH, Bethesda, MD, USA FX The study was supported by the Intramural program of the NINDS-NIH, Bethesda, MD, USA. NR 44 TC 1 Z9 1 U1 2 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1051-2284 EI 1552-6569 J9 J NEUROIMAGING JI J. Neuroimaging PD MAR-APR PY 2015 VL 25 IS 2 BP 200 EP 206 DI 10.1111/jon.12171 PG 7 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA CD7WO UT WOS:000351306000006 PM 25318661 ER PT J AU Grady, PA AF Grady, Patricia A. TI A Pathway for the Future: An Update on NINR's Innovative Questions Initiative SO JOURNAL OF NURSING SCHOLARSHIP LA English DT Editorial Material C1 NINR, Natl Inst Hlth, New York, NY 10011 USA. RP Grady, PA (reprint author), NINR, Natl Inst Hlth, New York, NY 10011 USA. EM info@ninr.nih.gov NR 1 TC 2 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1527-6546 EI 1547-5069 J9 J NURS SCHOLARSHIP JI J. Nurs. Scholarsh. PD MAR PY 2015 VL 47 IS 2 BP 105 EP 105 DI 10.1111/jnu.12124 PG 1 WC Nursing SC Nursing GA CD3ME UT WOS:000350981900001 PM 25641383 ER PT J AU Willis, G AF Willis, Gordon TI Sampling and Choosing Cases in Qualitative Research SO JOURNAL OF OFFICIAL STATISTICS LA English DT Book Review C1 [Willis, Gordon] NCI, NIH, Bethesda, MD 20892 USA. RP Willis, G (reprint author), NCI, NIH, Room 3E358,9609 Med Ctr Dr,Rm 3E358,MSC 9762, Bethesda, MD 20892 USA. EM willisg@mail.nih.gov NR 1 TC 0 Z9 0 U1 2 U2 11 PU DE GRUYTER OPEN LTD PI WARSAW PA SOLIPSKA 14A-1, 02-482 WARSAW, POLAND SN 0282-423X J9 J OFF STAT JI J. Off. Stat. PD MAR PY 2015 VL 31 IS 1 BP 147 EP 148 DI 10.1515/JOS-2015-0010 PG 2 WC Social Sciences, Mathematical Methods; Statistics & Probability SC Mathematical Methods In Social Sciences; Mathematics GA CE2GX UT WOS:000351634200010 ER PT J AU Read, KL Settipani, CA Peterman, J Kendall, PC Compton, S Piacentini, J McCracken, J Bergman, L Walkup, J Sakolsky, D Birmaher, B Albano, AM Rynn, M Ginsburg, G Keeton, C Gosch, E Suveg, C Sherrill, J March, J AF Read, Kendra L. Settipani, Cara A. Peterman, Jeremy Kendall, Philip C. Compton, Scott Piacentini, John McCracken, James Bergman, Lindsey Walkup, John Sakolsky, Dara Birmaher, Boris Albano, Anne Marie Rynn, Moira Ginsburg, Golda Keeton, Courtney Gosch, Elizabeth Suveg, Cynthia Sherrill, Joel March, John TI Predicting Anxiety Diagnoses and Severity with the CBCL-A: Improvement Relative to Other CBCL Scales? SO JOURNAL OF PSYCHOPATHOLOGY AND BEHAVIORAL ASSESSMENT LA English DT Article DE Child anxiety; Child behavior checklist; Assessment; Clinical utility ID CHILD-BEHAVIOR CHECKLIST; DISORDERS INTERVIEW SCHEDULE; EMPIRICALLY BASED ASSESSMENT; DSM-ORIENTED SCALES; PSYCHIATRIC DIAGNOSES; STRUCTURED INTERVIEW; SOCIAL ANXIETY; PRIMARY-CARE; ADOLESCENTS; IV AB The Child Behavior Checklist (CBCL) is a widely used parent-report of child and adolescent behavior. We examined the ability of the CBCL-A scale, a previously published subset of CBCL items, to predict the presence of generalized anxiety disorder (GAD), separation anxiety disorder (SAD), and social phobia (SoP), as well as anxiety severity, among 488 youth randomized in the Child Anxiety Multimodal Study (CAMS). We predicted that the CBCL-A's unique inclusion of items related to somatic symptoms would better identify anxiety disorder and severity than other CBCL scales, given that somatic complaints are often key features of anxiety among youth. Results support the use of the anxiety-based CBCL subscales as first-line screeners for generally elevated symptoms of anxiety, rather than tools to identify specific anxiety disorders. Although somatic symptoms are often reported and included in diagnostic criteria for certain anxiety disorders (e.g., SAD, GAD), the unique combination of somatic and non-somatic symptoms for the CBCL-A subscale did not increase its ability to consistently predict the presence of specific anxiety disorders. C1 [Read, Kendra L.; Settipani, Cara A.; Peterman, Jeremy; Kendall, Philip C.] Temple Univ, Dept Psychol, Philadelphia, PA 19122 USA. [Compton, Scott; March, John] Duke Univ, Dept Psychol, Philadelphia, PA 19122 USA. [Piacentini, John; McCracken, James; Bergman, Lindsey] Univ Calif Los Angeles, Dept Psychol, Philadelphia, PA 19122 USA. [Walkup, John] Cornell Univ, Dept Psychol, Philadelphia, PA 19122 USA. [Sakolsky, Dara; Birmaher, Boris] Univ Pittsburgh, Dept Psychol, Philadelphia, PA 19122 USA. [Albano, Anne Marie; Rynn, Moira] Columbia Univ, Dept Psychol, Philadelphia, PA 19122 USA. [Ginsburg, Golda; Keeton, Courtney] Johns Hopkins Univ, Sch Med, Dept Psychol, Philadelphia, PA 19122 USA. [Gosch, Elizabeth] Philadelphia Coll Osteopath Med, Dept Psychol, Philadelphia, PA 19122 USA. [Suveg, Cynthia] Univ Georgia, Dept Psychol, Philadelphia, PA 19122 USA. [Sherrill, Joel] NIMH, Dept Psychol, Philadelphia, PA 19122 USA. RP Read, KL (reprint author), Temple Univ, Dept Psychol, 1701 N 13th St, Philadelphia, PA 19122 USA. EM kendra.read@temple.edu; pkendall@temple.edu FU National Institute of Mental Health [U01 MH064089, U01 MH64092, U01 MH64003, U01 MH63747, U01 MH64107, U01 MH64088, U01 MH064003] FX This research was supported by grants (U01 MH064089, to Dr. Walkup; U01 MH64092, to Dr. Albano; U01 MH64003, to Dr. Birmaher; U01 MH63747, to Dr. Kendall; U01 MH64107, to Dr. March; U01 MH64088, to Dr. Piacentini; and U01 MH064003, to Dr. Compton) from the National Institute of Mental Health. Views expressed within this article represent those of the authors and are not intended to represent the position of NIMH, NIH, or DHHS. NR 50 TC 0 Z9 0 U1 0 U2 7 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0882-2689 EI 1573-3505 J9 J PSYCHOPATHOL BEHAV JI J. Psychopathol. Behav. Assess. PD MAR PY 2015 VL 37 IS 1 BP 100 EP 111 DI 10.1007/s10862-014-9439-9 PG 12 WC Psychology, Clinical SC Psychology GA CD7ZZ UT WOS:000351316200010 PM 26257470 ER PT J AU Chirinos, JA Segers, P Duprez, DA Brumback, L Bluemke, DA Zamani, P Kronmal, R Vaidya, D Ouyang, P Townsend, RR Jacobs, DR AF Chirinos, Julio A. Segers, Patrick Duprez, Daniel A. Brumback, Lyndia Bluemke, David A. Zamani, Payman Kronmal, Richard Vaidya, Dhananjay Ouyang, Pamela Townsend, Raymond R. Jacobs, David R., Jr. TI Late Systolic Central Hypertension as a Predictor of Incident Heart Failure: The Multi-Ethnic Study of Atherosclerosis SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE arterial hemodynamics; heart failure; late systolic load; left ventricular afterload ID LEFT-VENTRICULAR RELAXATION; VARYING MYOCARDIAL STRESS; WAVE REFLECTION MAGNITUDE; QUALITY-OF-LIFE; LOADING SEQUENCE; CARDIOVASCULAR EVENTS; ARTERIAL LOAD; PRESSURE FALL; WALL STRESS; RECLASSIFICATION AB Background-Experimental studies demonstrate that high aortic pressure in late systole relative to early systole causes greater myocardial remodeling and dysfunction, for any given absolute peak systolic pressure. Methods and Results-We tested the hypothesis that late systolic hypertension, defined as the ratio of late (last one third of systole) to early (first two thirds of systole) pressure-time integrals (PTI) of the aortic pressure waveform, independently predicts incident heart failure (HF) in the general population. Aortic pressure waveforms were derived from a generalized transfer function applied to the radial pressure waveform recorded noninvasively from 6124 adults. The late/early systolic PTI ratio (L/ESPTI) was assessed as a predictor of incident HF during median 8.5 years of follow-up. The L/ESPTI was predictive of incident HF (hazard ratio per 1% increase= 1.22; 95% CI= 1.15 to 1.29; P<0.0001) even after adjustment for established risk factors for HF (HR=1.23; 95% CI= 1.14 to 1.32: P<0.0001). In a multivariate model that included brachial systolic and diastolic blood pressure and other standard risk factors of HF, L/E-SPTI was the modifiable factor associated with the greatest improvements in model performance. A high L/E-SPTI (>58.38%) was more predictive of HF than the presence of hypertension. After adjustment for each other and various predictors of HF, the HR associated with hypertension was 1.39 (95% CI= 0.86 to 2.23; P=0.18), whereas the HR associated with a high L/E was 2.31 (95% CI=1.52 to 3.49; P<0.0001). Conclusions-Independently of the absolute level of peak pressure, late systolic hypertension is strongly associated with incident HF in the general population. C1 [Chirinos, Julio A.; Zamani, Payman] Univ Penn, Sch Med, Div Cardiovasc, Philadelphia, PA 19104 USA. [Townsend, Raymond R.] Univ Penn, Sch Med, Div Nephrol Hypertens, Philadelphia, PA 19104 USA. [Segers, Patrick] Univ Ghent, iMinds Future Hlth Dept, IBiTech, Biofluid Tissue & Solid Mech Med Applicat, B-9000 Ghent, Belgium. [Duprez, Daniel A.] Univ Minnesota, Sch Med, Div Cardiol, Minneapolis, MN 55455 USA. [Jacobs, David R., Jr.] Univ Minnesota, Div Epidemiol & Community Hlth, Sch Publ Hlth, Minneapolis, MN 55455 USA. [Brumback, Lyndia; Kronmal, Richard] Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA. [Vaidya, Dhananjay; Ouyang, Pamela] Johns Hopkins Sch Med, Baltimore, MD USA. [Bluemke, David A.] NIH, Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Jacobs, David R., Jr.] Univ Oslo, Dept Nutr, N-0316 Oslo, Norway. RP Chirinos, JA (reprint author), Univ Penn, Rm 8B111,Univ & Woodland Av, Philadelphia, PA 19104 USA. EM julio.chirinos@uphs.upenn.edu OI Vaidya, Dhananjay/0000-0002-7164-1601 FU National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC-95169]; American Heart Association [0885031N, R01-HL-098382, R21-AG043802]; [RR-024156] FX This research was supported by contracts N01-HC-95159 through N01-HC-95169 from the National Heart, Lung, and Blood Institute and RR-024156 as well as American Heart Association Grants 0885031N, R01-HL-098382, and R21-AG043802. NR 39 TC 8 Z9 8 U1 1 U2 7 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 MAR PY 2015 VL 4 IS 3 AR e001335 DI 10.1161/JAHA.114.001335 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CE0TV UT WOS:000351520300013 PM 25736440 ER PT J AU Kaess, BM Preis, SR Lieb, W Beiser, AS Yang, Q Chen, TC Hengstenberg, C Erdmann, J Schunkert, H Seshadri, S Vasan, RS AF Kaess, Bernhard M. Preis, Sarah R. Lieb, Wolfgang Beiser, Alexa S. Yang, Qiong Chen, Tai C. Hengstenberg, Christian Erdmann, Jeanette Schunkert, Heribert Seshadri, Sudha Vasan, Ramachandran S. CA CARDIoGRAM TI Circulating Brain-Derived Neurotrophic Factor Concentrations and the Risk of Cardiovascular Disease in the Community SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE cardiovascular disease; growth factors; Mendelian randomization; mortality; risk factors ID CORONARY-ARTERY-DISEASE; HEART-DISEASE; MENDELIAN RANDOMIZATION; FRAMINGHAM HEART; LOCI; METAANALYSES; ASSOCIATION; MORTALITY; OBESITY; BDNF AB Background-Brain-derived neurotrophic factor (BDNF) is a pleiotropic peptide involved in maintaining endothelial integrity. It is unknown if circulating BDNF levels are associated with risk of cardiovascular disease (CVD). Methods and Results-We prospectively investigated the association of circulating BDNF levels with cardiovascular events and mortality in 3687 participants (mean age 65 years, 2068 women) from the Framingham Heart Study (FHS). Using a common nonsynonomous single nucleotide polymorphism (SNP) in the BDNF gene (rs6265), we then performed a Mendelian randomization experiment in the CARDIoGRAM (Coronary ARtery DIsease Genome-Wide Replication And Meta-Analysis) consortium (> 22 000 coronary artery disease [CAD] cases, > 60 000 controls) to investigate whether SNP rs6265 was associated with CAD in CARDIoGRAM and, if so, whether the effect estimate differed from that predicted based on FHS data. On follow-up (median 8.9 years), 467 individuals (261 women) in FHS experienced a CVD event, and 835 (430 women) died. In multivariable-adjusted Cox regression, serum BDNF was associated inversely with CVD risk (hazard ratio [HR] per 1-SD increase 0.88, 95% CI 0.80 to 0.97, P=0.01) and with mortality (HR 0.87, 95% CI 0.80 to 0.93, P=0.0002). SNP rs6265 was associated with BDNF concentrations (0.772 ng/mL increase per minor allele copy) in FHS. In CARDIoGRAM, SNP rs6265 was associated with CAD (odds ratio 0.957, 95% CI 0.923 to 0.992), a magnitude consistent with the predicted effect (HR per minor allele copy 0.99, 95% CI 0.98 to 1.0; P=0.06 for difference between predicted and observed effect). Conclusion-Higher serum BDNF is associated with a decreased risk of CVD and mortality. Mendelian randomization suggests a causal protective role of BDNF in the pathogenesis of CVD. C1 [Kaess, Bernhard M.; Preis, Sarah R.; Beiser, Alexa S.; Yang, Qiong; Seshadri, Sudha; Vasan, Ramachandran S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Kaess, Bernhard M.; Hengstenberg, Christian; Schunkert, Heribert] Tech Univ Munich, Deutsch Herzzentrum Munchen, D-80290 Munich, Germany. [Kaess, Bernhard M.; Hengstenberg, Christian; Schunkert, Heribert] DZHK German Ctr Cardiovasc Res, Partner Site Munich Heart Alliance, Munich, Germany. [Preis, Sarah R.; Beiser, Alexa S.; Yang, Qiong] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Lieb, Wolfgang] Univ Kiel, Inst Epidemiol, Kiel, Germany. [Beiser, Alexa S.; Seshadri, Sudha] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Chen, Tai C.] Boston Univ, Sch Med, Endocrinol Sect, Boston, MA 02118 USA. [Chen, Tai C.] Boston Univ, Sch Med, Sect Diabet, Boston, MA 02118 USA. [Chen, Tai C.] Boston Univ, Sch Med, Sect Nutr, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Sect Prevent Med, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Sect Epidemiol & Cardiol, Boston, MA 02118 USA. [Erdmann, Jeanette] Univ Lubeck, Inst Integrat & Expt Genom, Lubeck, Germany. [Erdmann, Jeanette] DZHK German Res Ctr Cardiovasc Res, Partner Site Hamburg Lubeck Kiel Lubeck, Lubeck, Germany. RP Vasan, RS (reprint author), Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM bernhard_kaess@gmx.de; vasan@bu.edu RI Gudnason, Vilmundur/K-6885-2015; Meitinger, Thomas/O-1318-2015; Deloukas, Panos/B-2922-2013; Konig, Inke/A-4544-2009; Erdmann, Jeanette/P-7513-2014; Lieb, Wolfgang/C-1990-2012; OI Gudnason, Vilmundur/0000-0001-5696-0084; Deloukas, Panos/0000-0001-9251-070X; Erdmann, Jeanette/0000-0002-4486-6231; Seshadri, Sudha/0000-0001-6135-2622; Beiser, Alexa/0000-0001-8551-7778; Peters, Annette/0000-0001-6645-0985 FU National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195]; National Institute on Aging [AG031287] FX This work was supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (N01-HC-25195). BDNF measurements were supported by the National Institute on Aging (AG031287; Seshadri). Funding sources for the CARDIoGRAM consortium are detailed in Appendix S1. NR 35 TC 14 Z9 14 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD MAR PY 2015 VL 4 IS 3 AR e001544 DI 10.1161/JAHA.114.001544 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CE0TV UT WOS:000351520300016 PM 25762803 ER PT J AU Kishi, S Reis, JP Venkatesh, BA Gidding, SS Armstrong, AC Jacobs, DR Sidney, S Wu, CO Cook, NL Lewis, CE Schreiner, PJ Isogawa, A Liu, K Lima, JAC AF Kishi, Satoru Reis, Jared P. Venkatesh, Bharath A. Gidding, Samuel S. Armstrong, Anderson C. Jacobs, David R., Jr. Sidney, Stephen Wu, Colin O. Cook, Nakela L. Lewis, Cora E. Schreiner, Pamela J. Isogawa, Akihiro Liu, Kiang Lima, Joao A. C. TI Race-Ethnic and Sex Differences in Left Ventricular Structure and Function: The Coronary Artery Risk Development in Young Adults (CARDIA) Study SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE echocardiography; left ventricular function; left ventricular mass; speckle-tracking echocardiography ID SPECKLE TRACKING ECHOCARDIOGRAPHY; ASSOCIATION TASK-FORCE; INCIDENT HEART-FAILURE; DIASTOLIC FUNCTION; OF-CARDIOLOGY; ASYMPTOMATIC INDIVIDUALS; CARDIOVASCULAR EVENTS; PRACTICE GUIDELINES; MAGNETIC-RESONANCE; SYSTOLIC FUNCTION AB Background-We investigated race-ethnic and sex-specific relationships of left ventricular (LV) structure and LV function in African American and white men and women at 43 to 55 years of age. Methods and Results-The Coronary Artery Risk Development in Young Adults (CARDIA) Study enrolled African American and white adults, age 18 to 30 years, from 4 US field centers in 1985-1986 (Year-0) who have been followed prospectively. We included participants with echocardiographic assessment at the Year-25 examination (n=3320; 44% men, 46% African American). The end points of LV structure and function were assessed using conventional echocardiography and speckle-tracking echocardiography. In the multivariable models, we used, in addition to race-ethnic and gender terms, demographic (age, physical activity, and educational level) and cardiovascular risk variables (body mass index, systolic blood pressure, diastolic blood pressure, heart rate, presence of diabetes, use of antihypertensive medications, number of cigarettes/day) at Year-0 and -25 examinations as independent predictors of echocardiographic outcomes at the Year-25 examination (LV end-diastolic volume [LVEDV]/height, LV end-systolic volume [LVESV]/height, LV mass [LVM]/height, and LVM/LVEDV ratio for LV structural indices; LV ejection fraction [LVEF], Ell, and Ecc for systolic indices; and early diastolic and atrial ratio, mitral annulus early peak velocity, ratio of mitral early peak velocity/mitral annulus early peak velocity; ratio, left atrial volume/height, longitudinal peak early diastolic strain rate, and circumferential peak early diastolic strain rate for diastolic indices). Compared with women, African American and white men had greater LV volume and LV mass (P<0.05). For LV systolic function, African American men had the lowest LVEF as well as longitudinal (Ell) and circumferential (Ecc) strain indices among the 4 sex/race-ethnic groups (P<0.05). For LV diastolic function, African American men and women had larger left atrial volumes; African American men had the lowest values of Ell and Ecc for diastolic strain rate (P<0.05). These race/sex differences in LV structure and LV function persisted after adjustment. Conclusions-African American men have greater LV size and lower LV systolic and diastolic function compared to African American women and to white men and women. The reasons for these racial-ethnic differences are partially but not completely explained by established cardiovascular risk factors. C1 [Kishi, Satoru; Venkatesh, Bharath A.; Armstrong, Anderson C.; Lima, Joao A. C.] Johns Hopkins Univ, Baltimore, MD 21287 USA. [Reis, Jared P.; Wu, Colin O.; Cook, Nakela L.] NHLBI, Bethesda, MD 20892 USA. [Gidding, Samuel S.] Alfred I DuPont Hosp Children, Wilmington, DE USA. [Jacobs, David R., Jr.] Univ Minnesota, Minneapolis, MN USA. [Sidney, Stephen; Schreiner, Pamela J.] Kaiser Permanente Div Res, Oakland, CA USA. [Lewis, Cora E.] Univ Alabama Birmingham, Birmingham, AL USA. [Kishi, Satoru; Isogawa, Akihiro] Mitsui Mem Hosp, Tokyo 101, Japan. [Liu, Kiang] Northwestern Univ, Chicago, IL 60611 USA. RP Lima, JAC (reprint author), Johns Hopkins Univ, Div Cardiol, Sch Med, 600 N Wolfe St,Blalock 524, Baltimore, MD 21287 USA. EM jlima@jhmi.edu RI Ambale Venkatesh, Bharath/F-4941-2016 OI Ambale Venkatesh, Bharath/0000-0002-2330-2373 FU National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, HHSN268200900041C]; National Institute on Aging (NIA); NIA and NHLBI [AG0005] FX The Coronary Artery Risk Development in Young Adults Study (CARDIA) is supported by contracts HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, and HHSN268200900041C from the National Heart, Lung, and Blood Institute (NHLBI), the Intramural Research Program of the National Institute on Aging (NIA), and an intra-agency agreement between NIA and NHLBI (AG0005). NR 33 TC 9 Z9 9 U1 0 U2 5 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 MAR PY 2015 VL 4 IS 3 AR e001264 DI 10.1161/JAHA.114.001264 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CE0TV UT WOS:000351520300024 PM 25770024 ER PT J AU Murabito, JM Pedley, A Massaro, JM Vasan, RS Esliger, D Blease, SJ Hoffman, U Fox, CS AF Murabito, Joanne M. Pedley, Alison Massaro, Joseph M. Vasan, Ramachandran S. Esliger, Dale Blease, Susan J. Hoffman, Udo Fox, Caroline S. TI Moderate-to-Vigorous Physical Activity With Accelerometry is Associated With Visceral Adipose Tissue in Adults SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE accelerometry; physical activity; visceral adipose tissue ID LIFE-STYLE FACTORS; SEDENTARY BEHAVIOR; INSULIN-RESISTANCE; ACTIVITY PATTERNS; OBESITY; FAT; WOMEN; HEART; HEALTH; RISK AB Background-We examined the relation between objectively measured physical activity with accelerometry and subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) in a community-based sample. Methods and Results-We evaluated 1249 participants of the Framingham Third Generation and Omni II cohorts (mean age 51.7 years, 47% women) who underwent assessment of moderate-to-vigorous physical activity (MVPA) with accelerometry over 5 to 7 days, and multi-detector computed tomography for measurement of SAT and VAT volume; fat attenuation was estimated by SAT and VAT hounsfield units (HU). In women, higher levels of MVPA were associated with decreased SAT (P<0.0001) and VAT volume (P<0.0001). The average decrement in VAT per 30 minute/day increase in MVPA was -453 cm(3) (95% CI-574, -331). The association was attenuated but persisted upon adjustment for BMI (-122 cm(3), P=0.002). Higher levels of MVPA were associated with higher SAT HU (all P <= 0.01), a marker of fat quality, even after adjustment for SAT volume. Similar findings were observed in men but the magnitude of the association was less. Sedentary time was not associated with SAT or VAT volume or quality in men or women. Conclusions-MVPA was associated with less VAT and SAT and better fat quality. C1 [Murabito, Joanne M.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Sect Gen Internal Med,Sect Prevent Med, Boston, MA 02118 USA. [Murabito, Joanne M.; Pedley, Alison; Massaro, Joseph M.; Vasan, Ramachandran S.; Blease, Susan J.; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Massaro, Joseph M.] Boston Univ, Dept Biostat, Sch Publ Hlth, Boston, MA 02215 USA. [Esliger, Dale] Univ Loughborough, Sch Sport Exercise & Hlth Sci, Loughborough, Leics, England. [Hoffman, Udo] Dept Cardiac MR PET CT, Boston, MA USA. [Hoffman, Udo] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Fox, Caroline S.] NHLBI, Div Intramural Res, Framingham, MA USA. [Fox, Caroline S.] NHLBI, Ctr Populat Studies, Framingham, MA USA. [Fox, Caroline S.] Div Endocrinol, Boston, MA USA. [Fox, Caroline S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. RP Murabito, JM (reprint author), 73 Mt Wayte Ave, Framingham, MA 01702 USA. EM murabito@bu.edu FU National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195]; [R01AG047645] FX The National Heart, Lung and Blood Institute's Framingham Heart Study is supported by contract N01-HC-25195. The accelerometry study was supported by R01AG047645. NR 39 TC 3 Z9 3 U1 2 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 MAR PY 2015 VL 4 IS 3 AR e001379 DI 10.1161/JAHA.114.001379 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CE0TV UT WOS:000351520300014 PM 25736442 ER PT J AU Kurbatova, EV Cegielski, JP Lienhardt, C Akksilp, R Bayona, J Becerra, MC Caoili, J Contreras, C Dalton, T Danilovits, M Demikhova, OV Ershova, J Gammino, VM Gelmanova, I Heilig, CM Jou, R Kazennyy, B Keshavjee, S Kim, HJ Kliiman, K Kvasnovsky, C Leimane, V Mitnick, CD Quelapio, I Riekstina, V Smith, SE Tupasi, T van der Walt, M Vasilyeva, IA Via, LE Viiklepp, P Volchenkov, G Walker, AT Wolfgang, M Yagui, M Zignol, M AF Kurbatova, Ekaterina V. Cegielski, J. Peter Lienhardt, Christian Akksilp, Rattanawadee Bayona, Jaime Becerra, Mercedes C. Caoili, Janice Contreras, Carmen Dalton, Tracy Danilovits, Manfred Demikhova, Olga V. Ershova, Julia Gammino, Victoria M. Gelmanova, Irina Heilig, Charles M. Jou, Ruwen Kazennyy, Boris Keshavjee, Salmaan Kim, Hee Jin Kliiman, Kai Kvasnovsky, Charlotte Leimane, Vaira Mitnick, Carole D. Quelapio, Imelda Riekstina, Vija Smith, Sarah E. Tupasi, Thelma van der Walt, Martie Vasilyeva, Irina A. Via, Laura E. Viiklepp, Piret Volchenkov, Grigory Walker, Allison Taylor Wolfgang, Melanie Yagui, Martin Zignol, Matteo TI Sputum culture conversion as a prognostic marker for end-of-treatment outcome in patients with multidrug-resistant tuberculosis: a secondary analysis of data from two observational cohort studies SO LANCET RESPIRATORY MEDICINE LA English DT Article ID PULMONARY TUBERCULOSIS; CLINICAL-TRIALS; METAANALYSIS; MOXIFLOXACIN; PREDICTORS; DRUGS AB Background Sputum culture conversion is often used as an early microbiological endpoint in phase 2 dinical trials of tuberculosis treatment on the basis of its assumed predictive value for end-of-treatment outcome, particularly in patients with drug-susceptible tuberculosis. We aimed to assess the validity of sputum culture conversion on solid media at varying timepoints, and the time to conversion, as prognostic markers for end-of-treatment outcome in patients with multidrug-resistant (MDR) tuberculosis. Methods We analysed data from two large cohort studies of patients with MDR tuberculosis. We defined sputum culture conversion as two or more consecutive negative cultures from sputum samples obtained at least 30 days apart. To estimate the association of 2 month and 6 month conversion with successful treatment outcome, we calculated odds ratios (ORs) and 95% CIs with random-effects multivariable logistic regression. We calculated predictive values with bivariate random-effects generalised linear mixed modelling. Findings We assessed data for 1712 patients who had treatment success, treatment failure, or who died. Among patients with treatment success, median time to sputum culture conversion was significantly shorter than in those who had poor outcomes (2 months [IQR 1-3] vs 7 months [3 to >= 24]; log-rank p<0.0001). Furthermore, conversion status at 6 months (adjusted OR 14.07 [95% CI 10.05-19.71]) was significantly associated with treatment success compared with failure or death. Sputum culture conversion status at 2 months was significantly associated with treatment success only in patients who were HIV negative (adjusted OR 4.12 [95% CI 2.25-7.54]) or who had unknown HIV infection (3.59 [1.96-6.58]), but not in those who were HIV positive (0.38 [0.12-1.18]). Thus, the overall association of sputum culture conversion with a successful outcome was substantially greater at 6 months than at 2 months. 2 month conversion had low sensitivity (27.3% [95% confidence limit 16.6-41.4]) and high specificity (89.8% [82.3-94.4]) for prediction of treatment success. Conversely, 6 month sputum culture conversion status had high sensitivity (91.8% [85.9-95.4]), but moderate specificity (57.8% [42.5-71.6]). The maximum combined sensitivity and specificity for sputum culture conversion was reached between month 6 and month 10 of treatment. Interpretation Time to sputum culture conversion, conversion status at 6 months, and conversion status at 2 months in patients without known HIV infection can be considered as proxy markers of end-of-treatment outcome in patients with MDR tuberculosis, although the overall association with treatment success is substantially stronger for 6 month than for 2 month conversion status. Investigators should consider these results regarding the validity of sputum culture conversion at various timepoints as an early predictor of treatment efficacy when designing phase 2 studies before investing substantial resources in large, long-term, phase 3 trials of new treatments for MDR tuberculosis. Copyright (C) 2015. World Health Organization. Published by Elsevier Ltd/Inc/BV. All rights reserved. C1 [Kurbatova, Ekaterina V.; Cegielski, J. Peter; Dalton, Tracy; Ershova, Julia; Gammino, Victoria M.; Heilig, Charles M.; Kvasnovsky, Charlotte; Smith, Sarah E.; Walker, Allison Taylor; Wolfgang, Melanie] US Ctr Dis Control & Prevent, Div TB Eliminat, Atlanta, GA 30329 USA. [Lienhardt, Christian; Zignol, Matteo] WHO, CH-1211 Geneva, Switzerland. [Akksilp, Rattanawadee] Off Dis Prevent & Control, Ubon Ratchathani, Thailand. [Bayona, Jaime; Becerra, Mercedes C.; Gelmanova, Irina; Keshavjee, Salmaan; Mitnick, Carole D.] Harvard Univ, Sch Med, Boston, MA USA. [Bayona, Jaime; Becerra, Mercedes C.; Gelmanova, Irina; Keshavjee, Salmaan; Mitnick, Carole D.] Partners In Hlth, Boston, MA USA. [Caoili, Janice; Quelapio, Imelda; Tupasi, Thelma] Trop Dis Fdn, Manila, Philippines. [Contreras, Carmen] Socios Salud Sucursal, Lima, Peru. [Danilovits, Manfred; Kliiman, Kai] Tartu Univ Hosp, Tartu, Estonia. [Demikhova, Olga V.; Vasilyeva, Irina A.] Russian Acad Med Sci, Cent TB Res Inst, Moscow, Russia. [Jou, Ruwen] Taiwan Ctr Dis Control, Reference Lab Mycobacteriol, Taipei, Taiwan. [Kazennyy, Boris] Orel Oblast TB Dispensary, Oryol, Russia. [Kim, Hee Jin] Korean Inst TB, Seoul, South Korea. [Leimane, Vaira; Riekstina, Vija] Riga East Univ Hosp, TB & Lung Dis Ctr, Riga, Latvia. [van der Walt, Martie] MRC, Pretoria, South Africa. [Via, Laura E.] NIAID, NIH, Bethesda, MD 20892 USA. [Viiklepp, Piret] Natl Inst Hlth Dev, Natl TB Registry, Tallinn, Estonia. [Volchenkov, Grigory] Vladimir Oblast TB Dispensary, Vladimir, Russia. [Yagui, Martin] Natl Inst Hlth, Lima, Peru. RP Kurbatova, EV (reprint author), US Ctr Dis Control & Prevent, Div TB Eliminat, Atlanta, GA 30329 USA. EM ekurbatova@cdc.gov OI Heilig, Charles/0000-0003-1075-1310 FU United States Agency for International Development (USAID); US Centers for Disease Control and Prevention (CDC); Division of Intramural Research of the US National Institute of Allergy and Infectious Diseases; Korea Centers for Disease Control and Prevention FX The United States Agency for International Development (USAID) and US Centers for Disease Control and Prevention (CDC) provided funding for both the Preserving Effective TB Treatment Study (PETTS) study and the DOTS-Plus Pilot Projects Case-Based Study. The Division of Intramural Research of the US National Institute of Allergy and Infectious Diseases and the Korea Centers for Disease Control and Prevention partly supported the Korean sites. CL and MZ are WHO staff members. The authors alone are responsible for the views expressed in this publication and they do not necessarily represent the decisions or policies of WHO. The conclusions and interpretations of data presented in this report are solely those of the authors and do not necessarily represent an official position of the CDC, the US Government, WHO, or the governments of the nine participating countries. NR 26 TC 20 Z9 20 U1 1 U2 8 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2213-2600 J9 LANCET RESP MED JI Lancet Resp. Med. PD MAR PY 2015 VL 3 IS 3 BP 201 EP 209 DI 10.1016/S2213-2600(15)00036-3 PG 9 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA CE0FN UT WOS:000351480000016 PM 25726085 ER PT J AU Tsai, HT Pfeiffer, RM Warren, J Wilson, W Landgren, O AF Tsai, Huei-Ting Pfeiffer, Ruth M. Warren, Joan Wilson, Wyndham Landgren, Ola TI The effects of cardiovascular disease on the clinical outcome of elderly patients with diffuse large B-cell lymphoma SO LEUKEMIA & LYMPHOMA LA English DT Article DE Cardiovascular disease; doxorubicin; rituximab; elderly cardiac failure; prognosis; survival; outcome ID NON-HODGKINS-LYMPHOMA; SEER-MEDICARE DATA; RISK-FACTORS; PHASE-II; DOXORUBICIN; CHEMOTHERAPY; RITUXIMAB; EPOCH; CARDIOMYOPATHY; MULTICENTER AB We identified 3910 elderly (>65 yrs) patients with diffuse large B-cell lymphoma (DLBCL) who received doxorubicin-based (+/-rituximab) therapy and 77 347 cancer-free controls, and assessed cardiovascular events and survival in relation to preexisting cardiovascular comorbidities. Compared to controls, patients with DLBCL had a 3.4-fold (95% CI 3.0-3.9) and 2.5-fold (95% CI 2.3-2.7) increased risk of congestive heart failure (CHF)/cardiomyopathy (CM) within 6 months and 3 years of diagnosis, respectively. Risk of acute myocardial infarction (AMI) was similarly increased. The risk of CHF/CM and AMI was significantly higher in those patients with DLBCL (vs. controls) who did not report preexisting cardiovascular disease, compared to those who had preexisting cardiovascular disease; this was due to dose reductions of doxorubicin among patients with preexisting cardiovascular disease. Rituximab improved survival in patients with stage III-IV (but not I-II) disease (p-interaction=0.0003). Our novel findings emphasize the need to reduce cardiac toxicity of doxorubicin in elderly DLBCL patients. C1 [Tsai, Huei-Ting; Pfeiffer, Ruth M.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Warren, Joan] NCI, Div Canc Control & Populat Sci, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Wilson, Wyndham; Landgren, Ola] NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Landgren, Ola] Mem Sloan Kettering Canc Ctr, Dept Med, Myeloma Serv, New York, NY 10065 USA. RP Landgren, O (reprint author), Mem Sloan Kettering Canc Ctr, Dept Med, Myeloma Serv, 1275 York Ave, New York, NY 10065 USA. EM landgrec@mskcc.org FU Intramural Program of the NCI FX This research was supported by the Intramural Program of the NCI. NR 15 TC 3 Z9 3 U1 0 U2 3 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1042-8194 EI 1029-2403 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD MAR PY 2015 VL 56 IS 3 BP 682 EP 687 DI 10.3109/10428194.2014.921914 PG 6 WC Oncology; Hematology SC Oncology; Hematology GA CD5RC UT WOS:000351144500022 PM 24893799 ER PT J AU Lee, JA Kozikowski, RT Sorg, BS AF Lee, Jennifer A. Kozikowski, Raymond T. Sorg, Brian S. TI In vivo microscopy of microvessel oxygenation and network connections SO MICROVASCULAR RESEARCH LA English DT Article DE Angiogenesis; Cancer; Fluorescence; In vivo; Microscopy; Spectral imaging; Tumor; Wound healing ID DORSAL WINDOW CHAMBER; BLOOD-FLOW; TUMOR HYPOXIA; HEMOGLOBIN SATURATION; ANGIOGENESIS; TISSUES; COMBINATION; DISEASE; OXI4503 AB Abnormal or compromised microvascular function is a key component of various diseases. In vivo microscopy of microvessel function in preclinical models can be useful for the study of a disease state and effects of new treatments. Wide-field imaging of microvascular oxygenation via hemoglobin (Hb) saturation measurements has been applied in various applications alone and in combination with other measures of microvessel function, such as blood flow. However, most current combined imaging methods of microvessel function do not provide direct information on microvessel network connectivity or changes in connections and blood flow pathways. First-pass fluorescence (FPF) imaging of a systemically administered fluorescent contrast agent can be used to directly image blood flow pathways and connections relative to a local supplying arteriole in a quantitative manner through measurement of blood supply time (BST). Here, we demonstrate the utility of information produced by the combination of Hb saturation measurements via spectral imaging with BST measurements via FPF imaging for correlation of microvessel oxygenation with blood flow pathways and connections throughout a local network. Specifically, we show network pathway effects on oxygen transport in normal microvessels, dynamic changes associated with wound healing, and pathological effects of abnormal angiogenesis in tumor growth and development. (C) 2014 Elsevier Inc. All rights reserved. C1 [Lee, Jennifer A.] Univ Florida, J Crayton Pruitt Family Dept Biomed Engn, Gainesville, FL 32610 USA. [Kozikowski, Raymond T.] Ventana Med Syst Inc, Tucson, AZ 85755 USA. [Sorg, Brian S.] NCI, NIH, Bethesda, MD 20892 USA. RP Lee, JA (reprint author), Univ Florida, J Crayton Pruitt Family Dept Biomed Engn, Gainesville, FL 32610 USA. EM jalee2@ufl.edu FU Bankhead-Coley Cancer Research Program, Florida Department of Health FX Funding was provided in part by the Bankhead-Coley Cancer Research Program, Florida Department of Health. NR 33 TC 1 Z9 1 U1 0 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0026-2862 EI 1095-9319 J9 MICROVASC RES JI Microvasc. Res. PD MAR PY 2015 VL 98 BP 29 EP 39 DI 10.1016/j.mvr.2014.11.007 PG 11 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA CD8FU UT WOS:000351331400005 PM 25500481 ER PT J AU Danoch, H Kalechman, Y Albeck, M Longo, DL Sredni, B AF Danoch, Hila Kalechman, Yona Albeck, Michael Longo, Dan L. Sredni, Benjamin TI Sensitizing B- and T- cell Lymphoma Cells to Paclitaxel/Abraxane-Induced Death by AS101 via Inhibition of the VLA-4-IL10-Survivin Axis SO MOLECULAR CANCER RESEARCH LA English DT Article ID LUNG-CANCER PATIENTS; IMMUNOMODULATOR AS101; SERUM INTERLEUKIN-10; PROGNOSTIC-FACTOR; GENE-EXPRESSION; SURVIVIN GENE; BREAST-CANCER; TNF-ALPHA; IL-10; APOPTOSIS AB Cancer cell resistance to chemotherapy is a major concern in clinical oncology, resulting in increased tumor growth and decreased patient survival. Manipulation of apoptosis has emerged as a new therapeutic strategy to eliminate cancer cells. The focus of this study resides within a novel approach to target survivin, an integrator of both cell death and mitosis. This protein plays a pivotal role in the resistance of tumors to chemotherapy, especially to paclitaxel. The data herein demonstrate an indirect repression of survivin in both B- and T-cell lymphoma and human NHL by the nontoxic tellurium compound, AS101 [ammonium trichloro(dioxoethylene-o,o')tellurate], via inhibition of tumor autocrine IL10-STAT3-Survivin signaling. As a result of survivin abrogation, sensitization of lymphomas to paclitaxel or to Abraxane, the new albumin-stabilized nanoparticle formulation of paclitaxel, occurs both in vitro and in vivo. Importantly, inhibition of lymphoma cell IL10 secretion is mediated by inactivation of the VLA-4 integrin, recently shown to be an important target of AS101. This activity is followed by inhibition of the PI3K-AKT axis that mediates IL10 suppression. Because a wide variety of lymphomas and other tumor types express VLA-4 and secrete IL10 in an autocrine manner, inhibition of survivin with a small nontoxic agent has vast clinical significance in modulating chemosensitivity in many tumor types. (C) 2014 AACR. C1 [Danoch, Hila; Kalechman, Yona; Sredni, Benjamin] Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, Safdie AIDS & Immunol Res Ctr, CAIR Inst, IL-5290002 Ramat Gan, Israel. [Albeck, Michael] Bar Ilan Univ, Dept Chem, IL-5290002 Ramat Gan, Israel. [Longo, Dan L.] NIA, Biomed Res Ctr, Lab Mol Biol & Immunol, Baltimore, MD 21224 USA. RP Sredni, B (reprint author), Bar Ilan Univ, Max&Anna Webb 1, IL-5290002 Ramat Gan, Israel. EM srednib@mail.biu.ac.il FU Safdie Institute for AIDS and Immunology Research; Milton and Lois Shiffman Global Research Program; Dave and Florence Muskovitz Chair in Cancer Research; Comet Walerstein Cancer Research Program; Dorsha Wallman Cancer Research Endowment; Frida Stollman Cancer Memorial Fund FX This work was partly supported by The Safdie Institute for AIDS and Immunology Research, The Milton and Lois Shiffman Global Research Program, The Dave and Florence Muskovitz Chair in Cancer Research, The Comet Walerstein Cancer Research Program and the Dorsha Wallman Cancer Research Endowment, and Frida Stollman Cancer Memorial Fund. NR 48 TC 2 Z9 2 U1 2 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1541-7786 EI 1557-3125 J9 MOL CANCER RES JI Mol. Cancer Res. PD MAR PY 2015 VL 13 IS 3 BP 411 EP 422 DI 10.1158/1541-7786.MCR-14-0459 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CD6UA UT WOS:000351223800003 PM 25351768 ER PT J AU Gahl, WA AF Gahl, William A. CA NIH Undiagnosed Dis Program TI THE NIH UNDIAGNOSED DISEASE PROGRAM: SHEDDING LIGHT ON THE FUTURE OF DIAGNOSIS OF METABOLIC DISEASE SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 38th Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD) CY MAR 28-31, 2015 CL Salt Lake City, UT SP Soc Inherited Metab Disorders C1 [Gahl, William A.] NIH, NIH Common Fund, Off Director, Bethesda, MD 20892 USA. [Gahl, William A.; NIH Undiagnosed Dis Program] NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2015 VL 114 IS 3 BP 307 EP 307 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA CD6IC UT WOS:000351191800006 ER PT J AU Lodish, M AF Lodish, Maya TI The role of succinate dehydrogenase and fumarate hydratase in tumorigenesis SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 38th Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD) CY MAR 28-31, 2015 CL Salt Lake City, UT SP Soc Inherited Metab Disorders C1 [Lodish, Maya] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol Genet PDEGEN, NIH, Bethesda, MD 20892 USA. 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 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2015 VL 114 IS 3 BP 307 EP 308 PG 2 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA CD6IC UT WOS:000351191800009 ER PT J AU Class, B Celeste, F Xu, X Wang, A Malicdan, MC Latham, L Ciccone, C Mckew, J Huizing, M Gahl, WA Carrillo-Carrasco, N AF Class, Brad Celeste, Frank Xu, Xin Wang, Amy Malicdan, May Christine Latham, Lea Ciccone, Carla Mckew, John Huizing, Marjan Gahl, William A. Carrillo-Carrasco, Nuria TI N-acetylmannosamine (ManNAc) is safe and increased sialic acid production in GNE myopathy subjects SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 38th Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD) CY MAR 28-31, 2015 CL Salt Lake City, UT SP Soc Inherited Metab Disorders C1 [Class, Brad; Celeste, Frank; Xu, Xin; Wang, Amy; Latham, Lea; Mckew, John; Carrillo-Carrasco, Nuria] NIH, Therapeut Rare & Neglected Dis, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Malicdan, May Christine; Ciccone, Carla; Huizing, Marjan; Gahl, William A.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Gahl, William A.] NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA. RI Carrillo-Carrasco, Nuria/B-9034-2009 OI Carrillo-Carrasco, Nuria/0000-0003-0374-0808 NR 0 TC 0 Z9 0 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2015 VL 114 IS 3 BP 312 EP 313 PG 2 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA CD6IC UT WOS:000351191800019 ER PT J AU Francis, KR AF Francis, Kevin Richard TI Human IPS cell models of cholesterol synthesis disorders reveal WNT signaling defects underlie neurological dysfunction SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 38th Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD) CY MAR 28-31, 2015 CL Salt Lake City, UT SP Soc Inherited Metab Disorders C1 [Francis, Kevin Richard] NICHD, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2015 VL 114 IS 3 BP 314 EP 315 PG 2 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA CD6IC UT WOS:000351191800021 ER PT J AU Lam, C Ferreira, C Krasnewich, D Toro, C Latham, L Zein, W Lehky, T Brewer, C King, K Wassif, C Rosenzweig, S Lyons, J Gahl, W Wolfe, L AF Lam, Christina Ferreira, Carlos Krasnewich, Donna Toro, Camillo Latham, Lea Zein, Wadih Lehky, Tanya Brewer, Carmen King, Kelly Wassif, Christopher Rosenzweig, Sergio Lyons, Jonathan Gahl, William Wolfe, Lynne TI Clarifying the phenotype of NGLY1 deficiency, the first congenital disorder of deglycosylation SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 38th Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD) CY MAR 28-31, 2015 CL Salt Lake City, UT SP Soc Inherited Metab Disorders C1 [Lam, Christina; Ferreira, Carlos; Gahl, William] NHGRI, Med Genet Branch, NIH, Bethesda, MD USA. [Krasnewich, Donna] NIGMS, Div Genet & Dev Biol, NIH, Bethesda, MD USA. [Toro, Camillo; Gahl, William; Wolfe, Lynne] NIH, Undiagnosed Dis Program, Bethesda, MD USA. [Latham, Lea; Gahl, William; Wolfe, Lynne] NHGRI, Off Clin Director, NIH, Bethesda, MD USA. [Zein, Wadih] NEI, Ophthalm Clin Genet Sect, NIH, Bethesda, MD USA. [Lehky, Tanya] NINDS, Electromyog Sect, Bethesda, MD 20892 USA. [Brewer, Carmen; King, Kelly; Wassif, Christopher] NIDCD, Otolcayngol Branch, NIH, Bethesda, MD USA. [Rosenzweig, Sergio] NIH, CC, Serv Immunol, Bethesda, MD USA. [Lyons, Jonathan] NIAID, Genet & Pathogenesis Allergy Sect, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2015 VL 114 IS 3 BP 315 EP 316 PG 2 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA CD6IC UT WOS:000351191800023 ER PT J AU Regier, DS Golas, G Johnston, J Tifft, CJ AF Regier, Debra S. Golas, Gretchen Johnston, Jean Tifft, Cynthia J. TI GM1 Gangliosidosis Type II: Sub-classification of late infantile and juvenile patients based on age at symptom onset SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 38th Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD) CY MAR 28-31, 2015 CL Salt Lake City, UT SP Soc Inherited Metab Disorders C1 [Regier, Debra S.; Golas, Gretchen; Johnston, Jean; Tifft, Cynthia J.] NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA. 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 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2015 VL 114 IS 3 BP 317 EP 317 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA CD6IC UT WOS:000351191800026 ER PT J AU He, M Peng, M Li, X Ostrovsky, J Kwon, YJ Raihan, M Davids, M Boerkoel, C McCormick, E Suzuki, T Argon, Y Falk, M AF He, Miao Peng, Min Li, Xueli Ostrovsky, Julian Kwon, Young-Joon Raihan, Mohd Davids, Mariska Boerkoel, Cornelius McCormick, Elizabeth Suzuki, Tadashi Argon, Yair Falk, Marni TI NGLY1 deficiency lies in the crosshairs of CDG and mitochondrial diseases SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 38th Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD) CY MAR 28-31, 2015 CL Salt Lake City, UT SP Soc Inherited Metab Disorders C1 [He, Miao; Li, Xueli; Raihan, Mohd; Argon, Yair] Childrens Hosp Philadelphia, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [He, Miao; Peng, Min; Li, Xueli; Ostrovsky, Julian; Kwon, Young-Joon; Raihan, Mohd; McCormick, Elizabeth; Argon, Yair; Falk, Marni] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Peng, Min; Ostrovsky, Julian; Kwon, Young-Joon; McCormick, Elizabeth; Falk, Marni] Childrens Hosp Philadelphia, Dept Pediat, Div Human Genet, Philadelphia, PA 19104 USA. [Davids, Mariska; Boerkoel, Cornelius] NIH, Undiagnosed Dis Program, Bethesda, MA USA. [Suzuki, Tadashi] RIKEN, Inst Phys & Chem Res, Saitama, Japan. RI Suzuki, Tadashi/I-4536-2014 NR 0 TC 0 Z9 0 U1 1 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2015 VL 114 IS 3 BP 322 EP 323 PG 2 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA CD6IC UT WOS:000351191800034 ER PT J AU Ferreira, C Lam, C Wolfe, L Gahl, W Krasnewich, D AF Ferreira, C. Lam, C. Wolfe, L. Gahl, W. Krasnewich, D. TI The natural history protocol on congenital disorders of glycosylation SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 38th Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD) CY MAR 28-31, 2015 CL Salt Lake City, UT SP Soc Inherited Metab Disorders C1 [Ferreira, C.; Lam, C.; Wolfe, L.; Gahl, W.] NHGRI, NIH, Bethesda, MD 20892 USA. [Krasnewich, D.] NIGMS, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2015 VL 114 IS 3 MA 22 BP 335 EP 336 PG 2 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA CD6IC UT WOS:000351191800052 ER PT J AU Ferreira, C Devaney, J Hoffhei, S Pollard, L Cusmano-Ozog, K AF Ferreira, C. Devaney, J. Hoffhei, S. Pollard, Laura Cusmano-Ozog, K. TI Hereditary fructose intolerance mimicking a biochemical phenotype of mucolipidosis SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 38th Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD) CY MAR 28-31, 2015 CL Salt Lake City, UT SP Soc Inherited Metab Disorders C1 [Ferreira, C.] NHGRI, NIH, Bethesda, MD 20892 USA. [Devaney, J.; Hoffhei, S.; Cusmano-Ozog, K.] Childrens Natl Hlth Syst, Washington, DC USA. [Pollard, Laura] Greenwood Genet Ctr, Greenwood, SC 29646 USA. NR 0 TC 0 Z9 0 U1 1 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2015 VL 114 IS 3 MA 24 BP 336 EP 337 PG 2 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA CD6IC UT WOS:000351191800054 ER PT J AU Ferreira, C Lam, C Wolfe, L Krasnewich, D Gahl, W AF Ferreira, C. Lam, C. Wolfe, L. Krasnewich, D. Gahl, W. TI Cerebrospinal fluid findings in a cohort of patients with NGLY1 deficiency SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 38th Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD) CY MAR 28-31, 2015 CL Salt Lake City, UT SP Soc Inherited Metab Disorders C1 [Ferreira, C.; Lam, C.; Wolfe, L.; Gahl, W.] NHGRI, NIH, Bethesda, MD 20892 USA. [Krasnewich, D.] NIGMS, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2015 VL 114 IS 3 MA 23 BP 336 EP 336 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA CD6IC UT WOS:000351191800053 ER PT J AU Lam, C Wolfe, L Golas, GA Huizing, M Davids, M Kane, M Krasnewich, D Markello, T Zein, WM Maric, I Rosenzweig, S Ferreira, C Danylchuk, NR Kahler, S Gahl, WA Adams, DR AF Lam, Christina Wolfe, Lynne Golas, Gretchen A. Huizing, Marjan Davids, Mariska Kane, Megan Krasnewich, Donna Markello, Thomas Zein, Wadih M. Maric, Irina Rosenzweig, Sergio Ferreira, Carlos Danylchuk, Noelle R. Kahler, Stephen Gahl, William A. Adams, David R. TI A third case of PIGT-CDG: a clinical and molecular report of a newly discovered glycophosphatidylinositol anchor disorder SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 38th Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD) CY MAR 28-31, 2015 CL Salt Lake City, UT SP Soc Inherited Metab Disorders C1 [Lam, Christina; Wolfe, Lynne; Golas, Gretchen A.; Huizing, Marjan; Davids, Mariska; Kane, Megan; Markello, Thomas; Zein, Wadih M.; Maric, Irina; Rosenzweig, Sergio; Ferreira, Carlos; Gahl, William A.; Adams, David R.] NIH, Bethesda, MD 20892 USA. [Krasnewich, Donna; Danylchuk, Noelle R.; Kahler, Stephen] Univ Arkansas Med Sci, Little Rock, AR 72205 USA. [Krasnewich, Donna; Danylchuk, Noelle R.; Kahler, Stephen] Arkansas Childrens Hosp, Little Rock, AR 72202 USA. 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 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2015 VL 114 IS 3 MA 31 BP 340 EP 340 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA CD6IC UT WOS:000351191800060 ER PT J AU Estrada-Veras, J O'Brien, KJ Toro, C Gahl, W AF Estrada-Veras, Juvianee O'Brien, Kevin J. Toro, Camilo Gahl, William TI Cerebellar syndrome and cognitive deficits in Erdheim Chester disease: Just accumulation of histiocytes or secondary metabolic/endocrine deficit? SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 38th Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD) CY MAR 28-31, 2015 CL Salt Lake City, UT SP Soc Inherited Metab Disorders C1 [Estrada-Veras, Juvianee; O'Brien, Kevin J.; Gahl, William] NHGRI, Sect Human Biochem Genet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Toro, Camilo] NHGRI, Undiagnosed Dis Program, OCD, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2015 VL 114 IS 3 MA 36 BP 342 EP 342 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA CD6IC UT WOS:000351191800065 ER PT J AU Raval, D Merideth, M Sloan, J Manoli, I Venditti, CP AF Raval, Donna Merideth, Melissa Sloan, Jennifer Manoli, Irini Venditti, Charles P. TI Establishing a pregnancy registry for inborn errors of metabolism excluding hyperphenylalaninemia SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 38th Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD) CY MAR 28-31, 2015 CL Salt Lake City, UT SP Soc Inherited Metab Disorders C1 [Raval, Donna; Sloan, Jennifer; Manoli, Irini; Venditti, Charles P.] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Raval, Donna] Medstar Washington Hosp Ctr, Maternal Fetal Med, Dept Obstet & Gynecol, Washington, DC USA. [Merideth, Melissa] NHGRI, NIH, Off Clin Director, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2015 VL 114 IS 3 MA 44 BP 346 EP 347 PG 2 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA CD6IC UT WOS:000351191800073 ER PT J AU Ljubica, C Feldman, B Tuchman, M AF Ljubica, Caldovic Feldman, B. Tuchman, M. TI Discovery of drugs for neuroprotection from hyperammonemia SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 38th Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD) CY MAR 28-31, 2015 CL Salt Lake City, UT SP Soc Inherited Metab Disorders C1 [Ljubica, Caldovic; Tuchman, M.] Childrens Natl Hlth Syst, Washington, DC USA. [Feldman, B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2015 VL 114 IS 3 MA 48 BP 348 EP 349 PG 2 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA CD6IC UT WOS:000351191800077 ER PT J AU Manoli, I Myles, JG Carrillo-Carrasco, N Sloan, JL Strauss, KA Morton, H Venditti, CP AF Manoli, Irini Myles, Jennifer G. Carrillo-Carrasco, Nuria Sloan, Jennifer L. Strauss, Kevin A. Morton, Holmes Venditti, Charles P. TI Reappraising the dietary practices to manage cobalamin C deficiency SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 38th Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD) CY MAR 28-31, 2015 CL Salt Lake City, UT SP Soc Inherited Metab Disorders C1 [Manoli, Irini; Carrillo-Carrasco, Nuria; Sloan, Jennifer L.; Venditti, Charles P.] NHGRI, NIH, Organ Acid Res Sect, Genet & Mol Biol Branch, Bethesda, MD 20892 USA. [Myles, Jennifer G.] NIH, Dept Nutr, Bethesda, MD 20892 USA. [Carrillo-Carrasco, Nuria] NIH, Therapeut Rare & Neglected Dis, NCATS, Bethesda, MD 20892 USA. [Strauss, Kevin A.; Morton, Holmes] Clin Special Children, Strasburg, PA USA. RI Carrillo-Carrasco, Nuria/B-9034-2009 OI Carrillo-Carrasco, Nuria/0000-0003-0374-0808 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2015 VL 114 IS 3 MA 49 BP 349 EP 349 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA CD6IC UT WOS:000351191800078 ER PT J AU Tarasenko, TN Singh, LN Senac, J Epping, M Zerfas, PM Venditti, CP McGuire, PJ AF Tarasenko, Tatiana N. Singh, Larry N. Senac, Julien Epping, Madeline Zerfas, Patricia M. Venditti, Charles P. McGuire, Peter J. TI Hepatic metabolic reprogramming of mitochondrial fatty acid oxidation in response to influenza infection SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 38th Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD) CY MAR 28-31, 2015 CL Salt Lake City, UT SP Soc Inherited Metab Disorders C1 [Tarasenko, Tatiana N.; McGuire, Peter J.] NHGRI, Metab Infect & Immun Unit, NIH, Bethesda, MD 20892 USA. [Singh, Larry N.] Childrens Hosp Philadelphia, Ctr Mitochondrial & Epigen Med, Philadelphia, PA 19104 USA. [Senac, Julien; Epping, Madeline; Venditti, Charles P.] NHGRI, Organ Add Res Sect, NIH, Bethesda, MD 20892 USA. [Zerfas, Patricia M.] NIH, Off Res Serv, Div Vet Resources, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2015 VL 114 IS 3 MA 80 BP 363 EP 364 PG 2 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA CD6IC UT WOS:000351191800145 ER PT J AU Fraser, JL Sloan, J Harrington, E Manoli, I Venditti, CP AF Fraser, Jamie L. Sloan, Jennifer Harrington, Elizabeth Manoli, Irini Venditti, Charles P. TI Bone health in isolated methyhnalonic acidemia: Insights from patient studies and animal models SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 38th Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD) CY MAR 28-31, 2015 CL Salt Lake City, UT SP Soc Inherited Metab Disorders C1 [Fraser, Jamie L.] Med Genet Training Program, New York, NY USA. [Fraser, Jamie L.; Sloan, Jennifer; Harrington, Elizabeth; Manoli, Irini; Venditti, Charles P.] NHGRI, Organ Acid Res Sect, Med Genet Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2015 VL 114 IS 3 MA 99 BP 373 EP 374 PG 2 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA CD6IC UT WOS:000351191800124 ER PT J AU Falk, MJ Shen, LS Gonzalez, M Leipzig, J Lott, MT Stassen, APM Diroma, MA Navarro-Gomez, D Yeske, P Bai, RK Boles, RG Brilhante, V Ralph, D DaRe, JT Shelton, R Terry, SF Zhang, Z Copeland, WC van Oven, M Prokisch, H Wallace, DC Attimonelli, M Krotoski, D Zuchner, S Gai, XW AF Falk, Marni J. Shen, Lishuang Gonzalez, Michael Leipzig, Jeremy Lott, Marie T. Stassen, Alphons P. M. Diroma, Maria Angela Navarro-Gomez, Daniel Yeske, Philip Bai, Renkui Boles, Richard G. Brilhante, Virginia Ralph, David DaRe, Jeana T. Shelton, Robert Terry, Sharon F. Zhang, Zhe Copeland, William C. van Oven, Mannis Prokisch, Holger Wallace, Douglas C. Attimonelli, Marcella Krotoski, Danuta Zuchner, Stephan Gai, Xiaowu CA MSeqDR Consortium TI Mitochondrial Disease Sequence Data Resource (MSeqDR): A global grass-roots consortium to facilitate deposition, curation, annotation, and integrated analysis of genomic data for the mitochondrial disease clinical and research communities SO MOLECULAR GENETICS AND METABOLISM LA English DT Review DE Mitochondrial disease; Genomics; Exome; Data sharing ID HUMAN PHENOTYPE ONTOLOGY; PRIORITIZATION; COMPILATION; DISORDERS AB Success rates for genomic analyses of highly heterogeneous disorders can be greatly improved if a large cohort of patient data is assembled to enhance collective capabilities for accurate sequence variant annotation, analysis, and interpretation. Indeed, molecular diagnostics requires the establishment of robust data resources to enable data sharing that informs accurate understanding of genes, variants, and phenotypes. The "Mitochondrial Disease Sequence Data Resource (MSeqDR) Consortium" is a grass-roots effort facilitated by the United Mitochondria] Disease Foundation to identify and prioritize specific genomic data analysis needs of the global mitochondrial disease clinical and research community. A central Web portal (https://mseqdr.org) facilitates the coherent compilation, organization, annotation, and analysis of sequence data from both nuclear and mitochondrial genomes of individuals and families with suspected mitochondria! disease. This Web portal provides users with a flexible and expandable suite of resources to enable variant-, gene-, and exome-level sequence analysis in a secure, Web-based, and user-friendly fashion. Users can also elect to share data with other MSeqDR Consortium members, or even the general public, either by custom annotation tracks or through the use of a convenient distributed annotation system (DAS) mechanism. A range of data visualization and analysis tools are provided to facilitate user interrogation and understanding of genomic, and ultimately phenotypic, data of relevance to mitochondrial biology and disease. Currently available tools for nuclear and mitochondrial gene analyses include an MSeqDR GBrowse instance that hosts optimized mitochondrial disease and mitochondrial DNA (mtDNA) specific annotation tracks, as well as an MSeqDR locus-specific database (LSDB) that curates variant data on more than 1300 genes that have been implicated in mitochondrial disease and/or encode mitochondria-localized proteins. MSeqDR is integrated with a diverse array of mtDNA data analysis tools that are both freestanding and incorporated into an online exome-level dataset curation and analysis resource (GEM.app) that is being optimized to support needs of the MSeqDR community. In addition, MSeqDR supports mitochondrial disease phenotyping and ontology tools, and provides variant pathogenicity assessment features that enable community review, feedback, and integration with the public ClinVar variant annotation resource. A centralized Web-based informed consent process is being developed, with implementation of a Global Unique Identifier (GUID) system to integrate data deposited on a given individual from different sources. Community-based data deposition into MSeqDR has already begun. Future efforts will enhance capabilities to incorporate phenotypic data that enhance genomic data analyses. MSeqDR will fill the existing void in bioinformatics tools and centralized knowledge that are necessary to enable efficient nuclear and mtDNA genomic data interpretation by a range of shareholders across both clinical diagnostic and research settings. Ultimately, MSeqDR is focused on empowering the global mitochondrial disease community to better define and explore mitochondrial diseases. (C) 2014 Elsevier Inc. All rights reserved. C1 [Falk, Marni J.] Childrens Hosp Philadelphia, Dept Pediat, Div Human Genet, Philadelphia, PA 19104 USA. [Falk, Marni J.; Wallace, Douglas C.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Shen, Lishuang; Navarro-Gomez, Daniel; Gai, Xiaowu] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA. [Gonzalez, Michael; Zuchner, Stephan] Univ Miami, Miller Sch Med, Dr John T Macdonald Fdn, Dept Human Genet, Coral Gables, FL 33124 USA. [Leipzig, Jeremy; Zhang, Zhe] Childrens Hosp Philadelphia, Ctr Biomed Informat, Philadelphia, PA 19104 USA. [Lott, Marie T.; Wallace, Douglas C.] Childrens Hosp Philadelphia, Ctr Mitochondrial & Epigen Med, Philadelphia, PA 19104 USA. [Stassen, Alphons P. M.] Maastricht Univ, Med Ctr, Dept Clin Genet, NL-6200 MD Maastricht, Netherlands. [Diroma, Maria Angela] Univ Bari, Dept Biosci Biotechnol & Biopharmaceut, Bari, Italy. [Yeske, Philip] United Mitochondrial Dis Fdn, Pittsburgh, PA USA. [Bai, Renkui] GeneDx Inc, Gaithersburg, MD USA. [Boles, Richard G.] Courtagen Life Sci, Woburn, MA USA. [Brilhante, Virginia] Univ Helsinki, Biomedicum Helsinki, Res Programs Unit, Mol Neurol, FIN-00014 Helsinki, Finland. [Ralph, David; DaRe, Jeana T.] Transgenomic Inc, New Haven, CT USA. [Terry, Sharon F.] Genet Alliance, Bethesda, MD USA. [Copeland, William C.] NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. [van Oven, Mannis] Univ Med Ctr Rotterdam, Erasmus MC, Dept Forens Mol Biol, Rotterdam, Netherlands. [Prokisch, Holger] Tech Univ Munich, Inst Human Genet, D-80290 Munich, Germany. [Prokisch, Holger] Helmholtz Zentrum Munich, Munich, Germany. [Wallace, Douglas C.] Childrens Hosp Philadelphia, Dept Pathol, Philadelphia, PA 19104 USA. [Krotoski, Danuta] NICHD, NIH, Bethesda, MD USA. RP Falk, MJ (reprint author), ARC, 1002c,3615 Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM falkm@email.chop.edu; Xiaowu_Gai@meei.harvard.edu RI Shen, Lishuang/B-3040-2013; OI Leipzig, Jeremy/0000-0001-7224-9620; van Oven, Mannis/0000-0003-0026-7998; Pujol, Aurora/0000-0002-9606-0600; Christodoulou, John/0000-0002-8431-0641; Diroma, Maria Angela/0000-0003-1427-8946 FU Medical Research Council [MR/K000608/1]; NHGRI NIH HHS [U41 HG006834, U41-HG006834]; NINDS NIH HHS [R01 NS021328, R01 NS083726, U54 NS078059, U54-NS078059] NR 21 TC 14 Z9 14 U1 1 U2 16 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2015 VL 114 IS 3 BP 388 EP 396 DI 10.1016/j.ymgme.2014.11.016 PG 9 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA CD6IC UT WOS:000351191800127 PM 25542617 ER EF