FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Chowell, G Sattenspiel, L Bansal, S Viboud, C AF Chowell, Gerardo Sattenspiel, Lisa Bansal, Shweta Viboud, Cecile TI Mathematical models to characterize early epidemic growth: A review SO PHYSICS OF LIFE REVIEWS LA English DT Review DE Epidemic modeling; Epidemic growth patterns; Reproduction number; Sub-exponential epidemic growth; Spatial models; Individual-based model ID NONLINEAR INCIDENCE RATES; SMALL-WORLD NETWORKS; INFECTIOUS-DISEASE; SOCIAL NETWORKS; MEASLES EPIDEMICS; METAPOPULATION DYNAMICS; CLUSTERED POPULATIONS; SPATIAL HIERARCHIES; PANDEMIC INFLUENZA; CONTACT NETWORKS AB There is a long tradition of using mathematical models to generate insights into the transmission dynamics of infectious diseases and assess the potential impact of different intervention strategies. The increasing use of mathematical models for epidemic forecasting has highlighted the importance of designing reliable models that capture the baseline transmission characteristics of specific pathogens and social contexts. More refined models are needed however, in particular to account for variation in the early growth dynamics of real epidemics and to gain a better understanding of the mechanisms at play. Here, we review recent progress on modeling and characterizing early epidemic growth patterns from infectious disease outbreak data, and survey the types of mathematical formulations that are most useful for capturing a diversity of early epidemic growth profiles, ranging from sub-exponential to exponential growth dynamics. Specifically, we review mathematical models that incorporate spatial details or realistic population mixing structures, including meta-population models, individual-based network models, and simple SIR-type models that incorporate the effects of reactive behavior changes or inhomogeneous mixing. In this process, we also analyze simulation data stemming from detailed large-scale agent-based models previously designed and calibrated to study how realistic social networks and disease transmission characteristics shape early epidemic growth patterns, general transmission dynamics, and control of international disease emergencies such as the 2009 A/H1N1 influenza pandemic and the 2014-2015 Ebola epidemic in West Africa. (C) 2016 Elsevier B.V. All rights reserved. C1 [Chowell, Gerardo] Georgia State Univ, Sch Publ Hlth, Atlanta, GA 30303 USA. [Chowell, Gerardo; Bansal, Shweta; Viboud, Cecile] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Sattenspiel, Lisa] Univ Missouri, Dept Anthropol, 200 Swallow Hall, Columbia, MO 65211 USA. [Bansal, Shweta] Georgetown Univ, Dept Biol, Washington, DC 20057 USA. RP Chowell, G (reprint author), Georgia State Univ, Sch Publ Hlth, Atlanta, GA 30303 USA. EM gchowell@gsu.edu OI Bansal, Shweta/0000-0002-1740-5421 FU NSF [1414374, 1318788]; UK Biotechnology and Biological Sciences Research Council [BB/M008894/1]; NSF-IIS RAPID [1518939]; Division of International Epidemiology and Population Studies, The Fogarty International Center, US National Institutes of Health; RAPIDD Program of the Science & Technology Directorate FX GC acknowledges financial support from the NSF grant 1414374 as part of the joint NSF-NTH-USDA Ecology and Evolution of Infectious Diseases program; UK Biotechnology and Biological Sciences Research Council grant BB/M008894/1, NSF-IIS RAPID award #1518939, and NSF grant 1318788 III: Small: Data Management for Real Time Data Driven Epidemic simulation, and the Division of International Epidemiology and Population Studies, The Fogarty International Center, US National Institutes of Health. SB and CV acknowledge financial support from the RAPIDD Program of the Science & Technology Directorate. The funders had no role in decision to publish, or preparation of the manuscript. We gratefully acknowledge the use of high-performance computing resources supported by Georgia State University's Research Solutions. NR 114 TC 11 Z9 11 U1 20 U2 20 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1571-0645 EI 1873-1457 J9 PHYS LIFE REV JI Phys. Life Rev. PD SEP PY 2016 VL 18 BP 66 EP 97 PG 32 WC Biology; Biophysics SC Life Sciences & Biomedicine - Other Topics; Biophysics GA ED0PV UT WOS:000388545300018 PM 27451336 ER PT J AU Chowell, G Sattenspiel, L Bansal, S Viboud, C AF Chowell, Gerardo Sattenspiel, Lisa Bansal, Shweta Viboud, Cecile TI Early sub-exponential epidemic growth: Simple models, nonlinear incidence rates, and additional mechanisms Reply to comments on "Mathematical models to characterize early epidemic growth: A review" SO PHYSICS OF LIFE REVIEWS LA English DT Editorial Material ID INFECTIOUS-DISEASE C1 [Chowell, Gerardo] Georgia State Univ, Sch Publ Hlth, Atlanta, GA 30303 USA. [Chowell, Gerardo; Bansal, Shweta; Viboud, Cecile] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Sattenspiel, Lisa] Univ Missouri, Dept Anthropol, 200 Swallow Hall, Columbia, MO 65211 USA. [Bansal, Shweta] Georgetown Univ, Dept Biol, Washington, DC 20057 USA. RP Chowell, G (reprint author), Georgia State Univ, Sch Publ Hlth, Atlanta, GA 30303 USA. EM gchowell@gsu.edu NR 13 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1571-0645 EI 1873-1457 J9 PHYS LIFE REV JI Phys. Life Rev. PD SEP PY 2016 VL 18 BP 114 EP 117 DI 10.1016/j.plrev.2016.08.016 PG 4 WC Biology; Biophysics SC Life Sciences & Biomedicine - Other Topics; Biophysics GA ED0PV UT WOS:000388545300025 PM 27632895 ER PT J AU Stein, BD Adams, AS Chambers, DA AF Stein, Bradley D. Adams, Alyce S. Chambers, David A. TI A Learning Behavioral Health Care System: Opportunities to Enhance Research SO PSYCHIATRIC SERVICES LA English DT Article ID IMPLEMENTATION-RESEARCH; TRIAL AB Sweeping changes in health care financing combined with the increased use of technology across health care systems are making it possible to address long-standing challenges to the behavioral health services delivery system. This Open Forum outlines opportunities and challenges facing health services researchers in this rapidly changing landscape. Inspired by a 2012 report by the Institute of Medicine, the authors discuss innovative research endeavors, promising study designs, and challenges involved in integrating high-impact behavioral health services research within a learning behavioral health care framework. The Open Forum concludes with a discussion of the critical next steps in this process: building consensus around common metrics for high-quality care, relevant outcomes, and contextual factors; connecting researchers to community and clinical settings; creating a data commons to pool information across sites; and designing and evaluating evidence-based decision support tools to drive improved care and outcomes. C1 [Stein, Bradley D.] Univ Pittsburgh, RAND Corp, Pittsburgh, PA USA. [Stein, Bradley D.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. [Adams, Alyce S.] Kaiser Permanente Northern Calif, Div Res, Oakland, CA USA. [Chambers, David A.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Stein, BD (reprint author), Univ Pittsburgh, RAND Corp, Pittsburgh, PA USA.; Stein, BD (reprint author), Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. FU Kaiser Permanente Community Benefit [RNG021579]; Agency for Healthcare Research and Quality [R01HS018577] FX Dr. Adams' time was supported in part by Kaiser Permanente Community Benefit RNG021579 (co-principal investigators (PIs): Dr. Adams and Constance Weisner, Dr. P.H.) and the Agency for Healthcare Research and Quality grant R01HS018577 (PI: Stephen B. Soumerai, Sc.D.). The authors thank the speakers and attendees at the 2014 Conference on Mental Health Services Research for their contributions to the ideas in this paper and Gina Boyd, M.L.I.S., Hilary Peterson, B.A., and Elizabeth May, Ph.D., for their assistance. The views expressed are those of the authors and not necessarily those of the National Cancer Institute. NR 16 TC 0 Z9 0 U1 0 U2 0 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 1075-2730 EI 1557-9700 J9 PSYCHIAT SERV JI Psychiatr. Serv. PD SEP 1 PY 2016 VL 67 IS 9 BP 1019 EP 1022 DI 10.1176/appi.ps.201500180 PG 4 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA EC6SS UT WOS:000388267600014 PM 27133723 ER PT J AU Dominguez, C Tsang, KY Palena, C AF Dominguez, Charli Tsang, Kwong-Yok Palena, Claudia TI Short-term EGFR blockade enhances immune-mediated cytotoxicity of EGFR mutant lung cancer cells: rationale for combination therapies SO CELL DEATH & DISEASE LA English DT Article ID EPITHELIAL-MESENCHYMAL TRANSITION; TRANSCRIPTION FACTOR BRACHYURY; STEM-LIKE CELLS; AUTOPHAGY INDUCTION; TUMOR-CELLS; INHIBITORS; RESISTANCE; EXPRESSION; CARCINOMA; NSCLC AB The epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) erlotinib has been approved for years as a first-line therapy for patients harboring EGFR-sensitizing mutations. With the promising implementation of immunotherapeutic strategies for the treatment of lung cancer, there is a growing interest in developing combinatorial therapies that could utilize immune approaches in the context of conventional or targeted therapies. Tumor cells are known to evade immune attack by multiple strategies, including undergoing phenotypic plasticity via a process designated as the epithelial-mesenchymal transition (EMT). As signaling through EGFR is a major inducer of EMT in epithelial cells, we have investigated the effect of EGFR inhibition with erlotinib on tumor phenotype and susceptibility to immune attack. Our data shows that short-term exposure of tumor cells to low-dose erlotinib modulates tumor plasticity and immune-mediated cytotoxicity in lung cancer cells harboring a sensitizing EGFR mutation, leading to a remarkable enhancement of tumor lysis mediated by innate NK cells and antigen-specific T cells. This effect positively correlated with the ability of short-term EGFR blockade to modulate tumor phenotype towards a more epithelial one, as well as to increase susceptibility to caspase-mediated apoptosis. The effect, however, was lost when erlotinib was utilized for long periods of time in vitro or in vivo, which resulted in gain of mesenchymal features and decreased (rather than increased) tumor lysis in response to immune effector mechanisms. Our data provides rationale for potential combinations of erlotinib and immunotherapies for the treatment of lung carcinomas in the early setting, before the establishment of tumor relapse with long-term EGFR inhibition. C1 [Dominguez, Charli; Tsang, Kwong-Yok; Palena, Claudia] NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, 10 Ctr Dr,Room 8B14,MSC 1750, Bethesda, MD 20892 USA. RP Palena, C (reprint author), NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, 10 Ctr Dr,Room 8B14,MSC 1750, Bethesda, MD 20892 USA. EM palenac@mail.nih.gov FU NIH Intramural Research Program, National Cancer Institute, Center for Cancer Research FX We thank Dr. Udayan Guha for providing cell lines and sharing expertise on erlotinib treatment in vivo, and Ms. Kristen McCampbell for her technical assistance with IHC assays. This research was supported by funds of the NIH Intramural Research Program, National Cancer Institute, Center for Cancer Research. NR 61 TC 0 Z9 0 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-4889 J9 CELL DEATH DIS JI Cell Death Dis. PD SEP PY 2016 VL 7 AR e2380 DI 10.1038/cddis.2016.297 PG 13 WC Cell Biology SC Cell Biology GA EC2QF UT WOS:000387968100029 PM 27685624 ER PT J AU Zhang, JF Han, BS Li, XX Bies, J Jiang, PL Koller, RP Wolff, L AF Zhang, Junfang Han, Bingshe Li, Xiaoxia Bies, Juraj Jiang, Penglei Koller, Richard P. Wolff, Linda TI Distal regulation of c-myb expression during IL-6-induced differentiation in murine myeloid progenitor M1 cells SO CELL DEATH & DISEASE LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; T-CELL; HEMATOPOIETIC-CELLS; NEGATIVE REGULATION; MESSENGER-RNA; TRANSCRIPTION ELONGATION; BINDING-SITES; CANCER-CELLS; STEM-CELLS; GENE AB The c-Myb transcription factor is a major regulator that controls differentiation and proliferation of hematopoietic progenitor cells, which is frequently deregulated in hematological diseases, such as lymphoma and leukemia. Understanding of the mechanisms regulating the transcription of c-myb gene is challenging as it lacks a typical promoter and multiple factors are involved. Our previous studies identified some distal regulatory elements in the upstream regions of c-myb gene in murine myeloid progenitor M1 cells, but the detailed mechanisms still remain unclear. In the present study, we found that a cell differentiation-related DNase1 hypersensitive site is located at a -28k region upstream of c-myb gene and that transcription factors Hoxa9, Meis1 and PU. 1 bind to the -28k region. Circular chromosome conformation capture (4C) assay confirmed the interaction between the -28k region and the c-myb promoter, which is supported by the enrichment of CTCF and Cohesin. Our analysis also points to a critical role for Hoxa9 and PU. 1 in distal regulation of c-myb expression in murine myeloid cells and cell differentiation. Overexpression of Hoxa9 disrupted the IL-6-induced differentiation of M1 cells and upregulated c-myb expression through binding of the -28k region. Taken together, our results provide an evidence for critical role of the -28k region in distal regulatory mechanism for c-myb gene expression during differentiation of myeloid progenitor M1 cells. C1 [Zhang, Junfang; Han, Bingshe; Li, Xiaoxia; Jiang, Penglei] Shanghai Ocean Univ, Coll Fishery & Life Sci, Minist Educ, Key Lab Aquacultural Resources & Utilizat, 999 Huchenghuan Rd, Shanghai 201306, Peoples R China. [Bies, Juraj; Koller, Richard P.; Wolff, Linda] NCI, Cellular Oncol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Zhang, JF (reprint author), Shanghai Ocean Univ, Coll Fishery & Life Sci, Minist Educ, Key Lab Aquacultural Resources & Utilizat, 999 Huchenghuan Rd, Shanghai 201306, Peoples R China. EM jfzhang@shou.edu.cn FU National Natural Science Foundation of China [31372516]; Shanghai Municipal Education Commission; Intramural Program at the National Cancer Institute, Center for Cancer Research FX This study was supported by grants from National Natural Science Foundation of China (grant no. 31372516 awarded to JZ), Shanghai Municipal Education Commission (Oriental scholar program awarded to JZ). The work was also supported by the Intramural Program at the National Cancer Institute, Center for Cancer Research. We thank Dr Jay L Hess for the kind gift of MIGR-Hoxa9-ER vector. NR 40 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 2041-4889 J9 CELL DEATH DIS JI Cell Death Dis. PD SEP PY 2016 VL 7 AR e2364 DI 10.1038/cddis.2016.267 PG 8 WC Cell Biology SC Cell Biology GA EC2QF UT WOS:000387968100011 PM 27607579 ER PT J AU Oberg, K Krenning, E Sundin, A Bodei, L Kidd, M Tesselaar, M Ambrosini, V Baum, RP Kulke, M Pavel, M Cwikla, J Drozdov, I Falconi, M Fazio, N Frilling, A Jensen, R Koopmans, K Korse, T Kwekkeboom, D Maecke, H Paganelli, G Salazar, R Severi, S Strosberg, J Prasad, V Scarpa, A Grossman, A Walenkamp, A Cives, M Virgolini, I Kjaer, A Modlin, IM AF Oberg, Kjell Krenning, Eric Sundin, Anders Bodei, Lisa Kidd, Mark Tesselaar, Margot Ambrosini, Valentina Baum, Richard P. Kulke, Matthew Pavel, Marianne Cwikla, Jaroslaw Drozdov, Ignat Falconi, Massimo Fazio, Nicola Frilling, Andrea Jensen, Robert Koopmans, Klaus Korse, Tiny Kwekkeboom, Dik Maecke, Helmut Paganelli, Giovanni Salazar, Ramon Severi, Stefano Strosberg, Jonathan Prasad, Vikas Scarpa, Aldo Grossman, Ashley Walenkamp, Annemeik Cives, Mauro Virgolini, Irene Kjaer, Andreas Modlin, Irvin M. TI A Delphic consensus assessment: imaging and biomarkers in gastroenteropancreatic neuroendocrine tumor disease management SO ENDOCRINE CONNECTIONS LA English DT Article DE biomarker; carcinoid; CTC; CT scan; Delphic consensus; imaging; mRNA; MRI; multianalyte; NETest; neuroendocrine tumor; PET; RECIST; somatostatin ID MEDIATED RADIONUCLIDE THERAPY; POSITRON-EMISSION-TOMOGRAPHY; ENDOCRINE NEOPLASIA TYPE-1; CHROMOGRANIN-A; PROGNOSTIC-FACTORS; GA-68-DOTA-TYR(3)-OCTREOTIDE PET; TRANSCRIPT ANALYSIS; GUIDELINES UPDATE; CLINICAL UTILITY; BREAST-CANCER AB The complexity of the clinical management of neuroendocrine neoplasia (NEN) is exacerbated by limitations in imaging modalities and a paucity of clinically useful biomarkers. Limitations in currently available imaging modalities reflect difficulties in measuring an intrinsically indolent disease, resolution inadequacies and inter-/intra-facility device variability and that RECIST (Response Evaluation Criteria in Solid Tumors) criteria are not optimal for NEN. Limitations of currently used biomarkers are that they are secretory biomarkers (chromogranin A, serotonin, neuron-specific enolase and pancreastatin); monoanalyte measurements; and lack sensitivity, specificity and predictive capacity. None of them meet the NIH metrics for clinical usage. A multinational, multidisciplinary Delphi consensus meeting of NEN experts (n = 33) assessed current imaging strategies and biomarkers in NEN management. Consensus (> 75%) was achieved for 78% of the 142 questions. The panel concluded that morphological imaging has a diagnostic value. However, both imaging and current single-analyte biomarkers exhibit substantial limitations in measuring the disease status and predicting the therapeutic efficacy. RECIST remains suboptimal as a metric. A critical unmet need is the development of a clinico-biological tool to provide enhanced information regarding precise disease status and treatment response. The group considered that circulating RNA was better than current general NEN biomarkers and preliminary clinical data were considered promising. It was resolved that circulating multianalyte mRNA (NETest) had clinical utility in both diagnosis and monitoring disease status and therapeutic efficacy. Overall, it was concluded that a combination of tumor spatial and functional imaging with circulating transcripts (mRNA) would represent the future strategy for real-time monitoring of disease progress and therapeutic efficacy. C1 [Oberg, Kjell; Sundin, Anders] Uppsala Univ, Uppsala, Sweden. [Krenning, Eric; Kwekkeboom, Dik] Erasmus MC, Rotterdam, Netherlands. [Bodei, Lisa] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Kidd, Mark; Drozdov, Ignat] Wren Labs, Branford, CT USA. [Tesselaar, Margot; Korse, Tiny] Netherlands Canc Inst, Amsterdam, Netherlands. [Ambrosini, Valentina] Univ Bologna, Bologna, Italy. [Baum, Richard P.] Zent Klin Bad Berka, Bad Berka, Germany. [Kulke, Matthew] Dana Farber Canc Inst, Boston, MA 02115 USA. [Pavel, Marianne; Prasad, Vikas] Charite Hosp, Berlin, Germany. [Cwikla, Jaroslaw] Univ Warmia & Mazury, Olsztyn, Poland. [Falconi, Massimo] Osped San Raffaele, Milan, Italy. [Fazio, Nicola] IEO European Inst Oncol, Milan, Italy. [Frilling, Andrea] Imperial Coll London, London, England. [Jensen, Robert] NIH, Bldg 10, Bethesda, MD 20892 USA. [Koopmans, Klaus] Martini Ziekenhuis, Groningen, Netherlands. [Maecke, Helmut] Univ Hosp Freiburg, Freiburg, Germany. [Paganelli, Giovanni; Severi, Stefano] Inst Sci Romagnolo Studio & Cura Tumori, Meldola, Italy. [Salazar, Ramon] Inst Catala Oncol, Barcelona, Spain. [Strosberg, Jonathan; Cives, Mauro] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Scarpa, Aldo] Univ Verona, Verona, Italy. [Grossman, Ashley] Univ Oxford, Oxford, England. [Walenkamp, Annemeik] Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands. [Virgolini, Irene] Med Univ Innsbruck, Innsbruck, Austria. [Kjaer, Andreas] Univ Copenhagen, Copenhagen, Denmark. [Modlin, Irvin M.] Yale Univ, New Haven, CT USA. RP Modlin, IM (reprint author), Yale Univ, New Haven, CT USA. EM imodlin@optonline.net OI Kjaer, Andreas/0000-0002-2706-5547; fazio, nicola/0000-0001-6869-0704 FU Clifton Life Sciences FX Financial support was provided by Clifton Life Sciences. NR 87 TC 2 Z9 2 U1 5 U2 5 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 2049-3614 J9 ENDOCR CONNECT JI Endocr. Connect. PD SEP 1 PY 2016 VL 5 IS 5 BP 174 EP 187 DI 10.1530/EC-16-0043 PG 14 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EB6FL UT WOS:000387476900009 PM 27582247 ER PT J AU Khankari, NK Shu, XO Wen, WQ Kraft, P Lindstrom, S Peters, U Schildkraut, J Schumacher, F Bofetta, P Risch, A Bickeboller, H Amos, CI Easton, D Eeles, RA Gruber, SB Haiman, CA Hunter, DJ Chanock, SJ Pierce, BL Zheng, W AF Khankari, Nikhil K. Shu, Xiao-Ou Wen, Wanqing Kraft, Peter Lindstrom, Sara Peters, Ulrike Schildkraut, Joellen Schumacher, Fredrick Bofetta, Paolo Risch, Angela Bickeboeller, Heike Amos, Christopher I. Easton, Douglas Eeles, Rosalind A. Gruber, Stephen B. Haiman, Christopher A. Hunter, David J. Chanock, Stephen J. Pierce, Brandon L. Zheng, Wei CA Colorectal Transdisciplinary Study Discovery Biol Risk Inherited Vari Elucidating Loci Involved Prostate Transdisciplinary Res Canc Lung TR TI Association between Adult Height and Risk of Colorectal, Lung, and Prostate Cancer: Results from Meta-analyses of Prospective Studies and Mendelian Randomization Analyses SO PLOS MEDICINE LA English DT Article ID BODY-MASS-INDEX; DIFFERENT ANATOMIC SITES; GROWTH-FACTOR (IGF)-I; IGF-BINDING PROTEINS; FOLLOW-UP; NORWEGIAN MEN; RECTAL-CANCER; NETHERLANDS COHORT; JAPANESE MEN; OLDER WOMEN AB Background Observational studies examining associations between adult height and risk of colorectal, prostate, and lung cancers have generated mixed results. We conducted meta-analyses using data from prospective cohort studies and further carried out Mendelian randomization analyses, using height-associated genetic variants identified in a genome-wide association study (GWAS), to evaluate the association of adult height with these cancers. Methods and Findings A systematic review of prospective studies was conducted using the PubMed, Embase, and Web of Science databases. Usingmeta-analyses, results obtained from 62 studies were summarized for the association of a 10-cm increase in height with cancer risk. Mendelian randomization analyses were conducted using summary statistics obtained for 423 genetic variants identified froma recent GWAS of adult height and from a cancer genetics consortiumstudy of multiple cancers that included 47,800 cases and 81,353 controls. For a 10-cm increase in height, the summary relative risks derived from themeta-analyses of prospective studies were 1.12 (95% CI 1.10, 1.15), 1.07 (95% CI 1.05, 1.10), and 1.06 (95% CI 1.02, 1.11) for colorectal, prostate, and lung cancers, respectively. Mendelian randomization analyses showed increased risks of colorectal (odds ratio [OR] = 1.58, 95% CI 1.14, 2.18) and lung cancer (OR = 1.10, 95% CI 1.00, 1.22) associated with each 10-cm increase in genetically predicted height. No association was observed for prostate cancer (OR = 1.03, 95% CI 0.92, 1.15). Our meta-analysis was limited to published studies. The sample size for the Mendelian randomization analysis of colorectal cancer was relatively small, thus affecting the precision of the point estimate. Conclusions Our study provides evidence for a potential causal association of adult height with the risk of colorectal and lung cancers and suggests that certain genetic factors and biological pathways affecting adult height may also affect the risk of these cancers. C1 [Khankari, Nikhil K.; Shu, Xiao-Ou; Wen, Wanqing; Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med,Vanderbilt Epidemiol Ctr, Nashville, TN 37212 USA. [Kraft, Peter; Lindstrom, Sara] Harvard TH Chan Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA USA. [Peters, Ulrike] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Schildkraut, Joellen] Duke Canc Inst, Canc Prevent Detect & Control Res Program, Durham, NC USA. [Schumacher, Fredrick] Univ Southern Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Dept Prevent Med, Los Angeles, CA USA. [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. [Risch, Angela] Salzburg Univ, Div Canc Genet Epigenet, Dept Mol Biol, Salzburg, Austria. [Risch, Angela] German Canc Res Ctr, Div Epigen & Canc Risk Factors, Heidelberg, Germany. [Risch, Angela] German Ctr Lung Res DZL, Translat Lung Res Ctr Heidelberg, Heidelberg, Germany. [Bickeboeller, Heike] Georg August Univ Gottingen, Univ Med Ctr, Dept Genet Epidemiol, Gottingen, Germany. [Amos, Christopher I.] Dartmouth Coll, Geisel Sch Med, Ctr Genom Med, 1 Med Ctr Dr, Lebanon, NH 03756 USA. [Easton, Douglas] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England. [Eeles, Rosalind A.] Inst Canc Res, London, England. [Eeles, Rosalind A.] Royal Marsden NHS Fdn Trust, London, England. [Gruber, Stephen B.; Haiman, Christopher A.] Univ Southern Calif, USC Norris Comprehens Canc Ctr, Los Angeles, CA USA. [Haiman, Christopher A.] Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA. [Hunter, David J.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Pierce, Brandon L.] Univ Chicago, Dept Publ Hlth Studies, Chicago, IL 60637 USA. RP Zheng, W (reprint author), Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med,Vanderbilt Epidemiol Ctr, Nashville, TN 37212 USA. EM wei.zheng@vanderbilt.edu OI Pierce, Brandon/0000-0002-7829-952X FU US NIH [R37CA070867]; Ingram Professorship; Anne Potter Wilson endowments; NIH [R25CA160056-03, U19CA148065, U19CA148107, U19CA148127, U19CA148537]; Cancer Research UK; Prostate Cancer UK; Institute of Cancer Research; Royal Marsden Biomedical Research Centre; National Institute of Health Research [C5047/A17528] FX The work for this project at Vanderbilt University was supported primarily by US NIH (http://www.nih.gov) grant R37CA070867 and by funds from the Ingram Professorship and Anne Potter Wilson endowments. NKK was supported by NIH grant R25CA160056-03. The Post-Cancer GWAS (GAMEON) initiative was supported by NIH grants U19CA148065 (DRIVE, PI: DJH), U19CA148107 (CORECT, PI: SBG), U19CA148127 (TRICL, PI: CIA), and U19CA148537 (ELLIPSE, PI: CAH). RAE is supported by Cancer Research UK (http://www.cancerresearchuk.org/), Prostate Cancer UK (http://prostatecanceruk.org/), The Institute of Cancer Research (http://www.icr.ac.uk/), and Royal Marsden Biomedical Research Centre, which receives support from the National Institute of Health Research (http://www.nihr.ac.uk) (C5047/A17528). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 77 TC 0 Z9 0 U1 7 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1549-1676 J9 PLOS MED JI PLos Med. PD SEP PY 2016 VL 13 IS 9 AR e1002118 DI 10.1371/journal.pmed.1002118 PG 19 WC Medicine, General & Internal SC General & Internal Medicine GA EB8QG UT WOS:000387655300004 PM 27598322 ER PT J AU Homer, MJ Raulli, R DiCarlo-Cohen, AL Esker, J Hrdina, C Maidment, BW Moyer, B Rios, C Macchiarini, F Prasanna, PG Wathen, L AF Homer, Mary J. Raulli, Robert DiCarlo-Cohen, Andrea L. Esker, John Hrdina, Chad Maidment, Bert W. Moyer, Brian Rios, Carmen Macchiarini, Francesca Prasanna, Pataje G. Wathen, Lynne TI UNITED STATES DEPARTMENT OF HEALTH AND HUMAN SERVICES BIODOSIMETRY AND RADIOLOGICAL/NUCLEAR MEDICAL COUNTERMEASURE PROGRAMS SO RADIATION PROTECTION DOSIMETRY LA English DT Article; Proceedings Paper CT 14th Coordination and Planning Meeting of the World-Health-Organization's Radiation-Emergency-Medical-Preparedness-and-Assistance-Network (WHO-REMPAN) - Radiation Emergency Medical Preparedness and Assistance Network CY MAY 07-09, 2014 CL Wuerzburg, GERMANY SP World Hlth Org, Radiat Emergency Med Preparedness & Assistance Network ID ACUTE-RADIATION-SYNDROME; DOSE IRRADIATED MICE; GASTROINTESTINAL SYNDROME; BODY IRRADIATION; MODEL; MANAGEMENT AB The United States Department of Health and Human Services (HHS) is fully committed to the development of medical countermeasures to address national security threats from chemical, biological, radiological, and nuclear agents. Through the Public Health Emergency Medical Countermeasures Enterprise, HHS has launched and managed a multi-agency, comprehensive effort to develop and operationalize medical countermeasures. Within HHS, development of medical countermeasures includes the National Institutes of Health (NIH), (led by the National Institute of Allergy and Infectious Diseases), the Office of the Assistant Secretary of Preparedness and Response/Biomedical Advanced Research and Development Authority (BARDA); with the Division of Medical Countermeasure Strategy and Requirements, the Centers for Disease Control and Prevention, and the Food and Drug Administration as primary partners in this endeavor. This paper describes various programs and coordinating efforts of BARDA and NIH for the development of medical countermeasures for radiological and nuclear threats. C1 [Homer, Mary J.; Raulli, Robert; Esker, John; Moyer, Brian; Wathen, Lynne] US Dept Hlth & Human Serv, Biomed Adv Res & Dev Author, Off Assistant Secretary Preparedness & Response, 330 Independence Ave SW,Room G644, Washington, DC 20201 USA. [DiCarlo-Cohen, Andrea L.; Maidment, Bert W.; Rios, Carmen; Macchiarini, Francesca] NIAID, Radiat Nucl Countermeasures Program, Div Allergy Immunol & Transplantat, NIH,US Dept Hlth & Human Serv, 5601 Fishers Lane, Bethesda, MD 20892 USA. [Hrdina, Chad] US Dept Hlth & Human Serv, Med Utilizat & Response Integrat, Div Med Countermeasure Strategy & Requirements, Off Policy & Planning,Off Assistant Secretary Pre, 330 Independence Ave SW,Room G644, Washington, DC 20201 USA. [Prasanna, Pataje G.] NCI, Radiat Res Program, Div Canc Treatment & Diag, NIH,US Dept Hlth & Human Serv, 9608 Med Ctr Dr,Room 3W230,MSC9727, Bethesda, MD 20892 USA. RP Homer, MJ (reprint author), US Dept Hlth & Human Serv, Biomed Adv Res & Dev Author, Off Assistant Secretary Preparedness & Response, 330 Independence Ave SW,Room G644, Washington, DC 20201 USA. EM mary.homer@hhs.gov NR 19 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0144-8420 EI 1742-3406 J9 RADIAT PROT DOSIM JI Radiat. Prot. Dosim. PD SEP PY 2016 VL 171 IS 1 BP 85 EP 98 DI 10.1093/rpd/ncw226 PG 14 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA EC1NG UT WOS:000387872100017 PM 27590469 ER PT J AU Zarate-Blades, CR Horai, R Caspi, RR AF Zarate-Blades, Carlos R. Horai, Reiko Caspi, Rachel R. TI Regulation of Autoimmunity by the Microbiome SO DNA AND CELL BIOLOGY LA English DT Article ID INTESTINAL MICROBIOTA; FECAL MICROBIOTA; CELLS; IMMUNITY; DISEASE; INFLAMMATION; AUTOANTIGEN; ANTIGENS; MICE AB Intestinal microbes have profound effects on inflammatory autoimmunity in sites distant from the gut. The mechanisms whereby this happens are only now beginning to be understood and may include such diverse effects as innate stimulation of migrating immune cells and effects of circulating bacterial metabolites. Our studies add to this the demonstration that microbiota may provide a source of cross-reactive antigenic material that activates autoreactive lymphocytes within the gut environment. In a spontaneous model of autoimmune uveitis, T lymphocytes specific to a retinal autoantigen are activated through their specific antigen receptor in the gut and acquire the ability to fuel inflammatory autoimmunity in the eye. In view of the huge diversity of commensals, it is conceivable that they may provide surrogate antigens for activation of autoreactive lymphocytes(s) of other tissue specificities, and might therefore be involved in the etiology of autoimmune diseases more frequently than is currently appreciated. C1 [Zarate-Blades, Carlos R.] Univ Fed Santa Catarina, Dept Microbiol Immunol & Parasitol, Immunoregulat Lab, Florianopolis, SC, Brazil. [Zarate-Blades, Carlos R.; Horai, Reiko; Caspi, Rachel R.] NEI, Immunol Lab, NIH, 10 Ctr Dr,Bldg 10,Room 10N222, Bethesda, MD 20892 USA. RP Caspi, RR (reprint author), NEI, Immunol Lab, NIH, 10 Ctr Dr,Bldg 10,Room 10N222, Bethesda, MD 20892 USA. EM caspir@nei.nih.gov OI Caspi, Rachel/0000-0002-7140-7671; Zarate-Blades, Carlos/0000-0002-7728-7869 FU NIH/NEI [EY000184] FX Funding was provided by NIH/NEI Intramural funding, Project number EY000184. NR 28 TC 1 Z9 1 U1 5 U2 5 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1044-5498 EI 1557-7430 J9 DNA CELL BIOL JI DNA Cell Biol. PD SEP PY 2016 VL 35 IS 9 BP 455 EP 458 DI 10.1089/dna.2016.3432 PG 4 WC Biochemistry & Molecular Biology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Cell Biology; Genetics & Heredity GA DW3VU UT WOS:000383572000001 PM 27463238 ER PT J AU Albert, SM Lunney, JR Ye, L Boudreau, R Ives, D Satterfield, S Ayonayon, HN Rubin, SM Newman, AB Harris, T AF Albert, Steven M. Lunney, June R. Ye, Lei Boudreau, Robert Ives, Diane Satterfield, Suzanne Ayonayon, Hilsa N. Rubin, Susan M. Newman, Anne B. Harris, Tamara CA Hlth ABC Study TI Symptom Burden and End-of-Life Treatment Preferences in the Very Old SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Article DE Symptom burden; treatment preferences; old age; cohort study ID ADVANCE DIRECTIVES; CANCER-PATIENTS; CARE; AGGRESSIVENESS; ADULTS; ILL AB Context. End-of-life (EOL) treatment preferences among the very old (age 85+) may differ from preferences in younger aged populations because of high levels of symptom burden and disability and high risk of mortality. It is unclear if symptom burden or level of disability is more important for such preferences. Objectives. To investigate whether distress from daily symptom burden was an independent correlate of EOL treatment preferences over two years of follow-up in people with median age 86 (participants) and 88 (reported by proxies) at baseline. Methods. The End of Life in Very Old Age is an ancillary study to the Health, Aging and Body Composition study. At baseline in Year 15 of Health, Aging and Body Composition, 1038 participants and 189 proxies reported levels of symptom distress every quarter, as well as 0-8 EOL treatment preferences elicited once each year. Results. At baseline, the mean (SD) count of EOL treatment preferences was 4.2 (2.1) in participants, and 2.9 (2.3) in proxies. EOL treatment preference was not associated with symptom distress. By contrast, black race, male gender, and reported ease walking a quarter mile were independently associated with more aggressive EOL treatment preferences. Conclusion. Preferences for more aggressive EOL treatment were not related to daily symptom distress but were significantly more likely to be endorsed among those with better mobility, suggesting that disability is an independent predictor of EOL treatment preferences in the very old. (C) 2016 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved. C1 [Albert, Steven M.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Behav & Community Hlth Sci, 130 De Soto St, Pittsburgh, PA 15261 USA. [Ye, Lei; Boudreau, Robert; Ives, Diane; Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Lunney, June R.] Hosp & Palliat Nursing Assoc, Pittsburgh, PA USA. [Satterfield, Suzanne] Univ Tennessee, Dept Prevent Med, Memphis, TN USA. [Ayonayon, Hilsa N.; Rubin, Susan M.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Harris, Tamara] NIA, Lab Epidemiol Biometry & Demog, Bethesda, MD 20892 USA. RP Albert, SM (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, Dept Behav & Community Hlth Sci, 130 De Soto St, Pittsburgh, PA 15261 USA. EM smalbert@pitt.edu FU National Institute on Aging [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; NIA [R01-AG028050]; National Institute of Nursing Research [R01-NR012459]; Intramural Research Program of the NIH, National Institute on Aging FX This research was supported by National Institute on Aging contracts N01-AG-6-2101; N01-AG-6-2103; N01-AG-6-2106; NIA grant R01-AG028050, and National Institute of Nursing Research grant R01-NR012459 and supported in part by the Intramural Research Program of the NIH, National Institute on Aging. The authors declare no conflicts of interest. NR 18 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0885-3924 EI 1873-6513 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD SEP PY 2016 VL 52 IS 3 BP 404 EP 411 DI 10.1016/j.jpainsymman.2016.03.009 PG 8 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA EA7RV UT WOS:000386830500014 PM 27265815 ER PT J AU Cassel, JB Del Fabbro, E Arkenau, T Higginson, IJ Hurst, S Jansen, LA Poklepovic, A Rid, A Rodon, J Strasser, F Miller, FG AF Cassel, J. Brian Del Fabbro, Egidio Arkenau, Tobias Higginson, Irene J. Hurst, Samia Jansen, Lynn A. Poklepovic, Andrew Rid, Annette Rodon, Jordi Strasser, Florian Miller, Franklin G. TI Phase I Cancer Trials and Palliative Care: Antagonism, Irrelevance, or Synergy? SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Article DE Palliative care; Phase I clinical trials; cancer; ethics; informed consent; end-of-life care ID CELL LUNG-CANCER; MOLECULARLY TARGETED AGENTS; QUALITY-OF-LIFE; CLINICAL-TRIALS; THERAPEUTIC MISCONCEPTION; PATIENT SELECTION; CENTER EXPERIENCE; INFORMED-CONSENT; ONCOLOGY TRIALS; SYMPTOM BURDEN AB This article synthesizes the presentations and conclusions of an international symposium on Phase 1 oncology trials, palliative care, and ethics held in 2014. The purpose of the symposium was to discuss the intersection of three independent trends that unfolded in the past decade. First, large-scale reviews of hundreds of Phase I trials have indicated there is a relatively low risk of serious harm and some prospect of clinical benefit that can be meaningful to patients. Second, changes in the design and analysis of Phase I trials, the introduction of ''targeted'' investigational agents that are generally less toxic, and an increase in Phase I trials that combine two or more agents in a novel way have changed the conduct of these trials and decreased fears and apprehensions about participation. Third, the field of palliative care in cancer has expanded greatly, offering symptom management to late-stage cancer patients, and demonstrated that it is not mutually exclusive with disease-targeted therapies or clinical research. Opportunities for collaboration and further research at the intersection of Phase 1 oncology trials and palliative care are highlighted. (C) 2016 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved. C1 [Cassel, J. Brian; Del Fabbro, Egidio; Poklepovic, Andrew] Virginia Commonwealth Univ, Richmond, VA USA. [Arkenau, Tobias] Sarah Cannon Res Inst, London, England. [Arkenau, Tobias] UCL, London, England. [Higginson, Irene J.] Kings Coll London, Cicely Saunders Inst, London, England. [Hurst, Samia] Ctr Med Univ Geneva, Inst Eth Biomed, Geneva, Switzerland. [Jansen, Lynn A.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Rid, Annette] Kings Coll London, London, England. [Rodon, Jordi] Vall dHebron Inst Oncol, Barcelona, Spain. [Strasser, Florian] Kantonsspital St Gallen, ABHPM, St Gallen, Switzerland. [Miller, Franklin G.] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Cassel, JB (reprint author), VCU Sch Med, 1101 East Marshall St,Suite 6030, Richmond, VA 23298 USA. EM jbcassel@vcu.edu RI Hurst, Samia/A-9661-2008 OI Hurst, Samia/0000-0002-1980-5226 FU Fondation Brocher (Brocher Foundation) of Hermance Switzerland FX The Fondation Brocher (Brocher Foundation) of Hermance Switzerland funded and hosted the symposium, "Recent developments in Phase I oncology trials: Implications for ethics, palliative care, and society" in July 2014, on which this article is based and for which the authors were speakers. The funder had no role in the content of this article. The symposium was co-directed by two of the authors, J.B.C. and F.G.M. NR 78 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0885-3924 EI 1873-6513 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD SEP PY 2016 VL 52 IS 3 BP 437 EP 445 DI 10.1016/j.jpainsymman.2016.02.014 PG 9 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA EA7RV UT WOS:000386830500018 PM 27233136 ER PT J AU Doshi, A Ryu, J Thornburg, CD Hershey, D Cherry, R Milligan, K Rosenzweig, S Leonard, S AF Doshi, Ashmi Ryu, Julie Thornburg, Courtney D. Hershey, Dan Cherry, Rebecca Milligan, Ki Rosenzweig, Sergio Leonard, Stephanie TI Ataxia telangiectasia presenting as hyper IgM syndrome without neurologic signs SO ANNALS OF ALLERGY ASTHMA & IMMUNOLOGY LA English DT Editorial Material ID ATM MUTATIONS; PATIENT C1 [Doshi, Ashmi; Leonard, Stephanie] Univ Calif San Diego, Rady Childrens Hosp, Div Allergy Immunol & Rheumatol, BSB 5064,9500 Gilman Dr, La Jolla, CA 92093 USA. [Ryu, Julie] Univ Calif San Diego, Rady Childrens Hosp, Div Pulm Med, La Jolla, CA 92093 USA. [Thornburg, Courtney D.] Univ Calif San Diego, Rady Childrens Hosp, Div Hematol & Oncol, La Jolla, CA 92093 USA. [Hershey, Dan] Univ Calif San Diego, Rady Childrens Hosp, Div Hosp Med, La Jolla, CA 92093 USA. [Cherry, Rebecca] Univ Calif San Diego, Rady Childrens Hosp, Div Gastroenterol Hepatol & Nutr, La Jolla, CA 92093 USA. [Milligan, Ki; Rosenzweig, Sergio] NIH, Primary Immunodeficiency Clin, Bldg 10, Bethesda, MD 20892 USA. RP Doshi, A (reprint author), Univ Calif San Diego, Rady Childrens Hosp, Div Allergy Immunol & Rheumatol, BSB 5064,9500 Gilman Dr, La Jolla, CA 92093 USA. EM ashmi.doshi@gmail.com NR 19 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 1081-1206 EI 1534-4436 J9 ANN ALLERG ASTHMA IM JI Ann. Allergy Asthma Immunol. PD SEP PY 2016 VL 117 IS 3 BP 221 EP 226 DI 10.1016/j.anai.2016.07.028 PG 6 WC Allergy; Immunology SC Allergy; Immunology GA EA3IN UT WOS:000386495600003 PM 27613453 ER PT J AU Perkins, NJ Mitchell, EM Lyles, RH Schisterman, EF AF Perkins, Neil J. Mitchell, Emily M. Lyles, Robert H. Schisterman, Enrique F. TI Case-control data analysis for randomly pooled biomarkers SO BIOMETRICAL JOURNAL LA English DT Article DE Biomarkers; Gamma distribution; Odds ratio; Pooled specimens; Skewness ID EXPOSURE ASSESSMENT; BIOSPECIMENS; ACCURACY; SAMPLES AB Pooled study designs, where individual biospecimens are combined prior to measurement via a laboratory assay, can reduce lab costs while maintaining statistical efficiency. Analysis of the resulting pooled measurements, however, often requires specialized techniques. Existing methods can effectively estimate the relation between a binary outcome and a continuous pooled exposure when pools are matched on disease status. When pools are of mixed disease status, however, the existing methods may not be applicable. By exploiting characteristics of the gamma distribution, we propose a flexible method for estimating odds ratios from pooled measurements of mixed and matched status. We use simulation studies to compare consistency and efficiency of risk effect estimates from our proposed methods to existing methods. We then demonstrate the efficacy of our method applied to an analysis of pregnancy outcomes and pooled cytokine concentrations. Our proposed approach contributes to the toolkit of available methods for analyzing odds ratios of a pooled exposure, without restricting pools to be matched on a specific outcome. C1 [Perkins, Neil J.; Mitchell, Emily M.; Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, Bethesda, MD 20892 USA. [Lyles, Robert H.] Emory Univ, Dept Biostat & Bioinformat, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. RP Perkins, NJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, Bethesda, MD 20892 USA. EM perkinsn@mail.nih.gov OI Perkins, Neil/0000-0002-6802-4733; Schisterman, Enrique/0000-0003-3757-641X FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland. NR 18 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0323-3847 EI 1521-4036 J9 BIOMETRICAL J JI Biom. J. PD SEP PY 2016 VL 58 IS 5 BP 1007 EP 1020 DI 10.1002/bimj.201500010 PG 14 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA DW5LQ UT WOS:000383687100001 PM 26824757 ER PT J AU Kane, MS Vilboux, T Wolfe, LA Lee, PR Wang, YP Huddleston, KC Vockley, JG Niederhuber, JE Solomon, BD AF Kane, Megan S. Vilboux, Thierry Wolfe, Lynne A. Lee, Paul R. Wang, Yupeng Huddleston, Kathi C. Vockley, Joseph G. Niederhuber, John E. Solomon, Benjamin D. TI Aberrant splicing induced by the most common EPG5 mutation in an individual with Vici syndrome SO BRAIN LA English DT Letter ID NONSENSE-MEDIATED DECAY; MESSENGER-RNA; DISORDERS C1 [Kane, Megan S.; Vilboux, Thierry; Wang, Yupeng; Huddleston, Kathi C.; Vockley, Joseph G.; Niederhuber, John E.; Solomon, Benjamin D.] Inova Hlth Syst, Inova Translat Med Inst, 3300 Gallows Rd, Falls Church, VA 22042 USA. [Wolfe, Lynne A.; Lee, Paul R.] Off Director, Common Fund, NIH Undiagnosed Dis Program, Bethesda, MD USA. [Wolfe, Lynne A.; Lee, Paul R.] NHGRI, NIH, Bethesda, MD 20892 USA. [Wolfe, Lynne A.] NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Niederhuber, John E.] Johns Hopkins Univ, Sch Med, Oncol, 733 North Broadway St, Baltimore, MD 21205 USA. [Solomon, Benjamin D.] Inova Hlth Syst, Inova Childrens Hosp, 3300 Gallows Rd, Falls Church, VA 22042 USA. RP Vilboux, T (reprint author), Inova Hlth Syst, Inova Translat Med Inst, 3300 Gallows Rd, Falls Church, VA 22042 USA. EM thierry.vilboux@inova.org NR 16 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 EI 1460-2156 J9 BRAIN JI Brain PD SEP PY 2016 VL 139 AR e52 DI 10.1093/brain/aww135 PN 9 PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DW5WX UT WOS:000383719500005 PM 27343256 ER PT J AU Van't Veer, A Smith, KL Cohen, BM Carlezon, WA Bechtholt, AJ AF Van't Veer, Ashlee Smith, Karen L. Cohen, Bruce M. Carlezon, William A., Jr. Bechtholt, Anita J. TI Kappa-opioid receptors differentially regulate low and high levels of ethanol intake in female mice SO BRAIN AND BEHAVIOR LA English DT Article DE drinking; ethanol; kappa ID CONDITIONED PLACE PREFERENCE; HIGH ALCOHOL-DRINKING; CONTROLLED TRIAL; NUCLEUS-ACCUMBENS; C57BL/6J MICE; ORAL ETHANOL; DOUBLE-BLIND; DOPAMINE RELEASE; SELF-STIMULATION; NALTREXONE AB Introduction: Studies in laboratory animals and humans indicate that endogenous opioids play an important role in regulating the rewarding value of various drugs, including ethanol (EtOH). Indeed, opioid antagonists are currently a front-line treatment for alcoholism in humans. Although roles for mu- and delta-opioid receptors have been characterized, the contribution of kappa-opioid receptors (KORs) is less clear. There is evidence that changes in KOR system function can decrease or increase EtOH drinking, depending on test conditions. For example, female mice lacking preprodynorphin - the precursor to the endogenous KOR ligand dynorphin - have reduced EtOH intake. Considering that KORs can regulate dopamine (DA) transmission, we hypothesized that KORs expressed on DA neurons would play a prominent role in EtOH intake in females. Methods: We used a Cre/loxP recombination strategy to ablate KORs throughout the body or specifically on dopamine uptake transporter (DAT)-expressing neurons to investigate the role of KORs on preference for and intake of EtOH (2-bottle choice), the transition from moderate to excessive EtOH drinking (intermittent EtOH access), and binge EtOH drinking (drinking in the dark [DID]). Results: KOR deletion decreased preference for EtOH, although this effect was less pronounced when EtOH intake increased beyond relatively low levels. Discussion: Our findings indicate that KOR activation increases EtOH drinking via effects mediated, at least in part, by KORs on DA neurons. While the mechanisms of this regulation remain unknown, previous work suggests that alterations in negative reinforcement processes or sensitivity to the sensory properties of EtOH can affect preference and intake. C1 [Van't Veer, Ashlee; Smith, Karen L.; Cohen, Bruce M.; Carlezon, William A., Jr.; Bechtholt, Anita J.] Harvard Med Sch, Dept Psychiat, McLean Hosp, Belmont, MA USA. [Van't Veer, Ashlee] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Bechtholt, Anita J.] NIAAA, NIH, Bethesda, MD USA. RP Bechtholt, AJ (reprint author), NIAAA, NIH, Bethesda, MD USA. EM anita.bechtholt@gmail.com FU NIH [R03AA019577, MH063266]; National Defense Science and Engineering Graduate Fellowship; Shervert Frazier Research Institute; Englehard Foundation FX Funding for this work was provided by NIH (R03AA019577 to AJB; MH063266 to WAC), a National Defense Science and Engineering Graduate Fellowship (to AVV), the Shervert Frazier Research Institute (to BMC), and the Englehard Foundation (to BMC). NR 68 TC 0 Z9 0 U1 8 U2 8 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 2162-3279 J9 BRAIN BEHAV JI Brain Behav. PD SEP PY 2016 VL 6 IS 9 AR e00523 DI 10.1002/brb3.523 PG 9 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA DZ8OB UT WOS:000386128600013 PM 27688945 ER PT J AU High, M Cho, HY Marzec, J Wiltshire, T Verhein, KC Caballero, MT Acosta, PL Ciencewicki, J Mccaw, ZR Kobzik, L Miller-DeGraff, L Gladwell, W Peden, DB Serra, ME Shi, M Weinberg, C Suzuki, O Wang, XT Bell, DA Polack, FP Kleeberger, SR AF High, Monica Cho, Hye-Youn Marzec, Jacqui Wiltshire, Tim Verhein, Kirsten C. Caballero, Mauricio T. Acosta, Patricio L. Ciencewicki, Jonathan McCaw, Zackary R. Kobzik, Lester Miller-DeGraff, Laura Gladwell, Wes Peden, David B. Serra, M. Elina Shi, Min Weinberg, Clarice Suzuki, Oscar Wang, Xuting Bell, Douglas A. Polack, Fernando P. Kleeberger, Steven R. TI Determinants of host susceptibility to murine respiratory syncytial virus (RSV) disease identify a role for the innate immunity scavenger receptor MARCO gene in human infants SO EBIOMEDICINE LA English DT Article DE Infectious disease; Innate immunity; Lung; Single nucleotide polymorphism; SNP; Promoter; Haplotype ID ACUTE LUNG INJURY; INBRED MICE; VIRAL-INFECTIONS; ASSOCIATION; EXPRESSION; ASTHMA; INFLAMMATION; PARTICLES; RESPONSES; STRAINS AB Background: Respiratory syncytial virus (RSV) is the global leading cause of lower respiratory tract infection in infants. Nearly 30% of all infected infants develop severe disease including bronchiolitis, but susceptibility mechanisms remain unclear. Methods: We infected a panel of 30 inbred strains of mice with RSV and measured changes in lung disease parameters 1 and 5 days post-infection and they were used in genome-wide association (GWA) studies to identify quantitative trait loci (QTL) and susceptibility gene candidates. Findings: GWA identified QTLs for RSV disease phenotypes, and the innate immunity scavenger receptor Marco was a candidate susceptibility gene; targeted deletion of Marco worsened murine RSV disease. We characterized a human MARCO promoter SNP that caused loss of gene expression, increased in vitro cellular response to RSV infection, and associated with increased risk of disease severity in two independent populations of children infected with RSV. Interpretation: Translational integration of a genetic animal model and in vitro human studies identified a role for MARCO in human RSV disease severity. Because no RSV vaccines are approved for clinical use, genetic studies have implications for diagnosing individuals who are at risk for severe RSV disease, and disease prevention strategies (e.g. RSV antibodies). Published by Elsevier B.V. C1 [High, Monica; Cho, Hye-Youn; Marzec, Jacqui; Verhein, Kirsten C.; Ciencewicki, Jonathan; McCaw, Zackary R.; Miller-DeGraff, Laura; Gladwell, Wes; Kleeberger, Steven R.] Natl Inst Environm Hlth Sci, Immun Inflammat & Dis Lab, 111 TW Alexander Dr,Bldg 101,MD D-201, Res Triangle Pk, NC 27709 USA. [Wiltshire, Tim; Suzuki, Oscar] Univ N Carolina, Eshelman Sch Pharm, Div Pharmacotherapy & Expt Therapeut, Chapel Hill, NC USA. [Caballero, Mauricio T.; Acosta, Patricio L.; Serra, M. Elina; Polack, Fernando P.] Fdn INFANT, Buenos Aires, DF, Argentina. [Acosta, Patricio L.] Consejo Nacl Invest Cient & Tecn, Buenos Aires, DF, Argentina. [Kobzik, Lester] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Peden, David B.] Univ North Carolina Chapel Hill, Ctr Environm Med Asthma & Lung Biol, Sch Med, Chapel Hill, NC USA. [Shi, Min; Weinberg, Clarice] Natl Inst Environm Hlth Sci, Biostat & Computat Biol Branch, Res Triangle Pk, NC USA. [Wang, Xuting; Bell, Douglas A.] Natl Inst Environm Hlth Sci, Genome Integr & Struct Biol Lab, Res Triangle Pk, NC USA. [Polack, Fernando P.] Vanderbilt Univ, Dept Pediat, B-3307 MCN,1161 21st Ave South, Nashville, TN USA. RP Kleeberger, SR (reprint author), Natl Inst Environm Hlth Sci, Immun Inflammat & Dis Lab, 111 TW Alexander Dr,Bldg 101,MD D-201, Res Triangle Pk, NC 27709 USA.; Polack, FP (reprint author), Vanderbilt Univ, Dept Pediat, B-3307 MCN,1161 21st Ave South, Nashville, TN USA. EM fernando.p.polack@vanderbilt.edu; kleeber1@niehs.nih.gov OI Wang, Xuting/0000-0001-6781-8008 FU NIEHS NIH HHS [P30 ES010126] NR 58 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2352-3964 J9 EBIOMEDICINE JI EBioMedicine PD SEP PY 2016 VL 11 BP 73 EP 84 DI 10.1016/j.ebiom.2016.08.011 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA EA8II UT WOS:000386878100020 PM 27554839 ER PT J AU Palazzo, L Daniels, CM Nettleship, JE Rahman, N McPherson, RL Ong, SE Kato, K Nureki, O Leung, AKL Ahel, I AF Palazzo, Luca Daniels, Casey M. Nettleship, Joanne E. Rahman, Nahid McPherson, Robert Lyle Ong, Shao-En Kato, Kazuki Nureki, Osamu Leung, Anthony K. L. Ahel, Ivan TI ENPP1 processes protein ADP-ribosylation in vitro SO FEBS JOURNAL LA English DT Article DE ENPP1; mass spectrometry; PAR; PARP1; phosphodiesterase; poly(ADP-ribose); post-translational modification; protein ADP-ribosylation ID NUCLEOTIDE PYROPHOSPHATASES/PHOSPHODIESTERASES; POLY(ADP-RIBOSE) GLYCOHYDROLASE; NUDIX HYDROLASES; BONE MINERALIZATION; CELLULAR FUNCTIONS; SPINDLE STRUCTURE; EXPRESSION; RIBOSE; CELLS; PURIFICATION AB ADP-ribosylation is a conserved post-translational protein modification that plays a role in all major cellular processes, particularly DNA repair, transcription, translation, stress response and cell death. Hence, dysregulation of ADP-ribosylation is linked to the physiopathology of several human diseases including cancers, diabetes and neurodegenerative disorders. Protein ADP-ribosylation can be reversed by the macrodomain-containing proteins PARG, TARG1, MacroD1 and MacroD2, which hydrolyse the ester bond known to link proteins to ADP-ribose as well as consecutive ADP-ribose subunits; targeting this bond can thus result in the complete removal of the protein modification or the conversion of poly(ADP-ribose) to mono(ADP-ribose). Recently, proteins containing the NUDIX domain - namely human NUDT16 and bacterial RppH - have been shown to process in vitro protein ADP-ribosylation through an alternative mechanism, converting it into protein-conjugated ribose-5-phosphate (R5P, also known as pR). Though this protein modification was recently identified in mammalian tissues, its physiological relevance and the mechanism of generating protein phosphoribosylation are currently unknown. Here, we identified ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) as the first known mammalian enzyme lacking a NUDIX domain to generate pR from ADP-ribose on modified proteins in vitro. Thus, our data show that at least two enzyme families - Nudix and ENPP/NPP - are able to metabolize protein-conjugated ADP-ribose to pR in vitro, suggesting that pR exists and may be conserved from bacteria to mammals. We also demonstrate the utility of ENPP1 for converting protein-conjugated mono(ADP-ribose) and poly(ADP-ribose) into mass spectrometry-friendly pR tags, thus facilitating the identification of ADP-ribosylation sites. C1 [Palazzo, Luca; Ahel, Ivan] Univ Oxford, Sir William Dunn Sch Pathol, Oxford OX1 3RE, England. [Daniels, Casey M.; McPherson, Robert Lyle; Leung, Anthony K. L.] Johns Hopkins Univ, Dept Biochem & Mol Biol, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Nettleship, Joanne E.; Rahman, Nahid] Rutherford Appleton Lab, OPPF UK, Res Complex Harwell, Harwell Oxford, England. [Nettleship, Joanne E.; Rahman, Nahid] Univ Oxford, Div Struct Biol, Henry Wellcome Bldg Genom Med, Oxford, England. [Ong, Shao-En] Univ Washington, Dept Pharmacol, Seattle, WA 98195 USA. [Kato, Kazuki; Nureki, Osamu] Univ Tokyo, Grad Sch Sci, Dept Biophys & Biochem, Tokyo 1138654, Japan. [Leung, Anthony K. L.] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Daniels, Casey M.] NIAID, Lab Syst Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Ahel, I (reprint author), Univ Oxford, Sir William Dunn Sch Pathol, Oxford OX1 3RE, England.; Leung, AKL (reprint author), Johns Hopkins Univ, Dept Biochem & Mol Biol, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. EM anthony.leung@jhu.edu; ivan.ahel@path.ox.ac.uk OI Palazzo, Luca/0000-0002-5556-5549 FU Wellcome Trust [101794]; European Research Council [281739]; Italian Cancer Research Foundation (FIRC) fellowship; NIH [R01-GM104135]; American Cancer Society [129539-RSG-16-062-01-RMC]; Safeway Research Foundation; Patrick C. Walsh Prostate Cancer Research Fund; Allegheny Health Network-Johns Hopkins Cancer Research Fund; Johns Hopkins Catalyst Award; NCI [5T32CA009110]; NIAMS [R01AR065459]; Medical Research Council [MR/K018779/1]; [R01-GM104135S1] FX The authors thank Bernhard Luscher and Friedrich Koch-Nolte for sharing pGEX-4T1 GST-PARP10cd, peGFP-PARP10 and pASK60-OmpA-mARTC2.2 6xHis-Flag tag respectively. The authors also thank Benjamin Thomas (Central Proteomic Facility, Sir William Dunn School of Pathology) and members of IA and AKLL laboratories for their helpful suggestions. The work in IA laboratory was supported by the Wellcome Trust (grant number 101794) and the European Research Council (grant number 281739). LP was supported by an Italian Cancer Research Foundation (FIRC) fellowship for abroad and currently supported by Wellcome Trust. The work in AKLL laboratory was funded by an NIH grant R01-GM104135, American Cancer Society Research Scholar Award 129539-RSG-16-062-01-RMC, the Safeway Research Foundation, the Patrick C. Walsh Prostate Cancer Research Fund, the Allegheny Health Network-Johns Hopkins Cancer Research Fund and the Johns Hopkins Catalyst Award. CMD was supported by an NCI training grant 5T32CA009110. RLM was supported by R01-GM104135S1. SEO was supported by an NIAMS grant R01AR065459. The OPPF-UK was funded by the Medical Research Council (grant no. MR/K018779/1). NR 62 TC 4 Z9 4 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1742-464X EI 1742-4658 J9 FEBS J JI FEBS J. PD SEP PY 2016 VL 283 IS 18 BP 3371 EP 3388 DI 10.1111/febs.13811 PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DW5QN UT WOS:000383701600008 PM 27406238 ER PT J AU Mendola, P Gilboa, SM AF Mendola, Pauline Gilboa, Suzanne M. TI Reporting of birth defects in SART CORS: time to rely on data linkage SO FERTILITY AND STERILITY LA English DT Editorial Material C1 [Mendola, Pauline] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, Rockville, MD 20847 USA. [Gilboa, Suzanne M.] Ctr Dis Control & Prevent, Div Congenital & Dev Disorders, Natl Ctr Birth Defects & Dev Disabil, Atlanta, GA USA. RP Mendola, P (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, Rockville, MD 20847 USA. OI Mendola, Pauline/0000-0001-5330-2844 FU Intramural CDC HHS [CC999999] NR 5 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP 1 PY 2016 VL 106 IS 3 BP 554 EP 555 DI 10.1016/j.fertnstert.2016.06.020 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA EA4GT UT WOS:000386569800013 PM 27343954 ER PT J AU Healy, MW Yauger, BJ James, AN Jezior, JR Parker, P Dean, RC AF Healy, Mae Wu Yauger, Belinda J. James, Aidita N. Jezior, James R. Parker, Patrick Dean, Robert C. TI Seminal vesicle sperm aspiration from wounded warriors SO FERTILITY AND STERILITY LA English DT Article DE Seminal vesicle sperm aspiration; trauma; genital injuries; pregnancy ID EJACULATORY DUCT OBSTRUCTION; SPERMATOZOA; POSTMORTEM; PENTOXIFYLLINE; AZOOSPERMIA; RETRIEVAL; QUALITY AB Objective: To assess whether seminal vesicle sperm aspiration (SVSA) is an option for wounded warriors with severe genital and testicular injuries, with the goal of cryopreservation to use in future assisted reproductive technology (ART) cycles. Design: Retrospective case series. Setting: Tertiary care military hospital. Patient(s): Six wounded warriors. Intervention(s): None. Main Outcome Measure(s): Seminal vesicle fluid analysis after harvest, after thaw analysis, fertilization rates, pregnancy rates (PRs), live birth. Result(s): Six patients with lower extremity, pelvic, and genital injuries from dismounted improvised explosive devices underwent SVSA within 5-12 days of the initial injury. Sperm retrieved were analyzed (volume, 0.4-1.8 mL; concentration, 40-2,200 K; motility, 0-5%), washed, and cryopreserved. Two patients underwent IVF/intracytoplasmic sperm injection (ICSI) cycles using their samples. In one couple, fertilization rate was 38%. One grade V embryo was transferred with a negative pregnancy test. The second couple underwent two cycles. In their first cycle, fertilization rate was 44%, with one blastocyst transferred and a negative pregnancy test. In the second cycle, fertilization rate was 47%. Two blastocysts were cryopreserved due to ovarian hyperstimulation syndrome (OHSS) concerns. One blastocyst was later transferred in a frozen cycle resulting in a live birth. Conclusion(s): The SVSA is a reasonable option to retrieve sperm in wounded warriors or trauma patients with extensive genital injuries. (C) 2016 by American Society for Reproductive Medicine. C1 [Healy, Mae Wu; Yauger, Belinda J.] Walter Reed Natl Mil Med Ctr, Div Reprod Endocrinol & Infertil, Dept Obstet & Gynecol, Bethesda, MD USA. [Healy, Mae Wu; Yauger, Belinda J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [James, Aidita N.] ART Inst Washington Inc, Bethesda, MD USA. [Jezior, James R.; Parker, Patrick; Dean, Robert C.] Walter Reed Natl Mil Med Ctr, Div Androl, Dept Urol, Bethesda, MD USA. RP Healy, MW (reprint author), 10 Ctr Dr, Bethesda, MD 20876 USA. EM mae.healy@mail.nih.gov FU Intramural research program of the Program in Reproductive and Adult Endocrinology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland FX Supported, in part, by Intramural research program of the Program in Reproductive and Adult Endocrinology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland. NR 24 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP 1 PY 2016 VL 106 IS 3 BP 579 EP 583 DI 10.1016/j.fertnstert.2016.05.028 PG 5 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA EA4GT UT WOS:000386569800019 PM 27341990 ER PT J AU Connell, MT Patounakis, G Healy, MW DeCherney, AH Devine, K Widra, E Levy, MJ Hill, MJ AF Connell, Matthew T. Patounakis, George Healy, Mae Wu DeCherney, Alan H. Devine, Kate Widra, Eric Levy, Michael J. Hill, Micah J. TI Is the effect of premature elevated progesterone augmented by human chorionic gonadotropin versus gonadotropin-releasing hormone agonist trigger? SO FERTILITY AND STERILITY LA English DT Article DE Elevated progesterone; IVF; ART; hCG trigger; GnRH agonist trigger ID IN-VITRO FERTILIZATION; INTRACYTOPLASMIC SPERM INJECTION; FOLLICLE-STIMULATING-HORMONE; ASSISTED REPRODUCTION CYCLES; OVARIAN STIMULATION; SERUM PROGESTERONE; EMBRYO-TRANSFER; LUTEINIZING-HORMONE; OOCYTE MATURATION; PREGNANCY RATE AB Objective: To compare the effect of P on live birth rate between hCG and GnRH agonist (GnRH-a) trigger cycles. Design: Retrospective cohort study. Setting: Large private assisted reproductive technology (ART) practice. Patient(s): A total of 3,326 fresh autologous ART cycles. Intervention(s): None. Main Outcome Measure(s): Live birth. Result(s): A total of 647 GnRH-a trigger cycles were compared with 2,679 hCG trigger cycles. Live birth was negatively associated with P in both the hCG trigger (odds ratio [OR] 0.62, 95% confidence interval [CI] 0.52-0.76) and the agonist trigger cohorts (OR 0.56, 95% CI 0.45-0.69). Interaction testing evaluating P and trigger medication was not significant, indicating that P had a similar negative effect on live birth rates in both cohorts. Progesterone >= 2 ng/mL occurred more commonly in GnRH-a trigger cycles compared with hCG trigger cycles (5.5% vs. 3.1%) and was negatively associated with live birth in both the hCG trigger (OR 0.28, 95% CI 0.11-0.73) and agonist trigger cohorts (OR 0.35, 95% CI 0.14-0.90). When P >= 2 ng/mL, the live birth rates were poor and similar in the hCG and GnRH-a cohorts (5.9% vs. 14.2%), indicating that P >= 2 ng/mL had a similar negative effect on live birth in both cohorts. Conclusion(s): Elevated serum P on the day of hCG was negatively associated with live birth rates in both hCG and GnRH-a trigger cycles. (C) 2016 by American Society for Reproductive Medicine. C1 [Connell, Matthew T.; Patounakis, George; Healy, Mae Wu; Devine, Kate; Widra, Eric; Levy, Michael J.; Hill, Micah J.] Shady Grove Fertil Reprod Sci Ctr, Rockville, MD USA. [Connell, Matthew T.; Patounakis, George; Healy, Mae Wu; DeCherney, Alan H.; Hill, Micah J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. RP Hill, MJ (reprint author), 10 Ctr Dr, Bethesda, MD 20876 USA. EM hillmicah@mail.nih.gov OI Hill, Micah/0000-0002-3104-7763 FU Intramural research program of the Program in Reproductive and Adult Endocrinology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland FX Supported, in part, by the Intramural research program of the Program in Reproductive and Adult Endocrinology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland. NR 27 TC 2 Z9 2 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP 1 PY 2016 VL 106 IS 3 BP 584 EP + DI 10.1016/j.fertnstert.2016.04.024 PG 7 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA EA4GT UT WOS:000386569800020 PM 27178228 ER PT J AU White, AJ Sandler, DP D'Aloisio, AA Stanczyk, F Whitworth, KW Baird, DD Nichols, HB AF White, Alexandra J. Sandler, Dale P. D'Aloisio, Aimee A. Stanczyk, Frank Whitworth, Kristina W. Baird, Donna D. Nichols, Hazel B. TI Antimullerian hormone in relation to tobacco and marijuana use and sources of indoor heating/cooking SO FERTILITY AND STERILITY LA English DT Article DE Tobacco; environmental tobacco smoke; Anti-Mullerian Hormone; breast cancer; indoor air pollution ID ANTI-MULLERIAN HORMONE; BREAST-CANCER RISK; YOUNG-ADULT WOMEN; OVARIAN RESERVE; REPRODUCTIVE HISTORY; ENVIRONMENTAL-FACTORS; PREMENOPAUSAL WOMEN; ANTRAL FOLLICLE; AIR-POLLUTION; LIFE-STYLE AB Objective: To evaluate exposure to tobacco, marijuana, and indoor heating/cooking sources in relation to antimullerian hormone (AMH) levels. Design: Cross-sectional analysis in a sample of premenopausal women (n = 913) enrolled in the Sister Study cohort (n = 50,884). Setting: Not applicable. Patient(s): Women, ages 35-54 years at time of enrollment, with an archived serum sample and at least one intact ovary and classified as premenopausal. Intervention(s): Not applicable. Main Outcome Measure(s): Serum AMH (ng/mL) levels ascertained by ultrasensitive ELISA assay. Result(s): Lower AMH levels were associated with sources of indoor heating, including burning wood (-36.0%; 95% confidence interval [CI], -55.7%, -7.8%) or artificial fire logs (-45.8%; 95% CI, -67.2%, -10.4%) at least 10 times/year in a residential indoor stove/fireplace. Lower AMH levels were also observed in women who were current smokers of >= 20 cigarettes/day relative to nonsmokers (-56.2%; 95% CI, -80.3%, -2.8%) and in women with 10+ years of adult environmental tobacco smoke (ETS) exposure (-31.3%; 95% CI, -51.3%, -3.1%), but no associations were observed for marijuana use. Conclusion(s): We confirmed previously reported findings of lower AMH levels in current heavy smokers and also found associations for long-term ETS exposure and indoor burning of wood or artificial fire logs. These findings suggest that combustion by-products from common exposures can have toxic effects on the human ovary. (C) 2016 by American Society for Reproductive Medicine. C1 [White, Alexandra J.; Sandler, Dale P.; D'Aloisio, Aimee A.; Baird, Donna D.] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [D'Aloisio, Aimee A.] Social & Sci Syst Inc, Durham, NC USA. [Stanczyk, Frank] Univ Southern Calif, Keck Sch Med, Dept Obstet & Gynecol, Los Angeles, CA 90033 USA. [Stanczyk, Frank] Univ Southern Calif, Keck Sch Med, Dept Preventat Med, Los Angeles, CA 90033 USA. [Whitworth, Kristina W.] Univ Texas Sch Publ Hlth Houston, Dept Epidemiol Human Genet & Environm Sci, San Antonio Reg Campus, San Antonio, TX USA. [Whitworth, Kristina W.] Univ Texas Sch Publ Hlth Houston, Southwest Ctr Occupat & Environm Hlth, Houston, TX USA. [Nichols, Hazel B.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. RP White, AJ (reprint author), NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. EM alexandra.white@nih.gov RI Baird, Donna/D-5214-2017; OI Baird, Donna/0000-0002-5544-2653; Sandler, Dale/0000-0002-6776-0018 FU Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences [Z01-ES044005]; Avon Foundation [02-2012-085]; National Center for Advancing Translational Sciences [KL2-TR001109]; University of North Carolina Lineberger Cancer Control Education Program [R25 CA57726] FX Supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences (Z01-ES044005); the Avon Foundation (02-2012-085); the National Center for Advancing Translational Sciences (KL2-TR001109); and the University of North Carolina Lineberger Cancer Control Education Program (R25 CA57726). NR 39 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP 1 PY 2016 VL 106 IS 3 BP 723 EP 730 DI 10.1016/j.fertnstert.2016.05.015 PG 8 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA EA4GT UT WOS:000386569800039 PM 27240193 ER PT J AU Willner-Reid, J Whitaker, D Epstein, DH Phillips, KA Pulaski, AR Preston, KL Willner, P AF Willner-Reid, Jessica Whitaker, Damiya Epstein, David H. Phillips, Karran A. Pulaski, Amber R. Preston, Kenzie L. Willner, Paul TI Cognitive-behavioural therapy for heroin and cocaine use: Ecological momentary assessment of homework simplification and compliance SO PSYCHOLOGY AND PSYCHOTHERAPY-THEORY RESEARCH AND PRACTICE LA English DT Article ID INTELLECTUAL DISABILITIES; CONTINGENCY MANAGEMENT; FOLLOW-UP; ASSIGNMENTS; DEPENDENCE; PATIENT; PSYCHOTHERAPY; METAANALYSIS; INDIVIDUALS; IMPAIRMENT AB Objectives. The purpose of this study was to evaluate the effects of homework-task difficulty and electronic-diary reminders on written homework completion during cognitive-behavioural therapy (CBT) for addiction. Completion of homework is an important element in CBT that may affect outcome. Design. All participants received all combinations of our two interventions in a factorial 2 x 2 counterbalanced Latin-square design. Methods. Methadone-maintained cocaine and heroin users were given homework between each of 12 weekly CBT sessions and carried electronic diaries that collected ecological momentary assessment (EMA) data on craving and exposure to drug-use triggers in four 3-week blocks assessing two levels of homework difficulty and prompted and unprompted homework. Results. Neither simplified (picture-based) homework nor electronic reminders increased homework completion. In EMAreports, standard but not simplified homework seemed to buffer the craving that followed environmental exposure to drug cues. EMA recordings before and after the CBT intervention confirmed a decrease over time in craving for cocaine and heroin. Conclusions. These findings demonstrate the utility ofEMAto assess treatment effects. However, the hypothesis that simplified homework would increase compliance was not supported. C1 [Willner-Reid, Jessica; Whitaker, Damiya; Epstein, David H.; Phillips, Karran A.; Pulaski, Amber R.; Preston, Kenzie L.] NIDA, Clin Pharmacol & Therapeut Res Branch, Intramural Res Program, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. [Willner, Paul] Swansea Univ, Dept Psychol, Swansea, W Glam, Wales. RP Preston, KL (reprint author), NIDA, Clin Pharmacol & Therapeut Res Branch, Intramural Res Program, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM kpreston@intra.nida.nih.gov FU NIDA Intramural Research Program, NIH FX This research was supported by the NIDA Intramural Research Program, NIH. NR 48 TC 0 Z9 0 U1 7 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1476-0835 EI 2044-8341 J9 PSYCHOL PSYCHOTHER-T JI Psychol. Psychother.-Theory Res. Pract. PD SEP PY 2016 VL 89 IS 3 BP 276 EP 293 DI 10.1111/papt.12080 PG 18 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA EA8UA UT WOS:000386913300003 PM 26530031 ER PT J AU Henkle, E Aksamit, T Barker, A Daley, CL Griffith, D Leitman, P Leitman, A Malanga, E Marras, TK Olivier, KN Prevots, DR Prieto, D Quittner, AL Skach, W Walsh, JW Winthrop, KL AF Henkle, Emily Aksamit, Timothy Barker, Alan Daley, Charles L. Griffith, David Leitman, Philip Leitman, Amy Malanga, Elisha Marras, Theodore K. Olivier, Kenneth N. Prevots, D. Rebecca Prieto, Delia Quittner, Alexandra L. Skach, William Walsh, John W. Winthrop, Kevin L. CA NTMRC Patient Advisory Panel TI Patient-Centered Research Priorities for Pulmonary Nontuberculous Mycobacteria (NTM) Infection An NTM Research Consortium Workshop Report SO ANNALS OF THE AMERICAN THORACIC SOCIETY LA English DT Article AB Nontuberculous mycobacteria (NTM) cause an increasingly important chronic and debilitating lung disease in older adults. Diagnosis is often delayed, although awareness among clinicians and patients is increasing. When necessary, treatment often lasts 18-24 months and consists of three or four antibiotics that can have serious side effects. Relapses are common and commonly require resumption of prolonged therapy. Given the need for improved diagnostic techniques and clinical trials to identify new therapies or to improve existing therapies, a group of North American clinicians and researchers formed the NTM Research Consortium (NTMRC) in 2014. The NTMR Crecognized the importance of including the patient voice in determining research priorities for NTM. In November 2015, patients, caregivers, patient advocates, clinical experts, and researchers gathered for a 1-day meeting in Portland, Oregon funded by the Patient-Centered Outcomes Research Institute. The meeting goal was to define patient-centered research priorities for NTM lung infections. Patients expressed frustration with the number of people who have endured years of missed diagnoses or inadequate treatment of NTM. Participants identified as top research priorities the prevention of NTM infection; approval of more effective treatments with fewer side effects and easier administration; understanding the best chest physiotherapy methods; validating and using tools to measure quality of life; and developing a disease-specific activity and severity assessment tool. Workshop participants agreed that two complementary objectives are critical to ensure the best achievable outcomes for patients: (1) additional clinician education to improve screening and diagnosis of NTMinfections; and (2) development of a geographically distributed network of experts in NTM disease to offer consultation or direct therapy after a diagnosis is made. C1 [Henkle, Emily] Portland State Univ, Oregon Hlth & Sci Univ, Sch Publ Hlth, Portland, OR 97207 USA. [Aksamit, Timothy] Mayo Clin, Pulm Dis & Crit Care Med, Rochester, MN USA. [Barker, Alan] Oregon Hlth & Sci Univ, Pulm Crit Care Med, Portland, OR 97201 USA. [Daley, Charles L.] Natl Jewish Hlth, Dept Med, Denver, CO USA. [Griffith, David] Univ Texas Tyler, Hlth Sci Ctr, Tyler, TX 75799 USA. [Leitman, Philip; Leitman, Amy] NTM Info & Res, Miami, FL USA. [Malanga, Elisha; Prieto, Delia; Walsh, John W.] COPD Fdn, Washington, DC USA. [Marras, Theodore K.] Univ Toronto, Dept Med, Toronto, ON, Canada. [Olivier, Kenneth N.] NHLBI, Cardiovasc & Pulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Prevots, D. Rebecca] Natl Inst Allergy & Infect Dis, Lab Clin Infect Dis, NIH, Bethesda, MD USA. [Quittner, Alexandra L.] Univ Miami, Dept Psychol, POB 248185, Coral Gables, FL 33124 USA. [Skach, William] Cyst Fibrosis Fdn, Bethesda, MD USA. [Winthrop, Kevin L.] Oregon Hlth & Sci Univ, Div Infect Dis Publ Hlth & Prevent Med, Portland, OR 97201 USA. RP Henkle, E (reprint author), 3181 SW Sam Jackson Pk Rd,Mailcode GH104, Portland, OR 97239 USA. EM emhenkle@gmail.com NR 0 TC 0 Z9 0 U1 4 U2 4 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1546-3222 EI 2325-6621 J9 ANN AM THORAC SOC JI Ann. Am. Thoracic Society PD SEP PY 2016 VL 13 IS 9 BP S379 EP S384 DI 10.1513/AnnalsATS.201605-387WS PG 6 WC Respiratory System SC Respiratory System GA DZ8KB UT WOS:000386118200001 PM 27627485 ER PT J AU Larson, NB McDonnell, S Albright, LC Teerlink, C Stanford, J Ostrander, EA Isaacs, WB Xu, JF Cooney, KA Lange, E Schleutker, J Carpten, JD Powell, I Bailey-Wilson, J Cussenot, O Cancel-Tassin, G Giles, G MacInnis, R Maier, C Whittemore, AS Hsieh, CL Wiklund, F Catolona, WJ Foulkes, W Mandal, D Eeles, R Kote-Jarai, Z Ackerman, MJ Olson, TM Klein, CJ Thibodeau, SN Schaid, DJ AF Larson, Nicholas B. McDonnell, Shannon Albright, Lisa Cannon Teerlink, Craig Stanford, Janet Ostrander, Elaine A. Isaacs, William B. Xu, Jianfeng Cooney, Kathleen A. Lange, Ethan Schleutker, Johanna Carpten, John D. Powell, Isaac Bailey-Wilson, Joan Cussenot, Olivier Cancel-Tassin, Geraldine Giles, Graham MacInnis, Robert Maier, Christiane Whittemore, Alice S. Hsieh, Chih-Lin Wiklund, Fredrik Catolona, William J. Foulkes, William Mandal, Diptasri Eeles, Rosalind Kote-Jarai, Zsofia Ackerman, Michael J. Olson, Timothy M. Klein, Christopher J. Thibodeau, Stephen N. Schaid, Daniel J. TI Post hoc Analysis for Detecting Individual Rare Variant Risk Associations Using Probit Regression Bayesian Variable Selection Methods in Case-Control Sequencing Studies SO GENETIC EPIDEMIOLOGY LA English DT Article DE Next-generation sequencing; MCMC; prostate cancer; burden testing ID STATISTICAL-ANALYSIS; GENETIC-VARIANTS; GIBBS SAMPLER; MODELS; COMMON; FRAMEWORK; DISEASES; BINARY AB Rare variants (RVs) have been shown to be significant contributors to complex disease risk. By definition, these variants have very low minor allele frequencies and traditional single-marker methods for statistical analysis are underpowered for typical sequencing study sample sizes. Multimarker burden-type approaches attempt to identify aggregation of RVs across case-control status by analyzing relatively small partitions of the genome, such as genes. However, it is generally the case that the aggregative measure would be a mixture of causal and neutral variants, and these omnibus tests do not directly provide any indication of which RVs may be driving a given association. Recently, Bayesian variable selection approaches have been proposed to identify RV associations from a large set of RVs under consideration. Although these approaches have been shown to be powerful at detecting associations at the RV level, there are often computational limitations on the total quantity of RVs under consideration and compromises are necessary for large-scale application. Here, we propose a computationally efficient alternative formulation of this method using a probit regression approach specifically capable of simultaneously analyzing hundreds to thousands of RVs. We evaluate our approach to detect causal variation on simulated data and examine sensitivity and specificity in instances of high RV dimensionality as well as apply it to pathway-level RV analysis results from a prostate cancer (PC) risk case-control sequencing study. Finally, we discuss potential extensions and future directions of this work. (C) 2016 Wiley Periodicals, Inc. C1 [Larson, Nicholas B.; McDonnell, Shannon; Schaid, Daniel J.] Mayo Clin, Div Biomed Stat & Informat, Dept Hlth Sci Res, Rochester, MN USA. [Albright, Lisa Cannon; Teerlink, Craig] Univ Utah, Sch Med, Dept Internal Med, Salt Lake City, UT USA. [Stanford, Janet] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Ostrander, Elaine A.] NHGRI, Bethesda, MD 20892 USA. [Isaacs, William B.] Johns Hopkins Univ Hosp, Dept Urol, Baltimore, MD 21287 USA. [Xu, Jianfeng] NorthShore Univ HealthSyst Res Inst, Chicago, IL USA. [Cooney, Kathleen A.] Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI USA. [Cooney, Kathleen A.] Univ Michigan, Sch Med, Dept Urol, Ann Arbor, MI USA. [Lange, Ethan] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Schleutker, Johanna] Univ Turku, Inst Biomed, Dept Med Biochem & Genet, SF-20500 Turku, Finland. [Carpten, John D.] Translat Genom Res Inst, Integrated Canc Genom Div, Phoenix, AZ USA. [Powell, Isaac] Wayne State Univ, Detroit, MI USA. [Bailey-Wilson, Joan] NHGRI, Stat Genet Sect, Bethesda, MD 20892 USA. [Cussenot, Olivier; Cancel-Tassin, Geraldine] Hop Tenon, CeRePP, Paris, France. [Giles, Graham; MacInnis, Robert] Univ Melbourne, Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Giles, Graham; MacInnis, Robert] Univ Melbourne, Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia. [Maier, Christiane] Univ Ulm, Dept Urol, Ulm, Germany. [Whittemore, Alice S.] Stanford Univ, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Hsieh, Chih-Lin] Univ Southern Calif, Dept Urol, Los Angeles, CA USA. [Wiklund, Fredrik] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Catolona, William J.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Foulkes, William] Montreal Gen Hosp, Dept Oncol & Human Genet, Montreal, PQ, Canada. [Foulkes, William] Montreal Gen Hosp, Dept Human Genet, Montreal, PQ, Canada. [Mandal, Diptasri] LSU Hlth Sci Ctr, Dept Genet, New Orleans, LA USA. [Eeles, Rosalind; Kote-Jarai, Zsofia] Inst Canc Res, Genet & Epidemiol, Sutton, Surrey, England. [Ackerman, Michael J.; Olson, Timothy M.] Mayo Clin, Dept Pediat & Adolescent Med, Rochester, MN USA. [Klein, Christopher J.] Mayo Clin, Dept Neurol, Rochester, MN USA. [Thibodeau, Stephen N.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. RP Larson, NB (reprint author), Mayo Clin, Dept Hlth Sci Res, 200 First St SW, Rochester, MN 55905 USA. EM Larson.nicholas@mayo.edu OI Teerlink, Craig/0000-0002-1992-2326; albright, lisa/0000-0003-2602-3668; Ostrander, Elaine/0000-0001-6075-9738; Cancel-Tassin, Geraldine/0000-0002-9583-6382 FU US Public Health Service, National Institutes of Health (NIH) [GM065450]; National Cancer Institute [U01 CA 89600] FX This research was supported by the US Public Health Service, National Institutes of Health (NIH), contract grant number GM065450 (D.J.S.) and National Cancer Institute, grant number U01 CA 89600 (S.N.T.). There are no conflicts of interest to declare. NR 41 TC 0 Z9 0 U1 3 U2 3 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 SEP PY 2016 VL 40 IS 6 BP 461 EP 469 DI 10.1002/gepi.21983 PG 9 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA DZ7HU UT WOS:000386036300002 PM 27312771 ER PT J AU Tirosh, A Lodish, MB Papadakis, GZ Lyssikatos, C Belyavskaya, E Stratakis, CA AF Tirosh, A. Lodish, M. B. Papadakis, G. Z. Lyssikatos, C. Belyavskaya, E. Stratakis, C. A. TI Diurnal Plasma Cortisol Measurements Utility in Differentiating Various Etiologies of Endogenous Cushing Syndrome SO HORMONE AND METABOLIC RESEARCH LA English DT Article DE cortisol; cushing syndrome; diurnal ID CIRCADIAN-RHYTHM; SERUM CORTISOL; DIAGNOSIS; ADRENOCORTICOTROPIN; DEXAMETHASONE; MUTATIONS; PATIENT; DISEASE; TUMORS AB Cortisol diurnal variation may be abnormal among patients with endogenous Cushing syndrome (CS). The study objective was to compare the plasma cortisol AM/PM ratios between different etiologies of CS. This is a retrospective cohort study, conducted at a clinical research center. Adult patients with CS that underwent adrenalectomy or trans-sphenoidal surgery (n=105) were divided to those with a pathologically confirmed diagnosis of Cushing disease (n=21) and those with primary adrenal CS, including unilateral adrenal adenoma (n=28), adrenocortical hyperplasia (n=45), and primary pigmented nodular adrenocortical disease (PPNAD, n=11). Diurnal plasma cortisol measurements were obtained at 11:30 PM and midnight and at 7:30 and 8:00 AM. The ratios between the mean morning levels and mean late-night levels were calculated. Mean plasma cortisol AM/PM ratio was lower among CD patients compared to those with primary adrenal CS (1.4 +/- 0.6 vs. 2.3 +/- 1.5, p<0.001, respectively). An AM/PM cortisol ratio2.0 among patients with unsuppressed ACTH (>15pg/ml) excludes CD with a 85.0% specificity and a negative predictive value (NPV) of 90.9%. Among patients with primary adrenal CS, an AM/PM cortisol1.2 had specificity and NPV of 100% for ruling out a diagnosis of PPNAD. Plasma cortisol AM/PM ratios are lower among patients with CD compared with primary adrenal CS, and may aid in the differential diagnosis of endogenous hypercortisolemia. C1 [Tirosh, A.; Lodish, M. B.; Lyssikatos, C.; Belyavskaya, E.; Stratakis, C. A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Sect Endocrinol & Genet, Bethesda, MD USA. [Papadakis, G. Z.] NIH, Warren Grant Magnuson Clin Ctr, Radiol & Imaging Sci, Bethesda, MD USA. [Tirosh, A.] Tel Aviv Univ, Sackler Fac Med, Tel Aviv, Israel. RP Tirosh, A (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20814 USA. EM amit.tirosh@nih.gov FU Intramural Research Program of Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH) FX This research was supported in part by the Intramural Research Program of Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH). NR 21 TC 0 Z9 0 U1 1 U2 1 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0018-5043 EI 1439-4286 J9 HORM METAB RES JI Horm. Metab. Res. PD SEP PY 2016 VL 48 IS 10 BP 677 EP 681 DI 10.1055/s-0042-115644 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DZ5QY UT WOS:000385917800009 PM 27643448 ER PT J AU Bolnick, AD Bolnick, JM Kilburn, BA Stewart, T Oakes, J Rodriguez-Kovacs, J Kohan-Ghadr, HR Dai, J Diamond, MP Hirota, Y Drewlo, S Dey, SK Armant, DR AF Bolnick, Alan D. Bolnick, Jay M. Kilburn, Brian A. Stewart, Tamika Oakes, Jonathan Rodriguez-Kovacs, Javier Kohan-Ghadr, Hamid-Reza Dai, Jing Diamond, Michael P. Hirota, Yasushi Drewlo, Sascha Dey, Sudhansu K. Armant, D. Randall CA NICHD Natl Cooperative Reproductiv TI Reduced homeobox protein MSXI in human endometrial tissue is linked to infertility SO HUMAN REPRODUCTION LA English DT Article DE endometrium; implantation; menstrual cycle; secretory phase; female infertility; transcription factor; muscle segment homeobox I; messenger RNA; immunohistochemistry; E-cadherin ID GENE-EXPRESSION PROFILES; LEUKEMIA INHIBITORY FACTOR; DNA MICROARRAY ANALYSIS; BLASTOCYST IMPLANTATION; UTERINE RECEPTIVITY; SIGNALING PATHWAY; MENSTRUAL-CYCLE; CANDIDATE GENES; GROWTH-FACTOR; WOMEN AB STUDY QUESTION: Is protein expression of the muscle segment homeoboxgene family member MSX1 altered in the human secretory endometrium by cell type, developmental stage or fertility? SUMMARY ANSWER: MSX1 protein levels, normally elevated in the secretory phase endometrium,were significantly reduced in endometrial biopsies obtained from women of infertile couples. WHAT IS KNOWN ALREADY: Molecular changes in the endometrium are important for fertility in both animals and humans. Msx1 is expressed in the preimplantation mouse uterus and regulates uterine receptivity for implantation. The MSX protein persists a short time, after its message has been down-regulated. Microarray analysis of the human endometrium reveals a similar pattern of MSX1 mRNA expression that peaks before the receptive period, with depressed expression at implantation. Targeted deletion of uterine Msx1 and Msx2 in mice prevents the loss of epithelial cell polarity during implantation and causes infertility. STUDY DESIGN, SIZE DURATION: MSX1 mRNA and cell type-specific levels of MSX1 protein were quantified from two retrospective cohorts during the human endometrial cycle. MSX1 protein expression patterns were compared between fertile and infertile couples. Selected samples were dual-labeled by immunofluorescence microscopy to localize E-cadherin and beta-catenin in epithelial cells. PARTICIPANTS/MATERIALS, SETTING METHODS: MSX1 mRNA was quantified by PCR in endometrium from hysterectomies (n = 14) determined by endometrial dating to be in the late-proliferative (cycle days 10-13), early-secretory (cycle days 14-19) or mid-secretory (cycle days 20-24) phase. MSX1 protein was localized using high-throughput, semi-quantitative immunohistochemistry with sectioned endometrial biopsy tissues from fertile (n = 89) and infertile (n = 89) couples. Image analysis measured stain intensity specifically within the luminal epithelium, glands and stroma during the early-, mid- and late- (cycle days 25-28) secretory phases. MAIN RESULTS AND THE ROLE OF CHANCE: MSX1 transcript increased 5-fold (P < 0.05) between the late-proliferative and early secretory phase and was then down-regulated (P < 0.05) prior to receptivity for implantation. In fertile patients, MSX1 protein displayed strong nuclear localization in the luminal epithelium and glands, while it was weakly expressed in nuclei of the stroma. MSX1 protein levels accumulated throughout the secretory phase in all endometrial cellular compartments. MSX1 protein decreased (P < 0.05) in the glands between mid- and late-secretory phases. However, infertile patients demonstrated a broad reduction (P < 0.001) of MSX1 accumulation in all cell types throughout the secretory phase that was most pronounced (similar to 3-fold) in stroma and glands. Infertility was associated with persistent co-localization of E-cadherin and beta-catenin in epithelial cell junctions in the mid- and late-secretory phases. LIMITATIONS, REASONS FOR CAUTION: Details of the infertility diagnoses and other patient demographic data were not available. Therefore, patients with uterine abnormalities (Mullerian) could not be distinguished from other sources of infertility. Antibody against human MSX2 is not available, limiting the study to MSX1. However, both RNAs in the human endometrium are similarly regulated. In mice, Msx1 and Msx2 are imperative for murine embryo implantation, with Msx2 compensating for genetic ablation of Msx1 through its up-regulation in a knockout model. WIDER IMPLICATIONS OF THE FINDINGS: This investigation establishes that the MSX1 homeobox protein accumulation is associated with the secretory phase in endometrium of fertile couples, and is widely disrupted in infertile patients. It is the first study to examine MSX1 protein localization in the human endometrium, and supported by genetic findings in mice, suggests that genes regulated by MSX1 are linked to the loss of epithelial cell polarity required for uterine receptivity during implantation. STUDY FUNDING/COMPETING INTERESTS: This research was supported by the NICHD National Cooperative Reproductive Medicine Network grant HD039005 (M.P.D.), NIH grants HD068524 (S.K.D.), HD071408 (D.R.A., M.P.D.), and HL128628 (S.D.), the Intramural Research Program of the NICHD, March of Dimes (S.K.D., S.D.) and JSPS KAKENHI grant 26112506 (Y.H.). There were no conflicts or competing interests. C1 [Bolnick, Alan D.; Bolnick, Jay M.; Kilburn, Brian A.; Stewart, Tamika; Oakes, Jonathan; Rodriguez-Kovacs, Javier; Kohan-Ghadr, Hamid-Reza; Dai, Jing; Drewlo, Sascha; Armant, D. Randall] Wayne State Univ, Obstet & Gynecol, Detroit, MI USA. [Diamond, Michael P.] Augusta Univ, Obstet & Gynecol, Augusta, GA USA. [Hirota, Yasushi] Univ Tokyo, Obstet & Gynecol, Tokyo, Japan. [Dey, Sudhansu K.] Cincinnati Childrens Hosp Med Ctr, Div Reprod Sci, Cincinnati, OH 45229 USA. [Armant, D. Randall] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. RP Armant, DR (reprint author), Wayne State Univ, Mott Ctr Human Growth & Dev, 275 East Hancock St, Detroit, MI 48201 USA. EM d.armant@wayne.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) National Cooperative Reproductive Medicine Network [HD039005]; NIH [HD068524, HD071408, HL128628]; Intramural Research Program of the NICHD; March of Dimes; Japan Society for the Promotion of Science [26112506] FX This research was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) National Cooperative Reproductive Medicine Network grant HD039005, NIH grants HD068524 (S.K.D.), HD071408 (D.R.A., M.P.D.), and HL128628 (S.D.), the Intramural Research Program of the NICHD, March of Dimes (S.K.D., S.D.) and the Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research Program grant 26112506 (Y.H.). NR 59 TC 0 Z9 1 U1 5 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 EI 1460-2350 J9 HUM REPROD JI Hum. Reprod. PD SEP PY 2016 VL 31 IS 9 BP 2042 EP 2050 DI 10.1093/humrep/dew143 PG 9 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA DZ7YW UT WOS:000386085700014 PM 27312535 ER PT J AU Smarr, MM Grantz, KL Sundaram, R Maisog, JM Honda, M Kannan, K Louis, GMB AF Smarr, Melissa M. Grantz, Katherine L. Sundaram, Rajeshwari Maisog, Jose M. Honda, Masato Kannan, Kurunthachalam Louis, Germaine M. Buck TI Urinary paracetamol and time-to-pregnancy SO HUMAN REPRODUCTION LA English DT Article DE acetaminophen; biomarkers; fecundity; paracetamol; p-aminophenol; TTP ID OVER-THE-COUNTER; UNITED-STATES; INTRAUTERINE EXPOSURE; ACETYLSALICYLIC-ACID; REGRESSION-MODELS; COUPLE FECUNDITY; DETECTION LIMITS; MILD ANALGESICS; SERUM COTININE; MEDICATION USE AB STUDY QUESTION: Is preconception urinary paracetamol (acetaminophen) associated with time-to-pregnancy (TTP)? SUMMARY ANSWER: Higher urinary paracetamol concentrations among male partners were associated with a longer TTP. WHAT IS KNOWN ALREADY: Paracetamol is a commonly used analgesic among women and men of all ages. As metabolites of select chemicals used in the manufacturing of polyurethane foam, dyes and various industrial products, as well as a common medicinal product, paracetamol and its primary metabolite p-aminophenol, are ubiquitous in the environment. Studies investigating the relationship between adult urinary concentrations of paracetamol and TTP are lacking. STUDY DESIGN, SIZE, DURATION: This prospective cohort included 501 couples discontinuing contraception for the purposes of attempting conception during the years 2005-2009 and residing in Michigan or Texas. USA. PARTICIPANTS/MATERIALS, SETTING, METHODS: Total urinary paracetamol, its metabolite para-aminophenol (p-aminophenol), and a summary measure of both urinary biomarkers were quantified by ultra-performance liquid chromatography coupled with an electrospray triple quadrupole mass spectrometry (UPLC-ESI-MS/MS). Female partners used the Clearblue (R) digital home test to confirm pregnancy. Cox's proportional odds models for discrete survival time were used to estimate fecundability odds ratios (FORs) and 95% confidence intervals (CIs), adjusting for age, body mass index (BMI), urinary creatinine, preconception smoking status, race/ethnicity and household income. Models were further adjusted for hypothyroidism and hypertension as an attempt to account for possible indications of paracetamol medication use. FOR estimates < 1.0 denote a longer TTP (diminished fecundity). Models were performed to examine urinary concentrations of paracetamol as a continuous and variable or categorized into quartiles. In light of TTP being a couple-dependent outcome, models were first performed for females and males, modeled separately, and then modeled for couples with each partner's concentrations being adjusted for the other. MAIN RESULTS AND THE ROLE OF CHANCE: Among the 501 enrolled couples. 347 (69%) had an human chorionic gonadotrophin confirmed pregnancy. Urinary concentrations of paracetamol were lowest among females and males who achieved pregnancy and p-aminophenol concentrations were lowest among those not achieving pregnancy. Urinary paracetamol concentrations were higher among female than male partners (Median = 26.6 and 13.2 ng/ml, respectively; P < 0.0001). After adjustment for age, BMI, urinary creatinine, preconception smoking status, race/ethnicity and household income, the highest quartile of male urinary paracetamol was associated with a longer TTP [FOR = 0.67; 95% CI = (0.47, 0.95)]. This association remained after adjustment for chronic health conditions, hypothyroidism and hypertension and female partner's urinary paracetamol concentration [FOR = 0.65; 95% Cl = (0.45. 0.94)]. No associations were observed between female or male partners' urinary concentrations of paracetamol or of its metabolite p-aminophenol when urinary concentrations were modeled continuously. LIMITATIONS, REASONS FOR CAUTION: Only a single spot urine was available for analysis despite the short-lived nature of paracetamol. Additionally, participants were not asked to provide information on indication of use for paracetamol medications; any underlying conditions for the paracetamol use would have been potential confounders. WIDER IMPLICATIONS OF THE FINDINGS: If corroborated with more robust studies, findings from our exploratory analysis may have both clinical and public health relevance among reproductive aged individuals, including those trying for pregnancy, given the prevalent use of paracetamol/acetaminophen medications and the ubiquitous nature of paracetamol in the environment. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by the National Institutes of Health, Intramural Research Program, and Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts N01-HD-3-3355; N01-HD-3-3356; NOH-HD-3-3358; HHSN27500001/HHSN27500001). None of the authors have any conflicts to declare. C1 [Smarr, Melissa M.; Louis, Germaine M. Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd,Room 7B05, Rockville, MD 20852 USA. [Grantz, Katherine L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidcmiol Branch, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd,Room 7B05, Rockville, MD 20852 USA. [Sundaram, Rajeshwari] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd,Room 7B05, Rockville, MD 20852 USA. [Maisog, Jose M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Glotech Inc, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd,Room 7B05, Rockville, MD 20852 USA. [Honda, Masato; Kannan, Kurunthachalam] SUNY Albany, New York State Dept Hlth, Wadsworth Ctr, Sch Publ Hlth, Albany, NY 12201 USA. [Honda, Masato; Kannan, Kurunthachalam] SUNY Albany, Sch Publ Hlth, Dept Environm Hlth Sci, Albany, NY 12201 USA. RP Smarr, MM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd,Room 7B05, Rockville, MD 20852 USA. EM melissa.smarr@mail.nih.gov OI Sundaram, Rajeshwari/0000-0002-6918-5002; Buck Louis, Germaine/0000-0002-1774-4490; Grantz, Katherine/0000-0003-0276-8534 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development [N01-HD-3-3355, N01-HD-3-3356, NOH-HD-3-3358]; Eunice Kennedy Shriver National Institute of Child Health and Human Development, Division of Intramural Population Health Research FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts N01-HD-3-3355, N01-HD-3-3356 and NOH-HD-3-3358). M.M.S. was supported by an Intramural Research Training Award from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Division of Intramural Population Health Research. NR 51 TC 0 Z9 0 U1 3 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 EI 1460-2350 J9 HUM REPROD JI Hum. Reprod. PD SEP PY 2016 VL 31 IS 9 BP 2119 EP 2127 DI 10.1093/humrep/dew172 PG 9 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA DZ7YW UT WOS:000386085700022 PM 27412248 ER PT J AU Gitik, M Srivastava, V Hodgkinson, CA Shen, PH Goldman, D Meyerhoff, DJ AF Gitik, Miri Srivastava, Vibhuti Hodgkinson, Colin A. Shen, Pei-Hong Goldman, David Meyerhoff, Dieter J. TI Association of Superoxide Dismutase 2 (SOD2) Genotype with Gray Matter Volume Shrinkage in Chronic Alcohol Users: Replication and Further Evaluation of an Addiction Gene Panel SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Article DE Alcohol use disorder; gray matter volume; superoxide dismutase 2 (SOD2); neuroimaging; genetics ID OXIDATIVE STRESS; CANDIDATE GENES; BRAIN; RECOVERY; BEHAVIOR; MECHANISMS; DEPENDENCE; HMO AB Reduction in brain volume, especially gray matter volume, has been shown to be one of the many deleterious effects of prolonged alcohol consumption. High variance in the degree of gray matter tissue shrinkage among alcohol-dependent individuals and a previous neuroimaging genetics report suggest the involvement of environmental and/or genetic factors, such as superoxide dismutase 2 (SOD2). Identification of such underlying factors will help in the clinical management of alcohol dependence. We analyzed quantitative magnetic resonance imaging and genotype data from 103 alcohol users, including both light drinkers and treatment-seeking alcohol-dependent individuals. Genotyping was performed using a custom gene array that included genes selected from 8 pathways relevant to chronic alcohol-related brain volume loss. We replicated a significant association of a functional SOD2 single nucleotide polymorphism with normalized gray matter volume, which had been reported previously in an independent smaller sample of alcohol-dependent individuals. The SOD2-related genetic protection was observed only at the cohort's lower drinking range. Additional associations between normalized gray matter volume and other candidate genes such as alcohol dehydrogenase gene cluster (ADH), GCLC, NOS3, and SYT1 were observed across the entire sample but did not survive corrections for multiple comparisons. Converging independent evidence for a SOD2 gene association with gray matter volume shrinkage in chronic alcohol users suggests that SOD2 genetic variants predict differential brain volume loss mediated by free radicals. This study also provides the first catalog of genetic variations relevant to gray matter loss in chronic alcohol users. The identified gene-brain structure relationships are functionally pertinent and merit replication. C1 [Gitik, Miri; Srivastava, Vibhuti; Hodgkinson, Colin A.; Shen, Pei-Hong; Goldman, David] NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. [Meyerhoff, Dieter J.] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [Meyerhoff, Dieter J.] Vet Adm Med Ctr, Ctr Imaging Neurodegenerat Dis, San Francisco, CA 94121 USA. [Srivastava, Vibhuti] Univ Texas MD Anderson Canc Ctr, Sch Hlth Profess, Mol Genet Technol Program, 1515 Holcombe Blvd, Houston, TX 77030 USA. RP Meyerhoff, DJ (reprint author), UCSF, Sch Med, CIND, DVA Med Ctr, 4150 Clement St 114M, San Francisco, CA 94121 USA. EM dieter.meyerhoff@ucsf.edu RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 NR 29 TC 0 Z9 0 U1 3 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1461-1457 EI 1469-5111 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD SEP PY 2016 VL 19 IS 9 DI 10.1093/ijnp/pyw033 PG 8 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DZ8OO UT WOS:000386130300003 ER PT J AU Yue, C Zipunnikov, V Bazin, PL Pham, D Reich, D Crainiceanu, C Caffo, B AF Yue, Chen Zipunnikov, Vadim Bazin, Pierre-Louis Dzung Pham Reich, Daniel Crainiceanu, Ciprian Caffo, Brian TI Parameterization of White Matter Manifold-Like Structures Using Principal Surfaces SO JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION LA English DT Article DE Corpus callosum; Principal curves and surfaces; Thin plate splines ID MULTIPLE-SCLEROSIS; COMPONENT ANALYSIS; CORPUS-CALLOSUM; NEURAL-NETWORKS; CURVES; REGRESSION; STATISTICS; DISABILITY; TRACTS; MRI AB In this article, we are concerned with data generated from a diffusion tensor imaging (DTI). experiment. The goal is to parameterize manifold-like white matter tracts, such as the corpus callosum, using principal surfaces. The problem is approached by finding a geometrically motivated surface-based representation of the corpus callosum and visualized fractional anisotropy (FA) values projected onto the surface. The method also applies to any other diffusion summary. An algorithm is proposed that (a) constructs the principal surface of a corpus callosum; (b) flattens the surface into,a parametric two-dimensional (2D) map; and (c) projects associated FA values on the map. The algorithm is applied to a longitudinal study containing 466 diffusion tensor images of 176 multiple sclerosis (MS) patients observed at multiple visits. For each subject and visit, the study contains a registered DTI scan of the corpus callosum at roughly 20,000 voxels. Extensive simulation studies, demonstrate fast convergence and robust performance of the algorithm under a variety of challenging scenarios. C1 [Yue, Chen; Zipunnikov, Vadim; Crainiceanu, Ciprian; Caffo, Brian] Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21205 USA. [Bazin, Pierre-Louis] Max Planck Inst, Dept Neurophys, Leipzig, Germany. [Dzung Pham] NIH, Ctr Neurosci & Regenerat Med, Bldg 10, Bethesda, MD 20892 USA. [Reich, Daniel] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Yue, C (reprint author), Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21205 USA. EM cyue@jhsph.edu FU NIH [R01EB012547]; NIH from the National Institute of Biomedical Imaging And Bioengineering [P41 EB015909]; National Institute of Neurological Disorders and Stroke [R01NS060910]; NINDS [R01 NS070906]; National Multiple Sclerosis Society; EMD Serono; Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health FX The project described was supported by the NIH grant RO1 Number R01EB012547 and NIH grant P41 EB015909 from the National Institute of Biomedical Imaging And Bioengineering. The project described was also supported by Grant Number R01NS060910 from the National Institute of Neurological Disorders and Stroke. The project described was partially supported by grant NINDS R01 NS070906. Data for this study was acquired with grants from the National Multiple Sclerosis Society and EMD Serono. In addition, this research was partially supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health. NR 41 TC 0 Z9 0 U1 2 U2 2 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 0162-1459 EI 1537-274X J9 J AM STAT ASSOC JI J. Am. Stat. Assoc. PD SEP PY 2016 VL 111 IS 515 BP 1050 EP 1060 DI 10.1080/01621459.2016.1164050 PG 11 WC Statistics & Probability SC Mathematics GA EA0ZN UT WOS:000386318200012 PM 28090127 ER PT J AU Weissman, SJ Hansen, NI Zaterka-Baxter, K Higgins, RD Stoll, BJ AF Weissman, Scott J. Hansen, Nellie I. Zaterka-Baxter, Kristen Higgins, Rosemary D. Stoll, Barbara J. TI Emergence of Antibiotic Resistance-Associated Clones Among Escherichia coli Recovered From Newborns With Early-Onset Sepsis and Meningitis in the United States, 2008-2009 SO JOURNAL OF THE PEDIATRIC INFECTIOUS DISEASES SOCIETY LA English DT Article DE antibiotic resistance; early-onset sepsis; Escherichia coli; ST131 ID K1 CAPSULAR POLYSACCHARIDE; EXTENDED VIRULENCE GENOTYPES; BETA-LACTAM RESISTANCE; NEONATAL MENINGITIS; PHYLOGENETIC DISTRIBUTION; PLASMIDS; CTX-M-15; CYSTITIS; STRAINS; ORIGINS AB Background. Escherichia coli associated with early-onset sepsis (EOS) have historically been antibiotic-susceptible and K1-encapsulated. In the era of emerging antibiotic resistance, however, the clonal makeup of E coli associated with EOS has not been well characterized. Methods. Escherichia coli isolates were collected from 28 cases of EOS and early-onset meningitis (EOM) from April 2008 through December 2009, during a parent study conducted at National Institute of Child Health and Human Development Neonatal Research Network centers from February 2006 through December 2009. Clinical and microbiologic data were collected for the parent study. We applied polymerase chain reaction-and sequence-based molecular techniques to determine clonal, virulence-associated and antibiotic resistance-associated traits of the E coli isolates. Results. Among 28 E coli strains, phylogroup B2 strains predominated (68%), of which more than half were K1-encapsulated (53%). Phylogroup D strains were prominent as well (18%), but none were K1-encapsulated. Across the strain collection, the rate of ampicillin resistance was high (78%). The sole strain resistant to either extended-spectrum cephalosporins or fluoroquinolones represented ST131 H30-Rx, the multidrug-resistant subclone that has emerged worldwide in the last decade. This strain encoded extended-spectrum beta-lactamase CTX-M-15 and carried an IncF plasmid of type F2:A1:B-. Conclusions. In this collection of EOS/EOM-associated E coli isolates, we observed a high rate of ampicillin resistance, a low rate of fluoroquinolone resistance, and no aminoglycoside resistance, with resistance to third-generation cephalosporins appearing in only a single strain, from the worldwide emerging ST131 clone. Ongoing surveillance of antibiotic resistance among EOS isolates is warranted, to ensure that standard empiric regimens remain effective. C1 [Weissman, Scott J.] Seattle Childrens Res Inst, Ctr Global Infect Dis Res, Washington, DC USA. [Hansen, Nellie I.; Zaterka-Baxter, Kristen] RTI Int, Social Stat & Environm Sci, Res Triangle Pk, NC USA. [Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Stoll, Barbara J.] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA. [Stoll, Barbara J.] Childrens Healthcare Atlanta, Atlanta, GA USA. [Stoll, Barbara J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Neonatal Res Network, Bethesda, MD USA. RP Weissman, SJ (reprint author), 1900 9th Ave, Seattle, WA 98101 USA. EM scott.weissman@seattlechildrens.org FU NCRR NIH HHS [M01 RR008084, UL1 RR025764, M01 RR006022, UL1 RR024139]; NIAID NIH HHS [K08 AI057737]; NICHD NIH HHS [U10 HD040689, U10 HD053109, U10 HD053124, U10 HD027904, UG1 HD087229, UG1 HD087226, UG1 HD027880, UG1 HD027856, UG1 HD027853, U01 HD036790, U10 HD021364, U10 HD021373, U10 HD053119, U10 HD021385, U10 HD053089, U10 HD040492, U10 HD036790, U10 HD027853, U10 HD027856, U10 HD027871, U10 HD034216, U10 HD027880, U10 HD027851] NR 39 TC 1 Z9 1 U1 3 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 2048-7193 EI 2048-7207 J9 J PEDIATR INFECT DIS JI J. Pediatr. Infect. Dis. Soc. PD SEP PY 2016 VL 5 IS 3 BP 269 EP 276 DI 10.1093/jpids/piv013 PG 8 WC Infectious Diseases SC Infectious Diseases GA DZ8RH UT WOS:000386138100008 PM 26407251 ER PT J AU Soheilipour, F Fazilaty, H Jesmi, F Gahl, WA Behnam, B AF Soheilipour, Fahimeh Fazilaty, Hassan Jesmi, Fatemeh Gahl, William A. Behnam, Babak TI First report of inherited thyroxine-binding globulin deficiency in Iran caused by a known de novo mutation in SERPINA7 SO MOLECULAR GENETICS AND METABOLISM REPORTS LA English DT Article DE TBG; SERPINA7; Mutation; Iran ID COMPLETE TBG DEFICIENCY; 2 NUCLEOTIDE SUBSTITUTIONS; GENE; VARIANT; FAMILY; TERMINATION; FRAMESHIFT; SEQUENCE; DELETION AB Background: Thyroxine-binding globulin (TBG) is the main transporter of thyroid hormones in human serum, encoded by the gene TBG (SERPINA7), located in long arm of X-chromosome (Xq21-q22). Deficiency of SERPINA7 (serum protease inhibitor, clade A [alpha-1 antiproteinase, antitrypsin], member 7) leads to inherited TBG deficiency. Several mutations have been reported in the coding and noncoding regions of SERPINA7 in association with TGB deficiency. Methods: Automated chemiluminescence immunoassays were used to determine TSH, free and total T4 and T3 (fT4, TT4, TT3) and TBG. Direct DNA sequencing identified the mutation in SERPINA7. Results: We present a 3 and 4/12 year old boy, born premature, whowasmismanaged as hypothyroidismbefore referral to our center, and was diagnosed with TBG deficiency at our center with a hemizygous substitution in exon 1, position c.347T>A, leading to replacement of isoleucine for arginine in position 96 (considering the first 20 amino acid signal peptide). Conclusion: This known mutation, reported as the first SERPINA7 mutation in Iran, emphasizes the point that endocrinologists should pay more attention to inherited TBG to prevent unnecessary treatment. Published by Elsevier Inc. C1 [Soheilipour, Fahimeh] Iran Univ Med Sci, Inst Endocrinol & Metab, Endocrine Res Ctr, Tehran, Iran. [Fazilaty, Hassan; Behnam, Babak] Iran Univ Med Sci, Dept Med Genet & Mol Biol, Tehran, Iran. [Jesmi, Fatemeh] Iran Univ Med Sci, Minimally Invas Surg Res Ctr, Tehran, Iran. [Gahl, William A.; Behnam, Babak] NIH, NIH Undiagnosed Dis Program, Common Fund, Off Director, Bldg 10, Bethesda, MD 20892 USA. [Gahl, William A.; Behnam, Babak] NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Fazilaty, Hassan] CSIC UMH, Inst Nuerociencias, Alacant, Spain. [Behnam, Babak] NHGRI, NIH Undiagnosed Dis Program, Off Clin Director, NIH, Bethesda, MD 20892 USA. RP Behnam, B (reprint author), NHGRI, NIH Undiagnosed Dis Program, NIH, Bethesda, MD 20892 USA.; Behnam, B (reprint author), NHGRI, NIH Undiagnosed Dis Program, Off Clin Director, NIH, Bethesda, MD 20892 USA. EM Babak.Behnam@nih.gov OI Behnam, Babak/0000-0002-1266-1602 NR 36 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2214-4269 J9 MOLEC GENET METAB RE JI Molec. Genet. Metab. Rep. PD SEP PY 2016 VL 8 BP 13 EP 16 DI 10.1016/j.ymgmr.2016.06.001 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA DZ7DK UT WOS:000386024400004 PM 27331012 ER PT J AU Waikar, SS Sabbisetti, V Arnlov, J Carlsson, AC Coresh, J Feldman, HI Foster, MC Fufaa, GD Helmersson-Karlqvist, J Hsu, CY Kimmel, PL Larsson, A Liu, YM Lind, L Liu, KD Mifflin, TE Nelson, RG Riserus, U Vasan, RS Xie, DW Zhang, XM Bonventre, JV AF Waikar, Sushrut S. Sabbisetti, Venkata Arnlov, Johan Carlsson, Axel C. Coresh, Josef Feldman, Harold I. Foster, Meredith C. Fufaa, Gudeta D. Helmersson-Karlqvist, Johanna Hsu, Chi-yuan Kimmel, Paul L. Larsson, Anders Liu, Yumin Lind, Lars Liu, Kathleen D. Mifflin, Theodore E. Nelson, Robert G. Riserus, Ulf Vasan, Ramachandran S. Xie, Dawei Zhang, Xiaoming Bonventre, Joseph V. CA Chronic Kidney Dis Biomarkers TI Relationship of proximal tubular injury to chronic kidney disease as assessed by urinary kidney injury molecule-1 in five cohort studies SO NEPHROLOGY DIALYSIS TRANSPLANTATION LA English DT Article DE albuminuria; chronic kidney disease; KIM-1 ID CHRONIC RENAL-INSUFFICIENCY; GLOMERULAR-FILTRATION-RATE; DIABETIC-NEPHROPATHY; RACIAL-DIFFERENCES; CIGARETTE-SMOKING; AMERICAN-INDIANS; ACE-INHIBITION; HEART-FAILURE; UNITED-STATES; KAPPA-B AB The primary biomarkers used to define CKD are serum creatinine and albuminuria. These biomarkers have directed focus on the filtration and barrier functions of the kidney glomerulus even though albuminuria results from tubule dysfunction as well. Given that proximal tubules make up similar to 90% of kidney cortical mass, we evaluated whether a sensitive and specific marker of proximal tubule injury, urinary kidney injury molecule-1 (KIM-1), is elevated in individuals with CKD or with risk factors for CKD. We measured urinary KIM-1 in participants of five cohort studies from the USA and Sweden. Participants had a wide range of kidney function and were racially and ethnically diverse. Multivariable linear regression models were used to test the association of urinary KIM-1 with demographic, clinical and laboratory values. In pooled, multivariable-adjusted analyses, log-transformed, creatinine-normalized urinary KIM-1 levels were higher in those with lower eGFR {beta = -0.03 per 10 mL/min/1.73 m(2) [95% confidence interval (CI) -0.05 to -0.02]} and greater albuminuria [beta = 0.16 per unit of log albumin:creatinine ratio (95% CI 0.15-0.17)]. Urinary KIM-1 levels were higher in current smokers, lower in blacks than nonblacks and lower in users versus nonusers of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Proximal tubule injury appears to be an integral and measurable element of multiple stages of CKD. C1 [Waikar, Sushrut S.; Sabbisetti, Venkata; Liu, Yumin; Bonventre, Joseph V.] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA USA. [Arnlov, Johan; Carlsson, Axel C.; Helmersson-Karlqvist, Johanna; Larsson, Anders; Lind, Lars; Riserus, Ulf] Uppsala Univ, Uppsala, Sweden. [Arnlov, Johan] Dalarna Univ, Falun, Sweden. [Carlsson, Axel C.] Karolinska Inst, Huddinge, Sweden. [Coresh, Josef] Johns Hopkins Univ, Baltimore, MD USA. [Feldman, Harold I.; Mifflin, Theodore E.; Xie, Dawei; Zhang, Xiaoming] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Foster, Meredith C.] Tufts Med Ctr, Boston, MA USA. [Fufaa, Gudeta D.; Kimmel, Paul L.; Nelson, Robert G.] NIDDK, Bethesda, MD USA. [Hsu, Chi-yuan; Liu, Kathleen D.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Hsu, Chi-yuan] Kaiser Permanente Northern Calif, Oakland, CA USA. [Vasan, Ramachandran S.] Boston Univ, Boston, MA 02215 USA. RP Waikar, SS (reprint author), Brigham & Womens Hosp, MRB-4,75 Francis St, Boston, MA 02115 USA. EM swaikar@partners.org FU Chronic Kidney Disease Biomarker Consortium [DK072381, R37DK39773]; NIDDK [U01DK85649, U01DK085673, U01DK085660, U01DK085688, U01DK085651, U01DK085689]; National Center for Advancing Translational Sciences of the National Institutes of Health [UL1TR000003]; Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; Swedish Research Council; Swedish Heart-Lung Foundation; Marianne and Marcus Wallenberg Foundation, Dalarna University; National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN26820-1100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C]; National Institute of Diabetes and Digestive and Kidney Diseases [U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, U01DK060902]; Perelman School of Medicine at the University of Pennsylvania Clinical and Translational Science Award [NIH/NCATS UL1TR000003]; Johns Hopkins University [UL1 TR-000424]; University of Maryland GCRC [M01 RR-16500]; Clinical and Translational Science Collaborative of Cleveland; National Center for Advancing Translational Sciences (NCATS) component of the National Institutes of Health [UL1TR000439]; NIH roadmap for Medical Research; Michigan Institute for Clinical and Health Research (MICHR) [UL1TR000433]; University of Illinois at Chicago CTSA [UL1RR029879]; Tulane University Translational Research in Hypertension and Renal Biology [P30GM103337]; Kaiser Permanente NIH/NCRR UCSF-CTSI [UL1 RR-024131] FX The authors thank the staff and participants of the studies for their important contributions. Results from this study were presented at the American Society of Nephrology Annual Meeting in November 2014. This work was supported by the Chronic Kidney Disease Biomarker Consortium (funded by NIDDK U01DK85649, U01DK085673, U01DK085660, U01DK085688, U01DK085651 and U01DK085689), DK072381, R37DK39773, the National Center for Advancing Translational Sciences of the National Institutes of Health (UL1TR000003), the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, the Swedish Research Council, Swedish Heart-Lung Foundation and the Marianne and Marcus Wallenberg Foundation, Dalarna University. The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contract (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN26820-1100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). Funding for the CRIC Study was obtained under a cooperative agreement from the National Institute of Diabetes and Digestive and Kidney Diseases (U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, and U01DK060902). In addition, this work was supported in part by the Perelman School of Medicine at the University of Pennsylvania Clinical and Translational Science Award NIH/NCATS UL1TR000003, Johns Hopkins University UL1 TR-000424, University of Maryland GCRC M01 RR-16500, Clinical and Translational Science Collaborative of Cleveland, UL1TR000439 from the National Center for Advancing Translational Sciences (NCATS) component of the National Institutes of Health and NIH roadmap for Medical Research, Michigan Institute for Clinical and Health Research (MICHR) UL1TR000433, University of Illinois at Chicago CTSA UL1RR029879, Tulane University Translational Research in Hypertension and Renal Biology P30GM103337, Kaiser Permanente NIH/NCRR UCSF-CTSI UL1 RR-024131. NR 70 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0931-0509 EI 1460-2385 J9 NEPHROL DIAL TRANSPL JI Nephrol. Dial. Transplant. PD SEP PY 2016 VL 31 IS 9 BP 1460 EP 1470 DI 10.1093/ndt/gfw203 PG 11 WC Transplantation; Urology & Nephrology SC Transplantation; Urology & Nephrology GA DW5UN UT WOS:000383712600018 PM 27270293 ER PT J AU Oken, E Rifas-Shiman, SL Amarasiriwardena, C Jayawardene, I Bellinger, DC Hibbeln, JR Wright, RO Gillman, MW AF Oken, Emily Rifas-Shiman, Sheryl L. Amarasiriwardena, Chitra Jayawardene, Innocent Bellinger, David C. Hibbeln, Joseph R. Wright, Robert O. Gillman, Matthew W. TI Maternal prenatal fish consumption and cognition in mid childhood: Mercury, fatty acids, and selenium SO NEUROTOXICOLOGY AND TERATOLOGY LA English DT Article DE Pregnancy; Fishes; Mercury; Child development; n-3 Fatty acids; Selenium ID FOOD FREQUENCY QUESTIONNAIRE; METHYLMERCURY EXPOSURE; HAIR MERCURY; CORD BLOOD; US COHORT; PREGNANCY; ASSOCIATIONS; VALIDITY; WOMEN; AGE AB Background: Few studies of maternal prenatal fish intake have included biomarkers of exposure to mercury, long-chain n-3 fatty acids, and selenium, which are hypothesized to mediate associations with child neurodevelopment. Objectives: Examine associations of maternal prenatal fish intake with child neurodevelopment accounting for biomarkers. Methods: In 1999-2002 we enrolled pregnant women into the Project Viva cohort. At median 27.9 weeks gestation, we estimated maternal fish intake using food frequency questionnaires, and collected blood. We assayed erythrocytes for total mercury and selenium, and plasma for fatty acids including n-3 docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). In mid-childhood (median 7.7 years), we administered cognitive tests including the Kauffman Brief Intelligence Test (KBIT). We performed multivariable linear regression analyses adjusting for maternal and child characteristics including home environment and maternal intelligence. Results: Among 1068 pairs (872 with blood), mean (SD) exposures were: maternal fish intake 1.7 (1.5) servings/week, mercury 4.0 (3.6) ng/g, DHA + EPA 98.4 (41.8) mcg/ml, selenium 205.6 (34.6) ng/ml. Child KBIT verbal scores (mean 112.2, SD 15.0) were not related to any exposures: maternal fish intake (0.15; 95% CI: -0.50, 0.79), mercury (0.08; -0.18, 0.35), DHA + EPA (0.01; -0.22, 0.24), and selenium (0.20; -0.09, 0.50). Associations with KBIT nonverbal scores and tests of memory and visual motor abilities were similarly null. Mutual adjustment for each of the exposure measures did not substantially change estimates. Conclusions: In this population with an average fish consumption of about 1 1/2 weekly servings, we did not see any evidence for an association of maternal prenatal fish intake, or of mercury, DHA + EPA, or selenium status, with verbal or non-verbal intelligence, visual motor function, or visual memory at median 7.7 years of age. (C) 2016 Elsevier Inc. All rights reserved. C1 [Oken, Emily; Rifas-Shiman, Sheryl L.; Gillman, Matthew W.] Harvard Med Sch, Dept Populat Med, 401 Pk Dr Suite 401E, Boston, MA 02215 USA. [Oken, Emily; Rifas-Shiman, Sheryl L.; Gillman, Matthew W.] Harvard Pilgrim Hlth Care Inst, 401 Pk Dr Suite 401E, Boston, MA 02215 USA. [Oken, Emily; Gillman, Matthew W.] Harvard Sch Publ Hlth, Dept Nutr, Boston, MA USA. [Amarasiriwardena, Chitra; Wright, Robert O.] Icahn Sch Med Mt Sinai, Dept Prevent Med, New York, NY 10029 USA. [Amarasiriwardena, Chitra; Jayawardene, Innocent; Bellinger, David C.] Harvard Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA. [Bellinger, David C.] Boston Childrens Hosp, Dept Neurol, Boston, MA USA. [Bellinger, David C.] Harvard Med Sch, Boston, MA USA. [Hibbeln, Joseph R.] NIAAA, Sect Nutr Neurosci, New York, NY USA. [Wright, Robert O.] Mt Sinai Sch Med, Dept Pediat, New York, NY USA. RP Oken, E (reprint author), Harvard Med Sch, Dept Populat Med, 401 Pk Dr Suite 401E, Boston, MA 02215 USA.; Oken, E (reprint author), Harvard Pilgrim Hlth Care Inst, 401 Pk Dr Suite 401E, Boston, MA 02215 USA. EM emily_oken@harvardpilgrim.org FU National Institutes of Health [K24 HD069408, R01 ES016314, R37 HD034568, R01 HL064925, R01ES013744, P30ES023515, P30ES000002]; National Institutes of Health, Intramural Program of NIAAA FX This work was supported by the National Institutes of Health (grant numbers K24 HD069408, R01 ES016314, R37 HD034568, R01 HL064925, R01ES013744, P30ES023515, P30ES000002, and the Intramural Program of NIAAA). The funding sources had no involvement in the collection, analysis, or interpretation of the data, in the writing of the report, or in the decision to submit the paper for publication. NR 42 TC 0 Z9 0 U1 6 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0892-0362 EI 1872-9738 J9 NEUROTOXICOL TERATOL JI Neurotoxicol. Teratol. PD SEP-OCT PY 2016 VL 57 BP 71 EP 78 DI 10.1016/j.ntt.2016.07.001 PG 8 WC Neurosciences; Toxicology SC Neurosciences & Neurology; Toxicology GA DZ9IG UT WOS:000386187900007 PM 27381635 ER PT J AU Demidowich, AP Kundu, A Reynolds, JC Celi, FS AF Demidowich, Andrew Paul Kundu, Amartya Reynolds, James C. Celi, Francesco S. TI False-Positive Radioactive Iodine Uptake Mimicking Miliary Lung Metastases in a Patient Affected by Papillary Thyroid Cancer and IgA Deficiency SO NUCLEAR MEDICINE AND MOLECULAR IMAGING LA English DT Editorial Material DE Radionuclide imaging; Scintigraphy; Papillary thyroid carcinoma; False-positive reactions; IgA deficiency AB A 42-year-old female with immunoglobulin A deficiency and recurrent sinopulmonary infections underwent thyroidectomy for papillary thyroid cancer (PTC). Follow-up 123I scintigraphy demonstrated diffuse pulmonary uptake, suggesting metastatic disease. However, subsequent pathologic, biochemical and radiographic testing proved that she was in fact disease free, and the initial 123I pulmonary uptake was identified as a false positive. Inflammatory conditions may rarely cause iodine uptake in non-thyroidal tissues due to local retention, organification, and/or immunologic utilization. To avoid exposing patients to unnecessary treatments, it is critical for clinicians to recognize that comorbid pulmonary conditions may mimic metastatic PTC on radioiodine scintigraphy. C1 [Demidowich, Andrew Paul] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, Program Dev Endocrinol & Genet, NIH, 9000 Rockville Pk,Bldg 10-1-3330, Bethesda, MD 20892 USA. [Kundu, Amartya] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA 01605 USA. [Reynolds, James C.] NIH, Div Nucl Med, Radiol & Imaging Sci Dept, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Celi, Francesco S.] Virginia Commonwealth Univ, Div Endocrinol & Metab, Richmond, VA USA. RP Demidowich, AP (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, Program Dev Endocrinol & Genet, NIH, 9000 Rockville Pk,Bldg 10-1-3330, Bethesda, MD 20892 USA. EM andrew.demidowich@nih.gov NR 10 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1869-3474 EI 1869-3482 J9 NUCL MED MOLEC IMAG JI NUCL. MED. MOLEC. IMAG. PD SEP PY 2016 VL 50 IS 3 BP 270 EP 272 DI 10.1007/s13139-015-0375-8 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EA0DU UT WOS:000386256500014 PM 27540434 ER PT J AU Taylor, AM Phillips, K Patel, KV Turk, DC Dworkin, RH Beaton, D Clauw, DJ Gignac, MAM Markman, JD Williams, DA Bujanover, S Burke, LB Carr, DB Choy, EH Conaghan, PG Cowan, P Farrar, JT Freeman, R Gewandter, J Gilron, I Goli, V Gover, TD Haddox, JD Kerns, RD Kopecky, EA Lee, DA Malamut, R Mease, P Rappaport, BA Simon, LS Singh, JA Smith, SM Strand, V Tugwell, P Vanhove, GF Veasley, C Walco, GA Wasan, AD Witter, J AF Taylor, Ann M. Phillips, Kristine Patel, Kushang V. Turk, Dennis C. Dworkin, Robert H. Beaton, Dorcas Clauw, Daniel J. Gignac, Monique A. M. Markman, John D. Williams, David A. Bujanover, Shay Burke, Laurie B. Carr, Daniel B. Choy, Ernest H. Conaghan, Philip G. Cowan, Penney Farrar, John T. Freeman, Roy Gewandter, Jennifer Gilron, Ian Goli, Veeraindar Gover, Tony D. Haddox, J. David Kerns, Robert D. Kopecky, Ernest A. Lee, David A. Malamut, Richard Mease, Philip Rappaport, Bob A. Simon, Lee S. Singh, Jasvinder A. Smith, Shannon M. Strand, Vibeke Tugwell, Peter Vanhove, Gertrude F. Veasley, Christin Walco, Gary A. Wasan, Ajay D. Witter, James TI Assessment of physical function and participation in chronic pain clinical trials: IMMPACT/OMERACT recommendations SO PAIN LA English DT Review DE OMERACT; IMMPACT; Pain; Physical performance measures; Patient-reported outcomes; Physical functioning; Physical activity; Accelerometer; Work; Employment; HRQOL; Social participation; Caregiver burden; Clinical trials ID PATIENT-REPORTED OUTCOMES; LOW-BACK-PAIN; EARLY RHEUMATOID-ARTHRITIS; QUALITY-OF-LIFE; COMMUNITY INTEGRATION QUESTIONNAIRE; HEALTH-ASSESSMENT QUESTIONNAIRE; WORK LIMITATIONS QUESTIONNAIRE; SICKNESS IMPACT PROFILE; TASK-FORCE REPORT; PSYCHOMETRIC PROPERTIES AB Although pain reduction is commonly the primary outcome in chronic pain clinical trials, physical functioning is also important. A challenge in designing chronic pain trials to determine efficacy and effectiveness of therapies is obtaining appropriate information about the impact of an intervention on physical function. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) and Outcome Measures in Rheumatology (OMERACT) convened a meeting to consider assessment of physical functioning and participation in research on chronic pain. The primary purpose of this article is to synthesize evidence on the scope of physical functioning to inform work on refining physical function outcome measurement. We address issues in assessing this broad construct and provide examples of frequently used measures of relevant concepts. Investigators can assess physical functioning using patient-reported outcome (PRO), performance-based, and objective measures of activity. This article aims to provide support for the use of these measures, covering broad aspects of functioning, including work participation, social participation, and caregiver burden, which researchers should consider when designing chronic pain clinical trials. Investigators should consider the inclusion of both PROs and performance-based measures as they provide different but also important complementary information. The development and use of reliable and valid PROs and performance-based measures of physical functioning may expedite development of treatments, and standardization of these measures has the potential to facilitate comparison across studies. We provide recommendations regarding important domains to stimulate research to develop tools that are more robust, address consistency and standardization, and engage patients early in tool development. C1 [Taylor, Ann M.] Cardiff Univ, Sch Med, Ctr Med Educ, Cardiff, S Glam, Wales. [Phillips, Kristine] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Patel, Kushang V.; Turk, Dennis C.; Walco, Gary A.] Univ Washington, Dept Anesthesiol & Pain Med, Box 356540, Seattle, WA 98195 USA. [Dworkin, Robert H.; Gewandter, Jennifer; Smith, Shannon M.] Univ Rochester, Sch Med & Dent, Dept Anesthesiol, Rochester, NY USA. [Beaton, Dorcas] Univ Toronto, Dept Occupat Sci & Occupat Therapy, Toronto, ON M5S 1A1, Canada. [Beaton, Dorcas; Gignac, Monique A. M.] Univ Toronto, Inst Work & Hlth, Toronto, ON M5S 1A1, Canada. [Clauw, Daniel J.; Williams, David A.] Univ Michigan, Dept Anesthesiol, Ann Arbor, MI 48109 USA. [Markman, John D.] Univ Rochester, Dept Neurol, Rochester, NY USA. [Bujanover, Shay] Depomed, Newark, CA USA. [Burke, Laurie B.] LORAGroup LLC, Royal Oak, MD USA. [Burke, Laurie B.] Univ Maryland, Dept Hlth Serv Res, Baltimore, MD 21201 USA. [Carr, Daniel B.] Tufts Univ, Sch Med, Publ Hlth & Community Med, Boston, MA 02111 USA. [Choy, Ernest H.] Cardiff Univ, Div Infect & Immun, Cardiff, S Glam, Wales. [Conaghan, Philip G.] Univ Leeds, NIHR Leeds Musculoskeletal Biomed Res Unit, Leeds, W Yorkshire, England. [Conaghan, Philip G.] Univ Leeds, Inst Rheumat & Musculoskeletal Med, Leeds, W Yorkshire, England. [Cowan, Penney] Amer Chron Pain Assoc, Rocklin, CA USA. [Farrar, John T.] Univ Penn, Dept Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Freeman, Roy] Harvard Univ, Dept Neurol, Cambridge, MA 02138 USA. [Gilron, Ian] Queens Univ, Dept Anesthesiol, Ottawa, ON, Canada. [Goli, Veeraindar] Duke Univ, Med Ctr, Dept Psychiat, Durham, NC 27710 USA. [Goli, Veeraindar] Pfizer Inc, Durham, NC USA. [Gover, Tony D.] US Army Med Res & Mat Command, Clin & Rehabil Med Res Program, Ft Detrick, MD USA. [Haddox, J. David] Purdue Pharma LP, Stamford, CT USA. [Kerns, Robert D.] Vet Affairs Connecticut Healthcare Syst, Dept Vet Affairs, West Haven, CT USA. [Kerns, Robert D.] Yale Univ, Dept Psychiat & Psychol, New Haven, CT USA. [Kopecky, Ernest A.] Collegium Pharmaceut Inc, Canton, MA USA. [Lee, David A.] Chadds Ford, Pennsylvania, PA USA. [Malamut, Richard] Teva Pharmaceut, N Wales, PA USA. [Mease, Philip] Swedish Med Ctr, Rheumatol Clin Res Div, Seattle, WA USA. [Mease, Philip] Univ Washington, Sch Med, Seattle, WA USA. [Mease, Philip] Stanford Univ, Div Immunol Rheumatol, Palo Alto, CA 94304 USA. [Rappaport, Bob A.] Analges Concepts LLC, Arlington, VA USA. [Simon, Lee S.] SDG Consulting LLC, Cambridge, MA USA. [Singh, Jasvinder A.] Birmingham Vet Affairs Med Ctr, Med Serv, Birmingham, AL USA. [Singh, Jasvinder A.] Mayo Clin, Coll Med, Dept Orthoped Surg, Rochester, MN USA. [Strand, Vibeke] Stanford Univ, Sch Med, Div Immunol Rheumatol, Palo Alto, CA 94304 USA. [Tugwell, Peter] Univ Ottawa, Fac Med, Ctr Global Hlth, Ottawa, ON, Canada. [Vanhove, Gertrude F.] Jazz Pharmaceut, Palo Alto, CA USA. [Veasley, Christin] Chron Pain Res Alliance, Washington, DC USA. [Wasan, Ajay D.] Univ Pittsburgh, Sch Med, Dept Anesthesiol, Pittsburgh, PA USA. [Witter, James] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Turk, DC (reprint author), Univ Washington, Dept Anesthesiol & Pain Med, Box 356540, Seattle, WA 98195 USA. EM turkdc@uw.edu OI Tugwell, Peter/0000-0001-5062-0556 FU Analgesic; Anesthetic; Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION); FDA FX The views expressed in this article are those of the authors. The reader should infer no official endorsement by the US Department of Veterans Affairs, US FDA, or the US National Institutes of Health. Support for the meeting was provided by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership with the FDA, which has received grants, contracts, and other revenue for its activities from the FDA, multiple pharmaceutical and device companies, and other sources. NR 210 TC 0 Z9 0 U1 13 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0304-3959 EI 1872-6623 J9 PAIN JI Pain PD SEP PY 2016 VL 157 IS 9 BP 1836 EP 1850 DI 10.1097/j.pain.0000000000000577 PG 15 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA DZ7AH UT WOS:000386014700002 PM 27058676 ER PT J AU Edwards, RR Dworkin, RH Turk, DC Angst, MS Dionne, R Freeman, R Hansson, P Haroutounian, S Arendt-Nielsen, L Attal, N Baron, R Brell, J Bujanover, S Burke, LB Carr, D Chappell, AS Cowan, P Etropolski, M Fillingim, RB Gewandter, JS Katz, NP Kopecky, EA Markman, JD Nomikos, G Porter, L Rappaport, BA Rice, ASC Scavone, JM Scholz, J Simon, LS Smith, SM Tobias, J Tockarshewsky, T Veasley, C Versavel, M Wasan, AD Wen, W Yarnitsky, D AF Edwards, Robert R. Dworkin, Robert H. Turk, Dennis C. Angst, Martin S. Dionne, Raymond Freeman, Roy Hansson, Per Haroutounian, Simon Arendt-Nielsen, Lars Attal, Nadine Baron, Ralf Brell, Joanna Bujanover, Shay Burke, Laurie B. Carr, Daniel Chappell, Amy S. Cowan, Penney Etropolski, Mila Fillingim, Roger B. Gewandter, Jennifer S. Katz, Nathaniel P. Kopecky, Ernest A. Markman, John D. Nomikos, George Porter, Linda Rappaport, Bob A. Rice, Andrew S. C. Scavone, Joseph M. Scholz, Joachim Simon, Lee S. Smith, Shannon M. Tobias, Jeffrey Tockarshewsky, Tina Veasley, Christine Versavel, Mark Wasan, Ajay D. Wen, Warren Yarnitsky, David TI Patient phenotyping in clinical trials of chronic pain treatments: IMMPACT recommendations SO PAIN LA English DT Review DE Phenotype; Central pain modulation; Neuropathic; Quantitative sensory testing; Psychosocial; Sleep ID LOW-BACK-PAIN; PLACEBO-CONTROLLED TRIAL; PERIPHERAL NEUROPATHIC PAIN; TAPENTADOL PROLONGED RELEASE; RANDOMIZED CONTROLLED-TRIAL; INTRAVENOUS KETAMINE TEST; SPINAL-CORD STIMULATION; TOTAL KNEE REPLACEMENT; QUALITY-OF-LIFE; ORAL DEXTROMETHORPHAN TREATMENT AB There is tremendous interpatient variability in the response to analgesic therapy (even for efficacious treatments), which can be the source of great frustration in clinical practice. This has led to calls for "precision medicine" or personalized pain therapeutics (ie, empirically based algorithms that determine the optimal treatments, or treatment combinations, for individual patients) that would presumably improve both the clinical care of patients with pain and the success rates for putative analgesic drugs in phase 2 and 3 clinical trials. However, before implementing this approach, the characteristics of individual patients or subgroups of patients that increase or decrease the response to a specific treatment need to be identified. The challenge is to identify the measurable phenotypic characteristics of patients that are most predictive of individual variation in analgesic treatment outcomes, and the measurement tools that are best suited to evaluate these characteristics. In this article, we present evidence on the most promising of these phenotypic characteristics for use in future research, including psychosocial factors, symptom characteristics, sleep patterns, responses to noxious stimulation, endogenous pain-modulatory processes, and response to pharmacologic challenge. We provide evidence-based recommendations for core phenotyping domains and recommend measures of each domain. C1 [Edwards, Robert R.; Freeman, Roy] Harvard Med Sch, Boston, MA USA. [Dworkin, Robert H.; Gewandter, Jennifer S.; Markman, John D.; Smith, Shannon M.] Univ Rochester, Rochester, NY USA. [Turk, Dennis C.] Univ Washington, Seattle, WA 98195 USA. [Angst, Martin S.] Stanford Univ, Palo Alto, CA 94304 USA. [Dionne, Raymond] East Carolina Univ, Greenville, NC USA. [Hansson, Per] Oslo Univ Hosp, Oslo, Norway. [Hansson, Per] Karolinska Inst, Stockholm, Sweden. [Haroutounian, Simon] Washington Univ, St Louis, MO USA. [Arendt-Nielsen, Lars] Aalborg Univ, Aalborg, Denmark. [Attal, Nadine] Hop Ambroise Pare, APHP, Boulogne, France. [Attal, Nadine] INSERM U987, Boulogne, France. [Attal, Nadine] Univ Versailles St Quentin, Versailles, France. [Baron, Ralf] Univ Kiel, Kiel, Germany. [Brell, Joanna] MetroHlth Med Ctr, Cleveland, OH USA. [Bujanover, Shay] Depomed, Newark, CA USA. [Burke, Laurie B.] LORA Grp LLC, Royal Oak, MD USA. [Burke, Laurie B.] Univ Maryland, Baltimore, MD 21201 USA. [Carr, Daniel; Katz, Nathaniel P.] Tufts Univ, Boston, MA 02111 USA. [Chappell, Amy S.] Eli Lilly, Indianapolis, IN USA. [Cowan, Penney] Amer Chron Pain Assoc, Rocklin, CA USA. [Etropolski, Mila] Johnson & Johnson, Titusville, NJ USA. [Fillingim, Roger B.] Univ Florida, Gainesville, FL USA. [Katz, Nathaniel P.] Analges Solut, Natick, MA USA. [Kopecky, Ernest A.] Collegium Pharmaceut Inc, Canton, MA USA. [Nomikos, George] Astellas Pharma, Northbrook, IL USA. [Porter, Linda] NIH, Bldg 10, Bethesda, MD 20892 USA. [Rice, Andrew S. C.] Imperial Coll, London, England. [Scavone, Joseph M.] Pfizer Inc, Groton, CT 06340 USA. [Scholz, Joachim] Columbia Univ, New York, NY USA. [Simon, Lee S.] SDG LLC, Cambridge, MA USA. [Tobias, Jeffrey] Jazz Pharmaceut, Palo Alto, CA USA. [Tockarshewsky, Tina] Ceres Consulting, Ft Montgomery, NY USA. [Veasley, Christine] Chron Pain Res Alliance, North Kingstown, RI USA. [Versavel, Mark] Zalicus, Cambridge, MA USA. [Wasan, Ajay D.] Univ Pittsburgh, Pittsburgh, PA USA. [Wen, Warren] Purdue Pharma, Stamford, CT USA. [Yarnitsky, David] Rambam Hlth Care Campus, Haifa, Israel. [Yarnitsky, David] Technion Israel Inst Technol, Fac Med, Haifa, Israel. RP Edwards, RR (reprint author), Brigham & Womens Hosp, Boston, MA 02467 USA. EM rredwards@partners.org FU ACTTION FX The views expressed in this article are those of the authors, none of whom have financial conflicts of interest specifically related to the issues discussed in this article. At the time of the meeting on which this article is based, several authors were employed by pharmaceutical companies and others had received consulting fees or honoraria from one or more pharmaceutical or device companies. Authors of this article who were not employed by industry or government at the time of the meeting received travel stipends, hotel accommodations, and meals during the meeting provided by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership with the US Food and Drug Administration (FDA), which has received research contracts, grants, or other revenue from the FDA, multiple pharmaceutical and device companies, and other sources. Preparation of background literature reviews and draft manuscripts was supported by ACTTION. No official endorsement by the FDA, US National Institutes of Health, or the pharmaceutical and device companies that have provided unrestricted grants to support the activities of ACTTION should be inferred. NR 273 TC 3 Z9 3 U1 10 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0304-3959 EI 1872-6623 J9 PAIN JI Pain PD SEP PY 2016 VL 157 IS 9 BP 1851 EP 1871 DI 10.1097/j.pain.0000000000000602 PG 21 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA DZ7AH UT WOS:000386014700003 PM 27152687 ER PT J AU Hutchins, BI Yuan, X Anderson, JM Santangelo, GM AF Hutchins, B. Ian Yuan, Xin Anderson, James M. Santangelo, George M. TI Relative Citation Ratio (RCR): A New Metric That Uses Citation Rates to Measure Influence at the Article Level SO PLOS BIOLOGY LA English DT Article ID JOURNAL IMPACT FACTOR; CARDIOVASCULAR R01 GRANTS; SCIENTIFIC IMPACT; EIGENFACTOR(TM) METRICS; PERCENTILE RANKING; INDICATORS; SCIENCE; VALIDATION; OUTPUT; INDEX AB Despite their recognized limitations, bibliometric assessments of scientific productivity have been widely adopted. We describe here an improved method to quantify the influence of a research article by making novel use of its co-citation network to field-normalize the number of citations it has received. Article citation rates are divided by an expected citation rate that is derived from performance of articles in the same field and benchmarked to a peer comparison group. The resulting Relative Citation Ratio is article level and field independent and provides an alternative to the invalid practice of using journal impact factors to identify influential papers. To illustrate one application of our method, we analyzed 88,835 articles published between 2003 and 2010 and found that the National Institutes of Health awardees who authored those papers occupy relatively stable positions of influence across all disciplines. We demonstrate that the values generated by this method strongly correlate with the opinions of subject matter experts in biomedical research and suggest that the same approach should be generally applicable to articles published in all areas of science. A beta version of iCite, our web tool for calculating Relative Citation Ratios of articles listed in PubMed, is available at https://icite.od.nih.gov. C1 [Hutchins, B. Ian; Yuan, Xin; Santangelo, George M.] NIH, Off Portfolio Anal, Bldg 10, Bethesda, MD 20892 USA. [Anderson, James M.] NIH, Div Program Coordinat Planning & Strateg Initiat, Bldg 10, Bethesda, MD 20892 USA. RP Santangelo, GM (reprint author), NIH, Off Portfolio Anal, Bldg 10, Bethesda, MD 20892 USA. EM george.santangelo@nih.gov OI Anderson, James/0000-0003-2765-7996; Hutchins, B. Ian/0000-0001-7657-552X NR 78 TC 3 Z9 3 U1 15 U2 15 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1545-7885 J9 PLOS BIOL JI PLoS. Biol. PD SEP PY 2016 VL 14 IS 9 AR e1002541 DI 10.1371/journal.pbio.1002541 PG 25 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA DZ8OD UT WOS:000386128900003 PM 27599104 ER PT J AU Sun, X Fu, K Hodgson, A Wier, EM Wen, MG Kamenyeva, O Xia, X Koo, LY Wan, FY AF Sun, Xin Fu, Kai Hodgson, Andrea Wier, Eric M. Wen, Matthew G. Kamenyeva, Olena Xia, Xue Koo, Lily Y. Wan, Fengyi TI Sam68 Is Required for DNA Damage Responses via Regulating Poly(ADP-ribosyl)ation SO PLOS BIOLOGY LA English DT Article ID NF-KAPPA-B; BINDING PROTEIN SAM68; DOUBLE-STRAND BREAKS; RNA-BINDING; CELL-DEATH; GENE-EXPRESSION; ATAXIA-TELANGIECTASIA; POLYMERASE-1 PARP-1; REPAIR DEFECT; LIVING CELLS AB The rapid and robust synthesis of polymers of adenosine diphosphate (ADP)-ribose (PAR) chains, primarily catalyzed by poly(ADP-ribose) polymerase 1 (PARP1), is crucial for cellular responses to DNA damage. However, the precise mechanisms through which PARP1 is activated and PAR is robustly synthesized are not fully understood. Here, we identified Src-associated substrate during mitosis of 68 kDa (Sam68) as a novel signaling molecule in DNA damage responses (DDRs). In the absence of Sam68, DNA damage-triggered PAR production and PAR-dependent DNA repair signaling were dramatically diminished. With serial cellular and biochemical assays, we demonstrated that Sam68 is recruited to and significantly overlaps with PARP1 at DNA lesions and that the interaction between Sam68 and PARP1 is crucial for DNA damage-initiated and PARP1-conferred PAR production. Utilizing cell lines and knockout mice, we illustrated that Sam68-deleted cells and animals are hypersensitive to genotoxicity caused by DNA-damaging agents. Together, our findings suggest that Sam68 plays a crucial role in DDR via regulating DNA damage-initiated PAR production. C1 [Sun, Xin; Fu, Kai; Hodgson, Andrea; Wier, Eric M.; Wen, Matthew G.; Xia, Xue; Wan, Fengyi] Johns Hopkins Univ, Dept Biochem & Mol Biol, Bloomberg Sch Publ Hlth, Baltimore, MD 21218 USA. [Kamenyeva, Olena; Koo, Lily Y.] NIAID, Biol Imaging Facil, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Wan, Fengyi] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Wan, Fengyi] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21218 USA. RP Wan, FY (reprint author), Johns Hopkins Univ, Dept Biochem & Mol Biol, Bloomberg Sch Publ Hlth, Baltimore, MD 21218 USA.; Wan, FY (reprint author), Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA.; Wan, FY (reprint author), Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21218 USA. EM fwan1@jhu.edu FU American Cancer Society [RSG-13-052-01-MPC]; National Institutes of Health [R01GM111682, T32CA009110] FX EMW and AH are Hopkins Sommer Scholars. FW was supported by a Research Scholar Grant, RSG-13-052-01-MPC from the American Cancer Society. This work was supported in part by grants R01GM111682 (FW) and T32CA009110 (EMW) from the 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 83 TC 1 Z9 1 U1 4 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1545-7885 J9 PLOS BIOL JI PLoS. Biol. PD SEP PY 2016 VL 14 IS 9 AR e1002543 DI 10.1371/journal.pbio.1002543 PG 28 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA DZ8OD UT WOS:000386128900005 PM 27635653 ER PT J AU Lee, H Cho, DY Whitworth, C Eisman, R Phelps, M Roote, J Kaufman, T Cook, K Russell, S Przytycka, T Oliver, B AF Lee, Hangnoh Cho, Dong-Yeon Whitworth, Cale Eisman, Robert Phelps, Melissa Roote, John Kaufman, Thomas Cook, Kevin Russell, Steven Przytycka, Teresa Oliver, Brian TI Effects of Gene Dose, Chromatin, and Network Topology on Expression in Drosophila melanogaster SO PLOS GENETICS LA English DT Article ID RNA-SEQ EXPERIMENTS; DOSAGE SENSITIVITY; X-CHROMOSOME; CELL-DEATH; GENOME; TRANSCRIPTION; IDENTIFICATION; INSULATORS; GERMLINE; ELEMENTS AB Deletions, commonly referred to as deficiencies by Drosophila geneticists, are valuable tools for mapping genes and for genetic pathway discovery via dose-dependent suppressor and enhancer screens. More recently, it has become clear that deviations from normal gene dosage are associated with multiple disorders in a range of species including humans. While we are beginning to understand some of the transcriptional effects brought about by gene dosage changes and the chromosome rearrangement breakpoints associated with them, much of this work relies on isolated examples. We have systematically examined deficiencies of the left arm of chromosome 2 and characterize gene-by-gene dosage responses that vary from collapsed expression through modest partial dosage compensation to full or even over compensation. We found negligible long-range effects of creating novel chromosome domains at deletion breakpoints, suggesting that cases of gene regulation due to altered nuclear architecture are rare. These rare cases include trans de-repression when deficiencies delete chromatin characterized as repressive in other studies. Generally, effects of breakpoints on expression are promoter proximal (similar to 100bp) or in the gene body. Effects of deficiencies genome-wide are in genes with regulatory relationships to genes within the deleted segments, highlighting the subtle expression network defects in these sensitized genetic backgrounds. C1 [Lee, Hangnoh; Whitworth, Cale; Oliver, Brian] NIDDK, Sect Dev Genom, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. [Cho, Dong-Yeon; Przytycka, Teresa] Natl Lib Med, Computat Biol Branch, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD USA. [Whitworth, Cale; Eisman, Robert; Phelps, Melissa; Kaufman, Thomas; Cook, Kevin] Indiana Univ, Dept Biol, Bloomington, IN USA. [Roote, John; Russell, Steven] Univ Cambridge, Dept Genet, Cambridge, England. [Roote, John; Russell, Steven] Univ Cambridge, Cambridge Syst Biol Ctr, Cambridge, England. RP Oliver, B (reprint author), NIDDK, Sect Dev Genom, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. EM briano@helix.nih.gov FU NIH, The National Institute of Diabetes and Digestive Diseases; National Library of Medicine; Korean Visiting Scientist Training Award (KVSTA) [HI13C1282] FX This research was supported in part by the Intramural Research Program of the NIH, The National Institute of Diabetes and Digestive Diseases (BO) and the National Library of Medicine (TP). HL was supported by Korean Visiting Scientist Training Award (KVSTA, HI13C1282). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 99 TC 0 Z9 0 U1 4 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD SEP PY 2016 VL 12 IS 9 AR e1006295 DI 10.1371/journal.pgen.1006295 PG 33 WC Genetics & Heredity SC Genetics & Heredity GA DZ7TF UT WOS:000386069000028 PM 27599372 ER PT J AU Lubitz, SA Brody, JA Bihlmeyer, NA Roselli, C Weng, LC Christophersen, IE Alonso, A Boerwinkle, E Gibbs, RA Bis, JC Cupples, LA Mohler, PJ Nickerson, DA Muzny, D Perez, MV Psaty, BM Soliman, EZ Sotoodehnia, N Lunetta, KL Benjamin, EJ Heckbert, SR Arking, DE Ellinor, PT Lin, HH AF Lubitz, Steven A. Brody, Jennifer A. Bihlmeyer, Nathan A. Roselli, Carolina Weng, Lu-Chen Christophersen, Ingrid E. Alonso, Alvaro Boerwinkle, Eric Gibbs, Richard A. Bis, Joshua C. Cupples, L. Adrienne Mohler, Peter J. Nickerson, Deborah A. Muzny, Donna Perez, Marco V. Psaty, Bruce M. Soliman, Elsayed Z. Sotoodehnia, Nona Lunetta, Kathryn L. Benjamin, Emelia J. Heckbert, Susan R. Arking, Dan E. Ellinor, Patrick T. Lin, Honghuang CA NHLBI GO Exome Sequencing Project TI Whole Exome Sequencing in Atrial Fibrillation SO PLOS GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; CODING VARIANTS; FOLLOW-UP; RISK-FACTORS; RARE; PROTEIN; HEART; INDIVIDUALS; IL17REL; DISEASE AB Atrial fibrillation (AF) is a morbid and heritable arrhythmia. Over 35 genes have been reported to underlie AF, most of which were described in small candidate gene association studies. Replication remains lacking for most, and therefore the contribution of coding variation to AF susceptibility remains poorly understood. We examined whole exome sequencing data in a large community-based sample of 1,734 individuals with and 9,423 without AF from the Framingham Heart Study, Cardiovascular Health Study, Atherosclerosis Risk in Communities Study, and NHLBI-GO Exome Sequencing Project and meta-analyzed the results. We also examined whether genetic variation was enriched in suspected AF genes (N = 37) in AF cases versus controls. The mean age ranged from 59 to 73 years; 8,656 (78%) were of European ancestry. None of the 99,404 common variants evaluated was significantly associated after adjusting for multiple testing. Among the most significantly associated variants was a common (allele frequency = 86%) missense variant in SYNPO2L (rs3812629, p.Pro707Leu, [odds ratio 1.27, 95% confidence interval 1.13-1.43, P = 6.6x10(-5)]) which lies at a known AF susceptibility locus and is in linkage disequilibrium with a top marker from prior analyses at the locus. We did not observe significant associations between rare variants and AF in gene-based tests. Individuals with AF did not display any statistically significant enrichment for common or rare coding variation in previously implicated AF genes. In conclusion, we did not observe associations between coding genetic variants and AF, suggesting that large-effect coding variation is not the predominant mechanism underlying AF. A coding variant in SYNPO2L requires further evaluation to determine whether it is causally related to AF. Efforts to identify biologically meaningful coding variation underlying AF may require large sample sizes or populations enriched for large genetic effects. C1 [Lubitz, Steven A.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Lubitz, Steven A.; Roselli, Carolina; Weng, Lu-Chen; Christophersen, Ingrid E.; Ellinor, Patrick T.] Broad Insitute Harvard & MIT, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Brody, Jennifer A.; Bis, Joshua C.; Heckbert, Susan R.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Bihlmeyer, Nathan A.; Arking, Dan E.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Weng, Lu-Chen; Christophersen, Ingrid E.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Christophersen, Ingrid E.] Vestre Viken Hosp Trust, Dept Med Res, Baerum Hosp, Baerum, Norway. [Alonso, Alvaro] Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. [Boerwinkle, Eric] UTHlth, Ctr Human Genet, Houston, TX USA. [Boerwinkle, Eric; Gibbs, Richard A.; Muzny, Donna] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Cupples, L. Adrienne; Lunetta, Kathryn L.; Benjamin, Emelia J.; Lin, Honghuang] Boston Univ, Framingham, MA 01702 USA. [Cupples, L. Adrienne; Lunetta, Kathryn L.; Benjamin, Emelia J.; Lin, Honghuang] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Mohler, Peter J.] Ohio State Univ, Wexner Med Ctr, Dorothy M Davis Heart & Lung Res Inst, Columbus, OH 43210 USA. [Nickerson, Deborah A.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Perez, Marco V.] Stanford Univ, Dept Med, Sch Med, Div Cardiovasc Med, Stanford, CA 94305 USA. [Psaty, Bruce M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Soliman, Elsayed Z.] Wake Forest Sch Med, Epidemiol Cardiol Res Ctr EPICARE, Winston Salem, NC USA. [Sotoodehnia, Nona] Univ Washington, Div Cardiol, Seattle, WA 98195 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Sect Cardiovasc Med, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Prevent Med Sect, Boston, MA 02118 USA. [Heckbert, Susan R.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Lin, Honghuang] Boston Univ, Sch Med, Dept Med, Sect Computat Biomed, Boston, MA 02118 USA. RP Lubitz, SA (reprint author), Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA.; Lubitz, SA (reprint author), Broad Insitute Harvard & MIT, Program Med & Populat Genet, Cambridge, MA 02142 USA.; Lin, HH (reprint author), Boston Univ, Framingham, MA 01702 USA.; Lin, HH (reprint author), NHLBI, Framingham Heart Study, Framingham, MA 01702 USA.; Lin, HH (reprint author), Boston Univ, Sch Med, Dept Med, Sect Computat Biomed, Boston, MA 02118 USA. EM slubitz@mgh.harvard.edu; hhlin@bu.edu RI Alonso, Alvaro/A-4917-2010; OI Alonso, Alvaro/0000-0002-2225-8323; Bihlmeyer, Nathan/0000-0002-4415-7419; Body, Jennifer/0000-0001-8509-148X FU NIH [K23HL114724, 1R01HL128914, 2R01HL092577, 3R01HL092577-06S1]; Doris Duke Charitable Foundation Clinical Scientist Development Award [2014105]; Laughlin Family Endowment; NIH through the American Recovery and Reinvestment Act (ARRA) [5RC2HL102419]; National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C]; American Heart Association [16EIA26410001]; NHLBI; Boston University [HHSN2682015000011, N01-HC-25195]; Affymetrix, Inc. [N02-HL-6-4278]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine; Boston Medical Center; NHLBI [HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, R01 HL102214, RC2 HL-103010, RC2 HL-102925, RC2 HL-102926]; National Institute of Neurological Disorders and Stroke (NINDS); National Institute on Aging (NIA) [R01AG023629]; [HL111089]; [HL116747] FX This work was supported by NIH grants K23HL114724 (SAL) and a Doris Duke Charitable Foundation Clinical Scientist Development Award 2014105 (SAL). NS was supported by HL111089, HL116747, and the Laughlin Family Endowment. Funding support for "Building on GWAS for NHLBI-diseases: the U.S. CHARGE Consortium" was provided by the NIH through the American Recovery and Reinvestment Act of 2009 (ARRA) (5RC2HL102419). Data for "Building on GWAS for NHLBI-diseases: the U.S. CHARGE Consortium" was provided by EB on behalf of the Atherosclerosis Risk in Communities (ARIC) Study; LAC, principal investigator for the Framingham Heart Study; and BMP, principal investigator for the Cardiovascular Health Study. Sequencing was carried out at the Baylor Genome Center (U54 HG003273). The ARIC Study was carried out as a collaborative study supported by National Heart, Lung, and Blood Institute (NHLBI) contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). This work was additionally supported by American Heart Association grant 16EIA26410001 (AA). The Framingham Heart Study was conducted and supported by the NHLBI in collaboration with Boston University (Contract No. HHSN2682015000011; N01-HC-25195), and its contract with Affymetrix, Inc., for genome-wide genotyping services (Contract No. N02-HL-6-4278), for quality control by Framingham Heart Study investigators using genotypes in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. Also funding was provided by NIH grants 1R01HL128914; 2R01HL092577; 3R01HL092577-06S1. CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, and R01 HL102214 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. Funding for GO ESP was provided by NHLBI grants RC2 HL-103010 (HeartGO) and exome sequencing was performed through NHLBI grants RC2 HL-102925 (BroadGO) and RC2 HL-102926 (SeattleGO). The content is solely the responsibility of the authors and does not necessarily represent the official views of the 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 39 TC 0 Z9 0 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD SEP PY 2016 VL 12 IS 9 AR e1006284 DI 10.1371/journal.pgen.1006284 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA DZ7TF UT WOS:000386069000019 PM 27589061 ER PT J AU Ha, NH Long, J Cai, Q Shu, XO Hunter, KW AF Ngoc-Han Ha Long, Jirong Cai, Qiuyin Shu, Xiao Ou Hunter, Kent W. TI The Circadian Rhythm Gene Arntl2 Is a Metastasis Susceptibility Gene for Estrogen Receptor-Negative Breast Cancer SO PLOS GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; EXPRESSION; PROGRESSION; SURVIVAL; TUMORS; LOCUS; IDENTIFICATION; TRANSCRIPTION; DISEASE; BINDING AB Breast cancer mortality is primarily due to metastasis rather than primary tumors, yet relatively little is understood regarding the etiology of metastatic breast cancer. Previously, using a mouse genetics approach, we demonstrated that inherited germline polymorphisms contribute to metastatic disease, and that these single nucleotide polymorphisms (SNPs) could be used to predict outcome in breast cancer patients. In this study, a backcross between a highly metastatic (FVB/NJ) and low metastatic (MOLF/EiJ) mouse strain identified Arntl2, a gene encoding a circadian rhythm transcription factor, as a metastasis susceptibility gene associated with progression, specifically in estrogen receptor-negative breast cancer patients. Integrated whole genome sequence analysis with DNase hypersensitivity sites reveals SNPs in the predicted promoter of Arntl2. Using CRISPR/Cas9-mediated substitution of the MOLF promoter, we demonstrate that the SNPs regulate Arntl2 transcription and affect metastatic burden. Finally, analysis of SNPs associated with ARNTL2 expression in human breast cancer patients revealed reproducible associations of ARNTL2 expression quantitative trait loci (eQTL) SNPs with disease-free survival, consistent with the mouse studies. C1 [Ngoc-Han Ha; Hunter, Kent W.] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Long, Jirong; Cai, Qiuyin; Shu, Xiao Ou] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med,Vanderbilt Epidemiol Ctr, Nashville, TN 37212 USA. RP Hunter, KW (reprint author), NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. EM hunterk@mail.nih.gov OI Hunter, Kent/0000-0001-5963-8808 FU DOD IDEA grant [BC122861]; NIH, National Cancer Institute, Center for Cancer Research FX This study was funded partially by the DOD IDEA grant BC122861 and in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 38 TC 2 Z9 2 U1 4 U2 4 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 SEP PY 2016 VL 12 IS 9 AR e1006267 DI 10.1371/journal.pgen.1006267 PG 20 WC Genetics & Heredity SC Genetics & Heredity GA DZ7TF UT WOS:000386069000010 PM 27656887 ER PT J AU Maximova, OA Bernbaum, JG Pletnev, AG AF Maximova, Olga A. Bernbaum, John G. Pletnev, Alexander G. TI West Nile Virus Spreads Transsynaptically within the Pathways of Motor Control: Anatomical and Ultrastructural Mapping of Neuronal Virus Infection in the Primate Central Nervous System SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID RED NUCLEUS; SUBSTANTIA-NIGRA; NONHUMAN PRIMATE; INFERIOR OLIVE; TRANSPORT; ENCEPHALITIS; NEUROPATHOLOGY; BRAIN; ENTRY; NEUROPATHOGENESIS AB Background During recent West Nile virus (WNV) outbreaks in the US, half of the reported cases were classified as neuroinvasive disease. WNV neuroinvasion is proposed to follow two major routes: hematogenous and/or axonal transport along the peripheral nerves. How virus spreads once within the central nervous system (CNS) remains unknown. Methodology/Principal Findings Using immunohistochemistry, we examined the expression of viral antigens in the CNS of rhesus monkeys that were intrathalamically inoculated with a wild-type WNV. The localization of WNV within the CNS was mapped to specific neuronal groups and anatomical structures. The neurological functions related to structures containing WNV-labeled neurons were reviewed and summarized. Intraneuronal localization of WNV was investigated by electron microscopy. The known anatomical connectivity of WNV-labeled neurons was used to reconstruct the directionality of WNV spread within the CNS using a connectogram design. Anatomical mapping revealed that all structures identified as containing WNV-labeled neurons belonged to the pathways of motor control. Ultrastructurally, virions were found predominantly within vesicular structures (including autophagosomes) in close vicinity to the axodendritic synapses, either at pre- or post-synaptic positions (axonal terminals and dendritic spines, respectively), strongly indicating transsynaptic spread of the virus between connected neurons. Neuronal connectivity-based reconstruction of the directionality of transsynaptic virus spread suggests that, within the CNS, WNV can utilize both anterograde and retrograde axonal transport to infect connected neurons. Conclusions/Significance This study offers a new insight into the neuropathogenesis of WNV infection in a primate model that closely mimics WNV encephalomyelitis in humans. We show that within the primate CNS, WNV primarily infects the anatomical structures and pathways responsible for the control of movement. Our findings also suggest that WNV most likely propagates within the CNS transsynaptically, by both, anterograde and retrograde axonal transport. C1 [Maximova, Olga A.; Pletnev, Alexander G.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Bernbaum, John G.] NIAID, Off Chief Scientist, Integrated Res Facil, NIH, Frederick, MD USA. RP Maximova, OA (reprint author), NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. EM maximovao@niaid.nih.gov; APLETNEV@niaid.nih.gov FU NIAID Intramural Research Program FX This work was supported by funds provided by the NIAID Intramural Research Program. 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 0 U2 0 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 SEP PY 2016 VL 10 IS 9 AR e0004980 DI 10.1371/journal.pntd.0004980 PG 23 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA DZ1UZ UT WOS:000385627900039 PM 27617450 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 Mode Network in People With Schizophrenia When Focusing Attention in Space SO SCHIZOPHRENIA BULLETIN LA English DT Article DE fMRI; default network; top-down ID POSTERIOR CINGULATE CORTEX; TASK-INDUCED DEACTIVATION; WORKING-MEMORY CAPACITY; FUNCTIONAL CONNECTIVITY; VISUOSPATIAL ATTENTION; SELECTIVE ATTENTION; NEURAL MECHANISMS; SPATIAL ATTENTION; DORSAL ATTENTION; BRAIN NETWORKS AB When studying selective attention in people with schizophrenia (PSZ), a counterintuitive but replicated finding has been that PSZ display larger performance benefits than healthy control subjects (HCS) by cues that predicts the location of a target stimulus relative to non-predictive cues. Possible explanations are that PSZ hyperfocus attention in response to predictive cues, or that an inability to maintain a broad attentional window impairs performance when the cue is non-predictive. Over-recruitment of regions involved in top-down focusing of spatial attention in response to predictive cues would support the former possibility, and an inappropriate recruitment of these regions in response to non-predictive cues the latter. We probed regions of the dorsal attention network while PSZ (N = 20) and HCS (N = 20) performed a visuo-spatial attention task. A central cue either predicted at which of 4 peripheral locations a target signal would appear, or it gave no information about the target location. As observed previously, PSZ displayed a larger reaction time difference between predictive and non-predictive cue trials than HCS. Activity in frontoparietal and occipital regions was greater for predictive than non-predictive cues. This effect was almost identical between PSZ and HCS. There was no sign of over-recruitment when the cue was predictive, or of inappropriate recruitment when the cue was non-predictive. However, PSZ differed from HCS in their cue-dependent deactivation of the default mode network. Unexpectedly, PSZ displayed significantly greater deactivation than HCS in predictive cue trials, which may reflect a tendency to expend more processing resources when focusing attention in space. C1 [Hahn, Britta; Harvey, Alexander N.; Gold, James M.; Fischer, Bernard A.; Keller, William R.] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, POB 21247, Baltimore, MD 21228 USA. [Ross, Thomas J.; Stein, Elliot A.] NIDA, Neuroimaging Res Branch, Intramural Res Program, Baltimore, MD USA. RP Hahn, B (reprint author), Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, POB 21247, Baltimore, MD 21228 USA. EM bhahn@mprc.umaryland.edu FU Brain & Behavior Research Foundation Young Investigator Award; Intramural Research Program of the NIH, National Institute on Drug Abuse FX This work was supported by a Brain & Behavior Research Foundation Young Investigator Award to B.H. and by the Intramural Research Program of the NIH, National Institute on Drug Abuse. NR 65 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 SEP PY 2016 VL 42 IS 5 BP 1158 EP 1166 DI 10.1093/schbul/sbw019 PG 9 WC Psychiatry SC Psychiatry GA DZ9PK UT WOS:000386209900012 PM 26926831 ER PT J AU McLaughlin, D Carrion, RE Auther, AM Olvet, DM Addington, J Bearden, CE Cadenhead, KS Cannon, TD Heinssen, RK Mathalon, DH McGlashan, TH Perkins, DO Seidman, LJ Tsuang, MT Walker, EF Woods, SW Goldberg, TE Harvey, PD Cornblatt, BA AF McLaughlin, Danielle Carrion, Ricardo E. Auther, Andrea M. Olvet, Doreen M. Addington, Jean Bearden, Carrie E. Cadenhead, Kristin S. Cannon, Tyrone D. Heinssen, Robert K. Mathalon, Daniel H. McGlashan, Thomas H. Perkins, Diana O. Seidman, Larry J. Tsuang, Ming T. Walker, Elaine F. Woods, Scott W. Goldberg, Terry E. Harvey, Philip D. Cornblatt, Barbara A. TI Functional Capacity Assessed by the Map Task in Individuals at Clinical High-Risk for Psychosis SO SCHIZOPHRENIA BULLETIN LA English DT Article DE prodromal; role functioning; disability; prediction; CHR; NAPLS ID SKILLS ASSESSMENT UPSA; ULTRA-HIGH RISK; INTERRATER RELIABILITY; PREDICTIVE-VALIDITY; PRODROMAL SYNDROMES; SCHIZOPHRENIA; PERFORMANCE; DISABILITY; PEOPLE; SYMPTOMS AB Objectives: Recent studies have recognized that signs of functional disability in schizophrenia are evident in early phases of the disorder, and, as a result, can potentially serve as vulnerability markers of future illness. However, functional measures in the psychosis prodrome have focused exclusively on real-world achievements, rather than on the skills required to carry-out a particular real-world function (ie, capacity). Despite growing evidence that diminished capacity is critical to the etiology of the established disorder, virtually no attention has been directed towards assessing functional capacity in the pre-illness stages. In the present study, we introduce the Map task, a measure to assess functional capacity in adolescent and young-adult high-risk populations. Methods: The Map task was administered to 609 subjects at Clinical High-Risk (CHR) for psychosis and 242 Healthy Controls (HCs) participating in the North American Prodrome Longitudinal Study (NAPLS2). Subjects were required to efficiently complete a set of specified errands in a fictional town. Results: CHR participants showed large impairments across major indices of the Map task, relative to the HCs. Most importantly, poor performance on the Map task significantly predicted conversion to psychosis, even after adjusting for age, IQ, clinical state, and other potential confounders. Conclusions: To the best of our knowledge, the Map task is one of the first laboratory-based measures to assess functional capacity in high-risk populations. Functional capacity deficits prior to the onset of psychosis may reflect a basic mechanism that underlies risk for psychosis. Early intervention targeting this domain may help to offset risk and independently improve long-term outcome. C1 [McLaughlin, Danielle; Carrion, Ricardo E.; Auther, Andrea M.; Olvet, Doreen M.; Goldberg, Terry E.; Cornblatt, Barbara A.] Northwell Hlth Syst, Zucker Hillside Hosp, Div Psychiat Res, 75-59 263rd St, Glen Oaks, NY 11004 USA. [Carrion, Ricardo E.; Goldberg, Terry E.; Cornblatt, Barbara A.] Northwell Hlth Syst, Feinstein Inst Med Res, Ctr Psychiat Neurosci, Manhasset, NY USA. [Carrion, Ricardo E.; Auther, Andrea M.; Goldberg, Terry E.; Cornblatt, Barbara A.] Hofstra Northwell Sch Med, Dept Psychiat, Hempstead, NY USA. [Addington, Jean] Univ Calgary, Dept Psychiat, Calgary, AB, Canada. [Bearden, Carrie E.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90024 USA. [Bearden, Carrie E.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA USA. [Cadenhead, Kristin S.; Tsuang, Ming T.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Cannon, Tyrone D.] Yale Univ, Sch Med, Dept Psychol, New Haven, CT USA. [Cannon, Tyrone D.; McGlashan, Thomas H.; Woods, Scott W.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Heinssen, Robert K.] NIMH, Div Treatment & Prevent Res, Rockville, MD 20857 USA. [Mathalon, Daniel H.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Perkins, Diana O.] Univ North Carolina Chapel Hill, Dept Psychiat, Chapel Hill, NC USA. [Seidman, Larry J.; Tsuang, Ming T.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Psychiat, Boston, MA USA. [Seidman, Larry J.; Tsuang, Ming T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Walker, Elaine F.] Emory Univ, Dept Psychol, Atlanta, GA 30322 USA. [Harvey, Philip D.] Univ Miami, Miller Sch Med, Dept Psychiat & Behav Sci, Miami, FL 33136 USA. [Harvey, Philip D.] Bruce W Carter VA Med Ctr, Res Serv, Miami, FL USA. [Cornblatt, Barbara A.] Hofstra Northwell Sch Med, Dept Mol Med, Hempstead, NY USA. RP McLaughlin, D (reprint author), Northwell Hlth Syst, Zucker Hillside Hosp, Div Psychiat Res, 75-59 263rd St, Glen Oaks, NY 11004 USA. EM Dmclaugh@northwell.edu FU National Institute of Mental Health [U01 MH081984, U01 MH081928, P50 MH080272]; Commonwealth of Massachusetts [SCDMH82101008006, R01 MH60720, U01 MH082022, K24 MH76191, U01 MH081902, P50 MH066286, U01 MH082004, U01 MH081988, RO1 MH076989-01, U01 MH081857, MH61523]; Zucker Hillside Hospital NIMH Advanced Center for Intervention and Services Research for the Study of Schizophrenia [MH 074543-01]; Brain and Behavior Research Foundation (NARSAD): Young Investigator Grant [19740]; Let the Sun Shine Run/Walk, Cold Spring, MN FX Supported by grants from the National Institute of Mental Health: U01 MH081984 to J.A.; U01 MH081928; P50 MH080272; Commonwealth of Massachusetts SCDMH82101008006 to L.J.S.; R01 MH60720, U01 MH082022, and K24 MH76191 to K.S.C.; U01 MH081902 to T.D.C.; P50 MH066286 (Prodromal Core) to C.E.B.; grant U01 MH082004 to D.O.P.; U01 MH081988 to E.F.W.; RO1 MH076989-01 to D.H.M.; U01 MH082022 to S.W.W.; U01 MH081857 and MH61523 to B.A.C.; the Zucker Hillside Hospital NIMH Advanced Center for Intervention and Services Research for the Study of Schizophrenia MH 074543-01 to John M. Kane, M.D. REC received funding from the Brain and Behavior Research Foundation (NARSAD): Young Investigator Grant 19740 and the Let the Sun Shine Run/Walk, Cold Spring, MN. No funding agency had any role in the collection, analysis, and interpretation of data, in the writing of the report, and in the decision to submit the article for publication. NR 46 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 SEP PY 2016 VL 42 IS 5 BP 1234 EP 1242 DI 10.1093/schbul/sbw039 PG 9 WC Psychiatry SC Psychiatry GA DZ9PK UT WOS:000386209900020 PM 27105902 ER PT J AU Castle, IJP Dong, CH Haughwout, SP White, AM AF Castle, I-Jen P. Dong, Chuanhui Haughwout, Sarah P. White, Aaron M. TI Emergency Department Visits for Adverse Drug Reactions Involving Alcohol: United States, 2005 to 2011 SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Adverse Drug Reactions; Alcohol; Sex Differences; Age Differences; Emergency Department Visits ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; NATIONALLY REPRESENTATIVE SAMPLE; SELF-MEDICATION; EPIDEMIOLOGIC SURVEY; ANXIETY DISORDERS; YOUNG-ADULTS; DRINKING; GENDER; CONSUMPTION; TRENDS AB Background: Alcohol consumption may interfere with absorption, distribution, metabolism, and excretion of medications and increase risk of adverse drug reactions (ADR). Studies report increasing prescription medication use over time, with many U.S. drinkers using alcohol-interactive medication. This study identified trends in incidence of U.S. emergency department (ED) visits for ADR with alcohol involvement (ADR-A), compared characteristics and disposition between ADR-A visits and ADR visits without alcohol involvement (ADR-NA), and examined frequency of implicated medications in such visits for 2005 to 2011. Methods: ADR visits were identified through the Drug Abuse Warning Network, a national surveillance system monitoring drug-related ED visits. Analysis accounted for sampling design effects and sampling weights. Estimates are presented for totals (ages 12+), age group, and/or sex. Trends were assessed by joinpoint log-linear regression. Differences between ADR-A and ADR-NA visits were compared using two-tailed Rao-Scott chi-square tests. Results: From 2005 to 2011, incidence of ADR-A visits increased for males and females ages 21 to 34 and females ages 55+. An average of 25,303 ADR-A visits ages 12+ occurred annually. Compared with ADR-NA visits, ADR-A visits were more likely to involve males, patients ages 21 to 54, and 2+ implicated drugs. Alcohol involvement increased odds of more serious outcomes from ADR visits. Central nervous system (CNS) agents were the most common medications in ADR-A visits (59.1%), with nearly half being analgesics (mainly opioid). About 13.8% of ADR-A visits involved psychotherapeutic agents, including antidepressants. Besides CNS and psychotherapeutic agents, ADR-A visits involved a higher percentage of genitourinary-tract agents (mainly for impotence) than ADR-NA visits. Sex and age variations were observed with certain implicated medications. Conclusions: ED visits for alcohol-drug interactions can be prevented by avoiding alcohol when taking alcohol-interactive medications. Our results underscore the need for healthcare professionals to routinely ask patients about alcohol consumption and warn of ADR risks before prescribing and dispensing alcohol-interactive medications. C1 [Castle, I-Jen P.; Dong, Chuanhui; Haughwout, Sarah P.] CSR Inc, 4250 N Fairfax Dr,Suite 500, Arlington, VA 22203 USA. [Dong, Chuanhui] Univ Miami, Dept Neurol, Miami, FL USA. [White, Aaron M.] NIAAA, NIH, Bethesda, MD USA. RP Castle, IJP (reprint author), CSR Inc, 4250 N Fairfax Dr,Suite 500, Arlington, VA 22203 USA. EM icastle@csrincorporated.com FU NICHD NIH HHS [HHSN275201300016C] NR 54 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD SEP PY 2016 VL 40 IS 9 DI 10.1111/acer.13167 PG 13 WC Substance Abuse SC Substance Abuse GA DZ0TQ UT WOS:000385553000012 PM 27488763 ER PT J AU Loehr, LR Meyer, ML Poon, AK Selvin, E Palta, P Tanaka, H Pankow, JS Wright, JD Griswold, ME Wagenknecht, LE Heiss, G AF Loehr, Laura R. Meyer, Michelle L. Poon, Anna K. Selvin, Elizabeth Palta, Priya Tanaka, Hirofumi Pankow, James S. Wright, Jacqueline D. Griswold, Michael E. Wagenknecht, Lynne E. Heiss, Gerardo TI Prediabetes and Diabetes Are Associated With Arterial Stiffness in Older Adults: The ARIC Study SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Article DE arterial stiffness; blood pressure; diabetes; hypertension; peripheral arterial stiffness; prediabetes; pulse wave velocity; race ID PULSE-WAVE VELOCITY; IMPAIRED FASTING GLUCOSE; EXPERT CONSENSUS DOCUMENT; GLYCATION END-PRODUCTS; CARDIOVASCULAR-DISEASE; INSULIN-RESISTANCE; EUROPEAN-SOCIETY; YOUNG-ADULTS; ATHEROSCLEROSIS; METAANALYSIS AB To determine whether prediabetes and diabetes in older adults are associated with arterial stiffness measured in central and peripheral arteries and to examine characteristics that modify these associations. Cohort members attending the 5th exam (2011-2013) of the Atherosclerosis Risk in Communities (ARIC) study had pulse wave velocity (PWV) measures performed at the carotid-femoral (cfPWV), brachial-ankle (baPWV), and femoral-ankle (faPWV) segments. Fasting glucose a parts per thousand yen126mg/dl, glycated hemoglobin (HbA1c) a parts per thousand yen6.5%, or currently taking diabetes medication defined diabetes. Fasting glucose 100-125mg/dl or HbA1c 5.7%-6.4% among those without diabetes defined prediabetes. Cross-sectional associations were modeled using multivariable linear regression. Among 4,279 eligible participants with cfPWV measures (mean age 75 years), 22% were African-American, 25.5% had diabetes, and 54.7% had prediabetes. Compared to those with normal glucose, cfPWV was 95.8cm/s higher (stiffer) on average for those with diabetes (for reference: being 1 year older was associated with 14.4cm/s higher cfPWV). Similar findings were seen for diabetes and baPWV, although attenuated. Interestingly, faPWV was 17.6cm/s lower for those with diabetes compared to normal glucose. There was a significant positive association between baPWV and prediabetes. Among those with diabetes, cfPWV was higher for those with albuminuria, reduced kidney function, duration of diabetes a parts per thousand yen10 years, and elevated HbA1c (HbA1c a parts per thousand yen7). Among older adults, diabetes is associated with higher central arterial stiffness and lower peripheral arterial stiffness, and prediabetes is associated with higher baPWV. Cross-sectionally, the magnitude of the effect of diabetes on central stiffness is equivalent to 6 years of arterial aging. C1 [Loehr, Laura R.; Meyer, Michelle L.; Poon, Anna K.; Palta, Priya; Heiss, Gerardo] Univ North Carolina Chapel Hill, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Selvin, Elizabeth] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Tanaka, Hirofumi] Univ Texas Austin, Austin, TX 78712 USA. [Pankow, James S.] Univ Minnesota, Minneapolis, MN USA. [Wright, Jacqueline D.] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Griswold, Michael E.] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. [Wagenknecht, Lynne E.] Wake Forest Sch Med, Winston Salem, NC USA. RP Loehr, LR (reprint author), Univ North Carolina Chapel Hill, Dept Epidemiol, Chapel Hill, NC 27599 USA. EM lloehr@email.unc.edu FU National Heart, Lung, and Blood Institute contracts [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268 201100009C, HHSN268201100010C, HHSN26820110001 1C, HHSN268201100012C]; NIH/NIDDK [K24 DK106414] FX The ARIC study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268 201100009C, HHSN268201100010C, HHSN26820110001 1C, and HHSN268201100012C). The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the US Department of Health and Human Services. E.S. was supported by NIH/NIDDK grant K24 DK106414. The authors thank the staff and participants of the ARIC study for their important contributions. NR 35 TC 1 Z9 2 U1 0 U2 0 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 SEP PY 2016 VL 29 IS 9 BP 1038 EP 1045 DI 10.1093/ajh/hpw036 PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DY5ES UT WOS:000385122400007 PM 27068705 ER PT J AU Li, W Prabakaran, P Chen, WZ Zhu, ZY Feng, Y Dimitrov, DS AF Li, Wei Prabakaran, Ponraj Chen, Weizao Zhu, Zhongyu Feng, Yang Dimitrov, Dimiter S. TI Antibody Aggregation: Insights from Sequence and Structure SO ANTIBODIES LA English DT Review DE monoclonal antibodies; antibody aggregation; protein unfolding; antibody domains; antibody drug conjugates ID CHAIN VARIABLE DOMAIN; COMPLEMENTARITY-DETERMINING REGIONS; CONCENTRATED MONOCLONAL-ANTIBODY; REVERSIBLE SELF-ASSOCIATION; IMMUNOGLOBULIN LIGHT-CHAIN; V-H DOMAINS; PROTEIN AGGREGATION; THERMAL-STABILITY; ANTIGEN-BINDING; DRUG CONJUGATE AB Monoclonal antibodies (mAbs) are the fastest-growing biological therapeutics with important applications ranging from cancers, autoimmunity diseases and metabolic disorders to emerging infectious diseases. Aggregation of mAbs continues to be a major problem in their developability. Antibody aggregation could be triggered by partial unfolding of its domains, leading to monomer-monomer association followed by nucleation and growth. Although the aggregation propensities of antibodies and antibody-based proteins can be affected by the external experimental conditions, they are strongly dependent on the intrinsic antibody properties as determined by their sequences and structures. In this review, we describe how the unfolding and aggregation susceptibilities of IgG could be related to their cognate sequences and structures. The impact of antibody domain structures on thermostability and aggregation propensities, and effective strategies to reduce aggregation are discussed. Finally, the aggregation of antibody-drug conjugates (ADCs) as related to their sequence/structure, linker payload, conjugation chemistry and drug-antibody ratio (DAR) is reviewed. C1 [Li, Wei; Chen, Weizao; Zhu, Zhongyu; Feng, Yang; Dimitrov, Dimiter S.] NCI, Prot Interact Sect, Canc & Inflammat Program, Ctr Canc Res,NIH, Frederick, MD 21702 USA. [Prabakaran, Ponraj] Intrexon Corp, Germantown, MD 20876 USA. RP Li, W (reprint author), NCI, Prot Interact Sect, Canc & Inflammat Program, Ctr Canc Res,NIH, Frederick, MD 21702 USA. EM wei.li3@nih.gov; praba.ponraj@gmail.com; chenw3@mail.nih.gov; zhuzhongyu@mail.nih.gov; fengya@mail.nih.gov; dimitrdi@mail.nih.gov NR 141 TC 2 Z9 2 U1 6 U2 6 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 2073-4468 J9 ANTIBODIES JI Antibodies PD SEP PY 2016 VL 5 IS 3 AR 19 DI 10.3390/antib5030019 PG 23 WC Immunology SC Immunology GA DZ0KQ UT WOS:000385528100002 ER PT J AU Wennerstrom, ECM Risques, RA Prunkard, D Giffen, C Corley, DA Murray, LJ Whiteman, DC Wu, AH Bernstein, L Ye, WM Chow, WH Vaughan, TL Liao, LM AF Wennerstrom, E. Christina M. Risques, Rosa A. Prunkard, Donna Giffen, Carol Corley, Douglas A. Murray, Liam J. Whiteman, David C. Wu, Anna H. Bernstein, Leslie Ye, Weimin Chow, Wong-Ho Vaughan, Thomas L. Liao, Linda M. TI Leukocyte telomere length in relation to the risk of Barrett's esophagus and esophageal adenocarcinoma SO CANCER MEDICINE LA English DT Article DE Barrett's esophagus; esophageal Adenocarcinoma; epidemiology; telomere ID EXTRACTION METHOD IMPLICATIONS; CANCER-RISK; EPIDEMIOLOGIC RESEARCH; CIGARETTE-SMOKING; GASTRIC CARDIA; ACID REFLUX; BODY-MASS; OBESITY; DNA; ASSOCIATION AB Chronic inflammation and oxidative damage caused by obesity, cigarette smoking, and chronic gastroesophageal reflux disease (GERD) are major risk factors associated with Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). EAC has been increasing the past few decades, and early discovery and treatment are crucial for survival. Telomere shortening due to cell division and oxidative damage may reflect the impact of chronic inflammation and could possibly be used as predictor for disease development. We examined the prevalence of shorter leukocyte telomere length (LTL) among individuals with GERD, BE, or EAC using a pooled analysis of studies from the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON). Telomere length was measured in leukocyte DNA samples by Q-PCR. Participants included 1173 patients (386 with GERD, 384 with EAC, 403 with BE) and 736 population-based controls. The association of LTL (in tertiles) along the continuum of disease progression from GERD to BE to EAC was calculated using study-specific odds ratios (ORs) and 95% confidence intervals (CIs) from logistic regression models adjusted for potential confounders. Shorter LTL were less prevalent among GERD patients (OR 0.57; 95% CI: 0.35-0.93), compared to population-based controls. No statistically significant increased prevalence of short/long LTL among individuals with BE or EAC was observed. In contrast to some earlier reports, our findings add to the evidence that leukocyte telomere length is not a biomarker of risk related to the etiology of EAC. The findings do not suggest a relationship between LTL and BE or EAC. C1 [Wennerstrom, E. Christina M.; Liao, Linda M.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Wennerstrom, E. Christina M.] Statens Serum Inst, Dept Epidemiol Res, Copenhagen, Denmark. [Risques, Rosa A.; Prunkard, Donna] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [Giffen, Carol] Informat Management Serv Inc, Bethesda, MD USA. [Corley, Douglas A.] Kaiser Permanente Northern Calif, Div Res, Oakland, CA USA. [Corley, Douglas A.] Kaiser Permanente Northern Calif, Oakland Med Ctr, Oakland, CA USA. [Murray, Liam J.] Queens Univ, Ctr Publ Hlth, Belfast, Antrim, North Ireland. [Whiteman, David C.] QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia. [Whiteman, David C.] Univ Queensland, Sch Populat Hlth, Brisbane, Qld, Australia. [Wu, Anna H.] Univ Southern Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Dept Prevent Med, Los Angeles, CA USA. [Bernstein, Leslie] City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Div Canc Etiol, Duarte, CA USA. [Ye, Weimin] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Chow, Wong-Ho] UT MD Anderson Canc Ctr, Houston, TX USA. [Vaughan, Thomas L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. RP Liao, LM (reprint author), NCI, Div Canc Epidemiol & Genet, Metab Epidemiol Branch, 9609 Med Ctr Dr,Rm 6-E632,MSC 9771, Bethesda, MD 20892 USA. EM linda.liao@nih.gov OI Wennerstrom, E. Christina M./0000-0002-0111-3416; Whiteman, David/0000-0003-2563-9559 FU Intramural Research Program of NIH (National Cancer Institute) FX This study was supported by the Intramural Research Program of NIH (National Cancer Institute). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. NR 36 TC 0 Z9 0 U1 5 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2045-7634 J9 CANCER MED-US JI Cancer Med. PD SEP PY 2016 VL 5 IS 9 BP 2657 EP 2665 DI 10.1002/cam4.810 PG 9 WC Oncology SC Oncology GA DY8CG UT WOS:000385355500052 PM 27384379 ER PT J AU Wu, LT McNeely, J Subramaniam, GA Sharma, G VanVeldhuisen, P Schwartz, RP AF Wu, Li-Tzy McNeely, Jennifer Subramaniam, Geetha A. Sharma, Gaurav VanVeldhuisen, Paul Schwartz, Robert P. TI Design of the NIDA clinical trials network validation study of tobacco, alcohol, prescription medications, and substance use/misuse (TAPS) tool SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE Instrument; Screening; Substance use disorder; Tool; Validation ID SCREENING-TEST ASSIST; PRIMARY-CARE PATIENTS; USE DISORDERS; DRUG-USE; SMOKING; DEPENDENCE; ABUSE; HEALTH; MISUSE AB Background: Substance use and its associated use disorders are under-detected and under-treated in primary care. There is a need for a clinically useful brief screening and assessment instrument to identify primary care patients with substance use, sub-threshold substance use disorder (SUD), and SUD to facilitate brief intervention and treatment. Methods: We describe the design of the recently completed National Drug Abuse Treatment Clinical Trials Network's tobacco, alcohol, prescription medications, and substance use/misuse screen and brief assessment tool validation study. Study aims included to: develop a 2-stage screening and brief assessment tool (TAPS Tool) to detect substance use, problem use, and SUD among adult primary care patients; examine the validity of both the screen component and the TAPS Tool by comparing them to reference standard screening and assessment measures of no use, problem use, and SUD; and determine the feasibility and acceptability of the self-administration and interviewer-administration of the tool. The design included a pilot testing phase (n = 30) and the main study of 2000 adult primary care participants who were randomly assigned in counter-balanced order to have the interviewer-administration or the self-administration of the TAPS Tool followed by the other administration format. Participants' views of feasibility, acceptability and preference for format of self-administration versus interviewer-administration of the TAPS Tool were assessed. Criterion measures of use and DSM-5 SUDs were administered. Discussion: The TAPS Tool study builds on prior work to develop a 2-stage clinical tool for facilitating the adoption of screening, brief assessment and treatment for SUDs in primary care. (C) 2016 Elsevier Inc. All rights reserved. C1 [Wu, Li-Tzy] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Box 3903, Durham, NC 27708 USA. [Wu, Li-Tzy] Duke Univ, Med Ctr, Dept Med, Div Gen Internal Med, Durham, NC 27710 USA. [Wu, Li-Tzy] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. [Wu, Li-Tzy] Duke Univ, Ctr Child & Family Policy, Durham, NC USA. [McNeely, Jennifer] NYU, Sch Med, Dept Populat Hlth, New York, NY USA. [Subramaniam, Geetha A.] NIDA, Bethesda, MD 20892 USA. [Sharma, Gaurav; VanVeldhuisen, Paul] EMMES Corp, Rockville, MD USA. [Schwartz, Robert P.] Friends Res Inst Inc, Baltimore, MD USA. RP Wu, LT (reprint author), Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Box 3903, Durham, NC 27708 USA. EM Litzy.wu@duke.edu OI McNeely, Jennifer/0000-0003-4601-6940 FU National Institute on Drug Abuse of the National Institutes of Health [UG1DA040317, U10DA013727, UG1DA013034, UG1DA013035]; [R01MD007658]; [R01DA019623]; [R33DA027503] FX This work was made possible by research support from the National Institute on Drug Abuse of the National Institutes of Health (UG1DA040317, U10DA013727, UG1DA013034, and UG1DA013035). LT Wu also has received funding from other research grants (R01MD007658, R01DA019623, and R33DA027503). The sponsoring agencies had no further role in the study design and analysis, the writing of the report, or the decision to submit the paper for publication. The opinions expressed in this paper are solely those of the authors and do not represent the official position of the U.S. government NR 37 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 SEP PY 2016 VL 50 BP 90 EP 97 DI 10.1016/j.cct.2016.07.013 PG 8 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA DY7PM UT WOS:000385321600012 PM 27444426 ER PT J AU Fox, RJ Coffey, CS Cudkowicz, ME Gleason, T Goodman, A Klawiter, EC Matsuda, K McGovern, M Conwit, R Naismith, R Ashokkumar, A Bermel, R Ecklund, D Koepp, M Long, J Natarajan, S Ramachandran, S Skaramagas, T Thornell, B Yankey, J Agius, M Bashir, K Cohen, B Coyle, P Delgado, S Dewitt, D Flores, A Giesser, B Goldman, M Jubelt, B Lava, N Lynch, S Miravalle, A Moses, H Ontaneda, D Perumal, J Racke, M Repovic, P Riley, C Severson, C Shinnar, S Suski, V Weinstock-Gutman, B Yadav, V Zabeti, A AF Fox, Robert J. Coffey, Christopher S. Cudkowicz, Merit E. Gleason, Trevis Goodman, Andrew Klawiter, Eric C. Matsuda, Kazuko McGovern, Michelle Conwit, Robin Naismith, Robert Ashokkumar, Akshata Bermel, Robert Ecklund, Dixie Koepp, Maxine Long, Jeffrey Natarajan, Sneha Ramachandran, Srividya Skaramagas, Thomai Thornell, Brenda Yankey, Jon Agius, Mark Bashir, Khurram Cohen, Bruce Coyle, Patricia Delgado, Silvia Dewitt, Dana Flores, Angela Giesser, Barbara Goldman, Myla Jubelt, Burk Lava, Neil Lynch, Sharon Miravalle, Augusto Moses, Harold Ontaneda, Daniel Perumal, Jai Racke, Michael Repovic, Pavle Riley, Claire Severson, Christopher Shinnar, Shlomo Suski, Valerie Weinstock-Gutman, Bianca Yadav, Vijayshree Zabeti, Aram TI Design, rationale, and baseline characteristics of the randomized double-blind phase II clinical trial of ibudilast in progressive multiple sclerosis SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE Clinical trial; Ibudilast; Progressive multiple sclerosis; Magnetic resonance imaging ID BRAIN ATROPHY; FUNCTIONAL COMPOSITE; PHOSPHODIESTERASE INHIBITORS; MECHANICAL ALLODYNIA; NEUROPATHIC PAIN; LESION LOAD; RATS; NEUROPROTECTION; IMPAIRMENT; DISABILITY AB Background: Primary and secondary progressive multiple sclerosis (MS), collectively called progressive multiple sclerosis (PMS), is characterized by gradual progression of disability. The current anti-inflammatory treatments for MS have little or no efficacy in PMS in the absence of obvious active inflammation. Optimal biomarkers for phase II PMS trials is unknown. Ibudilast is an inhibitor of macrophage migration inhibitor factor and phosphodiesterases-4 and -10 and exhibits possible neuroprotective properties. The goals of SPRINT-MS study are to evaluate the safety and efficacy of ibudilast in PMS and to directly compare several imaging metrics for utility in PMS trials. Methods: SPRINT-MS is a randomized, placebo-controlled, phase II trial of ibudilast in patients with PMS. Eligible subjects were randomized 1:1 to receive either ibudilast (100 mg/day) or placebo for 96 weeks. Imaging is conducted every 24 weeks for whole brain atrophy, magnetization transfer ratio, diffusion tensor imaging, cortical brain atrophy, and retinal nerve fiber layer thickness. Clinical outcomes include neurologic disability and patient reported quality of life. Safety assessments include laboratory testing, electrocardiography, and suicidality screening. Results: A total of 331 subjects were enrolled, of which 255 were randomized onto active study treatment. Randomized subjects were 53.7% female and mean age 55.7 (SD 7.3) years. The last subject is projected to complete the study in May 2017. Conclusion: SPRINT-MS is designed to evaluate the safety and efficacy of ibudilast as a treatment for PMS while simultaneously validating five different imaging biomarkers as outcome metrics for use in future phase II proof-of concept PMS trials. (C) 2016 Elsevier Inc. All rights reserved. C1 [Fox, Robert J.; Bermel, Robert; Natarajan, Sneha; Ramachandran, Srividya; Skaramagas, Thomai; Ontaneda, Daniel] Cleveland Clin, Neurol Inst, Cleveland, OH 44106 USA. [Coffey, Christopher S.; Ashokkumar, Akshata; Ecklund, Dixie; Koepp, Maxine; Long, Jeffrey; Yankey, Jon] Univ Iowa, Data Coordinating Ctr, NeuroNEXT, Iowa City, IA USA. [Cudkowicz, Merit E.; McGovern, Michelle; Thornell, Brenda] Harvard Partners, Clin Coordinating Ctr, NeuroNEXT, Boston, MA USA. [Gleason, Trevis] Patient Advocate, Seattle, WA USA. [Goodman, Andrew] Univ Rochester, Med Ctr, Rochester, NY 14642 USA. [Klawiter, Eric C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Matsuda, Kazuko] Medicinova Inc, La Jolla, CA USA. [Conwit, Robin] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Naismith, Robert] Washington Univ, Sch Med, St Louis, MO USA. [Agius, Mark] Univ Calif Davis, Sacramento, CA 95817 USA. [Agius, Mark] Barrows Neurol Inst, Phoenix, AZ USA. [Bashir, Khurram] Univ Alabama Birmingham, Birmingham, AL USA. [Cohen, Bruce] Northwestern Univ, Chicago, IL 60611 USA. [Coyle, Patricia] SUNY Stony Brook, Stony Brook, NY 11794 USA. [Delgado, Silvia] Univ Miami, Sch Med, Miami, FL USA. [Dewitt, Dana] Univ Utah, Salt Lake City, UT USA. [Flores, Angela] Univ Texas Southwestern Med Ctr, Dallas, TX USA. [Giesser, Barbara] Univ Calif Los Angeles, Los Angeles, CA USA. [Goldman, Myla] Univ Virginia, Charlottesville, VA USA. [Jubelt, Burk] SUNY Upstate Med Univ, Syracuse, NY 13210 USA. [Lava, Neil] Emory Univ, Atlanta, GA 30322 USA. [Lynch, Sharon] Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. [Miravalle, Augusto] Univ Colorado Denver, Aurora, CO USA. [Moses, Harold] Vanderbilt Univ, 221 Kirkland Hall, Nashville, TN 37235 USA. [Perumal, Jai] Weill Cornell Med Coll, New York, NY USA. [Racke, Michael] Ohio State Univ, Columbus, OH 43210 USA. [Repovic, Pavle] Swedish Med Ctr Seattle, Seattle, WA USA. [Riley, Claire] Columbia Univ, Med Ctr, New York, NY USA. [Severson, Christopher] Brigham & Womens Hosp, Brookline, MA USA. [Shinnar, Shlomo] Montefiore Med Ctr, 111 E 210th St, Bronx, NY 10467 USA. [Suski, Valerie] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Weinstock-Gutman, Bianca] SUNY Buffalo, Buffalo, NY USA. [Yadav, Vijayshree] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Zabeti, Aram] Univ Cincinnati, Cincinnati, OH USA. RP Fox, RJ (reprint author), Cleveland Clin, Mellen Ctr Multiple Sclerosis, 9500 Euclic Ave,U10, Cleveland, OH 44195 USA. EM foxr@ccf.org RI Goldman, Myla/D-1955-2017 FU NINDS [U01NS082329]; NMSS [RG 4778-A-6]; NINDS (Central Coordinating Center) [U01NS077179]; NINDS (Data Coordinating Center) [U01NS077352] FX This study was funded by the NINDS (U01NS082329) and NMSS (RG 4778-A-6). Ibudilast study drug was provided at no cost by MediciNova Inc. The NeuroNEXT Network is supported by the NINDS (Central Coordinating Center: U01NS077179, Data Coordinating Center: U01NS077352). We thank Dr. Elizabeth McNeil, the former program manager at NINDS, for her steady support through the trial development and start-up process. This study was made possible by the dedication and support of people with MS who volunteered to participate as well as their families and friends who support their involvement in this study. NR 54 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 1551-7144 EI 1559-2030 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD SEP PY 2016 VL 50 BP 166 EP 177 DI 10.1016/j.cct.2016.08.009 PG 12 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA DY7PM UT WOS:000385321600021 PM 27521810 ER PT J AU Devine, EG Ryan, ML Falk, DE Fertig, JB Litten, RZ AF Devine, Eric G. Ryan, Megan L. Falk, Daniel E. Fertig, Joanne B. Litten, Raye Z. TI An exploratory evaluation of Take Control: A novel computer-delivered behavioral platform for placebo-controlled pharmacotherapy trials for alcohol use disorder SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE Behavioral platform; Alcohol use disorder; Randomized controlled trial; Computer-based intervention; Take control ID DOUBLE-BLIND; DEPENDENT PATIENTS; EFFICACY; ADHERENCE AB Placebo-controlled pharmacotherapy trials for alcohol use disorder (AUD) require an active behavioral platform to avoid putting participants at risk for untreated AUD and to better assess the effectiveness of the medication. Therapist-delivered platforms (TDP) can be costly and present a risk to study design because of the variability in therapist fidelity. Take Control is a novel computer-delivered behavioral platform developed for use in pharmacotherapy trials sponsored by the National Institute on Alcohol Abuse and Alcoholism Clinical Investigations Group (NCIG). This behavioral platform was developed with the goal of reducing trial implementation costs and limiting potential bias introduced by therapists providing TDP. This exploratory study is the first to compare Take Control with TDP on measures related to placebo response rate, medication adherence, and participant retention. Data were drawn from the placebo arms of four multisite, double-blind, randomized controlled trials (RCT) for AUD conducted by NCIG from 2007 to 2015. Data were compared from subjects receiving TDP (n = 156) in two RCTs and Take Control (n = 155) in another two RCTs. Placebo response rate, as represented by weekly percentage of heavy drinking days, was similar between groups. Subjects who received Take Control had a higher rate of medication adherence than those who received TDP. Subject retention was not significantly different between groups. The findings suggest that Take Control is comparable to TDP on measures of retention, medication adherence, and placebo response. Additional research is needed to evaluate Take Control directly against TDPs in a randomized trial. (C) 2016 Elsevier Inc All rights reserved. C1 [Devine, Eric G.] Boston Univ, Sch Med, Dept Psychiat, Suite 1150,Doctors Off Bldg,720 Harrison Ave, Boston, MA 02118 USA. [Ryan, Megan L.; Falk, Daniel E.; Fertig, Joanne B.; Litten, Raye Z.] NIAAA, NCIG, Div Medicat Dev, Bethesda, MD USA. RP Devine, EG (reprint author), Boston Univ, Sch Med, Dept Psychiat, Suite 1150,Doctors Off Bldg,720 Harrison Ave, Boston, MA 02118 USA. EM eric.devine@bmc.org FU National Institute on Alcohol Abuse and Alcoholism [HHSN275200900005C, HHSN275201400001I] FX This work was supported by the National Institute on Alcohol Abuse and Alcoholism [Contracts HHSN275200900005C and HHSN275201400001I]. NR 27 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 1551-7144 EI 1559-2030 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD SEP PY 2016 VL 50 BP 178 EP 185 DI 10.1016/j.cct.2016.08.006 PG 8 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA DY7PM UT WOS:000385321600022 PM 27521807 ER PT J AU Lee, JD Nunes, EV Novo, P Bailey, GL Brigham, GS Cohen, AJ Fishman, M Ling, W Lindblad, R Shmueli-Blumberg, D Stablein, D May, J Salazar, D Liu, D Rotrosen, J AF Lee, Joshua D. Nunes, Edward V. Novo, Patricia Bailey, Genie L. Brigham, Gregory S. Cohen, Allan J. Fishman, Marc Ling, Walter Lindblad, Robert Shmueli-Blumberg, Dikla Stablein, Don May, Jeanine Salazar, Dagmar Liu, David Rotrosen, John TI NIDA Clinical Trials Network CTN-0051, Extended-Release Naltrexone vs. Buprenorphine for Opioid Treatment (X:BOT): Study design and rationale SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE Extended-release naltrexone; Buprenorphine-naloxone; Opioid dependence; Medication assisted therapy; Methods or experimental design; Clinical trials network ID FAGERSTROM TOLERANCE QUESTIONNAIRE; MEDICATION-ASSISTED TREATMENT; MULTICENTER RANDOMIZED-TRIAL; ORAL NALTREXONE; NICOTINE DEPENDENCE; COUNSELOR ATTITUDES; HEROIN DEPENDENCE; SUBSTANCE-ABUSE; DETOXIFICATION; RELAPSE AB Introduction: For opioid-dependent patients in the US and elsewhere, detoxification and counseling-only aftercare are treatment mainstays. Long-term abstinence is rarely achieved; many patients relapse and overdose after detoxification. Methadone, buprenorphine-naloxone (BUP-NX) and extended-release naltrexone (XR-NIX) can prevent opioid relapse but are underutilized. This study is intended to develop an evidence-base to help patients and providers make informed choices and to foster wider adoption of relapse-prevention pharmacotherapies. Methods: The National Institute on Drug Abuse's Clinical Trials Network (CTN) study CTN-0051, X:BOT, is a comparative effectiveness study of treatment for 24 weeks with XR-NIX, an opioid antagonist, versus BUP-NX, a high affinity partial opioid agonist, for opioid dependent patients initiating treatment at 8 short-term residential (detoxification) units and continuing care as outpatients. Up to 600 participants are randomized (1:1) to XR-NDC or BUP-NX. Results: The primary outcome is time to opioid relapse (i.e., loss of persistent abstinence) across the 24-week treatment phase. Differences between arms in the distribution of time-to-relapse will be compared (construction of the asymptotic 95% CI for the hazard ratio of the difference between arms). Secondary outcomes include proportions retained in treatment, rates of opioid abstinence, adverse events, cigarette, alcohol, and other drug use, and ITN risk behaviors; opioid cravings, quality of life, cognitive function, genetic moderators, and cost effectiveness. Conclusions: XR-NTX and BUP-NX differ considerably in their characteristics and clinical management; no studies to date have compared XR-NTX with buprenorphine maintenance. Study design choices and compromises inherent to a comparative effectiveness trial of distinct treatment regimens are reviewed. (C) 2016 Elsevier Inc. All rights reserved. C1 [Lee, Joshua D.; Novo, Patricia; Rotrosen, John] NYU, Sch Med, New York, NY USA. [Nunes, Edward V.] Columbia Univ, Med Ctr, New York State Psychiat Inst, New York, NY USA. [Bailey, Genie L.] Brown Univ, Warren Alpert Med Sch, Providence, RI 02912 USA. [Bailey, Genie L.] Stanley St Treatment & Resources, Fall River, MA USA. [Brigham, Gregory S.] Adapt, Roseburg, OR USA. [Cohen, Allan J.] Bay Area Addict Res & Treatment, San Francisco, CA USA. [Fishman, Marc] Mt Manor Treatment Ctr, Baltimore, MD USA. [Ling, Walter] UCLA Integrated Subst Abuse Program, Los Angeles, CA USA. [Lindblad, Robert; Shmueli-Blumberg, Dikla; Stablein, Don; May, Jeanine; Salazar, Dagmar] Emmes Corp, Rockville, MD USA. [Liu, David] NIDA, Rockville, MD USA. [Brigham, Gregory S.] Maryhaven, Columbus, OH USA. [Brigham, Gregory S.] Univ Cincinnati, Cincinnati, OH USA. RP Lee, JD (reprint author), NYU, Sch Med, Dept Populat Hlth, 227 E-30th St 712, New York, NY 10016 USA. EM joshua.lee@nyumc.org FU NIDA FX NIDA. NR 54 TC 1 Z9 1 U1 4 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7144 EI 1559-2030 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD SEP PY 2016 VL 50 BP 253 EP 264 DI 10.1016/j.cct.2016.08.004 PG 12 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA DY7PM UT WOS:000385321600031 PM 27521809 ER PT J AU Sherling, ES van Ooij, C AF Sherling, Emma S. van Ooij, Christiaan TI Host cell remodeling by pathogens: the exomembrane system in Plasmodium-infected erythrocytes SO FEMS MICROBIOLOGY REVIEWS LA English DT Review DE malaria; host-parasite interaction; pathogenesis; exomembrane system; plasmodium ID RED-BLOOD-CELLS; PARASITOPHOROUS VACUOLE MEMBRANE; CAVEOLA-VESICLE COMPLEXES; PERFORIN-LIKE PROTEIN; FALCIPARUM MALARIA PARASITES; GREEN FLUORESCENT PROTEIN; SKELETON-BINDING PROTEIN-1; MAURERS CLEFT ORGANELLES; RING-EXPORTED PROTEIN-1; FINE-STRUCTURE AB Malaria is caused by infection of erythrocytes by parasites of the genus Plasmodium. To survive inside erythrocytes, these parasites induce sweeping changes within the host cell, one of the most dramatic of which is the formation of multiple membranous compartments, collectively referred to as the exomembrane system. As an uninfected mammalian erythrocyte is devoid of internal membranes, the parasite must be the force and the source behind the formation of these compartments. Even though the first evidence of the presence these of internal compartments was obtained over a century ago, their functions remain mostly unclear, and in some cases completely unknown, and the mechanisms underlying their formation are still mysterious. In this review, we provide an overview of the different parts of the exomembrane system, describing the parasitophorous vacuole, the tubovesicular network, Maurer's clefts, the caveola-vesicle complex, J dots and other mobile compartments, and the small vesicles that have been observed in Plasmodium-infected cells. Finally, we combine the data into a simplified view of the exomembrane system and its relation to the alterations of the host erythrocyte.Plasmodium parasites remodel the host erythrocyte in various ways, including the formation of several membranous compartments, together referred to as the exomembrane system, within the erythrocyte cytosol that together are key to the sweeping changes in the host cell.Plasmodium parasites remodel the host erythrocyte in various ways, including the formation of several membranous compartments, together referred to as the exomembrane system, within the erythrocyte cytosol that together are key to the sweeping changes in the host cell. C1 [Sherling, Emma S.; van Ooij, Christiaan] Francis Crick Inst, Mill Hill Lab, Mill Hill, London NW7 1AA, England. [Sherling, Emma S.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. RP van Ooij, C (reprint author), Francis Crick Inst, Mill Hill Lab, Mill Hill, London NW7 1AA, England. EM Christiaan.vanOoij@crick.ac.uk OI Sherling, Emma Sophia/0000-0002-8339-7060 FU Wellcome Trust [095836/Z/1/Z]; Wellcome Trust; NIH FX This work was supported by the Wellcome Trust [Career Re-Entry Fellowship 095836/Z/1/Z (to C.v.O.) and Wellcome Trust and NIH Four-year PhD Studentship (to E.S.S.)]. NR 271 TC 1 Z9 1 U1 3 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0168-6445 EI 1574-6976 J9 FEMS MICROBIOL REV JI Fems Microbiol. Rev. PD SEP PY 2016 VL 40 IS 5 BP 701 EP 721 DI 10.1093/femsre/fuw016 PG 21 WC Microbiology SC Microbiology GA DY5KJ UT WOS:000385138200008 PM 27587718 ER PT J AU Zhao, XN Usdin, K AF Zhao, Xiao-Nan Usdin, Karen TI Ups and Downs: Mechanisms of Repeat Instability in the Fragile X-Related Disorders SO GENES LA English DT Review DE Fragile X syndrome; Fragile X-related disorders; repeat expansion; base excision repair; mismatch repair; transcription coupled repair ID EMBRYONIC STEM-CELLS; PREMUTATION MOUSE MODEL; COUPLED REPAIR PROTEIN; DM1 TRANSGENIC MICE; GROUP-B PROTEIN; KNOCK-IN MICE; FULL MUTATION; TRINUCLEOTIDE REPEATS; SOMATIC EXPANSION; TRIPLET REPEATS AB The Fragile X-related disorders (FXDs) are a group of clinical conditions resulting from the expansion of a CGG/CCG-repeat tract in exon 1 of the Fragile X mental retardation 1 (FMR1) gene. While expansions of the repeat tract predominate, contractions are also seen with the net result being that individuals can show extensive repeat length heterogeneity in different tissues. The mechanisms responsible for expansion and contraction are still not well understood. This review will discuss what is known about these processes and current evidence that supports a model in which expansion arises from the interaction of components of the base excision repair, mismatch repair and transcription coupled repair pathways. C1 [Zhao, Xiao-Nan; Usdin, Karen] NIDDK, Sect Gene Struct & Dis, Lab Cell & Mol Biol, NIH, Bldg 8,Room 2A19,8 Ctr Dr MSC 0830, Bethesda, MD 20892 USA. RP Usdin, K (reprint author), NIDDK, Sect Gene Struct & Dis, Lab Cell & Mol Biol, NIH, Bldg 8,Room 2A19,8 Ctr Dr MSC 0830, Bethesda, MD 20892 USA. EM xiaonan.zhao@nih.gov; ku@helix.nih.gov RI Zhao, Xiaonan/S-3139-2016 FU Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [DK057808] FX This work was made possible by funding to Karen Usdin from the Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (DK057808). NR 81 TC 0 Z9 0 U1 8 U2 8 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 2073-4425 J9 GENES-BASEL JI Genes PD SEP PY 2016 VL 7 IS 9 AR 70 DI 10.3390/genes7090070 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA DZ0MX UT WOS:000385535300016 ER PT J AU Chalamalasetty, RB Ajima, R Garriock, RJ Kennedy, MW Tessarollo, L Yamaguchi, TP AF Chalamalasetty, Ravindra B. Ajima, Rieko Garriock, Robert J. Kennedy, Mark W. Tessarollo, Lino Yamaguchi, Terry P. TI A new gain-of-function mouse line to study the role of Wnt3a in development and disease SO GENESIS LA English DT Article DE development; gastrulation; growth factor; mouse embryo; presomitic mesoderm (PSM); primitive streak (PS); stem cells; Wnt3a ID BETA-CATENIN; SIGNALING PATHWAY; NEGATIVE REGULATOR; SELF-RENEWAL; STEM-CELLS; DIFFERENTIATION; SEGMENTATION; PROTEINS; EMBRYO; GENE AB Wnt/-catenin signals are important regulators of embryonic and adult stem cell self-renewal and differentiation and play causative roles in tumorigenesis. Purified recombinant Wnt3a protein, or Wnt3a-conditioned culture medium, has been widely used to study canonical Wnt signaling in vitro or ex vivo. To study the role of Wnt3a in embryogenesis and cancer models, we developed a Cre recombinase activatable Rosa26(Wnt3a) allele, in which a Wnt3a cDNA was inserted into the Rosa26 locus to allow for conditional, spatiotemporally defined expression of Wnt3a ligand for gain-of-function (GOF) studies in mice. To validate this reagent, we ectopically overexpressed Wnt3a in early embryonic progenitors using the T-Cre transgene. This resulted in up-regulated expression of a -catenin/Tcf-Lef reporter and of the universal Wnt/-catenin pathway target genes, Axin2 and Sp5. Importantly, T-Cre; Rosa26(Wnt3a) mutants have expanded presomitic mesoderm (PSM) and compromised somitogenesis and closely resemble previously studied T-Cre; Ctnnb1(ex3) (-catenin(GOF)) mutants. These data indicate that the exogenously expressed Wnt3a stimulates the Wnt/-catenin signaling pathway, as expected. The Rosa26(Wnt3a) mouse line should prove to be an invaluable tool to study the function of Wnt3a in vivo. C1 [Chalamalasetty, Ravindra B.; Garriock, Robert J.; Kennedy, Mark W.; Yamaguchi, Terry P.] NCI, Canc & Dev Biol Lab, Ctr Canc Res, NIH, 1050 Boyles St Bldg 539,Rm 218, Frederick, MD 21702 USA. [Ajima, Rieko] Natl Inst Genet, Mammalian Dev Lab, Mishima, Shizuoka 4118540, Japan. [Tessarollo, Lino] NCI, Mouse Canc Genet Program, Ctr Canc Res, NIH, 1050 Boyles St Bldg 539,Rm 218, Frederick, MD 21702 USA. RP Yamaguchi, TP (reprint author), NCI, Canc & Dev Biol Lab, Ctr Canc Res, NIH, 1050 Boyles St Bldg 539,Rm 218, Frederick, MD 21702 USA. EM yamagute@mail.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX The authors thank Ruth Wolfe for technical assistance with animal experiments. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 29 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1526-954X EI 1526-968X J9 GENESIS JI Genesis PD SEP PY 2016 VL 54 IS 9 BP 497 EP 502 DI 10.1002/dvg.22959 PG 6 WC Developmental Biology; Genetics & Heredity SC Developmental Biology; Genetics & Heredity GA DW4AB UT WOS:000383583100005 PM 27411055 ER PT J AU Baker, SG Bonetti, M AF Baker, Stuart G. Bonetti, Marco TI Evaluating Markers for Guiding Treatment SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID RANDOMIZED CLINICAL-TRIALS; CANCER PREVENTION TRIAL; BREAST-CANCER; POSTMENOPAUSAL WOMEN; TAMOXIFEN; BIOMARKERS; LETROZOLE; SUBGROUPS; SEQUENCE; SUBSETS AB Background: The subpopulation treatment effect pattern plot (STEPP) is an appealing method for assessing the clinical impact of a predictive marker on patient outcomes and identifying a promising subgroup for further study. However, its original formulation lacked a decision analytic justification and applied only to a single marker. Methods: We derive a decision-analytic result that motivates STEPP. We discuss the incorporation of multiple predictive markers into STEPP using risk difference, cadit, and responders-only benefit functions. Results: Applying STEPP to data from a breast cancer treatment trial with multiple markers, we found that none of the three benefit functions identified a promising subgroup for further study. Applying STEPP to hypothetical data from a trial with 100 markers, we found that all three benefit functions identified promising subgroups as evidenced by the large statistically significant treatment effect in these subgroups. Conclusions: Because the method has desirable decision-analytic properties and yields an informative plot, it is worth applying to randomized trials on the chance there is a large treatment effect in a subgroup determined by the predictive markers. C1 [Baker, Stuart G.] NCI, Canc Prevent Div, 9609 Med Ctr Dr,Room 5E638,MSC 9789, Bethesda, MD 20892 USA. [Bonetti, Marco] Carlo F Dondena Ctr Res Social Dynam & Publ Polic, Milan, Italy. [Bonetti, Marco] Bocconi Univ, Milan, Italy. RP Baker, SG (reprint author), NCI, Canc Prevent Div, 9609 Med Ctr Dr,Room 5E638,MSC 9789, Bethesda, MD 20892 USA. EM sb16i@nih.gov FU National Institutes of Health FX This research was supported by the National Institutes of Health. NR 30 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 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD SEP PY 2016 VL 108 IS 9 AR djw101 DI 10.1093/jnci/djw101 PG 6 WC Oncology SC Oncology GA DZ0KH UT WOS:000385527000010 ER PT J AU Baris, D Waddell, R Freeman, LEB Schwenn, M Colt, JS Ayotte, JD Ward, MH Nuckols, J Schned, A Jackson, B Clerkin, C Rothman, N Moore, LE Taylor, A Robinson, G Hosain, GMM Armenti, KR McCoy, R Samanic, C Hoover, RN Fraumeni, JF Johnson, A Karagas, MR Silverman, DT AF Baris, Dalsu Waddell, Richard Freeman, Laura E. Beane Schwenn, Molly Colt, Joanne S. Ayotte, Joseph D. Ward, Mary H. Nuckols, John Schned, Alan Jackson, Brian Clerkin, Castine Rothman, Nathaniel Moore, Lee E. Taylor, Anne Robinson, Gilpin Hosain, G. M. Monawar Armenti, Karla R. McCoy, Richard Samanic, Claudine Hoover, Robert N. Fraumeni, Joseph F., Jr. Johnson, Alison Karagas, Margaret R. Silverman, Debra T. TI Elevated Bladder Cancer in Northern New England: The Role of Drinking Water and Arsenic SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID UNITED-STATES; OCCUPATIONAL RISKS; ENVIRONMENTAL FATE; ATTRIBUTABLE RISK; POULTRY LITTER; EXPOSURE; MORTALITY; CARCINOMA; ROXARSONE; PATTERNS AB Background: Bladder cancer mortality rates have been elevated in northern New England for at least five decades. Incidence rates in Maine, New Hampshire, and Vermont are about 20% higher than the United States overall. We explored reasons for this excess, focusing on arsenic in drinking water from private wells, which are particularly prevalent in the region. Methods: In a population-based case-control study in these three states, 1213 bladder cancer case patients and 1418 control subjects provided information on suspected risk factors. Log transformed arsenic concentrations were estimated by linear regression based on measurements in water samples from current and past homes. All statistical tests were two-sided. Results: Bladder cancer risk increased with increasing water intake (P-trend = .003). This trend was statistically significant among participants with a history of private well use (P-trend = .01). Among private well users, this trend was apparent if well water was derived exclusively from shallow dug wells (which are vulnerable to contamination from manmade sources, P-trend = .002) but not if well water was supplied only by deeper drilled wells (P-trend = .48). If dug wells were used pre-1960, when arsenical pesticides were widely used in the region, heavier water consumers (>2.2 L/day) had double the risk of light users (<1.1 L/day, P-trend = .01). Among all participants, cumulative arsenic exposure from all water sources, lagged 40 years, yielded a positive risk gradient (P-trend = .004); among the highest-exposed participants (97.5th percentile), risk was twice that of the lowest-exposure quartile (odds ratio = 2.24, 95% confidence interval = 1.29 to 3.89). Conclusions: Our findings support an association between low-to-moderate levels of arsenic in drinking water and bladder cancer risk in New England. In addition, historical consumption of water from private wells, particularly dug wells in an era when arsenical pesticides were widely used, was associated with increased bladder cancer risk and may have contributed to the New England excess. C1 [Baris, Dalsu; Freeman, Laura E. Beane; Colt, Joanne S.; Ward, Mary H.; Rothman, Nathaniel; Moore, Lee E.; Samanic, Claudine; Hoover, Robert N.; Fraumeni, Joseph F., Jr.; Silverman, Debra T.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, 9609 Med Ctr Dr,MSC 9774, Bethesda, MD 20892 USA. [Waddell, Richard; Schned, Alan; Karagas, Margaret R.] Geisel Sch Med Dartmouth, Hanover, NH USA. [Schwenn, Molly; Clerkin, Castine] Maine Canc Registry, Augusta, ME USA. US Geol Survey, Pembroke, NH USA. [Robinson, Gilpin] US Geol Survey, Reston, VA USA. [Nuckols, John] Colorado State Univ, Ft Collins, CO 80523 USA. [Jackson, Brian] Dartmouth Coll, Hanover, NH 03755 USA. [Taylor, Anne] Informat Management Serv Inc, Calverton, MD USA. [Hosain, G. M. Monawar] New Hampshire State Canc Registry, Concord, NH USA. [Armenti, Karla R.] New Hampshire State Occupat Surveillance Program, Concord, NH USA. [McCoy, Richard; Johnson, Alison] Vermont Dept Hlth, Burlington, VT 05402 USA. RP Baris, D; Silverman, DT (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, DHHS, 9609 Med Ctr Dr,MSC 9774, Bethesda, MD 20892 USA. EM dalsubaris@gmail.com; silvermd@mail.nih.gov RI Beane Freeman, Laura/C-4468-2015 OI Beane Freeman, Laura/0000-0003-1294-4124 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics [N02-CP-01037] FX Supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics (contract number N02-CP-01037). NR 39 TC 2 Z9 2 U1 7 U2 7 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 SEP PY 2016 VL 108 IS 9 AR djw099 DI 10.1093/jnci/djw099 PG 9 WC Oncology SC Oncology GA DZ0KH UT WOS:000385527000008 ER PT J AU Mirabello, L Yeager, M Cullen, M Boland, JF Chen, ZG Wentzensen, N Zhang, XJ Yu, K Yang, Q Mitchell, J Roberson, D Bass, S Xiao, YZ Burdett, L Raine-Bennett, T Lorey, T Castle, PE Burk, RD Schiffman, M AF Mirabello, Lisa Yeager, Meredith Cullen, Michael Boland, Joseph F. Chen, Zigui Wentzensen, Nicolas Zhang, Xijun Yu, Kai Yang, Qi Mitchell, Jason Roberson, David Bass, Sara Xiao, Yanzi Burdett, Laurie Raine-Bennett, Tina Lorey, Thomas Castle, Philip E. Burk, Robert D. Schiffman, Mark TI HPV16 Sublineage Associations With Histology-Specific Cancer Risk Using HPV Whole-Genome Sequences in 3200 Women SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID HUMAN-PAPILLOMAVIRUS TYPE-16; ASIAN-AMERICAN VARIANTS; LONG CONTROL REGION; CERVICAL-CANCER; POPULATION; PERSISTENCE; WORLDWIDE; NEOPLASIA; LINEAGES; CYTOLOGY AB Background: HPV16 is a common sexually transmitted infection although few infections lead to cervical precancer/cancer; we cannot distinguish nor mechanistically explain why only certain infections progress. HPV16 can be classified into four main evolutionary-derived variant lineages (A, B, C, D) that have been previously suggested to have varying disease risks. Methods: We used a high-throughput HPV16 whole-genome sequencing assay to investigate variant lineage risk among 3215 HPV16-infected women. Using sublineages A1/A2 as the reference, we assessed all variant lineage associations with infection outcome over three or more years of follow-up: 1107 control subjects (= 4 + 3), while standard biopsy detected 469 cases of prostate cancer, of which 122 (26.5%) were high grade. The percentage of biopsy cores positive for prostate cancer, irrespective of grade, was statistically significantly higher for targeted than for standard biopsies (27.9% vs 13.5%, respectively, P < .001), with 11.5 targeted cores vs 26.2 standard cores utilized per diagnosis of prostate cancer. For detection of high-grade cancer, 30.7 targeted vs 100.8 standard cores were utilized per diagnosis. Conclusion: In men with MR-visible prostate lesions, targeted biopsy is more efficient than standard biopsy, diagnosing a similar number of cancer cases and more high-grade cases while sampling 56.1% fewer biopsy cores. C1 [Siddiqui, M. Minhaj; George, Arvin K.; Rubin, Rachel; Rais-Bahrami, Soroush; Wood, Bradford J.; Pinto, Peter A.] NCI, Urol Oncol Branch, NIH, 10 Ctr Dr,MSC 1210,Bldg 10,CRC Room 2W-5940, Bethesda, MD 20892 USA. [Turkbey, Baris; Choyke, Peter L.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Parnes, Howard L.] NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Merino, Maria J.] NCI, Pathol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Wood, Bradford J.; Pinto, Peter A.] NCI, Ctr Intervent Oncol, Dept Radiol & Imaging Sci, NIH, Bethesda, MD 20892 USA. [Simon, Richard M.] NCI, Biometr Res Branch, Div Canc Treatment & Diag, NIH, Rockville, MD USA. [Siddiqui, M. Minhaj] Univ Maryland, Dept Surg, Div Urol, Baltimore, MD 21201 USA. [Rais-Bahrami, Soroush] Univ Alabama Birmingham, Dept Urol, Birmingham, AL USA. [Rais-Bahrami, Soroush] Univ Alabama Birmingham, Dept Radiol, Birmingham, AL USA. RP Pinto, PA (reprint author), NCI, Urol Oncol Branch, NIH, 10 Ctr Dr,MSC 1210,Bldg 10,CRC Room 2W-5940, Bethesda, MD 20892 USA. EM pintop@mail.nih.gov OI Rais-Bahrami, Soroush/0000-0001-9466-9925 FU Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research, and Center for Interventional Oncology FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research, and Center for Interventional Oncology. The NIH, Philips Healthcare, and Invivo have a cooperative research and development agreement. The NIH, Philips Healthcare, and Invivo share intellectual property in the field. NR 15 TC 2 Z9 3 U1 3 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD SEP PY 2016 VL 108 IS 9 AR djw039 DI 10.1093/jnci/djw039 PG 7 WC Oncology SC Oncology GA DZ0KH UT WOS:000385527000002 ER PT J AU Asare, AL Carey, VJ Rotrosen, D Nepom, GT AF Asare, Adam L. Carey, Vincent J. Rotrosen, Daniel Nepom, Gerald T. TI Clinical trial data access: Opening doors with TrialShare SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Clinical trials; data sharing; clinical immunology; immune tolerance C1 [Asare, Adam L.; Nepom, Gerald T.] Immune Tolerance Network, Bethesda, MD USA. [Carey, Vincent J.] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA USA. [Rotrosen, Daniel] NIAID, NIH, Bethesda, MD 20892 USA. [Nepom, Gerald T.] Benaroya Res Inst, Seattle, WA USA. RP Nepom, GT (reprint author), Benaroya Res Inst, Immune Tolerance Network, 1201 Ninth Ave, Seattle, WA 98101 USA. EM nepom@benaroyaresearch.org OI Nepom, Gerald/0000-0002-8063-1464 FU National Institutes of Health [UM1AI109565] FX ITN Trialshare is supported by National Institutes of Health award no. UM1AI109565 (Immune Tolerance Network). The contents of this article are solely the responsibility of the authors and do not necessarily represent the views of the National Institutes of Health. NR 9 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD SEP PY 2016 VL 138 IS 3 BP 724 EP 726 DI 10.1016/j.jaci.2016.05.034 PG 3 WC Allergy; Immunology SC Allergy; Immunology GA DY9ZM UT WOS:000385496000007 PM 27474121 ER PT J AU Caucheteux, SM Jane, HL Guo, LY Bhattacharyya, N Crank, M Collins, MT Paul, WE AF Caucheteux, Stephan M. Jane Hu-Li Guo, Liying Bhattacharyya, Nisan Crank, Michelle Collins, Michael T. Paul, William E. TI IL-1 beta enhances inflammatory T(H)2 differentiation SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Letter ID CD4 T-CELLS; IL-1 ACTS; TH2 CELLS; INDUCTION; GAMMA C1 [Caucheteux, Stephan M.; Jane Hu-Li; Guo, Liying; Crank, Michelle; Paul, William E.] NIAID, Immunol Lab, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Caucheteux, Stephan M.; Jane Hu-Li; Guo, Liying; Crank, Michelle; Paul, William E.] NIH, Div Intramural Res, Bldg 10, Bethesda, MD 20892 USA. [Bhattacharyya, Nisan; Collins, Michael T.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. [Crank, Michelle] NIH, Viral Pathogenesis Lab, Vaccine Res Ctr, Bldg 10, Bethesda, MD 20892 USA. RP Caucheteux, SM (reprint author), NIAID, Immunol Lab, 9000 Rockville Pike, Bethesda, MD 20892 USA.; Caucheteux, SM (reprint author), NIH, Div Intramural Res, Bldg 10, Bethesda, MD 20892 USA. EM caucheteuxs@cardiff.ac.uk FU Intramural NIH HHS [Z01 AI000493-21] NR 8 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD SEP PY 2016 VL 138 IS 3 BP 898 EP 901 DI 10.1016/j.jaci.2016.02.033 PG 5 WC Allergy; Immunology SC Allergy; Immunology GA DY9ZM UT WOS:000385496000028 PM 27212084 ER PT J AU Lovell, JP Foruraghi, L Freeman, AF Uzel, G Zerbe, CS Su, H Hsu, AP Holland, SM AF Lovell, Jana P. Foruraghi, Ladan Freeman, Alexandra F. Uzel, Gulbu Zerbe, Christa S. Su, Helen Hsu, Amy P. Holland, Steven M. TI Persistent nodal histoplasmosis in nuclear factor kappa B essential modulator deficiency: Report of a case and review of infection in primary immunodeficiencies SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Letter C1 [Lovell, Jana P.; Foruraghi, Ladan; Freeman, Alexandra F.; Uzel, Gulbu; Zerbe, Christa S.; Hsu, Amy P.; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Su, Helen] NIAID, Host Def Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Holland, SM (reprint author), NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM smh@nih.gov NR 9 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD SEP PY 2016 VL 138 IS 3 BP 903 EP 905 DI 10.1016/j.jaci.2016.02.040 PG 3 WC Allergy; Immunology SC Allergy; Immunology GA DY9ZM UT WOS:000385496000030 PM 27266944 ER PT J AU Tota, JE Ramanakumar, AV Villa, LL Richardson, H Burchell, AN Coutlee, F Franco, EL AF Tota, Joseph E. Ramanakumar, Agnihotram V. Villa, Luisa L. Richardson, Harriet Burchell, Ann N. Coutlee, Francois Franco, Eduardo L. TI Cervical Infection With Vaccine-Associated Human Papillomavirus (HPV) Genotypes as a Predictor of Acquisition and Clearance of Other HPV Infections SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE human papillomavirus; vaccination; type replacement; type competition; females ID POLYMERASE-CHAIN-REACTION; REPLACEMENT POSTVACCINATION; PARTICLE VACCINE; CONSENSUS PCR; CONDOM USE; FOLLOW-UP; PERSISTENCE; PREVALENCE; WOMEN; CLASSIFICATION AB Background. Recent birth cohorts vaccinated against human papillomavirus (HPV) may be protected against up to 4 genotypes (HPV-6, -11, -16, and -18). If natural competition exists between these and other HPV types, then the prevalence of other types may increase after vaccination. Methods.aEuro integral Cohort information from 3 studies was used to compare acquisition and clearance of 30 different HPV types (individually and grouped by species), according to infection status with vaccine-targeted types at baseline and the time of the index infection, respectively. Hazard ratios (HRs) were adjusted for predictors of multiple-type infection. Results.aEuro integral Among 3200 females across all studies, 857 were infected with HPV at baseline, and 994 acquired new infections during follow-up. Females infected with HPV-16 were at higher risk of acquiring other alpha-9 HPV types (HR, 1.9; 95% confidence interval [CI], 1.2-3.0) but at similar risk of clearing existing alpha-9 HPV infections (HR, 0.9; 95% CI, .7-1.3). Females infected with vaccine-targeted types were generally at higher risk of acquiring additional types (HRs, > 1.0) and at equal risk of clearing existing infections. Accounting for multiple comparisons, none of the HRs of < 1.0 or > 1.0 were statistically significant in our analyses of acquisition or clearance. Conclusions.aEuro integral Vaccine-targeted HPV types do not appear to compete with other types, suggesting that HPV type replacement is unlikely to occur. C1 [Tota, Joseph E.; Ramanakumar, Agnihotram V.; Burchell, Ann N.; Franco, Eduardo L.] McGill Univ, Dept Oncol, Div Canc Epidemiol, Montreal, PQ H3A 2T5, Canada. [Tota, Joseph E.; Franco, Eduardo L.] McGill Univ, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ H3A 2T5, Canada. [Coutlee, Francois] Univ Montreal, Dept Microbiol & Infectiol, Montreal, PQ H3C 3J7, Canada. [Richardson, Harriet] Queens Univ, Dept Community Hlth & Epidemiol, Kingston, ON, Canada. [Burchell, Ann N.] St Michaels Hosp, Dept Family & Community Med, Toronto, ON, Canada. [Burchell, Ann N.] Li Ka Shing Knowledge Inst, Ctr Res Inner City Hlth, Toronto, ON, Canada. [Tota, Joseph E.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Rm 6E228, Rockville, MD 20850 USA. [Villa, Luisa L.] Univ Sao Paulo, Sch Med, Dept Radiol & Oncol, BR-05508 Sao Paulo, Brazil. RP Tota, JE (reprint author), NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Rm 6E228, Rockville, MD 20850 USA. EM joseph.tota@nih.gov OI Franco, Eduardo/0000-0002-4409-8084 FU Canadian Institutes of Health Research [MA13647, MOP49396, MOP53111, MOP68893, CRN83320]; National Institutes of Health [CA70269, AI73889]; Ludwig Institute for Cancer Research; Society of Gynecologic Oncology of Canada; Canadian Institutes of Health Research FX This work was supported by the Canadian Institutes of Health Research (grants MA13647, MOP49396, MOP53111, MOP68893, and CRN83320 to E. L. F.), the National Institutes of Health (grants CA70269 and AI73889 to E. L. F.), the Ludwig Institute for Cancer Research (intramural grant to L. L. V. and E. L. F.), the Society of Gynecologic Oncology of Canada, and the Canadian Institutes of Health Research (new investigator award to A. N. B.). NR 38 TC 0 Z9 0 U1 4 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD SEP 1 PY 2016 VL 214 IS 5 BP 676 EP 684 DI 10.1093/infdis/jiw215 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DY7YY UT WOS:000385346400004 PM 27256157 ER PT J AU Kutty, G Davis, AS Ferreyra, GA Qiu, J Huang, DW Sassi, M Bishop, L Handley, G Sherman, B Lempicki, R Kovacs, JA AF Kutty, Geetha Davis, A. Sally Ferreyra, Gabriela A. Qiu, Ju Huang, Da Wei Sassi, Monica Bishop, Lisa Handley, Grace Sherman, Brad Lempicki, Richard Kovacs, Joseph A. TI beta-Glucans Are Masked but Contribute to Pulmonary Inflammation During Pneumocystis Pneumonia SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Pneumocystis; glucan; cell wall; Msg ID MAJOR SURFACE GLYCOPROTEIN; ACQUIRED-IMMUNODEFICIENCY-SYNDROME; LARGE GENE LISTS; CARINII-PNEUMONIA; FUNGAL-INFECTION; HOST-DEFENSE; DECTIN-1; RESPONSES; RECEPTOR; MICE AB beta-glucans, which can activate innate immune responses, are a major component in the cell wall of the cyst form of Pneumocystis. In the current study, we examined whether beta-1,3-glucans are masked by surface proteins in Pneumocystis and what role beta-glucans play in Pneumocystis-associated inflammation. For 3 species, including Pneumocystis jirovecii, which causes Pneumocystis pneumonia in humans, Pneumocystis carinii, and Pneumocystis murina, beta-1,3-glucans were masked in most organisms, as demonstrated by increased exposure following trypsin treatment. Using quantitative polymerase chain reaction and microarray techniques, we demonstrated in a mouse model of Pneumocystis pneumonia that treatment with caspofungin, an inhibitor of beta-1,3-glucan synthesis, for 21 days decreased expression of a broad panel of inflammatory markers, including interferon gamma, tumor necrosis factor alpha, interleukin 1 beta, interleukin 6, and multiple chemokines/chemokine ligands. Thus, beta-glucans in Pneumocystis cysts are largely masked, which likely decreases innate immune activation; this mechanism presumably was developed for interactions with immunocompetent hosts, in whom organism loads are substantially lower. In immunosuppressed hosts with a high organism burden, organism death and release of glucans appears to be an important contributor to deleterious host inflammatory responses. C1 [Kutty, Geetha; Ferreyra, Gabriela A.; Sassi, Monica; Bishop, Lisa; Handley, Grace; Kovacs, Joseph A.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Qiu, Ju; Huang, Da Wei; Sherman, Brad; Lempicki, Richard] Frederick Natl Lab Canc Res, Leidos Biomed Res, Lab Immunopathogenesis & Bioinformat, Bethesda, MD USA. [Davis, A. Sally] Kansas State Univ, Coll Vet Med, Diagnost Med Pathobiol, Manhattan, KS 66506 USA. RP Kovacs, JA (reprint author), Bldg 10,Rm 2C145,MSC 1662, Bethesda, MD 20892 USA. EM jkovacs@nih.gov RI Leidos, LHRI/C-2876-2017 FU National Institutes of Health Clinical Center; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work was supported by the Intramural Research Program, National Institutes of Health Clinical Center; and the National Cancer Institute, National Institutes of Health (contract HHSN261200800001E). NR 44 TC 0 Z9 0 U1 4 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD SEP 1 PY 2016 VL 214 IS 5 BP 782 EP 791 DI 10.1093/infdis/jiw249 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DY7YY UT WOS:000385346400017 PM 27324243 ER PT J AU Moore, SM Schiffman, R Waldrop-Valverde, D Redeker, NS McCloskey, DJ Kim, MT Heitkemper, MM Guthrie, BJ Dorsey, SG Docherty, SL Barton, D Bailey, DE Austin, JK Grady, P AF Moore, Shirley M. Schiffman, Rachel Waldrop-Valverde, Drenna Redeker, Nancy S. McCloskey, Donna Jo Kim, Miyong T. Heitkemper, Margaret M. Guthrie, Barbara J. Dorsey, Susan G. Docherty, Sharron L. Barton, Debra Bailey, Donald E., Jr. Austin, Joan K. Grady, Patricia TI Recommendations of Common Data Elements to Advance the Science of Self-Management of Chronic Conditions SO JOURNAL OF NURSING SCHOLARSHIP LA English DT Article DE Common data elements; research data harmonization; self-management ID PATIENT ACTIVATION MEASURE; RANDOMIZED-TRIAL; HEALTH; CARE; OUTCOMES; DISEASE; INDIVIDUALS; MECHANISMS; EDUCATION; FAILURE AB PurposeCommon data elements (CDEs) are increasingly being used by researchers to promote data sharing across studies. The purposes of this article are to (a) describe the theoretical, conceptual, and definition issues in the development of a set of CDEs for research addressing self-management of chronic conditions; (b) propose an initial set of CDEs and their measures to advance the science of self-management; and (c) recommend implications for future research and dissemination. Design and MethodsBetween July 2014 and December 2015 the directors of the National Institute of Nursing Research (NINR)-funded P20 and P30 centers of excellence and NINR staff met in a series of telephone calls and a face-to-face NINR-sponsored meeting to select a set of recommended CDEs to be used in self-management research. A list of potential CDEs was developed from examination of common constructs in current self-management frameworks, as well as identification of variables frequently used in studies conducted in the centers of excellence. FindingsThe recommended CDEs include measures of three self-management processes: activation, self-regulation, and self-efficacy for managing chronic conditions, and one measure of a self-management outcome, global health. ConclusionsThe self-management of chronic conditions, which encompasses a considerable number of processes, behaviors, and outcomes across a broad range of chronic conditions, presents several challenges in the identification of a parsimonious set of CDEs. This initial list of recommended CDEs for use in self-management research is provisional in that it is expected that over time it will be refined. Comment and recommended revisions are sought from the research and practice communities. Clinical RelevanceThe use of CDEs can facilitate generalizability of research findings across diverse population and interventions. C1 [Moore, Shirley M.] Case Western Reserve Univ, Frances Payne Bolton Sch Nursing, Nursing, 10900 Euclid Ave, Cleveland, OH 44106 USA. [Schiffman, Rachel] Univ Wisconsin, Res, Milwaukee, WI 53201 USA. [Waldrop-Valverde, Drenna] Emory Univ, Nell Hodgson Woodruff Sch Nursing, Atlanta, GA 30322 USA. [Redeker, Nancy S.] Yale Univ, Nursing, New Haven, CT USA. [Redeker, Nancy S.] Yale Univ, Sect Pulm Crit Care & Sleep Med, New Haven, CT USA. [McCloskey, Donna Jo; Austin, Joan K.; Grady, Patricia] NINR, NIH, Bethesda, MD 20892 USA. [Kim, Miyong T.] Univ Texas Austin, Community Hlth Engagement, Austin, TX 78712 USA. [Heitkemper, Margaret M.] Univ Washington, Dept Biobehav Nursing & Hlth Syst, Seattle, WA 98195 USA. [Guthrie, Barbara J.] Northwestern Univ, PhD Program, Boston, MA USA. [Dorsey, Susan G.] Univ Maryland, Dept Pain & Translat Symptom Sci, Baltimore, MD 21201 USA. [Docherty, Sharron L.] Duke Univ, Sch Nursing, Durham, NC USA. [Docherty, Sharron L.] Duke Univ, Dept Pediat, Sch Med, Durham, NC 27706 USA. [Docherty, Sharron L.] Duke Univ, Ctr Cognit Affect Symptom Sci P30, Durham, NC 27706 USA. [Barton, Debra] Univ Michigan, Oncol Nursing, Ann Arbor, MI 48109 USA. [Bailey, Donald E., Jr.] Duke Univ, Durham, NC USA. [Austin, Joan K.] Indiana Univ, Sch Nursing, Indianapolis, IN 46204 USA. RP Moore, SM (reprint author), Case Western Reserve Univ, Frances Payne Bolton Sch Nursing, Nursing, 10900 Euclid Ave, Cleveland, OH 44106 USA. EM smm8@case.edu RI Redeker, Nancy/Q-8252-2016 OI Redeker, Nancy/0000-0001-7817-2708 FU [P20NR015339]; [P30NR015326]; [P20NR014126]; [P20NR015320]; [P30NR014129]; [P30NR011396]; [1P30NR014139] FX This work was supported through the following grants: P20NR015339; P30NR015326; P20NR014126; P20NR015320; P30NR014129; P30NR011396; and 1P30NR014139. NR 39 TC 0 Z9 0 U1 3 U2 3 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 SEP PY 2016 VL 48 IS 5 BP 437 EP 447 DI 10.1111/jnu.12233 PG 11 WC Nursing SC Nursing GA DW4IV UT WOS:000383607300002 PM 27486851 ER PT J AU Scheiermann, J Klinman, DM AF Scheiermann, Julia Klinman, Dennis M. TI Suppressive oligonucleotides inhibit inflammation in a murine model of mechanical ventilator induced lung injury SO JOURNAL OF THORACIC DISEASE LA English DT Article DE Mechanical ventilation (MV); ventilator-induced lung injury (VILI); macrophage, polymorphonuclear cell (PMN); suppressive oligonucleotide (Sup ODN) ID RESPIRATORY-DISTRESS-SYNDROME; BRONCHOALVEOLAR LAVAGE FLUID; INDUCED IMMUNE ACTIVATION; IMMUNOSUPPRESSIVE OLIGONUCLEOTIDES; MACROPHAGE ACTIVATION; ALVEOLAR MACROPHAGES; CANCER-PATIENTS; HEALTHY MICE; OLIGODEOXYNUCLEOTIDES; PULMONARY AB Background: Mechanical ventilation (MV) is commonly used to improve blood oxygenation in critically ill patients and for general anesthesia. Yet the cyclic mechanical stress induced at even moderate ventilation volume settings [tidal volume (Vt) < 10 mL/kg] can injure the lungs and induce an inflammatory response. This work explores the effect of treatment with suppressive oligonucleotides (Sup ODN) in a mouse model of ventilator-induced lung injury (VILI). Methods: Balb/cJ mice were mechanically ventilated for 4 h using clinically relevant Vt and a positive end-expiratory pressure of 3 cmH(2)O under 2-3% isoflurane anesthesia. Lung tissue and bronchoalveolar lavage fluid were collected to assess lung inflammation and lung function was monitored using a FlexiVent((R)). Results: MV induced significant pulmonary inflammation characterized by the influx and activation of CD11c(+)/F4/80(+) macrophages and CD11b(+)/Ly6G(+) polymorphonuclear cells into the lung and bronchoalveolar lavage fluid. The concurrent administration of Sup ODN attenuated pulmonary inflammation as evidenced by reduced cellular influx and production of inflammatory cytokines. Oligonucleotide treatment did not worsen lung function as measured by static compliance or resistance. Conclusions: Treatment with Sup ODN reduces the lung injury induced by MV in mice. C1 [Scheiermann, Julia; Klinman, Dennis M.] Frederick Natl Lab Canc Res, Canc & Inflammat Program, Frederick, MD 21702 USA. RP Klinman, DM (reprint author), Frederick Natl Lab Canc Res, Bldg 567 Rm 205, Frederick, MD 21702 USA. EM klinmand@mail.nih.gov FU Intramural Research Program of the NIH, NCI FX Thanks to Dr. Springer and Michele Allen from the murine phenotyping core (Bethesda, MD, USA) for their help and support during the project. This manuscript was supported by the Intramural Research Program of the NIH, NCI. NR 50 TC 0 Z9 0 U1 1 U2 1 PU PIONEER BIOSCIENCE PUBL CO PI HONG KONG PA 9A GOLD SHINE TOWER, 346-348 QUEEN'S RD CENTRAL, SHEUNG WAN, HONG KONG, 00000, PEOPLES R CHINA SN 2072-1439 EI 2077-6624 J9 J THORAC DIS JI J. Thorac. Dis. PD SEP PY 2016 VL 8 IS 9 BP 2434 EP 2443 DI 10.21037/jtd.2016.08.18 PG 10 WC Respiratory System SC Respiratory System GA DZ1RA UT WOS:000385615400100 PM 27746995 ER PT J AU Ferrucci, L Cooper, R Shardell, M Simonsick, EM Schrack, JA Kuh, D AF Ferrucci, Luigi Cooper, Rachel Shardell, Michelle Simonsick, Eleanor M. Schrack, Jennifer A. Kuh, Diana TI Age-Related Change in Mobility: Perspectives From Life Course Epidemiology and Geroscience SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Review DE Epidemiology; Geroscience; Mobility; Life course ID BRITISH BIRTH COHORT; EARLY OLD-AGE; SERUM MICRONUTRIENT CONCENTRATIONS; WALKING INCHIANTI TOOLKIT; PERIPHERAL-NERVE FUNCTION; LOWER-EXTREMITY FUNCTION; PHYSICAL PERFORMANCE; MUSCLE STRENGTH; BODY-COMPOSITION; GRIP STRENGTH AB Mobility is the most studied and most relevant physical ability affecting quality of life with strong prognostic value for disability and survival. Natural selection has built the "engine" of mobility with great robustness, redundancy, and functional reserve. Efficient patterns of mobility can be acquired during development even by children affected by severe impairments. Analogously, age-associated impairments in mobility-related physiological systems are compensated and overt limitations of mobility only occur when the severity can no longer be compensated. Mobility loss in older persons usually results from multiple impairments in the central nervous system, muscles, joints, and energetic and sensory physiological systems. Early preclinical changes in these physiological systems that precede mobility loss have been poorly studied. Peak performance, rate of decline, compensatory behaviors, or subclinical deterioration of physiological resources may cumulatively influence both timing of mobility loss and chances of recovery, but their role as risk factors has not been adequately characterized. Understanding the natural history of these early changes and intervening on them would likely be the most effective strategy to reduce the burden of disability in the population. For example, young women with low bone peak mass could be counseled to start strength resistance exercise to reduce their high risk of developing osteoporosis and fracture later in life. Expanding this approach to other physiological domains requires collecting and interpreting data from life course epidemiological studies, establishing normative measures of mobility, physical function, and physical activity, and connecting them with life course trajectories of the mobility-relevant physiological domains. C1 [Ferrucci, Luigi; Shardell, Michelle; Simonsick, Eleanor M.] NIA, 251 BayView Blvd, Baltimore, MD 21224 USA. [Cooper, Rachel; Kuh, Diana] UCL, Unit Lifelong Hlth & Ageing, MRC, London, England. [Schrack, Jennifer A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. RP Ferrucci, L (reprint author), NIA, 251 BayView Blvd, Baltimore, MD 21224 USA. EM ferruccilu@mail.nih.gov FU Intramural Research Program of the National Institute on Aging, NIH, Baltimore, MD; UK Medical Research Council [MC_UU_12019/4]; National Institute on Aging (NIH, NIA, Bethesda, MA); [K01AG048765]; [HHSN311210300177P] FX This study was supported in part by the Intramural Research Program of the National Institute on Aging, NIH, Baltimore, MD.R.C. and D.K. receive financial support from the UK Medical Research Council (programme code: MC_UU_12019/4). J.A.S is supported by K01AG048765 and HHSN311210300177P. The InCHIANTI Study (Invecchiare in Chianti) was supported by a grant from the National Institute on Aging (NIH, NIA, Bethesda, MA) and co-ordinated by the Tuscany Regional Health Agency in partnership with the Florence Health Care Agency, the local Administrators and the primary care physicians of Greve in Chianti and Bagno a Ripoli. NR 134 TC 4 Z9 4 U1 11 U2 11 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD SEP PY 2016 VL 71 IS 9 BP 1184 EP 1194 DI 10.1093/gerona/glw043 PG 11 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA DY5LA UT WOS:000385139900009 PM 26975983 ER PT J AU Fabbri, E An, Y Gonzalez-Freire, M Zoli, M Maggio, M Studenski, SA Egan, JM Chia, CW Ferrucci, L AF Fabbri, Elisa An, Yang Gonzalez-Freire, Marta Zoli, Marco Maggio, Marcello Studenski, Stephanie A. Egan, Josephine M. Chia, Chee W. Ferrucci, Luigi TI Bioavailable Testosterone Linearly Declines Over A Wide Age Spectrum in Men and Women From The Baltimore Longitudinal Study of Aging SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Aging; Testosterone; Trajectories; Men; Women ID HORMONE-BINDING GLOBULIN; COMMUNITY-DWELLING MEN; BODY-FAT DISTRIBUTION; BONE-MINERAL DENSITY; LIFE-STYLE FACTORS; GROWTH-FACTOR-I; SERUM TESTOSTERONE; SEX-HORMONES; OLDER MEN; WAIST CIRCUMFERENCE AB Age-related changes in testosterone levels in older persons and especially in women have not been fully explored. The objective of this study was to describe age-related trajectories of total testosterone (TT), ammonium sulfate precipitation-measured bioavailable testosterone (mBT), and sex hormone-binding glycoprotein (SHBG) in men and women from the Baltimore Longitudinal Study of Aging, with special focus on the oldest adults. Participants included 788 White men and women aged 30-96 years with excellent representation of old and oldest old, who reported not taking medications known to interfere with testosterone. Longitudinal data were included when available. TT, mBT, and SHBG were assayed. Age-related trajectories of mBT were compared with those obtained using calculated bioavailable testosterone (cBT). Generalized least square models were performed to describe age-related trajectories of TT, mBT, and SHBG in men and women. mBT linearly declines over the life span and even at older ages in both sexes. In men, TT remains quite stable until the age of 70 years and then declines at older ages, whereas in women TT progressively declines in premenopausal years and slightly increases at older ages. Differences in age-related trajectories between total and bioavailable testosterone are only partially explained by age changes in SHBG, whose levels increases at accelerated rates in old persons. Noteworthy, although mBT and cBT highly correlated with one another, mBT is a much stronger correlate of chronological age than cBT. In both men and women, mBT linearly declines over the life span and even at old ages. Its relationship with age-related phenotypes should be further investigated. C1 [Fabbri, Elisa; Gonzalez-Freire, Marta; Studenski, Stephanie A.; Ferrucci, Luigi] NIA, Translat Gerontol Branch, Longitudinal Study Sect, Intramural Res Program,NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. [Fabbri, Elisa; Zoli, Marco] Univ Bologna, Dept Med & Surg Sci, I-40126 Bologna, Italy. [An, Yang] NIA, Lab Behav Neurosci, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Maggio, Marcello] Univ Parma, Dept Clin & Expt Med, I-43100 Parma, Italy. [Egan, Josephine M.; Chia, Chee W.] NIA, Clin Invest Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Fabbri, E (reprint author), NIA, Translat Gerontol Branch, Longitudinal Study Sect, Intramural Res Program,NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM elisa.fabbri@nih.gov FU Intramural Research Program of NIH, National Institute on Aging FX This research was supported by the Intramural Research Program of NIH, National Institute on Aging. Data for these analyses were obtained from the Baltimore Longitudinal Study of Aging, a study performed by the National Institute on Aging. NR 63 TC 0 Z9 0 U1 2 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD SEP PY 2016 VL 71 IS 9 BP 1202 EP 1209 DI 10.1093/gerona/glw021 PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA DY5LA UT WOS:000385139900011 PM 26921861 ER PT J AU Driscoll, I Gaussoin, SA Wassertheil-Smoller, S Limacher, M Casanova, R Yaffe, K Resnick, SM Espeland, MA AF Driscoll, Ira Gaussoin, Sarah A. Wassertheil-Smoller, Sylvia Limacher, Marian Casanova, Ramon Yaffe, Kristine Resnick, Susan M. Espeland, Mark A. TI Obesity and Structural Brain Integrity in Older Women: The Women's Health Initiative Magnetic Resonance Imaging Study SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Brain volume; Lesion volume; White matter hyperintensities; Aging; BMI ID BODY-MASS INDEX; POSTMENOPAUSAL HORMONE-THERAPY; VASCULAR RISK-FACTORS; WHITE-MATTER LESIONS; MIDDLE-AGED ADULTS; LATE-LIFE OBESITY; ALZHEIMER-DISEASE; WHIMS-MRI; FOLLOW-UP; MIDLIFE OBESITY AB Midlife obesity has been linked to age-related brain atrophy and risk of dementia, but the relationships are less clear for older individuals. These associations may be explained by changes in appetite or metabolism in the dementia prodrome; thus, prospective studies with adequate follow-up are needed. We examined the associations that obesity (body mass index, BMI) and change in BMI over an average of 6.6 (1.0-9.1) years have with global and regional brain and white matter lesion volumes in a sample of 1,366 women aged 65-80. Least square means for regional brain volumes and white matter lesion loads for women grouped by BMI and changes in BMI were generated from multivariable linear models with and without adjustment for demographic and health covariates. Both global obesity and increase in BMI were associated with lower cerebrospinal fluid and higher specific brain volumes (ps < .05), after controlling for diabetes and other cerebrovascular disease risk factors. Obesity, but not change in BMI, predicted lower lesion loads for the total, parietal, and occipital white matter (ps < .05). Obesity in this cohort is associated with less brain atrophy and lower ischemic lesion loads. The findings are consistent with our previous report of worse cognitive performance in association with weight loss (probably not due to frailty) in this cohort and in line with the idea of the "obesity paradox" as differences in dementia risk vary across time, whereby midlife obesity seems to be a predictor of dementia, whereas weight loss seems to be a better predictor at older ages. C1 [Driscoll, Ira] Univ Wisconsin, Dept Psychol, 224 Garland Hall,2441 E Hartford Ave, Milwaukee, WI 53211 USA. [Gaussoin, Sarah A.; Casanova, Ramon; Espeland, Mark A.] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC USA. [Wassertheil-Smoller, Sylvia] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Limacher, Marian] Univ Florida, Coll Med, Gainesville, FL USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat Neurol & Epidemiol & Biostat, San Francisco, CA 94143 USA. [Resnick, Susan M.] NIA, Lab Behav Neurosci, NIH, Baltimore, MD 21224 USA. RP Driscoll, I (reprint author), Univ Wisconsin, Dept Psychol, 224 Garland Hall,2441 E Hartford Ave, Milwaukee, WI 53211 USA. EM driscoli@uwm.edu FU National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C]; Wyeth Pharmaceuticals, Inc., St. Davids, Pennsylvania; National Institute on Aging [K99R00 AG032361] FX The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. The WHIMS was funded in part by Wyeth Pharmaceuticals, Inc., St. Davids, Pennsylvania. This work was supported by K99R00 AG032361 (National Institute on Aging) to I.D. NR 40 TC 1 Z9 1 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD SEP PY 2016 VL 71 IS 9 BP 1216 EP 1222 DI 10.1093/gerona/glw023 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA DY5LA UT WOS:000385139900013 ER PT J AU Nahin, RL Boineau, R Khalsa, PS Stussman, BJ Weber, WJ AF Nahin, Richard L. Boineau, Robin Khalsa, Partap S. Stussman, Barbara J. Weber, Wendy J. TI Evidence-Based Evaluation of Complementary Health Approaches for Pain Management in the United States SO MAYO CLINIC PROCEEDINGS LA English DT Article ID LOW-BACK-PAIN; RANDOMIZED-CONTROLLED-TRIAL; CHRONIC NECK PAIN; SPINAL MANIPULATIVE THERAPY; TENSION-TYPE HEADACHE; PILOT CLINICAL-TRIAL; IYENGAR YOGA THERAPY; SELF-CARE BOOK; KNEE OSTEOARTHRITIS; TAI-CHI AB Although most pain is acute and resolves within a few days or weeks, millions of Americans have persistent or recurring pain that may become chronic and debilitating. Medications may provide only partial relief from this chronic pain and can be associated with unwanted effects. As a result, many individuals turn to complementary health approaches as part of their pain management strategy. This article examines the clinical trial evidence for the efficacy and safety of several specific approaches-acupuncture, manipulation, massage therapy, relaxation techniques including meditation, selected natural product supplements (chondroitin, glucosamine, methylsulfonylmethane, S-adenosylmethionine), tai chi, and yoga-as used to manage chronic pain and related disability associated with back pain, fibromyalgia, osteoarthritis, neck pain, and severe headaches or migraines. (C) 2016 Mayo Foundation for Medical Education and Research C1 [Nahin, Richard L.; Boineau, Robin; Khalsa, Partap S.; Stussman, Barbara J.; Weber, Wendy J.] NIH, Natl Ctr Complementary & Integrat Hlth, 6707 Democracy Blvd,Ste 401, Bethesda, MD 20892 USA. RP Nahin, RL (reprint author), NIH, Natl Ctr Complementary & Integrat Hlth, 6707 Democracy Blvd,Ste 401, Bethesda, MD 20892 USA. EM NahinR@mail.nih.gov FU Intramural NIH HHS [Z99 AT999999] NR 134 TC 6 Z9 6 U1 25 U2 42 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0025-6196 EI 1942-5546 J9 MAYO CLIN PROC JI Mayo Clin. Proc. PD SEP PY 2016 VL 91 IS 9 BP 1292 EP 1306 DI 10.1016/j.mayocp.2016.06.007 PG 15 WC Medicine, General & Internal SC General & Internal Medicine GA DZ6AK UT WOS:000385943700019 PM 27594189 ER PT J AU Vanegas-Arroyave, N Zaghloul, KA Hallett, M Lungu, C AF Vanegas-Arroyave, Nora Zaghloul, Kareem A. Hallett, Mark Lungu, Codrin TI Leg Movements During General Anesthesia SO MOVEMENT DISORDERS CLINICAL PRACTICE LA English DT Article DE leg movements; Parkinson disease; general anesthesia ID SLEEP AB The authors describe a case of atypical leg movements during general anesthesia. The differential diagnosis of this presentation includes rhythmic movement phenomena, such as leg myoclonus, alternating leg muscle activation, and periodic leg movements of sleep. The patient had a history of tremor-predominant Parkinson's disease since age 43 years. He underwent deep brain stimulation surgery at the National Institutes of Health after an overnight dopaminergic medication withdrawal. Shortly after anesthetic induction, he developed periodic, involuntary movements of his legs that were stereotyped, bilateral and synchronous. The movements were characterized by partial flexion of the ankle, knee, and hip for 3 or 4 seconds at intervals of 5 to 10 seconds. After cessation of the anesthetic infusion, his movements promptly subsided. The total duration of the event was approximately 2 minutes. There were no residual motor or sensory deficits on neurologic examination. Although the exact mechanism responsible for the described observation requires further investigation, this phenomenology should be known, because its occurrence under intravenous anesthetics could be confused for other, pathophysiologically different phenomena. C1 [Vanegas-Arroyave, Nora] Columbia Univ Coll Phys & Surg, Dept Neurol, New York, NY 10032 USA. [Zaghloul, Kareem A.] NINDS, Surg Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Lungu, Codrin] NINDS, Off Clin Director, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Vanegas-Arroyave, N (reprint author), 710 W168th St,NI-3, New York, NY 10032 USA. EM nv2281@cumc.columbia.edu NR 9 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2330-1619 J9 MOV DISORD CLIN PRAC JI MOV. DISORD. CLIN. PRACT. PD SEP-OCT PY 2016 VL 3 IS 5 BP 510 EP 512 DI 10.1002/mdc3.12310 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA DY9BD UT WOS:000385426200013 PM 28239614 ER PT J AU Barton, K Hiener, B Winckelmann, A Rasmussen, TA Shao, W Byth, K Lanfear, R Solomon, A McMahon, J Harrington, S Buzon, M Lichterfeld, M Denton, PW Olesen, R Ostergaard, L Tolstrup, M Lewin, SR Sogaard, OS Palmer, S AF Barton, Kirston Hiener, Bonnie Winckelmann, Anni Rasmussen, Thomas Aagaard Shao, Wei Byth, Karen Lanfear, Robert Solomon, Ajantha McMahon, James Harrington, Sean Buzon, Maria Lichterfeld, Mathias Denton, Paul W. Olesen, Rikke Ostergaard, Lars Tolstrup, Martin Lewin, Sharon R. Sogaard, Ole Schmeltz Palmer, Sarah TI Broad activation of latent HIV-1 in vivo SO NATURE COMMUNICATIONS LA English DT Article ID CD4(+) T-CELLS; ACTIVE ANTIRETROVIRAL THERAPY; INFECTED-CELLS; GENETIC-CHARACTERIZATION; REVERSE-TRANSCRIPTASE; PERSISTENCE; PROLIFERATION; MULTIPLE; DNA; INDIVIDUALS AB The 'shock and kill' approach to cure human immunodeficiency virus (HIV) includes transcriptional induction of latent HIV-1 proviruses using latency-reversing agents (LRAs) with targeted immunotherapy to purge infected cells. The administration of LRAs (panobinostat or vorinostat) to HIV-1-infected individuals on antiretroviral therapy induces a significant increase in cell-associated unspliced (CA-US) HIV-1 RNA from CD4(+) T cells. However, it is important to discern whether the increases in CA-US HIV-1 RNA are due to limited or broad activation of HIV-1 proviruses. Here we use single-genome sequencing to find that the RNA transcripts observed following LRA administration are genetically diverse, indicating activation of transcription from an extensive range of proviruses. Defective sequences are more frequently found in CA HIV-1 RNA than in HIV-1 DNA, which has implications for developing an accurate measure of HIV-1 reservoir size. Our findings provide insights into the effects of panobinostat and vorinostat as LRAs for latent HIV-1. C1 [Barton, Kirston; Hiener, Bonnie; Winckelmann, Anni; Palmer, Sarah] Univ Sydney, Ctr Virus Res, Westmead Inst Med Res, 176 Hawkesbury Rd, Sydney, NSW 2145, Australia. [Winckelmann, Anni; Rasmussen, Thomas Aagaard; Denton, Paul W.; Olesen, Rikke; Ostergaard, Lars; Tolstrup, Martin; Sogaard, Ole Schmeltz] Aarhus Univ Hosp, Dept Infect Dis, Palle Juul Jensens Blvd 99, DK-8200 Aarhus N, Denmark. [Rasmussen, Thomas Aagaard; Solomon, Ajantha; Lewin, Sharon R.] Univ Melbourne, Peter Doherty Inst Infect & Immun, 792 Elizabeth St, Melbourne, Vic 3000, Australia. [Rasmussen, Thomas Aagaard; Solomon, Ajantha; Sogaard, Ole Schmeltz] Royal Melbourne Hosp, 792 Elizabeth St, Melbourne, Vic 3000, Australia. [Shao, Wei] Leidos Biomed Res Inc, Adv Biomed Comp Ctr, POB B, Frederick, MD 21702 USA. [Shao, Wei] NCI, HIV Dynam & Replicat Program, POB B, Frederick, MD 21702 USA. [Byth, Karen] NWSLHD Res & Educ Network, Darcy Rd, Westmead, NSW 2145, Australia. [Byth, Karen] Univ Sydney, NHMRC Clin Trials Ctr, Sydney, NSW 2006, Australia. [Lanfear, Robert] Macquarie Univ, Dept Biol Sci, Sydney, NSW 2109, Australia. [Solomon, Ajantha; McMahon, James; Lewin, Sharon R.] Alfred Hosp, Dept Infect Dis, 55 Commercial Rd, Melbourne, Vic 3181, Australia. [Solomon, Ajantha; McMahon, James; Lewin, Sharon R.] Monash Univ, 55 Commercial Rd, Melbourne, Vic 3181, Australia. [Harrington, Sean; Buzon, Maria; Lichterfeld, Mathias] Ragon Inst MGH MIT Harvard, 400 Technol Sq, Cambridge, MA 02139 USA. [Harrington, Sean; Buzon, Maria; Lichterfeld, Mathias] Harvard Med Sch, 25 Shattuck St, Boston, MA 02115 USA. [Denton, Paul W.] Aarhus Inst Adv Studies, Hoegh Guldbergs Gade 6B, DK-8000 Aarhus C, Denmark. [Denton, Paul W.; Ostergaard, Lars; Tolstrup, Martin; Sogaard, Ole Schmeltz] Aarhus Univ, Dept Clin Med, Palle Juul Jensens Blvd 82,Bldg B, DK-8200 Aarhus N, Denmark. RP Barton, K; Palmer, S (reprint author), Univ Sydney, Ctr Virus Res, Westmead Inst Med Res, 176 Hawkesbury Rd, Sydney, NSW 2145, Australia. EM Kirston.Barton@sydney.edu.au; Sarah.Palmer@sydney.edu.au OI Rasmussen, Thomas Aagaard/0000-0001-5354-2442; Olesen, Rikke/0000-0002-5157-080X; Lewin, Sharon Ruth/0000-0002-0330-8241; Denton, Paul/0000-0003-2458-8147 FU Delaney AIDS Research Enterprise (DARE) [1U19AI096109]; National Institutes of Health [1R21AI113096]; amfAR [108830]; FAIR: the Foundation for AIDS and Immune Research; amfAR Research Consortium on HIV Eradication [108928-56-RGRL]; National Health and Medical Research Council (NHMRC) of Australia [APP1061681]; NHMRC of Australia; Danish Council for Strategic Research [0603-00521B] FX This work was supported by the Delaney AIDS Research Enterprise (DARE) to Find a Cure 1U19AI096109, the National Institutes of Health grant 1R21AI113096 (S.P., S.R.L. and T.A.R.), amfAR grant 108830 with support from FAIR: the Foundation for AIDS and Immune Research, the amfAR Research Consortium on HIV Eradication (108928-56-RGRL) and the National Health and Medical Research Council (NHMRC) of Australia (grant APP1061681). S.R.L. is supported by a practitioner fellowship and J.M. by an early career fellowship from the NHMRC of Australia. T.A.R., L.O., M.T., O.S.S. and S.R.L. were supported by a grant from the Danish Council for Strategic Research (grant #0603-00521B). We thank Dr Timothy Schlub for statistics consultation. We acknowledge the participation and commitment of study participants, which made the study possible. NR 40 TC 2 Z9 2 U1 4 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD SEP PY 2016 VL 7 AR 12731 DI 10.1038/ncomms12731 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DY7CA UT WOS:000385285600003 PM 27605062 ER PT J AU Billesbolle, CB Mortensen, JS Sohail, A Schmidt, SG Shi, L Sitte, HH Gether, U Loland, CJ AF Billesbolle, Christian B. Mortensen, Jonas S. Sohail, Azmat Schmidt, Solveig G. Shi, Lei Sitte, Harald H. Gether, Ulrik Loland, Claus J. TI Transition metal ion FRET uncovers K+ regulation of a neurotransmitter/sodium symporter SO NATURE COMMUNICATIONS LA English DT Article ID X-RAY STRUCTURES; DOPAMINE TRANSPORTER; SODIUM SYMPORTERS; PLATELET 5-HYDROXYTRYPTAMINE; CONFORMATIONAL DYNAMICS; SEROTONIN TRANSPORTER; ALTERNATING ACCESS; BACTERIAL HOMOLOG; MECHANISM; SUBSTRATE AB Neurotransmitter/sodium symporters (NSSs) are responsible for Na+-dependent reuptake of neurotransmitters and represent key targets for antidepressants and psychostimulants. LeuT, a prokaryotic NSS protein, constitutes a primary structural model for these transporters. Here we show that K+ inhibits Na+-dependent binding of substrate to LeuT, promotes an outward-closed/inward-facing conformation of the transporter and increases uptake. To assess K+-induced conformational dynamics we measured fluorescence resonance energy transfer (FRET) between fluorescein site-specifically attached to inserted cysteines and Ni2+ bound to engineered di-histidine motifs (transition metal ion FRET). The measurements supported K+-induced closure of the transporter to the outside, which was counteracted by Na+ and substrate. Promoting an outward-open conformation of LeuT by mutation abolished the K+-effect. The K+-effect depended on an intact Na1 site and mutating the Na2 site potentiated K+ binding by facilitating transition to the inward-facing state. The data reveal an unrecognized ability of K+ to regulate the LeuT transport cycle. C1 [Billesbolle, Christian B.; Mortensen, Jonas S.; Schmidt, Solveig G.; Gether, Ulrik; Loland, Claus J.] Univ Copenhagen, Fac Hlth & Med Sci, Dept Neurosci & Pharmacol, Mol Neuropharmacol & Genet Lab, DK-2200 Copenhagen N, Denmark. [Sohail, Azmat; Sitte, Harald H.] Med Univ Vienna, Inst Pharmacol, Ctr Physiol & Pharmacol, A-1090 Vienna, Austria. [Shi, Lei] NIDA, Computat Chem & Mol Biophys Unit, NIH, Baltimore, MD 20852 USA. RP Loland, CJ (reprint author), Univ Copenhagen, Fac Hlth & Med Sci, Dept Neurosci & Pharmacol, Mol Neuropharmacol & Genet Lab, DK-2200 Copenhagen N, Denmark. EM cllo@sund.ku.dk OI Gether, Ulrik/0000-0002-0020-3807; Sitte, Harald/0000-0002-1339-7444; Loland, Claus/0000-0002-1773-1446; Mortensen, Jonas Sigurd/0000-0002-6743-276X FU Danish Independent Research Council - Sapere Aude [0602-02100B]; Lundbeck Foundation [R108-A10755]; National Institute of Health [P01 DA 12408]; Lundbeck Foundation Center for Biomembranes in Nanomedicine; UNIK Center for Synthetic Biology; European Community's Seventh Framework Programme [HEALTH-F4-2007-201924]; bioSYNergy; University of Copenhagen's Excellence Program for Interdisciplinary Research; Austrian Science Fund/FWF [F3506]; Graduate School of Health and Medical Science, University of Copenhagen; Bikuben Foundation New York; Intramural Research Program of the NIH, NIDA [ZIA DA000606-01] FX The pET16b LeuT WT plasmid was kindly provided by Dr Eric Gouaux, Vollum Institute, Oregon Health Science University. Lone Rosenquist is thanked for excellent technical assistance. Professor Jonathan Javitch, Professor Harel Weinstein, Professor Baruch Kanner, Associate Professor Soren G.F. Rasmussen and Dr Lars Borre are thanked for discussions and helpful suggestions. The work was supported in part by the Danish Independent Research Council - Sapere Aude (0602-02100B) (C.J.L.), the Lundbeck Foundation (R108-A10755) (C.J.L.), the National Institute of Health Grants P01 DA 12408 (U.G.), the Lundbeck Foundation Center for Biomembranes in Nanomedicine (U.G.), the UNIK Center for Synthetic Biology (U.G. and C.J.L.), the European Community's Seventh Framework Programme FP7/2007-2013 HEALTH-F4-2007-201924 (U.G.) and bioSYNergy, University of Copenhagen's Excellence Program for Interdisciplinary Research (C.J.L. and U.G.), the Austrian Science Fund/FWF (F3506) (H.H.S.), Graduate School of Health and Medical Science, University of Copenhagen (C.B.B.), The Bikuben Foundation New York (C.B.B.) and the Intramural Research Program of the NIH, NIDA (ZIA DA000606-01) (L.S.). NR 45 TC 3 Z9 3 U1 15 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 SEP PY 2016 VL 7 AR 12755 DI 10.1038/ncomms12755 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DY8LR UT WOS:000385382100001 PM 27678200 ER PT J AU Drelon, C Berthon, A Sahut-Barnola, I Mathieu, M Dumontet, T Rodriguez, S Batisse-Lignier, M Tabbal, H Tauveron, I Lefrancois-Martinez, AM Pointud, JC Gomez-Sanchez, CE Vainio, S Shan, JD Sacco, S Schedl, A Stratakis, CA Martinez, A Val, P AF Drelon, Coralie Berthon, Annabel Sahut-Barnola, Isabelle Mathieu, Mickael Dumontet, Typhanie Rodriguez, Stephanie Batisse-Lignier, Marie Tabbal, Houda Tauveron, Igor Lefrancois-Martinez, Anne-Marie Pointud, Jean-Christophe Gomez-Sanchez, Celso E. Vainio, Seppo Shan, Jingdong Sacco, Sonia Schedl, Andreas Stratakis, Constantine A. Martinez, Antoine Val, Pierre TI PKA inhibits WNT signalling in adrenal cortex zonation and prevents malignant tumour development SO NATURE COMMUNICATIONS LA English DT Article ID DEPENDENT PROTEIN-KINASE; TRANSGENIC MOUSE LINE; BETA-CATENIN GENE; ADRENOCORTICAL TUMORS; ALDOSTERONE PRODUCTION; WNT/BETA-CATENIN; PRKAR1A DEFECTS; PHOSPHORYLATION; SUPPRESSOR; CELLS AB Adrenal cortex physiology relies on functional zonation, essential for production of aldosterone by outer zona glomerulosa (ZG) and glucocorticoids by inner zona fasciculata (ZF). The cortex undergoes constant cell renewal, involving recruitment of subcapsular progenitors to ZG fate and subsequent lineage conversion to ZF identity. Here we show that WNT4 is an important driver of WNT pathway activation and subsequent ZG differentiation and demonstrate that PKA activation prevents ZG differentiation through WNT4 repression and WNT pathway inhibition. This suggests that PKA activation in ZF is a key driver of WNT inhibition and lineage conversion. Furthermore, we provide evidence that constitutive PKA activation inhibits, whereas partial inactivation of PKA catalytic activity stimulates beta-catenin-induced tumorigenesis. Together, both lower PKA activity and higher WNT pathway activity lead to poorer prognosis in adrenocortical carcinoma (ACC) patients. These observations suggest that PKA acts as a tumour suppressor in the adrenal cortex, through repression of WNT signalling. C1 [Drelon, Coralie; Berthon, Annabel; Sahut-Barnola, Isabelle; Mathieu, Mickael; Dumontet, Typhanie; Rodriguez, Stephanie; Batisse-Lignier, Marie; Tabbal, Houda; Tauveron, Igor; Lefrancois-Martinez, Anne-Marie; Pointud, Jean-Christophe; Martinez, Antoine; Val, Pierre] Clermont Univ, CNRS, UMR 6293, GReD,Inserm U1103, F-63171 Aubiere, France. [Berthon, Annabel; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Dev Endocrine Oncol & Genet, Sect Genet & Endocrinol, Bethesda, MD 20892 USA. [Batisse-Lignier, Marie; Tauveron, Igor] Ctr Hosp Univ, Serv Endocrinol, Fac Med, F-63000 Clermont Ferrand, France. [Gomez-Sanchez, Celso E.] GV Sonny Montgomery VA Med Ctr, Div Endocrinol, Jackson, MS 39216 USA. [Gomez-Sanchez, Celso E.] Univ Mississippi, Dept Med Endocrinol, Med Ctr, Jackson, MS 39216 USA. [Vainio, Seppo; Shan, Jingdong] Univ Oulu, Bioctr Oulu, Dev Biol Lab, InfoTech Oulu,Ctr Cell Matrix Res,Fac Biochem & M, SF-90220 Oulu, Finland. [Sacco, Sonia; Schedl, Andreas] CNRS, Inst Biol Valrose, Inserm UMR1091, UMR 7277, F-06108 Nice, France. RP Val, P (reprint author), Clermont Univ, CNRS, UMR 6293, GReD,Inserm U1103, F-63171 Aubiere, France. EM pierre.val@univ-bpclermont.fr RI Schedl, Andreas/F-8823-2015 FU Centre National de la Recherche Scientifique; Institut National de la Sante et de la Recherche Medicale; Universite Blaise Pascal; Universite d'Auvergne; Fondation de France; La Ligue Contre le Cancer (Allier & Puy de Dome committees); Fondation ARC; Societe Francaise d'Endocrinologie; Agence Nationale de la Recherche [ANR-14-CE12-0007-01-DevMiCar]; Academy of Finland [206038, 121647]; Centre of Excellence Grant of the Academy of Finland [251314]; Sigrid Juselius; Finnish Cancer Research; European Community's Seventh Framework Programme [FP7] [305608, FP7-HEALTH-F5-INNOVATION-1] FX We thank Khirredine Ouchen, Sandrine Plantade and Philippe Mazuel for animal care, Jean-Paul Saru for western blot analyses, Christelle Damon-Soubeyrand for management of histological analyses facilities (Anipath Clermont), Corinne Belville for RNA quality analyses, Sebastien Jacques and Florent Dumont (Plateforme Genomic, Inserm U1016-CNRS UMR8104-Universite Paris Descartes) for expert contributions, Clara Panzolini for Lac Z staining and Michelina Plateroti (CGPMC, Lyon) for helpful discussions. This work was funded through institutional support from Centre National de la Recherche Scientifique, Institut National de la Sante et de la Recherche Medicale, Universite Blaise Pascal, Universite d'Auvergne and through grants from Fondation de France, La Ligue Contre le Cancer (Allier & Puy de Dome committees), Fondation ARC, Societe Francaise d'Endocrinologie (young researcher grant to C.D.) and Agence Nationale de la Recherche (ANR-14-CE12-0007-01-DevMiCar). Generation of Wnt4 floxed mice by S.V. and J.S. was supported by grants from the Academy of Finland (206038, 121647) the Centre of Excellence Grant 2012-2017 of the Academy of Finland (251314), the Sigrid Juselius, Finnish Cancer Research, the European Community's Seventh Framework Programme [FP7/2007-2013] under grant agreement FP7-HEALTH-F5-2012-INNOVATION-1 EURenOmics 305608. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. NR 50 TC 1 Z9 1 U1 1 U2 2 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 SEP PY 2016 VL 7 AR 12751 DI 10.1038/ncomms12751 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DY8ET UT WOS:000385362300002 PM 27624192 ER PT J AU Kato, M Wang, M Chen, Z Bhatt, K Oh, HJ Lanting, L Deshpande, S Jia, Y Lai, JYC O'Connor, CL Wu, YF Hodgin, JB Nelson, RG Bitzer, M Natarajan, R AF Kato, Mitsuo Wang, Mei Chen, Zhuo Bhatt, Kirti Oh, Hyung Jung Lanting, Linda Deshpande, Supriya Jia, Ye Lai, Jennifer Y. C. O'Connor, Christopher L. Wu, YiFan Hodgin, Jeffrey B. Nelson, Robert G. Bitzer, Markus Natarajan, Rama TI An endoplasmic reticulum stress-regulated lncRNA hosting a microRNA megacluster induces early features of diabetic nephropathy SO NATURE COMMUNICATIONS LA English DT Article ID GROWTH-FACTOR-BETA; LONG NONCODING RNA; KIDNEY-DISEASE; MESSENGER-RNA; ER-STRESS; TRANSFORMING GROWTH-FACTOR-BETA-1; TRANSCRIPTION FACTOR; BINDING PROTEIN; GENE-EXPRESSION; RENAL FIBROSIS AB It is important to find better treatments for diabetic nephropathy (DN), a debilitating renal complication. Targeting early features of DN, including renal extracellular matrix accumulation (ECM) and glomerular hypertrophy, can prevent disease progression. Here we show that a megacluster of nearly 40 microRNAs and their host long non-coding RNA transcript (lnc-MGC) are coordinately increased in the glomeruli of mouse models of DN, and mesangial cells treated with transforming growth factor-beta 1 (TGF-beta 1) or high glucose. Lnc-MGC is regulated by an endoplasmic reticulum (ER) stress-related transcription factor, CHOP. Cluster microRNAs and lnc-MGC are decreased in diabetic Chop(-/-) mice that showed protection from DN. Target genes of megacluster microRNAs have functions related to protein synthesis and ER stress. A chemically modified oligonucleotide targeting lnc-MGC inhibits cluster microRNAs, glomerular ECM and hypertrophy in diabetic mice. Relevance to human DN is also demonstrated. These results demonstrate the translational implications of targeting lnc-MGC for controlling DN progression. C1 [Kato, Mitsuo; Wang, Mei; Chen, Zhuo; Bhatt, Kirti; Oh, Hyung Jung; Lanting, Linda; Deshpande, Supriya; Jia, Ye; Natarajan, Rama] Beckman Res Inst City Hope, Diabet Metab Res Inst, Dept Diabet Complicat & Metab, Duarte, CA 91010 USA. [Lai, Jennifer Y. C.; O'Connor, Christopher L.; Wu, YiFan; Bitzer, Markus] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Hodgin, Jeffrey B.] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. [Nelson, Robert G.] NIDDK, Diabet Epidemiol & Clin Res Sect, NIH, Phoenix, AZ 85014 USA. RP Kato, M; Natarajan, R (reprint author), Beckman Res Inst City Hope, Diabet Metab Res Inst, Dept Diabet Complicat & Metab, Duarte, CA 91010 USA. EM mkato@coh.org; rnatarajan@coh.org RI Kato, Mitsuo/D-5411-2009; OI Kato, Mitsuo/0000-0002-1783-1084 FU National Institutes of Health (NIH) [R01 DK081705, R01 DK058191, R01 HL106089, R01 DK100449]; Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; National Cancer Institute of the NIH [P30CA33572] FX We are grateful to Varun Dang and Katharine Ishida for technical assistance (RT-PCRs), and to members of the Natarajan laboratory for helpful discussions. Supported by grants from the National Institutes of Health (NIH), R01 DK081705, R01 DK058191 and R01 HL106089 (to RN), R01 DK100449 (to MB) and by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (to RGN). Research reported in this publication included work performed in the following Cores: Pathology, Integrative Genomics, Analytical Pharmacology and DNA/RNA synthesis, supported by the National Cancer Institute of the NIH under award number P30CA33572. EM studies were conducted in the City of Hope EM/AFM Core. NR 69 TC 1 Z9 1 U1 10 U2 10 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 SEP PY 2016 VL 7 AR 12864 DI 10.1038/ncomms12864 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DY8MF UT WOS:000385383600011 PM 27686049 ER PT J AU Lawrenson, K Kar, S McCue, K Kuchenbaeker, K Michailidou, K Tyrer, J Beesley, J Ramus, SJ Li, QY Delgado, MK Lee, JM Aittomaki, K Andrulis, IL Anton-Culver, H Arndt, V Arun, BK Arver, B Bandera, EV Barile, M Barkardottir, RB Barrowdale, D Beckmann, MW Benitez, J Berchuck, A Bisogna, M Bjorge, L Blomqvist, C Blot, W Bogdanova, N Bojesen, A Bojesen, SE Bolla, MK Bonanni, B Borresen-Dale, AL Brauch, H Brennan, P Brenner, H Bruinsma, F Brunet, J Buhari, SA Burwinkel, B Butzow, R Buys, SS Cai, QY Caldes, T Campbell, I Canniotto, R Chang-Claude, J Chiquette, J Choi, JY Claes, KBM Cook, LS Cox, A Cramer, DW Cross, SS Cybulski, C Czene, K Daly, MB Damiola, F Dansonka-Mieszkowska, A Darabi, H Dennis, J Devilee, P Diez, O Doherty, JA Domchek, SM Dorfling, CM Dork, T Dumont, M Ehrencrona, H Ejlertsen, B Ellis, S Engel, C Lee, E Evans, DG Fasching, PA Feliubadalo, L Figueroa, J Flesch-Janys, D Fletcher, O Flyger, H Foretova, L Fostira, F Foulkes, WD Fridley, BL Friedman, E Frost, D Gambino, G Ganz, PA Garber, J Garcia-Closas, M Gentry-Maharaj, A Ghoussaini, M Giles, GG Glasspool, R Godwin, AK Goldberg, MS Goldgar, DE Gonzalez-Neira, A Goode, EL Goodman, MT Greene, MH Gronwald, J Guenel, P Haiman, CA Hall, P Hallberg, E Hamann, U Hansen, TVO Harrington, PA Hartman, M Hassan, N Healey, S Heitz, F Herzog, J Hogdall, E Hogdall, CK Hogervorst, FBL Hollestelle, A Hopper, JL Hulick, PJ Huzarski, T Imyanitov, EN Isaacs, C Ito, H Jakubowska, A Janavicius, R Jensen, A John, EM Johnson, N Kabisch, M Kang, D Kapuscinski, M Karlan, BY Khan, S Kiemeney, LA Kjaer, SK Knight, JA Konstantopoulou, I Kosma, VM Kristensen, V Kupryjanczyk, J Kwong, A de la Hoya, M Laitman, Y Lambrechts, D Le, N De Leeneer, K Lester, J Levine, DA Li, JM Lindblom, A Long, J Lophatananon, A Loud, JT Lu, KR Lubinski, J Mannermaa, A Manoukian, S Le Marchand, L Margolin, S Marme, F Massuger, LFAG Matsuo, K Mazoyer, S McGuffog, L McLean, C McNeish, I Meindl, A Menon, U Mensenkamp, AR Milne, RL Montagna, M Moysich, KB Muir, K Mulligan, AM Nathanson, KL Ness, RB Neuhausen, SL Nevanlinna, H Nord, S Nussbaum, RL Odunsi, K Offit, K Olah, E Olopade, OI Olson, JE Olswold, C O'Malley, D Orlow, I Orr, N Osorio, A Park, SK Pearce, CL Pejovic, T Peterlongo, P Pfeiler, G Phelan, CM Poole, EM Pylkas, K Radice, P Rantala, J Rashid, MU Rennert, G Rhenius, V Rhiem, K Risch, HA Rodriguez, G Rossing, MA Rudolph, A Salvesen, HB Sangrajrang, S Sawyer, EJ Schildkraut, JM Schmidt, MK Schmutzler, RK Sellers, TA Seynaeve, C Shah, M Shen, CY Shu, XO Sieh, W Singer, CF Sinilnikova, OM Slager, S Song, HL Soucy, P Southey, MC Stenmark-Askmalm, M Stoppa-Lyonnet, D Sutter, C Swerdlow, A Tchatchou, S Teixeira, MR Teo, SH Terry, KL Terry, MB Thomassen, M Tibiletti, MG Tihomirova, L Tognazzo, S Toland, AE Tomlinson, I Torres, D Truong, T Tseng, CC Tung, N Tworoger, SS Vachon, C van den Ouweland, AMW van Doorn, HC van Rensburg, EJ Van't Veer, LJ Vanderstichele, A Vergote, I Vijai, J Wang, Q Wang-Gohrke, S Weitzel, JN Wentzensen, N Whittemore, AS Wildiers, H Winqvist, R Wu, AH Yannoukakos, D Yoon, SY Yu, JC Zheng, W Zheng, Y Khanna, KK Simard, J Monteiro, AN French, JD Couch, FJ Freedman, ML Easton, DF Dunning, AM Pharoah, PD Edwards, SL Chenevix-Trench, G Antoniou, AC Gayther, SA AF Lawrenson, Kate Kar, Siddhartha McCue, Karen Kuchenbaeker, Karoline Michailidou, Kyriaki Tyrer, Jonathan Beesley, Jonathan Ramus, Susan J. Li, Qiyuan Delgado, Melissa K. Lee, Janet M. Aittomaki, Kristiina Andrulis, Irene L. Anton-Culver, Hoda Arndt, Volker Arun, Banu K. Arver, Brita Bandera, Elisa V. Barile, Monica Barkardottir, Rosa B. Barrowdale, Daniel Beckmann, Matthias W. Benitez, Javier Berchuck, Andrew Bisogna, Maria Bjorge, Line Blomqvist, Carl Blot, William Bogdanova, Natalia Bojesen, Anders Bojesen, Stig E. Bolla, Manjeet K. Bonanni, Bernardo Borresen-Dale, Anne-Lise Brauch, Hiltrud Brennan, Paul Brenner, Hermann Bruinsma, Fiona Brunet, Joan Buhari, Shaik Ahmad Burwinkel, Barbara Butzow, Ralf Buys, Saundra S. Cai, Qiuyin Caldes, Trinidad Campbell, Ian Canniotto, Rikki Chang-Claude, Jenny Chiquette, Jocelyne Choi, Ji-Yeob Claes, Kathleen B. M. Cook, Linda S. Cox, Angela Cramer, Daniel W. Cross, Simon S. Cybulski, Cezary Czene, Kamila Daly, Mary B. Damiola, Francesca Dansonka-Mieszkowska, Agnieszka Darabi, Hatef Dennis, Joe Devilee, Peter Diez, Orland Doherty, Jennifer A. Domchek, Susan M. Dorfling, Cecilia M. Doerk, Thilo Dumont, Martine Ehrencrona, Hans Ejlertsen, Bent Ellis, Steve Engel, Christoph Lee, Eunjung Evans, D. Gareth Fasching, Peter A. Feliubadalo, Lidia Figueroa, Jonine Flesch-Janys, Dieter Fletcher, Olivia Flyger, Henrik Foretova, Lenka Fostira, Florentia Foulkes, William D. Fridley, Brooke L. Friedman, Eitan Frost, Debra Gambino, Gaetana Ganz, Patricia A. Garber, Judy Garcia-Closas, Montserrat Gentry-Maharaj, Aleksandra Ghoussaini, Maya Giles, Graham G. Glasspool, Rosalind Godwin, Andrew K. Goldberg, Mark S. Goldgar, David E. Gonzalez-Neira, Anna Goode, Ellen L. Goodman, Marc T. Greene, Mark H. Gronwald, Jacek Guenel, Pascal Haiman, Christopher A. Hall, Per Hallberg, Emily Hamann, Ute Hansen, Thomas V. O. Harrington, Patricia A. Hartman, Mikael Hassan, Norhashimah Healey, Sue Heitz, Florian Herzog, Josef Hogdall, Estrid Hogdall, Claus K. Hogervorst, Frans B. L. Hollestelle, Antoinette Hopper, John L. Hulick, Peter J. Huzarski, Tomasz Imyanitov, Evgeny N. Isaacs, Claudine Ito, Hidemi Jakubowska, Anna Janavicius, Ramunas Jensen, Allan John, Esther M. Johnson, Nichola Kabisch, Maria Kang, Daehee Kapuscinski, Miroslav Karlan, Beth Y. Khan, Sofia Kiemeney, Lambertus A. Kjaer, Susanne Kruger Knight, Julia A. Konstantopoulou, Irene Kosma, Veli-Matti Kristensen, Vessela Kupryjanczyk, Jolanta Kwong, Ava de la Hoya, Miguel Laitman, Yael Lambrechts, Diether Le, Nhu De Leeneer, Kim Lester, Jenny Levine, Douglas A. Li, Jingmei Lindblom, Annika Long, Jirong Lophatananon, Artitaya Loud, Jennifer T. Lu, Karen Lubinski, Jan Mannermaa, Arto Manoukian, Siranoush Le Marchand, Loic Margolin, Sara Marme, Frederik Massuger, Leon F. A. G. Matsuo, Keitaro Mazoyer, Sylvie McGuffog, Lesley McLean, Catriona McNeish, Iain Meindl, Alfons Menon, Usha Mensenkamp, Arjen R. Milne, Roger L. Montagna, Marco Moysich, Kirsten B. Muir, Kenneth Mulligan, Anna Marie Nathanson, Katherine L. Ness, Roberta B. Neuhausen, Susan L. Nevanlinna, Heli Nord, Silje Nussbaum, Robert L. Odunsi, Kunle Offit, Kenneth Olah, Edith Olopade, Olufunmilayo I. Olson, Janet E. Olswold, Curtis O'Malley, David Orlow, Irene Orr, Nick Osorio, Ana Park, Sue Kyung Pearce, Celeste L. Pejovic, Tanja Peterlongo, Paolo Pfeiler, Georg Phelan, Catherine M. Poole, Elizabeth M. Pylkas, Katri Radice, Paolo Rantala, Johanna Rashid, Muhammad Usman Rennert, Gad Rhenius, Valerie Rhiem, Kerstin Risch, Harvey A. Rodriguez, Gus Rossing, Mary Anne Rudolph, Anja Salvesen, Helga B. Sangrajrang, Suleeporn Sawyer, Elinor J. Schildkraut, Joellen M. Schmidt, Marjanka K. Schmutzler, Rita K. Sellers, Thomas A. Seynaeve, Caroline Shah, Mitul Shen, Chen-Yang Shu, Xiao-Ou Sieh, Weiva Singer, Christian F. Sinilnikova, Olga M. Slager, Susan Song, Honglin Soucy, Penny Southey, Melissa C. Stenmark-Askmalm, Marie Stoppa-Lyonnet, Dominique Sutter, Christian Swerdlow, Anthony Tchatchou, Sandrine Teixeira, Manuel R. Teo, Soo H. Terry, Kathryn L. Terry, Mary Beth Thomassen, Mads Tibiletti, Maria Grazia Tihomirova, Laima Tognazzo, Silvia Toland, Amanda Ewart Tomlinson, Ian Torres, Diana Truong, Therese Tseng, Chiu-chen Tung, Nadine Tworoger, Shelley S. Vachon, Celine van den Ouweland, Ans M. W. van Doorn, Helena C. van Rensburg, Elizabeth J. Van't Veer, Laura J. Vanderstichele, Adriaan Vergote, Ignace Vijai, Joseph Wang, Qin Wang-Gohrke, Shan Weitzel, Jeffrey N. Wentzensen, Nicolas Whittemore, Alice S. Wildiers, Hans Winqvist, Robert Wu, Anna H. Yannoukakos, Drakoulis Yoon, Sook-Yee Yu, Jyh-Cherng Zheng, Wei Zheng, Ying Khanna, Kum Kum Simard, Jacques Monteiro, Alvaro N. French, Juliet D. Couch, Fergus J. Freedman, Matthew L. Easton, Douglas F. Dunning, Alison M. Pharoah, Paul D. Edwards, Stacey L. Chenevix-Trench, Georgia Antoniou, Antonis C. Gayther, Simon A. CA GEMO Study Collaborators EMBRACE Hereditary Breast & Ovarian Canc R KConFab Investigators Australian Ovarian Canc Study Grp TI Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus SO NATURE COMMUNICATIONS LA English DT Article ID GENOME-WIDE ASSOCIATION; BRCA2 MUTATION CARRIERS; EPITHELIAL-CELLS; COMMON VARIANTS; IDENTIFIES 3; MODIFIERS; REVEALS; GWAS; GENE; INVESTIGATORS AB A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P = 9.2 x 10(-20)), ER-negative BC (P = 1.1 x 10(-13)), BRCA1-associated BC (P = 7.7 x 10(-16)) and triple negative BC (P-diff = 2 x 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P = 2 x 10(-3)) and ABHD8 (P<2 x 10(-3)). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 30-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk. C1 [Lawrenson, Kate; Ramus, Susan J.; Delgado, Melissa K.; Lee, Janet M.; Lee, Eunjung; Haiman, Christopher A.; Le, Nhu; Pearce, Celeste L.; Tseng, Chiu-chen; Wu, Anna H.; Gayther, Simon A.] Univ Southern Calif, Kenneth Norris Jr Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. 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[Figueroa, Jonine; Garcia-Closas, Montserrat] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20892 USA. [Flesch-Janys, Dieter] Univ Med Ctr Hamburg Eppendorf, Inst Med Biometr & Epidemiol, D-20246 Hamburg, Germany. [Flesch-Janys, Dieter] Univ Med Ctr Hamburg Eppendorf, Clin Canc Registry, Dept Canc Epidemiol, D-20246 Hamburg, Germany. [Fletcher, Olivia; Johnson, Nichola; Orr, Nick] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England. [Fletcher, Olivia; Johnson, Nichola; Swerdlow, Anthony] Inst Canc Res, Div Breast Canc Res, London SW7 3RP, England. [Flyger, Henrik] Copenhagen Univ Hosp, Herlev Hosp, Dept Breast Surg, DK-2730 Herlev, Denmark. [Foretova, Lenka] Masaryk Mem Canc Inst, Brno 62500, Czech Republic. [Foretova, Lenka] Med Fac MU, Brno 62500, Czech Republic. [Fostira, Florentia; Konstantopoulou, Irene] Aghia Paraskevi Attikis, Natl Ctr Sci Res Demokritos, INRASTES Inst Nucl & Radiol Sci & Technol, Mol Diagnost Lab, Athens 15310, Greece. [Foulkes, William D.] McGill Univ, Dept Human Genet, Program Canc Genet, Montreal, PQ H2W 1S6, Canada. [Foulkes, William D.] McGill Univ, Dept Oncol, Montreal, PQ H2W 1S6, Canada. [Fridley, Brooke L.] Univ Kansas, Med Ctr, Biostat & Informat Shared Resource, Kansas City, KS 66103 USA. [Friedman, Eitan; Laitman, Yael] Chaim Sheba Med Ctr, Susanne Levy Gertner Oncogenet Unit, IL-52621 Tel Hashomer, Israel. [Gambino, Gaetana] Univ & Univ Hosp Pisa, Dept Lab Med, Sect Genet Oncol, I-56126 Pisa, Italy. [Ganz, Patricia A.] Jonsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, UCLA Sch Med & Publ Hlth, Los Angeles, CA 90024 USA. [Garber, Judy] Dana Farber Canc Inst, Canc Risk & Prevent Clin, Boston, MA 02215 USA. [Garcia-Closas, Montserrat; Swerdlow, Anthony] Inst Canc Res, Div Genet & Epidemiol, London SW7 3RP, England. [Gentry-Maharaj, Aleksandra; Menon, Usha] UCL EGA Inst Womens Hlth, Womens Canc, London WC1E 6AU, England. [Giles, Graham G.; Hopper, John L.; Milne, Roger L.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Biostat & Epidemiol, Melbourne, Vic 3010, Australia. [Glasspool, Rosalind] Beatson West Scotland Canc Ctr, Canc Res UK Clin Trials Unit, Glasgow G12 0YN, Lanark, Scotland. [Godwin, Andrew K.] Univ Kansas, Univ Kansas Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66160 USA. [Goldberg, Mark S.] McGill Univ, Royal Victoria Hosp, Div Clin Epidemiol, Montreal H3A 1A1, PQ, Canada. [Goldberg, Mark S.] McGill Univ, Dept Med, Montreal, PQ H3A 1A1, Canada. [Goldgar, David E.] Univ Utah, Sch Med, Huntsman Canc Inst, Dept Dermatol, Salt Lake City, UT 84132 USA. [Goode, Ellen L.; Hallberg, Emily; Olswold, Curtis; Slager, Susan; Vachon, Celine; Couch, Fergus J.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55902 USA. [Goodman, Marc T.] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Canc Prevent & Control, Los Angeles, CA 90048 USA. [Goodman, Marc T.] Cedars Sinai Med Ctr, Dept Biomed Sci, Community & Populat Hlth Res Inst, Los Angeles, CA 90048 USA. [Greene, Mark H.; Loud, Jennifer T.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20892 USA. [Gronwald, Jacek] Pomeranian Med Univ, Dept Genet & Pathol, PL-70204 Szczecin, Poland. [Guenel, Pascal; Truong, Therese] INSERM, Ctr Res Epidemiol & Populat Hlth, Environm Epidemiol Canc, F-94805 Villejuif, France. [Guenel, Pascal; Truong, Therese] Univ Paris 11, F-91405 Villejuif, France. [Hamann, Ute; Kabisch, Maria; Rashid, Muhammad Usman; Torres, Diana] German Canc Res Ctr, Mol Genet Breast Canc, D-69120 Heidelberg, Germany. [Hansen, Thomas V. O.] Copenhagen Univ Hosp, Rigshosp, Ctr Genom Med, DK-2100 Copenhagen, Denmark. [Harrington, Patricia A.] Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Dept Oncol, Cambridge CB1 8RN, England. [Hartman, Mikael] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 119077, Singapore. [Hassan, Norhashimah; Teo, Soo H.] Univ Malaya, Med Ctr, Canc Res Inst, Breast Canc Res Unit, Kuala Lumpur 50603, Malaysia. [Hassan, Norhashimah; Teo, Soo H.] Canc Res Initiat Fdn, Subang Jaya 47500, Selangor, Malaysia. [Heitz, Florian] Kliniken Essen Mitte, Dept Gynecol & Gynecol Oncol, D-45136 Essen, Germany. [Heitz, Florian] Dr Horst Schmidt Kliniken Wiesbaden, Dept Gynecol & Gynecol Oncol, D-65199 Wiesbaden, Germany. [Herzog, Josef; Weitzel, Jeffrey N.] City Hope Clin Canc Genet Community Res Network, Clin Canc Genet, Duarte, CA 91010 USA. [Hogdall, Estrid] Univ Copenhagen, Herlev Hosp, Dept Pathol, Mol Unit, DK-2730 Copenhagen, Denmark. [Hogdall, Estrid; Kjaer, Susanne Kruger] Danish Canc Soc Res Ctr, Dept Virus Lifestyle & Genes, DK-2100 Copenhagen, Denmark. [Hogdall, Claus K.; Jensen, Allan; Kjaer, Susanne Kruger] Univ Copenhagen, Rigshosp, Dept Gynecol, DK-2100 Copenhagen, Denmark. [Hogervorst, Frans B. L.] Netherlands Canc Inst, Family Canc Clin, NL-1006 Amsterdam, Netherlands. [Hollestelle, Antoinette; Seynaeve, Caroline] Erasmus MC Canc Inst, Dept Med Oncol, Family Canc Clin, NL-3015 Rotterdam, Netherlands. [Hulick, Peter J.] NorthShore Univ Hlth Syst, Ctr Med Genet, Evanston, IL 60201 USA. [Imyanitov, Evgeny N.] NN Petrov Inst Oncol, St Petersburg 197758, Russia. [Isaacs, Claudine] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA. [Ito, Hidemi] Aichi Canc Ctr, Res Inst, Div Epidemiol & Prevent, Aichi 4648681, Japan. [Janavicius, Ramunas] Ctr Innovat Med, State Res Inst, LT-01102 Vilnius, Lithuania. [John, Esther M.] Canc Prevent Inst Calif, Dept Epidemiol, Fremont, CA 94538 USA. [Kang, Daehee; Park, Sue Kyung] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul 08826, South Korea. [Kapuscinski, Miroslav] Univ Melbourne, Ctr Biostat & Epidemiol, Melbourne, Vic 3010, Australia. [Karlan, Beth Y.; Lester, Jenny] Cedars Sinai Med Ctr, Womens Canc Program Samuel Oschin Comprehens Canc, Los Angeles, CA 90048 USA. [Kiemeney, Lambertus A.] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, NL-6500 Nijmegen, Netherlands. [Bojesen, Anders; Knight, Julia A.] Lunenfeld Tanenbaum Res Inst Mt Sinai Hosp, Prosserman Ctr Hlth Res, Toronto, ON M5G 1X5, Canada. [Knight, Julia A.] Univ Toronto, Dalla Lana Sch Publ Hlth, Div Epidemiol, Toronto, ON M5T 3M7, Canada. [Kosma, Veli-Matti; Mannermaa, Arto] Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, Kuopio 70210, Finland. [Kosma, Veli-Matti; Mannermaa, Arto] Kuopio Univ Hosp, Ctr Canc, Kuopio 70210, Finland. [Kosma, Veli-Matti; Mannermaa, Arto] Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Kuopio 70210, Finland. [Kristensen, Vessela] Univ Oslo, Oslo Univ Hosp, Dept Clin Mol Biol, N-1478 Oslo, Norway. [Kwong, Ava] Hong Kong Sanat & Hosp, Canc Genet Ctr, Hong Kong Hereditary Breast Canc Family Registry, Hong Kong, Hong Kong, Peoples R China. [Kwong, Ava] Univ Hong Kong, Dept Surg, Hong Kong, Hong Kong, Peoples R China. [Lambrechts, Diether] VIB, Vesalius Res Ctr, B-3000 Louvain, Belgium. [Lambrechts, Diether] Univ Leuven, Dept Oncol, Lab Translat Genet, B-3000 Louvain, Belgium. [Lindblom, Annika] Karolinska Inst, Dept Mol Med & Surg, SE-17177 Stockholm, Sweden. [Lophatananon, Artitaya; Muir, Kenneth] Univ Warwick, Warwick Med Sch, Div Hlth Sci, Coventry CV4 7AL, W Midlands, England. [Lu, Karen] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA. [Manoukian, Siranoush] Ist Nazl Tumori, Fdn IRCCS Ist Ricovero & Cura Carattere Sci, Dept Prevent & Predict Med, Unit Med Genet, I-20133 Milan, Italy. [Le Marchand, Loic] Univ Hawaii, Ctr Canc, Honolulu, HI 96813 USA. [Margolin, Sara] Karolinska Inst, Dept Oncol Pathol, SE-17177 Stockholm, Sweden. [Marme, Frederik] Heidelberg Univ, Natl Ctr Tumour Dis, D-69117 Heidelberg, Germany. [Massuger, Leon F. A. G.] Radboud Univ Nijmegen, Med Ctr, Dept Gynaecol, NL-6500 Nijmegen, Netherlands. [Matsuo, Keitaro] Kyushu Univ, Fac Med Sci, Dept Prevent Med, Fukuoka 8128582, Japan. [McLean, Catriona] Alfred Hosp, Anat Pathol, Melbourne, Vic 3004, Australia. [McNeish, Iain] Univ Glasgow, Inst Canc Sci, Wolfson Wohl Canc Res Ctr, Beatson Inst Canc Res, Glasgow G61 1BD, Lanark, Scotland. [Meindl, Alfons] Tech Univ Munich, Div Gynaecol & Obstet, D-81675 Munich, Germany. [Mensenkamp, Arjen R.] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6500 Nijmegen, Netherlands. [Montagna, Marco] IRCCS, Inst Oncol Veneto IOV, Immunol & Mol Oncol Unit, I-35128 Padua, Italy. [Moysich, Kirsten B.] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Muir, Kenneth] Univ Manchester, Inst Populat Hlth, Manchester M13 9PL, Lancs, England. [Mulligan, Anna Marie] Univ Hlth Network, Lab Med Program, Toronto, ON M5G 1L7, Canada. [Mulligan, Anna Marie] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5G 1L7, Canada. [Ness, Roberta B.] Univ Texas Houston, Sch Publ Hlth, Houston, TX 77030 USA. [Neuhausen, Susan L.] Beckman Res Inst City Hope, Dept Populat Sci, Duarte, CA 91010 USA. [Nussbaum, Robert L.] Univ Calif San Francisco, Dept Med & Genet, San Francisco, CA 94143 USA. [Odunsi, Kunle] Roswell Pk Canc Inst, Dept Gynecol Oncol, Buffalo, NY 14263 USA. [Offit, Kenneth; Vijai, Joseph] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA. [Olah, Edith] Natl Inst Oncol, Dept Mol Genet, H-1122 Budapest, Hungary. [Olopade, Olufunmilayo I.] Univ Chicago, Med Ctr, Ctr Clin Canc Genet & Global Hlth, Chicago, IL 60637 USA. [O'Malley, David] Ohio State Univ, Columbus, OH 43210 USA. [O'Malley, David] James Graham Brown Canc Ctr, Columbus, OH 43210 USA. [Orlow, Irene] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10017 USA. [Osorio, Ana] Spanish Natl Canc Ctr CNIO, Human Canc Genet Program, Human Genet Grp, Madrid 28019, Spain. [Osorio, Ana] Biomed Network Rare Dis CIBERER, Madrid 28029, Spain. [Park, Sue Kyung] Seoul Natl Univ, Coll Med, Dept Surg, Seoul 03080, South Korea. [Pejovic, Tanja] Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Portland, OR 97239 USA. [Pejovic, Tanja] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97239 USA. [Peterlongo, Paolo] FIRC Italian Fdn Canc Res, Inst Mol Oncol, IFOM, I-20139 Milan 16, Italy. [Pfeiler, Georg; Singer, Christian F.] Med Univ Vienna, Ctr Comprehens Canc, Dept Obstet & Gynecol, A-1090 Vienna, Austria. [Phelan, Catherine M.; Sellers, Thomas A.] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL 33606 USA. [Poole, Elizabeth M.; Tworoger, Shelley S.] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Poole, Elizabeth M.; Tworoger, Shelley S.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Pylkas, Katri; Winqvist, Robert] Ctr NordLab, Northern Finland Lab, Lab Canc Genet & Tumour Biol, FI-90014 Oulu, Finland. [Pylkas, Katri; Winqvist, Robert] Univ Oulu, Dept Clin Chem & Biocenter Oulu, Lab Canc Genet & Tumour Biol, FI-90014 Oulu, Finland. [Radice, Paolo] Ist Nazl Tumori, Fdn IRCCS Ist Ricovero & Cura Carattere Sci, Dept Prevent & Predict Med, Unit Mol Bases Genet Risk & Genet Testing, I-20133 Milan, Italy. [Rantala, Johanna] Karolinska Univ Hosp, Dept Clin Genet, S-17176 Stockholm, Sweden. [Rashid, Muhammad Usman] Shaukat Khanum Mem Canc Hosp & Res Ctr SKMCH & RC, Dept Basic Sci, Lahore 54000, Pakistan. [Rennert, Gad] Clalit Natl Israeli Canc Control Ctr, IL-34362 Haifa, Israel. [Rennert, Gad] Carmel Hosp, B Rappaport Fac Med, Dept Community Med & Epidemiol, IL-34362 Haifa, Israel. [Rhiem, Kerstin] Univ Hosp Cologne, Ctr Mol Med Cologne, Dept Obstet & Gynaecol, Ctr Familial Breast & Ovarian Canc, D-50931 Cologne, Germany. [Rhiem, Kerstin] Univ Hosp Cologne, Ctr Mol Med Cologne, Ctr Integrated Oncol, D-50931 Cologne, Germany. [Risch, Harvey A.] Yale Univ, Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT 06510 USA. [Rodriguez, Gus] NorthShore Univ HealthSyst, Div Gynecol Oncol, Evanston, IL 60201 USA. [Rossing, Mary Anne] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Program Epidemiol, Seattle, WA 98109 USA. [Rossing, Mary Anne] Univ Washington, Dept Epidemiol, Seattle, WA 98109 USA. [Sangrajrang, Suleeporn] Natl Canc Inst, Bangkok 10400, Thailand. [Sawyer, Elinor J.] Kings Coll London, Guys Hosp, Res Oncol, London SE1 9RT, England. [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 27710 USA. [Schmidt, Marjanka K.; Van't Veer, Laura J.] Netherlands Canc Inst, Antoni van Leeuwenhoek Hosp, NL-1066 CX Amsterdam, Netherlands. [Schmutzler, Rita K.] Univ Hosp Cologne, Dept Obstet & Gynaecol, Div Mol Gynecooncol, D-50676 Cologne, Germany. [Schmutzler, Rita K.] Univ Hosp Cologne, Ctr Integrated Oncol, D-50676 Cologne, Germany. [Schmutzler, Rita K.] Univ Hosp Cologne, Ctr Mol Med, D-50676 Cologne, Germany. [Schmutzler, Rita K.] Univ Hosp Cologne, Ctr Familial Breast & Ovarian Canc, D-50676 Cologne, Germany. [Shen, Chen-Yang] Acad Sinica, Inst Biomed Sci, Taiwan Biobank, Taipei 115, Taiwan. [Shen, Chen-Yang] China Med Univ, Sch Publ Hlth, Taichung 404, Taiwan. [Sieh, Weiva; Whittemore, Alice S.] Stanford Univ, Sch Med, Dept Hlth Res & Policy Epidemiol, Stanford, CA 94305 USA. [Sinilnikova, Olga M.] Ctr Leon Berard, Hosp Civils Lyon, Unite Mixte Genet Constitut Canc Frequent, F-69008 Lyon, France. [Sinilnikova, Olga M.] Univ Lyon 1, Ctr Rech Cancerol Lyon, CNRS UMR5286, INSERM U1052, F-69003 Lyon, France. [Southey, Melissa C.] Univ Melbourne, Dept Pathol, Parkville, Vic 3010, Australia. [Stenmark-Askmalm, Marie] Linkoping Univ, Dept Clin & Expt Med, Div Clin Genet, S-58183 Linkoping, Sweden. [Stoppa-Lyonnet, Dominique] Inst Curie, Dept Tumour Biol, Paris, France. [Stoppa-Lyonnet, Dominique] Inst Curie, INSERM, U830, F-75248 Paris, France. [Stoppa-Lyonnet, Dominique] Sorbonne Paris Cite, Univ Paris Descartes, F-75270 Paris, France. [Sutter, Christian] Univ Heidelberg Hosp, Dept Human Genet, Inst Human Genet, D-69120 Heidelberg, Germany. [Teixeira, Manuel R.] Portuguese Oncol Inst, Dept Genet, P-4200072 Oporto, Portugal. [Teixeira, Manuel R.] Univ Porto, Biomed Sci Inst ICBAS, P-4099002 Oporto, Portugal. [Terry, Mary Beth] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10027 USA. [Thomassen, Mads] Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense C, Denmark. [Tibiletti, Maria Grazia] Univ Insubria, Osped Circolo, UO Anat Patol, I-21100 Varese, Italy. [Tihomirova, Laima] Latvian Biomed Res & Study Ctr, LV-1067 Riga, Latvia. [Tognazzo, Silvia] IRCCS, Ist Oncol Veneto, Immunol & Mol Oncol Unit, I-35128 Padua 64, Italy. [Toland, Amanda Ewart] Ohio State Univ, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA. [Tomlinson, Ian] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Tomlinson, Ian] Univ Oxford, Oxford Biomed Res Ctr, Oxford OX3 7BN, England. [Torres, Diana] Pontificia Univ Javeriana, Inst Human Genet, Bogota, Colombia. [Tung, Nadine] Beth Israel Deaconess Med Ctr, Dept Med Oncol, Boston, MA 02215 USA. [van den Ouweland, Ans M. W.] Erasmus Univ, Med Ctr, Dept Clin Genet, NL-3015 CE Rotterdam, Netherlands. [van Doorn, Helena C.] Erasmus MC Canc Inst, Dept Gynecol, Family Canc Clin, NL-3015 CE Rotterdam, Netherlands. [Vanderstichele, Adriaan; Vergote, Ignace] Univ Hosp Leuven, Dept Oncol, Div Gynecol Oncol, B-3000 Louvain, Belgium. [Wang-Gohrke, Shan] Univ Hosp Ulm, D-89069 Ulm, Germany. [Wentzensen, Nicolas] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Wildiers, Hans] Univ Hosp Leuven, Dept Gen Med Oncol, Multidisciplinary Breast Ctr, B-3000 Louvain, Belgium. [Yannoukakos, Drakoulis] Natl Ctr Sci Res Demokritos, IRRP, Mol Diagnost Lab, Athens 15310, Greece. [Yoon, Sook-Yee] Sime Darby Med Ctr, Canc Res Initiat Fdn, Subang Jaya 47500, Malaysia. [Yoon, Sook-Yee] Univ Malaya, Univ Malaya Med Ctr, Fac Med, Univ Malaya Canc Res Inst, Kuala Lumpur 59100, Malaysia. [Yu, Jyh-Cherng] Natl Def Med Ctr, Triserv Gen Hosp, Dept Surg, Taipei 114, Taiwan. [Zheng, Ying] Shanghai Ctr Dis Control & Prevent, Shanghai, Peoples R China. [Monteiro, Alvaro N.] H Lee Moffitt Canc Ctr & Res Inst, Div Populat Sci, Canc Epidemiol Program, Tampa, FL 33612 USA. [Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA. [Lawrenson, Kate] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Los Angeles, CA 90048 USA. [Gayther, Simon A.] Cedars Sinai Med Ctr, Ctr Bioinformat & Funct Genom, Los Angeles, CA 90048 USA. RP Antoniou, AC (reprint author), Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England. EM aca20@medschl.cam.ac.uk RI manoukian, siranoush/E-7132-2017; Dork, Thilo/J-8620-2012; montagna, marco/E-2225-2012; Nord, Silje/R-5212-2016; Li, Jingmei/I-2904-2012; Gronwald, Jacek/A-4576-2017; Brenner, Hermann/B-4627-2017; Jansen van Rensburg, Elizabeth (Lizette)/B-9104-2011; Bjorge, Line/C-1307-2017; salvesen, Helga/C-1187-2017; Knight, Julia/A-6843-2012; Osorio, Ana/I-4324-2014 OI Ehrencrona, Hans/0000-0002-5589-3622; Brunet, Joan/0000-0003-1945-3512; Yannoukakos, Drakoulis/0000-0001-7509-3510; Dunning, Alison Margaret/0000-0001-6651-7166; Fox, Stephen/0000-0002-7648-8896; VENAT-BOUVET, Laurence/0000-0002-0716-2550; Evans, Gareth/0000-0002-8482-5784; manoukian, siranoush/0000-0002-6034-7562; montagna, marco/0000-0002-4929-2150; Nord, Silje/0000-0002-3271-5356; Li, Jingmei/0000-0001-8587-7511; Gronwald, Jacek/0000-0002-3643-2871; Brenner, Hermann/0000-0002-6129-1572; Bjorge, Line/0000-0002-0240-2770; salvesen, Helga/0000-0002-4438-8831; Osorio, Ana/0000-0001-8124-3984 FU National Cancer Institute (USA) [UM1 CA164920, CA 27469]; National Health and Medical Research Council of Australia; New South Wales Cancer Council; Victorian Health Promotion Foundation (Australia); Victorian Breast Cancer Research Consortium; Dutch Cancer Society [NKI 2007-3839, 2009 4363, RUL 1997-1505, DDHK 2004-3124, DDHK 2009-4318, NKI1998-1854, NKI2004-3088, NKI2007-3756]; Breast Cancer Research Trust, UK; Breakthrough Breast Cancer; NHS; National Cancer Research Network (NCRN); NIHR Comprehensive Biomedical Research Centre; Guy's and St. Thomas' NHS Foundation Trust; King's College London, United Kingdom; Oxford Biomedical Research Centre; Dietmar-Hopp Foundation; Helmholtz Society; German Cancer Research Center (DKFZ); Chief Physician Johan Boserup and Lise Boserup Fund; Danish Medical Research Council; Instituto de Salud Carlos III; Red Tematica de Investigacion Cooperativa en Cancer; Asociacion Espanola Contra el Cancer; Fondo de Investigacion Sanitario [PI11/00923, PI12/00070]; California Breast Cancer Act of 1993; California Breast Cancer Research Fund [97-10500]; National Institutes of Health [R01 CA77398, CA128978]; California Department of Public Health; Lon V Smith Foundation [LVS39420]; Baden Wurttemberg Ministry of Science, Research and Arts; Deutsche Krebshilfe [107 352]; Federal Ministry of Education and Research (BMBF) Germany [01KW9975/5, 01KW9976/8, 01KW9977/0, 01KW0114, 01KH0402]; Robert Bosch Foundation, Stuttgart; Deutsches Krebsforschungszentrum (DKFZ), Heidelberg; Institute for Prevention and Occupational Medicine of the German Social Accident Insurance; Institute of the Ruhr University Bochum (IPA), Bochum; Department of Internal Medicine; Evangelische Kliniken Bonn gGmbH; Johanniter Krankenhaus, Bonn, Germany; Helsinki University Central Hospital Research Fund; Academy of Finland [266528, 250083, 122715]; Finnish Cancer Society; Nordic Cancer Union; Sigrid Juselius Foundation; Friends of Hannover Medical School; Rudolf Bartling Foundation; special Government Funding (EVO) of Kuopio University Hospital grants; Cancer Fund of North Savo; Finnish Cancer Organizations; University of Eastern Finland; National Breast Cancer Foundation; National Health and Medical Research Council (NHMRC); Queensland Cancer Fund; Cancer Council of New South Wales, Victoria; Cancer Council of New South Wales, Tasmania; Cancer Council of New South Wales, South Australia; Cancer Foundation of Western Australia; United States Army Medical Research and Materiel Command [DAMD17-01-1-0729]; Cancer Council Victoria; Cancer Council New South Wales; Cancer Council South Australia; Cancer Council Tasmania; National Health and Medical Research Council of Australia (NHMRC) [400413, 400281, 199600]; California Breast Cancer Research Program [1RB-0287, 3PB-0102, 5PB-0018, 10PB-0098]; California Department of Health; National Cancer Institute's Division of Cancer Prevention and Control Surveillance, Epidemiology, and End Results Program [N01CN25403]; 'Stichting tegen Kanker' [232-2008, 196-2010]; FWO; Deutsche Krebshilfe e.V. [70-2892-BR I, 106332, 108253, 108419]; Hamburg Cancer Society; Italian Association for Cancer Research (AIRC); Italian citizens [5/1000]; Fondazione IRCCS Istituto Nazionale Tumori; Quebec Breast Cancer Foundation; Canadian Institutes of Health Research for the 'CIHR Team in Familial Risks of Breast Cancer' program [CRN-87521]; Ministry of Economic Development, Innovation and Export Trade [PSR-SIIRI-701]; Malaysian Ministry of Science, Technology and Innovation (MOSTI); Malaysian Ministry of Higher Education [UM.C/HlR/MOHE/06]; Cancer Research Initiatives Foundation (CARIF); Biomedical Research Council, Singapore [BMRC08/1/35/19/550]; National medical Research Council, Singapore [NMRC/CG/SERI/2010]; NIH [CA128978, R01CA100374, CA116167, CA176785, R01CA64277, R01CA148667, R37CA70867]; Finnish Cancer Foundation; Academy of Finland (Center of Excellence) [251314]; University of Oulu; University of Oulu Support Foundation; special Governmental EVO funds; Biobanking and Biomolecular Resources Research Infrastructure [BBMRI-NL CP16]; Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA; Marit and Hans Rausings Initiative Against Breast Cancer; Agency for Science, Technology and Research of Singapore (AstarSTAR); US National Institute of Health (NIH); Susan G. Komen Breast Cancer Foundation; Genetic Associations and Mechanisms in Oncology (GAME-ON) Network [U19 CA148065]; Yorkshire Cancer Research [S295, S299, S305PA]; Sheffield Experimental Cancer Medicine Centre; Cancer Research UK [C490/A10124, C490/A6187, C490/A10119, C536/A13086, C536/A6689, C1287/A10118, C1287/A11990, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565]; UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge; NUS start-up Grant; National University Cancer Institute Singapore (NCIS) Centre Grant; NMRC Clinician Scientist Award; Biomedical Research Council [05/1/21/19/425]; DKFZ; Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]; Breast Cancer Research Foundation; David F. and Margaret T. Grohne Family Foundation; Hellenic Cooperative Oncology Group research grant [HR R_BG/04]; Greek General Secretary for Research and Technology (GSRT) Program, Research Excellence II; European Union (European Social Fund - ESF); Greek national funds through Operational Program 'Education and Lifelong Learning' of the National Strategic Reference Framework (NSRF) - ARISTEIA; Institute of Cancer Research (ICR), London; American Cancer Society [CRTG-00-196-01-CCE]; California Cancer Research Program [00-01389 V-20170, N01-CN25403, 2II0200]; Canadian Institutes for Health Research [MOP-86727]; Cancer Council Queensland; Cancer Institute of New Jersey; Celma Mastry Ovarian Cancer Foundation; Danish Cancer Society [94-222-52]; ELAN Program of the University of Erlangen-Nuremberg; Eve Appeal; Helse Vest; Imperial Experimental Cancer Research Centre [C1312/A15589]; Norwegian Cancer Society; Norwegian Research Council; Ovarian Cancer Research Fund; Nationaal Kankerplan of Belgium; Ministry of Health Labour and Welfare of Japan; L and S Milken Foundation; Polish Ministry of Science and Higher Education [4 PO5C 028 14, 2 PO5A 068 27]; Cancer Research Initiatives Foundation; Roswell Park Cancer Institute Alliance Foundation; US National Cancer Institute [K07-CA095666, K07-CA143047, K22-CA138563, N01-CN55424, N01-PC067010, N01-PC035137, P01-CA017054, P01-CA087696, P30-CA15083, P50-CA105009, P50-CA136393, R01-CA014089, R01-CA016056, R01-CA017054, R01-CA049449, R01-CA050385, R01-CA054419, R01-CA058598, R01-CA058860, R01-CA061107, R01-CA061132, R01-CA063682, R01-CA064277, R01-CA067262, R01-CA071766, R01-CA074850, R01-CA076016, R01-CA080742, R01-CA080978, R01-CA083918, R01-CA087538, R01-CA092044, R01-095023, R01-CA106414, R01-CA122443, R01-CA112523, R01-CA114343, R01-CA126841, R01-CA136924, R01-CA149429, R03-CA113148, R03-CA115195, R37-CA070867, R37-CA70867, U01-CA069417, U01-CA071966, R01-CA063678]; US National Cancer Institute (Intramural research funds); US Army Medical Research and Material Command [DAMD17-01-1-0729, DAMD17-98-1-8659, DAMD17-02-1-0666, DAMD17-02-10669, W81XWH-10-1-0280]; National Health and Medical Research Council of Australia [400281, 199600]; German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research [01 GB 9401]; state of Baden-Wurttemberg through Medical Faculty of the University of Ulm [P.685]; Minnesota Ovarian Cancer Alliance; Mayo Foundation; Fred C. and Katherine B. Andersen Foundation; Lon V. Smith Foundation [LVS-39420]; Oak Foundation; OHSU Foundation; Mermaid I project; Rudolf-Bartling Foundation; UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; Imperial College London; University College Hospital 'Womens Health Theme'; Royal Marsden Hospital; WorkSafeBC; National Cancer Institute [UM1 CA164920, RC4CA153828]; Lithuania (BFBOCC-LT): Research Council of Lithuania grant [LIG-07/2012]; Cancer Association of South Africa (CANSA); Morris and Horowitz Familes Endowed Professorship; NEYE Foundation; Spanish Association against Cancer [AECC08]; RTICC [06/0020/1060]; Mutua Madrilena Foundation (FMMA); City of Hope Clinical Cancer Genetics Community Network (COH-CCGCRN) [SAF2010-20493]; Hereditary Cancer Research Registry; Office of the Director, National Institutes of Health; Cancer Research - UK [C1287/A10118, C12292/A11174]; NHMRC Program Grant; Greek national funds through Operational Program 'Education and Lifelong Learning' of the National Strategic Reference Framework (NSRF) - Research Funding Program of the General Secretariat for Research and Technology: ARISTEIA; European Social Fund; NIHR grant; Royal Marsden NHS Foundation Trust; University of Kansas Cancer Center [P30 CA168524]; Kansas Bioscience Authority Eminent Scholar Program; German Cancer Aid [109076]; Center for Molecular Medicine Cologne (CMMC); Ligue Nationale Contre le Cancer; Association 'Le cancer du sein, parlons-en!' Award; Canadian Institutes of Health Research for the 'CIHR Team in Familial Risks of Breast Cancer' program; French National Institute of Cancer (INCa); Non-Therapeutic Subject Registry Shared Resource at Georgetown University (NIH/NCI grant) [P30-CA051008]; Fisher Center for Familial Cancer Research; Swing Fore the Cure; GOA grant (Ghent University) [BOF10/GOA/019]; Ghent University Hospital; ISCIII (Spain) [RD12/0036/0006, 12/00539]; European Regional Development FEDER funds; Helsinki University Hospital Research Fund; Pink Ribbon grant [110005]; BBMRI grant [NWO 184.021.007/CP46]; Hong Kong Hereditary Breast Cancer Family Registry; Dr Ellen Li Charitable Foundation; Hungarian Research Grants [KTIA-OTKA CK-80745, OTKA K-112228]; Norwegian EEA Financial Mechanism [Hu0115/NA/2008-3/OP-9]; Asociacion Espanola Contra el Cancer, Spanish Health Research Fund; Carlos III Health Institute; Catalan Health Institute and Autonomous Government of Catalonia [ISCIIIRETIC RD06/0020/1051, RD12/0036/008, PI10/01422, PI10/00748, PI13/00285, PIE13/00022, 2009SGR290, 2014SGR364]; Icelandic Association 'Walking for Breast Cancer Research'; Landspitali University Hospital Research Fund; Canadian Breast Cancer Research Alliance [019511]; Ministero della Salute; Istituto Oncologico Veneto grant; Liga Portuguesa Contra o Cancro; National R&D Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea [1020350]; NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201, CA125183, R01 CA142996, 1U01CA161032]; U.S. Department of Defence Ovarian Cancer Idea award [W81XWH-10-1-0341]; MH CZ - DRO (MMCI) [00209805]; European Regional Development Fund; State Budget of the Czech Republic (RECAMO) [CZ.1.05/2.1.00/03.0101]; Charles University in Prague project [UNCE204024]; Robert and Kate Niehaus Clinical Cancer Genetics Initiative; Andrew Sabin Research Fund; Intramural Research Program of the US National Cancer Institute, NIH; Westat, Inc, Rockville, MD [NO2-CP-11019-50, N02-CP-65504]; Clalit Health Services in Israel; Israel Cancer Association; Breast Cancer Research Foundation (BCRF), NY; Russian Federation for Basic Research [13-04-92613, 14-04-93959, 15-04-01744]; NRG Oncology Statistical and Data Center [CA 37517]; NRG Oncology's Cancer Prevention and Control Committee [CA 101165]; Ohio State University Comprehensive Cancer Center; ITT (Istituto Toscano Tumori); Isreal cancer association; Swedish Cancer Society; Ralph and Marion Falk Medical Research Trust; Entertainment Industry Fund National Women's Cancer Research Alliance; CRUK; National Institutes of Health (NIH) [R01-CA102776, R01-CA083855]; Susan G. Komen Foundation; European Community's Seventh Framework Programme [223175, HEALTH-F2-2009-223175]; Post-Cancer GWAS initiative (GAME-ON initiative) [1U19 CA148537, 1U19 CA148065, 1U19 CA148112]; Department of Defence [W81XWH-10-1-0341]; Canadian Institutes of Health Research (CIHR) for CIHR Team in Familial Risks of Breast Cancer; Komen Foundation for the Cure; [KULPFV/10/016-SymBioSysII]; [P30 CA68485]; [FISPI08/1120]; [PBZ_KBN_122/P05/2004] FX Funding: BCAC: The Australian Breast Cancer Family Study (ABCFS) was supported by grant UM1 CA164920 from the National Cancer Institute (USA). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centres in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. The ABCFS was also supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia) and the Victorian Breast Cancer Research Consortium. The ABCS study was supported by the Dutch Cancer Society [grants NKI 2007-3839; 2009 4363]. The ACP study is funded by the Breast Cancer Research Trust, UK. The BBCS is funded by Cancer Research UK and Breakthrough Breast Cancer and acknowledges NHS funding to the NIHR Biomedical Research Centre, and the National Cancer Research Network (NCRN). ES is supported by NIHR Comprehensive Biomedical Research Centre, Guy's and St. Thomas' NHS Foundation Trust in partnership with King's College London, United Kingdom. IT is supported by the Oxford Biomedical Research Centre. The BSUCH study was supported by the Dietmar-Hopp Foundation, the Helmholtz Society and the German Cancer Research Center (DKFZ). The CGPS was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council and Herlev HospitalThe CNIO-BCS was supported by the Instituto de Salud Carlos III, the Red Tematica de Investigacion Cooperativa en Cancer and grants from the Asociacion Espanola Contra el Cancer and the Fondo de Investigacion Sanitario (PI11/00923 and PI12/00070). The CTS was initially supported by the California Breast Cancer Act of 1993 and the California Breast Cancer Research Fund (contract 97-10500) and is currently funded through the National Institutes of Health (R01 CA77398). Collection of cancer incidence data was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885. HAC receives support from the Lon V Smith Foundation (LVS39420). The ESTHER study was supported by a grant from the Baden Wurttemberg Ministry of Science, Research and Arts. Additional cases were recruited in the context of the VERDI study, which was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe). The GC-HBOC was supported by Deutsche Krebshilfe (107 352). The GENICA was funded by the Federal Ministry of Education and Research (BMBF) Germany grants 01KW9975/5, 01KW9976/8, 01KW9977/0 and 01KW0114, the Robert Bosch Foundation, Stuttgart, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, the Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, as well as the Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany. The HEBCS was financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society, The Nordic Cancer Union and the Sigrid Juselius Foundation. The HMBCS was supported by a grant from the Friends of Hannover Medical School and by the Rudolf Bartling Foundation.; The KBCP was financially supported by the special Government Funding (EVO) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations, and by the strategic funding of the University of Eastern Finland. kConFab is supported by a grant from the National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. Financial support for the AOCS was provided by the United States Army Medical Research and Materiel Command [DAMD17-01-1-0729], Cancer Council Victoria, Queensland Cancer Fund, Cancer Council New South Wales, Cancer Council South Australia, The Cancer Foundation of Western Australia, Cancer Council Tasmania and the National Health and Medical Research Council of Australia (NHMRC; 400413, 400281, 199600). LAABC is supported by grants (1RB-0287, 3PB-0102, 5PB-0018, 10PB-0098) from the California Breast Cancer Research Program. Incident breast cancer cases were collected by the USC Cancer Surveillance Program (CSP), which is supported under subcontract by the California Department of Health. The CSP is also part of the National Cancer Institute's Division of Cancer Prevention and Control Surveillance, Epidemiology, and End Results Program, under contract number N01CN25403. LMBC is supported by the 'Stichting tegen Kanker' (232-2008 and 196-2010). Diether Lambrechts is supported by the FWO and the KULPFV/10/016-SymBioSysII. The MARIE study was supported by the Deutsche Krebshilfe e.V. [70-2892-BR I, 106332, 108253, 108419], the Hamburg Cancer Society, the German Cancer Research Center (DKFZ) and the Federal Ministry of Education and Research (BMBF) Germany [01KH0402]. (MBCSG) is supported by grants from the Italian Association for Cancer Research (AIRC) and by funds from the Italian citizens who allocated the 5/1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects '5x1000'). The work of MTLGEBCS was supported by the Quebec Breast Cancer Foundation, the Canadian Institutes of Health Research for the 'CIHR Team in Familial Risks of Breast Cancer' program - grant # CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade - grant # PSR-SIIRI-701. MYBRCA is funded by research grants from the Malaysian Ministry of Science, Technology and Innovation (MOSTI), Malaysian Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation (CARIF). Additional controls were recruited by the Singapore Eye Research Institute, which was supported by a grant from the Biomedical Research Council (BMRC08/1/35/19/550), Singapore and the National medical Research Council, Singapore (NMRC/CG/SERI/2010). The NBHS was supported by NIH grant R01CA100374. Biological sample preparation was conducted the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485. The OBCS was supported by research grants from the Finnish Cancer Foundation, the Academy of Finland (grant number 250083, 122715 and Center of Excellence grant number 251314), the Finnish Cancer Foundation, the Sigrid Juselius Foundation, the University of Oulu, the University of Oulu Support Foundation and the special Governmental EVO funds for Oulu University Hospital-based research activities.; The Ontario Familial Breast Cancer Registry (OFBCR) was supported by grant UM1 CA164920 from the National Cancer Institute (USA). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centres in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. The ORIGO study was supported by the Dutch Cancer Society (RUL 1997-1505) and the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL CP16). The PBCS was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The pKARMA study was supported by Marit and Hans Rausings Initiative Against Breast CancerThe RBCS was funded by the Dutch Cancer Society (DDHK 2004-3124, DDHK 2009-4318). The SASBAC study was supported by funding from the Agency for Science, Technology and Research of Singapore (AstarSTAR), the US National Institute of Health (NIH) and the Susan G. Komen Breast Cancer Foundation. The SBCGS was supported primarily by NIH grants R01CA64277, R01CA148667, and R37CA70867. Biological sample preparation was conducted the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485. The scientific development and funding of this project were, in part, supported by the Genetic Associations and Mechanisms in Oncology (GAME-ON) Network U19 CA148065. The SBCS was supported by Yorkshire Cancer Research S295, S299, S305PA and Sheffield Experimental Cancer Medicine Centre. SEARCH is funded by a programme grant from Cancer Research UK [C490/A10124] and supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge. SGBCC is funded by the NUS start-up Grant, National University Cancer Institute Singapore (NCIS) Centre Grant and the NMRC Clinician Scientist Award. Additional controls were recruited by the Singapore Consortium of Cohort Studies-Multi-ethnic cohort (SCCS-MEC), which was funded by the Biomedical Research Council, grant number: 05/1/21/19/425. SKKDKFZS is supported by the DKFZ. The TNBCC was supported by: a Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a grant from the Breast Cancer Research Foundation, a generous gift from the David F. and Margaret T. Grohne Family Foundation, the Hellenic Cooperative Oncology Group research grant (HR R_BG/04) and the Greek General Secretary for Research and Technology (GSRT) Program, Research Excellence II, the European Union (European Social Fund - ESF), and Greek national funds through the Operational Program 'Education and Lifelong Learning' of the National Strategic Reference Framework (NSRF) - ARISTEIA. The UKBGS is funded by Breakthrough Breast Cancer and the Institute of Cancer Research (ICR), London. ICR acknowledges NHS funding to the NIHR Biomedical Research Centre.; OCAC: Funding of the constituent studies was provided by the American Cancer Society (CRTG-00-196-01-CCE); the California Cancer Research Program (00-01389 V-20170, N01-CN25403, 2II0200); the Canadian Institutes for Health Research (MOP-86727); Cancer Council Victoria; Cancer Council Queensland; Cancer Council New South Wales; Cancer Council South Australia; Cancer Council Tasmania; Cancer Foundation of Western Australia; the Cancer Institute of New Jersey; Cancer Research UK (C490/A6187, C490/A10119, C490/A10124, C536/A13086, C536/A6689); the Celma Mastry Ovarian Cancer Foundation; the Danish Cancer Society (94-222-52); the ELAN Program of the University of Erlangen-Nuremberg; the Eve Appeal; the Helsinki University Central Hospital Research Fund; Helse Vest; Imperial Experimental Cancer Research Centre (C1312/A15589); the Norwegian Cancer Society; the Norwegian Research Council; the Ovarian Cancer Research Fund; Nationaal Kankerplan of Belgium; Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health Labour and Welfare of Japan; the L and S Milken Foundation; the Polish Ministry of Science and Higher Education (4 PO5C 028 14, 2 PO5A 068 27); Malaysian Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation; the Roswell Park Cancer Institute Alliance Foundation; the US National Cancer Institute (K07-CA095666, K07-CA143047, K22-CA138563, N01-CN55424, N01-PC067010, N01-PC035137, P01-CA017054, P01-CA087696, P30-CA15083, P50-CA105009, P50-CA136393, R01-CA014089, R01-CA016056, R01-CA017054, R01-CA049449, R01-CA050385, R01-CA054419, R01-CA058598, R01-CA058860, R01-CA061107, R01-CA061132, R01-CA063682, R01-CA064277, R01-CA067262, R01-CA071766, R01-CA074850, R01-CA076016, R01-CA080742, R01-CA080978, R01-CA083918, R01-CA087538, R01-CA092044, R01-095023, R01-CA106414, R01-CA122443, R01-CA112523, R01-CA114343, R01-CA126841, R01-CA136924, R01-CA149429, R03-CA113148, R03-CA115195, R37-CA070867, R37-CA70867, U01-CA069417, U01-CA071966, R01-CA063678 and Intramural research funds); the US Army Medical Research and Material Command (DAMD17-98-1-8659, DAMD17-01-1-0729, DAMD17-02-1-0666, DAMD17-02-10669, W81XWH-10-1-0280); the National Health and Medical Research Council of Australia (199600 and 400281); the German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research (01 GB 9401); the state of Baden-Wurttemberg through Medical Faculty of the University of Ulm (P.685); the Minnesota Ovarian Cancer Alliance; the Mayo Foundation; the Fred C. and Katherine B. Andersen Foundation; the Lon V. Smith Foundation (LVS-39420); the Oak Foundation; the OHSU Foundation; the Mermaid I project; the Rudolf-Bartling Foundation; the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge, Imperial College London, University College Hospital 'Womens Health Theme' and the Royal Marsden Hospital; WorkSafeBC.; CIMBA (BCFR-all): This work was supported by grant UM1 CA164920 from the National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centres in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the BCFR. (BFBOCC-LT) BFBOCC is partly supported by: Lithuania (BFBOCC-LT): Research Council of Lithuania grant LIG-07/2012; (BIDMC) BIDMC is supported by the Breast Cancer Research Foundation. (BMBSA) BRCA-gene mutations and breast cancer in South African women (BMBSA) was supported by grants from the Cancer Association of South Africa (CANSA) to Elizabeth J. van Rensburg. (BRICOH) SLN was partially supported by the Morris and Horowitz Familes Endowed Professorship. (CBCS) This work was supported by the NEYE Foundation. (CNIO) This work was partially supported by Spanish Association against Cancer (AECC08), RTICC 06/0020/1060, FISPI08/1120, Mutua Madrilena Foundation (FMMA) and SAF2010-20493 (COH-CCGCRN) City of Hope Clinical Cancer Genetics Community Network and the Hereditary Cancer Research Registry, supported in part by Award Number RC4CA153828 (PI: J. Weitzel) from the National Cancer Institute and the Office of the Director, National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. (CONSIT TEAM) Funds from Italian citizens who allocated the 5x1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects '5x1000') to Siranoush Manoukian. (CORE) The CIMBA data management and data analysis were supported by Cancer Research - UK grants C12292/A11174 and C1287/A10118. SH is supported by an NHMRC Program Grant to GCT. ACA is a Cancer Research - UK Senior Cancer Research Fellow. (DEMOKRITOS) This research has been co-financed by the European Union (European Social Fund - ESF) and Greek national funds through the Operational Program 'Education and Lifelong Learning' of the National Strategic Reference Framework (NSRF) - Research Funding Program of the General Secretariat for Research and Technology: ARISTEIA. Investing in knowledge society through the European Social Fund.(DKFZ) The DKFZ study was supported by the DKFZ. (EMBRACE) EMBRACE is supported by Cancer Research UK Grants C1287/A10118 and C1287/A11990. D. Gareth Evans and Fiona Lalloo are supported by an NIHR grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. (FCCC) The authors acknowledge support from The University of Kansas Cancer Center (P30 CA168524) and the Kansas Bioscience Authority Eminent Scholar Program. (GC-HBOC) The German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC) is supported by the German Cancer Aid (grant no 109076, Rita K. Schmutzler) and by the Center for Molecular Medicine Cologne (CMMC). (GEMO) The study was supported by the Ligue Nationale Contre le Cancer; the Association 'Le cancer du sein, parlons-en!' Award; the Canadian Institutes of Health Research for the 'CIHR Team in Familial Risks of Breast Cancer' program and the French National Institute of Cancer (INCa).; (GEORGETOWN) CI received support from the Non-Therapeutic Subject Registry Shared Resource at Georgetown University (NIH/NCI grant P30-CA051008), the Fisher Center for Familial Cancer Research, and Swing Fore the Cure. (G-FAST) Kim De Leeneer is supported by GOA grant BOF10/GOA/019 (Ghent University) and spearhead financing of Ghent University Hospital. (HCSC) HCSC supported by a grant RD12/0036/0006 and 12/00539 from ISCIII (Spain), partially supported by European Regional Development FEDER funds. (HEBCS) The HEBCS was financially supported by the Helsinki University Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society and the Sigrid Juselius Foundation. (HEBON) The HEBON study is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the Netherlands Organization of Scientific Research grant NWO 91109024, the Pink Ribbon grant 110005 and the BBMRI grant NWO 184.021.007/CP46. HEBON thanks the registration teams of the Comprehensive Cancer Centre Netherlands and Comprehensive Centre South (together the Netherlands Cancer Registry) and PALGA (Dutch Pathology Registry) for part of the data collection. (HRBCP) HRBCP is supported by The Hong Kong Hereditary Breast Cancer Family Registry and the Dr Ellen Li Charitable Foundation, Hong Kong (HUNBOCS) Hungarian Breast and Ovarian Cancer Study was supported by Hungarian Research Grants KTIA-OTKA CK-80745, OTKA K-112228 and the Norwegian EEA Financial Mechanism Hu0115/NA/2008-3/OP-9. (ICO) Contract grant sponsor: Asociacion Espanola Contra el Cancer, Spanish Health Research Fund; Carlos III Health Institute; Catalan Health Institute and Autonomous Government of Catalonia. Contract grant numbers: ISCIIIRETIC RD06/0020/1051, RD12/0036/008, PI10/01422, PI10/00748, PI13/00285, PIE13/00022, 2009SGR290 and 2014SGR364. (IHCC) The IHCC was supported by Grant PBZ_KBN_122/P05/2004(ILUH) The ILUH group was supported by the Icelandic Association 'Walking for Breast Cancer Research' and by the Landspitali University Hospital Research Fund. (INHERIT) This work was supported by the Canadian Institutes of Health Research for the 'CIHR Team in Familial Risks of Breast Cancer' program, the Canadian Breast Cancer Research Alliance-grant # 019511 and the Ministry of Economic Development, Innovation and Export Trade - grant # PSR-SIIRI-701. (IOVHBOCS) IOVHBOCS is supported by Ministero della Salute and '5x1,000' Istituto Oncologico Veneto grant. (IPOBCS) This study was in part supported by Liga Portuguesa Contra o Cancro.(KCONFAB) kConFab is supported by a grant from the National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia; (KOHBRA) KOHBRA is supported by a grant from the National R&D Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea (1020350). (MAYO) MAYO is supported by NIH grants CA116167, CA128978 and CA176785, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a U.S. Department of Defence Ovarian Cancer Idea award (W81XWH-10-1-0341), a grant from the Breast Cancer Research Foundation, a generous gift from the David F. and Margaret T. Grohne Family Foundation and the Ting Tsung and Wei Fong Chao Foundation.; (MCGILL) Jewish General Hospital Weekend to End Breast Cancer, Quebec Ministry of Economic Development, Innovation and Export Trade (MODSQUAD) MODSQUAD was supported by MH CZ - DRO (MMCI, 00209805) and by the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101) to LF, and by Charles University in Prague project UNCE204024 (MZ). (MSKCC) MSKCC is supported by grants from the Breast Cancer Research Foundation, the Robert and Kate Niehaus Clinical Cancer Genetics Initiative, and the Andrew Sabin Research Fund. (NAROD) 1R01 CA149429-01. (NCI) The research of Drs MH Greene, JT Loud and PL Mai was supported by the Intramural Research Program of the US National Cancer Institute, NIH, and by support services contracts NO2-CP-11019-50 and N02-CP-65504 with Westat, Inc, Rockville, MD. (NICCC) NICCC is supported by Clalit Health Services in Israel. Some of it's activities are supported by the Israel Cancer Association and the Breast Cancer Research Foundation (BCRF), NY. (NNPIO) This work has been supported by the Russian Federation for Basic Research (grants 13-04-92613, 14-04-93959 and 15-04-01744). (NRG Oncology) This study was supported by National Cancer Institute grants to the NRG Oncology Administrative Office and Tissue Bank (CA 27469), the NRG Oncology Statistical and Data Center (CA 37517), and NRG Oncology's Cancer Prevention and Control Committee (CA 101165). (OSU CCG) OSUCCG is supported by the Ohio State University Comprehensive Cancer Center. (PBCS) This work was supported by the ITT (Istituto Toscano Tumori) grants 2011-2013. (SEABASS) Ministry of Science, Technology and Innovation, Ministry of Higher Education (UM. C/HlR/MOHE/06) and Cancer Research Initiatives Foundation. (SMC) This project was partially funded through a grant by the Isreal cancer association and the funding for the Israeli Inherited breast cancer consortium (SWE-BRCA) SWE-BRCA collaborators are supported by the Swedish Cancer Society. (UCHICAGO) UCHICAGO is supported by NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA125183), R01 CA142996, 1U01CA161032 and by the Ralph and Marion Falk Medical Research Trust, the Entertainment Industry Fund National Women's Cancer Research Alliance and the Breast Cancer research Foundation. OIO is an ACS Clinical Research Professor.(UCLA) Jonsson Comprehensive Cancer Center Foundation; Breast Cancer Research Foundation. (UCSF) UCSF Cancer Risk Program and Helen Diller Family Comprehensive Cancer Center. (UKFOCR) UKFOCR was supported by a project grant from CRUK to Paul Pharoah. (UPENN) National Institutes of Health (NIH) (R01-CA102776 and R01-CA083855; Breast Cancer Research Foundation; Susan G. Komen Foundation for the cure, Basser Research Center for BRCA. (UPITT/MWH) Frieda G. and Saul F. Shapira BRCA-Associated Cancer Research Program; Hackers for Hope Pittsburgh. (VFCTG) Victorian Cancer Agency, Cancer Australia, National Breast Cancer Foundation.; Funding for the iCOGS infrastructure came from: the European Community's Seventh Framework Programme under grant agreement no 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund and grants R01-CA122443 and P50-CA136393. NR 56 TC 2 Z9 2 U1 22 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 SEP PY 2016 VL 7 AR 12675 DI 10.1038/ncomms12675 PG 22 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DY7BV UT WOS:000385285100002 PM 27601076 ER PT J AU Palermo, V Rinalducci, S Sanchez, M Grillini, F Sommers, JA Brosh, RM Zolla, L Franchitto, A Pichierri, P AF Palermo, Valentina Rinalducci, Sara Sanchez, Massimo Grillini, Francesca Sommers, Joshua A. Brosh, Robert M., Jr. Zolla, Lello Franchitto, Annapaola Pichierri, Pietro TI CDK1 phosphorylates WRN at collapsed replication forks SO NATURE COMMUNICATIONS LA English DT Article ID WERNER-SYNDROME PROTEIN; STRAND BREAK REPAIR; DNA END RESECTION; CELL-CYCLE; HOMOLOGOUS RECOMBINATION; PATHWAY CHOICE; S-PHASE; SYNDROME HELICASE; DAMAGE RESPONSE; MRE11 COMPLEX AB Regulation of end-processing is critical for accurate repair and to switch between homologous recombination (HR) and non-homologous end joining (NHEJ). End resection is a two-stage process but very little is known about regulation of the long-range resection, especially in humans. WRN participates in one of the two alternative long-range resection pathways mediated by DNA2 or EXO1. Here we demonstrate that phosphorylation of WRN by CDK1 is essential to perform DNA2-dependent end resection at replication-related DSBs, promoting HR, replication recovery and chromosome stability. Mechanistically, S1133 phosphorylation of WRN is dispensable for relocalization in foci but is involved in the interaction with the MRE11 complex. Loss of WRN phosphorylation negatively affects MRE11 foci formation and acts in a dominant negative manner to prevent long-range resection altogether, thereby licensing NHEJ at collapsed forks. Collectively, we unveil a CDK1-dependent regulation of the WRN-DNA2-mediated resection and identify an undescribed function of WRN as a DSB repair pathway switch. C1 [Palermo, Valentina; Grillini, Francesca; Pichierri, Pietro] Ist Super Sanita, Dept Environm & Hlth, Sect Expt & Computat Carcinogenesis, I-00161 Rome, Italy. [Rinalducci, Sara; Zolla, Lello] Univ Tuscia, Dept Ecol & Biol, Prote Lab, I-01100 Viterbo, Italy. [Sanchez, Massimo] Ist Super Sanita, Dept Neurosci, Sect Gene & Cell Therapy, I-00161 Rome, Italy. [Sommers, Joshua A.; Brosh, Robert M., Jr.] NIA, Lab Mol Gerontol, NIH, NIH Biomed Res Ctr, Baltimore, MD 21224 USA. [Franchitto, Annapaola] Ist Super Sanita, Dept Environm & Hlth, Sect Mol Epidemiol, I-00161 Rome, Italy. RP Pichierri, P (reprint author), Ist Super Sanita, Dept Environm & Hlth, Sect Expt & Computat Carcinogenesis, I-00161 Rome, Italy. EM pietro.pichierri@iss.it RI Pichierri, Pietro/C-1991-2009; OI Pichierri, Pietro/0000-0002-2702-3523; RINALDUCCI, Sara/0000-0002-2703-6105 FU Fondazione Telethon [GGP12144]; investigator grants from Associazione Italiana per la Ricerca sul Cancro (AIRC) [IG17383, IG11871]; National Institutes of Health, NIA, Intramural Research Program FX We are grateful to Dr Alessandra De Masi (Universita di Roma Tre, Roma, Italy) for providing the NHEJ reporter plasmid, and to Dr Alessandro Vindigni (University of St. Louis, USA) for providing the siDNA2 oligos. We thank Dr Filomena Mazzei for critical reading of the manuscript. This work was supported by Fondazione Telethon to P.P. (grant no. GGP12144) and, in part, by investigator grants from Associazione Italiana per la Ricerca sul Cancro (AIRC) to P.P. (IG17383) and to A.F. (IG11871), and by the National Institutes of Health, NIA, Intramural Research Program to R.M.B. Jr. NR 54 TC 2 Z9 2 U1 7 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD SEP PY 2016 VL 7 AR 12880 DI 10.1038/ncomms12880 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DY8MJ UT WOS:000385384100014 PM 27634057 ER PT J AU O'Neill, CM Kazantzidis, A Ryan, MJ Barber, N Sempos, CT Durazo-Arvizu, RA Jorde, R Grimnes, G Eiriksdottir, G Gudnason, V Cotch, MF Kiely, M Webb, AR Cashman, KD AF O'Neill, Colette M. Kazantzidis, Andreas Ryan, Mary J. Barber, Niamh Sempos, Christopher T. Durazo-Arvizu, Ramon A. Jorde, Rolf Grimnes, Guri Eiriksdottir, Gudny Gudnason, Vilmundur Cotch, Mary Frances Kiely, Mairead Webb, Ann R. Cashman, Kevin D. TI Seasonal Changes in Vitamin D-Effective UVB Availability in Europe and Associations with Population Serum 25-Hydroxyvitamin D SO NUTRIENTS LA English DT Article DE vitamin D status; UVB; Europe; vitamin D intake ID STANDARDIZATION PROGRAM PROTOCOLS; D DEFICIENCY; HUMAN-SKIN; EXPOSURE; SUSCEPTIBILITY; RADIATION; CALCIUM; DIETARY; COHORT; ADULTS AB Low vitamin D status is common in Europe. The major source of vitamin D in humans is ultraviolet B (UVB)-induced dermal synthesis of cholecalciferol, whereas food sources are believed to play a lesser role. Our objectives were to assess UVB availability (Jm(-2)) across several European locations ranging from 35 degrees N to 69 degrees N, and compare these UVB data with representative population serum 25-hydroxyvitamin D (25(OH)D) data from Ireland (51-54 degrees N), Iceland (64 degrees N) and Norway (69 degrees N), as exemplars. Vitamin D-effective UVB availability was modelled for nine European countries/regions using a validated UV irradiance model. Standardized serum 25(OH)D data was accessed from the EC-funded ODIN project. The results showed that UVB availability decreased with increasing latitude (from 35 degrees N to 69 degrees N), while all locations exhibited significant seasonal variation in UVB. The UVB data suggested that the duration of vitamin D winters ranged from none (at 35 degrees N) to eight months (at 69 degrees N). The large seasonal fluctuations in serum 25(OH)D in Irish adults was much dampened in Norwegian and Icelandic adults, despite considerably lower UVB availability at these northern latitudes but with much higher vitamin D intakes. In conclusion, increasing the vitamin D intake can ameliorate the impact of low UVB availability on serum 25(OH)D status in Europe. C1 [O'Neill, Colette M.; Ryan, Mary J.; Barber, Niamh; Kiely, Mairead; Cashman, Kevin D.] Univ Coll Cork, Sch Food & Nutr Sci, Cork Ctr Vitamin & Nutr Res D, Cork T12 YN60, Ireland. [Kazantzidis, Andreas] Univ Patras, Dept Phys, Lab Atmospher Phys, Patras 26504, Greece. [Kazantzidis, Andreas; Webb, Ann R.] Univ Manchester, Sch Earth Atmospher & Environm Sci, Manchester M13 9PL, Lancs, England. [Sempos, Christopher T.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Durazo-Arvizu, Ramon A.] Loyola Univ, Dept Publ Hlth Sci, Stritch Sch Med, Chicago, IL 60153 USA. [Jorde, Rolf; Grimnes, Guri] UiT, Dept Clin Med, Tromso Endocrine Res Grp, N-9019 Tromso, Norway. [Eiriksdottir, Gudny; Gudnason, Vilmundur] Iceland Heart Assoc, IS-201 Kopavogur, Iceland. [Gudnason, Vilmundur] Univ Iceland, IS-101 Reykjavik, Iceland. [Cotch, Mary Frances] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Kiely, Mairead] Univ Coll Cork, Irish Ctr Fetal & Neonatal Translat Res, Cork T12 YN60, Ireland. [Cashman, Kevin D.] Univ Coll Cork, Dept Med, Cork T12 YN60, Ireland. RP Cashman, KD (reprint author), Univ Coll Cork, Sch Food & Nutr Sci, Cork Ctr Vitamin & Nutr Res D, Cork T12 YN60, Ireland.; Cashman, KD (reprint author), Univ Coll Cork, Dept Med, Cork T12 YN60, Ireland. EM colette.oneill@ucc.ie; akaza@upatras.gr; 112361636@umail.ucc.ie; 112473748@umail.ucc.ie; semposch@od.nih.gov; rdurazo@luc.edu; Rolf.Jorde@unn.no; Guri.Grimnes@unn.no; gudny@hjarta.is; villi@hjarta.is; mfc@nei.nih.gov; m.kiely@ucc.ie; ann.webb@manchester.ac.uk; k.cashman@ucc.ie OI Cashman, Kevin/0000-0002-8185-1039 FU European Union's Seventh Framework Programme (FP7) [613977] FX The research leading to these results has received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 613977 (ODIN). NR 38 TC 1 Z9 1 U1 6 U2 6 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 2072-6643 J9 NUTRIENTS JI Nutrients PD SEP PY 2016 VL 8 IS 9 AR 533 DI 10.3390/nu8090533 PG 15 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DZ0MM UT WOS:000385534000016 ER PT J AU Chattaway, J Ramirez-Valdez, RA Chappell, PE Caesar, JJE Lea, SM Kaufman, J AF Chattaway, John Ramirez-Valdez, R. Andrei Chappell, Paul E. Caesar, Joseph J. E. Lea, Susan M. Kaufman, Jim TI Different modes of variation for each BG lineage suggest different functions SO OPEN BIOLOGY LA English DT Article DE avian; gene conversion; segmental exchange; selection; SKINT; B-G ID MAJOR HISTOCOMPATIBILITY COMPLEX; GENE CONVERSION; IMMUNOGLOBULIN SUPERFAMILY; MULTIGENE FAMILY; IG SUPERFAMILY; MILK-FAT; T-CELLS; CHICKEN; REGION; BUTYROPHILINS AB Mammalian butyrophilins have various important functions, one for lipid binding but others as ligands for co-inhibition of alpha beta T cells or for stimulation of gamma delta T cells in the immune system. The chicken BG homologues are dimers, with extracellular immunoglobulin variable (V) domains joined by cysteines in the loop equivalent to complementarity-determining region 1 (CDR1). BG genes are found in three genomic locations: BG0 on chromosome 2, BG1 in the classical MHC (the BF-BL region) and many BG genes in the BG region just outside the MHC. Here, we show that BG0 is virtually monomorphic, suggesting housekeeping function(s) consonant with the ubiquitous tissue distribution. BG1 has allelic polymorphism but minimal sequence diversity, with the few polymorphic residues at the interface of the two V domains, suggesting that BG1 is recognized by receptors in a conserved fashion. Any phenotypic variation should be due to the intracellular region, with differential exon usage between alleles. BG genes in the BG region can generate diversity by exchange of sequence cassettes located in loops equivalent to CDR1 and CDR2, consonant with recognition of many ligands or antigens for immune defence. Unlike the mammalian butyrophilins, there are at least three modes by which BG genes evolve. C1 [Chattaway, John; Ramirez-Valdez, R. Andrei; Kaufman, Jim] Univ Cambridge, Dept Pathol, Cambridge CB2 1QP, England. [Chappell, Paul E.; Caesar, Joseph J. E.; Lea, Susan M.] Univ Oxford, Sir William Dunn Sch Pathol, Oxford 0X1 3RE, England. [Kaufman, Jim] Univ Cambridge, Dept Vet Med, Cambridge CB3 0ES, England. [Ramirez-Valdez, R. Andrei] NIAID, Vaccine Res Ctr, NIH, 40 Convent Dr,Bldg 40, Bethesda, MA 20892 USA. RP Kaufman, J (reprint author), Univ Cambridge, Dept Pathol, Cambridge CB2 1QP, England.; Kaufman, J (reprint author), Univ Cambridge, Dept Vet Med, Cambridge CB3 0ES, England. EM jfk31@cam.ac.uk FU Wellcome Trust [RG49834, 089305]; Senior Investigator Award; Biotechnology and Biological Sciences Research Council (BBSRC) FX This work was supported by the Wellcome Trust, through studentship RG49834 for J.J.E.C., programme grant 089305 to J.K. and a Senior Investigator Award to S.M.L., as well as by the Biotechnology and Biological Sciences Research Council (BBSRC) through a studentship to P.E.C. NR 33 TC 0 Z9 0 U1 1 U2 1 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 2046-2441 J9 OPEN BIOL JI Open Biol PD SEP PY 2016 VL 6 IS 9 AR 160188 DI 10.1098/rsob.160188 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DY9DR UT WOS:000385434300008 ER PT J AU Wang, SB Dougherty, EJ Danner, RL AF Wang, Shuibang Dougherty, Edward J. Danner, Robert L. TI PPAR gamma signaling and emerging opportunities for improved therapeutics SO PHARMACOLOGICAL RESEARCH LA English DT Review DE Peroxisome proliferator-activated receptor gamma (PPAR gamma); Thiazolidinediones (TZDs); G protein-coupled receptor 40 (GPR40); P38 mitogen-activated protein kinase (p38 MAPK); PPAR gamma co-activator-1alpha (PGC-1 alpha); E1A binding protein p300 (EP300) ID PROLIFERATOR-ACTIVATED-RECEPTOR; STIMULATED INSULIN-SECRETION; TYPE-2 DIABETIC-PATIENTS; PANCREATIC BETA-CELLS; NITRO-FATTY ACIDS; PEROXISOME-PROLIFERATOR; PROTEIN-KINASE; 15-DEOXY-DELTA(12,14)-PROSTAGLANDIN J(2); ADIPOCYTE DIFFERENTIATION; GENE-EXPRESSION AB Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a ligand-activated nuclear receptor that regulates glucose and lipid metabolism, endothelial function and inflammation. Rosiglitazone (RGZ) and other thiazolidinedione (TZD) synthetic ligands of PPAR gamma are insulin sensitizers that have been used for the treatment of type 2 diabetes. However, undesirable side effects including weight gain, fluid retention, bone loss, congestive heart failure, and a possible increased risk of myocardial infarction and bladder cancer, have limited the use of TZDs. Therefore, there is a need to better understand PPAR gamma signaling and to develop safer and more effective PPAR gamma-directed therapeutics. In addition to PPAR gamma itself, many PPAR gamma ligands including TZDs bind to and activate G protein-coupled receptor 40 (GPR40), also known as free fatty acid receptor 1. GPR40 signaling activates stress kinase pathways that ultimately regulate downstream PPAR gamma responses. Recent studies in human endothelial cells have demonstrated that RGZ activation of GPR40 is essential to the optimal propagation of PPAR gamma genomic signaling. RGZ/GPR40/p38 MAPK signaling induces and activates PPAR gamma co-activator-1 alpha, and recruits E1A binding protein p300 to the promoters of target genes, markedly enhancing PPAR gamma-dependent transcription. Therefore in endothelium, GPR40 and PPAR gamma function as an integrated signaling pathway. However, GPR40 can also activate ERK1/2, a proinflammatory kinase that directly phosphorylates and inactivates PPAR gamma. Thus the role of GPR40 in PPAR gamma signaling may have important implications for drug development. Ligands that strongly activate PPAR gamma, but do not bind to or activate GPR40 may be safer than currently approved PPAR gamma agonists. Alternatively, biased GPR40 agonists might be sought that activate both p38 MAPK and PPAR gamma, but not ERK1/2, avoiding its harmful effects on PPAR gamma signaling, insulin resistance and inflammation. Such next generation drugs might be useful in treating not only type 2 diabetes, but also diverse chronic and acute forms of vascular inflammation such as atherosclerosis and septic shock. Published by Elsevier Ltd. C1 [Wang, Shuibang; Dougherty, Edward J.; Danner, Robert L.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Wang, SB; Danner, RL (reprint author), NIH, Dept Crit Care Med, 10 Ctr Dr,Room 2C145, Bethesda, MD 20892 USA. EM swang@cc.nih.gov; rdanner@nih.gov FU National Institutes of Health intramural funds FX This work was supported, in whole or in part, by National Institutes of Health intramural funds. NR 138 TC 3 Z9 3 U1 16 U2 16 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-6618 J9 PHARMACOL RES JI Pharmacol. Res. PD SEP PY 2016 VL 111 BP 76 EP 85 DI 10.1016/j.phrs.2016.02.028 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DY0JV UT WOS:000384784000007 PM 27268145 ER PT J AU Singh, NS Bernier, M Wainer, IW AF Singh, Nagendra S. Bernier, Michel Wainer, Irving W. TI Selective GPR55 antagonism reduces chemoresistance in cancer cells SO PHARMACOLOGICAL RESEARCH LA English DT Article DE GPR55; Multidrug resistance (MDR); Pyruvate kinase M2 (PKM2); beta-Catenin; Hypoxia-inducible factor 1 alpha (HIF-1 alpha); Cancer biomarkers ID P-GLYCOPROTEIN EXPRESSION; GROWTH-FACTOR RECEPTOR; MULTIDRUG-RESISTANCE; CATENIN PATHWAY; CARCINOMA CELLS; IN-VITRO; PROTEIN; TRANSPORTERS; INVOLVEMENT; ACTIVATION AB G protein-coupled receptor 55 (GPR55) possesses pro-oncogenic activity and its function can be competitively inhibited with (R,R')-4'-methoxy-1-naphthylfenoterol (MNF) through poorly defined signaling pathways. Here, the anti-tumorigenic effect of MNF was investigated in the human pancreatic cancer cell line, PANC-1, by focusing on the expression of known cancer biomarkers and the expression and function of multidrug resistance (MDR) exporters such as P-glycoprotein (Pgp) and breast cancer resistance protein,(BCRP). Incubation of PANC1 cells with MNF (1 mu M) for 24 h significantly decreased EGF receptor, pyruvate kinase M2 (PKM2), and beta-catenin protein levels and was accompanied by significant reduction in nuclear accumulation of HIF-1 alpha and the phospho-active forms of PKM2 and beta-catenin. Inhibition of GPR55 with either MNF or the GPR55 antagonist CID 16020046 lowered the amount of MDR proteins in total cellular extracts while diminishing the nuclear expression of Pgp and BCRP. There was significant nuclear accumulation of doxorubicin in PANC-1 cells treated with MNF and the pre-incubation with MNF increased the cytotoxicity of doxorubicin and gemcitabine in these cells. Potentiation of doxorubicin cytotoxicity by MNF was also observed in MDA-MB-231 breast cancer cells and U87MG glioblastoma cells, which express high levels of GPR55. The data suggest that inhibition of GPR55 activity produces antitumor effects via attenuation of the MEK/ERK and PI3K-AICT pathways leading to a reduction in the expression and function of MDR proteins. (C) Published by Elsevier Ltd. C1 [Singh, Nagendra S.; Wainer, Irving W.] NIA, Clin Invest Lab, NIH, Baltimore, MD 21224 USA. [Bernier, Michel] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. [Wainer, Irving W.] Mitchell Woods Pharmaceut, Shelton, CT 06484 USA. RP Bernier, M (reprint author), NIA, Translat Gerontol Branch, Biomed Res Ctr, 251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. EM nagendrasingh1980@gmail.com; Bernierm@mail.nih.gov; iwwainer@mitchellwoods.com FU Intramural Research Program of the National Institute on Aging at NIH FX This work was supported by funds from the Intramural Research Program of the National Institute on Aging at NIH. This paper is subject to the NIH Public Access Policy. NR 46 TC 0 Z9 0 U1 2 U2 2 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-6618 J9 PHARMACOL RES JI Pharmacol. Res. PD SEP PY 2016 VL 111 BP 757 EP 766 DI 10.1016/j.phrs.2016.07.013 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DY0JV UT WOS:000384784000073 PM 27423937 ER PT J AU El Najjar, F Cifuentes-Munoz, N Chen, J Zhu, HN Buchholz, UJ Moncman, CL Dutch, RE AF El Najjar, Farah Cifuentes-Munoz, Nicolas Chen, Jing Zhu, Haining Buchholz, Ursula J. Moncman, Carole L. Dutch, Rebecca Ellis TI Human metapneumovirus Induces Reorganization of the Actin Cytoskeleton for Direct Cell-to-Cell Spread SO PLOS PATHOGENS LA English DT Article ID RESPIRATORY SYNCYTIAL VIRUS; HUMAN MONOCLONAL-ANTIBODY; MEASLES-VIRUS; FUSION PROTEIN; TUNNELING NANOTUBES; IN-VIVO; VIROLOGICAL SYNAPSES; HIV-1 TRANSMISSION; PARTICLE FORMATION; EPITHELIAL-CELLS AB Paramyxovirus spread generally involves assembly of individual viral particles which then infect target cells. We show that infection of human bronchial airway cells with human metapneumovirus (HMPV), a recently identified paramyxovirus which causes significant respiratory disease, results in formation of intercellular extensions and extensive networks of branched cell-associated filaments. Formation of these structures is dependent on actin, but not microtubule, polymerization. Interestingly, using a co-culture assay we show that conditions which block regular infection by HMPV particles, including addition of neutralizing antibodies or removal of cell surface heparan sulfate, did not prevent viral spread from infected to new target cells. In contrast, inhibition of actin polymerization or alterations to Rho GTPase signaling pathways significantly decreased cell-to-cell spread. Furthermore, viral proteins and viral RNA were detected in intercellular extensions, suggesting direct transfer of viral genetic material to new target cells. While roles for paramyxovirus matrix and fusion proteins in membrane deformation have been previously demonstrated, we show that the HMPV phosphoprotein extensively co-localized with actin and induced formation of cellular extensions when transiently expressed, supporting a new model in which a paramyxovirus phosphoprotein is a key player in assembly and spread. Our results reveal a novel mechanism for HMPV direct cell-to-cell spread and provide insights into dissemination of respiratory viruses. C1 [El Najjar, Farah; Cifuentes-Munoz, Nicolas; Chen, Jing; Zhu, Haining; Moncman, Carole L.; Dutch, Rebecca Ellis] Univ Kentucky, Dept Mol & Cellular Biochem, Lexington, KY 40506 USA. [Buchholz, Ursula J.] NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. RP Dutch, RE (reprint author), Univ Kentucky, Dept Mol & Cellular Biochem, Lexington, KY 40506 USA. EM rdutc2@uky.edu FU NIH from National Center for Research Resources [R01AI051517, 2P20RR020171]; Intramural Program of the NIH, National Institute of Allergy and Infectious Diseases; COBRE grant from NIH/NIGMS [P20GM103486] FX RED was supported by NIH grants R01AI051517 and 2P20RR020171 from the National Center for Research Resources. UJB was supported by the Intramural Program of the NIH, National Institute of Allergy and Infectious Diseases. The University of Kentucky Proteomics Core and the Department Imaging Core were partially supported by a COBRE grant from the NIH/NIGMS (P20GM103486). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 100 TC 1 Z9 1 U1 4 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD SEP PY 2016 VL 12 IS 9 AR e1005922 DI 10.1371/journal.ppat.1005922 PG 30 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA DZ1TB UT WOS:000385621900061 PM 27683250 ER PT J AU Ganti, K Massimi, P Manzo-Merino, J Tomaic, V Pim, D Playford, MP Lizano, M Roberts, S Kranjec, C Doorbar, J Banks, L AF Ganti, Ketaki Massimi, Paola Manzo-Merino, Joaquin Tomaic, Vjekoslav Pim, David Playford, Martin P. Lizano, Marcela Roberts, Sally Kranjec, Christian Doorbar, John Banks, Lawrence TI Interaction of the Human Papillomavirus E6 Oncoprotein with Sorting Nexin 27 Modulates Endocytic Cargo Transport Pathways SO PLOS PATHOGENS LA English DT Article ID TUMOR-SUPPRESSOR PROTEIN; CERVICAL-CANCER; BINDING MOTIF; CELL-LINE; IN-VIVO; DOMAIN; TYPE-16; DIFFERENTIATION; DEGRADATION; POLARITY AB A subset of high-risk Human Papillomaviruses ( HPVs) are the causative agents of a large number of human cancers, of which cervical is the most common. Two viral oncoproteins, E6 and E7, contribute directly towards the development and maintenance of malignancy. A characteristic feature of the E6 oncoproteins from cancer-causing HPV types is the presence of a PDZ binding motif ( PBM) at its C-terminus, which confers interaction with cellular proteins harbouring PDZ domains. Here we show that this motif allows E6 interaction with Sorting Nexin 27 ( SNX27), an essential component of endosomal recycling pathways. This interaction is highly conserved across E6 proteins from multiple high-risk HPV types and is mediated by a classical PBM-PDZ interaction but unlike many E6 targets, SNX27 is not targeted for degradation by E6. Rather, in HPV-18 positive cell lines the association of SNX27 with components of the retromer complex and the endocytic transport machinery is altered in an E6 PBM-dependent manner. Analysis of a SNX27 cargo, the glucose transporter GLUT1, reveals an E6-dependent maintenance of GLUT1 expression and alteration in its association with components of the endocytic transport machinery. Furthermore, knockdown of E6 in HPV-18 positive cervical cancer cells phenocopies the loss of SNX27, both in terms of GLUT1 expression levels and its vesicular localization, with a concomitant marked reduction in glucose uptake, whilst loss of SNX27 results in slower cell proliferation in low nutrient conditions. These results demonstrate that E6 interaction with SNX27 can alter the recycling of cargo molecules, one consequence of which is modulation of nutrient availability in HPV transformed tumour cells. C1 [Ganti, Ketaki; Massimi, Paola; Tomaic, Vjekoslav; Pim, David; Banks, Lawrence] Int Ctr Genet Engn & Biotechnol, Padriciano, Trieste, Italy. [Manzo-Merino, Joaquin] Univ Nacl Autonoma Mexico, Inst Nacl Cancerol, Mexico Inst Invest Biomed, CONACyT, Col Secc 16, Tlalpan, Mexico. [Tomaic, Vjekoslav] Rudjer Boskovic Inst, Div Mol Med, Zagreb, Croatia. [Playford, Martin P.] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Lizano, Marcela] Univ Nacl Autonoma Mexico, Mexico Inst Invest Biomed, Inst Nacl Cancerol, Col Secc 16, Tlalpan, Mexico. [Roberts, Sally] Univ Birmingham, Inst Canc & Genom Sci, Birmingham, W Midlands, England. [Kranjec, Christian; Doorbar, John] Univ Cambridge, Dept Pathol, Tennis Court Rd, Cambridge, England. RP Banks, L (reprint author), Int Ctr Genet Engn & Biotechnol, Padriciano, Trieste, Italy. EM banks@icgeb.org FU Associazione Italiana per la Ricerca sul Cancro (AIRC) [IG14025]; Wellcome Trust [0923450/Z10/Z, 09345/B/10/Z]; CONACYT Mexico [SS/IMSS/ISSSTE-CONACYT S0008-2015-1 261499] FX This work was supported by research grants from the Associazione Italiana per la Ricerca sul Cancro (AIRC) (www.airc.it) to LB (Grant number IG14025) and the Wellcome Trust (www.wellcome.ac.uk) Grant number 0923450/Z10/Z to LB and Grant number 09345/B/10/Z to SR. CONACYT Mexico Grant number SS/IMSS/ISSSTE-CONACYT S0008-2015-1 261499 to ML. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 1 Z9 1 U1 4 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD SEP PY 2016 VL 12 IS 9 AR e1005854 DI 10.1371/journal.ppat.1005854 PG 22 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA DZ1TB UT WOS:000385621900025 PM 27649450 ER PT J AU Hall, OJ Limjunyawong, N Vermillion, MS Robinson, DP Wohlgemuth, N Pekosz, A Mitzner, W Klein, SL AF Hall, Olivia J. Limjunyawong, Nathachit Vermillion, Meghan S. Robinson, Dionne P. Wohlgemuth, Nicholas Pekosz, Andrew Mitzner, Wayne Klein, Sabra L. TI Progesterone-Based Therapy Protects Against Influenza by Promoting Lung Repair and Recovery in Females SO PLOS PATHOGENS LA English DT Article ID REGULATORY T-CELLS; VIRUS-INFECTION; EPITHELIAL-CELLS; TISSUE PROTECTION; DENDRITIC CELLS; C57BL/6J MICE; AMPHIREGULIN; AIRWAY; DIFFERENTIATION; DISEASES AB Over 100 million women use progesterone therapies worldwide. Despite having immunomodulatory and repair properties, their effects on the outcome of viral diseases outside of the reproductive tract have not been evaluated. Administration of exogenous progesterone ( at concentrations that mimic the luteal phase) to progesterone-depleted adult female mice conferred protection from both lethal and sublethal influenza A virus ( IAV) infection. Progesterone treatment altered the inflammatory environment of the lungs, but had no effects on viral load. Progesterone treatment promoted faster recovery by increasing TGF-beta, IL-6, IL-22, numbers of regulatory Th17 cells expressing CD39, and cellular proliferation, reducing protein leakage into the airway, improving pulmonary function, and upregulating the epidermal growth factor amphiregulin ( AREG) in the lungs. Administration of rAREG to progesterone-depleted females promoted pulmonary repair and improved the outcome of IAV infection. Progesterone-treatment of AREG-deficient females could not restore protection, indicating that progesterone-mediated induction of AREG caused repair in the lungs and accelerated recovery from IAV infection. Repair and production of AREG by damaged respiratory epithelial cell cultures in vitro was increased by progesterone. Our results illustrate that progesterone is a critical host factor mediating production of AREG by epithelial cells and pulmonary tissue repair following infection, which has important implications for women's health. C1 [Hall, Olivia J.; Vermillion, Meghan S.; Robinson, Dionne P.; Wohlgemuth, Nicholas; Pekosz, Andrew; Klein, Sabra L.] Johns Hopkins Bloomberg Sch Publ Hlth, W Harry Feinstone Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. [Limjunyawong, Nathachit; Pekosz, Andrew; Mitzner, Wayne] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD USA. [Vermillion, Meghan S.] Johns Hopkins Univ, Sch Med, Dept Mol & Comparat Pathobiol, Baltimore, MD USA. [Klein, Sabra L.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biochem & Mol Biol, Baltimore, MD 21205 USA. [Limjunyawong, Nathachit] Johns Hopkins Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD USA. [Robinson, Dionne P.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD USA. RP Klein, SL (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, W Harry Feinstone Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA.; Klein, SL (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biochem & Mol Biol, Baltimore, MD 21205 USA. EM Sklein2@jhu.edu OI Wohlgemuth, Nicholas/0000-0002-6450-6452 FU National Institutes of Health, National Institute of Allergy and Infectious Diseases [AI112838, HHSN272201400007C, AI097417] FX This study was supported by grants from the National Institutes of Health, National Institute of Allergy and Infectious Diseases (grant numbers AI112838 and HHSN272201400007C to SLK and AI097417 to AP). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 60 TC 2 Z9 2 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD SEP PY 2016 VL 12 IS 9 AR e1005840 DI 10.1371/journal.ppat.1005840 PG 22 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA DZ1TB UT WOS:000385621900020 PM 27631986 ER PT J AU Hughson, AG Race, B Kraus, A Sangare, LR Robins, L Groveman, BR Saijo, E Phillips, K Contreras, L Dhaliwal, V Manca, M Zanusso, G Terry, D Williams, JF Caughey, B AF Hughson, Andrew G. Race, Brent Kraus, Allison Sangare, Laura R. Robins, Lori Groveman, Bradley R. Saijo, Eri Phillips, Katie Contreras, Luis Dhaliwal, Virkamal Manca, Matteo Zanusso, Gianluigi Terry, Daniel Williams, Jeffrey F. Caughey, Byron TI Inactivation of Prions and Amyloid Seeds with Hypochlorous Acid SO PLOS PATHOGENS LA English DT Article ID QUAKING-INDUCED CONVERSION; CREUTZFELDT-JAKOB-DISEASE; CHRONIC WASTING DISEASE; BOVINE SPONGIFORM ENCEPHALOPATHY; CEREBROSPINAL-FLUID; NASAL BRUSHINGS; SCRAPIE PRIONS; STEEL-SURFACE; TRANSMISSION; VIRUS AB Hypochlorous acid (HOCl) is produced naturally by neutrophils and other cells to kill conventional microbes in vivo. Synthetic preparations containing HOCl can also be effective as microbial disinfectants. Here we have tested whether HOCl can also inactivate prions and other self-propagating protein amyloid seeds. Prions are deadly pathogens that are notoriously difficult to inactivate, and standard microbial disinfection protocols are often inadequate. Recommended treatments for prion decontamination include strongly basic (pH >=similar to 12) sodium hypochlorite bleach, >= 1 N sodium hydroxide, and/or prolonged autoclaving. These treatments are damaging and/or unsuitable for many clinical, agricultural and environmental applications. We have tested the anti-prion activity of a weakly acidic aqueous formulation of HOCl (BrioHOCl) that poses no apparent hazard to either users or many surfaces. For example, BrioHOCl can be applied directly to skin and mucous membranes and has been aerosolized to treat entire rooms without apparent deleterious effects. Here, we demonstrate that immersion in BrioHOCl can inactivate not only a range of target microbes, including spores of Bacillus subtilis, but also prions in tissue suspensions and on stainless steel. Real-time quaking-induced conversion (RT-QuIC) assays showed that BrioHOCl treatments eliminated all detectable prion seeding activity of human Creutzfeldt-Jakob disease, bovine spongiform encephalopathy, cervine chronic wasting disease, sheep scrapie and hamster scrapie; these findings indicated reductions of >= 10(3)- to 10(6)-fold. Transgenic mouse bioassays showed that all detectable hamster-adapted scrapie infectivity in brain homogenates or on steel wires was eliminated, representing reductions of >=similar to 10(5.75)-fold and >10(4)-fold, respectively. Inactivation of RT-QuIC seeding activity correlated with free chlorine concentration and higher order aggregation or destruction of proteins generally, including prion protein. BrioHOCl treatments had similar effects on amyloids composed of human a-synuclein and a fragment of human tau. These results indicate that HOCl can block the self-propagating activity of prions and other amyloids. C1 [Hughson, Andrew G.; Race, Brent; Kraus, Allison; Groveman, Bradley R.; Saijo, Eri; Phillips, Katie; Manca, Matteo; Caughey, Byron] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Sangare, Laura R.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Robins, Lori; Contreras, Luis; Dhaliwal, Virkamal] Univ Washington, Dept Phys Sci, Bothell, WA USA. [Zanusso, Gianluigi] Univ Verona, Dept Neurosci Biomed & Movement Sci, Policlin GB Rossi, Verona, Italy. [Terry, Daniel; Williams, Jeffrey F.] Briotech Inc, Woodinville, WA USA. RP Caughey, B (reprint author), NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM bcaughey@nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases FX This work was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (BC), a gift to LR's department from BrioTech Inc and self-funding by BrioTech Inc (DT). The NIAID administration had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. However, the authors from BrioTech, Inc played roles in all of these aspects of the study. NR 77 TC 1 Z9 1 U1 9 U2 9 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 SEP PY 2016 VL 12 IS 9 AR e1005914 DI 10.1371/journal.ppat.1005914 PG 27 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA DZ1TB UT WOS:000385621900059 PM 27685252 ER PT J AU Raghwani, J Rose, R Sheridan, I Lemey, P Suchard, MA Santantonio, T Farci, P Klenerman, P Pybus, OG AF Raghwani, Jayna Rose, Rebecca Sheridan, Isabelle Lemey, Philippe Suchard, Marc A. Santantonio, Teresa Farci, Patrizia Klenerman, Paul Pybus, Oliver G. TI Exceptional Heterogeneity in Viral Evolutionary Dynamics Characterises Chronic Hepatitis C Virus Infection SO PLOS PATHOGENS LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; BLOOD MONONUCLEAR-CELLS; ADJACENT NONTUMOR TISSUE; PROOF-OF-CONCEPT; PHASE 2A COHORT; LIVER-TRANSPLANTATION; GENOTYPE 1; TYPE-1 INFECTION; HIV-1 INFECTION; IN-VIVO AB The treatment of HCV infection has seen significant progress, particularly since the approval of new direct-acting antiviral drugs. However these clinical achievements have been made despite an incomplete understanding of HCV replication and within-host evolution, especially compared with HIV-1. Here, we undertake a comprehensive analysis of HCV within-host evolution during chronic infection by investigating over 4000 viral sequences sampled longitudinally from 15 HCV-infected patients. We compare our HCV results to those from a well-studied HIV-1 cohort, revealing key differences in the evolutionary behaviour of these two chronic-infecting pathogens. Notably, we find an exceptional level of heterogeneity in the molecular evolution of HCV, both within and among infected individuals. Furthermore, these patterns are associated with the long-term maintenance of viral lineages within patients, which fluctuate in relative frequency in peripheral blood. Together, our findings demonstrate that HCV replication behavior is complex and likely comprises multiple viral subpopulations with distinct evolutionary dynamics. The presence of a structured viral population can explain apparent paradoxes in chronic HCV infection, such as rapid fluctuations in viral diversity and the reappearance of viral strains years after their initial detection. C1 [Raghwani, Jayna; Pybus, Oliver G.] Univ Oxford, Dept Zool, Oxford, England. [Rose, Rebecca] BioInfoExperts, Los Angeles, CA USA. [Sheridan, Isabelle; Klenerman, Paul] Univ Oxford, Peter Medawar Bldg Pathogen Res, Oxford, England. [Lemey, Philippe] KU Leuven Univ Leuven, Rega Inst, Dept Microbiol & Immunol, Leuven, Belgium. [Suchard, Marc A.] Univ Calif Los Angeles, Dept Biomath, Los Angeles, CA USA. [Suchard, Marc A.] Univ Calif Los Angeles, Dept Biostat, Los Angeles, CA USA. [Suchard, Marc A.] Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA USA. [Santantonio, Teresa] Univ Foggia, Clin Infect Dis, Foggia, Italy. [Farci, Patrizia] NIAID, Hepat Pathogenesis Sect, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Raghwani, J; Pybus, OG (reprint author), Univ Oxford, Dept Zool, Oxford, England. EM jayna.raghwani@zoo.ox.ac.uk; oliver.pybus@zoo.ox.ac.uk OI Raghwani, Jayna/0000-0001-8538-4995; klenerman, paul/0000-0003-4307-9161 FU Oxford Martin School; Medical Research Council under Methodology Research Fellowship [99204]; European Research Council under European Union / ERC [614725-PATHPHYLODYN]; National Institute of Allergy and Infectious Diseases (NIAID); WT grant [WT091663]; NIHR Biomedical Research Centre, Oxford FX JR is supported by the Oxford Martin School. RR received funding from the Medical Research Council under a Methodology Research Fellowship grant agreement no. 99204. OGP received funding from the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013) / ERC grant agreement no. 614725-PATHPHYLODYN. PF is supported by the intramural research program of the National Institute of Allergy and Infectious Diseases (NIAID). PK is supported by WT grant (WT091663 MA), the Oxford Martin School and the NIHR Biomedical Research Centre, Oxford. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 78 TC 1 Z9 1 U1 6 U2 6 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 SEP PY 2016 VL 12 IS 9 AR e1005894 DI 10.1371/journal.ppat.1005894 PG 20 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA DZ1TB UT WOS:000385621900051 PM 27631086 ER PT J AU Epstein, JA Blank, PS Searle, BC Catlin, AD Cologna, SM Olson, MT Backlund, PS Coorssen, JR Yergey, AL AF Epstein, Jonathan A. Blank, Paul S. Searle, Brian C. Catlin, Aaron D. Cologna, Stephanie M. Olson, Matthew T. Backlund, Peter S. Coorssen, Jens R. Yergey, Alfred L. TI ProteinProcessor: A probabilistic analysis using mass accuracy and the MS spectrum SO PROTEOMICS LA English DT Article DE Bayesian analysis; Bioinformatics; Protein sequencing; MALDI; Tandem mass spectrometry ID PROTEIN IDENTIFICATION; SEQUENCE DATABASES; STATISTICAL-MODEL; SPECTROMETRY AB Current approaches to protein identification rely heavily on database matching of fragmentation spectra or precursor peptide ions. We have developed a method for MALDI TOF-TOF instrumentation that uses peptide masses and their measurement errors to confirm protein identifications from a first pass MS/MS database search. The method uses MS1-level spectral data that have heretofore been ignored by most search engines. This approach uses the distribution of mass errors of peptide matches in the MS1 spectrum to develop a probability model that is independent of the MS/MS database search identifications. Peptide mass matches can come from both precursor ions that have been fragmented as well as those that are tentatively identified by accurate mass alone. This additional corroboration enables us to confirm protein identifications to MS/MS-based scores that are otherwise considered to be only of moderate quality. Straightforward and easily applicable to current proteomic analyses, this tool termed "Protein-Processor" provides a robust and invaluable addition to current protein identification tools. C1 [Epstein, Jonathan A.; Catlin, Aaron D.; Backlund, Peter S.; Yergey, Alfred L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Blank, Paul S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Integrat Biophys, NIH, Bethesda, MD USA. [Searle, Brian C.] Proteome Software Inc, Portland, OR USA. [Cologna, Stephanie M.] Univ Illinois, Dept Chem, Chicago, IL USA. [Olson, Matthew T.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Coorssen, Jens R.] Brock Univ, Fac Grad Studies, St Catharines, ON, Canada. [Coorssen, Jens R.] Brock Univ, Dept Hlth Sci, St Catharines, ON, Canada. [Coorssen, Jens R.] Brock Univ, Dept Biol Sci, St Catharines, ON, Canada. RP Yergey, AL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. EM aly@helix.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services FX This work has been supported by the intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services. NR 14 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1615-9853 EI 1615-9861 J9 PROTEOMICS JI Proteomics PD SEP PY 2016 VL 16 IS 18 SI SI BP 2480 EP 2490 DI 10.1002/pmic.201600137 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DZ4FJ UT WOS:000385813600007 PM 27546229 ER PT J AU Shadding, CR Whittington, D Wallace, LE Wandu, WS Wilson, RK AF Shadding, Cherilynn R. Whittington, Dawayne Wallace, Latricia E. Wandu, Wambul S. Wilson, Richard K. TI Cost-Effective Recruitment Strategies That Attract Underrepresented Minority Undergraduates Who Persist to STEM Doctorates SO SAGE OPEN LA English DT Article DE recruitment; underrepresented minority; cost-effective; summer programs; undergraduate research; STEM ID SCIENCES; PROGRAMS AB The paucity of underrepresented minorities (URMs) earning science, technology, engineering, and mathematics (STEM) degrees remains an issue in revitalizing the U.S. biomedical workforce. Due to reductions in federal funding, maintaining the integrity of programs that focus on URM retention and recruitment is crucial. We present data on the mechanisms used to recruit URM students to our program (e.g., email, events, referrals, website), which individually were equally effective in attracting applicants to the program. Recruitment mechanisms were grouped and further classified relative to their cost to implement as lower and higher cost. Our results indicate that lower cost mechanisms, statistically, were as effective as higher cost mechanisms in recruiting students who persisted to PhD programs. Using a binary logistic regression model to predict PhD matriculation, higher cost mechanisms were not significant predictors of PhD matriculation. Collectively, these data demonstrate for the first time that lower cost mechanisms can be as successful in recruiting URM students to summer programs who pursue PhDs in STEM fields. C1 [Shadding, Cherilynn R.; Wallace, Latricia E.; Wilson, Richard K.] Washington Univ, Sch Med, St Louis, MO USA. [Whittington, Dawayne] Strateg Evaluat Inc, Durham, NC USA. [Wandu, Wambul S.] NEI, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Shadding, CR (reprint author), Washington Univ, Sch Med, McDonnell Genome Inst, Dept Genet, 4444 Forest Pk Ave,Campus Box 8501, St Louis, MO 63108 USA. EM cshadding@wustl.edu NR 37 TC 0 Z9 0 U1 3 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 2158-2440 J9 SAGE OPEN JI SAGE Open PD SEP PY 2016 VL 6 IS 3 AR 2158244016657143 DI 10.1177/2158244016657143 PG 15 WC Social Sciences, Interdisciplinary SC Social Sciences - Other Topics GA DY9ZK UT WOS:000385495800008 ER PT J AU Klein, HG AF Klein, Harvey G. TI Blood collection and use in the United States: you can't manage what you can't measure SO TRANSFUSION LA English DT Editorial Material C1 [Klein, Harvey G.] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. RP Klein, HG (reprint author), NIH, Dept Transfus Med, Bethesda, MD 20892 USA. EM hklein@dtm.cc.nih.gov NR 7 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2016 VL 56 IS 9 BP 2157 EP 2159 DI 10.1111/trf.13724 PG 3 WC Hematology SC Hematology GA DZ4OL UT WOS:000385837900001 PM 27624207 ER PT J AU Smith, AW Mitchell, SA De Aguiar, CK Moy, C Riley, WT Wagster, MV Werner, EM AF Smith, Ashley Wilder Mitchell, Sandra A. De Aguiar, Cheryl K. Moy, Claudia Riley, William T. Wagster, Molly V. Werner, Ellen M. TI News from the NIH: Person-centered outcomes measurement: NIH-supported measurement systems to evaluate self-assessed health, functional performance, and symptomatic toxicity SO TRANSLATIONAL BEHAVIORAL MEDICINE LA English DT Editorial Material ID PATIENT-REPORTED OUTCOMES; QUALITY-OF-LIFE; NEURO-QOL; CONTENT VALIDATION; ITEM BANKS; ONCOLOGY; CLINICIAN; ADULTS C1 [Smith, Ashley Wilder; Mitchell, Sandra A.; De Aguiar, Cheryl K.] NCI, Outcomes Res Branch, Div Canc Control & Populat Sci, NIH, Rockville, MD 20850 USA. [Moy, Claudia] NINDS, Off Clin Res, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Riley, William T.] NIH, Off Behav & Social Sci Res, Bldg 10, Bethesda, MD 20892 USA. [Wagster, Molly V.] NIA, Behav & Syst Neurosci Branch, Div Neurosci, NIH, Bethesda, MD 20892 USA. [Werner, Ellen M.] NHLBI, Blood Epidemiol & Clin Therapeut Branch, Div Blood Dis & Blood Resources, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Smith, AW (reprint author), NCI, Outcomes Res Branch, Div Canc Control & Populat Sci, NIH, Rockville, MD 20850 USA. EM smithas@mail.nih.gov NR 23 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER INTERNATIONAL PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 1869-6716 EI 1613-9860 J9 TRANSL BEHAV MED JI Transl. Behav. Med. PD SEP PY 2016 VL 6 IS 3 BP 470 EP 474 DI 10.1007/s13142-015-0345-9 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DY6TP UT WOS:000385261500016 PM 27528535 ER PT J AU Comas-Garcia, M Davis, SR Rein, A AF Comas-Garcia, Mauricio Davis, Sean R. Rein, Alan TI On the Selective Packaging of Genomic RNA by HIV-1 SO VIRUSES-BASEL LA English DT Review DE retroviruses; retroviral RNA; virus assembly; HIV-1; selective RNA packaging; genomic RNA; packaging; encapsidation; capsid; RNA-protein interactions ID IMMUNODEFICIENCY-VIRUS TYPE-1; ACID-CHAPERONE ACTIVITY; GAG PROTEIN; IN-VITRO; RETROVIRUS PARTICLES; NUCLEOCAPSID PROTEIN; VIRAL REPLICATION; CELLULAR RNAS; BINDING; DIMERIZATION AB Like other retroviruses, human immunodeficiency virus type 1 (HIV-1) selectively packages genomic RNA (gRNA) during virus assembly. However, in the absence of the gRNA, cellular messenger RNAs (mRNAs) are packaged. While the gRNA is selected because of its cis-acting packaging signal, the mechanism of this selection is not understood. The affinity of Gag (the viral structural protein) for cellular RNAs at physiological ionic strength is not much higher than that for the gRNA. However, binding to the gRNA is more salt-resistant, implying that it has a higher non-electrostatic component. We have previously studied the spacer 1 (SP1) region of Gag and showed that it can undergo a concentration-dependent conformational transition. We proposed that this transition represents the first step in assembly, i.e., the conversion of Gag to an assembly-ready state. To explain selective packaging of gRNA, we suggest here that binding of Gag to gRNA, with its high non-electrostatic component, triggers this conversion more readily than binding to other RNAs; thus we predict that a Gag-gRNA complex will nucleate particle assembly more efficiently than other Gag-RNA complexes. New data shows that among cellular mRNAs, those with long 3-untranslated regions (UTR) are selectively packaged. It seems plausible that the 3-UTR, a stretch of RNA not occupied by ribosomes, offers a favorable binding site for Gag. C1 [Comas-Garcia, Mauricio; Rein, Alan] NCI, HIV Dynam & Replicat Program, Ctr Canc Res, Frederick, MD 21702 USA. [Davis, Sean R.] NCI, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Rein, A (reprint author), NCI, HIV Dynam & Replicat Program, Ctr Canc Res, Frederick, MD 21702 USA. EM mauricio.comasgarcia@nih.gov; sdavis2@mail.nih.gov; reina@mail.nih.gov OI Davis, Sean/0000-0002-8991-6458; Comas-Garcia, Mauricio/0000-0002-7733-5138 FU NIH, National Cancer Institute, Center for Cancer Research; Intramural AIDS Targeted Antiviral Program FX This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and by the Intramural AIDS Targeted Antiviral Program. We acknowledge Siddhartha Datta, Olga Nikolaitchik, Ioulia Rouzina and Karin Musier-Forsyth for critical discussions. This work utilized the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov). NR 52 TC 1 Z9 1 U1 4 U2 4 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD SEP PY 2016 VL 8 IS 9 AR 246 DI 10.3390/v8090246 PG 12 WC Virology SC Virology GA DY8RC UT WOS:000385396800006 ER PT J AU Mlera, L Melik, W Offerdahl, DK Dahlstrom, E Porcella, SF Bloom, ME AF Mlera, Luwanika Melik, Wessam Offerdahl, Danielle K. Dahlstrom, Eric Porcella, Stephen F. Bloom, Marshall E. TI Analysis of the Langat Virus Genome in Persistent Infection of an Ixodes scapularis Cell Line SO VIRUSES-BASEL LA English DT Article DE Langat virus genome; tick-borne flavivirus; persistent infection; Ixodes scapularis; ISE6 cells; deep-sequencing ID TICK-BORNE ENCEPHALITIS; NON-VIREMIC TRANSMISSION; FLAVIVIRUSES; VIEWER AB Tick-borne flaviviruses (TBFVs) cause a broad spectrum of disease manifestations ranging from asymptomatic to mild febrile illness and life threatening encephalitis. These single-stranded positive-sense (ss(+)) RNA viruses are naturally maintained in a persistent infection of ixodid ticks and small-medium sized mammals. The development of cell lines from the ixodid ticks has provided a valuable surrogate system for studying the biology of TBFVs in vitro. When we infected ISE6 cells, an Ixodes scapularis embryonic cell line, with Langat virus (LGTV) we observed that the infection proceeded directly into persistence without any cytopathic effect. Analysis of the viral genome at selected time points showed that no defective genomes were generated during LGTV persistence by 10 weeks of cell passage. This was in contrast to LGTV persistence in 293T cells in which defective viral genomes are detectable by five weeks of serial cell passage. We identified two synonymous nucleotide changes i.e., 1893AC (29% of 5978 reads at 12 h post infection (hpi)) and 2284TA (34% of 4191 reads at 12 hpi) in the region encoding for the viral protein E. These results suggested that the mechanisms supporting LGTV persistence are different between tick and mammalian cells. C1 [Mlera, Luwanika; Melik, Wessam; Offerdahl, Danielle K.; Bloom, Marshall E.] NIH, Biol Vector Borne Viruses Sect, Virol Lab, Hamilton, MT 59840 USA. [Dahlstrom, Eric; Porcella, Stephen F.] Res Technol Branch, Genom Unit, Hamilton, MT 59840 USA. [Melik, Wessam] Univ Orebro, Fac Med, S-70281 Orebro, Sweden. RP Bloom, ME (reprint author), NIH, Biol Vector Borne Viruses Sect, Virol Lab, Hamilton, MT 59840 USA. EM Luwanika.Mlera@nih.gov; Wessam.Melik@oru.se; offerdahld@niaid.nih.gov; eric.dahlstrom@nih.gov; SPORCELLA@niaid.nih.gov; mbloom@niaid.nih.gov FU Division of Intramural Research of the NIAID, NIH FX This study was supported by the Division of Intramural Research of the NIAID, NIH. We thank Kimmo Virtaneva and Stacey Ricklefs for technical assistance. NR 30 TC 0 Z9 0 U1 6 U2 6 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD SEP PY 2016 VL 8 IS 9 AR 252 DI 10.3390/v8090252 PG 6 WC Virology SC Virology GA DY8RC UT WOS:000385396800012 ER PT J AU Tawa, EA Hall, SD Lohoff, FW AF Tawa, Elisabeth A. Hall, Samuel D. Lohoff, Falk W. TI Overview of the Genetics of Alcohol Use Disorder SO ALCOHOL AND ALCOHOLISM LA English DT Review ID GENOME-WIDE ASSOCIATION; BIPOLAR DISORDER; DRUG-DEPENDENCE; PSYCHIATRIC-DISORDERS; RISK; VARIANTS; GENES; SCHIZOPHRENIA; RECEPTOR; COMMON AB Alcohol Use Disorder (AUD) is a chronic psychiatric illness characterized by harmful drinking patterns leading to negative emotional, physical, and social ramifications. While the underlying pathophysiology of AUD is poorly understood, there is substantial evidence for a genetic component; however, identification of universal genetic risk variants for AUD has been difficult. Recent efforts in the search for AUD susceptibility genes will be reviewed in this article. In this review, we provide an overview of genetic studies on AUD, including twin studies, linkage studies, candidate gene studies, and genome-wide association studies (GWAS). Several potential genetic susceptibility factors for AUD have been identified, but the genes of alcohol metabolism, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), have been found to be protective against the development of AUD. GWAS have also identified a heterogeneous list of SNPs associated with AUD and alcohol-related phenotypes, emphasizing the complexity and heterogeneity of the disorder. In addition, many of these findings have small effect sizes when compared to alcohol metabolism genes, and biological relevance is often unknown. Although studies spanning multiple approaches have suggested a genetic basis for AUD, identification of the genetic risk variants has been challenging. Some promising results are emerging from GWAS studies; however, larger sample sizes are needed to improve GWAS results and resolution. As the field of genetics is rapidly developing, whole genome sequencing could soon become the new standard of interrogation of the genes and neurobiological pathways which contribute to the complex phenotype of AUD. This review examines the genetic underpinnings of Alcohol Use Disorder (AUD), with an emphasis on GWAS approaches for identifying genetic risk variants. The most promising results associated with AUD and alcohol-related phenotypes have included SNPs of the alcohol metabolism genes ADH and ALDH. C1 [Tawa, Elisabeth A.; Hall, Samuel D.; Lohoff, Falk W.] NIAAA, Sect Clin Genom & Expt Therapeut, NIH, Bethesda, MD USA. RP Lohoff, FW (reprint author), NIAAA, Sect Clin Genom & Expt Therapeut CGET, NIH, 10 Ctr Dr,10CRC 2-2352, Bethesda, MD 20892 USA.; Lohoff, FW (reprint author), NIAAA, NIH, 10 Ctr Dr,10CRC 2-2352, Bethesda, MD 20892 USA. EM falk.lohoff@nih.gov RI Lohoff, Falk/M-7951-2016 FU National Institute on Alcohol Abuse and Alcoholism FX The review was supported by intramural research funding from the National Institute on Alcohol Abuse and Alcoholism. There are no competing financial interests. NR 74 TC 1 Z9 1 U1 14 U2 14 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0735-0414 EI 1464-3502 J9 ALCOHOL ALCOHOLISM JI Alcohol Alcohol. PD SEP PY 2016 VL 51 IS 5 BP 507 EP 514 DI 10.1093/alcalc/agw046 PG 8 WC Substance Abuse SC Substance Abuse GA DX8OF UT WOS:000384647700001 PM 27445363 ER PT J AU Li, Y Cui, XZ Xu, WY Ohanjanian, L Sampath-Kumar, H Suffredini, D Moayeri, M Leppla, S Fitz, Y Eichacker, PQ AF Li, Yan Cui, Xizhong Xu, Wanying Ohanjanian, Lernik Sampath-Kumar, Hanish Suffredini, Dante Moayeri, Mahtab Leppla, Stephen Fitz, Yvonne Eichacker, Peter Q. TI Nitric oxide production contributes to Bacillus anthracis edema toxin-associated arterial hypotension and lethality: ex vivo and in vivo studies in the rat SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE anthrax; edema toxin; nitric oxide; NOS inhibitor; arterial contraction; hypotension ID METHYL-L-THIOCITRULLINE; HYPERTENSIVE-RATS; ESCHERICHIA-COLI; CONSCIOUS RATS; CYCLIC-AMP; SYNTHASE; MODEL; SHOCK; INHIBITION; ACTIVATION AB We showed previously that Bacillus anthracis edema toxin (ET), comprised of protective antigen (PA) and edema factor (EF), inhibits phenylephrine (PE)-induced contraction in rat aortic rings and these effects are diminished in endothelial-denuded rings. Therefore, employing rat aortic ring and in vivo models, we tested the hypothesis that nitric oxide (NO) contributes to ET's arterial effects. Compared with rings challenged with PA alone, ET (PA + EF) reduced PE-stimulated maximal contractile force (MCF) and increased the PE concentration producing 50% MCF (EC50) (P < 0.0001). Compared with placebo, L-nitro-arginine methyl-ester (L-NAME), an NO synthase (NOS) inhibitor, reduced ET's effects on MCF and EC50 in patterns that approached or were significant (P = 0.06 and 0.03, respectively). In animals challenged with 24-h ET infusions, L-NAME (0.5 or 1.0 mg . kg(-1) . h(-1)) coadministration increased survival to 17 of 28 animals (60.7%) compared with 4 of 27 (14.8%) given placebo (P = 0.01). Animals receiving L-NAME but no ET all survived. Compared with PBS challenge, ET increased NO levels at 24 h and L-NAME decreased these increases (P < 0.0001). ET infusion decreased mean arterial blood pressure (MAP) in placebo and L-NAME-treated animals (P < 0.0001) but L-NAME reduced decreases in MAP with ET from 9 to 24 h (P = 0.03 for the time interaction). S-methyl-Lthiocitrulline, a selective neuronal NOS inhibitor, had effects in rings and, at a high dose in vivo models, comparable to L-NAME, whereas N'-[3-(aminomethyl) benzyl]-acetimidamide, a selective inducible NOS inhibitor, did not. NO production contributes to ET's arterial relaxant, hypotensive, and lethal effects in the rat. C1 [Li, Yan; Cui, Xizhong; Xu, Wanying; Ohanjanian, Lernik; Sampath-Kumar, Hanish; Suffredini, Dante; Fitz, Yvonne; Eichacker, Peter Q.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Moayeri, Mahtab; Leppla, Stephen] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Eichacker, PQ (reprint author), NIH, Dept Crit Care Med, Bldg 10,Rm 2C145,9000 Rockville Pike, Bethesda, MD 20892 USA. EM peichacker@mail.cc.nih.gov FU Intramural Programs of the National Institutes of Health, Clinical Center, Critical Care Medicine Department; National Institutes of Allergy and Infectious Diseases FX This research was supported by the Intramural Programs of the National Institutes of Health, Clinical Center, Critical Care Medicine Department and the National Institutes of Allergy and Infectious Diseases. NR 53 TC 0 Z9 0 U1 3 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 EI 1522-1539 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD SEP PY 2016 VL 311 IS 3 BP H781 EP H793 DI 10.1152/ajpheart.00163.2016 PG 13 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA DY3DT UT WOS:000384971700028 PM 27448553 ER PT J AU Li, Y Sirenko, S Riordon, DR Yang, DM Spurgeon, H Lakatta, EG Vinogradova, TM AF Li, Yue Sirenko, Syevda Riordon, Daniel R. Yang, Dongmei Spurgeon, Harold Lakatta, Edward G. Vinogradova, Tatiana M. TI CaMKII-dependent phosphorylation regulates basal cardiac pacemaker function via modulation of local Ca2+ releases SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE sinoatrial node cells; CaMKII-dependent phosphorylation; phospholamban; ryanodine receptors; sarcoplasmic reticulum Ca2+ -ATPase ID PROTEIN-KINASE-II; THR(17) PHOSPHOLAMBAN PHOSPHORYLATION; SPONTANEOUS BEATING RATE; SINOATRIAL NODE; RYANODINE RECEPTOR; SER(16) PHOSPHORYLATION; MYOCARDIAL HYPERTROPHY; CALCIUM-CHANNELS; SODIUM-CHANNELS; HEART-DISEASE AB Spontaneous beating of the heart pacemaker, the sinoatrial node, is generated by sinoatrial node cells (SANC) due to gradual change of the membrane potential called diastolic depolarization (DD). Spontaneous, submembrane local Ca2+ releases (LCR) from ryanodine receptors (RyR) occur during late DD and activate an inward Na+/Ca2+ exchange current to boost the DD rate and fire an action potential (AP). Here we studied the extent of basal Ca2+/calmodulin-dependent protein kinase II (CaMKII) activation and the role of basal CaMKII-dependent protein phosphorylation in generation of LCRs and regulation of normal automaticity of intact rabbit SANC. The basal level of activated (autophosphorylated) CaMKII in rabbit SANC surpassed that in ventricular myocytes (VM) by approximately twofold, and this was accompanied by high basal level of protein phosphorylation. Specifically, phosphorylation of phospholamban (PLB) at the CaMKII-dependent Thr(17) site was approximately threefold greater in SANC compared with VM, and RyR phosphorylation at CaMKIIdependent Ser(2815) site was similar to 10-fold greater in the SA node, compared with that in ventricle. CaMKII inhibition reduced phosphorylation of PLB and RyR, decreased LCR size, increased LCR periods (time from AP-induced Ca2+ transient to subsequent LCR), and suppressed spontaneous SANC firing. Graded changes in CaMKIIdependent phosphorylation (indexed by PLB phosphorylation at the Thr(17)site) produced by CaMKII inhibition, beta-AR stimulation or phosphodiesterase inhibition were highly correlated with changes in SR Ca2+ replenishment times and LCR periods and concomitant changes in spontaneous SANC cycle lengths (R-2 = 0.96). Thus high basal CaMKII activation modifies the phosphorylation state of Ca2+ cycling proteins PLB, RyR, L-type Ca2+ channels (and likely others), adjusting LCR period and characteristics, and ultimately regulates both normal and reserve cardiac pacemaker function. C1 [Li, Yue; Sirenko, Syevda; Riordon, Daniel R.; Yang, Dongmei; Spurgeon, Harold; Lakatta, Edward G.; Vinogradova, Tatiana M.] NIA, Cardiovasc Sci Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Vinogradova, TM (reprint author), NIA, Cardiovasc Sci Lab, NIH, Biomed Res Ctr, 251 Bayview Blvd,Suite 8B-123, Baltimore, MD 21224 USA. EM vinogradovat@grc.nia.nih.gov FU Intramural Research Program of the National Institute on Aging FX This work was supported by the Intramural Research Program of the National Institute on Aging. NR 53 TC 0 Z9 0 U1 1 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 EI 1522-1539 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD SEP PY 2016 VL 311 IS 3 BP H532 EP H544 DI 10.1152/ajpheart.00765.2015 PG 13 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA DY3DT UT WOS:000384971700003 PM 27402669 ER PT J AU Kordasti, S Costantini, B Seidl, T Abellan, PP Llordella, MM McLornan, D Diggins, KE Kulasekararaj, A Benfatto, C Feng, XM Smith, A Mian, SA Melchiotti, R de Rinaldis, E Ellis, R Petrov, N Povoleri, GAM Chung, SS Thomas, NSB Farzaneh, F Irish, JM Heck, S Young, NS Marsh, JCW Mufti, GJ AF Kordasti, Shahram Costantini, Benedetta Seidl, Thomas Abellan, Pilar Perez Llordella, Marc Martinez McLornan, Donal Diggins, Kirsten E. Kulasekararaj, Austin Benfatto, Cinzia Feng, Xingmin Smith, Alexander Mian, Syed A. Melchiotti, Rossella de Rinaldis, Emanuele Ellis, Richard Petrov, Nedyalko Povoleri, Giovanni A. M. Chung, Sun Sook Thomas, N. Shaun B. Farzaneh, Farzin Irish, Jonathan M. Heck, Susanne Young, Neal S. Marsh, Judith C. W. Mufti, Ghulam J. TI Deep phenotyping of Tregs identifies an immune signature for idiopathic aplastic anemia and predicts response to treatment SO BLOOD LA English DT Article ID REGULATORY T-CELLS; MASS CYTOMETRY; IMMUNOSUPPRESSIVE THERAPY; SOMATIC MUTATIONS; TELOMERE LENGTH; EXPRESSION; BLOOD; TRANSPLANTATION; HEMATOPOIESIS; CYCLE AB Idiopathic aplastic anemia (AA) is an immune-mediated and serious form of bone marrow failure. Akin to other autoimmune diseases, we have previously shown that in AA regulatory T cells (Tregs) are reduced in numberand function. The aim of this study was to further characterize Treg subpopulations in AA and investigate the potential correlation between specific Treg subsets and response to immunosuppressive therapy (IST) as well as their in vitro expandability for potential clinical use. Using mass cytometry and an unbiased multidimensional analytical approach, we identified 2 specific human Treg subpopulations (Treg A and Treg B) with distinct phenotypes, gene expression, expandability, and function. Treg B predominates in IST responder patients, has a memory/activated phenotype (with higher expression of CD95, CCR4, andCD45ROwithin FOXP3(hi), CD127(lo) Tregs), expresses the interleukin-2 (IL-2)/STAT5 pathway and cell-cycle commitment genes. Furthermore, in vitro-expanded Tregs become functional and take on the characteristics of Treg B. Collectively, this study identifies human Treg subpopulations that can be used as predictive biomarkers for response to IST in AA and potentially other autoimmune diseases. We also show that Tregs from AA patients are IL-2-sensitive and expandable in vitro, suggesting novel therapeutic approaches such as low-dose IL-2 therapy and/or expanded autologous Tregs and meriting further exploration. C1 [Kordasti, Shahram; Costantini, Benedetta; Seidl, Thomas; Benfatto, Cinzia; Smith, Alexander; Mian, Syed A.; Chung, Sun Sook; Thomas, N. Shaun B.; Farzaneh, Farzin; Marsh, Judith C. W.; Mufti, Ghulam J.] Kings Coll London, Dept Haematol Med, London, England. [Kordasti, Shahram; Costantini, Benedetta; Abellan, Pilar Perez; McLornan, Donal; Kulasekararaj, Austin; Smith, Alexander; Marsh, Judith C. W.; Mufti, Ghulam J.] Kings Coll Hosp London, Haematol Med, London, England. [Llordella, Marc Martinez; Povoleri, Giovanni A. M.] Kings Coll London, Div Transplantat Immunol & Mucosal Biol, London, England. [Diggins, Kirsten E.; Irish, Jonathan M.] Vanderbilt Univ, Dept Canc Biol, 221 Kirkland Hall, Nashville, TN 37235 USA. [Feng, Xingmin; Young, Neal S.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Melchiotti, Rossella; de Rinaldis, Emanuele; Ellis, Richard; Petrov, Nedyalko; Heck, Susanne] Kings Coll London, Biomed Res Ctr, Natl Inst Hlth Res, London, England. RP Mufti, GJ (reprint author), Kings Coll London, Dept Haematol Med, Rayne Inst, 123 Coldharbour Ln, London SE5 9NU, England. EM ghulam.mufti@kcl.ac.uk OI Mian, Syed Asif/0000-0001-8005-2860; Irish, Jonathan/0000-0001-9428-8866 FU Department of Health via the National Institute for Health Research comprehensive Biomedical Research Centre Award to Guy's & St Thomas' National Health Service Foundation Trust; King's College Hospital National Health Service Foundation Trust; Bloodwise UK [14017]; Aplastic Anemia and MDS International Foundation, USA; King's College London FX This work is supported by financial support from the Department of Health via the National Institute for Health Research comprehensive Biomedical Research Centre Award to Guy's & St Thomas' National Health Service Foundation Trust in partnership with King's College London and King's College Hospital National Health Service Foundation Trust. This work is also supported by a research program grant from Bloodwise UK (grant number 14017) and a grant from The Aplastic Anemia and MDS International Foundation, USA (research grant awarded to S.K.). NR 53 TC 4 Z9 4 U1 5 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD SEP 1 PY 2016 VL 128 IS 9 BP 1193 EP 1205 DI 10.1182/blood-2016-03-703702 PG 13 WC Hematology SC Hematology GA DX9YU UT WOS:000384754100012 PM 27281795 ER PT J AU Zhu, B Mukherjee, A Machiela, MJ Song, L Hua, X Shi, JX Garcia-Closas, M Chanock, SJ Chatterjee, N AF Zhu, Bin Mukherjee, Anwesha Machiela, Mitchell J. Song, Lei Hua, Xing Shi, Jianxin Garcia-Closas, Montserrat Chanock, Stephen J. Chatterjee, Nilanjan TI An investigation of the association of genetic susceptibility risk with somatic mutation burden in breast cancer SO BRITISH JOURNAL OF CANCER LA English DT Article DE association study; breast cancer; exome sequencing; polygenic risk score; single-nucleotide polymorphisms; somatic mutations ID GENOME-WIDE ASSOCIATION; LOCI; LANDSCAPE; COMMON AB Background: Genome-wide association studies have reported nearly 100 common germline susceptibility loci associated with the risk for breast cancer. Tumour sequencing studies have characterised somatic mutation profiles in breast cancer patients. The relationship between breast cancer susceptibility loci and somatic mutation patterns in breast cancer remains largely unexplored. Methods: We used single-nucleotide polymorphism (SNP) genotyping array data and tumour exome sequencing data available from 638 breast cancer patients of European ancestry from The Cancer Genome Atlas (TCGA) project. We analysed both genotype data and, when necessary, imputed genotypes for 90 known breast cancer susceptibility loci. We performed linear regression models to investigate possible associations between germline risk variants with total somatic mutation count (TSMC), as well as specific mutation types. We examined individual SNP genotypes, as well as a multi-SNP polygenic risk score (PRS). Models were statistically adjusted for age at diagnosis, stage, oestrogen-receptor (ER) and progesterone-receptor (PR) status of breast cancer. We also performed stratified analyses by ER and PR status. Results: We observed a significant inverse association (P = 8.75 x 10(-6); FDR = 0.001) between the risk allele in rs2588809 of the gene RAD51B and TSMC across all breast cancer patients, for both ER+ and ER- tumours. This association was also evident for different types of mutations. The PRS analysis for all patients, with or without rs2588809, showed a significant inverse association (P = 0.01 and 0.04, respectively) with TSMC. This inverse association was significant in ER+ patients with the ER+-specific PRS (P = 0.02), but not among ER- patients for the ER--specific PRS (P = 0.39). Conclusions: We observed an inverse association between common germline risk variants and TSMC, which, if confirmed, could provide new insights into how germline variation informs our understanding of somatic mutation patterns in breast cancer. C1 [Zhu, Bin; Machiela, Mitchell J.; Song, Lei; Hua, Xing; Shi, Jianxin; Garcia-Closas, Montserrat; Chanock, Stephen J.; Chatterjee, Nilanjan] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Mukherjee, Anwesha] Florida State Univ, Dept Stat, Tallahassee, FL 32306 USA. [Chatterjee, Nilanjan] Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21205 USA. [Chatterjee, Nilanjan] Johns Hopkins Univ, Dept Oncol, Baltimore, MD 21205 USA. RP Zhu, B; Chatterjee, N (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA.; Chatterjee, N (reprint author), Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21205 USA.; Chatterjee, N (reprint author), Johns Hopkins Univ, Dept Oncol, Baltimore, MD 21205 USA. EM bin.zhu@nih.go; nilanjan@jhu.edu FU Intramural Research Program of the National Cancer Institute, National Institutes of Health, MD, USA FX This work was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, MD, USA. NR 31 TC 0 Z9 0 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD SEP PY 2016 VL 115 IS 6 BP 752 EP 760 DI 10.1038/bjc.2016.223 PG 9 WC Oncology SC Oncology GA DX7MC UT WOS:000384570600016 PM 27467053 ER PT J AU Wang, ML Liu, HL Liu, ZS Yi, XH Bickeboller, H Hung, RJ Brennan, P Landi, MT Caporaso, N Christiani, DC Doherty, JA Amos, CI Wei, QY AF Wang, Meilin Liu, Hongliang Liu, Zhensheng Yi, Xiaohua Bickeboller, Heike Hung, Rayjean J. Brennan, Paul Landi, Maria Teresa Caporaso, Neil Christiani, David C. Doherty, Jennifer Anne Amos, Christopher I. Wei, Qingyi CA TRICL Res Team TI Genetic variant in DNA repair gene GTF2H4 is associated with lung cancer risk: a large-scale analysis of six published GWAS datasets in the TRICL consortium SO CARCINOGENESIS LA English DT Article ID GENOME-WIDE ASSOCIATION; NUCLEOTIDE EXCISION-REPAIR; SUSCEPTIBILITY LOCUS; FAMILY-HISTORY; POOLED ANALYSIS; PATHWAY GENES; SNPS; POLYMORPHISMS; METAANALYSIS; EXPRESSION AB DNA repair pathways maintain genomic integrity and stability, and dysfunction of DNA repair leads to cancer. We hypothesize that functional genetic variants in DNA repair genes are associated with risk of lung cancer. We performed a large-scale meta-analysis of 123,371 single nucleotide polymorphisms (SNPs) in 169 DNA repair genes obtained from six previously published genome-wide association studies (GWASs) of 12160 lung cancer cases and 16838 controls. We calculated odds ratios (ORs) with 95% confidence intervals (CIs) using the logistic regression model and used the false discovery rate (FDR) method for correction of multiple testing. As a result, 14 SNPs had a significant odds ratio (OR) for lung cancer risk with P (FDR) < 0.05, of which rs3115672 in MSH5 (OR = 1.20, 95% CI = 1.14-1.27) and rs114596632 in GTF2H4 (OR = 1.19, 95% CI = 1.12-1.25) at 6q21.33 were the most statistically significant (P (combined) = 3.99x10(-11) and P (combined) = 5.40x10(-10), respectively). The MSH5 rs3115672, but not GTF2H4 rs114596632, was strongly correlated with MSH5 rs3131379 in that region (r (2) = 1.000 and r (2) = 0.539, respectively) as reported in a previous GWAS. Importantly, however, the GTF2H4 rs114596632 T, but not MSH5 rs3115672 T, allele was significantly associated with both decreased DNA repair capacity phenotype and decreased mRNA expression levels. These provided evidence that functional genetic variants of GTF2H4 confer susceptibility to lung cancer. C1 [Wang, Meilin; Liu, Hongliang; Liu, Zhensheng; Yi, Xiaohua; Wei, Qingyi] Duke Univ, Med Ctr, Duke Canc Inst, 905 Lasalle St, Durham, NC 27710 USA. [Wang, Meilin; Liu, Hongliang; Liu, Zhensheng; Yi, Xiaohua; Wei, Qingyi] Duke Univ, Sch Med, Dept Med, Durham, NC 27710 USA. [Wang, Meilin] Nanjing Med Univ, Collaborat Innovat Ctr Canc Personalized Med, Jiangsu Key Lab Canc Biomarkers Prevent & Treatme, Dept Environm Genom, Nanjing 21116, Jiangsu, Peoples R China. [Bickeboller, Heike] Univ Gottingen, Univ Med Ctr, Dept Genet Epidemiol, D-37073 Gottingen, Germany. [Hung, Rayjean J.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada. [Brennan, Paul] Int Agcy Res Canc, Genet Epidemiol Grp, F-69372 Lyon, France. [Landi, Maria Teresa; Caporaso, Neil] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Christiani, David C.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Christiani, David C.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Doherty, Jennifer Anne; Amos, Christopher I.] Dartmouth Coll, Geisel Sch Med, Community & Family Med, 1 Med Ctr Dr, Lebanon, NH 03756 USA. RP Wei, QY (reprint author), Duke Univ, Med Ctr, Duke Canc Inst, 905 Lasalle St, Durham, NC 27710 USA.; Wei, QY (reprint author), Duke Univ, Sch Med, Dept Med, Durham, NC 27710 USA. EM qingyi.wei@duke.edu RI Hung, Rayjean/A-7439-2013 FU Duke Cancer Institute of the P30 Cancer Center Support Grant [NIH CA014236]; Duke Cancer Institute, Duke University Medical Center; Genetic Associations and Mechanisms in Oncology (GAME-ON) Network [U19-CA148127]; Canadian Cancer Society Research Institute [020214]; Ontario Institute of Cancer; Cancer Care Ontario Chair Award; Cancer Research UK [C1298/A8780, C1298/A8362]; NCRN; HEAL; Sanofi-Aventis; NIH [5R01CA055769, 5R01CA127219, 5R01CA133996, 5R01CA121197, P50 CA70907, R01CA121197, R01CA127219, U19 CA148127, R01 CA55769, K07CA160753, HHSN268200782096C]; Roy Castle Lung Cancer Foundation, UK; Deutsche Krebshilfe [70-2919]; Helmholtz-DAAD fellowship [A/07/97379]; GSF - German Federal Ministry of Education, Science, Research and Technology; State of Bavaria; National Genome Research Network (NGFN); DFG [BI576/2-1, BI 576/2-2]; Helmholtzgemeinschaft (HGF); Federal office for Radiation Protection [BfS: STSch4454]; Institut National du Cancer, France; European Community [LSHG-CT-2005-512113]; Norwegian Cancer Association; Functional Genomics Programme of Research Council of Norway; European Regional Development Fund; State Budget of the Czech Republic (RECAMO) [CZ.1.05/2.1.00/03.0101]; US National Cancer Institute, NIH [R01 CA111703, UO1 CA63673]; Fred Hutchinson Cancer Research Center; US National Cancer Institute [R01 CA092039]; FP7 grant [REGPOT245536]; Estonian Government [SF0180142s08]; EU RDF in the frame of Centre of Excellence in Genomics; Estoinian Research Infrastructure's Roadmap; University of Tartu (SP1GVARENG); IARC; NIH, NCI, Division of Cancer Epidemiology and Genetics; US Public Health Service from the NCI [N01-CN-45165, N01-RC-45035, N01-RC-37004]; NCI [NO1-CN-25514, NO1-CN-25522, NO1-CN-25515, NO1-CN-25512, NO1-CN-25513, NO1-CN-25516, NO1-CN-25511, NO1-CN-25524, NO1-CN-25518, NO1-CN-75022, NO1-CN-25476, NO1-CN-25404]; American Cancer Society; NIH Genes, Environment and Health Initiative (GEI) [HG-06-033-NCI-01, RO1HL091172-01]; CPRIT [RP100443]; NIH (National Cancer Institute) [CA092824, CA090578, CA074386]; [P30 CA023108] FX As Duke Cancer Institute members, Q.W. acknowledge support from the Duke Cancer Institute as part of the P30 Cancer Center Support Grant (NIH CA014236). Q.W. was also supported by a start-up fund from Duke Cancer Institute, Duke University Medical Center. TRICL: This work was supported by P30 CA023108 (CA) and the Transdisciplinary Research in Cancer of the Lung (TRICL) Study, U19-CA148127 on behalf of the Genetic Associations and Mechanisms in Oncology (GAME-ON) Network. The SLRI study was supported by Canadian Cancer Society Research Institute(020214), Ontario Institute of Cancer and Cancer Care Ontario Chair Award to RH The ICR study was supported by Cancer Research UK (C1298/A8780 andC1298/A8362-Bobby Moore Fund for Cancer Research UK) and NCRN, HEAL and Sanofi-Aventis. Additional funding was obtained from NIH grants (5R01CA055769, 5R01CA127219, 5R01CA133996, and 5R01CA121197). The Liverpool Lung Project (LLP) was supported by The Roy Castle Lung Cancer Foundation, UK. The ICR and LLP studies made use of genotyping data from the Wellcome Trust Case Control Consortium 2 (WTCCC2); a full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Sample collection for the Heidelberg lung cancer study was in part supported by a grant (70-2919) from the Deutsche Krebshilfe. The work was additionally supported by a Helmholtz-DAAD fellowship (A/07/97379 to MNT). The KORA Surveys were financed by the GSF, which is funded by the German Federal Ministry of Education, Science, Research and Technology and the State of Bavaria. The Lung Cancer in the Young study (LUCY) was funded in part by the National Genome Research Network (NGFN), the DFG (BI576/2-1; BI 576/2-2), the Helmholtzgemeinschaft (HGF) and the Federal office for Radiation Protection (BfS: STSch4454). Genotyping was performed in the Genome Analysis Center (GAC) of the Helmholtz Zentrum Muenchen. Support for the Central Europe, HUNT2/Tromso and CARET genome-wide studies was provided by Institut National du Cancer, France. Support for the HUNT2/Tromso genome-wide study was also provided by the European Community (Integrated Project DNA repair, LSHG-CT-2005-512113), the Norwegian Cancer Association and the Functional Genomics Programme of Research Council of Norway. Support for the Central Europe study, Czech Republic, was also provided by the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101). Support for the CARET genome-wide study was also provided by grants from the US National Cancer Institute, NIH (R01 CA111703 and UO1 CA63673), and by funds from the Fred Hutchinson Cancer Research Center. Additional funding for study coordination, genotyping of replication studies and statistical analysis was provided by the US National Cancer Institute (R01 CA092039). The lung cancer GWAS from Estonia was partly supported by a FP7 grant (REGPOT245536), by the Estonian Government (SF0180142s08), by EU RDF in the frame of Centre of Excellence in Genomics and Estoinian Research Infrastructure's Roadmap and by University of Tartu (SP1GVARENG). The work reported in this paper was partly undertaken during the tenure of a Postdoctoral Fellowship from the IARC (for MNT).; The Environment and Genetics in Lung Cancer Etiology (EAGLE), the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC), and the Prostate, Lung, Colon, Ovary Screening Trial (PLCO) studies and the genotyping of ATBC, the Cancer Prevention Study II Nutrition Cohort (CPS-II) and part of PLCO were supported by the Intramural Research Program of NIH, NCI, Division of Cancer Epidemiology and Genetics. ATBC was also supported by US Public Health Service contracts (N01-CN-45165, N01-RC-45035 and N01-RC-37004) from the NCI. PLCO was also supported by individual contracts from the NCI to the University of Colorado Denver (NO1-CN-25514), Georgetown University(NO1-CN-25522), Pacific Health Research Institute (NO1-CN-25515), Henry Ford Health System (NO1-CN-25512), University of Minnesota(NO1-CN-25513), Washington University(NO1-CN-25516), University of Pittsburgh (NO1-CN-25511), University of Utah (NO1-CN-25524), Marshfield Clinic Research Foundation (NO1-CN-25518), University of Alabama at Birmingham (NO1-CN-75022, Westat, Inc. NO1-CN-25476), University of California, Los Angeles (NO1-CN-25404). The Cancer Prevention Study II Nutrition Cohort was supported by the American Cancer Society. The NIH Genes, Environment and Health Initiative (GEI) partly funded DNA extraction and statistical analyses (HG-06-033-NCI-01 andRO1HL091172-01), genotyping at the Johns Hopkins University Center for Inherited Disease Research (U01HG004438 and NIH HHSN268200782096C) and study coordination at the GENEVA Coordination Center (U01 HG004446) for EAGLE and part of PLCO studies. Funding for the MD Anderson Cancer Study was provided by NIH grants (P50 CA70907, R01CA121197, R01CA127219, U19 CA148127, R01 CA55769, K07CA160753) and CPRIT grant (RP100443). Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is funded through a federal contract from the NIH to The Johns Hopkins University (HHSN268200782096C). The Harvard Lung Cancer Study was supported by the NIH (National Cancer Institute) grants CA092824, CA090578, and CA074386. NR 58 TC 0 Z9 0 U1 3 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 EI 1460-2180 J9 CARCINOGENESIS JI Carcinogenesis PD SEP PY 2016 VL 37 IS 9 BP 888 EP 896 DI 10.1093/carcin/bgw070 PG 9 WC Oncology SC Oncology GA DY5IV UT WOS:000385133900007 PM 27288692 ER PT J AU Mills, M Estes, MK AF Mills, Melody Estes, Mary K. TI Physiologically relevant human tissue models for infectious diseases SO DRUG DISCOVERY TODAY LA English DT Review ID PLURIPOTENT STEM-CELLS; ENTERICA SEROVAR TYPHIMURIUM; ORGANS-ON-CHIPS; INTESTINAL ORGANOIDS; IN-VITRO; CLOSTRIDIUM-DIFFICILE; HELICOBACTER-PYLORI; MICROPHYSIOLOGICAL SYSTEMS; CEREBRAL ORGANOIDS; CULTURE AB Limitations of animal infection models have engendered longstanding obstacles in basic science and translational research. Lack of suitable animal models, the need for better predictors of human immune responses and pathogens that grow poorly or not at all outside the human host impact our ability to study infectious agents that cause human disease, generation of essential tools for genetic manipulation of microbial pathogens and development of vaccines, therapeutics and host-targeted immunotherapies. The advent of conceptual and methodological advances in tissue engineering along with collaborative efforts between the bioengineering and infectious diseases scientific communities hold great promise to overcome these significant barriers. C1 [Mills, Melody] NIAID, Div Microbiol & Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Estes, Mary K.] Baylor Coll Med, Mol Virol & Microbiol & Med GI, Houston, TX 77030 USA. RP Mills, M (reprint author), NIAID, Div Microbiol & Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. 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A.] NIA, Baltimore, MD 21224 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 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD SEP PY 2016 VL 57 SU 1 MA DR-11 BP S68 EP S68 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA DW4BQ UT WOS:000383587400108 ER PT J AU Grimm, SA Shimbo, T Mav, D Thomas, JW Auerbach, S Bennett, BD Bucher, JR Burkholder, AB Dai, S Du, Y French, JE Li, J Merrick, BA Tice, RR Wang, T Xu, X Shah, R Bushel, PR Fargo, DC Mullikin, JC Wade, PA AF Grimm, S. A. Shimbo, T. Mav, D. Thomas, J. W. Auerbach, S. Bennett, B. D. Bucher, J. R. Burkholder, A. B. Dai, S. Du, Y. French, J. E. Li, J. Merrick, B. A. Tice, R. R. Wang, T. Xu, X. Shah, R. Bushel, P. R. Fargo, D. C. Mullikin, J. C. Wade, P. A. CA NISC Comparative Sequencing TI Inheritance of DNA Methylation in the Mouse. 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C.; Waidyanatha, S.; Dixon, D.; Devito, M. J.; Paules, R. S.; Ferguson, S. S.] NIEHS, Div Natl Toxicol Program, Durham, NC USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD SEP PY 2016 VL 57 SU 1 MA S16 BP S43 EP S43 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA DW4BQ UT WOS:000383587400022 ER PT J AU Simeonov, A AF Simeonov, A. TI NCATS: Advancing Stem Cell Technologies for Efficacy and Toxicity Testing in Cellular and Tissue-Chip Models. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 47th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society CY SEP 24-28, 2016 CL Kansas City, MO SP Environm Mutagenesis & Genom Soc C1 [Simeonov, A.] Natl Ctr Adv Translat Sci, Bethesda, MD 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 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD SEP PY 2016 VL 57 SU 1 MA S19 BP S44 EP S44 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA DW4BQ UT WOS:000383587400025 ER PT J AU Smith-Roe, SL Swartz, CD Hobbs, CA Blystone, CR Waidyanatha, S Garantziotis, S Witt, KL AF Smith-Roe, S. L. Swartz, C. D. Hobbs, C. A. Blystone, C. R. Waidyanatha, S. Garantziotis, S. Witt, K. L. TI Comparative In Vitro Genotoxicity of Multiple Cohosh Samples Assessed with the Micronucleus Assay. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 47th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society CY SEP 24-28, 2016 CL Kansas City, MO SP Environm Mutagenesis & Genom Soc C1 [Smith-Roe, S. L.; Blystone, C. R.; Waidyanatha, S.; Witt, K. L.] NIEHS, Div Natl Toxicol Program, POB 12233, Res Triangle Pk, NC 27709 USA. [Swartz, C. D.; Hobbs, C. A.] ILS, Genet & Mol Toxicol Program, Res Triangle Pk, NC USA. [Garantziotis, S.] NIEHS, Clin Res Unit, POB 12233, Res Triangle Pk, NC 27709 USA. RI Garantziotis, Stavros/A-6903-2009 OI Garantziotis, Stavros/0000-0003-4007-375X 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 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD SEP PY 2016 VL 57 SU 1 MA GT-80 BP S65 EP S65 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA DW4BQ UT WOS:000383587400103 ER PT J AU Sykora, P Woodgate, S Witt, K Smith-Roe, S Engelward, B George, J Sobol, R AF Sykora, P. Woodgate, S. Witt, K. Smith-Roe, S. Engelward, B. George, J. Sobol, R. TI Next Generation High Capacity DNA Damage Detection Assay for Chemotherapeutic and Genotoxic Compound Screening. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 47th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society CY SEP 24-28, 2016 CL Kansas City, MO SP Environm Mutagenesis & Genom Soc C1 [Sykora, P.; Sobol, R.] Univ S Alabama, Mitchell Canc Inst, Mobile, AL USA. [Woodgate, S.; George, J.] Trevigen Inc, Gaithersburg, MD USA. [Witt, K.; Smith-Roe, S.] NIEHS, Div Natl Toxicol Program, POB 12233, Res Triangle Pk, NC 27709 USA. [Engelward, B.] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 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 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD SEP PY 2016 VL 57 SU 1 MA DR-25 BP S72 EP S72 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA DW4BQ UT WOS:000383587400122 ER PT J AU Troisi, R AF Troisi, R. TI Health Effects of Prenatal Diethylstilbestrol Exposure. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 47th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society CY SEP 24-28, 2016 CL Kansas City, MO SP Environm Mutagenesis & Genom Soc C1 [Troisi, R.] NCI, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD SEP PY 2016 VL 57 SU 1 MA S14 BP S42 EP S42 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA DW4BQ UT WOS:000383587400020 ER PT J AU Witt, KL Smith-Roe, SL Hsieh, JH Xia, M Huang, R Ramaiahgari, S Ferguson, SS Sykora, P Sobol, RW Bryce, S Dertinger, SD Tice, RR Paules, RS AF Witt, K. L. Smith-Roe, S. L. Hsieh, J-H Xia, M. Huang, R. Ramaiahgari, S. Ferguson, S. S. Sykora, P. Sobol, R. W. Bryce, S. Dertinger, S. D. Tice, R. R. Paules, R. S. TI Predicting Genotoxicity Using Tox21 High-Throughput Screening Data. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 47th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society CY SEP 24-28, 2016 CL Kansas City, MO SP Environm Mutagenesis & Genom Soc C1 [Witt, K. L.; Smith-Roe, S. L.; Ramaiahgari, S.; Ferguson, S. S.; Tice, R. R.; Paules, R. S.] NIEHS, DNTP, POB 12233, Res Triangle Pk, NC 27709 USA. [Hsieh, J-H] NIEHS, Kelly Sci Staffing, DNTP, POB 12233, Res Triangle Pk, NC 27709 USA. [Xia, M.; Huang, R.] NIH, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA. [Sykora, P.; Sobol, R. W.] Univ S Alabama, Mitchell Canc Inst, Mobile, AL USA. [Bryce, S.; Dertinger, S. D.] Litron Labs, Rochester, NY USA. NR 0 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD SEP PY 2016 VL 57 SU 1 MA GT-87 BP S80 EP S80 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA DW4BQ UT WOS:000383587400157 ER PT J AU Blackwood, JC Cummings, DAT Iamsirithaworn, S Rohani, P AF Blackwood, J. C. Cummings, D. A. T. Iamsirithaworn, S. Rohani, P. TI Using age-stratified incidence data to examine the transmission consequences of pertussis vaccination SO EPIDEMICS LA English DT Article DE Disease transmission; Epidemiology; Pertussis; Mathematical model; Immunity ID CHANGING EPIDEMIOLOGY; UNITED-STATES; VACCINES; RESURGENCE; EFFICACY AB Pertussis is a highly infectious respiratory disease that has been on the rise in many countries worldwide over the past several years. The drivers of this increase in pertussis incidence remain hotly debated, with a central and long-standing hypothesis that questions the ability of vaccines to eliminate pertussis transmission rather than simply modulate the severity of disease. In this paper, we present age-structured case notification data from all provinces of Thailand between 1981 and 2014, a period during which vaccine uptake rose substantially, permitting an evaluation of the transmission impacts of vaccination. Our analyses demonstrate decreases in incidence across all ages with increased vaccine uptake - an observation that is at odds with pertussis case notification data in a number of other countries. To explore whether these observations are consistent with a rise in herd immunity and a reduction in bacterial transmission, we analyze an age-structured model that incorporates contrasting hypotheses concerning the immunological and transmission consequences of vaccines. Our results lead us to conclude that the most parsimonious explanation for the combined reduction in incidence and the shift to older age groups in the Thailand data is vaccine-induced herd immunity. (C) 2016 The Authors. Published by Elsevier B.V. C1 [Blackwood, J. C.] Williams Coll, Dept Math & Stat, Williamstown, MA 01267 USA. [Cummings, D. A. T.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Iamsirithaworn, S.] Minist Publ Hlth, Bur Epidemiol, Nonthaburi, Thailand. [Rohani, P.] Univ Georgia, Odum Sch Ecol, Athens, GA 30606 USA. [Rohani, P.] Univ Georgia, Sch Vet Med, Dept Infect Dis, Athens, GA 30606 USA. [Rohani, P.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. RP Blackwood, JC (reprint author), Williams Coll, Dept Math & Stat, Williamstown, MA 01267 USA. EM jcb5@williams.edu FU Research and Policy in Infectious Disease Dynamics program of the Science and Technology Directorate, Department of Homeland Security, the Fogarty International Center, National Institutes of Health; National Institutes of Health [1R01AI101155]; MIDAS, National Institute of General Medical Sciences [U54-GM111274] FX We thank an anonymous reviewer for their helpful feedback on earlier drafts of this manuscript. This work is supported by the Research and Policy in Infectious Disease Dynamics program of the Science and Technology Directorate, Department of Homeland Security, the Fogarty International Center, National Institutes of Health and by a research grant from the National Institutes of Health (1R01AI101155) and by MIDAS, National Institute of General Medical Sciences U54-GM111274. NR 42 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1755-4365 J9 EPIDEMICS-NETH JI Epidemics PD SEP PY 2016 VL 16 BP 1 EP 7 DI 10.1016/j.epidem.2016.02.001 PG 7 WC Infectious Diseases SC Infectious Diseases GA DY1FX UT WOS:000384841400001 PM 27663785 ER PT J AU Zabel, MK Zhao, L Zhang, YK Gonzalez, SR Ma, WX Wang, X Fariss, RN Wong, WT AF Zabel, Matthew K. Zhao, Lian Zhang, Yikui Gonzalez, Shaimar R. Ma, Wenxin Wang, Xu Fariss, Robert N. Wong, Wai T. TI Microglial Phagocytosis and Activation Underlying Photoreceptor Degeneration is Regulated by CX3CL1-CX3CR1 Signaling in a Mouse Model of Retinitis Pigmentosa SO GLIA LA English DT Article DE retina; inflammation; apoptosis; chemokine; neuroprotection ID INHERITED RETINAL DEGENERATION; FRACTALKINE RECEPTOR; MACULAR DEGENERATION; CX(3)CR1 DEFICIENCY; AMYLOID DEPOSITION; ALZHEIMERS-DISEASE; BETA-SUBUNIT; CELL-DEATH; CX3CR1; MICE AB Retinitis pigmentosa (RP), a disease characterized by the progressive degeneration of mutation-bearing photoreceptors, is a significant cause of incurable blindness in the young worldwide. Recent studies have found that activated retinal microglia contribute to photoreceptor demise via phagocytosis and proinflammatory factor production, however mechanisms regulating these contributions are not well-defined. In this study, we investigate the role of CX3CR1, a microglia-specific receptor, in regulating microglia-mediated degeneration using the well-established rd10 mouse model of RP. We found that in CX3CR1-deficient (CX3CR1(GFP/GFP)) rd10 mice microglial infiltration into the photoreceptor layer was significantly augmented and associated with accelerated photoreceptor apoptosis and atrophy compared with CX3CR1-sufficient (CX3CR1(GFP/+)) rd10 litter-mates. CX3CR1-deficient microglia demonstrated increased phagocytosis as evidenced by (1) having increased numbers of phagosomes in vivo, (2) an increased rate of phagocytosis of fluorescent beads and photoreceptor cellular debris in vitro, and (3) increased photoreceptor phagocytosis dynamics on live cell imaging in retinal explants, indicating that CX3CR1 signaling in microglia regulates the phagocytic clearance of at-risk photoreceptors. We also found that CX3CR1 deficiency in retinal microglia was associated with increased expression of inflammatory cytokines and microglial activation markers. Significantly, increasing CX3CL1-CX3CR1 signaling in the rd10 retina via exogenous intravitreal delivery of recombinant CX3CL1 was effective in (1) decreasing microglial infiltration, phagocytosis and activation, and (2) improving structural and functional features of photoreceptor degeneration. These results indicate that CX3CL1-CX3CR1 signaling is a molecular mechanism capable of modulating microglial-mediated degeneration and represents a potential molecular target in therapeutic approaches to RP. C1 [Zabel, Matthew K.; Zhao, Lian; Zhang, Yikui; Gonzalez, Shaimar R.; Ma, Wenxin; Wang, Xu; Wong, Wai T.] NEI, Unit Neuron Glia Interact Retinal Dis, NIH, Bldg 6,Room 215, Bethesda, MD 20892 USA. [Fariss, Robert N.] NEI, Biol Imaging Core, NIH, Bethesda, MD 20892 USA. RP Wong, WT (reprint author), NEI, Unit Neuron Glia Interact Retinal Dis, NIH, Bldg 6,Room 215, Bethesda, MD 20892 USA. EM wongw@nei.nih.gov RI Wong, Wai/B-6118-2017; OI Wong, Wai/0000-0003-0681-4016; Zabel, Matthew/0000-0003-2591-7379 FU National Eye Institute Intramural Research Program FX Grant sponsor: National Eye Institute Intramural Research Program. NR 66 TC 4 Z9 4 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0894-1491 EI 1098-1136 J9 GLIA JI Glia PD SEP PY 2016 VL 64 IS 9 BP 1479 EP 1491 DI 10.1002/glia.23016 PG 13 WC Neurosciences SC Neurosciences & Neurology GA DY2OG UT WOS:000384931300002 PM 27314452 ER PT J AU Jaacks, LM Barr, DB Sundaram, R Grewal, J Zhang, CL Louis, GMB AF Jaacks, Lindsay M. Barr, Dana Boyd Sundaram, Rajeshwari Grewal, Jagteshwar Zhang, Cuilin Louis, Germaine M. Buck TI Pre-Pregnancy Maternal Exposure to Persistent Organic Pollutants and Gestational Weight Gain: A Prospective Cohort Study SO INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH LA English DT Article DE persistent organic pollutants; organochlorine pesticides; pregnancy; obesity ID POLYCHLORINATED-BIPHENYLS; HUMAN SERUM; OBESITY; PREGNANCY; LIFE; POSTPARTUM; EXTRACTION; WINDOWS AB Persistent organic pollutants (POPs) have been implicated in the development of obesity in non-pregnant adults. However, few studies have explored the association of POPs with gestational weight gain (GWG), an important predictor of future risk of obesity in both the mother and offspring. We estimated the association of maternal pre-pregnancy levels of 63 POPs with GWG. Data are from women (18-40 years; n = 218) participating in a prospective cohort study. POPs were assessed using established protocols in pre-pregnancy, non-fasting blood samples. GWG was assessed using three techniques: (1) total GWG (difference between measured pre-pregnancy weight and final self-reported pre-delivery weight); (2) category based on pre-pregnancy body mass index (BMI)-specific Institute of Medicine (IOM) recommendations; and (3) area under the GWG curve (AUC). In an exploratory analysis, effects were estimated separately for women with BMI < 25 kg/m(2) versus BMI 25 kg/m(2). Multivariable polytomous logistic regression and linear regression were used to estimate the association between each chemical or congener and the three GWG outcomes. p,p'-dichlorodiphenyl trichloroethane (p,p'-DDT) was significantly inversely associated with AUC after adjustment for lipids and pre-pregnancy BMI: beta {95% confidence interval (CI)}, -378.03 (-724.02, -32.05). Perfluorooctane sulfonate (PFOS) was significantly positively associated with AUC after adjustment for lipids among women with a BMI < 25 kg/m(2) {beta (95% CI), 280.29 (13.71, 546.86)}, but not among women with a BMI 25 kg/m(2) {beta (95% CI), 56.99 (-328.36, 442.34)}. In summary, pre-pregnancy levels of select POPs, namely, p,p'-DDT and PFOS, were moderately associated with GWG. The association between POPs and weight gain during pregnancy may be more complex than previously thought, and adiposity prior to pregnancy may be an important effect modifier. C1 [Jaacks, Lindsay M.] Harvard Univ, Harvard TH Chan Sch Publ Hlth, Dept Global Hlth & Populat, Boston, MA 02115 USA. [Barr, Dana Boyd] Emory Univ, Rollins Sch Publ Hlth, Dept Environm Hlth, Atlanta, GA 30322 USA. [Sundaram, Rajeshwari] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Biostat & Bioinformat Branch, Rockville, MD 20852 USA. [Grewal, Jagteshwar; Louis, Germaine M. Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Off Director, Rockville, MD 20852 USA. [Zhang, Cuilin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Epidemiol Branch, Rockville, MD 20852 USA. RP Jaacks, LM (reprint author), Harvard Univ, Harvard TH Chan Sch Publ Hlth, Dept Global Hlth & Populat, Boston, MA 02115 USA. EM jaacks@hsph.harvard.edu; dbbarr@emory.edu; sundaramr2@mail.nih.gov; grewalja@mail.nih.gov; zhangcu@mail.nih.gov; louisg@mail.nih.gov OI Jaacks, Lindsay/0000-0002-7791-5167; Grewal, Jagteshwar/0000-0002-0141-4876; Sundaram, Rajeshwari/0000-0002-6918-5002; Buck Louis, Germaine/0000-0002-1774-4490 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development [N01-HD-3-3355, N01-HD-3-3356, N01-HD-3-3358]; Rollins School of Public Health Hubert Chair Fund; Emory Health and Exposome Research Center: Understanding Lifetime Exposures; National Institute of Environmental Health Sciences [P30 ES019776] FX The LIFE Study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Contracts N01-HD-3-3355, N01-HD-3-3356, N01-HD-3-3358). Lindsay M. Jaacks was supported by the Rollins School of Public Health Hubert Chair Fund. Dana Boyd Barr is partially supported by the Emory Health and Exposome Research Center: Understanding Lifetime Exposures, funded by the National Institute of Environmental Health Sciences (P30 ES019776). None of the aforementioned funding sources had a role in the design, analysis or writing of this article. NR 30 TC 1 Z9 1 U1 9 U2 9 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 1660-4601 J9 INT J ENV RES PUB HE JI Int. J. Environ. Res. Public Health PD SEP PY 2016 VL 13 IS 9 AR 905 DI 10.3390/ijerph13090905 PG 12 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA DX9EG UT WOS:000384695800069 ER PT J AU Ceccon, A Clore, GM Tugarinov, V AF Ceccon, Alberto Clore, G. Marius Tugarinov, Vitali TI Towards interpretation of intermolecular paramagnetic relaxation enhancement outside the fast exchange limit SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE Paramagnetic relaxation enhancement; Chemical exchange; Ligand binding; Liposomes; Protein-nanoparticle interactions ID MAGNETIC-RESONANCE; NMR-SPECTROSCOPY; COMPLEXES; LIPOSOMES; DYNAMICS; STATES AB In an exchanging system between major and minor species, the transverse paramagnetic relaxation enhancement rate observed on the resonances of the major species (I" (2) (app) ) is dependent upon the exchange regime between the species. Quantitative analysis of PRE data in such systems typically assumes that the overall exchange rate k (ex) between the species is fast on the PRE time scale (k (ex) ae << I"(2)). Recently, we have characterized the kinetics of binding of the model protein ubiquitin to large (LUV) and small (SUV) unilamellar lipid-based nanoparticles or liposomes (Ceccon A, Tugarinov V, Bax A, Clore GM (2016). J Am Chem Soc 138:5789-5792). Building upon these results and taking advantage of a strong paramagnetic agent with an isotropic g-tensor, Gd3+, we were able to measure intermolecular methyl carbon and proton PREs between paramagnetically-tagged liposomes and ubiquitin. In the limit of fast exchange (k (ex) ae << I"(2)) the ratio of the apparent proton to carbon methyl PREs, (H-1(m)-I" (2) (app) )/(C-13(m)-I" (2) (app) ), is equal to the square of the ratio of the gyromagnetic ratios of the two nuclei, (gamma(Iu)/gamma(C))(2). However, outside the fast exchange regime, under intermediate exchange conditions (e.g. when I"(2) is comparable in magnitude to k (ex)) the (H-1(m)-I" (2) (app) )/(C-13(m)-I" (2) (app) ) ratio provides a reliable measure of the 'true' methyl PREs. C1 [Ceccon, Alberto; Clore, G. Marius; Tugarinov, Vitali] NIDDK, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. RP Clore, GM; Tugarinov, V (reprint author), NIDDK, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. EM mariusc@mail.nih.gov; vitali.tugarinov@nih.gov OI Clore, G. Marius/0000-0003-3809-1027 FU Intramural Program of the NIH, NIDDK; Intramural AIDS Targeted Antiviral Program of the Office of the Director of the NIH FX This work was supported by funds from the Intramural Program of the NIH, NIDDK, and the Intramural AIDS Targeted Antiviral Program of the Office of the Director of the NIH (to G.M.C.). NR 23 TC 0 Z9 0 U1 3 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0925-2738 EI 1573-5001 J9 J BIOMOL NMR JI J. Biomol. NMR PD SEP PY 2016 VL 66 IS 1 BP 1 EP 7 DI 10.1007/s10858-016-0053-x PG 7 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA DY6CZ UT WOS:000385195000001 PM 27558624 ER PT J AU Travers, TS Harlow, L Rosas, IO Gochuico, BR Mikuls, TR Bhattacharya, SK Camacho, CJ Ascherman, DP AF Travers, Timothy S. Harlow, Lisa Rosas, Ivan O. Gochuico, Bernadette R. Mikuls, Ted R. Bhattacharya, Sanjoy K. Camacho, Carlos J. Ascherman, Dana P. TI Extensive Citrullination Promotes Immunogenicity of HSP90 through Protein Unfolding and Exposure of Cryptic Epitopes SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INTERSTITIAL LUNG-DISEASE; MOLECULAR-DYNAMICS SIMULATIONS; PARTICLE MESH EWALD; RHEUMATOID-ARTHRITIS; PEPTIDE ANTIBODY; EXTRAARTICULAR MANIFESTATIONS; AUTOIMMUNITY; ASSOCIATION; MECHANISMS; MORTALITY AB Post-translational protein modifications such as citrullination have been linked to the breach of immune tolerance and clinical autoimmunity. Previous studies from our laboratory support this concept, demonstrating that autoantibodies targeting citrullinated isoforms of heat shock protein 90 (HSP90) are associated with rheumatoid arthritis complicated by interstitial lung disease. To further explore the relationship between citrullination and structural determinants of HSP90 immunogenicity, we employed a combination of ELISA-based epitope profiling, computational modeling, and mass-spectrometric sequencing of peptidylarginine deiminase (PAD)-modified protein. Remarkably, ELISAs involving selected citrullinated HSP90 beta/alpha peptides identified a key epitope corresponding to an internal Arg residue (R502 [HSP90 beta]/R510 [HSP90 alpha]) that is normally buried within the crystal structure of native/unmodified HSP90. In vitro time/dose-response experiments reveal an ordered pattern of PAD-mediated deimination events culminating in citrullination of R502/R510. Conventional as well as scaled molecular dynamics simulations further demonstrate that citrullination of selected Arg residues leads to progressive disruption of HSP90 tertiary structure, promoting exposure of R502/R510 to PAD modification and subsequent autoantibody binding. Consistent with this process, ELISAs incorporating variably deiminated HSP90 as substrate Ag indicate a direct relationship between the degree of citrullination and the level of ex vivo Ab recognition. Overall, these data support a novel structural paradigm whereby citrullination-induced shifts in protein structure generate cryptic epitopes capable of bypassing B cell tolerance in the appropriate genetic context. C1 [Travers, Timothy S.; Camacho, Carlos J.] Univ Pittsburgh, Sch Med, Dept Computat & Syst Biol, Suite 3064,Biomed Sci Tower 3,3501 5th Ave, Pittsburgh, PA 15213 USA. [Harlow, Lisa; Ascherman, Dana P.] Univ Miami, Miller Sch Med, Dept Med, Div Rheumatol, Rosenstiel Med Sci Bldg 7152,1600 NW 10th Ave, Miami, FL 33136 USA. [Rosas, Ivan O.] Brigham & Womens Hosp, Dept Med, Div Pulm & Crit Care Med, 75 Francis St, Boston, MA 02115 USA. [Gochuico, Bernadette R.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Mikuls, Ted R.] Univ Nebraska Med Ctr, Dept Med, Div Rheumatol, Omaha, NE 68198 USA. [Bhattacharya, Sanjoy K.] Univ Miami, Dept Ophthalmol, Miller Sch Med, Miami, FL 33136 USA. [Travers, Timothy S.] Los Alamos Natl Lab, Theoret Biol & Biophys Grp, Los Alamos, NM USA. RP Camacho, CJ (reprint author), Univ Pittsburgh, Sch Med, Dept Computat & Syst Biol, Suite 3064,Biomed Sci Tower 3,3501 5th Ave, Pittsburgh, PA 15213 USA.; Ascherman, DP (reprint author), Univ Miami, Miller Sch Med, Dept Med, Div Rheumatol, Rosenstiel Med Sci Bldg 7152,1600 NW 10th Ave, Miami, FL 33136 USA. EM CCamacho@pitt.edu; DAscherman@med.miami.edu FU BLRD VA [I01 BX000788]; NIGMS NIH HHS [R01 GM097082] NR 58 TC 0 Z9 0 U1 3 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 SEP 1 PY 2016 VL 197 IS 5 BP 1926 EP 1936 DI 10.4049/jimmunol.1600162 PG 11 WC Immunology SC Immunology GA DY3OA UT WOS:000385002300040 PM 27448590 ER PT J AU Akkaya, B Miozzo, P Holstein, AH Shevach, EM Pierce, SK Akkaya, M AF Akkaya, Billur Miozzo, Pietro Holstein, Amanda H. Shevach, Ethan M. Pierce, Susan K. Akkaya, Munir TI A Simple, Versatile Antibody-Based Barcoding Method for Flow Cytometry SO JOURNAL OF IMMUNOLOGY LA English DT Article ID B-CELLS; LYMPHOCYTE-ACTIVATION; MASS-CYTOMETRY; CALCIUM; DNA; FLUO-3; CD45 AB Barcoding of biological samples is a commonly used strategy to mark or identify individuals within a complex mixture. However, cell barcoding has not yet found wide use in flow cytometry that would benefit greatly from the ability to analyze pooled experimental samples simultaneously. This is due, in part, to technical and practical limitations of current fluorescent dye-based methods. In this study, we describe a simple, versatile barcoding strategy that relies on combinations of a single Ab conjugated to different fluorochromes and thus in principle can be integrated into any flow cytometry application. To demonstrate the efficacy of the approach, we describe the results of a variety of experiments using live cells as well as fixed and permeabilized cells. The results of these studies show that Ab-based barcoding provides a simple, practical method for identifying cells from individual samples pooled for analysis by flow cytometry that has broad applications in immunological research. C1 [Akkaya, Billur; Holstein, Amanda H.; Shevach, Ethan M.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Miozzo, Pietro; Pierce, Susan K.; Akkaya, Munir] NIAID, Lab Immunogenet, NIH, Twinbrook 2,12441 Parklawn Dr,Room 213, Rockville, MD 20852 USA. RP Akkaya, M (reprint author), NIAID, Lab Immunogenet, NIH, Twinbrook 2,12441 Parklawn Dr,Room 213, Rockville, MD 20852 USA. EM munir.akkaya@nih.gov OI Miozzo, Pietro/0000-0003-3486-4061; AKKAYA, Munir/0000-0002-9949-9424 FU Intramural NIH HHS NR 27 TC 1 Z9 1 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD SEP 1 PY 2016 VL 197 IS 5 BP 2027 EP 2038 DI 10.4049/jimmunol.1600727 PG 12 WC Immunology SC Immunology GA DY3OA UT WOS:000385002300050 PM 27439517 ER PT J AU Lee, IH Zan, E Bell, WR Burger, PC Sung, H Yousem, DM AF Lee, In Ho Zan, Elcin Bell, W. Robert Burger, Peter C. Sung, Heejong Yousem, David M. TI Craniopharyngiomas : Radiological Differentiation of Two Types SO JOURNAL OF KOREAN NEUROSURGICAL SOCIETY LA English DT Article DE Craniopharyngioma; Tomography scanners; X-ray computed; Magnetic resonance imaging ID PAPILLARY CRANIOPHARYNGIOMAS; PEDIATRIC CRANIOPHARYNGIOMA; RECURRENCE; CHILDHOOD; FEATURES; OUTCOMES; EPIDEMIOLOGY; MANAGEMENT; PATTERNS; MRI AB Objective : To determine imaging features that may separate adamantinomatous and papillary variants of craniopharyngiomas given that tumors with adamantinomatous signature features are associated with higher recurrence rates, morbidity, and mortality. We specifically reviewed calcification on CT, T1 bright signal intensity, and cystic change on T2 weighted images for differentiating these two types. Methods : We retrospectively reviewed the MRI and CT studies in 38 consecutive patients with pathologically proven craniopharyngiomas between January 2004 and February 2014 for the presence of calcification on CT scans, bright signal intensity on T1 weighted images, and cystic change on T2 weighted images. Results : Of the 38 craniopharyngiomas, 30 were adamantinomatous type and 8 were papillary type. On CT scans, calcification was present in 25 of 38 tumors. All calcified tumors were adamantinomatous type. Twenty four of 38 tumors had bright signal intensity on T1 weighted images. Of these 24 tumors, 22 (91.7%) were adamantinomatous and 2 were papillary type. Cystic change on T2 weighted images was noted in 37 of 38 tumors; only 1 tumor with papillary type did not show cystic change. Conclusion : T1 bright signal intensity and calcification on CT scans uniformly favor the adamantinomatous type over papillary type of craniopharyngioma in children. However, these findings are more variable in adults where calcification and T1 bright signal intensity occur in 70.6% and 58.8% respectively of adult adamantinomatous types of craniopharyngiomas. C1 [Lee, In Ho; Zan, Elcin; Yousem, David M.] Johns Hopkins Med Inst, Russell H Morgan Dept Radiol & Radiol Sci, 600 N Wolfe St, Baltimore, MD 21205 USA. [Bell, W. Robert; Burger, Peter C.] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. [Lee, In Ho] Chungnam Natl Univ, Sch Med, Chungnam Natl Univ Hosp, Dept Radiol, 282 Munhwa Ro, Daejeon 35015, South Korea. [Sung, Heejong] NHGRI, Genometr Sect, Computat & Stat Genom Branch, NIH, Baltimore, MD USA. RP Lee, IH (reprint author), Chungnam Natl Univ, Sch Med, Chungnam Natl Univ Hosp, Dept Radiol, 282 Munhwa Ro, Daejeon 35015, South Korea. EM leeinho1974@hanmail.net NR 29 TC 0 Z9 0 U1 0 U2 0 PU KOREAN NEUROSURGICAL SOC PI SEOUL PA #402 POSCO # OFFICE BUILDING 151 SUNHWA-DONG, JUNG-GU, SEOUL, 100-130, SOUTH KOREA SN 2005-3711 EI 1598-7876 J9 J KOREAN NEUROSURG S JI J. Korean. Neurosurg. Soc. PD SEP PY 2016 VL 59 IS 5 BP 466 EP 470 DI 10.3340/jkns.2016.59.5.466 PG 5 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA DY2OY UT WOS:000384933100007 PM 27651864 ER PT J AU Denlinger, DS Li, AY Durham, SL Lawyer, PG Anderson, JL Bernhardt, SA AF Denlinger, David S. Li, Andrew Y. Durham, Susan L. Lawyer, Phillip G. Anderson, Joseph L. Bernhardt, Scott A. TI Comparison of In Vivo and In Vitro Methods for Blood Feeding of Phlebotomus papatasi (Diptera: Psychodidae) in the Laboratory SO JOURNAL OF MEDICAL ENTOMOLOGY LA English DT Article DE Phlebotomus papatasi; blood feed; Hemotek; glass feeder; mouse ID SAND FLIES DIPTERA; MAINTENANCE; MEMBRANE; BIOLOGY; VECTOR; FLY; COLONIZATION; RESPONSES; COLONY; FIELD AB Phlebotomus papatasi Scopoli is a medically important insect that has been successfully colonized in the laboratory, and blood feeding is critical for colony propagation. There has been much interest in developing established protocols for in vitro blood-feeding systems. The objective of this study was to determine if a Parafilm membrane and a hog's gut membrane could be successfully used with in vitro feeding systems. We evaluated percentages of P. papatasi females that blood fed on different blood-feeding systems (a mouse, a Hemotek feeder, or a glass feeder) used with either a Parafilm or a hog's gut membrane, with cohorts of 250 and 500 P. papatasi females, and with or without external exhalations. For all feeding system combinations, female P. papatasi blood fed in higher percentages when in cohorts of 500 individuals and in the presence of exhalations. Higher percentages of P. papatasi fed on a mouse, but this study also demonstrates that P. papatasi will readily feed with in vitro feeding systems using a Parafilm membrane or a hog's gut membrane. This study suggests that female P. papatasi may use an invitation effect to blood feed and are attracted to blood sources via chemical olfaction cues, both of which have been characterized in other blood-feeding arthropods. Our study demonstrates that a Parafilm membrane or a hog's gut membrane, in conjunction with the Hemotek or glass feeder system, is potentially a viable alternative to live rodents to blood feed a colony of P. papatasi. C1 [Denlinger, David S.; Anderson, Joseph L.; Bernhardt, Scott A.] Utah State Univ, Dept Biol, Logan, UT 84322 USA. [Li, Andrew Y.] ARS, USDA, Knipling Bushland US Livestock Insect Res Lab, Kerrville, TX 78028 USA. [Li, Andrew Y.] ARS, USDA, Invas Insect Biocontrol & Behav Lab, Beltsville, MD 20705 USA. [Durham, Susan L.] Utah State Univ, Ctr Ecol, Logan, UT 84322 USA. [Lawyer, Phillip G.] NIH, Parasit Dis Lab, Intracellular Parasite Biol Sect, Bethesda, MD 20892 USA. RP Bernhardt, SA (reprint author), Utah State Univ, Dept Biol, Logan, UT 84322 USA. EM david.denlinger@aggiemail.usu.edu; Andrew.Li@ars.usda.gov; susan.durham@usu.edu; plawyer349@verizon.net; j.laine.anderson@gmail.com; scott.bernhardt@usu.edu FU Deployed Warfighter Protection Research Program of the U.S. Department of Defense through the Armed Forces Pest Management Board [6205-32000-033-20] FX We thank Darci Burchers and Samuel Ewalefo (USDA-ARS-KBUSLIRL) for technical assistance with sand fly feeding experiments and Nick Kiriazis for photographing of sand flies. The maintenance of SKH1 hairless mice (Charles River, Wilmington, MA) and the experimental protocol was approved by Utah State University's Institutional Care and Use Committee. A. Li was partially supported by a fund (6205-32000-033-20) from Deployed Warfighter Protection Research Program of the U.S. Department of Defense through the Armed Forces Pest Management Board. NR 35 TC 0 Z9 0 U1 4 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-2585 EI 1938-2928 J9 J MED ENTOMOL JI J. Med. Entomol. PD SEP PY 2016 VL 53 IS 5 BP 1112 EP 1116 DI 10.1093/jme/tjw074 PG 5 WC Entomology; Veterinary Sciences SC Entomology; Veterinary Sciences GA DW5SV UT WOS:000383708100013 ER PT J AU Chou, A Nuila, RE Franco, LM Stager, CE Atmar, RL Zechiedrich, L AF Chou, Andrew Nuila, Ricardo E. Franco, Luis M. Stager, Charles E. Atmar, Robert L. Zechiedrich, Lynn TI Prevalence of hypervirulent Klebsiella pneumoniae-associated genes rmpA and magA in two tertiary hospitals in Houston, TX, USA SO JOURNAL OF MEDICAL MICROBIOLOGY LA English DT Letter ID PYOGENIC LIVER-ABSCESS C1 [Chou, Andrew; Atmar, Robert L.] Baylor Coll Med, Div Infect Dis, Houston, TX 77030 USA. [Chou, Andrew; Stager, Charles E.; Atmar, Robert L.; Zechiedrich, Lynn] Baylor Coll Med, Dept Mol Virol & Microbiol, Houston, TX 77030 USA. [Chou, Andrew; Nuila, Ricardo E.; Franco, Luis M.; Atmar, Robert L.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Franco, Luis M.] Baylor Coll Med, Dept Human Mol Genet, Houston, TX 77030 USA. [Stager, Charles E.] Baylor Coll Med, Dept Pathol & Immunol, Houston, TX 77030 USA. [Zechiedrich, Lynn] Baylor Coll Med, Verna & Marrs McLean Dept Biochem & Mol Biol, Houston, TX 77030 USA. [Zechiedrich, Lynn] Baylor Coll Med, Dept Pharmacol, Houston, TX 77030 USA. [Franco, Luis M.] NIAID, Lab Syst Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Chou, A (reprint author), Baylor Coll Med, Div Infect Dis, Houston, TX 77030 USA.; Chou, A; Zechiedrich, L (reprint author), Baylor Coll Med, Dept Mol Virol & Microbiol, Houston, TX 77030 USA.; Chou, A (reprint author), Baylor Coll Med, Dept Med, Houston, TX 77030 USA.; Zechiedrich, L (reprint author), Baylor Coll Med, Verna & Marrs McLean Dept Biochem & Mol Biol, Houston, TX 77030 USA.; Zechiedrich, L (reprint author), Baylor Coll Med, Dept Pharmacol, Houston, TX 77030 USA. EM achou@bcm.edu; elz@bcm.edu FU NIAID NIH HHS [T32 AI055413, R56 AI054830, R01 AI054830]; NIGMS NIH HHS [R01 GM115501] NR 19 TC 0 Z9 0 U1 0 U2 0 PU MICROBIOLOGY SOC PI LONDON PA CHARLES DARWIN HOUSE, 12 ROGER ST, LONDON WC1N 2JU, ERKS, ENGLAND SN 0022-2615 EI 1473-5644 J9 J MED MICROBIOL JI J. Med. Microbiol. PD SEP PY 2016 VL 65 BP 1047 EP 1048 DI 10.1099/jmm.0.000309 PN 9 PG 2 WC Microbiology SC Microbiology GA DY3SU UT WOS:000385015600021 PM 27392968 ER PT J AU Cabrera, EA Wiers, CE Lindgren, E Miller, G Volkow, ND Wang, GJ AF Cabrera, Elizabeth A. Wiers, Corinde E. Lindgren, Elsa Miller, Gregg Volkow, Nora D. Wang, Gene-Jack TI Neuroimaging the Effectiveness of Substance Use Disorder Treatments SO JOURNAL OF NEUROIMMUNE PHARMACOLOGY LA English DT Article DE Addiction; MRI; Neuroimaging; PET; Substance use disorder; Treatment ID TRANSCRANIAL MAGNETIC STIMULATION; ALCOHOL-DEPENDENT PATIENTS; ANTERIOR CINGULATE CORTEX; METHADONE-MAINTENANCE TREATMENT; POSITRON-EMISSION-TOMOGRAPHY; ATTENTIONAL BIAS MODIFICATION; INDUCED BRAIN ACTIVATION; CUE EXPOSURE TREATMENT; SMOKING-RELATED CUES; HEROIN-RELATED CUES AB Neuroimaging techniques to measure the function and biochemistry of the human brain such as positron emission tomography (PET), proton magnetic resonance spectroscopy (H-1 MRS), and functional magnetic resonance imaging (fMRI), are powerful tools for assessing neurobiological mechanisms underlying the response to treatments in substance use disorders. Here, we review the neuroimaging literature on pharmacological and behavioral treatment in substance use disorder. We focus on neural effects of medications that reduce craving (e.g., naltrexone, bupropion hydrochloride, baclofen, methadone, varenicline) and that improve cognitive control (e.g., modafinil, N-acetylcysteine), of behavioral treatments for substance use disorders (e.g., cognitive bias modification training, virtual reality, motivational interventions) and neuromodulatory interventions such as neurofeedback and transcranial magnetic stimulation. A consistent finding for the effectiveness of therapeutic interventions identifies the improvement of executive control networks and the dampening of limbic activation, highlighting their values as targets for therapeutic interventions in substance use disorders. C1 [Cabrera, Elizabeth A.; Wiers, Corinde E.; Lindgren, Elsa; Miller, Gregg; Volkow, Nora D.; Wang, Gene-Jack] NIAAA, NIH, Bethesda, MD 20892 USA. [Volkow, Nora D.] NIDA, NIH, Bethesda, MD 20892 USA. RP Cabrera, EA (reprint author), NIAAA, NIH, Bethesda, MD 20892 USA. EM elizabeth.cabrera@nih.gov FU NIH/NIAAA [Y1AA-3009] FX This work was supported by NIH/NIAAA intramural grant Y1AA-3009 to NDV. NR 151 TC 2 Z9 2 U1 23 U2 23 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1557-1890 EI 1557-1904 J9 J NEUROIMMUNE PHARM JI J. Neuroimmune Pharm. PD SEP PY 2016 VL 11 IS 3 BP 408 EP 433 DI 10.1007/s11481-016-9680-y PG 26 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA DY1GV UT WOS:000384843800005 PM 27184387 ER PT J AU Kaneski, CR Brady, RO Hanover, JA Schueler, UH AF Kaneski, Christine R. Brady, Roscoe O. Hanover, John A. Schueler, Ulrike H. TI Development of a model system for neuronal dysfunction in Fabry disease SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Acetylcholine; Alpha-galactosidase A; Fabty disease; Gene silencing; Neuropathy ID HUMAN NEUROBLASTOMA-CELLS; VESICULAR ACETYLCHOLINE TRANSPORTER; ALPHA-GALACTOSIDASE; LA-N-2; DIFFERENTIATION; FIBROBLASTS; EXPRESSION; GROWTH; ASSAY; PAIN AB Fabry disease is a glycosphingolipid storage disorder that is caused by a genetic deficiency of the enzyme alphagalactosidase A (AGA, EC 3.2.1.22). It is a multisystem disease that affects the vascular, cardiac, renal, and nervous systems. One of the hallmarks of this disorder is neuropathic pain and sympathetic and parasympathetic nervous dysfunction. The exact mechanism by which changes in AGA activity result in change in neuronal function is not clear, partly due to of a lack of relevant model systems. In this study, we report the development of an in vitro model system to study neuronal dysfunction in Fabry disease by using short-hairpin RNA to create a stable knock-down of AGA in the human cholinergic neuronal cell line, LA-N-2. We show that gene-silenced cells show specifically reduced AGA activity and store globotriaosylceramide. In gene-silenced cells, release of the neurotransmitter acetylcholine is significantly reduced, demonstrating that this model may be used to study specific neuronal functions such as neurotransmitter release in Fabry disease. Published by Elsevier Inc. C1 [Kaneski, Christine R.; Brady, Roscoe O.] NINDS, NIH, Bethesda, MD 20892 USA. [Hanover, John A.; Schueler, Ulrike H.] NIDDK, NIH, Bethesda, MD 20892 USA. RP Kaneski, CR (reprint author), NIH, Bldg 8,Room 422, Bethesda, MD 20892 USA. EM kaneskic@ninds.nih.gov FU NIDDK Intramural Research Program; NINDS Intramural Research Program at the National Institutes of Health, Bethesda, MD; Pfizer Inc., New York, NY [IIR WI171341] FX This research was supported in part by the NIDDK Intramural Research Program and the NINDS Intramural Research Program at the National Institutes of Health, Bethesda, MD, and by Pfizer Inc., New York, NY (grant number IIR #WI171341 to UHS). NR 43 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 SEP-OCT PY 2016 VL 119 IS 1-2 SI SI BP 144 EP 150 DI 10.1016/j.ymgme.2016.07.010 PG 7 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA DX8IJ UT WOS:000384631000019 PM 27471012 ER PT J AU Whitehill, GD Amarnath, S Muranski, P Keyvanfar, K Battiwalla, M Barrett, AJ Chinnassamy, D AF Whitehill, Greg D. Amarnath, Shoba Muranski, Pawel Keyvanfar, Keyvan Battiwalla, Minoo Barrett, Austin J. Chinnassamy, Dhanalakshmi TI Adenosine Selectively Depletes Alloreactive T Cells to Prevent GVHD While Conserving Immunity to Viruses and Leukemia SO MOLECULAR THERAPY LA English DT Article ID VERSUS-HOST-DISEASE; BONE-MARROW-TRANSPLANTATION; POSTTRANSPLANTATION CYCLOPHOSPHAMIDE; ADOPTIVE IMMUNOTHERAPY; DONOR LYMPHOCYTES; RECONSTITUTION; INFECTIONS; MULTICENTER; GENERATION; RECEPTORS AB Selective depletion (SD) of alloreactive T cells from allogeneic hematopoeitic stem cell transplants to prevent graft-versus-host disease (GVHD) without compromising immune reconstitution and antitumor responses remains a challenge. Here, we demonstrate a novel SD strategy whereby alloreacting T cells are efficiently deleted ex vivo with adenosine. SD was achieved in human leukocyte antigen (HLA) mismatched cocultures by multiple exposures to 2 mmol/l adenosine over 7 days. Adenosine depleted greater than to 90% of alloproliferating T cells in mismatched, haploidentical, and matched sibling pairs while conserving response to third-party antigens. Alloreactive CD4 and CD8 T cells were targeted for depletion while NK and B cells were preserved. Our novel approach also preserved nonalloreactive naive, central, and effector memory T-cell subsets, Tregs, and notably preserved T-cell responses against DNA viruses that contribute to transplant related mortality after allogeneic hematopoeitic stem cell transplants. Additionally, T cells recognizing leukemia-associated antigens were efficiently generated in vitro from the cell product post-SD. This study is the first to demonstrate that adenosine depletion of alloactivated T cells maintains a complete immune cell profile and recall viral responses. Expansion of tumor antigen-specific subsets postdepletion opens the possibility of generating T-cell products capable of graft-versus-tumor responses without causing GVHD. C1 [Whitehill, Greg D.; Muranski, Pawel; Keyvanfar, Keyvan; Battiwalla, Minoo; Barrett, Austin J.; Chinnassamy, Dhanalakshmi] NHLBI, Stem Cell Allotransplantat Sect, Hematol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Amarnath, Shoba] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne, Tyne & Wear, England. [Chinnassamy, Dhanalakshmi] NHLBI, Lab Transplantat Immunotherapy, Hematol Branch, NIH, Bldg 10,Hatfield CRC,Rm 5-5264,10 Ctr Dr, Bethesda, MD 20892 USA. RP Chinnassamy, D (reprint author), NHLBI, Lab Transplantat Immunotherapy, Hematol Branch, NIH, Bldg 10,Hatfield CRC,Rm 5-5264,10 Ctr Dr, Bethesda, MD 20892 USA. EM dchinnas@mail.nih.gov FU National Institutes of Health at the NHLBI FX This research was supported by the Intramural Research Program of the National Institutes of Health at the NHLBI. The authors thank Nancy Hensel and Fariba Chinian (Hematology Branch, NHLBI, NIH, Bethesda, MD) for their technical assistance. The authors declare no competing financial interests. NR 35 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD SEP PY 2016 VL 24 IS 9 BP 1655 EP 1664 DI 10.1038/mt.2016.147 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA DY3AD UT WOS:000384962300017 PM 27401140 ER PT J AU Vogel, RM Erez, A Altan-Bonnet, G AF Vogel, Robert M. Erez, Amir Altan-Bonnet, Gregoire TI Dichotomy of cellular inhibition by small-molecule inhibitors revealed by single-cell analysis SO NATURE COMMUNICATIONS LA English DT Article ID EPIDERMAL-GROWTH-FACTOR; KINASE INHIBITOR; LUNG-CANCER; MASS CYTOMETRY; T-CELLS; VARIABILITY; RESPONSES; ACTIVATION; DIFFERENTIATION; PROLIFERATION AB Despite progress in drug development, a quantitative and physiological understanding of how small-molecule inhibitors act on cells is lacking. Here, we measure the signalling and proliferative response of individual primary T-lymphocytes to a combination of antigen, cytokine and drug. We uncover two distinct modes of signalling inhibition: digital inhibition (the activated fraction of cells diminishes upon drug treatment, but active cells appear unperturbed), versus analogue inhibition (the activated fraction is unperturbed whereas activation response is diminished). We introduce a computational model of the signalling cascade that accounts for such inhibition dichotomy, and test the model predictions for the phenotypic variability of cellular responses. Finally, we demonstrate that the digital/analogue dichotomy of cellular response as revealed on short (signal transduction) timescales, translates into similar dichotomy on longer (proliferation) timescales. Our single-cell analysis of drug action illustrates the strength of quantitative approaches to translate in vitro pharmacology into functionally relevant cellular settings. C1 [Vogel, Robert M.; Erez, Amir; Altan-Bonnet, Gregoire] Mem Sloan Kettering Canc Ctr, Program Computat Biol & Immunol, ImmunoDynam Grp, 1275 York Ave,Box 460, New York, NY 10065 USA. [Erez, Amir; Altan-Bonnet, Gregoire] NCI, ImmunoDynam Grp, Canc & Inflammat Program, Ctr Canc Res, Bldg 37,Room 4134B,37 Convent Dr, Bethesda, MD 20892 USA. RP Altan-Bonnet, G (reprint author), Mem Sloan Kettering Canc Ctr, Program Computat Biol & Immunol, ImmunoDynam Grp, 1275 York Ave,Box 460, New York, NY 10065 USA.; Altan-Bonnet, G (reprint author), NCI, ImmunoDynam Grp, Canc & Inflammat Program, Ctr Canc Res, Bldg 37,Room 4134B,37 Convent Dr, Bethesda, MD 20892 USA. EM gregoire.altan-bonnet@nih.gov OI Vogel, Robert/0000-0001-5400-5024 FU NIH [U54 CA148967]; Geoffrey Beene Cancer Center at MSKCC; intramural research program of the National Cancer Institute; Human Frontier Science Program grant [LT000123/2014] FX This research was funded by NIH U54 CA148967, the Geoffrey Beene Cancer Center at MSKCC and the intramural research program of the National Cancer Institute. A.E. is supported by the Human Frontier Science Program grant LT000123/2014. Furthermore, we thank Neal Rosen for commentary and for generously sharing inhibitors. We would also like to thank Jacqueline Bromberg for her valuable comments and discussions. NR 48 TC 0 Z9 0 U1 1 U2 1 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 SEP PY 2016 VL 7 AR 12428 DI 10.1038/ncomms12428 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DY6QY UT WOS:000385254300001 PM 27687249 ER PT J AU Wells, MA Vendrov, KC Edin, ML Ferslew, BC Zha, WB Nguyen, BKH Church, RJ Lih, FB DeGraff, LM Brouwer, KLR Barritt, AS Zeldin, DC Lee, CR AF Wells, Michael A. Vendrov, Kimberly C. Edin, Matthew L. Ferslew, Brian C. Zha, Weibin Nguyen, Bobbie K. H. Church, Rachel J. Lih, Fred B. DeGraff, Laura M. Brouwer, Kim L. R. Barritt, A. Sidney Zeldin, Darryl C. Lee, Craig R. TI Characterization of the Cytochrome P450 epoxyeicosanoid pathway in non-alcoholic steatohepatitis SO PROSTAGLANDINS & OTHER LIPID MEDIATORS LA English DT Article DE Non-alcoholic fatty liver disease; Soluble epoxide hydrolase; CYP2J; CYP2C; Epoxyeicosatrienoic acids; Mice; Humans ID SOLUBLE EPOXIDE HYDROLASE; HIGH-FAT DIET; P450-DERIVED EPOXYEICOSATRIENOIC ACIDS; ENDOPLASMIC-RETICULUM STRESS; LIVER-DISEASE; EICOSANOID METABOLISM; INSULIN-RESISTANCE; ANIMAL-MODELS; GENE DELETION; RENAL INJURY AB Non-alcoholic steatohepatitis (NASH) is an emerging public health problem without effective therapies. Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid into bioactive epoxyeicosatrienoic acids (EETs), which have potent anti-inflammatory and protective effects. However, the functional relevance of the CYP epoxyeicosanoid metabolism pathway in the pathogenesis of NASH remains poorly understood. Our studies demonstrate that both mice with methionine-choline deficient (MCD) diet-induced NASH and humans with biopsy-confirmed NASH exhibited significantly higher free EET concentrations compared to healthy controls. Targeted disruption of Ephx2 (the gene encoding for soluble epoxide hydrolase) in mice further increased EET levels and significantly attenuated MCD diet-induced hepatic steatosis, inflammation and injury, as well as high fat diet-induced adipose tissue inflammation, systemic glucose intolerance and hepatic steatosis. Collectively, these findings suggest that dysregulation of the CYP epoxyeicosanoid pathway is a key pathological consequence of NASH in vivo, and promoting the anti-inflammatory and protective effects of EETs warrants further investigation as a novel therapeutic strategy for NASH. (C) 2016 Elsevier Inc. All rights reserved. C1 [Wells, Michael A.; Vendrov, Kimberly C.; Ferslew, Brian C.; Zha, Weibin; Nguyen, Bobbie K. H.; Brouwer, Kim L. R.; Lee, Craig R.] Univ North Carolina Chapel Hill, UNC Eshelman Sch Pharm, Div Pharmacotherapy & Expt Therapeut, Chapel Hill, NC USA. [Edin, Matthew L.; Lih, Fred B.; DeGraff, Laura M.; Zeldin, Darryl C.] NIEHS, Div Intramural Res, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Church, Rachel J.] Univ North Carolina Chapel Hill, Inst Drug Safety Sci, UNC Eshelman Sch Pharm, Chapel Hill, NC USA. [Barritt, A. Sidney] Univ North Carolina Chapel Hill, UNC Sch Med, Div Gastroenterol & Hepatol, Chapel Hill, NC USA. RP Lee, CR (reprint author), UNC Eshelman Sch Pharm, Div Pharmacotherapy & Expt Therapeut, CB 7569,3318 Kerr Hall, Chapel Hill, NC 27599 USA. EM craig_lee@unc.edu OI Lee, Craig/0000-0003-3595-5301 FU UNC Center for Gastrointestinal Biology and Disease Cell Services Histology Core [P30 DK34987]; UNC Nutrition Obesity Research Center Digital Histology & Quantitative Analysis Lab [P30 DK056350]; National Institute of General Medical Sciences of the National Institutes of Health (NIH) [R01 GM088199, R01 GM041935]; Gateway to Research Scholarship from American Foundation for Pharmaceutical Education; Amgen Predoctoral Fellowship in Pharmacokinetics and Drug Disposition; NIH National Center for Advancing Translational Sciences [1UL1TR001111]; Intramural Research Program of the NIH/NIEHS [Z01 ES025034] FX The authors gratefully acknowledge the UNC Center for Gastrointestinal Biology and Disease Cell Services & Histology Core (supported by grant P30 DK34987), the UNC Nutrition Obesity Research Center Digital Histology & Quantitative Analysis Lab (supported by grant P30 DK056350), and the UNC Department of Cell and Molecular Physiology Histology Core Facility (Kirk McNaughton, director) for their contributions to the histology analysis, and the National Institute of Environmental Health Sciences (NIEHS) Mass Spectrometry Core for their contributions to the eicosanoid metabolite analyses. This work was supported by the National Institute of General Medical Sciences of the National Institutes of Health (NIH) under Award Numbers R01 GM088199 to CRL and R01 GM041935 to KLRB, a Gateway to Research Scholarship from the American Foundation for Pharmaceutical Education to MAW, an Amgen Predoctoral Fellowship in Pharmacokinetics and Drug Disposition to BCF, the NIH National Center for Advancing Translational Sciences through Award Number 1UL1TR001111, and funds from the Intramural Research Program of the NIH/NIEHS to DCZ (Z01 ES025034). The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. NR 51 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 1098-8823 EI 2212-196X J9 PROSTAG OTH LIPID M JI Prostaglandins Other Lipid Mediat. PD SEP PY 2016 VL 125 SI SI BP 19 EP 29 DI 10.1016/j.prostaglandins.2016.07.002 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DY1PO UT WOS:000384867100004 PM 27401401 ER PT J AU Mischkowski, D Crocker, J Way, BM AF Mischkowski, Dominik Crocker, Jennifer Way, Baldwin M. TI From painkiller to empathy killer: acetaminophen (paracetamol) reduces empathy for pain SO SOCIAL COGNITIVE AND AFFECTIVE NEUROSCIENCE LA English DT Article DE acetaminophen; paracetamol; empathy; cyberball; psychopharmacology ID POSTOPERATIVE PAIN; MIRROR NEURONS; PLACEBO ANALGESIA; EXPERIENCED PAIN; PHYSICAL PAIN; DOUBLE-BLIND; MIND; METAANALYSIS; BEHAVIOR; AGGRESSION AB Simulation theories of empathy hypothesize that empathizing with others' pain shares some common psychological computations with the processing of one's own pain. Support for this perspective has largely relied on functional neuroimaging evidence of an overlap between activations during the experience of physical pain and empathy for other people's pain. Here, we extend the functional overlap perspective to the neurochemical level and test whether a common physical painkiller, acetaminophen (paracetamol), can reduce empathy for another's pain. In two double-blind placebo-controlled experiments, participants rated perceived pain, personal distress and empathic concern in response to reading scenarios about another's physical or social pain, witnessing ostracism in the lab, or visualizing another study participant receiving painful noise blasts. As hypothesized, acetaminophen reduced empathy in response to others' pain. Acetaminophen also reduced the unpleasantness of noise blasts delivered to the participant, which mediated acetaminophen's effects on empathy. Together, these findings suggest that the physical painkiller acetaminophen reduces empathy for pain and provide a new perspective on the neurochemical bases of empathy. Because empathy regulates prosocial and antisocial behavior, these drug-induced reductions in empathy raise concerns about the broader social side effects of acetaminophen, which is taken by almost a quarter of adults in the United States each week. C1 [Mischkowski, Dominik] NIH, Natl Ctr Complementary & Integrat Hlth, 10 Ctr Dr, Bethesda, MD 20814 USA. [Crocker, Jennifer; Way, Baldwin M.] Ohio State Univ, Dept Psychol, 1835 Neil Ave, Columbus, OH 43210 USA. [Way, Baldwin M.] Ohio State Wexner Med Ctr, Inst Behav Med Res, Columbus, OH USA. RP Mischkowski, D (reprint author), NIH, Natl Ctr Complementary & Integrat Hlth, 10 Ctr Dr, Bethesda, MD 20814 USA.; Way, BM (reprint author), Ohio State Univ, Dept Psychol, 1835 Neil Ave, Columbus, OH 43210 USA. EM dominik.mischkowski@nih.gov; way.37@osu.edu OI Crocker, Jennifer/0000-0002-6590-4647 FU Ohio State University; National Center for Advancing Translational Sciences [8KL2TR000112-05] FX This project was supported in part by funds from the Ohio State University as well as from the National Center for Advancing Translational Sciences (Award Number 8KL2TR000112-05). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Advancing Translational Sciences or the National Institutes of Health. Data are available upon request. NR 61 TC 1 Z9 1 U1 16 U2 16 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1749-5016 EI 1749-5024 J9 SOC COGN AFFECT NEUR JI Soc. Cogn. Affect. Neurosci. PD SEP PY 2016 VL 11 IS 9 BP 1345 EP 1353 DI 10.1093/scan/nsw057 PG 9 WC Neurosciences; Psychology; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA DW5ZY UT WOS:000383727400001 PM 27217114 ER PT J AU Mijinarends, DM Koster, A Schols, JMGA Meijers, JMM Halfens, RJG Gudnason, V Eiriksdottir, G Siggeirsdottir, K Sigurdsson, S Jonsson, PV Meirelles, O Harris, T AF Mijinarends, Donja M. Koster, Annemarie Schols, Jos M. G. A. Meijers, Judith M. M. Halfens, Ruud J. G. Gudnason, Vilmundur Eiriksdottir, Gudny Siggeirsdottir, Kristin Sigurdsson, Sigurdur Jonsson, Palmi V. Meirelles, Osorio Harris, Tamara TI Physical activity and incidence of sarcopenia: the population-based AGES-Reykavik Study SO AGE AND AGEING LA English DT Article DE older people; sarcopenia; incidence proportion; physical activity; EWGSOP ID DWELLING OLDER-ADULTS; MUSCLE STRENGTH; EXERCISE; LIFE; INTERVENTIONS; DEFINITION; PREVALENCE; DISABILITY; EWGSOP; HEALTH AB Background: the prevalence of sarcopenia increases with age. Physical activity might slow the rate of muscle loss and therewith the incidence of sarcopenia. Objective: to examine the association of physical activity with incident sarcopenia over a 5-year period. Design: data from the population-based Age, Gene/Environment, Susceptibility-Reykjavik Study were used. Setting: people residing in the Reykjavik area at the start of the study. Subjects: the study included people aged 66-93 years (n = 2309). Methods: the amount of moderate-vigorous physical activity (MVPA) was assessed by a self-reported questionnaire. Sarcopenia was identified using the European Working Group on Sarcopenia in Older People algorithm, including muscle mass (computed tomography imaging), grip strength (computerised dynamometer) and gait speed (6 m). Results: mean age of the participants was 74.9 +/- 4.7 years. The prevalence of sarcopenia was 7.3% at baseline and 16.8% at follow-up. The incidence proportion of sarcopenia over 5 years was 14.8% in the least-active individuals and 9.0% in the most-active individuals. Compared with the least-active participants, those reporting a moderate-high amount of MVPA had a significantly lower likelihood of incident sarcopenia (OR = 0.64, 95% CI 0.45-0.91). Participants with a high amount of MVPA had higher baseline levels of muscle mass, strength and walking speed, but baseline MVPA was not associated with the rate of muscle loss. Conclusion: a higher amount of MVPA seems to contribute to counteracting the development of sarcopenia. To delay the onset of sarcopenia and its potential adverse outcomes, attention should be paid to increasing physical activity levels in older adults. C1 [Mijinarends, Donja M.; Schols, Jos M. G. A.; Meijers, Judith M. M.; Halfens, Ruud J. G.] Maastricht Univ, Dept Hlth Serv Res, CAPHRI, Maastricht, Netherlands. [Koster, Annemarie] Maastricht Univ, Dept Social Med, CAPHRI, Maastricht, Netherlands. [Schols, Jos M. G. A.] Maastricht Univ, Dept Family Med, CAPHRI, Maastricht, Netherlands. [Gudnason, Vilmundur; Jonsson, Palmi V.] Univ Iceland, Fac Med, Reykjavik, Iceland. [Gudnason, Vilmundur; Eiriksdottir, Gudny; Siggeirsdottir, Kristin; Sigurdsson, Sigurdur] Iceland Heart Assoc Res Inst, Kopavogur, Iceland. [Jonsson, Palmi V.] Landspitali Natl Univ Hosp, Dept Geriatr, Reykjavik, Iceland. [Meirelles, Osorio; Harris, Tamara] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. RP Mijinarends, DM (reprint author), Maastricht Univ, Dept Hlth Serv Res, CAPHRI, Maastricht, Netherlands. EM d.mijnarends@maastrichtuniversity.nl RI Koster, Annemarie/E-7438-2010 FU National Institutes of Health, National Institute on Aging [N01-AG-1-2100]; National Institute on Aging; Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament) FX This work was supported by National Institutes of Health, National Institute on Aging (N01-AG-1-2100), the National Institute on Aging Intramural Research Program, Hjartavernd (the Icelandic Heart Association) and the Althingi (the Icelandic Parliament). NR 30 TC 0 Z9 0 U1 3 U2 3 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 SEP PY 2016 VL 45 IS 5 BP 614 EP 621 DI 10.1093/ageing/afw090 PG 9 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA DX8ON UT WOS:000384648500011 ER PT J AU Souza-Smith, FM Lang, CH Nagy, LE Bailey, SM Parsons, LH Murray, GJ AF Souza-Smith, Flavia M. Lang, Charles H. Nagy, Laura E. Bailey, Shannon M. Parsons, Loren H. Murray, Gary J. TI Physiological processes underlying organ injury in alcohol abuse SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Review DE alcohol; circadian clock; muscle atrophy; adipose tissue; endocannabinoids ID MUSCLE PROTEIN-SYNTHESIS; FEAR-POTENTIATED STARTLE; CIRCADIAN TIMING SYSTEM; ACID AMIDE HYDROLASE; WHITE ADIPOSE-TISSUE; SKELETAL-MUSCLE; CHRONIC ETHANOL; ENDOCANNABINOID SYSTEM; INDUCED DECREASE; GENE-EXPRESSION AB This review summarizes the American Physiological Society (APS) Presidential Symposium 1 entitled "Physiological Processes Underlying Organ Injury in Alcohol Abuse" at the 2016 Experimental Biology meeting. The symposium was organized by Dr. Patricia Molina, past president of the APS, was held on April 3 at the Convention Center in San Diego, CA, and was funded by the National Institute on Alcohol Abuse and Alcoholism. The "Physiological Processes Underlying Organ Injury in Alcohol Abuse Symposium" assembled experts and leaders in the field and served as a platform to discuss and share knowledge on the latest developments and scientific advances on the mechanisms underlying organ injury in alcohol abuse. This symposium provided unique, interdisciplinary alcohol research, including several organs, liver, muscle, adipose, and brain, affected by excessive alcohol use. C1 [Souza-Smith, Flavia M.] Louisiana State Univ, Hlth Sci Ctr, Dept Physiol, 1901 Perdido St, New Orleans, LA 70112 USA. [Lang, Charles H.] Penn State Coll Med, Dept Cellular & Mol Physiol, Hershey, PA USA. [Nagy, Laura E.] Cleveland Clin Fdn, Dept Pathobiol, Lerner Res Inst, 9500 Euclid Ave, Cleveland, OH 44195 USA. [Bailey, Shannon M.] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA. [Parsons, Loren H.] Scripps Res Inst, La Jolla, CA 92037 USA. [Murray, Gary J.] NIAAA, Bethesda, MD USA. RP Souza-Smith, FM (reprint author), Louisiana State Univ, Hlth Sci Ctr, Dept Physiol, 1901 Perdido St, New Orleans, LA 70112 USA. EM fsouz1@lsuhsc.edu FU National Institute on Alcohol Abuse and Alcoholism [1 R13 AA-024974-01] FX Funding for this conference was made possible (in part) by 1 R13 AA-024974-01 from the National Institute on Alcohol Abuse and Alcoholism. The views expressed in written conference materials or publications and by speakers and 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 US Government. NR 95 TC 0 Z9 0 U1 1 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 EI 1522-1555 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD SEP 1 PY 2016 VL 311 IS 3 BP E605 EP E619 DI 10.1152/ajpendo.00270.2016 PG 15 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA DY0FG UT WOS:000384772100007 PM 27436613 ER PT J AU Gong, Y Fu, ZJ Edin, ML Liu, CH Wang, ZX Shao, Z Fredrick, TW Saba, NJ Morss, PC Burnim, SB Meng, SS Lih, FB Lee, KSS Moran, EP SanGiovanni, JP Hellstrom, A Hammock, BD Zeldin, DC Smith, LEH AF Gong, Yan Fu, Zhongjie Edin, Matthew L. Liu, Chi-Hsiu Wang, Zhongxiao Shao, Zhuo Fredrick, Thomas W. Saba, Nicholas J. Morss, Peyton C. Burnim, Samuel B. Meng, Steven S. Lih, Fred B. Lee, Kin Sing Stephen Moran, Elizabeth P. SanGiovanni, John Paul Hellstrom, Ann Hammock, Bruce D. Zeldin, Darryl C. Smith, Lois E. H. TI Cytochrome P450 Oxidase 2C Inhibition Adds to-3 Long-Chain Polyunsaturated Fatty Acids Protection Against Retinal and Choroidal Neovascularization SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE arachidonic acid; choroidal neovascularization; CYP2C inhibitor; diabetic retinopathy; docosahexaenoic acid ID SOLUBLE EPOXIDE HYDROLASE; ENDOTHELIAL GROWTH-FACTOR; LEUKOTRIENE CYSLT(1) RECEPTOR; MACULAR DEGENERATION; DIABETIC-RETINOPATHY; MOUSE; ANGIOGENESIS; MONTELUKAST; PREMATURITY; METABOLITES AB Objective Pathological ocular neovascularization is a major cause of blindness. Increased dietary intake of -3 long-chain polyunsaturated fatty acids (LCPUFA) reduces retinal neovascularization and choroidal neovascularization (CNV), but -3 LCPUFA metabolites of a major metabolizing pathway, cytochrome P450 oxidase (CYP) 2C, promote ocular pathological angiogenesis. We hypothesized that inhibition of CYP2C activity will add to the protective effects of -3 LCPUFA on neovascular eye diseases. Approach and Results The mouse models of oxygen-induced retinopathy and laser-induced CNV were used to investigate pathological angiogenesis in the retina and choroid, respectively. The plasma levels of -3 LCPUFA metabolites of CYP2C were determined by mass spectroscopy. Aortic ring and choroidal explant sprouting assays were used to investigate the effects of CYP2C inhibition and -3 LCPUFA-derived CYP2C metabolic products on angiogenesis ex vivo. We found that inhibition of CYP2C activity by montelukast added to the protective effects of -3 LCPUFA on retinal neovascularization and CNV by 30% and 20%, respectively. In CYP2C8-overexpressing mice fed a -3 LCPUFA diet, montelukast suppressed retinal neovascularization and CNV by 36% and 39% and reduced the plasma levels of CYP2C8 products. Soluble epoxide hydrolase inhibition, which blocks breakdown and inactivation of CYP2C -3 LCPUFA-derived active metabolites, increased oxygen-induced retinopathy and CNV in vivo. Exposure to selected -3 LCPUFA metabolites of CYP2C significantly reversed the suppression of both angiogenesis ex vivo and endothelial cell functions in vitro by the CYP2C inhibitor montelukast. Conclusions Inhibition of CYP2C activity adds to the protective effects of -3 LCPUFA on pathological retinal neovascularization and CNV. C1 [Gong, Yan; Fu, Zhongjie; Liu, Chi-Hsiu; Wang, Zhongxiao; Shao, Zhuo; Fredrick, Thomas W.; Saba, Nicholas J.; Morss, Peyton C.; Burnim, Samuel B.; Meng, Steven S.; Moran, Elizabeth P.; Smith, Lois E. H.] Harvard Med Sch, Boston Childrens Hosp, Dept Ophthalmol, Boston, MA USA. [Edin, Matthew L.; Lih, Fred B.; Zeldin, Darryl C.] NIEHS, Div Intramural Res, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Lee, Kin Sing Stephen; Hammock, Bruce D.] Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA. [Lee, Kin Sing Stephen; Hammock, Bruce D.] Univ Calif Davis, Ctr Comprehens Canc, Davis, CA 95616 USA. [SanGiovanni, John Paul] NIAAA, Sect Nutr Neurosci, Lab Membrane Biophys & Biochem, NIH, Bethesda, MD USA. [Hellstrom, Ann] Univ Gothenburg, Sahlgrenska Acad, Dept Ophthalmol, Gothenburg, Sweden. RP Smith, LEH (reprint author), Boston Childrens Hosp, Dept Ophthalmol, 300 Longwood Ave, Boston, MA 02115 USA. EM lois.smith@childrens.harvard.edu FU National Institutes of Health/ National Eye Institute [R01 EY022275, EY024864, EY017017, P01 HD18655]; Lowy Medical Foundation; European Commission FP7 PREVENT-ROP project [305485]; Knights Templar Eye Foundation; Bernadotte Foundation (ZF); Republic of China Ministry of Science and Technology Postdoctoral Research Abroad Program [104-2917-I-564-026]; National Institutes of Health/National Institute of Environmental Health Sciences [1K99ES024806-01, Z01 025034, R01 ES002710, P42 ES04699] FX This work was supported by the National Institutes of Health/ National Eye Institute (R01 EY022275, EY024864, EY017017, and P01 HD18655), Lowy Medical Foundation, European Commission FP7 PREVENT-ROP project (305485 LEHS), Knights Templar Eye Foundation and Bernadotte Foundation (ZF), Republic of China Ministry of Science and Technology Postdoctoral Research Abroad Program (104-2917-I-564-026 CHL), and in part by National Institutes of Health/National Institute of Environmental Health Sciences (1K99ES024806-01 KSSL, Z01 025034 DCZ, R01 ES002710 and P42 ES04699 BDH). NR 50 TC 1 Z9 1 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1079-5642 EI 1524-4636 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD SEP PY 2016 VL 36 IS 9 BP 1919 EP 1927 DI 10.1161/ATVBAHA.116.307558 PG 9 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA DW3ZZ UT WOS:000383582900028 PM 27417579 ER PT J AU Matveeva, OV Nechipurenko, YD Riabenko, E Ragan, C Nazipova, NN Ogurtsov, AY Shabalina, SA AF Matveeva, Olga V. Nechipurenko, Yury D. Riabenko, Evgeniy Ragan, Chikako Nazipova, Nafisa N. Ogurtsov, Aleksey Y. Shabalina, Svetlana A. TI Optimization of signal-to-noise ratio for efficient microarray probe design SO BIOINFORMATICS LA English DT Article; Proceedings Paper CT 15th European Conference on Computational Biology (ECCB) CY SEP 03-07, 2016 CL The Hague, NETHERLANDS ID SHORT OLIGONUCLEOTIDE MICROARRAYS; NEAREST-NEIGHBOR PARAMETERS; AFFYMETRIX MICROARRAYS; INTERGENIC REGIONS; SIRNA DESIGN; FREE-ENERGY; HYBRIDIZATION; MODEL; INTENSITIES; BINDING AB Motivation: Target-specific hybridization depends on oligo-probe characteristics that improve hybridization specificity and minimize genome-wide cross-hybridization. Interplay between specific hybridization and genome-wide cross-hybridization has been insufficiently studied, despite its crucial role in efficient probe design and in data analysis. Results: In this study, we defined hybridization specificity as a ratio between oligo target-specific hybridization and oligo genome-wide cross-hybridization. A microarray database, derived from the Genomic Comparison Hybridization (GCH) experiment and performed using the Affymetrix platform, contains two different types of probes. The first type of oligo-probes does not have a specific target on the genome and their hybridization signals are derived from genome-wide cross-hybridization alone. The second type includes oligonucleotides that have a specific target on the genomic DNA and their signals are derived from specific and cross-hybridization components combined together in a total signal. A comparative analysis of hybridization specificity of oligo-probes, as well as their nucleotide sequences and thermodynamic features was performed on the database. The comparison has revealed that hybridization specificity was negatively affected by low stability of the fully-paired oligo-target duplex, stable probe self-folding, G-rich content, including GGG motifs, low sequence complexity and nucleotide composition symmetry. Conclusion: Filtering out the probes with defined 'negative' characteristics significantly increases specific hybridization and dramatically decreasing genome-wide cross-hybridization. Selected oligo-probes have two times higher hybridization specificity on average, compared to the probes that were filtered from the analysis by applying suggested cutoff thresholds to the described parameters. A new approach for efficient oligo-probe design is described in our study. C1 [Matveeva, Olga V.] Biopolymer Design LLC, Acton, MA 01721 USA. [Matveeva, Olga V.; Nechipurenko, Yury D.] Engelhardt Inst Mol Biol, Moscow 119991, Russia. [Riabenko, Evgeniy] Moscow Inst Phys & Technol, Dolgoprudnyi 141701, Moscow Region, Russia. [Ragan, Chikako] Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia. [Nazipova, Nafisa N.] Inst Math Problems Biol, Pushchino 142290, Moscow Region, Russia. [Ogurtsov, Aleksey Y.; Shabalina, Svetlana A.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Matveeva, OV (reprint author), Biopolymer Design LLC, Acton, MA 01721 USA.; Matveeva, OV (reprint author), Engelhardt Inst Mol Biol, Moscow 119991, Russia.; Shabalina, SA (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM olga.matveeva@gmail.com; shabalin@ncbi.nlm.nih.gov NR 31 TC 0 Z9 0 U1 5 U2 5 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 SEP 1 PY 2016 VL 32 IS 17 BP 552 EP 558 DI 10.1093/bioinformatics/btw451 PG 7 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 DX8VA UT WOS:000384666800021 PM 27587674 ER PT J AU Alves, G Yu, YK AF Alves, Gelio Yu, Yi-Kuo TI Confidence assignment for mass spectrometry based peptide identifications via the extreme value distribution SO BIOINFORMATICS LA English DT Article; Proceedings Paper CT 15th European Conference on Computational Biology (ECCB) CY SEP 03-07, 2016 CL The Hague, NETHERLANDS ID FALSE DISCOVERY RATE; STATISTICAL SIGNIFICANCE; PROTEIN IDENTIFICATIONS; DATABASE SEARCHES; SCORING SCHEMES; RAID-DBS; ALGORITHM; ALIGNMENT AB Motivation: There is a growing trend for biomedical researchers to extract evidence and draw conclusions from mass spectrometry based proteomics experiments, the cornerstone of which is peptide identification. Inaccurate assignments of peptide identification confidence thus may have far-reaching and adverse consequences. Although some peptide identification methods report accurate statistics, they have been limited to certain types of scoring function. The extreme value statistics based method, while more general in the scoring functions it allows, demands accurate parameter estimates and requires, at least in its original design, excessive computational resources. Improving the parameter estimate accuracy and reducing the computational cost for this method has two advantages: it provides another feasible route to accurate significance assessment, and it could provide reliable statistics for scoring functions yet to be developed. Results: We have formulated and implemented an efficient algorithm for calculating the extreme value statistics for peptide identification applicable to various scoring functions, bypassing the need for searching large random databases. C1 [Alves, Gelio; Yu, Yi-Kuo] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Yu, YK (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM yyu@ncbi.nlm.nih.gov NR 31 TC 0 Z9 0 U1 0 U2 0 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 SEP 1 PY 2016 VL 32 IS 17 BP 2642 EP 2649 DI 10.1093/bioinformatics/btw225 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 DX8VA UT WOS:000384666800060 PM 27153659 ER PT J AU Niu, L Xu, ZL Taylor, JA AF Niu, Liang Xu, Zongli Taylor, Jack A. TI RCP: a novel probe design bias correction method for Illumina Methylation BeadChip SO BIOINFORMATICS LA English DT Article; Proceedings Paper CT 15th European Conference on Computational Biology (ECCB) CY SEP 03-07, 2016 CL The Hague, NETHERLANDS ID IDENTIFICATION; NORMALIZATION; QUANTILE; ARRAY AB Motivation: The Illumina HumanMethylation450 BeadChip has been extensively utilized in epigenome-wide association studies. This array and its successor, the MethylationEPIC array, use two types of probes-Infinium I (type I) and Infinium II (type II)-in order to increase genome coverage but differences in probe chemistries result in different type I and II distributions of methylation values. Ignoring the difference in distributions between the two probe types may bias downstream analysis. Results: Here, we developed a novel method, called Regression on Correlated Probes (RCP), which uses the existing correlation between pairs of nearby type I and II probes to adjust the beta values of all type II probes. We evaluate the effect of this adjustment on reducing probe design type bias, reducing technical variation in duplicate samples, improving accuracy of measurements against known standards, and retention of biological signal. We find that RCP is statistically significantly better than unadjusted data or adjustment with alternative methods including SWAN and BMIQ. C1 [Niu, Liang] Univ Cincinnati, Coll Med, Dept Environm Hlth, Div Biostat & Bioinformat, Cincinnati, OH 45267 USA. [Xu, Zongli; Taylor, Jack A.] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. [Taylor, Jack A.] NIEHS, Epigenet & Stem Cell Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RP Niu, L (reprint author), Univ Cincinnati, Coll Med, Dept Environm Hlth, Div Biostat & Bioinformat, Cincinnati, OH 45267 USA. EM niulg@ucmail.uc.edu OI xu, zongli/0000-0002-9034-8902; taylor, jack/0000-0001-5303-6398 NR 11 TC 1 Z9 1 U1 0 U2 0 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 SEP 1 PY 2016 VL 32 IS 17 BP 2659 EP 2663 DI 10.1093/bioinformatics/btw285 PG 5 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 DX8VA UT WOS:000384666800062 PM 27153672 ER PT J AU Hauptmann, M Johannesen, TB Gilbert, ES Stovall, M van Leeuwen, FE Rajaraman, P Smith, SA Weathers, RE Aleman, BMP Andersson, M Curtis, RE Dores, GM Fraumeni, JF Hall, P Holowaty, EJ Joensuu, H Kaijser, M Kleinerman, RA Langmark, F Lynch, CF Pukkala, E Storm, HH Vaalavirta, L van den Belt-Dusebout, AW Morton, LM Fossa, SD Travis, LB AF Hauptmann, Michael Johannesen, Tom Borge Gilbert, Ethel S. Stovall, Marilyn van Leeuwen, Flora E. Rajaraman, Preetha Smith, Susan A. Weathers, Rita E. Aleman, Berthe M. P. Andersson, Michael Curtis, Rochelle E. Dores, Graca M. Fraumeni, Joseph F., Jr. Hall, Per Holowaty, Eric J. Joensuu, Heikki Kaijser, Magnus Kleinerman, Ruth A. Langmark, Froydis Lynch, Charles F. Pukkala, Eero Storm, Hans H. Vaalavirta, Leila van den Belt-Dusebout, Alexandra W. Morton, Lindsay M. Fossa, Sophie D. Travis, Lois B. TI Increased pancreatic cancer risk following radiotherapy for testicular cancer SO BRITISH JOURNAL OF CANCER LA English DT Article DE pancreatic cancer; radiotherapy; testicular cancer; chemotherapy; logistic regression ID LONG-TERM SURVIVORS; STAGE-I SEMINOMA; MALIGNANT NEOPLASMS; UNITED-STATES; 2ND CANCERS; MORTALITY; THERAPY; SURVEILLANCE; CHEMOTHERAPY; STATISTICS AB Background: Pancreatic cancer risk is elevated among testicular cancer (TC) survivors. However, the roles of specific treatments are unclear. Methods: Among 23982 5-year TC survivors diagnosed during 1947-1991, doses from radiotherapy to the pancreas were estimated for 80 pancreatic cancer patients and 145 matched controls. Chemotherapy details were recorded. Logistic regression was used to estimate odds ratios (ORs). Results: Cumulative incidence of second primary pancreatic cancer was 1.1% at 30 years after TC diagnosis. Radiotherapy (72 (90%) cases and 115 (80%) controls) was associated with a 2.9-fold (95% confidence interval (CI) 1.0-7.8) increased risk. The OR increased linearly by 0.12 per Gy to the pancreas (P-trend<0.001), with an OR of 4.6 (95% CI 1.9-11.0) for >= 25 Gy vs < 25 Gy. Radiation-related risks remained elevated >= 20 years after TC diagnosis (P = 0.020). The risk increased with the number of cycles of chemotherapy with alkylating or platinum agents (P = 0.057), although only one case was exposed to platinum. Conclusions: A dose-response relationship exists between radiation to the pancreas and subsequent cancer risk, and persists for over 20 years. These excesses, although small, should be considered when radiotherapy with exposure to the pancreas is considered for newly diagnosed patients. Additional data are needed on the role of chemotherapy. C1 [Hauptmann, Michael; van Leeuwen, Flora E.; van den Belt-Dusebout, Alexandra W.; Fossa, Sophie D.; Travis, Lois B.] Netherlands Canc Inst, Dept Epidemiol & Biostat, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands. [Johannesen, Tom Borge; Langmark, Froydis] Canc Registry Norway, Oslo, Norway. [Gilbert, Ethel S.; Rajaraman, Preetha; Curtis, Rochelle E.; Dores, Graca M.; Fraumeni, Joseph F., Jr.; Kleinerman, Ruth A.; Morton, Lindsay M.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Stovall, Marilyn; Smith, Susan A.; Weathers, Rita E.] Univ Texas MD Anderson Canc Ctr, Dept Radiat Phys, Houston, TX 77030 USA. [Aleman, Berthe M. P.] Netherlands Canc Inst, Dept Radiat Oncol, Amsterdam, Netherlands. [Andersson, Michael] Univ Copenhagen Hosp, Dept Oncol, Copenhagen, Denmark. [Hall, Per; Kaijser, Magnus] Karolinska Inst, Dep Med Epidemiol & Biostat, Stockholm, Sweden. [Hall, Per] Karolinska Inst, Clin Epidemiol Unit, Dept Med, Stockholm, Sweden. [Holowaty, Eric J.] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [Joensuu, Heikki; Vaalavirta, Leila] Univ Helsinki Hosp, Ctr Comprehens Canc, Helsinki, Finland. [Joensuu, Heikki; Vaalavirta, Leila] Univ Helsinki, Helsinki, Finland. [Lynch, Charles F.] Univ Iowa, Dept Epidemiol, Iowa City, IA USA. [Pukkala, Eero] Finnish Canc Registry, Inst Stat & Epidemiol Canc Res, Helsinki, Finland. [Pukkala, Eero] Tampere Univ, Sch Hlth Sci, Tampere, Finland. [Storm, Hans H.] Danish Canc Soc, Copenhagen, Denmark. [Fossa, Sophie D.] Oslo Univ Hosp, Dept Oncol, Oslo, Norway. [Fossa, Sophie D.] Univ Oslo, Oslo, Norway. [Travis, Lois B.] Univ Indianapolis, Sch Med, Melvin & Bren Simon Canc Ctr, Indianapolis, IN 46227 USA. RP Hauptmann, M (reprint author), Netherlands Canc Inst, Dept Epidemiol & Biostat, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands. EM m.hauptmann@nki.nl OI Joensuu, Heikki/0000-0003-0281-2507 FU Intramural Research Program of the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, and National Cancer Institute contracts to Cancer Care Ontario, Toronto, Canada [N01-CP-31157]; Danish Cancer Society, Copenhagen, Denmark [N01-CP-31019]; Finnish Cancer Registry, Helsinki, Finland [N01-CP-31154]; Information Management Services, Inc., Silver Spring, USA [N01-CP-31003]; Karolinska Institute, Stockholm, Sweden [N01-CP-31156]; University of Iowa, Iowa City, USA [N01-CP-31155]; University of Texas MD Anderson Cancer Center, Houston, USA [N02-CP-55503]; Westat, Inc., Rockville, USA [N02-CP-31136]; Lance Armstrong Foundation; Dutch Cancer Society [NKI 04-3068]; National Cancer Institute [1R01 CA 157823-01A1] FX We thank Diane Fuchs, Janet Lawler-Heavner, and their staff at Westat, Inc. (Rockville, MD, USA) for administrative assistance in conducting the field studies, and Jeremy Miller (Information Management Services, Silver Spring, MD, USA) for computer programming support. This work was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, and National Cancer Institute contracts to Cancer Care Ontario, Toronto, Canada (N01-CP-31157); Danish Cancer Society, Copenhagen, Denmark (N01-CP-31019); Finnish Cancer Registry, Helsinki, Finland (N01-CP-31154); Information Management Services, Inc., Silver Spring, USA (N01-CP-31003); Karolinska Institute, Stockholm, Sweden (N01-CP-31156); University of Iowa, Iowa City, USA (N01-CP-31155); The University of Texas MD Anderson Cancer Center, Houston, USA (N02-CP-55503); and Westat, Inc., Rockville, USA (N02-CP-31136). The Dutch study was also supported by the Lance Armstrong Foundation and the Dutch Cancer Society (Grant No. NKI 04-3068). Dr Travis was supported by National Cancer Institute 1R01 CA 157823-01A1. NR 42 TC 0 Z9 0 U1 5 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD SEP PY 2016 VL 115 IS 7 BP 901 EP 908 DI 10.1038/bjc.2016.272 PG 8 WC Oncology SC Oncology GA DX7NY UT WOS:000384576100019 PM 27599043 ER PT J AU Censor, N Buch, ER Nader, K Cohen, LG AF Censor, Nitzan Buch, Ethan R. Nader, Karim Cohen, Leonardo G. TI Altered Human Memory Modification in the Presence of Normal Consolidation SO CEREBRAL CORTEX LA English DT Article DE diffusion; DWI; MRI; procedural memory consolidation; sequence learning; reconsolidation ID MOTOR CORTEX; FEAR MEMORIES; RECONSOLIDATION; STROKE; NEUROSCIENCE; MECHANISMS; PLASTICITY; STORAGE; MOTION; TRACT AB Following initial learning, the memory is stabilized by consolidation mechanisms, and subsequent modification of memory strength occurs via reconsolidation. Yet, it is not clear whether consolidation and memory modification are the same or different systems-level processes. Here, we report disrupted memory modification in the presence of normal consolidation of human motor memories, which relate to differences in lesioned brain structure after stroke. Furthermore, this behavioral dissociation was associated with macrostructural network architecture revealed by a graph-theoretical approach, and with white-matter microstructural integrity measured by diffusion-weighted MRI. Altered macrostructural network architecture and microstructural integrity of white-matter underlying critical nodes of the related network predicted disrupted memory modification. To the best of our knowledge, this provides the first evidence of mechanistic differences between consolidation, and subsequent memory modification through reconsolidation, in human procedural learning. These findings enable better understanding of these memory processes, which may guide interventional strategies to enhance brain function and resulting behavior. C1 [Censor, Nitzan; Buch, Ethan R.; Cohen, Leonardo G.] Natl Inst Neurol Disorders & Stroke, Human Cort Physiol & Neurorehabil Sect, NIH, Bethesda, MD 20892 USA. [Censor, Nitzan] Tel Aviv Univ, Sch Psychol Sci, IL-69978 Tel Aviv, Israel. [Censor, Nitzan] Tel Aviv Univ, Sagol Sch Neurosci, IL-69978 Tel Aviv, Israel. [Nader, Karim] McGill Univ, Dept Psychol, Montreal, PQ, Canada. RP Censor, N (reprint author), Natl Inst Neurol Disorders & Stroke, Human Cort Physiol & Neurorehabil Sect, NIH, Bethesda, MD 20892 USA.; Censor, N (reprint author), Tel Aviv Univ, Sch Psychol Sci, IL-69978 Tel Aviv, Israel.; Censor, N (reprint author), Tel Aviv Univ, Sagol Sch Neurosci, IL-69978 Tel Aviv, Israel. EM censornitzan@post.tau.ac.il FU Intramural Research Program of the National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health; NINDS Ruth L. Kirschstein National Research Service Award (NRSA); Center for Neuroscience and Regenerative Medicine (CNRM); Canadian Institutes of Health Research (CIHR); Natural Sciences and Engineering Research Council (NSERC) FX This research was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health. N.C. was supported by the NINDS Ruth L. Kirschstein National Research Service Award (NRSA). E.R.B. was supported by the Center for Neuroscience and Regenerative Medicine (CNRM). K.N. was supported by the Canadian Institutes of Health Research (CIHR) and the Natural Sciences and Engineering Research Council (NSERC). NR 44 TC 0 Z9 0 U1 4 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 EI 1460-2199 J9 CEREB CORTEX JI Cereb. Cortex PD SEP PY 2016 VL 26 IS 9 BP 3828 EP 3837 DI 10.1093/cercor/bhv180 PG 10 WC Neurosciences SC Neurosciences & Neurology GA DX8VN UT WOS:000384668600013 PM 26271110 ER PT J AU Carlson, DE Wang, WC Scott, JD AF Carlson, Drew E. Wang, Wayne C. Scott, Jane D. TI Initial Outcomes for the NHLBI K99/R00 Pathway to Independence Program in Relation to Long-Standing Career Development Programs Implications for Trainees, Mentors, and Institutions SO CIRCULATION RESEARCH LA English DT Editorial Material DE bibliometrics; biomedical research; career development FD; NIH grants; research training ID CITATION IMPACT; DEVELOPMENT AWARDS; R01 GRANTS; TRENDS; K08 AB Sufficient history now exists to assess the National Institutes of Health Pathway to Independence Award (K99/R00), first offered in 2007 to support the career development of biomedical researchers. The success of K99 (Mentored Phase of the K99/R00) principal investigators in obtaining subsequent grant support was compared with that of principal investigators supported by the long-standing K08 (Mentored Clinical Scientist Research Career Development Award) and K23 (Mentored Patient-Oriented Research Career Development Award) programs. For cardiovascular K awards initiated in fiscal years 2007 to 2009, K99 principal investigators were more successful in obtaining subsequent grant support than the other groups. Although a bibliometric analysis showed similar publication quality for all groups, the K99 group was most persistent in applying for the next grant. Possible implications of these findings for all K Award principal investigators, their mentors, and institutions are presented. C1 [Carlson, Drew E.; Wang, Wayne C.; Scott, Jane D.] NHLBI, Div Cardiovasc Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Carlson, DE (reprint author), NHLBI, Off Res Training & Career Dev, Div Cardiovasc Sci, Rockledge Ctr RKL2 2, Rm 8142,MSC 7940,6701 Rockledge Dr, Bethesda, MD 20892 USA. EM carlsonde@nhlbi.nih.gov FU Intramural NIH HHS [Z99 HL999999] NR 11 TC 0 Z9 0 U1 4 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD SEP PY 2016 VL 119 IS 8 BP 904 EP + DI 10.1161/CIRCRESAHA.116.309238 PG 11 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA DX6YJ UT WOS:000384531700008 PM 27688307 ER PT J AU O'Neal, WT Qureshi, WT Nazarian, S Kawel-Boehm, N Bluemke, DA Lima, JAC Soliman, EZ AF O'Neal, Wesley T. Qureshi, Waqas T. Nazarian, Saman Kawel-Boehm, Nadine Bluemke, David A. Lima, Joao A. C. Soliman, Elsayed Z. TI Electrocardiographic Time to Intrinsicoid Deflection and Heart Failure: The Multi-Ethnic Study of Atherosclerosis SO CLINICAL CARDIOLOGY LA English DT Article DE Heart failure/cardiac transplantation/cardiomyopathy/myocarditis; Electrocardiography ambulatory ECG; Epidemiology ID RISK AB Background: Time to intrinsicoid deflection (ID), the time from onset of the QRS complex to the peak of the R wave on the electrocardiogram, represents delayed ventricular activation and suggests that impaired myocardial function is present. It is unknown whether delayed time to ID is predictive of future heart failure (HF) events. Hypothesis: Delayed time to ID is predictive of future HF events. Methods: A total of 6394 participants (mean age, 62 +/- 10 years; 54% women; 38% whites, 28% blacks, 22% Hispanics, 12% Chinese Americans) without clinically apparent cardiovascular disease or major ventricular conduction delay (QRS >= 120 ms) from the Multi-Ethnic Study of Atherosclerosis were included. Time to ID was automatically measured from baseline electrocardiograms (2000-2002) as the maximum value in leads V-5 and V-6. Cox regression was used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between time to ID and HF. Results: Over a median follow-up of 11.2 years, a total of 217 (3.4%) participants developed HF (incidence rate per 1000 person-years: 3.33, 95% CI: 2.91-3.80). In a multivariable Cox regression analysis adjusted for demographics, cardiovascular risk factors, and potential confounders, each 10-ms increase in maximum time to ID was associated with an increased risk for HF (HR: 1.42, 95% CI: 1.15-1.74). The results remained similar when stratified by age, sex, and race/ethnicity. Conclusions: Delayed time to ID is able to identify individuals at risk for developing HF before major ventricular conduction delays (eg, bundle branch block) are evident. C1 [O'Neal, Wesley T.] Emory Univ, Sch Med, Dept Med, Div Cardiol, 101 Woodruff Circle,Woodruff Mem Bldg, Atlanta, GA 30322 USA. [Qureshi, Waqas T.; Soliman, Elsayed Z.] Wake Forest Sch Med, Dept Internal Med, Div Cardiol, Winston Salem, NC USA. [Nazarian, Saman] Johns Hopkins Univ, Sch Med, Div Cardiol, Sect Cardiac Electrophysiol, Baltimore, MD USA. [Kawel-Boehm, Nadine] Kantonsspital Graubuenden, Dept Radiol, Chur, Switzerland. [Bluemke, David A.] NIH, Dept Radiol & Imaging Sci, Bldg 10, Bethesda, MD 20892 USA. [Lima, Joao A. C.] Johns Hopkins Univ, Dept Med, Div Cardiol, Baltimore, MD USA. [Lima, Joao A. C.] Johns Hopkins Univ, Dept Radiol, Baltimore, MD USA. [Soliman, Elsayed Z.] Wake Forest Sch Med, Dept Epidemiol & Prevent, Epidemiol Cardiol Res Ctr EPICARE, Winston Salem, NC USA. RP O'Neal, WT (reprint author), Emory Univ, Sch Med, Dept Med, Div Cardiol, 101 Woodruff Circle,Woodruff Mem Bldg, Atlanta, GA 30322 USA. EM oneal@emory.edu OI Bluemke, David/0000-0002-8323-8086 FU Biosense Webster Inc.; National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169]; National Center for Research Resources [UL1-TR-000040, UL1-TR-001079] FX Dr. Nazarian is a consultant and principal investigator for research funding awarded to Johns Hopkins University from Biosense Webster Inc. This research was supported by contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 from the National Heart, Lung, and Blood Institute and by grants UL1-TR-000040 and UL1-TR-001079 from the National Center for Research Resources. The authors have no other funding, financial relationships, or conflicts of interest to disclose. NR 17 TC 1 Z9 1 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0160-9289 EI 1932-8737 J9 CLIN CARDIOL JI Clin. Cardiol. PD SEP PY 2016 VL 39 IS 9 BP 531 EP 536 DI 10.1002/clc.22561 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DY0UO UT WOS:000384811900006 PM 27552258 ER PT J AU Wickner, RB AF Wickner, Reed B. TI Yeast and Fungal Prions SO COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY LA English DT Article ID BETA-SHEET STRUCTURE; DISEASE-RELATED PROTEIN; 2-MU-M CIRCLE PLASMID; DE-NOVO APPEARANCE; HET-S PRION; SACCHAROMYCES-CEREVISIAE; URE3 PRION; SUP35 PROTEIN; PSI+ PRION; IN-VITRO AB Yeast and fungal prions are infectious proteins, most being self-propagating amyloids of normally soluble proteins. Their effects range from a very mild detriment to lethal, with specific effects dependent on the prion protein and the specific prion variant ("prion strain"). The prion amyloids of Sup35p, Ure2p, and Rnq1p are in-register, parallel, folded b-sheets, an architecture that naturally suggests a mechanism by which a protein can template its conformation, just as DNA or RNA templates its sequence. Prion propagation is critically affected byan array of chaperone systems, most notably the Hsp104/Hsp70/Hsp40 combination, which is responsible for generating new prion seeds from old filaments. The Btn2/Cur1 antiprion system cures most [URE3] prions that develop, and the Ssb antiprion system blocks [PSI+] generation. C1 [Wickner, Reed B.] NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Wickner, RB (reprint author), NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. EM wickner@helix.nih.gov FU Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health FX This work is supported by the Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. NR 137 TC 2 Z9 2 U1 2 U2 2 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1943-0264 J9 CSH PERSPECT BIOL JI Cold Spring Harbor Perspect. Biol. PD SEP PY 2016 VL 8 IS 9 AR a023531 DI 10.1101/cshperspect.a023531 PG 15 WC Cell Biology SC Cell Biology GA DY1CK UT WOS:000384832300007 ER PT J AU Dosemeci, A Toy, D Burch, A Bayer, KU Tao-Cheng, JH AF Dosemeci, Ayse Toy, Dana Burch, Amelia Bayer, K. Ulrich Tao-Cheng, Jung-Hwa TI CaMKII-mediated displacement of AIDA-1 out of the postsynaptic density core SO FEBS LETTERS LA English DT Article DE AIDA-1; CaMKII; postsynaptic density ID NEURONS; SYNGAP; MECHANISM; PROTEINS; RECEPTOR; LTP AB Ankyrin repeat and sterile alpha motif domain-containing protein 1B (ANKS1B, also known as AIDA-1) is a major component of the postsynaptic density (PSD) in excitatory neurons where it concentrates at the electron-dense core under basal conditions and moves out during activity. This study investigates the molecular mechanism underlying activity-induced displacement of AIDA-1. Experiments with PSD fractions from brain indicate phosphorylation of AIDA-1 upon activation of endogenous CaMKII. Immuno-electron microscopy studies show that treatment of hippocampal neurons with NMDA results in an similar to 30 nm shift in the median distance of the AIDA-1 label from the postsynaptic membrane, an effect that is blocked by the CaMKII inhibitor tatCN21. CaMKII-mediated redistribution of AIDA-1 is similar to that observed for SynGAP. CaMKII-mediated removal of two abundant PSD-95-binding proteins from the PSD core during activity is expected to initiate a molecular reorganization at the PSD. C1 [Dosemeci, Ayse; Toy, Dana; Burch, Amelia] NINDS, Neurobiol Lab, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Bayer, K. Ulrich] Univ Colorado Denver, Sch Med, Dept Pharmacol, Aurora, CO USA. [Tao-Cheng, Jung-Hwa] NINDS, EM Facil, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Dosemeci, A (reprint author), NINDS, Neurobiol Lab, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM dosemeca@mail.nih.gov OI Burch, Amelia/0000-0001-8533-4293 FU Intramural Research Program of the NIH, NINDS; [R01NS081248] FX We thank Dr. Thomas Reese for support and discussion, Christine A. Winters for hippocampal cultures, Rita Azzam and Virginia Crocker for EM technical assistance. Supported by the Intramural Research Program of the NIH, NINDS, and by R01NS081248 (to K.U.B.). NR 23 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-5793 EI 1873-3468 J9 FEBS LETT JI FEBS Lett. PD SEP PY 2016 VL 590 IS 17 BP 2934 EP 2939 DI 10.1002/1873-3468.12334 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA DY0SW UT WOS:000384807500013 PM 27477489 ER PT J AU Guerrerio, AL Frischmeyer-Guerrerio, PA Huang, CR Wu, YQ Haritunians, T McGovern, DPB MacCarrick, GL Brant, SR Dietz, HC AF Guerrerio, Anthony L. Frischmeyer-Guerrerio, Pamela A. Huang, Chengrui Wu, Yuqiong Haritunians, Talin McGovern, Dermot P. B. MacCarrick, Gretchen L. Brant, Steven R. Dietz, Harry C. TI Increased Prevalence of Inflammatory Bowel Disease in Patients with Mutations in Genes Encoding the Receptor Subunits for TGF beta SO INFLAMMATORY BOWEL DISEASES LA English DT Article DE Loeys-Dietz syndrome; very early-onset IBD; TGF beta receptor; pediatric; genetic predisposition; syndromes associated with IBD ID THORACIC AORTIC-ANEURYSM; DISSECTIONS; FEATURES; MARFAN AB Background: TGF beta is a multifunctional cytokine that is critical in regulating mucosal immunity. Murine studies have revealed that disruption of canonical TGF beta signaling leads to systemic inflammation including colitis. Loeys-Dietz syndrome (LDS) results from heterozygous mutations in the genes encoding the subunits of the TGF beta receptor. Methods: All patients with confirmed mutations in TGFBR1 or TGFBR2, seen in the Johns Hopkins Connective Tissue Disorders clinic, were asked to participate in the study. Ninety-three consecutive patients were enrolled, including 4 with inflammatory bowel disease (IBD). Using the Illumina Immunochip array, we undertook an exploratory analysis to evaluate the potential genetic risk factors that could predict which patients with LDS would develop IBD. Results: We report an increased prevalence of IBD in patients with LDS types I and II. We describe the course of several patients. In this small sample, the 3 whites with IBD had a genetic risk score in the top 6 highest scores of patients evaluated. Conclusion: We report a 10-fold increase in the prevalence of IBD in patients with LDS compared with the general population. Onset of disease in 3 of the 4 patients was at less than 18 years, and the clinical course in 2 of the 4 was severe with a poor response to traditional medications. Further evaluation of the genetic risk score is needed to determine whether it can predict which patients with LDS are most likely to develop IBD. This case series of patients with LDS with IBD suggests that defective TGF beta signaling may have an influence on IBD risk. C1 [Guerrerio, Anthony L.] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21287 USA. [Frischmeyer-Guerrerio, Pamela A.] NIAID, Div Intramural Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Huang, Chengrui; Wu, Yuqiong; Brant, Steven R.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Huang, Chengrui; Wu, Yuqiong; Brant, Steven R.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Haritunians, Talin; McGovern, Dermot P. B.] Cedars Sinai Med Ctr, F Widjaja Fdn Inflammatory Bowel & Immunol Res In, Los Angeles, CA 90048 USA. [MacCarrick, Gretchen L.; Dietz, Harry C.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Dietz, Harry C.] Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21205 USA. RP Guerrerio, AL (reprint author), Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21287 USA. EM aguerrerio@jhmi.edu FU NIH [T32 DK07632]; George Ferry Young Investigator Development Award (North American Society for Pediatric Gastroenterology, Hepatology and Nutrition); NIH Mentored Research Development Award [1K08DK106463]; NIH K23 Mentored Research Development Award [K23AI091869]; ARTrust Faculty Development Award; Johns Hopkins University Clinician Scientist Award; Hopkins Conte Digestive Diseases Basic and Translational Research Core Grant; National Marfan Foundation; Howard Hughes Medical Institute; Intramural Research Program of the NIH, NIAID; Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center at The Johns Hopkins Hospital, Baltimore, USA; Robert E. Sadler, Jr. Family; USPHS [PO1DK046763]; Cedars-Sinai F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute Research Funds; Helmsley Charitable Trust; European Union; Crohn's and Colitis Foundation of America (CCFA); Joshua L. and Lisa Z. Greer Chair in IBD Genetics; [DK062431]; [DK062413]; [DK046763-19]; [AI067068]; [HS021747] FX This work was supported by an NIH Training Grant (T32 DK07632), and a George Ferry Young Investigator Development Award (North American Society for Pediatric Gastroenterology, Hepatology and Nutrition) and an NIH Mentored Research Development Award (1K08DK106463) (to A.L.G.), an NIH K23 Mentored Research Development Award (K23AI091869), an ARTrust Faculty Development Award, a Johns Hopkins University Clinician Scientist Award, a Hopkins Conte Digestive Diseases Basic and Translational Research Core Grant (to P.A.F.-G.), as well as research grants from the NIH, the National Marfan Foundation, and the Howard Hughes Medical Institute (to H.C.D.). This research was supported in part by the Intramural Research Program of the NIH, NIAID (P.A.F.-G.). The authors also gratefully acknowledge funding support for CH and SRB from The Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center at The Johns Hopkins Hospital, Baltimore, USA, the Robert E. Sadler, Jr. Family and grant DK062431. IBD Research at Cedars-Sinai is supported by USPHS grant PO1DK046763 and the Cedars-Sinai F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute Research Funds. DPBM is supported by The Helmsley Charitable Trust, The European Union, The Crohn's and Colitis Foundation of America (CCFA), The Joshua L. and Lisa Z. Greer Chair in IBD Genetics, and grants, DK062413, DK046763-19, AI067068, and HS021747. NR 27 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1078-0998 EI 1536-4844 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD SEP PY 2016 VL 22 IS 9 BP 2058 EP 2062 DI 10.1097/MIB.0000000000000872 PG 5 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DX6AS UT WOS:000384464800010 PM 27508510 ER PT J AU Andrews, C McLean, MH Durum, SK AF Andrews, Caroline McLean, Mairi H. Durum, Scott K. TI Interleukin-27 as a Novel Therapy for Inflammatory Bowel Disease: A Critical Review of the Literature SO INFLAMMATORY BOWEL DISEASES LA English DT Review DE Crohn's disease; IBD; IL-27; ulcerative colitis ID CHINESE HAN POPULATION; JANUS KINASE INHIBITOR; EXPERIMENTAL COLITIS; CROHNS-DISEASE; T-CELLS; INTESTINAL INFLAMMATION; IL-27 GENE; ULCERATIVE-COLITIS; INDUCED PATHOLOGY; AMG 827 AB Inflammatory bowel disease (IBD) is an inflammatory disorder of the intestine that affects an estimated 329 per 100,000 people in the United States and is increasing in incidence within a number of cultures worldwide. Likely due to its incompletely understood pathophysiology and etiology, the standard treatments for IBD are only efficacious in subsets of patients and often do not induce lasting remission. As a result, novel therapies are needed. The success of anti-tumor necrosis factor-alpha treatment in a subset of patients with IBD demonstrated that therapy targeting a single cytokine could be efficacious in IBD, and clinical trials investigating the blockade of a variety of cytokines have commenced. Interleukin (IL) 27 is a relatively recently discovered type I cytokine with established roles in infectious disease, autoimmunity, and cancer in a variety of organs. IL-27 was identified as a candidate gene for IBD, and a number of studies in mouse models of IBD have demonstrated that IL-27 therapy is protective. However, in contrast to these investigations, genetic deletion of the IL-27 receptor has been shown to be protective in some mouse models of IBD. The purpose of this review is to highlight the recent literature investigating the role of IL-27 in IBD and to discuss the possible explanations for the sometimes conflicting results of these studies. Evidence supporting IL-27 therapy as a treatment for IBD will also be discussed. C1 [Andrews, Caroline; Durum, Scott K.] NCI, Canc & Inflammat Program, Ctr Canc Res, NIH, Frederick, MD 21701 USA. [McLean, Mairi H.] Univ Aberdeen, Sch Med Med Sci & Nutr, Aberdeen, Scotland. RP Andrews, C (reprint author), Frederick Natl Lab Canc Res, 1050 Boyles St, Frederick, MD 21702 USA. EM caroline.andrews@nih.gov FU National Institutes of Health, National Cancer Institute FX C. Andrews and S. K. Durum are supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 78 TC 1 Z9 1 U1 4 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1078-0998 EI 1536-4844 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD SEP PY 2016 VL 22 IS 9 BP 2255 EP 2264 DI 10.1097/MIB.0000000000000818 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DX6AS UT WOS:000384464800034 PM 27243591 ER PT J AU Purswani, MU Patel, K Winkler, CA Spector, SA Hazra, R Seage, GR Mofenson, L Karalius, B Scott, GB Van Dyke, RB Kopp, JB AF Purswani, Murli U. Patel, Kunjal Winkler, Cheryl A. Spector, Stephen A. Hazra, Rohan Seage, George R., III Mofenson, Lynne Karalius, Brad Scott, Gwendolyn B. Van Dyke, Russell B. Kopp, Jeffrey B. CA Pediat HIV AIDS Cohort Study TI APOL1 Renal Risk Variants Are Associated With Chronic Kidney Disease in Children and Youth With Perinatal HIV Infection SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE perinatal; HIV; chronic kidney disease; APOL1; African ancestry; youth ID ACQUIRED-IMMUNODEFICIENCY-SYNDROME; VIREMIA COPY-YEARS; ANTIRETROVIRAL THERAPY; AFRICAN-AMERICANS; SOUTH-AFRICANS; NEPHROPATHY; GLOMERULOPATHY; ADOLESCENTS; HIV/AIDS; GENE AB APOL1 renal risk alleles are associated with chronic kidney disease (CKD) in adults, with the strongest effect being for HIV-associated nephropathy. Their role in youth with perinatal HIV-1 infection (PHIV) has not been studied. In a nested case-control study of 451 PHIV participants in the Pediatric HIV/AIDS Cohort Study, we found a 3.5-fold increased odds of CKD in those carrying high-risk APOL1 genotypes using a recessive model [95% confidence interval (CI): 1.2 to 10.0]. We report an unadjusted incidence of 1.2 CKD cases/100 person-years (95% CI: 0.5 to 2.5) in PHIV youth carrying APOL1 high-risk genotypes, with important implications for sub-Saharan Africa. C1 [Purswani, Murli U.] Albert Einstein Coll Med, Div Pediat Infect Dis, Dept Pediat, Bronx Lebanon Hosp Ctr, Bronx, NY 10467 USA. [Patel, Kunjal; Seage, George R., III; Karalius, Brad] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Winkler, Cheryl A.] Leidos Biomed Inc, Basic Sci Lab, Ctr Canc Res, NCI,Frederick Natl Lab, Frederick, MD USA. [Spector, Stephen A.] Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA. [Spector, Stephen A.] Rady Childrens Hosp, San Diego, CA USA. [Hazra, Rohan; Mofenson, Lynne] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Scott, Gwendolyn B.] Univ Miami, Miller Sch Med, Dept Pediat, Miami, FL 33136 USA. [Van Dyke, Russell B.] Tulane Univ, Sch Med, Dept Pediat, New Orleans, LA 70112 USA. [Kopp, Jeffrey B.] NIDDK, NIH, Bethesda, MD 20892 USA. RP Purswani, MU (reprint author), Bronx Lebanon Hosp Ctr, Div Pediat Infect Dis, 1685 Morris Ave,Suite 1G, Bronx, NY 10457 USA. EM mpurswan@bronxleb.org FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute on Drug Abuse; National Institute of Allergy and Infectious Diseases; Office of AIDS Research; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; National Institute on Deafness and Other Communication Disorders; National Heart Lung and Blood Institute; National Institute of Dental and Craniofacial Research; National Institute on Alcohol Abuse and Alcoholism [HD052102, HD052104]; Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases; National Cancer Institute, the National Institute of Neurological Disorders and Stroke [5 R01NS077874]; National Cancer Institute [HSN26120080001E] FX The Pediatric HIV/AIDS Cohort Study (PHACS) was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development with co-funding from the National Institute on Drug Abuse, the National Institute of Allergy and Infectious Diseases, the Office of AIDS Research, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, the National Institute on Deafness and Other Communication Disorders, the National Heart Lung and Blood Institute, the National Institute of Dental and Craniofacial Research, and the National Institute on Alcohol Abuse and Alcoholism, through cooperative agreements with the Harvard T.H. Chan School of Public Health (HD052102) (Principal Investigator: George Seage; Project Director: Julie Alperen) and the Tulane University School of Medicine (HD052104) (Principal Investigator: Russell Van Dyke; Co-Principal Investigator: Kenneth Rich; Project Director: Patrick Davis). This work was also supported in part by the Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases and the National Cancer Institute, the National Institute of Neurological Disorders and Stroke (5 R01NS077874), and the National Cancer Institute (under contract HSN26120080001E). Data management services were provided by Frontier Science and Technology Research Foundation (Principal Investigator: Suzanne Siminski), and regulatory services and logistical support were provided by Westat, Inc. (Principal Investigator: Julie Davidson). NR 32 TC 1 Z9 1 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD SEP 1 PY 2016 VL 73 IS 1 BP 63 EP 68 DI 10.1097/QAI.0000000000001010 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DW3SQ UT WOS:000383563500011 PM 27035887 ER PT J AU Klein, HG AF Klein, Harvey G. TI Blood Donor Demographics and Transfusion Recipient Survival-No Country for Old Men? SO JAMA INTERNAL MEDICINE LA English DT Editorial Material ID EPIDEMIOLOGY C1 [Klein, Harvey G.] NIH, Dept Transfus Med, Ctr Clin, Bldg 10,Room 1C-711, Bethesda, MD 20892 USA. RP Klein, HG (reprint author), NIH, Dept Transfus Med, Ctr Clin, Bldg 10,Room 1C-711, Bethesda, MD 20892 USA. EM hklein@dtm.cc.nih.gov NR 8 TC 1 Z9 1 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD SEP PY 2016 VL 176 IS 9 BP 1315 EP 1316 DI 10.1001/jamainternmed.2016.3355 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DX2MR UT WOS:000384204800018 PM 27400131 ER PT J AU Zonderman, AB Mode, NA Ejiogu, N Evans, MK AF Zonderman, Alan B. Mode, Nicolle A. Ejiogu, Ngozi Evans, Michele K. TI Race and Poverty Status as a Risk for Overall Mortality in Community-Dwelling Middle-aged Adults SO JAMA INTERNAL MEDICINE LA English DT Letter ID UNITED-STATES; HEALTH; MEN C1 [Zonderman, Alan B.; Mode, Nicolle A.; Ejiogu, Ngozi; Evans, Michele K.] NIA, Lab Epidemiol & Populat Sci, Intramural Res Program, 251 Bayview Blvd, Baltimore, MD 21224 USA. RP Zonderman, AB (reprint author), NIA, Lab Epidemiol & Populat Sci, Intramural Res Program, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM zondermana@mail.nih.gov OI Zonderman, Alan B/0000-0002-6523-4778 NR 6 TC 1 Z9 1 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD SEP PY 2016 VL 176 IS 9 BP 1394 EP 1395 DI 10.1001/jamainternmed.2016.3649 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DX2MR UT WOS:000384204800036 PM 27428269 ER PT J AU Choi, AD Leifer, ES Yu, J Shanbhag, SM Bronson, K Arai, AE Chen, MY AF Choi, Andrew D. Leifer, Eric S. Yu, Jeannie Shanbhag, Sujata M. Bronson, Kathie Arai, Andrew E. Chen, Marcus Y. TI Prospective evaluation of the influence of iterative reconstruction on the reproducibility of coronary calcium quantification in reduced radiation dose 320 detector row CT SO JOURNAL OF CARDIOVASCULAR COMPUTED TOMOGRAPHY LA English DT Article DE Cardiac computed tomography; Coronary artery calcium; Agatston score; Radiation reduction; Iterative reconstruction ID ELECTRON-BEAM CT; ARTERY CALCIUM; COMPUTED-TOMOGRAPHY; INTERSCAN VARIABILITY; MODEL RECONSTRUCTION; IMAGE QUALITY; ANGIOGRAPHY; REDUCTION; ACCURACY; CALCIFICATION AB Background: Coronary artery calcium (CAC) predicts coronary heart disease events and is important for individualized cardiac risk assessment. This report assesses the interscan variability of CT for coronary calcium quantification using image acquisition with standard and reduced radiation dose protocols and whether the use of reduced radiation dose acquisition with iterative reconstruction (IR; "reduced-dose/IR") allows for similar image quality and reproducibility when compared to standard radiation dose acquisition with filtered back projection (FBP; "standard-dose/FBP") on 320-detector row computed tomography (320-CT). Methods: 200 consecutive patients (60 +/- 9 years, 59% male) prospectively underwent two standard- and two reduced-dose acquisitions (800 total scans, 1600 reconstructions) using 320 slice CT and 120 kV tube voltage. Automated tube current modulation was used and for reduced-dose scans, prescribed tube current was lowered by 70%. Image noise and Agatston scores were determined and compared. Results: Regarding stratification by Agatston score categories (0, 1-10, 11-100, 101-400, >400), reduced-dose/IR versus standard-dose/FBP had excellent agreement at 89% (95% CI: 86-92%) with kappa 0.86 (95% CI: 0.81-0.90). Standard-dose/FBP rescan agreement was 93% (95% CI: 89-96%) with kappa = 0.91 (95% CI: 0.86-0.95) while reduced-dose/IR rescan agreement was similar at 91% (95% CI: 87 -94%) with kappa 0.88 (95% CI: 0.83-0.93). Image noise was significantly higher but clinically acceptable for reduced-dose/IR (18 Hounsfield Unit [HU] mean) compared to standard-dose/FBP (16 HU; p < 0.0001). Median radiation exposure was 74% lower for reduced- (0.37 mSv) versus standard-dose (1.4 mSv) acquisitions. Conclusion: Rescan agreement was excellent for reduced-dose image acquisition with iterative reconstruction and standard-dose acquisition with filtered back projection for the quantification of coronary calcium by CT. These methods make it possible to reduce radiation exposure by 74%. Published by Elsevier Inc. on behalf of Society of Cardiovascular Computed Tomography. C1 [Choi, Andrew D.; Yu, Jeannie; Shanbhag, Sujata M.; Bronson, Kathie; Arai, Andrew E.; Chen, Marcus Y.] NHLBI, Adv Cardiovasc Imaging Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Leifer, Eric S.] NHLBI, Off Biostat Res, NIH, Bldg 10, Bethesda, MD 20892 USA. [Choi, Andrew D.] George Washington Univ, Div Cardiol, Sch Med, Washington, DC USA. [Choi, Andrew D.] George Washington Univ, Sch Med, Dept Radiol, Washington, DC USA. RP Chen, MY (reprint author), NHLBI, Adv Cardiovasc Imaging Lab, Cardiovasc & Pulm Branch, NIH, 10 Ctr Dr,Bldg 10,Room B1D416, Bethesda, MD 20892 USA. EM marcus.chen@nih.gov FU Intramural Research Program of the National Institutes of Health; National Heart, Lung, and Blood Institute [ZIA-HL006138-05, ZIE-HL006139-05] FX This research was supported by the Intramural Research Program of the National Institutes of Health and National Heart, Lung, and Blood Institute under Grant Numbers: ZIA-HL006138-05 and ZIE-HL006139-05. NR 32 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 1934-5925 J9 J CARDIOVASC COMPUT JI J. Cardiovasc. Comput. Tomogr. PD SEP-OCT PY 2016 VL 10 IS 5 BP 359 EP 363 DI 10.1016/j.jcct.2016.07.016 PG 5 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA DY0JR UT WOS:000384783600003 PM 27591767 ER PT J AU Kuhrova, P Best, RB Bottaro, S Bussi, G Sponer, J Otyepka, M Banas, P AF Kuhrova, Petra Best, Robert B. Bottaro, Sandro Bussi, Giovanni Sponer, Jiri Otyepka, Michal Banas, Pavel TI Computer Folding of RNA Tetraloops: Identification of Key Force Field Deficiencies SO JOURNAL OF CHEMICAL THEORY AND COMPUTATION LA English DT Article ID MOLECULAR-DYNAMICS SIMULATIONS; BASE-PAIRS; TERTIARY INTERACTIONS; EXPLICIT-SOLVENT; REPLICA-EXCHANGE; ENERGY LANDSCAPE; GNRA TETRALOOP; PARAMETERS; DNA; PROTEIN AB The computer-aided folding of biomolecules, particularly RNAs, is one of the most difficult challenges in computational structural biology. RNA tetraloops are fundamental RNA motifs playing key roles in RNA folding and RNA RNA and RNA protein interactions. Although state-of-the-art Molecular Dynamics (MD) force fields correctly describe the native state of these tetraloops as a stable free-energy basin on the microsecond time scale,. enhanced sampling techniques reveal that the native state is not the global free energy minimum, suggesting yet unidentified significant imbalances in the force fields. Here, we tested our ability to fold the RNA tetraloops in various force fields and simulation settings. We employed three different enhanced sampling techniques, namely, temperature replica exchange MD (T-REMD), replica exchange with solute tempering (REST2), and well-tempered metadynamics (WT-MetaD). We aimed to separate problems caused by limited sampling from those due to force-field inaccuracies. We found that none of the contemporary force fields is able to correctly describe folding of the 5'-GAGA-3' tetraloop over a range of simulation conditions. We thus aimed to identify which terms of the force field are responsible for this poor description of TL folding. We showed that at least two different imbalances contribute to this behavior, namely, overstabilization of base phosphate and/or sugar phosphate interactions and underestimated stability of the hydrogen bonding interaction in base pairing. The first artifact stabilizes the unfolded ensemble, while the second one destabilizes the folded state. The former problem might be partially alleviated by reparametrization of the van der Waals parameters of the phosphate oxygens suggested by Case et al., while in order to overcome the latter effect we suggest local potentials to better capture hydrogen bonding interactions. C1 [Kuhrova, Petra; Sponer, Jiri; Otyepka, Michal; Banas, Pavel] Palacky Univ Olomouc, Reg Ctr Adv Technol & Mat, Dept Phys Chem, Fac Sci, 17 Listopadu 12, Olomouc 77146, Czech Republic. [Best, Robert B.] NIDDK, NIH, Chem Phys Lab, Bethesda, MD 20892 USA. [Bottaro, Sandro; Bussi, Giovanni] Scuola Int Superiore Studi Avanzati, Via Bonomea 26S, I-34136 Trieste, Italy. [Sponer, Jiri; Otyepka, Michal; Banas, Pavel] Acad Sci Czech Republic, Inst Biophys, Kralovopolska 135, Brno 61265, Czech Republic. RP Sponer, J; Banas, P (reprint author), Palacky Univ Olomouc, Reg Ctr Adv Technol & Mat, Dept Phys Chem, Fac Sci, 17 Listopadu 12, Olomouc 77146, Czech Republic.; Sponer, J; Banas, P (reprint author), Acad Sci Czech Republic, Inst Biophys, Kralovopolska 135, Brno 61265, Czech Republic. EM sponer@ncbr.muni.cz; pavel.banas@upol.cz RI Bussi, Giovanni/A-1776-2009; Otyepka, Michal/D-1220-2017 OI Bussi, Giovanni/0000-0001-9216-5782; Otyepka, Michal/0000-0002-1066-5677 FU Czech Science Foundation [P208/12/1878]; Ministry of Education, Youth and Sports of the Czech Republic [LO1305]; Praemium Academiae; National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health; European Research Council under the European Union/ERC [306662]; Neuron fund FX This work was supported by Grant P208/12/1878 (J.S., M.O., P.K.) from the Czech Science Foundation. Further institutional funding was provided by project LO1305 of the Ministry of Education, Youth and Sports of the Czech Republic (M.O., P.B., P.K.). J.S. acknowledges support by Praemium Academiae. R.B. was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. G.B and S.B received funding from the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013)/ERC Grant Agreement n. 306662, S-RNA-S. M.O. acknowledges the Neuron fund to support science. NR 94 TC 5 Z9 5 U1 9 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1549-9618 EI 1549-9626 J9 J CHEM THEORY COMPUT JI J. Chem. Theory Comput. PD SEP PY 2016 VL 12 IS 9 BP 4534 EP 4548 DI 10.1021/acs.jctc.6b00300 PG 15 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA DW0FG UT WOS:000383315700033 PM 27438572 ER PT J AU Darr, R Bursztyn, M Pamporaki, C Peitzsch, M Siegert, G Bornstein, SR Eisenhofer, G AF Daerr, Roland Bursztyn, Michael Pamporaki, Christina Peitzsch, Mirko Siegert, Gabriele Bornstein, Stefan R. Eisenhofer, Graeme TI Dipping in Ambulatory Blood Pressure Monitoring Correlates With Overnight Urinary Excretion of Catecholamines and Sodium SO JOURNAL OF CLINICAL HYPERTENSION LA English DT Article ID OBSTRUCTIVE SLEEP-APNEA; SYMPATHETIC-NERVOUS-SYSTEM; ALL-CAUSE MORTALITY; ESSENTIAL-HYPERTENSION; PLASMA-CATECHOLAMINES; CIRCADIAN-RHYTHM; VARIABILITY; HUMANS; SENSITIVITY; PREDICTORS AB Nondipping blood pressure (BP) is associated with increased morbidity and mortality. This study examines the relationship of dipping in 24-hour ambulatory BP monitoring (ABPM) with awake and sleeping urinary norepinephrine (NE) and epinephrine (EPI), and that of urinary NE and EPI with urinary sodium (UNa). Fifty nondippers and 65 dippers were included in the present study. Collected data included age, sex, body mass index, history of hypertension, current antihypertensive treatment, ABPM data, and NE, EPI, and UNa values. Hierarchical multiple regression analysis with the night-to-day ratio (NDR) of systolic BP as a dependent variable showed that the composite term of the NDRs of urinary NE and EPI was a significant predictor for dipping. Results also show a differential role of NE and EPI in circadian UNa excretion in dippers and nondippers. These results indicate that the sympathetic nervous system is involved in the regulation of circadian BP variations and UNa excretion. C1 [Daerr, Roland; Pamporaki, Christina; Bornstein, Stefan R.; Eisenhofer, Graeme] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Dept Med 3, Dresden, Germany. [Bursztyn, Michael] Hadassah Hebrew Univ, Med Ctr, Hypertens Unit, Dept Med, Jerusalem, Israel. [Peitzsch, Mirko; Siegert, Gabriele; Eisenhofer, Graeme] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Inst Clin Chem & Lab Med, Dresden, Germany. RP Darr, R (reprint author), NICHD, NIH, Bldg 10 Ctr Dr,Room 1-3140, Bethesda, MD 20814 USA. EM roland.daerr@nih.gov FU German-Israeli Foundation FX This research was supported by a research grant from the German-Israeli Foundation. Otherwise, the authors report no specific funding in relation to this research and no conflicts of interest to disclose. NR 40 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1524-6175 EI 1751-7176 J9 J CLIN HYPERTENS JI J. Clin. Hypertens. PD SEP PY 2016 VL 18 IS 9 BP 921 EP 926 DI 10.1111/jch.12791 PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DX9WF UT WOS:000384747000015 PM 26864704 ER PT J AU Lamis, DA Ballard, ED May, AM Dvorak, RD AF Lamis, Dorian A. Ballard, Elizabeth D. May, Alexis M. Dvorak, Robert D. TI Depressive Symptoms and Suicidal Ideation in College Students: The Mediating and Moderating Roles of Hopelessness, Alcohol Problems, and Social Support SO JOURNAL OF CLINICAL PSYCHOLOGY LA English DT Article ID CONFIRMATORY FACTOR-ANALYSIS; MULTIDIMENSIONAL SCALE; LONGITUDINAL TRAJECTORIES; COGNITIVE VULNERABILITY; UNITED-STATES; RELIABILITY; VALIDITY; BEHAVIOR; INPATIENTS; ANXIETY AB ObjectiveMixed evidence for the associations among depression, hopelessness, alcohol problems, and suicidal ideation in college students may be due to the influence of social support. MethodA moderated-mediation analysis was conducted to examine relationships among suicide risk factors in 2,034 college students. ResultsSocial support moderated the relation between depressive symptoms and hopelessness in predicting suicidal thoughts; specifically, the association between depressive symptoms and hopelessness was diminished among those students with high levels of social support. This resulted in attenuated indirect associations between depressive symptoms and suicidal ideation via hopelessness. Alcohol problems were associated with likelihood of experiencing suicidal ideation, but not severity. ConclusionSocial support may be a key variable for suicide prevention among college students. C1 [Lamis, Dorian A.] Emory Univ, Sch Med, Atlanta, GA 30322 USA. [Ballard, Elizabeth D.] NIMH, Bethesda, MD 20892 USA. [May, Alexis M.] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Dvorak, Robert D.] North Dakota State Univ, Fargo, ND USA. RP Lamis, DA (reprint author), Grady Hosp, Emory Sch Med, Dept Psychiat & Behav Sci, 10 Pk Pl SE, Atlanta, GA 30303 USA. EM Dalamis@gmail.com NR 61 TC 0 Z9 0 U1 9 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9762 EI 1097-4679 J9 J CLIN PSYCHOL JI J. Clin. Psychol. PD SEP PY 2016 VL 72 IS 9 BP 919 EP 932 DI 10.1002/jclp.22295 PG 14 WC Psychology, Clinical SC Psychology GA DW4NW UT WOS:000383621000005 PM 27008096 ER PT J AU Han, MAT Rehman, RB Kleiner, D Cohen, J Heller, T AF Han, M. A. T. Rehman, R. B. Kleiner, D. Cohen, J. Heller, T. TI Hepatobiliary and Pancreatic: Not all that "Glisson's" is fat SO JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY LA English DT Editorial Material C1 [Han, M. A. T.; Rehman, R. B.; Heller, T.] NIDDK, Translat Hepatol Unit, Liver Dis Branch, Bethesda, MD 20892 USA. [Kleiner, D.] NCI, Pathol Lab, Bldg 10, Bethesda, MD 20892 USA. [Cohen, J.] NIAID, Med Virol Sect, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Han, MAT (reprint author), NIDDK, Translat Hepatol Unit, Liver Dis Branch, 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 0815-9319 EI 1440-1746 J9 J GASTROEN HEPATOL JI J. Gastroenterol. Hepatol. PD SEP PY 2016 VL 31 IS 9 BP 1515 EP 1515 DI 10.1111/jgh.13429 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DX8TG UT WOS:000384661700005 PM 27131048 ER PT J AU Lukyanenko, YO Younes, A Lyashkov, AE Tarasov, KV Riordon, DR Lee, J Sirenko, SG Kobrinsky, E Ziman, B Tarasova, YS Juhaszova, M Sollott, SJ Graham, DR Lakatta, EG AF Lukyanenko, Yevgeniya O. Younes, Antoine Lyashkov, Alexey E. Tarasov, Kirill V. Riordon, Daniel R. Lee, Joonho Sirenko, Syevda G. Kobrinsky, Evgeny Ziman, Bruce Tarasova, Yelena S. Juhaszova, Magdalena Sollott, Steven J. Graham, David R. Lakatta, Edward G. TI Ca2+/calmodulin-activated phosphodiesterase 1A is highly expressed in rabbit cardiac sinoatrial nodal cells and regulates pacemaker function SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Article DE Heart; Sinoatrial node pacemaker cells; Phosphodiesterase Type 1A; Calcium; cAMP ID CYCLIC-NUCLEOTIDE PHOSPHODIESTERASE; CALMODULIN-DEPENDENT PHOSPHODIESTERASE; RAT VENTRICULAR MYOCYTES; LOCAL CA2+ RELEASES; CYCLASE TYPE-8 AC8; ADENYLYL-CYCLASE; RYANODINE-RECEPTOR; HL-1 CARDIOMYOCYTES; CAMP SIGNALS; GUINEA-PIG AB Constitutive Ca2+/calmodulin (CaM)-activation of adenylyl cyclases (ACs) types 1 and 8 in sinoatrial nodal cells (SANC) generates cAMP within lipid-raft-rich microdomains to initiate cAMP-protein kinase A (PKA) signaling, that regulates basal state rhythmic action potential firing of these cells. Mounting evidence in other cell types points to a balance between Ca2+-activated counteracting enzymes, ACs and phosphodiesterases (PDEs) within these cells. We hypothesized that the expression and activity of Ca2+/CaM-activated PDE Type 1A is higher in SANC than in other cardiac cell types. We found that PDE1A protein expression was 5-fold higher in sinoatrial nodal tissue than in left ventricle, and its mRNA expression was 12-fold greater in the corresponding isolated cells. PDE1 activity (nimodipine-sensitive) accounted for 39% of the total PDE activity in SANC lysates, compared to only 4% in left ventricular cardiomyocytes (LVC). Additionally, total PDE activity in SANC lysates was lowest (10%) in lipid-raft-rich and highest (76%) in lipid-raft-poor fractions (equilibrium sedimentation on a sucrose density gradient). In intact cells PDE1A immunolabeling was not localized to the cell surface membrane (structured illumination microscopy imaging), but located approximately within about 150 nm inside of immunolabeling of hyperpolarization-activated cyclic nucleotide-gated potassium channels (HCN4), which reside within lipid-raft-rich microenvironments. In permeabilized SANC, in which surface membrane ion channels are not functional, nimodipine increased spontaneous SR Ca2+ cycling. PDE1A mRNA silencing in HL-1 cells increased the spontaneous beating rate, reduced the cAMP, and increased cGMP levels in response to IBMX, a broad spectrum PDE inhibitor (detected via fluorescence resonance energy transfer microscopy). We conclude that signaling via cAMP generated by Ca2+/CaM-activated AC in SANC lipid raft domains is limited by CAMP degradation by Ca2+/CaM-activated PDE1A in non-lipid raft domains. This suggests that local gradients of [Ca2+]-CaM or different AC and PDE1A affinity regulate both cAMP production and its degradation, and this balance determines the intensity of Ca2+-AC-cAMP-PKA signaling that drives SANC pacemaker function. (C) 2016 Published by Elsevier Ltd. C1 [Lukyanenko, Yevgeniya O.; Younes, Antoine; Lyashkov, Alexey E.; Tarasov, Kirill V.; Riordon, Daniel R.; Lee, Joonho; Sirenko, Syevda G.; Kobrinsky, Evgeny; Ziman, Bruce; Tarasova, Yelena S.; Juhaszova, Magdalena; Sollott, Steven J.; Lakatta, Edward G.] NIA, Lab Cardiovasc Sci, 251 Bayview Blvd, Baltimore, MD 21224 USA. [Lyashkov, Alexey E.; Graham, David R.] Johns Hopkins Sch Med, Dept Mol & Comparat Pathobiol, 733 N Broadway,MRB 835, Baltimore, MD 21205 USA. RP Lukyanenko, YO; Lakatta, EG (reprint author), Cardiovasc Sci Lab, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM Lukyanenkoy@nia.nih.gov; Younesa@nia.nih.gov; Alexey.lyashkov@nih.gov; Tarasovkv@mail.nih.gov; RiordonD@grc.nia.nih.gov; Joon.lee@nih.gov; Sirenkos@grc.nia.nih.gov; KobrinskiEv@grc.nia.nih.gov; ZimanB@grc.nia.nih.gov; Tarasovay@grc.nia.nih.gov; Juhaszovam@grc.nia.nih.gov; SollottS@grc.nia.nih.gov; Dgraham@jhmi.edu; lakattae@grc.nia.nih.gov FU National Institute on Aging, National Institutes of Health; NIA; NIH [TAS::75 0872::TAS] FX This work was supported by the National Institute on Aging, National Institutes of Health Intramural Research Program, NIA and NIH contract number TAS::75 0872::TAS. NR 70 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD SEP PY 2016 VL 98 BP 73 EP 82 DI 10.1016/j.yjmcc.2016.06.064 PG 10 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA DY0KQ UT WOS:000384786100009 PM 27363295 ER PT J AU Mummidi, S Das, NA Carpenter, AJ Kandikattu, H Krenz, M Siebenlist, U Valente, AJ Chandrasekar, B AF Mummidi, Srinivas Das, Nitin A. Carpenter, Andrea J. Kandikattu, Hemanthkumar Krenz, Maike Siebenlist, Ulrich Valente, Anthony J. Chandrasekar, Bysani TI Metformin inhibits aldosterone-induced cardiac fibroblast activation, migration and proliferation in vitro, and reverses aldosterone plus salt-induced cardiac fibrosis in vivo SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Article DE Aldosterone; Metformin; AMPK activators; TRAF3IP2; Cardiac fibrosis ID NF-KAPPA-B; GENE-EXPRESSION; PROTEIN-KINASE; TRAF3IP2; INTERLEUKIN-6; HYPERTROPHY; STRESS; INFLAMMATION; CATALASE; PROMOTER AB The overall goals of this study were to investigate whether metformin exerts anti-fibrotic effects in aldosterone (Aldo) + salt-treated wild type mouse hearts, and determine the underlying molecular mechanisms in isolated adult cardiac fibroblasts (CF). In vitro, Aldo induced CF activation, migration, and proliferation, and these effects were inhibited by metformin. Further, Aldo induced PPM1A (Protein Phosphatase Magnesium Dependent-IA) activation and inhibited AMPK phosphorylation. At a pharmacologically relevant concentration, metformin restored AMPK activation, and inhibited Aldo-induced Nox4/H2O2-dependent TRAF3IP2 induction, pro-inflammatory cytokine expression, and CF migration and proliferation. Further, metformin potentiated the inhibitory effects of spironolactone, a mineralocorticoid receptor antagonist, on Aldo-induced collagen expression, and CF migration and proliferation. These results were recapitulated in vivo, where metformin reversed Aldo + salt-induced oxidative stress, suppression of AMPK activation, TRAF3IP2 induction, pro-inflammatory cytokine expression, and cardiac fibrosis, without significantly modulating systolic blood pressure. These in vitro and in vivo data indicate that metformin has the potential to reduce adverse cardiac remodeling in hypertensive heart disease. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Mummidi, Srinivas; Valente, Anthony J.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Das, Nitin A.; Carpenter, Andrea J.] Univ Texas Hlth Sci Ctr San Antonio, Dept Cardiothorac Surg, San Antonio, TX 78229 USA. [Kandikattu, Hemanthkumar; Chandrasekar, Bysani] Univ Missouri, Sch Med, Med Cardiol, Columbia, MO 65211 USA. [Krenz, Maike] Univ Missouri, Sch Med, Med Pharmacol & Physiol, Columbia, MO 65211 USA. [Siebenlist, Ulrich] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Chandrasekar, Bysani] Harry S Truman Mem Vet Hosp, Res Serv, Columbia, MO 65201 USA. RP Chandrasekar, B (reprint author), Univ Missouri, Sch Med, Med Cardiol, 1 Hosp Dr, Columbia, MO 65212 USA. EM chandrasekarb@health.missouri.edu FU Department of Veterans Affairs; U.S. Department of Veterans Affairs, Office of Research and Development-Biomedical Laboratory Research and Development (ORD-BLRD) Service [VA-I01-BX002255]; NIH/NIAID FX BC is a recipient of the Department of Veterans Affairs Research Career Scientist award, and is supported by the U.S. Department of Veterans Affairs, Office of Research and Development-Biomedical Laboratory Research and Development (ORD-BLRD) Service Award VA-I01-BX002255. US is supported by the Intramural Research Program of the NIH/NIAID. The contents of this report do not represent the views of the Department of Veterans Affairs or the United States government. NR 38 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD SEP PY 2016 VL 98 BP 95 EP 102 DI 10.1016/j.yjmcc.2016.07.006 PG 8 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA DY0KQ UT WOS:000384786100011 PM 27423273 ER PT J AU Weathers, SP Han, XS Liu, DD Conrad, CA Gilbert, MR Loghin, ME O'Brien, BJ Penas-Prado, M Puduvalli, VK Tremont-Lukats, I Colen, RR Yung, WKA de Groot, JF AF Weathers, Shiao-Pei Han, Xiaosi Liu, Diane D. Conrad, Charles A. Gilbert, Mark R. Loghin, Monica E. O'Brien, Barbara J. Penas-Prado, Marta Puduvalli, Vinay K. Tremont-Lukats, Ivo Colen, Rivka R. Yung, W. K. Alfred de Groot, John F. TI A randomized phase II trial of standard dose bevacizumab versus low dose bevacizumab plus lomustine (CCNU) in adults with recurrent glioblastoma SO JOURNAL OF NEURO-ONCOLOGY LA English DT Article DE Glioblastoma; Bevacizumab; Lomustine; Angiogenesis; VEGF ID NEWLY-DIAGNOSED GLIOBLASTOMA; ANTIANGIOGENIC THERAPY; TUMOR VASCULATURE; MALIGNANT GLIOMA; TEMOZOLOMIDE; COMBINATION; IRINOTECAN; NORMALIZATION; CHEMOTHERAPY; PROGRESSION AB Antiangiogenic therapy can rapidly reduce vascular permeability and cerebral edema but high doses of bevacizumab may induce selective pressure to promote resistance. This trial evaluated the efficacy of low dose bevacizumab in combination with lomustine (CCNU) compared to standard dose bevacizumab in patients with recurrent glioblastoma. Patients (N = 71) with recurrent glioblastoma who previously received radiation and temozolomide were randomly assigned 1:1 to receive bevacizumab monotherapy (10 mg/kg) or low dose bevacizumab (5 mg/kg) in combination with lomustine (90 mg/m(2)). The primary end point was progression-free survival (PFS) based on a blinded, independent radiographic assessment of post-contrast T1-weighted and non-contrast T2/FLAIR weighted magnetic resonance imaging (MRI) using RANO criteria. For 69 evaluable patients, median PFS was not significantly longer in the low dose bevacizumab + lomustine arm (4.34 months, CI 2.96-8.34) compared to the bevacizumab alone arm (4.11 months, CI 2.69-5.55, p = 0.19). In patients with first recurrence, there was a trend towards longer median PFS time in the low dose bevacizumab + lomustine arm (4.96 months, CI 4.17-13.44) compared to the bevacizumab alone arm (3.22 months CI 2.5-6.01, p = 0.08). The combination of low dose bevacizumab plus lomustine was not superior to standard dose bevacizumab in patients with recurrent glioblastoma. Although the study was not designed to exclusively evaluate patients at first recurrence, a strong trend towards improved PFS was seen in that subgroup for the combination of low dose bevacizumab plus lomustine. Further studies are needed to better identify such subgroups that may most benefit from the combination treatment. C1 [Weathers, Shiao-Pei; Conrad, Charles A.; Gilbert, Mark R.; Loghin, Monica E.; O'Brien, Barbara J.; Penas-Prado, Marta; Puduvalli, Vinay K.; Tremont-Lukats, Ivo; Yung, W. K. Alfred; de Groot, John F.] Univ Texas MD Anderson Canc Ctr, Dept Neurooncol, 1515 Holcombe Blvd,Unit 431, Houston, TX 77030 USA. [Han, Xiaosi] Univ Alabama Birmingham, 1020 Fac Off Tower,510 20th St South, Birmingham, AL 35294 USA. [Liu, Diane D.] Univ MD Anderson Canc Ctr, Dept Biostat, 1400 Pressler St, Houston, TX 77030 USA. [Colen, Rivka R.] Univ Texas MD Anderson Canc Ctr, Dept Neuroradiol, 1400 Pressler St Unit 1482, Houston, TX 77030 USA. [Conrad, Charles A.] Texas Oncol, 901 W 38th St, Austin, TX 78705 USA. [Gilbert, Mark R.] NIH, 9030 Old Georgetown Rd, Bethesda, MD 20892 USA. [Puduvalli, Vinay K.] M410 Starling Loving Hall,320 W,10th Ave, Columbus, OH 43210 USA. [Tremont-Lukats, Ivo] Houston Methodist Hosp, Dept Neurosurg, 6560 Fannin,Scurlock Suite 900, Houston, TX 77030 USA. RP Weathers, SP (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Neurooncol, 1515 Holcombe Blvd,Unit 431, Houston, TX 77030 USA. EM sweathers@mdanderson.org FU National Institutes of Health [1R21CA152024-01, CCSG-P30 CA016672] FX National Institutes of Health [1R21CA152024-01] to J. D. National Institutes of Health [CCSG-P30 CA016672] to R. D. NR 32 TC 1 Z9 1 U1 0 U2 0 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 SEP PY 2016 VL 129 IS 3 BP 487 EP 494 DI 10.1007/s11060-016-2195-9 PG 8 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA DX7JU UT WOS:000384563800012 PM 27406589 ER PT J AU Tanner, AE Philbin, MM DuVal, A Ellen, J Kapogiannis, B Fortenberry, JD AF Tanner, Amanda E. Philbin, Morgan M. DuVal, Anna Ellen, Jonathan Kapogiannis, Bill Fortenberry, J. Dennis CA Adolescent Trials Network HIV AIDS TI Transitioning HIV-Positive Adolescents to Adult Care: Lessons Learned From Twelve Adolescent Medicine Clinics SO JOURNAL OF PEDIATRIC NURSING-NURSING CARE OF CHILDREN & FAMILIES LA English DT Article DE HIV; Transition; Adolescents; Young adults; Healthcare ID PERINATALLY-ACQUIRED HIV; HEALTH-CARE; INFECTED ADOLESCENTS; YOUNG-ADULTS; BARRIERS; YOUTH; INTERVENTIONS; PERSPECTIVES; GUARDIANS; HIV/AIDS AB Purpose To maximize positive health outcomes for youth with HIV as they transition from youth to adult care, clinical staff need strategies and protocols to help youth maintain clinic engagement andmedication adherence. Accordingly, this paper describe transition processes across twelve clinics within the Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) to provide lessons learned and inform the development of transition protocols to improve health outcomes as youth shift from adolescent to adult HIV care. Design and Methods: During a large multi-method Care Initiative program evaluation, three annual visits were completed at each site from 2010-2012 and conducted 174 semi-structured interviews with clinical and program staff (baseline n = 64, year 1 n = 56, year 2 = 54). Results: The results underscore the value of adhering to recent American Academy of Pediatrics (AAP) transition recommendations, including: developing formal transition protocols, preparing youth for transition, facilitating youth's connection to the adult clinic, and identifying necessary strategies for transition evaluation. Conclusions: Transitioning youth with HIV involves targeting individual-, provider-, and system-level factors. Acknowledging and addressing key barriers is essential for developing streamlined, comprehensive, and context-specific transition protocols. Practice Implications: Adolescent and adult clinic involvement in transition is essential to reduce service fragmentation, provide coordinated and continuous care, and support individual and community level health. (C) 2016 Elsevier Inc. All rights reserved. C1 [Tanner, Amanda E.] Univ North Carolina Greensboro, Dept Publ Hlth Educ, Greensboro, NC 27412 USA. [Philbin, Morgan M.] Columbia Univ, HIV Ctr Clin & Behav Studies, New York, NY USA. [Philbin, Morgan M.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [DuVal, Anna] Johns Hopkins Sch Med, Dept Emergency Med, Baltimore, MD USA. [Ellen, Jonathan] Johns Hopkins Sch Med, Dept Pediat, Baltimore, MD USA. [Ellen, Jonathan] All Childrens Hosp, St Petersburg, FL USA. [Kapogiannis, Bill] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS Branch, NIH, Bethesda, MD USA. [Fortenberry, J. Dennis] Indiana Univ Sch Med, Dept Pediat, Indianapolis, IN 46202 USA. RP Tanner, AE (reprint author), Univ North Carolina Greensboro, Dept Publ Hlth Educ, Greensboro, NC 27412 USA. EM aetanner@uncg.edu FU National Institutes of Health through the National Institute of Child Health and Human Development [5 U01 HD 40533, 5 U01 HD 40474]; National Institute on Drug Abuse; National Institute on Mental Health; American Recovery and Reinvestment Act (ARRA); ATN Data and Operations Center at Westat, Inc.; National Institute of Mental Health (Behavioral Sciences Research in HIV Infection) at the HIV Center for Clinical and Behavioral Studies at NY State Psychiatric Institute and Columbia University [T32MH19139, P30-MH43520] FX This work was supported by grants to the Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN): 5 U01 HD 40533 and 5 U01 HD 40474 from the National Institutes of Health through the National Institute of Child Health and Human Development (Bill Kapogiannis, MD) with supplemental funding from the National Institutes on Drug Abuse (Nicolette Borek, PhD) and Mental Health (Susannah Allison, PhD; Pim Brouwers, PhD). Additional support was provided by an administrative supplement awarded through funds from the American Recovery and Reinvestment Act (ARRA) of 2009.; The study was scientifically reviewed by the ATN Community Prevention Leadership Group. Network, scientific, and logistical support was provided by the ATN Coordinating Center (Craig Wilson, MD; Cynthia Partlow, MEd). ATN Data and Operations Center at Westat, Inc. (Jim Korelitz, PhD; Barbara Driver RN, MS) provided project support and coordination. We also acknowledge the contribution of the investigators and staff at the following sites that participated in this study: University of South Florida, Tampa (Emmanuel, Straub, McKinney), Children's Hospital of Los Angeles (Belzer, Brown), Children's National Medical Center (D'Angelo, Fawehinmi, Hoyte), Children's Hospital of Philadelphia (Douglas, Tanney, Kerfren, Louis), John H. Stroger Jr. Hospital of Cook County and the Ruth M. Rothstein CORE Center (Martinez, Henry-Reid, McFadden), University of Puerto Rico (Febo, Cruz), Montefiore Medical Center (Futterman, Jackson), Mount Sinai Medical Center (Steever, Maxwell), University of California-San Francisco (Moscicki, Auerswald, Bowman), Tulane University Health Sciences Center (Abdalian, McFarlane, Jeanjacques), University of Maryland (Peralta, Bishop), University of Miami School of Medicine (Friedman, Mills), Children's Diagnostic and Treatment Center (Puga, Archibald), St. Jude's Children's Research Hospital (Flynn, Askew), Children's Memorial Hospital (Garofalo, Vulpas, Heine).; Dr. Philbin was supported by a training grant from the National Institute of Mental Health (T32MH19139, Behavioral Sciences Research in HIV Infection; Principal Investigator: Theo Sandfort, Ph.D.) at the HIV Center for Clinical and Behavioral Studies at NY State Psychiatric Institute and Columbia University (P30-MH43520; Principal Investigator: Robert H. Remien, Ph.D. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. NR 38 TC 2 Z9 2 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0882-5963 J9 J PEDIATR NURS JI J. Pediatr. Nurs. PD SEP-OCT PY 2016 VL 31 IS 5 BP 537 EP 543 DI 10.1016/j.pedn.2016.04.002 PG 7 WC Nursing; Pediatrics SC Nursing; Pediatrics GA DX1NO UT WOS:000384134300015 PM 27133767 ER PT J AU Foy, CG Newman, JC Berlowitz, DR Russell, LP Kimmel, PL Wadley, VG Thomas, HN Lerner, AJ Riley, WT AF Foy, Capri G. Newman, Jill C. Berlowitz, Dan R. Russell, Laurie P. Kimmel, Paul L. Wadley, Virginia G. Thomas, Holly N. Lerner, Alan J. Riley, William T. CA SPRINT Study Res Grp TI Blood Pressure, Sexual Activity, and Dysfunction in Women With Hypertension: Baseline Findings From the Systolic Blood Pressure Intervention Trial (SPRINT) SO JOURNAL OF SEXUAL MEDICINE LA English DT Article DE Sexual Activity; Sexual Function; Blood Pressure; Older Women; Antihypertensive Medications ID QUALITY-OF-LIFE; FUNCTION INDEX; OLDER WOMEN; POSTMENOPAUSAL WOMEN; UNITED-STATES; MEN; PREDICTORS; THERAPY; DISEASE; PREVALENCE AB Introduction: Sexual function, an important component of quality of life, is gaining increased research and clinical attention in older women with hypertension. Aim: To assess the association between systolic blood pressure (SBP) and other variables, and sexual activity and sexual dysfunction in hypertensive women. Methods: Baseline analysis of 635 women participants of a larger randomized clinical trial of 9361 men and women. Main Outcome Measures: Self-reported sexual activity (yes/no), and sexual function using the Female Sexual Function Inventory (FSFI). Results: 452 participants (71.2%) reported having no sexual activity during the previous 4 weeks. The mean (SD) FSFI score for sexually active participants was 25.3 (6.0), and 52.6% of the sample reported a FSFI score <= 26.55 designating sexual dysfunction. In logistic regression models, SBP was not significantly associated with sexual activity (AOR = 1.002; P>. 05). Older age (AOR = 0.95, P<. 05), and lower education (AOR for< high school vs college degree = 0.29, P <.05) were associated with lower odds of being sexually active, as was living alone versus living with others (AOR = 0.56, P <.05). Higher weekly alcohol consumption was associated with increased odds of being sexually active (AOR = 1.39; P<. 05). In logistic regression models among sexually active participants, SBP was not associated with sexual dysfunction (AOR = 1.01; P >.05). Higher depressive symptoms from the Patient Health Questionnaire-9 (PHQ-9) was associated with higher odds of sexual dysfunction (AOR = 1.24, P<. 05), as was increased number of physical comorbidities (AOR = 1.25, P<. 05). Diuretic use was associated with lower odds of being sexually active in participants with chronic kidney disease (AOR = 0.33, P <.05). Conclusion: Younger age, higher education, living with others, and higher weekly alcohol consumption were significantly associated with higher odds of being sexually active in a sample of middle-aged and older women with hypertension. Increased depressive symptoms and increased physical comorbidities were significantly associated with increased odds of sexual dysfunction. SBP was not significantly associated with sexual activity or sexual dysfunction. Copyright (C) 2016, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved. C1 [Foy, Capri G.] Wake Forest Sch Med, Div Publ Hlth Sci, Dept Social Sci & Hlth Policy, Winston Salem, NC USA. [Newman, Jill C.; Russell, Laurie P.] Wake Forest Sch Med, Div Publ Hlth Sci, Dept Biostat Sci, Winston Salem, NC USA. [Berlowitz, Dan R.] Bedford VA Hosp, Bedford, MA USA. [Berlowitz, Dan R.] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Kimmel, Paul L.] NIDDK, Div Kidney Urol & Hematol Dis, Bethesda, MD 20892 USA. [Wadley, Virginia G.] Univ Alabama Birmingham, Sch Med, Dept Psychiat, Birmingham, AL USA. [Thomas, Holly N.] Univ Pittsburgh, Div Gen Internal Med, Sect Womens Hlth, Pittsburgh, PA USA. [Lerner, Alan J.] Case Western Reserve Univ, Sch Med, Dept Neurol, Cleveland, OH 44106 USA. [Lerner, Alan J.] Brain Hlth & Memory Ctr, Cleveland, OH USA. [Riley, William T.] NIH, Off Behav & Social Sci Res, Bldg 10, Bethesda, MD 20892 USA. RP Foy, CG (reprint author), Wake Forest Sch Med, Dept Social Sci & Hlth Policy, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM cfoy@wakehealth.edu FU National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI); National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Institutes of Health (NIH), National Institute on Aging (NIA); National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke (NINDS) [HHSN268200 900040C, HHSN268200900046C, HHSN268200900047C, HHSN268200900048C, HHSN268200900049C]; NCATS [CWRU: UL1TR000439, OSU: UL1RR025755, U Penn: UL1RR024134, UL1TR 000003, Boston: UL1RR025771, Stanford: UL1TR000093, Tufts: UL1RR025752, UL1TR000073, UL1TR001064]; NCATS. [University of Illinois: UL1TR000050, University of Pittsburgh: UL1TR000005, UT Southwestern: 9U54TR000017-06, University of Utah: UL1TR000105-05, Vanderbilt University: UL1 TR000445, George Washington University: UL1TR000075]; NCATS, [University of CA, Davis: UL1 TR000002, University of Florida: UL1 TR000064, University of Michigan: UL1TR000433, Tulane University: P30GM103337 COBRE Award NIGMS]; [A-HL-13-002-001] FX The Systolic Blood Pressure Intervention Trial is funded with Federal funds from the National Institutes of Health (NIH), including the National Heart, Lung, and Blood Institute (NHLBI), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute on Aging (NIA), and the National Institute of Neurological Disorders and Stroke (NINDS), under Contract Numbers HHSN268200 900040C, HHSN268200900046C, HHSN268200900047C, HHSN268200900048C, HHSN268200900049C, and InterAgency Agreement Number A-HL-13-002-001. It was also supported in part with resources and use of facilities through the Department of Veterans Affairs. The SPRINT investigators acknowledge the contribution of study medications (azilsartan and azilsartan combined with chlorthalidone) from Takeda Pharmaceuticals International, Inc. All components of the SPRINT study protocol were designed and implemented by the investigators. The investigative team collected, analyzed, and interpreted the data. All aspects of manuscript writing and revision were carried out by the coauthors. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, the U.S. Department of Veterans Affairs, or the United States Government. For a full list of contributors to SPRINT, please see the supplementary acknowledgement list: ClinicalTrials.gov Identifier: NCT01206062. We also acknowledge the support from the following CTSAs funded by NCATS: CWRU: UL1TR000439, OSU: UL1RR025755, U Penn: UL1RR024134 & UL1TR 000003, Boston: UL1RR025771, Stanford: UL1TR000093, Tufts: UL1RR025752, UL1TR000073 & UL1TR001064, University of Illinois: UL1TR000050, University of Pittsburgh: UL1TR000005, UT Southwestern: 9U54TR000017-06, University of Utah: UL1TR000105-05, Vanderbilt University: UL1 TR000445, George Washington University: UL1TR000075, University of CA, Davis: UL1 TR000002, University of Florida: UL1 TR000064, University of Michigan: UL1TR000433, Tulane University: P30GM103337 COBRE Award NIGMS. NR 46 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1743-6095 EI 1743-6109 J9 J SEX MED JI J. Sex. Med. PD SEP PY 2016 VL 13 IS 9 BP 1333 EP 1346 DI 10.1016/j.jsxm.2016.06.014 PG 14 WC Urology & Nephrology SC Urology & Nephrology GA DX9QL UT WOS:000384730100008 PM 27555505 ER PT J AU Serafine, KM Rice, KC France, CP AF Serafine, Katherine M. Rice, Kenner C. France, Charles P. TI Characterization of the discriminative stimulus effects of lorcaserin in rats SO JOURNAL OF THE EXPERIMENTAL ANALYSIS OF BEHAVIOR LA English DT Article DE serotonin receptor; lorcaserin; drug discrimination; lever press; rat ID 5-HT2C RECEPTOR AGONIST; PHARMACOLOGICAL CHARACTERIZATION; M-CHLOROPHENYLPIPERAZINE; DRUG DISCRIMINATION; COCAINE-SEEKING; IN-VITRO; BEHAVIOR; REINSTATEMENT; BINDING AB Lorcaserin is approved by the Food and Drug Administration for treating obesity and is under consideration for treating substance use disorders; it has agonist properties at serotonin (5-HT)(2C) receptors and might also have agonist properties at other 5-HT receptor subtypes. This study used drug discrimination to investigate the mechanism(s) of action of lorcaserin. Male Sprague-Dawley rats discriminated 0.56 mg/kg i.p. lorcaserin from saline while responding under a fixed-ratio 5 schedule for food. Lorcaserin (0.178-1.0 mg/kg) dose-dependently increased lorcaserin-lever responding. The 5-HT2C receptor agonist mCPP and the 5-HT2A receptor agonist DOM each occasioned greater than 90% lorcaserin-lever responding in seven of eight rats. The 5-HT1A receptor agonist 8-OH-DPAT occasioned greater than 90% lorcaserin-lever responding in four of seven rats. The 5-HT2C receptor selective antagonist SB 242084 attenuated lorcaserin-lever responding in all eight rats and the 5-HT2A receptor selective antagonist MDL 100907 attenuated lorcaserin-lever responding in six of seven rats. These results suggest that, in addition to agonist properties at 5-HT2C receptors, lorcaserin also has agonist properties at 5-HT2A and 5-HT1A receptors. Because some drugs with 5-HT2A receptor agonist properties are abused, it is important to fully characterize the behavioral effects of lorcaserin while considering its potential for treating substance use disorders. C1 [Serafine, Katherine M.; France, Charles P.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, 7703 Floyd Curl Dr,Mail Code 7764, San Antonio, TX 78229 USA. [France, Charles P.] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Rice, Kenner C.] NIDA, Drug Design & Synth Sect, Mol Targets & Medicat Discovery Branch, NIH, Bethesda, MD 20892 USA. [Rice, Kenner C.] NIAAA, NIH, Bethesda, MD USA. RP France, CP (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, 7703 Floyd Curl Dr,Mail Code 7764, San Antonio, TX 78229 USA. EM france@uthscsa.edu FU United States Public Health Service Grants from the National Institute on Drug Abuse, National Institutes of Health [T32DA031115, K05DA17918]; Welch Foundation [AQ-0039]; Intramural Research Programs of the National Institute on Drug Abuse; National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health FX This work was supported by United States Public Health Service Grants T32DA031115 and K05DA17918 (CPF) from the National Institute on Drug Abuse, National Institutes of Health and by the Welch Foundation Grant AQ-0039. A portion of this research was supported by the Intramural Research Programs of the National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Drug Abuse or the National Institutes of Health. The authors thank Elise Rush and Peter Weed for technical assistance. NR 22 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-5002 EI 1938-3711 J9 J EXP ANAL BEHAV JI J. Exp. Anal. Behav. PD SEP PY 2016 VL 106 IS 2 BP 107 EP 116 DI 10.1002/jeab.222 PG 10 WC Psychology, Biological; Behavioral Sciences; Psychology, Experimental SC Psychology; Behavioral Sciences GA DY0XC UT WOS:000384818500001 PM 27640338 ER PT J AU Ozel, AB McGee, B Siemieniak, D Jacobi, PM Haberichter, SL Brody, LC Mills, JL Molloy, AM Ginsburg, D Li, JZ Desch, KC AF Ozel, A. B. McGee, B. Siemieniak, D. Jacobi, P. M. Haberichter, S. L. Brody, L. C. Mills, J. L. Molloy, A. M. Ginsburg, D. Li, J. Z. Desch, K. C. TI Genome-wide studies of von Willebrand factor propeptide identify loci contributing to variation in propeptide levels and von Willebrand factor clearance SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Article DE genetic linkage analysis; genome-wide association study; venous thromboembolism; von Willebrand disease; von Willebrand factor ID PLASMA-LEVELS; FACTOR-VIII; GENOTYPE IMPUTATION; GENETIC-VARIANTS; LINKAGE ANALYSIS; VWF PROPEPTIDE; ABO LOCUS; ASSOCIATION; DISEASE; THROMBOSIS AB Background Previous studies identified common variants at the ABO and VWF loci and unknown variants in a chromosome 2q12 linkage interval that contributed to the variation in plasma von Willebrand factor (VWF) levels. Whereas the association with ABO haplotypes can be explained by differential VWF clearance, little is known about the mechanisms underlying the association with VWF single-nucleotide polymorphisms (SNPs) or with variants in the chromosome 2 linkage interval. VWF propeptide (VWFpp) and mature VWF are encoded by the VWF gene and secreted at the same rate, but have different plasma half-lives. Therefore, comparison of VWFpp and VWF association signals can be used to assess whether the variants are primarily affecting synthesis/secretion or clearance. Methods We measured plasma VWFpp levels and performed genome-wide linkage and association studies in 3238 young and healthy individuals for whom VWF levels had been analyzed previously. Results and conclusions Common variants in an intergenic region on chromosome 7q11 were associated with VWFpp levels. We found that ABO serotype-specific SNPs were associated with VWFpp levels in the same direction as for VWF, but with a much lower effect size. Neither the association at VWF nor the linkage on chromosome 2 previously reported for VWF was observed for VWFpp. Taken together, these results suggest that the major genetic factors affecting plasma VWF levels, i.e. variants at ABO, VWF and a locus on chromosome 2, operate primarily through their effects on VWF clearance. C1 [Ozel, A. B.; Ginsburg, D.; Li, J. Z.] Univ Michigan, Human Genet, Ann Arbor, MI 48109 USA. [McGee, B.; Siemieniak, D.; Ginsburg, D.] Univ Michigan, Howard Hughes Med Inst, Ann Arbor, MI 48109 USA. [Jacobi, P. M.; Haberichter, S. L.] Blood Ctr Wisconsin, Milwaukee, WI USA. [Brody, L. C.] NHGRI, NIH, Bethesda, MD 20892 USA. [Mills, J. L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Molloy, A. M.] Trinity Coll Dublin, Sch Med, Dublin, Ireland. [Ginsburg, D.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Ginsburg, D.; Desch, K. C.] Univ Michigan, Dept Pediat & Communicable Dis, Ann Arbor, MI 48109 USA. RP Desch, KC (reprint author), Univ Michigan, Inst Life Sci, Dept Pediat & Communicable Dis, Rm 5028,210 Washtenaw Ave, Ann Arbor, MI 48109 USA. EM kdesch@umich.edu FU National Institutes of Health [P01HL081588, R37HL039693, R01HL112642]; National Human Genome Research Institute; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX We would like to recognize the contributions of the participants of the GABC and the TSS to this study. This study was supported by grants from the National Institutes of Health (P01HL081588 to S. L. Haberichter; R37HL039693 to K. C. Desch, and D. Ginsburg; and R01HL112642 to D. Ginsburg, J. Z. Li, A. B. Ozel, and K. C. Desch). Additionally, D. Ginsburg is a Howard Hughes Medical Institute Investigator. The TSS was supported by the Intramural Research Programs of the National Human Genome Research Institute and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 52 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1538-7933 EI 1538-7836 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD SEP PY 2016 VL 14 IS 9 BP 1888 EP 1898 DI 10.1111/jth.13401 PG 11 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA DY0ZL UT WOS:000384824600027 PM 27359253 ER PT J AU Godbole, SV Nandy, K Gauniyal, M Nalawade, P Sane, S Koyande, S Toyama, J Hegde, A Virgo, P Bhatia, K Paranjape, RS Risbud, AR Mbulaiteye, SM Mitsuyasu, RT AF Godbole, Sheela V. Nandy, Karabi Gauniyal, Mansi Nalawade, Pallavi Sane, Suvarna Koyande, Shravani Toyama, Joy Hegde, Asha Virgo, Phil Bhatia, Kishor Paranjape, Ramesh S. Risbud, Arun R. Mbulaiteye, Sam M. Mitsuyasu, Ronald T. TI HIV and cancer registry linkage identifies a substantial burden of cancers in persons with HIV in India SO MEDICINE LA English DT Article DE AIDS-defining cancers; cancers; HIV; AIDS; India; non-AIDS-defining cancers; record-linkage ID SQUAMOUS-CELL CARCINOMA; RANDOMIZED CONTROLLED-TRIAL; UNITED-STATES; PAPILLOMAVIRUS INFECTION; KAPOSI-SARCOMA; AIDS; UGANDA; PEOPLE; CONJUNCTIVA; PREVALENCE AB We utilized computerized record-linkage methods to link HIV and cancer databases with limited unique identifiers in Pune, India, to determine feasibility of linkage and obtain preliminary estimates of cancer risk in persons living with HIV (PLHIV) as compared with the general population.Records of 32,575 PLHIV were linked to 31,754 Pune Cancer Registry records (1996-2008) using a probabilistic-matching algorithm. Cancer risk was estimated by calculating standardized incidence ratios (SIRs) in the early (4-27 months after HIV registration), late (28-60 months), and overall (4-60 months) incidence periods. Cancers diagnosed prior to or within 3 months of HIV registration were considered prevalent.Of 613 linked cancers to PLHIV, 188 were prevalent, 106 early incident, and 319 late incident. Incident cancers comprised 11.5% AIDS-defining cancers (ADCs), including cervical cancer and non-Hodgkin lymphoma (NHL), but not Kaposi sarcoma (KS), and 88.5% non-AIDS-defining cancers (NADCs). Risk for any incident cancer diagnosis in early, late, and combined periods was significantly elevated among PLHIV (SIRs: 5.6 [95% CI 4.6-6.8], 17.7 [95% CI 15.8-19.8], and 11.5 [95% CI 10-12.6], respectively). Cervical cancer risk was elevated in both incidence periods (SIRs: 9.6 [95% CI 4.8-17.2] and 22.6 [95% CI 14.3-33.9], respectively), while NHL risk was elevated only in the late incidence period (SIR: 18.0 [95% CI 9.8-30.20]). Risks for NADCs were dramatically elevated (SIR>100) for eye-orbit, substantially (SIR>20) for all-mouth, esophagus, breast, unspecified-leukemia, colon-rectum-anus, and other/unspecified cancers; moderately elevated (SIR>10) for salivary gland, penis, nasopharynx, and brain-nervous system, and mildly elevated (SIR>5) for stomach. Risks for 6 NADCs (small intestine, testis, lymphocytic leukemia, prostate, ovary, and melanoma) were not elevated and 5 cancers, including multiple myeloma not seen.Our study demonstrates the feasibility of using probabilistic record-linkage to study cancer/other comorbidities among PLHIV in India and provides preliminary population-based estimates of cancer risks in PLHIV in India. Our results, suggesting a potentially substantial burden and slightly different spectrum of cancers among PLHIV in India, support efforts to conduct multicenter linkage studies to obtain precise estimates and to monitor cancer risk in PLHIV in India. C1 [Godbole, Sheela V.; Gauniyal, Mansi; Nalawade, Pallavi; Sane, Suvarna; Paranjape, Ramesh S.; Risbud, Arun R.] Natl AIDS Res Inst ICMR, Pune, Maharashtra, India. [Nandy, Karabi] Univ Calif Los Angeles, Sch Nursing, Los Angeles, CA 90024 USA. [Nandy, Karabi] Univ Calif Los Angeles, Dept Biostat, Los Angeles, CA USA. [Koyande, Shravani] Indian Canc Soc, Mumbai Bombay Canc Registry, Bombay, Maharashtra, India. [Toyama, Joy] Univ Calif Los Angeles, Sch Publ Hlth, Dept Biostat, Los Angeles, CA 90024 USA. [Hegde, Asha] Maharashtra State AIDS Control Soc, Bombay, Maharashtra, India. [Virgo, Phil] Comp Serv Corp, Rockville, MD USA. [Bhatia, Kishor; Mbulaiteye, Sam M.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Mitsuyasu, Ronald T.] Univ Calif Los Angeles, David Geffen Sch Med, Ctr AIDS Res & Educ, Los Angeles, CA 90095 USA. RP Godbole, SV (reprint author), Natl AIDS Res Inst ICMR, MIDC Bhosari, 73,G Block, Pune 411026, Maharashtra, India. EM sgodbole@nariindia.org FU UCLA CFAR (NIH); ICMR; NCI FX The study was supported by a seed grant from UCLA CFAR (NIH), as well as intramural funds from ICMR and NCI. The sponsors had no role in the study design, data collection, data analysis, data interpretation, writing of the report, or the decision to submit the paper for publication. NR 40 TC 0 Z9 0 U1 4 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0025-7974 EI 1536-5964 J9 MEDICINE JI Medicine (Baltimore) PD SEP PY 2016 VL 95 IS 37 AR e4850 DI 10.1097/MD.0000000000004850 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA DX5ZO UT WOS:000384461600047 PM 27631245 ER PT J AU Zhan, CD Qi, RX Wei, GH Guven-Maiorov, E Nussinov, R Ma, BY AF Zhan, Chendi Qi, Ruxi Wei, Guanghong Guven-Maiorov, Emine Nussinov, Ruth Ma, Buyong TI Conformational dynamics of cancer-associated MyD88-TIR domain mutant L252P (L265P) allosterically tilts the landscape toward homo-dimerization SO PROTEIN ENGINEERING DESIGN & SELECTION LA English DT Article DE MyD88; TIR domain; TLR; inflammation; protein dynamics ID SOMATIC MUTATION; SWISS-MODEL; WALDENSTROMS MACROGLOBULINEMIA; TIR-DOMAIN; PROTEIN; BINDING; CELL; COMPLEXES; NETWORKS; PATHWAYS AB MyD88 is an essential adaptor protein, which mediates the signaling of the toll-like and interleukin-1 receptors' superfamily. The MyD88 L252P (L265P) mutation has been identified in diffuse large B-cell lymphoma. The identification of this mutation has been a major advance in the diagnosis of patients with aldenstrom macroglobulinemia and related lymphoid neoplasms. Here we used computational methods to characterize the conformational effects of the mutation. Our molecular dynamics simulations revealed that the mutation allosterically quenched the global conformational dynamics of the toll/IL-1R (TIR) domain, and readjusted its salt bridges and dynamic community network. Specifically, the mutation changed the orientation and reduced the fluctuation of a-helix 3, possibly through eliminating/weakening similar to 8 salt bridges and enhancing the salt bridge D225-K258. Using the energy landscape of the TIR domains of MyD88, we identified two dynamic conformational basins, which correspond to the binding sites used in homo- and hetero-oligomerization, respectively. Our results indicate that the mutation stabilizes the core of the homo-dimer interface of the MyD88-TIR domain, and increases the population of homo-dimer-compatible conformational states in MyD88 family proteins. However, the dampened motion restricts its ability to heterodimerize with other TIR domains, thereby curtailing physiological signaling. In conclusion, the L252P both shifts the landscape toward homo-dimerization and restrains the dynamics of the MyD88-TIR domain, which disfavors its hetero-dimerization with other TIR domains. We further put these observations within the framework of MyD88-mediated cell signaling. C1 [Zhan, Chendi; Qi, Ruxi; Wei, Guanghong] Fudan Univ, Dept Phys, State Key Lab Surface Phys, Key Lab Computat Phys Sci MOE, Shanghai, Peoples R China. [Guven-Maiorov, Emine; Nussinov, Ruth; Ma, Buyong] NCI, Basic Sci Program, Leidos Biomed Res Inc, Canc & Inflammat Program, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Inst Mol Med, Sackler Sch Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Wei, GH (reprint author), Fudan Univ, Dept Phys, State Key Lab Surface Phys, Key Lab Computat Phys Sci MOE, Shanghai, Peoples R China.; Ma, BY (reprint author), NCI, Basic Sci Program, Leidos Biomed Res Inc, Canc & Inflammat Program, Frederick, MD 21702 USA. EM ghwei@fudan.edu.cn; mabuyong@mail.nih.gov FU National Science Foundation of China [11274075]; MOST of China [2016YFA0501702]; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX G.W. acknowledges the financial support from the National Science Foundation of China (Grant No.: 11274075) and the MOST of China (Grant No.: 2016YFA0501702). R.N., E.G.-M. and B.M. thank the financial support from National Cancer Institute, National Institutes of Health, under contract number HHSN261200800001E. This research was supported (in part) by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. Simulations were performed at the NIH Biowulf supercomputer cluster. NR 42 TC 0 Z9 0 U1 5 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1741-0126 EI 1741-0134 J9 PROTEIN ENG DES SEL JI Protein Eng. Des. Sel. PD SEP PY 2016 VL 29 IS 9 SI SI BP 347 EP 354 DI 10.1093/protein/gzw033 PG 8 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA DX9LA UT WOS:000384715700002 PM 27503954 ER PT J AU Appel, CD Feld, GK Wallace, BD Williams, RS AF Appel, C. Denise Feld, Geoffrey K. Wallace, Bret D. Williams, R. Scott TI Structure of the sirtuin-linked macrodomain SAV0325 from Staphylococcus aureus SO PROTEIN SCIENCE LA English DT Article DE ADP-ribose; SauMacro; SAV0325; lipoate; ADP-ribosylation; macrodomain; adenosine diphosphate ribose; lipolyation; oxidative stress; Staphylococcus aureus; X-ray crystallography ID ADP-RIBOSYLATING TOXINS; DIPHTHERIA-TOXIN; PROTEIN; POLY(ADP-RIBOSE); DOMAIN; ELECTROSTATICS; IDENTIFICATION; RECOGNITION; MECHANISM; FEATURES AB Cells use the post-translational modification ADP-ribosylation to control a host of biological activities. In some pathogenic bacteria, an operon-encoded mono-ADP-ribosylation cycle mediates response to host-induced oxidative stress. In this system, reversible mono ADP-ribosylation of a lipoylated target protein represses oxidative stress response. An NAD(+)-dependent sirtuin catalyzes the single ADP-ribose (ADPr) addition, while a linked macrodomain-containing protein removes the ADPr. Here we report the crystal structure of the sitruin-linked macrodomain protein from Staphylococcus aureus, SauMacro (also known as SAV0325) to 1.75-angstrom resolution. The monomeric SauMacro bears a previously unidentified Zn2+-binding site that putatively aids in substrate recognition and catalysis. An amino-terminal three-helix bundle motif unique to this class of macrodomain proteins provides a structural scaffold for the Zn2+ site. Structural features of the enzyme further indicate a cleft proximal to the Zn2+ binding site appears well suited for ADPr binding, while a deep hydrophobic channel in the protein core is suitable for binding the lipoate of the lipoylated protein target. C1 [Appel, C. Denise; Feld, Geoffrey K.; Wallace, Bret D.; Williams, R. Scott] NIEHS, Genome Integr & Struct Biol Lab, US NIH, US Dept HHS, POB 12233, Res Triangle Pk, NC 27709 USA. RP Williams, RS (reprint author), NIEHS, Genome Integr & Struct Biol Lab, US NIH, US Dept HHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM williamsrs@niehs.nih.gov FU U. S. Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; US National Institute of Health Intramural Program: US National Institute of Environmental Health Sciences (NIEHS) [1Z01ES102765] FX C.D.A. expressed and purified recombinant SauMacro, as well as performed the trypsinolysis and crystallization. R.S.W. collected diffraction data and determined the SauMacro crystal structure; G.K.F., B.D.W. and R.S.W. refined and interpreted the structure and homology data. G.K.F., C.D.A, and R.S.W. wrote the manuscript. The authors thank A. Moon and S. Andres for comments and I. Ahel for the gift of the SauMacro expression vector. The authors declare no competing financial interest. We thank L. Pedersen of the NIEHS collaborative crystallography core for help with data collection, and M. Schellenberg for conducting fluorescence scans. Use of the Advanced Photon Source was supported by the U. S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. W-31-109-Eng-38. Our studies are supported by the US National Institute of Health Intramural Program: US National Institute of Environmental Health Sciences (NIEHS), 1Z01ES102765 (R.S.W.). NR 37 TC 1 Z9 1 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-8368 EI 1469-896X J9 PROTEIN SCI JI Protein Sci. PD SEP PY 2016 VL 25 IS 9 BP 1682 EP 1691 DI 10.1002/pro.2974 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DW4NE UT WOS:000383619100011 PM 27345688 ER PT J AU Ruszkowski, M Dauter, Z AF Ruszkowski, Milosz Dauter, Zbigniew TI On methylene-bridged cysteine and lysine residues in proteins SO PROTEIN SCIENCE LA English DT Article DE cysteine; lysine; crosslink; methylene bridge; intermolecular; intramolecular ID BIOSYNTHESIS; PLANTS; STEP AB Cysteine residues ubiquitously stabilize tertiary and quaternary protein structure by formation of disulfide bridges. Here we investigate another linking interaction that involves sulfhydryl groups of cysteines, namely intra- and intermolecular methylene-bridges between cysteine and lysine residues. A number of crystal structures possessing such a linkage were identified in the Protein Data Bank. Inspection of the electron density maps and re-refinement of the nominated structures unequivocally confirmed the presence of Lys-CH2-Cys bonds in several cases. C1 [Ruszkowski, Milosz; Dauter, Zbigniew] NCI, Synchrotron Radiat Res Sect, MCL, S Cass Ave 9700,Bldg 202,Rm Q-141, Argonne, IL 60439 USA. RP Ruszkowski, M (reprint author), NCI, Synchrotron Radiat Res Sect, MCL, S Cass Ave 9700,Bldg 202,Rm Q-141, Argonne, IL 60439 USA. EM mruszkowski@anl.gov FU Intramural Research Program of the NCI, Center for Cancer Research FX Grant sponsor: Intramural Research Program of the NCI, Center for Cancer Research. NR 8 TC 1 Z9 1 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-8368 EI 1469-896X J9 PROTEIN SCI JI Protein Sci. PD SEP PY 2016 VL 25 IS 9 BP 1734 EP 1736 DI 10.1002/pro.2958 PG 3 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DW4NE UT WOS:000383619100015 PM 27261771 ER PT J AU Malinska, M Dauter, M Dauter, Z AF Malinska, Maura Dauter, Miroslawa Dauter, Zbigniew TI Geometry of guanidinium groups in arginines SO PROTEIN SCIENCE LA English DT Article DE X-ray crystal structures; stereochemical restrains; structure validation; guanidinium geometry; arginine residues ID STRUCTURE REFINEMENT; PROTEIN AB The restraints in common usage today have been obtained based on small molecule X-ray crystal structures available 25 years ago and recent reports have shown that the values of bond lengths and valence angles can be, in fact, significantly different from those stored in libraries, for example for the peptide bond or the histidine ring geometry. We showed that almost 50% of outliers found in protein validation reports released in the Protein Data Bank on 23 March 2016 come from geometry of guanidine groups in arginines. Therefore, structures of small molecules and atomic resolution protein crystal structures have been used to derive new target values for the geometry of this group. The most significant difference was found for NE-CZ-NH1 and NE-CZ-NH2 angles, showing that the guanidinium group is not symmetric. The NE-CZ-NH1 angle is larger, 121.5(10), than NE-CZ-NH2, 119.2(10), due to the repulsive interaction between NH1 and CD1 atom. C1 [Malinska, Maura; Dauter, Zbigniew] Argonne Natl Lab, Synchrotron Radiat Res Sect, Macromol Crystallog Lab, Natl Canc Inst, 9700 S Cass Ave, Argonne, IL 60439 USA. [Malinska, Maura] Univ Warsaw, Fac Chem, PL-02093 Warsaw, Poland. [Dauter, Miroslawa] Argonne Natl Lab, Leidos Biomed Res Inc, Basic Sci Program, 9700 S Cass Ave, Argonne, IL 60439 USA. RP Dauter, Z (reprint author), Argonne Natl Lab, Synchrotron Radiat Res Sect, Macromol Crystallog Lab, Natl Canc Inst, 9700 S Cass Ave, Argonne, IL 60439 USA. EM dauter@anl.gov OI Malinska, Maura/0000-0002-7138-7041 FU Intramural Research Program of the National Cancer Institute, Center for Cancer Research; National Cancer Institute, National Institutes of Health [HHSN261200800E] FX Grant sponsor: Intramural Research Program of the National Cancer Institute, Center for Cancer Research and with Federal funds from the National Cancer Institute, National Institutes of Health; Grant number: HHSN261200800E. NR 13 TC 1 Z9 1 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-8368 EI 1469-896X J9 PROTEIN SCI JI Protein Sci. PD SEP PY 2016 VL 25 IS 9 BP 1753 EP 1756 DI 10.1002/pro.2970 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DW4NE UT WOS:000383619100018 PM 27326702 ER PT J AU Womack, VY De Chavez, PJ Albrecht, SS Durant, N Loucks, EB Puterman, E Redmond, N Siddique, J Williams, DR Carnethon, MR AF Womack, Veronica Y. De Chavez, Peter John Albrecht, Sandra S. Durant, Nefertiti Loucks, Eric B. Puterman, Eli Redmond, Nicole Siddique, Juned Williams, David R. Carnethon, Mercedes R. TI A Longitudinal Relationship Between Depressive Symptoms and Development of Metabolic Syndrome: The Coronary Artery Risk Development in Young Adults Study SO PSYCHOSOMATIC MEDICINE LA English DT Article DE depressive symptoms; metabolic syndrome; race; longitudinal ID NUTRITION EXAMINATION SURVEY; 3RD NATIONAL-HEALTH; TYPE-2 DIABETES-MELLITUS; INSULIN-RESISTANCE; MAJOR DEPRESSION; SEX-DIFFERENCES; OLDER-ADULTS; ASSOCIATION; CARDIA; WOMEN AB Objective Despite variability in the burden of elevated depressive symptoms by sex and race and differences in the incidence of metabolic syndrome, few prior studies describe the longitudinal association of depressive symptoms with metabolic syndrome in a diverse cohort. We tested whether baseline and time-varying depressive symptoms were associated with metabolic syndrome incidence in black and white men and women from the Coronary Artery Risk Development in Young Adults study. Methods Participants reported depressive symptoms using the Center for Epidemiologic Studies Depression Scale at four examinations between 1995 and 2010. At those same examinations, metabolic syndrome was determined. Cox proportional hazards models were used to examine the associations of depressive symptoms on the development of metabolic syndrome in 3208 participants without metabolic syndrome at baseline. Results For 15 years, the incidence rate of metabolic syndrome (per 10,000 person-years) varied by race and sex, with the highest rate in black women (279.2), followed by white men (241.9), black men (204.4), and white women (125.3). Depressive symptoms (per standard deviation higher) were associated with incident metabolic syndrome in white men (hazard ratio = 1.25, 95% confidence interval = 1.08-1.45) and white women (hazard ratio = 1.17, 95% confidence interval = 1.00-1.37) after adjustment for demographic characteristics and health behaviors. There was no significant association between depression and metabolic syndrome among black men or black women. Conclusions Higher depressive symptoms contribute modestly to the onset of metabolic syndrome among white adults. C1 [Womack, Veronica Y.] Northwestern Univ, Feinberg Sch Med, Div Fac Affairs, Chicago, IL 60611 USA. [De Chavez, Peter John; Siddique, Juned; Carnethon, Mercedes R.] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, 680 N Lake Shore Dr,Suite 1400, Chicago, IL 60611 USA. [Albrecht, Sandra S.] Univ North Carolina Chapel Hill, Gillings Sch Publ Hlth, Dept Nutr, Chapel Hill, NC USA. [Durant, Nefertiti] Univ Alabama Birmingham, Sch Med, Dept Pediat, Birmingham, AL USA. [Loucks, Eric B.] Brown Univ, Sch Publ Hlth, Dept Epidemiol, Providence, RI 02912 USA. [Puterman, Eli] Univ Calif San Francisco, Sch Med, Dept Psychiat, San Francisco, CA USA. [Redmond, Nicole] NIH, Div Prevent Med, Bldg 10, Bethesda, MD 20892 USA. [Williams, David R.] Harvard Univ, Sch Publ Hlth, NHLBI, 665 Huntington Ave, Boston, MA 02115 USA. [Redmond, Nicole] Univ Alabama Birmingham, Birmingham, AL USA. RP Carnethon, MR (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, 680 N Lake Shore Dr,Suite 1400, Chicago, IL 60611 USA. EM carnethon@northwestern.edu FU National Heart, Lung, and Blood Institute [T32-HL-069771-07, HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, HHSN268200900041C]; Intramural Research Program of the National Institute on Aging; National Institute on Aging and the National Heart, Lung, and Blood Institute [AG0005] FX This research was supported by Grant T32-HL-069771-07 from the National Heart, Lung, and Blood Institute. The Coronary Artery Risk Development in Young Adults study is supported by contracts HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, and HHSN268200900041C from the National Heart, Lung, and Blood Institute, the Intramural Research Program of the National Institute on Aging, and an intra-agency agreement between the National Institute on Aging and the National Heart, Lung, and Blood Institute (AG0005). A portion of this manuscript was presented at the American Heart Association Epidemiology and Prevention/Nutrition, Physical Activity and Metabolism 2013 Scientific Sessions. The authors have no conflicts of interest to disclose. NR 48 TC 0 Z9 0 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0033-3174 EI 1534-7796 J9 PSYCHOSOM MED JI Psychosom. Med. PD SEP PY 2016 VL 78 IS 7 BP 867 EP 873 DI 10.1097/PSY.0000000000000347 PG 7 WC Psychiatry; Psychology; Psychology, Multidisciplinary SC Psychiatry; Psychology GA DW9RK UT WOS:000383999400012 PM 27490849 ER PT J AU Hutchinson, EB Schwerin, SC Radomski, KL Irfanoglu, MO Juliano, SL Pierpaoli, CM AF Hutchinson, Elizabeth B. Schwerin, Susan C. Radomski, Kryslaine L. Irfanoglu, Mustafa O. Juliano, Sharon L. Pierpaoli, Carlo M. TI QUANTITATIVE MRI AND DTI ABNORMALITIES DURING THE ACUTE PERIOD FOLLOWING CCI IN THE FERRET SO SHOCK LA English DT Article DE Anisotropy; diffusion tensor imaging; microgliosis; T2 relaxometry; traumatic axonal injury ID TRAUMATIC BRAIN-INJURY; COMMON DATA ELEMENTS; WHITE-MATTER INJURY; AXONAL INJURY; DIFFEOMORPHIC REGISTRATION; MOUSE MODEL; DIFFUSION; RAT AB During the acute time period following traumatic brain injury (TBI), noninvasive brain imaging tools such as magnetic resonance imaging (MRI) can provide important information about the clinical and pathological features of the injury and may help predict long-term outcomes. In addition to standard imaging approaches, several quantitative MRI techniques including relaxometry and diffusion MRI have been identified as promising reporters of cellular alterations after TBI and may provide greater sensitivity and specificity for identifying brain abnormalities especially in mild TBI. However, for these imaging tools to be useful, it is crucial to define their relationship with the neurophysiological response to brain injury. Recently, a model of controlled cortical impact (CCI) has been developed in the ferret which has many advantages compared with rodent models (e.g., gyrencephalic cortex and high white matter volume). The objective of this study was to evaluate quantitative MRI metrics in the ferret CCI model, including T2 values and diffusion tensor imaging (DTI) metrics, during the acute time period. Longitudinal quantitative comparisons of in vivo MRI and DTI metrics were evaluated to identify abnormalities and characterize their spatial patterns in the ferret brain. Ex vivo MRI and DTI maps were then compared with histological staining for glial and neuronal abnormalities. The main findings of this article describe T2, diffusivity, and anisotropy markers of tissue change during the acute time period following mild TBI, and ex vivo analyses suggest that MRI and DTI markers are sensitive to subtle cellular alterations in this model. This was confirmed by comparison with immunohistochemistry, also showing altered markers in regions of MRI and DTI change. C1 [Hutchinson, Elizabeth B.; Irfanoglu, Mustafa O.; Pierpaoli, Carlo M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bldg 13,Room 3W16,13 South Dr, Bethesda, MD 20892 USA. [Schwerin, Susan C.; Radomski, Kryslaine L.; Juliano, Sharon L.] Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, Bethesda, MD 20814 USA. [Hutchinson, Elizabeth B.; Schwerin, Susan C.; Radomski, Kryslaine L.; Irfanoglu, Mustafa O.] Henry M Jackson Fdn Adv Mil Med Inc, Bethesda, MD USA. RP Hutchinson, EB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bldg 13,Room 3W16,13 South Dr, Bethesda, MD 20892 USA. EM elizabeth.hutchinson@nih.gov OI Schwerin, Susan/0000-0001-5435-2448; Radomski, Kryslaine/0000-0001-9624-623X NR 23 TC 1 Z9 1 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1073-2322 EI 1540-0514 J9 SHOCK JI Shock PD SEP PY 2016 VL 46 IS 3 SU 1 BP 167 EP 176 DI 10.1097/SHK.0000000000000659 PG 10 WC Critical Care Medicine; Hematology; Surgery; Peripheral Vascular Disease SC General & Internal Medicine; Hematology; Surgery; Cardiovascular System & Cardiology GA DX3HG UT WOS:000384263600024 PM 27294688 ER PT J AU Martin, RH Yeatts, SD Hill, MD Moy, CS Ginsberg, MD Palesch, YY AF Martin, Renee' H. Yeatts, Sharon D. Hill, Michael D. Moy, Claudia S. Ginsberg, Myron D. Palesch, Yuko Y. TI ALIAS (Albumin in Acute Ischemic Stroke) Trials Analysis of the Combined Data From Parts 1 and 2 SO STROKE LA English DT Article DE acute stroke; albumin; randomized trial; risk; serum albumin ID MARKED NEUROPROTECTIVE EFFICACY; MULTICENTER CLINICAL-TRIAL; THERAPY; DESIGN; SAFETY AB Background and Purpose The ALIAS (Albumin in Acute Ischemic Stroke) part 1 and 2 trials evaluated whether 25% human serum albumin improves clinical outcomes after acute ischemic stroke above and beyond standard of care using similar protocols. The part 1 trial ended prematurely because of safety concerns, and the part 2 trial terminated early because of futility of finding a statistically significant effect of albumin over saline (control) administration. We combine the subject-level data of the part 1 and 2 trials to reevaluate the efficacy and safety outcomes with the larger sample size. Methods The combined data analyses closely follow those conducted in the part 2 trial. The primary outcome is the composite of the modified Rankin Scale and the National Institutes of Health Stroke Scale defined as a composite of modified Rankin Scale score 0 to 1 and National Institutes of Health Stroke Scale score 0 to 1 at 90 days from randomization. The unadjusted analyses use a simple Chi-square test, and those adjusting for baseline covariates use a generalized linear model with log link (to obtain relative risks). Results The participant characteristics at baseline were generally similar between the treatment groups and between the trials; however, thrombolysis use was greater in part 2 (84% versus 75%), and the upper age limit imposed in part 2 resulted in a younger sample (mean age in part 1 was 69 versus 64 in part 2). In the combined sample, the proportions of good outcome in the 2 treatment groups were identical (41%). Similar results were observed in all secondary efficacy outcomes. Pulmonary edema was a consistent safety concern, with a 6-fold increase in the albumin arm (13%) compared with saline (2%; relative risk =7.76, 95% confidence interval 3.87-15.57). Conclusions Treatment with intravenous albumin 25% at 2 g/kg was not associated with improved outcome at 90 days and was associated with increased rates of intracerebral hemorrhage and pulmonary edema. C1 [Martin, Renee' H.; Yeatts, Sharon D.; Palesch, Yuko Y.] Med Univ South Carolina, Dept Publ Hlth Sci, 135 Cannon St,Ste 305, Charleston, SC 29425 USA. [Hill, Michael D.] Univ Calgary, Dept Clin Neurosci Med Radiol & Community Hlth Sc, Hotchkiss Brain Inst, Calgary Stroke Program,Cumming Sch Med, Calgary, AB T2N 1N4, Canada. [Moy, Claudia S.] NINDS, Off Clin Res, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Ginsberg, Myron D.] Univ Miami, Miller Sch Med, Dept Neurol, Coral Gables, FL 33124 USA. RP Martin, RH (reprint author), Med Univ South Carolina, Dept Publ Hlth Sci, 135 Cannon St,Ste 305, Charleston, SC 29425 USA. EM hebertrl@musc.edu FU National Institute of Neurological Disorders and Stroke, National Institutes of Health (National Institute of Neurological Disorders and Stroke [NINDS] [University of Miami]) [U01NS040406]; National Institute of Neurological Disorders and Stroke, National Institutes of Health (National Institute of Neurological Disorders and Stroke [NINDS] [Medical University of South Carolina]) [U01NS054630]; National Institute of Neurological Disorders and Stroke, National Institutes of Health (National Institute of Neurological Disorders and Stroke [NINDS] [University of Michigan]) [U01NS056975] FX Supported by cooperative agreements from the National Institute of Neurological Disorders and Stroke, National Institutes of Health (National Institute of Neurological Disorders and Stroke [NINDS] grants U01NS040406 [University of Miami]; U01NS054630 [Medical University of South Carolina]; and U01NS056975 [University of Michigan]). NR 13 TC 0 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD SEP PY 2016 VL 47 IS 9 BP 2355 EP 2359 DI 10.1161/STROKEAHA.116.012825 PG 5 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA DW3RD UT WOS:000383559300041 PM 27462118 ER PT J AU Simpkins, AN Dias, C Leigh, R AF Simpkins, Alexis N. Dias, Christian Leigh, Richard CA Natl Inst Hlth Nat Hist Stroke TI Identification of Reversible Disruption of the Human Blood-Brain Barrier Following Acute Ischemia SO STROKE LA English DT Article DE acute stroke; blood-brain barrier; hemorrhagic transformation; magnetic resonance imaging; permeability imaging ID STROKE AB Background and Purpose Animal models of acute cerebral ischemia have demonstrated that diffuse blood-brain barrier (BBB) disruption can be reversible after early reperfusion. However, irreversible, focal BBB disruption in humans is associated with hemorrhagic transformation in patients receiving intravenous thrombolytic therapy. The goal of this study was to use a magnetic resonance imaging biomarker of BBB permeability to differentiate these 2 forms of BBB disruption. Methods Acute stroke patients imaged with magnetic resonance imaging before, 2 hours after, and 24 hours after treatment with intravenous tissue-type plasminogen activator were included. The average BBB permeability of the acute ischemic region before and 2 hours after treatment was calculated using a T2* perfusion-weighted source images. Change in average permeability was compared with percent reperfusion using linear regression. Focal regions of maximal BBB permeability from the pretreatment magnetic resonance imaging were compared with the occurrence of parenchymal hematoma (PH) formation on the 24-hour magnetic resonance imaging scan using logistic regression. Results Signals indicating reversible BBB permeability were detected in 18/36 patients. Change in average BBB permeability correlated inversely with percent reperfusion (P=0.006), indicating that early reperfusion is associated with decreased BBB permeability, whereas sustained ischemia is associated with increased BBB disruption. Focal regions of maximal BBB permeability were significantly associated with subsequent formation of PH (P=0.013). Conclusions This study demonstrates that diffuse, mild BBB disruption in the acutely ischemic human brain is reversible with reperfusion. This study also confirms prior findings that focal severe BBB disruption confers an increased risk of hemorrhagic transformation in patients treated with intravenous tissue-type plasminogen activator. C1 [Simpkins, Alexis N.; Dias, Christian; Leigh, Richard; Natl Inst Hlth Nat Hist Stroke] NINDS, Neuro Vasc Brain Imaging Unit, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Leigh, R (reprint author), Bldg 10,B1D733 MSC 1063,10 Ctr Dr, Bethesda, MD 20892 USA. EM richard.leigh@nih.gov FU Intramural Program of the National Institutes of Health (NIH); National Institute of Neurological Disorders and Stroke (NINDS) FX All the authors are supported by the Intramural Program of the National Institutes of Health (NIH) and National Institute of Neurological Disorders and Stroke (NINDS). NR 8 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD SEP PY 2016 VL 47 IS 9 BP 2405 EP 2408 DI 10.1161/STROKEAHA.116.013805 PG 4 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA DW3RD UT WOS:000383559300049 PM 27462115 ER PT J AU Mihalek, AD Haney, C Merino, M Roy-Chowdhuri, S Moss, J Olivier, KN AF Mihalek, Andrew D. Haney, Carissa Merino, Maria Roy-Chowdhuri, Sinchita Moss, Joel Olivier, Kenneth N. TI Exercise-induced haemoptysis as a rare presentation of a rare lung disease SO THORAX LA English DT Editorial Material DE Imaging; CT MRI etc; Rare lung diseases; Interstitial Fibrosis ID PULMONARY AB Amyloid primarily affecting the lungs is a seldom seen clinical entity. This case discusses the work-up of a patient presenting with exercise-induced haemoptysis and diffuse cystic lung disease on radiographic imaging. The common clinical and radiographic findings of diffuse cystic lung diseases as well as a brief overview of pulmonary amyloid are presented. C1 [Mihalek, Andrew D.; Moss, Joel; Olivier, Kenneth N.] NHLBI, Cardiovasc & Pulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Mihalek, Andrew D.] Univ Virginia, Dept Med, Div Pulm & Crit Care Med, Charlottesville, VA USA. [Mihalek, Andrew D.] Lovelace Resp Res Inst, Albuquerque, NM USA. [Haney, Carissa; Olivier, Kenneth N.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Merino, Maria; Roy-Chowdhuri, Sinchita] NCI, Dept Pathol, NIH, Bethesda, MD 20892 USA. [Roy-Chowdhuri, Sinchita] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. RP Olivier, KN (reprint author), NHLBI, Cardiovasc & Pulm Branch, 10 Ctr Dr,MSC 1454,Bldg 10-CRC,Rm 3130, Bethesda, MD 20892 USA. EM olivierk@nhlbi.nih.gov FU Intramural Research Program, National Institutes of Health, National Heart, Lung, and Blood Institute and National Institute of Allergy and Infectious Diseases FX Supported in part by the Intramural Research Program, National Institutes of Health, National Heart, Lung, and Blood Institute and National Institute of Allergy and Infectious Diseases. NR 14 TC 0 Z9 0 U1 1 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0040-6376 EI 1468-3296 J9 THORAX JI Thorax PD SEP PY 2016 VL 71 IS 9 BP 865 EP 868 DI 10.1136/thoraxjnl-2015-208020 PG 4 WC Respiratory System SC Respiratory System GA DW3ME UT WOS:000383544900015 PM 27272655 ER PT J AU Appakalai, BN Ricordi, C Goldstein, JS AF Appakalai, B. N. Ricordi, C. Goldstein, J. S. CA M CMC Comm TI Clinical Islet Transplantation Consortium (CIT) Multicenter Analysis of Pancreas Donor Factors Affecting Human Islet Isolation Success SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 22-25, 2016 CL Orlando, FL SP AABB C1 [Appakalai, B. N.] Univ Louisville, Dept Surg, Louisville, KY 40292 USA. [Ricordi, C.] Univ Miami, Miami, FL USA. [Goldstein, J. S.; M CMC Comm] NIH, Washington, DC 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 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2016 VL 56 SU 4 SI SI MA S3-010A BP 6A EP 6A PG 1 WC Hematology SC Hematology GA DX8NS UT WOS:000384646400010 ER PT J AU Reems, J Jacobson, P Fisher, S Ma, Y Jin, P Stroncek, D Pierce, J AF Reems, J. Jacobson, P. Fisher, S. Ma, Y. Jin, P. Stroncek, D. Pierce, J. TI Comparative Analyses of Industrial Scale Human Platelet Lysate (PL) Preparations SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 22-25, 2016 CL Orlando, FL SP AABB C1 [Reems, J.; Jacobson, P.; Pierce, J.] Univ Utah, Cell Therapy Facil, Salt Lake City, UT USA. [Fisher, S.; Ma, Y.] Arteriocyte, Cleveland, OH USA. [Jin, P.; Stroncek, D.] NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2016 VL 56 SU 4 SI SI MA S5-010A BP 7A EP 7A PG 1 WC Hematology SC Hematology GA DX8NS UT WOS:000384646400012 ER PT J AU Eder, AF Yau, Y West, K AF Eder, A. F. Yau, Y. West, K. TI The Effect of Iron Replacement on Platelet Counts in Blood Donors SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 22-25, 2016 CL Orlando, FL SP AABB C1 [Eder, A. F.; Yau, Y.; West, K.] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. [Eder, A. F.] Georgetown Univ, Sch Med, Washington, DC 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 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2016 VL 56 SU 4 SI SI MA S8-010B BP 8A EP 8A PG 1 WC Hematology SC Hematology GA DX8NS UT WOS:000384646400015 ER PT J AU Williams, JD Ritter, JL Williamson, P Leparc, G Caglioti, S Spizman, R Stewart, A Botti, T DiAnni, J Cascaddan, R Williams, RC AF Williams, J. Dunn Ritter, J. L. Williamson, P. Leparc, G. Caglioti, S. Spizman, R. Stewart, A. Botti, T. DiAnni, J. Cascaddan, R. Williams, R. C. TI A Comparative Study of Plasma Protein Levels within Source Plasma Donors SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 22-25, 2016 CL Orlando, FL SP AABB C1 [Williams, J. Dunn; Ritter, J. L.; Williamson, P.; Leparc, G.; Caglioti, S.; Spizman, R.] Creat Testing Solut, Tempe, AZ USA. [Leparc, G.] OneBlood Inc, St Petersburg, FL USA. [Stewart, A.; Botti, T.; DiAnni, J.; Cascaddan, R.] Octapharma Plasma Inc, Charlotte, NC USA. [Williams, R. C.] NIDDK, NIH, Phoenix Epidemiol & Clin Res Branch, Phoenix, AZ 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 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2016 VL 56 SU 4 SI SI MA S12-010B BP 10A EP 10A PG 1 WC Hematology SC Hematology GA DX8NS UT WOS:000384646400019 ER PT J AU Montemayor-Garcia, C Coward, RP Albitar, M Battiwalla, M Keel, S Klein, HG Barrett, AJ Ito, S AF Montemayor-Garcia, C. Coward, R. P. Albitar, M. Battiwalla, M. Keel, S. Klein, H. G. Barrett, A. J. Ito, S. TI Mixed-Field Agglutination in RhD Typing as a Marker of Fibrotic Transformation in Thrombopoietin Receptor-Mutated Essential Thrombocythemia SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 22-25, 2016 CL Orlando, FL SP AABB C1 [Montemayor-Garcia, C.; Coward, R. P.; Klein, H. G.] NIH, Dept Transfus Med, North Bethesda, MD USA. [Albitar, M.] Neogen Labs, Res & Dev, Irvine, CA USA. [Battiwalla, M.; Barrett, A. J.; Ito, S.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Keel, S.] Univ Washington, Div Hematol, Seattle, WA 98195 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 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2016 VL 56 SU 4 SI SI MA S34-020C BP 18A EP 18A PG 1 WC Hematology SC Hematology GA DX8NS UT WOS:000384646400041 ER PT J AU Srivastava, K Polin, H Wagner, FF Grabmer, C Gabriel, C Flegel, WA AF Srivastava, K. Polin, H. Wagner, F. F. Grabmer, C. Gabriel, C. Flegel, W. A. TI The DAU Cluster: A Comparative Analysis of 18 RHD Alleles SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 22-25, 2016 CL Orlando, FL SP AABB C1 [Srivastava, K.; Flegel, W. A.] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. [Polin, H.; Gabriel, C.] Red Cross Transfus Serv Upper Austria, Linz, Austria. [Wagner, F. F.] Inst Springe, Red Cross Blood Serv NSTOB, Springe, Germany. [Grabmer, C.] SALK Paracelsus Med Univ, Dept Blood Grp Serol & Transfus Med, Salzburg, Austria. 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 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2016 VL 56 SU 4 SI SI MA S33-020C BP 18A EP 18A PG 1 WC Hematology SC Hematology GA DX8NS UT WOS:000384646400040 ER PT J AU Montemayor-Garcia, C Karagianni, P Reese, EM Klein, HG Miller, JL AF Montemayor-Garcia, C. Karagianni, P. Reese, E. M. Klein, H. G. Miller, J. L. TI Blood Group Alleles in the Population: Lessons from the Thousand Genomes Project SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 22-25, 2016 CL Orlando, FL SP AABB C1 [Montemayor-Garcia, C.; Reese, E. M.; Klein, H. G.] NIH, Dept Transfus Med, North Bethesda, MD USA. [Karagianni, P.] BSRC Alexander Fleming, Vari, Greece. [Miller, J. L.] NIDDK, Mol Med Branch, 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 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2016 VL 56 SU 4 SI SI MA S36-020C BP 19A EP 19A PG 1 WC Hematology SC Hematology GA DX8NS UT WOS:000384646400043 ER PT J AU Allen, ES Hsieh, MM Fitzhugh, CD Klein, HG Tisdale, JF Flegel, WA AF Allen, E. S. Hsieh, M. M. Fitzhugh, C. D. Klein, H. G. Tisdale, J. F. Flegel, W. A. TI Red Cell Antibodies in Patients with Sickle Cell Disease Undergoing Hematopoietic Progenitor Cell Transplantation SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 22-25, 2016 CL Orlando, FL SP AABB C1 [Allen, E. S.; Klein, H. G.; Flegel, W. A.] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. [Hsieh, M. M.; Fitzhugh, C. D.; Tisdale, J. F.] NHLBI, 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 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2016 VL 56 SU 4 SI SI MA S60-030H BP 27A EP 28A PG 2 WC Hematology SC Hematology GA DX8NS UT WOS:000384646400067 ER PT J AU Puch, IC Suffredini, DA Xu, W Sun, J West, K Barea-Mendoza, J Solomon, S Natanson, C Klein, HG AF Puch, I. Cortes Suffredini, D. A. Xu, W. Sun, J. West, K. Barea-Mendoza, J. Solomon, S. Natanson, C. Klein, H. G. TI Increases in Temperature within the Recommended Range Increase in vitro Hemolysis of Canine Red Blood Cells over 42 Days of Storage: A Pilot Study SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 22-25, 2016 CL Orlando, FL SP AABB C1 [Puch, I. Cortes; Suffredini, D. A.; Xu, W.; Sun, J.; Barea-Mendoza, J.; Solomon, S.; Natanson, C.] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. [West, K.; Klein, H. G.] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. [Barea-Mendoza, J.] Hosp Univ 12 Octubre, Dept Crit Care Med, Madrid, Spain. 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 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2016 VL 56 SU 4 SI SI MA SP37 BP 55A EP 56A PG 2 WC Hematology SC Hematology GA DX8NS UT WOS:000384646400140 ER PT J AU Donahue, RE Metzger, ME Leitman, SF Cullis, HM AF Donahue, R. E. Metzger, M. E. Leitman, S. F. Cullis, H. M. TI Caloric Loss Associated with Apheresis SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 22-25, 2016 CL Orlando, FL SP AABB C1 [Donahue, R. E.; Metzger, M. E.] NHLBI, Hematol Branch, Bldg 10, Bethesda, MD 20892 USA. [Leitman, S. F.] NIH, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2016 VL 56 SU 4 SI SI MA SP104 BP 80A EP 81A PG 2 WC Hematology SC Hematology GA DX8NS UT WOS:000384646400207 ER PT J AU Donahue, RE Metzger, ME Bonifacino, AC Leitman, SF Cullis, HM Lienesch, M Parker, DM AF Donahue, R. E. Metzger, M. E. Bonifacino, A. C. Leitman, S. F. Cullis, H. M. Lienesch, M. Parker, D. M. TI Optimization of the Spectra Optia for Apheresis of Very Small Subjects SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 22-25, 2016 CL Orlando, FL SP AABB C1 [Donahue, R. E.; Metzger, M. E.; Bonifacino, A. C.] NHLBI, Hematol Branch, Bethesda, MD 20892 USA. [Leitman, S. F.] NIH, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Lienesch, M.; Parker, D. M.] Terumo BCT Inc, Lakewood, CO 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 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2016 VL 56 SU 4 SI SI MA SP116 BP 84A EP 84A PG 1 WC Hematology SC Hematology GA DX8NS UT WOS:000384646400219 ER PT J AU Levy, KY Barracchini, KC Adams, SD Flegel, WA AF Levy, K. Y. Barracchini, K. C. Adams, S. D. Flegel, W. A. TI Evaluation of 2 New Reverse Sequence-Specific Oligonucleotide Assays for Human Leukocyte Antigen Typing SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 22-25, 2016 CL Orlando, FL SP AABB C1 [Levy, K. Y.; Barracchini, K. C.; Adams, S. D.; Flegel, W. A.] NIH, Dept Transfus Med, Ctr Clin, 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 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2016 VL 56 SU 4 SI SI MA SP213 BP 119A EP 120A PG 2 WC Hematology SC Hematology GA DX8NS UT WOS:000384646400317 ER PT J AU Montemayor-Garcia, C West, K Klein, HG AF Montemayor-Garcia, C. West, K. Klein, H. G. TI Platelet Transfusion Refractoriness and Delayed Platelet Recovery Associated with Anti-HPA-1b Alloantibodies in Nonmyeloablative Hematopoietic Progenitor Cell Transplantation SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 22-25, 2016 CL Orlando, FL SP AABB C1 [Montemayor-Garcia, C.; West, K.; Klein, H. G.] NIH, Dept Transfus Med, North Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2016 VL 56 SU 4 SI SI MA SP345 BP 162A EP 163A PG 2 WC Hematology SC Hematology GA DX8NS UT WOS:000384646400449 ER PT J AU Suffredini, DA Puch, IC Sun, J Solomon, S Natanson, C Klein, HG AF Suffredini, D. A. Puch, I. Cortes Sun, J. Solomon, S. Natanson, C. Klein, H. G. TI A Pilot Study Comparing Mortality of Intravenous Iron Therapy versus Fresh and Older RBCs in a Septic Canine Model SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 22-25, 2016 CL Orlando, FL SP AABB C1 [Suffredini, D. A.; Puch, I. Cortes; Sun, J.; Solomon, S.; Natanson, C.] NIH, Crit Care Med, Bldg 10, Bethesda, MD 20892 USA. [Klein, H. G.] NIH, Dept Transfus Med, 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 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2016 VL 56 SU 4 SI SI MA SP349 BP 164A EP 164A PG 1 WC Hematology SC Hematology GA DX8NS UT WOS:000384646400453 ER PT J AU Williams, LA Kennell, T Siniard, RC Feldman, AZ Staley, EM Pham, HP AF Williams, L. A., III Kennell, T. Siniard, R. C. Feldman, A. Z. Staley, E. M. Pham, H. P. TI Fetomaternal Hemorrhage (FMH) and Rh Immunoglobulin (RhIG) Dosage: A Novel Consideration from a Mathematical Modeling Perspective SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 22-25, 2016 CL Orlando, FL SP AABB C1 [Williams, L. A., III; Siniard, R. C.; Feldman, A. Z.; Staley, E. M.; Pham, H. P.] Univ Alabama Birmingham, Pathol, Birmingham, AL USA. [Kennell, T.] Univ Alabama Birmingham, NIH Med Scientist Training Program, Birmingham, AL 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 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2016 VL 56 SU 4 SI SI MA SP390 BP 180A EP 180A PG 1 WC Hematology SC Hematology GA DX8NS UT WOS:000384646400494 ER PT J AU Williams, JD Williamson, P Leparc, G Haubert, N Phillips, M Caglioti, S Spizman, R Stewart, A Botti, T DiAnni, J Cascaddan, R Williams, RC AF Williams, J. Dunn Williamson, P. Leparc, G. Haubert, N. Phillips, M. Caglioti, S. Spizman, R. Stewart, A. Botti, T. DiAnni, J. Cascaddan, R. Williams, R. C. TI Prevalence of Infectious Disease Markers (IDMs) in Source Plasma and Whole-Blood Donations SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 22-25, 2016 CL Orlando, FL SP AABB C1 [Williams, J. Dunn; Williamson, P.; Leparc, G.; Haubert, N.; Phillips, M.; Caglioti, S.; Spizman, R.] Creat Testing Solut, Tempe, AZ USA. [Leparc, G.] OneBlood Inc, St Petersburg, FL USA. [Stewart, A.; Botti, T.; DiAnni, J.; Cascaddan, R.] Octapharma Plasma Inc, Charlotte, NC USA. [Williams, R. C.] NIDDK, NIH, Phoenix Epidemiol & Clin Res Branch, Phoenix, AZ 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 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2016 VL 56 SU 4 SI SI MA SP427 BP 192A EP 192A PG 1 WC Hematology SC Hematology GA DX8NS UT WOS:000384646400531 ER PT J AU Semba, RD Trehan, I Gonzalez-Freire, M Kraemer, K Moaddel, R Ordiz, MI Ferrucci, L Manary, MJ AF Semba, Richard D. Trehan, Indi Gonzalez-Freire, Marta Kraemer, Klaus Moaddel, Ruin Ordiz, M. Isabel Ferrucci, Luigi Manary, Mark J. TI Perspective: The Potential Role of Essential Amino Acids and the Mechanistic Target of Rapamycin Complex 1 (mTORC1) Pathway in the Pathogenesis of Child Stunting SO ADVANCES IN NUTRITION LA English DT Article DE amino acids; children; diet; food; growth; mTORC1; proteins; stunting ID GOBLET CELL-DIFFERENTIATION; RANDOMIZED CONTROLLED-TRIAL; NOVO PYRIMIDINE SYNTHESIS; MIDDLE-INCOME COUNTRIES; TRANSFER-RNA SYNTHETASE; P70 S6 KINASE; MAMMALIAN TARGET; SKELETAL-MUSCLE; PROTEIN-SYNTHESIS; GROWING-RATS AB Stunting is the best summary measure of chronic malnutrition in children. Approximately one-quarter of children under age 5 worldwide are stunted. Lipid-based or micronutrient supplementation has little to no impact in reducing stunting, which suggests that other critical dietary nutrients are missing. A dietary pattern of poor-quality protein is associated with stunting. Stunted children have significantly lower circulating essential amino acids than do nonstunted children. Inadequate dietary intakes of essential amino acids could adversely affect growth, because amino acids are required for synthesis of proteins. The master growth regulation pathway, the mechanistic target of rapamycin complex 1 (mTORC1) pathway, is exquisitely sensitive to amino acid availability. mTORC1 integrates cues such as nutrients, growth factors, oxygen, and energy to regulate growth of bone, skeletal muscle, nervous system, gastrointestinal tract, hematopoietic cells, immune effector cells, organ size, and whole-body energy balance. mTORC1 represses protein and lipid synthesis and cell and organismal growth when amino acids are deficient. Over the past 4 decades, the main paradigm for child nutrition in developing countries has been micronutrient malnutrition, with relatively less attention paid to protein. In this Perspective, we present the view that essential amino acids and the mTORC1 pathway play a key role in child growth. The current assumption that total dietary protein intake is adequate for growth among most children in developing countries needs reevaluation. C1 [Semba, Richard D.] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21205 USA. [Trehan, Indi; Ordiz, M. Isabel; Manary, Mark J.] Washington Univ, Dept Pediat, St Louis, MO 63130 USA. [Gonzalez-Freire, Marta; Moaddel, Ruin; Ferrucci, Luigi] NIA, NIH, Baltimore, MD 21224 USA. [Kraemer, Klaus] Sight & Life, Basel, Switzerland. [Kraemer, Klaus] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. RP Semba, RD (reprint author), Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21205 USA. EM rdsemba@jhmi.edu FU NIH [R01 AG027012, R01 EY024596, R01 HL11271]; Intramural Research Program of the National Institute on Aging; Children's Discovery Institute of Washington University; Hickey Family Foundation; St. Louis Children's Hospital FX Supported by NIH grants R01 AG027012, R01 EY024596, and R01 HL11271, the Intramural Research Program of the National Institute on Aging; the Children's Discovery Institute of Washington University and St. Louis Children's Hospital; and the Hickey Family Foundation. NR 173 TC 1 Z9 1 U1 4 U2 4 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 2161-8313 EI 2156-5376 J9 ADV NUTR JI Adv. Nutr. PD SEP PY 2016 VL 7 IS 5 BP 853 EP 865 DI 10.3945/an.116.013276 PG 13 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DX5AM UT WOS:000384392200001 PM 27633102 ER PT J AU Mahajan, A Rodan, AR Le, TH Gaulton, KJ Haessler, J Stilp, AM Kamatani, Y Zhu, G Sofer, T Puri, S Schellinger, JN Chu, PL Cechova, S van Zuydam, N Arnlov, J Flessner, MF Giedraitis, V Heath, AC Kubo, M Larsson, A Lindgren, CM Madden, PAF Montgomery, GW Papanicolaou, GJ Reiner, AP Sundstrom, J Thornton, TA Lind, L Ingelsson, E Cai, J Martin, NG Kooperberg, C Matsuda, K Whitfield, JB Okada, Y Laurie, CC Morris, AP Franceschini, N AF Mahajan, Anubha Rodan, Aylin R. Le, Thu H. Gaulton, Kyle J. Haessler, Jeffrey Stilp, Adrienne M. Kamatani, Yoichiro Zhu, Gu Sofer, Tamar Puri, Sanjana Schellinger, Jeffrey N. Chu, Pei-Lun Cechova, Sylvia van Zuydam, Natalie Arnlov, Johan Flessner, Michael F. Giedraitis, Vilmantas Heath, Andrew C. Kubo, Michiaki Larsson, Anders Lindgren, Cecilia M. Madden, Pamela A. F. Montgomery, Grant W. Papanicolaou, George J. Reiner, Alex P. Sundstrom, Johan Thornton, Timothy A. Lind, Lars Ingelsson, Erik Cai, Jianwen Martin, Nicholas G. Kooperberg, Charles Matsuda, Koichi Whitfield, John B. Okada, Yukinori Laurie, Cathy C. Morris, Andrew P. Franceschini, Nora CA SUMMIT Consortium TI Trans-ethnic Fine Mapping Highlights Kidney-Function Genes Linked to Salt Sensitivity SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; STAGE RENAL-DISEASE; TRANSETHNIC METAANALYSIS; NITRIC-OXIDE; CELL-TYPES; HYPERTENSION; VARIANTS; LOCI; MAP; DYSFUNCTION AB We analyzed genome-wide association studies (GWASs), including data from 71,638 individuals from four ancestries, for estimated glomerular filtration rate (eGFR), a measure of kidney function used to define chronic kidney disease (CKD). We identified 20 loci attaining genome-wide-significant evidence of association (p < 5 x 10(-8)) with kidney function and highlighted that allelic effects on eGFR at lead SNPs are homogeneous across ancestries. We leveraged differences in the pattern of linkage disequilibrium between diverse populations to fine-map the 20 loci through construction of "credible sets" of variants driving eGFR association signals. Credible variants at the 20 eGFR loci were enriched for DNase I hypersensitivity sites (DHSS) in human kidney cells. DHS credible variants were expression quantitative trait loci for NFATC1 and RGS14 (at the SLC34A1 locus) in multiple tissues. Loss-of-function mutations in ancestral orthologs of both genes in Drosophila melanogaster were associated with altered sensitivity to salt stress. Renal mRNA expression of Nfatcl and Rgs14 in a salt-sensitive mouse model was also reduced after exposure to a high-salt diet or induced CKD. Our study (1) demonstrates the utility of trans-ethnic fine mapping through integration of GWASs involving diverse populations with genomic annotation from relevant tissues to define molecular mechanisms by which association signals exert their effect and (2) suggests that salt sensitivity might be an important marker for biological processes that affect kidney function and CKD in humans. C1 [Mahajan, Anubha; van Zuydam, Natalie; Lindgren, Cecilia M.; Morris, Andrew P.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Rodan, Aylin R.; Puri, Sanjana; Schellinger, Jeffrey N.] Univ Texas Southwestern Med Ctr Dallas, Dept Internal Med, Dallas, TX 75229 USA. [Le, Thu H.; Chu, Pei-Lun; Cechova, Sylvia] Univ Virginia, Dept Med, Charlottesville, VA 22908 USA. [Gaulton, Kyle J.] Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA. [Haessler, Jeffrey; Kooperberg, Charles] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Stilp, Adrienne M.; Sofer, Tamar; Thornton, Timothy A.; Laurie, Cathy C.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Kamatani, Yoichiro; Okada, Yukinori] RIKEN, Lab Stat Anal, Ctr Integrat Med Sci, Yokohama, Kanagawa 2300045, Japan. [Zhu, Gu; Martin, Nicholas G.; Whitfield, John B.] QIMR Berghofer Med Res Inst, Genet Epidemiol Lab, Brisbane, Qld 4006, Australia. [Arnlov, Johan; Larsson, Anders; Sundstrom, Johan; Lind, Lars] Uppsala Univ, Dept Med Sci, Cardiovasc Epidemiol, S-75185 Uppsala, Sweden. [Arnlov, Johan] Dalama Univ, Sch Hlth & Social Studies, S-79188 Falun, Sweden. [Flessner, Michael F.] Natl Inst Diabet Digest & Kidney Dis, NIH, Bethesda, MD 20892 USA. [Giedraitis, Vilmantas] Uppsala Univ, Dept Publ Hlth & Caring Sci, Mol Geriatr, S-75237 Uppsala, Sweden. [Heath, Andrew C.; Madden, Pamela A. F.] Washington Univ, Dept Psychiat, St Louis, MO 63110 USA. [Kubo, Michiaki] RIKEN, Lab Genotyping Dev, Ctr Integrat Med Sci, Yokohama, Kanagawa 2300045, Japan. [Lindgren, Cecilia M.] Univ Oxford, Big Data Inst, Li Ka Shing Ctr Hlth Informat & Discovery, Oxford OX3 7BN, England. [Montgomery, Grant W.] QIMR Berghofer Med Res Inst, Mol Epidemiol Lab, Brisbane, Qld 4006, Australia. [Papanicolaou, George J.] NHLBI, Epidemiol Branch, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Ingelsson, Erik] Uppsala Univ, Mol Epidemiol & Sci Life Lab, Dept Med Sci, S-75237 Uppsala, Sweden. [Ingelsson, Erik] Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, Stanford, CA 94305 USA. [Cai, Jianwen] Univ N Carolina, Collaborat Studies Coordinating Ctr, Dept Biostat, Chapel Hill, NC 27599 USA. [Matsuda, Koichi] Univ Tokyo, Inst Med Sci, Ctr Human Genome, Lab Mol Med, Tokyo 1088639, Japan. [Okada, Yukinori] Osaka Univ, Dept Stat Genet, Grad Sch Med, 2-2 Yamadaoka, Suita, Osaka 5650871, Japan. [Morris, Andrew P.] Univ Liverpool, Dept Biostat, Liverpool L69 3GL, Merseyside, England. [Franceschini, Nora] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27514 USA. RP Morris, AP (reprint author), Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England.; Morris, AP (reprint author), Univ Liverpool, Dept Biostat, Liverpool L69 3GL, Merseyside, England.; Franceschini, N (reprint author), Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27514 USA. EM apmorris@liverpool.ac.uk; noraf@unc.edu OI Matsuda, Koichi/0000-0001-7292-2686; Sofer, Tamar/0000-0001-8520-8860 FU US NIH [K08DK091316, R25DK101401, 5R21HL123677-02]; National Institute of Diabetes and Digestive and Kidney Diseases [1R01DK094907-01]; Australian National Health and Medical Research Council; Japan Society for the Promotion of Science KAKENHI [15H05911, 15H05670, 15K14429]; Japan Science and Technology Agency; Mochida Memorial Foundation for Medical and Pharmaceutical Research; Takeda Science Foundation; Gout Research Foundation; Tokyo Biochemical Research Foundation; Japan Rheumatism Foundation; Wellcome Trust [WT098017] FX A.R.R. and J.N.S. are supported by the US NIH (K08DK091316). T.H.L. is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK094907-01). S.P. is supported by the US NIH (R25DK101401). G.W.M. is supported by the Australian National Health and Medical Research Council Fellowship Scheme. Yukinori Okada was supported by the Japan Society for the Promotion of Science KAKENHI (15H05911, 15H05670, 15K14429), the Japan Science and Technology Agency, Mochida Memorial Foundation for Medical and Pharmaceutical Research, Takeda Science Foundation, Gout Research Foundation, the Tokyo Biochemical Research Foundation, and the Japan Rheumatism Foundation. A.P.M. is a Wellcome Trust Senior Fellow in Basic Biomedical Science (grant WT098017). N.F. is supported by the US NIH (5R21HL123677-02). The ESRD data reported here have been supplied by the United States Renal Data System. The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as official policy or interpretation of the US government. Additional acknowledgments are provided in the Supplemental Data. NR 55 TC 0 Z9 0 U1 1 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD SEP 1 PY 2016 VL 99 IS 3 BP 636 EP 646 DI 10.1016/j.ajhg.2016.07.012 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA DV7KM UT WOS:000383114800009 PM 27588450 ER PT J AU Lodder, EM De Nittis, P Koopman, CD Wiszniewski, W de Souza, CFM Lahrouchi, N Guex, N Napolioni, V Tessadori, F Beekman, L Nannenberg, EA Boualla, L Blom, NA de Graaff, W Kamermans, M Cocciadiferro, D Malerba, N Mandriani, B Akdemir, ZHC Fish, RJ Eldomery, MK Ratbi, I Wilde, AAM de Boer, T Simonds, WF Neerman-Arbez, M Sutton, VR Kok, F Lupski, JR Reymond, A Bezzina, CR Bakkers, J Merla, G AF Lodder, Elisabeth M. De Nittis, Pasquelena Koopman, Charlotte D. Wiszniewski, Wojciech Moura de Souza, Carolina Fischinger Lahrouchi, Najim Guex, Nicolas Napolioni, Valerio Tessadori, Federico Beekman, Leander Nannenberg, Eline A. Boualla, Lamiae Blom, Nico A. de Graaff, Wim Kamermans, Maarten Cocciadiferro, Dario Malerba, Natascia Mandriani, Barbara Akdemir, Zeynep Hande Coban Fish, Richard J. Eldomery, Mohammad K. Ratbi, Ilham Wilde, Arthur A. M. de Boer, Teun Simonds, William F. Neerman-Arbez, Marguerite Sutton, V. Reid Kok, Fernando Lupski, James R. Reymond, Alexandre Bezzina, Connie R. Bakkers, Jeroen Merla, Giuseppe TI GNBS Mutations Cause an Autosomal-Recessive Multisystem Syndrome with Sinus Bradycardia and Cognitive Disability SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID HEART-RATE; BETA-SUBUNIT; COMPLEX; GENE; POLYMORPHISM; ACTIVATION; G-BETA-5; BRAIN; LIGHT; MICE AB GNB5 encodes the G protein beta subunit 5 and is involved in inhibitory G protein signaling. Here, we report mutations in GNB5 that are associated with heart-rate disturbance, eye disease, intellectual disability, gastric problems, hypotonia, and seizures in nine individuals from six families. We observed an association between the nature of the variants and clinical severity; individuals with loss-of-function alleles had more severe symptoms, including substantial developmental delay, speech defects, severe hypotonia, pathological gastro-esophageal re flux, retinal disease, and sinus-node dysfunction, whereas related heterozygotes harboring missense variants presented with a clinically milder phenotype. Zebrafish gnb5 knockouts recapitulated the phenotypic spectrum of affected individuals, including cardiac, neurological, and ophthalmological abnormalities, supporting a direct role of GNB5 in the control of heart rate, hypotonia, and vision. C1 [Lodder, Elisabeth M.; Lahrouchi, Najim; Beekman, Leander; Wilde, Arthur A. M.; Bezzina, Connie R.] Univ Amsterdam, Acad Med Ctr, Ctr Heart, Dept Clin & Expt Cardiol, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. [De Nittis, Pasquelena; Guex, Nicolas; Reymond, Alexandre] Univ Lausanne, Ctr Integrat Genom, CH-1015 Lausanne, Switzerland. [De Nittis, Pasquelena; Cocciadiferro, Dario; Malerba, Natascia; Mandriani, Barbara; Merla, Giuseppe] IRCCS Casa Sollievo Sofferenza, Med Genet Unit, Viale Cappuccini, I-71013 Foggia, Italy. [Koopman, Charlotte D.; de Boer, Teun; Bakkers, Jeroen] Univ Med Ctr Utrecht, Dept Med Physiol, Div Heart & Lungs, NL-3584 CT Utrecht, Netherlands. [Koopman, Charlotte D.; Tessadori, Federico; Bakkers, Jeroen] Univ Med Ctr Utrecht, Royal Netherlands Acad Arts & Sci KNAW, Hubrecht Inst, NL-3584 CT Utrecht, Netherlands. [Wiszniewski, Wojciech; Akdemir, Zeynep Hande Coban; Eldomery, Mohammad K.; Sutton, V. Reid; Lupski, James R.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Moura de Souza, Carolina Fischinger] Hosp Clin Porto Alegre, Med Genet Serv, BR-2350 Porto Alegre, RS, Brazil. [Guex, Nicolas] SSwiss Inst Bioinformat, CH-1015 Lausanne, Switzerland. [Napolioni, Valerio] Stanford Univ, Sch Med, Dept Neurol & Neurol Sci, Palo Alto, CA 94304 USA. [Nannenberg, Eline A.] Univ Amsterdam, Acad Med Ctr, Dept Clin Genet, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. [Boualla, Lamiae; Ratbi, Ilham] Mohammed V Univ Rabat, Fac Med & Pharm, Ctr Genom Humaine, Rabat 8007, Morocco. [Blom, Nico A.] Acad Med Ctr, Dept Pediat Cardiol, Emma Childrens Hosp, NL-1105 AZ Amsterdam, Netherlands. [de Graaff, Wim; Kamermans, Maarten] Netherlands Inst Neurosci, Rebinal Signal Proc Lab, NL-1105 BA Amsterdam, Netherlands. [Kamermans, Maarten] Univ Amsterdam, Acad Med Ctr, Dept Genome Anal, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. [Cocciadiferro, Dario; Malerba, Natascia] Univ Foggia, PhD Program Expt & Regenerat Med, Fac Med, I-71121 Foggia, Italy. [Mandriani, Barbara] Univ Brescia, Dept Mol & Translat Med, PhD Program Mol Genet Appl Med Sci, I-25121 Brescia, Italy. [Fish, Richard J.; Neerman-Arbez, Marguerite] Univ Med Ctr CMU, Dept Genet Med & Dev, CH-1211 Geneva, Switzerland. [Simonds, William F.] Natl Inst Diabet & Digest & Kidney Dis, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. [Sutton, V. Reid; Lupski, James R.] Texas Childrens Hosp, Houston, TX 77030 USA. [Kok, Fernando] Univ Sao Paulo, Sch Med, Dept Neurol, Child Neurol Div, BR-01246903 Sao Paulo, Brazil. [Lupski, James R.] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. RP Merla, G (reprint author), IRCCS Casa Sollievo Sofferenza, Med Genet Unit, Viale Cappuccini, I-71013 Foggia, Italy.; Bakkers, J (reprint author), Univ Med Ctr Utrecht, Dept Med Physiol, Div Heart & Lungs, NL-3584 CT Utrecht, Netherlands.; Bakkers, J (reprint author), Univ Med Ctr Utrecht, Royal Netherlands Acad Arts & Sci KNAW, Hubrecht Inst, NL-3584 CT Utrecht, Netherlands. EM j.bakkers@hubrecht.eu; g.merla@operapadrepio.it RI Fapesp-Cepid, CEGH-CEL/J-3613-2015; OI Lodder, Elisabeth/0000-0001-6017-3796 FU Regeneron Pharmaceuticals; Takeda Pharmaceutical Company FX J.R.L. has stock ownership in 23andMe, is a paid consultant for Regeneron Pharmaceuticals, has stock options in Lasergen, is a member of the Scientific Advisory Board of Baylor Miraca Genetics Laboratories, and is a co-inventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, and bacterial genomic fingerprinting. Baylor College of Medicine (BCM) and Miraca Holdings have formed a joint venture with shared ownership and governance of the Baylor Miraca Genetics Laboratories (BMGL), which performs clinical exome sequencing. The Department of Molecular and Human Genetics at BCM derives revenue from the chromosomal microarray analysis and clinical exome sequencing offered in the BMGL (http://www.bmgl.com/BMGL/Default.aspx/website). G.M. is a paid consultant for Takeda Pharmaceutical Company. NR 32 TC 2 Z9 2 U1 7 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD SEP 1 PY 2016 VL 99 IS 3 BP 704 EP 710 DI 10.1016/j.ajhg.2016.06.025 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA DV7KM UT WOS:000383114800015 PM 27523599 ER PT J AU Namburi, P Ratnapriya, R Khateb, S Lazar, CH Kinarty, Y Obolensky, A Erdinest, I Marks-Ohana, D Pras, E Ben-Yosef, T Newman, H Gross, M Swaroop, A Banin, E Sharon, D AF Namburi, Prasanthi Ratnapriya, Rinki Khateb, Samer Lazar, Csilla H. Kinarty, Yael Obolensky, Alexey Erdinest, Inbar Marks-Ohana, Devorah Pras, Eran Ben-Yosef, Tamar Newman, Hadas Gross, Menachem Swaroop, Anand Banin, Eyal Sharon, Dror TI Bi-allelic Truncating Mutations in CEP78, Encoding Centrosomal Protein 78, Cause Cone-Rod Degeneration with Sensorineural Hearing Loss SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID ATYPICAL USHER-SYNDROME; RETINITIS-PIGMENTOSA; GENETIC-HETEROGENEITY; RETINAL CILIOPATHIES; DISEASE; CILIA; PREVALENCE; EVOLUTION; THERAPY AB Inherited retinal diseases (IRDs) are a diverse group of genetically and clinically heterogeneous retinal abnormalities. The present study was designed to identify genetic defects in individuals with an uncommon combination of autosomal recessive progressive cone-rod degeneration accompanied by sensorineural hearing loss (arCRD-SNHL). Homozygosity mapping followed by whole-exome sequencing (WES) and founder mutation screening revealed two truncating rare variants (c.893-1G>A and c.534delT) in CEP78, which encodes centrosomal protein 78, in six individuals of Jewish ancestry with CRD and SNHL. RT-PCR analysis of CEP78 in blood leukocytes of affected individuals revealed that the c.893-1G>A mutation causes exon 7 skipping leading to deletion of 65bp, predicted to result in a frameshift and therefore a truncated protein (p.Asp298Valfs*17). RT-PCR analysis of 17 human tissues demonstrated ubiquitous expression of different CEP78 transcripts. RNA-seq analysis revealed three transcripts in the human retina and relatively higher expression in S-cone-like photoreceptors of Nrl-knockout retina compared to rods. Immunohistochemistry studies in the human retina showed intense labeling of cone inner segments compared to rods. CEP78 was reported previously to interact with c-napl, encoded by CEP250 that we reported earlier to cause atypical Usher syndrome. We conclude that truncating mutations in CEP78 result in a phenotype involving both the visual and auditory systems but different from typical Usher syndrome. C1 [Namburi, Prasanthi; Khateb, Samer; Kinarty, Yael; Obolensky, Alexey; Erdinest, Inbar; Marks-Ohana, Devorah; Banin, Eyal; Sharon, Dror] Hadassah Hebrew Univ Med Ctr, Dept Ophthalmol, IL-91120 Jerusalem, Israel. [Ratnapriya, Rinki; Lazar, Csilla H.; Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. [Lazar, Csilla H.] Univ Babes Bolyai, Ctr Mol Biol, Interdisciplinary Res Inst Bionano Sci, Cluj Napoca 400271, Romania. [Kinarty, Yael] Hebrew Univ Hadassah Med Sch, Dept Med Neurobiol, Inst Med Res Israel Canada, IL-91120 Jerusalem, Israel. [Pras, Eran] Assaf Harofeh Med Ctr, Dept Ophthalmol, IL-70300 Zerifin, Israel. [Pras, Eran; Newman, Hadas] Tel Aviv Univ, Sackler Fac Med, IL-6997801 Tel Aviv, Israel. [Ben-Yosef, Tamar] Technion Israel Inst Technol, Rappaport Fac Med, IL-3525433 Haifa, Israel. [Newman, Hadas] Tel Aviv Med Ctr & Sch Med, Dept Ophthalmol, IL-64239 Tel Aviv, Israel. [Gross, Menachem] Hadassah Hebrew Univ Med Ctr, Dept Otolaryngol Head & Neck Surg, IL-91120 Jerusalem, Israel. RP Banin, E; Sharon, D (reprint author), Hadassah Hebrew Univ Med Ctr, Dept Ophthalmol, IL-91120 Jerusalem, Israel. EM banine@cc.huji.ac.il; dror.sharon1@gmail.com FU United States Israel Binational Science Foundation [2011202]; Foundation Fighting Blindness USA [BR-GE-0214-0639]; Israel Science Foundation [2154/15]; Chief Scientist office of the Israeli Ministry of Health; Lirot association [300009177]; Yedidut Research Grant; Intramural Research Program of the National Eye Institute, National Institutes of Health FX The authors thank all affected individuals and family members for their participation in this study. We are grateful to Lilach Binyamini and Shelly Stika for assistance in recruitment and clinical evaluation of the individuals and Alaa Abu-Diab for technical assistance. Whole-exome analysis utilized the computational resources of the NIH HPC Biowulf cluster. We thank Matthew Brooks, Jung-Woong Kim, Hyunjin Yang, and Ashley Walton for help with RNA-seq analysis. This research was supported by the United States Israel Binational Science Foundation (grant number 2011202, to D.S. and A.S.), Foundation Fighting Blindness USA (BR-GE-0214-0639 to D.S., E.B., E.P., H.N., and T.B.-Y.), Israel Science Foundation (#2154/15 to S.K.), Chief Scientist office of the Israeli Ministry of Health and the Lirot association (#300009177 to S.K.), the Yedidut Research Grant (to E.B.), and the Intramural Research Program of the National Eye Institute, National Institutes of Health (to A.S.). NR 30 TC 1 Z9 1 U1 1 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD SEP 1 PY 2016 VL 99 IS 3 BP 777 EP 784 DI 10.1016/j.ajhg.2016.07.010 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA DV7KM UT WOS:000383114800024 PM 27588452 ER PT J AU Kar, SP Beesley, J Al Olama, AA Michailidou, K Tyrer, J Kote-Jarai, ZA Lawrenson, K Lindstrom, S Ramus, SJ Thompson, DJ Kibel, AS Dansonka-Mieszkowska, A Michael, A Dieffenbach, AK Gentry-Maharaj, A Whittemore, AS Wolk, A Monteiro, A Peixoto, A Kierzek, A Cox, A Rudolph, A Gonzalez-Neira, A Wu, AH Lindblom, A Swerdlow, A Ziogas, A Ekici, AB Burwinkel, B Karlan, BY Nordestgaard, BG Blomqvist, C Phelan, C McLean, C Pearce, CL Vachon, C Cybulski, C Slavov, C Stegmaier, C Maier, C Ambrosone, CB Hogdall, CK Teerlink, CC Kang, D Tessier, DC Schaid, DJ Stram, DO Cramer, DW Neal, DE Eccles, D Flesch-Janys, D Edwards, DRV Wokozorczyk, D Levine, DA Yannoukakos, D Sawyer, EJ Bandera, EV Poole, EM Goode, EL Khusnutdinova, E Hogdall, E Song, FJ Bruinsma, F Heitz, F Modugno, F Hamdy, FC Wiklund, F Giles, GG Olsson, H Wildiers, H Ulmer, HU Pandha, H Risch, HA Darabi, H Salvesen, HB Nevanlinna, H Gronberg, H Brenner, H Brauch, H Anton-Culver, H Song, HL Lim, HY McNeish, I Campbell, I Vergote, I Gronwald, J Lubinski, J Stanford, JL Bentez, J Doherty, JA Permuth, JB Chang-Claude, J Donovan, JL Dennis, J Schildkraut, JM Schleutker, J Hopper, JL Kupryjanczyk, J Park, JY Figueroa, J Clements, JA Knight, JA Peto, J Cunningham, JM Pow-Sang, J Batra, J Czene, K Lu, KH Herkommer, K Khaw, KT Matsuo, K Muir, K Offitt, K Chen, KX Moysich, KB Aittomaki, K Odunsi, K Kiemeney, LA Massuger, LFAG Fitzgerald, LM Cook, LS Cannon-Albright, L Hooning, MJ Pike, MC Bolla, MK Luedeke, M Teixeira, MR Goodman, MT Schmidt, MK Riggan, M Aly, M Rossing, MA Beckmann, MW Moisse, M Sanderson, M Southey, MC Jones, M Lush, M Hildebrandt, MAT Hou, MF Schoemaker, MJ Garcia-Closas, M Bogdanova, N Rahman, N Le, ND Orr, N Wentzensen, N Pashayan, N Peterlongo, P Guenel, P Brennan, P Paulo, P Webb, PM Broberg, P Fasching, PA Devilee, P Wang, Q Cai, QY Li, QY Kaneva, R Butzow, R Kopperud, RK Schmutzler, RK Stephenson, RA MacInnis, RJ Hoover, RN Winqvist, R Ness, R Milne, RL Travis, RC Benlloch, S Olson, SH McDonnell, SK Tworoger, SS Maia, SA Berndt, S Lee, SC Teo, SH Thibodeau, SN Bojesen, SE Gapstur, SM Kjaer, SK Pejovic, T Tammela, TLJ Dork, T Bruning, T Wahlfors, T Key, TJ Edwards, TL Menon, U Hamann, U Mitev, V Kosma, VM Setiawan, VW Kristensen, V Arndt, V Vogel, W Zheng, W Sieh, W Blot, WJ Kluzniak, W Shu, XO Gao, YT Schumacher, F Freedman, ML Berchuck, A Dunning, AM Simard, J Haiman, CA Spurdle, A Sellers, TA Hunter, DJ Henderson, BE Kraft, P Chanock, SJ Couch, FJ Hall, P Gayther, SA Easton, DF Chenevix-Trench, G Eeles, R Pharoah, PDP Lambrechts, D AF Kar, Siddhartha P. Beesley, Jonathan Al Olama, Ali Amin Michailidou, Kyriaki Tyrer, Jonathan Kote-Jarai, Zsofi A. Lawrenson, Kate Lindstrom, Sara Ramus, Susan J. Thompson, Deborah J. Kibel, Adam S. Dansonka-Mieszkowska, Agnieszka Michael, Agnieszka Dieffenbach, Aida K. Gentry-Maharaj, Aleksandra Whittemore, Alice S. Wolk, Alicja Monteiro, Alvaro Peixoto, Ana Kierzek, Andrzej Cox, Angela Rudolph, Anja Gonzalez-Neira, Anna Wu, Anna H. Lindblom, Annika Swerdlow, Anthony Ziogas, Argyrios Ekici, Arif B. Burwinkel, Barbara Karlan, Beth Y. Nordestgaard, Borge G. Blomqvist, Carl Phelan, Catherine McLean, Catriona Pearce, Celeste Leigh Vachon, Celine Cybulski, Cezary Slavov, Chavdar Stegmaier, Christa Maier, Christiane Ambrosone, Christine B. Hogdall, Claus K. Teerlink, Craig C. Kang, Daehee Tessier, Daniel C. Schaid, Daniel J. Stram, Daniel O. Cramer, Daniel W. Neal, David E. Eccles, Diana Flesch-Janys, Dieter Edwards, Digna R. Velez Wokozorczyk, Dominika Levine, Douglas A. Yannoukakos, Drakoulis Sawyer, Elinor J. Bandera, Elisa V. Poole, Elizabeth M. Goode, Ellen L. Khusnutdinova, Elza Hogdall, Estrid Song, Fengju Bruinsma, Fiona Heitz, Florian Modugno, Francesmary Hamdy, Freddie C. Wiklund, Fredrik Giles, Graham G. Olsson, Hakan Wildiers, Hans Ulmer, Hans-Ulrich Pandha, Hardev Risch, Harvey A. Darabi, Hatef Salvesen, Helga B. Nevanlinna, Heli Gronberg, Henrik Brenner, Hermann Brauch, Hiltrud Anton-Culver, Hoda Song, Honglin Lim, Hui-Yi McNeish, Iain Campbell, Ian Vergote, Ignace Gronwald, Jacek Lubinski, Jan Stanford, Janet L. Bentez, Javier Doherty, Jennifer A. Permuth, Jennifer B. Chang-Claude, Jenny Donovan, Jenny L. Dennis, Joe Schildkraut, Joellen M. Schleutker, Johanna Hopper, John L. Kupryjanczyk, Jolanta Park, Jong Y. Figueroa, Jonine Clements, Judith A. Knight, Julia A. Peto, Julian Cunningham, Julie M. Pow-Sang, Julio Batra, Jyotsna Czene, Kamila Lu, Karen H. Herkommer, Kathleen Khaw, Kay-Tee Matsuo, Keitaro Muir, Kenneth Offitt, Kenneth Chen, Kexin Moysich, Kirsten B. Aittomaki, Kristiina Odunsi, Kunle Kiemeney, Lambertus A. Massuger, Leon F. A. G. Fitzgerald, Liesel M. Cook, Linda S. Cannon-Albright, Lisa Hooning, Maartje J. Pike, Malcolm C. Bolla, Manjeet K. Luedeke, Manuel Teixeira, Manuel R. Goodman, Marc T. Schmidt, Marjanka K. Riggan, Marjorie Aly, Markus Rossing, Mary Anne Beckmann, Matthias W. Moisse, Matthieu Sanderson, Maureen Southey, Melissa C. Jones, Michael Lush, Michael Hildebrandt, Michelle A. T. Hou, Ming-Feng Schoemaker, Minouk J. Garcia-Closas, Montserrat Bogdanova, Natalia Rahman, Nazneen Le, Nhu D. Orr, Nick Wentzensen, Nicolas Pashayan, Nora Peterlongo, Paolo Guenel, Pascal Brennan, Paul Paulo, Paula Webb, Penelope M. Broberg, Per Fasching, Peter A. Devilee, Peter Wang, Qin Cai, Qiuyin Li, Qiyuan Kaneva, Radka Butzow, Ralf Kopperud, Reidun Kristin Schmutzler, Rita K. Stephenson, Robert A. MacInnis, Robert J. Hoover, Robert N. Winqvist, Robert Ness, Roberta Milne, Roger L. Travis, Ruth C. Benlloch, Sara Olson, Sara H. McDonnell, Shannon K. Tworoger, Shelley S. Maia, Sofi A. Berndt, Sonja Lee, Soo Chin Teo, Soo-Hwang Thibodeau, Stephen N. Bojesen, Stig E. Gapstur, Susan M. Kjaer, Susanne Krueger Pejovic, Tanja Tammela, Teuvo L. J. Doerk, Thilo Bruening, Thomas Wahlfors, Tiina Key, Tim J. Edwards, Todd L. Menon, Usha Hamann, Ute Mitev, Vanio Kosma, Veli-Matti Setiawan, Veronica Wendy Kristensen, Vessela Arndt, Volker Vogel, Walther Zheng, Wei Sieh, Weiva Blot, William J. Kluzniak, Wojciech Shu, Xiao-Ou Gao, Yu-Tang Schumacher, Fredrick Freedman, Matthew L. Berchuck, Andrew Dunning, Alison M. Simard, Jacques Haiman, Christopher A. Spurdle, Amanda Sellers, Thomas A. Hunter, David J. Henderson, Brian E. Kraft, Peter Chanock, Stephen J. Couch, Fergus J. Hall, Per Gayther, Simon A. Easton, Douglas F. Chenevix-Trench, Georgia Eeles, Rosalind Pharoah, Paul D. P. Lambrechts, Diether CA ABCTB Investigators AOCS Study Grp Australian Canc APCB BioResource KConFab Investigators NBCS Investigators GENICA Network PRACTICAL Consortium TI Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types SO CANCER DISCOVERY LA English DT Article ID TRAIL-INDUCED APOPTOSIS; PASSENGER COMPLEX CPC; BIOLOGICAL PATHWAYS; ENRICHMENT ANALYSIS; DEATH RECEPTORS; RISK LOCI; VARIANTS; CELLS; GENE; POPULATION AB Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10 -8 seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type-specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10(-5) in the three-cancer meta-analysis. SIGNIFICANCE: We demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers. (C) 2016 AACR. C1 [Kar, Siddhartha P.; Al Olama, Ali Amin; Michailidou, Kyriaki; Thompson, Deborah J.; Dennis, Joe; Bolla, Manjeet K.; Lush, Michael; Wang, Qin; Benlloch, Sara; Easton, Douglas F.; Pharoah, Paul D. P.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Beesley, Jonathan; Chenevix-Trench, Georgia] QIMR Berghofer Med Res Inst, Dept Genet, Herston, Qld, Australia. [Tyrer, Jonathan; Song, Honglin; Pashayan, Nora; Dunning, Alison M.; Easton, Douglas F.; Pharoah, Paul D. P.] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England. [Kote-Jarai, Zsofi A.; Eeles, Rosalind] Inst Canc Res, Sutton, Surrey, England. [Lawrenson, Kate; Ramus, Susan J.; Wu, Anna H.; Stram, Daniel O.; Setiawan, Veronica Wendy; Schumacher, Fredrick; Haiman, Christopher A.; Henderson, Brian E.; Gayther, Simon A.] Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Norris Comprehens Canc Ctr, Los Angeles, CA USA. [Lindstrom, Sara; Hunter, David J.; Kraft, Peter] Harvard Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA USA. [ABCTB Investigators] Univ Sydney, Westmead Millennium Inst, Australian Breast Canc Tissue Bank ABCTB Investig, Sydney, NSW, Australia. [Kibel, Adam S.] Brigham & Womens Hosp, Dana Farber Canc Inst, Div Urol Surg, 75 Francis St, Boston, MA 02115 USA. [Dansonka-Mieszkowska, Agnieszka; Kupryjanczyk, Jolanta] Maria Sklodowska Curie Mem Canc Ctr, Dept Pathol & Lab Diagnost, Warsaw, Poland. [Dansonka-Mieszkowska, Agnieszka; Kupryjanczyk, Jolanta] Inst Oncol, Warsaw, Poland. [Michael, Agnieszka; Kierzek, Andrzej; Pandha, Hardev] Univ Surrey, Guildford, Surrey, England. [Dieffenbach, Aida K.; Brenner, Hermann; Arndt, Volker] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Dieffenbach, Aida K.; Brenner, Hermann; Brauch, Hiltrud] German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany. [Gentry-Maharaj, Aleksandra; Menon, Usha] UCL, Inst Womens Hlth, Womens Canc, London, England. [Whittemore, Alice S.; Sieh, Weiva] Stanford Univ, Sch Med, Dept Hlth Res & Policy Epidemiol, Stanford, CA 94305 USA. [Wolk, Alicja] Karolinska Inst, Dept Environm Med, Div Nutr Epidemiol, Stockholm, Sweden. [Monteiro, Alvaro; Phelan, Catherine; Permuth, Jennifer B.; Park, Jong Y.; Pow-Sang, Julio; Sellers, Thomas A.] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL USA. [Peixoto, Ana; Teixeira, Manuel R.; Paulo, Paula; Maia, Sofi A.] Portuguese Oncol Inst, Dept Genet, Oporto, Portugal. [Cox, Angela] Univ Sheffield, Dept Oncol, Sheffield Canc Res, Sheffield, S Yorkshire, England. [Rudolph, Anja; Chang-Claude, Jenny] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Gonzalez-Neira, Anna; Bentez, Javier] Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Program, Madrid, Spain. [Gonzalez-Neira, Anna; Bentez, Javier] Spanish Natl Genotyping Ctr CEGEN, Madrid, Spain. [Lindblom, Annika] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. [Swerdlow, Anthony; Jones, Michael; Schoemaker, Minouk J.; Garcia-Closas, Montserrat] Inst Canc Res, Div Genet & Epidemiol, London, England. [Swerdlow, Anthony] Inst Canc Res, Div Breast Canc Res, London, England. Queensland Univ Technol, Inst Hlth & Biomed Innovat, Australian Prostate Canc Res Ctr, Brisbane, Qld, Australia. [APCB BioResource] Queensland Univ Technol, Sch Biomed Sci, Brisbane, Qld, Australia. [Ziogas, Argyrios; Anton-Culver, Hoda] Univ Calif Irvine, Sch Med, Dept Epidemiol, UCI Ctr Canc Genet Res & Prevent, Irvine, CA 92717 USA. [Ekici, Arif B.] Univ Erlangen Nurnberg, Comprehens Canc Ctr Erlangen EMN, Univ Hosp Erlangen, Inst Human Genet, Erlangen, Germany. [Burwinkel, Barbara] German Canc Res Ctr, Mol Epidemiol Grp, Heidelberg, Germany. [Burwinkel, Barbara] German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany. [Karlan, Beth Y.] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Los Angeles, CA 90048 USA. [Nordestgaard, Borge G.; Bojesen, Stig E.] Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, Herlev, Denmark. [Blomqvist, Carl] Helsinki Univ Hosp, Dept Oncol, Helsinki, Finland. [Blomqvist, Carl; Nevanlinna, Heli; Aittomaki, Kristiina; Butzow, Ralf] Univ Helsinki, Helsinki, Finland. [McLean, Catriona] Alfred Hosp, Anat Pathol, Melbourne, Vic, Australia. [Pearce, Celeste Leigh] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Vachon, Celine; Goode, Ellen L.] Mayo Clin, Div Epidemiol, Dept Hlth Sci Res, Rochester, MN USA. [Cybulski, Cezary; Wokozorczyk, Dominika; Gronwald, Jacek; Lubinski, Jan; Kluzniak, Wojciech] Pomeranian Med Univ, Dept Genet & Pathol, Int Hereditary Canc Ctr, Szczecin, Poland. [Slavov, Chavdar] Med Univ, Alexandrovska Univ Hosp, Dept Urol, Sofia, Bulgaria. [Stegmaier, Christa] Saarland Canc Registry, Saarbrucken, Germany. [Maier, Christiane; Luedeke, Manuel] Univ Hosp Ulm, Dept Urol, Ulm, Germany. [Ambrosone, Christine B.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Hogdall, Claus K.] Univ Copenhagen, Dept Gynecol, Juliane Marie Ctr, Rigshosp, Copenhagen, Denmark. [Teerlink, Craig C.] Univ Utah, Sch Med, Dept Internal Med, Div Genet Epidemiol, Salt Lake City, UT USA. [Kang, Daehee] Seoul Natl Univ, Canc Res Inst, Seoul, South Korea. 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Velez] Vanderbilt Univ, Med Ctr, Dept Obstet & Gynecol, Vanderbilt Epidemiol Ctr,Vanderbilt Genet Inst, Nashville, TN 37232 USA. [Levine, Douglas A.] Mem Sloan Kettering Canc Ctr, Dept Surg, Gynecol Serv, New York, NY 10021 USA. [Yannoukakos, Drakoulis] NCSR Demokritos, Mol Diagnost Lab, Athens, Greece. [Sawyer, Elinor J.] Kings Coll London, Guys Hosp, Res Oncol, London, England. [Bandera, Elisa V.] State Univ New Jersey, Rutgers Canc Inst New Jersey, Canc Prevent & Control Program, New Brunswick, NJ USA. [Poole, Elizabeth M.; Tworoger, Shelley S.] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Poole, Elizabeth M.; Tworoger, Shelley S.] Harvard Med Sch, Boston, MA USA. [Poole, Elizabeth M.; Tworoger, Shelley S.] Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Khusnutdinova, Elza] Bashkir State Univ, Dept Genet & Fundamental Med, Ufa, Russia. [Khusnutdinova, Elza] Russian Acad Sci, Inst Biochem & Genet, Ufa Sci Ctr, Ufa, Russia. [Hogdall, Estrid; Kjaer, Susanne Krueger] Danish Canc Soc Res Ctr, Dept Virus Lifestyle & Genes, Copenhagen, Denmark. [Hogdall, Estrid] Univ Copenhagen, Herlev Hosp, Dept Pathol, Mol Unit, Copenhagen, Denmark. [Song, Fengju; Chen, Kexin] Tianjin Med Univ Canc Inst & Hosp, Natl Clin Res Ctr Canc, Key Lab Canc Prevent & Therapy, Dept Epidemiol & Biostat, Tianjin, Peoples R China. [Bruinsma, Fiona; Giles, Graham G.; Fitzgerald, Liesel M.; MacInnis, Robert J.; Milne, Roger L.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Heitz, Florian] Kliniken Essen Mitte Evang Huyssens Stiftung Knap, Dept Gynecol & Gynecol Oncol, Essen, Germany. [Heitz, Florian] Dr Horst Schmidt Kliniken Wiesbaden, Dept Gynecol & Gynecol Oncol, Wiesbaden, Germany. [Modugno, Francesmary] Univ Pittsburgh, Sch Med, Dept Obstet Gynecol & Reprod Sci, Div Gynecol Oncol, Pittsburgh, PA USA. [Modugno, Francesmary] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Modugno, Francesmary] Magee Womens Res Inst, Womens Canc Res Program, Pittsburgh, PA USA. [Modugno, Francesmary] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Hamdy, Freddie C.] Univ Oxford, Nuffield Dept Surg Sci, Oxford, England. [Hamdy, Freddie C.] Univ Oxford, John Radcliffe Hosp, Fac Med Sci, Oxford, England. [Wiklund, Fredrik; Darabi, Hatef; Gronberg, Henrik; Czene, Kamila; Aly, Markus; Hall, Per] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Giles, Graham G.; MacInnis, Robert J.; Milne, Roger L.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic 3010, Australia. [Giles, Graham G.] Monash Univ, Dept Epidemiol & Prevent Med, Melbourne, Vic, Australia. [Olsson, Hakan] Univ Hosp, Dept Canc Epidemiol, Lund, Sweden. [Olsson, Hakan] Univ Hosp, Dept Oncol, Lund, Sweden. [Wildiers, Hans] Univ Hosp Leuven, Leuven Canc Inst, Dept Gen Med Oncol, Leuven, Belgium. [Ulmer, Hans-Ulrich; Hamann, Ute] Frauenklin Stadtklin Baden Baden, Baden Baden, Germany. [Risch, Harvey A.] Yale Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT USA. [Salvesen, Helga B.; Kopperud, Reidun Kristin] Haukeland Hosp, Dept Gynecol & Obstet, Bergen, Norway. [Salvesen, Helga B.; Kopperud, Reidun Kristin] Univ Bergen, Ctr Canc Biomarkers, Dept Clin Sci, Bergen, Norway. [Nevanlinna, Heli] Helsinki Univ Hosp, Dept Obstet & Gynecol, Helsinki, Finland. [Brenner, Hermann] Natl Ctr Tumor Dis NCT, Div Prevent Oncol, Heidelberg, Germany. [Brenner, Hermann] German Canc Res Ctr, Heidelberg, Germany. [Brauch, Hiltrud] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany. [Brauch, Hiltrud] Univ Tubingen, Tubingen, Germany. [Lim, Hui-Yi] H Lee Moffitt Canc Ctr & Res Inst, Biostat Program, Tampa, FL USA. [McNeish, Iain] Univ Glasgow, Inst Canc Sci, Beatson Inst Canc Res, Wolfson Wohl Canc Res Ctr, Glasgow, Lanark, Scotland. [Campbell, Ian] Peter MacCallum Canc Ctr, Div Res, Canc Genet Lab, St Andrews Pl, East Melbourne, Vic, Australia. [Campbell, Ian; Southey, Melissa C.] Univ Melbourne, Dept Pathol, Parkville, Vic, Australia. [Vergote, Ignace] Katholieke Univ Leuven, Univ Hosp Leuven, Leuven Canc Inst, Dept Gynaecol Oncol, Leuven, Belgium. [Stanford, Janet L.; Rossing, Mary Anne] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Program Epidemiol, 1124 Columbia St, Seattle, WA 98104 USA. [Stanford, Janet L.; Rossing, Mary Anne] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Doherty, Jennifer A.] Geisel Sch Med Dartmouth, Dept Epidemiol, Hanover, NH USA. [Donovan, Jenny L.] Univ Bristol, Sch Social & Community Med, Bristol, Avon, England. [Schildkraut, Joellen M.] Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC USA. [Schildkraut, Joellen M.] Duke Canc Inst, Canc Control & Populat Sci, Durham, NC USA. [Schleutker, Johanna; Wahlfors, Tiina] Univ Turku, Dept Med Biochem, Turku, Finland. [Schleutker, Johanna; Wahlfors, Tiina] Univ Turku, Genet Inst Biomed, Turku, Finland. [Schleutker, Johanna] Univ Tampere, BioMediTech, Tampere, Finland. [Schleutker, Johanna] FimLab Labs, Tampere, Finland. [Hopper, John L.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia. [Figueroa, Jonine; Garcia-Closas, Montserrat; Wentzensen, Nicolas; Hoover, Robert N.; Berndt, Sonja; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Clements, Judith A.; Batra, Jyotsna] Queensland Univ Technol, Australian Prostate Canc Res Ctr, Inst Hlth & Biomed Innovat, Brisbane, Qld, Australia. [Clements, Judith A.; Batra, Jyotsna] Queensland Univ Technol, Sch Biomed Sci, Brisbane, Qld, Australia. [Knight, Julia A.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Prosserman Ctr Hlth Res, Toronto, ON, Canada. [Knight, Julia A.] Univ Toronto, Dalla Lana Sch Publ Hlth, Div Epidemiol, Toronto, ON, Canada. [Peto, Julian] London Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, London, England. [Cunningham, Julie M.; Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Lu, Karen H.] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA. [Herkommer, Kathleen] Tech Univ Munich, Klinikum Rechts Isar, Dept Urol, Munich, Germany. [Khaw, Kay-Tee] Univ Cambridge, Clin Gerontol Unit, Cambridge, England. [Matsuo, Keitaro] Kyushu Univ, Fac Med Sci, Dept Prevent Med, Nagoya, Aichi, Japan. [Muir, Kenneth] Univ Manchester, Inst Populat Hlth, Manchester, Lancs, England. [Muir, Kenneth] Univ Warwick, Warwick Med Sch, Coventry, W Midlands, England. [Offitt, Kenneth] Mem Sloan Kettering Canc Ctr, Clin Genet Res Lab, Dept Canc Biol & Genet, 1275 York Ave, New York, NY 10021 USA. [Offitt, Kenneth] Mem Sloan Kettering Canc Ctr, Dept Med, Clin Genet Serv, 1275 York Ave, New York, NY 10021 USA. [Moysich, Kirsten B.] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Aittomaki, Kristiina] Helsinki Univ Hosp, Dept Clin Genet, Helsinki, Finland. [Odunsi, Kunle] Roswell Pk Canc Inst, Dept Gynecol Oncol, Buffalo, NY 14263 USA. [Kiemeney, Lambertus A.] Radboud Univ Nijmegen, Med Ctr, Radbond Inst Hlth Sci, Nijmegen, Netherlands. [Massuger, Leon F. A. G.] Radboud Univ Nijmegen, Med Ctr, Dept Gynaecol, Nijmegen, Netherlands. [Cook, Linda S.] Univ New Mexico, Dept Internal Med, Div Epidemiol & Biostat, Albuquerque, NM 87131 USA. [Cannon-Albright, Lisa] George E Wahlen Dept Vet Affairs Med Ctr, Salt Lake City, UT USA. [Hooning, Maartje J.] Erasmus MC, Canc Inst, Family Canc Clin, Dept Med Oncol, Rotterdam, Netherlands. [Pike, Malcolm C.; Olson, Sara H.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Teixeira, Manuel R.] Univ Porto, Biomed Sci Inst ICBAS, Oporto, Portugal. [Goodman, Marc T.] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Canc Prevent & Control, Los Angeles, CA 90048 USA. [Goodman, Marc T.] Cedars Sinai Med Ctr, Dept Biomed Sci, Community & Populat Hlth Res Inst, Los Angeles, CA 90048 USA. [Schmidt, Marjanka K.] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands. [Riggan, Marjorie; Berchuck, Andrew] Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC 27710 USA. [Aly, Markus] Danderyd Hosp, Dept Clin Sci, Stockholm, Sweden. [Beckmann, Matthias W.; Fasching, Peter A.] Univ Erlangen Nurnberg, Comprehens Canc Ctr Erlangen EMN, Univ Hosp Erlangen, Dept Obstet & Gynaecol, Erlangen, Germany. Katholieke Univ Leuven, VIB Vesalius Res Ctr, Leuven, Belgium. [Sanderson, Maureen] Meharry Med Coll, Dept Family & Community Med, Nashville, TN 37208 USA. [Hildebrandt, Michelle A. T.] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Hou, Ming-Feng] Kaohsiung Med Univ, Chung Ho Mem Hosp, Ctr Canc, Kaohsiung, Taiwan. [Hou, Ming-Feng] Kaohsiung Med Univ, Chung Ho Mem Hosp, Dept Surg, Kaohsiung, Taiwan. [Bogdanova, Natalia] Hannover Med Sch, Radiat Oncol Res Unit, Hannover, Germany. [Rahman, Nazneen] Inst Canc Res, Sect Canc Genet, London, England. [Le, Nhu D.] British Columbia Canc Agcy, Canc Control Res, Vancouver, BC, Canada. [Orr, Nick] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London, England. [Pashayan, Nora] UCL, Dept Appl Hlth Res, London, England. [Peterlongo, Paolo] FIRC Inst Mol Oncol, IFOM, Milan, Italy. [Guenel, Pascal] INSERM, Ctr Res Epidemiol & Populat Hlth, Environm Epidemiol Canc, Villejuif, France. [Guenel, Pascal] Univ Paris 11, Villejuif, France. [Brennan, Paul] Int Agcy Res Canc, Lyon, France. [Webb, Penelope M.] QIMR Berghofer Med Res Inst, Populat Hlth Dept, Herston, Qld, Australia. [Broberg, Per] Univ Hosp, Dept Canc Epidemiol, Lund, Sweden. [Devilee, Peter] Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands. [Devilee, Peter] Leiden Univ, Med Ctr, Dept Pathol, Leiden, Netherlands. [Cai, Qiuyin; Zheng, Wei; Shu, Xiao-Ou] Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, Nashville, TN 37212 USA. [Li, Qiyuan] Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Dept Med Oncol, Boston, MA 02115 USA. [Li, Qiyuan] Xiamen Univ, Coll Med, Xiamen, Peoples R China. [Kaneva, Radka; Mitev, Vanio] Med Univ, Mol Med Ctr, Dept Med Chem & Biochem, Sofia, Bulgaria. [Butzow, Ralf] Helsinki Univ Hosp, Dept Pathol, Helsinki, Finland. [Schmutzler, Rita K.] Univ Hosp Cologne, CIO, Cologne, Germany. [Schmutzler, Rita K.] Univ Hosp Cologne, Ctr Hereditary Breast & Ovarian Canc, Cologne, Germany. [Schmutzler, Rita K.] Univ Cologne, CMMC, Cologne, Germany. [Stephenson, Robert A.] Univ Utah, Sch Med, Dept Surg, Salt Lake City, UT USA. [Winqvist, Robert] Univ Oulu, Bioctr Oulu, Lab Canc Genet & Tumor Biol Canc Res & Translat M, Oulu, Finland. [Winqvist, Robert] Northern Finland Lab Ctr, Oulu, Finland. [Ness, Roberta] Univ Texas Sch Publ Hlth, Houston, TX USA. [Travis, Ruth C.; Key, Tim J.] Univ Oxford, Nuffield Dept Populat Hlth, Canc Epidemiol Unit, Oxford, England. [Lee, Soo Chin] Natl Univ Hlth Syst, Dept Hematol Oncol, Singapore, Singapore. [Lee, Soo Chin] Natl Univ Singapore, Canc Sci Inst Singapore, Singapore, Singapore. [Teo, Soo-Hwang] Sime Darby Med Ctr, Canc Res Initiat Fdn, Subang Jaya, Malaysia. [Teo, Soo-Hwang] Univ Malaya, Med Ctr, Canc Res Inst, Kuala Lumpur, Malaysia. [Bojesen, Stig E.] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark. [Bojesen, Stig E.] Copenhagen Univ Hosp, Herlev Hosp, Copenhagen Gen Populat Study, Herlev, Denmark. [Gapstur, Susan M.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Kjaer, Susanne Krueger] Univ Copenhagen, Rigshosp, Dept Gynaecol, Copenhagen, Denmark. [Pejovic, Tanja] Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Portland, OR 97201 USA. [Pejovic, Tanja] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. [Tammela, Teuvo L. J.] Tampere Univ Hosp, Dept Urol, Tampere, Finland. [Tammela, Teuvo L. J.] Tampere Univ, Sch Med, Tampere, Finland. [Doerk, Thilo] Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany. [Bruening, Thomas] Inst Ruhr Univ Bochum IPA, German Social Accid Insurance, Inst Prevent & Occupat Med, Bochum, Germany. [Edwards, Todd L.] Vanderbilt Univ, Dept Med, Vanderbilt Genet Inst, Vanderbilt Epidemiol Ctr,Div Epidemiol, Nashville, TN USA. [Kosma, Veli-Matti] Univ Eastern Finland, Inst Clin Med, Dept Pathol & Forens Med, Kuopio, Finland. [Kosma, Veli-Matti] Kuopio Univ Hosp, Dept Pathol, Kuopio, Finland. [Kristensen, Vessela] Oslo Univ Hosp, Radiumhosp, Inst Canc Res, Dept Genet, Oslo, Norway. [Kristensen, Vessela] Univ Oslo, Fac Med, Inst Clin Med, KG Jebsen Ctr Breast Canc Res, Oslo, Norway. [Kristensen, Vessela] Univ Oslo, Oslo Univ Hosp, Dept Clin Mol Biol, Oslo, Norway. [Vogel, Walther] Univ Hosp Ulm, Inst Human Genet, Ulm, Germany. [Blot, William J.] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37212 USA. [Gao, Yu-Tang] Shanghai Canc Inst, Shanghai, Peoples R China. [Freedman, Matthew L.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Freedman, Matthew L.] Eli & Edythe L Broad Inst, Cambridge, MA USA. [Simard, Jacques] Univ Laval, Ctr Hosp Univ Quebec, Res Ctr, Genom Ctr, Quebec City, PQ, Canada. [Spurdle, Amanda] QIMR Berghofer Med Res Inst, Mol Canc Epidemiol Lab, Herston, Qld, Australia. [Eeles, Rosalind] Royal Marsden Natl Hlth Serv NHS Fdn Trust, London, England. [Eeles, Rosalind] Royal Marsden Natl Hlth Serv NHS Fdn Trust, Sutton, Surrey, England. RP Kar, SP (reprint author), Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. EM sk718@medschl.cam.ac.uk RI Knight, Julia/A-6843-2012; Zheng, Wei/O-3351-2013; Bruning, Thomas/G-8120-2015; Dork, Thilo/J-8620-2012; Khusnutdinova, Elza/A-4810-2013; Gronwald, Jacek/A-4576-2017; Brenner, Hermann/B-4627-2017; salvesen, Helga/C-1187-2017; OI Dunning, Alison Margaret/0000-0001-6651-7166; Clements, Judith/0000-0001-6026-1964; Zheng, Wei/0000-0003-1226-070X; Bruning, Thomas/0000-0001-9560-5464; Gronwald, Jacek/0000-0002-3643-2871; Brenner, Hermann/0000-0002-6129-1572; salvesen, Helga/0000-0002-4438-8831; Moisse, Matthieu/0000-0001-8880-9311; Yannoukakos, Drakoulis/0000-0001-7509-3510 FU Cancer Research UK [C1287/A12014, C5047/A7357, C5047/A3354, C5047/A10692, C16913/A6135, C490/A6187, C490/A10119, C490/A10124, C536/A13086, C536/A6689, C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C8197/A16565]; European Community [223175 (HEALTH-F2-2009-223175)]; NIH [CA128978]; Post-Cancer GWAS Genetic Associations and Mechanisms in Oncology (GAME-ON) initiative [1U19 CA148537, 1U19 CA148065, 1U19 CA148112]; U.S. Department of Defense [W81XWH-10-1-0341]; Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer; Komen Foundation for the Cure; Breast Cancer Research Foundation; Ovarian Cancer Research Fund FX The Breast Cancer Association Consortium (BCAC), the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL), and the Ovarian Cancer Association Consortium (OCAC) that contributed breast, prostate, and ovarian cancer data analyzed in this study were in part funded by Cancer Research UK (C1287/A10118 and C1287/A12014 for BCAC; C5047/A7357, C1287/A10118, C5047/A3354, C5047/A10692, and C16913/A6135 for PRACTICAL; and C490/A6187, C490/A10119, C490/A10124, C536/A13086, and C536/A6689 for OCAC). Funding for the Collaborative Oncological Gene-Environment Study (COGS) infrastructure came from the European Community's Seventh Framework Programme under grant agreement number 223175 (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, and C8197/A16565), the NIH (CA128978) and the Post-Cancer GWAS Genetic Associations and Mechanisms in Oncology (GAME-ON) initiative (1U19 CA148537, 1U19 CA148065, and 1U19 CA148112), the U.S. Department of Defense (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund [with donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07)]. Additional financial support for contributing studies is documented in the Supplementary Financial Support. NR 84 TC 6 Z9 6 U1 16 U2 16 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2159-8274 EI 2159-8290 J9 CANCER DISCOV JI Cancer Discov. PD SEP PY 2016 VL 6 IS 9 BP 1052 EP 1067 DI 10.1158/2159-8290.CD-15-1227 PG 16 WC Oncology SC Oncology GA DW0TT UT WOS:000383356400028 PM 27432226 ER PT J AU Belluscio, L Zhou, ZS AF Belluscio, Leonardo Zhou, Zhishang TI Using the Olfactory System to Study Traumatic Brain injury SO CHEMICAL SENSES LA English DT Meeting Abstract CT 38th Annual Meeting of the Association-for-Chemoreception-Sciences (AChemS) CY APR 20-23, 2016 CL Bonita Springs, FL SP Assoc Chemorecept Sci C1 [Belluscio, Leonardo; Zhou, Zhishang] NINDS, NIH, Bldg 36,Rm 4D04, 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 0379-864X EI 1464-3553 J9 CHEM SENSES JI Chem. Senses PD SEP PY 2016 VL 41 IS 7 MA O6 BP E2 EP E3 PG 2 WC Behavioral Sciences; Food Science & Technology; Neurosciences; Physiology SC Behavioral Sciences; Food Science & Technology; Neurosciences & Neurology; Physiology GA DW7TH UT WOS:000383854300007 ER PT J AU Duffy, VB Stone, A Swede, H Rawal, S Tishler, DS Zoghbi, M Papasavas, PK AF Duffy, Valerie B. Stone, Andrea Swede, Helen Rawal, Shristi Tishler, Darren S. Zoghbi, Marina Papasavas, Pavlos K. TI Are Low Bitter Tasters More Successful at Weight Loss One Year Post-Bariatric Surgery? SO CHEMICAL SENSES LA English DT Meeting Abstract CT 38th Annual Meeting of the Association-for-Chemoreception-Sciences (AChemS) CY APR 20-23, 2016 CL Bonita Springs, FL SP Assoc Chemorecept Sci C1 [Duffy, Valerie B.; Zoghbi, Marina] UConn, Allied Hlth Sci, Storrs, CT USA. [Stone, Andrea; Tishler, Darren S.; Papasavas, Pavlos K.] Hartford Hosp, Dept Surg, Hartford, CT 06115 USA. [Swede, Helen] UConn Hlth, Dept Community Med & Hlth Care, Farmington, CT USA. [Rawal, Shristi] NICHD, NIH, DIPHR, EB, Rockville, 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 0379-864X EI 1464-3553 J9 CHEM SENSES JI Chem. Senses PD SEP PY 2016 VL 41 IS 7 MA 212 BP E46 EP E46 PG 1 WC Behavioral Sciences; Food Science & Technology; Neurosciences; Physiology SC Behavioral Sciences; Food Science & Technology; Neurosciences & Neurology; Physiology GA DW7TH UT WOS:000383854300115 ER PT J AU Hoffman, HJ Rawal, S Li, CM Duffy, VB AF Hoffman, Howard J. Rawal, Shristi Li, Chuan-Ming Duffy, Valerie B. TI Measured Olfactory Dysfunction for US Adults Aged 40+Years: Prevalence and Risk Factors Derived from the 2012 National Health and Nutrition Examination Survey (NHANES) SO CHEMICAL SENSES LA English DT Meeting Abstract CT 38th Annual Meeting of the Association-for-Chemoreception-Sciences (AChemS) CY APR 20-23, 2016 CL Bonita Springs, FL SP Assoc Chemorecept Sci C1 [Hoffman, Howard J.; Li, Chuan-Ming] NIDCD, NIH, Epidemiol & Stat Program, Bethesda, MD USA. [Rawal, Shristi] NICHD, NIH, DIPHR, EB, Bethesda, MD USA. [Duffy, Valerie B.] Univ Connecticut, Sch Allied Hlth, Storrs, CT 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 0379-864X EI 1464-3553 J9 CHEM SENSES JI Chem. Senses PD SEP PY 2016 VL 41 IS 7 MA 108 BP E27 EP E27 PG 1 WC Behavioral Sciences; Food Science & Technology; Neurosciences; Physiology SC Behavioral Sciences; Food Science & Technology; Neurosciences & Neurology; Physiology GA DW7TH UT WOS:000383854300069 ER PT J AU Rother, KI Sylvetsky, AC Blau, JE Bauman, V Garraffo, HM Walter, PJ AF Rother, Kristina I. Sylvetsky, Allison C. Blau, Jenny E. Bauman, Viviana Garraffo, H. M. Walter, Peter J. TI Plasma Concentrations of Sucralose after Ingestion of Sucralose Containing Beverages in Children and Adults SO CHEMICAL SENSES LA English DT Meeting Abstract CT 38th Annual Meeting of the Association-for-Chemoreception-Sciences (AChemS) CY APR 20-23, 2016 CL Bonita Springs, FL SP Assoc Chemorecept Sci C1 [Rother, Kristina I.; Blau, Jenny E.; Bauman, Viviana; Garraffo, H. M.; Walter, Peter J.] NIDDK, NIH, 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 0379-864X EI 1464-3553 J9 CHEM SENSES JI Chem. Senses PD SEP PY 2016 VL 41 IS 7 MA 209 BP E45 EP E45 PG 1 WC Behavioral Sciences; Food Science & Technology; Neurosciences; Physiology SC Behavioral Sciences; Food Science & Technology; Neurosciences & Neurology; Physiology GA DW7TH UT WOS:000383854300112 ER PT J AU Zoghbi, M Stone, A Swede, H Rawal, S Tishler, DS Papasavas, PK Duffy, VB AF Zoghbi, Marina Stone, Andrea Swede, Helen Rawal, Shristi Tishler, Darren S. Papasavas, Pavlos K. Duffy, Valerie B. TI Evaluating Dietary Quality and Taste Preferences with a Simple Liking Survey: Application to Studying Individuals with Morbid Obesity SO CHEMICAL SENSES LA English DT Meeting Abstract CT 38th Annual Meeting of the Association-for-Chemoreception-Sciences (AChemS) CY APR 20-23, 2016 CL Bonita Springs, FL SP Assoc Chemorecept Sci C1 [Zoghbi, Marina; Duffy, Valerie B.] UConn, Allied Hlth Sci, Storrs, CT USA. [Stone, Andrea; Tishler, Darren S.; Papasavas, Pavlos K.] Hartford Hosp, Dept Surg, Hartford, CT 06115 USA. [Swede, Helen] Dept Community Med, Farmington, CT USA. [Rawal, Shristi] NICHD, NIH, DIPHR, EB, Rockville, 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 0379-864X EI 1464-3553 J9 CHEM SENSES JI Chem. Senses PD SEP PY 2016 VL 41 IS 7 MA 302 BP E59 EP E59 PG 1 WC Behavioral Sciences; Food Science & Technology; Neurosciences; Physiology SC Behavioral Sciences; Food Science & Technology; Neurosciences & Neurology; Physiology GA DW7TH UT WOS:000383854300145 ER PT J AU Kalil, AC Metersky, ML Klompas, M Muscedere, J Sweeney, DA Palmer, LB Napolitano, LM O'Grady, NP Bartlett, JG Carratala, J El Solh, AA Ewig, S Fey, PD File, TM Restrepo, MI Roberts, JA Waterer, GW Cruse, P Knight, SL Brozek, JL AF Kalil, Andre C. Metersky, Mark L. Klompas, Michael Muscedere, John Sweeney, Daniel A. Palmer, Lucy B. Napolitano, Lena M. O'Grady, Naomi P. Bartlett, John G. Carratala, Jordi El Solh, Ali A. Ewig, Santiago Fey, Paul D. File, Thomas M., Jr. Restrepo, Marcos I. Roberts, Jason A. Waterer, Grant W. Cruse, Peggy Knight, Shandra L. Brozek, Jan L. TI Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID CONSENSUS; COLISTIN AB It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances. These guidelines are intended for use by healthcare professionals who care for patients at risk for hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP), including specialists in infectious diseases, pulmonary diseases, critical care, and surgeons, anesthesiologists, hospitalists, and any clinicians and healthcare providers caring for hospitalized patients with nosocomial pneumonia. The panel's recommendations for the diagnosis and treatment of HAP and VAP are based upon evidence derived from topic-specific systematic literature reviews. C1 [Kalil, Andre C.] Univ Nebraska Med Ctr, Div Infect Dis, Dept Internal Med, Omaha, NE 68198 USA. [Metersky, Mark L.] Univ Connecticut, Sch Med, Div Pulm & Crit Care Med, Farmington, CT USA. [Klompas, Michael] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Klompas, Michael] Harvard Med Sch, Boston, MA USA. [Klompas, Michael] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Muscedere, John] Queens Univ, Dept Med, Crit Care Program, Kingston, ON, Canada. [Sweeney, Daniel A.] Univ Calif San Diego, Div Pulm Crit Care & Sleep Med, San Diego, CA 92103 USA. [Palmer, Lucy B.] SUNY Stony Brook, Dept Med, Div Pulm Crit Care & Sleep Med, Stony Brook, NY 11794 USA. [Napolitano, Lena M.] Univ Michigan, Dept Surg, Div Trauma Crit Care & Emergency Surg, Ann Arbor, MI 48109 USA. [O'Grady, Naomi P.] NIH, Dept Crit Care Med, Bldg 10, Bethesda, MD 20892 USA. [Bartlett, John G.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Carratala, Jordi] Univ Barcelona, Dept Infect Dis, Hosp Univ Bellvitge, Bellvitge Biomed Res Inst,Spanish Network Res Inf, E-08007 Barcelona, Spain. [El Solh, Ali A.] SUNY Buffalo, Vet Affairs Western New York Healthcare Syst, Dept Med, Div Pulm Crit Care & Sleep Med, New York, NY USA. [Ewig, Santiago] EVK Herne, Dept Resp & Infect Dis, Thoraxzentrum Ruhrgebiet, Herne, Germany. [Ewig, Santiago] Augusta Kranken Anstalt Bochum, Bochum, Germany. [Fey, Paul D.] Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE USA. [File, Thomas M., Jr.] Summa Hlth Syst, Akron, OH USA. [Restrepo, Marcos I.] South Texas Vet Hlth Care Syst, Div Pulm & Crit Care Med, Dept Med, San Antonio, TX USA. [Restrepo, Marcos I.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Roberts, Jason A.] Univ Queensland, Burns Trauma & Crit Care Res Ctr, Brisbane, Qld 4072, Australia. [Roberts, Jason A.] Royal Brisbane & Womens Hosp, Herston, Qld, Australia. [Waterer, Grant W.] Univ Western Australia, Sch Med & Pharmacol, Perth, WA, Australia. [Cruse, Peggy; Knight, Shandra L.] Natl Jewish Hlth, Lib Serv, Denver, CO USA. [Cruse, Peggy; Knight, Shandra L.] Natl Jewish Hlth, Knowledge Serv, Denver, CO USA. [Brozek, Jan L.] McMaster Univ, Dept Clin Epidemiol & Biostat, Hamilton, ON, Canada. [Brozek, Jan L.] McMaster Univ, Dept Med, Hamilton, ON, Canada. RP Kalil, AC (reprint author), Univ Nebraska Med Ctr, Div Infect Dis, Dept Internal Med, Omaha, NE 68198 USA. EM akalil@unmc.edu FU IDSA; ATS FX The IDSA and the ATS provided meeting facilities for face-to-face meetings, financial support for conference calls, and administrative support. Industry funding to support guideline development was not permitted. NR 6 TC 6 Z9 6 U1 11 U2 11 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 SEP 1 PY 2016 VL 63 IS 5 BP 575 EP 582 DI 10.1093/cid/ciw504 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DW7TZ UT WOS:000383856300002 PM 27521441 ER PT J AU Knisely, JM Liu, BY Ranallo, RT Zou, LL AF Knisely, Jane M. Liu, Baoying Ranallo, Ryan T. Zou, Lanling TI Vaccines for Healthcare-associated Infections: Promise and Challenge SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE vaccines; healthcare-associated infections; Clostridium difficile; Staphylococcus aureus; antibiotic resistance ID CLOSTRIDIUM-DIFFICILE INFECTION; STAPHYLOCOCCUS-AUREUS INFECTIONS; PNEUMOCOCCAL CONJUGATE VACCINE; POPULATION-BASED SURVEILLANCE; BACTERIA-INDUCED LETHALITY; UNITED-STATES; VESICLES PROTECTS; CLINICAL-TRIALS; BURDEN; DIARRHEA AB As antibiotic resistance increases and the rate of antibiotic development slows, it is becoming more urgent to develop novel approaches to prevent and mitigate serious bacterial and fungal infections. Healthcare-associated infections (HAIs), including those caused by Clostridium difficile, Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter baumannii, carbapenem-resistant Enterobacteriaceae, and Candida species, are a major cause of morbidity, mortality, and healthcare costs. HAIs are also a key driver of antibiotic use. Vaccines directed toward these pathogens could help prevent a large number of HAIs and associated antibiotic use if administered to targeted populations. Despite numerous scientific and operational challenges, there are vaccine candidates in late-stage clinical development for C. difficile, S. aureus, and P. aeruginosa. Basic, preclinical, and early clinical research to develop vaccines for other types of HAIs is also under way. In addition, other prophylactic immune interventions, such as monoclonal antibodies, for several of these pathogens are in advanced development. Here we describe the promise, challenges, and current pipeline of vaccines to prevent HAIs. C1 [Knisely, Jane M.; Liu, Baoying; Ranallo, Ryan T.; Zou, Lanling] NIAID, Div Microbiol & Infect Dis, NIH, Rockville, MD 20852 USA. RP Knisely, JM (reprint author), NIAID, Div Microbiol & Infect Dis, NIH, Rockville, MD 20852 USA. EM jane.knisely@nih.gov NR 41 TC 0 Z9 0 U1 8 U2 10 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 SEP 1 PY 2016 VL 63 IS 5 BP 657 EP 662 DI 10.1093/cid/ciw333 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DW7TZ UT WOS:000383856300016 PM 27208045 ER PT J AU Kalil, AC Metersky, ML Klompas, M Muscedere, J Sweeney, DA Palmer, LB Napolitano, LM O'Grady, NP Bartlett, JG Carratala, J El Solh, AA Ewig, S Fey, PD File, TM Restrepo, MI Roberts, JA Waterer, GW Cruse, P Knight, SL Brozek, JL AF Kalil, Andre C. Metersky, Mark L. Klompas, Michael Muscedere, John Sweeney, Daniel A. Palmer, Lucy B. Napolitano, Lena M. O'Grady, Naomi P. Bartlett, John G. Carratala, Jordi El Solh, Ali A. Ewig, Santiago Fey, Paul D. File, Thomas M., Jr. Restrepo, Marcos I. Roberts, Jason A. Waterer, Grant W. Cruse, Peggy Knight, Shandra L. Brozek, Jan L. TI Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID INTENSIVE-CARE-UNIT; RESISTANT STAPHYLOCOCCUS-AUREUS; CRITICALLY-ILL PATIENTS; GRAM-NEGATIVE BACTERIA; COMBINATION ANTIBIOTIC-THERAPY; RANDOMIZED CONTROLLED-TRIAL; DE-ESCALATION THERAPY; PSEUDOMONAS-AERUGINOSA BACTEREMIA; RESPIRATORY-TRACT INFECTIONS; PROTECTED SPECIMEN BRUSH AB It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances. These guidelines are intended for use by healthcare professionals who care for patients at risk for hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP), including specialists in infectious diseases, pulmonary diseases, critical care, and surgeons, anesthesiologists, hospitalists, and any clinicians and healthcare providers caring for hospitalized patients with nosocomial pneumonia. The panel's recommendations for the diagnosis and treatment of HAP and VAP are based upon evidence derived from topic-specific systematic literature reviews. C1 [Kalil, Andre C.] Univ Nebraska Med Ctr, Div Infect Dis, Dept Internal Med, Omaha, NE 68198 USA. [Metersky, Mark L.] Univ Connecticut, Sch Med, Div Pulm & Crit Care Med, Farmington, CT USA. [Klompas, Michael] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Klompas, Michael] Harvard Med Sch, Boston, MA USA. [Klompas, Michael] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Muscedere, John] Queens Univ, Dept Med, Crit Care Program, Kingston, ON, Canada. [Sweeney, Daniel A.] Univ Calif San Diego, Div Pulm Crit Care & Sleep Med, San Diego, CA 92103 USA. [Palmer, Lucy B.] SUNY Stony Brook, Dept Med, Div Pulm Crit Care & Sleep Med, Stony Brook, NY 11794 USA. [Napolitano, Lena M.] Univ Michigan, Dept Surg, Div Trauma Crit Care & Emergency Surg, Ann Arbor, MI 48109 USA. [O'Grady, Naomi P.] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. [Bartlett, John G.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Carratala, Jordi] Univ Barcelona, Spanish Network Res Infect Dis, Bellvitge Biomed Res Inst, Dept Infect Dis,Hosp Univ Bellvitge, E-08007 Barcelona, Spain. [El Solh, Ali A.] SUNY Buffalo, Dept Med, Div Pulm Crit Care & Sleep Med, Vet Affairs Western New York Healthcare Syst, New York, NY USA. [Ewig, Santiago] EVK Herne, Thoraxzentrum Ruhrgebiet, Dept Resp & Infect Dis, Herne, Germany. [Ewig, Santiago] Augusta Kranken Anstalt Bochum, Bochum, Germany. [Fey, Paul D.] Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE USA. [File, Thomas M., Jr.] Summa Hlth Syst, Akron, OH USA. [Restrepo, Marcos I.] South Texas Vet Hlth Care Syst, Div Pulm & Crit Care Med, Dept Med, San Antonio, TX USA. [Restrepo, Marcos I.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Roberts, Jason A.] Univ Queensland, Burns Trauma & Crit Care Res Ctr, Brisbane, Qld 4072, Australia. [Roberts, Jason A.] Royal Brisbane & Womens Hosp, Herston, Qld, Australia. [Waterer, Grant W.] Univ Western Australia, Sch Med & Pharmacol, Perth, WA, Australia. [Cruse, Peggy; Knight, Shandra L.] Natl Jewish Hlth, Lib Serv, Denver, CO USA. [Cruse, Peggy; Knight, Shandra L.] Natl Jewish Hlth, Knowledge Serv, Denver, CO USA. [Brozek, Jan L.] McMaster Univ, Dept Clin Epidemiol & Biostat, Hamilton, ON, Canada. [Brozek, Jan L.] McMaster Univ, Dept Med, Hamilton, ON, Canada. RP Kalil, AC (reprint author), Univ Nebraska Med Ctr, Div Infect Dis, Dept Internal Med, Omaha, NE 68198 USA. EM akalil@unmc.edu FU IDSA; ATS FX The IDSA and the ATS provided meeting facilities for face-to-face meetings, financial support for conference calls, and administrative support. Industry funding to support guideline development was not permitted. NR 364 TC 38 Z9 41 U1 5 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD SEP 1 PY 2016 VL 63 IS 5 BP E61 EP E111 DI 10.1093/cid/ciw353 PG 51 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DW7TZ UT WOS:000383856300001 PM 27418577 ER PT J AU Saproo, S Faller, J Shih, V Sajda, P Waytowich, NR Bohannon, A Lawhern, VJ Lance, BJ Jangraw, D AF Saproo, Sameer Faller, Josef Shih, Victor Sajda, Paul Waytowich, Nicholas R. Bohannon, Addison Lawhern, Vernon J. Lance, Brent J. Jangraw, David TI Cortically Coupled Computing: A New Paradigm for Synergistic Human-Machine Interaction SO COMPUTER LA English DT Article ID VISION AB Unlike traditional brain-computer interfaces that use brain signals for direct control of computers and robotics, a cortically coupled computer system opportunistically senses the brain state, capturing a user's implicit or explicit computation, and then communicates this information to a traditional computer system via a neural interface. C1 [Saproo, Sameer; Shih, Victor; Sajda, Paul] Columbia Univ, Dept Biomed Engn, New York, NY 10027 USA. [Faller, Josef; Sajda, Paul] Columbia Univ, Lab Intelligent Imaging & Neural Comp, New York, NY 10027 USA. [Sajda, Paul] Columbia Univ, Dept Elect Engn, New York, NY 10027 USA. [Sajda, Paul] Columbia Univ, Dept Radiol, New York, NY 10027 USA. [Waytowich, Nicholas R.; Lawhern, Vernon J.; Lance, Brent J.] US Army Res Lab, Human Res & Engn Directorate, Adelphi, MD USA. [Bohannon, Addison] US Army Res Lab, Adelphi, MD USA. [Jangraw, David] NIMH, Sect Funct Imaging Methods, Bethesda, MD 20892 USA. RP Saproo, S (reprint author), Columbia Univ, Dept Biomed Engn, New York, NY 10027 USA. EM ssaproo.ucsd@gmail.com; josef.faller@columbia.edu; vs2481@columbia.edu; psajda@columbia.edu; nick.waytowich@gmail.com; addisonb@math.umd.edu; vernon.j.lawhern.civ@mail.mil; brent.j.lance.civ@mail.mil; david.jangraw@nih.gov FU Defense Advanced Research Projects Agency (DARPA); Army Research Office (ARO) [W911NF-11-1-0219]; Army Research Laboratory (ARL) [W911NF-10-2-0022]; Office of the Secretary of Defense Autonomy Research Pilot Initiative program [MIPR DWAM31168]; UK Economic and Social Research Council [ES/L012995/1] FX This work was funded by the Defense Advanced Research Projects Agency (DARPA), the Army Research Office (ARO) under grant number W911NF-11-1-0219, the Army Research Laboratory (ARL) under cooperative agreement number W911NF-10-2-0022, the Office of the Secretary of Defense Autonomy Research Pilot Initiative program MIPR DWAM31168, and the UK Economic and Social Research Council under grant number ES/L012995/1. NR 13 TC 0 Z9 0 U1 2 U2 2 PU IEEE COMPUTER SOC PI LOS ALAMITOS PA 10662 LOS VAQUEROS CIRCLE, PO BOX 3014, LOS ALAMITOS, CA 90720-1314 USA SN 0018-9162 EI 1558-0814 J9 COMPUTER JI Computer PD SEP PY 2016 VL 49 IS 9 BP 60 EP 68 PG 9 WC Computer Science, Hardware & Architecture; Computer Science, Software Engineering SC Computer Science GA DX1MX UT WOS:000384132600009 ER PT J AU Heidemann, LA Navarro, VJ Ahmad, J Hayashi, PH Stolz, A Kleiner, DE Fontana, RJ AF Heidemann, Lauren A. Navarro, Victor J. Ahmad, Jawad Hayashi, Paul H. Stolz, Andrew Kleiner, David E. Fontana, Robert J. TI Severe Acute Hepatocellular Injury Attributed to OxyELITE Pro: A Case Series SO DIGESTIVE DISEASES AND SCIENCES LA English DT Article DE Hepatotoxicity; Herbal and dietary supplement; Drug-induced liver injury ID INDUCED LIVER-INJURY; DIETARY-SUPPLEMENTS; CAUSALITY ASSESSMENT; ADVERSE EVENTS; HEPATOTOXICITY; HEPATITIS AB Herbal and dietary supplement (HDS) hepatotoxicity is increasingly being reported in the USA. This case series describes the presenting clinical features and outcomes of seven patients with liver injury attributed to OxyELITE Pro enrolled in the Drug-Induced Liver Injury Network (DILIN) study. The 6-month outcomes of patients with hepatotoxicity attributed to OxyELITE Pro enrolled in the DILIN prospective registry between 2004 and 2015 are presented. Six of the seven patients (86 %) presented in 2013 with symptoms of hepatitis and acute hepatocellular injury. The median duration of OxyELITE Pro use was 18 weeks (range 5-102 weeks). Median age was 36 years (range 28-62), 86 % were female, and 43 % were Asian. One patient had rash, none had eosinophilia, and three had antinuclear antibody reactivity. The median peak ALT was 2242 U/L, alkaline phosphatase 284 U/L and bilirubin 15.0 mg/dL. Six patients (86 %) were hospitalized, three developed acute liver failure and two underwent liver transplantation. DILIN causality scores for OxyELITE Pro were definite in 1, highly likely in 3, probable in 2, and possible in 1. Four of the five patients without liver transplant recovered completely within 6 months, while one patient had mild residual ALT elevations. Seven cases of severe acute hepatocellular injury attributed to OxyELITE Pro are reported. These results reinforce the need to assess for HDS supplement use in patients presenting with unexplained acute hepatitis and point to the need for additional regulatory oversight of HDS products. C1 [Heidemann, Lauren A.; Fontana, Robert J.] Univ Michigan, Dept Internal Med, Med Ctr, 3912 Taubman Ctr, Ann Arbor, MI 48109 USA. [Navarro, Victor J.] Einstein Healthcare Network, Dept Med, Philadelphia, PA USA. [Ahmad, Jawad] Icahn Sch Med Mt Sinai, Dept Med, Med Ctr, New York, NY 10029 USA. [Hayashi, Paul H.] Univ N Carolina, Chapel Hill, NC USA. [Stolz, Andrew] Univ Southern Calif, Los Angeles, CA USA. [Kleiner, David E.] NCI, Pathol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Fontana, RJ (reprint author), Univ Michigan, Dept Internal Med, Med Ctr, 3912 Taubman Ctr, Ann Arbor, MI 48109 USA. EM rfontana@med.umich.edu FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) [U01DK065211, U01DK065184, U01DK065201, U01DK083020, U01DK083027, U01DK100928, U01DK065176]; Intramural Division of the National Cancer Institute (NCI), NIH FX The Drug-Induced Liver Injury Network (DILIN) is structured as an U01 cooperative agreement supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) with funds provided by the following grants: U01DK065211 (Indiana University [Indianapolis]), U01DK065184 (University of Michigan [Ann Arbor]), U01DK065201 (University of North Carolina [Chapel Hill], Asheville, Wake Forest Baptist Medical Center), U01DK083020 (University of Southern California, University of California-Los Angeles [Pfleger Liver Institute]), U01DK083027 (Albert Einstein Medical Center), U01DK100928 (Icahn School of Medicine at Mount Sinai), U01DK065176 (Duke Clinical Research Institute). Additional support was provided by the Intramural Division of the National Cancer Institute (NCI), NIH. NR 27 TC 3 Z9 3 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0163-2116 EI 1573-2568 J9 DIGEST DIS SCI JI Dig. Dis. Sci. PD SEP PY 2016 VL 61 IS 9 BP 2741 EP 2748 DI 10.1007/s10620-016-4181-7 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DU1TP UT WOS:000381992700035 PM 27142670 ER PT J AU Bandettini, WP Karageorgiadis, AS Sinaii, N Rosing, DR Sachdev, V Schernthaner-Reiter, MH Gourgari, E Papadakis, GZ Keil, MF Lyssikatos, C Carney, JA Arai, AE Lodish, M Stratakis, CA AF Bandettini, W. Patricia Karageorgiadis, Alexander S. Sinaii, Ninet Rosing, Douglas R. Sachdev, Vandana Schernthaner-Reiter, Marie Helene Gourgari, Evgenia Papadakis, Georgios Z. Keil, Meg F. Lyssikatos, Charalampos Carney, J. Aidan Arai, Andrew E. Lodish, Maya Stratakis, Constantine A. TI Growth hormone and risk for cardiac tumors in Carney complex SO ENDOCRINE-RELATED CANCER LA English DT Article DE tumor; acromegaly; growth hormone; insulin like growth factor-I (IGF-I); myxoma ID PROTEIN-KINASE-A; MCCUNE-ALBRIGHT SYNDROME; IGF-BINDING PROTEIN-3; CANCER-RISK; COLORECTAL-CANCER; NEOPLASIA; PRKAR1A; MYXOMA; STERNOTOMY; EXPERIENCE AB Carney complex (CNC) is a multiple neoplasia syndrome that is caused mostly by PRKAR1A mutations. Cardiac myxomas are the leading cause of mortality in CNC patients who, in addition, often develop growth hormone (GH) excess. We studied patients with CNC, who were observed for over a period of 20 years (1995-2015) for the development of both GH excess and cardiac myxomas. GH secretion was evaluated by standard testing; dedicated cardiovascular imaging was used to detect cardiac abnormalities. Four excised cardiac myxomas were tested for the expression of insulin-like growth factor-1 (IGF-1). A total of 99 CNC patients (97 with a PRKAR1A mutation) were included in the study with a mean age of 25.8 +/- 16.6 years at presentation. Over an observed mean follow-up of 25.8 years, 60% of patients with GH excess (n = 46) developed a cardiac myxoma compared with only 36% of those without GH excess (n = 54) (P = 0.016). Overall, patients with GH excess were also more likely to have a tumor vs those with normal GH secretion (OR: 2.78, 95% CI: 1.23-6.29; P = 0.014). IGF-1 mRNA and protein were higher in CNC myxomas than in normal heart tissue. We conclude that the development of cardiac myxomas in CNC may be associated with increased GH secretion, in a manner analogous to the association between fibrous dysplasia and GH excess in McCune-Albright syndrome, a condition similar to CNC. We speculate that treatment of GH excess in patients with CNC may reduce the likelihood of cardiac myxoma formation and/or recurrence of this tumor. C1 [Bandettini, W. Patricia; Rosing, Douglas R.; Sachdev, Vandana; Arai, Andrew E.] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Karageorgiadis, Alexander S.; Schernthaner-Reiter, Marie Helene; Gourgari, Evgenia; Keil, Meg F.; Lyssikatos, Charalampos; Lodish, Maya; Stratakis, Constantine A.] NICHD, NIH, Bethesda, MD 20894 USA. [Karageorgiadis, Alexander S.; Gourgari, Evgenia] Georgetown Univ Hosp, Dept Pediat, Washington, DC USA. [Sinaii, Ninet] NIH, Ctr Clin, Biostat & Clin Epidemiol Serv, Bldg 10, Bethesda, MD 20892 USA. [Papadakis, Georgios Z.] NIH, Ctr Clin, Dept Radiol & Imaging Sci, Bldg 10, Bethesda, MD 20892 USA. [Carney, J. Aidan] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. RP Stratakis, CA (reprint author), NICHD, NIH, Bethesda, MD 20894 USA. EM stratakc@mail.nih.gov OI Schernthaner-Reiter, Marie Helene/0000-0002-7972-7610 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development FX Intramural research support of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 40 TC 0 Z9 0 U1 0 U2 0 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 1351-0088 EI 1479-6821 J9 ENDOCR-RELAT CANCER JI Endocr.-Relat. Cancer PD SEP PY 2016 VL 23 IS 9 BP 739 EP 746 DI 10.1530/ERC-16-0246 PG 8 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA DX2HX UT WOS:000384190100011 PM 27535175 ER PT J AU Varoquaux, A Kebebew, E Sebag, F Wolf, K Henry, JF Pacak, K Taieb, D AF Varoquaux, Arthur Kebebew, Electron Sebag, Frederic Wolf, Katherine Henry, Jean-Francois Pacak, Karel Taieb, David TI Endocrine tumors associated with the vagus nerve SO ENDOCRINE-RELATED CANCER LA English DT Review DE vagus nerve; paragangliomas; hyperparathyroidism; diagnostic imaging ID FUNCTIONAL IMAGING MODALITIES; PRIMARY HYPERPARATHYROIDISM; NECK PARAGANGLIOMAS; MUTATION CARRIERS; PARAPHARYNGEAL SPACE; GERMLINE MUTATIONS; PARATHYROID TISSUE; MR-ANGIOGRAPHY; SDHB-MUTATION; HEAD AB The vagus nerve (cranial nerve X) is the main nerve of the parasympathetic division of the autonomic nervous system. Vagal paragangliomas (VPGLs) are a prime example of an endocrine tumor associated with the vagus nerve. This rare, neural crest tumor constitutes the second most common site of hereditary head and neck paragangliomas (HNPGLs), most often in relation to mutations in the succinate dehydrogenase complex subunit D (SDHD) gene. The treatment paradigm for VPGL has progressively shifted from surgery to abstention or therapeutic radiation with curative-like outcomes. Parathyroid tissue and parathyroid adenoma can also be found in close association with the vagus nerve in intra or paravagal situations. Vagal parathyroid adenoma can be identified with preoperative imaging or suspected intraoperatively by experienced surgeons. Vagal parathyroid adenomas located in the neck or superior mediastinum can be removed via initial cervicotomy, while those located in the aortopulmonary window require a thoracic approach. This review particularly emphasizes the embryology, molecular genetics, and modern imaging of these tumors. C1 [Varoquaux, Arthur] Aix Marseille Univ, Concept Hosp, Dept Radiol, Marseille, France. [Kebebew, Electron] NCI, Endocrine Oncol Branch, NIH, Bethesda, MD 20892 USA. [Sebag, Frederic; Henry, Jean-Francois] Aix Marseille Univ, Concept Hosp, Dept Endocrine Surg, Marseille, France. [Wolf, Katherine; Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Med Neuroendocrinol, NIH, Bethesda, MD USA. [Taieb, David] Aix Marseille Univ, CERIMED, La Timone Univ Hosp, Dept Nucl Med, Marseille, France. RP Taieb, D (reprint author), Aix Marseille Univ, CERIMED, La Timone Univ Hosp, Dept Nucl Med, Marseille, France. EM david.taieb@ap-hm.fr FU Intramural NIH HHS [ZIA HD008735-15] NR 48 TC 0 Z9 0 U1 0 U2 0 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 1351-0088 EI 1479-6821 J9 ENDOCR-RELAT CANCER JI Endocr.-Relat. Cancer PD SEP PY 2016 VL 23 IS 9 BP R371 EP R379 DI 10.1530/ERC-16-0241 PG 9 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA DX2HX UT WOS:000384190100001 PM 27406876 ER PT J AU Merriman, DK Sajdak, BS Li, W Jones, BW AF Merriman, Dana K. Sajdak, Benjamin S. Li, Wei Jones, Bryan W. TI Seasonal and post-trauma remodeling in cone-dominant ground squirrel retina SO EXPERIMENTAL EYE RESEARCH LA English DT Review DE Cone photoreceptor; Microglia; Muller cell; Reactive gliosis; Retinal detachment; Retinal pigment epithelium; Synaptic plasticity ID OPTIC-NERVE FIBERS; MAMMALIAN RETINA; SPERMOPHILUS-BEECHEYI; BIPOLAR CELLS; SUPERIOR COLLICULUS; GANGLION-CELLS; CITELLUS-TRIDECEMLINEATUS; LATERAL GENICULATE; VISUAL-SYSTEM; ICTIDOMYS-TRIDECEMLINEATUS AB With a photoreceptor mosaic containing similar to 85% cones, the ground squirrel is one of the richest known mammalian sources of these important retinal cells. It also has a visual ecology much like the human's. While the ground squirrel retina is understandably prominent in the cone biochemistry, physiology, and circuitry literature, far less is known about the remodeling potential of its retinal pigment epithelium, neurons, macroglia, or microglia. This review aims to summarize the data from ground squirrel retina to this point in time, and to relate them to data from other brain areas where appropriate. We begin with a survey of the ground squirrel visual system, making comparisons with traditional rodent models and with human. Because this animal's status as a hibernator often goes unnoticed in the vision literature, we then present a brief primer on hibernation biology. Next we review what is known about ground squirrel retinal remodeling concurrent with deep torpor and with rapid recovery upon re-warming. Notable here is rapidly-reversible, temperature-dependent structural plasticity of cone ribbon synapses, as well as pre- and post-synaptic plasticity throughout diverse brain regions. It is not yet clear if retinal cell types other than cones engage in torpor-associated synaptic remodeling. We end with the small but intriguing literature on the ground squirrel retina's remodeling responses to insult by retinal detachment. Notable for widespread loss of (cone) photoreceptors, there is surprisingly little remodeling of the RPE or Muller cells. Microglial activation appears minimal, and remodeling of surviving second- and third-order neurons seems absent, but both require further study. In contrast, traumatic brain injury in the ground squirrel elicits typical macroglial and microglial responses. Overall, the data to date strongly suggest a heretofore unrecognized, natural checkpoint between retinal deafferentiation and RPE and Muller cell remodeling events. As we continue to discover them, the unique ways by which ground squirrel retina responds to hibernation or injury may be adaptable to therapeutic use. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Merriman, Dana K.] Univ Wisconsin, Dept Biol, Oshkosh, WI 54901 USA. [Sajdak, Benjamin S.] Med Coll Wisconsin, Dept Cell Biol Neurobiol & Anat, Milwaukee, WI 53226 USA. [Li, Wei] NEI, Unit Retinal Neurobiol, Bethesda, MD USA. [Jones, Bryan W.] Univ Utah, Sch Med, Dept Ophthalmol & Visual Sci, Salt Lake City, UT USA. RP Merriman, DK (reprint author), Biol UW Oshkosh, Oshkosh, WI 54901 USA. EM merrimad@uwosh.edu; besajdak@mcw.edu; liwei2@nei.nih.gov; bryan.jones@m.cc.utah.edu FU University of Wisconsin Oshkosh; AxleTech International Endowed Professorship; NEI [P30EY001931]; NIH [EY015128, EY02576, EY014800]; Research to Prevent Blindness FX This work was funded by the University of Wisconsin Oshkosh Faculty Development and Student Collaborative Grant Programs and the AxleTech International Endowed Professorship (D.K.M.), NEI Core Grant P30EY001931 (B.S.S.), the NEI Intramural Research Program (W.L.), and NIH EY015128, EY02576, EY014800 Vision Core, and an unrestricted grant from Research to Prevent Blindness to the Moran Eye Center (B.W.J.). NR 182 TC 1 Z9 1 U1 5 U2 5 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0014-4835 EI 1096-0007 J9 EXP EYE RES JI Exp. Eye Res. PD SEP PY 2016 VL 150 SI SI BP 90 EP 105 DI 10.1016/j.exer.2016.01.011 PG 16 WC Ophthalmology SC Ophthalmology GA DX5BR UT WOS:000384395300009 PM 26808487 ER PT J AU Visco, AG Zyczynski, H Brubaker, L Nygaard, I Xu, X Lukacz, ES Paraiso, MF Greer, J Rahn, DD Meikle, SF Honeycutt, AA AF Visco, Anthony G. Zyczynski, Halina Brubaker, Linda Nygaard, Ingrid Xu, Xiao Lukacz, Emily S. Paraiso, Marie Fidela Greer, Jerod Rahn, David D. Meikle, Susan F. Honeycutt, Amanda A. TI Cost-Effectiveness Analysis of Anticholinergics Versus Botox for Urgency Urinary Incontinence: Results From the Anticholinergic Versus Botox Comparison Randomized Trial SO FEMALE PELVIC MEDICINE AND RECONSTRUCTIVE SURGERY LA English DT Article DE botulinum toxin; urge urinary incontinence; anticholinergic medication; cost-effectiveness; randomized trial ID OVERACTIVE BLADDER QUESTIONNAIRE; DETRUSOR OVERACTIVITY; OAB-Q; PERSISTENCE; TOXIN; SOLIFENACIN; THERAPY; HEALTH AB Objectives: This study aimed to compare the cost-effectiveness of Botox and anticholinergic (AC) medications for the management of urgency urinary incontinence (UUI). Methods: Cost and effectiveness data were analyzed from participants in the Anticholinergic versus Botox Comparison randomized trial of daily AC medication versus 100 U of intradetrusor Botox injection. Societal costs included the following: treatment costs, patient costs, and medical and nonmedical utilization during the 6-month trial. Quality-adjusted life-years (QALYs) were calculated based on questionnaire-derived utility measures and annualized based on data collected at baseline through 6 months. We also estimated the average direct costs for each treatment through 9 months - the duration of time when approximately half the Botox participants maintained adequate symptom control. Results: Data were analyzed on the 231 women who completed a 6-month follow-up in the Anticholinergic versus Botox Comparison trial (119 AC and 112 Botox). The mean reduction in UUI episodes per day was not significantly different per group. The cumulative mean direct costs through the first 6 months also were similar: $1339 for the AC group and $1266 for the Botox group with AC costs exceeding Botox costs after 5 months. Both groups had considerable QALY gains. Annualizing the 6-month trial results to a 12-month measure, the AC and Botox groups averaged 0.702 and 0.707 QALYs, respectively. Estimates through 9 months favored Botox, showing that AC participants incurred a higher cost per month of adequate symptoms control ($305) compared with Botox participants ($207). Conclusions: Botox and AC medications have similar costs and effectiveness in the first 6 months of UUI treatment. If costs and outcomes are considered through 9 months, Botox may have significantly lower costs but similar UUI symptom control as AC. C1 [Visco, Anthony G.] Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC 27710 USA. [Zyczynski, Halina] Univ Pittsburgh, Pittsburgh, PA USA. [Brubaker, Linda] Loyola Univ, Stritch Sch Med, Dept Obstet & Gynecol, Chicago, IL 60611 USA. [Brubaker, Linda] Loyola Univ, Stritch Sch Med, Dept Urol, Chicago, IL 60611 USA. [Nygaard, Ingrid] Univ Utah, Dept Obstet & Gynecol, Salt Lake City, UT USA. [Xu, Xiao] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Lukacz, Emily S.] UC San Diego Hlth Syst, Dept Reprod Med, San Diego, CA USA. [Paraiso, Marie Fidela] Cleveland Clin, Dept Obstet & Gynecol, Cleveland, OH 44106 USA. [Greer, Jerod] Univ Alabama Birmingham, Dept Obstet & Gynecol, Birmingham, AL 35294 USA. [Rahn, David D.] Univ Texas Southwestern Med Ctr Dallas, Dept Obstet & Gynecol, Dallas, TX 75390 USA. [Meikle, Susan F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Gynecol Hlth & Dis Branch, NIH, Bethesda, MD USA. [Honeycutt, Amanda A.] RTI Int, Res Triangle Pk, NC USA. RP Visco, AG (reprint author), Duke Univ, Med Ctr, Dept Obstet & Gynecol, Div Urogynecol & Reconstruct Pelv Surg, 5324 McFarland Dr,Suite 310, Durham, NC 27707 USA. EM anthony.visco@duke.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (Duke) [2-U10-HD04267-12]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (Pittsburgh) [1-U10-HD069006-01]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (Loyola) [U10-HD054136]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (Utah) [U10-HD041250]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (University of Michigan) [U01-HD41249]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (UCSD) [2-U10-HD054214-06]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (Cleveland Clinic) [2-U10-HD054215-06]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (UAB) [2-U10-HD041261-11]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (UTSW) [2-U10-HD054241-06]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (RTI) [1-U01-HD069010-01]; NIH Office of Research on Women's Health FX This study was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Duke, 2-U10-HD04267-12; Pittsburgh, 1-U10-HD069006-01; Loyola, U10-HD054136; Utah, U10-HD041250; University of Michigan, U01-HD41249; UCSD, 2-U10-HD054214-06; Cleveland Clinic, 2-U10-HD054215-06; UAB, 2-U10-HD041261-11; UTSW, 2-U10-HD054241-06, and RTI, 1-U01-HD069010-01) and the NIH Office of Research on Women's Health. NR 30 TC 0 Z9 0 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 2151-8378 EI 2154-4212 J9 FEMALE PELVIC MED RE JI Female Pelvic Med. Reconstr. Surg. PD SEP-OCT PY 2016 VL 22 IS 5 BP 311 EP 316 DI 10.1097/SPV.0000000000000277 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DW9SP UT WOS:000384003300008 PM 27564385 ER PT J AU Iranzo, J Puigbo, P Lobkovsky, AE Wolf, YI Koonin, EV AF Iranzo, Jaime Puigbo, Pere Lobkovsky, Alexander. E. Wolf, Yuri I. Koonin, Eugene V. TI Inevitability of Genetic Parasites SO GENOME BIOLOGY AND EVOLUTION LA English DT Article DE horizontal gene transfer; Muller's ratchet; genetic parasites; homologous recombination; mathematical modeling ID BRANCHING-PROCESS MODEL; TRANSPOSABLE ELEMENTS; GENOME EVOLUTION; DELETERIOUS MUTATIONS; BACTERIAL GENOMES; MULLERS RATCHET; MENDELIAN POPULATIONS; RECOMBINATION RATES; INSERTION SEQUENCES; REPLICATOR SYSTEMS AB Almost all cellular life forms are hosts to diverse genetic parasites with various levels of autonomy including plasmids, transposons and viruses. Theoretical modeling of the evolution of primordial replicators indicates that parasites (cheaters) necessarily evolve in such systems and can be kept at bay primarily via compartmentalization. Given the (near) ubiquity, abundance and diversity of genetic parasites, the question becomes pertinent: are such parasites intrinsic to life? At least in prokaryotes, the persistence of parasites is linked to the rate of horizontal gene transfer (HGT). We mathematically derive the threshold value of the minimal transfer rate required for selfish element persistence, depending on the element duplication and loss rates as well as the cost to the host. Estimation of the characteristic gene duplication, loss and transfer rates for transposons, plasmids and virus-related elements in multiple groups of diverse bacteria and archaea indicates that most of these rates are compatible with the long term persistence of parasites. Notably, a small but non-zero rate of HGT is also required for the persistence of non-parasitic genes. We hypothesize that cells cannot tune their horizontal transfer rates to be below the threshold required for parasite persistence without experiencing highly detrimental side-effects. As a lower boundary to the minimum DNA transfer rate that a cell can withstand, we consider the process of genome degradation and mutational meltdown of populations through Muller's ratchet. A numerical assessment of this hypothesis suggests that microbial populations cannot purge parasites while escaping Muller's ratchet. Thus, genetic parasites appear to be virtually inevitable in cellular organisms. C1 [Iranzo, Jaime; Puigbo, Pere; Lobkovsky, Alexander. E.; Wolf, Yuri I.; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. [Puigbo, Pere] Univ Turku, Dept Biol, SF-20500 Turku, Finland. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM koonin@ncbi.nlm.nih.gov RI Iranzo, Jaime/H-5197-2011 OI Iranzo, Jaime/0000-0002-4538-7726 FU US Department of Health and Human Services FX We thank David Kristensen for expert advice on ATGC analysis and Koonin group members for useful discussion. The authors' research is supported by intramural funds of the US Department of Health and Human Services (to the National Library of Medicine). NR 121 TC 3 Z9 3 U1 15 U2 15 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1759-6653 J9 GENOME BIOL EVOL JI Genome Biol. Evol. PD SEP PY 2016 VL 8 IS 9 BP 2856 EP 2869 DI 10.1093/gbe/evw193 PG 14 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA DX3WP UT WOS:000384307900017 ER PT J AU Vitale, S Clemons, TE Agron, E Ferris, FL Domalpally, A Danis, RP Chew, EY AF Vitale, Susan Clemons, Traci E. Agron, Elvira Ferris, Frederick L., III Domalpally, Amitha Danis, Ronald P. Chew, Emily Y. CA Age-Related Eye Dis Study 2 AREDS2 TI Evaluating the Validity of the Age-Related Eye Disease Study Grading Scale for Age-Related Macular Degeneration AREDS2 Report 10 SO JAMA OPHTHALMOLOGY LA English DT Article ID SEVERITY SCALE; CLINICAL-TRIAL; UNITED-STATES; PREVALENCE; MODEL AB ` IMPORTANCE To test potential treatments for age-related macular degeneration (AMD), clinical trials need standardized outcome measures that are valid for predicting AMD progression in different study populations. OBJECTIVE To evaluate the validity of the Age-Related Eye Disease Study (AREDS) detailed and simple AMD severity scales by comparing rates of development of late AMD (neovascular AMD and/ or central geographic atrophy) between AREDS and AREDS2 participants. DESIGN, SETTING, AND PARTICIPANTS Both AREDS (1992-2001) and AREDS2 (2006-2012) enrolled patients from academic and community-based retinal practices across the United States. In AREDS (n = 4519), participants with varying severity of AMD-from no AMD to late AMD in 1 eye-were enrolled. In AREDS2 (n = 4203), participants with bilateral large drusen or large drusen in the study eye and late AMD in the fellow eye were enrolled. MAIN OUTCOMES AND MEASURES Five-year incidence of late AMD, assessed by annual masked centralized fundus photograph grading. RESULTS In AREDS, the mean (SD) age of the patients was 69.3 (5.7) years, and 2519 (55.7%) were female. In AREDS2, the mean (SD) age of the patients was 73.1 (7.7) years, and 2388 (56.8%) were female. The 5-year rates of late AMD did not differ between AREDS2 and AREDS participants within nearly all baseline AMD detailed severity scale levels: levels 1 to 3: 2.4% vs 0.5%(difference, 1.9%; 95% CI, -0.2% to 4.0%; P<.001); level 4: 6.5% vs 4.9% (difference, 1.6%; 95% CI, -1.7% to 4.8%; P=.34); level 5: 8.0% vs 5.6%(difference, 2.4%; 95% CI, -1.2% to 5.9%; P=.22); level 6: 12.8% vs 13.7%(difference, -0.9%; 95% CI, -4.8% to 3.1%; P=.66); level 7: 26.2% vs 27.8%(difference, -1.5%; 95% CI, -6.6% to 3.5%; P=.54); and level 8: 46.4% vs 44.7%(difference, 1.7%; 95% CI, -7.5% to 10.9%; P=.72). Within simple scale levels, AREDS2 and AREDS 5-year rates did not differ significantly except for level 1 (9.4% vs 3.1%, P=.02; level 2: 12.8% vs 11.8%, P=.65; level 3: 26.3% vs 25.9%, P=.90; and level 4: 45.6% vs 47.3%, P=.57). CONCLUSIONS AND RELEVANCE The AREDS detailed and simple AMD severity scales were useful measures for assessing the risk of developing late AMD in the AREDS2 population; these data suggest that they should be useful tools for clinical trials of AMD treatments. C1 [Vitale, Susan; Agron, Elvira; Ferris, Frederick L., III; Chew, Emily Y.] NEI, Div Epidemiol & Clin Applicat, NIH, 10 Ctr Dr,Room 10D45, Bethesda, MD 20892 USA. [Clemons, Traci E.] EMMES Corp, Rockville, MD USA. [Domalpally, Amitha; Danis, Ronald P.] Univ Wisconsin, Fundus Photog Reading Ctr, Madison, WI 53706 USA. RP Vitale, S (reprint author), NEI, Div Epidemiol & Clin Applicat, NIH, 10 Ctr Dr,Room 10D45, Bethesda, MD 20892 USA. EM sev@nei.nih.gov FU ABD from National Eye Institute (NEI), National Institutes of Health (NIH), Department of Health and Human Services, Bethesda, Maryland [N01-EY-5-00007]; Research to Prevent Blindness; intramural program funds; [HHS-N-260-2005-00007-C] FX This study was supported by the intramural program funds and contract HHS-N-260-2005-00007-C and ABD contract N01-EY-5-00007 from the National Eye Institute (NEI), National Institutes of Health (NIH), Department of Health and Human Services, Bethesda, Maryland (design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication), and in part by an unrestricted grant from Research to Prevent Blindness to the Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison (Drs Domalpally and Danis) (collection, management, analysis, and interpretation of the data). NR 15 TC 2 Z9 2 U1 1 U2 1 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 SEP PY 2016 VL 134 IS 9 BP 1041 EP 1047 DI 10.1001/jamaophthalmol.2016.2383 PG 7 WC Ophthalmology SC Ophthalmology GA DW9NY UT WOS:000383988800021 PM 27442263 ER PT J AU Higgins, RD Patel, RM Josephson, CD AF Higgins, Rosemary D. Patel, Ravi Mangal Josephson, Cassandra D. TI Preoperative Anemia and Neonates SO JAMA PEDIATRICS LA English DT Editorial Material ID TRANSFUSION; OUTCOMES C1 [Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, NIH, 6710B Rockledge Dr,Room 2233,Mail Stop Code 7002, Bethesda, MD 20892 USA. [Patel, Ravi Mangal] Emory Univ, Sch Med, Dept Pediat, Div Neonatol, Atlanta, GA USA. [Patel, Ravi Mangal] Childrens Healthcare Atlanta, Atlanta, GA USA. [Josephson, Cassandra D.] Emory Univ, Sch Med, Pathol & Pediat, Atlanta, GA USA. [Josephson, Cassandra D.] Childrens Healthcare Atlanta, Transfus Tissue & Apheresis Serv, Atlanta, GA USA. RP Higgins, RD (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, NIH, 6710B Rockledge Dr,Room 2233,Mail Stop Code 7002, Bethesda, MD 20892 USA. EM higginsr@mail.nih.gov FU Intramural NIH HHS [Z99 HD999999]; NHLBI NIH HHS [P01 HL086773, K23 HL128942] NR 6 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6203 EI 2168-6211 J9 JAMA PEDIATR JI JAMA Pediatr. PD SEP PY 2016 VL 170 IS 9 BP 835 EP 836 DI 10.1001/jamapediatrics.2016.1354 PG 3 WC Pediatrics SC Pediatrics GA DX2PL UT WOS:000384212700011 PM 27428663 ER PT J AU Shaikh, N Mattoo, TK Keren, R Ivanova, A Cui, G Moxey-Mims, M Majd, M Ziessman, HA Hoberman, A AF Shaikh, Nader Mattoo, Tej K. Keren, Ron Ivanova, Anastasia Cui, Gang Moxey-Mims, Marva Majd, Massoud Ziessman, Harvey A. Hoberman, Alejandro TI Early Antibiotic Treatment for Pediatric Febrile Urinary Tract Infection and Renal Scarring SO JAMA PEDIATRICS LA English DT Article ID RISK-FACTORS; CHILDREN; PYELONEPHRITIS; REFLUX; DIAGNOSIS; THERAPY; UTI AB IMPORTANCE Existing data regarding the association between delayed initiation of antimicrobial therapy and the development of renal scarring are inconsistent. OBJECTIVE To determine whether delay in the initiation of antimicrobial therapy for febrile urinary tract infections (UTIs) is associated with the occurrence and severity of renal scarring. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study that combined data from 2 previously conducted longitudinal studies (the Randomized Intervention for Children With Vesicoureteral Reflux trial and the Careful Urinary Tract Infection Evaluation Study). Children younger than 6 years with a first or second UTI were followed up for 2 years. EXPOSURE Duration of the child's fever prior to initiation of antimicrobial therapy for the index UTI. MAIN OUTCOMES AND MEASURES New renal scarring defined as the presence of photopenia plus contour change on a late dimercaptosuccinic acid renal scan (obtained at study exit) that was not present on the baseline scan. RESULTS Of the 482 children included in the analysis, 434 were female (90%), 375 were white (78%), and 375 had vesicoureteral reflux (78%). The median age was 11 months. A total of 35 children (7.2%) developed new renal scarring. Delay in the initiation of antimicrobial therapy was associated with renal scarring; the median (25th, 75th percentiles) duration of fever prior to initiation of antibiotic therapy in those with and without renal scarring was 72 (30, 120) and 48 (24, 72) hours, respectively (P =.003). Older age (OR, 1.03; 95% CI, 1.01-1.05), Hispanic ethnicity (OR, 5.24; 95% CI, 2.15-12.77), recurrent urinary tract infections (OR, 0.97; 95% CI, 0.27-3.45), and bladder and bowel dysfunction (OR, 6.44; 95% CI, 2.89-14.38) were also associated with new renal scarring. Delay in the initiation of antimicrobial therapy remained significantly associated with renal scarring even after adjusting for these variables. CONCLUSIONS AND RELEVANCE Delay in treatment of febrile UTIs and permanent renal scarring are associated. In febrile children, clinicians should not delay testing for UTI. C1 [Shaikh, Nader; Hoberman, Alejandro] Univ Pittsburgh, Childrens Hosp Pittsburgh, Sch Med, Med Ctr,Div Gen Acad Pediat, Pittsburgh, PA USA. [Mattoo, Tej K.] Wayne State Univ, Childrens Hosp Michigan, Detroit, MI USA. [Keren, Ron] Childrens Hosp Philadelphia, Div Gen Pediat, Ctr Pediat Clin Effectiveness, Philadelphia, PA 19104 USA. [Ivanova, Anastasia] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Cui, Gang] Univ N Carolina, Dept Biostat, Collaborat Studies Coordinating Ctr, Chapel Hill, NC USA. [Moxey-Mims, Marva] NIDDK, NIH, Bethesda, MD 20892 USA. [Majd, Massoud] George Washington Univ, Sch Med, Childrens Natl Med Ctr, Div Radiol, Washington, DC USA. [Ziessman, Harvey A.] Johns Hopkins Univ, Dept Radiol, Baltimore, MD USA. RP Shaikh, N (reprint author), UPMC, Childrens Hosp Pittsburgh, One Childrens Hosp Dr,4401 Penn Ave, Pittsburgh, PA 15224 USA. EM nader.shaikh@chp.edu FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services [U01 DK074059, U01 DK074053, U01 DK074082, U01 DK074064, U01 DK074062, U01 DK074063] FX This research was supported by grants U01 DK074059, U01 DK074053, U01 DK074082, U01 DK074064, U01 DK074062, and U01 DK074063 from the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services. NR 16 TC 7 Z9 7 U1 1 U2 1 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 SEP PY 2016 VL 170 IS 9 BP 848 EP 854 DI 10.1001/jamapediatrics.2016.1181 PG 7 WC Pediatrics SC Pediatrics GA DX2PL UT WOS:000384212700014 PM 27455161 ER PT J AU Volkow, ND AF Volkow, Nora D. TI Effects of Cannabis Use on Human Behavior: A Call for Standardization of Cannabis Use Metrics SO JAMA PSYCHIATRY LA English DT Letter ID PSYCHOSIS C1 [Volkow, Nora D.] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Volkow, ND (reprint author), NIDA, NIH, 6001 Execut Blvd, Bethesda, MD 20892 USA. EM nvolkow@nida.nih.gov NR 3 TC 0 Z9 0 U1 4 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-622X EI 2168-6238 J9 JAMA PSYCHIAT JI JAMA Psychiatry PD SEP PY 2016 VL 73 IS 9 BP 996 EP 996 DI 10.1001/jamapsychiatry.2016.1332 PG 1 WC Psychiatry SC Psychiatry GA DW9PB UT WOS:000383992300021 PM 27463420 ER PT J AU Weeks, J Briggs, J AF Weeks, John Briggs, Josephine TI The New USA NIH Strategic Plan for Complementary and Integrative Health: Interview with Josephine Briggs, MD Director, National Center for Complementary and Integrative Health (Part 1) SO JOURNAL OF ALTERNATIVE AND COMPLEMENTARY MEDICINE LA English DT Editorial Material C1 [Briggs, Josephine] NIH, NCCIH, Bldg 10, Bethesda, MD 20892 USA. [Briggs, Josephine] NIH, Precis Med Initiat, Cohort Program, Bldg 10, Bethesda, MD 20892 USA. [Briggs, Josephine] NIH, Steering Comm, Bldg 10, Bethesda, MD 20892 USA. [Briggs, Josephine] NIH, Sci Management Review Board, Bldg 10, Bethesda, MD 20892 USA. [Briggs, Josephine] NIH Pain Consortium, Execut Comm, New York, NY 10013 USA. [Briggs, Josephine] Univ Munich, Inst Physiol, Munich, Germany. [Briggs, Josephine] Univ Michigan, Dept Med, Ann Arbor, MI 48109 USA. [Briggs, Josephine] NIH, Div Kidney Urol & Hematol Diseases, Bldg 10, Bethesda, MD 20892 USA. RP Briggs, J (reprint author), NIH, NCCIH, Bldg 10, Bethesda, MD 20892 USA.; Briggs, J (reprint author), NIH, Precis Med Initiat, Cohort Program, Bldg 10, Bethesda, MD 20892 USA.; Briggs, J (reprint author), NIH, Steering Comm, Bldg 10, Bethesda, MD 20892 USA.; Briggs, J (reprint author), NIH, Sci Management Review Board, Bldg 10, Bethesda, MD 20892 USA.; Briggs, J (reprint author), NIH Pain Consortium, Execut Comm, New York, NY 10013 USA. NR 7 TC 1 Z9 1 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1075-5535 EI 1557-7708 J9 J ALTERN COMPLEM MED JI J. Altern. Complement Med. PD SEP PY 2016 VL 22 IS 9 BP 680 EP 683 DI 10.1089/acm.2016.29009.jjb PG 4 WC Integrative & Complementary Medicine SC Integrative & Complementary Medicine GA DW9SL UT WOS:000384002900002 PM 27559747 ER PT J AU Jacoby, GA Bonomo, RA Bradford, PA Bush, K Doi, Y Feldgarden, M Haft, D Klimke, W Nordmann, P Palzkill, T Poirel, L Prasad, A Rossolini, GM Walsh, T AF Jacoby, George A. Bonomo, Robert A. Bradford, Patricia A. Bush, Karen Doi, Yohei Feldgarden, Michael Haft, Daniel Klimke, William Nordmann, Patrice Palzkill, Timothy Poirel, Laurent Prasad, Arjun Rossolini, Gian Maria Walsh, Timothy TI Comment on: Resistance gene naming and numbering: is it a new gene or not? SO JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY LA English DT Letter ID BETA-LACTAMASES; KLEBSIELLA-PNEUMONIAE; ENZYME C1 [Jacoby, George A.] Lahey Hosp & Med Ctr, Burlington, MA USA. [Bonomo, Robert A.] Louis Stokes Cleveland Vet Affairs Med Ctr, Res Serv, Cleveland, OH USA. [Bradford, Patricia A.] AstraZeneca, Dev Microbiol, Waltham, MA USA. [Bush, Karen] Indiana Univ, Bloomington, IN USA. [Doi, Yohei] Univ Pittsburgh, Sch Med, Div Infect Dis, Pittsburgh, PA USA. [Feldgarden, Michael; Haft, Daniel; Klimke, William; Prasad, Arjun] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. [Nordmann, Patrice; Poirel, Laurent] Univ Fribourg, Fac Sci, Emerging Antibiot Resistance Unit, Med & Mol Microbiol,Dept Med, Fribourg, Switzerland. [Palzkill, Timothy] Baylor Coll Med, Dept Pharmacol, Houston, TX 77030 USA. [Rossolini, Gian Maria] Univ Florence, Dept Expt & Clin Med, Florence, Italy. [Rossolini, Gian Maria] Univ Siena, Dept Med Biotechnol, Siena, Italy. [Walsh, Timothy] Cardiff Univ, Dept Med Microbiol & Infect Dis, Cardiff, S Glam, Wales. RP Jacoby, GA (reprint author), Lahey Hosp & Med Ctr, Burlington, MA USA. EM gajacoby50@gmail.com OI Prasad, Arjun/0000-0002-1343-8664 NR 10 TC 4 Z9 4 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-7453 EI 1460-2091 J9 J ANTIMICROB CHEMOTH JI J. Antimicrob. Chemother. PD SEP PY 2016 VL 71 IS 9 BP 2677 EP 2678 DI 10.1093/jac/dkw204 PG 2 WC Infectious Diseases; Microbiology; Pharmacology & Pharmacy SC Infectious Diseases; Microbiology; Pharmacology & Pharmacy GA DW8NB UT WOS:000383911600048 PM 27261266 ER PT J AU Maiga, M Cohen, K Baya, B Srikrishna, G Siddiqui, S Sanogo, M Somboro, AM Diarra, B Diallo, MH Mazumdar, V Yoder, C Orsega, S Belson, M Kassambara, H Goita, D Murphy, RL Dao, S Polis, M Diallo, S Timmins, GS Dodd, L Earl, AM Bishai, WR AF Maiga, Mamoudou Cohen, Keira Baya, Bocar Srikrishna, Geetha Siddiqui, Sophia Sanogo, Moumine Somboro, Anou M. Diarra, Bassirou Diallo, Mariam H. Mazumdar, Varun Yoder, Christian Orsega, Susan Belson, Michael Kassambara, Hamadoun Goita, Drissa Murphy, Robert L. Dao, Sounkalo Polis, Michael Diallo, Souleymane Timmins, Graham S. Dodd, Lori Earl, Ashlee M. Bishai, William R. TI Stool microbiome reveals diverse bacterial ureases as confounders of oral urea breath testing for Helicobacter pylori and Mycobacterium tuberculosis in Bamako, Mali SO JOURNAL OF BREATH RESEARCH LA English DT Article DE oral urease breath test; urease; TB; H. pylori ID CAMPYLOBACTER-PYLORI; INFECTION; PATHOGENESIS; DIAGNOSIS; C-13-UREA AB Detection of bacterial urease activity has been utilized successfully to diagnose Helicobacter pylori (H. pylori). While Mycobacterium tuberculosis (M. tuberculosis) also possesses an active urease, it is unknown whether detection of mycobacterial urease activity by oral urease breath test (UBT) can be exploited as a rapid point of care biomarker for tuberculosis (TB) in humans. We enrolled 34 individuals newly diagnosed with pulmonary TB and 46 healthy subjects in Bamako, Mali and performed oral UBT, mycobacterial sputum culture and H. pylori testing. Oral UBT had a sensitivity and specificity (95% CI) of 70% (46-88%) and 11% (3-26%), respectively, to diagnose culture-confirmed M. tuberculosis disease among patients without H. pylori, and 100% sensitivity (69-100%) and 11% specificity (3-26%) to diagnose H. pylori among patients without pulmonary TB. Stool microbiome analysis of controls without TB or H. pylori but with positive oral UBT detected high levels of non-H. pylori urease producing organisms, which likely explains the low specificity of oral UBT in this setting and in other reports of oral UBT studies in Africa. C1 [Maiga, Mamoudou; Baya, Bocar; Sanogo, Moumine; Somboro, Anou M.; Diarra, Bassirou; Diallo, Mariam H.; Kassambara, Hamadoun; Goita, Drissa; Dao, Sounkalo; Diallo, Souleymane] USTTB, SEREFO HIV TB, Bamako, Mali. [Maiga, Mamoudou; Srikrishna, Geetha; Bishai, William R.] Johns Hopkins Univ, Sch Med, Ctr TB Res, Baltimore, MD 21231 USA. [Cohen, Keira] Brigham & Womens Hosp, Dept Med, Div Pulm & Crit Care Med, 75 Francis St, Boston, MA 02115 USA. [Siddiqui, Sophia; Yoder, Christian; Orsega, Susan; Belson, Michael; Polis, Michael; Dodd, Lori] NIAID, Div Clin Res, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Mazumdar, Varun; Earl, Ashlee M.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Murphy, Robert L.] Northwestern Univ, Div Infect Dis, Chicago, IL 60611 USA. [Timmins, Graham S.] Univ New Mexico, Div Pharmaceut Sci, Albuquerque, NM 87131 USA. [Bishai, William R.] Johns Hopkins Univ, Sch Med, Ctr TB Res, 1550 Orleans St Suite 103, Baltimore, MD 21287 USA. RP Bishai, WR (reprint author), Johns Hopkins Univ, Sch Med, Ctr TB Res, Baltimore, MD 21231 USA.; Bishai, WR (reprint author), Johns Hopkins Univ, Sch Med, Ctr TB Res, 1550 Orleans St Suite 103, Baltimore, MD 21287 USA. EM wbishai@jhmi.edu FU NIAID Division of Clinical Research, NIH; NIH [AI36973, AI37856, AI097138, AI069471]; Howard Hughes Medical Institute; University of Sciences, Techniques and Technologies of Bamako; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN272200900018C, U19AI110818] FX We are grateful to Otsuka America Pharmaceutical, Inc., Rockville, MD for generously providing us 650 blue and pink bags of BreathTek (R) UBT kits. The support of the NIAID Division of Clinical Research, NIH intramural funding to SEREFO, as well as NIH extramural grants AI36973, AI37856, AI097138 and AI069471, the Howard Hughes Medical Institute, the University of Sciences, Techniques and Technologies of Bamako, and the volunteers who participated in the study is gratefully acknowledged. This project has also been funded in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN272200900018C and Grant Number U19AI110818 to the Broad Institute. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. NR 27 TC 0 Z9 0 U1 4 U2 4 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 1752-7155 EI 1752-7163 J9 J BREATH RES JI J. Breath Res. PD SEP PY 2016 VL 10 IS 3 AR 036012 DI 10.1088/1752-7155/10/3/036012 PG 7 WC Biochemical Research Methods; Respiratory System SC Biochemistry & Molecular Biology; Respiratory System GA DX0MX UT WOS:000384058300001 PM 27532494 ER PT J AU McDuffie, LA Sabesan, A Allgaeuer, M Xin, LQ Koh, C Heller, T Davis, JL Raffeld, M Miettienen, M Quezado, M Rudloff, U AF McDuffie, Lucas A. Sabesan, Arvind Allgaeuer, Michael Xin, Liqiang Koh, Christopher Heller, Theo Davis, Jeremy L. Raffeld, Mark Miettienen, Markku Quezado, Martha Rudloff, Udo TI -Catenin activation in fundic gland polyps, gastric cancer and colonic polyps in families afflicted by "gastric adenocarcinoma and proximal polyposis of the stomach' (GAPPS) SO JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE GASTRIC CANCER; GASTRIC PATHOLOGY; FAMILIAL CANCERS ID HIGH-GRADE DYSPLASIA; ADENOMATOUS POLYPOSIS; MUTATION; GERMLINE; PATIENT; MODEL AB Aim To evaluate possible colon involvement in the gastric adenocarcinoma and proximal polyposis of the stomach' (GAPPS) gastrointestinal polyposis syndrome. Methods Prospective clinicopathological evaluation of two GAPPS families and expression of nuclear -catenin, p53 and Ki67 measured by immunohistochemistry on endoscopic and surgical specimens from patients with GAPPS. Results Patients with the GAPPS phenotype were more frequently affected by colonic polyps than patients at risk within the same families (p<0.01). Colonic polyps shared immunohistochemical features of fundic gland polyps and gastric cancers including increased expression of nuclear -catenin, Ki67 and p53. Both gastric and colonic lesions harboured activating somatic variants of -catenin signalling. Conclusions Similarities in expression markers in fundic gland and colonic polyps, together with an enrichment of colonic adenomas in family members affected by GAPPS phenotype compared with family members at risk, support mild colonic involvement of this rare cancer syndrome. Colonoscopic screening might be warranted. C1 [McDuffie, Lucas A.; Sabesan, Arvind; Davis, Jeremy L.; Rudloff, Udo] NCI, Thorac & Gastrointestinal Oncol Branch, NIH, Bethesda, MD 20892 USA. [Allgaeuer, Michael; Xin, Liqiang; Raffeld, Mark; Miettienen, Markku; Quezado, Martha] NCI, Pathol Lab, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. [Koh, Christopher; Heller, Theo] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. RP Rudloff, U (reprint author), NCI, Thorac & Gastrointestinal Oncol Branch, Gastrointestinal Oncol Sect, Ctr Canc Res, Bldg 10 Hatfield CRC,Room 4-5950, Bethesda, MD 20892 USA. EM rudloffu@mail.nih.gov FU National Cancer Institute [CCR NCI-09-0079] FX National Cancer Institute (grant no CCR NCI-09-0079). NR 24 TC 0 Z9 0 U1 1 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0021-9746 EI 1472-4146 J9 J CLIN PATHOL JI J. Clin. Pathol. PD SEP PY 2016 VL 69 IS 9 BP 826 EP 833 DI 10.1136/jclinpath-2016-203746 PG 8 WC Pathology SC Pathology GA DX4BN UT WOS:000384323700015 PM 27406052 ER PT J AU Qi, X Davis, B Chiang, YH Filichia, E Barnett, A Greig, NH Hoffer, B Luo, Y AF Qi, Xin Davis, Brandon Chiang, Yung-Hsiao Filichia, Emily Barnett, Austin Greig, Nigel H. Hoffer, Barry Luo, Yu TI Dopaminergic neuron-specific deletion of p53 gene is neuroprotective in an experimental Parkinson's disease model SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE apopotosis; cell specific knockout; MPTP; p53; parkinson's disease ID TUMOR-SUPPRESSOR P53; SUBSTANTIA-NIGRA; CELL-DEATH; MOUSE MODEL; MICE; APOPTOSIS; BAX; 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE; EXPRESSION; PROTEIN AB p53, a stress response gene, is involved in diverse cell death pathways and its activation has been implicated in the pathogenesis of Parkinson's disease (PD). However, whether the neuronal p53 protein plays a direct role in regulating dopaminergic (DA) neuronal cell death is unknown. In this study, in contrast to the global inhibition of p53 function by pharmacological inhibitors and in traditional p53 knock-out (KO) mice, we examined the effect of DA specific p53 gene deletion in DAT-p53KO mice. These DAT-p53KO mice did not exhibit apparent changes in the general structure and neuronal density of DA neurons during late development and in aging. However, in DA-p53KO mice treated with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), we found that the induction of Bax and p53 up-regulated modulator of apoptosis (PUMA) mRNA and protein levels by MPTP were diminished in both striatum and substantia nigra of these mice. Notably, deletion of the p53 gene in DA neurons significantly reduced dopaminergic neuronal loss in substantia nigra, dopaminergic neuronal terminal loss at striatum and, additionally, decreased motor deficits in mice challenged with MPTP. In contrast, there was no difference in astrogliosis between WT and DAT-p53KO mice in response to MPTP treatment. These findings demonstrate a specific contribution of p53 activation in DA neuronal cell death by MPTP challenge. Our results further support the role of programmed cell death mediated by p53 in this animal model of PD and identify Bax, BAD and PUMA genes as downstream targets of p53 in modulating DA neuronal death in the in vivo MPTP-induced PD model. C1 [Qi, Xin] Case Western Reserve Univ, Dept Physiol & Biophys, 2109 Adelbert Rd, Cleveland, OH 44106 USA. [Davis, Brandon; Filichia, Emily; Barnett, Austin; Hoffer, Barry; Luo, Yu] Case Western Reserve Univ, Dept Neurol Surg, 2109 Adelbert Rd, Cleveland, OH 44106 USA. [Chiang, Yung-Hsiao] Taipei Med Univ, Coll Med, Dept Surg, Div Neurosurg, Taipei, Taiwan. [Greig, Nigel H.] NIA, Drug Design & Dev Sect, Translat Gerontol Branch, Intramural Res Program, Baltimore, MD 21224 USA. RP Luo, Y (reprint author), Case Western Reserve Univ, Dept Neurol Surg, 2109 Adelbert Rd, Cleveland, OH 44106 USA. EM yxl710@case.edu FU NLNDS [R01NS094152, R01 NS091213]; Spitz Brain Health Innovation Award from Taiwan [MOST 101-2632-B-038-001-MY3]; Research Program of the National Institute on Aging, NIH FX This study is supported by NLNDS R01NS094152, R01 NS091213, the Spitz Brain Health Innovation Award, MOST 101-2632-B-038-001-MY3 from Taiwan, and by the intramural Research Program of the National Institute on Aging, NIH. We would like to thank Larimee Cortnik for help in preparation of the manuscript. The authors declare no competing financial interests. NR 49 TC 0 Z9 0 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD SEP PY 2016 VL 138 IS 5 BP 746 EP 757 DI 10.1111/jnc.13706 PG 12 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA DX0DF UT WOS:000384031000008 PM 27317935 ER PT J AU Aschrafi, A Verheijen, JM Gordebeke, PM Loohuis, NFO Menting, K Jager, A Palkovits, M Geenen, B Kos, A Martens, GJM Glennon, JC Kaplan, BB Gaszner, B Kozicz, T AF Aschrafi, Armaz Verheijen, Jan M. Gordebeke, Peter M. Loohuis, Nikkie F. Olde Menting, Kelly Jager, Amanda Palkovits, Miklos Geenen, Bram Kos, Aron Martens, Gerard J. M. Glennon, Jeffrey C. Kaplan, Barry B. Gaszner, Balazs Kozicz, Tamas TI MicroRNA-326 acts as a molecular switch in the regulation of midbrain urocortin 1 expression SO JOURNAL OF PSYCHIATRY & NEUROSCIENCE LA English DT Article ID EDINGER-WESTPHAL NUCLEUS; MAJOR DEPRESSION; CITALOPRAM TREATMENT; SUICIDE VICTIMS; GENE-EXPRESSION; MICRO-RNA; STRESS; NEURONS; BRAIN; TRANSCRIPT AB Background Altered levels of urocortin 1 (Ucn1) in the centrally projecting Edinger-Westphal nucleus (EWcp) of depressed suicide attempters or completers mediate the brain's response to stress, while the mechanism regulating Ucn1 expression is unknown. We tested the hypothesis that microRNAs (miRNAs), which are vital fine-tuners of gene expression during the brain's response to stress, have the capacity to modulate Ucn1 expression. Methods Computational analysis revealed that the Ucn1 3 untranslated region contained a conserved binding site for miR-326. We examined miR-326 and Ucn1 levels in the EWcp of depressed suicide completers. In addition, we evaluated miR-326 and Ucn1 levels in the serum and the EWcp of a chronic variable mild stress (CVMS) rat model of behavioural despair and after recovery from CVMS, respectively. Gain and loss of miR-326 function experiments examined the regulation of Ucn1 by this miRNA in cultured midbrain neurons. Results We found reduced miR-326 levels concomitant with elevated Ucn1 levels in the EWcp of depressed suicide completers as well as in the EWcp of CVMS rats. In CVMS rats fully recovered from stress, both serum and EWcp miR-326 levels rebounded to nonstressed levels. While downregulation of miR-326 levels in primary midbrain neurons enhanced Ucn1 expression levels, miR-326 overexpression selectively reduced the levels of this neuropeptide. Limitations This study lacked experiments showing that in vivo alteration of miR-326 levels alleviate depression-like behaviours. We show only correlative data for miR-325 and cocaine- and amphetamine-regulated transcript levels in the EWcp. Conclusion We identified miR-326 dysregulation in depressed suicide completers and characterized this miRNA as an upstream regulator of the Ucn1 neuropeptide expression in midbrain neurons. C1 [Aschrafi, Armaz; Verheijen, Jan M.; Gordebeke, Peter M.; Menting, Kelly; Geenen, Bram; Kozicz, Tamas] Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Dept Anat, Nijmegen, Netherlands. [Loohuis, Nikkie F. Olde; Jager, Amanda; Kos, Aron; Glennon, Jeffrey C.] Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Dept Cognit Neurosci, Nijmegen, Netherlands. [Palkovits, Miklos] Semmelweis Univ, Dept Anat, Budapest, Hungary. [Martens, Gerard J. M.] Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Dept Mol Anim Physiol, Nijmegen, Netherlands. [Aschrafi, Armaz; Kaplan, Barry B.] NIMH, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Gaszner, Balazs] Univ Pecs, Fac Med, Dept Anat, Pecs, Hungary. [Kozicz, Tamas] Tulane Univ, Hayward Genet Ctr, Dept Pediat, New Orleans, LA 70118 USA. VIB, Dept Mol Genet, Neurodegenerat Brain Dis Grp, Antwerp, Belgium. [Verheijen, Jan M.] Univ Antwerp, Inst Born Bunge, Antwerp, Belgium. RP Aschrafi, A (reprint author), Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Dept Anat, Nijmegen, Netherlands. EM armaz.aschrafi@gmail.com RI Geenen, Bram/D-9659-2016; Glennon, Jeffrey/D-2379-2013; OI Geenen, Bram/0000-0001-7838-3097; Verheijen, Jan/0000-0003-0481-9649 FU Donders Center for Neuroscience fellowship award of the Radboud University Nijmegen Medical Centre; FP7-Marie Curie International Reintegration FX The authors thank the individuals who provided technical assistance. This work was supported by a Donders Center for Neuroscience fellowship award of the Radboud University Nijmegen Medical Centre and a grant from FP7-Marie Curie International Reintegration to A. Aschrafi. NR 56 TC 0 Z9 0 U1 8 U2 8 PU CMA-CANADIAN MEDICAL ASSOC PI OTTAWA PA 1867 ALTA VISTA DR, OTTAWA, ONTARIO K1G 5W8, CANADA SN 1180-4882 EI 1488-2434 J9 J PSYCHIATR NEUROSCI JI J. Psychiatry Neurosci. PD SEP PY 2016 VL 41 IS 5 BP 342 EP 353 DI 10.1503/jpn.150154 PG 12 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DW9NJ UT WOS:000383986700009 PM 27045550 ER PT J AU Kendall, GM Wakeford, R Bunch, KJ Vincent, TJ Little, MP AF Kendall, G. M. Wakeford, R. Bunch, K. J. Vincent, T. J. Little, M. P. TI Residential mobility and associated factors in relation to the assessment of exposure to naturally occurring radiation in studies of childhood cancer (vol 35, pg 835, 2015) SO JOURNAL OF RADIOLOGICAL PROTECTION LA English DT Correction C1 [Kendall, G. M.] Univ Oxford, Canc Epidemiol Unit, Richard Doll Bldg,Old Rd Campus, Oxford OX3 7LF, England. [Wakeford, R.] Univ Manchester, Inst Populat Hlth, Ctr Occupat & Environm Hlth, Ellen Wilkinson Bldg,Oxford Rd, Manchester M13 9PL, Lancs, England. [Bunch, K. J.] Univ Oxford, Natl Perinatal Epidemiol Unit, Richard Doll Bldg,Old Rd Campus, Oxford OX3 7LF, England. [Vincent, T. J.] Univ Oxford, Childhood Canc Res Grp, New Richards Bldg,Old Rd Campus, Oxford OX3 7LF, England. [Little, M. P.] NCI, Radiat Epidemiol Branch, DHHS, NIH,Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Kendall, GM (reprint author), Univ Oxford, Canc Epidemiol Unit, Richard Doll Bldg,Old Rd Campus, Oxford OX3 7LF, England. EM Gerald.Kendall@CEU.ox.ac.uk NR 1 TC 0 Z9 0 U1 0 U2 0 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0952-4746 EI 1361-6498 J9 J RADIOL PROT JI J. Radiol. Prot. PD SEP PY 2016 VL 36 IS 3 BP 719 EP 720 DI 10.1088/0952-4746/36/3/719 PG 2 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA DW9MA UT WOS:000383982900006 ER PT J AU Li, KG Simons-Morton, B Gee, B Hingson, R AF Li, Kaigang Simons-Morton, Bruce Gee, Benjamin Hingson, Ralph TI Marijuana-, alcohol-, and drug-impaired driving among emerging adults: Changes from high school to one-year post-high school SO JOURNAL OF SAFETY RESEARCH LA English DT Article DE Adolescents; Impaired driving; Alcohol drinking; Marijuana use; Illicit drug use ID COLLEGE-STUDENTS; PROTECTIVE FACTORS; SUBSTANCE USE; PARENTING PRACTICES; DRINKING; RISK; PEER; ADOLESCENTS; INVOLVEMENT; BEHAVIORS AB Introduction: Driving while impaired (DWI) increases the risk of a motor vehicle crash by impairing performance. Few studies have examined the prevalence and predictors of marijuana, alcohol, and drug-specific DWI among emerging adults. Methods: The data from wave 3 (W3, high school seniors, 2012, N = 2407) and wave 4 (W4, one year after high school, N = 2178) of the NEXT Generation Health Study with a nationally representative cohort. W4 DWI (>= 1 day of past 30 days) was specified for alcohol-specific, marijuana-specific, alcohol/marijuana-combined, illicit drug-related DWI. Multinomial logistic regression models estimated the association of W4 DWI with W3 covariates (perceived peer/parent influence, drinking/binge drinking, marijuana/illicit drug use), and W4 environmental status variables (work/school/residence) adjusting for W3 overall DWI, demographic, and complex survey variables. Results: Overall DWI prevalence from W3 to W4 changed slightly (14% to 15%). W4 DWI consisted of 4.34% drinking-specific, 5.02% marijuana-specific, 2.41% drinking/marijuana combined, and 3.37% illicit drug-related DWI. W3 DWI was significantly associated with W4 alcohol-related and alcohol/marijuana-combined DWI, but not other DWI. W3 marijuana use, binge drinking, and illicit drug use were positively associated with W4 marijuana-specific, alcohol/marijuana-combined, and illicit drug-related DWI, respectively. W3 friend drunkenness and marijuana use were positively associated with W4 alcohol-specific and marijuana related DWI, respectively. W3 peer marijuana use was negatively associated with W4 alcohol-specific DWI. Conclusions: Driving under the influence of alcohol, marijuana, and illicit drugs is a persistent, threatening public health concern among emerging U.S. adults. High school seniors' binge drinking as well as regular alcohol drinking and marijuana/illicit drug use were independently associated with respective DWI one year after high school. Peer drunkenness and marijuana use in high school may be related to subsequent DWI of emerging adults. Practical applications: The results support the use of injunctive peer norms about getting drunk and smoking marijuana in guiding the development of prevention programs to reduce youth DWI. (C) 2016 National Safety Council and Elsevier Ltd. All rights reserved. C1 [Li, Kaigang] Colorado State Univ, Dept Hlth & Exercise Sci, B 215E Moby Complex, Ft Collins, CO 80523 USA. [Simons-Morton, Bruce; Gee, Benjamin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Bethesda, MD USA. [Hingson, Ralph] Natl Inst Alcohol Abuse & Alcoholism, Div Epidemiol & Prevent Res, Bethesda, MD USA. RP Li, KG (reprint author), Colorado State Univ, Dept Hlth & Exercise Sci, B 215E Moby Complex, Ft Collins, CO 80523 USA. EM kaigang.li@colostate.edu OI Simons-Morton, Bruce/0000-0003-1099-6617 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development [HHSN275201200001I]; National Heart, Lung and Blood Institute (NHLBI); National Institute on Alcohol Abuse and Alcoholism (NIAAA); Maternal and Child Health Bureau (MCHB) of the Health Resources and Services Administration (HRSA) FX Funding/support: This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (contract #HHSN275201200001I), and the National Heart, Lung and Blood Institute (NHLBI), the National Institute on Alcohol Abuse and Alcoholism (NIAAA), and the Maternal and Child Health Bureau (MCHB) of the Health Resources and Services Administration (HRSA), with supplemental support from the National Institute on Drug Abuse (NIDA). NR 35 TC 0 Z9 0 U1 4 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-4375 EI 1879-1247 J9 J SAFETY RES JI J. Saf. Res. PD SEP PY 2016 VL 58 BP 15 EP 20 DI 10.1016/j.jsr.2016.05.003 PG 6 WC Ergonomics; Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary; Transportation SC Engineering; Public, Environmental & Occupational Health; Social Sciences - Other Topics; Transportation GA DW8VR UT WOS:000383934100002 PM 27620930 ER PT J AU Figueiredo, P Marques, EA Lepers, R AF Figueiredo, Pedro Marques, Elisa A. Lepers, Romuald TI Changes in Contributions of Swimming, Cycling, and Running Performances on Overall Triathlon Performance Over a 26-Year Period SO JOURNAL OF STRENGTH AND CONDITIONING RESEARCH LA English DT Article DE Olympic triathlon; ironman triathlon; endurance ID OLYMPIC DISTANCE TRIATHLON; PACING STRATEGIES; ENERGY-COST; ELITE; RUN; COMPETITION; INTENSITY; HAWAII; GENDER; FEMALE AB Figueiredo, P, Marques, EA, and Lepers, R. Changes in contributions of swimming, cycling, and running performances on overall triathlon performance over a 26-year period. J Strength Cond Res 30(9): 2406-2415, 2016This study examined the changes in the individual contribution of each discipline to the overall performance of Olympic and Ironman distance triathlons among men and women. Between 1989 and 2014, overall performances and their component disciplines (swimming, cycling and running) were analyzed from the top 50 overall male and female finishers. Regression analyses determined that for the Olympic distance, the split times in swimming and running decreased over the years (r(2) = 0.25-0.43, p 0.05), whereas the cycling split and total time remained unchanged (p > 0.05), for both sexes. For the Ironman distance, the cycling and running splits and the total time decreased (r(2) = 0.19-0.88, p 0.05), whereas swimming time remained stable, for both men and women. The average contribution of the swimming stage (approximate to 18%) was smaller than the cycling and running stages (p 0.05), for both distances and both sexes. Running (approximate to 47%) and then cycling (approximate to 36%) had the greatest contribution to overall performance for the Olympic distance (approximate to 47%), whereas for the Ironman distance, cycling and running presented similar contributions (approximate to 40%, p > 0.05). Across the years, in the Olympic distance, swimming contribution significantly decreased for women and men (r(2) = 0.51 and 0.68, p < 0.001, respectively), whereas running increased for men (r(2) = 0.33, p = 0.014). In the Ironman distance, swimming and cycling contributions changed in an undulating fashion, being inverse between the two segments, for both sexes (p < 0.01), whereas running contribution decreased for men only (r(2) = 0.61, p = 0.001). These findings highlight that strategies to improve running performance should be the main focus on the preparation to compete in the Olympic distance; whereas, in the Ironman, both cycling and running are decisive and should be well developed. C1 [Figueiredo, Pedro] Univ Fed Rio Grande do Sul, Sch Phys Educ, Porto Alegre, RS, Brazil. [Figueiredo, Pedro] Univ Maryland, Dept Kinesiol, College Pk, MD 20742 USA. [Marques, Elisa A.] NIA, Lab Epidemiol & Populat Sci, NIH, Bethesda, MD 20892 USA. [Marques, Elisa A.] Univ Inst Maia ISMAI, Res Ctr Sports Sci Hlth & Human Dev CIDESD, Maia, Portugal. [Lepers, Romuald] Univ Burgundy, Fac Sport Sci, INSERM U1093, Dijon, France. RP Figueiredo, P (reprint author), Univ Fed Rio Grande do Sul, Sch Phys Educ, Porto Alegre, RS, Brazil. EM pedfig@me.com OI Lepers, Romuald/0000-0002-3870-4017 NR 40 TC 0 Z9 0 U1 13 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1064-8011 EI 1533-4287 J9 J STRENGTH COND RES JI J. Strength Cond. Res. PD SEP PY 2016 VL 30 IS 9 BP 2406 EP 2415 DI 10.1519/JSC.0000000000001335 PG 10 WC Sport Sciences SC Sport Sciences GA DW8LN UT WOS:000383907500008 PM 26808853 ER PT J AU Patel, RD Starkman, S Hamilton, S Craig, S Grace, A Conwit, R Saver, JL AF Patel, Richa D. Starkman, Sidney Hamilton, Scott Craig, Sharon Grace, Anna Conwit, Robin Saver, Jeffrey L. TI The Rankin Focused Assessment-Ambulation: A Method to Score the Modified Rankin Scale with Emphasis on Walking Ability SO JOURNAL OF STROKE & CEREBROVASCULAR DISEASES LA English DT Article DE Scales; disability; ambulation; Rankin; assessment ID CLINICAL-TRIALS; STROKE; RELIABILITY; AGREEMENT; OUTCOMES AB Background: In the assessment of poststroke functional outcome, there are 2 alternative approaches to rating patient independence in motion: (1) focusing solely on patient ambulation (discounting self-use of wheelchair) and (2) focusing broadly on patient mobility (counting self-use of wheelchair). This study was undertaken to create and assess the inter-rater reliability of a version of the Rankin Focused Assessment (RFA) that focuses on ambulation (Rankin Focused Assessment-Ambulation [RFA-A]), as an alternative to the original RFA that focused on mobility (Rankin Focused Assessment-Mobility [RFA-M]). Methods: The RFA-A was created by changing instructions in the RFA-M for handling of nonambulatory, wheelchair-using patients. Paired study coordinators then applied the RFA-A to 50 consecutive patients enrolled in a phase 3 acute stroke trial. Results: Among the 50 patients, the mean age was 72 years (range 43-93) and 48% were female. Overall, study coordinator pairs assigned the same modified Rankin Scale (mRS) grades to 48 of the 50 patients, yielding a weighted kappa of .98 (95% confidence interval [CI] .96-1.00) and an unweighted kappa of .95 (95% CI.89-1.02). At day 90, 43 patients were alive and 7 had died. Among surviving patients, the weighted. was .98 (95% CI.95-1.00) and the unweighted kappa was .94 (95% CI.86-1.02). The kappa values for all 6 dichotomizations of the mRS score ranged from .93 to 1.00. Conclusions: The RFA-A demonstrates high inter-rater reliability in grading global functional outcome. The RFA-A is a useful tool for assigning an mRS score in research and clinical practice when functional assessment focused on ambulation is desired. C1 [Patel, Richa D.; Starkman, Sidney; Craig, Sharon; Grace, Anna; Saver, Jeffrey L.] Univ Calif Los Angeles, Dept Neurol, Comprehens Stroke Ctr, 710 Westwood Plaza, Los Angeles, CA 90095 USA. [Patel, Richa D.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Hamilton, Scott] Stanford Univ, Dept Neurol, Stanford Stroke Ctr, Palo Alto, CA 94304 USA. [Conwit, Robin] NINDS, Bethesda, MD USA. RP Saver, JL (reprint author), Univ Calif Los Angeles, Dept Neurol, Comprehens Stroke Ctr, 710 Westwood Plaza, Los Angeles, CA 90095 USA. EM jsaver@ucla.edu FU National Institutes of Health-National Institute of Neurological Disorders and Stroke Awards [U01 NS 44364, P50 NS044378] FX This study was supported by the National Institutes of Health-National Institute of Neurological Disorders and Stroke Awards U01 NS 44364 and P50 NS044378. NR 14 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1052-3057 EI 1532-8511 J9 J STROKE CEREBROVASC JI J. Stroke Cerebrovasc. Dis. PD SEP PY 2016 VL 25 IS 9 BP 2172 EP 2176 DI 10.1016/j.jstrokecerebrovasdis.2015.10.030 PG 5 WC Neurosciences; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA DX0AK UT WOS:000384023700021 PM 27450385 ER PT J AU Merz, CNB Shaw, LJ Azziz, R Stanczyk, FZ Sopko, G Braunstein, GD Kelsey, SF Kip, KE Cooper-DeHoff, RM Johnson, BD Vaccarino, V Reis, SE Bittner, V Hodgson, TK Rogers, W Pepine, CJ AF Merz, C. Noel Bairey Shaw, Leslee J. Azziz, Ricardo Stanczyk, Frank Z. Sopko, George Braunstein, Glenn D. Kelsey, Sheryl F. Kip, Kevin E. Cooper-DeHoff, Rhonda M. Johnson, B. Delia Vaccarino, Viola Reis, Steven E. Bittner, Vera Hodgson, T. Keta Rogers, William Pepine, Carl J. TI Cardiovascular Disease and 10-Year Mortality in Postmenopausal Women with Clinical Features of Polycystic Ovary Syndrome SO JOURNAL OF WOMENS HEALTH LA English DT Article ID ISCHEMIA SYNDROME EVALUATION; SYNDROME EVALUATION WISE; CORONARY-ARTERY CALCIFICATION; ENDOGENOUS SEX-HORMONES; INTIMA-MEDIA THICKNESS; TERM-FOLLOW-UP; DIABETES-MELLITUS; FREE TESTOSTERONE; YOUNG-WOMEN; RISK AB Background: Women with polycystic ovary syndrome (PCOS) have greater cardiac risk factor clustering but the link with mortality is incompletely described. Objective: To evaluate outcomes in 295 postmenopausal women enrolled in the National Institutes of Health National Heart, Lung, and Blood Institute (NIH-NHLBI) sponsored Women's Ischemia Syndrome Evaluation (WISE) study according to clinical features of PCOS. Materials and Methods: A total of 25/295 (8%) women had clinical features of PCOS defined by a premenopausal history of irregular menses and current biochemical evidence of hyperandrogenemia, defined as the top quartile of androstenedione (>= 701 pg/mL), testosterone (>= 30.9 ng/dL), or free testosterone (>= 4.5 pg/mL). Cox proportional hazard model estimated death (n = 80). Results: Women with clinical features of PCOS had an earlier menopause (p = 0.01), were more often smokers (p < 0.04), and trended toward more angiographic coronary artery disease (CAD) (p = 0.07) than women without these features. Cumulative 10-year mortality was 28% for women with (n=25) versus 27% without clinical features of PCOS (n = 270) (p = 0.85). PCOS was not a significant predictor (p = NS) in prognostic models including diabetes, waist circumference, hypertension, and angiographic CAD. Conclusion: From this longer-term follow up of a relatively small cohort of postmenopausal women with suspected ischemia, the prevalence of PCOS is similar to the general population, and clinical features of PCOS are not associated with CAD or mortality. These findings question whether identification of clinical features of PCOS in postmenopausal women who already have known cardiovascular disease provides any additional opportunity for risk factor intervention. C1 [Merz, C. Noel Bairey] Cedars Sinai Med Ctr, Cedars Sinai Heart Inst, Barbra Streisand Womens Heart Ctr, 127 South San Vicente Blvd, Los Angeles, CA 90048 USA. [Shaw, Leslee J.] Emory Univ, Clin Cardiovasc Res Inst, Atlanta, GA 30322 USA. [Azziz, Ricardo] Med Coll Georgia, Augusta, GA 30912 USA. [Stanczyk, Frank Z.] Univ Southern Calif, Los Angeles, CA USA. [Sopko, George] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Braunstein, Glenn D.; Hodgson, T. Keta] Cedars Sinai Med Ctr, Dept Med, Los Angeles, CA 90048 USA. [Kelsey, Sheryl F.; Kip, Kevin E.; Johnson, B. Delia] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Cooper-DeHoff, Rhonda M.; Vaccarino, Viola; Pepine, Carl J.] Univ Florida, Dept Med, Div Cardiol, Gainesville, FL USA. [Reis, Steven E.] Univ Pittsburgh, Med Ctr, Cardiovasc Inst, Pittsburgh, PA USA. [Bittner, Vera; Rogers, William] Univ Alabama Birmingham, Dept Med, Div Cardiovasc Dis, Birmingham, AL 35294 USA. RP Merz, CNB (reprint author), Cedars Sinai Med Ctr, Cedars Sinai Heart Inst, Barbra Streisand Womens Heart Ctr, 127 South San Vicente Blvd, Los Angeles, CA 90048 USA. EM merz@cshs.org FU National Heart, Lung, and Blood Institutes [N01-HV-68161, N01-HV-68162, N01-HV-68163, N01-HV-68164]; National Institute on Aging [U0164829, U01 HL649141, U01 HL649241, K23HL105787, T32HL69751, R01 HL090957, 1R03AG032631]; National Center for Research Resources [MO1-RR00425]; National Center for Advancing Translational Sciences [UL1TR000124, UL1TR000064]; Gustavus and Louis Pfeiffer Research Foundation, Danville, NJ; The Women's Guild of Cedars-Sinai Medical Center, Los Angeles, CA; The Ladies Hospital Aid Society of Western Pennsylvania, Pittsburgh, PA; QMED, Inc., Laurence Harbor, NJ; Edythe L. Broad Fellowship; Constance Austin Women's Heart Research Fellowship; Cedars-Sinai Medical Center, Los Angeles, California; Barbra Streisand Women's Cardiovascular Research and Education Program; Cedars-Sinai Medical Center, Los Angeles; Society for Women's Health Research (SWHR), Washington, D.C.; Linda Joy Pollin Women's Heart Health Program; Erika Glazer Women's Heart Health Project, Cedars-Sinai Medical Center, Los Angeles, California FX This work was supported by contracts from the National Heart, Lung, and Blood Institutes Nos. N01-HV-68161, N01-HV-68162, N01-HV-68163, N01-HV-68164, grants U0164829, U01 HL649141, U01 HL649241, K23HL105787, T32HL69751, R01 HL090957, 1R03AG032631 from the National Institute on Aging, GCRC grant MO1-RR00425 from the National Center for Research Resources, the National Center for Advancing Translational Sciences Grant UL1TR000124 and UL1TR000064, and grants from the Gustavus and Louis Pfeiffer Research Foundation, Danville, NJ, The Women's Guild of Cedars-Sinai Medical Center, Los Angeles, CA, The Ladies Hospital Aid Society of Western Pennsylvania, Pittsburgh, PA, and QMED, Inc., Laurence Harbor, NJ, the Edythe L. Broad and the Constance Austin Women's Heart Research Fellowships, Cedars-Sinai Medical Center, Los Angeles, California, the Barbra Streisand Women's Cardiovascular Research and Education Program, Cedars-Sinai Medical Center, Los Angeles, The Society for Women's Health Research (SWHR), Washington, D.C., The Linda Joy Pollin Women's Heart Health Program, and the Erika Glazer Women's Heart Health Project, Cedars-Sinai Medical Center, Los Angeles, California. This work is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or National Institutes of Health. None of the authors have other conflicts or disclosures with regards to this article except for the NIH-NHLBI funding noted above. NR 39 TC 0 Z9 0 U1 1 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 EI 1931-843X J9 J WOMENS HEALTH JI J. Womens Health PD SEP PY 2016 VL 25 IS 9 BP 875 EP 881 DI 10.1089/jwh.2015.5441 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA DW9YP UT WOS:000384019000005 PM 27267867 ER PT J AU Spector, SA Brummel, SS Nievergelt, CM Maihofer, AX Singh, KK Purswani, MU Williams, PL Hazra, R Van Dyke, R Seage, GR AF Spector, Stephen A. Brummel, Sean S. Nievergelt, Caroline M. Maihofer, Adam X. Singh, Kumud K. Purswani, Murli U. Williams, Paige L. Hazra, Rohan Van Dyke, Russell Seage, George R. CA PHACS TI Genetically determined ancestry is more informative than self-reported race in HIV-infected and -exposed children SO MEDICINE LA English DT Article DE ancestry informative markers; genetically determined ancestry; HIV exposed uninfected; HIV-infected children; Pediatric HIV; AIDS Cohort Study; self-reported race; ethnicity ID HUMAN-IMMUNODEFICIENCY-VIRUS; MULTILOCUS GENOTYPE DATA; GENOME-WIDE ASSOCIATION; ANTIRETROVIRAL THERAPY; UNINFECTED CHILDREN; UNITED-STATES; BIOGEOGRAPHICAL ANCESTRY; RISK-FACTORS; ASTHMA; INFERENCE AB The Pediatric HIV/AIDS Cohort Study (PHACS), the largest ongoing longitudinal study of perinatal HIV-infected (PHIV) and HIV-exposed, uninfected (PHEU) children in the United States, comprises the Surveillance Monitoring of Antiretroviral Therapy [ART] Toxicities (SMARTT) Study in PHEU children and the Adolescent Master Protocol (AMP) that includes PHIV and PHEU children 7 years. Although race/ethnicity is often used to assess health outcomes, this approach remains controversial and may fail to accurately reflect the backgrounds of ancestry-diverse populations as represented in the PHACS participants.In this study, we compared genetically determined ancestry (GDA) and self-reported race/ethnicity (SRR) in the PHACS cohort. GDA was estimated using a highly discriminative panel of 41 single nucleotide polymorphisms and compared to SRR. Because SRR was similar between the PHIV and PHEU, and between the AMP and SMARTT cohorts, data for all unique 1958 participants were combined.According to SRR, 63% of study participants identified as Black/African-American, 27% White, and 34% Hispanic. Using the highest percentage of ancestry/ethnicity to identify GDA, 9.5% of subjects were placed in the incorrect superpopulation based on SRR. When 50% or 75% GDA of a given superpopulation was required, 12% and 25%, respectively, of subjects were placed in the incorrect superpopulation based on SRR, and the percent of subjects classified as multiracial increased. Of 126 participants with unidentified SRR, 71% were genetically identified as Eurasian.GDA provides a more robust assessment of race/ethnicity when compared to self-report, and study participants with unidentified SRR could be assigned GDA using genetic markers. In addition, identification of continental ancestry removes the taxonomic identification of race as a variable when identifying risk for clinical outcomes. C1 [Spector, Stephen A.; Nievergelt, Caroline M.; Maihofer, Adam X.; Singh, Kumud K.] Univ Calif San Diego, 9500 Gilman Dr,Stein Clin Res Bldg,MC 0672, La Jolla, CA 92093 USA. [Spector, Stephen A.] Rady Childrens Hosp San Diego, San Diego, CA USA. [Brummel, Sean S.; Williams, Paige L.; Seage, George R.] Harvard TH Chan Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA USA. [Purswani, Murli U.] Bronx Lebanon Hosp Ctr, Albert Einstein Coll Med, Bronx, NY USA. [Williams, Paige L.] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Williams, Paige L.; Seage, George R.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Hazra, Rohan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Van Dyke, Russell] Tulane Univ, Sch Med, 1430 Tulane Ave, New Orleans, LA 70112 USA. RP Spector, SA (reprint author), Univ Calif San Diego, 9500 Gilman Dr,Stein Clin Res Bldg,MC 0672, La Jolla, CA 92093 USA. EM saspector@ucsd.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute on Drug Abuse; National Institute of Allergy and Infectious Diseases; Office of AIDS Research; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; National Institute on Deafness and Other Communication Disorders; National Heart Lung and Blood Institute; National Institute of Dental and Craniofacial Research; National Institute on Alcohol Abuse and Alcoholism; Harvard T.H. Chan School of Public Health [HD052102]; Tulane University School of Medicine [HD052104]; [1R01NS077874] FX This research was supported in part by 1R01NS077874 (SAS). The Pediatric HIV/AIDS Cohort Study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development with cofunding from the National Institute on Drug Abuse, the National Institute of Allergy and Infectious Diseases, the Office of AIDS Research, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, the National Institute on Deafness and Other Communication Disorders, the National Heart Lung and Blood Institute, the National Institute of Dental and Craniofacial Research, and the National Institute on Alcohol Abuse and Alcoholism, through cooperative agreements with the Harvard T.H. Chan School of Public Health (HD052102; Principal Investigator: George Seage; Project Director: Julie Alperen) and the Tulane University School of Medicine (HD052104; Principal Investigator: Russell Van Dyke; Co-Principal Investigator: Kenneth Rich); Data management services were provided by Frontier Science and Technology Research Foundation (Principal Investigator: Suzanne Siminski), and regulatory services and logistical support were provided by Westat, Inc (Principal Investigator: Julie Davidson). NR 33 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0025-7974 EI 1536-5964 J9 MEDICINE JI Medicine (Baltimore) PD SEP PY 2016 VL 95 IS 36 AR e4733 DI 10.1097/MD.0000000000004733 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA DX4JE UT WOS:000384346200042 PM 27603370 ER PT J AU Aschrafi, A Kar, AN Gale, JR Elkahloun, AG Vargas, JNS Sales, N Wilson, G Tompkins, M Gioio, AE Kaplan, BB AF Aschrafi, Armaz Kar, Amar N. Gale, Jenna R. Elkahloun, Abdel G. Vargas, Jose Noberto S. Sales, Naomi Wilson, Gabriel Tompkins, Miranda Gioio, Anthony E. Kaplan, Barry B. TI A heterogeneous population of nuclear-encoded mitochondrial mRNAs is present in the axons of primary sympathetic neurons SO MITOCHONDRION LA English DT Article DE Microarray analyses; mRNAs; Subcellular localization; Superior cervical ganglion; Campenot cell culture chambers ID LOCAL TRANSLATION; DYSFUNCTION; EXPRESSION; PROTEINS; VICINITY; DISEASE; YEAST AB Mitochondria are enriched in subcellular regions of high energy consumption, such as axons and pre-synaptic nerve endings. Accumulating evidence suggests that mitochondrial maintenance in these distal structural/functional domains of the neuron depends on the "in-situ" translation of nuclear-encoded mitochondrial mRNAs. In support of this notion, we recently provided evidence for the axonal targeting of several nuclear-encoded mRNAs, such as cytochrome c oxidase, subunit 4 (COXIV) and ATP synthase, H + transporting and mitochondrial Fo complex, subunit Cl (ATP5G1). Furthermore, we showed that axonal trafficking and local translation of these mRNAs plays a critical role in the generation of axonal ATP. Using a global gene expression analysis, this study identified a highly diverse population of nuclear-encoded mRNAs that were enriched in the axon and presynaptic nerve terminals. Among this population of mRNAs, fifty seven were found to be at least two-fold more abundant in distal axons, as compared with the parental cell bodies. Gene ontology analysis of the nuclear-encoded mitochondrial mRNAs suggested functions for these gene products in molecular and biological processes, including but not limited to oxidoreductase and electron carrier activity and proton transport Based on these results, we postulate that local translation of nuclear-encoded mitochondrial mRNAs present in the axons may play an essential role in local energy production and maintenance of mitochondrial function. Published by Elsevier B.V. on behalf of Mitochondria Research Society. C1 [Aschrafi, Armaz; Kar, Amar N.; Gale, Jenna R.; Elkahloun, Abdel G.; Vargas, Jose Noberto S.; Sales, Naomi; Wilson, Gabriel; Tompkins, Miranda; Gioio, Anthony E.; Kaplan, Barry B.] NIMH, Mol Biol Lab, Div Intramural Res Programs, NIH, Bethesda, MD 20892 USA. [Elkahloun, Abdel G.] NHGRI, Canc Genet & Comparat Genom Branch, NIH, Bethesda, MD 20892 USA. RP Kaplan, BB (reprint author), NIMH, Neurobiol Sect, Mol Biol Lab, NIH, 49 Convent Dr,Room B1B80, Bethesda, MD 20892 USA. EM kaplanb@mail.nih.gov OI Kar, Amar/0000-0003-2380-7504 FU Division of Intramural Research Programs of the National Institute of Mental Health [Z01MH002768]; Division of Intramural Research Programs of the National Human Genome Research Institute FX The authors wish to thank Ms. Cai Chen and Weiwei Wu for invaluable technical assistance. This work was supported by the Division of Intramural Research Programs of the National Institute of Mental Health (Z01MH002768) and by the Division of Intramural Research Programs of the National Human Genome Research Institute. NR 26 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1567-7249 EI 1872-8278 J9 MITOCHONDRION JI Mitochondrion PD SEP PY 2016 VL 30 BP 18 EP 23 DI 10.1016/j.mito.2016.06.002 PG 6 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA DX0FN UT WOS:000384037300003 PM 27318271 ER PT J AU Gaitan, MI Yanes, P Sati, P Romero, C Reich, DS Correale, J AF Gaitan, Maria I. Yanes, Paulina Sati, Pascal Romero, Carlos Reich, Daniel S. Correale, Jorge TI Optimal detection of infratentorial lesions with a combined dual-echo MRI sequence: "PT2" SO MULTIPLE SCLEROSIS JOURNAL LA English DT Article DE Multiple sclerosis; MRI; infratentorial brain; T2 lesions ID CLINICALLY ISOLATED SYNDROMES; MULTIPLE-SCLEROSIS; DISABILITY; BRAIN AB Background: The infratentorial compartment is cardinal for multiple sclerosis (MS) diagnosis. T2-weighted (T2) and proton density-weighted (PD) magnetic resonance imaging (MRI) can visualize infratentorial lesions, but only suboptimally. Objective: To combine PD and T2 for better lesion assessment. Methods: T2 and PD from 35 cases were averaged to form PT2 images. Two raters counted infratentorial lesions and qualitatively assessed their conspicuity. Results: PT2 showed 244 infratentorial lesions, of which 94% and 74% were seen in PD and T2. PT2 received higher grades for image quality and lesion conspicuity (p<0.001 for all comparisons). Conclusion: PT2 could improve our ability to diagnose and monitor MS. C1 [Gaitan, Maria I.; Yanes, Paulina; Romero, Carlos; Correale, Jorge] FLENI, Dr Raul Carrea Inst Neurol Res, Dept Neurol, Montaneses 2325, RA-1428 Buenos Aires, DF, Argentina. [Sati, Pascal; Reich, Daniel S.] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Gaitan, MI (reprint author), FLENI, Dr Raul Carrea Inst Neurol Res, Dept Neurol, Montaneses 2325, RA-1428 Buenos Aires, DF, Argentina. EM migaitan@fleni.org.ar FU Raul Carrea Institute for Neurological Research, FLENI FX This study was supported by funding from the Raul Carrea Institute for Neurological Research, FLENI. NR 10 TC 1 Z9 1 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2016 VL 22 IS 10 BP 1367 EP 1370 DI 10.1177/1352458515615226 PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DV5KP UT WOS:000382966300016 PM 26552729 ER PT J AU Levy, S Ryan, SA Gonzalez, PK Patrick, SW Quigley, J Siqueira, L Walker, LR Faden, VB Tau, G Jarrett, R AF Levy, Sharon Ryan, Sheryl A. Gonzalez, Pamela K. Patrick, Stephen W. Quigley, Joanna Siqueira, Lorena Walker, Leslie R. Faden, Vivian B. Tau, Gregory Jarrett, Renee CA Comm Subst Use Prevention TI Medication-Assisted Treatment of Adolescents With Opioid Use Disorders SO PEDIATRICS LA English DT Article ID DEPENDENT ADOLESCENTS; DRUG-USERS; BUPRENORPHINE; RETENTION; TRIAL AB Opioid use disorder is a leading cause of morbidity and mortality among US youth. Effective treatments, both medications and substance use disorder counseling, are available but underused, and access to developmentally appropriate treatment is severely restricted for adolescents and young adults. Resources to disseminate available therapies and to develop new treatments specifically for this age group are needed to save and improve lives of youth with opioid addiction. C1 [Faden, Vivian B.] NIAAA, New York, NY USA. [Tau, Gregory] Amer Acad Child & Adolescent Psychiat, New York, NY USA. NR 20 TC 0 Z9 0 U1 5 U2 5 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 SEP PY 2016 VL 138 IS 3 AR e20161893 DI 10.1542/peds.2016-1893 PG 4 WC Pediatrics SC Pediatrics GA DW9SE UT WOS:000384002100070 ER PT J AU Sisk, BA Bluebond-Langner, M Wiener, L Mack, J Wolfe, J AF Sisk, Bryan A. Bluebond-Langner, Myra Wiener, Lori Mack, Jennifer Wolfe, Joanne TI Prognostic Disclosures to Children: A Historical Perspective SO PEDIATRICS LA English DT Article ID OF-LIFE CARE; FATALLY ILL CHILDREN; CANCER-PATIENTS; DYING CHILD; PEDIATRIC ONCOLOGISTS; INFORMED-CONSENT; COMMUNICATION; PARENTS; DEATH; ILLNESS AB Prognostic disclosure to children has perpetually challenged clinicians and parents. In this article, we review the historical literature on prognostic disclosure to children in the United States using cancer as an illness model. Before 1948, there was virtually no literature focused on prognostic disclosure to children. As articles began to be published in the 1950s and 1960s, many clinicians and researchers initially recommended a "protective" approach to disclosure, where children were shielded from the harms of bad news. We identified 4 main arguments in the literature at this time supporting this "protective" approach. By the late 1960s, however, a growing number of clinicians and researchers were recommending a more "open" approach, where children were included in discussions of diagnosis, which at the time was often synonymous with a terminal prognosis. Four different arguments in the literature were used at this time supporting this "open" approach. Then, by the late 1980s, the recommended approach to prognostic disclosure in pediatrics shifted largely from "never tell" to "always tell." In recent years, however, there has been a growing appreciation for the complexity of prognostic disclosure in pediatrics. Current understanding of pediatric disclosure does not lead to simple "black-and-white" recommendations for disclosure practices. As with most difficult questions, we are left to balance competing factors on a case-by-case basis. We highlight 4 categories of current considerations related to prognostic disclosure in pediatrics, and we offer several approaches to prognostic disclosure for clinicians who care for these young patients and their families. C1 [Sisk, Bryan A.] St Louis Childrens Hosp, Dept Pediat, St Louis, MO USA. [Bluebond-Langner, Myra] UCL, Inst Child Hlth, Louis Dundas Ctr Childrens Palliat Care, London, England. [Wiener, Lori] NCI, Ctr Canc Res, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Mack, Jennifer] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Mack, Jennifer] Dana Farber Canc Inst, Div Populat Sci, Boston, MA 02115 USA. [Wolfe, Joanne] Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, Boston, MA 02115 USA. [Mack, Jennifer] Boston Childrens Hosp, Div Pediat Hematol Oncol, Boston, MA USA. [Wolfe, Joanne] Boston Childrens Hosp, Dept Med, Boston, MA USA. RP Sisk, BA (reprint author), St Louis Childrens Hosp, 1 Childrens Pl,3S34, St Louis, MO 63110 USA. EM sisk_b@kids.wustl.edu FU True Colours Trust, London, England; Intramural Research Programs of the Center for Cancer Research, National Institutes of Health; National Institutes of Health (NIH) FX This work was supported in part by the True Colours Trust, London, England, and by the Intramural Research Programs of the Center for Cancer Research, National Institutes of Health. Funded by the National Institutes of Health (NIH). NR 101 TC 0 Z9 0 U1 7 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 SEP PY 2016 VL 138 IS 3 AR e20161278 DI 10.1542/peds.2016-1278 PG 10 WC Pediatrics SC Pediatrics GA DW9SE UT WOS:000384002100050 ER PT J AU Churchyard, G Mlisana, K Karuna, S Williamson, AL Williamson, C Morris, L Tomaras, GD De Rosa, SC Gilbert, PB Gu, N Yu, CC Mkhize, NN Hermanus, T Allen, M Pensiero, M Barnett, SW Gray, G Bekker, LG Montefiori, DC Kublin, J Corey, L AF Churchyard, Gavin Mlisana, Koleka Karuna, Shelly Williamson, Anna-Lise Williamson, Carolyn Morris, Lynn Tomaras, Georgia D. De Rosa, Stephen C. Gilbert, Peter B. Gu, Niya Yu, Chenchen Mkhize, Nonhlanhla N. Hermanus, Tandile Allen, Mary Pensiero, Michael Barnett, Susan W. Gray, Glenda Bekker, Linda-Gail Montefiori, David C. Kublin, James Corey, Lawrence TI Sequential Immunization with gp140 Boosts Immune Responses Primed by Modified Vaccinia Ankara or DNA in HIV-Uninfected South African Participants SO PLOS ONE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; TYPE-1 SUBTYPE-C; T-CELL RESPONSES; SMALLPOX VACCINATION; CLINICAL-TRIAL; EFFICACY TRIAL; DOUBLE-BLIND; MVA-B; IMMUNOGENICITY; ANTIBODIES AB Background The safety and immunogenicity of SAAVI DNA-C2 (4 mg IM), SAAVI MVA-C (2.9 x 10(9) pfu IM) and Novartis V2-deleted subtype C gp140 (100 mcg) with MF59 adjuvant in various vaccination regimens was evaluated in HIV-uninfected adults in South Africa. Methods Participants at three South African sites were randomized (1:1:1:1) to one of four vaccine regimens: MVA prime, sequential gp140 protein boost (M/M/P/P); concurrent MVA/gp140 (MP/MP); DNA prime, sequential MVA boost (D/D/M/M); DNA prime, concurrentMVA/gp140 boost (D/D/MP/MP) or placebo. Peak HIV specific humoral and cellular responses were measured. Results 184 participants were enrolled: 52% were female, all were Black/African, median age was 23 years (range, 18-42 years) and 79% completed all vaccinations. 159 participants reported at least one adverse event, 92.5% were mild or moderate. Five, unrelated, serious adverse events were reported. The M/M/P/P and D/D/MP/MP regimens induced the strongest peak neutralizing and binding antibody responses and the greatest CD4+ T-cell responses to Env. All peak neutralizing and binding antibody responses decayed with time. The MVA, but not DNA, prime contributed to the humoral and cellular immune responses. The D/D/M/M regimen was poorly immunogenic overall but did induce modest CD4+ T-cell responses to Gag and Pol. CD8+ T-cell responses to any antigen were low for all regimens. Conclusions The SAAVI DNA-C2, SAAVI MVA-C and Novartis gp140 with MF59 adjuvant in various combinations were safe and induced neutralizing and binding antibodies and cellular immune responses. Sequential immunization with gp140 boosted immune responses primed by MVA or DNA. The best overall immune responses were seen with the M/M/P/P regimen. C1 [Churchyard, Gavin] Aurum Inst Hlth Res, Klerksdorp, South Africa. [Churchyard, Gavin] Univ Witwatersrand, Sch Publ Hlth, Johannesburg, South Africa. [Churchyard, Gavin] Med Res Council Collaborating Ctr, Adv Care & Treatment TB & HIV, Klerksdorp, South Africa. [Mlisana, Koleka] Univ KwaZulu Natal, Durban, South Africa. [Karuna, Shelly; De Rosa, Stephen C.; Gilbert, Peter B.; Gu, Niya; Yu, Chenchen; Kublin, James; Corey, Lawrence] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98104 USA. [Williamson, Anna-Lise; Williamson, Carolyn] Univ Cape Town, Inst Infect Dis & Mol Med, Div Med Virol, Cape Town, South Africa. [Williamson, Anna-Lise; Williamson, Carolyn] Natl Hlth Lab Serv Observ, Cape Town, South Africa. [Morris, Lynn; Mkhize, Nonhlanhla N.; Hermanus, Tandile] Natl Inst Communicable Dis, Natl Hlth Lab Serv, Johannesburg, South Africa. [Tomaras, Georgia D.] Duke Univ, Med Ctr, Duke Human Vaccine Inst, Durham, NC USA. [De Rosa, Stephen C.; Corey, Lawrence] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. [Allen, Mary; Pensiero, Michael] NIAID, Vaccine Res Program, Div Aids, NIH, Bethesda, MD USA. [Barnett, Susan W.] Novartis Vaccines & Diagnost, Cambridge, MA USA. [Gray, Glenda] South African Med Res Council, Cape Town, South Africa. [Gray, Glenda] Univ Witwatersrand, Fac Hlth Sci, Perinatal HIV Res Unit, Johannesburg, South Africa. [Bekker, Linda-Gail] Univ Cape Town, Desmond Tutu HIV Ctr, Inst Infect Dis & Mol Med, Cape Town, South Africa. [Montefiori, David C.] Duke Univ, Med Ctr, Lab AIDS Vaccine Res & Dev, Durham, NC USA. RP Churchyard, G (reprint author), Aurum Inst Hlth Res, Klerksdorp, South Africa.; Churchyard, G (reprint author), Univ Witwatersrand, Sch Publ Hlth, Johannesburg, South Africa.; Churchyard, G (reprint author), Med Res Council Collaborating Ctr, Adv Care & Treatment TB & HIV, Klerksdorp, South Africa. EM GChurchyard@auruminstitute.org FU National Institute of Allergy and Infectious Diseases (NIAID) (U.S. Public Health Service) [UM1 AI068614, UM1 AI068635, UM1 AI068618, UM1 AI069469, UM1 AI069453, UM1 AI069519]; NIAID-NIH [N01-AI-25473]; South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation (NRF), South Africa; Division of Acquired Immunodeficiency Syndrome of the U. S. National Institute of Allergy and Infectious Diseases (NIAID); Novartis Vaccines and Diagnostics FX This work was supported by the National Institute of Allergy and Infectious Diseases (NIAID) (https://www.niaid.nih.gov/) (U.S. Public Health Service Grants UM1 AI068614 [LOC: HIV Vaccine Trials Network], UM1 AI068635 [HVTN SDMC FHCRC], UM1 AI068618 [HVTN Laboratory Center FHCRC, Duke], UM1 AI069469 [Klerksdorp Clinical Research Site], UM1 AI069453 [Soweto-Bara Clinical Research Site] and UM1 AI069519 [Cape Town Clinical Research Site]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIAID or National Institutes of Health (NIH). Funding for the production of the TV1 gp140 protein was provided to Novartis Vaccines and Diagnostics from NIAID-NIH contract N01-AI-25473, TO#1. The SAAVI/MRC are acknowledged for supporting the product development and funding the potency assays for SAAVI DNA-C2. Part of this work (ALW) is based on the research supported by the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation (NRF), South Africa (http://www.nrf.ac.za/division/rcce/instruments/research-chairs). Any opinion, finding and conclusion or recommendation expressed in this material is that of the ALW and the NRF does not accept any liability in this regard. Susan W. Barnett was an employee and stakeholder of Novartis Vaccines and Diagnostics and contributed to the study design, data analysis and writeup of the manuscript. Mary Allen and Michael Pensiero are employed by the National Institute of Allergy and Infectious Diseases (NIAID), the study sponsor. The funder provided partial salary support for the following authors: GC, KM, SK, CW, A-LW, LM, GDT, SCD, PG, NG, CY, GG, LGB, DCM, JK, LC. The funder (U. S. National Institute of Allergy and Infectious Diseases (NIAID)) represented by MA and MP contributed to the study design, review of data analysis, the decision to publish, and review of the manuscript. The specific roles of these authors are articulated in the 'author contributions' section. Role of the Funding Source: The study and report were reviewed by the Division of Acquired Immunodeficiency Syndrome of the U. S. National Institute of Allergy and Infectious Diseases (NIAID), as well as Novartis Vaccines and Diagnostics. The corresponding author had full access to all of the data in the study and had final responsibility for the decision to submit for publication. Novartis Vaccines provided support in the form of salary for author Susan W. Barnett (SWB) and provision of study products. NIAID and SWB contributed to the study design, review of data analysis, the decision to publish and review of the manuscript. The specific roles of the NIAID and SWB are articulated in the 'author contributions' section. NR 55 TC 1 Z9 1 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 1 PY 2016 VL 11 IS 9 AR e0161753 DI 10.1371/journal.pone.0161753 PG 27 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DV3WN UT WOS:000382855600054 PM 27583368 ER PT J AU Hanif, A Edin, ML Zeldin, DC Morisseau, C Nayeem, MA AF Hanif, Ahmad Edin, Matthew L. Zeldin, Darryl C. Morisseau, Christophe Nayeem, Mohammed A. TI Effect of Soluble Epoxide Hydrolase on the Modulation of Coronary Reactive Hyperemia: Role of Oxylipins and PPAR gamma SO PLOS ONE LA English DT Article ID ARACHIDONIC-ACID METABOLISM; BLOOD-PRESSURE REGULATION; SMOOTH-MUSCLE-CELLS; EPOXYEICOSATRIENOIC ACIDS; ENDOTHELIAL-CELLS; LINOLEIC-ACID; LIPOXYGENASE PRODUCTS; POTENTIAL ROLE; HYPERTENSION; INHIBITION AB Coronary reactive hyperemia (CRH) is a physiological response to ischemic insult that prevents the potential harm associated with an interruption of blood supply. The relationship between the pharmacologic inhibition of soluble epoxide hydrolase (sEH) and CRH response to a brief ischemia is not known. sEH is involved in the main catabolic pathway of epoxyeicosatrienoic acids (EETs), which are converted into dihydroxyeicosatrienoic acids (DHETs). EETs protect against ischemia/reperfusion injury and have numerous beneficial physiological effects. We hypothesized that inhibition of sEH by t-AUCB enhances CRH in isolated mouse hearts through changing the oxylipin profiles, including an increase in EETs/DHETs ratio. Compared to controls, t-AUCB-treated mice had increased CRH, including repayment volume (RV), repayment duration, and repayment/debt ratio (p < 0.05). Treatment with t-AUCB significantly changed oxylipin profiles, including an increase in EET/DHET ratio, increase in EpOME/DiHOME ratio, increase in the levels of HODEs, decrease in the levels of mid-chain HETEs, and decrease in prostanoids (p < 0.05). Treatment with MS-PPOH (CYP epoxygenase inhibitor) reduced CRH, including RV (p < 0.05). Involvement of PPAR gamma in the modulation of CRH was demonstrated using a PPAR gamma-antagonist (T0070907) and a PPAR gamma-agonist (rosiglitazone). T0070907 reduced CRH (p < 0.05), whereas rosiglitazone enhanced CRH (p < 0.05) in isolated mouse hearts compared to the non-treated. These data demonstrate that sEH inhibition enhances, whereas CYP epoxy-genases- inhibition attenuates CRH, PPAR gamma mediate CRH downstream of the CYP epoxy-genases-EET pathway, and the changes in oxylipin profiles associated with sEH-inhibition collectively contributed to the enhanced CRH. C1 [Hanif, Ahmad; Nayeem, Mohammed A.] West Virginia Univ, Ctr Basic & Translat Stroke Res, Sch Pharm, Basic Pharmaceut Sci, Morgantown, WV 26506 USA. [Edin, Matthew L.; Zeldin, Darryl C.] NIEHS, Div Intramural Res, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Morisseau, Christophe] Univ Calif Davis, One Shields Ave, Davis, CA 95616 USA. RP Nayeem, MA (reprint author), West Virginia Univ, Ctr Basic & Translat Stroke Res, Sch Pharm, Basic Pharmaceut Sci, Morgantown, WV 26506 USA. EM mnayeem@hsc.wvu.edu RI Nayeem, Mohammed/A-3949-2017 OI Nayeem, Mohammed/0000-0002-7827-4760 FU National Institutes of Health / National Heart, Lung, and Blood Institute [HL-114559]; Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences [Z01 ES025034]; NIGMS of the National Institutes of Health [U54GM104942] FX This work was supported by a National Institutes of Health / National Heart, Lung, and Blood Institute grant (HL-114559) to M. A. Nayeem (http://www.nhlbi.nih.gov) and the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences (Z01 ES025034 to D. C. Zeldin) (http://www.niehs.nih.gov).; This work was supported by National Institutes of Health Grant (HL-114559) to M. A. Nayeem and the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01 ES025034 to D. C. Zeldin). We thank Brandi Talkington, PhD, and the West Virginia Clinical and Translational Science Institute (WVCTSI) for editorial support. The WVCTSI is supported by the NIGMS of the National Institutes of Health under award number U54GM104942. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 73 TC 1 Z9 1 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 1 PY 2016 VL 11 IS 9 AR e0162147 DI 10.1371/journal.pone.0162147 PG 22 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DV3WN UT WOS:000382855600112 PM 27583776 ER PT J AU Nagaraju, K Ghimbovschi, S Rayavarapu, S Phadke, A Rider, LG Hoffman, EP Miller, FW AF Nagaraju, Kanneboyina Ghimbovschi, Svetlana Rayavarapu, Sree Phadke, Aditi Rider, Lisa G. Hoffman, Eric P. Miller, Frederick W. TI Muscle myeloid type I interferon gene expression may predict therapeutic responses to rituximab in myositis patients SO RHEUMATOLOGY LA English DT Article DE myositis; rituximab; biomarker; IFN signature ID IDIOPATHIC INFLAMMATORY MYOPATHIES; DISEASE-ACTIVITY; JUVENILE DERMATOMYOSITIS; CLINICAL IMPROVEMENT; RHEUMATOID-ARTHRITIS; ADULT POLYMYOSITIS; PERIPHERAL-BLOOD; REFRACTORY ADULT; SIGNATURE; BIOMARKERS AB Objective. To identify muscle gene expression patterns that predict rituximab responses and assess the effects of rituximab on muscle gene expression in PM and DM. Methods. In an attempt to understand the molecular mechanism of response and non-response to rituximab therapy, we performed Affymetrix gene expression array analyses on muscle biopsy specimens taken before and after rituximab therapy from eight PM and two DM patients in the Rituximab in Myositis study. We also analysed selected muscle-infiltrating cell phenotypes in these biopsies by immunohistochemical staining. Partek and Ingenuity pathway analyses assessed the gene pathways and networks. Results. Myeloid type I IFN signature genes were expressed at higher levels at baseline in the skeletal muscle of rituximab responders than in non-responders, whereas classic non-myeloid IFN signature genes were expressed at higher levels in non-responders at baseline. Also, rituximab responders have a greater reduction of the myeloid and non-myeloid type I IFN signatures than non-responders. The decrease in the type I IFN signature following administration of rituximab may be associated with the decreases in muscle-infiltrating CD19(+) B cells and CD68(+) macrophages in responders. Conclusion. Our findings suggest that high levels of myeloid type I IFN gene expression in skeletal muscle predict responses to rituximab in PM/DM and that rituximab responders also have a greater decrease in the expression of these genes. These data add further evidence to recent studies defining the type I IFN signature as both a predictor of therapeutic responses and a biomarker of myositis disease activity. C1 [Nagaraju, Kanneboyina; Ghimbovschi, Svetlana; Rayavarapu, Sree; Phadke, Aditi; Hoffman, Eric P.] George Washington Univ, Childrens Natl Med Ctr, Med Genet Res Ctr, Washington, DC USA. [Nagaraju, Kanneboyina; Rayavarapu, Sree; Hoffman, Eric P.] George Washington Univ, Inst Biomed Sci, Dept Integrat Syst Biol, Washington, DC USA. [Rider, Lisa G.; Miller, Frederick W.] NIEHS, Environm Autoimmun Grp, NIH, Bethesda, MD USA. RP Miller, FW (reprint author), NIEHS, Environm Autoimmun Grp, NIH, Hatfield Clin Res Ctr, 10 Ctr Dr, Bethesda, MD 20892 USA. EM millerf@mail.nih.gov OI Rider, Lisa/0000-0002-6912-2458; Miller, Frederick/0000-0003-2831-9593 FU Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health FX This study was supported in part by the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health. NR 20 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-0324 EI 1462-0332 J9 RHEUMATOLOGY JI RHEUMATOLOGY PD SEP PY 2016 VL 55 IS 9 BP 1673 EP 1680 DI 10.1093/rheumatology/kew213 PG 8 WC Rheumatology SC Rheumatology GA DW7RP UT WOS:000383849100019 PM 27215813 ER PT J AU Yaffe, K Nasrallah, I Hoang, TD Lauderdale, DS Knutson, KL Carnethon, MR Launer, LJ Lewis, CE Sidney, S AF Yaffe, Kristine Nasrallah, Ilya Hoang, Tina D. Lauderdale, Diane S. Knutson, Kristen L. Carnethon, Mercedes R. Launer, Lenore J. Lewis, Cora E. Sidney, Stephen TI Sleep Duration and White Matter Quality in Middle-Aged Adults SO SLEEP LA English DT Article DE sleep duration; white matter integrity; white matter hyperintensities; midlife ID COGNITIVE DECLINE; OLDER-ADULTS; MEMORY IMPAIRMENT; TEST-PERFORMANCE; HEALTH; WOMEN; RISK; METAANALYSIS; INTEGRITY; DISEASE AB Study Objectives: Sleep duration has been associated with risk of dementia and stroke, but few studies have investigated the relationship between sleep duration and brain MRI measures, particularly in middle age. Methods: In a prospective cohort of 613 black and white adults (mean age = 45.4 years) enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) study, participants reported typical sleep duration, dichotomized into moderate sleep duration (> 6 to <= 8 h) and short sleep duration (<= 6 h) at baseline (2005-2006). Five years later, we obtained brain MRI markers of white matter including fractional anisotropy, mean diffusivity, and white matter hyperintensities. Results: Compared to moderate sleepers, short sleepers had an elevated ratio of white matter hyperintensities to normal tissue in the parietal region (OR = 2.31, 95% CI: 1.47, 3.61) adjusted for age, race/sex, education, hypertension, stroke/TIA, depression, smoking status, and physical activity. White matter diffusivity was also higher, approximately a 0.2 standard deviation difference, in frontal, parietal, and temporal white matter regions, among those reporting shorter sleep duration in (P < 0.05 for all). Conclusions: Short sleep duration was associated with worse markers of white matter integrity in midlife. These mid-life differences in white matter may underlie the link between poor sleep and risk of dementia and stroke. C1 [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA 94143 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Biostat, San Francisco, CA 94143 USA. [Yaffe, Kristine] San Francisco VA Med Ctr, San Francisco, CA USA. [Nasrallah, Ilya] Hosp Univ Penn, Dept Radiol, 3400 Spruce St, Philadelphia, PA 19104 USA. [Hoang, Tina D.] Northern Calif Inst Res & Educ, San Francisco, CA USA. [Lauderdale, Diane S.] Univ Chicago, Dept Publ Hlth Sci, Chicago, IL 60637 USA. [Knutson, Kristen L.] Univ Chicago, Dept Med, 5841 S Maryland Ave, Chicago, IL 60637 USA. [Carnethon, Mercedes R.] Northwestern Univ, Dept Prevent Med, Chicago, IL 60611 USA. [Launer, Lenore J.] NIA, Intramural Res Program, Bethesda, MD 20892 USA. [Lewis, Cora E.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Sidney, Stephen] Kaiser Permanente Northern Calif, Div Res, Oakland, CA USA. RP Yaffe, K (reprint author), Univ Calif San Francisco, Box 181,4150 Clement St, San Francisco, CA 94121 USA. EM kristine.yaffe@ucsf.edu FU National Heart, Lung, and Blood Institute (NHLBI); University of Alabama at Birmingham [HHSN268201300025C, HHSN268201300026C]; Northwestern University [HHSN268201300027C]; University of Minnesota [HHSN268201300028C]; Kaiser Foundation Research Institute [HHSN268201300029C]; Johns Hopkins University School of Medicine [HHSN268200900041C]; Intramural Research Program of the National Institute on Aging (NIA); NIA [AG0005, K24 AG031155]; NHLBI [HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300029C, AG0005, HL122658] FX This was not an industry supported study. The Coronary Artery Risk Development in Young Adults Study (CARDIA) is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with the University of Alabama at Birmingham (HHSN268201300025C & HHSN268201300026C), Northwestern University (HHSN268201300027C), University of Minnesota (HHSN268201300028C), Kaiser Foundation Research Institute (HHSN268201300029C), and Johns Hopkins University School of Medicine (HHSN268200900041C). CARDIA is also partially supported by the Intramural Research Program of the National Institute on Aging (NIA) and an intra-agency agreement between NIA and NHLBI (AG0005). The CARDIA Cognitive Function Ancillary Study is supported by NHLBI HL122658. Dr. Yaffe is also supported by NIA K24 AG031155. This manuscript has been reviewed by CARDIA for scientific content. Drs. Yaffe, Carnethon, Lewis, and Sidney report grant support for the CARDIA study NHLBI HL122658, HHSN268201300027C, HHSN268201300025C & HHSN268201300026C, HHSN268201300029C. The other authors have indicated no financial conflicts of interest. NR 47 TC 0 Z9 0 U1 4 U2 4 PU AMER ACAD SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CTR, STE 920, WESTCHESTER, IL 60154 USA SN 0161-8105 EI 1550-9109 J9 SLEEP JI Sleep PD SEP 1 PY 2016 VL 39 IS 9 BP 1743 EP 1747 DI 10.5665/sleep.6104 PG 5 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DX4EG UT WOS:000384333400014 PM 27397561 ER PT J AU Puurunen, MK Gona, PN Larson, MG Murabito, JM Magnani, JW O'Donnell, CJ AF Puurunen, Marja K. Gona, Philimon N. Larson, Martin G. Murabito, Joanne M. Magnani, Jared W. O'Donnell, Christopher J. TI Epidemiology of venous thromboembolism in the Framingham Heart Study SO THROMBOSIS RESEARCH LA English DT Article DE Venous thromboembolism; Deep venous thrombosis; Pulmonary embolism; Epidemiology; Incidence; Mortality; Risk factors ID CARDIOVASCULAR RISK-FACTORS; POPULATION-BASED COHORT; DEEP-VEIN THROMBOSIS; PULMONARY-EMBOLISM; ASSOCIATION; MORTALITY; COMMUNITY; DISEASE; CANCER; HOSPITALIZATIONS AB Background: Reports of the crude incidence of venous thromboembolism (VTE) in Western countries vary widely. Data regarding risk factors, incidence and recurrence of VTE from deeply-phenotyped community-based cohort studies are needed. Objectives: To study the incidence, associated mortality, and predisposing factors of VTE in the prospective, longitudinal community-based Framingham Heart Study. Patients/Methods: The study sample consisted of the Framingham Heart Study Original, Offspring, Third Generation, and Omni cohorts (N = 9754). Incidence rates (IR) were standardized to the 2000 US population. Cox proportional hazards regression models were used to study risk factor associations. Results: During 1995-2014 (total follow-up time 104,091 person-years [median 9.8 (range 0-20) years]), 297 incident VIE events were observed. Age-adjusted IR of VIE was 20.3/10,000 (95% Cl 17.9-22.6). Of the events 120 (40%) were pulmonary embolism (PE) and 177 (60%) were deep venous thrombosis (Dvr); 29% were unprovoked, 40% provoked, and 31% cancer-related. Cancer-related VTE was associated with high mortality at 30 days (24.2%), 1 year (66.3%), and 5 years (75.6%). In multivariable models, age and obesity, but no other traditional cardiovascular risk factors, were significantly associated with VTE (hazard ratio [FIR] per 10-year increase in age 1.69, 95% CI 1.48-1.92; HR for obesity (BMI 30 kg/m(2)) 1.88, 95% CI 1.44-2.45). Conclusions: We provide data on the epidemiology of VTE. VW is associated with significant mortality, and prognosis after cancer-related VIE is particularly poor. Traditional cardiovascular risk factors beyond age and obesity are not associated with VIE. Published by Elsevier Ltd. C1 [Puurunen, Marja K.; Larson, Martin G.; Murabito, Joanne M.; Magnani, Jared W.; O'Donnell, Christopher J.] Boston Univ, Sch Med, Framingham Heart Study, Framingham, MA USA. [Puurunen, Marja K.; Larson, Martin G.; Murabito, Joanne M.; Magnani, Jared W.; O'Donnell, Christopher J.] NHLBI, Framingham, MA USA. [Gona, Philimon N.] Univ Massachusetts, Boston, MA 02125 USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Larson, Martin G.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Murabito, Joanne M.] Boston Univ, Sch Med, Dept Med, Gen Internal Med Sect, Boston, MA 02118 USA. [Magnani, Jared W.] Boston Univ, Sch Med, Dept Med, Sect Cardiovasc Med, Boston, MA 02118 USA. [O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Bldg 10, Bethesda, MD 20892 USA. [O'Donnell, Christopher J.] Boston Vet Adm Healthcare, Cardiol Sect, Dept Med, Boston, MA USA. RP O'Donnell, CJ (reprint author), Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM Christopher.odonnell@va.gov FU NHLBI [NO1-HL 25195, HHSN268201500001I] FX This work was supported by the NHLBI contracts NO1-HL 25195 and HHSN268201500001I. NR 44 TC 4 Z9 4 U1 2 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0049-3848 J9 THROMB RES JI Thromb. Res. PD SEP PY 2016 VL 145 BP 27 EP 33 DI 10.1016/j.thromres.2016.06.033 PG 7 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA DX0QS UT WOS:000384069800006 PM 27442716 ER PT J AU Puurunen, MK Enserro, D Xanthakis, V Larson, MG Benjamin, EJ Tofler, GH Wollert, KC O'Donnell, CJ Vasan, RS AF Puurunen, Marja K. Enserro, Danielle Xanthakis, Vanessa Larson, Martin G. Benjamin, Emelia J. Tofler, Geoffrey H. Wollert, Kai C. O'Donnell, Christopher J. Vasan, Ramachandran S. TI Biomarkers for the prediction of venous thromboembolism in the community SO THROMBOSIS RESEARCH LA English DT Article DE Biomarkers; Epidemiology; Risk factors; Thrombosis; Venous thromboembolism ID GROWTH-DIFFERENTIATION FACTOR-15; DEEP-VEIN THROMBOSIS; RISK PREDICTION; D-DIMER; INTEGRIN ACTIVATION; PULMONARY-EMBOLISM; PROSPECTIVE COHORT; HEART-DISEASE; ATHEROSCLEROSIS; RECURRENCE AB Background & objectives: Venous and arterial thrombosis share common pathophysiology. Multiple biomarkers reflecting various biological pathways can predict arterial thrombosis. We studied whether this approach could identify persons at risk of first venous thromboembolism (VTE). (C) 2016 Elsevier Ltd. All rights reserved. C1 [Puurunen, Marja K.; Xanthakis, Vanessa; Larson, Martin G.; Benjamin, Emelia J.; O'Donnell, Christopher J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Framingham Heart Study, Framingham, MA USA. [Puurunen, Marja K.; Xanthakis, Vanessa; Larson, Martin G.; Benjamin, Emelia J.; O'Donnell, Christopher J.; Vasan, Ramachandran S.] NHLBI, Framingham, MA USA. [Enserro, Danielle; Xanthakis, Vanessa; Larson, Martin G.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Xanthakis, Vanessa; Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Sect Prevent Med & Epidemiol, Boston, MA 02118 USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Cardiol Sect, Boston, MA 02118 USA. [Tofler, Geoffrey H.] Univ Sydney, Royal North Shore Hosp, Dept Cardiol, Sydney, NSW 2006, Australia. [Wollert, Kai C.] Hannover Med Sch, Div Mol & Translat Cardiol, Dept Cardiol & Angiol, Hannover, Germany. [O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Bldg 10, Bethesda, MD 20892 USA. [O'Donnell, Christopher J.] Boston Vet Adm Healthcare, Cardiol Sect, Dept Med, Boston, MA USA. RP Puurunen, MK (reprint author), Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave, Framingham, MA 01702 USA. EM marjap@bu.edu OI Ramachandran, Vasan/0000-0001-7357-5970 FU National Heart, Lung, and Blood Institute (NHLBI) [NO1-HL 25195, HHSN268201500001I] FX This work was supported by the National Heart, Lung, and Blood Institute (NHLBI) contracts NO1-HL 25195 and HHSN268201500001I. The funding source played no role in study design, data analysis, or reporting. NR 33 TC 2 Z9 2 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0049-3848 J9 THROMB RES JI Thromb. Res. PD SEP PY 2016 VL 145 BP 34 EP 39 DI 10.1016/j.thromres.2016.07.006 PG 6 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA DX0QS UT WOS:000384069800007 PM 27447083 ER PT J AU Mjoen, G Reisaeter, AV Dahle, DO AF Mjoen, Geir Reisaeter, Anna Varberg Dahle, Dag Olav TI HLA Mismatch and Allograft Survival SO TRANSPLANTATION LA English DT Letter C1 [Mjoen, Geir; Reisaeter, Anna Varberg; Dahle, Dag Olav] Natl Hosp Norway, Oslo Univ Hosp, Pb 4950 Nydalen, N-0027 Oslo, Norway. [Mjoen, Geir; Reisaeter, Anna Varberg; Dahle, Dag Olav] NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ USA. Heidelberg Univ, Inst Immunol, Dept Transplantat Immunol, Heidelberg, Germany. Mayo Clin, Mayo Clin Hosp, Phoenix, AZ USA. RP Mjoen, G (reprint author), Natl Hosp Norway, Oslo Univ Hosp, Pb 4950 Nydalen, N-0027 Oslo, Norway. EM geimjo@ous-hf.no NR 1 TC 1 Z9 1 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD SEP PY 2016 VL 100 IS 9 BP E52 EP E52 DI 10.1097/TP.0000000000001366 PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA DW8NG UT WOS:000383912100004 PM 27399204 ER PT J AU Williams, RC Opelz, G Weil, EJ McGarvey, CJ Chakkera, HA AF Williams, Robert C. Opelz, Gerhard Weil, E. Jennifer McGarvey, Chelsea J. Chakkera, Harini A. TI HLA Mismatch and Allograft Survival The Authors' Reply SO TRANSPLANTATION LA English DT Letter C1 [Williams, Robert C.; Weil, E. Jennifer] NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, 445 North 5th St,Suite 210, Phoenix, AZ 85004 USA. [Opelz, Gerhard] Heidelberg Univ, Inst Immunol, Dept Transplantat Immunol, Heidelberg, Germany. [McGarvey, Chelsea J.] Mayo Clin, Mayo Clin Hosp, Phoenix, AZ USA. [Chakkera, Harini A.] Mayo Clin, Div Nephrol, Phoenix, AZ USA. RP Williams, RC (reprint author), NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, 445 North 5th St,Suite 210, Phoenix, AZ 85004 USA. EM williamsr@mail.nih.gov FU Intramural NIH HHS [Z99 DK999999] NR 2 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD SEP PY 2016 VL 100 IS 9 BP E52 EP E53 DI 10.1097/TP.0000000000001365 PG 2 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA DW8NG UT WOS:000383912100005 PM 27479169 ER PT J AU Habes, M Toledo, JB Resnick, SM Doshi, J Van der Auwera, S Erus, G Janowitz, D Hegenscheid, K Homuth, G Volzke, H Hoffmann, W Grabe, HJ Davatzikos, C AF Habes, M. Toledo, J. B. Resnick, S. M. Doshi, J. Van der Auwera, S. Erus, G. Janowitz, D. Hegenscheid, K. Homuth, G. Voelzke, H. Hoffmann, W. Grabe, H. J. Davatzikos, C. TI Relationship between APOE Genotype and Structural MRI Measures throughout Adulthood in the Study of Health in Pomerania Population-Based Cohort SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Article ID WHITE-MATTER INTEGRITY; ALZHEIMERS-DISEASE; APOLIPOPROTEIN-E; COGNITIVE DECLINE; CEREBROSPINAL-FLUID; GENERAL-POPULATION; SPATIAL-PATTERNS; BRAIN ATROPHY; TYPE-4 ALLELE; GENETIC RISK AB BACKGROUND AND PURPOSE: The presence of the apolipoprotein E epsilon 4 allele is the strongest sporadic Alzheimer disease genetic risk factor. We hypothesized that apolipoprotein E epsilon 4 carriers and noncarriers may already differ in imaging patterns in midlife. We therefore sought to identify the effect of apolipoprotein E genotype on brain atrophy across almost the entire adult age span by using advanced MR imaging based pattern analysis. MATERIALS AND METHODS: We analyzed MR imaging scans of 1472 participants from the Study of Health in Pomerania (22-90 years of age). We studied the association among age, apolipoprotein E epsilon 4 carrier status, and brain atrophy, which was quantified by using 2 MR imaging based indices: Spatial Pattern of Atrophy for Recognition of Brain Aging (summarizing age-related brain atrophy) and Spatial Pattern of Abnormality for Recognition of Early Alzheimer Disease (summarizing Alzheimer disease-like brain atrophy patterns), as well as the gray matter volumes in several Alzheimer disease- and apolipoprotein E related ROIs (lateral frontal, lateral temporal, medial frontal, and hippocampus). RESULTS: No significant association was found between apolipoprotein E 84 carrier status and the studied ROls or the MR imaging based indices in linear regression models adjusted for age, sex, and education, including an interaction term between apolipoprotein E and age. CONCLUSIONS: Our study indicates that measurable apolipoprotein E related brain atrophy does not occur in early adulthood and midlife and suggests that such atrophy may only occur more proximal to the onset of clinical symptoms of dementia. C1 [Habes, M.; Voelzke, H.; Hoffmann, W.] Ernst Moritz Arndt Univ Greifswald, Inst Community Med, Greifswald, Germany. [Habes, M.; Van der Auwera, S.; Janowitz, D.; Grabe, H. J.] Ernst Moritz Arndt Univ Greifswald, Dept Psychiat, Greifswald, Germany. [Hegenscheid, K.] Ernst Moritz Arndt Univ Greifswald, Dept Radiol, Greifswald, Germany. [Homuth, G.] Ernst Moritz Arndt Univ Greifswald, Inst Genet & Funct Genom, Greifswald, Germany. [Habes, M.; Doshi, J.; Erus, G.; Davatzikos, C.] Univ Penn, Ctr Biomed Image Comp & Analyt, 3700 Hamilton Walk, Philadelphia, PA 19104 USA. [Toledo, J. B.] Univ Penn, Dept Pathol & Lab Med, Inst Aging, Perelman Sch Med,Ctr Neurodegenerat Dis Res, Third Floor Maloney Bldg,3600 Spruce St, Philadelphia, PA 19104 USA. [Resnick, S. M.] NIA, Lab Behav Neurosci, Bethesda, MD 20892 USA. [Hoffmann, W.; Grabe, H. J.] German Ctr Neurodegenerat Dis, Rostock, Germany. RP Habes, M (reprint author), Univ Penn, Ctr Biomed Image Comp & Analyt, 3700 Hamilton Walk, Philadelphia, PA 19104 USA.; Toledo, JB (reprint author), Univ Penn, Dept Pathol & Lab Med, Inst Aging, Perelman Sch Med,Ctr Neurodegenerat Dis Res, Third Floor Maloney Bldg,3600 Spruce St, Philadelphia, PA 19104 USA. EM habesm@uphs.upenn.edu; jtoledo@mail.med.upenn.edu RI Habes, Mohamad/M-2865-2016 OI Habes, Mohamad/0000-0001-9447-5805 FU Federal Ministry of Education and Research [01ZZ9603, 01ZZ0103, 01ZZ0403]; Ministry of Cultural Affairs; Social Ministry of the Federal State of Mecklenburg-West Pomerania; Siemens, Erlangen, Germany; Federal State of Mecklenburg-West Pomerania [03ZIK012]; Alfried Krupp von Bohlen und Halbach Foundation; Intramural Research Program, National Institute on Aging, National Institutes of Health; [P01 AG032953]; [PO1 AG017586]; [P30 AG010124]; [P50 NS053488] FX SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs, and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genomewide data in SHIP and MR imaging scans in SHIP and SHIP-TREND have been supported by a joint grant from Siemens, Erlangen, Germany, and the Federal State of Mecklenburg-West Pomerania. Genomewide geno typing in SHIP TREND-0 was supported by the Federal Ministry of Education and Research (grant No. 03ZIK012). M.H. was supported by the Alfried Krupp von Bohlen und Halbach Foundation. J.B.T. is supported by P01 AG032953, PO1 AG017586, P30 AG010124, and P50 NS053488. S.M.R. is supported by the Intramural Research Program, National Institute on Aging, National Institutes of Health. NR 40 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC NEURORADIOLOGY PI DENVILLE PA PO BOX 3000, DENVILLE, NJ 07834-9349 USA SN 0195-6108 EI 1936-959X J9 AM J NEURORADIOL JI Am. J. Neuroradiol. PD SEP PY 2016 VL 37 IS 9 BP 1636 EP 1642 DI 10.3174/ajnr.A4805 PG 7 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DV7JR UT WOS:000383112700011 PM 27173368 ER PT J AU Lintner, KE Patwardhan, A Rider, LG Abdul-Aziz, R Wu, YL Lundstrom, E Padyukov, L Zhou, B Alhomosh, A Newsom, D White, P Jones, KB O'Hanlon, TP Miller, FW Spencer, CH Yu, CY AF Lintner, Katherine E. Patwardhan, Anjali Rider, Lisa G. Abdul-Aziz, Rabheh Wu, Yee Ling Lundstrom, Emeli Padyukov, Leonid Zhou, Bi Alhomosh, Alaaedin Newsom, David White, Peter Jones, Karla B. O'Hanlon, Terrance P. Miller, Frederick W. Spencer, Charles H. Yu, Chack Yung TI Gene copy-number variations (CNVs) of complement C4 and C4A deficiency in genetic risk and pathogenesis of juvenile dermatomyositis SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article DE Autoimmune Diseases; Dermatomyositis; Epidemiology; Gene Polymorphism; Disease Activity ID MAJOR HISTOCOMPATIBILITY COMPLEX; IDIOPATHIC INFLAMMATORY MYOPATHIES; SYSTEMIC-LUPUS-ERYTHEMATOSUS; RP-C4-CYP21-TNX RCCX MODULES; MEMBRANE ATTACK COMPLEX; COMPONENT C4; STRUCTURAL BASIS; DISEASE; MHC; RETROVIRUSES AB Objective Complement-mediated vasculopathy of muscle and skin are clinical features of juvenile dermatomyositis (JDM). We assess gene copy-number variations (CNVs) for complement C4 and its isotypes, C4A and C4B, in genetic risks and pathogenesis of JDM. Methods The study population included 105 patients with JDM and 500 healthy European Americans. Gene copy-numbers (GCNs) for total C4, C4A, C4B and HLA-DRB1 genotypes were determined by Southern blots and qPCRs. Processed activation product C4d bound to erythrocytes (E-C4d) was measured by flow cytometry. Global gene-expression microarrays were performed in 19 patients with JDM and seven controls using PAXgene-blood RNA. Differential expression levels for selected genes were validated by qPCR. Results Significantly lower GCNs and differences in distribution of GCN groups for total C4 and C4A were observed in JDM versus controls. Lower GCN of C4A in JDM remained among HLA DR3-positive subjects (p=0.015). Homozygous or heterozygous C4A-deficiency was present in 40.0% of patients with JDM compared with 18.2% of controls (OR=3.00 (1.87 to 4.79), p=8.2x10(-6)). Patients with JDM had higher levels of E-C4d than controls (p=0.004). In JDM, C4A-deficient subjects had higher levels of E-C4d (p=0.0003) and higher frequency of elevated levels of multiple serum muscle enzymes at diagnosis (p=0.0025). Microarray profiling of blood RNA revealed upregulation of type I interferon-stimulated genes and lower abundance of transcripts for T-cell and chemokine function genes in JDM, but this was less prominent among C4A-deficient or DR3-positive patients. Conclusions Complement C4A deficiency appears to be an important factor for the genetic risk and pathogenesis of JDM, particularly in patients with a DR3-positive background. C1 [Lintner, Katherine E.; Patwardhan, Anjali; Abdul-Aziz, Rabheh; Wu, Yee Ling; Zhou, Bi; Alhomosh, Alaaedin; Newsom, David; White, Peter; Jones, Karla B.; Spencer, Charles H.; Yu, Chack Yung] Ohio State Univ, Dept Pediat, Nationwide Childrens Hosp, Res Inst, Columbus, OH 43210 USA. [Rider, Lisa G.; O'Hanlon, Terrance P.; Miller, Frederick W.] NIEHS, Environm Autoimmun Grp, Clin Res Branch, NIH, Bethesda, MD USA. [Lundstrom, Emeli; Padyukov, Leonid] Karolinska Univ Hosp, Dept Med, Rheumatol Unit, Stockholm, Sweden. RP Yu, CY (reprint author), Nationwide Childrens Hosp, Res Inst, 700 Childrens Dr, Columbus, OH 43205 USA. EM chack-yung.yu@nationwidechildrens.org RI White, Peter/E-4301-2011; OI White, Peter/0000-0002-5218-5903; Rider, Lisa/0000-0002-6912-2458; Miller, Frederick/0000-0003-2831-9593; Padyukov, Leonid/0000-0003-2950-5670 FU National Institute of Arthritis, Musculoskeletal and Skin Diseases, the National Institutes of Health [5R01 AR054459]; CureJM Foundation; Research Institute of the Nationwide Children's Hospital; National Institute of Environmental Health Sciences, National Institutes of Health FX This work was supported in part by National Institute of Arthritis, Musculoskeletal and Skin Diseases, the National Institutes of Health grant 5R01 AR054459, the CureJM Foundation, an institutional grant from the Research Institute of the Nationwide Children's Hospital, and the intramural research programme of the National Institute of Environmental Health Sciences, National Institutes of Health. NR 50 TC 2 Z9 2 U1 5 U2 5 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD SEP PY 2016 VL 75 IS 9 BP 1599 EP 1606 DI 10.1136/annrheumdis-2015-207762 PG 8 WC Rheumatology SC Rheumatology GA DV9OW UT WOS:000383271700009 PM 26493816 ER PT J AU Grayson, PC Schauer, C Herrmann, M Kaplan, MJ AF Grayson, Peter C. Schauer, Christine Herrmann, Martin Kaplan, Mariana J. TI Neutrophils as Invigorated Targets in Rheumatic Diseases SO ARTHRITIS & RHEUMATOLOGY LA English DT Review ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; PEPTIDYLARGININE DEIMINASE INHIBITION; T-CELL RESPONSES; EXTRACELLULAR TRAPS; ANTIPHOSPHOLIPID SYNDROME; CIRCULATING NEUTROPHILS; NETTING NEUTROPHILS; IMMUNE-RESPONSES; NADPH OXIDASE; VASCULITIS C1 [Grayson, Peter C.; Kaplan, Mariana J.] NIAMSD, NIH, Bethesda, MD 20892 USA. [Schauer, Christine; Herrmann, Martin] Univ Erlangen Nurnberg, Erlangen, Germany. [Schauer, Christine; Herrmann, Martin] Univ Klinikum Erlangen, Erlangen, Germany. RP Kaplan, MJ (reprint author), NIAMSD, System Autoimmun Branch, NIH, 10 Ctr Dr,Bldg 10,Room 6D-47C, Bethesda, MD 20892 USA. EM mariana.kaplan@nih.gov RI herrmann, martin/A-9597-2013 OI herrmann, martin/0000-0002-0258-2484 FU NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases Intramural Research Program) [ZIA-AR-041199] FX Supported in part by the NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases Intramural Research Program, project ZIA-AR-041199). NR 85 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2326-5191 EI 2326-5205 J9 ARTHRITIS RHEUMATOL JI Arthritis Rheumatol. PD SEP PY 2016 VL 68 IS 9 BP 2071 EP 2082 DI 10.1002/art.39745 PG 12 WC Rheumatology SC Rheumatology GA DW2VB UT WOS:000383498800004 PM 27159737 ER PT J AU Beer, JC Smith, AR Jarcho, JM Chen, G Reynolds, RC Pine, DS Nelson, EE AF Beer, Joanne C. Smith, Ashley R. Jarcho, Johanna M. Chen, Gang Reynolds, Richard C. Pine, Daniel S. Nelson, Eric E. TI Anxiously elaborating the social percept: Anxiety and age differences in functional connectivity of the fusiform face area in a peer evaluation paradigm SO AUSTRALIAN JOURNAL OF PSYCHOLOGY LA English DT Article DE development; face perception; psychophysiological interaction; social anxiety ID NEURAL MECHANISMS; FEARFUL FACES; DISORDER; AMYGDALA; CORTEX; MEMORY; ADOLESCENCE; RECOGNITION; MODULATION; ATTENTION AB Objectives: Social anxiety disorder involves biased cognition and altered neural responses to social stimuli. This study further assesses the precise ways in which neural activation associated with perceptual processing of faces differs in socially anxious and non-anxious individuals. Method: Functional magnetic resonance imaging data were acquired as 90 anxious or healthy juveniles and adults performed a peer feedback task. Psychophysiological functional connectivity analysis was performed on all participants using a seed placed in the right fusiform face area (rFFA). Results: Social anxiety was associated with enhanced rFFA coupling in several areas of ventral visual stream when viewing feedback from peers previously rejected by participants; healthy participants demonstrated the opposite pattern. Moreover, anxious juveniles had greater positive rFFA coupling with right inferior temporal gyrus during feedback from rejected peers; other groups showed the opposite pattern. Finally, anxious juveniles had greater positive rFFA coupling with pregenual anterior cingulate cortex during negative peer feedback; other groups displayed the opposite pattern. Conclusions: Anxious individuals, and juveniles in particular, may dedicate more neural resources to stimuli associated with potentially negative, relative to positive, social outcomes; non-anxious individuals may do the opposite. C1 [Beer, Joanne C.; Smith, Ashley R.; Jarcho, Johanna M.; Pine, Daniel S.; Nelson, Eric E.] NIMH, Sect Dev & Affect Neurosci, Bethesda, MD 20892 USA. [Chen, Gang; Reynolds, Richard C.] NIMH, Sci & Stat Comp Core, Bethesda, MD 20892 USA. RP Beer, JC (reprint author), Univ Pittsburgh, Dept Biostat, 311 Parran Hall,130 De Soto St, Pittsburgh, PA 15261 USA. EM beerj2@upmc.edu FU NIMH [01-M-0192] FX This research (NCT# 00018057; Protocol ID 01-M-0192) was supported by the NIMH intramural research programme. NR 53 TC 0 Z9 0 U1 5 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0004-9530 EI 1742-9536 J9 AUST J PSYCHOL JI Aust. J. Psychol. PD SEP PY 2016 VL 68 IS 3 SI SI BP 154 EP 165 DI 10.1111/ajpy.12130 PG 12 WC Psychology, Multidisciplinary SC Psychology GA DW0XJ UT WOS:000383366000003 ER PT J AU Ballen, K Ahn, KW Chen, M Abdel-Azim, H Ahmed, I Aljurf, M Antin, J Bhatt, AS Boeckh, M Chen, G Dandoy, C George, B Laughlin, MJ Lazarus, HM MacMillan, ML Margolis, DA Marks, DI Norkin, M Rosenthal, J Saad, A Savani, B Schouten, HC Storek, J Szabolcs, P Ustun, C Verneris, MR Waller, EK Weisdorf, DJ Williams, KM Wingard, JR Wirk, B Wolfs, T Young, JAH Auletta, J Komanduri, KV Lindemans, C Riches, ML AF Ballen, Karen Ahn, Kwang Woo Chen, Min Abdel-Azim, Hisham Ahmed, Ibrahim Aljurf, Mahmoud Antin, Joseph Bhatt, Ami S. Boeckh, Michael Chen, George Dandoy, Christopher George, Biju Laughlin, Mary J. Lazarus, Hillard M. MacMillan, Margaret L. Margolis, David A. Marks, David I. Norkin, Maxim Rosenthal, Joseph Saad, Ayman Savani, Bipin Schouten, Harry C. Storek, Jan Szabolcs, Paul Ustun, Celalettin Verneris, Michael R. Waller, Edmund K. Weisdorf, Daniel J. Williams, Kirsten M. Wingard, John R. Wirk, Baldeep Wolfs, Tom Young, Jo-Anne H. Auletta, Jeffrey Komanduri, Krishna V. Lindemans, Caroline Riches, Marcie L. TI Infection Rates among Acute Leukemia Patients Receiving Alternative Donor Hematopoietic Cell Transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Umbilical cord blood; Leukemia; Infection ID UMBILICAL-CORD BLOOD; INVASIVE FUNGAL DISEASE; ACUTE MYELOID-LEUKEMIA; UNRELATED DONORS; BONE-MARROW; HEMATOLOGIC MALIGNANCIES; PERIPHERAL-BLOOD; IMMUNE RECONSTITUTION; CONDITIONING REGIMEN; INTERNATIONAL BLOOD AB Alternative graft sources (umbilical cord blood [UCB], matched unrelated donors [MUD], or mismatched unrelated donors [MMUD]) enable patients without a matched sibling donor to receive potentially curative hematopoietic cell transplantation (HCT). Retrospective studies demonstrate comparable outcomes among different graft sources. However, the risk and types of infections have not been compared among graft sources. Such information may influence the choice of a particular graft source. We compared the incidence of bacterial, viral, and fungal infections in 1781 adults with acute leukemia who received alternative donor HCT (UCB, n = 568; MUD, n = 930; MMUD, n = 283) between 2008 and 2011. The incidences of bacterial infection at 1 year were 72%, 59%, and 65% (P < .0001) for UCB, MUD, and MMUD, respectively. Incidences of viral infection at 1 year were 68%, 45%, and 53% (P < .0001) for UCB, MUD, and MMUD, respectively. In multivariable analysis, bacterial, fungal, and viral infections were more common after either UCB or MMUD than after MUD (P < .0001). Bacterial and viral but not fungal infections were more common after UCB than MMUD (P = .0009 and < .0001, respectively). The presence of viral infection was not associated with an increased mortality. Overall survival (OS) was comparable among UCB and MMUD patients with Karnofsky performance status (KPS) >= 90% but was inferior for UCB for patients with KPS < 90%. Bacterial and fungal infections were associated with poorer OS. Future strategies focusing on infection prevention and treatment are indicated to improve HCT outcomes. (C) 2016 American Society for Blood and Marrow Transplantation. C1 [Ballen, Karen] Massachusetts Gen Hosp, Div Hematol Oncol, Suite 118, Boston, MA 02115 USA. [Ahn, Kwang Woo; Chen, Min] Med Coll Wisconsin, Dept Med, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Ahn, Kwang Woo] Med Coll Wisconsin, Inst Hlth & Soc, Div Biostat, Milwaukee, WI 53226 USA. [Abdel-Azim, Hisham] Univ Southern Calif, Keck Sch Med, Childrens Hosp Los Angeles, Div Hematol Oncol & Blood & Marrow Transplantat, Los Angeles, CA USA. [Ahmed, Ibrahim] Childrens Mercy Hosp & Clin, Dept Hematol Oncol & Bone Marrow Transplantat, Kansas City, MO USA. [Aljurf, Mahmoud] King Faisal Specialist Hosp Ctr & Res, Dept Oncol, Riyadh, Saudi Arabia. [Antin, Joseph] Dana Farber Canc Inst, Dept Med Oncol, Ctr Hematol Oncol, Boston, MA 02115 USA. [Bhatt, Ami S.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Boeckh, Michael] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, 1124 Columbia St, Seattle, WA 98104 USA. [Chen, George] Roswell Pk Canc Inst, Dept Med, Buffalo, NY 14263 USA. [Dandoy, Christopher] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [George, Biju] Christian Med Coll & Hosp, Vellore, Tamil Nadu, India. [Laughlin, Mary J.] Cleveland Cord Blood Ctr, Cleveland, OH USA. [Lazarus, Hillard M.] Univ Hosp Case Med Ctr, Seidman Canc Ctr, Cleveland, OH USA. [MacMillan, Margaret L.; Verneris, Michael R.; Young, Jo-Anne H.] Univ Minnesota, Dept Pediat, Div Blood & Marrow Transplantat, Minneapolis, MN 55455 USA. [Margolis, David A.] Med Coll Wisconsin, Dept Pediat, Sect Hematol Oncol & BMT, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. [Marks, David I.] Univ Hosp Bristol NHS Trust, Pediat Bone Marrow Transplant, Bristol, Avon, England. [Norkin, Maxim; Wingard, John R.] Univ Florida, Coll Med, Div Hematol Oncol, Gainesville, FL USA. [Rosenthal, Joseph] City Hope Natl Med Ctr, 1500 E Duarte Rd, Duarte, CA 91010 USA. [Saad, Ayman] Univ Alabama Birmingham, Dept Med, Div Hematol Oncol, Birmingham, AL 35294 USA. [Savani, Bipin] Vanderbilt Univ, Med Ctr, Dept Med, Div Hematol Oncol, Nashville, TN USA. [Schouten, Harry C.] Acad Ziekenhuis, Dept Hematol, Maastricht, Netherlands. [Storek, Jan] Univ Calgary, Dept Med, Calgary, AB, Canada. [Szabolcs, Paul] Childrens Natl Hlth Syst, Div Blood & Marrow Transplantat, Washington, DC USA. [Ustun, Celalettin; Weisdorf, Daniel J.] Univ Minnesota, Med Ctr, Dept Med, Div Hematol Oncol & Transplantat, Minneapolis, MN 55455 USA. [Waller, Edmund K.] Emory Univ, Winship Canc Inst, Dept Hematol & Med Oncol, Atlanta, GA 30322 USA. [Williams, Kirsten M.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Wirk, Baldeep] Seattle Canc Care Alliance, Div Bone Marrow Transplant, Seattle, WA USA. [Wolfs, Tom] Wilhelmina Childrens Hosp, Div Pediat, Utrecht, Netherlands. [Auletta, Jeffrey] Nationwide Childrens Hosp, Host Def Program, Div Hematol, Columbus, OH USA. [Auletta, Jeffrey] Nationwide Childrens Hosp, Host Def Program, Div Oncol, Columbus, OH USA. [Auletta, Jeffrey] Nationwide Childrens Hosp, Host Def Program, Div Bone Marrow Transplant, Columbus, OH USA. [Auletta, Jeffrey] Nationwide Childrens Hosp, Host Def Program, Div Infect Dis, Columbus, OH USA. [Komanduri, Krishna V.] Univ Miami, Adult Stem Cell Transplantat Program, Miami, FL USA. [Lindemans, Caroline] Univ Med Ctr Utrecht, Pediat Blood & Marrow Transplantat Program, Utrecht, Netherlands. [Riches, Marcie L.] Univ North Carolina Chapel Hill, Div Hematol Oncol, Chapel Hill, NC USA. RP Ballen, K (reprint author), Massachusetts Gen Hosp, Div Hematol Oncol, Suite 118, Boston, MA 02115 USA. EM kballen@partners.org OI Saad, Ayman /0000-0003-0003-0130 FU National Cancer Institute, the National Heart, Lung and Blood Institute [5U24-CA076518]; National Institute of Allergy and Infectious Diseases; NCI [5U10HL069294]; Health Resources and Services Administration (HRSA/DHHS) [HHSH250201200016C]; Office of Naval Research [N00014-13-1-0039, N00014-14-1-0028]; Alexion; Amgen, Inc.; NHLBI FX The CIBMTR is supported by public health service grant/cooperative agreement 5U24-CA076518 from the National Cancer Institute, the National Heart, Lung and Blood Institute, and the National Institute of Allergy and Infectious Diseases; a grant/cooperative Agreement 5U10HL069294 from NHLBI and NCI; a contract HHSH250201200016C with Health Resources and Services Administration (HRSA/DHHS); 2 grants N00014-13-1-0039 and N00014-14-1-0028 from the Office of Naval Research; and grants from Alexion; daggerAmgen, Inc.; an anonymous donation to the Medical College of Wisconsin; Be the Match Foundation; daggerBristol Myers Squibb Oncology; daggerCelgene Corporation; daggerChimerix, Inc.; Fred Hutchinson Cancer Research Center; Gamida Cell Ltd.; Genentech, Inc.; Genzyme Corporation; daggerGilead Sciences, Inc.; Health Research, Inc. Roswell Park Cancer Institute; HistoGenetics, Inc.; Incyte Corporation; daggerJazz Pharmaceuticals, Inc.; Jeff Gordon Children's Foundation; The Leukemia & Lymphoma Society; The Medical College of Wisconsin; Merck & Co, Inc.; Mesoblast; daggerMillennium: The Takeda Oncology Co.; daggerMiltenyi Biotec, Inc.; National Marrow Donor Program; Neovii Biotech NA, Inc.; Novartis Pharmaceuticals Corporation; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Otsuka America Pharmaceutical, Inc.; Otsuka Pharmaceutical Co, Ltd. - Japan; Oxford Immunotec; Perkin Elmer, Inc.; Pharmacyclics; daggerSanofi US; Seattle Genetics; Sigma Tau Pharmaceuticals; daggerSpectrum Pharmaceuticals, Inc.; St. Baldrick's Foundation; daggerSunesis Pharmaceuticals, Inc.; Swedish Orphan Biovitrum, Inc.; Telomere Diagnostics, -Inc.; TerumoBCT; Therakos, Inc.; University of Minnesota; and daggerWellpoint, Inc. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, Health Resources and Services Administration or any other agency of the US Government. daggerIndicates corporate members. NR 40 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 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD SEP PY 2016 VL 22 IS 9 BP 1636 EP 1645 DI 10.1016/j.bbmt.2016.06.012 PG 10 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DT8YK UT WOS:000381781400015 PM 27343716 ER PT J AU Baker, SG AF Baker, Stuart G. TI The Latent Class Twin Method SO BIOMETRICS LA English DT Article DE Breast cancer; Latent class; Missing heritability; Phantom heritability; Propensity score; Survival variance components ID GENOME-WIDE ASSOCIATION; CANCER; SUSCEPTIBILITY; BREAST; HERITABILITY; PREVALENCE; BRCA1 AB The twin method refers to the use of data from same-sex identical and fraternal twins to estimate the genetic and environmental contributions to a trait or outcome. The standard twin method is the variance component twin method that estimates heritability, the fraction of variance attributed to additive genetic inheritance. The latent class twin method estimates two quantities that are easier to interpret than heritability: the genetic prevalence, which is the fraction of persons in the genetic susceptibility latent class, and the heritability fraction, which is the fraction of persons in the genetic susceptibility latent class with the trait or outcome. We extend the latent class twin method in three important ways. First, we incorporate an additive genetic model to broaden the sensitivity analysis beyond the original autosomal dominant and recessive genetic models. Second, we specify a separate survival model to simplify computations and improve convergence. Third, we show how to easily adjust for covariates by extending the method of propensity scores from a treatment difference to zygosity. Applying the latent class twin method to data on breast cancer among Nordic twins, we estimated a genetic prevalence of 1%, a result with important implications for breast cancer prevention research. C1 [Baker, Stuart G.] NCI, Biometry Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. RP Baker, SG (reprint author), NCI, Biometry Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. EM sb16i@nih.gov FU National Institutes of Health FX This work was supported by the National Institutes of Health. NR 23 TC 0 Z9 0 U1 8 U2 8 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 SEP PY 2016 VL 72 IS 3 BP 827 EP 834 DI 10.1111/biom.12460 PG 8 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA DW0YJ UT WOS:000383369000016 PM 26753781 ER PT J AU Kim, S Albert, PS AF Kim, Sungduk Albert, Paul S. TI A Class of Joint Models for Multivariate Longitudinal Measurements and a Binary Event SO BIOMETRICS LA English DT Article DE Asymmetric link; Generalized t-distribution; Macrosomia; Prediction; Skewed multivariate random effects model; Ultrasound measurement ID RESPONSE DATA; BAYESIAN-ANALYSIS; GROWTH AB Predicting binary events such as newborns with large birthweight is important for obstetricians in their attempt to reduce both maternal and fetal morbidity and mortality. Such predictions have been a challenge in obstetric practice, where longitudinal ultrasound measurements taken at multiple gestational times during pregnancy may be useful for predicting various poor pregnancy outcomes. The focus of this article is on developing a flexible class of joint models for the multivariate longitudinal ultrasound measurements that can be used for predicting a binary event at birth. A skewed multivariate random effects model is proposed for the ultrasound measurements, and the skewed generalized t-link is assumed for the link function relating the binary event and the underlying longitudinal processes. We consider a shared random effect to link the two processes together. Markov chain Monte Carlo sampling is used to carry out Bayesian posterior computation. Several variations of the proposed model are considered and compared via the deviance information criterion, the logarithm of pseudomarginal likelihood, and with a training-test set prediction paradigm. The proposed methodology is illustrated with data from the NICHD Successive Small-for-Gestational-Age Births study, a large prospective fetal growth cohort conducted in Norway and Sweden. C1 [Kim, Sungduk; Albert, Paul S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, Rockville, MD 20847 USA. RP Kim, S (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, Rockville, MD 20847 USA. EM kims2@mail.nih.gov FU Intramural Research program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development FX The research of Drs Kim and Albert was supported by the Intramural Research program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 15 TC 0 Z9 0 U1 2 U2 2 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 SEP PY 2016 VL 72 IS 3 BP 917 EP 925 DI 10.1111/biom.12463 PG 9 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA DW0YJ UT WOS:000383369000025 PM 26753988 ER PT J AU Lyles, RH Mitchell, EM Weinberg, CR Umbach, DM Schisterman, EF AF Lyles, Robert H. Mitchell, Emily M. Weinberg, Clarice R. Umbach, David M. Schisterman, Enrique F. TI An Efficient Design Strategy for Logistic Regression Using Outcome- and Covariate-Dependent Pooling of Biospecimens Prior to Assay SO BIOMETRICS LA English DT Article DE Bootstrap; Efficiency; Epidemiology; Pooling; Study design ID DISEASE INCIDENCE; PREVALENCE; SERA; HIV AB Potential reductions in laboratory assay costs afforded by pooling equal aliquots of biospecimens have long been recognized in disease surveillance and epidemiological research and, more recently, have motivated design and analytic developments in regression settings. For example, Weinberg and Umbach (1999, Biometrics 55, 718-726) provided methods for fitting set-based logistic regression models to case-control data when a continuous exposure variable (e.g., a biomarker) is assayed on pooled specimens. We focus on improving estimation efficiency by utilizing available subject-specific information at the pool allocation stage. We find that a strategy that we call "(y,c)-pooling," which forms pooling sets of individuals within strata defined jointly by the outcome and other covariates, provides more precise estimation of the risk parameters associated with those covariates than does pooling within strata defined only by the outcome. We review the approach to set-based analysis through offsets developed by Weinberg and Umbach in a recent correction to their original paper. We propose a method for variance estimation under this design and use simulations and a real-data example to illustrate the precision benefits of (y, c)-pooling relative to y-pooling. We also note and illustrate that set-based models permit estimation of covariate interactions with exposure. C1 [Lyles, Robert H.] Emory Univ, Dept Biostat & Bioinformat, Rollins Sch Publ Hlth, 1518 Clifton Rd NE,Mailstop 1518-002-3AA, Atlanta, GA 30322 USA. [Mitchell, Emily M.; Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Res, NIH, Bethesda, MD 20892 USA. [Weinberg, Clarice R.; Umbach, David M.] NIEHS, Biostat & Computat Biol Branch, NIH, MD A303,POB 12233, Res Triangle Pk, NC 27709 USA. RP Lyles, RH (reprint author), Emory Univ, Dept Biostat & Bioinformat, Rollins Sch Publ Hlth, 1518 Clifton Rd NE,Mailstop 1518-002-3AA, Atlanta, GA 30322 USA. EM rlyles@sph.emory.edu OI Schisterman, Enrique/0000-0003-3757-641X FU Intramural Research Program of the National Institute of Environmental Health Sciences [Z01-ES040006]; National Institute of Nursing Research [1RC4NR012527-01]; National Institute of Environmental Health Sciences [5R01ES012458-07]; National Center for Advancing Translational Sciences [UL1TR000454] FX This research was supported in part by the Intramural Research Program of the National Institute of Environmental Health Sciences (Z01-ES040006), the National Institute of Nursing Research (1RC4NR012527-01), the National Institute of Environmental Health Sciences (5R01ES012458-07), and the National Center for Advancing Translational Sciences (UL1TR000454). NR 19 TC 0 Z9 0 U1 1 U2 1 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 SEP PY 2016 VL 72 IS 3 BP 965 EP 975 DI 10.1111/biom.12489 PG 11 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA DW0YJ UT WOS:000383369000030 PM 26964741 ER PT J AU Kirch, R Reaman, G Feudtner, C Wiener, L Schwartz, LA Sung, L Wolfe, J AF Kirch, Rebecca Reaman, Gregory Feudtner, Chris Wiener, Lori Schwartz, Lisa A. Sung, Lillian Wolfe, Joanne TI Advancing a comprehensive cancer care agenda for children and their families: Institute of Medicine Workshop highlights and next steps SO CA-A CANCER JOURNAL FOR CLINICIANS LA English DT Article DE end of life; oncology; palliative care; patient-reported outcomes; pediatric; psychosocial care; quality of life; supportive care; survivorship ID PEDIATRIC PALLIATIVE CARE; PSYCHOSOCIAL ASSESSMENT-TOOL; PATIENT-REPORTED OUTCOMES; CHRONIC HEALTH CONDITIONS; CHILDHOOD-CANCER; FOLLOW-UP; ADULT SURVIVORS; HIGH-RISK; ONCOLOGY; LIFE AB This article highlights key findings from the Comprehensive Cancer Care for Children and Their Families March 2015 joint workshop by the Institute of Medicine (IOM) and the American Cancer Society. This initiative convened more than 100 family members, clinician investigators, advocates, and members of the public to discuss emerging evidence and care models and to determine the next steps for optimizing quality-of-life outcomes and well-being for children and families during pediatric cancer treatment, after treatment completion, and across the life spectrum. Participants affirmed the triple aim of pediatric oncology that strives for every child with cancer to be cured; provides high-quality palliative and psychosocial supportive, restorative, and rehabilitative care to children and families throughout the illness course and survivorship; and assures receipt of high-quality end-of-life care for patients with advancing disease. Workshop outcomes emphasized the need for new pediatric cancer drug development and identified critical opportunities to prioritize palliative care and psychosocial support as an integral part of pediatric cancer research and treatment, including the necessity for adequately resourcing these supportive services to minimize suffering and distress, effectively address quality-of-life needs for children and families at all stages of illness, and mitigate the long-term health risks associated with childhood cancer and its treatment. Next steps include dismantling existing silos and enhancing collaboration between clinical investigators, disease-directed specialists, and supportive care services; expanding the use of patient-reported and parent-reported outcomes; effectively integrating palliative and psychosocial care; and clinical communication skills development. CA Cancer J Clin 2016;66:398-407. (c) 2016 American Cancer Society. C1 [Kirch, Rebecca] Ctr Adv Palliat Care, New York, NY USA. [Kirch, Rebecca] Cameron & Hayden Lord Fdn, New York, NY USA. [Reaman, Gregory] USDA, Off Hematol & Oncol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Feudtner, Chris] Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA. [Feudtner, Chris] Univ Penn, Dept Med Eth & Hlth Policy, Perelman Sch Med, Philadelphia, PA 19104 USA. [Wiener, Lori] NCI, Behav Hlth Core, Bethesda, MD 20892 USA. [Wiener, Lori] NCI, Psychosocial Support & Res Program, Bethesda, MD 20892 USA. [Schwartz, Lisa A.] Childrens Hosp Philadelphia, Dept Pediat, Div Oncol, Philadelphia, PA 19104 USA. [Schwartz, Lisa A.] Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Sung, Lillian] Hosp Sick Children, Hematol Oncol, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. [Wolfe, Joanne] Dana Farber Canc Inst, Pediat Palliat Care Serv, Dept Psychosocial Oncol & Palliat Care, 450 Brookline Ave, Boston, MA 02115 USA. [Wolfe, Joanne] Boston Childrens Hosp, Pediat Palliat Care, Boston, MA USA. RP Wolfe, J (reprint author), Dana Farber Canc Inst, Pediat Palliat Care Serv, Dept Psychosocial Oncol & Palliat Care, 450 Brookline Ave, Boston, MA 02115 USA. EM joanne_wolfe@dfci.harvard.edu NR 83 TC 0 Z9 0 U1 6 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-9235 EI 1542-4863 J9 CA-CANCER J CLIN JI CA-Cancer J. Clin. PD SEP-OCT PY 2016 VL 66 IS 5 BP 398 EP 407 DI 10.3322/caac.21347 PG 10 WC Oncology SC Oncology GA DX0CQ UT WOS:000384029500007 PM 27145249 ER PT J AU Ambudkar, IS Muallem, S AF Ambudkar, Indu S. Muallem, Shmuel TI ROS in Ca2+ signaling and disease-part 2 SO CELL CALCIUM LA English DT Editorial Material C1 [Ambudkar, Indu S.] NIDCR, Secretory Physiol Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. NIDCR, Epithelial Secret & Transport Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. RP Ambudkar, IS (reprint author), NIDCR, Secretory Physiol Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. EM iambudkar@dir.nidcr.nih.gov NR 8 TC 0 Z9 0 U1 1 U2 1 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0143-4160 EI 1532-1991 J9 CELL CALCIUM JI Cell Calcium PD SEP PY 2016 VL 60 IS 3 SI SI BP 153 EP 154 DI 10.1016/j.ceca.2016.08.001 PG 2 WC Cell Biology SC Cell Biology GA DW8YB UT WOS:000383940300001 PM 27553171 ER PT J AU Arroyo, J Farkas, V Sanz, AB Cabib, E AF Arroyo, Javier Farkas, Vladimir Belen Sanz, Ana Cabib, Enrico TI "Strengthening the fungal cell wall through chitin-glucan cross-links: effects on morphogenesis and cell integrity' SO CELLULAR MICROBIOLOGY LA English DT Article; Proceedings Paper CT Fungal Cell Wall Meeting CY OCT, 2015 CL Inst Pasteur, Paris, FRANCE HO Inst Pasteur ID MOTHER-BUD NECK; SACCHAROMYCES-CEREVISIAE; ASPERGILLUS-FUMIGATUS; CANDIDA-ALBICANS; BUDDING YEAST; SIGNALING PATHWAY; SEPTUM FORMATION; PROTEINS; GROWTH; BIOSYNTHESIS AB The cross-linking of polysaccharides to assemble new cell wall in fungi requires transglycosylation mechanisms by which preexisting glycosidic linkages are broken and new linkages are created between the polysaccharides. The molecular mechanisms for these processes, which are essential for fungal cell biology, are only now beginning to be elucidated. Recent development of in vivo and in vitro biochemical approaches has allowed characterization of important aspects about the formation of chitin-glucan covalent cell wall cross-links by cell wall transglycosylases of the CRH family and their biological function. Covalent linkages between chitin and glucan mediated by Crh proteins control morphogenesis and also play important roles in the remodeling of the fungal cell wall as part of the compensatory responses necessary to counterbalance cell wall stress. These enzymes are encoded by multigene families of redundant proteins very well conserved in fungal genomes but absent in mammalian cells. Understanding the molecular basis of fungal adaptation to cell wall stress through these and other cell wall remodeling enzymatic activities offers an opportunity to explore novel antifungal treatments and to identify potential fungal virulence factors. C1 [Arroyo, Javier; Belen Sanz, Ana] Univ Complutense Madrid, Fac Farm, Dept Microbiol 2, IRYCIS, E-28040 Madrid, Spain. [Farkas, Vladimir] Slovak Acad Sci, Inst Chem, Dept Glycobiol, Ctr Glyc, Bratislava 84538, Slovakia. [Cabib, Enrico] NIDDK, Lab Biochem & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Arroyo, J (reprint author), Univ Complutense Madrid, Fac Farm, Dept Microbiol 2, IRYCIS, E-28040 Madrid, Spain. EM jarroyo@ucm.es OI Arroyo, Javier/0000-0002-1971-1721 NR 81 TC 0 Z9 0 U1 12 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1462-5814 EI 1462-5822 J9 CELL MICROBIOL JI Cell Microbiol. PD SEP PY 2016 VL 18 IS 9 SI SI BP 1239 EP 1250 DI 10.1111/cmi.12615 PG 12 WC Cell Biology; Microbiology SC Cell Biology; Microbiology GA DW2AR UT WOS:000383445800007 PM 27185288 ER PT J AU Ngalame, NNO Waalkes, MP Tokar, EJ AF Ngalame, Ntube N. O. Waalkes, Michael P. Tokar, Erik J. TI Silencing KRAS Overexpression in Cadmium-Transformed Prostate Epithelial Cells Mitigates Malignant Phenotype SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID RAS ONCOGENE ACTIVATION; NORMAL STEM-CELLS; IN-VITRO; K-RAS; MATRIX METALLOPROTEINASES; PANCREATIC-CANCER; EXPRESSION; GROWTH; STEM/PROGENITOR; ACQUISITION AB Cadmium (Cd) is a potential human prostate carcinogen. Chronic Cd exposure malignantly transforms RWPE-1 human prostate epithelial cells into CTPE cells by an unclear mechanism. Previous studies show that RWPE-1 can also be malignantly transformed by arsenic, and KRAS activation is key to causation and maintenance of this phenotype. Although Cd and arsenic can both transform prostate epithelial cells, it is uncertain whether their mechanisms are similar. Thus, here we determined whether KRAS activation is critical in causing and maintaining Cd-induced malignant transformation in CTPE cells. Expression of KRAS, miRNAs, and other genes of interest was analyzed by Western blot and RT-PCR. Following stable KRAS knockdown (KD) by RNA interference using shRNAmir, the malignant phenotype was assessed by various physical and genetic parameters. CTPE cells greatly overexpressed KRAS by 20-fold, indicating a likely role in Cd transformation. Thus, we attempted to reverse the malignant phenotype via KRAS KD. Two weeks after shRNAmir transduction, KRAS protein was undetectable in CTPE KD cells, confirming stable KID. KRAS KD reduced stimulated RAS/ERK and PI3K/AKT signaling pathways and markedly mitigated multiple physical and molecular malignant cell characteristics including: hypersecretion of MMP-2, colony formation, cell survival, and expression of cancer-relevant genes (reduced proliferation and cell cycle-related genes; activated tumor suppressor PTEN). However, KRAS KD did not reverse miRNA expression originally down-regulated by Cd transformation. These data strongly suggest KRAS is a key gene in development and maintenance of the Cd-induced malignant phenotype, at least in the prostate. It is not, however, the only genetic factor sustaining this phenotype. C1 [Ngalame, Ntube N. O.; Waalkes, Michael P.; Tokar, Erik J.] NIEHS, Stem Cell Toxicol Grp, Natl Toxicol Program Lab, Div Natl Toxicol Program, POB 12233, Res Triangle Pk, NC 27709 USA. RP Tokar, EJ (reprint author), NIEHS, Stem Cell Toxicol Grp, Natl Toxicol Program Lab, Div Natl Toxicol Program, POB 12233, Res Triangle Pk, NC 27709 USA. EM tokare@niehs.nih.gov FU National Institute of Environmental Health Sciences of the National Institutes of Health (NIH); National Toxicology Program (NTP) FX This work was supported by the intramural program of the National Institute of Environmental Health Sciences of the National Institutes of Health (NIH) and the National Toxicology Program (NTP). NR 40 TC 1 Z9 1 U1 4 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X EI 1520-5010 J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD SEP PY 2016 VL 29 IS 9 BP 1458 EP 1467 DI 10.1021/acs.chemrestox.6b00137 PG 10 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA DW6CF UT WOS:000383733300009 PM 27510461 ER PT J AU Kadigamuwa, CC Mapa, MST Wimalasena, K AF Kadigamuwa, Chamila C. Mapa, Mapa S. T. Wimalasena, Kandatege TI Lipophilic Cationic Cyanines Are Potent Complex I Inhibitors and Specific in Vitro Dopaminergic Toxins with Mechanistic Similarities to Both Rotenone and MPP+ SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID RAPID COLORIMETRIC ASSAY; PARKINSONS-DISEASE; 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE MPTP; MONOAMINE TRANSPORTER; RAT HEPATOCYTES; ORGANIC CATIONS; HUMAN-CELLS; NEURONS; APOPTOSIS; NEUROTOXICITY AB We have recently reported that simple lipophilic cationic cyanines are specific and potent dopaminergic toxins with a mechanism of toxicity similar to that of the Parkinsonian toxin MPP+. In the present study, a group of fluorescent lipophilic cyanines have been used to further exploit the structure activity relationship of the specific dopaminergic toxicity of cyanines. Here, we report that all cyanines tested were highly toxic to dopaminergic MN9D cells with IC(50)s in the range of 60-100 nM and not toxic to non-neuronal HepG2 cells parallel to that previously reported for 2,2'- and 4,4'-cyanines. All cyanines nonspecifically accumulate in the mitochondria of both MN9D and HepG2 cells at high concentrations, inhibit the mitochondrial complex I with the inhibition potencies similar to the potent complex I inhibitor, rotenone. They increase the reactive oxygen species (ROS) production specifically in dopaminergic cells causing apoptotic cell death. These and other findings suggest that the complex I inhibition, the expression of low levels of antioxidant enzymes, and presence of high levels of oxidatively labile radical propagator, dopamine, could be responsible for the specific increase in ROS production in dopaminergic cells. Thus, the predisposition of dopaminergic cells to produce high levels of ROS in response to mitochondrial toxins together with their inherent greater demand for energy may contribute to their specific vulnerability toward these toxins. The novel findings that cyanines are an unusual class of potent mitochondrial toxins with specific dopaminergic toxicity suggest that their presence in the environment could contribute to the etiology of PD similar to that of MPP+ and rotenone. C1 [Kadigamuwa, Chamila C.; Mapa, Mapa S. T.; Wimalasena, Kandatege] Wichita State Univ, Dept Chem, Wichita, KS 67260 USA. [Kadigamuwa, Chamila C.] NCI, Center Canc Res, Bldg 37,Room 1130, Bethesda, MD 20892 USA. RP Wimalasena, K (reprint author), Wichita State Univ, Dept Chem, Wichita, KS 67260 USA. EM kandatege.wimalasena@wichita.edu FU National Institutes of Health National Center for Research Resources INBRE Program [P20 RR016475] FX Funds to purchase an inverted florescent microscope in part was provided by the National Institutes of Health National Center for Research Resources INBRE Program [Grant P20 RR016475] (to K.W.). NR 48 TC 0 Z9 0 U1 4 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X EI 1520-5010 J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD SEP PY 2016 VL 29 IS 9 BP 1468 EP 1479 DI 10.1021/acs.chemrestox.6b00138 PG 12 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA DW6CF UT WOS:000383733300010 PM 27510327 ER PT J AU Kouprina, N Larionov, V AF Kouprina, Natalay Larionov, Vladimir TI Transformation-associated recombination (TAR) cloning for genomics studies and synthetic biology SO CHROMOSOMA LA English DT Review DE Transformation-associated recombination; TAR cloning; Human artificial chromosome; HAC; Synthetic biology ID HUMAN ARTIFICIAL CHROMOSOMES; YEAST SACCHAROMYCES-CEREVISIAE; MYCOPLASMA-GENITALIUM GENOME; EMBRYONIC STEM-CELLS; VSG EXPRESSION SITE; GENE-CLUSTER; HETEROLOGOUS EXPRESSION; PROSTATE-CANCER; COMPLEX GENOMES; SECONDARY METABOLITES AB Transformation-associated recombination (TAR) cloning represents a unique tool for isolation and manipulation of large DNA molecules. The technique exploits a high level of homologous recombination in the yeast Sacharomyces cerevisiae. So far, TAR cloning is the only method available to selectively recover chromosomal segments up to 300 kb in length from complex and simple genomes. In addition, TAR cloning allows the assembly and cloning of entire microbe genomes up to several Mb as well as engineering of large metabolic pathways. In this review, we summarize applications of TAR cloning for functional/structural genomics and synthetic biology. C1 [Kouprina, Natalay; Larionov, Vladimir] NCI, Dev Therapeut Branch, Bethesda, MD 20892 USA. RP Kouprina, N (reprint author), NCI, Dev Therapeut Branch, Bethesda, MD 20892 USA. EM kouprinn@mail.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, USA FX This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, USA (V.L. and N.K). NR 100 TC 0 Z9 0 U1 23 U2 23 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-5915 EI 1432-0886 J9 CHROMOSOMA JI Chromosoma PD SEP PY 2016 VL 125 IS 4 BP 621 EP 632 DI 10.1007/s00412-016-0588-3 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA DW2HZ UT WOS:000383464800004 PM 27116033 ER PT J AU Lu, MT Onuma, OK Massaro, JM D'Agostino, RB O'Donnell, CJ Hoffmann, U AF Lu, Michael T. Onuma, Oyere K. Massaro, Joseph M. D'Agostino, Ralph B. O'Donnell, Christopher J. Hoffmann, Udo TI Lung Cancer Screening Eligibility in the Community Cardiovascular Risk Factors, Coronary Artery Calcification, and Cardiovascular Events SO CIRCULATION LA English DT Letter DE cardiac computed tomography; coronary artery calcium; prevention; screening smoking ID TRIAL C1 [Lu, Michael T.; Hoffmann, Udo] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Cardiac MR PET CT Program, 165 Cambridge St,Suite 400, Boston, MA 02114 USA. [Onuma, Oyere K.] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [Onuma, Oyere K.; Massaro, Joseph M.; D'Agostino, Ralph B.; O'Donnell, Christopher J.; Hoffmann, Udo] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Onuma, Oyere K.; Massaro, Joseph M.; D'Agostino, Ralph B.; O'Donnell, Christopher J.; Hoffmann, Udo] Boston Univ, Framingham, MA 01702 USA. [Massaro, Joseph M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [D'Agostino, Ralph B.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Bldg 10, Bethesda, MD 20892 USA. [O'Donnell, Christopher J.] Harvard Med Sch, Boston Vet Adm Healthcare Syst, Dept Med, Cardiol Sect, Boston, MA 02114 USA. RP Lu, MT (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Cardiac MR PET CT Program, 165 Cambridge St,Suite 400, Boston, MA 02114 USA. EM mlu@mgh.harvard.edu FU NHLBI NIH HHS [R01 HL071039, R01 HL077447, N01HC25195, N01 HC025195, R01 HL060040, T32 HL076136, R01 HL107385, R01 HL080124, R01 HL076784, R01 HL070100, K24 HL113128]; NIA NIH HHS [R01 AG028321] NR 4 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD SEP PY 2016 VL 134 IS 12 BP 897 EP 899 DI 10.1161/CIRCULATIONAHA.116.023957 PG 3 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DX0NI UT WOS:000384059400013 PM 27647299 ER PT J AU Steinberger, J Daniels, SR Hagberg, N Isasi, CR Kelly, AS Lloyd-Jones, D Pate, RR Pratt, C Shay, CM Towbin, JA Urbina, E Van Horn, LV Zachariah, JP AF Steinberger, Julia Daniels, Stephen R. Hagberg, Nancy Isasi, Carmen R. Kelly, Aaron S. Lloyd-Jones, Donald Pate, Russell R. Pratt, Charlotte Shay, Christina M. Towbin, Jeffrey A. Urbina, Elaine Van Horn, Linda V. Zachariah, Justin P. CA Amer Heart Assoc Atherosclerosis Council Cardiovasc Stroke Nursing Council Epidemiology Prevention Council Functional Genomics Stroke Council TI Cardiovascular Health Promotion in Children: Challenges and Opportunities for 2020 and Beyond A Scientific Statement From the American Heart Association SO CIRCULATION LA English DT Article DE AHA Scientific Statements; blood pressure; body mass index; cholesterol; diet; glucose; pediatrics; physical activity; smoking ID BODY-MASS INDEX; METABOLIC SYNDROME COMPONENTS; AMBULATORY BLOOD-PRESSURE; FASTING PLASMA-GLUCOSE; INTIMA-MEDIA THICKNESS; ASSESS DIETARY-INTAKE; HIGH-SCHOOL-STUDENTS; RISK-FACTORS; UNITED-STATES; US CHILDREN AB This document provides a pediatric-focused companion to "Defining and Setting National Goals for Cardiovascular Health Promotion and Disease Reduction: The American Heart Association's Strategic Impact Goal Through 2020 and Beyond," focused on cardiovascular health promotion and disease reduction in adults and children. The principles detailed in the document reflect the American Heart Association's new dynamic and proactive goal to promote cardiovascular health throughout the life course. The primary focus is on adult cardiovascular health and disease prevention, but critical to achievement of this goal is maintenance of ideal cardiovascular health from birth through childhood to young adulthood and beyond. Emphasis is placed on the fundamental principles and metrics that define cardiovascular health in children for the clinical or research setting, and a balanced and critical appraisal of the strengths and weaknesses of the cardiovascular health construct in children and adolescents is provided. Specifically, this document discusses 2 important factors: the promotion of ideal cardiovascular health in all children and the improvement of cardiovascular health metric scores in children currently classified as having poor or intermediate cardiovascular health. Other topics include the current status of cardiovascular health in US children, opportunities for the refinement of health metrics, improvement of health metric scores, and possibilities for promoting ideal cardiovascular health. Importantly, concerns about the suitability of using single thresholds to identify elevated cardiovascular risk throughout the childhood years and the limits of our current knowledge are noted, and suggestions for future directions and research are provided. C1 [Steinberger, Julia; Kelly, Aaron S.] Univ Minnesota, Minneapolis, MN 55455 USA. [Daniels, Stephen R.] Univ Colorado, Sch Med, Boulder, CO 80309 USA. [Hagberg, Nancy] Child Heart Associates, Worcester, MA 01605 USA. [Isasi, Carmen R.] Albert Einstein Coll Med, Bronx, NY 10461 USA. [Lloyd-Jones, Donald; Van Horn, Linda V.] Northwestern Univ, Evanston, IL 60208 USA. [Pate, Russell R.] Univ So Calif, Los Angeles, CA 90089 USA. [Pratt, Charlotte] NHLBI, Bethesda, MD 20892 USA. [Shay, Christina M.] Univ N Carolina, Chapel Hill, NC 27599 USA. [Towbin, Jeffrey A.] Le Bonheur Childrens Hosp, Inst Heart, Memphis, TN 38105 USA. [Urbina, Elaine] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Zachariah, Justin P.] Baylor Coll Med, Houston, TX 77030 USA. RP Steinberger, J (reprint author), Univ Minnesota, Minneapolis, MN 55455 USA. FU NCATS NIH HHS [UL1 TR001422, UL1 TR001073, UL1 TR001425]; NHLBI NIH HHS [K23 HL111335, R01 HL102130] NR 125 TC 4 Z9 4 U1 8 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD SEP PY 2016 VL 134 IS 12 BP E236 EP E255 DI 10.1161/CIR.0000000000000441 PG 20 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DX0NI UT WOS:000384059400001 PM 27515136 ER PT J AU McCoy, JP AF McCoy, J. Philip, Jr. TI Issue Highlights - September 2016 SO CYTOMETRY PART B-CLINICAL CYTOMETRY LA English DT Editorial Material ID FLOW-CYTOMETRY; T-LYMPHOCYTES; CELLS; EXPRESSION; NEOPLASMS; LEUKEMIA C1 [McCoy, J. Philip, Jr.] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. RP McCoy, JP (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. EM mccoyjp@mail.nih.gov NR 24 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4949 EI 1552-4957 J9 CYTOM PART B-CLIN CY JI Cytom. Part B-Clin. Cytom. PD SEP PY 2016 VL 90 IS 5 BP 401 EP 403 DI 10.1002/cyto.b.21477 PG 3 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA DW0XG UT WOS:000383365700001 PM 27638251 ER PT J AU Kim, S Dogan, RI Chatr-Aryamontri, A Chang, CS Oughtred, R Rust, J Batista-Navarro, R Carter, J Ananiadou, S Matos, S Santos, A Campos, D Oliveira, JL Singh, O Jonnagaddala, J Dai, HJ Su, ECY Chang, YC Su, YC Chu, CH Chen, CC Hsu, WL Peng, YF Arighi, C Wu, CH Vijay-Shanker, K Aydin, F Husunbeyi, ZM Ozgur, A Shin, SY Kwon, D Dolinski, K Tyers, M Wilbur, WJ Comeau, DC AF Kim, Sun Dogan, Rezarta Islamaj Chatr-Aryamontri, Andrew Chang, Christie S. Oughtred, Rose Rust, Jennifer Batista-Navarro, Riza Carter, Jacob Ananiadou, Sophia Matos, Sergio Santos, Andre Campos, David Oliveira, Jose Luis Singh, Onkar Jonnagaddala, Jitendra Dai, Hong-Jie Su, Emily Chia-Yu Chang, Yung-Chun Su, Yu-Chen Chu, Chun-Han Chen, Chien Chin Hsu, Wen-Lian Peng, Yifan Arighi, Cecilia Wu, Cathy H. Vijay-Shanker, K. Aydin, Ferhat Husunbeyi, Zehra Melce Ozgur, Arzucan Shin, Soo-Yong Kwon, Dongseop Dolinski, Kara Tyers, Mike Wilbur, W. John Comeau, Donald C. TI BioCreative V BioC track overview: collaborative biocurator assistant task for BioGRID SO DATABASE-THE JOURNAL OF BIOLOGICAL DATABASES AND CURATION LA English DT Article ID INTERACTING PROTEINS; INTERACTION DATABASE; RECOGNITION; UPDATE; INFORMATION; TEXT AB BioC is a simple XML format for text, annotations and relations, and was developed to achieve interoperability for biomedical text processing. Following the success of BioC in BioCreative IV, the BioCreative V BioC track addressed a collaborative task to build an assistant system for BioGRID curation. In this paper, we describe the framework of the collaborative BioC task and discuss our findings based on the user survey. This track consisted of eight subtasks including gene/protein/organism named entity recognition, protein-protein/genetic interaction passage identification and annotation visualization. Using BioC as their data-sharing and communication medium, nine teams, world-wide, participated and contributed either new methods or improvements of existing tools to address different subtasks of the BioC track. Results from different teams were shared in BioC and made available to other teams as they addressed different subtasks of the track. In the end, all submitted runs were merged using a machine learning classifier to produce an optimized output. The biocurator assistant system was evaluated by four BioGRID curators in terms of practical usability. The curators' feedback was overall positive and highlighted the user-friendly design and the convenient gene/protein curation tool based on text mining. C1 [Kim, Sun; Dogan, Rezarta Islamaj; Wilbur, W. John; Comeau, Donald C.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Chatr-Aryamontri, Andrew; Tyers, Mike] Univ Montreal, Inst Res Immunol & Canc, Montreal, PQ H3C 3J7, Canada. [Chang, Christie S.; Oughtred, Rose; Rust, Jennifer; Dolinski, Kara] Princeton Univ, Lewis Sigler Inst Integrat Genom, Princeton, NJ 08544 USA. [Batista-Navarro, Riza; Carter, Jacob; Ananiadou, Sophia] Univ Manchester, Sch Comp Sci, Natl Ctr Text Min, Manchester, Lancs, England. [Matos, Sergio; Santos, Andre; Oliveira, Jose Luis] Univ Aveiro, DETI IEETA, Campus Univ Santiago, P-3810193 Aveiro, Portugal. [Campos, David] BMD Software Lda, Rua Calouste Gulbenkian 1, P-3810074 Aveiro, Portugal. [Singh, Onkar; Su, Emily Chia-Yu] Taipei Med Univ, Grad Inst Biomed Informat, Coll Med Sci & Technol, Taipei, Taiwan. [Jonnagaddala, Jitendra] Univ New South Wales, Sch Publ Hlth & Community Med, Kensington, NSW 2033, Australia. [Jonnagaddala, Jitendra] Univ New South Wales, Prince Wales Clin Sch, Kensington, NSW 2033, Australia. [Dai, Hong-Jie] Natl Taitung Univ, Dept Comp Sci & Informat Engn, Taitung, Taiwan. [Chang, Yung-Chun; Chu, Chun-Han; Hsu, Wen-Lian] Acad Sinica, Inst Informat Sci, Taipei, Taiwan. [Chang, Yung-Chun; Chen, Chien Chin] Natl Taiwan Univ, Dept Informat Management, Taipei, Taiwan. [Su, Yu-Chen] Natl Tsing Hua Univ, Dept Comp Sci, Hsinchu, Taiwan. [Peng, Yifan; Arighi, Cecilia; Wu, Cathy H.; Vijay-Shanker, K.] Univ Delaware, Comp & Informat Sci, Newark, DE 19716 USA. [Arighi, Cecilia; Wu, Cathy H.] Univ Delaware, Ctr Bioinformat & Computat Biol, Newark, DE 19716 USA. [Aydin, Ferhat; Husunbeyi, Zehra Melce; Ozgur, Arzucan] Bogazici Univ, Dept Comp Engn, TR-34342 Istanbul, Turkey. [Shin, Soo-Yong] Asan Med Ctr, Dept Biomed Informat, Seoul 138736, South Korea. [Kwon, Dongseop] Myongji Univ, Dept Comp Engn, Yongin 449728, South Korea. [Tyers, Mike] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada. RP Comeau, DC (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM comeau@ncbi.nlm.nih.gov RI Matos, Sergio/G-4941-2010; OI Matos, Sergio/0000-0003-1941-3983; Arighi, Cecilia/0000-0002-0803-4817 FU Intramural Research Program of the NIH, National Library of Medicine; National Institutes of Health [R01OD010929, R24OD011194]; Genome Quebec International Recruitment Award; FCT-Foundation for Science and Technology under the FCT Investigator program; European Union [634143]; National Science Foundation [DBI-1062520]; National Institute of Health [DE-INBRE P20GM103446]; Marie Curie FP7-Reintegration-Grants within the 7th European Community Framework Programme; National Research Foundation of Korea [2012R1A1A2044389, 2011-0022437] FX Intramural Research Program of the NIH, National Library of Medicine to S.K., R.I.D., W.J.W. and D.C.C.; National Institutes of Health [R01OD010929 and R24OD011194] to K.D and M.T.; Genome Quebec International Recruitment Award to M.T.; FCT-Foundation for Science and Technology under the FCT Investigator program to S.M.; The European Union's H2020 project MedBioinformatics (Grant Agreement No 634143) to D.C.; National Science Foundation [DBI-1062520] and the National Institute of Health [DE-INBRE P20GM103446] to Y.P., C.A., C.H.W. and K.V.; Marie Curie FP7-Reintegration-Grants within the 7th European Community Framework Programme to F.A., Z.M.H. and A.O.; Basic Science Research Program through the National Research Foundation of Korea [2012R1A1A2044389 and 2011-0022437] to D.K. Funding for open access charge: Intramural Research Program of the NIH, National Library of Medicine. NR 39 TC 3 Z9 3 U1 4 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1758-0463 J9 DATABASE-OXFORD JI Database PD SEP 1 PY 2016 AR baw121 DI 10.1093/database/baw121 PG 13 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA DW7MG UT WOS:000383834200001 ER PT J AU Wang, QH Abdul, SS Almeida, L Ananiadou, S Balderas-Martinez, YI Batista-Navarro, R Campos, D Chilton, L Chou, HJ Contreras, G Cooper, L Dai, HJ Ferrell, B Fluck, J Gama-Castro, S George, N Gkoutos, G Irin, AK Jensen, LJ Jimenez, S Jue, TR Keseler, I Madan, S Matos, S McQuilton, P Milacic, M Mort, M Natarajan, J Pafilis, E Pereira, E Rao, S Rinaldi, F Rothfels, K Salgado, D Silva, RM Singh, O Stefancsik, R Su, CH Subramani, S Tadepally, HD Tsaprouni, L Vasilevsky, N Wang, XD Chatr-Aryamontri, A Laulederkind, SJF Matis-Mitchell, S McEntyre, J Orchard, S Pundir, S Rodriguez-Esteban, R Van Auken, K Lu, ZY Schaeffer, M Wu, CH Hirschman, L Arighi, CN AF Wang, Qinghua Abdul, Shabbir S. Almeida, Lara Ananiadou, Sophia Balderas-Martinez, Yalbi I. Batista-Navarro, Riza Campos, David Chilton, Lucy Chou, Hui-Jou Contreras, Gabriela Cooper, Laurel Dai, Hong-Jie Ferrell, Barbra Fluck, Juliane Gama-Castro, Socorro George, Nancy Gkoutos, Georgios Irin, Afroza K. Jensen, Lars J. Jimenez, Silvia Jue, Toni R. Keseler, Ingrid Madan, Sumit Matos, Sergio McQuilton, Peter Milacic, Marija Mort, Matthew Natarajan, Jeyakumar Pafilis, Evangelos Pereira, Emiliano Rao, Shruti Rinaldi, Fabio Rothfels, Karen Salgado, David Silva, Raquel M. Singh, Onkar Stefancsik, Raymund Su, Chu-Hsien Subramani, Suresh Tadepally, Hamsa D. Tsaprouni, Loukia Vasilevsky, Nicole Wang, Xiaodong Chatr-Aryamontri, Andrew Laulederkind, Stanley J. F. Matis-Mitchell, Sherri McEntyre, Johanna Orchard, Sandra Pundir, Sangya Rodriguez-Esteban, Raul Van Auken, Kimberly Lu, Zhiyong Schaeffer, Mary Wu, Cathy H. Hirschman, Lynette Arighi, Cecilia N. TI Overview of the interactive task in BioCreative V SO DATABASE-THE JOURNAL OF BIOLOGICAL DATABASES AND CURATION LA English DT Article ID TEXT; INTEGRATION; ANNOTATION; BIOLOGY; SCALE AB Fully automated text mining (TM) systems promote efficient literature searching, retrieval, and review but are not sufficient to produce ready-to-consume curated documents. These systems are not meant to replace biocurators, but instead to assist them in one or more literature curation steps. To do so, the user interface is an important aspect that needs to be considered for tool adoption. The BioCreative Interactive task (IAT) is a track designed for exploring user-system interactions, promoting development of useful TM tools, and providing a communication channel between the biocuration and the TM communities. In BioCreative V, the IAT track followed a format similar to previous interactive tracks, where the utility and usability of TM tools, as well as the generation of use cases, have been the focal points. The proposed curation tasks are user-centric and formally evaluated by biocurators. In BioCreative V IAT, seven TM systems and 43 biocurators participated. Two levels of user participation were offered to broaden curator involvement and obtain more feedback on usability aspects. The full level participation involved training on the system, curation of a set of documents with and without TM assistance, tracking of time-on-task, and completion of a user survey. The partial level participation was designed to focus on usability aspects of the interface and not the performance per se. In this case, biocurators navigated the system by performing pre-designed tasks and then were asked whether they were able to achieve the task and the level of difficulty in completing the task. In this manuscript, we describe the development of the interactive task, from planning to execution and discuss major findings for the systems tested. C1 [Wang, Qinghua; Wu, Cathy H.; Arighi, Cecilia N.] Univ Delaware, Ctr Bioinformat & Computat Biol, Newark, DE 19711 USA. [Wang, Qinghua; Wu, Cathy H.; Arighi, Cecilia N.] Univ Delaware, Dept Comp & Informat Sci, Newark, DE 19711 USA. [Abdul, Shabbir S.] Taipei Med Univ, Int Ctr Hlth Informat Technol, Taipei, Taiwan. [Almeida, Lara; Matos, Sergio] Univ Aveiro, DETI IEETA, Campus Univ Santiago, P-3810193 Aveiro, Portugal. [Ananiadou, Sophia; Batista-Navarro, Riza] Univ Manchester, Natl Ctr Text Min, Manchester, Lancs, England. [Balderas-Martinez, Yalbi I.] Univ Nacl Autonoma Mexico, Fac Ciencias, Mexico City 04510, DF, Mexico. [Campos, David] BMD Software, Aveiro, Portugal. [Chilton, Lucy] Newcastle Univ, Northern Inst Canc Res, Newcastle Upon Tyne, Tyne & Wear, England. [Chou, Hui-Jou] Rutgers Univ Camden, Camden, NJ 08102 USA. [Contreras, Gabriela; Gama-Castro, Socorro] Univ Nacl Autonoma Mexico, Ctr Ciencias Genom, Mexico City 04510, DF, Mexico. [Cooper, Laurel] Oregon State Univ, Dept Bot & Plant Pathol, Corvallis, OR 97331 USA. [Dai, Hong-Jie] Natl Taitung Univ, Dept Comp Sci & Informat Engn, Taitung, Taiwan. [Ferrell, Barbra] Univ Delaware, Coll Agr & Nat Resources, Newark, DE 19711 USA. [Fluck, Juliane; Madan, Sumit] Fraunhofer Inst Algorithms & Sci Comp, D-53754 St Augustin, Germany. [George, Nancy] EMBO, SourceData, Heidelberg, Germany. [Gkoutos, Georgios] Univ Birmingham, Inst Canc & Genom Sci, Coll Med & Dent Sci, Ctr Computat Biol, Birmingham B15 2TT, W Midlands, England. [Gkoutos, Georgios] Univ Hosp Birmingham NHS Fdn Trust, Inst Translat Med, Birmingham B15 2TT, W Midlands, England. [Irin, Afroza K.] Univ Bonn, Life Sci Informat, Bonn, Germany. [Jensen, Lars J.] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Prot Res, Copenhagen, Denmark. [Jimenez, Silvia] EPFL, Blue Brain Project, Biotech Campus, Geneva, Switzerland. [Jue, Toni R.] Univ New South Wales NSW, Prince Wales Clin Sch, Sydney, NSW, Australia. [Keseler, Ingrid] SRI Int, Menlo Pk, CA 94025 USA. [McQuilton, Peter] Univ Oxford, Oxford E Res Ctr, Oxford, England. [Milacic, Marija; Rothfels, Karen] Ontario Inst Canc Res, Dept Informat & Biocomp, Toronto, ON M5G 0A3, Canada. [Mort, Matthew] Cardiff Univ, Inst Med Genet, HGMD, Heath Pk, Cardiff, S Glam, Wales. [Natarajan, Jeyakumar; Subramani, Suresh] Bharathiar Univ, Dept Bioinformat, Coimbatore, Tamil Nadu, India. [Pafilis, Evangelos] Hellen Ctr Marine Res, Inst Marine Biol Biotechnol & Aquaculture, Iraklion, Crete, Greece. [Pereira, Emiliano] Max Planck Inst Marine Microbiol, Microbial Genom & Bioinformat Grp, Bremen, Germany. [Rao, Shruti] Georgetown Univ, ICBI, Washington, DC 20007 USA. [Rinaldi, Fabio] Univ Zurich, Inst Computat Linguist, Zurich, Switzerland. [Salgado, David] Aix Marseille Univ, GMGF, F-13385 Marseille, France. [Salgado, David] INSERM, UMR S 910, F-13385 Marseille, France. [Silva, Raquel M.] Univ Aveiro, Dept Med Sci, iBiMED, P-3810193 Aveiro, Portugal. [Silva, Raquel M.] Univ Aveiro, IEETA, P-3810193 Aveiro, Portugal. [Singh, Onkar] Taipei Med Univ, Grad Inst Biomed informat, Taipei, Taiwan. [Stefancsik, Raymund] Univ Cambridge, Dept Genet, Cambridge, England. [Su, Chu-Hsien] Acad Sinica, Inst Informat Sci, Taipei, Taiwan. [Tsaprouni, Loukia] Univ Bedfordshire, ISPAR, Bedford, England. [Vasilevsky, Nicole] Oregon Hlth & Sci Univ, Ontol Dev Grp, Portland, OR 97239 USA. [Wang, Xiaodong; Van Auken, Kimberly] CALTECH, WormBase Consortium, Div Biol & Biol Engn, Pasadena, CA 91125 USA. [Chatr-Aryamontri, Andrew] Univ Montreal, Inst Res Immunol & Canc, Montreal, PQ, Canada. [Laulederkind, Stanley J. F.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Matis-Mitchell, Sherri] Reed Elsevier, Philadelphia, PA 19103 USA. [McEntyre, Johanna; Orchard, Sandra; Pundir, Sangya] European Bioinformat Inst EMBL EBI, Hinxton, England. [Rodriguez-Esteban, Raul] F Hoffmann La Roche Ltd, Roche Innovat Ctr Basel, Basel, Switzerland. [Lu, Zhiyong] NIH, NCBI, Bethesda, MD 20894 USA. [Schaeffer, Mary] ARS, USDA, MaizeGDB, Columbia, MO 65211 USA. [Schaeffer, Mary] Univ Missouri, Columbia, MO 65211 USA. [Hirschman, Lynette] Mitre Corp, Bedford, MA 01730 USA. RP Arighi, CN (reprint author), Univ Delaware, Ctr Bioinformat & Computat Biol, Newark, DE 19711 USA.; Arighi, CN (reprint author), Univ Delaware, Dept Comp & Informat Sci, Newark, DE 19711 USA. EM arighi@dbi.udel.edu RI Matos, Sergio/G-4941-2010; Silva, Raquel/B-8337-2008; OI Rinaldi, Fabio/0000-0001-5718-5462; Matos, Sergio/0000-0003-1941-3983; Silva, Raquel/0000-0001-5926-8042; Rodriguez-Esteban, Raul/0000-0002-9494-9609; Vasilevsky, Nicole/0000-0001-5208-3432; Jensen, Lars Juhl/0000-0001-7885-715X; Arighi, Cecilia/0000-0002-0803-4817; McEntyre, Jo/0000-0002-1611-6935; Orchard, Sandra/0000-0002-8878-3972; Stefancsik, Raymund/0000-0001-8314-2140; Jue, Toni Rose/0000-0002-8449-5973 FU National Institutes of Health [R13GM109648, P41HG003751, U54GM114833]; Intramural Research Program at National Library of Medicine; National Institutes of Health Office of Director [R24OD011883]; US Department of Energy [DE-SC0010838]; National Science Foundation [1340112]; National Science Foundation [DBI] [1356374]; Ontario Research Fund; European Molecular Biology Laboratory; Facultad de Ciencias, UNAM; DGAPA-UNAM FX National Institutes of Health [R13GM109648 to C.N.A., P41HG003751 and U54GM114833 to K.R. and M.M.]; Intramural Research Program at National Library of Medicine to Z.L.]; National Institutes of Health Office of Director [R24OD011883 to N.V.]; the US Department of Energy [DE-SC0010838 to C.H.W. and L.H.]; National Science Foundation [#1340112 to L.C., DBI#1356374 for B.F.]; Ontario Research Fund; the European Molecular Biology Laboratory; Facultad de Ciencias, UNAM; the post-doctoral program fellowship from DGAPA-UNAM to Y.I.B.-M. NR 37 TC 3 Z9 3 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1758-0463 J9 DATABASE-OXFORD JI Database PD SEP 1 PY 2016 AR baw119 DI 10.1093/database/baw119 PG 18 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA DW7MF UT WOS:000383834100001 ER PT J AU Morales, AV Espeso-Gil, S Ocana, I Nieto-Lopez, F Calleja, E Bovolenta, P Lewandoski, M del Corral, RD AF Morales, Aixa V. Espeso-Gil, Sergio Ocana, Inmaculada Nieto-Lopez, Francisco Calleja, Elena Bovolenta, Paola Lewandoski, Mark Diez del Corral, Ruth TI FGF Signaling Enhances a Sonic Hedgehog Negative Feedback Loop at the Initiation of Spinal Cord Ventral Patterning SO DEVELOPMENTAL NEUROBIOLOGY LA English DT Article DE chick embryo; mouse embryo; neural tube; gene regulatory network; FGF; Shh; Ptch ID VERTEBRATE NEURAL-TUBE; TRANSCRIPTION-FACTOR; PATCHED GENE; LIMB BUDS; IN-VIVO; SHH; EXPRESSION; GROWTH; PTCH2; MICE AB A prevalent developmental mechanism for the assignment of cell identities is the production of spatiotemporal concentration gradients of extracellular signaling molecules that are interpreted by the responding cells. One of such signaling systems is the Shh gradient that controls neuronal subtype identity in the ventral spinal cord. Using loss and gain of function approaches in chick and mouse embryos, we show here that the fibroblast growth factor (FGF) signaling pathway is required to restrict the domains of ventral gene expression as neuroepithelial cells become exposed to Shh during caudal extension of the embryo. FGF signaling activates the expression of the Shh receptor and negative pathway regulator Patched 2 (Ptch2) and therefore can enhance a negative feedback loop that restrains the activity of the pathway. Thus, we identify one of the mechanisms by which FGF signaling acts as a modulator of the onset of Shh signaling activity in the context of coordination of ventral patterning and caudal axis extension. (C) 2015 Wiley Periodicals, Inc. C1 [Morales, Aixa V.; Espeso-Gil, Sergio; Ocana, Inmaculada; Nieto-Lopez, Francisco; Calleja, Elena; Bovolenta, Paola; Diez del Corral, Ruth] CSIC, Inst Cajal, E-28002 Madrid, Spain. [Ocana, Inmaculada; Nieto-Lopez, Francisco; Bovolenta, Paola] CIBER Enfermedades Raras, Barcelona, Spain. [Nieto-Lopez, Francisco; Bovolenta, Paola] UAM, CSIC, Ctr Biol Mol Severo Ochoa, Canto Blanco 28049, Spain. [Lewandoski, Mark] Natl Canc Inst, Canc & Dev Biol Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Espeso-Gil, Sergio] Ctr Regulac Genom, Barcelona 08003, Spain. [Diez del Corral, Ruth] Champalimaud Ctr Unknown, Champalimaud Neurosci Program, P-1400038 Lisbon, Portugal. RP Morales, AV; del Corral, RD (reprint author), CSIC, Inst Cajal, E-28002 Madrid, Spain.; del Corral, RD (reprint author), Champalimaud Ctr Unknown, Champalimaud Neurosci Program, P-1400038 Lisbon, Portugal. EM aixamorales@cajal.csic.es; r.diez@cajal.csic.es RI Morales, Aixa V./M-2135-2016; OI Morales, Aixa V./0000-0001-6295-5142; DIEZ DEL CORRAL, RUTH/0000-0003-2649-7214 FU Spanish government [BFU2014-57494-R, BFU2011-29490, BFU2010-15665, BFU2005-02972, BFU2007-61774, BFU2010-16031-P]; Madrid Local Government [CCG07-CSIC/SAL-1930]; CIBERER FX Contract grant sponsor: Spanish government; contract grant numbers: BFU2014-57494-R, BFU2011-29490, BFU2010-15665, BFU2005-02972 (to A. M. and R. D.) and BFU2007-61774, BFU2010-16031-P (to P. B.).; Contract grant sponsor: Madrid Local Government; contract grant number: CCG07-CSIC/SAL-1930 (to R. D.).; Contract grant sponsor: CIBERER (to P. B.). NR 68 TC 0 Z9 0 U1 7 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1932-8451 EI 1932-846X J9 DEV NEUROBIOL JI Dev. Neurobiol. PD SEP PY 2016 VL 76 IS 9 BP 956 EP 971 DI 10.1002/dneu.22368 PG 16 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA DW7UW UT WOS:000383859000002 PM 26600420 ER PT J AU Bornstein, MH Putnick, DL Suwalsky, JTD AF Bornstein, Marc H. Putnick, Diane L. Suwalsky, Joan T. D. TI Emotional Interactions in European American Mother-Infant Firstborn and Secondborn Dyads: A Within-Family Study SO DEVELOPMENTAL PSYCHOLOGY LA English DT Article DE emotional availability; birth order; mother-infant interaction; siblings ID BIRTH-ORDER; INDIVIDUAL-DIFFERENCES; SHARED ENVIRONMENT; SIBLINGS; CHILD; STABILITY; BEHAVIOR; AVAILABILITY; CONSISTENCY; DETERMINANTS AB The developmental science literature is riven with respect to (a) parental similar versus different treatment of siblings and (b) sibling similarities and differences. Most methodologies in the field are flawed or confounded. To address these issues, this study employed a within-family longitudinal design to examine developmental processes of continuity and stability in emotional interactions in mothers with their firstborn and secondborn 5-month-old infants (ns = 61 mothers and 122 infants). As independently rated by the Emotional Availability Scales, mothers' observed and coded behavioral expressions of sensitivity, structuring, nonintrusiveness, and nonhostility were consistent in group mean levels between firstborns and secondborns and (largely) between daughters and sons. Neither firstborns and secondborns, nor girls and boys, differed in their responsiveness or involvement of mother. However, mothers' emotional interactions with their firstborn and secondborn children were uncorrelated, as were firstborn and secondborn infants' interactions with their mother. These group-mean consistencies and individual-differences inconsistencies in emotional interactions are discussed in relation to the shared and nonshared lives of siblings in the same family. C1 [Bornstein, Marc H.; Putnick, Diane L.; Suwalsky, Joan T. D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, US Dept HHS, Bethesda, MD USA. RP Bornstein, MH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Child & Family Res, NIH, Suite 8030,6705 Rockledge Dr, Bethesda, MD 20892 USA. EM Marc_H_Bornstein@nih.gov OI Putnick, Diane/0000-0002-6323-749X FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 51 TC 0 Z9 0 U1 6 U2 6 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0012-1649 EI 1939-0599 J9 DEV PSYCHOL JI Dev. Psychol. PD SEP PY 2016 VL 52 IS 9 BP 1363 EP 1369 DI 10.1037/dev0000158 PG 7 WC Psychology, Developmental SC Psychology GA DW8BM UT WOS:000383878300003 PM 27505695 ER PT J AU Vehik, K Lynch, KF Schatz, DA Akolkar, B Hagopian, W Rewers, M She, JX Simell, O Toppari, J Ziegler, AG Lernmark, A Bonifacio, E Krischer, JP AF Vehik, Kendra Lynch, Kristian F. Schatz, Desmond A. Akolkar, Beena Hagopian, William Rewers, Marian She, Jin-Xiong Simell, Olli Toppari, Jorma Ziegler, Anette-G. Lernmark, Ake Bonifacio, Ezio Krischer, Jeffrey P. CA TEDDY Study Grp TI Reversion of beta-Cell Autoimmunity Changes Risk of Type 1 Diabetes: TEDDY Study SO DIABETES CARE LA English DT Article ID ISLET AUTOANTIBODIES; NATURAL-HISTORY; ENVIRONMENTAL DETERMINANTS; GENERAL-POPULATION; YOUNG TEDDY; CHILDHOOD; PROGRESSION; PREDICTION; APPEARANCE; CHILDREN AB OBJECTIVE beta-Cell autoantibodies are a feature of the preclinical phase of type 1 diabetes. Here, we asked how frequently they revert in a cohort of children at risk for type 1 diabetes and whether reversion has any effect on type 1 diabetes risk. RESEARCH DESIGN AND METHODS Children were up to 10 years of age and screened more than once for insulin autoantibody, GAD antibody, and insulinoma antigen-2 antibodies. Persistent autoantibody was defined as an autoantibody present on two or more consecutive visits and confirmed in two reference laboratories. Reversion was defined as two or more consecutive negative visits after persistence. Time-dependent Cox regression was used to examine how reversion modified the risk of development of multiple autoantibodies and type 1 diabetes. RESULTS Reversion was relatively frequent for autoantibodies to GAD65 (19%) and insulin (29%), but was largely restricted to children who had single autoantibodies (24%) and rare in children who had developed multiple autoantibodies (<1%). Most (85%) reversion of single autoantibodies occurred within 2 years of seroconversion. Reversion was associated with HLA genotype, age, and decreasing titer. Children who reverted from single autoantibodies to autoantibody negative had, from birth, a risk for type 1 diabetes of 0.14 per 100 person-years; children who never developed autoantibodies, 0.06 per 100 person-years; and, children who remained single-autoantibody positive, 1.8 per 100 person-years. CONCLUSIONS Type 1 diabetes risk remained high in children who had developed multiple beta-cell autoantibodies even when individual autoantibodies reverted. We suggest that monitoring children with single autoantibodies for at least 1 year after seroconversion is beneficial for stratification of type 1 diabetes risk. C1 [Vehik, Kendra; Lynch, Kristian F.; Krischer, Jeffrey P.] Univ S Florida, Dept Pediat, Morsani Coll Med, Hlth Informat Inst, Tampa, FL 33620 USA. [Schatz, Desmond A.] Univ Florida, Coll Med, Dept Pediat, Gainesville, FL USA. [Akolkar, Beena] NIDDK, Bethesda, MD 20892 USA. [Hagopian, William] Pacific Northwest Diabet Res Inst, Seattle, WA USA. [Rewers, Marian] Univ Colorado, Barbara Davis Ctr Childhood Diabet, Aurora, CO USA. [She, Jin-Xiong] Georgia Regents Univ, Med Coll Georgia, Ctr Biotechnol & Genom Med, Augusta, GA USA. [Simell, Olli; Toppari, Jorma] Turku Univ Hosp, Dept Pediat, Turku, Finland. [Ziegler, Anette-G.] Tech Univ Munich, Helmholtz Zentrum Munchen, Inst Diabet Res, Neuherberg, Germany. [Ziegler, Anette-G.] Tech Univ Munich, Klinikum Rechts Isar, Neuherberg, Germany. [Ziegler, Anette-G.] Forschergrp Diabet eV Neuherberg, Neuherberg, Germany. [Lernmark, Ake] Skane Univ, Univ Lund, CRC, Dept Clin Sci, Malmo, Sweden. [Bonifacio, Ezio] Tech Univ Dresden, Ctr Regenerat Therapies, Dresden, Germany. [Bonifacio, Ezio] German Ctr Diabet Res DZD, Paul Langerhans Inst Dresden, Dresden, Germany. RP Vehik, K (reprint author), Univ S Florida, Dept Pediat, Morsani Coll Med, Hlth Informat Inst, Tampa, FL 33620 USA. EM kendra.vehik@epi.usf.edu RI Bonifacio, Ezio/E-7700-2010 OI Bonifacio, Ezio/0000-0002-8704-4713 FU National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Allergy and Infectious Diseases; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Environmental Health Sciences; JDRF; Centers for Disease Control and Prevention [U01-DK-63829, U01-DK-63861, U01-DK-63821, U01-DK-63865, U01-DK-63863, U01-DK-63836, U01-DK-63790, UC4-DK-63829, UC4-DK-63861, UC4-DK-63821, UC4-DK-63865, UC4-DK-63863, UC4-DK-63836, UC4-DK-95300, UC4-DK-100238, HHSN267200700014C]; National Institutes of Health/National Center for Advancing Translational Sciences Clinical and Translational Science Awards [UL1-TR-000064, UL1-TR-001082] FX This study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Allergy and Infectious Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Environmental Health Sciences, JDRF, and Centers for Disease Control and Prevention grants U01-DK-63829, U01-DK-63861, U01-DK-63821, U01-DK-63865, U01-DK-63863, U01-DK-63836, U01-DK-63790, UC4-DK-63829, UC4-DK-63861, UC4-DK-63821, UC4-DK-63865, UC4-DK-63863, UC4-DK-63836, UC4-DK-95300, and UC4-DK-100238 and Contract No. HHSN267200700014C. This work was partly supported by the National Institutes of Health/National Center for Advancing Translational Sciences Clinical and Translational Science Awards to the University of Florida (UL1-TR-000064) and the University of Colorado (UL1-TR-001082). NR 25 TC 3 Z9 3 U1 1 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD SEP PY 2016 VL 39 IS 9 BP 1535 EP 1542 DI 10.2337/dc16-0181 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DW5DT UT WOS:000383663000021 PM 27311490 ER PT J AU Gong, QH Zhang, P Wang, JP An, YL Gregg, EW Li, H Zhang, B Shuai, Y Yang, WY Chen, YY Liu, SQ Engelgau, MM Hu, YH Bennett, PH Li, GW AF Gong, Qiuhong Zhang, Ping Wang, Jinping An, Yali Gregg, Edward W. Li, Hui Zhang, Bo Shuai, Ying Yang, Wenying Chen, Yanyan Liu, Shuqian Engelgau, Michael M. Hu, Yinghua Bennett, Peter H. Li, Guangwei TI Changes in Mortality in People With IGT Before and After the Onset of Diabetes During the 23-Year Follow-up of the Da Qing Diabetes Prevention Study SO DIABETES CARE LA English DT Article ID IMPAIRED GLUCOSE-TOLERANCE; ALL-CAUSE MORTALITY; CARDIOVASCULAR MORTALITY; FASTING GLUCOSE; LIFE-STYLE; RISK; MELLITUS; POPULATION; DISEASE; DEATH AB OBJECTIVE People with impaired glucose tolerance (IGT) have increased risk of mortality and a high risk of progression to diabetes, but the extent that the excess mortality is associated with IGT per se or is the result of subsequent diabetes is unclear. RESEARCH DESIGN AND METHODS We compared mortality before and after the development of diabetes among 542 persons with IGT initially who participated in a 6-year lifestyle diabetes prevention trial and were followed-up from 1986 to 2009. RESULTS During the 23-year follow-up, 174 (32.1%) died, with an overall death rate of 15.9/1,000 person-years. The majority of deaths (74.7%; 130 of 174) occurred after progression to type 2 diabetes, with age-adjusted death rates of 11.1/1,000 person-years (95% CI 8.2-12.0) before and 19.4/1,000 person-years (95% CI 11.9-23.3) after the development of type 2 diabetes. The cumulative mortality was 37.8% (95% CI 33.1-42.2%) in participants who developed type 2 diabetes during first 10 years of follow-up, 28.6% (95% CI 21.6-35.0%) in those who progressed to type 2 diabetes in 10-20 years, and 13.9% (95% CI 7.0-20.3%) in those who did not develop to type 2 diabetes within 20 years. Time-dependent multivariate Cox proportional hazards analyses, with adjustment for baseline age, sex, intervention, and other potential confounding risk factors, showed that the development of type 2 diabetes was associated with a 73% higher risk of death (hazard ratio 1.73 [95% CI 1.18-2.52]). CONCLUSIONS As elsewhere, IGT is associated with increased risk of mortality in China, but much of this excess risk is attributable to the development of type 2 diabetes. C1 [Gong, Qiuhong; An, Yali; Chen, Yanyan; Li, Guangwei] Chinese Acad Med Sci, Fuwai Hosp, Dept Endocrinol, Beijing, Peoples R China. [Zhang, Ping; Gregg, Edward W.] Ctr Dis Control & Prevent, Div Diabet Translat, Atlanta, GA 30333 USA. [Wang, Jinping; Li, Hui; Hu, Yinghua] Da Qing First Hosp, Dept Cardiol, Da Qing, Peoples R China. [Zhang, Bo; Shuai, Ying; Yang, Wenying; Li, Guangwei] China Japan Friendship Hosp, Dept Endocrinol, Beijing, Peoples R China. [Liu, Shuqian] Tulane Univ, Sch Publ Hlth & Trop Med, Dept Global Hlth Management & Policy, New Orleans, LA USA. [Engelgau, Michael M.] NHLBI, Ctr Translat Res & Implementat Sci, Bldg 10, Bethesda, MD 20892 USA. [Bennett, Peter H.] NIDDK, Phoenix Epidemiol & Clin Res Branch, Phoenix, AZ USA. RP Li, GW (reprint author), Chinese Acad Med Sci, Fuwai Hosp, Dept Endocrinol, Beijing, Peoples R China.; Zhang, P (reprint author), Ctr Dis Control & Prevent, Div Diabet Translat, Atlanta, GA 30333 USA.; Li, GW (reprint author), China Japan Friendship Hosp, Dept Endocrinol, Beijing, Peoples R China. EM pzhang@cdc.gov; guangwei_li@medmail.com.cn FU National Center for Chronic Disease Prevention and Health Promotion through CDC/WHO [U58/CCU424123-01-02]; China-Japan Friendship Hospital FX This study was supported by the National Center for Chronic Disease Prevention and Health Promotion through CDC/WHO Cooperative Agreement No. U58/CCU424123-01-02 and by the China-Japan Friendship Hospital. NR 27 TC 1 Z9 1 U1 2 U2 2 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD SEP PY 2016 VL 39 IS 9 BP 1550 EP 1555 DI 10.2337/dc16-0429 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DW5DT UT WOS:000383663000023 PM 27411697 ER PT J AU Shankar, SS Vella, A Raymond, RH Staten, MA Calle, RA Bergman, RN Cao, C Chen, D Cobelli, C Man, CD Deeg, M Dong, JQ Lee, DS Polidori, D Robertson, RP Ruetten, H Stefanovski, D Vassileva, MT Weir, GC Fryburg, DA AF Shankar, Sudha S. Vella, Adrian Raymond, Ralph H. Staten, Myrlene A. Calle, Roberto A. Bergman, Richard N. Cao, Charlie Chen, Danny Cobelli, Claudio Man, Chiara Dalla Deeg, Mark Dong, Jennifer Q. Lee, Douglas S. Polidori, David Robertson, R. Paul Ruetten, Hartmut Stefanovski, Darko Vassileva, Maria T. Weir, Gordon C. Fryburg, David A. CA Fdn Natl Inst Hlth B-Cell TI Standardized Mixed-Meal Tolerance and Arginine Stimulation Tests Provide Reproducible and Complementary Measures of beta-Cell Function: Results From the Foundation for the National Institutes of Health Biomarkers Consortium Investigative Series SO DIABETES CARE LA English DT Article ID DEPENDENT DIABETES-MELLITUS; IMPAIRED GLUCOSE-TOLERANCE; INSULIN SENSITIVITY; MINIMAL-MODEL; ORAL GLUCOSE; PLUS METFORMIN; TYPE-2; SECRETION; RESISTANCE; INDEXES AB OBJECTIVE Standardized, reproducible, and feasible quantification of beta-cell function (BCF) is necessary for the evaluation of interventions to improve insulin secretion and important for comparison across studies. We therefore characterized the responses to, and reproducibility of, standardized methods of in vivo BCF across different glucose tolerance states. RESEARCH DESIGN AND METHODS Participants classified as having normal glucose tolerance (NGT; n = 23), prediabetes (PDM; n = 17), and type 2 diabetes mellitus (T2DM; n = 22) underwent two standardized mixed-meal tolerance tests (MMTT) and two standardized arginine stimulation tests (AST) in a test-retest paradigm and one frequently sampled intravenous glucose tolerance test (FSIGT). RESULTS From the MMTT, insulin secretion in T2DM was > 86% lower compared with NGT or PDM (P < 0.001). Insulin sensitivity (Si) decreased from NGT to PDM (similar to 50%) to T2DM (93% lower [P < 0.001]). In the AST, insulin secretory response to arginine at basal glucose and during hyperglycemia was lower in T2DM compared with NGT and PDM (>58%; all P < 0.001). FSIGT showed decreases in both insulin secretion and Si across populations (P < 0.001), although Si did not differ significantly between PDM and T2DM populations. Reproducibility was generally good for the MMTT, with intraclass correlation coefficients (ICCs) ranging from similar to 0.3 to similar to 0.8 depending on population and variable. Reproducibility for the AST was very good, with ICC values >0.8 across all variables and populations. CONCLUSIONS Standardized MMTT and AST provide reproducible and complementary measures of BCF with characteristics favorable for longitudinal interventional trials use. C1 [Shankar, Sudha S.; Deeg, Mark] Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA. [Vella, Adrian] Mayo Clin, Coll Med, Div Endocrinol Diabet & Metab, Rochester, MN USA. [Raymond, Ralph H.] R Squared Solut, Skillman, NJ USA. [Staten, Myrlene A.] NIDDK, Kelly Govt Solut, Rockville, MD USA. [Calle, Roberto A.; Chen, Danny; Dong, Jennifer Q.; Lee, Douglas S.] Pfizer, Cambridge, MA USA. [Calle, Roberto A.; Chen, Danny; Dong, Jennifer Q.; Lee, Douglas S.] Pfizer, Groton, CT USA. [Bergman, Richard N.] Cedars Sinai Diabet & Obes Res Inst, Los Angeles, CA USA. [Cao, Charlie] Takeda Dev Ctr Amer, Deerfield, IL USA. [Cobelli, Claudio; Man, Chiara Dalla] Univ Padua, Dept Informat Engn, Padua, Italy. [Polidori, David] Janssen Res & Dev, San Diego, CA USA. [Robertson, R. Paul] Pacific Northwest Diabet Res Inst, Seattle, WA USA. [Robertson, R. Paul] Univ Washington, Dept Med, Div Endocrinol, Seattle, WA USA. [Robertson, R. Paul] Univ Washington, Dept Pharmacol, Div Endocrinol, Seattle, WA 98195 USA. [Ruetten, Hartmut] Sanofi, Paris, France. [Stefanovski, Darko] Univ Penn, Philadelphia, PA 19104 USA. [Vassileva, Maria T.] Fdn Natl Inst Hlth, Bethesda, MD USA. [Weir, Gordon C.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Fryburg, David A.] ROI Biopharma Consulting, East Lyme, CT 06333 USA. RP Fryburg, DA (reprint author), ROI Biopharma Consulting, East Lyme, CT 06333 USA. EM dfryburg@roibiopharma.com FU FNIH Biomarkers Consortium; FNIH; NIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); FDA; AstraZeneca; Janssen; Eli Lilly and Company; Merck; Novartis; Novo Nordisk; Pfizer; Sanofi; Takeda; American Diabetes Association; JDRF FX The methodological study described in this report was designed and implemented under the auspices of the FNIH Biomarkers Consortium. The Biomarkers Consortium is a public private partnership that develops and validates biological markers, which speed up the development of therapies for the detection, prevention, diagnosis, and treatment of disease and are ultimately aimed at improving patient care. For this study, the Consortium brought together diabetes experts from leading academic institutions, the U.S. Food and Drug Administration (FDA), the National Institutes of Health (NIH), the nonprofit sector, and the pharmaceutical industry to develop the project. The results of the partnership, discussed in this study, are important because they address a critical unmet medical need and involve key stakeholders in the diabetes treatment field. FNIH has acted as a neutral convener for the partners and provided the project management expertise needed for the execution of the overall project. In the future, this type of partnership can be used as a model for establishing common standards for testing in other therapeutic areas as well. Under the auspices of the FNIH, this project was jointly funded by the NIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the FDA and the following participating pharmaceutical companies: Amylin (now AstraZeneca), Janssen, Eli Lilly and Company, Merck, Novartis, Novo Nordisk, Pfizer, Sanofi, and Takeda. An in-kind donation of P800 tubes was made by Becton Dickinson (D. Craft). Additional support was also received from the American Diabetes Association and JDRF. NR 44 TC 2 Z9 2 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD SEP PY 2016 VL 39 IS 9 BP 1602 EP 1613 DI 10.2337/dc15-0931 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DW5DT UT WOS:000383663000030 PM 27407117 ER PT J AU Sapio, MR Goswami, SC Gross, JR Mannes, AJ Iadarola, MJ AF Sapio, Matthew R. Goswami, Samridhi C. Gross, Jacklyn R. Mannes, Andrew J. Iadarola, Michael J. TI Transcriptomic analyses of genes and tissues in inherited sensory neuropathies SO EXPERIMENTAL NEUROLOGY LA English DT Article DE Pain; Proprioception; Charcot Marie Tooth; Neuropathy; Pain channelopathy; Transcriptomics; Schwann cells; Gene expression; Glia; RNA-Seq; Dorsal root ganglion; Spinal cord; Sodium channels; TRPV1; TRPA1; Inherited peripheral neuropathy; HSAN; Sciatic nerve; Adipocytes; Myelin protein zero ID MARIE-TOOTH-DISEASE; LYSOPHOSPHATIDIC ACID LPA; LYSYL OXIDASE ACTIVITY; SCHWANN-CELLS; MENKES DISEASE; CANDIDATE GENE; CONGENITAL INSENSITIVITY; BINDING-PROTEIN; PAIN PERCEPTION; NERVE INJURY AB Inherited sensory neuropathies are caused by mutations in genes affecting either primary afferent neurons, or the Schwann cells that myelinate them. Using RNA-Seq, we analyzed the transcriptome of human and rat DRG and peripheral nerve, which contain sensory neurons and Schwann cells, respectively. We subdivide inherited sensory neuropathies based on expression of the mutated gene in these tissues, as well as in mouse TRPV1 lineage DRG nociceptive neurons, and across 32 human tissues from the Human Protein Atlas. We propose that this comprehensive approach to neuropathy gene expression leads to better understanding of the involved cell types in patients with these disorders. We also characterize the genetic "fingerprint" of both tissues, and present the highly tissue-specific genes in DRG and sciatic nerve that may aid in the development of gene panels to improve diagnostics for genetic neuropathies, and may represent specific drug targets for diseases of these tissues. (C) 2016 Published by Elsevier Inc. C1 [Sapio, Matthew R.; Goswami, Samridhi C.; Gross, Jacklyn R.; Mannes, Andrew J.; Iadarola, Michael J.] NIH, Ctr Clin, Dept Perioperat Med, Bldg 10, Bethesda, MD 20182 USA. RP Iadarola, MJ (reprint author), NIH, Ctr Clin, Bldg 10,Room 2C401,MSC 1510,10 Ctr Dr, Bethesda, MD 20182 USA. EM miadarol@cc.nih.gov OI Iadarola, Michael/0000-0001-7188-9810 FU Intramural Research Program of the NIH Clinical Center; National Center for Complementary and Integrative Health FX This research was supported by the Intramural Research Program of the NIH Clinical Center. We thank Ruth Yaskovich for her help with tissue sectioning and histology. The support of the National Center for Complementary and Integrative Health is gratefully acknowledged. NR 77 TC 1 Z9 1 U1 3 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 EI 1090-2430 J9 EXP NEUROL JI Exp. Neurol. PD SEP PY 2016 VL 283 BP 375 EP 395 DI 10.1016/j.expneurol.2016.06.023 PN A PG 21 WC Neurosciences SC Neurosciences & Neurology GA DW0EU UT WOS:000383314500035 PM 27343803 ER PT J AU Conley, BA Sorg, BS Tricoli, JV AF Conley, Barbara A. Sorg, Brian S. Tricoli, James V. TI Implications and opportunities of precision medicine in rare malignancies SO EXPERT OPINION ON ORPHAN DRUGS LA English DT Review DE Next generation sequencing; genomic abnormalities; precision medicine; rare cancers ID CLINICAL-TRIALS; CANCERS; THERAPY; EVEROLIMUS; MUTATIONS AB Introduction: In aggregate, about 20% of all cancers can be considered rare. In addition, molecularly defined subsets of more common cancers are generally rare. Many rare cancers urgently need development of efficacious therapeutics, yet their rarity makes it difficult to conduct standard clinical trials. The advent of molecular profiling of cancers, however, may offer an opportunity for more thoughtful and successful development of new effective treatments.Areas covered: This manuscript describes instances in which drugs have been approved for rare cancers, and describes the potential value and challenges of new policies and research that may lead to more broad development of drugs based on the molecular characterization of a patient's tumor.Expert opinion: Although challenges in use of any methods for development of therapeutics for rare cancers exist, international collaboration, broad molecular profiling for research, and new trial designs such as basket designs and tumor agnostic designs, have promise to develop the evidence needed to assure that drugs will or will not be effective in rare cancers. Complimentary studies, such as those of exceptional responders, will add to the body of understanding that will hopefully lead to the discovery and development of effective treatments for many rare cancers. C1 [Conley, Barbara A.; Sorg, Brian S.; Tricoli, James V.] NCI, Canc Diag Program, Div Canc Diag & Treatment, 9609 Med Ctr Dr,Rm 4W410,MSC 9730, Bethesda, MD 20892 USA. RP Conley, BA (reprint author), NCI, Canc Diag Program, Div Canc Diag & Treatment, 9609 Med Ctr Dr,Rm 4W410,MSC 9730, Bethesda, MD 20892 USA. EM conleyba@mail.nih.gov NR 34 TC 0 Z9 0 U1 5 U2 5 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 2167-8707 J9 EXPERT OPIN ORPHAN D JI Exp. Opin. Orphan Drugs PD SEP PY 2016 VL 4 IS 9 BP 953 EP 960 DI 10.1080/21678707.2016.1214071 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DV6IO UT WOS:000383037800007 ER PT J AU Barr, FG AF Barr, Frederic G. TI Fusion genes in solid tumors: the possibilities and the pitfalls SO EXPERT REVIEW OF MOLECULAR DIAGNOSTICS LA English DT Editorial Material DE Fusion gene; fusion transcript; fusion protein; chromosomal translocation; RT-PCR; FISH; immunohistochemistry; next generation sequencing; molecular pathology; targeted therapy ID GROWTH-FACTOR; CANCER; SARCOMA; REARRANGEMENTS; TRANSCRIPT; CARCINOMA C1 [Barr, Frederic G.] NCI, Pathol Lab, Ctr Canc Res, 10 Ctr Dr,Room 2S235D,MSC1500, Bethesda, MD 20892 USA. RP Barr, FG (reprint author), NCI, Pathol Lab, Ctr Canc Res, 10 Ctr Dr,Room 2S235D,MSC1500, Bethesda, MD 20892 USA. EM barrfg@mail.nih.gov NR 20 TC 0 Z9 0 U1 1 U2 1 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1473-7159 EI 1744-8352 J9 EXPERT REV MOL DIAGN JI Expert Rev. Mol. Diagn. PD SEP PY 2016 VL 16 IS 9 BP 921 EP 923 DI 10.1080/14737159.2016.1220835 PG 3 WC Pathology SC Pathology GA DV9HO UT WOS:000383251600001 PM 27550633 ER PT J AU Geoffroy, PA Etain, B Lajnef, M Zerdazi, EH Brichant-Petitjean, C Heilbronner, U Hou, L Degenhardt, F Rietschel, M McMahon, FJ Schulze, TG Jamain, S Marie-Claire, C Bellivier, F AF Geoffroy, P. A. Etain, B. Lajnef, M. Zerdazi, E-H. Brichant-Petitjean, C. Heilbronner, U. Hou, L. Degenhardt, F. Rietschel, M. McMahon, F. J. Schulze, T. G. Jamain, S. Marie-Claire, C. Bellivier, F. TI Circadian genes and lithium response in bipolar disorders: associations with PPARGC1A (PGC-1) and RORA SO GENES BRAIN AND BEHAVIOR LA English DT Article DE Bipolar disorder; circadian genes; circadian rhythms; clock genes; lithium carbonate; lithium salts ID PROPHYLACTIC LITHIUM; INFLUENCES SLEEP; MOOD DISORDERS; CLOCK GENES; REV-ERBA; RHYTHMS; ALPHA; POLYMORPHISM; PGC-1-ALPHA; DEPRESSION AB Preliminary studies suggest that lithium (Li) response might be associated with some circadian gene polymorphisms, we therefore performed a pharmacogenetic study on the core clock genes in two independent samples suffering from bipolar disorder (BD) and thoroughly characterized for their Li response. Two independent Caucasian samples (165 and 58 bipolar patients) treated with Li were selected from samples recruited in a French multicenter study and assessed for their Li response using the Alda scale. The two samples were genotyped using the Human660 (H660) and OmniExpress (OE) BeadChips and gene-based association analyses of 22 core clock genes were conducted. In the first sample (H660 chip), the RAR-related orphan receptor-a gene (RORA) and the Peroxisome Proliferator-Activated Receptor Gamma, Coactivator 1 Alpha gene (PPARGC1A or PGC-1) were significantly associated with the Li response (empirical P-value = 0.0015 and 0.04, respectively), and remained significant only for RORA after Bonferroni correction. In the second sample (OE chip), PPARGC1A was significantly associated with the Li response (empirical P-value = 0.04), and did not remain significant after Bonferroni correction. PPARGC1A is a master regulator of mitochondrial function and a key component of the endogenous clock that stimulates the expression of Bmal1 and Rev-erb-alpha through coactivation of RORA. Although the observed associations deserve further replication and investigation, our results suggest genetic associations between Li response and these two close biological partners: PPARGC1A and RORA involved in circadian rhythms and bioenergetics processes in Li response. C1 [Geoffroy, P. A.; Etain, B.; Zerdazi, E-H.; Brichant-Petitjean, C.; Marie-Claire, C.; Bellivier, F.] INSERM, U1144, F-75006 Paris, France. [Geoffroy, P. A.; Etain, B.; Zerdazi, E-H.; Brichant-Petitjean, C.; Marie-Claire, C.; Bellivier, F.] Univ Paris 05, UMR S 1144, F-75006 Paris, France. [Geoffroy, P. A.; Etain, B.; Brichant-Petitjean, C.; Bellivier, F.] Univ Paris Diderot, Sorbonne Paris Cite, UMR S 1144, F-75013 Paris, France. [Geoffroy, P. A.; Etain, B.; Brichant-Petitjean, C.; Bellivier, F.] GH St Louis, AP HP, Pole Psychiatrie & Med Addictol, Lariboisiere, F-75475 Paris 10, France. [Geoffroy, P. A.; Etain, B.; Jamain, S.; Bellivier, F.] Fdn FondaMental, Creteil, France. [Lajnef, M.; Jamain, S.] INSERM, Psychiat Translat, U955, Creteil, France. [Jamain, S.] Univ Paris Est, Fac Med, Creteil, France. [Zerdazi, E-H.] Grp Hosp Henri Mondor, AP HP, Pole Psychiat, Creteil, France. [Heilbronner, U.] Univ Munich, Inst Psychiat Phen & Genom, Munich, Germany. [Hou, L.] NIMH, Intramural Res Program, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Degenhardt, F.] Univ Bonn, Inst Human Genet, Bonn, Germany. [Rietschel, M.] Heidelberg Univ, Cent Inst Mental Hlth, Med Fac Mannheim, Dept Genet Epidemiol Psychiat, Heidelberg, Germany. [McMahon, F. J.] NIMH, Human Genet Branch, Intramural Res Program, NIH, Baltimore, MD USA. [McMahon, F. J.] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. [Schulze, T. G.] Univ Munich, Inst Psychiat Phen & Genom, Munich, Germany. [Schulze, T. G.] Cent Inst Mental Hlth, Dept Genet Epidemiol Psychiat, Mannheim, Germany. [Schulze, T. G.] Univ Gottingen, Dept Psychiat & Psychotherapy, Univ Med Ctr, Gottingen, Germany. RP Geoffroy, PA (reprint author), Hop Fernand Widal, Serv Psychiat Adulte Pr Bellivier, 200 Rue Faubourg St Denis, F-75475 Paris 10, France. EM pierre.a.geoffroy@gmail.com RI BELLIVIER, FRANK/H-5197-2012 FU INSERM (Institut National de la Sante et de la Recherche Medicale); AP-HP (Assistance Publique des Hopitaux de Paris); Fondation FondaMental (RTRS Sante Mentale, Marcel Dassault-FondaMental Research Prize); labex Bio-PSY (Investissements d'Avenir program) [ANR-11-IDEX-0004-02]; Deutsche Forschungsgemeinschaft (DFG) [RI 908/7-1]; Dr-Lisa-Oehler-Foundation (Kassel, Germany); NIMH Intramural Research Program [1ZIAMH002843-12]; Sanofi-Aventis; Lundbeck; AstraZeneca; Eli Lilly; Bristol-Myers Squibb FX This work was supported by INSERM (Institut National de la Sante et de la Recherche Medicale); AP-HP (Assistance Publique des Hopitaux de Paris); the Fondation FondaMental (RTRS Sante Mentale, Marcel Dassault-FondaMental Research Prize) and the labex Bio-PSY (Investissements d'Avenir program managed by the ANR under reference ANR-11-IDEX-0004-02). Genotyping was in part funded by the Deutsche Forschungsgemeinschaft (DFG; grant no RI 908/7-1 to MR and TGS). T.G. Schulze and U. Heilbronne received support from the Dr-Lisa-Oehler-Foundation (Kassel, Germany). The group of F. Bellivier is a member of the Bio-Psy Labex. FJ McMahon is supported by the NIMH Intramural Research Program (1ZIAMH002843-12).; We thank patients with BD who agreed to participate in these studies. We thank C Brichant, E. Abadie and J.R. Richard for their assistance. We thank C. Henry, C. Boudebesse, A. Raust and B. Cochet (AP-HP, Hopital H. Mondor - A. Chenevier, Creteil, France), S. Gard and L. Zanouy (Hopital Charles Perrens, Centre Expert Trouble Bipolaire, Bordeaux, France), J.P. Kahn, RF. Cohen and O. Wajsbrot-Elgrabli (CHU de Nancy, Hopitaux de Brabois, Vandoeuvre Les Nancy, France) for their involvement in patients' assessment. Dr. P.A. Geoffroy has received travel awards or financial compensation from AstraZeneca, Lundbeck, Menarini France and Otsuka. M.L., Dr. E.H.Z., Pr U.H., Pr L.H., Pr F.D., Pr M.R., Pr F.J.M., Pr T.G.S., Dr. S.J., Dr. C.M.-C. have no conflicts of interest. Dr. S. Gard has received honoraria and financial compensation as independent symposium speakers from Astra Zeneca, BMS and Otsuka. Pr. C. Henry has received honoraria and financial compensation as independent symposium speakers from Sanofi-Aventis, Lundbeck, AstraZeneca, Eli Lilly, Bristol-Myers Squibb. Pr. M. Leboyer has received honoraria and financial compensation as an independent symposium speaker from AstraZeneca and Servier. Dr. B. Etain has received honoraria and financial compensation as independent symposium speakers from Sanofi-Aventis, Lundbeck, AstraZeneca, Eli Lilly, Bristol-Myers Squibb and Servier. Pr. F. Bellivier has received honoraria and financial compensation as independent symposium speakers from Sanofi-Aventis, Lundbeck, AstraZeneca, Eli Lilly, Bristol-Myers Squibb and Servier. NR 66 TC 0 Z9 0 U1 6 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1601-1848 EI 1601-183X J9 GENES BRAIN BEHAV JI Genes Brain Behav. PD SEP PY 2016 VL 15 IS 7 BP 660 EP 668 DI 10.1111/gbb.12306 PG 9 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA DW6QC UT WOS:000383775000005 PM 27324142 ER PT J AU Herrero, R Ferreccio, C Acevedo, J Cook, P Gahona, J Gonzalez, C Heise, K Bertran, E Vargas, S Rinaldi, S Murillo, R Park, J Camargo, M Megraud, F Hildesheim, A Hernandez, M Gonzalez, P AF Herrero, R. Ferreccio, C. Acevedo, J. Cook, P. Gahona, J. Gonzalez, C. Heise, K. Bertran, E. Vargas, S. Rinaldi, S. Murillo, R. Park, J. Camargo, M. Megraud, F. Hildesheim, A. Hernandez, M. Gonzalez, P. TI Prevalence of Helicobacter pylori infection and cofactors in high and low gastric cancer risk areas of Chile: The ENIGMA 1 Study SO HELICOBACTER LA English DT Meeting Abstract CT 29th International Workshop on Helicobacter and Microbiota in Inflammation and Cancer CY SEP 15-17, 2016 CL Magdeburg, GERMANY C1 [Herrero, R.; Rinaldi, S.; Murillo, R.; Park, J.; Hernandez, M.] Int Agcy Res Canc, Lyon, France. [Ferreccio, C.; Acevedo, J.; Cook, P.] Pontificia Univ Catolica Chile, Santiago, Chile. [Gahona, J.] Univ Antofagasta, Antofagasta, Chile. [Gonzalez, C.] Secretaria Ministerial Salud, Antofagasta, Chile. [Heise, K.; Bertran, E.] Hosp Valdivia, Valdivia, Chile. [Vargas, S.] Secretaria Ministerial Salad, Valdivia, Chile. [Camargo, M.; Hildesheim, A.] NCI, Gaithersburg, MD USA. [Megraud, F.] INSERM, U853, Bordeaux, France. [Gonzalez, P.] Fdn INCIENSA, San Jose, Costa Rica. 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 1083-4389 EI 1523-5378 J9 HELICOBACTER JI Helicobacter PD SEP PY 2016 VL 21 SU 1 SI SI MA W1.4 BP 77 EP 78 PG 2 WC Gastroenterology & Hepatology; Microbiology SC Gastroenterology & Hepatology; Microbiology GA DW3BR UT WOS:000383517600028 ER PT J AU Matsuura, K De Giorgi, V Schechterly, C Wang, RY Farci, P Tanaka, Y Alter, HJ AF Matsuura, Kentaro De Giorgi, Valeria Schechterly, Cathy Wang, Richard Y. Farci, Patrizia Tanaka, Yasuhito Alter, Harvey J. TI Circulating let-7 levels in plasma and extracellular vesicles correlate with hepatic fibrosis progression in chronic hepatitis C SO HEPATOLOGY LA English DT Article ID GENOME-WIDE ASSOCIATION; VIRUS-INFECTION; LIVER FIBROSIS; PROFILING REVEALS; DOWN-REGULATION; RENAL FIBROSIS; HCV INFECTION; UP-REGULATION; BLOOD-DONORS; MICRORNAS AB The goal of this study was to determine whether an association exists between circulating microRNA (miRNA) levels and disease progression in chronic hepatitis C (CHC), whether plasma or extracellular vesicles (EVs) were optimal for miRNA measurement and their correlation with hepatic miRNA expression, and the mechanistic plausibility of this association. We studied 130 CHC patients prospectively followed over several decades. A comprehensive miRNA profile in plasma using microarray with 2578 probe sets showed 323 miRNAs differentially expressed between healthy individuals and CHC patients, but only six that distinguished patients with mild versus severe chronic hepatitis. Eventually, let-7a/7c/7d-5p and miR-122-5p were identified as candidate predictors of disease progression. Cross-sectional analyses at the time of initial liver biopsy showed that reduced levels of let-7a/7c/7d-5p (let-7s) in plasma were correlated with advanced histological hepatic fibrosis stage and other fibrotic markers, whereas miR-122-5p levels in plasma were positively correlated with inflammatory activity, but not fibrosis. Measuring let-7s levels in EVs was not superior to intact plasma for discriminating significant hepatic fibrosis. Longitudinal analyses in 60 patients with paired liver biopsies showed that let-7s levels in plasma markedly declined over time in parallel with fibrosis progression. However, circulating let-7s levels did not parallel those in the liver. Conclusion: Of all miRNAs screened, the let-7 family showed the best correlation with hepatic fibrosis in CHC. A single determination of let-7s levels in plasma did not have superior predictive value for significant hepatic fibrosis compared with that of fibrosis-4 index, but the rate of let-7s decline in paired longitudinal samples correlated well with fibrosis progression. Pathway analysis suggested that low levels of let-7 may influence hepatic fibrogenesis through activation of transforming growth factor signaling in hepatic stellate cells. (Hepatology 2016;64:732-745) C1 [Matsuura, Kentaro; De Giorgi, Valeria; Schechterly, Cathy; Wang, Richard Y.; Alter, Harvey J.] NIH, Dept Transfus Med, Ctr Clin, Bldg 10,Room 1C-711,10 Ctr Dr, Bethesda, MD 20892 USA. [Matsuura, Kentaro] Nagoya City Univ, Dept Gastroenterol & Metab, Grad Sch Med Sci, Nagoya, Aichi, Japan. [Matsuura, Kentaro; Tanaka, Yasuhito] Nagoya City Univ, Dept Virol, Grad Sch Med Sci, Nagoya, Aichi, Japan. [Matsuura, Kentaro; Tanaka, Yasuhito] Nagoya City Univ, Liver Unit, Grad Sch Med Sci, Nagoya, Aichi, Japan. [Farci, Patrizia] NIAID, Hepat Pathogenesis Sect, Lab Infecf Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Alter, HJ (reprint author), NIH, Dept Transfus Med, Ctr Clin, Bldg 10,Room 1C-711,10 Ctr Dr, Bethesda, MD 20892 USA. EM halter@dtm.cc.nih.gov RI De Giorgi, Valeria/D-4582-2017 FU Intramural Research Program of the Warren G. Magnuson Clinical Center; Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health; Uehara Memorial Foundation of Japan FX This study was supported by the Intramural Research Program of the Warren G. Magnuson Clinical Center and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. Kentaro Matsuura was supported by the Uehara Memorial Foundation of Japan. NR 50 TC 2 Z9 2 U1 12 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD SEP PY 2016 VL 64 IS 3 BP 732 EP 745 DI 10.1002/hep.28660 PG 14 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DV9TU UT WOS:000383285900007 PM 27227815 ER PT J AU Ploeger, C Waldburger, N Fraas, A Goeppert, B Pusch, S Breuhahn, K Wang, XW Schirmacher, P Roessler, S AF Ploeger, Carolin Waldburger, Nina Fraas, Angelika Goeppert, Benjamin Pusch, Stefan Breuhahn, Kai Wang, Xin Wei Schirmacher, Peter Roessler, Stephanie TI Chromosome 8p tumor suppressor genes SH2D4A and SORBS3 cooperate to inhibit interleukin-6 signaling in hepatocellular carcinoma SO HEPATOLOGY LA English DT Article ID ESTROGEN-RECEPTOR; LIVER-CANCER; MICROENVIRONMENTAL REGULATION; PATIENT SURVIVAL; CROSS-TALK; STAT3; PHOSPHORYLATION; INFLAMMATION; EXPRESSION; TUMORIGENESIS AB Several chronic inflammatory liver diseases, e.g., chronic hepatitis B or C viral infection and steatohepatitis, have been shown to predispose to the development of hepatocellular carcinoma (HCC). In patients with chronic liver disease, interleukin-6 (IL-6) serum levels are elevated and increase even more when HCC develops. However, the impact and regulatory mechanisms of IL-6 signaling during hepatocarcinogenesis are still poorly defined. Here, we show that gene expression profiles of patients with chromosome 8p loss correlate with increased IL-6 signaling. In addition, the chromosome 8p tumor suppressor genes Src homology 2 domain containing 4A (SH2D4A) and Sorbin and Src homology 3 domain containing 3 (SORBS3) together exerted greater inhibition of cell growth and clonogenicity compared to a single gene. Overexpression of SH2D4A and SORBS3 in HCC cells led to decreased IL-6 target gene expression and reduced signal transducer and activator of transcription 3 (STAT3) signaling. In situ and in vitro coimmunoprecipitation assays revealed that SH2D4A directly interacts with STAT3, thereby retaining STAT3 in the cytoplasm and inhibiting STAT3 transcriptional activity. On the other hand, SORBS3 coactivated estrogen receptor signaling, leading indirectly to repression of STAT3 signaling. In human HCC tissues, SH2D4A was positively associated with infiltrating regulatory and cytotoxic T-cell populations, suggesting distinct immunophenotypes in HCC subgroups with chromosome 8p loss. Thus, the genetically linked tumor suppressors SH2D4A and SORBS3 functionally cooperate to inhibit STAT3 signaling in HCC. Conclusion: The chromosome 8p tumor suppressor genes SORBS3 and SH2D4A are physically and functionally linked and provide a molecular mechanism of inhibiting STAT3-mediated IL-6 signaling in HCC cells. (Hepatology 2016;64:828-842) C1 [Ploeger, Carolin; Waldburger, Nina; Fraas, Angelika; Goeppert, Benjamin; Breuhahn, Kai; Schirmacher, Peter; Roessler, Stephanie] Univ Heidelberg Hosp, Inst Pathol, Dept Gen Pathol, Heidelberg, Germany. [Pusch, Stefan] Univ Heidelberg Hosp, Inst Pathol, Dept Neuropathol, Heidelberg, Germany. [Pusch, Stefan] German Canc Res Ctr, Clin Cooperat Unit Neuropathol, Heidelberg, Germany. [Wang, Xin Wei] NCI, Human Carcinogenesis Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. RP Roessler, S (reprint author), Univ Heidelberg Hosp, Inst Pathol, Neuenheimer Feld 224, D-69120 Heidelberg, Germany. EM Stephanie.Roessler@med.uni-heidelberg.de RI Wang, Xin/B-6162-2009; OI Pusch, Stefan/0000-0002-3407-4249 FU Deutsche Forschungsgemeinschaft [SFB/TRR77, Z2, RO 4673]; Olympia-Morata Program; Brigitte-Schiebenlange Fellowship; NCT Heidelberg School of Oncology Fellowship; Center for Cancer Research, US National Cancer Institute FX Supported by the Deutsche Forschungsgemeinschaft (SFB/TRR77, Z2, to P.S.; RO 4673, to S.R.); by the Olympia-Morata Program, Brigitte-Schiebenlange Fellowship, and NCT Heidelberg School of Oncology Fellowship (to S.R.); and by the intramural research program of the Center for Cancer Research, US National Cancer Institute (to X.W.W.). NR 48 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD SEP PY 2016 VL 64 IS 3 BP 828 EP 842 DI 10.1002/hep.28684 PG 15 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DV9TU UT WOS:000383285900014 PM 27311882 ER PT J AU Shmagel, KV Saidakova, EV Shmagel, NG Korolevskaya, LB Chereshnev, VA Robinson, J Grivel, JC Douek, DC Margolis, L Anthony, DD Lederman, MM AF Shmagel, K. V. Saidakova, E. V. Shmagel, N. G. Korolevskaya, L. B. Chereshnev, V. A. Robinson, J. Grivel, J-C Douek, D. C. Margolis, L. Anthony, D. D. Lederman, M. M. TI Systemic inflammation and liver damage in HIV/hepatitis C virus coinfection SO HIV MEDICINE LA English DT Article DE antigens; CD31; hepatitis C; highly active antiretroviral therapy; HIV infections; inflammation mediators ID CHRONIC HEPATITIS-C; HIV-INFECTED PATIENTS; CD4(+) T-CELLS; IMMUNE ACTIVATION; ANTIRETROVIRAL THERAPY; DISEASE PROGRESSION; MICROBIAL TRANSLOCATION; HCV INFECTION; EXPRESSION; CIRRHOSIS AB ObjectivesChronic hepatitis C virus (HCV) and HIV viral infections are characterized by systemic inflammation. Yet the relative levels, drivers and correlates of inflammation in these settings are not well defined. MethodsSeventy-nine HIV-infected patients who had been receiving antiretroviral therapy (ART) for more than 2 years and who had suppressed plasma HIV levels (< 50 HIV-1 RNA copies/mL) were included in the study. Two patient groups, HCV-positive/HIV-positive and HCV-negative/HIV-positive, and a control group comprised of healthy volunteers (n = 20) were examined. Markers of systemic inflammation [interleukin (IL)-6, interferon gamma-induced protein (IP)-10, soluble tumour necrosis factor receptor-I (sTNF-RI) and sTNF-RII], monocyte/macrophage activation [soluble CD163 (sCD163), soluble CD14 and neopterin], intestinal epithelial barrier loss [intestinal fatty acid binding protein (I-FABP) and lipopolysaccharide (LPS)] and coagulation (d-dimers) were analysed. CD4 naive T cells and CD4 recent thymic emigrants (RTEs) were enumerated. ResultsPlasma levels of IP-10, neopterin and sCD163 were higher in HCV/HIV coinfection than in HIV monoinfection and were positively correlated with indices of hepatic damage [aspartate aminotransferase (AST), alanine aminotransferase (ALT) and the AST to platelet ratio index (APRI)]. Levels of I-FABP were comparably increased in HIV monoinfection and HIV/HCV coinfection but LPS concentrations were highest in HCV/HIV coinfection, suggesting impaired hepatic clearance of LPS. Plasma HCV levels were not related to any inflammatory indices except sCD163. In coinfected subjects, a previously recognized relationship of CD4 naive T-cell and RTE counts to hepatocellular injury was defined more mechanistically by an inverse relationship to sCD163. ConclusionsHepatocellular injury in HCV/HIV coinfection is linked to elevated levels of certain inflammatory cytokines and an apparent failure to clear systemically translocated microbial products. A related decrease in CD4 naive T cells and RTEs also merits further exploration. C1 [Shmagel, K. V.; Saidakova, E. V.; Korolevskaya, L. B.; Chereshnev, V. A.] RAS, Inst Ecol & Genet Microorganisms, UB, Perm, Russia. [Shmagel, K. V.; Saidakova, E. V.; Shmagel, N. G.; Korolevskaya, L. B.; Chereshnev, V. A.] Perm State Univ, Perm, Russia. [Shmagel, N. G.] Perm Reg Ctr Protect AIDS & Infect Dis, Perm, Russia. [Chereshnev, V. A.] RAS, Inst Immunol & Physiol, UB, Ekaterinburg, Russia. [Robinson, J.; Anthony, D. D.; Lederman, M. M.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Grivel, J-C; Margolis, L.] NICHD, Bethesda, MD USA. [Douek, D. C.] NIH, Vaccine Res Ctr, Bldg 10, Bethesda, MD 20892 USA. RP Shmagel, KV (reprint author), 13 Goleva St, Perm 614081, Russia. EM shmagel@iegm.ru RI Saidakova, Evgeniya/C-8333-2015; OI Saidakova, Evgeniya/0000-0002-4342-5362; Shmagel, Konstantin/0000-0001-6355-6178 FU NIAID NIH HHS [P30 AI036219, UM1 AI069501] NR 40 TC 1 Z9 1 U1 7 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-2662 EI 1468-1293 J9 HIV MED JI HIV Med. PD SEP PY 2016 VL 17 IS 8 BP 581 EP 589 DI 10.1111/hiv.12357 PG 9 WC Infectious Diseases SC Infectious Diseases GA DW2KG UT WOS:000383470700002 PM 27187749 ER PT J AU Menon, R Bonney, EA Condon, J Mesiano, S Taylor, RN AF Menon, Ramkumar Bonney, Elizabeth A. Condon, Jennifer Mesiano, Sam Taylor, Robert N. TI Novel concepts on pregnancy clocks and alarms: redundancy and synergy in human parturition SO HUMAN REPRODUCTION UPDATE LA English DT Review DE labor and delivery; corticosteroids; senescence; oxidative stress; NK cells; progesterone receptors; endoplasmic reticulum; unfolded proteins; p38MAPK; aging ID ENDOPLASMIC-RETICULUM STRESS; NF-KAPPA-B; UNFOLDED PROTEIN RESPONSE; HUMAN FETAL MEMBRANES; PROGESTERONE-RECEPTOR-A; PRETERM PREMATURE RUPTURE; CORTICOTROPIN-RELEASING FACTOR; FACTOR-BINDING PROTEIN-1; HUMAN AMNION FIBROBLASTS; DECIDUAL STROMAL CELLS AB In this review, we put forth the core hypothesis that fetal membrane (amnion and chorion) senescence is the initiator of a coordinated, redundant signal cascade leading to parturition. Whether modified by oxidative stress or other factors, this process constitutes a counting device, i.e. a clock, that measures maturation of the fetal organ systems and the production of hormones and other soluble mediators (including alarmins) and that promotes inflammation and orchestrates an immune cascade to propagate signals across different uterine compartments. This mechanism in turn sensitizes decidual responsiveness and eventually promotes functional progesterone withdrawal in the myometrium, leading to increased myometrial cell contraction and the triggering of parturition. Linkage of these processes allows convergence and integration of the gestational clocks and alarms, prompting a timely and safe birth. In summary, we provide a comprehensive synthesis of the mediators that contribute to the timing of human labor. Integrating these concepts will provide a better understanding of human parturition and ultimately improve pregnancy outcomes. C1 [Menon, Ramkumar] Univ Texas Med Branch, Dept Obstet & Gynecol, Div Maternal Fetal Med & Perinatal Res, MRB, 301 Univ Blvd,Room 11-138, Galveston, TX 77555 USA. [Bonney, Elizabeth A.] Univ Vermont, Coll Med, Dept Obstet Gynecol & Reprod Sci, 792 Coll Pkwy,Fanny Allen Campus,Suite 101, Burlington, VT 05446 USA. [Condon, Jennifer] Wayne State Univ, Dept Obstet & Gynecol, Perinatal Res Branch, NICHD, Detroit, MI 48201 USA. [Mesiano, Sam] Case Western Reserve Univ, Dept Reprod Biol & Obstet & Gynecol, 11100 Euclid Ave, Cleveland, OH 44106 USA. [Taylor, Robert N.] Wake Forest Sch Med, Dept Obstet & Gynecol, Med Ctr Blvd, Winston Salem, NC 27157 USA. RP Menon, R (reprint author), Univ Texas Med Branch, Dept Obstet & Gynecol, Div Maternal Fetal Med & Perinatal Res, MRB, 301 Univ Blvd,Room 11-138, Galveston, TX 77555 USA. EM Ram.menon@utmb.edu FU Innovation Catalyst grant from March of Dimes Prematurity Research Center, Ohio; National Institutes of Health [HD086354, P20 RR021905, RO1H0065011, HD069819]; Faculty Development Fund, The University of Texas Medical Branch, Galveston, TX; University of Vermont College of Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences; March of Dimes [21 FY2012-152] FX R.M. received funding from Innovation Catalyst grant from March of Dimes Prematurity Research Center, Ohio collaborative; National Institutes of Health (Grant # HD086354); and Faculty Development Fund, The University of T