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 Texas Medical Branch, Galveston, TX. E.B. received funding from University of Vermont College of Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences and National Institutes of Health (Grant # P20 RR021905). J.C. received funding from the March of Dimes (21 FY2012-152) and National Institutes of Health (Grant # RO1H0065011). S.M. received funding from National Institutes of Health (Grant# HD069819). NR 321 TC 3 Z9 3 U1 10 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1355-4786 EI 1460-2369 J9 HUM REPROD UPDATE JI Hum. Reprod. Update PD SEP-OCT PY 2016 VL 22 IS 5 BP 535 EP 560 DI 10.1093/humupd/dmw022 PG 26 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA DW8JU UT WOS:000383902200001 PM 27363410 ER PT J AU Kemper, C AF Kemper, Claudia TI Functionally selective C5aR2 ligands discovery Targeting the Dark Horse of complement: the first generation of functionally selective C5aR2 ligands SO IMMUNOLOGY AND CELL BIOLOGY LA English DT Editorial Material ID RECEPTOR; SITES C1 [Kemper, Claudia] Kings Coll London, Div Transplant Immunol & Mucosal Biol, MRC Ctr Transplantat, London, England. [Kemper, Claudia] NHLBI, Lab Mol Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA. [Kemper, Claudia] NHLBI, Ctr Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Kemper, C (reprint author), Kings Coll London, Div Transplant Immunol & Mucosal Biol, MRC Ctr Transplantat, London, England.; Kemper, C (reprint author), NHLBI, Lab Mol Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA.; Kemper, C (reprint author), NHLBI, Ctr Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA. EM Claudia.kemper@kcl.ac.uk FU Medical Research Council [MR/J006742/1] NR 9 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0818-9641 EI 1440-1711 J9 IMMUNOL CELL BIOL JI Immunol. Cell Biol. PD SEP PY 2016 VL 94 IS 8 BP 717 EP 718 DI 10.1038/icb.2016.62 PG 2 WC Cell Biology; Immunology SC Cell Biology; Immunology GA DW6YB UT WOS:000383796200002 PM 27457155 ER PT J AU Yoon, J Wang, HS Kim, YC Yoshimoto, M Abbasi, S Morse, HC AF Yoon, Jeongheon Wang, Hongsheng Kim, Yong Chan Yoshimoto, Momoko Abbasi, Sadia Morse, Herbert C., III TI Plasma cell alloantigen ENPP1 is expressed by a subset of human B cells with potential regulatory functions SO IMMUNOLOGY AND CELL BIOLOGY LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; B-1 CELLS; B10 CELLS; MICE; MOUSE; DIFFERENTIATION; INFLAMMATION; POPULATION; PERITONEAL; RESPONSES AB Plasma cell alloantigen 1 (PC1), also known as ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase 1), is an enzyme involved primarily in hydrolysis of adenosine triphosphate at the cell surface. Although the expression pattern of PC1 is relatively broad, its expression in B cells is found at significant levels only in terminally differentiated germinal center B cells, plasma cells and a subset of B-1a cells in mice. Here we describe studies designed to determine whether expression of PC1 might define novel populations of human B cells with similarities to mouse B cells. We found that PC1 is expressed in small populations of human B lineage cells in peripheral blood, cord blood, tonsils, bone marrow and pediatric peritoneal fluid, with the highest levels in plasma cells. The characteristics of human PC1(+) B cells differ from mouse peritoneal B-1a subsets and from features of the human CD20(+)CD27(+)CD43(+)CD70(-) B-cell subset proposed to be human B-1 cells. Expression of PC1 was greatly increased in B cells stimulated with the combination of CD40 ligand, interleukin (IL)-4 and IL-21. In addition, PC1(+) B cells activated CD4(+) T regulatory cells. ENPP1 thus defines a subset of human B cells that differs significantly from mouse peritoneal B-1a and proposed human B-1 cells. C1 [Yoon, Jeongheon; Wang, Hongsheng; Abbasi, Sadia; Morse, Herbert C., III] NIAID, Virol & Cellular Immunol Sect, Immunogenet Lab, NIH, 5640 Fishers Lane, Rockville, MD 20852 USA. [Yoon, Jeongheon; Kim, Yong Chan] Uniformed Serv Univ Hlth Sci, Dept Med, Room A3060, Bethesda, MD 20814 USA. [Yoshimoto, Momoko] Indiana Univ Sch Med, Dept Pediat, Herman B Wells Ctr Pediat Res, Indianapolis, IN 46202 USA. RP Morse, HC (reprint author), NIAID, Virol & Cellular Immunol Sect, Immunogenet Lab, NIH, 5640 Fishers Lane, Rockville, MD 20852 USA. EM hmorse@niaid.nih.gov FU Intramural Research Program of the NIH, National institute of Allergy and Infectious Diseases; Project Development Team within the ICTSI NIH/NCRR [UL1TR001108] FX This work was supported in part by the Intramural Research Program of the NIH, National institute of Allergy and Infectious Diseases and in part by a Project Development Team within the ICTSI NIH/NCRR Grant Number UL1TR001108. We are indebted to Lucy C Miller, Michelle Mellencamp, Shirley Wright-Coltart, Troy Markel, Charles Leys, Frederick Rescorla, Thomas Rouse, Allen Ladd and Deborah Billmire for their efforts in providing pediatric samples for analysis, and to Dr Leonid B Margolis (National Institute of Child Health and Human Development, NIH) for providing tonsils. NR 33 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0818-9641 EI 1440-1711 J9 IMMUNOL CELL BIOL JI Immunol. Cell Biol. PD SEP PY 2016 VL 94 IS 8 BP 719 EP 728 DI 10.1038/icb.2016.31 PG 10 WC Cell Biology; Immunology SC Cell Biology; Immunology GA DW6YB UT WOS:000383796200003 PM 27029896 ER PT J AU Watson, HA Dolton, G Ohme, J Ladell, K Vigar, M Wehenkel, S Hindley, J Mohammed, RN Miners, K Luckwell, RA Price, DA Matthews, RJ Ager, A AF Watson, H. Angharad Dolton, Garry Ohme, Julia Ladell, Kristin Vigar, Miriam Wehenkel, Sophie Hindley, James Mohammed, Rebar N. Miners, Kelly Luckwell, Rhys A. Price, David A. Matthews, R. James Ager, Ann TI Purity of transferred CD8(+) T cells is crucial for safety and efficacy of combinatorial tumor immunotherapy in the absence of SHP-1 SO IMMUNOLOGY AND CELL BIOLOGY LA English DT Article ID PROTEIN-TYROSINE-PHOSPHATASE; TCR SIGNALING THRESHOLDS; SODIUM STIBOGLUCONATE; MOTHEATEN LOCUS; IN-VIVO; CANCER; AUTOIMMUNITY; INHIBITOR; DOMAIN; DEPHOSPHORYLATION AB Adoptive transfer of tumor-specific cytotoxic T cells is a promising advance in cancer therapy. Similarly, checkpoint inhibition has shown striking clinical results in some patients. Here we combine adoptive cell transfer with ablation of the checkpoint protein Src homology 2-domain-containing phosphatase 1 (SHP-1, Ptpn6). Naturally occurring motheaten mice lack SHP-1 and do not survive weaning due to extensive immunopathology. To circumvent this limitation, we created a novel SHP-1(null) mouse that is viable up to 12 weeks of age by knocking out IL1r1. Using this model, we demonstrate that the absence of SHP-1 augments the ability of adoptively transferred CD8(+) T cells to control tumor growth. This therapeutic effect was only observed in situations where T-cell numbers were limited, analogous to clinical settings. However, adoptive transfer of non-CD8(+) SHP-1(null) hematopoietic cells resulted in lethal motheaten-like pathology, indicating that systemic inhibition of SHP-1 could have serious adverse effects. Despite this caveat, our findings support the development of SHP-1 inhibition strategies in human T cells to complement adoptive transfer therapies in the clinic. C1 [Watson, H. Angharad; Dolton, Garry; Ohme, Julia; Ladell, Kristin; Vigar, Miriam; Wehenkel, Sophie; Hindley, James; Mohammed, Rebar N.; Miners, Kelly; Luckwell, Rhys A.; Price, David A.; Matthews, R. James; Ager, Ann] Cardiff Univ, Sch Med, Div Infect & Immun, Henry Wellcome Bldg, Cardiff CF14 4XN, S Glam, Wales. [Watson, H. Angharad; Dolton, Garry; Ohme, Julia; Ladell, Kristin; Vigar, Miriam; Wehenkel, Sophie; Hindley, James; Mohammed, Rebar N.; Miners, Kelly; Luckwell, Rhys A.; Price, David A.; Matthews, R. James; Ager, Ann] Cardiff Univ, Syst Immun Univ Res Inst, Cardiff, S Glam, Wales. [Price, David A.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Watson, HA (reprint author), Cardiff Univ, Sch Med, Div Infect & Immun, Henry Wellcome Bldg, Cardiff CF14 4XN, S Glam, Wales. EM Watsonha1@cf.ac.uk; agera@cf.ac.uk RI Price, David/C-7876-2013 OI Price, David/0000-0001-9416-2737 FU Wellcome Trust [094511/Z/10/Z]; Wales Cancer Research Centre FX We thank Professor A Gallimore for advice on the B16 model, Dr A Schauenburg for help with tetramer preparation, Dr D Kioussis (National Institute of Medical Research, London) and Professor K Mills (Trinity College, Dublin) for the provision of F5 transgenic and B6.126S7-IL1r1tm1Imx/J knockout mice, respectively, and biological services at Cardiff University for mouse care. DAP is a Wellcome Trust Senior Investigator. This work was supported by the Wellcome Trust (094511/Z/10/Z) and the Wales Cancer Research Centre. NR 36 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0818-9641 EI 1440-1711 J9 IMMUNOL CELL BIOL JI Immunol. Cell Biol. PD SEP PY 2016 VL 94 IS 8 BP 802 EP 808 DI 10.1038/icb.2016.45 PG 7 WC Cell Biology; Immunology SC Cell Biology; Immunology GA DW6YB UT WOS:000383796200011 PM 27430370 ER PT J AU Wong, KCL Tee, M Chen, M Bluemke, DA Summers, RM Yao, JH AF Wong, Ken C. L. Tee, Michael Chen, Marcus Bluemke, David A. Summers, Ronald M. Yao, Jianhua TI Regional infarction identification from cardiac CT images: a computer-aided biomechanical approach SO INTERNATIONAL JOURNAL OF COMPUTER ASSISTED RADIOLOGY AND SURGERY LA English DT Article; Proceedings Paper CT 18th International Conference on Medical Image Computing and Computer-Assisted Intervention (MICCAI) CY OCT 05-09, 2015 CL Munich, GERMANY SP Tech Univ Munich, Friedrich Alexander Univ Erlangen Nuremberg DE Biomechanics; Cardiac computed tomography; Computer-aided diagnosis; Infarction identification; Machine learning; Myocardial strain estimation ID ACUTE MYOCARDIAL-INFARCTION; AMERICAN-HEART-ASSOCIATION; DEFORMATION RECOVERY; STRAIN ANALYSIS; STRATEGIES; VIABILITY; DISEASE; MOTION; MRI AB Regional infarction identification is important for heart disease diagnosis and management, and myocardial deformation has been shown to be effective for this purpose. Although tagged and strain-encoded MR images can provide such measurements, they are uncommon in clinical routine. On the contrary, cardiac CT images are more available with lower costs, but they only provide motion of cardiac boundaries and additional constraints are required to obtain the myocardial strains. The goal of this study is to verify the potential of contrast-enhanced CT images on computer-aided regional infarction identification. We propose a biomechanical approach combined with machine learning algorithms. A hyperelastic biomechanical model is used with deformable image registration to estimate 3D myocardial strains from CT images. The regional strains and CT image intensities are input to a classifier for regional infarction identification. Cross-validations on ten canine image sequences with artificially induced infarctions were used to study the performances of using different feature combinations and machine learning algorithms. Radial strain, circumferential strain, first principal strain, and image intensity were shown to be discriminative features. The highest identification accuracy ( %) was achieved when combining radial strain with image intensity. Random forests gave better results than support vector machines on less discriminative features. Random forests also performed better when all strains were used together. Although CT images cannot directly measure myocardial deformation, with the use of a biomechanical model, the estimated strains can provide promising identification results especially when combined with CT image intensity. C1 [Wong, Ken C. L.; Tee, Michael; Bluemke, David A.; Summers, Ronald M.; Yao, Jianhua] NIH, Radiol & Imaging Sci, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Chen, Marcus] NHLBI, Cardiovasc & Pulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Tee, Michael] Univ Oxford, Inst Biomed Engn, Oxford, England. RP Yao, JH (reprint author), NIH, Radiol & Imaging Sci, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM jyao@cc.nih.gov OI Bluemke, David/0000-0002-8323-8086 NR 31 TC 0 Z9 0 U1 4 U2 4 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1861-6410 EI 1861-6429 J9 INT J COMPUT ASS RAD JI Int. J. Comput. Assist. Radiol. Surg. PD SEP PY 2016 VL 11 IS 9 SI SI BP 1573 EP 1583 DI 10.1007/s11548-016-1404-5 PG 11 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging; Surgery SC Engineering; Radiology, Nuclear Medicine & Medical Imaging; Surgery GA DW0IJ UT WOS:000383323800003 PM 27072840 ER PT J AU Santosh, KC Vajda, S Antani, S Thoma, GR AF Santosh, K. C. Vajda, Szilard Antani, Sameer Thoma, George R. TI Edge map analysis in chest X-rays for automatic pulmonary abnormality screening SO INTERNATIONAL JOURNAL OF COMPUTER ASSISTED RADIOLOGY AND SURGERY LA English DT Article; Proceedings Paper CT 18th International Conference on Medical Image Computing and Computer-Assisted Intervention (MICCAI) CY OCT 05-09, 2015 CL Munich, GERMANY SP Tech Univ Munich, Friedrich Alexander Univ Erlangen Nuremberg DE Automation; Thoracic edge map; Pulmonary abnormalities; Screening; Tuberculosis; Chest X-rays ID RAPID MOLECULAR-DETECTION; TUBERCULOSIS; RADIOGRAPHS; RESISTANCE; TEXTURE AB Our particular motivator is the need for screening HIV+ populations in resource-constrained regions for the evidence of tuberculosis, using posteroanterior chest radiographs (CXRs). The proposed method is motivated by the observation that abnormal CXRs tend to exhibit corrupted and/or deformed thoracic edge maps. We study histograms of thoracic edges for all possible orientations of gradients in the range at different numbers of bins and different pyramid levels, using five different regions-of-interest selection. We have used two CXR benchmark collections made available by the U.S. National Library of Medicine and have achieved a maximum abnormality detection accuracy (ACC) of 86.36 % and area under the ROC curve (AUC) of 0.93 at 1 s per image, on average. We have presented an automatic method for screening pulmonary abnormalities using thoracic edge map in CXR images. The proposed method outperforms previously reported state-of-the-art results. C1 [Santosh, K. C.] Univ South Dakota, Dept Comp Sci, 414 E Clark St, Vermillion, SD 57069 USA. [Vajda, Szilard] Cent Washington Univ, Dept Comp Sci, 400 E Univ Way, Ellensburg, WA 98926 USA. [Santosh, K. C.; Antani, Sameer; Thoma, George R.] US Natl Lib Med, NIH, 8600 Rockville Pike, Bethesda, MD 20894 USA. RP Santosh, KC (reprint author), Univ South Dakota, Dept Comp Sci, 414 E Clark St, Vermillion, SD 57069 USA.; Santosh, KC (reprint author), US Natl Lib Med, NIH, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM santosh.kc@usd.edu OI Santosh, K.C./0000-0003-4176-0236 NR 32 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1861-6410 EI 1861-6429 J9 INT J COMPUT ASS RAD JI Int. J. Comput. Assist. Radiol. Surg. PD SEP PY 2016 VL 11 IS 9 SI SI BP 1637 EP 1646 DI 10.1007/s11548-016-1359-6 PG 10 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging; Surgery SC Engineering; Radiology, Nuclear Medicine & Medical Imaging; Surgery GA DW0IJ UT WOS:000383323800008 PM 26995600 ER PT J AU Reinhardt, M Parigi, AD Chen, K Reiman, EM Thiyyagura, P Krakoff, J Hohenadel, MG Le, DSNT Weise, CM AF Reinhardt, M. Parigi, A. D. Chen, K. Reiman, E. M. Thiyyagura, P. Krakoff, J. Hohenadel, M. G. Le, D. S. N. T. Weise, C. M. TI Deactivation of the left dorsolateral prefrontal cortex in Prader-Willi syndrome after meal consumption SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; DIRECT-CURRENT STIMULATION; ANTERIOR CINGULATE CORTEX; DECISION-MAKING; LESS ACTIVATION; WEIGHT-LOSS; HUMAN BRAIN; LEAN WOMEN; OBESITY; HUNGER AB BACKGROUND/OBJECTIVES: Prader- Willi syndrome (PWS) is a type of human genetic obesity that may give us information regarding the physiology of non-syndromic obesity. The objective of this study was to investigate the functional correlates of hunger and satiety in individuals with PWS in comparison with healthy controls with obesity, hypothesizing that we would see significant differences in activation in the left dorsolateral prefrontal cortex (DLPFC) based on prior findings. SUBJECTS/METHODS: This study compared the central effects of food consumption in nine individuals with PWS (7 men, 2 women; body fat 35.3 +/- 10.0%) and seven controls (7 men; body fat 28.8 +/- 7.6%), matched for percentage body fat. (H2O)-O-15-PET (positron emission tomography) scans were performed before and after consumption of a standardized liquid meal to obtain quantitative measures of regional cerebral blood flow (rCBF), a marker of neuronal activity. RESULTS: Compared with obese controls, PWS showed altered (P < 0.05 family-wise error cluster-level corrected; voxelwise P < 0.001) rCBF before and after meal consumption in multiple brain regions. There was a significant differential rCBF response within the left DLPFC after meal ingestion with decreases in DLPFC rCBF in PWS; in controls, DLPFC rCBF tended to remain unchanged. In more liberal analyses (P < 0.05 family-wise error cluster-level corrected; voxelwise P < 0.005), rCBF of the right orbitofrontal cortex (OFC) increased in PWS and decreased in controls. In PWS,Delta rCBF of the right OFC was associated with changes in appetite ratings. CONCLUSIONS: The pathophysiology of eating behavior in PWS is characterized by a paradoxical meal-induced deactivation of the left DLPFC and activation in the right OFC, brain regions implicated in the central regulation of eating behavior. C1 [Reinhardt, M.; Krakoff, J.; Hohenadel, M. G.; Le, D. S. N. T.; Weise, C. M.] NIDDK, Obes & Diabet Clin Res Sect, Phoenix Epidemiol & Clin Res Branch, NIH,Dept Hlth & Human Serv, Phoenix, AZ USA. [Reinhardt, M.] Univ Leipzig, Dept Diagnost & Intervent Radiol, Leipzig, Germany. [Parigi, A. D.] Drexel Univ, Dept Nutr Sci, Philadelphia, PA 19104 USA. [Parigi, A. D.] Boehringer Ingelheim Pharmaceut, Ridgefield, CT USA. [Chen, K.; Reiman, E. M.; Thiyyagura, P.] Banner Alzheimers Inst, Phoenix, AZ USA. [Reiman, E. M.] Univ Arizona, Translat Genom Res Inst, Neurogen Div, Phoenix, AZ USA. [Reiman, E. M.] Arizona State Univ, Phoenix, AZ USA. [Weise, C. M.] Univ Leipzig, Dept Neurol, Leipzig, Germany. RP Reinhardt, M (reprint author), NIDDK, Obes & Diabet Clin Res Sect, Phoenix Epidemiol & Clin Res Branch, Natl Inst Hlth North 4212, 16th St, Phoenix, AZ 85016 USA. EM martin.reinhardt@nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases FX We thank the dietary, nursing and technical staff of the National Institutes of Health Clinical Unit in Phoenix, AZ, for their assistance. Most of all, the we thank the volunteers for their participation in the study. This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. NR 41 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 0307-0565 EI 1476-5497 J9 INT J OBESITY JI Int. J. Obes. PD SEP PY 2016 VL 40 IS 9 BP 1360 EP 1368 DI 10.1038/ijo.2016.75 PG 9 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA DW6SI UT WOS:000383781100005 PM 27121248 ER PT J AU Muthigi, A Sidana, A George, AK Kongnyuy, M Shakir, N Kadakia, M Maruf, M Frye, TP Mertan, F Su, D Merino, MJ Choyke, PL Turkbey, B Wood, BJ Pinto, PA AF Muthigi, Akhil Sidana, Abhinav George, Arvin K. Kongnyuy, Michael Shakir, Nabeel Kadakia, Meet Maruf, Mahir Frye, Thomas P. Mertan, Francesca Su, Daniel Merino, Maria J. Choyke, Peter L. Turkbey, Baris Wood, Bradford J. Pinto, Peter A. TI Midline lesions of the prostate: role of MRI/TRUS fusion biopsy and implications in Gleason risk stratification SO INTERNATIONAL UROLOGY AND NEPHROLOGY LA English DT Article DE Prostate cancer; Multiparametric MRI; Fusion biopsy; Midline ID RESONANCE-ULTRASOUND FUSION; TARGETED BIOPSY; GUIDED BIOPSY; MULTIPARAMETRIC MRI; CANCER-DETECTION; NEEDLE-BIOPSY; DIAGNOSIS; IDENTIFICATION; DETECT AB MRI-TRUS fusion biopsy (FBx) has proven efficacy in targeting suspicious areas that are traditionally missed by systematic 12-core biopsy (SBx). Midline prostate lesions are undersampled during SBx, as traditional approaches aim laterally during TRUS biopsy. The aim of our study was to determine the utility of FBx for targeting midline lesions identified on multiparametric MRI (mpMRI). A review was performed of a prospectively maintained database of patients undergoing mpMRI followed by FBx and SBx from 2007 to 2015. Midline location was defined as any lesion crossing the midline on axial imaging and involving both prostatic lobes. Index lesion was defined as lesion with highest Gleason score on biopsy. Patient demographic, imaging, and histopathologic data were collected. Multivariate logistic regression was conducted to determine independent predictors of having clinically significant (CS) cancer (Gleason aeyen 7) in midline lesions. Out of 1266 patients, we identified 202 suspicious midline lesions in 190 patients [median (IQR) age 63 (10) years; PSA 7.6 (6.6)]. Eighty-eight (46.3 %) patients had cancer detection on FBx of midline lesion. A midline target represented the index lesion of the prostate in 63/190 (33.2 %) patients. Risk category upgrading based on FBx of a midline lesion compared to SBx occurred in 45/190 patients (23.7 %). On multivariate analysis, higher PSA (p = .001), lower MRI-derived prostate volume (p < .001), and moderate-high or high suspicion on mpMRI (p = .014) predicted CS cancer in midline lesions. MRI-TRUS FBx facilitates sampling of midline lesions. Integration of mpMRI and FBx for targeting of midline lesions improves detection of CS prostate cancer. C1 [Muthigi, Akhil; Sidana, Abhinav; George, Arvin K.; Kongnyuy, Michael; Shakir, Nabeel; Kadakia, Meet; Maruf, Mahir; Frye, Thomas P.; Su, Daniel; Pinto, Peter A.] NCI, Urol Oncol Branch, NIH, 10 Ctr Dr,Bldg 10,Room 1-5940, Bethesda, MD 20892 USA. [Merino, Maria J.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Mertan, Francesca; Choyke, Peter L.; Turkbey, Baris] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Wood, Bradford J.] NCI, Ctr Intervent Oncol, Bethesda, MD 20892 USA. [Wood, Bradford J.] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Muthigi, A (reprint author), NCI, Urol Oncol Branch, NIH, 10 Ctr Dr,Bldg 10,Room 1-5940, Bethesda, MD 20892 USA. EM akhil.muthigi@nih.gov FU Intramural Research Program of the National Institutes of Health (NIH); National Cancer Institute; Center for Cancer Research; Center for Interventional Oncology; NIH 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 the Center for Interventional Oncology. NIH and Philips Healthcare have a cooperative research and development agreement. NIH and Philips share intellectual property in the field. This research was also made possible through the National Institutes of Health Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from Pfizer Inc., The Doris Duke Charitable Foundation, The Alexandria Real Estate Equities, Inc. and Mr. and Mrs. Joel S. Marcus, and the Howard Hughes Medical Institute, as well as other private donors. For a complete list, please visit the Foundation Web site at: http://fnih.org/work/education-training-0/medical-research-scholars-prog ram. NR 29 TC 1 Z9 1 U1 4 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0301-1623 EI 1573-2584 J9 INT UROL NEPHROL JI Int. Urol. Nephrol. PD SEP PY 2016 VL 48 IS 9 BP 1445 EP 1452 DI 10.1007/s11255-016-1336-6 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA DU1NV UT WOS:000381975400010 PM 27305918 ER PT J AU Kent, EE Prestin, A Gaysynsky, A Galica, K Rinker, R Graff, K Chou, WYS AF Kent, Erin E. Prestin, Abby Gaysynsky, Anna Galica, Kasia Rinker, Robin Graff, Kaitlin Chou, Wen-Ying Sylvia TI "Obesity is the New Major Cause of Cancer": Connections Between Obesity and Cancer on Facebook and Twitter SO JOURNAL OF CANCER EDUCATION LA English DT Article DE Social media; Obesity; Cancer; Mixed methods; Risk perception ID SOCIAL MEDIA; BREAST-CANCER; HEALTH; CAUSATION; EPIDEMIOLOGY; POPULATION; DIAGNOSIS; WEIGHT; TRENDS AB Social media interactions can inform public health risk perceptions. While research has examined the risk relationships between obesity and cancer, public attitudes about their associations remain largely unknown. We explored how these constructs were discussed together on two social media platforms. Publicly accessible Facebook and Twitter posts from a 2-month period in 2012 containing references to obesity ("obese/obesity," "overweight," and "fat") and cancer-related words were extracted (N = 3702 posts). Data cleaning yielded a final set of 1382 posts (Facebook: N = 291; Twitter: N = 1091). Using a mixed-methods approach, themes were inductively generated, and sentiment valence, structural elements, and epistemic stance were coded. Seven relational themes emerged: obesity is associated with cancer (n = 389), additional factors are associated with both obesity and cancer (n = 335), obesity causes cancer (n = 85), cancer causes obesity (n = 6), obesity is not linked to cancer (n = 13), co-occurrence (n = 492), and obesity is valued differently than cancer (n = 60). Fifty-nine percent of posts focused on an associative or causal link between obesity and cancer. Thirty-one percent of posts contained positive and/or negative sentiment. Facebook was more likely to contain any sentiment, but Twitter contained proportionately more negative sentiment. Concurrent qualitative analysis revealed a dominance of individual blame for overweight/obese persons and more support and empathy for cancer survivors. Our study reflects wide recognition of the evidence linking obesity to increased risk of cancer, a diverse set of factors perceived to be dually associated with both conditions and differing attribution of responsibility. We demonstrate that social media monitoring can provide an important gauge of public health risk perception. C1 [Kent, Erin E.] NCI, Outcomes Res Branch, Healthcare Deliver Res Program, Div Canc Control & Populat Sci, Rockville, MD 20850 USA. [Prestin, Abby; Gaysynsky, Anna; Chou, Wen-Ying Sylvia] NCI, Hlth Commun & Informat Branch, Behav Res Program, Div Canc Control & Populat Sci, Rockville, MD USA. [Galica, Kasia] ICF Int, Rockville, MD USA. [Rinker, Robin] NCI, Off Advocacy Relat, Bethesda, MD 20892 USA. [Graff, Kaitlin] Washington Univ, St Louis, MO USA. [Kent, Erin E.] 9609 Med Ctr Dr, Rockville, MD 20850 USA. RP Kent, EE (reprint author), NCI, Outcomes Res Branch, Healthcare Deliver Res Program, Div Canc Control & Populat Sci, Rockville, MD 20850 USA.; Kent, EE (reprint author), 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM Erin.Kent@nih.gov NR 25 TC 0 Z9 0 U1 7 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0885-8195 EI 1543-0154 J9 J CANCER EDUC JI J. Cancer Educ. PD SEP PY 2016 VL 31 IS 3 BP 453 EP 459 DI 10.1007/s13187-015-0824-1 PG 7 WC Oncology; Education, Scientific Disciplines; Public, Environmental & Occupational Health SC Oncology; Education & Educational Research; Public, Environmental & Occupational Health GA DU1UA UT WOS:000381993900006 PM 25865399 ER PT J AU Raine, A Cheney, RA Ho, RG Portnoy, J Liu, JL Soyfer, L Hibbeln, J Richmond, TS AF Raine, Adrian Cheney, Rose A. Ho, Ringo Portnoy, Jill Liu, Jianghong Soyfer, Liana Hibbeln, Joseph Richmond, Therese S. TI Nutritional supplementation to reduce child aggression: a randomized, stratified, single-blind, factorial trial SO JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY LA English DT Article DE Aggression; omega-3; cognitive behavioral therapy; reactive; callous; nutrition; externalizing ID YOUNG-ADULT PRISONERS; PROACTIVE AGGRESSION; ANTISOCIAL-BEHAVIOR; DOCOSAHEXAENOIC ACID; PSYCHOPATHIC TRAITS; QUESTIONNAIRE; ADOLESCENTS; RECRUITMENT; ENRICHMENT; DISORDERS AB BackgroundWhile some studies suggest that nutritional supplementation may reduce aggressive behavior in children, they have not examined whether its efficacy may be enhanced in conjunction with other treatment approaches. This study tests the hypothesis that a nutritional supplementation of omega-3, multivitamins, and minerals over 3months, combined with cognitive behavior therapy, will reduce childhood aggression. MethodsIn this randomized, single-blind, stratified, factorial trial, a high-risk community sample of 290 children aged 11-12years were randomized into Nutrition only, cognitive behavioral therapy (CBT) only, Nutrition+CBT, and Control groups. The primary outcome measures of child- and parent-reported aggressive and antisocial behavior were collected at 0months (baseline), 3months (end of treatment), 6months (3months posttreatment), and 12months (9months posttreatment). The trial (Healthy Brains & Behavior: Understanding and Treating Youth Aggression (HBB)' was registered at ClinicalTrials.gov at ResultsFor child self-reports, children in the Nutrition only group showed reduced externalizing behavior compared to Controls at 3months. At 6months, the Nutrition+CBT group scored lower on externalizing behavior compared to both CBT only and Control groups. Findings were more in evidence for an Aggressive-Reactive form of antisocial behavior than for a Callous-Proactive form. Effect sizes were in the small-to-medium range (d=-.33 to -.37). Group differences were not sustained 9months posttreatment, and no other effects were significant. ConclusionsFindings provide some limited support for the efficacy of omega-3, vitamin, and mineral supplementation in reducing aggressive behavior in children, and represent the first evaluation of nutritional supplements in conjunction with CBT. C1 [Raine, Adrian; Portnoy, Jill; Soyfer, Liana] Univ Penn, Dept Criminol, 3809 Walnut St, Philadelphia, PA 19104 USA. [Raine, Adrian] Univ Penn, Dept Psychiat, 3809 Walnut St, Philadelphia, PA 19104 USA. [Raine, Adrian] Univ Penn, Dept Psychol, 3809 Walnut St, Philadelphia, PA 19104 USA. [Cheney, Rose A.] Univ Penn, Dept Surg, Perelman Sch Med, Philadelphia, PA 19104 USA. [Ho, Ringo] Nanyang Technol Univ, Div Psychol, Singapore, Singapore. [Liu, Jianghong; Richmond, Therese S.] Univ Penn, Sch Nursing, Philadelphia, PA 19104 USA. [Hibbeln, Joseph] NIAAA, Sect Nutr Neurosci, Bethesda, MD USA. RP Raine, A (reprint author), Univ Penn, Dept Criminol, 3809 Walnut St, Philadelphia, PA 19104 USA.; Raine, A (reprint author), Univ Penn, Dept Psychiat, 3809 Walnut St, Philadelphia, PA 19104 USA.; Raine, A (reprint author), Univ Penn, Dept Psychol, 3809 Walnut St, Philadelphia, PA 19104 USA. EM araine@sas.upenn.edu FU Pennsylvania Department of Health (SAP) [4100043366]; Clinical & Translational Research Center, Perelman School of Medicine, University of Pennsylvania [UL1-RR-024134]; Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism, Rockville, MD FX This project was funded, in part, under a grant from the Pennsylvania Department of Health (SAP# 4100043366). The Department specifically disclaims responsibility for any analyses, interpretations, or conclusions. It was also supported in part by the Clinical & Translational Research Center, Perelman School of Medicine, University of Pennsylvania (grant number UL1-RR-024134), and by the Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism, Rockville, MD (J.H.). The authors thank the CHOP Pediatric Research Consortium for their help during the recruitment stage. The authors declare that they have no competing or potential conflicts of interest. NR 41 TC 0 Z9 0 U1 13 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9630 EI 1469-7610 J9 J CHILD PSYCHOL PSYC JI J. Child Psychol. Psychiatry PD SEP PY 2016 VL 57 IS 9 BP 1038 EP 1046 DI 10.1111/jcpp.12565 PG 9 WC Psychology, Developmental; Psychiatry; Psychology SC Psychology; Psychiatry GA DW1JK UT WOS:000383399300007 PM 27166583 ER PT J AU Briggs-Gowan, MJ Grasso, D Bar-Haim, Y Voss, J McCarthy, KJ Pine, DS Wakschlag, LS AF Briggs-Gowan, Margaret J. Grasso, Damion Bar-Haim, Yair Voss, Joel McCarthy, Kimberly J. Pine, Daniel S. Wakschlag, Lauren S. TI Attention bias in the developmental unfolding of post-traumatic stress symptoms in young children at risk SO JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY LA English DT Article DE Attention bias; stress; violence; anxiety; posttraumatic stress; trauma ID THREAT; ANXIETY; EXPOSURE; PTSD; PSYCHOPATHOLOGY; RELIABILITY; PRESCHOOL; VIOLENCE AB BackgroundThreat-related attention bias relates to anxiety and posttraumatic stress symptoms in adults and adolescents, but few longitudinal studies examine such associations in young children. This study examines prospective relations among attention bias, trauma exposure, and anxiety and trauma symptoms in a sample previously reported to manifest cross-sectional associations between attention bias and observed anxiety at preschool age. MethodsYoung children [mean (MN)=5.0, 0.7years, n=208] from a community-based sample completed the dot-probe task to assess their attention biases in response to angry faces. At baseline (T1) and at follow-up approximately 9months later (T2), anxiety and trauma exposure (i.e. violent and noninterpersonal events) and symptoms were assessed by maternal report. ResultsNeither attention bias nor baseline or recent trauma exposure predicted later anxiety. In contrast, attention bias toward threat and recent trauma exposure significantly predicted later trauma symptoms. There was evidence of symptom specificity such that attention bias toward threat significantly predicted hyperarousal and dissociation, but not avoidance or re-experiencing symptoms. Finally, moderation analyses indicated that the relationship between attention bias and trauma symptoms may differ according to children's experiences of probable abuse. ConclusionsAttention profiles and trauma exposure may increase the risk that young children will develop trauma symptoms. Individual differences in these attentional patterns and children's exposure history may impact outcomes among high-risk children with potential implications for intervention. C1 [Briggs-Gowan, Margaret J.; Grasso, Damion; McCarthy, Kimberly J.] Univ Connecticut, Dept Psychiat, Sch Med, Farmington, CT 06107 USA. [Bar-Haim, Yair] Tel Aviv Univ, Sch Psychol Sci, Tel Aviv, Israel. [Voss, Joel; Wakschlag, Lauren S.] Northwestern Univ, Feinberg Sch Med, Dept Med Social Sci, Chicago, IL 60611 USA. [Pine, Daniel S.] NIMH, Div Intramural Res Programs, Bethesda, MD 20892 USA. RP Briggs-Gowan, MJ (reprint author), Univ Connecticut, Ctr Hlth, Dept Psychiat, 263 Farmington Ave,MC 1410, Farmington, CT 06030 USA. EM mbriggsgowan@uchc.edu FU National Institute of Mental Health [U01MH090301, R01MH082830]; National Institute of Mental Health Intramural Research Program FX Financial support for this study was provided by grants from the National Institute of Mental Health (U01MH090301; R01MH082830) and by the National Institute of Mental Health Intramural Research Program. The authors have declared that they have no conflicts of interest in relation to this article. NR 33 TC 0 Z9 0 U1 9 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9630 EI 1469-7610 J9 J CHILD PSYCHOL PSYC JI J. Child Psychol. Psychiatry PD SEP PY 2016 VL 57 IS 9 BP 1083 EP 1091 DI 10.1111/jcpp.12577 PG 9 WC Psychology, Developmental; Psychiatry; Psychology SC Psychology; Psychiatry GA DW1JK UT WOS:000383399300012 PM 27296760 ER PT J AU Yoon, J Leyva-Castillo, JM Wang, GX Galand, C Oyoshi, MK Kumar, L Hoff, S He, R Chervonsky, A Oppenheim, JJ Kuchroo, VK van den Brink, MRM Malefyt, RD Tessier, PA Fuhlbrigge, R Rosenstiel, P Terhorst, C Murphy, G Geha, RS AF Yoon, Juhan Leyva-Castillo, Juan Manuel Wang, Guoxing Galand, Claire Oyoshi, Michiko K. Kumar, Lalit Hoff, Sabine He, Rui Chervonsky, Alexander Oppenheim, Joost J. Kuchroo, Vijay K. van den Brink, Marcel R. M. Malefyt, Rene De Waal Tessier, Philippe A. Fuhlbrigge, Robert Rosenstiel, Philip Terhorst, Cox Murphy, George Geha, Raif S. TI IL-23 induced in keratinocytes by endogenous TLR4 ligands polarizes dendritic cells to drive IL-22 responses to skin immunization SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID INNATE LYMPHOID-CELLS; PATHOGENIC T(H)17 CELLS; ATOPIC-DERMATITIS; CUTTING EDGE; T-CELLS; IMMUNE-RESPONSES; EPITHELIAL-CELLS; INTERLEUKIN 22; HOST-DEFENSE; INFLAMMATION AB Atopic dermatitis (AD) is a Th2-dominated inflammatory skin disease characterized by epidermal thickening. Serum levels of IL-22, a cytokine known to induce keratinocyte proliferation, are elevated in AD, and Th22 cells infiltrate AD skin lesions. We show that application of antigen to mouse skin subjected to tape stripping, a surrogate for scratching, induces an IL-22 response that drives epidermal hyperplasia and keratinocyte proliferation in a mouse model of skin inflammation that shares many features of AD. DC- derived IL-23 is known to act on CD4(+) T cells to induce IL-22 production. However, the mechanisms that drive IL-23 production by skin DCs in response to cutaneous sensitization are not well understood. We demonstrate that IL-23 released by keratinocytes in response to endogenous TLR4 ligands causes skin DCs, which selectively express IL-23R, to up-regulate their endogenous IL-23 production and drive an IL-22 response in naive CD4(+) T cells that mediates epidermal thickening. We also show that IL-23 is released in human skin after scratching and polarizes human skin DCs to drive an IL-22 response, supporting the utility of IL-23 and IL-22 blockade in AD. C1 [Yoon, Juhan; Leyva-Castillo, Juan Manuel; Galand, Claire; Oyoshi, Michiko K.; Kumar, Lalit; Hoff, Sabine; He, Rui; Fuhlbrigge, Robert; Geha, Raif S.] Harvard Med Sch, Div Immunol, Childrens Hosp, Boston, MA 02115 USA. [Yoon, Juhan; Leyva-Castillo, Juan Manuel; Galand, Claire; Oyoshi, Michiko K.; Kumar, Lalit; Hoff, Sabine; He, Rui; Fuhlbrigge, Robert; Geha, Raif S.] Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA. [Wang, Guoxing; Terhorst, Cox] Harvard Med Sch, Div Immunol, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. [Murphy, George] Harvard Med Sch, Dept Dermatol, Boston, MA 02115 USA. [Kuchroo, Vijay K.] Harvard Med Sch, Ctr Neurol Dis, Brigham & Womens Hosp, Boston, MA 02115 USA. [Murphy, George] Harvard Med Sch, Div Dermatopathol, Brigham & Womens Hosp, Boston, MA 02115 USA. [Chervonsky, Alexander] Univ Chicago, Dept Pathol, 5841 S Maryland Ave, Chicago, IL 60637 USA. [Oppenheim, Joost J.] NCI, Mol Immunoregulat Lab, Frederick, MD 21702 USA. [van den Brink, Marcel R. M.] Mem Sloan Kettering Canc Ctr, Dept Immunol & Med, New York, NY 10065 USA. [Malefyt, Rene De Waal] Merck Res Labs, Palo Alto, CA 94304 USA. [Tessier, Philippe A.] Ctr Hosp Univ Laval, Ctr Rech, Ste Foy, PQ G1V 4G2, Canada. [Rosenstiel, Philip] Univ Kiel, Inst Clin Mol Biol, D-24105 Kiel, Germany. [Yoon, Juhan] Sungkyunkwan Univ, DRC, C&C Res Labs, 2066 Seobu Ro, Suwon 440746, Gyeonggi Do, South Korea. [Hoff, Sabine] Bayer Pharma AG, Dept Immunotherapy & Antibody Drug Conjugates, D-13353 Berlin, Germany. [He, Rui] Fudan Univ, Shanghai Med Coll, Dept Immunol, Shanghai 200030, Peoples R China. RP Geha, RS (reprint author), Harvard Med Sch, Div Immunol, Childrens Hosp, Boston, MA 02115 USA.; Geha, RS (reprint author), Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA. EM raif.geha@childrens.harvard.edu OI Rosenstiel, Philip/0000-0002-9692-8828; He, Rui/0000-0001-5288-9786 FU National Institutes of Health Atopic Dermatitis Research Network [HHSN2722020000200]; Deutsche Forschungsgemeinschaft (DFG) [CRC877 B9]; DFG Cluster of Excellence Inflammation of Interfaces; Consejo Nacional de Ciencia y Tecnologia (CONACYT, Mexico) FX This work was supported by the National Institutes of Health Atopic Dermatitis Research Network contract HHSN2722020000200. P. Rosenstiel was supported by the Deutsche Forschungsgemeinschaft (DFG) CRC877 B9 project and the DFG Cluster of Excellence Inflammation of Interfaces. J.M. Leyva-Castillo was supported by a postdoctoral fellowship from Consejo Nacional de Ciencia y Tecnologia (CONACYT, Mexico). NR 71 TC 0 Z9 0 U1 3 U2 3 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD SEP PY 2016 VL 213 IS 10 BP 2147 EP 2166 DI 10.1084/jem.20150376 PG 20 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA DX1ED UT WOS:000384107700015 PM 27551155 ER PT J AU Kong, DP Shen, YJ Liu, GZ Zuo, SK Ji, Y Lu, AK Nakamura, M Lazarus, M Stratakis, CA Breyer, RM Yu, Y AF Kong, Deping Shen, Yujun Liu, Guizhu Zuo, Shengkai Ji, Yong Lu, Ankang Nakamura, Masataka Lazarus, Michael Stratakis, Constantine A. Breyer, Richard M. Yu, Ying TI PKA regulatory II alpha subunit is essential for PGD(2)-mediated resolution of inflammation SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID PROTEIN-KINASE-A; ACUTE MYOCARDIAL-INFARCTION; MACROPHAGE ACTIVATION; IN-VIVO; INTERFERON; CELLS; PHOSPHORYLATION; PROSTAGLANDINS; POLARIZATION; MECHANISMS AB The kinetic participation of macrophages is critical for inflammatory resolution and recovery from myocardial infarction (MI), particularly with respect to the transition from the M1 to the M2 phenotype; however, the underlying mechanisms are poorly understood. In this study, we found that the deletion of prostaglandin (PG) D-2 receptor subtype 1 (DP1) in macrophages retarded M2 polarization, antiinflammatory cytokine production, and resolution in different inflammatory models, including the MI model. DP1 deletion up-regulated proinflammatory genes expression via JAK2/STAT1 signaling in macrophages, whereas its activation facilitated binding of the separated PKA regulatory IIa subunit (PRK AR2A) to the transmembrane domain of IFN-gamma receptor, suppressed JAK2-STAT1 axis-mediated M1 polarization, and promoted resolution. PRK AR2A deficiency attenuated DP1 activation-mediated M2 polarization and resolution of inflammation. Collectively, PGD(2)-DP1 axis-induced M2 polarization facilitates resolution of inflammation through the PRK AR2A-mediated suppression of JAK2/STAT1 signaling. These observations indicate that macrophage DP1 activation represents a promising strategy in the management of inflammation- associated diseases, including post-MI healing. C1 [Kong, Deping; Shen, Yujun; Liu, Guizhu; Zuo, Shengkai; Yu, Ying] Univ Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Nutr Sci, Key Lab Food Safety Res,CAS Ctr Excellence Mol Ce, Shanghai 200031, Peoples R China. [Shen, Yujun; Yu, Ying] Tianjin Med Univ, Sch Basic Med Sci, Dept Pharmacol, Tianjin 300070, Peoples R China. [Ji, Yong] Nanjing Med Univ, Sch Pharm, Key Lab Cardiovasc Dis & Mol Intervent, Nanjing 211166, Jiangsu, Peoples R China. [Lu, Ankang] Shanghai Jiao Tong Univ, Ruijin Hosp, Dept Cardiol, Sch Med, Shanghai 200025, Peoples R China. [Nakamura, Masataka] Tokyo Med & Dent Univ, Human Gene Sci Ctr, Bunkyo Ku, Tokyo 1138510, Japan. [Lazarus, Michael] Univ Tsukuba, Int Inst Integrat Sleep Med, Tsukuba, Ibaraki 3058575, Japan. [Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Endocrinol Interinst Training Program, NIH, Bethesda, MD 20892 USA. [Breyer, Richard M.] Tennessee Valley Hlth Author, Dept Vet Affairs, Nashville, TN 37212 USA. [Breyer, Richard M.] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN 37232 USA. RP Yu, Y (reprint author), Univ Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Nutr Sci, Key Lab Food Safety Res,CAS Ctr Excellence Mol Ce, Shanghai 200031, Peoples R China.; Yu, Y (reprint author), Tianjin Med Univ, Sch Basic Med Sci, Dept Pharmacol, Tianjin 300070, Peoples R China. EM yuying@sibs.ac.cn OI Breyer, Richard/0000-0001-5828-4403 FU Chinese Ministry of Science and Technology [2012CB945100]; National Natural Science Foundation of China [81525004, 91439204, 81030004, 31200860]; Science and Technology Commission of Shanghai Municipality key program [14JC1407400, 15140902000]; Science and Technology Service Network Initiative [KFJ-EW-STS-099]; postdoctoral fellowship program of Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences [2012KIP514, 2013KIP312]; National Institutes of Health [GM15431, DK37097]; Department of Veterans Affairs [1BX000616] FX This work was supported by grants from the Chinese Ministry of Science and Technology (2012CB945100), the National Natural Science Foundation of China (81525004, 91439204, 81030004, and 31200860), the Science and Technology Commission of Shanghai Municipality key program (14JC1407400 and 15140902000), the Science and Technology Service Network Initiative (KFJ-EW-STS-099), the postdoctoral fellowship program of Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences (2012KIP514 and 2013KIP312), the National Institutes of Health (GM15431 and DK37097), and a merit award from the Department of Veterans Affairs (1BX000616 to R.M. Breyer). Y. Ji and Y. Yu are fellows at the Jiangsu Collaborative Innovation Center for Cardiovascular Disease Translational Medicine. NR 40 TC 2 Z9 2 U1 3 U2 3 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD SEP PY 2016 VL 213 IS 10 BP 2209 EP 2226 DI 10.1084/jem.20160459 PG 18 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA DX1ED UT WOS:000384107700019 PM 27621415 ER PT J AU Brennan, PF AF Brennan, Patricia Flatley TI Crafting the third century of the National Library of Medicine SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Editorial Material C1 [Brennan, Patricia Flatley] Wisconsin Inst Discovery, Madison, WI 53715 USA. [Brennan, Patricia Flatley] NIH, Natl Lib Med, Bldg 38,8600 Rockville Pike, Bethesda, MD 20894 USA. RP Brennan, PF (reprint author), Wisconsin Inst Discovery, Madison, WI 53715 USA.; Brennan, PF (reprint author), NIH, Natl Lib Med, Bldg 38,8600 Rockville Pike, Bethesda, MD 20894 USA. EM pbrennan@discovery.wisc.edu 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 1067-5027 EI 1527-974X J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD SEP PY 2016 VL 23 IS 5 BP 858 EP 858 DI 10.1093/jamia/ocw122 PG 1 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA DW6SU UT WOS:000383782300002 PM 27562747 ER PT J AU Lin, CH Fann, YC Liou, DM AF Lin, Ching-Heng Fann, Yang-Cheng Liou, Der-Ming TI An exploratory study using an openEHR 2-level modeling approach to represent common data elements SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article DE common data element; openEHR archetype; modeling approach ID ELECTRONIC HEALTH RECORDS; DOMAIN KNOWLEDGE GOVERNANCE; CLINICAL-RESEARCH; DATA STANDARDS; SNOMED-CT; SEMANTIC INTEROPERABILITY; METADATA REGISTRIES; ARCHETYPES; CARE; INTEGRATION AB Background and Objective In order to facilitate clinical research across multiple institutions, data harmonization is a critical requirement. Common data elements (CDEs) collect data uniformly, allowing data interoperability between research studies. However, structural limitations have hindered the application of CDEs. An advanced modeling structure is needed to rectify such limitations. The openEHR 2-level modeling approach has been widely implemented in the medical informatics domain. The aim of our study is to explore the feasibility of applying an openEHR approach to model the CDE concept. Materials and Methods Using the National Institute of Neurological Disorders and Stroke General CDEs as material, we developed a semiautomatic mapping tool to assist domain experts mapping CDEs to existing openEHR archetypes in order to evaluate their coverage and to allow further analysis. In addition, we modeled a set of CDEs using the openEHR approach to evaluate the ability of archetypes to structurally represent any type of CDE content. Results Among 184 CDEs, 28% (51) of the archetypes could be directly used to represent CDEs, while 53% (98) of the archetypes required further development (extension or specialization). A comprehensive comparison between CDEs and openEHR archetypes was conducted based on the lessons learnt from the practical modeling. Discussion CDEs and archetypes have dissimilar modeling approaches, but the data structure of both models are essentially similar. This study proposes to develop a comprehensive structure to model CDE concepts instead of improving the structure of CED. Conclusion The findings from this research show that the openEHR archetype has structural coverage for the CDEs, namely the openEHR archetype is able to represent the CDEs and meet the functional expectations of the CDEs. This work can be used as a reference when improving CDE structure using an advanced modeling approach. C1 [Lin, Ching-Heng; Liou, Der-Ming] Natl Yang Ming Univ, Inst Biomed Informat, Taipei, Taiwan. [Fann, Yang-Cheng] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Liou, DM (reprint author), 155,Sec 2,Li Nong St, Taipei 112, Taiwan. EM dmliou@ym.edu.tw FU Taiwan Ministry of Science and Technology (MOST) [MOST 103-2221-E-010-004] FX This work was supported by the Taiwan Ministry of Science and Technology (MOST) grant no. MOST 103-2221-E-010-004. NR 61 TC 0 Z9 0 U1 5 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1067-5027 EI 1527-974X J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD SEP PY 2016 VL 23 IS 5 BP 956 EP 967 DI 10.1093/jamia/ocv137 PG 12 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA DW6SU UT WOS:000383782300015 PM 26911823 ER PT J AU Abi-Jaoudeh, N Fisher, T Jacobus, J Skopec, M Radaelli, A Van der Born, IM Wesley, R Wood, BJ AF Abi-Jaoudeh, Nadine Fisher, Teresa Jacobus, John Skopec, Marlene Radaelli, Alessandro Van der Born, Imramsjah Martijn Wesley, Robert Wood, Bradford J. TI Prospective Randomized Trial for Image Guided Biopsy Using Cone-Beam CT Navigation Compared with Conventional CT SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article ID TRANSTHORACIC NEEDLE-BIOPSY; LUNG NODULES; GUIDANCE; PATIENT; FUSION; FLUOROSCOPY; EXPERIENCE; THERAPY; MASSES; PANEL AB Purpose: To compare cone-beam computed tomography (CT) navigation vs conventional CT image guidance during biopsies. Materials and Methods: Patients scheduled for image-guided biopsies were prospectively and randomly assigned to conventional CT guidance vs cone-beam CT navigation. Radiation dose, accuracy of final needle position, rate of histopathologic diagnosis, and number of needle repositions to reach the target (defined as pullback to adjust position) were compared. Results: A total of 58 patients (mean age, 57 y; 62.1% men) were randomized: 29 patients underwent 33 biopsies with CT guidance and 29 patients with 33 lesions underwent biopsy with cone-beam CT navigation. The average body mass index (BMI) was similar between groups, at 28.8 kg/m(2) 6.55 (P = .18). There was no difference between groups in terms of patient and lesion characteristics (eg, size, depth). The average lesion size was 29.1 +/- 12.7 mm for CT group vs 32.1 mm +/- 16.8 mm for cone beam CT group (P < 0.59). Location of lesions was equally divided between the 2 groups, 20 lung lesions, 18 renal lesions and 20 other abdominal lesions. Mean number of needle repositions in the cone-beam CT group was 0.3 +/- 0.5, compared with 1.9 +/- 2.3 with conventional CT (P < .001). The average skin entry dose was 29% lower with cone-beam CT than with conventional CT (P < .04 accounting for BMI). The average estimated effective dose for the planning scan from phantom data was 49% lower with cone-beam CT vs conventional CT (P = .018). Accuracy, defined as the difference between planned and final needle positions, was 4.9 mm +/- 4.1 for the cone-beam CT group, compared with 12.2 mm +/- 8.1 for conventional CT (P < .001). Histopathologic diagnosis rates were similar between groups, at 90.9% for conventional CT and 93.9% for cone-beam CT (P = .67). Conclusions: Cone-beam CT navigation for biopsies improved targeting accuracy with fewer needle repositions, lower skin entry dose, and lower effective dose for planning scan, and a comparable histopathologic diagnosis rate. C1 [Abi-Jaoudeh, Nadine; Skopec, Marlene; Wood, Bradford J.] NIH, Dept Radiol & Imaging Sci, Bldg 10, Bethesda, MD 20892 USA. [Fisher, Teresa; Jacobus, John] NIH, Div Radiat Safety, Off Res Serv, Bldg 10, Bethesda, MD 20892 USA. [Wesley, Robert] NIH, Off Deputy Director, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Radaelli, Alessandro; Van der Born, Imramsjah Martijn] Philips Healthcare, iXR Div, Best, Netherlands. RP Abi-Jaoudeh, N (reprint author), Univ Calif Irvine, Dept Radiol Sci, Bldg 1,Room 115,Route 140,101 City Dr S, Orange, CA 92868 USA. EM nadine@uci.edu FU Intramural Research Program of the NIH Grant [ZID BC 011242-05]; NIH [ZIA CL040011-06]; Philips [ZIA CL040011-06]; National Institutes of Health (NIH) Center for Interventional Oncology FX This work is supported in part by the National Institutes of Health (NIH) Center for Interventional Oncology, Intramural Research Program of the NIH Grant ZID BC 011242-05, and collaborative research and development agreements between NIH and Philips (Intramural Grant ZIA CL040011-06). NR 26 TC 1 Z9 1 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1051-0443 EI 1535-7732 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD SEP PY 2016 VL 27 IS 9 BP 1342 EP 1349 DI 10.1016/j.jvir.2016.05.034 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA DW1OC UT WOS:000383411500011 PM 27461586 ER PT J AU Matlawska-Wasowska, K Kang, H Devidas, M Wen, J Harvey, RC Nickl, CK Ness, SA Rusch, M Li, Y Onozawa, M Martinez, C Wood, BL Asselin, BL Chen, IM Roberts, KG Baruchel, A Soulier, J Dombret, H Zhang, J Larson, RS Raetz, EA Carroll, WL Winick, NJ Aplan, PD Loh, ML Mullighan, CG Hunger, SP Heerema, NA Carroll, AJ Dunsmore, KP Winter, SS AF Matlawska-Wasowska, K. Kang, H. Devidas, M. Wen, J. Harvey, R. C. Nickl, C. K. Ness, S. A. Rusch, M. Li, Y. Onozawa, M. Martinez, C. Wood, B. L. Asselin, B. L. Chen, I-M Roberts, K. G. Baruchel, A. Soulier, J. Dombret, H. Zhang, J. Larson, R. S. Raetz, E. A. Carroll, W. L. Winick, N. J. Aplan, P. D. Loh, M. L. Mullighan, C. G. Hunger, S. P. Heerema, N. A. Carroll, A. J. Dunsmore, K. P. Winter, S. S. TI MLL rearrangements impact outcome in HOXA-deregulated T-lineage acute lymphoblastic leukemia: a Children's Oncology Group Study SO LEUKEMIA LA English DT Letter ID CELL; STAGE; RISK C1 [Matlawska-Wasowska, K.; Nickl, C. K.; Martinez, C.; Winter, S. S.] Univ New Mexico, Hlth Sci Ctr, Div Hematol Oncol, Dept Pediat, Albuquerque, NM 87131 USA. [Matlawska-Wasowska, K.; Nickl, C. K.; Martinez, C.; Winter, S. S.] Univ New Mexico, Hlth Sci Ctr, Div Pediat Res, Dept Pediat, Albuquerque, NM 87131 USA. [Kang, H.] Univ New Mexico, Dept Internal Med, Div Epidemiol Biostat & Prevent Med, Albuquerque, NM 87131 USA. [Devidas, M.] Univ Florida, Coll Med, Dept Biostat, Gainesville, FL USA. [Wen, J.; Roberts, K. G.; Mullighan, C. G.] St Jude Childrens Res Hosp, Dept Pathol, 332 N Lauderdale St, Memphis, TN 38105 USA. [Harvey, R. C.; Chen, I-M] Univ New Mexico, Dept Pathol, Hlth Sci Ctr, Albuquerque, NM 87131 USA. [Ness, S. A.] Univ New Mexico, Sect Mol Med, Hlth Sci Ctr, Dept Internal Med, Albuquerque, NM 87131 USA. [Rusch, M.; Li, Y.; Zhang, J.] St Jude Childrens Res Hosp, Dept Computat Biol & Bioinformat, 332 N Lauderdale St, Memphis, TN 38105 USA. [Onozawa, M.; Aplan, P. D.] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. [Onozawa, M.] Hokkaido Univ, Ctr Med Educ, Dept Hematol, Sapporo, Hokkaido, Japan. [Wood, B. L.] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. [Asselin, B. L.] Univ Rochester, Med Ctr, Dept Pediat, Rochester, NY 14642 USA. [Asselin, B. L.] Univ Rochester, Sch Med, Rochester, NY 14642 USA. [Baruchel, A.; Soulier, J.; Dombret, H.] Hosp St Louis, Inst Univ Hematol, Hematol Lab, Paris, France. [Larson, R. S.] Univ New Mexico, Dept Pathol, Hlth Sci Ctr, UNM Clin & Translat Sci Ctr, Albuquerque, NM 87131 USA. [Raetz, E. A.] Univ Utah, Dept Pediat, Huntsman Canc Inst, Salt Lake City, UT USA. [Carroll, W. L.] NYU, Laura & Isaac Perlmutter Canc Ctr, Langone Med Ctr, New York, NY USA. [Winick, N. J.] Univ Texas Southwestern Med Ctr, Dept Pediat, Dallas, TX USA. [Loh, M. L.] Univ Calif San Francisco, Dept Pediat, Benioff Childrens, San Francisco, CA USA. [Loh, M. L.] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Hunger, S. P.] Univ Penn, Div Oncol, Philadelphia, PA 19104 USA. [Hunger, S. P.] Univ Penn, Childrens Hosp Philadelphia, Ctr Childhood Canc Res, Philadelphia, PA 19104 USA. [Hunger, S. P.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Heerema, N. A.] Ohio State Univ, Dept Pathol, Wexner Med Ctr, Columbus, OH 43210 USA. [Carroll, A. J.] Univ Alabama Birmingham, Dept Genet, Birmingham, AL USA. [Dunsmore, K. P.] Univ Virginia, Dept Pediat, Charlottesville, VA USA. RP Matlawska-Wasowska, K (reprint author), Univ New Mexico, Hlth Sci Ctr, Div Hematol Oncol, Dept Pediat, Albuquerque, NM 87131 USA.; Matlawska-Wasowska, K (reprint author), Univ New Mexico, Hlth Sci Ctr, Div Pediat Res, Dept Pediat, Albuquerque, NM 87131 USA. EM kmatlawska-wasowska@salud.unm.edu FU NCATS NIH HHS [KL2 TR000089, UL1 TR001449]; NCI NIH HHS [P30 CA118100, R01 CA114589, R01 CA170250, U10 CA098413, U10 CA098543, U10 CA180886, U10 CA180899, U24 CA114766]; NCRR NIH HHS [KL2 RR031976]; NHGRI NIH HHS [R25 HG007630]; NIGMS NIH HHS [P50 GM115279] NR 15 TC 0 Z9 0 U1 4 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD SEP PY 2016 VL 30 IS 9 BP 1909 EP 1912 DI 10.1038/leu.2016.60 PG 4 WC Oncology; Hematology SC Oncology; Hematology GA DW6UH UT WOS:000383786400008 PM 26952838 ER PT J AU Suen, AA Jefferson, WN Wood, CE Padilla-Banks, E Bae-Jump, VL Williams, CJ AF Suen, Alisa A. Jefferson, Wendy N. Wood, Charles E. Padilla-Banks, Elizabeth Bae-Jump, Victoria L. Williams, Carmen J. TI SIX1 Oncoprotein as a Biomarker in a Model of Hormonal Carcinogenesis and in Human Endometrial Cancer SO MOLECULAR CANCER RESEARCH LA English DT Article ID EPITHELIAL-MESENCHYMAL TRANSITION; BREAST-CANCER; UTERINE ADENOCARCINOMA; HOMEOPROTEIN SIX1; CERVICAL-CANCER; INFANT FORMULA; FEEDBACK LOOP; MOUSE UTERUS; EXPRESSION; EXPOSURE AB The oncofetal protein sine oculis-related homeobox 1 (SIX1) is a developmental transcription factor associated with carcinogenesis in several human cancer types but has not been investigated in human endometrial cancer. In a model of hormonal carcinogenesis, mice neonatally exposed to the soy phytoestrogen genistein (GEN) or the synthetic estrogen diethylstilbestrol (DES) develop endometrial cancer as adults. Previously, we demonstrated that SIX1 becomes aberrantly expressed in the uteri of these mice. Here, we used this mouse model to investigate the role of SIX1 expression in endometrial carcinoma development and used human tissue microarrays to explore the utility of SIX1 as a biomarker in human endometrial cancer. In mice neonatally exposed to GEN or DES, the Six1 transcript level increased dramatically over time in uteri at 6, 12, and 18 months of age and was associated with development of endometrial carcinoma. SIX1 protein localized within abnormal basal cells and all atypical hyperplastic and neoplastic lesions. These findings indicate that developmental estrogenic chemical exposure induces persistent endometrial SIX1 expression that is strongly associated with abnormal cell differentiation and cancer development. In human endometrial tissue specimens, SIX1 was not present in normal endometrium but was expressed in a subset of endometrial cancers in patients who were also more likely to have late-stage disease. These findings identify SIX1 as a disease biomarker in a model of hormonal carcinogenesis and suggest that SIX1 plays a role in endometrial cancer development in both mice and women. (C) 2016 AACR. C1 [Suen, Alisa A.; Jefferson, Wendy N.; Padilla-Banks, Elizabeth; Williams, Carmen J.] NIEHS, Reprod & Dev Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Suen, Alisa A.; Williams, Carmen J.] Univ N Carolina, Curriculum Toxicol, Chapel Hill, NC USA. [Wood, Charles E.] US EPA, Off Res & Dev, Res Triangle Pk, NC 27711 USA. [Bae-Jump, Victoria L.] Univ N Carolina, Div Gynecol Oncol, CB 7572,Phys Off Bldg,Rm B105, Chapel Hill, NC 27599 USA. [Bae-Jump, Victoria L.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. RP Bae-Jump, VL (reprint author), Univ N Carolina, Div Gynecol Oncol, CB 7572,Phys Off Bldg,Rm B105, Chapel Hill, NC 27599 USA.; Williams, CJ (reprint author), NIEHS, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM Victoria.Bae-Jump@unchealth.unc.edu; williamsc5@niehs.nih.gov FU Intramural Research Program of the NIH, National Institutes of Environmental Health Sciences [1ZIAES102985]; Steelman Fund; NIH/NCI K23 Mentored Patient-Oriented Research Career Development [1K23CA143154-01A1]; UNC Environmental Health Sciences Toxicology Training Grant [T32-ES007126] FX This work was supported by the Intramural Research Program of the NIH, National Institutes of Environmental Health Sciences, 1ZIAES102985 (to C.J. Williams), the Steelman Fund (to V.L. Bae-Jump), and the NIH/NCI K23 Mentored Patient-Oriented Research Career Development Grant, 1K23CA143154-01A1 (to V.L. Bae-Jump). A.A. Suen was supported in part by the UNC Environmental Health Sciences Toxicology Training Grant, T32-ES007126. NR 51 TC 1 Z9 1 U1 3 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1541-7786 EI 1557-3125 J9 MOL CANCER RES JI Mol. Cancer Res. PD SEP PY 2016 VL 14 IS 9 BP 849 EP 858 DI 10.1158/1541-7786.MCR-16-0084 PG 10 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DW0UY UT WOS:000383359700009 PM 27259717 ER PT J AU Haubenberger, D Abbruzzese, G Bain, PG Bajaj, N Benito-Leon, J Bhatia, KP Deuschl, G Forjaz, MJ Hallett, M Louis, ED Lyons, KE Mestre, TA Raethjen, J Stamelou, M Tan, EK Testa, CM Elble, RJ AF Haubenberger, Dietrich Abbruzzese, Giovanni Bain, Peter G. Bajaj, Nin Benito-Leon, Julian Bhatia, Kailash P. Deuschl, Guenther Joao Forjaz, Maria Hallett, Mark Louis, Elan D. Lyons, Kelly E. Mestre, Tiago A. Raethjen, Jan Stamelou, Maria Tan, Eng-King Testa, Claudia M. Elble, Rodger J. TI Transducer-based evaluation of tremor SO MOVEMENT DISORDERS LA English DT Review DE tremor; transducers; accelerometry; electromyography; reproducibility of results ID MINIMUM DETECTABLE CHANGE; PLACEBO-CONTROLLED TRIAL; DEEP BRAIN-STIMULATION; ESSENTIAL VOICE TREMOR; TOXIN TYPE-A; PARKINSONS-DISEASE; DOUBLE-BLIND; BOTULINUM TOXIN; PSYCHOGENIC TREMOR; DIGITIZING TABLET AB The International Parkinson and Movement Disorder Society established a task force on tremor that reviewed the use of transducer-based measures in the quantification and characterization of tremor. Studies of accelerometry, electromyography, activity monitoring, gyroscopy, digitizing tablet-based measures, vocal acoustic analysis, and several other transducer-based methods were identified by searching . The availability, use, acceptability, reliability, validity, and responsiveness were reviewed for each measure using the following criteria: (1) used in the assessment of tremor; (2) used in published studies by people other than the developers; and (3) adequate clinimetric testing. Accelerometry, gyroscopy, electromyography, and digitizing tablet-based measures fulfilled all three criteria. Compared to rating scales, transducers are far more sensitive to changes in tremor amplitude and frequency, but they do not appear to be more capable of detecting a change that exceeds random variability in tremor amplitude (minimum detectable change). The use of transducer-based measures requires careful attention to their limitations and validity in a particular clinical or research setting. (c) 2016 International Parkinson and Movement Disorder Society C1 [Haubenberger, Dietrich] NINDS, Clin Trials Unit, Off Clin Director, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Abbruzzese, Giovanni] DINOGMI Univ Genoa, Genoa, Italy. [Bain, Peter G.] Imperial Coll London, Charing Cross Hosp, Dept Neurol, London, England. [Bajaj, Nin] Nottingham Univ Hosp NHS Trust, Dept Neurol, Nottingham, England. [Benito-Leon, Julian] Univ Hosp 12 Octubre, Dept Neurol, Madrid, Spain. [Benito-Leon, Julian] Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain. [Benito-Leon, Julian] Univ Complutense, Dept Med, Madrid, Spain. [Bhatia, Kailash P.] UCL, Inst Neurol, Sobell Dept Movement Neurosci, Queen Sq, London, England. [Deuschl, Guenther; Raethjen, Jan] Univ Kiel, Dept Neurol, Kiel, Germany. [Joao Forjaz, Maria] Carlos III Inst Hlth, Natl Sch Publ Hlth, Madrid, Spain. [Joao Forjaz, Maria] Carlos III Inst Hlth, Red Invest Serv Sanitarios & Enfermedades Cron RE, Madrid, Spain. [Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Louis, Elan D.] Yale Sch Med, Dept Neurol, New Haven, CT USA. [Louis, Elan D.] Yale Sch Med, Dept Chron Dis Epidemiol, New Haven, CT USA. [Louis, Elan D.] Yale Univ, Yale Sch Publ Hlth, New Haven, CT USA. [Lyons, Kelly E.] Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. [Mestre, Tiago A.] Univ Ottawa, Parkinsons Dis & Movement Disorders Ctr, Ottawa Brain & Mind Res Inst, Div Neurol,Dept Med,Ottawa Hosp,Res Inst, Ottawa, ON, Canada. [Stamelou, Maria] Univ Athens, Dept Dept, GR-10679 Athens, Greece. [Stamelou, Maria] Philipps Univ, Dept Neurol, Marburg, Germany. [Tan, Eng-King] Singapore Gen Hosp, Duke NUS Med Sch, Dept Neurol, Natl Inst Neurosci, SGH Campus, Singapore, Singapore. Virginia Commonwealth Univ, Dept Neurol, Richmond, VA USA. [Testa, Claudia M.] Virginia Commonwealth Univ, Parkinsons & Movement Disorders Ctr, Richmond, VA USA. [Elble, Rodger J.] Southern Illinois Univ, Sch Med, Dept Neurol, Springfield, IL USA. RP Haubenberger, D (reprint author), NINDS, Intramural Res Program, NIH, 9000 Rockville Pike,Bldg 10,Room 6-5700, Bethesda, MD 20892 USA. EM dietrich.haubenberger@nih.gov OI Forjaz, Maria Joao/0000-0003-3935-962X FU International Parkinson and Movement Disorders Society FX The International Parkinson and Movement Disorders Society. NR 101 TC 2 Z9 2 U1 5 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 EI 1531-8257 J9 MOVEMENT DISORD JI Mov. Disord. PD SEP PY 2016 VL 31 IS 9 BP 1327 EP 1336 DI 10.1002/mds.26671 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA DW6PO UT WOS:000383773600050 PM 27273470 ER PT J AU Norris, S Perlmutter, JS Wright, L Rosen, AR Comella, C Hallett, M Mink, J Hieshetter, J Kuman, K Jinnah, HA AF Norris, S. Perlmutter, J. S. Wright, L. Rosen, A. R. Comella, C. Hallett, M. Mink, J. Hieshetter, J. Kuman, K. Jinnah, H. A. CA Dystonia Coalition TI The Dystonia Coalition Natural History Project: Seven Years of Progress SO MOVEMENT DISORDERS LA English DT Meeting Abstract C1 [Norris, S.; Perlmutter, J. S.; Wright, L.] Washington Univ, Dept Neurol, St Louis, MO USA. [Rosen, A. R.; Jinnah, H. A.] Emory Univ, Dept Neurol, Atlanta, GA 30322 USA. [Comella, C.] Rush Univ, Dept Neurol Sci, Chicago, IL 60612 USA. [Hallett, M.] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Mink, J.] Univ Rochester, Dept Neurol, Rochester, NY USA. [Hieshetter, J.] Dystonia Med Res Fdn, Chicago, IL USA. [Kuman, K.] Natl Spasmod Dysphonia Assoc, Itasca, IL 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 0885-3185 EI 1531-8257 J9 MOVEMENT DISORD JI Mov. Disord. PD SEP PY 2016 VL 31 IS 9 BP E4 EP E4 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA DW6PO UT WOS:000383773600011 ER PT J AU Fliedner, SMJ Shankavaram, U Marzouca, G Elkahloun, A Jochmanova, I Daerr, R Linehan, WM Timmers, H Tischler, AS Papaspyrou, K Brieger, J de Krijger, R Brezaoo, J Eisenhofer, G Zhuang, ZP Lehnert, H Pacak, K AF Fliedner, Stephanie M. J. Shankavaram, Uma Marzouca, Geena Elkahloun, Abdel Jochmanova, Ivana Daerr, Roland Linehan, W. Marston Timmers, Henri Tischler, Arthur S. Papaspyrou, Konstantinos Brieger, Juergen de Krijger, Ronald Brezaoo, Jan Eisenhofer, Graeme Zhuang, Zhengping Lehnert, Hendrik Pacak, Karel TI Hypoxia-Inducible Factor 2 alpha Mutation-Related Paragangliomas Classify as Discrete Pseudohypoxic Subcluster SO NEOPLASIA LA English DT Article ID HIPPEL-LINDAU-SYNDROME; OF-FUNCTION MUTATIONS; SUCCINATE-DEHYDROGENASE; HIF2A MUTATIONS; OXIDATIVE-PHOSPHORYLATION; NEUROENDOCRINE TUMORS; PHENOTYPIC FEATURES; PHEOCHROMOCYTOMAS; POLYCYTHEMIA; EXPRESSION AB Recently, activating mutations of the hypoxia-inducible factor 2 alpha gene ( HIF2A/EPAS1) have been recognized to predispose to multiple paragangliomas ( PGLs) and duodenal somatostatinomas associated with polycythemia, and ocular abnormalities. Previously, mutations in the SDHA/B/C/D, SDHAF2, VHL, FH, PHD1, and PHD2 genes have been associated with HIF activation and the development of pseudohypoxic ( cluster-1) PGLs. These tumors overlap in terms of tumor location, syndromic presentation, and noradrenergic phenotype to a certain extent. However, they also differ especially by clinical outcome and by presence of other tumors or abnormalities. In the present study, we aimed to establish additional molecular differences between HIF2A and non-HIF2A pseudohypoxic PGLs. RNA expression patterns of HIF2A PGLs ( n = 6) from 2 patients were compared with normal adrenal medullas ( n = 8) and other hereditary pseudohypoxic PGLs ( VHL: n = 13, SDHB: n = 15, and SDHD: n = 14). Unsupervised hierarchical clustering showed that HIF2A PGLs made up a separate cluster from other pseudohypoxic PGLs. Significance analysis of microarray yielded 875 differentially expressed genes between HIF2A and other pseudohypoxic PGLs after normalization to adrenal medulla ( false discovery rate 0.01). Prediction analysis of microarray allowed correct classification of all HIF2A samples based on as little as three genes ( TRHDE, LRRC63, IGSF10; error rate: 0.02). Genes with the highest expression difference between normal medulla and HIF2A PGLs were selected for confirmatory quantitative reverse transcriptase polymerase chain reaction. In conclusion, HIF2A PGLs show a characteristic expression signature that separates them from non-HIF2A pseudohypoxic PGLs. Unexpectedly, the most significantly differentially expressed genes have not been previously described as HIF target genes. C1 [Fliedner, Stephanie M. J.; Lehnert, Hendrik] Univ Med Ctr Schleswig Holstein, Dept Med 1, Campus Lubeck, Lubeck, Germany. [Fliedner, Stephanie M. J.; Marzouca, Geena; Jochmanova, Ivana; Daerr, Roland; Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Med Neuroendocrinol, NIH, 10 Ctr Dr,Bldg 10 CRC,Rm 1E-3140, Bethesda, MD 20814 USA. [Shankavaram, Uma] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Elkahloun, Abdel] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [Jochmanova, Ivana] PJ Safarik Univ Kosice, Dept Internal Med 1, Fac Med, Kosice, Slovakia. [Linehan, W. Marston] NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Timmers, Henri] Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, Nijmegen, Netherlands. [Tischler, Arthur S.] Tufts Med Ctr, Boston, MA USA. [Papaspyrou, Konstantinos] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Dept Otorhinolaryngol Head & Neck Surg, Mainz, Germany. [Brieger, Juergen] Erasmus MC, Josephine Nefkens Inst, Dept Pathol, Univ Med Ctr, Rotterdam, Netherlands. [de Krijger, Ronald] Reinier Graaf Hosp, Dept Pathol, Delft, Netherlands. [de Krijger, Ronald] Comenius Univ, Dept Urol, Bratislava, Slovakia. [Eisenhofer, Graeme] Tech Univ Dresden, Med Fac Carl Gustav Carus, Univ Hosp Carl Gustav Carus, Inst Clin Chem,Lab Med, Dresden, Germany. [Eisenhofer, Graeme] Tech Univ Dresden, Med Fac Carl Gustav Carus, Univ Hosp Carl Gustav Carus, Dept Med, Dresden, Germany. [Zhuang, Zhengping] NINDS, Surg Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Fliedner, SMJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Med Neuroendocrinol, NIH, 10 Ctr Dr,Bldg 10 CRC,Rm 1E-3140, Bethesda, MD 20814 USA.; Fliedner, SMJ (reprint author), Univ Med Ctr Schleswig Holstein, Dept Med 1, Res Lab Neuroendocrine Oncol, Campus Lubeck,Ratzeburger Allee 160, D-23538 Lubeck, Germany. EM stephanie.fliedner@uksh.de FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA FX This study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA. NR 58 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 1476-5586 J9 NEOPLASIA JI Neoplasia PD SEP PY 2016 VL 18 IS 9 BP 567 EP 576 DI 10.1016/j.neo.2016.07.008 PG 10 WC Oncology SC Oncology GA DW9ZH UT WOS:000384020800005 PM 27659016 ER PT J AU Marcum, CS Lin, JL Koehly, L AF Marcum, Christopher Steven Lin, Jielu Koehly, Laura TI Growing-up and coming-out: Are 4-cycles present in adult hetero/gay hook-ups? SO NETWORK SCIENCE LA English DT Article ID EPIDEMIC; NETWORKS C1 [Marcum, Christopher Steven; Lin, Jielu; Koehly, Laura] NHGRI, Social Network Methods Sect, Social Behav Res Branch, NIH, Bethesda, MD 20892 USA. RP Marcum, CS (reprint author), NHGRI, Social Network Methods Sect, Social Behav Res Branch, NIH, Bethesda, MD 20892 USA. EM chris.marcum@nih.gov; lin.jielu@nih.gov; koehlyl@mail.nih.gov NR 9 TC 0 Z9 0 U1 5 U2 5 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 2050-1242 EI 2050-1250 J9 NETW SCI JI Netw. Sci. PD SEP PY 2016 VL 4 IS 3 BP 400 EP 405 DI 10.1017/nws.2016.3 PG 6 WC Social Sciences, Interdisciplinary SC Social Sciences - Other Topics GA DW8DY UT WOS:000383885200007 ER PT J AU LeBlanc, AK Mazcko, C Brown, DE Koehler, JW Miller, AD Miller, CR Bentley, RT Packer, RA Breen, M Boudreau, CE Levine, JM Simpson, RM Halsey, C Kisseberth, W Rossmeisl, JH Dickinson, PJ Fan, TM Corps, K Aldape, K Puduvalli, V Pluhar, GE Gilbert, MR AF LeBlanc, Amy K. Mazcko, Christina Brown, Diane E. Koehler, Jennifer W. Miller, Andrew D. Miller, C. Ryan Bentley, R. Timothy Packer, Rebecca A. Breen, Matthew Boudreau, C. Elizabeth Levine, Jonathan M. Simpson, R. Mark Halsey, Charles Kisseberth, William Rossmeisl, John H., Jr. Dickinson, Peter J. Fan, Timothy M. Corps, Kara Aldape, Kenneth Puduvalli, Vinay Pluhar, G. Elizabeth Gilbert, Mark R. TI Creation of an NCI comparative brain tumor consortium: informing the translation of new knowledge from canine to human brain tumor patients SO NEURO-ONCOLOGY LA English DT Article DE comparative oncology; glioma; translational research ID CONVECTION-ENHANCED DELIVERY; CENTRAL-NERVOUS-SYSTEM; INTRACRANIAL GLIOBLASTOMA; COMPARATIVE ONCOLOGY; DRUG DEVELOPMENT; HUMAN CANCER; PDGFR-ALPHA; DOGS; MODELS; BIOPSY AB On September 14-15, 2015, a meeting of clinicians and investigators in the fields of veterinary and human neuro-oncology, clinical trials, neuropathology, and drug development was convened at the National Institutes of Health campus in Bethesda, Maryland. This meeting served as the inaugural event launching a new consortium focused on improving the knowledge, development of, and access to naturally occurring canine brain cancer, specifically glioma, as a model for human disease. Within the meeting, a SWOT (strengths, weaknesses, opportunities, and threats) assessment was undertaken to critically evaluate the role that naturally occurring canine brain tumors could have in advancing this aspect of comparative oncology aimed at improving outcomes for dogs and human beings. A summary of this meeting and subsequent discussion are provided to inform the scientific and clinical community of the potential for this initiative. Canine and human comparisons represent an unprecedented opportunity to complement conventional brain tumor research paradigms, addressing a devastating disease for which innovative diagnostic and treatment strategies are clearly needed. C1 [LeBlanc, Amy K.; Mazcko, Christina] NCI, Comparat Oncol Program, Ctr Canc Res, Bethesda, MD 20892 USA. [Brown, Diane E.] Amer Kennel Club Canine Hlth Fdn, Raleigh, NC USA. [Koehler, Jennifer W.] Auburn Univ, Coll Vet Med, Dept Pathobiol, Auburn, AL 36849 USA. [Miller, Andrew D.] Cornell Univ, Coll Vet Med, Dept Biomed Sci, Sect Anat Pathol, Ithaca, NY 14853 USA. [Miller, C. Ryan] Univ N Carolina, Sch Med, Dept Pathol & Lab Med, Lineberger Comprehens Canc Ctr, Chapel Hill, NC USA. [Miller, C. Ryan] Univ N Carolina, Sch Med, Dept Neurol, Lineberger Comprehens Canc Ctr, Chapel Hill, NC USA. [Miller, C. Ryan] Univ N Carolina, Sch Med, Neurosci Ctr, Chapel Hill, NC USA. [Bentley, R. Timothy] Purdue Univ, Coll Vet Med, Dept Vet Clin Sci, W Lafayette, IN 47907 USA. [Packer, Rebecca A.] Colorado State Univ, Coll Vet Med & Biomed Sci, Dept Clin Sci, Ft Collins, CO 80523 USA. [Breen, Matthew] North Carolina State Univ, Coll Vet Med, Dept Mol Biomed Sci, Raleigh, NC USA. [Boudreau, C. Elizabeth; Levine, Jonathan M.] Texas A&M Univ, Dept Small Anim Clin Sci, College Stn, TX USA. [Simpson, R. Mark; Halsey, Charles] NCI, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA. [Kisseberth, William] Ohio State Univ, Coll Vet Med, Dept Vet Clin Sci, Columbus, OH 43210 USA. [Rossmeisl, John H., Jr.] Virginia Tech, Virginia Maryland Coll Vet Med, Dept Small Anim Clin Sci, Vet & Comparat Neurooncol Lab, Blacksburg, VA USA. [Dickinson, Peter J.] Univ Calif Davis, Sch Vet Med, Dept Surg & Radiol, Davis, CA 95616 USA. [Fan, Timothy M.] Univ Illinois, Dept Vet Clin Med, Urbana, IL USA. [Corps, Kara; Gilbert, Mark R.] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Corps, Kara; Gilbert, Mark R.] NCI, Bethesda, MD 20892 USA. [Aldape, Kenneth] Univ Hlth Network, Dept Pathol, Toronto Med Discovery Tower, Toronto, ON, Canada. [Puduvalli, Vinay] Ohio State Univ, Coll Med, Dept Neurosurg, Columbus, OH 43210 USA. [Pluhar, G. Elizabeth] Univ Minnesota, Coll Vet Med, Dept Vet Clin Sci, St Paul, MN 55108 USA. [Gilbert, Mark R.] NCI, Neurooncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP LeBlanc, AK (reprint author), NCI, Ctr Canc Res, Bethesda, MD 20892 USA. EM amy.leblanc@nih.gov RI Rossmeisl, Jr., John/Q-7119-2016; Miller, Ryan/B-9365-2008 OI Rossmeisl, Jr., John/0000-0003-1655-7076; Miller, Ryan/0000-0002-0096-8762 NR 65 TC 1 Z9 1 U1 9 U2 9 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD SEP PY 2016 VL 18 IS 9 BP 1209 EP 1218 DI 10.1093/neuonc/now051 PG 10 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA DW9TP UT WOS:000384005900009 PM 27179361 ER PT J AU Cashion, AK Gill, J Hawes, R Henderson, WA Saligan, L AF Cashion, Ann K. Gill, Jessica Hawes, Rebecca Henderson, Wendy A. Saligan, Leorey TI National Institutes of Health Symptom Science Model sheds light on patient symptoms SO NURSING OUTLOOK LA English DT Article DE Biomarkers; Genotype; Model; Phenotype; Research; Symptom science ID CANCER-RELATED FATIGUE; IRRITABLE-BOWEL-SYNDROME; TRAUMATIC BRAIN-INJURY; MILITARY PERSONNEL; RADIATION-THERAPY; UNITED-STATES; DIFFERENTIAL EXPRESSION; DEPRESSION SYMPTOMS; SLEEP DISTURBANCE; PROSTATE-CANCER AB Since the establishment of the nursing profession, identifying and alleviating the subjective symptoms experienced by patients has been at the core of nursing practice. In supporting the scientific foundation for clinical practice, nursing science has maintained a consistent commitment to prevent, manage, and eliminate symptoms. Scientists from the intramural research program at the National Institute of Nursing Research (NINR), a component of the National Institutes of Health, developed a National Institutes of Health Symptom Science Model (NIH-SSM) to guide symptom science research programs engaged in the use of emerging "omic" methods such as the genotyping of symptom phenotypes. The NIH-SSM was developed based on the NINR intramural research program's success in designing and implementing methods for examining identified symptoms or symptom clusters. The NIH-SSM identifies the research process of characterizing symptom phenotypes, identifying and testing biomarkers, and ultimately developing clinical interventions in cancer-related fatigue, gastrointestinal disorders, and traumatic brain injuries. The purpose of this article was to demonstrate how scientists can apply the NIH-SSM, leading the broader scientific community in advancing personalized and precise clinical interventions. C1 [Cashion, Ann K.; Gill, Jessica; Henderson, Wendy A.; Saligan, Leorey] NINR, Div Intramural Res, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. [Hawes, Rebecca] NINR, Div Sci Policy & Publ Liaison, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP Cashion, AK (reprint author), Natl Inst Nursing, Dept Hlth & Human Serv, 3 Ctr Dr,Rm 5E26, Bethesda, MD 20892 USA. EM Ann.cashion@nih.gov OI Henderson, Wendy/0000-0003-3924-7118; Saligan, Leorey/0000-0001-9481-7836 FU Division of Intramural Research, National Institute of Nursing Research, National Institutes of Health [s ZIA-NR000018, ZIA-NR000019, ZIA-NR000027, ZIA-NR000030] FX Drs. A.K.C., J.G., W.A.H., and L.S. gratefully acknowledge the scientific contributions of the individuals in their labs and members of their research teams. This research was supported by the Division of Intramural Research, National Institute of Nursing Research, National Institutes of Health (Grant #s ZIA-NR000018, ZIA-NR000019, ZIA-NR000027, ZIA-NR000030). NR 45 TC 1 Z9 1 U1 7 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0029-6554 EI 1528-3968 J9 NURS OUTLOOK JI Nurs. Outlook PD SEP-OCT PY 2016 VL 64 IS 5 SI SI BP 499 EP 506 DI 10.1016/j.outlook.2016.05.008 PG 8 WC Nursing SC Nursing GA DW6CE UT WOS:000383733200013 PM 27349632 ER PT J AU Sayed, S Moloo, Z Ngugi, A Allidina, A Ndumia, R Mutuiri, A Wasike, R Wahome, C Abdihakin, M Kasmani, R Spears, CD Oigara, R Mwachiro, EB Busarla, SVP Kibor, K Ahmed, A Wawire, J Sherman, O Saleh, M Zujewski, JA Dawsey, SM AF Sayed, Shahin Moloo, Zahir Ngugi, Anthony Allidina, Amyn Ndumia, Rose Mutuiri, Anderson Wasike, Ronald Wahome, Charles Abdihakin, Mohamed Kasmani, Riaz Spears, Carol D. Oigara, Raymond Mwachiro, Elizabeth B. Busarla, Satya V. P. Kibor, Kibet Ahmed, Abdulaziz Wawire, Jonathan Sherman, Omar Saleh, Mansoor Zujewski, Jo Anne Dawsey, Sanford M. TI Breast Camps for Awareness and Early Diagnosis of Breast Cancer in Countries With Limited Resources: A Multidisciplinary Model From Kenya SO ONCOLOGIST LA English DT Article DE Breast cancer awareness and early detection; Kenya; Low; and middle-income countries; Breast cancer camps; Breast cancer diagnosis ID SELF-EXAMINATION; AGE; METHODOLOGY; TRIAL AB Background. Breast cancer is the most common cancer of women in Kenya. There are no national breast cancer early diagnosis programs in Kenya. Objective. The objective was to conduct a pilot breast cancer awareness and diagnosis program at three different types of facilities in Kenya. Methods. This program was conducted at a not-for-profit private hospital, a faith-based public hospital, and a government public referral hospital. Women aged 15 years and older were invited. Demographic, risk factor, knowledge, attitudes, and screening practice data were collected. Breast health information was delivered, and clinical breast examinations (CBEs) were performed. When appropriate, ultrasound imaging, fine-needle aspirate (FNA) diagnoses, core biopsies, and onward referrals were provided. Results. A total of 1,094 women were enrolled in the three breast camps. Of those, 56% knew the symptoms and signs of breast cancer, 44% knew how breast cancer was diagnosed, 37% performed regular breast self-exams, and 7% had a mammogram or breast ultrasound in the past year. Of the 1,094 women enrolled, 246 (23%) had previously noticed a lump in their breast. A total of 157 participants (14%) had abnormal CBEs, of whom 111 had ultrasound exams, 65 had FNAs, and 18 had core biopsies. A total of 14 invasive breast cancers and 1 malignant phyllodes tumor were diagnosed Conclusion. Conducting a multidisciplinary breast camp awareness and early diagnosis program is feasible in different types of health facilities within a low-and middle-income country setting. This can be a model for breast cancer awareness and point-of-care diagnosis in countries with limited resources like Kenya. C1 [Sayed, Shahin; Moloo, Zahir; Ngugi, Anthony; Ndumia, Rose; Mutuiri, Anderson; Wasike, Ronald; Kibor, Kibet; Ahmed, Abdulaziz; Wawire, Jonathan] Aga Khan Univ Hosp, Dept Pathol, 3rd Parklands Ave, Nairobi 00100, Kenya. [Allidina, Amyn] Aga Khan Hosp Dar Es Salaam, Dept Med, Dar Es Salaam, Tanzania. [Sherman, Omar] Aga Khan Hosp Dar Es Salaam, Dept Pathol, Dar Es Salaam, Tanzania. [Wahome, Charles] Aga Khan Hosp Mombasa, Dept Pathol, Mombasa, Kenya. [Abdihakin, Mohamed] Aga Khan Hosp Mombasa, Dept Surg, Mombasa, Kenya. [Kasmani, Riaz] Aga Khan Hosp Mombasa, Dept Med, Mombasa, Kenya. [Spears, Carol D.; Mwachiro, Elizabeth B.] Tenwek Mission Hosp, Dept Surg, Bomet, Kenya. [Spears, Carol D.] Univ Kentucky, Lexington, KY USA. [Oigara, Raymond] Kisii Teaching & Referral Hosp, Dept Surg, Kisii, Kenya. [Busarla, Satya V. P.] Aga Khan Hosp Kisumu, Dept Pathol, Kisumu, Kenya. [Saleh, Mansoor] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Saleh, Mansoor] Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL 35294 USA. [Zujewski, Jo Anne] NCI, Breast Canc Therapeut, Clin Invest Branch, Canc Therapy Evaluat Program, Rockville, MD USA. [Dawsey, Sanford M.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. RP Sayed, S (reprint author), Aga Khan Univ Hosp, Dept Pathol, 3rd Parklands Ave, Nairobi 00100, Kenya. EM shaheen.sayed@aku.edu OI Sayed, Shahin/0000-0002-3472-511X FU Intramural Research Program of the National Cancer Institute; AKUHN; AKHM; TH; KTRH; BCASG of Mombasa; BRECASCO in Mombasa; HRC NGO in Kisii FX We thank the following individuals and institutions for administrative support: the senior leadership team of Aga Khan University Hospital, Nairobi (AKUHN); Mr. Noorali Momin, Dr. Paul Makau, and Dr. Sultana Sherman of Aga Khan Hospital, Mombasa (AKHM); Dr. Chupp and Dr. Spears of Tenwek Mission Hospital (TH); and Dr. Oigara of Kisii Teaching and Referral Hospital (KTRH). We thank the following individuals and institutions for participating in data collection: the nurses, doctors, and support staff of AKUHN, AKHM, TH, and KTRH; Beckie Smith and volunteers from the Breast Cancer Awareness Support Group of Mombasa and the Breast Cancer Survivors of Coast in Mombasa; Rose Oigara; and the HealthCare Rescue Centre nongovernmental organization (NGO) in Kisii. The following institutions provided funding and contributions: AKUHN, AKHM, TH, KTRH, BCASG of Mombasa, BRECASCO in Mombasa, and the HRC NGO in Kisii. The analysis of this study was supported in part by the Intramural Research Program of the National Cancer Institute. The survey tool was designed and developed by Aga Khan Health Board-USA team and the Aga Khan Development Network eHealth Resource Centre for South-Central Asia and East Africa. Data management was provided by Donstefano Muninzwa of AKUHN. NR 20 TC 0 Z9 0 U1 1 U2 1 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1083-7159 EI 1549-490X J9 ONCOLOGIST JI Oncologist PD SEP PY 2016 VL 21 IS 9 BP 1138 EP 1148 DI 10.1634/theoncologist.2016-0004 PG 11 WC Oncology SC Oncology GA DW1HJ UT WOS:000383393600017 PM 27401898 ER PT J AU Nieman, CL Weinreich, HM Sharon, JD Chien, WW Francis, HW AF Nieman, Carrie L. Weinreich, Heather M. Sharon, Jeffrey D. Chien, Wade W. Francis, Howard W. TI Use of Pericranial Flap Coverage in Cochlear Implantation of the Radical Cavity: Rationale, Technique, and Experience SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Article DE cochlear implantation; open mastoid cavity; pericranial tissue flap; external auditory canal closure; retrospective cohort series; literature review ID SUPPURATIVE OTITIS-MEDIA; AUDITORY-CANAL CLOSURE; MIDDLE-EAR; MASTOID OBLITERATION; MANAGEMENT; SURGERY; DISEASE AB Cochlear implant (CI) surgery in the setting of an open mastoid cavity is evolving. Two strategies are commonly pursued: a staged approach, clearing the disease, closing the meatus or the external auditory canal (EAC), and reevaluating in 3 to 6 months prior to implantation, or a single-stage procedure with mastoid obliteration without EAC closure. Meatal closure is often employed in the setting of an open mastoid cavity to reduce the risk of electrode extrusion and infection. An open cavity offers the advantages of being a single-stage procedure, permitting direct surveillance for recurrent cholesteatoma, and reducing the need for repeat computed tomography scans. We describe an approach to the coverage of a CI within a dry, open mastoid cavity using an anteriorly-based postauricular pericranial flap. C1 [Nieman, Carrie L.; Weinreich, Heather M.; Sharon, Jeffrey D.; Chien, Wade W.; Francis, Howard W.] Johns Hopkins Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, 601 N Caroline St,Suite 6210, Baltimore, MD 21287 USA. [Chien, Wade W.] Natl Inst Deafness & Other Commun Disorders, Sect Sensory Cell Biol, NIH, Bethesda, MD USA. RP Francis, HW (reprint author), Johns Hopkins Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, 601 N Caroline St,Suite 6210, Baltimore, MD 21287 USA. EM hfrancis@jhmi.edu NR 23 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0194-5998 EI 1097-6817 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD SEP PY 2016 VL 155 IS 3 BP 533 EP 537 DI 10.1177/0194599816635642 PG 5 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA DV6HC UT WOS:000383032800025 PM 26980911 ER PT J AU Maurer, CW Liu, VD LaFaver, K Ameli, R Wu, TX Toledo, R Epstein, SA Hallett, M AF Maurer, Carine W. Liu, Victoria D. LaFaver, Kathrin Ameli, Rezvan Wu, Tianxia Toledo, Ryan Epstein, Steven A. Hallett, Mark TI Impaired resting vagal tone in patients with functional movement disorders SO PARKINSONISM & RELATED DISORDERS LA English DT Article DE Functional movement disorders; Psychogenic movement disorders; Conversion disorder; Stress; Autonomic nervous system ID HEART-RATE-VARIABILITY; PSYCHOGENIC NONEPILEPTIC SEIZURES; CONVERSION DISORDER; STRESS; PSYCHOPATHOLOGY; DEPRESSION AB Introduction: The autonomic nervous system plays an integral role in the maintenance of homeostasis during times of stress. The functioning of the autonomic nervous system in patients with functional movement disorders (FMD) is of particular interest given the hypothesis that converted psychological stress plays a critical role in FMD disease pathogenesis. We sought to investigate autonomic nervous system activity in FMD patients by examining heart rate variability (HRV), a quantitative marker of autonomic function. Methods: 35 clinically definite FMD patients and 38 age- and sex-matched healthy controls were hospitalized overnight for continuous electrocardiogram recording. Standard time and frequency domain measures of HRV were calculated in the awake and asleep stages. All participants underwent a thorough neuropsychological battery, including the Hamilton Anxiety and Depression scales and the Beck Depression Inventory. Results: Compared to controls, patients with FMD exhibited decreased root mean square of successive differences between adjacent NN intervals (RMSSD) (p = 0.02), a marker of parasympathetic activity, as well as increased mean heart rate (p = 0.03). These measures did not correlate with the depression and anxiety scores included in our assessment as potential covariates. Conclusion: In this exploratory study, patients with FMD showed evidence of impaired resting state vagal tone, as demonstrated by reduced RMSSD. This decreased vagal tone may reflect in-Creased stress vulnerability in patients with FMD. Published by Elsevier Ltd. C1 [Maurer, Carine W.; Liu, Victoria D.; LaFaver, Kathrin; Toledo, Ryan; Hallett, Mark] NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [LaFaver, Kathrin] Univ Louisville, Dept Neurol, Louisville, KY 40292 USA. [Ameli, Rezvan] NIMH, Expt Therapeut & Pathophysiol Branch, NIH, Bethesda, MD 20892 USA. [Wu, Tianxia] NINDS, Off Clin Director, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Epstein, Steven A.] Georgetown Univ, Dept Psychiat, Washington, DC USA. RP Maurer, CW (reprint author), NINDS, Human Motor Control Sect, NIH, Bldg 10,Room 7D42,10 Ctr Dr, Bethesda, MD 20892 USA. EM carine.maurer@nih.gov; victoriatl@gmail.com; kathrin.lafaver@louisville.edu; amelir@mail.nih.gov; wuti@mail.nih.gov; ryantoledo21@gmail.com; epsteins@gunet.georgetown.edu; hallettm@ninds.nih.gov FU NINDS Intramural Program FX This study was supported by the NINDS Intramural Program. We would like to thank Dr. Robert Brychta (NIDDK/NIH) and Peter Lauro (NINDS/NIH) for assistance with the Matlab program used for HRV analysis. We would like to acknowledge Elaine Considine, R.N., for her assistance with study coordination. NR 26 TC 0 Z9 0 U1 4 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8020 EI 1873-5126 J9 PARKINSONISM RELAT D JI Parkinsonism Relat. Disord. PD SEP PY 2016 VL 30 BP 18 EP 22 DI 10.1016/j.parkreldis.2016.06.009 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA DW3FJ UT WOS:000383527200004 PM 27334304 ER PT J AU Mehta, SH Dickson, DW Morgan, JC Singleton, AB Majounie, E Sethi, KD AF Mehta, Shyamal H. Dickson, Dennis W. Morgan, John C. Singleton, Andrew B. Majounie, Elisa Sethi, Kapil D. TI Juvenile onset Parkinsonism with "pure nigral" degeneration and POLG1 mutation SO PARKINSONISM & RELATED DISORDERS LA English DT Letter ID POLYMERASE-GAMMA MUTATIONS C1 [Mehta, Shyamal H.] Mayo Clin, Dept Neurol, Scottsdale, AZ 85259 USA. [Dickson, Dennis W.] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA. [Morgan, John C.; Sethi, Kapil D.] Med Coll Georgia, Dept Neurol, Augusta, GA 30912 USA. [Singleton, Andrew B.; Majounie, Elisa] NIA, Mol Genet Sect, Bethesda, MD 20892 USA. RP Mehta, SH (reprint author), Mayo Clin, Movement Disorders Div, Dept Neurol, Scottsdale, AZ 85259 USA. EM mehta.shyamal@mayo.edu NR 5 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8020 EI 1873-5126 J9 PARKINSONISM RELAT D JI Parkinsonism Relat. Disord. PD SEP PY 2016 VL 30 BP 83 EP 85 DI 10.1016/j.parkreldis.2016.06.013 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA DW3FJ UT WOS:000383527200017 PM 27349602 ER PT J AU Colegate, SM Gardner, DR Betz, JM Fischer, OW Liede-Schumann, S Boppre, M AF Colegate, Steven M. Gardner, Dale R. Betz, Joseph M. Fischer, Ottmar W. Liede-Schumann, Sigrid Boppre, Michael TI Pro-toxic 1,2-Dehydropyrrolizidine Alkaloid Esters, Including Unprecedented 10-Membered Macrocyclic Diesters, in the Medicinally-used Alafia cf. caudata and Amphineurion marginatum (Apocynaceae: Apocynoideae: Nerieae and Apocyneae) SO PHYTOCHEMICAL ANALYSIS LA English DT Article DE Amphineurine; marginatine; shimbaine; isoshimbaine; hydroxysenecioylretronecine; health risk; pyrrolizidine alkaloid-pharmacophagous insects ID ANODENDRON-AFFINE DRUCE; PYRROLIZIDINE ALKALOIDS; DEHYDROPYRROLIZIDINE ALKALOIDS; IDEA-LEUCONOE; N-OXIDES; PARSONSIA-LAEVIGATA; HOST-PLANT; BUTTERFLIES; DANAINAE; LYCOPSAMINE AB IntroductionWithin the Apocynoideae (Apocynaceae) pro-toxic dehydropyrrolizidine alkaloids have been reported only in Echiteae. However, attraction of pyrrolizidine alkaloid-pharmacophagous insects suggested their presence in Alafia cf. caudata Stapf (Nerieae: Alafiinae) and Amphineurion marginatum (Roxb.) D.J. Middleton (Apocyneae: Amphineuriinae), both used as medicinal plants. ObjectiveTo confirm the presence of dehydropyrrolizidine alkaloids in Alafia cf. caudata and Amphineurion marginatum and identify their structures. MethodsMethanol extracts of air-dried roots, stems and leaves of non-flowering plants were analysed using HPLC-ESI(+)MS and MS/MS or collision-induced dissociation MS in low and/or high resolution modes. Pyrrolizidine alkaloids were tentatively identified based on the mass spectrometry data. Solid phase extraction combined with semi-preparative HPLC were used to isolate major alkaloids. Structures were elucidated using NMR spectroscopy. ResultsMonoesters of retronecine with senecioic, hydroxysenecioic or syringic acids were identified in roots of Alafia cf. caudata. Two unprecedented 10-membered macrocyclic dehydropyrrolizidine alkaloid diesters were isolated from roots of Amphineurion marginatum. Pyrrolizidine alkaloids were detected in root and leaf material of Alafia cf. caudata at 0.34 and 0.01% dry weight (DW), and 0.13, 0.02 and 0.09% DW in root, leaf and stem material of Amphineurion marginatum. ConclusionsThe presence of pro-toxic dehydropyrrolizidine alkaloids suggests that medical preparations of these plants pose potential health risks to consumers. Dehydropyrrolizidine alkaloids are evidently more widespread in Apocynoideae than previously assumed, and it would seem rewarding to study other members of this family for the presence of pyrrolizidines, dehydropyrrolizidines and dihydropyrrolizines. Copyright (c) 2016 John Wiley & Sons, Ltd. The attraction of pyrrolizidine alkaloid-pharmacophagous insects indicated the presence of pro-toxic dehydropyrrolizidine alkaloids in Alafia cf. caudata Stapf (Nerieae: Alafinae) and Amphineurion marginatum (Roxb.) D.J. Middleton (Apocyneae: Amphineuriinae). Subsequently, monoesters of retronecine with senecioic, hydroxysenecioic or syringic acids were identified in Alafia cf. caudata, and 10-membered macrocyclic dehydropyrrolizidine alkaloid diesters, previously unprecedented in reports from natural sources, were isolated from Amphineurion marginatum. Since both plants are used as traditional medicine this suggests potential health risks to consumers. C1 [Colegate, Steven M.; Gardner, Dale R.] ARS, USDA, Poisonous Plant Res Lab, Logan, UT 84341 USA. [Colegate, Steven M.] Utah State Univ, Dept Anim Dairy & Vet Sci, Logan, UT 84322 USA. [Betz, Joseph M.] NIH, Off Dietary Supplements, 6100 Execut Blvd,Room 3B01, Bethesda, MD 20892 USA. [Fischer, Ottmar W.; Boppre, Michael] Univ Freiburg, Forstzool & Entomol, D-79085 Freiburg, Germany. [Liede-Schumann, Sigrid] Univ Bayreuth, LS Pflanzensystemat, D-95440 Bayreuth, Germany. RP Colegate, SM (reprint author), ARS, USDA, Poisonous Plant Res Lab, Logan, UT 84341 USA.; Boppre, M (reprint author), Univ Freiburg, Forstzool & Entomol, D-79085 Freiburg, Germany. EM steven.colegate@ars.usda.gov; boppre@fzi.uni-freiburg.de RI Boppre, Michael/P-4346-2016 FU National Science Foundation [CHE-1429195] FX The authors are indebted to Tim Burzlaff and the late Patrick Muthama who were involved in the original find of Alafia for which Quentin Luke kindly provided a tentative identification. MB thanks the Office of the President, Nairobi, Kenya, for research permits. Anita Kiesel, Monika Siegel and Eva Schottmuller are thanked for their continuous skillful assistance in rearing of and experimenting with insects, maintaining plant cultures and conducting chemical tests. Mary Endress kindly provided repeated advice with regards to apocynad taxonomy and made valuable comments on an earlier draft of this manuscript. Funding from the National Science Foundation (CHE-1429195) for the Bruker 500 MHz NMR spectrometer is gratefully acknowledged. Mention of trade names or commercial products in this publication is solely for the purpose of providing specific information and does not imply recommendation or endorsement by the US Department of Agriculture. The authors sincerely acknowledge the valuable advice from the anonymous reviewers. NR 76 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0958-0344 EI 1099-1565 J9 PHYTOCHEM ANALYSIS JI Phytochem. Anal. PD SEP-OCT PY 2016 VL 27 IS 5 BP 257 EP 276 DI 10.1002/pca.2624 PG 20 WC Biochemical Research Methods; Plant Sciences; Chemistry, Analytical SC Biochemistry & Molecular Biology; Plant Sciences; Chemistry GA DW2BO UT WOS:000383448100004 PM 27432636 ER PT J AU Weinberg, DH Signore, C Spong, CY AF Weinberg, David H. Signore, Caroline Spong, Catherine Y. TI THE HUMAN PLACENTA PROJECT: CURRENT PROGRESS AND FUTURE DIRECTIONS SO PLACENTA LA English DT Meeting Abstract CT Meeting of the International-Federation-of-Placenta-Associations (IFPA) - Placenta-Back to the Basics CY SEP 13-16, 2016 CL Portland, OR SP Int Federat Placenta Assoc C1 [Weinberg, David H.; Signore, Caroline; Spong, Catherine Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0143-4004 EI 1532-3102 J9 PLACENTA JI Placenta PD SEP PY 2016 VL 45 MA HPP BP 71 EP 71 PG 1 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA DV9WX UT WOS:000383294000038 ER PT J AU DeMayo, F AF DeMayo, Francesco TI INVESTIGATING THE MOLECULAR MECHANISMS REGULATED BY PROGESTERONE GOVERNING THE ABILITY OF THE UTERUS TO SUPPORT PREGNANCY SO PLACENTA LA English DT Meeting Abstract CT Meeting of the International-Federation-of-Placenta-Associations (IFPA) - Placenta-Back to the Basics CY SEP 13-16, 2016 CL Portland, OR SP Int Federat Placenta Assoc C1 [DeMayo, Francesco] Natl Inst Environm Hlth Sci, Reprod & Dev Biol Lab, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0143-4004 EI 1532-3102 J9 PLACENTA JI Placenta PD SEP PY 2016 VL 45 MA NIH BP 72 EP 72 PG 1 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA DV9WX UT WOS:000383294000041 ER PT J AU Morgan, S Vvedensky, D Shah, R Girardi, T Newschaffer, C Katzman, P Miller, R Moye, J Salafia, C AF Morgan, Simon Vvedensky, Dimitri Shah, Ruchit Girardi, Theresa Newschaffer, Craig Katzman, Philip Miller, Richard Moye, John Salafia, Carolyn TI ARTERIAL CHORIONIC SURFACE VESSEL BRANCH POINT DENSITY AND AUTISM RISK SO PLACENTA LA English DT Meeting Abstract CT Meeting of the International-Federation-of-Placenta-Associations (IFPA) - Placenta-Back to the Basics CY SEP 13-16, 2016 CL Portland, OR SP Int Federat Placenta Assoc C1 [Morgan, Simon; Vvedensky, Dimitri] Imperial Coll, London, England. [Shah, Ruchit; Girardi, Theresa; Salafia, Carolyn] LLC, Placental Analyt, New Rochelle, NY USA. [Newschaffer, Craig] Drexel Univ, Philadelphia, PA USA. [Katzman, Philip; Miller, Richard] Univ Rochester, Rochester, NY USA. [Katzman, Philip; Miller, Richard; Moye, John; Salafia, Carolyn] Placental Consortium, Bethesda, MD USA. [Moye, John] NICHD, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0143-4004 EI 1532-3102 J9 PLACENTA JI Placenta PD SEP PY 2016 VL 45 MA P1.7 BP 74 EP 74 PG 1 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA DV9WX UT WOS:000383294000049 ER PT J AU Schubert, D Leonard, A Lee, J Morgan, S Vvedensky, D Newschaffer, C Shah, R Miller, R Katzman, P Moye, J Salafia, C AF Schubert, David Leonard, Alexander Lee, Jonathan Morgan, Simon Vvedensky, Dimitri Newschaffer, Craig Shah, Ruchit Miller, Richard Katzman, Philip Moye, John Salafia, Carolyn TI FAMILIAL HIGH ASD RISK DIFFERS FROM A LOW RISK COHORT BY LONGER SEGMENT LENGTHS AND POTENTIAL REDUCED BRANCHING IN EARLY BUT NOT LATER BRANCH GENERATIONS SO PLACENTA LA English DT Meeting Abstract CT Meeting of the International-Federation-of-Placenta-Associations (IFPA) - Placenta-Back to the Basics CY SEP 13-16, 2016 CL Portland, OR SP Int Federat Placenta Assoc C1 [Schubert, David; Leonard, Alexander; Morgan, Simon; Vvedensky, Dimitri] Imperial Coll, London, England. [Lee, Jonathan; Morgan, Simon; Shah, Ruchit; Salafia, Carolyn] Placental Analyt LLC, New Rochelle, NY USA. [Miller, Richard; Katzman, Philip; Moye, John] Univ Rochester, Rochester, NY USA. [Schubert, David; Leonard, Alexander; Lee, Jonathan; Morgan, Simon; Vvedensky, Dimitri; Newschaffer, Craig; Shah, Ruchit; Miller, Richard; Katzman, Philip; Moye, John; Salafia, Carolyn] NICHD, Bethesda, MD USA. [Newschaffer, Craig] Drexel Univ, Philadelphia, PA USA. [Miller, Richard; Katzman, Philip; Salafia, Carolyn] Placental Consortium, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0143-4004 EI 1532-3102 J9 PLACENTA JI Placenta PD SEP PY 2016 VL 45 MA P1.8 BP 74 EP 75 PG 2 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA DV9WX UT WOS:000383294000050 ER PT J AU Chang, JM Chang, YM Han, RX Zeng, H Shah, R Newschaffer, C Miller, R Katzman, P Moye, J Salafia, C AF Chang, Jen-Mei Chang, Ya-Mei Han, Ruxu Zeng, Hui Shah, Ruchit Newschaffer, Craig Miller, Richard Katzman, Philip Moye, John Salafia, Carolyn TI WHOLE CHORIONIC SURFACE VESSEL FEATURE ANALYSIS WITH THE BORUTA METHOD, AND AUTISM RISK SO PLACENTA LA English DT Meeting Abstract CT Meeting of the International-Federation-of-Placenta-Associations (IFPA) - Placenta-Back to the Basics CY SEP 13-16, 2016 CL Portland, OR SP Int Federat Placenta Assoc C1 [Chang, Jen-Mei; Han, Ruxu; Zeng, Hui] Calif State Univ Long Beach, Long Beach, CA USA. [Chang, Ya-Mei] Tamkang Univ, Taipei, Taiwan. [Shah, Ruchit; Salafia, Carolyn] LLC, Placental Analyt, New Rochelle, NY USA. [Newschaffer, Craig] Drexel Univ, Philadelphia, PA USA. [Miller, Richard; Katzman, Philip] Univ Rochester, Rochester, NY USA. [Miller, Richard; Katzman, Philip] Placental Consortium, Bethesda, MD USA. [Moye, John] NICHD, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0143-4004 EI 1532-3102 J9 PLACENTA JI Placenta PD SEP PY 2016 VL 45 MA P1.9 BP 75 EP 75 PG 1 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA DV9WX UT WOS:000383294000051 ER PT J AU Shah, R Girardi, T Change, JM Straughen, J Newschaffer, C Misra, D Katzman, P Miller, R Moye, J Salafia, C AF Shah, Ruchit Girardi, Theresa Change, Jen-mei Straughen, Jennifer Newschaffer, Craig Misra, Dawn Katzman, Philip Miller, Richard Moye, John Salafia, Carolyn TI A PRIORI SPECIFIED RELATIONSHIPS AMONG ARTERIAL CHORIONIC SURFACE VESSEL NETWORK (PCSVN) AND AUTISM RISK SO PLACENTA LA English DT Meeting Abstract CT Meeting of the International-Federation-of-Placenta-Associations (IFPA) - Placenta-Back to the Basics CY SEP 13-16, 2016 CL Portland, OR SP Int Federat Placenta Assoc C1 [Shah, Ruchit; Girardi, Theresa; Salafia, Carolyn] LLC, Placental Analyt, New Rochelle, NY USA. [Change, Jen-mei] Calif State, Long Beach, CA USA. [Straughen, Jennifer] Henry Ford Hlth Syst, Detroit, MI USA. [Misra, Dawn] Wayne State Univ, Detroit, MI USA. [Newschaffer, Craig] Drexel Univ, Philadelphia, PA USA. [Katzman, Philip; Miller, Richard] Univ Rochester, Rochester, NY USA. [Katzman, Philip; Miller, Richard; Moye, John; Salafia, Carolyn] Placental Consortium, Bethesda, MD USA. [Moye, John] NICHD, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0143-4004 EI 1532-3102 J9 PLACENTA JI Placenta PD SEP PY 2016 VL 45 MA P1.10 BP 76 EP 76 PG 1 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA DV9WX UT WOS:000383294000052 ER PT J AU Awad, KS West, JD Perez, VD MacLean, M AF Awad, Keytam S. West, James D. Perez, Vinicio de Jesus MacLean, Margaret TI Novel signaling pathways in pulmonary arterial hypertension (2015 Grover Conference Series) SO PULMONARY CIRCULATION LA English DT Review DE vascular remodeling; sex hormones; microRNA; mitogen-activated protein kinase; Wnt ID ACTIVATED PROTEIN-KINASE; MUSCLE-CELL PROLIFERATION; ENDOTHELIAL GROWTH-FACTOR; SEROTONIN TRANSPORTER; ESTROGEN-RECEPTOR; P38 MAPK; PERICYTE RECRUITMENT; ENDOGENOUS ESTROGEN; CYTOCHROME-P450 1B1; NOONAN-SYNDROME AB The proliferative endothelial and smooth muscle cell phenotype, inflammation, and pulmonary vascular remodeling are prominent features of pulmonary arterial hypertension (PAH). Mutations in bone morphogenetic protein type 2 receptor (BMPR2) have been identified as the most common genetic cause of PAH and females with BMPR2 mutations are 2.5 times as likely to develop heritable forms of PAH than males. Higher levels of estrogen have also been observed in males with PAH, implicating sex hormones in PAH pathogenesis. Recently, the estrogen metabolite 16a-OHE1 (hydroxyestrone) was implicated in the regulation of miR29, a microRNA involved in modulating energy metabolism. In females, decreased miR96 enhances serotonin's effect by upregulating the 5-hydroxytryptamine 1B (5HT1B) receptor. Because PAH is characterized as a quasi-malignant disease, likely due to BMPR2 loss of function, altered signaling pathways that sustain this cancer-like phenotype are being explored. Extracellular signal-regulated kinases 1 and 2 and p38 mitogen-activated protein kinases (MAPKs) play a critical role in proliferation and cell motility, and dysregulated MAPK signaling is observed in various experimental models of PAH. Wnt signaling pathways preserve pulmonary vascular homeostasis, and dysregulation of this pathway could contribute to limited vascular regeneration in response to injury. In this review, we take a closer look at sex, sex hormones, and the interplay between sex hormones and microRNA regulation. We also focus on MAPK and Wnt signaling pathways in the emergence of a proproliferative, antiapoptotic endothelial phenotype, which then orchestrates an angioproliferative process of vascular remodeling, with the hope of developing novel therapies that could reverse the phenotype. C1 [Awad, Keytam S.] NIH, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. [West, James D.] Vanderbilt Univ, Med Ctr, Dept Med, 221 Kirkland Hall, Nashville, TN 37235 USA. [Perez, Vinicio de Jesus] Stanford Univ, Dept Med, Stanford, CA 94305 USA. [MacLean, Margaret] Univ Glasgow, Coll Med Vet & Life Sci, Res Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland. RP Awad, KS (reprint author), NIH, Dept Crit Care Med, 10 Ctr Dr,Room 2C145, Bethesda, MD 20892 USA. EM awadks@cc.nih.gov FU Intramural Research Program of the National Institutes of Health Clinical Center FX This research was supported in part by the Intramural Research Program of the National Institutes of Health Clinical Center. NR 87 TC 0 Z9 0 U1 3 U2 3 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 2045-8932 EI 2045-8940 J9 PULM CIRC JI Pulm. Circ. PD SEP PY 2016 VL 6 IS 3 BP 285 EP 294 DI 10.1086/688034 PG 10 WC Cardiac & Cardiovascular Systems; Respiratory System SC Cardiovascular System & Cardiology; Respiratory System GA DV6CL UT WOS:000383018300005 PM 27683605 ER PT J AU Yasuda, K Mili, S AF Yasuda, Kyota Mili, Stavroula TI Dysregulated axonal RNA translation in amyotrophic lateral sclerosis SO WILEY INTERDISCIPLINARY REVIEWS-RNA LA English DT Review ID ADENOMATOUS-POLYPOSIS-COLI; MOTOR-NEURON DEGENERATION; FRONTOTEMPORAL LOBAR DEGENERATION; STRESS GRANULE DYNAMICS; LOCAL PROTEIN-SYNTHESIS; LINKED SOD1 MUTANTS; MESSENGER-RNA; BINDING PROTEINS; NUCLEOCYTOPLASMIC TRANSPORT; DETYROSINATED MICROTUBULES AB Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disease that has been associated with a diverse array of genetic changes. Prominent among these are mutations in RNA-binding proteins (RBPs) or repeat expansions that give rise to toxic RNA species. RBPs are additionally central components of pathologic aggregates that constitute a disease hallmark, suggesting that dysregulation of RNA metabolism underlies disease progression. In the context of neuronal physiology, transport of RNAs and localized RNA translation in axons are fundamental to neuronal survival and function. Several lines of evidence suggest that axonal RNA translation is a central process perturbed by various pathogenic events associated with ALS. Dysregulated translation of specific RNA groups could underlie feedback effects that connect and reinforce disease manifestations. Among such candidates are RNAs encoding proteins involved in the regulation of microtubule dynamics. Further understanding of axonally dysregulated RNA targets and of the feedback mechanisms they induce could provide useful therapeutic insights. WIREs RNA 2016, 7:589-603. doi: 10.1002/wrna.1352 For further resources related to this article, please visit the . C1 [Yasuda, Kyota; Mili, Stavroula] NIH, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. RP Mili, S (reprint author), NIH, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. EM voula.mili@nih.gov NR 146 TC 1 Z9 1 U1 6 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1757-7004 EI 1757-7012 J9 WIRES RNA JI Wiley Interdiscip. Rev.-RNA PD SEP-OCT PY 2016 VL 7 IS 5 BP 589 EP 603 DI 10.1002/wrna.1352 PG 15 WC Cell Biology SC Cell Biology GA DW1FL UT WOS:000383388300003 PM 27038103 ER PT J AU Parlea, L Puri, A Kasprzak, W Bindewald, E Zakrevsky, P Satterwhite, E Joseph, K Afonin, KA Shapiro, BA AF Parlea, Lorena Puri, Anu Kasprzak, Wojciech Bindewald, Eckart Zakrevsky, Paul Satterwhite, Emily Joseph, Kenya Afonin, Kirill A. Shapiro, Bruce A. TI Cellular Delivery of RNA Nanoparticles SO ACS COMBINATORIAL SCIENCE LA English DT Review DE RNA; self-assembly; nanoconstruct; RNA nanoparticle; therapeutics; delivery ID SMALL INTERFERING RNA; DOUBLE-STRANDED-RNA; LIPID-BASED NANOPARTICLES; MEDIATED SIRNA DELIVERY; TARGETED CANCER-THERAPY; IN-VITRO SELECTION; SELF-CLEAVING RIBOZYMES; ELASTIC NETWORK MODELS; NUCLEIC-ACID; DRUG-DELIVERY AB RNA nanostructures can be programmed to exhibit defined sizes, shapes and stoichiometries from naturally occurring or,de novo designed RNA motifs. These constructs can be used as scaffolds to attach functional moieties, such as ligand binding motifs or gene expression regulators, for nanobiology applications. This review is focused on four areas of importance to RNA nanotechnology: the types of RNAs of particular interest for nanobiology, the assembly of RNA nanoconstructs, the challenges of cellular delivery of RNAs in vivo, and the delivery carriers that aid in the matter. The available strategies for the design of nucleic acid nanostructures, as well as for formulation of their carriers, make RNA nanotechnology an important tool in both basic research and applied biomedical science. C1 [Parlea, Lorena; Puri, Anu; Zakrevsky, Paul; Shapiro, Bruce A.] NCI, Gene Regulat & Chromosome Biol Lab, Frederick, MD 21702 USA. [Kasprzak, Wojciech; Bindewald, Eckart] Leidos Biomed Res Inc, Basic Sci Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Satterwhite, Emily; Joseph, Kenya] Univ North Carolina Charlotte, Dept Chem, Charlotte, NC 28223 USA. [Afonin, Kirill A.] Univ North Carolina Charlotte, Nanoscale Sci Program, Charlotte, NC 28223 USA. [Afonin, Kirill A.] Univ North Carolina Charlotte, Ctr Biomed Engn & Sci, Charlotte, NC 28223 USA. RP Shapiro, BA (reprint author), NCI, Gene Regulat & Chromosome Biol Lab, Frederick, MD 21702 USA. EM shapirbr@mail.nih.gov FU Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This work has been funded in whole or in part with Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under Contract No. HHSN261200800001E. This research was supported [in part] by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 249 TC 1 Z9 1 U1 26 U2 26 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 2156-8952 EI 2156-8944 J9 ACS COMB SCI JI ACS Comb. Sci. PD SEP PY 2016 VL 18 IS 9 BP 527 EP 547 DI 10.1021/acscombsci.6b00073 PG 21 WC Chemistry, Applied; Chemistry, Medicinal; Chemistry, Multidisciplinary SC Chemistry; Pharmacology & Pharmacy GA DV8UX UT WOS:000383213300002 PM 27509068 ER PT J AU Pettifor, A MacPhail, C Selin, A Gomez-Olive, FX Rosenberg, M Wagner, RG Mabuza, W Hughes, JP Suchindran, C Piwowar-Manning, E Wang, J Twine, R Daniel, T Andrew, P Laeyendecker, O Agyei, Y Tollman, S Kahn, K AF Pettifor, Audrey MacPhail, Catherine Selin, Amanda Gomez-Olive, F. Xavier Rosenberg, Molly Wagner, Ryan G. Mabuza, Wonderful Hughes, James P. Suchindran, Chirayath Piwowar-Manning, Estelle Wang, Jing Twine, Rhian Daniel, Tamu Andrew, Philip Laeyendecker, Oliver Agyei, Yaw Tollman, Stephen Kahn, Kathleen CA HPTN 068 Protocol Team TI HPTN 068: A Randomized Control Trial of a Conditional Cash Transfer to Reduce HIV Infection in Young Women in South Africa-Study Design and Baseline Results SO AIDS AND BEHAVIOR LA English DT Article DE HIV; Adolescents; South Africa; Young women; HIV prevention; Cash transfers; Education ID SUB-SAHARAN AFRICA; PREVALENCE; EDUCATION; SCHOOL; RISK AB Young women in South Africa are at high risk for HIV infection. Cash transfers offer promise to reduce HIV risk. We present the design and baseline results from HPTN 068, a phase III, individually randomized trial to assess the effect of a conditional cash transfer on HIV acquisition among South African young women. A total of 2533 young women were randomized to receive a monthly cash transfer conditional on school attendance or to a control group. A number of individual-, partner-, household- and school-level factors were associated with HIV and HSV-2 infection. After adjusting for age, all levels were associated with an increased odds of HIV infection with partner-level factors conveying the strongest association (aOR 3.05 95 % CI 1.84-5.06). Interventions like cash transfers that address structural factors such as schooling and poverty have the potential to reduce HIV risk in young women in South Africa. C1 [Pettifor, Audrey] Univ N Carolina, Dept Epidemiol, McGavran Greenberg Bldg CB 7435, Chapel Hill, NC 27599 USA. [Pettifor, Audrey; MacPhail, Catherine; Gomez-Olive, F. Xavier; Wagner, Ryan G.; Mabuza, Wonderful; Twine, Rhian; Tollman, Stephen; Kahn, Kathleen] Univ Witwatersrand, Sch Publ Hlth, MRC Wits Rural Publ Hlth & Hlth Transit Unit, Johannesburg, South Africa. [Pettifor, Audrey; MacPhail, Catherine] Univ Witwatersrand, Wits Reprod Hlth & HIV Inst, Johannesburg, South Africa. [Pettifor, Audrey; Selin, Amanda; Suchindran, Chirayath; Daniel, Tamu] Univ N Carolina, Carolina Populat Ctr, Chapel Hill, NC 27599 USA. [MacPhail, Catherine] Univ New England, Sch Hlth, Armidale, NSW, Australia. [Rosenberg, Molly] Harvard Univ, Ctr Populat & Dev Studies, Cambridge, MA 02138 USA. [Hughes, James P.; Wang, Jing] SCHARP, Seattle, WA USA. [Hughes, James P.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Suchindran, Chirayath] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Piwowar-Manning, Estelle; Agyei, Yaw] Johns Hopkins Univ, HPTN Lab Ctr, Baltimore, MD USA. [Andrew, Philip] FHI360, Durham, NC USA. [Laeyendecker, Oliver] NIAID, Immunoregulat Lab, NIH, Baltimore, MD USA. [Laeyendecker, Oliver] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Laeyendecker, Oliver] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Tollman, Stephen; Kahn, Kathleen] Umea Ctr Global Hlth Res, Umea, Sweden. [Tollman, Stephen; Kahn, Kathleen] INDEPTH Network, Accra, Ghana. RP Pettifor, A (reprint author), Univ N Carolina, Dept Epidemiol, McGavran Greenberg Bldg CB 7435, Chapel Hill, NC 27599 USA.; Pettifor, A (reprint author), Univ Witwatersrand, Sch Publ Hlth, MRC Wits Rural Publ Hlth & Hlth Transit Unit, Johannesburg, South Africa.; Pettifor, A (reprint author), Univ Witwatersrand, Wits Reprod Hlth & HIV Inst, Johannesburg, South Africa.; Pettifor, A (reprint author), Univ N Carolina, Carolina Populat Ctr, Chapel Hill, NC 27599 USA. EM apettif@email.unc.edu FU National Institute on Drug Abuse (NIDA) of the National Institutes of Health (NIH) [UM1AI068619, UM1AI068617, UM1AI068613]; [5R01MH087118-02]; [R24 HD050924] FX Overall support for the HIV Prevention Trials Network (HPTN) was provided by the National Institute of Allergy and Infectious Diseases (NIAID), the National Institute of Mental Health (NIMH) and the National Institute on Drug Abuse (NIDA) of the National Institutes of Health (NIH) under Award Numbers UM1AI068619 (HPTN Leadership and Operations Center), UM1AI068617 (HPTN Statistical and Data Management Center), and UM1AI068613 (HPTN Laboratory Center). The study was also funded under Award Number 5R01MH087118-02 and R24 HD050924 to the Carolina Population Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health. NR 27 TC 4 Z9 4 U1 3 U2 3 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 EI 1573-3254 J9 AIDS BEHAV JI AIDS Behav. PD SEP PY 2016 VL 20 IS 9 BP 1863 EP 1882 DI 10.1007/s10461-015-1270-0 PG 20 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA DU1SZ UT WOS:000381990800004 PM 26891839 ER PT J AU Gooden, L Metsch, LR Pereyra, MR Malotte, CK Haynes, LF Douaihy, A Chally, J Mandler, RN Feaster, DJ AF Gooden, Lauren Metsch, Lisa R. Pereyra, Margaret R. Malotte, C. Kevin Haynes, Louise F. Douaihy, Antoine Chally, Jack Mandler, Raul N. Feaster, Daniel J. TI Examining the Efficacy of HIV Risk-Reduction Counseling on the Sexual Risk Behaviors of a National Sample of Drug Abuse Treatment Clients: Analysis of Subgroups SO AIDS AND BEHAVIOR LA English DT Article DE HIV; Prevention; Counseling; Substance use; Drug treatment ID RANDOMIZED CLINICAL-TRIAL; NEW-YORK-CITY; TRANSMITTED-DISEASES; UNITED-STATES; CONDOM USE; TREATMENT PROGRAMS; SUBSTANCE USE; POSITIVE MEN; INJECT DRUGS; INFECTION AB HIV counseling with testing has been part of HIV prevention in the U.S. since the 1980s. Despite the long-standing history of HIV testing with prevention counseling, the CDC released HIV testing recommendations for health care settings contesting benefits of prevention counseling with testing in reducing sexual risk behaviors among HIV-negatives in 2006. Efficacy of brief HIV risk-reduction counseling (RRC) in decreasing sexual risk among subgroups of substance use treatment clients was examined using multi-site RCT data. Interaction tests between RRC and subgroups were performed; multivariable regression evaluated the relationship between RRC (with rapid testing) and sex risk. Subgroups were defined by demographics, risk type and level, attitudes/perceptions, and behavioral history. There was an effect (p < .0028) of counseling on number of sex partners among some subgroups. Certain subgroups may benefit from HIV RRC; this should be examined in studies with larger sample sizes, designed to assess the specific subgroup(s). C1 [Gooden, Lauren; Metsch, Lisa R.; Pereyra, Margaret R.] Columbia Univ, Mailman Sch Publ Hlth, Dept Sociomed Sci, New York, NY 10027 USA. [Gooden, Lauren; Metsch, Lisa R.; Pereyra, Margaret R.; Feaster, Daniel J.] Univ Miami, Miller Sch Med, Dept Publ Hlth Sci, Miami, FL 33136 USA. [Malotte, C. Kevin] Calif State Univ Long Beach, Dept Hlth Sci, Long Beach, CA 90840 USA. [Haynes, Louise F.] Med Univ South Carolina, Dept Psychiat & Behav Sci, Charleston, SC USA. [Douaihy, Antoine] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Chally, Jack] Johns Hopkins Univ, Baltimore, MD USA. [Chally, Jack] EMMES Corp Inc, Rockville, MD USA. [Mandler, Raul N.] NIDA, NIH, Bethesda, MD 20892 USA. [Gooden, Lauren; Pereyra, Margaret R.] Columbia Univ, Miami Res Ctr, Mailman Sch Publ Hlth, Dept Sociomed Sci, 1120 NW 14th St,Room 1030, Miami, FL 33136 USA. RP Gooden, L (reprint author), Columbia Univ, Mailman Sch Publ Hlth, Dept Sociomed Sci, New York, NY 10027 USA.; Gooden, L (reprint author), Univ Miami, Miller Sch Med, Dept Publ Hlth Sci, Miami, FL 33136 USA.; Gooden, L (reprint author), Columbia Univ, Miami Res Ctr, Mailman Sch Publ Hlth, Dept Sociomed Sci, 1120 NW 14th St,Room 1030, Miami, FL 33136 USA. EM lkg2129@cumc.columbia.edu FU National Drug Abuse Treatment Clinical Trials Network [U10DA013720, U10DA13720-09S, U10DA020036, U10DA15815, U10DA13034, U10DA013038, U10DA013732, U10DA13036, U10DA13727, U10DA015833, HHSN271200522081C, HHSN271200522071C] FX Funding for this study was provided by the National Drug Abuse Treatment Clinical Trials Network under the following cooperative agreements, awards, and contracts: U10DA013720, U10DA13720-09S, U10DA020036, U10DA15815, U10DA13034, U10DA013038, U10DA013732, U10DA13036, U10DA13727, U10DA015833, HHSN271200522081C, and HHSN271200522071C. Lisa R. Metsch, Ph.D. and Grant N. Colfax, M.D. were the Lead Investigators of the parent trial. Lauren Gooden, Lisa R. Metsch, Margaret R. Pereyra, C. Kevin Malotte, Louise F. Haynes, Antoine Douaihy, Jacky Chally and Daniel J. Feaster reported that their respective institutions received grant funds from the study sponsor in support of this study. NR 80 TC 0 Z9 0 U1 6 U2 6 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 EI 1573-3254 J9 AIDS BEHAV JI AIDS Behav. PD SEP PY 2016 VL 20 IS 9 BP 1893 EP 1906 DI 10.1007/s10461-016-1300-6 PG 14 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA DU1SZ UT WOS:000381990800006 PM 26837631 ER PT J AU Bynum, SA Wigfall, LT Brandt, HM Julious, CH Glover, SH Hebert, JR AF Bynum, Shalanda A. Wigfall, Lisa T. Brandt, Heather M. Julious, Carmen Hampton Glover, Saundra H. Hebert, James R. TI Social and Structural Determinants of Cervical Health among Women Engaged in HIV Care SO AIDS AND BEHAVIOR LA English DT Article DE Cervical cancer; Papanicolaou test; HIV/AIDS; Health status disparities; Women ID HUMAN-IMMUNODEFICIENCY-VIRUS; AFRICAN-AMERICAN WOMEN; UNITED-STATES; INFECTED WOMEN; LOW-INCOME; MEDICAL-CARE; RETROSPECTIVE-COHORT; SERVICES UTILIZATION; POSITIVE WOMEN; CANCER-RISK AB Cervical cancer prevention/control efforts among women living with HIV/AIDS (WLH) are socially and structurally challenging. Healthcare access and perceived HIV stigma and discrimination are factors that may challenge risk reduction efforts. This study examined socio-structural determinants of cervical cancer screening among women engaged in HIV care. One hundred forty-five WLH seeking health/social services from AIDS Service Organizations in the southeastern US completed a questionnaire assessing factors related to cervical cancer prevention/control. Ninety percent were African American, mean age 46.15 +/- A 10.65 years. Eighty-one percent had a Pap test < 1 year ago. Low healthcare access was positively associated with having a Pap test < 1 year ago, (Odds ratio [OR] 3.80; 95 % Confidence interval [CI] 1.34-10.78). About 36 % reported aeyen2 Pap tests during the first year after HIV diagnosis. Lower educational attainment was positively associated with having aeyen2 Pap tests, OR 3.22; CI 1.08-9.62. Thirty-five percent reported more frequent Pap tests after diagnosis. Lower income was moderately associated with more frequent Pap tests post-diagnosis, OR 2.47; CI .98-6.23. Findings highlight the successes of HIV initiatives targeting socio-economically disadvantaged women and provide evidence that health policy aimed at providing and expanding healthcare access for vulnerable WLH has beneficial health implications. C1 [Bynum, Shalanda A.] NIH, Div AIDS Behav & Populat Sci, Ctr Sci Review, 6701 Rockledge Dr, Bethesda, MD 20892 USA. [Wigfall, Lisa T.; Glover, Saundra H.] Univ South Carolina, Inst Partnerships Eliminate Hlth Dispar, Arnold Sch Publ Hlth, Columbia, SC USA. [Wigfall, Lisa T.; Glover, Saundra H.] Univ South Carolina, Arnold Sch Publ Hlth, Dept Hlth Serv Policy & Management, Columbia, SC USA. [Wigfall, Lisa T.; Brandt, Heather M.; Hebert, James R.] Univ South Carolina, Arnold Sch Publ Hlth, South Carolina Statewide Canc Prevent & Control P, Columbia, SC USA. [Brandt, Heather M.] Univ South Carolina, Arnold Sch Publ Hlth, Dept Hlth Promot Educ & Behav, Columbia, SC USA. [Julious, Carmen Hampton] Palmetto AIDS Life Support Serv Inc, Columbia, SC USA. [Hebert, James R.] Univ South Carolina, Arnold Sch Publ Hlth, Dept Epidemiol & Biostat, Columbia, SC USA. RP Bynum, SA (reprint author), NIH, Div AIDS Behav & Populat Sci, Ctr Sci Review, 6701 Rockledge Dr, Bethesda, MD 20892 USA. EM shalanda.bynum@nih.gov FU National Cancer Institute, Center to Reduce Cancer Health Disparities (Community Networks Program) [3U01 CA114601-05S4]; Established Investigator Award in Cancer Prevention and Control from the Cancer Training Branch of the National Cancer Institute [K05 CA136975]; National Cancer Institute Mentored Research Scientist Award to Promote Diversity [K01 CA175239] FX This work was supported by Grant Number 3U01 CA114601-05S4 [Hebert, JR (PI)] from the National Cancer Institute, Center to Reduce Cancer Health Disparities (Community Networks Program) to the South Carolina Cancer Disparities Community Network-II (SCCDCN-II). Dr. Hebert was supported by an Established Investigator Award in Cancer Prevention and Control from the Cancer Training Branch of the National Cancer Institute (K05 CA136975). Dr. Wigfall was supported by a National Cancer Institute Mentored Research Scientist Award to Promote Diversity (K01 CA175239). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, Department of Health and Human Services, or the United States Government. NR 48 TC 1 Z9 1 U1 6 U2 6 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 EI 1573-3254 J9 AIDS BEHAV JI AIDS Behav. PD SEP PY 2016 VL 20 IS 9 BP 2101 EP 2109 DI 10.1007/s10461-016-1345-6 PG 9 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA DU1SZ UT WOS:000381990800025 PM 26955821 ER PT J AU Stoff, DM Cargill, VA AF Stoff, David M. Cargill, Victoria A. TI Future HIV Mentoring Programs to Enhance Diversity SO AIDS AND BEHAVIOR LA English DT Editorial Material DE Research mentoring program development; Diversity; HIV research workforce ID HEALTH DISPARITIES AB This paper proposes a general template to guide future mentoring program development addressing: (i) considerations to ensure an adequate research workforce; (ii) key guidelines and principles of mentoring; and (iii) use of a logic model to develop program milestones, outcomes and evaluation. We focus on these areas to guide and inform the most effective mentoring program components, which we find to be more helpful than identifying specific features and ingredients. Although the focus is on the development of a new generation of investigators from diverse backgrounds, this template may also apply to mentoring programs for other investigators and for disciplines beyond HIV. C1 [Stoff, David M.] NIMH, Div AIDS Res, Bethesda, MD 20892 USA. [Cargill, Victoria A.] NIH, Off AIDS Res, Bldg 10, Bethesda, MD 20892 USA. RP Stoff, DM (reprint author), NIMH, Div AIDS Res, Bethesda, MD 20892 USA. EM dstoff@mail.nih.gov; CargillV@OD.NIH.GOV NR 24 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 EI 1573-3254 J9 AIDS BEHAV JI AIDS Behav. PD SEP PY 2016 VL 20 SU 2 BP S318 EP S325 DI 10.1007/s10461-016-1502-y PG 8 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA DU1SL UT WOS:000381989300014 PM 27484059 ER PT J AU Stoff, DM Cargill, VA AF Stoff, David M. Cargill, Victoria A. TI Building a More Diverse Workforce in HIV/AIDS Research: The Time has Come SO AIDS AND BEHAVIOR LA English DT Editorial Material DE Diversity; Mentoring; Research workforce; HIV/AIDS ID PARTICIPATORY RESEARCH; PERSISTENCE; INVESTIGATORS; DISPARITIES; MEDICINE; SCIENCE; CAREER AB Investigators from diverse racial and ethnic backgrounds are grossly underrepresented in the nation's biomedical research enterprise. Projections of current demographic trends suggest that population growth rates of minority populations will outpace that of the Caucasian population by 2060. Thus, this workforce will remain a poor reflection of the U.S. population. As a result of this underrepresentation of all sectors of the U.S. populace, the majority of the HIV research involving minority populations-those disproportionately impacted by HIV infection-will be conducted by investigators who do not resemble them. Although this does not necessarily preclude scientifically valid and important research, it produces research without the important cultural and contextual issues that can enhance the utility and generalizability of specific findings or interventions. The goal of this review is to not only raise awareness of the small numbers of minority investigators engaged in biomedical research, but also to identify the challenges to recruiting and retaining these investigators. In this article, while we discuss issues of diversity in general, the focus will be upon the mental health aspects of the HIV epidemic for illustrative purposes: to demonstrate the issues associated with enhancing investigator diversity as a strategy for remediating the chronic shortage of historically underrepresented investigators in scientific research. After presenting the magnitude of the problem and a rationale for enhancing diversity of the biomedical research workforce, we identify a number of potential reasons and challenges for the shortage of minority investigators. Aspects of the mentoring process, together with ten key suggestions, are discussed as the backdrop for the supplement papers that follow (dealing with mentoring principles, challenges, and mentoringrelated issues on mentee, mentor, mentee-mentor relationship, and programs). By identifying these realities we hope to: (1) promote greater discussions of these challenges in academic institutions and settings; (2) suggest meaningful strategies to address these challenges; and (3) foster a national discussion about the long-term investment necessary for permanent change, as there are no easy 'fixes' for these challenges. C1 [Stoff, David M.] NIMH, Div AIDS Res, Bethesda, MD 20892 USA. [Cargill, Victoria A.] NIH, Off AIDS Res, Bldg 10, Bethesda, MD 20892 USA. RP Stoff, DM (reprint author), NIMH, Div AIDS Res, Bethesda, MD 20892 USA. EM dstoff@mail.nih.gov; cargillv@od.nih.gov NR 48 TC 0 Z9 0 U1 6 U2 6 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 EI 1573-3254 J9 AIDS BEHAV JI AIDS Behav. PD SEP PY 2016 VL 20 SU 2 BP S222 EP S230 DI 10.1007/s10461-016-1501-z PG 9 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA DU1SL UT WOS:000381989300002 PM 27484058 ER PT J AU Valantine, HA AF Valantine, Hannah A. TI Advancing the Progress of Mentoring for Diversity in AIDS Research: Warming the Mentoring Climate SO AIDS AND BEHAVIOR LA English DT Editorial Material ID RANDOMIZED CONTROLLED-TRIAL; ACADEMIC MEDICINE; INTERVENTION; FACULTY; GAP C1 [Valantine, Hannah A.] NIH, Bldg 1 Room 316,1 Ctr Dr, Bethesda, MD 20814 USA. RP Valantine, HA (reprint author), NIH, Bldg 1 Room 316,1 Ctr Dr, Bethesda, MD 20814 USA. EM hannah.valantine@nih.gov NR 10 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 EI 1573-3254 J9 AIDS BEHAV JI AIDS Behav. PD SEP PY 2016 VL 20 SU 2 BP S219 EP S221 DI 10.1007/s10461-016-1490-y PG 3 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA DU1SL UT WOS:000381989300001 PM 27448825 ER PT J AU Lamers, SL Barbier, AE Ratmann, O Fraser, C Rose, R Laeyendecker, O Grabowski, MK AF Lamers, Susanna L. Barbier, Andrew E. Ratmann, Oliver Fraser, Christophe Rose, Rebecca Laeyendecker, Oliver Grabowski, Mary K. TI HIV-1 Sequence Data Coverage in Central East Africa from 1959 to 2013 SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID TYPE-1; EPIDEMIC; MUTATIONS; DIVERSITY; SUBTYPE; KENYA AB Central and Eastern African HIV sequence data have been most critical in understanding the establishment and evolution of the global HIV pandemic. Here we report on the extent of publicly available HIV genetic sequence data in the Los Alamos National Laboratory Sequence Database sampled from 1959 to 2013 from six African countries: Uganda, Kenya, Tanzania, Burundi, the Democratic Republic of Congo, and Rwanda. We have summarized these data, including HIV subtypes, the years sampled, and the genomic regions sequenced. We also provide curated alignments for this important geographic area in five HIV genomic regions with substantial coverage. C1 [Lamers, Susanna L.; Barbier, Andrew E.; Rose, Rebecca] Bioinfoexperts LLC, POB 693, Thibodaux, LA 70301 USA. [Ratmann, Oliver; Fraser, Christophe] Imperial Coll London, Dept Infect Dis Epidemiol, Med Res Council Ctr Outbreak Anal & Modeling, London, England. [Laeyendecker, Oliver] NIAID, NIH, Baltimore, MD USA. [Laeyendecker, Oliver] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Grabowski, Mary K.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. RP Lamers, SL (reprint author), Bioinfoexperts LLC, POB 693, Thibodaux, LA 70301 USA. EM susanna@bioinfox.com OI Ratmann, Oliver/0000-0001-8667-4118; Fraser, Christophe/0000-0003-2399-9657 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases FX This research was supported, in part, by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases. The authors would like to thank Brian T. Foley at The Los Alamos HIV Sequence Data base and James J. Dollar at the University of Florida for assistance with codon-based alignments. NR 14 TC 0 Z9 0 U1 1 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD SEP PY 2016 VL 32 IS 9 BP 904 EP 908 DI 10.1089/aid.2016.0079 PG 5 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA DV9SY UT WOS:000383283400013 PM 27353049 ER PT J AU Bhatnagar, A Bolli, R Johnstone, BH Traverse, JH Henry, TD Pepine, CJ Willerson, JT Perin, EC Ellis, SG Zhao, DXM Yang, PC Cooke, JP Schutt, RC Trachtenberg, BH Orozco, A Resende, M Ebert, RF Sayre, SL Simari, RD Moye, L Cogle, CR Taylor, DA AF Bhatnagar, Aruni Bolli, Roberto Johnstone, Brian H. Traverse, Jay H. Henry, Timothy D. Pepine, Car J. Willerson, James T. Perin, Emerson C. Ellis, Stephen G. Zhao, David X. M. Yang, Phillip C. Cooke, John P. Schutt, Robert C. Trachtenberg, Barry H. Orozco, Aaron Resende, Micheline Ebert, Ray F. Sayre, Shelly L. Simari, Robert D. Moye, Lem Cogle, Christopher R. Taylor, Doris A. CA CCTRN TI Bone marrow cell characteristics associated with patient profile and cardiac performance outcomes in the LateTIME-Cardiovascular Cell Therapy Research Network (CCTRN) trial SO AMERICAN HEART JOURNAL LA English DT Article ID LEFT-VENTRICULAR FUNCTION; ACUTE MYOCARDIAL-INFARCTION; ENDOTHELIAL PROGENITOR CELLS; MONONUCLEAR-CELLS; HEART-FAILURE; STEM-CELLS; ISCHEMIC-MYOCARDIUM; DISEASE; NEOVASCULARIZATION; DELIVERY AB Background Although several preclinical studies have shown that bone marrow cell (BMC) transplantation promotes cardiac recovery after myocardial infarction, clinical trials with unfractionated bone marrow have shown variable improvements in cardiac function. Methods To determine whether in a population of post myocardial infarction patients, functional recovery after BM transplant is associated with specific BMC subpopulation, we examined the association between BMCs with left ventricular (LV) function in the LateTIME-CCTRN trial. Results In this population, we found that older individuals had higher numbers of BM CD133(+) and CD3(+) cells. Bone marrow from individuals with high body mass index had lower CD45(di)m/CD11b(dim) levels, whereas those with hypertension and higher C-reactive protein levels had higher numbers of CD133(+) cells. Smoking was associated with higher levels of CD133(+)/CD34(+)/VEGFR2(+) cells and lower levels of CD3(+) cells. Adjusted multivariate analysis indicated that CD11b(dim) cells were negatively associated with changes in LV ejection fraction and wall motion in both the infarct and border zones. Change in LV ejection fraction was positively associated with CD133(+), CD34(+), and CD45(+)/CXCR4(dim) cells as well as faster BMC growth rates in endothelial colony forming assays. Conclusions In the LateTIME population, BM composition varied with patient characteristics and treatment. Irrespective of cell therapy, recovery of LV function was greater in patients with greater BM abundance of CD133(+) and CD34(+) cells and worse in those with higher levels of CD11b(dim) cells. Bone marrow phenotype might predict clinical response before BMC therapy and administration of selected BM constituents could potentially improve outcomes of other future clinical trials. C1 [Bhatnagar, Aruni; Bolli, Roberto] Univ Louisville, Louisville, KY 40292 USA. [Johnstone, Brian H.] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Traverse, Jay H.] Abbott NW Hosp, Minneapolis Heart Inst Fdn, Minneapolis, MN USA. [Henry, Timothy D.] Cedars Sinai Heart Inst, Los Angeles, CA USA. [Pepine, Car J.; Cogle, Christopher R.] Univ Florida, Coll Med, Gainesville, FL USA. [Willerson, James T.; Perin, Emerson C.; Orozco, Aaron; Resende, Micheline; Taylor, Doris A.] Baylor Coll Med, CHI St Lukes Hlth, Texas Heart Inst, Med Ctr, Houston, TX 77030 USA. [Ellis, Stephen G.] Cleveland Clin Fdn, 9500 Euclid Ave, Cleveland, OH 44195 USA. [Zhao, David X. M.] Wake Forest, Sch Med, Winston Salem, NC USA. [Yang, Phillip C.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Cooke, John P.; Schutt, Robert C.; Trachtenberg, Barry H.] Houston Methodist DeBakey Heart & Vasc Ctr, Houston, TX USA. [Ebert, Ray F.] NHLBI, Bldg 10, Bethesda, MD 20892 USA. [Sayre, Shelly L.; Moye, Lem] Univ Texas Houston, Sch Publ Hlth, 1200 Pressler St,E-1009, Houston, TX 77030 USA. [Simari, Robert D.] Univ Kansas, Sch Med, Kansas City, KS USA. RP Moye, L (reprint author), Univ Texas Houston, Sch Publ Hlth, 1200 Pressler St,E-1009, Houston, TX 77030 USA. EM Lemmoye@msn.com OI Cooke, John/0000-0003-0033-9138 FU National Heart, Lung, and Blood Institute [5 UM1 HL087318] FX This work was supported by the National Heart, Lung, and Blood Institute under cooperative agreement 5 UM1 HL087318. NR 36 TC 1 Z9 1 U1 4 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 EI 1097-5330 J9 AM HEART J JI Am. Heart J. PD SEP PY 2016 VL 179 BP 142 EP 150 DI 10.1016/j.ahj.2016.06.018 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DV7JL UT WOS:000383112100016 PM 27595689 ER PT J AU Liu, JJ Cahoon, EK Linet, MS Little, MP Dagnall, CL Higson, H Savage, SA Freedman, DM AF Liu, Jason J. Cahoon, Elizabeth K. Linet, Martha S. Little, Mark P. Dagnall, Casey L. Higson, Herbert Savage, Sharon A. Freedman, D. Michal TI Relationship between plasma 25-hydroxymitamin D and leucocyte telomere length by sex and race in a US study SO BRITISH JOURNAL OF NUTRITION LA English DT Article DE Vitamin D; 25-Hydroxymitamin D; Leucocyte telomere length; Sexes; Race ID VITAMIN-D; RADIOLOGIC TECHNOLOGISTS; HEALTH; DISEASE; LONGER; CANCER; COHORT; ADULTS; WOMEN; PCR AB A few studies have examined the association between vitamin D and telomere length, and fewer still have examined the relationship in black or male populations. We investigated the cross-sectional association between the vitamin D metabolite 25-hydroxyvitamin D (25(OH)D) concentration in plasma and relative leucocyte telomere length (LTL) in 1154 US radiologic technologists who were 48-93 years old (373 white females, 278 white males, 338 black females, 165 black males). Plasma 25(OH)D concentration was measured by the chemiluminescence immunoassay, and relative LTL was measured by quantitative PCR. Logistic regression was used to obtain OR and 95 % CI for long v. short (based on median) LTL in relation to continuous 25(OH)D, quartiles of 25(OH)D and 25(OH)D deficiency. We found no significant association between continuous 25(OH)D and long LTL in all participants (P-trend=0440), nor in white females (P-trend=0845), white males (P-trend=0636), black females (P-trend=0967) or black males (P-trend=0484). Vitamin D deficiency (defined as 25(OH)D<30 nmol/l), however, was significantly associated with short LTL in whites (P=0024), but not in other groups. In this population, we found little evidence to support associations between 25(OH)D and long LTL over the entire range of 25(OH)D in the overall study population or by sex and race. C1 [Liu, Jason J.; Cahoon, Elizabeth K.; Linet, Martha S.; Little, Mark P.; Dagnall, Casey L.; Higson, Herbert; Savage, Sharon A.; Freedman, D. Michal] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA. [Dagnall, Casey L.; Higson, Herbert] Frederick Natl Lab Canc Res, Canc Genom Res Lab, Leidos Biomed Res Inc, Frederick, MD 21702 USA. RP Freedman, DM (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA. EM freedmam@mail.nih.gov OI Dagnall, Casey/0000-0001-7334-4718 FU Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health FX This work was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health. NR 29 TC 1 Z9 1 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 0007-1145 EI 1475-2662 J9 BRIT J NUTR JI Br. J. Nutr. PD SEP PY 2016 VL 116 IS 6 BP 953 EP 960 DI 10.1017/S0007114516002075 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DV5UO UT WOS:000382996100001 PM 27515444 ER PT J AU Mayer, FP Wimmer, L Dillon-Carter, O Partilla, JS Burchardt, NV Mihovilovic, MD Baumann, MH Sitte, HH AF Mayer, F. P. Wimmer, L. Dillon-Carter, O. Partilla, J. S. Burchardt, N. V. Mihovilovic, M. D. Baumann, M. H. Sitte, H. H. TI Phase I metabolites of mephedrone display biological activity as substrates at monoamine transporters SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Article ID HUMAN SEROTONIN TRANSPORTER; PSYCHOACTIVE SUBSTANCES; 3,4-METHYLENEDIOXYMETHAMPHETAMINE MDMA; 4-METHYLMETHCATHINONE MEPHEDRONE; PHARMACOLOGICAL CHARACTERIZATION; MEDIATED EFFLUX; DESIGNER DRUGS; CONCISE GUIDE; BATH SALTS; DOPAMINE AB BACKGROUND AND PURPOSE 4-Methyl-N-methylcathinone (mephedrone) is a synthetic stimulant that acts as a substrate-type releaser at transporters for dopamine (DAT), noradrenaline (NET) and 5-HT (SERT). Upon systemic administration, mephedrone is metabolized to several phase I compounds: the N-demethylated metabolite, 4-methylcathinone (nor-mephedrone); the ring-hydroxylated metabolite, 4-hydroxytolylmephedrone (4-OH-mephedrone); and the reduced keto-metabolite, dihydromephedrone. EXPERIMENTAL APPROACH We used in vitro assays to compare the effects of mephedrone and synthetically prepared metabolites on transporter-mediated uptake and release in HEK293 cells expressing human monoamine transporters and in rat brain synaptosomes. In vivo microdialysis was employed to examine the effects of i.v. metabolite injection (1 and 3 mg.kg(-1)) on extracellular dopamine and 5-HT levels in rat nucleus accumbens. KEY RESULTS In cells expressing transporters, mephedrone and its metabolites inhibited uptake, although dihydromephedrone was weak overall. In cells and synaptosomes, nor-mephedrone and 4-OH-mephedrone served as transportable substrates, inducing release via monoamine transporters. When administered to rats, mephedrone and nor-mephedrone produced elevations in extracellular dopamine and 5-HT, whereas 4-OH-mephedrone did not. Mephedrone and nor-mephedrone, but not 4-OH-mephedrone, induced locomotor activity. CONCLUSIONS AND IMPLICATIONS Our results demonstrate that phase I metabolites of mephedrone are transporter substrates (i.e. releasers) at DAT, NET and SERT, but dihydromephedrone is weak in this regard. When administered in vivo, nor-mephedrone increases extracellular dopamine and 5-HT in the brain whereas 4-OH-mephedrone does not, suggesting the latter metabolite does not penetrate the blood-brain barrier. Future studies should examine the pharmacokinetics of nor-mephedrone to determine its possible contribution to the in vivo effects produced by mephedrone. C1 [Mayer, F. P.; Burchardt, N. V.; Sitte, H. H.] Med Univ Vienna, Ctr Physiol & Pharmacol, Inst Pharmacol, Wahringerstr 13A, A-1090 Vienna, Austria. [Wimmer, L.; Mihovilovic, M. D.] Vienna Univ Technol, Inst Appl Synthet Chem, Vienna, Austria. [Dillon-Carter, O.; Partilla, J. S.; Baumann, M. H.] NIDA, DDRU, Intramural Res Program, NIH, Baltimore, MD USA. [Sitte, H. H.] Med Univ Vienna, Ctr Addict Res & Sci, Vienna, Austria. RP Sitte, HH (reprint author), Med Univ Vienna, Ctr Physiol & Pharmacol, Inst Pharmacol, Wahringerstr 13A, A-1090 Vienna, Austria. EM harald.sitte@meduniwien.ac.at OI Sitte, Harald/0000-0002-1339-7444 FU Austrian Research Fund/FWF [F3506, W1232]; Intramural Research Program of the NIDA, NIH [DA000523-07]; FWF-DK MolTag, FWF [W1232]; DOC-fellowship of the Austrian Academy of Sciences FX We thank Dr Oliver Kudlacek and Marion Holy for providing HEK293-cells stably expressing the human serotonin transporter and Dr Lars Richter for calculating the distribution coefficients of mephedrone and its metabolites. The research was supported by Austrian Research Fund/FWF grants F3506 and W1232 (H.H.S.), the Intramural Research Program of the NIDA, NIH, grant DA000523-07 (M.H.B.), the FWF-DK MolTag, FWF W1232 (M.D.M.), and F.P.M. is a recipient of a DOC-fellowship of the Austrian Academy of Sciences. NR 65 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1188 EI 1476-5381 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD SEP PY 2016 VL 173 IS 17 BP 2657 EP 2668 DI 10.1111/bph.13547 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DV9KD UT WOS:000383258400008 PM 27391165 ER PT J AU Hallahan, B Ryan, T Hibbeln, JR Murray, IT Glynn, S Ramsden, CE SanGiovanni, JP Davis, JM AF Hallahan, Brian Ryan, Timothy Hibbeln, Joseph R. Murray, Ivan T. Glynn, Shauna Ramsden, Christopher E. SanGiovanni, John Paul Davis, John M. TI Efficacy of omega-3 highly unsaturated fatty acids in the treatment of depression SO BRITISH JOURNAL OF PSYCHIATRY LA English DT Review ID PLACEBO-CONTROLLED TRIAL; RANDOMIZED CONTROLLED-TRIAL; ETHYL-EICOSAPENTAENOIC ACID; QUALITY-OF-LIFE; OMEGA-3-FATTY-ACID DOCOSAHEXAENOIC ACID; FISH-OIL SUPPLEMENTATION; PRELIMINARY DOUBLE-BLIND; MIDDLE-AGED WOMEN; BIPOLAR DISORDER; CLINICAL-TRIAL AB Background Trials evaluating efficacy of omega-3 highly unsaturated fatty acids (HUFAS) in major depressive disorder report discrepant findings. Aims To establish the reasons underlying inconsistent findings among randomised controlled trials (RCTs) of omega-3 HUFAS for depression and to assess implications for further trials. Method A systematic bibliographic search of double-blind RCTs was conducted between January 1980 and July 2014 and an exploratory hypothesis-testing meta-analysis performed in 35 RCTs including 6665 participants receiving omega-3 HUFAs and 4373 participants receiving placebo. Results Among participants with diagnosed depression, eicosapentaenoic acid (EPA)-predominant formulations (>50% EPA) demonstrated clinical benefits compared with placebo (Hedge's G=0.61, P<0.001) whereas docosahexaenoic acid (DHA)-predominant formulation's (>50% DHA) did not. EPA failed to prevent depressive symptoms among populations not diagnosed for depression. Conclusions Further RCTs should be conducted on study populations with diagnosed or clinically significant depression of adequate duration using EPA-predominant omega-3 HUFA formulations. C1 [Hallahan, Brian] Natl Univ Ireland Galway, Dept Psychiat, Inst Clin Sci, Galway, Ireland. [Ryan, Timothy; Davis, John M.] Univ Illinois, Dept Psychiat, Chicago, IL 60612 USA. [Hibbeln, Joseph R.; Ramsden, Christopher E.; SanGiovanni, John Paul] NIAAA, Sect Nutr Neurosci, Lab Membrane Biochem & Biophys, NIH, Rockville, MD 20852 USA. [Murray, Ivan T.] Univ Hosp Galway, Dept Psychiat, Galway, Ireland. [Glynn, Shauna] Child & Adolescent Mental Hlth Serv, Castlebar, Mayo, Ireland. RP Hallahan, B (reprint author), Natl Univ Ireland Galway, Dept Psychiat, Inst Clin Sci, Galway, Ireland. EM brian.hallahan@nuigalway.ie OI Hallahan, Brian/0000-0003-0518-9757 FU National Institute of Alcohol Abuse and Alcoholism FX The intramural programme of the National Institute of Alcohol Abuse and Alcoholism provided support for this work. NR 81 TC 1 Z9 1 U1 27 U2 29 PU ROYAL COLLEGE OF PSYCHIATRISTS PI LONDON PA BRITISH JOURNAL OF PSYCHIATRY 17 BELGRAVE SQUARE, LONDON SW1X 8PG, ENGLAND SN 0007-1250 EI 1472-1465 J9 BRIT J PSYCHIAT JI Br. J. Psychiatry PD SEP PY 2016 VL 209 IS 3 BP 192 EP 201 DI 10.1192/bjp.bp.114.160242 PG 10 WC Psychiatry SC Psychiatry GA DW0FH UT WOS:000383315800005 PM 27103682 ER PT J AU Howlader, N Shiels, MS Mariotto, AB Engels, EA AF Howlader, Nadia Shiels, Meredith S. Mariotto, Angela B. Engels, Eric A. TI Contributions of HIV to Non-Hodgkin Lymphoma Mortality Trends in the United States SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID CHANGING INCIDENCE; KAPOSIS-SARCOMA; CANCER-RISK; POPULATION; PEOPLE; AIDS; SURVEILLANCE; RATES AB Background: The human immunodeficiency virus (HIV) epidemic has strongly influenced non-Hodgkin lymphoma (NHL) incidence in the U.S. general population, but its effects on NHL mortality trends are unknown. Methods: Using SEER cancer registry data, we assessed NHL mortality rates in the United States (2005-2012) and mapped NHL deaths to prior incident cases. Data included HIV status at NHL diagnosis. We describe the proportion of NHL deaths linked to an HIV-infected case, for 3 AIDS-defining subtypes [diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma, and central nervous system (CNS) lymphoma] and within demographic categories. We also present incidence-based mortality (IBM) rates showing the impact of HIV on mortality trends and describe survival after NHL diagnosis by calendar year. Results: Of 11,071 NHL deaths, 517 (4.6%) were in HIV-infected persons. This proportion was higher in deaths mapped to DLBCL (7.3% with HIV), Burkitt lymphoma (33.3%), and CNS lymphoma (17.6%), and among deaths from these subtypes, for people aged 20-49 years (46.6%), males (15.2%), and blacks (39.3%). IBM rates declined steeply during 2005-2012 for HIV-infectedNHLcases (-7.6% per year, P = 0.001). This trend reflects a steep decline in incident NHL among HIV-infected people after 1996, when highly active antiretroviral therapy was introduced. Five-year cancer-specific survival improved more markedly among HIV-infected cases (9%-54%) than HIV-uninfected cases (62%-76%) during 1990-2008. Conclusions: The HIV epidemic has strongly contributed to NHL deaths, especially for AIDS-defining NHL subtypes and groups with high HIV prevalence. Impact: Declining NHL mortality rates for HIV-infected cases reflect both declining incidence and improving survival. (C) 2016 AACR. C1 [Howlader, Nadia; Mariotto, Angela B.] NCI, Surveillance Res Program, Div Canc Control & Populat Sci, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. [Howlader, Nadia] George Washington Univ, Milken Inst Sch Publ Hlth, Dept Epidemiol & Biostat, Washington, DC USA. [Shiels, Meredith S.; Engels, Eric A.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Howlader, N (reprint author), NCI, Surveillance Res Program, Div Canc Control & Populat Sci, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM howladern@mail.nih.gov FU Surveillance Research Program in the Division of Cancer Control and Population Sciences; Intramural Research Program in the Division of Cancer Epidemiology and Genetics at the National Cancer Institute FX This study was supported by the Surveillance Research Program in the Division of Cancer Control and Population Sciences and the Intramural Research Program in the Division of Cancer Epidemiology and Genetics at the National Cancer Institute. NR 37 TC 1 Z9 1 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD SEP PY 2016 VL 25 IS 9 BP 1289 EP 1296 DI 10.1158/1055-9965.EPI-16-0273 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DV6KO UT WOS:000383044500002 PM 27418269 ER PT J AU Calo, WA Gilkey, MB Shah, PD Moss, JL Brewer, NT AF Calo, William A. Gilkey, Melissa B. Shah, Parth D. Moss, Jennifer L. Brewer, Noel T. TI Parents' Support for School-Entry Requirements for Human Papillomavirus Vaccination: A National Study SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID MANDATORY HPV VACCINATION; UNITED-STATES; ADOLESCENT IMMUNIZATION; NONMEDICAL EXEMPTIONS; ADVISORY-COMMITTEE; PUBLIC-HEALTH; LAWS; POLICY; RECOMMENDATIONS; CONTROVERSY AB Background: The number of states proposing school-entry requirements for human papillomavirus (HPV) vaccination has increased over the last decade. However, data are currently limited regarding parents' support of such laws. We sought to obtain the first national estimates of parents' support of HPV vaccination school-entry requirements. Methods: A national sample of 1,501 parents of 11- to 17-year-old children completed a web-based survey between November 2014 and January 2015. Analyses used multivariable logistic regression to assess correlates of support for school-entry requirements for HPV vaccination. Results: Overall, 21% of parents agreed that laws requiring HPV vaccination for school attendance "are a good idea," and 54% disagreed. If school-entry requirements included opt-out provisions, agreement increased to 57%, and only 21% disagreed. Parents more often agreed with requirements without opt-out provisions if they were Hispanic [OR = 1.53; 95% confidence interval (CI), 1.05-2.22], believed HPV vaccine was as or more important than other adolescent vaccines (OR = 2.76; 95% CI, 1.98-3.83), or believed HPV vaccine was effective for preventing cervical cancer (OR = 2.55; 95% CI, 1.93-3.37). Parents less often agreed if they resided in Midwest states or believed that HPV vaccine was being pushed to make money for drug companies (both P < 0.05). Conclusion: Opt-out provisions almost tripled parents' support for HPV vaccine school-entry requirements. Our findings suggest that race/ethnicity, attitudes about HPV vaccine, and region of residence may influence support for requirements without opt-out provisions. Impact: Opt-out provisions greatly increase parent support of school-entry requirements for HPV vaccination but may make them ineffective. (C) 2016 AACR. C1 [Calo, William A.] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Hlth Policy & Management, Chapel Hill, NC USA. [Gilkey, Melissa B.] Harvard Med Sch, Dept Populat Med, Boston, MA USA. [Gilkey, Melissa B.] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Gilkey, Melissa B.] Dana Farber Harvard Canc Ctr, Boston, MA USA. [Shah, Parth D.; Moss, Jennifer L.; Brewer, Noel T.] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Hlth Behav, 325A Rosenau Hall,CB 7440, Chapel Hill, NC 27599 USA. [Moss, Jennifer L.] NCI, Div Canc Prevent, Bethesda, MD 20892 USA. [Brewer, Noel T.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC USA. RP Brewer, NT (reprint author), Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Hlth Behav, 325A Rosenau Hall,CB 7440, Chapel Hill, NC 27599 USA. EM ntb@unc.edu FU Merck Sharp & Dohme Investigator Studies Program [50928]; National Cancer Institute [R25 CA116339, K22 CA186979, F31 CA189411] FX This study was funded by Merck Sharp & Dohme Investigator Studies Program, grant #50928 (to N.T. Brewer). This study was also supported by career development or training grants from the National Cancer Institute: R25 CA116339 (to W.A. Calo), K22 CA186979 (to M.B. Gilkey), and F31 CA189411 (to J.L. Moss). NR 52 TC 1 Z9 1 U1 10 U2 10 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD SEP PY 2016 VL 25 IS 9 BP 1317 EP 1325 DI 10.1158/1055-9965.EPI-15-1159 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DV6KO UT WOS:000383044500006 PM 27543621 ER PT J AU Sherman, ME Drapkin, RI Horowitz, NS Crum, CP Friedman, S Kwon, JS Levine, DA Shih, IM Shoupe, D Swisher, EM Walker, J Trabert, B Greene, MH Samimi, G Temkin, SM Minasian, LM AF Sherman, Mark E. Drapkin, Ronny I. Horowitz, Neil S. Crum, Christopher P. Friedman, Sue Kwon, Janice S. Levine, Douglas A. Shih, Ie-Ming Shoupe, Donna Swisher, Elizabeth M. Walker, Joan Trabert, Britton Greene, Mark H. Samimi, Goli Temkin, Sarah M. Minasian, Lori M. TI Rationale for Developing a Specimen Bank to Study the Pathogenesis of High-Grade Serous Carcinoma: A Review of the Evidence SO CANCER PREVENTION RESEARCH LA English DT Review ID TUBAL-INTRAEPITHELIAL-CARCINOMA; REDUCING SALPINGO-OOPHORECTOMY; BRCA-MUTATION CARRIERS; OVARIAN-CANCER RISK; RANDOMIZED CONTROLLED-TRIAL; FALLOPIAN-TUBE; OPPORTUNISTIC SALPINGECTOMY; COLLABORATIVE TRIAL; HEREDITARY BREAST; PRECURSOR LESIONS AB Women with clinically detected high-grade serous carcinomas (HGSC) generally present with advanced-stage disease, which portends a poor prognosis, despite extensive surgery and intensive chemotherapy. Historically, HGSCs were presumed to arise from the ovarian surface epithelium (OSE), but the inability to identify early-stage HGSCs and their putative precursors in the ovary dimmed prospects for advancing our knowledge of the pathogenesis of these tumors and translating these findings into effective prevention strategies. Over the last decade, increased BRCA1/2 mutation testing coupled with performance of risk-reducing surgeries has enabled studies that have provided strong evidence that many, but probably not all, HGSCs among BRCA1/2 mutation carriers appear to arise from the fallopian tubes, rather than from the ovaries. This shift in our understanding of the pathogenesis of HGSCs provides an important opportunity to achieve practice changing advances; however, the scarcity of clinically annotated tissues containing early lesions, particularly among women at average risk, poses challenges to progress. Accordingly, we review studies that have kindled our evolving understanding of the pathogenesis of HGSC and present the rationale for developing an epidemiologically annotated national specimen resource to support this research. (C) 2016 AACR. C1 [Sherman, Mark E.; Samimi, Goli; Temkin, Sarah M.; Minasian, Lori M.] NCI, Div Canc Prevent, Bethesda, MD 20892 USA. [Drapkin, Ronny I.] Univ Penn, Dept Obstet & Gynecol, Penn Ovarian Canc Res Ctr, Philadelphia, PA 19104 USA. [Horowitz, Neil S.] Harvard Med Sch, Dept Obstet Gynecol & Reprod Biol, Boston, MA USA. [Horowitz, Neil S.] Brigham & Womens Hosp, Dept Obstet & Gynecol, 75 Francis St, Boston, MA 02115 USA. [Crum, Christopher P.] Brigham & Womens Hosp, Dept Pathol, Div Womens & Perinatal Pathol, 75 Francis St, Boston, MA 02115 USA. [Crum, Christopher P.] Harvard Med Sch, Boston, MA USA. [Friedman, Sue] FORCE, Tampa, FL USA. [Kwon, Janice S.] Univ British Columbia, Div Gynecol Oncol, Vancouver, BC, Canada. [Kwon, Janice S.] BC Canc Agcy, Vancouver, BC, Canada. [Levine, Douglas A.] NYU, Langone Med Ctr, Laura & Isaac Perlmutter Canc Ctr, Gynecol Oncol, New York, NY USA. [Shih, Ie-Ming] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Shoupe, Donna] Univ Southern Calif, Keck Sch Med, Dept Obstet & Gynecol, Div Reprod Endocrinol, Los Angeles, CA 90033 USA. [Swisher, Elizabeth M.] Univ Washington, Sch Med, Dept Obstet & Gynecol, Div Gynecol Oncol, Seattle, WA 98195 USA. [Walker, Joan] Univ Oklahoma, Hlth Sci Ctr, Dept Gynecol Oncol, Oklahoma City, OK USA. [Walker, Joan] Charles Stephenson Canc Ctr, Oklahoma City, OK USA. [Trabert, Britton; Greene, Mark H.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Temkin, Sarah M.] Johns Hopkins Univ, Sch Med, Dept Gynecol & Obstet, Baltimore, MD 21205 USA. RP Sherman, ME (reprint author), NCI, Breast & Gynecol Canc Res Grp, Canc Prevent Div, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM ShermanM@mail.nih.gov RI Trabert, Britton/F-8051-2015 FU National Cancer Institute Intramural Program; Department of Defense [OC130500, W81XWH-11-2-0230/OC100517]; Stand Up To Cancer-Ovarian Cancer Research Fund Alliance-National Ovarian Cancer Coalition Dream Team Translational Research Grant [SU2C-AACR-DT16-15] FX This work was supported in part by funding from the National Cancer Institute Intramural Program (B. Trabert and M. Greene), Department of Defense OC130500 (C. Crum), Department of Defense (W81XWH-11-2-0230/OC100517 (I.-M. Shih), Stand Up To Cancer-Ovarian Cancer Research Fund Alliance-National Ovarian Cancer Coalition Dream Team Translational Research Grant (Grant Number SU2C-AACR-DT16-15; E. Swisher). Stand Up to Cancer is a program of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, a scientific partner of SU2C. NR 83 TC 3 Z9 3 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 EI 1940-6215 J9 CANCER PREV RES JI Cancer Prev. Res. PD SEP PY 2016 VL 9 IS 9 BP 713 EP 720 DI 10.1158/1940-6207.CAPR-15-0384 PG 8 WC Oncology SC Oncology GA DV7BJ UT WOS:000383090500001 PM 27221539 ER PT J AU Montrose, DC Zhou, XK McNally, EM Sue, E Yantiss, RK Gross, SS Leve, ND Karoly, ED Suen, CS Ling, LL Benezra, R Pamer, EG Dannenberg, AJ AF Montrose, David C. Zhou, Xi Kathy McNally, Erin M. Sue, Erika Yantiss, Rhonda K. Gross, Steven S. Leve, Nitai D. Karoly, Edward D. Suen, Chen S. Ling, Lilan Benezra, Robert Pamer, Eric G. Dannenberg, Andrew J. TI Celecoxib Alters the Intestinal Microbiota and Metabolome in Association with Reducing Polyp Burden SO CANCER PREVENTION RESEARCH LA English DT Article ID CYCLOOXYGENASE-2 INHIBITOR CELECOXIB; ADENOMATOUS POLYPOSIS; COLORECTAL-CANCER; STEM-CELLS; COLON; INFLAMMATION; SERINE; MICROENVIRONMENT; TUMORIGENESIS; PREVENTION AB Treatment with celecoxib, a selective COX-2 inhibitor, reduces formation of premalignant adenomatous polyps in the gastrointestinal tracts of humans and mice. In addition to its chemopreventive activity, celecoxib can exhibit antimicrobial activity. Differing bacterial profiles have been found in feces from colon cancer patients compared with those of normal subjects. Moreover, preclinical studies suggest that bacteria can modulate intestinal tumorigenesis by secreting specific metabolites. In the current study, we determined whether celecoxib treatment altered the luminal microbiota and metabolome in association with reducing intestinal polyp burden in mice. Administration of celecoxib for 10 weeks markedly reduced intestinal polyp burden in APC(Min/+) mice. Treatment with celecoxib also altered select luminal bacterial populations in both APC(Min/+) and wild-type mice, including decreased Lactobacillaceae and Bifidobacteriaceae as well as increased Coriobacteriaceae. Metabolomic analysis demonstrated that celecoxib caused a strong reduction in many fecal metabolites linked to carcinogenesis, including glucose, amino acids, nucleotides, and lipids. Ingenuity Pathway Analysis suggested that these changes in metabolites may contribute to reduced cell proliferation. To this end, we showed that celecoxib reduced cell proliferation in the base of normal appearing ileal and colonic crypts of APC(Min/+) mice. Consistent with this finding, lineage tracing indicated that celecoxib treatment reduced the rate at which Lgr5-positive stem cells gave rise to differentiated cell types in the crypts. Taken together, these results demonstrate that celecoxib alters the luminal microbiota and metabolome along with reducing epithelial cell proliferation in mice. Wehypothesize that these actions contribute to its chemopreventive activity. (C)2016 AACR. C1 [Montrose, David C.; McNally, Erin M.; Sue, Erika; Dannenberg, Andrew J.] Weill Cornell Med Coll, Dept Med, New York, NY USA. [Zhou, Xi Kathy; Leve, Nitai D.] Weill Cornell Med Coll, Dept Healthcare Policy & Res, New York, NY USA. [Yantiss, Rhonda K.] Weill Cornell Med Coll, Dept Pathol & Lab Med, New York, NY USA. [Gross, Steven S.] Weill Cornell Med Coll, Dept Pharmacol, New York, NY USA. [Karoly, Edward D.] Metabolon Inc, Durham, NC USA. [Suen, Chen S.] NCI, Div Canc Prevent, Rockville, MD USA. [Ling, Lilan; Pamer, Eric G.] Mem Sloan Kettering Canc Ctr, Lucille Castori Ctr Microbes Inflammat & Canc, 1275 York Ave, New York, NY 10021 USA. [Benezra, Robert] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, 1275 York Ave, New York, NY 10021 USA. [Pamer, Eric G.] Mem Sloan Kettering Canc Ctr, Immunol Program, 1275 York Ave, New York, NY 10021 USA. [Pamer, Eric G.] Mem Sloan Kettering Canc Ctr, Dept Med, Infect Dis Serv, New York, NY 10021 USA. RP Dannenberg, AJ (reprint author), Weill Cornell Med Coll, 1300 York Ave,Room F-206, New York, NY 10021 USA. EM ajdannen@med.cornell.edu FU NIH/NCATS [TL1 TR000459]; NIH/NCI [HHSN2612012000181]; New York Crohn's Foundation FX The project was supported by NIH/NCATS TL1 TR000459 (D.C. Montrose), NIH/NCI contract HHSN2612012000181 (A.J. Dannenberg and S.S. Gross), and the New York Crohn's Foundation (A.J. Dannenberg). NR 46 TC 3 Z9 3 U1 2 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 EI 1940-6215 J9 CANCER PREV RES JI Cancer Prev. Res. PD SEP PY 2016 VL 9 IS 9 BP 721 EP 731 DI 10.1158/1940-6207.CAPR-16-0095 PG 11 WC Oncology SC Oncology GA DV7BJ UT WOS:000383090500002 PM 27432344 ER PT J AU Osinga, TE van der Horst-Schrivers, ANA van Faassen, M Kerstens, MN Dullaart, RPF Pacak, K Links, TP Kema, IP AF Osinga, Thamara E. van der Horst-Schrivers, Anouk N. A. van Faassen, Martijn Kerstens, Michiel N. Dullaart, Robin P. F. Pacak, Karel Links, Thera P. Kema, Ido P. TI Mass spectrometric quantification of salivary metanephrines-A study in healthy subjects SO CLINICAL BIOCHEMISTRY LA English DT Article DE Saliva; Metanephrines; LC-MS/MS; Paraganglioma ID CLINICAL-PRACTICE GUIDELINE; NORMETANEPHRINE CONCENTRATIONS; PLASMA-CATECHOLAMINES; CUSHINGS-SYNDROME; PHEOCHROMOCYTOMA; DIAGNOSIS; METABOLITES; ADJUSTMENT; URINARY; DRUGS AB Background: Determination of metanephrine (MN), normetanephrine (NMN), and 3-methoxytyramine (3-MT) in saliva may offer potential diagnostic advantages in diagnosing pheochromocytoma. Methods: In this preliminary study, we determined metanephrine concentrations in saliva of healthy subjects and the relationship with simultaneously measured plasma metanephrines. We also studied the possible influence of pre-analytical conditions such as a collection device, awakening, posture, and eating on the salivary metanephrine levels. Results: Eleven healthy subjects were included. Fasting blood and saliva samples were collected in seated position and after 30 min of horizontal rest. Plasma and salivary MN, NMN, and 3-MT concentrations were determined using a high-performance liquid chromatography tandem mass spectrometric technique (LC-MS/MS) with automated solid phase extraction sample preparation. Metanephrines were detectable in saliva from all participants both in seated and supine position. No significant correlations were observed between the MN, NMN, and 3-MT concentrations in saliva and plasma in seated or supine position. Furthermore, there was no difference between MN, NMN, and 3-MT samples collected with or without a collection device. Conclusion: Metanephrines can be detected in saliva with LC-MS/MS with sufficient sensitivity and precision. Our findings warrant evaluation of salivary metanephrine measurement as a novel laboratory tool in the work-up of patients suspected of having a pheochromocytoma. (C) 2016 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. C1 [Osinga, Thamara E.; van der Horst-Schrivers, Anouk N. A.; Kerstens, Michiel N.; Dullaart, Robin P. F.; Links, Thera P.] Univ Groningen, Univ Med Ctr Groningen, Dept Endocrinol AA31, POB 30-001, NL-9700 RB Groningen, Netherlands. [van Faassen, Martijn; Kema, Ido P.] Univ Groningen, Univ Med Ctr Groningen, Dept Lab Med EA61, POB 30-001, NL-9700 RB Groningen, Netherlands. [Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bldg 10,Room 1-3140,10 Ctr Dr, Bethesda, MD 20892 USA. RP Kema, IP (reprint author), Univ Groningen, Univ Med Ctr Groningen, Dept Lab Med EA61, Hanzepl 1, NL-9700 RB Groningen, Netherlands. EM t.osinga@umcg.nl; a.n.a.van.der.horst@umcg.nl; hj.r.van.faassen@umcg.nl; m.n.kerstens@umcg.nl; r.p.f.dullaart@umcg.nl; karel@mail.nih.gov; t.p.links@umcg.nl; i.p.kema@umcg.nl FU Intramural NIH HHS [ZIA HD008735-15] NR 31 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 0009-9120 EI 1873-2933 J9 CLIN BIOCHEM JI Clin. Biochem. PD SEP PY 2016 VL 49 IS 13-14 SI SI BP 983 EP 988 DI 10.1016/j.clinbiochem.2016.02.003 PG 6 WC Medical Laboratory Technology SC Medical Laboratory Technology GA DV7JO UT WOS:000383112400008 PM 26874200 ER PT J AU Yuan, Y Hess, KR Hilsenbeck, SG Gilbert, MR AF Yuan, Ying Hess, Kenneth R. Hilsenbeck, Susan G. Gilbert, Mark R. TI Bayesian Optimal Interval Design: A Simple and Well-Performing Design for Phase I Oncology Trials SO CLINICAL CANCER RESEARCH LA English DT Article ID CONTINUAL REASSESSMENT METHOD; CLINICAL-TRIALS; DOWN DESIGNS; CANCER AB Despite more than two decades of publications that offer more innovative model-based designs, the classical 3 + 3 design remains the most dominant phase I trial design in practice. In this article, we introduce a new trial design, the Bayesian optimal interval (BOIN) design. The BOIN design is easy to implement in a way similar to the 3 + 3 design, but is more flexible for choosing the target toxicity rate and cohort size and yields a substantially better performance that is comparable with that of more complex model-based designs. The BOIN design contains the 3 + 3 design and the accelerated titration design as special cases, thus linking it to established phase I approaches. A numerical study shows that the BOIN design generally outperforms the 3 + 3 design and the modified toxicity probability interval (mTPI) design. The BOIN design is more likely than the 3 + 3 design to correctly select the MTD and allocate more patients to the MTD. Compared with the mTPI design, the BOIN design has a substantially lower risk of overdosing patients and generally a higher probability of correctly selecting the MTD. User-friendly software is freely available to facilitate the application of the BOIN design. (C) 2016 AACR. C1 [Yuan, Ying; Hess, Kenneth R.] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA. [Hilsenbeck, Susan G.] Baylor Coll Med, Duncan Canc Ctr, Houston, TX 77030 USA. [Gilbert, Mark R.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Yuan, Y (reprint author), Univ Texas MD Anderson Canc Ctr, Unit 1411,1400 Pressler St, Houston, TX 77030 USA. EM yyuan@mdanderson.org FU NIH [P50CA098258, R01CA154591] FX Y. Yuan was supported in part by the NIH under award numbers P50CA098258 and R01CA154591. NR 24 TC 1 Z9 1 U1 4 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 1 PY 2016 VL 22 IS 17 BP 4291 EP 4301 DI 10.1158/1078-0432.CCR-16-0592 PG 11 WC Oncology SC Oncology GA DV6IR UT WOS:000383038200004 PM 27407096 ER PT J AU Zeligs, KP Neuman, MK Annunziata, CM AF Zeligs, Kristen P. Neuman, Monica K. Annunziata, Christina M. TI Molecular Pathways: The Balance between Cancer and the Immune System Challenges the Therapeutic Specificity of Targeting Nuclear Factor-kappa B Signaling for Cancer Treatment SO CLINICAL CANCER RESEARCH LA English DT Article ID EPITHELIAL OVARIAN-CANCER; SMAC-MIMETIC BIRINAPANT; X-LINKED INHIBITOR; HUMAN COLON-CANCER; NF-KB ACTIVATION; PHASE-I; PROSTATE CARCINOMA; INDUCED APOPTOSIS; MULTIPLE-MYELOMA; DOWN-REGULATION AB The NF-kappa B signaling pathway is a complex network linking extracellular stimuli to cell survival and proliferation. Cytoplasmic signaling to activate NF-kappa B can occur as part of the DNA damage response or in response to a large variety of activators, including viruses, inflammation, and cell death. NF-kappa B transcription factors play a fundamental role in tumorigenesis and are implicated in the origination and propagation of both hematologic and solid tumor types, including melanoma, breast, prostate, ovarian, pancreatic, colon, lung, and thyroid cancers. On the other hand, NF-kappa B signaling is key to immune function and is likely necessary for antitumor immunity. This presents a dilemma when designing therapeutic approaches to target NF-kappa B. There is growing interest in identifying novel modulators to inhibit NF-kappa B activity as impeding different steps of the NF-kappa B pathway has potential to slow tumor growth, progression, and resistance to chemotherapy. Despite significant advances in our understanding of this pathway, our ability to effectively clinically block key targets for cancer therapy remains limited due to on-target effects in normal tissues. Tumor specificity is critical to developing therapeutic strategies targeting this antiapoptotic signaling pathway to maintain antitumor immune surveillance when applying such therapy to patients. (C) 2016 AACR. C1 [Zeligs, Kristen P.; Neuman, Monica K.; Annunziata, Christina M.] NCI, Ctr Canc Res, Womens Malignancies Branch, Bethesda, MD 20892 USA. [Zeligs, Kristen P.] Walter Reed Natl Mil Med Ctr, Dept Gynecol Oncol, Bethesda, MD USA. RP Annunziata, CM (reprint author), NCI, NIH, Bldg 10,Room 4B54,10 Ctr Dr, Bethesda, MD 20892 USA. EM annunzic@mail.nih.gov FU NCI Intramural Research Program [ZIA BC 011054] FX C.M. Annunziata is supported by the NCI Intramural Research Program (ZIA BC 011054). NR 94 TC 0 Z9 0 U1 13 U2 13 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 1 PY 2016 VL 22 IS 17 BP 4302 EP 4308 DI 10.1158/1078-0432.CCR-15-1374 PG 7 WC Oncology SC Oncology GA DV6IR UT WOS:000383038200005 PM 27422962 ER PT J AU Tanaka, H Fujiwara, H Ochi, F Tanimoto, K Casey, N Okamoto, S Mineno, J Kuzushima, K Shiku, H Sugiyama, T Barrett, AJ Yasukawa, M AF Tanaka, Hiroki Fujiwara, Hiroshi Ochi, Fumihiro Tanimoto, Kazushi Casey, Nicholas Okamoto, Sachiko Mineno, Junichi Kuzushima, Kiyotaka Shiku, Hiroshi Sugiyama, Takashi Barrett, A. John Yasukawa, Masaki TI Development of Engineered T Cells Expressing a Chimeric CD16-CD3 zeta Receptor to Improve the Clinical Efficacy of Mogamulizumab Therapy Against Adult T-Cell Leukemia SO CLINICAL CANCER RESEARCH LA English DT Article ID FC-GAMMA-RIIIA; MONOCLONAL-ANTIBODY KW-0761; NATURAL-KILLER-CELLS; PHASE-II; LYMPHOMA; IMMUNOTHERAPY; LEUKEMIA/LYMPHOMA; POLYMORPHISM; CD16; VIVO AB Purpose: Mogamulizumab (Mog), a humanized anti-CC chemokine receptor 4 (CCR4) mAb that mediates antibody-dependent cellular cytotoxicity (ADCC) using Fc gamma R IIIa (CD16)-expressing effector cells, has recently been approved for treatment of CCR4-positive adult T-cell leukemia (ATL) in Japan. However, Mog failure has sometimes been observed in patients who have accompanying chemotherapy-associated lymphocytopenia. In this study, we examined whether adoptive transfer of artificial ADCC effector cells combined with Mog would overcome this drawback. Experimental Design: We lentivirally gene-modified peripheral blood T cells from healthy volunteers and ATL patients expressing the affinity-increased chimeric CD16-CD3 zeta receptor (cCD16 zeta-T cells). Subsequently, we examined the ADCC effect mediated by those cCD16 zeta-T cells in the presence of Mog against ATL tumor cells both in vitro and in vivo. Results: cCD16 zeta-T cells derived from healthy donors killed in vitro Mog-opsonized ATL cell line cells (n = 7) and primary ATL cells (n = 4) depending on both the number of effector cells and the dose of the antibody. cCD16 zeta-T cells generated from ATL patients (n = 3) also exerted cytocidal activity in vitro against Mogopsonized autologous ATL cells. Using both intravenously disseminated model (n = 5) and subcutaneously inoculated model (n = 4), coadministration of Mog and human cCD16 zeta-T cells successfully suppressed tumor growth in xenografted immunodeficient mice, and significantly prolonged their survival (P < 0.01 and P = 0.02, respectively). Conclusions: These data strongly suggest clinical feasibility of the novel combined adoptive immunotherapy using cCD16 zeta-T cells and Mog for treatment of aggressive ATL, particularly in patients who are ineligible for allogeneic hematopoietic stem cell transplantation. (C) 2016 AACR. C1 [Tanaka, Hiroki; Sugiyama, Takashi] Ehime Univ, Grad Sch Med, Dept Obstet & Gynecol, Toon, Ehime, Japan. [Tanaka, Hiroki; Fujiwara, Hiroshi; Tanimoto, Kazushi; Casey, Nicholas; Yasukawa, Masaki] Ehime Univ, Grad Sch Med, Dept Hematol Clin Immunol & Infect Dis, Toon, Ehime, Japan. [Ochi, Fumihiro] Ehime Univ, Grad Sch Med, Dept Pediat, Toon, Ehime, Japan. [Okamoto, Sachiko; Mineno, Junichi] Takara Bio Inc, CDM Ctr, Otsu, Shiga, Japan. [Kuzushima, Kiyotaka] Aichi Canc Ctr, Div Immunol, Nagoya, Aichi, Japan. [Shiku, Hiroshi] Mie Univ, Grad Sch Med, Dept Canc Vaccine & Immunogene Therapy, Tsu, Mie, Japan. [Barrett, A. John] NHLBI, Hematol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Yasukawa, M (reprint author), Ehime Univ, Grad Sch Med, Dept Hematol Clin Immunol & Infect Dis, Toon, Ehime, Japan.; Fujiwara, H (reprint author), Ehime Univ, Grad Sch Med, Toon, Ehime 7910295, Japan. EM yunarief@m.ehime-u.ac.jp; yasukawa@m.ehime-u.ac.jp FU Ministry of Education, Culture, Sports, Science and Technology of Japan [KAKEN 24591426, 15K09506, KAKEN 15H04858]; Project for Development of Innovative Research on Cancer Therapeutics; Ministry of Health, Labor and Welfare; Takeda science Foundation; Uehara Memorial Foundation; Princess Takamatsu Cancer Research Fund FX This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan (KAKEN 24591426 and 15K09506; to H. Fujiwara; and KAKEN 15H04858, to M. Yasukawa), a grant from Project for Development of Innovative Research on Cancer Therapeutics (to M. Yasukawa), a Grant-in-Aid for Cancer Research from the Ministry of Health, Labor and Welfare (to M. Yasukawa), a grant from Takeda science Foundation (to M. Yasukawa), a grant from the Uehara Memorial Foundation (to M. Yasukawa), and a grant from Princess Takamatsu Cancer Research Fund (to M. Yasukawa). NR 42 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 1 PY 2016 VL 22 IS 17 BP 4405 EP 4416 DI 10.1158/1078-0432.CCR-15-2714 PG 12 WC Oncology SC Oncology GA DV6IR UT WOS:000383038200015 PM 27091408 ER PT J AU Boufraqech, M Zhang, LS Nilubol, N Sadowski, SM Kotian, S Quezado, M Kebebew, E AF Boufraqech, Myriem Zhang, Lisa Nilubol, Naris Sadowski, Samira M. Kotian, Shweta Quezado, Martha Kebebew, Electron TI Lysyl Oxidase (LOX) Transcriptionally Regulates SNAI2 Expression and TIMP4 Secretion in Human Cancers SO CLINICAL CANCER RESEARCH LA English DT Article ID ANAPLASTIC THYROID-CARCINOMA; BREAST-CANCER; CERVICAL-CANCER; COLORECTAL-CANCER; TISSUE INHIBITORS; VASCULOGENIC MIMICRY; CELL-MIGRATION; METASTASIS; INVASION; METALLOPROTEINASES AB Purpose: Epithelial-to-mesenchymal transition (EMT) is important in cancer progression and metastasis. We and others have previously reported that lysyl oxidase (LOX) is overexpressed in aggressive cancers, is associated with increased mortality, and regulates EMT. However, the mechanism by which LOX mediates EMT is unknown. In this study, we investigated the effect of LOX on mediators of EMT. Experimental Design: We used chromatin immunoprecipitation and promoter luciferase assays to determine the target gene of LOX. To determine the effects of SNAI2 in vivo, we used our metastatic anaplastic thyroid cancer (ATC) mouse model. To investigate the effects of LOX and SNAI2 on MMPs and TIMPs, protein arrays were used. Primary tumors from patients with metastatic, breast and colon cancer, and tissue array for thyroid cancer were assessed for SNAI2 and TIMP4 expression by immunohistochemistry. Results: We found that LOX knockdown decreases SNAI2 expression in cancer cell lines. Furthermore, knockdown of LOX reduced SNAI2 expression in a metastatic mouse model of thyroid cancer. We also demonstrated that LOX binds and transactivates the SNAI2 promoter. We found a direct correlation in thyroid and breast cancer samples between LOX and SNAI2 expression. To understand how LOX/SNAI2 axis mediates these effects, we performed a comprehensive analysis of MMPs/TIMPs. LOX and SNAI2 depletion reduced TIMP4 secretion. Analysis of SNAI2 and TIMP4 expression showed overexpression of both proteins in aggressive thyroid, colon, and breast tumors. Conclusions: Our findings provide new evidence that LOX regulates SNAI2 expression and that SNAI2-mediated TIMP4 secretion plays a role in cancer progression. (C) 2016 AACR. C1 [Boufraqech, Myriem; Zhang, Lisa; Nilubol, Naris; Sadowski, Samira M.; Kotian, Shweta; Kebebew, Electron] NCI, Endocrine Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Quezado, Martha] NCI, Pathol Lab, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Kebebew, E (reprint author), NCI, Endocrine Oncol Branch, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM kebebewe@mail.nih.gov FU intramural research program of the Center for Cancer Research, National Cancer Institute, NIH [1ZIABC011275-06] FX This research was supported by the intramural research program of the Center for Cancer Research, National Cancer Institute, NIH (grant number 1ZIABC011275-06). NR 48 TC 0 Z9 0 U1 5 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 1 PY 2016 VL 22 IS 17 BP 4491 EP 4504 DI 10.1158/1078-0432.CCR-15-2461 PG 14 WC Oncology SC Oncology GA DV6IR UT WOS:000383038200022 PM 27029493 ER PT J AU Pinal-Fernandez, I Pineda-Sanchez, V Pallisa-Nunez, E Simeon-Aznar, CP Selva-O'Callaghan, A Fonollosa-Pla, V Vilardell-Tarres, M AF Pinal-Fernandez, Iago Pineda-Sanchez, Victor Pallisa-Nunez, Esther Pilar Simeon-Aznar, Carmen Selva-O'Callaghan, Albert Fonollosa-Pla, Vicente Vilardell-Tarres, Miquel TI Fast 1.5 T chest MRI for the assessment of interstitial lung disease extent secondary to systemic sclerosis SO CLINICAL RHEUMATOLOGY LA English DT Article DE Computed x-ray tomography; Interstitial lung diseases; Magnetic resonance imaging; Pulmonary function test; Systemic sclerosis ID COMPUTED-TOMOGRAPHY; RADIATION-EXPOSURE; CLASSIFICATION; CT; CRITERIA; FIBROSIS AB This study aims to evaluate the utility of magnetic resonance imaging (MRI) to assess interstitial lung disease (ILD) extent in patients with systemic sclerosis (SSc). Patients with SSc and varying degrees of ILD with a high-resolution computed tomography (HRCT), pulmonary function tests (PFTs), and a chest MRI containing an ultrafast SE sequence performed less than 1 year apart were included in the study. Wells global disease extent and Goh's staging algorithm were used to measure and categorize ILD both for MRI and HRCT. Correlation and diagnostic performance of MRI compared with HRCT and PFTs were calculated. Eighteen SSc patients were studied. MRI showed a good performance to detect ILD (AUC = 0.96) and was correlated with forced vital capacity (r = -0.60, p = 0.01), diffusing capacity of the lung for carbon monoxide (r = -0.79, p = 0.04), and also with HRCT (r = 0.85, p < 0.001), but MRI extent values were consistently lower than HRCT and, thus, not directly comparable. Goh's algorithm using HRCT and transformed to be used with MRI showed a good agreement (kappa = 0.73, p < 0.001) and MRI-measured ILD extent presented good intra-observer (ICC = 0.86) and inter-observer (ICC = 0.90) reliability. In SSc patients, MRI proved to be a good technique to detect and categorize ILD extent compared with HRCT, suggesting that it may be a valuable x-ray sparing technique for selected cases. C1 [Pinal-Fernandez, Iago; Pilar Simeon-Aznar, Carmen; Selva-O'Callaghan, Albert; Fonollosa-Pla, Vicente; Vilardell-Tarres, Miquel] Vall dHebron Univ Hosp, Autoimmune System Dis Unit, Dept Internal Med, Barcelona, Spain. [Pinal-Fernandez, Iago] NIAMSD, Muscle Dis Unit, Lab Muscle Stem Cells & Gene Express, NIH, 50 South Dr,Room 1141,Bldg 50,MSC 8024, Bethesda, MD 20892 USA. [Pineda-Sanchez, Victor; Pallisa-Nunez, Esther] Univ Autonoma Barcelona, Vall dHebron Univ Hosp, Dept Radiol, Barcelona, Spain. [Pineda-Sanchez, Victor; Pallisa-Nunez, Esther] NIAMSD, Barcelona, Spain. RP Pinal-Fernandez, I (reprint author), Vall dHebron Univ Hosp, Autoimmune System Dis Unit, Dept Internal Med, Barcelona, Spain.; Pinal-Fernandez, I (reprint author), NIAMSD, Muscle Dis Unit, Lab Muscle Stem Cells & Gene Express, NIH, 50 South Dr,Room 1141,Bldg 50,MSC 8024, Bethesda, MD 20892 USA. EM iagopf@yahoo.es NR 25 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0770-3198 EI 1434-9949 J9 CLIN RHEUMATOL JI Clin. Rheumatol. PD SEP PY 2016 VL 35 IS 9 BP 2339 EP 2345 DI 10.1007/s10067-016-3267-0 PG 7 WC Rheumatology SC Rheumatology GA DU2BO UT WOS:000382016000024 PM 27107755 ER PT J AU Johnson, SR Taveira-DaSilva, AM Moss, J AF Johnson, Simon R. Taveira-DaSilva, Angelo M. Moss, Joel TI Lymphangioleiomyomatosis SO CLINICS IN CHEST MEDICINE LA English DT Article DE Cystic lung disease; Lymphatic disease; Angiomyolipoma; Pneumothorax; mTOR inhibitor ID TUBEROUS SCLEROSIS COMPLEX; INTERSTITIAL LUNG-DISEASES; PLACEBO-CONTROLLED TRIAL; TUMOR-SUPPRESSOR GENE; AIR-FLOW OBSTRUCTION; SMOOTH-MUSCLE-CELLS; GROWTH FACTOR-D; PULMONARY LYMPHANGIOLEIOMYOMATOSIS; SPORADIC LYMPHANGIOLEIOMYOMATOSIS; MATRIX METALLOPROTEINASES AB Lymphangioleiomyomatosis is a rare multisystem disease predominantly affecting women that can occur sporadically or in association with tuberous sclerosis. Lung cysts progressively replace the lung parenchyma, which leads to dyspnea, recurrent pneumothorax, and in some cases respiratory failure. Patients may also have lymphatic disease in the thorax, abdomen, and pelvis, and renal angiomyolipomas. Treatment includes supportive care, bronchodilators, and for those with progressive disease, mammalian target of rapamycin (mTOR) inhibitors. C1 [Johnson, Simon R.] Univ Nottingham, Univ Hosp NHS Trust, Div Resp Med, Natl Ctr Lymphangioleiomyomatosis, Nottingham NG7 2UH, England. [Taveira-DaSilva, Angelo M.] NHLBI, Cardiovasc & Pulm Branch, NIH, Bldg 10,Room 6D05, Bethesda, MD 20814 USA. [Moss, Joel] NHLBI, Cardiovasc & Pulm Branch, NIH, Bldg 10,Room 6D03, Bethesda, MD 20814 USA. RP Johnson, SR (reprint author), Univ Nottingham, Univ Hosp NHS Trust, Div Resp Med, Natl Ctr Lymphangioleiomyomatosis, Nottingham NG7 2UH, England. EM simon.johnson@nottingham.ac.uk OI Johnson, Simon/0000-0002-9837-2763 NR 108 TC 0 Z9 0 U1 3 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-5231 EI 1557-8216 J9 CLIN CHEST MED JI Clin. Chest Med. PD SEP PY 2016 VL 37 IS 3 BP 389 EP + DI 10.1016/j.ccm.2016.04.002 PG 16 WC Respiratory System SC Respiratory System GA DV3BF UT WOS:000382795300002 PM 27514586 ER PT J AU Freeman, AF Olivier, KN AF Freeman, Alexandra F. Olivier, Kenneth N. TI Hyper-IgE Syndromes and the Lung SO CLINICS IN CHEST MEDICINE LA English DT Article DE Hyper-IgE syndromes; Pulmonary manifestations; Job syndrome; DOCK8 deficiency; PGM3 deficiency; STAT3 ID STEM-CELL TRANSPLANTATION; HYPERIMMUNOGLOBULIN-E SYNDROME; BONE-MARROW-TRANSPLANTATION; CYTOKINESIS 8 DEFICIENCY; INFECTION JOBS SYNDROME; DOCK8 DEFICIENCY; IMMUNE-DEFICIENCY; SIGNAL TRANSDUCER; STAT3 MUTATIONS; CUTANEOUS MANIFESTATIONS AB Elevated serum IgE has many etiologies including parasitic infection, allergy and asthma, malignancy, and immune dysregulation. The hyper-IgE syndromes caused by mutations in STAT3, DOCK8, and PGM3 are monogenic primary immunodeficiencies associated with high IgE, eczema, and recurrent infections. These primary immunodeficiencies are associated with recurrent pneumonias leading to bronchiectasis; however, each has unique features and genetic diagnosis is essential in guiding therapy, discussing family planning, and defining prognosis. This article discusses the clinical features of these primary immunodeficiencies with a particular focus on the pulmonary manifestations and discussion of the genetics, pathogenesis, and approaches to therapy. C1 [Freeman, Alexandra F.; Olivier, Kenneth N.] NIAID, Lab Clin Infect Dis, NHLBI, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Freeman, AF (reprint author), NIH, Bldg 10,Room 12C103,9000 Rockville Pike, Bethesda, MD 20892 USA. EM freemaal@mail.nih.gov FU Intramural Research Programs of the NIAID; NHLBI; NIH FX This work was supported in part by the Intramural Research Programs of the NIAID and NHLBI, NIH. NR 69 TC 0 Z9 0 U1 4 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-5231 EI 1557-8216 J9 CLIN CHEST MED JI Clin. Chest Med. PD SEP PY 2016 VL 37 IS 3 BP 557 EP + DI 10.1016/j.ccm.2016.04.016 PG 12 WC Respiratory System SC Respiratory System GA DV3BF UT WOS:000382795300016 PM 27514600 ER PT J AU Pacheco-Rodriguez, G Taveira-DaSilva, AM Moss, J AF Pacheco-Rodriguez, Gustavo Taveira-DaSilva, Angelo M. Moss, Joel TI Benign Metastasizing Leiomyoma SO CLINICS IN CHEST MEDICINE LA English DT Article DE Leiomyomas; Metastasis; Estrogen; Rare lung disease; Smooth muscle cells ID OF-THE-LITERATURE; UTERINE LEIOMYOMA; LUNG-DISEASE; HYSTERECTOMY RATES; PULMONARY NODULES; SMOOTH-MUSCLE; UNITED-STATES; LYMPHANGIOLEIOMYOMATOSIS; TUMORS; MALIGNANCY AB Benign metastasizing leiomyoma (BML) is a rare and poorly characterized disease affecting primarily premenopausal women. Asymptomatic patients are often diagnosed incidentally by radiographs or other lung-imaging procedures performed for other indications, and the diagnosis is eventually confirmed by biopsy. Patients with BML are usually treated pharmacologically with antiestrogen therapies or surgically with oophorectomy or hysterectomy. Antiestrogen therapy is typically efficacious and, in general, most patients have a favorable prognosis. Asymptomatic patients with a confirmed diagnosis of BML, may be followed conservatively without treatment. C1 [Pacheco-Rodriguez, Gustavo] NHLBI, Cardiovasc & Pulm Branch, NIH, Bldg 10,Room 5N307,9000 Rockville Pike, Bethesda, MD 20892 USA. [Taveira-DaSilva, Angelo M.; Moss, Joel] NHLBI, Cardiovasc & Pulm Branch, NIH, Bldg 10,Room 6D05,MSC 1590,9000 Rockville Pike, Bethesda, MD 20892 USA. RP Moss, J (reprint author), NHLBI, Cardiovasc & Pulm Branch, NIH, Bldg 10,Room 6D05,MSC 1590,9000 Rockville Pike, Bethesda, MD 20892 USA. EM mossj@nhlbi.nih.gov FU Intramural Research Program of the National Institutes of Health, National Heart, Lung, and Blood Institute FX The authors report no conflict of interest. This work was supported by the Intramural Research Program of the National Institutes of Health, National Heart, Lung, and Blood Institute. NR 54 TC 0 Z9 0 U1 1 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-5231 EI 1557-8216 J9 CLIN CHEST MED JI Clin. Chest Med. PD SEP PY 2016 VL 37 IS 3 BP 589 EP + DI 10.1016/j.ccm.2016.04.019 PG 8 WC Respiratory System SC Respiratory System GA DV3BF UT WOS:000382795300019 PM 27514603 ER PT J AU Pappas, A Korzeniewski, SJ AF Pappas, Athina Korzeniewski, Steven J. TI Long-Term Cognitive Outcomes of Birth Asphyxia and the Contribution of Identified Perinatal Asphyxia to Cerebral Palsy SO CLINICS IN PERINATOLOGY LA English DT Article DE Neonatal encephalopathy; Hypoxic ischemic encephalopathy; Newborn; Cognitive outcome; Cerebral palsy ID HYPOXIC-ISCHEMIC ENCEPHALOPATHY; WHOLE-BODY HYPOTHERMIA; NEONATAL ENCEPHALOPATHY; NEWBORN ENCEPHALOPATHY; SYSTEMIC HYPOTHERMIA; UNITED-STATES; BRAIN-INJURY; BAYLEY-III; INFANTS; CHILDREN AB Neonatal encephalopathy among survivors of presumed perinatal asphyxia is recognized as an important cause of cerebral palsy (CP) and neuromotor impairment. Recent studies suggest that moderate to severe neonatal encephalopathy contributes to a wide range of neurodevelopmental and cognitive impairments among survivors with and without CP. Nearly 1 of every 4 to 5 neonates treated with hypothermia has or develops CP. Neonatal encephalopathy is diagnosed in only approximately 10% of all cases. This article reviews the long-term cognitive outcomes of children with presumed birth asphyxia and describes what is known about its contribution to CP. C1 [Pappas, Athina] Wayne State Univ, Sch Med, St John Hosp, Dept Pediat, 22101 Moross, Detroit, MI 48236 USA. [Pappas, Athina] Wayne State Univ, Sch Med, Med Ctr, NICU CCB 5, 22101 Moross, Detroit, MI 48236 USA. [Korzeniewski, Steven J.] NICHD, Hutzel Womens Hosp, Perinatol Res Branch, NIH, 4 Brush,Off 4817,3990 John R St, Detroit, MI 48201 USA. RP Pappas, A (reprint author), Wayne State Univ, Sch Med, St John Hosp, Dept Pediat, 22101 Moross, Detroit, MI 48236 USA.; Pappas, A (reprint author), Wayne State Univ, Sch Med, Med Ctr, NICU CCB 5, 22101 Moross, Detroit, MI 48236 USA. EM apappas@med.wayne.edu NR 53 TC 0 Z9 0 U1 6 U2 6 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0095-5108 EI 1557-9840 J9 CLIN PERINATOL JI Clin. Perinatol. PD SEP PY 2016 VL 43 IS 3 BP 559 EP + DI 10.1016/j.clp.2016.04.012 PG 15 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA DV8UZ UT WOS:000383213500014 PM 27524454 ER PT J AU Ferguson, KK Meeker, JD Cantonwine, DE Chen, YH Mukherjee, B McElrath, TF AF Ferguson, Kelly K. Meeker, John D. Cantonwine, David E. Chen, Yin-Hsiu Mukherjee, Bhramar McElrath, Thomas F. TI Urinary phthalate metabolite and bisphenol A associations with ultrasound and delivery indices of fetal growth SO ENVIRONMENT INTERNATIONAL LA English DT Article DE Endocrine disruptors; Fetal growth; Birthweight; Growth restriction; Plasticizers; Plastics ID LOW-BIRTH-WEIGHT; PRENATAL EXPOSURE; PRETERM BIRTH; GENERATION R; OXIDATIVE STRESS; PREGNANT-WOMEN; IN-VITRO; OUTCOMES; HEALTH; PHENOLS AB Growth of the fetus is highly sensitive to environmental perturbations, and disruption can lead to problems in pregnancy as well as later in life. This study investigates the relationship between maternal exposure to common plasticizers in pregnancy and fetal growth. Participants from a longitudinal birth cohort in Boston were recruited early in gestation and followed until delivery. Urine samples were collected at up to four time points and analyzed for concentrations of phthalate metabolites and bisphenol A (BPA). Ultrasound scans were performed at four time points during pregnancy for estimation of growth parameters, and birthweight was recorded at delivery. Growth measures were standardized to a larger population. For the present analysis we examined cross-sectional and repeated measures associations between exposure biomarkers and growth estimates in 482 non anomalous singleton pregnancies. Cross-sectional associations between urinary phthalate metabolites or BPA and growth indices were imprecise. However, in repeated measures models, we observed significant inverse associations between di-2-ethylhexyl phthalate (DEHP) metabolites and estimated or actual fetal weight. An inter quartile range increase in summed DEHP metabolites was associated with a 0.13 standard deviation decrease in estimated or actual fetal weight (95% confidence interval = -0.23, -0.03). Associations were consistent across different growth parameters (e.g., head circumference, femur length), and by fetal sex. No consistent associations were observed for other phthalate metabolites or BPA. Maternal exposure to DEHP during pregnancy was associated with decreased fetal growth, which could have repercussive effects. Published by Elsevier Ltd. C1 [Ferguson, Kelly K.] Natl Inst Environm Hlth Sci, Epidemiol Branch, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. [Ferguson, Kelly K.; Meeker, John D.] Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA. [Cantonwine, David E.; McElrath, Thomas F.] Harvard Med Sch, Brigham & Womens Hosp, Div Maternal Fetal Med, Boston, MA USA. [Chen, Yin-Hsiu; Mukherjee, Bhramar] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA. RP Ferguson, KK (reprint author), Natl Inst Environm Hlth Sci, Epidemiol Branch, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM kelly.ferguson2@nih.gov OI Ferguson, Kelly/0000-0001-8467-3250 FU Abbott Diagnostics [9MZ-04-06N03]; National Institute of Environmental Health Sciences, National Institutes of Health [R01ES018872, P42ES017198, P01ES022844, P50ES026049, P30ES017885]; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences FX We thank Gerry Pace and colleagues at NSF International (Ann Arbor, MI) for their analysis of urinary phthalate metabolites. Initial funding for the recruitment of the birth cohort was provided by Abbott Diagnostics (9MZ-04-06N03). All other funding was provided by the National Institute of Environmental Health Sciences, National Institutes of Health (R01ES018872, P42ES017198, P01ES022844, P50ES026049, and P30ES017885). Support for Dr. Ferguson was provided in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 49 TC 0 Z9 0 U1 13 U2 13 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0160-4120 EI 1873-6750 J9 ENVIRON INT JI Environ. Int. PD SEP PY 2016 VL 94 BP 531 EP 537 DI 10.1016/j.envint.2016.06.013 PG 7 WC Environmental Sciences SC Environmental Sciences & Ecology GA DU6QF UT WOS:000382339000059 PM 27320326 ER PT J AU Patlolla, AK Patra, PK Flountan, M Tchounwou, PB AF Patlolla, Anita K. Patra, Prabir K. Flountan, Moyesha Tchounwou, Paul B. TI Cytogenetic evaluation of functionalized single-walled carbon nanotube in mice bone marrow cells SO ENVIRONMENTAL TOXICOLOGY LA English DT Article DE single-walled carbon nanotube; reactive oxygen species; structural chromosomal aberrations; micronucleus; DNA damage; mitotic index Swiss-Webster mice ID NEAR-INFRARED FLUORESCENCE; HUMAN LYMPHOBLASTOID-CELLS; IN-VIVO GENOTOXICITY; SWISS-WEBSTER MICE; OXIDATIVE STRESS; DNA-DAMAGE; CHROMOSOME-ABERRATIONS; EPITHELIAL-CELLS; CYTOTOXICITY; VITRO AB With their unique structure and physicochemical properties, single\-walled carbon nanotubes (SWCNTs) have many potential new applications in medicine and industry. However, there is lack of detailed information concerning their impact on human health and the environment. The aim of this study was to assess the effects, after intraperitoneal injection of functionalized SWCNTs (f-SWCNT) on the induction of reactive oxygen species (ROS), frequency of structural chromosomal aberrations (SCA), frequency of micronuclei induction, mitotic index, and DNA damage in Swiss-Webster mice. Three doses of f-SWCNTs (0.25, 0.5, and 0.75 mg/kg) and two controls (negative and positive) were administered to mice, once a day for 5 days. Bone marrow and peripheral blood samples were collected 24 h after the last treatment following standard protocols. F-SWCNT exposure significantly enhanced ROS, increased (p<0.05) the number of SCA and the frequency of micronucleated cells, increased DNA damage, and decreased the mitotic index in exposed groups compared to negative control. The scientific findings reported here suggest that purified f-SWCNT have the potential to induce oxidative stress mediated genotoxicity in Swiss-Webster mice at higher level of exposure. Further characterization of their systemic toxicity, genotoxicity, and carcinogenicity is also essential. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1091-1102, 2016. C1 [Patlolla, Anita K.; Flountan, Moyesha; Tchounwou, Paul B.] Jackson State Univ, Dept Biol, Coll Sci Engn & Technol, Jackson, MS 39217 USA. [Patlolla, Anita K.; Tchounwou, Paul B.] Jackson State Univ, Coll Sci Engn & Technol, NIH RCMI Ctr Environm Hlth, Jackson, MS 39217 USA. [Patra, Prabir K.] Univ Bridgeport, Sch Engn, Dept Biomed Engn, Bridgeport, CT 06604 USA. [Patra, Prabir K.] Univ Bridgeport, Sch Engn, Dept Mech Engn, 126 Pk Ave, Bridgeport, CT 06604 USA. RP Patlolla, AK (reprint author), Jackson State Univ, Dept Biol, Coll Sci Engn & Technol, Jackson, MS 39217 USA.; Patlolla, AK (reprint author), Jackson State Univ, Coll Sci Engn & Technol, NIH RCMI Ctr Environm Hlth, Jackson, MS 39217 USA. EM anita.k.patlolla@jsums.edu FU Title III-Strengthening HBCUs-Center for University Scholar Program, Jackson State University; National Institutes of Health-RCMI Center for Environmental Health [2G12MD007581-16] FX This research was financially supported by Title III-Strengthening HBCUs-Center for University Scholar Program, Jackson State University and National Institutes of Health-RCMI Center for Environmental Health (Grant No. 2G12MD007581-16). NR 74 TC 3 Z9 3 U1 6 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1520-4081 EI 1522-7278 J9 ENVIRON TOXICOL JI Environ. Toxicol. PD SEP PY 2016 VL 31 IS 9 BP 1091 EP 1102 DI 10.1002/tox.22118 PG 12 WC Environmental Sciences; Toxicology; Water Resources SC Environmental Sciences & Ecology; Toxicology; Water Resources GA DV4ZF UT WOS:000382933800006 PM 25689286 ER PT J AU Chebel, A Catallo, R Mabon, C Bachy, E Wenner, T Salles, G Pouteil-Noble, C Ffrench, M AF Chebel, Amel Catallo, Regine Mabon, Celine Bachy, Emmanuel Wenner, Thomas Salles, Gilles Pouteil-Noble, Claire Ffrench, Martine TI Rapamycin safeguards lymphocytes from DNA damage accumulation in vivo SO EUROPEAN JOURNAL OF CELL BIOLOGY LA English DT Article DE Lymphocytes; Telomere length; DNA damage; Calcineurin inhibitors; Rapamycin ID RENAL-TRANSPLANT RECIPIENTS; OXIDATIVE STRESS; KIDNEY-TRANSPLANTATION; CYCLOSPORINE-A; T-CELLS; CALCINEURIN INHIBITORS; PREMATURE SENESCENCE; CONVERT TRIAL; TELOMERIC DNA; SIROLIMUS AB Several studies reported the benefits of switching from anticalcineurins to mTOR inhibitors to avoid cancer occurrence after organ transplantation. The purpose of our study was to determine in vivo biological markers to explain these benefits. Cellular changes related to cellular senescence and DNA damage were analyzed in peripheral blood lymphocytes. Thirty-five kidney transplanted patients receiving anticalcineurins were investigated: 17 patients were proposed to switch to rapamycin and 18 patients with similar age and transplantation duration, continued anticalcineurins. Rapamycin effects were studied one year after the switch. Thirteen healthy volunteers and 18 hemodialyzed patients were evaluated as control. Compared with the healthy group, hemodialyzed and transplanted patients exhibited a significant decrease in telomere length, an increase in p16(INK4A) mRNA expression and in lymphocytes with 53BP1 foci. A destabilization of the shelterin complexes was suggested by a significant TIN2 mRNA decrease in transplanted patients compared with controls and a significant increase in TRF1, TRF2 and POT1 expression in switch-proposed patients compared with the non-switched subgroup. Rapamycin treatment resulted in a significant decrease in DNA damage and a slight TIN2 increase. In vitro experiments strengthened in vivo results showing that rapamycin but not FK506 induced a significant DNA damage decrease and TIN2 expression increase compared with controls. The roles of rapamycin in the decrease in DNA damage in vivo and the rescue of shelterin gene expression are demonstrated for the first time. These data provide new insights into understanding of how rapamycin may overcome genomic injuries. (C) 2016 Elsevier GmbH. All rights reserved. C1 [Chebel, Amel; Catallo, Regine; Mabon, Celine; Wenner, Thomas; Salles, Gilles; Ffrench, Martine] Univ Lyon 1, Clin & Expt Models Lymphomagenesis, Fac Med Lyon Sud, CNRS,INSERM,U1052,UMR5286,Ctr Leon Berard,CRCL, Oullins, France. [Bachy, Emmanuel; Salles, Gilles; Ffrench, Martine] HCL, CHLS, Serv Hematol, Pierre Benite, France. [Bachy, Emmanuel] Univ Lyon, INSERM, U1111, Ctr Int Rech Infectiol, Lyon, France. [Pouteil-Noble, Claire] Univ Lyon 1, HCL, Hop Edouard Herriot, Serv Transplantat Nephrol & Immunol Clin, Lyon, France. [Bachy, Emmanuel] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Ffrench, M (reprint author), Fac Med Lyon Sud, Lab Clin & Expt Models Lymphomagenesis, 165 Chemin Grand Revoyet,BP12, F-69921 Oullins, France. EM ffrenchma@gmail.com OI Salles, Gilles/0000-0002-9541-8666 NR 52 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER GMBH, URBAN & FISCHER VERLAG PI JENA PA OFFICE JENA, P O BOX 100537, 07705 JENA, GERMANY SN 0171-9335 EI 1618-1298 J9 EUR J CELL BIOL JI Eur. J. Cell Biol. PD SEP PY 2016 VL 95 IS 9 BP 331 EP 341 DI 10.1016/j.ejcb.2016.06.004 PG 11 WC Cell Biology SC Cell Biology GA DW0AS UT WOS:000383303900004 PM 27349711 ER PT J AU Arnold, M Freisling, H Stolzenberg-Solomon, R Kee, F O'Doherty, MG Ordonez-Mena, JM Wilsgaard, T May, AM Bueno-de-Mesquita, HB Tjonneland, A Orfanos, P Trichopoulou, A Boffetta, P Bray, F Jenab, M Soerjomataram, I AF Arnold, Melina Freisling, Heinz Stolzenberg-Solomon, Rachael Kee, Frank O'Doherty, Mark George Ordonez-Mena, Jose Manuel Wilsgaard, Tom May, Anne Maria Bueno-de-Mesquita, Hendrik Bas Tjonneland, Anne Orfanos, Philippos Trichopoulou, Antonia Boffetta, Paolo Bray, Freddie Jenab, Mazda Soerjomataram, Isabelle CA CHANCES Consortium TI Overweight duration in older adults and cancer risk: a study of cohorts in Europe and the United States SO EUROPEAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE CHANCES; Ageing; Cohort; Obesity; Cancer; Prevention ID BODY-MASS INDEX; LUNG-CANCER; ATTRIBUTABLE FRACTION; WAIST CIRCUMFERENCE; COLORECTAL-CANCER; PANCREATIC-CANCER; COLON-CANCER; OBESITY; POPULATION; HEALTH AB Recent studies have shown that cancer risk related to overweight and obesity is mediated by time and might be better approximated by using life years lived with excess weight. In this study we aimed to assess the impact of overweight duration and intensity in older adults on the risk of developing different forms of cancer. Study participants from seven European and one US cohort study with two or more weight assessments during follow-up were included (n = 329,576). Trajectories of body mass index (BMI) across ages were estimated using a quadratic growth model; overweight duration (BMI aeyen 25) and cumulative weighted overweight years were calculated. In multivariate Cox models and random effects analyses, a longer duration of overweight was significantly associated with the incidence of obesity-related cancer [overall hazard ratio (HR) per 10-year increment: 1.36; 95 % CI 1.12-1.60], but also increased the risk of postmenopausal breast and colorectal cancer. Additionally accounting for the degree of overweight further increased the risk of obesity-related cancer. Risks associated with a longer overweight duration were higher in men than in women and were attenuated by smoking. For postmenopausal breast cancer, increased risks were confined to women who never used hormone therapy. Overall, 8.4 % of all obesity-related cancers could be attributed to overweight at any age. These findings provide further insights into the role of overweight duration in the etiology of cancer and indicate that weight control is relevant at all ages. This knowledge is vital for the development of effective and targeted cancer prevention strategies. C1 [Arnold, Melina; Bray, Freddie; Soerjomataram, Isabelle] Int Agcy Res Canc, Sect Canc Surveillance, 150 Cours Albert Thomas, F-69008 Lyon, France. [Freisling, Heinz] Int Agcy Res Canc, Sect Nutr & Metab, Dietary Exposure Assessment Grp, 150 Cours Albert Thomas, F-69008 Lyon, France. [Stolzenberg-Solomon, Rachael] NCI, Div Canc Epidemiol & Genet, Nutr Epidemiol Branch, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. [Kee, Frank; O'Doherty, Mark George] Queens Univ Belfast, UKCRC Ctr Excellence Publ Hlth, Sch Med Dent & Biomed Sci, Univ Rd, Belfast BT7 1NN, Antrim, North Ireland. [Ordonez-Mena, Jose Manuel] Heidelberg Univ, NAR, Bergheimer Str 20, D-69115 Heidelberg, Germany. [Ordonez-Mena, Jose Manuel] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Neuenheimer Feld 581, D-69120 Heidelberg, Germany. [Wilsgaard, Tom] Arctic Univ Norway, Dept Community Med, N-9037 Tromso, Norway. [May, Anne Maria] Univ Med Ctr Utrecht, Juliu Ctr Hlth Sci & Primary Care, Epidemiol, Utrecht, Netherlands. [Bueno-de-Mesquita, Hendrik Bas] Natl Inst Publ Hlth & Environm RIVM, Dept Determinants Chron Dis DCD, POB 1, NL-3720 BA Bilthoven, Netherlands. [Bueno-de-Mesquita, Hendrik Bas] Univ Med Ctr, Dept Gastroenterol & Hepatol, Huispost Str 6-131, NL-3508 GA Utrecht, Netherlands. [Bueno-de-Mesquita, Hendrik Bas] Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. [Bueno-de-Mesquita, Hendrik Bas] Univ Malaya, Dept Social & Prevent Med, Fac Med, Kuala Lumpur, Malaysia. [Tjonneland, Anne] Danish Canc Soc, Res Ctr, Strandblvd 49, DK-2100 Copenhagen O, Denmark. [Orfanos, Philippos; Trichopoulou, Antonia; Boffetta, Paolo] Hellen Hlth Fdn, 13 Kaisareias & Alexandroupoleos, Athens 11527, Greece. [Trichopoulou, Antonia] Univ Athens, Sch Med, Dept Hyg Epidemiol & Med Stat, Mikras Asias 75, GR-11527 Athens, Greece. [Boffetta, Paolo] Icahn Sch Med Mt Sinai, Inst Translat Epidemiol, One Gustave L Levy Pl,Box 1128, New York, NY 10029 USA. [Boffetta, Paolo] Icahn Sch Med Mt Sinai, Tisch Canc Inst, One Gustave L Levy Pl,Box 1128, New York, NY 10029 USA. [Jenab, Mazda] Int Agcy Res Canc, Nutr Epidemiol Grp, Sect Nutr & Metab, 150 Cours Albert Thomas, F-69008 Lyon, France. RP Arnold, M (reprint author), Int Agcy Res Canc, Sect Canc Surveillance, 150 Cours Albert Thomas, F-69008 Lyon, France. EM arnoldm@iarc.fr OI Ordonez-Mena, Jose Manuel/0000-0002-8965-104X; Linneberg, Allan/0000-0002-0994-0184 FU DG-RESEARCH in the European Commission [HEALTH-F3-2010242244]; Hellenic Health Foundation; European Commission; Dutch Ministry of Public Health, Welfare and Sports; National Institute for Public Health and the Environment; Dutch Cancer Society; Netherlands Organisation for Health Research and Development (ZONMW); World Cancer Research Fund (WCRF); Baden-Wurttemberg state Ministry of Science, Research and Arts (Stuttgart, Germany); Federal Ministry of Education and Research (Berlin, Germany); Federal Ministry of Family Affairs, Senior Citizens, Women and Youth (Berlin, Germany); Institut National de la Sante et de la Recherche Medicale (INSERM); Merck; Sharp; Dohme-Chibret Laboratory; Northern Ireland Health; Social Care Research and Development Office; National Institutes of Health (NIH)-AARP Diet; Intramural Research Program of the National Cancer Institute (NCI), NIH; UiT The Arctic University of Norway; National Screening Service; Research Council of Norway; World Cancer Research Fund International [SG 2012/619] FX Data used throughout the present study are derived from the CHANCES project. The project is coordinated by the Hellenic Health Foundation, Greece. The project received funding by the FP7 framework programme of DG-RESEARCH in the European Commission (Grant Agreement No. HEALTH-F3-2010242244). EPIC Greece: funded by the Hellenic Health Foundation. EPIC Netherlands: funded by European Commission (DG SANCO); Dutch Ministry of Public Health, Welfare and Sports (VWS); The National Institute for Public Health and the Environment; the Dutch Cancer Society, the Netherlands Organisation for Health Research and Development (ZONMW); World Cancer Research Fund (WCRF). EPIC Spain: supported by Health Research Fund (FIS) of the Spanish Ministry of Health RTICC 'Red Tematica de Investigacion Cooperativa en Cancer (Grant Numbers: Rd06/0020/0091 and Rd12/0036/0018), Regional Governments of Andalucia, Asturias, Basque Country, Murcia (Project 6236), and Navarra, Instituto de Salud Carlos III, Redes de Investigacion Cooperativa (RD06/0020). ESTHER: funded by the Baden-Wurttemberg state Ministry of Science, Research and Arts (Stuttgart, Germany), the Federal Ministry of Education and Research (Berlin, Germany), and the Federal Ministry of Family Affairs, Senior Citizens, Women and Youth (Berlin, Germany). PRIME Belfast: supported by grants from the Institut National de la Sante et de la Recherche Medicale (INSERM), the Merck, Sharp and Dohme-Chibret Laboratory and the Northern Ireland Health and Social Care Research and Development Office. NIH-AARP: support for the National Institutes of Health (NIH)-AARP Diet and Health Study was provided by the Intramural Research Program of the National Cancer Institute (NCI), NIH. Tromso: funded by: UiT The Arctic University of Norway, the National Screening Service, and the Research Council of Norway. MA and IS were additionally supported by the World Cancer Research Fund International (Grant Number SG 2012/619). NR 47 TC 0 Z9 0 U1 4 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0393-2990 EI 1573-7284 J9 EUR J EPIDEMIOL JI Eur. J. Epidemiol. PD SEP PY 2016 VL 31 IS 9 BP 893 EP 904 DI 10.1007/s10654-016-0169-z PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DV3UK UT WOS:000382849000006 PM 27300353 ER PT J AU Doulatov, S Vo, L Macari, E Wahlster, L Taylor, A Gupta, M McGrath, K Narla, A Alter, B Gazda, H Sieff, C Agrawal, S Beggs, A Ebert, B Schlaeger, T Zon, L Daley, G AF Doulatov, Sergei Vo, Linda Macari, Elizabeth Wahlster, Lara Taylor, Alison Gupta, Manav McGrath, Katherine Narla, Anupama Alter, Blanche Gazda, Hanna Sieff, Colin Agrawal, Suneet Beggs, Alan Ebert, Benjamin Schlaeger, Thorsten Zon, Leonard Daley, George TI DRUG DISCOVERY USING INDUCED PLURIPOTENT STEM CELLS IDENTIFIES AUTOPHAGY AS A THERAPEUTIC PATHWAY FOR ANEMIA SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract CT 45th Annual Scientific Meeting of the International-Society-for-Experimental-Hematology (ISEH) CY AUG 25-28, 2016 CL San Diego, CA SP Int Soc Expt Hematol C1 [Doulatov, Sergei; Vo, Linda; Macari, Elizabeth; Wahlster, Lara; Taylor, Alison; Gupta, Manav; McGrath, Katherine; Gazda, Hanna; Sieff, Colin; Agrawal, Suneet; Beggs, Alan; Schlaeger, Thorsten; Zon, Leonard; Daley, George] Boston Childrens Hosp, Boston, MA USA. [Doulatov, Sergei] Harvard Med Sch, Boston, MA USA. [Narla, Anupama] Stanford Univ, Stanford, CA 94305 USA. [Alter, Blanche] NIH, Rockville, MD USA. [Ebert, Benjamin] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X EI 1873-2399 J9 EXP HEMATOL JI Exp. Hematol. PD SEP PY 2016 VL 44 IS 9 SU 1 MA 2024 BP S48 EP S48 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA DU4LR UT WOS:000382184600051 ER PT J AU Kundu, S Park, E Chung, YJ Aplan, P AF Kundu, Subhadip Park, Eunsil Chung, Yang Jo Aplan, Peter TI THYMIC PRECURSOR CELLS GENERATE ACUTE MYELOID LEUKEMIA IN NUP98-PHF23/NUP98-HOXD13 DOUBLE TRANSGENIC MICE SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract CT 45th Annual Scientific Meeting of the International-Society-for-Experimental-Hematology (ISEH) CY AUG 25-28, 2016 CL San Diego, CA SP Int Soc Expt Hematol C1 [Park, Eunsil] Gyeongsang Natl Univ, Sch Med, Jinju, South Korea. [Chung, Yang Jo] NCI, NIH, CCR, Bethesda, MD 20892 USA. [Aplan, Peter] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X EI 1873-2399 J9 EXP HEMATOL JI Exp. Hematol. PD SEP PY 2016 VL 44 IS 9 SU 1 MA 3092 BP S85 EP S85 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA DU4LR UT WOS:000382184600158 ER PT J AU McCullen, MV Li, H Cam, M Sen, SK McVicar, DW Anderson, SK AF McCullen, M. V. Li, H. Cam, M. Sen, S. K. McVicar, D. W. Anderson, S. K. TI Analysis of Ly49 gene transcripts in mature NK cells supports a role for the Prol element in gene activation, not gene expression SO GENES AND IMMUNITY LA English DT Article ID NATURAL-KILLER-CELLS; REGULATORY ELEMENT; BONE-MARROW; T-CELLS; IDENTIFICATION; PROMOTER; RECEPTORS; MHC; REPERTOIRE; DOMINATE AB The variegated expression of murine Ly49 loci has been associated with the probabilistic behavior of an upstream promoter active in immature cells, the Prol element. However, recent data suggest that Prol may be active in mature natural killer (NK) cells and function as an enhancer element. To assess directly if Prol transcripts are present in mature Ly49-expressing NK cells, RNA-sequencing of the total transcript pool was performed on freshly isolated splenic NK cells sorted for expression of either Ly49G or Ly49l. No Prol transcripts were detected from the Ly49a, Ly49c or Ly49i genes in mature Ly49(+) NK cells that contained high levels of Pro2 transcripts. Low levels of Ly49g Prol transcripts were found in both Ly49G(+) and Ly49G(-) populations, consistent with the presence of a small population of mature NK cells undergoing Ly49g gene activation, as previously demonstrated by culture of splenic NK cells in interleukin-2. Ly49 gene reporter constructs containing Prol failed to show any enhancer activity of Prol on Pro2 in a mature Ly49-expressing cell line. Taken together, the results are consistent with Prol transcription having a role in gene activation in developing NK, and argue against a role for Prol in Ly49 gene transcription by mature NK cells. C1 [McCullen, M. V.; McVicar, D. W.; Anderson, S. K.] NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA. [Li, H.; Anderson, S. K.] Leidos Biomed Res Inc, Basic Sci Program, Frederick Natl Lab, Frederick, MD USA. [Cam, M.] NCI, Off Sci & Technol Resources, Ctr Canc Res, Bethesda, MD 20892 USA. [Sen, S. K.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Anderson, SK (reprint author), Leidos Biomed Res Inc, Canc & Inflammat Program, Frederick Natl Lab Canc Res, Bldg 560,Room 31-93, Ft Detrick, MD 21702 USA. EM andersonst@mail.nih.gov OI McCullen, Matthew/0000-0001-9138-1483 FU National Cancer Institute (NCI), National Institutes of Health (NIH) [HHSN261200800001E]; Intramural Research Program of the NIH, NCI, Center for Cancer Research FX This project has been funded in whole or in part with federal funds from the National Cancer Institute (NCI), National Institutes of Health (NIH), under Contract No. HHSN261200800001E. This research was supported in part by the Intramural Research Program of the NIH, NCI, Center for Cancer Research. NR 37 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 1466-4879 EI 1476-5470 J9 GENES IMMUN JI Genes Immun. PD SEP PY 2016 VL 17 IS 6 BP 349 EP 357 DI 10.1038/gene.2016.31 PG 9 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA DV7JF UT WOS:000383111500005 PM 27467282 ER PT J AU Levy, BR Moffat, S Resnick, SM Slade, MD Ferrucci, L AF Levy, Becca R. Moffat, Scott Resnick, Susan M. Slade, Martin D. Ferrucci, Luigi TI Buffer against Cumulative Stress Positive Age Self-Stereotypes Predict Lower Cortisol across 30 Years SO GEROPSYCH-THE JOURNAL OF GERONTOPSYCHOLOGY AND GERIATRIC PSYCHIATRY LA English DT Article DE age stereotypes; cortisol; stress; cumulative stress; stress buffer; longitudinal; resilience ID URINARY CORTISOL; OLDER-ADULTS; MEMORY; BRAIN; METAANALYSIS; PERCEPTIONS; RESPONSES; SALIVARY; DISEASE; EVENTS AB Prolonged elevation of cortisol, the primary stress biomarker, is associated with impaired cognitive and physical health. Cortisol tends to increase in later life among most, but not all, older individuals. The current study considered whether this pattern could be explained by more-positive age stereotypes acting as a stress buffer. The 439 participants drawn from the Baltimore Longitudinal Study of Aging provided 1,789 cortisol measurements, from 24-h collections of urine, across 30 years. Among those aged 50 or greater, the cortisol of the more-negative age-stereotype group increased by 44%, whereas the more-positive age-stereotype group showed no increase. Also as expected, there was no association of age stereotypes and cortisol level among the younger participants, for whom the age stereotypes were self-irrelevant. The findings indicate the importance of considering the relationship between both positive and negative stereotypes and stress biomarkers over time. C1 [Levy, Becca R.] Yale Univ, Sch Publ Hlth, Social & Behav Sci Div, New Haven, CT USA. [Moffat, Scott] Georgia Inst Technol, Sch Psychol, Atlanta, GA 30332 USA. [Resnick, Susan M.] NIA, Lab Behav Neurosci, Baltimore, MD 21224 USA. [Slade, Martin D.] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Translat Gerontol Branch, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Levy, BR (reprint author), Yale Sch Publ Hlth, Social & Behav Sci Div, 60 Coll St POB 208034, New Haven, CT 06520 USA. EM becca.levy@yale.edu NR 42 TC 0 Z9 0 U1 1 U2 1 PU HOGREFE & HUBER PUBLISHERS PI GOTTINGEN PA MERKELSTR 3, D-37085 GOTTINGEN, GERMANY SN 1662-9647 EI 1662-971X J9 GEROPSYCH JI GeroPsych PD SEP PY 2016 VL 29 IS 3 BP 141 EP 146 DI 10.1024/1662-9647/a000149 PG 6 WC Psychology, Developmental SC Psychology GA DV5OB UT WOS:000382976300002 ER PT J AU Bouaoun, L Sonkin, D Ardin, M Hollstein, M Byrnes, G Zavadil, J Olivier, M AF Bouaoun, Liacine Sonkin, Dmitriy Ardin, Maude Hollstein, Monica Byrnes, Graham Zavadil, Jiri Olivier, Magali TI TP53 Variations in Human Cancers: New Lessons from the IARC TP53 Database and Genomics Data SO HUMAN MUTATION LA English DT Article DE annotations; cancer; germline variations; locus-specific database; mutation hotspots; somatic mutations; TP53 ID CELL LINE ENCYCLOPEDIA; P53 GENE; MISSENSE MUTATIONS; DRUG-SENSITIVITY; TUMOR; MDM2; BIOINFORMATICS; CARCINOMA; FRAUMENI; IMPACT AB TP53 gene mutations are one of the most frequent somatic events in cancer. The IARC TP53 Database () is a popular resource that compiles occurrence and phenotype data on TP53 germline and somatic variations linked to human cancer. The deluge of data coming from cancer genomic studies generates new data on TP53 variations and attracts a growing number of database users for the interpretation of TP53 variants. Here, we present the current contents and functionalities of the IARC TP53 Database and perform a systematic analysis of TP53 somatic mutation data extracted from this database and from genomic data repositories. This analysis showed that IARC has more TP53 somatic mutation data than genomic repositories (29,000 vs. 4,000). However, the more complete screening achieved by genomic studies highlighted some overlooked facts about TP53 mutations, such as the presence of a significant number of mutations occurring outside the DNA-binding domain in specific cancer types. We also provide an update on TP53 inherited variants including the ones that should be considered as neutral frequent variations. We thus provide an update of current knowledge on TP53 variations in human cancer as well as inform users on the efficient use of the IARC TP53 Database. C1 [Bouaoun, Liacine; Byrnes, Graham] Int Agcy Res Canc, Grp Biostat, F-69372 Lyon 08, France. [Sonkin, Dmitriy] NCI, Div Canc Treatment & Diag, Biometr Res Program, Rockville, MD USA. [Ardin, Maude; Hollstein, Monica; Zavadil, Jiri; Olivier, Magali] Int Agcy Res Canc, Grp Mol Mech & Biomarkers, 150 Cours Albert Thomas, F-69372 Lyon 08, France. [Hollstein, Monica] Univ Leeds, Fac Med & Hlth, Leeds LS2 9JT, W Yorkshire, England. RP Olivier, M (reprint author), Int Agcy Res Canc, Grp Mol Mech & Biomarkers, 150 Cours Albert Thomas, F-69372 Lyon 08, France. EM olivierm@iarc.fr RI Olivier, Magali/G-3728-2010 OI Olivier, Magali/0000-0002-8202-342X FU International Agency for Research on Cancer (IARC) FX Contract Grant Sponsors: International Agency for Research on Cancer (IARC). NR 37 TC 2 Z9 2 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1059-7794 EI 1098-1004 J9 HUM MUTAT JI Hum. Mutat. PD SEP PY 2016 VL 37 IS 9 BP 865 EP 876 DI 10.1002/humu.23035 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA DV2UJ UT WOS:000382777100003 PM 27328919 ER PT J AU Chen, WY Perritt, AF Morissette, R Dreiling, JL Bohn, MF Mallappa, A Xu, Z Quezado, M Merke, DP AF Chen, Wuyan Perritt, Ashley F. Morissette, Rachel Dreiling, Jennifer L. Bohn, Markus-Frederik Mallappa, Ashwini Xu, Zhi Quezado, Martha Merke, Deborah P. TI Ehlers-Danlos Syndrome Caused by Biallelic TNXB Variants in Patients with Congenital Adrenal Hyperplasia SO HUMAN MUTATION LA English DT Article DE congenital adrenal hyperplasia; Ehlers-Danlos syndrome; tenascin-X; CAH-X; biallelic ID POLYCYSTIC KIDNEY-DISEASE; TENASCIN-X; TGF-BETA; DEFICIENCY; PREDICTION; MUTATIONS; GENES AB Some variants that cause autosomal-recessive congenital adrenal hyperplasia (CAH) also cause hypermobility type Ehlers-Danlos syndrome (EDS) due to the monoallelic presence of a chimera disrupting two flanking genes: CYP21A2, encoding 21-hydroxylase, necessary for cortisol and aldosterone biosynthesis, and TNXB, encoding tenascin-X, an extracellular matrix protein. Two types of CAH tenascin-X (CAH-X) chimeras have been described with a total deletion of CYP21A2 and characteristic TNXB variants. CAH-X CH-1 has a TNXB exon 35 120-bp deletion resulting in haploinsufficiency, and CAH-X CH-2 has a TNXB exon 40 c.12174C>G (p.Cys4058Trp) variant resulting in a dominant-negative effect. We present here three patients with biallelic CAH-X and identify a novel dominant-negative chimera termed CAH-X CH-3. Compared with monoallelic CAH-X, biallelic CAH-X results in a more severe phenotype with skin features characteristic of classical EDS. We present evidence for disrupted tenascin-X function and computational data linking the type of TNXB variant to disease severity. C1 [Chen, Wuyan] PreventionGenetics, Marshfield, WI USA. [Perritt, Ashley F.; Morissette, Rachel; Mallappa, Ashwini; Merke, Deborah P.] NIH, Ctr Clin, Bldg 10,Room 1-2740,10 Ctr Dr, Bethesda, MD 20892 USA. [Dreiling, Jennifer L.; Quezado, Martha] NCI, Pathol Lab, Bldg 10, Bethesda, MD 20892 USA. [Bohn, Markus-Frederik] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA USA. [Xu, Zhi] NIA, NIH, Baltimore, MD 21224 USA. [Merke, Deborah P.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Merke, DP (reprint author), NIH, Ctr Clin, Bldg 10,Room 1-2740,10 Ctr Dr, Bethesda, MD 20892 USA. EM dmerke@nih.gov FU National Institutes of Health Clinical Center; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Cancer Institute; National Institute on Aging FX Intramural research programs of the National Institutes of Health Clinical Center; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Cancer Institute; and National Institute on Aging. NR 21 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1059-7794 EI 1098-1004 J9 HUM MUTAT JI Hum. Mutat. PD SEP PY 2016 VL 37 IS 9 BP 893 EP 897 DI 10.1002/humu.23028 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA DV2UJ UT WOS:000382777100007 PM 27297501 ER PT J AU Doucet-O'Hare, TT Sharma, R Rodic, N Anders, RA Burns, KH Kazazian, HH AF Doucet-O'Hare, Tara T. Sharma, Reema Rodic, Nemanja Anders, Robert A. Burns, Kathleen H. Kazazian, Haig H., Jr. TI Somatically Acquired LINE-1 Insertions in Normal Esophagus Undergo Clonal Expansion in Esophageal Squamous Cell Carcinoma SO HUMAN MUTATION LA English DT Article DE LINE-1; L1; retrotransposition; sub-clonal; squamous cell carcinoma; esophagus ID L1 RETROTRANSPOSITION; HUMAN CANCERS; ORF1 PROTEIN; COLON-CANCER; HUMAN BRAIN; EVOLUTION; METHYLATION; EXPRESSION; LANDSCAPE; SEQUENCE AB Squamous cell carcinoma of the esophagus (SCC) is the most common form of esophageal cancer in the world and is typically diagnosed at an advanced stage when successful treatment is challenging. Understanding the mutational profile of this cancer may identify new treatment strategies. Because somatic retrotransposition has been shown in tumors of the gastrointestinal system, we focused on LINE-1 (L1) mobilization as a source of genetic instability in this cancer. We hypothesized that retrotransposition is ongoing in SCC patients. The expression of L1 encoded proteins is necessary for retrotransposition to occur; therefore, we evaluated the expression of L1 open reading frame 1 protein (ORF1p). Using immunohistochemistry, we detected ORF1p expression in all four SCC cases evaluated. Using L1-seq, we identified and validated 74 somatic insertions in eight tumors of the nine evaluated. Of these, 12 insertions appeared to be somatic, not genetically inherited, and sub-clonal (i.e., present in less than one copy per genome equivalent) in the adjacent normal esophagus (NE), while clonal in the tumor. Our results indicate that L1 retrotransposition is active in SCC of the esophagus and that insertion events are present in histologically NE that expands clonally in the subsequent tumor. C1 [Doucet-O'Hare, Tara T.; Burns, Kathleen H.; Kazazian, Haig H., Jr.] Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Sch Med, Baltimore, MD 21205 USA. [Doucet-O'Hare, Tara T.] McKusick Nathans Inst Genet Med, Predoctoral Training Program Human Genet, Baltimore, MD USA. [Doucet-O'Hare, Tara T.] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Sharma, Reema; Anders, Robert A.; Burns, Kathleen H.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Rodic, Nemanja] Yale Sch Med, Dept Dermatol, New Haven, CT USA. RP Kazazian, HH (reprint author), Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Sch Med, Baltimore, MD 21205 USA. EM hkazazi1@jhmi.edu FU National Institute of General Medical Sciences (NIGMS) [R01 GM 099875, P50 GM107632]; Sol Goldman Award; Burroughs Wellcome Fund Career Award for Biomedical Scientists; National Institutes of Health (NIH) [R01CA163705] FX Contract Grant Sponsors: National Institute of General Medical Sciences (NIGMS) (R01 GM 099875, P50 GM107632); the Sol Goldman Award; the Burroughs Wellcome Fund Career Award for Biomedical Scientists; National Institutes of Health (NIH) (R01CA163705). NR 64 TC 3 Z9 3 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1059-7794 EI 1098-1004 J9 HUM MUTAT JI Hum. Mutat. PD SEP PY 2016 VL 37 IS 9 BP 942 EP 954 DI 10.1002/humu.23027 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA DV2UJ UT WOS:000382777100013 PM 27319353 ER PT J AU Andersson, C Quiroz, R Enserro, D Larson, MG Hamburg, NM Vita, JA Levy, D Benjamin, EJ Mitchell, GF Vasan, RS AF Andersson, Charlotte Quiroz, Rene Enserro, Danielle Larson, Martin G. Hamburg, Naomi M. Vita, Joseph A. Levy, Daniel Benjamin, Emelia J. Mitchell, Gary F. Vasan, Ramachandran S. TI Association of Parental Hypertension With Arterial Stiffness in Nonhypertensive Offspring The Framingham Heart Study SO HYPERTENSION LA English DT Article DE adult; atherosclerosis; blood pressure; hypertension; phenotype ID GENOME-WIDE ASSOCIATION; CARDIOVASCULAR-DISEASE RISK; PULSE-WAVE VELOCITY; BLOOD-PRESSURE; AORTIC STIFFNESS; GENETIC-VARIATION; HERITABILITY; REFLECTION; FAMILIES; VARIANTS AB High arterial stiffness seems to be causally involved in the pathogenesis of hypertension. We tested the hypothesis that offspring of parents with hypertension may display higher arterial stiffness before clinically manifest hypertension, given that hypertension is a heritable condition. We compared arterial tonometry measures in a sample of 1564 nonhypertensive Framingham Heart Study third-generation cohort participants (mean age: 38 years; 55% women) whose parents were enrolled in the Framingham Offspring Study. A total of 468, 715, and 381 participants had 0 (referent), 1, and 2 parents with hypertension. Parental hypertension was associated with greater offspring mean arterial pressure (multivariable-adjusted estimate=2.9 mm Hg; 95% confidence interval, 1.9-3.9, and 4.2 mm Hg; 95% confidence interval, 2.9-5.5, for 1 and 2 parents with hypertension, respectively; P<0.001 for both) and with greater forward pressure wave amplitude (1.6 mm Hg; 95% confidence interval, 0.6-2.7, and 1.9 mm Hg; 95% confidence interval, 0.6-3.2, for 1 and 2 parents with hypertension, respectively; P= 0.003 for both). Carotid-femoral pulse wave velocity and augmentation index displayed similar dose-dependent relations with parental hypertension in sex-, age-, and height-adjusted models, but associations were attenuated on further adjustment. Offspring with at least 1 parent in the upper quartile of augmentation index and carotid-femoral pulse wave velocity had significantly higher values themselves (P= 0.02). In conclusion, in this community-based sample of young, nonhypertensive adults, we observed greater arterial stiffness in offspring of parents with hypertension. These observations are consistent with higher vascular stiffness at an early stage in the pathogenesis of hypertension. C1 [Andersson, Charlotte; Larson, Martin G.; Levy, Daniel; Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ & Natl Heart Lung & Blood Inst Framin, Framingham, MA USA. [Andersson, Charlotte] Glostrup Cty Hosp, Dept Internal Med, Cardiol Sect, Glostrup, Denmark. [Quiroz, Rene] Cardiol Clin San Antonio, San Antonio, TX USA. [Enserro, Danielle; Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Larson, Martin G.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Hamburg, Naomi M.; Vita, Joseph A.; Benjamin, Emelia J.; Vasan, Ramachandran S.] Whitaker Cardiovasc Inst, Boston, MA USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Sect Prevent Med & Epidemiol, Boston, MA 02118 USA. [Levy, Daniel] NHLBI, Bldg 10, Bethesda, MD 20892 USA. [Mitchell, Gary F.] Cardiovasc Engn Inc, Norwood, MA USA. RP Andersson, C (reprint author), Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM ca@heart.dk FU NIH Heart, Lung and Blood Institute [N01-HC-25195 HHSN268201500001I, R01 HL1 07385, 1R01HL126136-01]; Evans Scholar award from the Department of Medicine, Boston University School of Medicine FX The study was funded by the NIH Heart, Lung and Blood Institute (contract no: N01-HC-25195 HHSN268201500001I and R01 HL1 07385 and 1R01HL126136-01, principal investigator R.S. Vasan) with additional support from Evans Scholar award from the Department of Medicine, Boston University School of Medicine (principal investigator, R.S. Vasan). NR 31 TC 1 Z9 1 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0194-911X EI 1524-4563 J9 HYPERTENSION JI Hypertension PD SEP PY 2016 VL 68 IS 3 BP 584 EP + DI 10.1161/HYPERTENSIONAHA.116.07426 PG 13 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DT1ZK UT WOS:000381280400014 PM 27456526 ER PT J AU Shaikh, AY Wang, N Yin, XY Larson, MG Vasan, RS Hamburg, NM Magnani, JW Ellinor, PT Lubitz, SA Mitchell, GF Benjamin, EJ McManus, DD AF Shaikh, Amir Y. Wang, Na Yin, Xiaoyan Larson, Martin G. Vasan, Ramachandran S. Hamburg, Naomi M. Magnani, Jared W. Ellinor, Patrick T. Lubitz, Steven A. Mitchell, Gary F. Benjamin, Emelia J. McManus, David D. TI Relations of Arterial Stiffness and Brachial Flow-Mediated Dilation With New-Onset Atrial Fibrillation The Framingham Heart Study SO HYPERTENSION LA English DT Article DE arrhythmia; augmentation index; flow-mediated dilation; pulse wave velocity; tonometry ID INCIDENT CARDIOVASCULAR EVENTS; PULSE PRESSURE; ENDOTHELIAL DYSFUNCTION; RISK-FACTORS; AORTIC STIFFNESS; OLDER-ADULTS; SYSTOLIC HYPERTENSION; INDEPENDENT PREDICTOR; AUGMENTATION INDEX; BLOOD-PRESSURE AB The relations of measures of arterial stiffness, pulsatile hemodynamic load, and endothelial dysfunction to atrial fibrillation (AF) remain poorly understood. To better understand the pathophysiology of AF, we examined associations between noninvasive measures of vascular function and new-onset AF. The study sample included participants aged =45 years from the Framingham Heart Study offspring and third-generation cohorts. Using Cox proportional hazards regression models, we examined relations between incident AF and tonometry measures of arterial stiffness (carotid-femoral pulse wave velocity), wave reflection (augmentation index), pressure pulsatility (central pulse pressure), endothelial function (flow-mediated dilation), resting brachial arterial diameter, and hyperemic flow. AF developed in 407/5797 participants in the tonometry sample and 270/3921 participants in the endothelial function sample during follow-up (median 7.1 years, maximum 10 years). Higher augmentation index (hazard ratio, 1.16; 95% confidence interval, 1.02-1.32; P=0.02), baseline brachial artery diameter (hazard ratio, 1.20; 95% confidence interval, 1.01-1.43; P=0.04), and lower flowmediated dilation (hazard ratio, 0.79; 95% confidence interval, 0.63-0.99; P=0.04) were associated with increased risk of incident AF. Central pulse pressure, when adjusted for age, sex, and hypertension (hazard ratio, 1.14; 95% confidence interval, 1.02-1.28; P=0.02) was associated with incident AF. Higher pulsatile load assessed by central pulse pressure and greater apparent wave reflection measured by augmentation index were associated with increased risk of incident AF. Vascular endothelial dysfunction may precede development of AF. These measures may be additional risk factors or markers of subclinical cardiovascular disease associated with increased risk of incident AF. C1 [Shaikh, Amir Y.] Univ Massachusetts, Sch Med, Dept Med, 55 Lake Ave N, Worcester, MA 01655 USA. [Wang, Na] Boston Univ, Sch Publ Hlth, Data Coordinating Ctr, Boston, MA 02215 USA. [Yin, Xiaoyan; Larson, Martin G.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02215 USA. [Yin, Xiaoyan; Larson, Martin G.; Vasan, Ramachandran S.; Benjamin, Emelia J.] NHLBI, Boston, MA USA. [Yin, Xiaoyan; Larson, Martin G.; Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Framingham Heart Study, Boston, MA 02215 USA. [Vasan, Ramachandran S.] Boston Univ, Sect Cardiovasc Med Prevent Med & Epidemiol, Dept Med, Sch Med, Boston, MA 02215 USA. [Hamburg, Naomi M.; Magnani, Jared W.] Boston Univ, Div Cardiol, Dept Med, Sch Med, Boston, MA 02215 USA. [Ellinor, Patrick T.; Lubitz, Steven A.] Massachusetts Gen Hosp, Div Cardiol, Dept Med, Boston, MA 02114 USA. [Ellinor, Patrick T.; Lubitz, Steven A.] Harvard Med Sch, Cambridge, MA USA. [Ellinor, Patrick T.; Lubitz, Steven A.] Broad Inst Harvard & MIT, Cambridge, MA USA. [Mitchell, Gary F.] Cardiovasc Engn Inc, Norwood, MA USA. [Benjamin, Emelia J.] Boston Univ, Evans Mem Med Dept, Cardiol Sect, Boston, MA 02215 USA. [Benjamin, Emelia J.] Boston Univ, Prevent Med Sect, Sch Med, Boston, MA 02215 USA. [McManus, David D.] Univ Massachusetts, Sch Med, Dept Med, Div Cardiol, Worcester, MA USA. RP Shaikh, AY (reprint author), Univ Massachusetts, Sch Med, Dept Med, 55 Lake Ave N, Worcester, MA 01655 USA. EM Amir.Shaikh@umassmemorial.org FU National Heart Lung and Blood Institute (NHLBI) [N01-HC-25195, HHSN268201500001I, R01-DK-080739, R01-HL-107385, R01-HL-126136, 1R01HL60040, 1RO1-HL-70100, 1R01HL128914, 2R01HL092577, K24HL105780]; American Heart Association [13EIA14220013]; Foundation Leducq [14CVD01]; National Institutes of Health (NIH) [KL2RR031981, 1R15HL121761]; office of Naval Research work unit [N00014-12-1-0171] FX This study was supported, in part, by National Heart Lung and Blood Institute (NHLBI) contracts N01-HC-25195 and HHSN268201500001I (R.S. Vasan), R01-DK-080739 (R.S. Vasan), R01-HL-107385 (R.S. Vasan and G.F. Mitchell), R01-HL-126136 (R.S. Vasan and G.F. Mitchell), and 1R01HL60040 (E.J. Benjamin); 1RO1-HL-70100 (E.J. Benjamin); 1R01HL128914 (E.J. Benjamin and P.T. Ellinor); 2R01HL092577 (E.J. Benjamin and P.T. Ellinor) and K24HL105780 (P.T. Ellinor). P.T. Ellinor is also supported by an Established Investigator Award from the American Heart Association (13EIA14220013) and by the Foundation Leducq (14CVD01). D.D. McManus's time was funded by National Institutes of Health (NIH) grants KL2RR031981 and 1R15HL121761 and office of Naval Research work unit N00014-12-1-0171. NR 53 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 0194-911X EI 1524-4563 J9 HYPERTENSION JI Hypertension PD SEP PY 2016 VL 68 IS 3 BP 590 EP 596 DI 10.1161/HYPERTENSIONAHA.116.07650 PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DT1ZK UT WOS:000381280400015 PM 27456517 ER PT J AU Jackson, JN Hass, CJ Fregly, BJ AF Jackson, Jennifer N. Hass, Chris J. Fregly, Benjamin J. TI Development of a Subject-Specific Foot-Ground Contact Model for Walking SO JOURNAL OF BIOMECHANICAL ENGINEERING-TRANSACTIONS OF THE ASME LA English DT Article DE gait; foot-ground contact model; viscoelastic elements; optimization; ground reaction force; free moment; center of pressure; biomechanics ID REACTION FORCES; MUSCLE FUNCTION; HUMAN GAIT; SIMULATION; DYNAMICS; KINEMATICS; IMPACT; PARAMETERS; MOMENTS AB Computational walking simulations could facilitate the development of improved treatments for clinical conditions affecting walking ability. Since an effective treatment is likely to change a patient's foot-ground contact pattern and timing, such simulations should ideally utilize deformable foot-ground contact models tailored to the patient's foot anatomy and footwear. However, no study has reported a deformable modeling approach that can reproduce all six ground reaction quantities (expressed as three reaction force components, two center of pressure (CoP) coordinates, and a free reaction moment) for an individual subject during walking. This study proposes such an approach for use in predictive optimizations of walking. To minimize complexity, we modeled each foot as two rigid segments-a hindfoot (HF) segment and a forefoot (FF) segment-connected by a pin joint representing the toes flexion-extension axis. Ground reaction forces (GRFs) and moments acting on each segment were generated by a grid of linear springs with nonlinear damping and Coulomb friction spread across the bottom of each segment. The stiffness and damping of each spring and common friction parameter values for all springs were calibrated for both feet simultaneously via a novel three-stage optimization process that used motion capture and ground reaction data collected from a single walking trial. The sequential three-stage process involved matching (1) the vertical force component, (2) all three force components, and finally (3) all six ground reaction quantities. The calibrated model was tested using four additional walking trials excluded from calibration. With only small changes in input kinematics, the calibrated model reproduced all six ground reaction quantities closely (root mean square (RMS) errors less than 13 N for all three forces, 25 mm for anterior-posterior (AP) CoP, 8mm for medial-lateral (ML) CoP, and 2 N.m for the free moment) for both feet in all walking trials. The largest errors in AP CoP occurred at the beginning and end of stance phase when the vertical ground reaction force (vGRF) was small. Subject-specific deformable foot-ground contact models created using this approach should enable changes in foot-ground contact pattern to be predicted accurately by gait optimization studies, which may lead to improvements in personalized rehabilitation medicine. C1 [Jackson, Jennifer N.; Fregly, Benjamin J.] Univ Florida, Dept Biomed Engn, Gainesville, FL 32611 USA. [Jackson, Jennifer N.] NIH, Funct & Appl Biomech Sect, Dept Rehabil Med, Bldg 10, Bethesda, MD 20892 USA. [Hass, Chris J.] Univ Florida, Dept Appl Physiol & Kinesiol, Gainesville, FL 32611 USA. [Fregly, Benjamin J.] Univ Florida, Dept Mech & Aerosp Engn, Gainesville, FL 32611 USA. RP Fregly, BJ (reprint author), Univ Florida, Dept Biomed Engn, Gainesville, FL 32611 USA.; Fregly, BJ (reprint author), Univ Florida, Dept Mech & Aerosp Engn, Gainesville, FL 32611 USA. EM fregly@ufl.edu RI Fregly, Benjamin/O-6860-2016 OI Fregly, Benjamin/0000-0003-1166-4358 FU NSF [CBET 1052754, CBET 1159735]; National Institutes of Health FX This study was funded by NSF Grant Nos. CBET 1052754 and CBET 1159735. Additional support was provided by the National Institutes of Health. NR 37 TC 1 Z9 2 U1 8 U2 8 PU ASME PI NEW YORK PA TWO PARK AVE, NEW YORK, NY 10016-5990 USA SN 0148-0731 EI 1528-8951 J9 J BIOMECH ENG-T ASME JI J. Biomech. Eng.-Trans. ASME PD SEP PY 2016 VL 138 IS 9 AR 091002 DI 10.1115/1.4034060 PG 12 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA DV9KU UT WOS:000383260200002 ER PT J AU Tagliabue, E Gandini, S Garcia-Borron, JC Maisonneuve, P Newton-Bishop, J Polsky, D Lazovich, D Kumar, R Ghiorzo, P Ferrucci, L Gruis, NA Puig, S Kanetsky, PA Motokawa, T Ribas, G Landi, MT Fargnoli, MC Wong, TH Stratigos, A Helsing, P Guida, G Autier, P Han, JL Little, J Sera, F Raimondi, S AF Tagliabue, Elena Gandini, Sara Garcia-Borron, Jose C. Maisonneuve, Patrick Newton-Bishop, Julia Polsky, David Lazovich, Deann Kumar, Rajiv Ghiorzo, Paola Ferrucci, Leah Gruis, Nelleke A. Puig, Susana Kanetsky, Peter A. Motokawa, Tomonori Ribas, Gloria Landi, Maria Teresa Fargnoli, Maria Concetta Wong, Terence H. Stratigos, Alexander Helsing, Per Guida, Gabriella Autier, Philippe Han, Jiali Little, Julian Sera, Francesco Raimondi, Sara CA M-Skip Study Grp TI Association of Melanocortin-1 Receptor Variants with Pigmentary Traits in Humans: A Pooled Analysis from the M-Skip Project SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Letter ID MC1R VARIANTS; RED HAIR; MELANOMA; CANCER; RADIATION; PHENOTYPE; CAMP; RISK; GENE C1 [Tagliabue, Elena; Gandini, Sara; Maisonneuve, Patrick; Raimondi, Sara] European Inst Oncol, Div Epidemiol & Biostat, Milan, Italy. [Garcia-Borron, Jose C.] Univ Murcia, Dept Biochem Mol Biol & Immunol, Murcia, Spain. [Garcia-Borron, Jose C.] IMIB Arrixaca, Murcia, Spain. [Newton-Bishop, Julia] Univ Leeds, Inst Canc & Pathol, Sect Epidemiol & Biostat, Leeds, W Yorkshire, England. [Polsky, David] NYU, Sch Med, NYU Langone Med Ctr, Ronald O Perelman Dept Dermatol, New York, NY 10003 USA. [Lazovich, Deann] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN 55455 USA. [Kumar, Rajiv] German Canc Res Ctr, Div Mol Genet Epidemiol, Heidelberg, Germany. [Ghiorzo, Paola] Univ Genoa, Dept Internal Med & Med Specialties, Genoa, Italy. [Ghiorzo, Paola] IRCCS AOU San Martino IST, Genoa, Italy. [Ferrucci, Leah] Yale Sch Publ Hlth, Yale Canc Ctr, Dept Chron Dis Epidemiol, New Haven, CT 06510 USA. [Gruis, Nelleke A.] Leiden Univ, Med Ctr, Dept Dermatol, Leiden, Netherlands. [Puig, Susana] Univ Barcelona, Hosp Clin Barcelona, CIBER Enfermedades Raras, Melanoma Unit,Dermatol Dept, Barcelona, Spain. [Kanetsky, Peter A.] H Lee Moffitt Canc Ctr & Res Institute2, Dept Canc Epidemiol, Tampa, FL USA. [Motokawa, Tomonori] POLA Chem Ind, Skin Res Dept, Yokohama, Kanagawa, Japan. [Ribas, Gloria] Fdn Invest Clin Valencia, Inst Invest Sanitaria INCLIVA, Dept Med Oncol & Hematol, Valencia, Spain. [Landi, Maria Teresa] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Fargnoli, Maria Concetta] Univ Aquila, Dept Dermatol, Laquila, Italy. [Wong, Terence H.] NHS Forth Valley, London, England. [Stratigos, Alexander] Univ Athens, Sch Med, Andreas Sygros Hosp, Dept Dermatol 1, Athens, Greece. [Helsing, Per] Oslo Univ Hosp, Dept Pathol, Oslo, Norway. [Guida, Gabriella] Univ Bari, Dept Basic Med Sci Neurosci & Sense Organs, Bari, Italy. [Autier, Philippe] Int Prevent Res Inst, Lyon, France. [Han, Jiali] Indiana Univ, Melvin & Bren Simon Canc Ctr, Richard M Fairbanks Sch Publ Hlth, Dept Epidemiol, Indianapolis, IN 46204 USA. [Little, Julian] Univ Ottawa, Sch Epidemiol Publ Hlth & Prevent Med, Ottawa, ON, Canada. [Sera, Francesco] London Sch Hyg & Trop Med, Dept Social & Environm Hlth Res, London, England. RP Raimondi, S (reprint author), European Inst Oncol, Div Epidemiol & Biostat, Milan, Italy. EM sara.raimondi@ieo.it RI Guida, Stefania/Q-9530-2016; Liu, Fan/B-8833-2013; OI Maisonneuve, Patrick/0000-0002-5309-4704; Guida, Stefania/0000-0002-8221-6694; CARRERA, CRISTINA/0000-0003-1608-8820; Liu, Fan/0000-0001-9241-8161; Gimenez Xavier, Pol/0000-0003-1611-5083; Tell-Marti, Gemma/0000-0003-2728-6961; Potrony, Miriam/0000-0003-2766-0765; Palmieri, Giuseppe/0000-0002-4350-2276; Newton Bishop, Julia/0000-0001-9147-6802; Gandini, Sara/0000-0002-1348-4548; Raimondi, Sara/0000-0003-4673-9049 FU NCI NIH HHS [R01 CA092428, K07 CA080700, P01 CA087969, R01 CA049449, UM1 CA167552, UM1 CA186107] NR 15 TC 0 Z9 0 U1 11 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD SEP PY 2016 VL 136 IS 9 BP 1914 EP 1917 DI 10.1016/j.jid.2016.05.099 PG 5 WC Dermatology SC Dermatology GA DV7BP UT WOS:000383091200030 PM 27251790 ER PT J AU Guitart, JR Johnson, JL Chien, WW AF Guitart, Joan Ramon, Jr. Johnson, Jodi L. Chien, Wade W. TI Research Techniques Made Simple: The Application of CRISPR-Cas9 and Genome Editing in Investigative Dermatology SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID EPIDERMOLYSIS-BULLOSA; GENE CORRECTION; NUCLEASES AB Designer nucleases have gained widespread attention for their ability to precisely modify genomic DNA in a programmable manner. These genome-editing nucleases make double-stranded breaks at specified loci, and desired changes can be made to modify, ablate, or excise target genes. This technology has been used widely to develop human disease models in laboratory animals and to study gene functions by silencing, activating, or modifying them. Furthermore, the recent discovery of a bacterially derived programmable nuclease termed clustered regularly interspaced palindromic repeats (CRISPR)-associated protein 9 (Cas9) has revolutionized the field because of its versatility and wide applicability. In this article, we discuss various modalities used to achieve genome editing with an emphasison CRISPR-Cas9. We discussgenome-editing strategies to either repair or ablate target genes, with emphasis on their applications for investigating dermatological diseases. Additionally, we highlight preclinical studies showing the potential of genome editing as a therapy for congenital blistering diseases and as an antimicrobial agent, and we discuss limitations and future directions of this technology. C1 [Guitart, Joan Ramon, Jr.; Chien, Wade W.] Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD 20892 USA. [Johnson, Jodi L.] Northwestern Univ, Dept Pathol, Feinberg Sch Med, Chicago, IL 60611 USA. [Johnson, Jodi L.] Northwestern Univ, Feinberg Sch Med, Dept Dermatol, Chicago, IL 60611 USA. [Chien, Wade W.] Johns Hopkins Sch Med, Dept Otolaryngol Head & Neck Surg, Baltimore, MD 21205 USA. RP Guitart, JR (reprint author), NIDCD, NIH, Porter Neurosci Res Ctr, 35A Convent Dr 1F-220, Bethesda, MD 20892 USA. EM joan.guitart@northwestern.edu FU Intramural NIH HHS [Z99 DC999999] NR 20 TC 0 Z9 0 U1 14 U2 14 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD SEP PY 2016 VL 136 IS 9 BP E87 EP E93 DI 10.1016/j.jid.2016.06.007 PG 7 WC Dermatology SC Dermatology GA DV7BP UT WOS:000383091200001 PM 27542298 ER PT J AU Kirnbauer, R Buchman, G Fisher, M White, J Kennedy, M Sei, S Schellenbacher, C Roden, RB Shoemaker, R AF Kirnbauer, R. Buchman, G. Fisher, M. White, J. Kennedy, M. Sei, S. Schellenbacher, C. Roden, R. B. Shoemaker, R. TI cGMP production of a chimeric virus-like particle vaccine (RG1-VLP) for prevention of HPV-associated cancers SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT Annual Meeting of the European-Society-for-Dermatological-Research (ESDR) CY SEP 07-10, 2016 CL Munich, GERMANY SP European Soc Dermatol Res C1 [Kirnbauer, R.; Schellenbacher, C.] Med Univ Vienna, Dermatol, Vienna, Austria. [Buchman, G.; Fisher, M.] Paragon Bioserv, Baltimore, MD USA. [White, J.; Kennedy, M.] MRI Global, Kansas City, MO USA. [Sei, S.; Shoemaker, R.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Roden, R. B.] Johns Hopkins Univ, Pathol, Baltimore, MD USA. NR 0 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 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD SEP PY 2016 VL 136 IS 9 SU 2 MA 426 BP S233 EP S233 PG 1 WC Dermatology SC Dermatology GA DV7BV UT WOS:000383091900423 ER PT J AU Namiki, T Funazaumi, M Nojima, K Ishikawa, M Tanemura, A Katamaya, I Mori, T Yamazaki, N Yokozeki, H Hearing, V AF Namiki, T. Funazaumi, M. Nojima, K. Ishikawa, M. Tanemura, A. Katamaya, I. Mori, T. Yamazaki, N. Yokozeki, H. Hearing, V. TI Overexpression of NUAK2 has a significant impact on the survival of acral melanoma patients SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT Annual Meeting of the European-Society-for-Dermatological-Research (ESDR) CY SEP 07-10, 2016 CL Munich, GERMANY SP European Soc Dermatol Res C1 [Namiki, T.; Funazaumi, M.; Nojima, K.; Yokozeki, H.] Tokyo Med & Dent Univ, Dermatol, Tokyo, Japan. [Ishikawa, M.] Saitama Canc Ctr, Dermatol, Saitama, Japan. [Tanemura, A.; Katamaya, I.] Osaka Univ, Dermatol, Osaka, Japan. [Mori, T.] Natl Canc Ctr, Pathol, Tokyo, Japan. [Yamazaki, N.] Natl Canc Ctr, Dermatol Oncol, Tokyo, Japan. [Hearing, V.] NCI, Cell Biol Lab, Bldg 37, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD SEP PY 2016 VL 136 IS 9 SU 2 MA 464 BP S239 EP S239 PG 1 WC Dermatology SC Dermatology GA DV7BV UT WOS:000383091900461 ER PT J AU Takahashi, H Nomura, H Iriki, H Mikami, Y Kanno, Y Kubo, A O'Shea, J Amagai, M AF Takahashi, H. Nomura, H. Iriki, H. Mikami, Y. Kanno, Y. Kubo, A. O'Shea, J. Amagai, M. TI Novel immune regulation by CD4(+) T cells via cholesterol 25-hydroxylase pathway SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT Annual Meeting of the European-Society-for-Dermatological-Research (ESDR) CY SEP 07-10, 2016 CL Munich, GERMANY SP European Soc Dermatol Res C1 [Takahashi, H.; Nomura, H.; Iriki, H.; Amagai, M.] Keio Univ, Dermatol, Tokyo, Japan. [Mikami, Y.; Kanno, Y.; O'Shea, J.] NIAMS, NIH, Bethesda, MD USA. [Kubo, A.] Keio Univ, Biochem, Tokyo, Japan. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD SEP PY 2016 VL 136 IS 9 SU 2 MA 242 BP S202 EP S202 PG 1 WC Dermatology SC Dermatology GA DV7BV UT WOS:000383091900241 ER PT J AU Squires, A Xu, S Seifabadi, R Chen, Y Agarwal, H Bernardo, M Negussie, A Pinto, P Choyke, P Wood, B Tse, ZTH AF Squires, Alexander Xu, Sheng Seifabadi, Reza Chen, Yue Agarwal, Harsh Bernardo, Marcelino Negussie, Ayele Pinto, Peter Choyke, Peter Wood, Bradford Tse, Zion Tsz Ho TI Robot for Magnetic Resonance Imaging Guided Focal Prostate Laser Ablation SO JOURNAL OF MEDICAL DEVICES-TRANSACTIONS OF THE ASME LA English DT Article; Proceedings Paper CT University-of-Minnesota's Design of Medical Devices (DMD) Conference CY APR 11-14, 2016 CL Minneapolis, MN SP Univ Minnesota ID CANCER C1 [Squires, Alexander; Chen, Yue; Tse, Zion Tsz Ho] Univ Georgia, Coll Engn, Athens, GA 30602 USA. [Xu, Sheng; Seifabadi, Reza; Bernardo, Marcelino; Negussie, Ayele; Pinto, Peter; Choyke, Peter; Wood, Bradford] NIH, Dept Radiol & Imaging Sci, Ctr Intervent Oncol, Bethesda, MD 20892 USA. [Agarwal, Harsh] Philips Res North Amer, Briarcliff Manor, NY 10510 USA. RP Squires, A (reprint author), Univ Georgia, Coll Engn, Athens, GA 30602 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU ASME PI NEW YORK PA TWO PARK AVE, NEW YORK, NY 10016-5990 USA SN 1932-6181 EI 1932-619X J9 J MED DEVICES JI J. Med. Devices PD SEP PY 2016 VL 10 IS 3 AR 030942 DI 10.1115/1.4033805 PG 3 WC Engineering, Biomedical SC Engineering GA DV8KC UT WOS:000383184900043 ER PT J AU Lih, CJ Si, H Das, B Harrington, RD Harper, KN Sims, DJ McGregor, PM Camalier, CE Kayserian, AY Williams, PM He, HJ Almeida, JL Lund, SP Choquette, S Cole, KD AF Lih, Chih-Jian Si, Han Das, Biswajit Harrington, Robin D. Harper, Kneshay N. Sims, David J. McGregor, Paul M. Camalier, Corinne E. Kayserian, Andrew Y. Williams, P. Mickey He, Hua-Jun Almeida, Jamie L. Lund, Steve P. Choquette, Steve Cole, Kenneth D. TI Certified DNA Reference Materials to Compare HER2 Gene Amplification Measurements Using Next-Generation Sequencing Methods SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Article ID COPY NUMBER VARIATION; CANCER CELL-LINES; GUIDELINES MINIMUM INFORMATION; HUMAN-BREAST-CANCER; REAL-TIME PCR; VALIDATION; OVEREXPRESSION; HYBRIDIZATION; PUBLICATION; VARIANTS AB The National Institute of Standards and Technology (NIST) Standard Reference Materials 2373 is a set of genomic DNA samples prepared from five breast cancer cell lines with certified values for the ratio of the HER2 gene copy number to the copy numbers of reference genes determined by real-time quantitative PCR and digital PCR. Targeted-amplicon, whole-exome, and whole-genome sequencing measurements were used with the reference material to compare the performance of both the laboratory steps and the bioinformatic approaches of the different methods using a range of amplification ratios. Although good reproducibility was observed in each next-generation sequencing method, slightly different HER2 copy numbers' associated with platform-specific biases were obtained. This study clearly demonstrates the value of Standard Reference Materials 2373 as reference material and as a calibrator for evaluating assay performance as well as for increasing confidence in reporting HER2 amplification for clinical applications. C1 [Lih, Chih-Jian; Si, Han; Das, Biswajit; Harrington, Robin D.; Harper, Kneshay N.; Sims, David J.; McGregor, Paul M.; Camalier, Corinne E.; Kayserian, Andrew Y.; Williams, P. Mickey] Frederick Natl Lab Canc Res, Mol Characterizat & Clin Assay Dev Lab, Frederick, MD USA. [He, Hua-Jun; Almeida, Jamie L.; Choquette, Steve; Cole, Kenneth D.] NIST, Div Biosyst & Biomat, Gaithersburg, MD 20899 USA. [Lund, Steve P.] NIST, Div Stat Engn, Gaithersburg, MD 20899 USA. RP Cole, KD (reprint author), NIST, 100 Bur Dr,MS 8312, Gaithersburg, MD 20899 USA. EM kenneth.cole@nist.gov FU National Institute of Standards and Technology; National Cancer Institute, NIH [HHSN261200800001E, NO1-CO-2008-00001] FX Supported by internal funding from the National Institute of Standards and Technology and partially by the National Cancer Institute, NIH, contracts HHSN261200800001E and NO1-CO-2008-00001. NR 46 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 EI 1943-7811 J9 J MOL DIAGN JI J. Mol. Diagn. PD SEP PY 2016 VL 18 IS 5 BP 753 EP 761 DI 10.1016/j.jmoldx.2016.05.008 PG 9 WC Pathology SC Pathology GA DU7VK UT WOS:000382422500015 PM 27455875 ER PT J AU Hayward, BE Zhou, YF Kumari, D Usdin, K AF Hayward, Bruce E. Zhou, Yifan Kumari, Daman Usdin, Karen TI A Set of Assays for the Comprehensive Analysis of FMR1 Alleles in the Fragile X-Related Disorders SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Article ID POLYMERASE-CHAIN-REACTION; REPEAT PRIMED PCR; CGG REPEATS; AGG INTERRUPTIONS; EXPANDED ALLELES; METHYLATION ANALYSIS; PREMUTATION ALLELES; IDENTIFY COMPOUNDS; GENE; DNA AB The diagnosis and study of the fragile X-related disorders is complicated by the difficulty of amplifying the long CGG/CCG-repeat tracts that are responsible for disease pathology, the potential presence of AGG interruptions within the repeat tract that can ameliorate expansion risk, the occurrence of variable DNA methylation that modulates disease severity, and the high frequency of mosaicism for both repeat number and methylation status. These factors complicate patient risk assessment. In addition, the variability in these parameters that is seen when patient cells are grown in culture requires their frequent monitoring to ensure reproducible results in a research setting. Many existing assays have the limited ability to amplify long alleles, particularly in a mixture of different allele sizes. Others are better at this, but are too expensive for routine use in most laboratories or for newborn screening programs and use reagents that are proprietary. We describe herein a set of assays to routinely evaluate all of these important parameters in a time- and cost-effective way. C1 [Hayward, Bruce E.; Zhou, Yifan; Kumari, Daman; Usdin, Karen] NIDDK, Sect Gene Struct & Dis, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. RP Usdin, K (reprint author), NIH, Bldg 8,Room 2A19,8 Ctr Dr,MSC 0830, Bethesda, MD 20892 USA. EM ku@helix.nih.gov FU National Institute of Diabetes and Digestive Kidney Diseases, NIH intramural program [DK057808] FX Supported by a National Institute of Diabetes and Digestive Kidney Diseases, NIH intramural program (DK057808; K.U.). NR 40 TC 2 Z9 2 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 EI 1943-7811 J9 J MOL DIAGN JI J. Mol. Diagn. PD SEP PY 2016 VL 18 IS 5 BP 762 EP 774 DI 10.1016/j.jmoldx.2016.06.001 PG 13 WC Pathology SC Pathology GA DU7VK UT WOS:000382422500016 PM 27528259 ER PT J AU Braverman, DW Doernberg, SN Runge, CP Howard, DS AF Braverman, Derek W. Doernberg, Samuel N. Runge, Carlisle P. Howard, Dana S. TI OxRec model for assessing risk of recidivism: ethics SO LANCET PSYCHIATRY LA English DT Letter C1 [Braverman, Derek W.; Doernberg, Samuel N.; Runge, Carlisle P.; Howard, Dana S.] NIH, Dept Bioeth, Bldg 10, Bethesda, MD 20892 USA. RP Braverman, DW (reprint author), NIH, Dept Bioeth, Bldg 10, Bethesda, MD 20892 USA. EM derek.braverman@nih.gov FU Intramural Research Program of the National Institutes of Health FX DWB, SND, CPR, and DSH are supported by the Intramural Research Program of the National Institutes of Health, where DWB, SND, and DSH are fellows and CPR is a research associate in the Clinical Center Department of Bioethics. The views expressed are the authors' own. They do not represent the position or policy of the US National Institutes of Health, Public Health Service, or Department of Health and Human Services. We declare no other competing interests. NR 5 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2215-0374 J9 LANCET PSYCHIAT JI Lancet Psychiatry PD SEP PY 2016 VL 3 IS 9 BP 808 EP 809 PG 3 WC Psychiatry SC Psychiatry GA DU5TV UT WOS:000382276800016 PM 27568268 ER PT J AU Berikkhanova, K Omarbaev, R Gulyayev, A Shulgau, Z Ibrasheva, D Adilgozhina, G Sergazy, S Zhumadilov, Z Askarova, S AF Berikkhanova, Kulzhan Omarbaev, Rustam Gulyayev, Alexandr Shulgau, Zarina Ibrasheva, Dilbar Adilgozhina, Gulsim Sergazy, Shynggys Zhumadilov, Zhaxybay Askarova, Sholpan TI Red blood cell ghosts as promising drug carriers to target wound infections SO MEDICAL ENGINEERING & PHYSICS LA English DT Article DE RBC ghosts; Drug carriers; IL-1 beta; Wound infections ID HUMAN INTERLEUKIN-1-BETA; CLEARANCE; DELIVERY; ERYTHROCYTES; RATS AB Autologous red blood cell ghosts (RBC ghosts) can carry cytokines to the sites of inflammation. The targeting moiety of the RBC ghosts is associated with the nature of purulent inflammation, where the erythrocytes are phagocyted and encapsulated drugs are released. In the present study we have investigated the healing potential of RBC ghosts loaded with cytokine IL-1 beta and antibiotic. Additionally, the pharma-cokinetic properties of RBC ghosts loaded with IL-1 beta were studied. 35 Male Wistar rats (250-300 g) were used in the pharmacokinetic study and in a wound infection model where a suspension of Staphylococcus aureus was placed into a surgical cut of the skin and subcutaneous tissue in the femoral region. In order to monitor progression of the wound repair processes, wound swabs or aspiration biopsies were taken for analyses on the 1st-6th days. Wound repair dynamics assessment was based on suppression of S. aureus growth, signs of pain, time of disappearance of pus and infiltration around the wound. Visual observations, as well as microbiological and cytological analysis of wound exudates demonstrated a significant acceleration of healing processes in a group of animals treated with a local injection of IL-1 beta and ceftriaxone encapsulated into RBC ghosts when compared to the animals treated either with a local or IM injection of free drugs. For the pharmacokinetic study, single IV injections of either free or encapsulated IL-1 beta were made and the concentration of IL-1 beta in serum samples and tissue homogenates were determined. Encapsulation in RBC ghosts improved pharmacokinetic profiles of IL-1 beta by increasing the half-life, reducing its clearance, and increasing the deposition of the drug in the liver, spleen and lungs. These data suggest that RBC ghosts are effective drug carriers for targeted delivery of cytokines to the sites of inflammation, and have a potential for improving the treatment outcomes of purulent diseases. (C) 2016 IPEM. Published by Elsevier Ltd. All rights reserved. C1 [Berikkhanova, Kulzhan; Gulyayev, Alexandr; Ibrasheva, Dilbar; Adilgozhina, Gulsim; Sergazy, Shynggys; Zhumadilov, Zhaxybay; Askarova, Sholpan] Nazarbayev Univ, Ctr Life Sci, Natl Lab Astana, Astana, Kazakhstan. [Omarbaev, Rustam] City Hosp 2, Astana, Kazakhstan. [Shulgau, Zarina] Natl Biotechnol Ctr, Astana, Kazakhstan. [Adilgozhina, Gulsim] Nazarbayev Univ, Sch Sci & Technol, Astana, Kazakhstan. RP Askarova, S (reprint author), Nazarbayev Univ, Ctr Life Sci, Natl Lab Astana, Astana, Kazakhstan. EM shynggys.sergazy@nu.edu.kz; shaskarova@nu.edu.kz RI Berikkhanova, Kulzhan/E-2290-2016 OI Askarova, Sholpan/0000-0001-6161-1671; Berikkhanova, Kulzhan/0000-0002-6371-9210 FU Ministry of Education and Science of the Republic of Kazakhstan [0112PK02309, 0114PK00491] FX This work was supported by the grants of the Ministry of Education and Science of the Republic of Kazakhstan Nos. 0112PK02309 and 0114PK00491. We are grateful to Dr. Richard Koepsel (Carnegie Mellon University, USA) for language editing and proofreading. NR 29 TC 0 Z9 0 U1 17 U2 17 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1350-4533 EI 1873-4030 J9 MED ENG PHYS JI Med. Eng. Phys. PD SEP PY 2016 VL 38 IS 9 SI SI BP 877 EP 884 DI 10.1016/j.medengphy.2016.02.014 PG 8 WC Engineering, Biomedical SC Engineering GA DV5YN UT WOS:000383006700009 PM 27062487 ER PT J AU Gottimukkala, KP Jangid, R Patta, I Sultana, DA Sharma, A Misra-Sen, J Galande, S AF Gottimukkala, Kamalvishnu P. Jangid, Rahul Patta, Indumathi Sultana, Dil Afroz Sharma, Archna Misra-Sen, Jyoti Galande, Sanjeev TI Regulation of SATB1 during thymocyte development by TCR signaling SO MOLECULAR IMMUNOLOGY LA English DT Article DE T cell receptor; SATB1; GATA-3; Signaling ID CELL LINEAGE COMMITMENT; T-CELLS; IMMATURE THYMOCYTES; NEGATIVE SELECTION; GENE-REGULATION; EXPRESSION; DIFFERENTIATION; THYMUS; MOUSE; PROGRAM AB T lymphocyte development and differentiation is a multi-step process that begins in the thymus and completed in the periphery. Sequential development of thymocytes is dependent on T cell receptor (TCR) signaling and an array of transcription factors. In this study we show that special AT-rich binding protein 1 (SATB1), a T lineage-enriched chromatin organizer and regulator, is induced in response to TCR signaling during early thymocyte development. SATB1 expression profile coincides with T lineage commitment and upregulation of SATB1 correlates with positive selection of thymocytes. CD4 thymocytes exhibit a characteristic bimodal expression pattern that corresponds to immature and mature CD4 thymocytes: We also demonstrate that GATA3, the key transcriptional regulator of alpha beta T cells positively regulates SATB1 expression in thymocytes suggesting an important role for SATB1 during T cell development. (C) 2016 Published by Elsevier Ltd. C1 [Gottimukkala, Kamalvishnu P.; Jangid, Rahul; Patta, Indumathi; Galande, Sanjeev] Indian Inst Sci Educ & Res, Pune 411008, Maharashtra, India. [Sultana, Dil Afroz; Sharma, Archna; Misra-Sen, Jyoti] Johns Hopkins Univ, NIA, NIH, Baltimore, MD USA. [Sultana, Dil Afroz; Sharma, Archna; Misra-Sen, Jyoti] Johns Hopkins Univ, Sch Med, Grad Program Immunol, Baltimore, MD USA. [Galande, Sanjeev] Natl Ctr Cell Sci, Pune 411007, Maharashtra, India. RP Galande, S (reprint author), Indian Inst Sci Educ & Res, Ctr Excellence Epigenet, Dr Homi Bhabha Rd, Pune 411008, Maharashtra, India. EM sanjeev@iiserpune.ac.in RI Sharma, Archna/R-9377-2016 OI Sharma, Archna/0000-0003-4745-0220 FU Centre of Excellence in Epigenetics program of the Department of Biotechnology, Government of India; Department of Science and Technology, Government of India; Council of Scientific and Industrial Research, India FX Work was supported by grants from the Centre of Excellence in Epigenetics program of the Department of Biotechnology, Government of India, Swarnajayanti Fellowship Award from the Department of Science and Technology, Government of India to SG and NIH-intramural research program to JMS. KG and RJ were supported by fellowships from the Council of Scientific and Industrial Research, India. Authors wish to thank Dr. Krishanpal Karmodiya for help with ChIP-seq analysis, Dr. Satyajit Rath for valuable suggestions, and staff at the experimental animal facility of NCCS. NR 35 TC 0 Z9 0 U1 2 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD SEP PY 2016 VL 77 BP 34 EP 43 DI 10.1016/j.molimm.2016.07.005 PG 10 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA DV9ZV UT WOS:000383301600005 PM 27454343 ER PT J AU Jones, BG Penkert, RR Xu, BS Fan, YP Neale, G Gearhart, PJ Hurwitz, JL AF Jones, Bart G. Penkert, Rhiannon R. Xu, Beisi Fan, Yiping Neale, Geoff Gearhart, Patricia J. Hurwitz, Julia L. TI Binding of estrogen receptors to switch sites and regulatory elements in the immunoglobulin heavy chain locus of activated B cells suggests a direct influence of estrogen on antibody expression SO MOLECULAR IMMUNOLOGY LA English DT Article DE Estrogen response elements; Switch site; Enhancers; Immunoglobulin heavy chain locus; Class switch recombination ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; GENE-EXPRESSION; IGH LOCUS; TRANSCRIPTIONAL ACTIVATION; RESPONSE ELEMENTS; IMMUNE-RESPONSES; STRANDED-DNA; RECOMBINATION; AID; ENHANCER AB Females and males differ in antibody isotype expression patterns and in immune responses to foreign and self-antigens. For example, systemic lupus erythematosus is a condition that associates with the production of isotype-skewed anti-self antibodies, and exhibits a 9:1 female:male disease ratio. To explain differences between B cell responses in males and females, we sought to identify direct interactions of the estrogen receptor (ER) with the immunoglobulin heavy chain locus. This effort was encouraged by our previous identification of estrogen response elements (ERE) in heavy chain switch (S) regions. We conducted a full-genome chromatin immunoprecipitation analysis (ChIP-seq) using DNA from LPS-activated B cells and an ER alpha-specific antibody. Results revealed ER binding to a wide region of DNA, spanning sequences from the J(H) cluster to CB, with peaks in E mu and S mu. sites. Additional peaks of ER alpha binding were coincident with hs1,2 and hs4 sites in the 3' regulatory region (3'RR) of the heavy chain locus. This first demonstration of direct binding of ER to key regulatory elements in the immunoglobulin locus supports our hypothesis that estrogen and other nuclear hormone receptors and ligands may directly influence antibody expression and class switch recombination (CSR). Our hypothesis encourages the conduct of new experiments to evaluate the consequences of ER binding. A better understanding of ER:DNA interactions in the immunoglobulin heavy chain locus, and respective mechanisms, may ultimately translate to better control of antibody expression, better protection against pathogens, and prevention of pathologies caused by auto-immune disease. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Jones, Bart G.; Penkert, Rhiannon R.; Hurwitz, Julia L.] St Jude Childrens Res Hosp, Dept Infect Dis, 262 Danny Thomas Pl, Memphis, TN 38105 USA. [Xu, Beisi; Fan, Yiping] St Jude Childrens Res Hosp, Dept Computat Biol, 262 Danny Thomas Pl, Memphis, TN 38105 USA. [Neale, Geoff] St Jude Childrens Res Hosp, Hartwell Ctr, 262 Danny Thomas Pl, Memphis, TN 38105 USA. [Gearhart, Patricia J.] NIA, Lab Mol Biol & Immunol, NIH, Baltimore, MD 21224 USA. [Hurwitz, Julia L.] Univ Tennessee, Hlth Sci Ctr, Dept Microbiol Immunol & Biochem, Memphis, TN 38163 USA. RP Hurwitz, JL (reprint author), St Jude Childrens Res Hosp, Dept Infect Dis, 262 Danny Thomas Pl, Memphis, TN 38105 USA. EM julia.hurwitz@stjude.org OI Xu, Beisi/0000-0003-0099-858X FU NIH NIAID [R01 AI088729]; NCI [P30 CA21765]; American Lebanese Syrian Associated Charities (ALSAC); Intramural Research Program of the NIH, National Institute on Aging FX We thank Dr. Robert W. Maul of the Laboratory of Molecular Biology and Immunology at the NIH National Institute on Aging for consultations and expert advice. The research was funded in part by NIH NIAID R01 AI088729, NCI P30 CA21765, the American Lebanese Syrian Associated Charities (ALSAC), and the Intramural Research Program of the NIH, National Institute on Aging. NR 60 TC 1 Z9 1 U1 7 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD SEP PY 2016 VL 77 BP 97 EP 102 DI 10.1016/j.molimm.2016.07.015 PG 6 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA DV9ZV UT WOS:000383301600012 PM 27494228 ER PT J AU Miao, HX Panna, A Gomella, AA Bennett, EE Znati, S Chen, L Wen, H AF Miao, Houxun Panna, Alireza Gomella, Andrew A. Bennett, Eric E. Znati, Sami Chen, Lei Wen, Han TI A universal moire effect and application in X-ray phase-contrast imaging SO NATURE PHYSICS LA English DT Article ID GRATING INTERFEROMETER; FOURIER IMAGES; FABRICATION AB A moire pattern results from superimposing two black-and white or greyscale patterns of regular geometry, such as two sets of evenly spaced lines. Here, we report the observation of an analogous effect with two transparent phase masks put in a light beam. The phase moire effect and the classic moire effect are shown to be the two ends of a continuous spectrum. The former allows the detection of sub-resolution intensity or phase patterns with a transparent screen. When applied to X-ray imaging, it enables the realization of a polychromatic far-field interferometer (PFI) without the need for absorption gratings. X-ray interferometry can non-invasively detect refractive index variations inside an object(1-10). Current bench-top interferometers operate in the near field with limitations in sensitivity and X-ray dose efficiency(2,5,7-10). The universal moire effect helps overcome these limitations and obviates the need for using hard X-ray absorption gratings with sub-micrometre periods. C1 [Miao, Houxun; Panna, Alireza; Bennett, Eric E.; Znati, Sami; Wen, Han] NHLBI, Biophys & Biochem Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. [Gomella, Andrew A.] Thomas Jefferson Univ, Sidney Kimmel Med Coll, Philadelphia, PA 19107 USA. [Chen, Lei] NIST, Ctr Nanoscale Sci & Technol, Gaithersburg, MD 20899 USA. RP Wen, H (reprint author), NHLBI, Biophys & Biochem Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM miaoh@mail.nih.gov RI Wen, Han/G-3081-2010 OI Wen, Han/0000-0001-6844-2997 FU Intramural NIH HHS [Z01 HL004606-12, Z99 HL999999, Z01 HL004606-11]; Intramural NIST DOC [9999-NIST] NR 20 TC 4 Z9 4 U1 9 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1745-2473 EI 1745-2481 J9 NAT PHYS JI Nat. Phys. PD SEP PY 2016 VL 12 IS 9 BP 830 EP 834 PG 5 WC Physics, Multidisciplinary SC Physics GA DV8XK UT WOS:000383219800007 PM 27746823 ER PT J AU Dula, AN Pawate, S Dethrage, LM Conrad, BN Dewey, BE Barry, RL Smith, SA AF Dula, Adrienne N. Pawate, Siddharama Dethrage, Lindsey M. Conrad, Benjamin N. Dewey, Blake E. Barry, Robert L. Smith, Seth A. TI Chemical exchange saturation transfer of the cervical spinal cord at 7 T SO NMR IN BIOMEDICINE LA English DT Article DE spinal cord; chemical exchange saturation transfer; multiple sclerosis ID PULSED STEADY-STATE; MULTIPLE-SCLEROSIS; MAGNETIZATION-TRANSFER; HUMAN BRAIN; WATER RESONANCE; IN-VIVO; MRI; ABNORMALITIES; DISABILITY; METABOLITES AB High-magnetic-field (7T) chemical exchange saturation transfer (CEST) MRI provides information on the tissue biochemical environment. Multiple sclerosis (MS) affects the entire central nervous system, including the spinal cord. Optimal CEST saturation parameters found via simulation were implemented for CEST MRI in 10 healthy controls and 10 patients with MS, and the results were examined using traditional asymmetry analysis and a Lorentzian fitting method. In addition, T-1- and T-2*-weighted images were acquired for lesion localization and the transmitted B-1(+) field was evaluated to guide imaging parameters. Distinct spectral features for all tissue types studied were found both up- and downfield from the water resonance. The z spectra in healthy subjects had the expected z spectral shape with CEST effects apparent from 2.0 to 4.5ppm. The z spectra from patients with MS demonstrated deviations from this expected normal shape, indicating this method's sensitivity to known pathology as well as to tissues appearing normal on conventional MRI. Examination of the calculated CESTasym revealed increased asymmetry around the amide proton resonance (=3.5ppm), but it was apparent that this measure is complicated by detail in the CEST spectrum upfield from water, which is expected to result from the nuclear Overhauser effect. The z spectra upfield (negative ppm range) were also distinct between healthy and diseased tissue, and could not be ignored, particularly when considering the conventional asymmetry analysis used to quantify the CEST effect. For all frequencies greater than +1ppm, the Lorentzian differences (and z spectra) for lesions and normal-appearing white matter were distinct from those for healthy white matter. The increased frequency separation and signal-to-noise ratio, in concert with prolonged T-1 at 7T, resulted in signal enhancements necessary to detect subtle tissue changes not possible at lower field strengths. This study presents CEST imaging metrics that may be sensitive to the extensive and temporally varying biochemical neuropathology of MS in the spinal cord. Copyright (c) 2016 John Wiley & Sons, Ltd. C1 [Dula, Adrienne N.; Barry, Robert L.; Smith, Seth A.] Vanderbilt Univ, Med Ctr, Dept Radiol & Radiol Sci, Nashville, TN 37232 USA. [Dula, Adrienne N.; Dethrage, Lindsey M.; Conrad, Benjamin N.; Barry, Robert L.; Smith, Seth A.] Vanderbilt Univ, Med Ctr, Inst Imaging Sci, Nashville, TN 37232 USA. [Pawate, Siddharama] Vanderbilt Univ, Med Ctr, Dept Neurol, Nashville, TN 37232 USA. [Dewey, Blake E.] Vanderbilt Univ, Med Ctr, NIH, NINDS, Nashville, TN 37232 USA. [Smith, Seth A.] Vanderbilt Univ, Med Ctr, Dept Biomed Engn, Nashville, TN 37232 USA. [Smith, Seth A.] Vanderbilt Univ, Med Ctr, Dept Neurosci, Nashville, TN 37232 USA. RP Dula, AN (reprint author), Vanderbilt Univ, Inst Imaging Sci, 1161 21st Ave South, Nashville, TN 37232 USA. EM Adrienne.n.dula@vanderbilt.edu FU National Institutes of Health / National Institute of Biomedical Imaging and Bioengineering (NIH/NIBIB) [K01EB009120]; NIH/NIBIB [K25 EB013659, KL2 TR 000446]; Clinical and Translational Science Award (CTSA) Grant [RR024975] FX The authors would like to acknowledge all of the patients and subjects who volunteered for the study. They would also like to acknowledge funding sources: National Institutes of Health / National Institute of Biomedical Imaging and Bioengineering (NIH/NIBIB) K01EB009120, NIH/NIBIB K25 EB013659, KL2 TR 000446 and Clinical and Translational Science Award (CTSA) Grant (RR024975). NR 40 TC 0 Z9 0 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0952-3480 EI 1099-1492 J9 NMR BIOMED JI NMR Biomed. PD SEP PY 2016 VL 29 IS 9 SI SI BP 1249 EP 1257 DI 10.1002/nbm.3581 PG 9 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA DV9OX UT WOS:000383271800011 PM 27459342 ER PT J AU Inoue-Choi, M Weyer, PJ Jones, RR Booth, BJ Cantor, KP Robien, K Ward, MH AF Inoue-Choi, Maki Weyer, Peter J. Jones, Rena R. Booth, Benjamin J. Cantor, Kenneth P. Robien, Kim Ward, Mary H. TI Atrazine in public water supplies and risk of ovarian cancer among postmenopausal women in the Iowa Women's Health Study SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article DE atrazine; public water supplies; ovarian cancer ID MENSTRUAL-CYCLE CHARACTERISTICS; ENDOCRINE DISRUPTING CHEMICALS; DRINKING-WATER; TRIAZINE HERBICIDES; BIRTH-WEIGHT; AGRICULTURAL HEALTH; GESTATIONAL-AGE; EXPOSURE; NITRATE AB Background Few studies have evaluated environmental chemical exposures in relation to ovarian cancer. We previously found an increased risk of ovarian cancer among postmenopausal women in Iowa associated with higher nitrate levels in public water supplies (PWS). However, elevated nitrate levels may reflect the presence of other agricultural chemicals, such as atrazine, one of the most commonly detected pesticides in Iowa PWS. Methods We evaluated the association between atrazine in drinking water and incident ovarian cancer (N=145, 1986-2010) among 13041 postmenopausal women in the Iowa Women's Health Study who used their PWS for 11years as reported in 1989. Average levels of atrazine (1986-1987), nitrate-nitrogen (NO3-N, 1955-1988) and estimated levels of total trihalomethanes (TTHM, 1955-1988) from PWS monitoring data were linked to the participants' cities of residence. We computed HRs and 95% CIs by categories of the average atrazine level (not detected, or >0.37 parts per billion=median) using Cox proportional hazards regression adjusting for ovarian cancer risk factors. Results Atrazine was detected in water samples from 69 cities where 4155 women (32%) lived and levels were moderately correlated with NO3-N (=0.35) and TTHM (=0.24). Atrazine levels were not associated with ovarian cancer risk with or without adjusting for NO3-N and TTHM levels (p-trend=0.50 and 0.81, respectively). Further, there was no evidence for effect modification of the atrazine association by NO3-N or TTHM levels. Conclusions In our study with low atrazine detection rates, we found no association between atrazine in PWS and postmenopausal ovarian cancer risk. C1 [Inoue-Choi, Maki; Jones, Rena R.; Booth, Benjamin J.; Cantor, Kenneth P.; Ward, Mary H.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD USA. [Inoue-Choi, Maki] Natl Inst Minor Hlth & Hlth Dispar, NIH, Bethesda, MD USA. [Weyer, Peter J.] Univ Iowa, Ctr Hlth Effects Environm Contaminat, Iowa City, IA USA. [Robien, Kim] George Washington Univ, Sch Publ Hlth, Milken Inst, Dept Exercise & Nutr Sci, Washington, DC USA. RP Inoue-Choi, M (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr,6E314, Rockville, MD 20850 USA. EM maki.inoue-choi@nih.gov OI Robien, Kim/0000-0002-2120-2280 FU Intramural Research Program of the National Cancer Institute; National Cancer Institute [R01 CA039742]; Division of Intramural Research of the National Institute on Minority Health and Health Disparities FX This study was supported by the Intramural Research Program of the National Cancer Institute (MI-C, RRJ, MHW and BJB.) and National Cancer Institute R01 CA039742 (KR). MI-C was partly supported by the Division of Intramural Research of the National Institute on Minority Health and Health Disparities at the time of the study. NR 32 TC 0 Z9 0 U1 17 U2 17 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1351-0711 EI 1470-7926 J9 OCCUP ENVIRON MED JI Occup. Environ. Med. PD SEP PY 2016 VL 73 IS 9 BP 582 EP 587 DI 10.1136/oemed-2016-103575 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DV9RP UT WOS:000383279200003 PM 27371663 ER PT J AU Foca, M Yogev, R Wiznia, A Hazra, R Jean-Philippe, P Graham, B Britto, P Carey, VJ King, J Acosta, EP Cressey, TR AF Foca, Marc Yogev, Ram Wiznia, Andrew Hazra, Rohan Jean-Philippe, Patrick Graham, Bobbie Britto, Paula Carey, Vincent J. King, Jennifer Acosta, Edward P. Cressey, Tim R. CA IMPAACT P1058A Team TI Rilpivirine Pharmacokinetics Without and With Darunavir/Ritonavir Once Daily in Adolescents and Young Adults SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE antiretrovirals; rilpivirine; darunavir; pediatrics; adolescents ID ANTIRETROVIRAL THERAPY; RANDOMIZED-TRIAL; EMTRICITABINE; TENOFOVIR; EFAVIRENZ; PHASE-3; EFFICACY; TMC278; SAFETY; THRIVE AB Background: Rilpivirine (RPV), a recently developed, once daily human immunodeficiency virus non-nucleoside reverse transcriptase inhibitor, is not currently approved for pediatric patients, but is sometimes prescribed for adolescents with multiple treatment failures, for regimen simplification or to minimize toxicity. Darunavir/ritonavir (DRV/r) administered once daily is also increasingly used in adolescents and may alter RPV pharmacokinetics (PK). We evaluated the PK interactions between RPV and DRV/r once daily in adolescents and young adults. Methods: Human immunodeficiency virus-infected subjects 12 to <24 years old receiving a stable background therapy including RPV 25 mg once daily without or combined with DRV/r 800/100 mg once daily were enrolled. Intensive 24-hour blood sampling was performed, and PK indices were determined using noncompartmental analysis. Protocol-defined target drug exposure ranges based on adult data were used to assess the adequacy of each regimen. Results: Fifteen subjects receiving RPV without and 14 subjects with DRV/r were enrolled. When dosed without DRV/r, the RPV geometric mean (90% confidence interval) for RPV AUC(0-24), C-max and C-24 h were 2.38 mu g h/mL (1.92-2.94), 0.14 mu g/mL (0.12-0.18) and 0.07 mu g/mL (0.03-0.10), respectively, similar to adult values. RPV concentrations were significantly increased with concomitant DRV/r use: RPV AUC(24), C-max and C-24 h were 6.74 mu g h/mL (4.89-9.28), 0.39 mu g/mL (0.27-0.57) and 0.23 mu g/mL (0.17-0.32), respectively, well above the target ranges based on adult data. DRV/r PK was not affected by coadministration of RPV. Conclusions: RPV PK in this adolescent population was similar to adults when dosed without DRV/r. DRV/r coadministration increased RPV exposure 2- to 3-fold, indicating that drug-related side effects should be closely monitored. C1 [Foca, Marc] Columbia Univ, Med Ctr, New York, NY 10032 USA. [Yogev, Ram] Northwestern Univ, Lurie Childrens Hosp Chicago, Feinberg Sch Med, Chicago, IL 60611 USA. [Wiznia, Andrew] Albert Einstein Coll Med, Jacobi Med Ctr, Bronx, NY 10467 USA. [Hazra, Rohan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Maternal & Pediat Infect Dis Branch, Bethesda, MD USA. [Jean-Philippe, Patrick] HJF DAIDS, Bethesda, MD USA. [Jean-Philippe, Patrick] NIAID, NIH, DHHS, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Graham, Bobbie] Frontier Sci & Technol, Amherst, NY USA. [Britto, Paula; Carey, Vincent J.; Cressey, Tim R.] Harvard Sch Publ Hlth, Boston, MA USA. [King, Jennifer] Abbvie, Chicago, IL USA. [Acosta, Edward P.] Univ Alabama Birmingham, Birmingham, AL USA. [Cressey, Tim R.] Chiang Mai Univ, Fac Associated Med Sci, Chiang Mai, Thailand. RP Foca, M (reprint author), Columbia Univ, Med Ctr, New York, NY 10032 USA. EM mdf10@columbia.edu FU National Institutes of Health (NIH), USA; National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) [UM1AI068632, UM1AI068616, UM1AI106716]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute of Mental Health (NIMH) FX This study was supported by National Institutes of Health (NIH), USA. Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) was provided by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) under Award Numbers UM1AI068632 (IMPAACT LOC), UM1AI068616 (IMPAACT SDMC) and UM1AI106716 (IMPAACT LC), with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Mental Health (NIMH). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The authors have no conflicts of interest to disclose. NR 15 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 0891-3668 EI 1532-0987 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD SEP PY 2016 VL 35 IS 9 BP E271 EP E274 DI 10.1097/INF.0000000000001214 PG 4 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA DU5NP UT WOS:000382258800002 PM 27187753 ER PT J AU David, JM Dominguez, C Hamilton, DH Palena, C AF David, Justin M. Dominguez, Charli Hamilton, Duane H. Palena, Claudia TI The IL-8/IL-8R Axis: A Double Agent in Tumor Immune Resistance SO VACCINES LA English DT Review DE IL-8; CXCR1/2; EMT; neutrophil; MDSC; brachyury; immune resistance ID EPITHELIAL-MESENCHYMAL TRANSITION; BREAST-CANCER CELLS; HUMAN CARCINOMA-CELLS; SUPPRESSOR-CELLS; LUNG-CANCER; STEM-CELLS; T-CELLS; INFILTRATING NEUTROPHILS; INTERLEUKIN-8 EXPRESSION; CONFERS RESISTANCE AB Interleukin-8 (IL-8, CXCL8) is a pro-inflammatory chemokine produced by various cell types to recruit leukocytes to sites of infection or tissue injury. Acquisition of IL-8 and/or its receptors CXCR1 and CXCR2 are known to be a relatively common occurrence during tumor progression. Emerging research now indicates that paracrine signaling by tumor-derived IL-8 promotes the trafficking of neutrophils and myeloid-derived suppressor cells (MDSCs) into the tumor microenvironment, which have the ability to dampen anti-tumor immune responses. Furthermore, recent studies have also shown that IL-8 produced by the tumor mass can induce tumor cells to undergo the transdifferentiation process epithelial-to-mesenchymal transition (EMT) in which tumor cells shed their epithelial characteristics and acquire mesenchymal characteristics. EMT can increase metastatic dissemination, stemness, and intrinsic resistance, including to killing by cytotoxic immune cells. This review highlights the dual potential roles that the inflammatory cytokine IL-8 plays in promoting tumor resistance by enhancing the immunosuppressive microenvironment and activating EMT, and then discusses the potential for targeting the IL-8/IL-8 receptor axis to combat these various resistance mechanisms. C1 [David, Justin M.; Dominguez, Charli; Hamilton, Duane H.; Palena, Claudia] NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Palena, C (reprint author), NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. EM justin.david@nih.gov; charli.dominguez@nih.gov; hamiltondh@mail.nih.gov; palenac@mail.nih.gov NR 118 TC 0 Z9 0 U1 6 U2 6 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 2076-393X J9 VACCINES JI Vaccines PD SEP PY 2016 VL 4 IS 3 AR 22 DI 10.3390/vaccines4030022 PG 15 WC Immunology SC Immunology GA DV8PQ UT WOS:000383199300001 ER PT J AU Shen, JW Liu, Y Thornburgh, RP Kreshock, AR Wilbur, ML AF Shen, Jinwei Liu, Yi Thornburgh, Robert P. Kreshock, Andrew R. Wilbur, Matthew L. TI Design and optimisation of an aerofoil with active continuous trailing-edge flap SO AERONAUTICAL JOURNAL LA English DT Article DE Aerodynamics; CFD; Model-scale; Full-scale; Rotor in hover; structural dynamics; fluid structure interaction AB This paper presents the design and optimisation of an aerofoil with active continuous trailing edge flap (CTEF) investigated as a potential rotorcraft active control device. Several structural cross-section models are developed: high-fidelity NASA STRucture ANalysis (NASTRAN) and University of Michigan/Variational Asymptotic Beam Section Code (UM/VABS) models and a reduced-order analysis model. The validation of the reduced-order model is established by comparing its predictions of CTEF defoimations with those of NASTRAN and UM/VABS analyses, which both show good agreement. The 2D aerodynamic characteristics of the CTEF aerofoil are evaluated using XFOIL and Computational Fluid Dynamics (CFD) analyses: FUN3D and Overset Transonic Unsteady Rotor Navier-Stokes (OVERTURNS). XFOIL, coupled with the reduced-order structure model, is adopted for optimisation study. The accuracy of XFOIL in predicting the aerodynamic pressure of the CTEF aerofoil is verified using CFD simulations, which shows sufficient fidelity. The predicted variations of aerodynamic coefficients with a CTEF angle are compared among the aerodynamic analyses. The optimisation process is developed and applied to two bimorph bender configurations: a Macro-Fibre Composite (MFC) solid bender and an MFC stack bender. The solid bender is used to confirm the functioning of the optimisation procedure and to use its optimal layout as a reference to the stack design, the primary design object. A linear tapered shape is found to be the optimum for a MFC solid bender, which generates an average of 63% more CTEF angles than those of an optimal rectangular bender. An optimised MFC stack bender is shown to resemble the shape of the solid bender. A four-ply bimorph is considered the best choice among the stack layouts because of its large output of CTEF angles and relatively less plies required. The CTEF angle produced by the four-ply optimal layout ranges from 7.6 degrees to 5.3 degrees with speeds from 0 to 200 m/s at an angle of attack (AoA) of 6 degrees. The reduction in the CTEF angle with AoA is less steep than that with speed, ranging from 6.5 degrees to 5.8 degrees with AoA from 0 to 8 degrees at speed of 166 m/s. An average of 14% increase in CTEF angles is achieved through optimisation for the four-ply bimorph. C1 [Shen, Jinwei; Liu, Yi] NIA, Hampton, VA 23666 USA. [Thornburgh, Robert P.; Kreshock, Andrew R.; Wilbur, Matthew L.] US Army Res Lab Hampton, Vehicle Technol Directorate, Hampton, VA USA. [Shen, Jinwei] Univ Alabama, Aerosp Engn & Mech, Tuscaloosa, AL 35406 USA. RP Shen, JW (reprint author), NIA, Hampton, VA 23666 USA. EM jinwei.shen@eng.ua.edu NR 18 TC 0 Z9 0 U1 7 U2 7 PU ROYAL AERONAUTICAL SOC PI LONDON PA 4 HAMILTON PL, LONDON W1J 7BQ, ENGLAND SN 0001-9240 J9 AERONAUT J JI Aeronaut. J. PD SEP PY 2016 VL 120 IS 1231 BP 1468 EP 1486 DI 10.1017/aer.2016.62 PG 19 WC Engineering, Aerospace SC Engineering GA DV0FS UT WOS:000382594000006 ER PT J AU Qureshi, WT Michos, ED Flueckiger, P Blaha, M Sandfort, V Herrington, DM Burke, G Yeboah, J AF Qureshi, Waqas T. Michos, Erin D. Flueckiger, Peter Blaha, Michael Sandfort, Veit Herrington, David M. Burke, Gregory Yeboah, Joseph TI Impact of Replacing the Pooled Cohort Equation With Other Cardiovascular Disease Risk Scores on Atherosclerotic Cardiovascular Disease Risk Assessment (from the Multi-Ethnic Study of Atherosclerosis [MESA]) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID DECISION CURVE ANALYSIS; STATIN THERAPY; GUIDELINES; PREVENTION AB The increase in statin eligibility by the new cholesterol guidelines is mostly driven by the Pooled Cohort Equation (PCE) criterion (>= 7.5% 10-year PCE). The impact of replacing the PCE with either the modified Framingham Risk Score (FRS) or the Systematic Coronary Risk Evaluation (SCORE) on assessment of atherosclerotic cardiovascular disease (ASCVD) risk assessment and statin eligibility remains unknown. We assessed the comparative benefits of using the PCE, FRS, and SCORE for ASCVD risk assessment in the Multi-Ethnic Study of Atherosclerosis. Of 6,815 participants, 654 (mean age 61.4 +/- 10.3; 47.1% men; 37.1% whites; 27.2% blacks; 22.3% Hispanics; 12.0% Chinese-Americans) were included in analysis. Area under the curve (AUC) and decision curve analysis were used to compare the 3 risk scores. Decision curve analysis is the plot of net benefit versus probability thresholds; net benefit = true positive rate (false positive rate x weighting factor). Weighting factor = Threshold probability/1 threshold probability. After a median of 8.6 years, 342 (6.0%) ASCVD events (myocardial infarction, coronary heart disease death, fatal or nonfatal stroke) occurred. All 4 risk scores had acceptable discriminative ability for incident ASCVD events; (AUC [95% CI] PCE: 0.737 [0.713 to 0.762]; FRS: 0.717 [0.691 to 0.743], SCORE (high risk) 0.722 [0.696 to 0.747], and SCORE (low risk): 0.721 [0.696 to 0.746]. At the ASCVD risk threshold recommended for statin eligibility for primary prevention (>= 7.5%), the PCE provides the best net benefit. Replacing the PCE with the SCORE (high), SCORE (low) and FRS results in a 2.9%, 8.9%, and 17.1% further increase in statin eligibility. The PCE has the best discrimination and net benefit for primary ASCVD risk assessment in a US-based multiethnic cohort compared with the SCORE or the FRS. (C) 2016 Elsevier Inc. All rights reserved. C1 [Qureshi, Waqas T.; Flueckiger, Peter; Herrington, David M.; Yeboah, Joseph] Wake Forest Univ, Bowman Gray Sch Med, Dept Internal Med, Heart & Vasc Ctr Excellence, Winston Salem, NC 27103 USA. [Burke, Gregory] Wake Forest Univ, Bowman Gray Sch Med, Dept Publ Hlth Sci, Winston Salem, NC 27103 USA. [Michos, Erin D.; Blaha, Michael] Johns Hopkins Ciccarone Ctr Prevent Heart Dis, Dept Internal Med, Baltimore, MD USA. [Sandfort, Veit] NIH, Bethesda, MD USA. RP Qureshi, WT (reprint author), Wake Forest Univ, Bowman Gray Sch Med, Dept Internal Med, Heart & Vasc Ctr Excellence, Winston Salem, NC 27103 USA. EM wqureshi@wakehealth.edu FU National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169]; National Center for Research Resources Bethesda, Maryland [UL1-TR-000040, UL1-TR-001079] FX This research was supported by contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168 and N01-HC-95169 from the National Heart, Lung, and Blood Institute and by grants UL1-TR-000040 and UL1-TR-001079 from National Center for Research Resources Bethesda, Maryland. NR 21 TC 0 Z9 0 U1 3 U2 3 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 EI 1879-1913 J9 AM J CARDIOL JI Am. J. Cardiol. PD SEP 1 PY 2016 VL 118 IS 5 BP 691 EP 696 DI 10.1016/j.amjcard.2016.06.015 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DU7UP UT WOS:000382420400012 PM 27445216 ER PT J AU Levitan, EB Ahmed, A Arnett, DK Polak, JF Hundley, WG Bluemke, DA Heckbert, SR Jacobs, DR Nettleton, JA AF Levitan, Emily B. Ahmed, Ali Arnett, Donna K. Polak, Joseph F. Hundley, W. Gregory Bluemke, David A. Heckbert, Susan R. Jacobs, David R., Jr. Nettleton, Jennifer A. TI Mediterranean diet score and left ventricular structure and function: the Multi-Ethnic Study of Atherosclerosis SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE cardiovascular disease; epidemiology; Mediterranean diet pattern; left ventricular structure; left ventricular function; sub-clinical cardiovascular disease ID CORONARY-HEART-DISEASE; CARDIOVASCULAR RISK-FACTORS; SYSTOLIC FUNCTION; BLOOD-PRESSURE; STYLE DIET; MASS; FAILURE; ASSOCIATION; PREVENTION; HEALTH AB Background: Data are limited on the relation between dietary patterns and left ventricular (LV) structure and function. Objective: We examined cross-sectional associations of a diet score assessment of a Mediterranean dietary pattern with LV mass, volume, mass-to-volume ratio, stroke volume, and ejection fraction. Design: We measured LV variables with the use of cardiac MRI in 4497 participants in the Multi-Ethnic Study of Atherosclerosis study who were aged 45-84 y and without clinical cardiovascular disease. We calculated a Mediterranean diet score from intakes of fruit, vegetables, nuts, legumes, whole grains, fish, red meat, the mono-unsaturated fat:saturated fat ratio, and alcohol that were self reported with the use of a food-frequency questionnaire. We used linear regression with adjustment for body size, physical activity, and cardiovascular disease risk factors to model associations and assess the shape of these associations (linear or quadratic). Results: The Mediterranean diet score had a slight U-shaped association with LV mass (adjusted means: 146, 145, 146, and 147 g across quartiles of diet score, respectively; P-quadratic trend = 0.04). The score was linearly associated with LV volume, stroke volume, and ejection fraction: for each +1-U difference in score, LV volume was 0.4 mL higher (95% CI: 0.0, 0.8 mL higher), the stroke volume was 0.5 mL higher (95% CI: 0.2, 0.8 mL higher), and the ejection fraction was 0.2 percentage points higher (95% CI: 0.1, 0.3 percentage points higher). The score was not associated with the mass-to-volume ratio. Conclusions: A higher Mediterranean diet score is cross-sectionally associated with a higher LV mass, which is balanced by a higher LV volume as well as a higher ejection fraction and stroke volume. Participants in this healthy, multiethnic sample whose dietary patterns most closely conformed to a Mediterranean-type pattern had a modestly better LV structure and function than did participants with less Mediterranean-like dietary patterns. C1 [Levitan, Emily B.] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL 35233 USA. [Ahmed, Ali] Washington DC VA Med Ctr, Ctr Hlth & Aging, Washington, DC USA. [Arnett, Donna K.] Univ Kentucky, Coll Publ Hlth, Lexington, KY USA. [Polak, Joseph F.] Tufts Univ, Sch Med, Dept Radiol, Boston, MA 02111 USA. [Hundley, W. Gregory] Wake Forest Univ, Bowman Gray Sch Med, Dept Internal Med Cardiol, Winston Salem, NC USA. [Hundley, W. Gregory] Wake Forest Univ, Bowman Gray Sch Med, Dept Radiol, Winston Salem, NC USA. [Bluemke, David A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Heckbert, Susan R.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Jacobs, David R., Jr.] Univ Minnesota, Dept Epidemiol & Community Hlth, Minneapolis, MN USA. [Nettleton, Jennifer A.] Univ Texas Hlth Sci Ctr Houston, Div Epidemiol Human Genet & Environm Sci, Houston, TX USA. RP Levitan, EB (reprint author), Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL 35233 USA. EM elevitan@uab.edu OI Bluemke, David/0000-0002-8323-8086 FU National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95168]; National Center for Research Resources [UL1-TR-000040, UL1-TR-001079] FX Supported by the National Heart, Lung, and Blood Institute (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, and N01-HC-95168) and by the National Center for Research Resources (grants UL1-TR-000040 and UL1-TR-001079). NR 44 TC 0 Z9 0 U1 13 U2 13 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD SEP PY 2016 VL 104 IS 3 BP 595 EP 602 DI 10.3945/ajcn.115.128579 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DU7UU UT WOS:000382420900010 PM 27488238 ER PT J AU Miranti, EH Freedman, ND Weinstein, SJ Abnet, CC Selhub, J Murphy, G Diaw, L Mannisto, S Taylor, PR Albanes, D Stolzenberg-Solomon, RZ AF Miranti, Eugenia H. Freedman, Neal D. Weinstein, Stephanie J. Abnet, Christian C. Selhub, Jacob Murphy, Gwen Diaw, Lena Mannisto, Satu Taylor, Philip R. Albanes, Demetrius Stolzenberg-Solomon, Rachael Z. TI Prospective study of serum cysteine and cysteinylglycine and cancer of the head and neck, esophagus, and stomach in a cohort of male smokers SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE cysteine; esophageal neoplasms; head and neck neoplasms; stomach neoplasms; upper gastrointestinal tract cancers ID PLASMA TOTAL CYSTEINE; OXIDATIVE STRESS; HELICOBACTER-PYLORI; COLORECTAL-CANCER; GASTRIC-CANCER; BREAST-CANCER; RISK; HOMOCYSTEINE; METABOLISM; FOLATE AB Background: The nonessential amino acid cysteine is known to be involved in many antioxidant and anticarcinogenic pathways. Cysteinylglycine is a pro-oxidant metabolite of glutathione and a precursor of cysteine. Objective: To examine the relation between serum cysteine and cysteinylglycine and risk of gastric adenocarcinomas, esophageal squamous cell carcinomas, and head and neck squamous cell carcinomas, we conducted a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention study of male Finnish smokers aged 50-69 y at baseline. Design: In total, 170 gastric adenocarcinomas, 68 esophageal squamous cell carcinomas, and 270 head and neck squamous cell carcinomas (identified from the Finnish Cancer Registry) were matched one-to-one with cancer-free control subjects on age and the date of serum collection. We calculated ORs and 95% CIs with the use of a multivariate-adjusted conditional logistic regression. Results: Cysteine had a U-shaped association with gastric adenocarcinomas; a model that included a linear and a squared term had a significant global P-test (P = 0.036). Serum cysteinylglycine was inversely associated with adenocarcinomas of the gastric cardia (OR for above the median compared with below the median: 0.07; 95% CI: 0.01, 0.70; n = 38 cases) but not for other sites. Both cysteine and cysteinylglycine were not associated with esophageal squamous cell carcinoma or head and neck squamous cell carcinoma. Conclusions: We observed associations between serum cysteine and cysteinylglycine with upper gastrointestinal cancer risk. Future studies are needed to replicate these findings. C1 [Miranti, Eugenia H.; Freedman, Neal D.; Weinstein, Stephanie J.; Abnet, Christian C.; Murphy, Gwen; Taylor, Philip R.; Albanes, Demetrius; Stolzenberg-Solomon, Rachael Z.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Rockville, MD 20850 USA. [Selhub, Jacob] Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Diaw, Lena] NHLBI, Pulm & Vasc Med Branch, NIH, Dept Hlth & Human Serv, Bldg 10, Bethesda, MD 20892 USA. [Mannisto, Satu] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. RP Freedman, ND (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Rockville, MD 20850 USA. EM freedmanne@mail.nih.gov RI Abnet, Christian/C-4111-2015 OI Abnet, Christian/0000-0002-3008-7843 FU US Public Health Service (National Cancer Institute, National Institutes of Health, Department of Health and Human Services) [N01-CN-45165, N01-RC-45035, N01-RC-37004, HHSN261201000006C]; Intramural Research Program of the National Cancer Institute, the NIH Medical Research Scholars Program; NIH FX Supported in part by the US Public Health Service (contracts N01-CN-45165, N01-RC-45035, N01-RC-37004, and HHSN261201000006C from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services; for the Alpha-Tocopherol, Beta-Carotene Cancer Prevention study), in part by the Intramural Research Program of the National Cancer Institute, the NIH Medical Research Scholars Program, which is a public-private partnership that is supported jointly by the NIH and generous contributions to the Foundation for the NIH from the Doris Duke Charitable Foundation, The American Association for Dental Research, The Howard Hughes Medical Institute, and the Colgate-Palmolive Company as well as other private donors. For a complete list of contributors, please visit the Foundation website at http://fnih.org/what-we-do/current-education-and-training-programs/mrsp. NR 42 TC 0 Z9 0 U1 1 U2 2 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD SEP PY 2016 VL 104 IS 3 BP 686 EP 693 DI 10.3945/ajcn.115.125799 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DU7UU UT WOS:000382420900020 PM 27534643 ER PT J AU Playdon, MC Sampson, JN Cross, AJ Sinha, R Guertin, KA Moy, KA Rothman, N Irwin, ML Mayne, ST Stolzenberg-Solomon, R Moore, SC AF Playdon, Mary C. Sampson, Joshua N. Cross, Amanda J. Sinha, Rashmi Guertin, Kristin A. Moy, Kristin A. Rothman, Nathaniel Irwin, Melinda L. Mayne, Susan T. Stolzenberg-Solomon, Rachael Moore, Steven C. TI Comparing metabolite profiles of habitual diet in serum and urine SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE metabolomics; metabolite; serum; urine; diet; food; nutrition assessment; biomarker ID MASS-SPECTROMETRY; NUTRITIONAL EPIDEMIOLOGY; COLORECTAL-CANCER; FOOD-INTAKE; COFFEE CONSUMPTION; MEASUREMENT ERROR; ALPHA-TOCOPHEROL; PROLINE BETAINE; CITRUS-FRUIT; L-CARNITINE AB Background: Diet plays an important role in chronic disease etiology, but some diet-disease associations remain inconclusive because of methodologic limitations in dietary assessment. Metabolomics is a novel method for identifying objective dietary biomarkers, although it is unclear what dietary information is captured from metabolites found in serum compared with urine. Objective: We compared metabolite profiles of habitual diet measured from serum with those measured from urine. Design: We first estimated correlations between consumption of 56 foods, beverages, and supplements assessed by a food-frequency questionnaire, with 676 serum and 848 urine metabolites identified by untargeted liquid chromatography mass spectrometry, ultra-high performance liquid chromatography tandem mass spectrometry, and gas chromatography mass spectrometry in a colon adenoma case control study (n = 125 cases and 128 controls) while adjusting for age, sex, smoking, fasting, case-control status, body mass index, physical activity, education, and caloric intake. We controlled for multiple comparisons with the use of a false discovery rate of <0.1. Next, we created serum and urine multiple-metabolite models to predict food intake with the use of 10-fold crossvalidation least absolute shrinkage and selection operator regression for 80% of the data; predicted values were created in the remaining 20%. Finally, we compared predicted values with estimates obtained from self-reported intake for metabolites measured in serum and urine. Results: We identified metabolites associated with 46 of 56 dietary items; 417 urine and 105 serum metabolites were correlated with >= 1 food, beverage, or supplement. More metabolites in urine (n = 154) than in serum (n = 39) were associated uniquely with one food. We found previously unreported metabolite associations with leafy green vegetables, sugar-sweetened beverages, citrus, added sugar, red meat, shellfish, desserts, and wine. Prediction of dietary intake from multiple-metabolite profiles was similar between biofluids. Conclusions: Candidate metabolite biomarkers of habitual diet are identifiable in both serum and urine. Urine samples offer a valid alternative or complement to serum for metabolite biomarkers of diet in large-scale clinical or epidemiologic studies. C1 [Playdon, Mary C.; Irwin, Melinda L.; Mayne, Susan T.] Yale Univ, Yale Sch Publ Hlth, New Haven, CT 06520 USA. [Playdon, Mary C.; Sampson, Joshua N.; Sinha, Rashmi; Guertin, Kristin A.; Moy, Kristin A.; Rothman, Nathaniel; Stolzenberg-Solomon, Rachael; Moore, Steven C.] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA. [Cross, Amanda J.] Imperial Coll London, Sch Publ Hlth, Fac Med, London, England. [Irwin, Melinda L.] Yale Canc Ctr, New Haven, CT USA. [Mayne, Susan T.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. RP Playdon, MC (reprint author), Yale Univ, Yale Sch Publ Hlth, New Haven, CT 06520 USA.; Playdon, MC (reprint author), NCI, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA. EM mary.playdon@nih.gov RI Moore, Steven/D-8760-2016; Playdon, Mary/I-4050-2016 OI Moore, Steven/0000-0002-8169-1661; FU Yale National Cancer Institute [T32 CA105666]; Intramural Research Program of the NIH; National Cancer Institute FX This work was supported in part by Yale National Cancer Institute pre-doctoral training grant no. T32 CA105666 to STM and by the Intramural Research Program of the NIH and National Cancer Institute. NR 69 TC 1 Z9 1 U1 17 U2 20 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD SEP PY 2016 VL 104 IS 3 BP 776 EP 789 DI 10.3945/ajcn.116.135301 PG 14 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DU7UU UT WOS:000382420900031 PM 27510537 ER PT J AU Zhou, DL Gochman, P Broadnax, DD Rapoport, JL Ahn, K AF Zhou, Dale Gochman, Peter Broadnax, Diane D. Rapoport, Judith L. Ahn, Kwangmi TI 15q13.3 duplication in two patients with childhood-onset schizophrenia SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE neurodevelopmental disorders; childhood-onset schizophrenia; microduplication; 15q13; 3; CHRNA7 ID COPY NUMBER VARIATION; RECEPTOR SUBUNIT GENE; HIDDEN-MARKOV MODEL; SNP GENOTYPING DATA; DOUBLE-BLIND; CHRNA7; VARIANTS; AUTISM; MICRODELETION; ORGANIZATION AB We report two cases of paternally inherited 15q13.3 duplications in carriers diagnosed with childhood-onset schizophrenia (COS), a rare neurodevelopmental disorder of proposed polygenic origin with onset in children before age 13. This study documents that the 15q13.3 deletion and duplication exhibit pathogenicity for COS, with both copy number variants (CNVs) sharing a disrupted CHRNA7 gene. CHRNA7 encodes the neuronal alpha7 nicotinic acetylcholine receptor (7nAChR) and is a candidate gene that has been suggested as a pathophysiological process mediating adult-onset schizophrenia (AOS) and other neurodevelopmental disorders. These results support the incomplete penetrance and variable expressivity of this CNV and represent the first report of 15q13.3 duplication carriers exhibiting COS. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals, Inc. C1 [Zhou, Dale; Gochman, Peter; Broadnax, Diane D.; Rapoport, Judith L.; Ahn, Kwangmi] NIMH, Child Psychiat Branch, NIH, 10 Ctr Dr,Room 4N244, Bethesda, MD 20892 USA. RP Ahn, K (reprint author), NIMH, Child Psychiat Branch, NIH, 10 Ctr Dr,Room 4N244, Bethesda, MD 20892 USA. EM kwangmi.ahn@nih.gov NR 38 TC 0 Z9 0 U1 5 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4841 EI 1552-485X J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP PY 2016 VL 171 IS 6 BP 777 EP 783 DI 10.1002/ajmg.b.32439 PG 7 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA DV4CE UT WOS:000382871600002 PM 26968334 ER PT J AU Healy, MW Schexnayder, B Connell, MT Terry, N DeCherney, AH Csokmay, JM Yauger, BJ Hill, MJ AF Healy, Mae Wu Schexnayder, Brian Connell, Matthew T. Terry, Nancy DeCherney, Alan H. Csokmay, John M. Yauger, Belinda J. Hill, Micah J. TI Intrauterine adhesion prevention after hysteroscopy: a systematic review and meta-analysis SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Review DE intrauterine adhesion; meta-analysis; operative hysteroscopy; prevention strategy ID HYALURONIC-ACID GEL; ASHERMANS-SYNDROME; RANDOMIZED-TRIALS; UTERINE SYNECHIAE; ESTROGEN; SURGERY; MYOMECTOMY; MANAGEMENT; FERTILITY; EFFICACY AB BACKGROUND: Despite years of studies evaluating prevention strategies for intrauterine adhesion formation after operative hysteroscopy, it is still unclear which strategies are most effective. OBJECTIVE: The objective of the study was to perform a systematic review and meta-analysis to evaluate the effectiveness of postoperative prevention strategies on intrauterine adhesion formation following operative hysteroscopy. STUDY DESIGN: Literature searches were conducted in MEDLINE, Embase, ClinicalTrials.gov, and Cochrane Library databases. Inclusion criteria were published randomized controlled clinical trials from 1989 to 2014 comparing any postoperative preventative measures of intrauterine adhesion after hysteroscopy. The main outcome measure was a reduction in postoperative intrauterine adhesion. Heterogeneity of the studies was evaluated using a Q test and an I 2 index. Analyses were performed using a random-effects model with outcome data reported as relative risk with 95% confidence interval. RESULTS: Twelve studies were included in the systematic review. Eight studies compared similar treatment methods and were included in the meta-analysis. Three studies evaluated hyaluronic acid gel, of which 2 reported a significant decrease in intrauterine adhesion with treatment. The meta-analysis demonstrated a significant reduction of intrauterine adhesion when using hyaluronic acid gel. Two studies evaluated polyethylene oxide-sodium carboxymethylcellulose gel, 1 of which demonstrated a decrease in intrauterine adhesion with treatment. A meta-analysis showed a significant reduction of intrauterine adhesion with polyethylene oxide-sodium carboxymethyl cellulose gel. However, these 3 studies demonstrating a benefit of the gels in preventing adhesion formation were all conducted by the same research group. Other research groups have not confirmed these results. A sensitivity analysis excluding these trials from this single group demonstrated no benefit to adhesion prevention with either gel formation. Three studies investigated oral estrogen therapy after hysteroscopy and found no difference in intrauterine adhesion. A meta-analysis showed no decrease in intrauterine adhesion with estrogen therapy after hysteroscopy. Data were lacking to perform meta-analyses on the use of intrauterine balloon, intrauterine device, and other adhesion prevention barriers in preventing intrauterine adhesion. CONCLUSION: There was a lack of definitive evidence to conclude that any treatment is effective in preventing posthysteroscopy uterine adhesion formation. The available literature has significant heterogeneity and a high risk of bias, making any definitive conclusions difficult. C1 [Healy, Mae Wu; Connell, Matthew T.; DeCherney, Alan H.; Csokmay, John M.; Yauger, Belinda J.; Hill, Micah J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Schexnayder, Brian] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Terry, Nancy] Natl Inst Hlth Lib, NIH, Bethesda, MD USA. [Healy, Mae Wu; Connell, Matthew T.; Csokmay, John M.; Yauger, Belinda J.; Hill, Micah J.] Walter Reed Natl Mil Med Ctr, Dept Obstet & Gynecol, Bethesda, MD 20889 USA. RP Healy, MW (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. EM mae.healy@mail.nih.gov FU intramural research program of the Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This research was supported in part by the intramural research program of the Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 40 TC 0 Z9 0 U1 9 U2 9 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD SEP PY 2016 VL 215 IS 3 BP 267 EP + DI 10.1016/j.ajog.2016.05.001 PG 16 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DU8WA UT WOS:000382495100008 PM 27173082 ER PT J AU Troisi, R Hatch, EE Palmer, JR Titus, L Robboy, SJ Strohsnitter, WC Herbst, AL Adam, E Hyer, M Hoover, RN AF Troisi, Rebecca Hatch, Elizabeth E. Palmer, Julie R. Titus, Linda Robboy, Stanley J. Strohsnitter, William C. Herbst, Arthur L. Adam, Ervin Hyer, Marianne Hoover, Robert N. TI Prenatal diethylstilbestrol exposure and high-grade squamous cell neoplasia of the lower genital tract SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE cervical dysplasia; cervix; diethylstilbestrol; Pap smear screening; squamous neoplasia; vagina ID ADENOSIS DESAD PROJECT; YOUNG-WOMEN; BREAST-CANCER; NATIONAL-COOPERATIVE-DIETHYLSTILBESTROL-ADENOSIS-(DESAD)-PROJECT; STILBESTROL; DYSPLASIA; VAGINA; STATES AB BACKGROUND: Prenatal diethylstilbestrol (DES) exposure is associated with an excess risk of clear-cell adenocarcinoma of the vagina and cervix, and of high-grade squamous neoplasia. OBJECTIVE: We explored whether neoplasia risk remains elevated among DES-exposed women as they age. STUDY DESIGN: In all, 4062 DES-exposed and 1837 unexposed daughters were followed for approximately 30 years (1982 through 2013) for pathology-confirmed diagnoses of cervical intraepithelial neoplasia grade >= 2 (CIN2+) of the lower genital tract (n = 178). Hazard ratios (HR) and 95% confidence intervals (CI) were estimated adjusting for birth year and individual study cohort. RESULTS: The cumulative incidence of CIN2+ in the DES-exposed group was 5.3%(95% CI, 4.1-6.5%) and in the unexposed group was 2.6% (95% CI, 1.5-3.7%). The HR for DES and CIN2+ was 1.98 (95% CI, 1.33-2.94), and was similar with further adjustment for frequency of cervical cancer screening (HR, 1.97; 95% CI, 1.33-2.93). The HR was 2.10 (95% CI, 1.41-3.13) with additional adjustment for other potential confounders. The HR for DES exposure was elevated through age 44 years (age < 45 years HR, 2.47; 95% CI, 1.55-3.94), but not in women age >= 45 years (HR, 0.91; 95% CI, 0.39-2.10). In exposed women, HRs for DES were 1.74 (95% CI, 1.09-2.79) among those who had earlier evidence of vaginal epithelial changes (VEC), presumably reflecting glandular epithelium undergoing transformation to normal, adult-type squamous epithelium, and 1.24 (95% CI, 0.75-2.06) among those without VEC, compared with unexposed women. The HRs for DES and CIN2+ were higher among women with earlier intrauterine exposure (HR, 2.64; 95% CI, 1.64-4.25 for <8 weeks' gestation and HR, 1.41; 0.88-2.25 for >= 8 weeks' gestation), and lowest when exposure began > 15th week (HR, 1.14; 95% CI, 0.59-2.20). CONCLUSION: CIN2+ incidence was higher among the DES exposed, particularly those with early gestational exposure and VEC. The HR for DES and CIN2+ remained positive and significant until the mid-40s, confirming that the recommendation of annual cytological screening among these women is appropriate. Whether those >= 45 years of age continue to require increased screening is unclear, and would require a careful weighing of possible risks and benefits. C1 [Troisi, Rebecca; Hoover, Robert N.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Hatch, Elizabeth E.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02215 USA. [Palmer, Julie R.] Boston Univ, Slone Epidemiol Unit, Boston, MA 02215 USA. [Titus, Linda] Dartmouth Med Sch, Dept Community & Family Med, Lebanon, NH USA. [Titus, Linda] Dartmouth Med Sch, Dept Pediat, Lebanon, NH USA. [Titus, Linda] Norris Cotton Canc Ctr, Lebanon, NH USA. [Titus, Linda] Hood Ctr Children & Families, Lebanon, NH USA. [Robboy, Stanley J.] Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. [Robboy, Stanley J.] Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC 27710 USA. [Strohsnitter, William C.] Univ Massachusetts, Sch Med, Dept Mol Cell & Canc Biol, Worcester, MA 01605 USA. [Herbst, Arthur L.] Univ Chicago, Dept Obstet & Gynecol, Chicago, IL 60637 USA. [Adam, Ervin] Baylor Coll Med, Dept Mol Virol & Microbiol, Houston, TX 77030 USA. [Hyer, Marianne] Informat Management Serv Inc, Rockville, MD USA. RP Troisi, R (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM troisir@mail.nih.gov OI Robboy, Stanley/0000-0002-8343-9275 FU National Cancer Institute, National Institutes of Health, US Department of Health and Human Services FX The research was funded by the National Cancer Institute, National Institutes of Health, US Department of Health and Human Services. NR 17 TC 1 Z9 1 U1 3 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD SEP PY 2016 VL 215 IS 3 AR 322.e1-e8 DI 10.1016/j.ajog.2016.03.007 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DU8WA UT WOS:000382495100019 PM 26979629 ER PT J AU Wallace, ME Hoyert, D Williams, C Mendola, P AF Wallace, Maeve E. Hoyert, Donna Williams, Corrine Mendola, Pauline TI Pregnancy-associated homicide and suicide in 37 US states with enhanced pregnancy surveillance SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE postpartum; pregnancy; pregnancy-associated homicide; pregnancy-associated suicide; violence ID POSTPARTUM WOMEN; MATERNAL DEATH; PARTNER VIOLENCE; LEADING CAUSE; MORTALITY; INJURIES; HEALTH; CERTIFICATES; ABUSE; RISK AB BACKGROUND: Pregnant and postpartum women may be at increased risk of violent death including homicide and suicide relative to nonpregnant women, but US national data have not been reported since the implementation of enhanced mortality surveillance. OBJECTIVE: The objective of the study was to estimate homicide and suicide ratios among women who are pregnant or postpartum and to compare their risk of violent death with nonpregnant/nonpostpartum women. STUDY DESIGN: Death certificates (n = 465,097) from US states with enhanced pregnancy mortality surveillance from 2005 through 2010 were used to compare mortality among 4 groups of women aged 10-54 years: pregnant, early postpartum (pregnant within 42 days of death), late postpartum (pregnant within 43 days to 1 year of death), and nonpregnant/nonpostpartum. We estimated pregnancy-associated mortality ratios and compared with nonpregnant/nonpostpartum mortality ratios to identify differences in risk after adjusting for potential levels of pregnancy misclassification as reported in the literature. RESULTS: Pregnancy-associated homicide victims were most frequently young, black, and undereducated, whereas pregnancy-associated suicide occurred most frequently among older white women. After adjustments, pregnancy-associated homicide risk ranged from 2.2 to 6.2 per 100,000 live births, depending on the degree of misclassification estimated, compared with 2.5-2.6 per 100,000 nonpregnant/nonpostpartum women aged 10-54 years. Pregnancy-associated suicide risk ranged from 1.6-4.5 per 100,000 live births after adjustments compared with 5.3-5.5 per 100,000 women aged 10-54 years among nonpregnant/nonpostpartum women. Assuming the most conservative published estimate of misclassification, the risk of homicide among pregnant/postpartum women was 1.84 times that of nonpregnant/nonpostpartum women (95% confidence interval, 1.71-1.98), whereas risk of suicide was decreased (relative risk, 0.62, 95% confidence interval, 0.57-0.68). CONCLUSION: Pregnancy and postpartum appear to be times of increased risk for homicide and decreased risk for suicide among women in the United States. C1 [Wallace, Maeve E.; Mendola, Pauline] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, Rockville, MD 20892 USA. [Hoyert, Donna] Natl Ctr Hlth Stat, Mortal Stat Branch, Div Vital Stat, Hyattsville, MD 20782 USA. [Williams, Corrine] Univ Kentucky, Dept Hlth Behav, Lexington, KY USA. RP Mendola, P (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, Rockville, MD 20892 USA. EM pauline.mendola@nih.gov OI Mendola, Pauline/0000-0001-5330-2844 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; National Center for Health Statistics, Centers for Disease Control and Prevention FX This work was supported in part by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, as well as the National Center for Health Statistics, Centers for Disease Control and Prevention. NR 41 TC 1 Z9 1 U1 5 U2 5 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD SEP PY 2016 VL 215 IS 3 AR 364.e1-e10 DI 10.1016/j.ajog.2016.03.040 PG 10 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DU8WA UT WOS:000382495100038 PM 27026475 ER PT J AU Yang, J Pearl, M DeLorenze, GN Romero, R Dong, Z Jelliffe-Pawlowski, L Currier, R Flessel, M Kharrazi, M AF Yang, Juan Pearl, Michelle DeLorenze, Gerald N. Romero, Roberto Dong, Zhong Jelliffe-Pawlowski, Laura Currier, Robert Flessel, Monica Kharrazi, Martin TI Racial-ethnic differences in midtrimester maternal serum levels of angiogenic and antiangiogenic factors SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE early-onset preeclampsia; placental growth factor; racialethnic differences; soluble endoglin; soluble vascular endothelial growth factor receptor-1 ID PLACENTAL GROWTH-FACTOR; LATE-ONSET PREECLAMPSIA; EARLY-PREGNANCY; CLINICAL-MANIFESTATIONS; PLASMA-CONCENTRATIONS; CIRCULATING LEVELS; FACTOR RECEPTOR-1; AFRICAN-AMERICAN; HISPANIC WOMEN; PRETERM BIRTH AB BACKGROUND: Little is known about racial-ethnic differences in the distribution of maternal serum levels of angiogenic and antiangiogenic factors and their associations with early-onset preeclampsia. OBJECTIVE: We sought to investigate the distribution of midtrimester maternal serum levels of placental growth factor, soluble endoglin, and soluble vascular endothelial growth factor receptor 1 and their associations with early-onset preeclampsia in whites, Hispanics, and blacks. STUDY DESIGN: A population-based nested case-control design was used to identify cases and controls of white, Hispanic, and black origin from a 2000 through 2007 live-birth cohort in 5 southern California counties. Cases included 197 women (90 whites, 67 Hispanics, and 40 blacks) with early-onset preeclampsia defined as hypertension and proteinuria with onset < 32 weeks according to hospital records. Controls included a random sample of 2363 women without early-onset preeclampsia. Maternal serum specimens collected at 15-20 weeks' gestation as part of routine prenatal screening were tested for placental growth factor, soluble endoglin, and soluble vascular endothelial growth factor receptor 1. Serum levels of the 3 factors were log-normally distributed. Adjusted natural logarithmic means were compared between cases and controls and between racial-ethnic groups. Odds ratios and 95% confidence intervals derived from logistic regression models were calculated to measure the magnitude of the associations. RESULTS: Cases showed lower adjusted logarithmic means of placental growth factor but higher adjusted logarithmic means of soluble endoglin than controls across all 3 groups (P < .05). Cases also had higher adjusted means of soluble vascular endothelial growth factor receptor 1 than controls in whites (7.75 vs 7.52 log pg/mL, P < .05) and Hispanics (7.73 vs 7.40 log pg/mL, P < .05) but not in blacks (7.85 vs 7.69 log pg/mL, P = .47). Blacks were found to have higher levels of placental growth factor in both cases and controls when compared to whites and Hispanics (adjusted means: 4.69 and 5.20 log pg/mL in blacks, 4.08 and 4.78 log pg/mL in whites, and 3.89 and 4.70 log pg/mL in Hispanics, respectively, P < .05). Hispanic cases had the highest adjusted mean of soluble endoglin compared to white and black cases (9.24, 9.05, and 8.93 log pg/mL, respectively, P < .05). The weakest association of early-onset preeclampsia with placental growth factor and soluble endoglin was observed in blacks. The adjusted odds ratio per log pg/mL increase of the 2 analytes were 0.219 (95% confidence interval, 0.124-0.385) and 5.02 (95% confidence interval, 2.56-9.86) in blacks in comparison to 0.048 (95% confidence interval, 0.026-0.088) and 36.87 (95% confidence interval, 17.00-79.96) in whites (P < .05) and 0.028 (95% confidence interval, 0.013-0.060) and 86.68 (95% confidence interval, 31.46-238.81) in Hispanics (P < .05), respectively. As for soluble vascular endothelial growth factor receptor 1, the association was not significantly different among the racial-ethnic groups. CONCLUSION: Racial-ethnic differences were observed in the distribution of midtrimester maternal levels of placental growth factor and soluble endoglin and in the associations with early-onset preeclampsia. These differences should be considered in future studies to improve etiologic and prognostic understanding of early-onset preeclampsia. C1 [Yang, Juan; Currier, Robert; Flessel, Monica] Calif Dept Publ Hlth, Genet Dis Screening Program, Richmond, CA USA. [Kharrazi, Martin] Calif Dept Publ Hlth, Environm Hlth Invest Branch, Richmond, CA USA. [Pearl, Michelle] Sequoia Fdn, Richmond, CA USA. [DeLorenze, Gerald N.] Kaiser Permanente Northern Calif, Div Res, Oakland, CA USA. [Romero, Roberto; Dong, Zhong] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Detroit, MI USA. [Jelliffe-Pawlowski, Laura] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. RP Yang, J (reprint author), Calif Dept Publ Hlth, Genet Dis Screening Program, Richmond, CA USA. EM juan.yang@cdph.ca.gov FU Health Resources and Services Administration, US Department of Health and Human Services [R40MC21525] FX The project described was supported by Health Resources and Services Administration, US Department of Health and Human Services, through grant no. R40MC21525. The findings and conclusions in this article are those of the authors and do not necessarily represent the official position of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 50 TC 0 Z9 0 U1 3 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD SEP PY 2016 VL 215 IS 3 AR 359.e1-e9 DI 10.1016/j.ajog.2016.04.002 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DU8WA UT WOS:000382495100036 PM 27073062 ER PT J AU Cai, Y Jogasuria, A Yin, HQ Xu, MJ Hu, XD Wang, JY Kim, C Wu, JS Lee, K Gao, B You, M AF Cai, Yan Jogasuria, Alvin Yin, Huquan Xu, Ming-Jiang Hu, Xudong Wang, Jiayou Kim, Chunki Wu, Jiashin Lee, Kwangwon Gao, Bin You, Min TI The Detrimental Role Played by Lipocalin-2 in Alcoholic Fatty Liver in Mice SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID INSULIN-RESISTANCE; ELEVATED MICRORNA-34A; PARTIAL-HEPATECTOMY; DISEASE; INFLAMMATION; EXPRESSION; OBESITY; STEATOHEPATITIS; HEPATOCYTES; LIPIN-1 AB We have previously shown that the ethanol-mediated elevation of lipocaline-2 (LCN2) is closely associated with the development of alcoholic fatty liver disease (AFLD) in mice. Herein, we aimed to understand the functional significance of LCN2 induction by ethanol and to explore its underlying mechanisms. We evaluated the effects of LCN2 in an in vitro cellular alcoholic steatosis model and in an animal study using wild-type and LCN2 knockout mice fed for 4 weeks with an ethanol-supplemented Lieber-DeCarli diet. In the cellular model of alcoholic steatosis, recombinant LCN2 or overexpression of LCN2 exacerbated ethanol-induced fat accumulation, whereas knocking down LCN2 prevented steatosis in hepatocytes exposed to ethanol. Consistently, removal of LCN2 partially but significantly alleviated alcoholic fatty liver injury in mice. Mechanistically, LCN2 mediates detrimental effects of ethanol in the liver via disrupted multiple signaling pathways, including aberrant nicotinamide phosphoribosyltransferase-sirtuin 1 axis, perturbed endocrine metabolic regulatory fibroblast growth factor 15/19 signaling, and impaired chaperone-mediated autophagy. Finally, compared with healthy human livers, Liver samples from patients with AFLD had lower gene expression of several LCN2-regualted molecules. Our study demonstrated a pivotal and causal role of LCN2 in the development of AFLD and suggested that targeting the LCN2 could be of great value for the treatment of human AFLD. C1 [Cai, Yan; Xu, Ming-Jiang; Gao, Bin] NIAAA, Lab Liver Dis, NIH, Bethesda, MD USA. [Jogasuria, Alvin; Hu, Xudong; Wang, Jiayou; Kim, Chunki; Wu, Jiashin; Lee, Kwangwon; You, Min] Northeast Ohio Med Univ, Dept Pharmaceut Sci, Coll Pharm, 4209 State Rte 44, Rootstown, OH 44272 USA. [Yin, Huquan; Hu, Xudong] Univ S Florida, Hlth Sci Ctr, Dept Mol Pharmacol & Physiol, Tampa, FL USA. [Hu, Xudong] Shanghai Univ Tradit Chinese Med, Sch Basic Med Sci, Dept Biol, Shanghai, Peoples R China. [Wang, Jiayou] Guangzhou Univ Chinese Med, Sch Fundamental Med Sci, Dept Anat, Guangzhou, Guangdong, Peoples R China. RP You, M (reprint author), Northeast Ohio Med Univ, Dept Pharmaceut Sci, Coll Pharm, 4209 State Rte 44, Rootstown, OH 44272 USA. EM myou@neomed.edu FU National Institute on Alcoholism and Alcohol Abuse [AA013623, AA015951] FX Supported by National Institute on Alcoholism and Alcohol Abuse grants AA013623 and AA015951 (M.Y.). NR 38 TC 3 Z9 3 U1 5 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9440 EI 1525-2191 J9 AM J PATHOL JI Am. J. Pathol. PD SEP PY 2016 VL 186 IS 9 BP 2417 EP 2428 DI 10.1016/j.ajpath.2016.05.006 PG 12 WC Pathology SC Pathology GA DV0GE UT WOS:000382595200019 PM 27427417 ER PT J AU Jarlenski, M Baik, SH Zhang, YT AF Jarlenski, Marian Baik, Seo Hyon Zhang, Yuting TI Trends in Use of Medications for Smoking Cessation in Medicare, 2007-2012 SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID NEUROPSYCHIATRIC ADVERSE EVENTS; UNITED-STATES; VARENICLINE; SMOKERS; INTERVENTIONS; MORTALITY; ADULTS; QUIT AB Introduction: Smoking-related disease accounts for 10% of Medicare expenditures. Although clinical guidelines recommend smoking-cessation medications, they are subject to safety warnings from the U.S. Food and Drug Administration (FDA). This study investigated trends in utilization of smoking-cessation medications in Medicare from 2007 to 2012. Methods: Data on medical claims and prescription drugs for a nationally representative sample of Medicare beneficiaries were used to study trends from 2007 to 2012 in use of smoking-cessation medications (bupropion, nicotine-replacement therapy, varenicline), among beneficiaries who used tobacco (N = 205,675). Analyses were conducted in 2015. Multinomial logistic regression was used to examine differences in use of bupropion, nicotine-replacement therapy, varenicline, or more than one medication, relative to none, by beneficiaries' health and demographic characteristics. Binary logistic regression calculated average predicted probabilities of cardiovascular disease or depression among medication users before and after FDA safety warnings related to those conditions. Results: Sixteen percent of tobacco users ever filled a prescription for a smoking-cessation medication. The proportion of beneficiaries who filled prescriptions for varenicline increased in 2007 but sharply declined corresponding to public warnings about adverse effects, although the same trends did not occur for bupropion or nicotine-replacement therapy. After FDA safety concerns were published, the average predicted probability of beneficiaries filling varenicline prescriptions with cardiovascular disease declined by 31%, although the average predicted probability of depression did not decline. Conclusions: Use of smoking-cessation medications among Medicare beneficiaries remains low. Health effects of Medicare policies that increase coverage for medical support for smoking cessation may be limited by low utilization of effective medications. (C) 2016 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved. C1 [Jarlenski, Marian; Zhang, Yuting] Univ Pittsburgh, Dept Hlth Policy & Management, Grad Sch Publ Hlth, 130 DeSoto St,A647, Pittsburgh, PA 15261 USA. [Baik, Seo Hyon] Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, Bethesda, MD USA. [Zhang, Yuting] Univ Pittsburgh, Grad Sch Publ Hlth, Pharmaceut Econ Res Grp, Pittsburgh, PA USA. RP Jarlenski, M (reprint author), Univ Pittsburgh, Dept Hlth Policy & Management, Grad Sch Publ Hlth, 130 DeSoto St,A647, Pittsburgh, PA 15261 USA. EM marian.jarlenski@pitt.edu OI Jarlenski, Marian/0000-0001-6907-5447 FU Commonwealth Foundation and Agency for Healthcare Research and Quality [R01 HS018657]; National Institute of Mental Health [R21 MH100721] FX We acknowledge funding from Commonwealth Foundation and Agency for Healthcare Research and Quality (No. R01 HS018657) and from the National Institute of Mental Health (No. R21 MH100721). The research presented in this paper is that of the authors and does not reflect the official policy of the NIH. NR 24 TC 0 Z9 0 U1 6 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD SEP PY 2016 VL 51 IS 3 BP 301 EP 308 DI 10.1016/j.amepre.2016.02.018 PG 8 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA DU6CC UT WOS:000382299700007 PM 27036506 ER PT J AU Andersen, SW Zheng, W Sonderman, J Shu, XO Matthews, CE Yu, DX Steinwandel, M McLaughlin, JK Hargreaves, MK Blot, WJ AF Andersen, Shaneda Warren Zheng, Wei Sonderman, Jennifer Shu, Xiao-Ou Matthews, Charles E. Yu, Danxia Steinwandel, Mark McLaughlin, Joseph K. Hargreaves, Margaret K. Blot, William J. TI Combined Impact of Health Behaviors on Mortality in Low-Income Americans SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID SOUTHERN COMMUNITY COHORT; ALL-CAUSE MORTALITY; LIFE-STYLE BEHAVIORS; SOCIOECONOMIC-STATUS; US ADULTS; PHYSICAL-ACTIVITIES; RISK; QUESTIONNAIRE; DISPARITIES; SEDENTARY AB Introduction: African Americans and low-income whites have higher mortality than the U.S. general population. This study prospectively investigated the combined influence of major lifestyle factors and poverty on mortality in this vulnerable population. Methods: Data were collected in 2002-2009 from 79,101 Southern Community Cohort Study participants, of which 67% were African American and 55% had household incomes <$15,000. Mortality outcomes were identified from the National Death Index though December 31, 2011 (data analyzed in 2014-2015). Healthy behavior scores were created based on tobacco smoking, alcohol intake, diet, physical activity, and sedentary time. The primary analysis was performed based on the score created by counting each participant as having met/not met public health guidelines for each behavior. Results: Healthy behavior scores were associated with reduced cancer, cardiovascular disease, and all-cause mortality. Associations were stronger for whites than African Americans: hazard ratios for all-cause mortality comparing participants meeting four or five guidelines versus participants meeting zero were 0.41 (95% CI = 0.30, 0.55) for African American men; 0.36 (95% CI = 0.24, 0.55) for white men; 0.46 (95% CI = 0.36, 0.59) for African American women; and 0.27 (95% CI = 0.18, 0.43) for white women. The association between healthy lifestyle and all-cause mortality was weaker among those with incomes <$15,000 than those with higher income, particularly in men (p<0.05 for interaction). Conclusions: This study demonstrates the importance of health behaviors on mortality among all groups, but highlights the need for additional research to identify factors contributing to high risk of mortality among low-income and African American populations. (C) 2016 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved. C1 [Andersen, Shaneda Warren; Zheng, Wei; Shu, Xiao-Ou; Yu, Danxia; McLaughlin, Joseph K.; Blot, William J.] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med, Nashville, TN 37212 USA. [Sonderman, Jennifer; Steinwandel, Mark; McLaughlin, Joseph K.; Blot, William J.] Int Epidemiol Inst, Rockville, MD USA. [Matthews, Charles E.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Hargreaves, Margaret K.] Meharry Med Coll, Nashville, TN 37208 USA. RP Zheng, W (reprint author), Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med,Vanderbilt Epidemiol Ctr, 2525 West End Ave,8th Floor,Suite 800, Nashville, TN 37203 USA. EM wei.zheng@vanderbilt.edu RI Zheng, Wei/O-3351-2013; Dey, Kamalesh/E-6568-2017 OI Zheng, Wei/0000-0003-1226-070X; FU National Cancer Institute at NIH [R01 CA92447]; NIH [5P60 DK20593-24, 5U01 CA114641-05]; Vanderbilt Molecular and Genetic Epidemiology of Cancer training program (U.S. NIH grant) [R25 CA160056]; American Recovery and Reinvestment Act [3R01 CA092447-08S1] FX The Southern Community Cohort Study is funded by grant R01 CA92447 from the National Cancer Institute at NIH, including special allocations from the American Recovery and Reinvestment Act (3R01 CA092447-08S1). Partial support for Dr. Hargreaves is provided by NIH grants 5P60 DK20593-24 and 5U01 CA114641-05. Dr. Warren Andersen is supported by the Vanderbilt Molecular and Genetic Epidemiology of Cancer training program (U.S. NIH grant R25 CA160056). NR 41 TC 0 Z9 0 U1 7 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD SEP PY 2016 VL 51 IS 3 BP 344 EP 355 DI 10.1016/j.amepre.2016.03.018 PG 12 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA DU6CC UT WOS:000382299700012 ER PT J AU Klabunde, CN Zheng, YY Quinn, VP Beaber, EF Rutter, CM Halm, EA Chubak, J Doubeni, CA Haas, JS Kamineni, A Schapira, MM Vacek, PM Garcia, MP Corley, DA AF Klabunde, Carrie N. Zheng, Yingye Quinn, Virginia P. Beaber, Elisabeth F. Rutter, Carolyn M. Halm, Ethan A. Chubak, Jessica Doubeni, Chyke A. Haas, Jennifer S. Kamineni, Aruna Schapira, Marilyn M. Vacek, Pamela M. Garcia, Michael P. Corley, Douglas A. CA PROSPR Consortium TI Influence of Age and Comorbidity on Colorectal Cancer Screening in the Elderly SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID COST-EFFECTIVENESS; FOLLOW-UP; AMERICAN-COLLEGE; BREAST; HEALTH; WOMEN; CARE; RECOMMENDATIONS; COLONOSCOPY; STRATEGIES AB Introduction: Expert recommendations differ for colorectal cancer screening in the elderly. Recent studies suggest that healthy adults aged >75 years may benefit from screening. This study examined screening use and follow-up, and how they varied by health status within age strata, among a large cohort of elderly individuals in community settings. Methods: A population-based, longitudinal cohort study was conducted among health plan members aged 65-89 years enrolled during 2011-2012 in three integrated healthcare systems participating in the Population-Based Research Optimizing Screening through Personalized Regimens consortium. Comorbidity measurements used the Charlson index. Analyses, conducted in 2015, comprised descriptive statistics and multivariable modeling that estimated age by comorbidity-specific percentages of patients for two outcomes: colorectal cancer screening uptake and follow-up of abnormal fecal blood tests. Results: Among 846,267 patients, 72% were up-to-date with colorectal cancer screening. Of patients with a positive fecal blood test, 65% received follow-up colonoscopy within 3 months. Likelihood of being up-to-date and receiving timely follow-up was significantly lower for patients aged >= 76 years than their younger counterparts (p < 0.001). Comorbidity was less influential than age and more strongly related to timely follow-up than being up-to-date. In all age groups, considerable numbers of patients with no/low comorbidity were not up-to-date or did not receive timely follow-up. Conclusions: In three integrated healthcare systems, many older, relatively healthy patients were not screening up-to-date, and some relatively young, healthy patients did not receive timely follow-up. Findings suggest a need for re-evaluating age-based screening guidelines and improving screening completion among the elderly. Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine C1 [Klabunde, Carrie N.] NIH, Off Dis Prevent, Off Director, 6100 Execut Blvd,Suite 2B03, Rockville, MD 20852 USA. [Zheng, Yingye; Beaber, Elisabeth F.; Garcia, Michael P.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Quinn, Virginia P.] Kaiser Permanente Southern Calif, Res & Evaluat, Pasadena, CA USA. [Rutter, Carolyn M.] RAND Corp, Santa Monica, CA USA. [Halm, Ethan A.] Univ Texas Southwestern Med Ctr, Dept Internal Med & Clin Sci, Dallas, TX USA. [Chubak, Jessica; Kamineni, Aruna] Grp Hlth Res Inst, Seattle, WA USA. [Doubeni, Chyke A.] Univ Penn, Perelman Sch Med, Dept Family Med & Community Hlth, Philadelphia, PA 19104 USA. [Doubeni, Chyke A.] Univ Penn, Perelman Sch Med, Dept Epidemiol, Philadelphia, PA 19104 USA. [Haas, Jennifer S.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Haas, Jennifer S.] Harvard Med Sch, Boston, MA USA. [Schapira, Marilyn M.] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Schapira, Marilyn M.] Philadelphia VA Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Vacek, Pamela M.] Univ Vermont, Coll Med, Med Biostat Unit, Burlington, VT USA. [Corley, Douglas A.] Kaiser Permanente Div Res, Oakland, CA USA. RP Klabunde, CN (reprint author), NIH, Off Dis Prevent, Off Director, 6100 Execut Blvd,Suite 2B03, Rockville, MD 20852 USA. EM klabundc@od.nih.gov FU National Cancer Institute of NIH PROSPR cooperative agreements [U01CA163304, U54CA163261, U5U54CA163262, U54CA163303, U54CA 163307, U54CA163308, U54CA163313] FX The authors thank the participating Population-Based Research Optimizing Screening through Personalized Regimens (PROSPR) Research Centers for the data they have provided for this study. A list of PROSPR investigators and contributing research staff is provided at: http://healthcaredelivery.cancer.gov/prospr/. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of NIH. The National Cancer Institute of NIH supported the research for this manuscript through the PROSPR cooperative agreements (grant numbers U01CA163304, U54CA163261, U5U54CA163262, U54CA163303, U54CA 163307, U54CA163308, U54CA163313). NR 41 TC 1 Z9 1 U1 4 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD SEP PY 2016 VL 51 IS 3 BP E67 EP E75 DI 10.1016/j.amepre.2016.04.018 PG 9 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA DU6CC UT WOS:000382299700002 PM 27344108 ER PT J AU Andersson, M Scheidweiler, KB Sempio, C Barnes, AJ Huestis, MA AF Andersson, Maria Scheidweiler, Karl B. Sempio, Cristina Barnes, Allan J. Huestis, Marilyn A. TI Simultaneous quantification of 11 cannabinoids and metabolites in human urine by liquid chromatography tandem mass spectrometry using WAX-S tips SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article DE Cannabinoid; Urine; LC-MS/MS; DPX; THC ID DISPOSABLE PIPETTE EXTRACTION; WHOLE-BLOOD; ORAL FLUID; LC-MS/MS; DELTA-9-TETRAHYDROCANNABINOLIC ACID; GLUCURONIDATED CANNABINOIDS; DRUGS; HAIR; DELTA(9)-TETRAHYDROCANNABIVARIN; CONSUMPTION AB A comprehensive cannabinoid urine quantification method may improve clinical and forensic result interpretation and is necessary to support our clinical research. A liquid chromatography tandem mass spectrometry quantification method for a dagger(9)-tetrahydrocannabinol (THC), 11-hydroxy-THC (11-OH-THC), 11-nor-9-carboxy-THC (THCCOOH), a dagger(9)-tetrahydrocannabinolic acid (THCAA), cannabinol (CBN), cannabidiol (CBD), cannabigerol (CBG), a dagger(9)-tetrahydrocannabivarin (THCV), 11-nor-9-carboxy-THCV (THCVCOOH), THC-glucuronide (THC-gluc), and THCCOOH-glucuronide (THCCOOH-gluc) in urine was developed and validated according to the Scientific Working Group on Toxicology guidelines. Sample preparation consisted of disposable pipette extraction (WAX-S) of 200 mu L urine. Separation was achieved on a Kinetex C18 column using gradient elution with flow rate 0.5 mL/min, mobile phase A (10 mM ammonium acetate in water), and mobile phase B (15 % methanol in acetonitrile). Total run time was 14 min. Analytes were monitored in both positive and negative ionization modes by scheduled multiple reaction monitoring. Linear ranges were 0.5-100 mu g/L for THC and THCCOOH; 0.5-50 mu g/L for 11-OH-THC, CBD, CBN, THCAA, and THC-gluc; 1-100 mu g/L for CBG, THCV, and THCVCOOH; and 5-500 mu g/L for THCCOOH-gluc (R (2) > 0.99). Analytical biases were 88.3-113.7 %, imprecisions 3.3-14.3 %, extraction efficiencies 42.4-81.5 %, and matrix effect -10 to 32.5 %. We developed and validated a comprehensive, simple, and rapid LC-MS/MS cannabinoid urine method for quantification of 11 cannabinoids and metabolites. This method is being used in a controlled cannabis administration study, investigating urine cannabinoid markers documenting recent cannabis use, chronic frequent smoking, or route of drug administration and potentially improving urine cannabinoid result interpretation. C1 [Andersson, Maria; Scheidweiler, Karl B.; Sempio, Cristina; Barnes, Allan J.; Huestis, Marilyn A.] NIDA, Chem & Drug Metab Sect, Clin Pharmacol & Therapeut Res Branch, Intramural Res Program,NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. [Huestis, Marilyn A.] Univ Maryland, Sch Med, 655 W Baltimore St, Baltimore, MD 21201 USA. RP Scheidweiler, KB (reprint author), NIDA, Chem & Drug Metab Sect, Clin Pharmacol & Therapeut Res Branch, Intramural Res Program,NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM kscheidweiler@intra.nida.nih.gov FU Intramural Research Program (IRP) of the National Institute on Drug Abuse, National Institutes of Health FX This research was funded by the Intramural Research Program (IRP) of the National Institute on Drug Abuse, National Institutes of Health. NR 35 TC 1 Z9 1 U1 20 U2 23 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1618-2642 EI 1618-2650 J9 ANAL BIOANAL CHEM JI Anal. Bioanal. Chem. PD SEP PY 2016 VL 408 IS 23 BP 6461 EP 6471 DI 10.1007/s00216-016-9765-8 PG 11 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA DV1LF UT WOS:000382681900023 PM 27422645 ER PT J AU Gounden, V Zhao, Z AF Gounden, Verena Zhao, Zhen TI Eltrombopag interference in routine chemistry testing SO ANNALS OF CLINICAL BIOCHEMISTRY LA English DT Article DE Eltrombopag; interference; chemistry AB Background High doses of Eltrombopag have been previously reported to cause bilirubin interference. Following receipt of a sample from a patient receiving high-dose Eltrombopag therapy, the laboratory decided to investigate the effect of this drug on routine chemistry testing. Methods Interference studies were performed by spiking Eltrombopag into aliquots of a serum pool to give concentrations ranging from 0 to 500 mu g/mL. The following analytes, namely albumin, alkaline phosphatase, alanine transaminase, aspartate transaminase, Urea, total calcium, cholesterol, triglycerides, glucose, high-density lipoprotein cholesterol, iron, magnesium, inorganic phosphate, creatinine, bicarbonate, transferrin, ferritin, electrolytes, total and direct bilirubin and serum indices (hemolysis, icterus and lipaemia) were then measured on the Roche Cobas 6000 chemistry analyzer (Roche, Indianapolis, USA). Results Eltrombopag interference (>10% change of the baseline value) was observed for total cholesterol, triglycerides, inorganic phosphate and high-density lipoprotein cholesterol. Clinical significant interference was observed for total cholesterol, inorganic phosphate and high-density lipoprotein cholesterol Conclusions Presence of high Eltrombopag concentrations in blood samples has been demonstrated to cause interference in the measurement of certain spectrophotometric-based assays on the Roche Cobas 6000 analyzer. C1 [Gounden, Verena; Zhao, Zhen] NIH, Dept Lab Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. RP Gounden, V (reprint author), Inkosi Albert Luthuli Cent Hosp, Natl Hlth Lab Serv, Dept Chem Pathol, 800 Bellair Rd, ZA-4001 Durban, South Africa.; Gounden, V (reprint author), Univ KwaZulu Nata, 800 Bellair Rd, ZA-4001 Durban, South Africa. EM verenagounden@yahoo.com FU Intramural Research Program of the National Institutes of Health FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported by the Intramural Research Program of the National Institutes of Health. NR 6 TC 1 Z9 1 U1 4 U2 4 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0004-5632 EI 1758-1001 J9 ANN CLIN BIOCHEM JI Ann. Clin. Biochem. PD SEP PY 2016 VL 53 IS 5 BP 611 EP 614 DI 10.1177/0004563215609372 PG 4 WC Medical Laboratory Technology SC Medical Laboratory Technology GA DV3RA UT WOS:000382839500014 PM 26491115 ER PT J AU Nakamura, T Ramos-Alvarez, I Iordanskaia, T Moreno, P Mantey, SA Jensen, RT AF Nakamura, Taichi Ramos-Alvarez, Irene Iordanskaia, Tatiana Moreno, Paola Mantey, Samuel A. Jensen, R. T. TI Molecular basis for high affinity and selectivity of peptide antagonist, Bantag-1, for the orphan BB3 receptor SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE Bombesin; Gastrin-releasing peptide; Neuromedin B; Satiety; Obesity ID GASTRIN-RELEASING-PEPTIDE; NEUROMEDIN-B RECEPTOR; MAMMALIAN BOMBESIN RECEPTORS; PROTEIN-COUPLED RECEPTORS; AGOUTI-RELATED PROTEIN; LUNG-CANCER CELLS; AGONIST BINDING; TRANSMEMBRANE DOMAIN; SUBTYPE-3 BRS-3; NEUROKININ-1 RECEPTOR AB Bombesin-receptor-subtype-3 (BB3 receptor) is a G-protein-coupled-orphan-receptor classified in the mammalian Bombesin-family because of high homology to gastrin-releasing peptide (BB2 receptor)/neuromedin-B receptors (BB1 receptor). There is increased interest in BB3 receptor because studies primarily from knockout-mice suggest it plays roles in energy/glucose metabolism, insulin-secretion, as well as motility and tumor-growth. Investigations into its roles in physiological/pathophysiological processes are limited because of lack of selective ligands. Recently, a selective, peptide-antagonist, Bantag-1, was described. However, because BB3 receptor has low-affinity for all natural, Bn-related peptides, little is known of the molecular basis of its high-affinity/selectivity. This was systematically investigated in this study for Bantag-1 using a chimeric-approach making both Bantag-1 loss-/gain-of-affinity-chimeras, by exchanging extracellular (EC) domains of BB3/BB2 receptor, and using site-directed-mutagenesis. Receptors were transiently expressed and affinities determined by binding studies. Bantag-1 had >5000-fold selectivity for BB3 receptor over BB2/BB1 receptors and substitution of the first EC-domain (EC1) in loss-/gain-of affinity-chimeras greatly affected affinity. Mutagenesis of each amino acid difference in EC1 between BB3 receptor/BB2 receptor showed replacement of His(107) in BB3 receptor by Lys(707) (H107K-BB3 receptor-mutant) from BB2 receptor, decreased affinity 60-fold, and three replacements [H107K, E11D, G112R] decreased affinity 500-fold. Mutagenesis in EC1's surrounding transmembrane-regions (TMs) demonstrated TM2 differences were not important, but R127Q in TM3 alone decreased affinity 400-fold. Additional mutants in EC1/TM3 explored the molecular basis for these changes demonstrated in EC1, particularly important is the presence of aromatic-interactions by His107, rather than hydrogen-bonding or charge-charge interactions, for determining Bantag-1 high affinity/selectivity. In regard to Arg(127) in TM3, both hydrogen-bonding and charge-charge interactions contribute to the high-affinity/selectivity for Bantag-1. Published by Elsevier Inc. C1 [Nakamura, Taichi; Ramos-Alvarez, Irene; Iordanskaia, Tatiana; Moreno, Paola; Mantey, Samuel A.; Jensen, R. T.] NIDDK, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. RP Jensen, RT (reprint author), NIH NIDDK DDB, Bldg 10,Rm 9C-103,10 Ctr Dr MSC 1804, Bethesda, MD 20892 USA. EM robertj@bdg10.niddk.nih.gov FU intramural funds of NIDDK, NIH FX This study was supported by intramural funds of NIDDK, NIH. NR 80 TC 0 Z9 0 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 EI 1873-2968 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD SEP 1 PY 2016 VL 115 BP 64 EP 76 DI 10.1016/j.bcp.2016.06.013 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DT5TO UT WOS:000381545700007 PM 27346274 ER PT J AU Lastres-Becker, I Nonis, D Eich, F Klinkenberg, M Gorospe, M Kotter, P Klein, FAC Kedersha, N Auburger, G AF Lastres-Becker, Isabel Nonis, David Eich, Florian Klinkenberg, Michael Gorospe, Myriam Koetter, Peter Klein, Fabrice A. C. Kedersha, Nancy Auburger, Georg TI Mammalian ataxin-2 modulates translation control at the pre-initiation complex via PI3K/mTOR and is induced by starvation SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE LA English DT Article DE Diabetes mellitus; Spinocerebellar Ataxia type 2; Amyotrophic lateral sclerosis; TORC1; mRNA translation ID LENGTH POLYGLUTAMINE EXPANSIONS; STRESS GRANULES; TYPE-2 SCA2; CELL-SIZE; POLY(A)-BINDING PROTEIN; PROCESSING BODIES; GENE-EXPRESSION; SPINOCEREBELLAR; MICE; PHOSPHORYLATION AB Ataxin-2 is a cytoplasmic protein, product of the ATXN2 gene, whose deficiency leads to obesity, while its gain-of-function leads to neural atrophy. Ataxin-2 affects RNA homeostasis, but its effects are unclear. Here, immunofluorescence analysis suggested that ataxin-2 associates with 48S pre-initiation components at stress granules in neurons and mouse embryonic fibroblasts, but is not essential for stress granule formation. Coimmunoprecipitation analysis showed associations of ataxin-2 with initiation factors, which were concentrated at monosome fractions of polysome gradients like ataxin-2, unlike its known interactor PABP. Mouse embryonic fibroblasts lacking ataxin-2 showed increased phosphorylation of translation modulators 4E-BP1 and ribosomal protein S6 through the PI3K-mTOR pathways. Indeed, human neuroblastoma cells after trophic deprivation showed a strong induction of ATXN2 transcript via mTOR inhibition. Our results support the notion that ataxin-2 is a nutritional stress-inducible modulator of mRNA translation at the pre-initiation complex. (C) 2016 Elsevier B.V. All rights reserved. C1 [Lastres-Becker, Isabel; Nonis, David; Eich, Florian; Klinkenberg, Michael; Auburger, Georg] Goethe Univ Frankfurt, Sch Med, Sect Mol Neurogenet, Dept Neurol, Bldg 89,3rd Floor,Theodor Stem Kai 7, D-60590 Frankfurt, Germany. [Gorospe, Myriam] NIA, Genet Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Koetter, Peter] Goethe Univ Frankfurt, Inst Mol Biosci, Ctr Excellence Macromol Complexes, D-60590 Frankfurt, Germany. [Klein, Fabrice A. C.] UMR7104 CNRS U964 INSERM UDS, Translat Med & Neurogenet Dept, Inst Genet & Biol Mol & Cellulaire, BP10142, F-67404 Illkirch Graffenstaden, France. [Kedersha, Nancy] Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, One Jimmy Fund Way, Boston, MA 02115 USA. [Kedersha, Nancy] Harvard Med Sch, One Jimmy Fund Way, Boston, MA 02115 USA. [Lastres-Becker, Isabel] Inst Invest Biomed Alberto Sols, Dept Bioquim, Madrid, Spain. [Lastres-Becker, Isabel] Ctr Invest Red Enfermedades Neurodegenerat CIBERN, Madrid, Spain. [Nonis, David] Cedars Sinai Med Ctr, Regenerat Med Inst, 8700 Beverly Blvd,AHSP 8400, Los Angeles, CA 90048 USA. [Klinkenberg, Michael] German Ctr Neurodegenerat Dis DZNE, Ludwig Erhard Allee 2, D-53175 Bonn, Germany. RP Lastres-Becker, I; Auburger, G (reprint author), Goethe Univ Frankfurt, Sch Med, Sect Mol Neurogenet, Dept Neurol, Bldg 89,3rd Floor,Theodor Stem Kai 7, D-60590 Frankfurt, Germany.; Lastres-Becker, I (reprint author), Inst Invest Biomed Alberto Sols, Dept Bioquim, Madrid, Spain.; Lastres-Becker, I (reprint author), Ctr Invest Red Enfermedades Neurodegenerat CIBERN, Madrid, Spain. EM ilbecker@iib.uam.es; auburger@em.uni-frankfurt.de FU EU project EuroSCA [LSHM-CT-2004-005033]; Deutsche Forschungs-Gemeinschaft (DFG) [AU96/9-1, AU96/11-1, AU96/13-1]; German Ministry of Education, Research and Technology [0313128B]; Deutsche Forschungs-Gemeinschaft (SFB) [645]; NIA-IRP, NIH [National Institute on Aging-Intramural Research Program, National Institutes of Health]; NIH [RO1 AI 033600] FX I.L.-B. was a fellow of the Alexander von Humboldt Foundation. This work was supported by the EU project EuroSCA [LSHM-CT-2004-005033], the Deutsche Forschungs-Gemeinschaft (DFG) [AU96/9-1,11-1,13-1], the German Ministry of Education, Research and Technology [0313128B] and the Deutsche Forschungs-Gemeinschaft (SFB) 645 [B3]. M.G. was supported by the NIA-IRP, NIH [National Institute on Aging-Intramural Research Program, National Institutes of Health]. N.K. was supported by the NIH [RO1 AI 033600]. NR 71 TC 4 Z9 4 U1 5 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4439 EI 0006-3002 J9 BBA-MOL BASIS DIS JI Biochim. Biophys. Acta-Mol. Basis Dis. PD SEP PY 2016 VL 1862 IS 9 BP 1558 EP 1569 DI 10.1016/j.bbadis.2016.05.017 PG 12 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA DT5PU UT WOS:000381535900010 PM 27240544 ER PT J AU Nowacki, TM Remaley, AT Bettenworth, D Eisenblatter, M Vowinkel, T Becker, F Vogl, T Roth, J Tietge, UJ Lugering, A Heidemann, J Nofer, JR AF Nowacki, Tobias M. Remaley, Alan T. Bettenworth, Dominik Eisenblaetter, Michel Vowinkel, Thorsten Becker, Felix Vogl, Thomas Roth, Johannes Tietge, Uwe J. Luegering, Andreas Heidemann, Jan Nofer, Jerzy-Roch TI The 5A apolipoprotein A-I (apoA-I) mimetic peptide ameliorates experimental colitis by regulating monocyte infiltration SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; HIGH-DENSITY-LIPOPROTEIN; CHOLESTEROL EFFLUX; ANTIINFLAMMATORY PROPERTIES; IMMUNE-RESPONSES; CONCISE GUIDE; HDL; MACROPHAGES; ACTIVATION; CELLS AB Background and PurposeNew therapies for inflammatory bowel disease (IBD) are highly desirable. As apolipoprotein (apo)A-I mimetic peptides are beneficial in several animal models of inflammation, we hypothesized that they might be effective at inhibiting murine colitis. Experimental ApproachDaily injections of 5A peptide, a synthetic bihelical apoA-I mimetic dissolved in PBS, or PBS alone were administered to C57BL/6 mice fed 3% (w v(-1)) dextran sodium sulfate (DSS) in drinking water or healthy controls. Key ResultsDaily treatment with 5A peptide potently restricted DSS-induced inflammation, as indicated by improved disease activity indices and colon histology, as well as decreased intestinal tissue myeloperoxidase levels and plasma TNF and IL-6 concentrations. Additionally, plasma levels of monocyte chemoattractant protein-1 and the monocyte expression of adhesion-mediating molecule CD11b were down-regulated, pro-inflammatory CD11b(+)/Ly6c(high) monocytes were decreased, and the number of intestinal monocytes was reduced in 5A peptide-treated animals as determined by intravital macrophage-related peptide-8/14-directed fluorescence-mediated tomography and post-mortem immunhistochemical F4/80 staining. Intravital fluorescence microscopy of colonic microvasculature demonstrated inhibitory effects of 5A peptide on leukocyte adhesion accompanied by reduced plasma levels of the soluble adhesion molecule sICAM-1. In vitro 5A peptide reduced monocyte adhesion and transmigration in TNF-stimulated monolayers of human intestinal microvascular endothelial cells. Increased susceptibility to DSS-induced inflammation was noted in apoA-I-/- mice. Conclusions and ImplicationsThe 5A peptide is effective at ameliorating murine colitis by preventing intestinal monocyte infiltration and activation. These findings point to apoA-I mimetics as a potential treatment approach for IBD. C1 [Nowacki, Tobias M.; Bettenworth, Dominik; Heidemann, Jan] Univ Hosp Munster, Dept Med B, Albert Schweitzer Campus 1,Gebaude A1, D-48149 Munster, Germany. [Remaley, Alan T.] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Eisenblaetter, Michel] Univ Hosp Munster, Dept Clin Radiol, Translat Res Imaging Ctr, Munster, Germany. [Vowinkel, Thorsten; Becker, Felix] Univ Hosp Munster, Dept Gen & Visceral Surg, Munster, Germany. [Vogl, Thomas; Roth, Johannes] Univ Hosp Munster, Inst Immunol, Munster, Germany. [Tietge, Uwe J.] Univ Groningen, Univ Med Ctr Groningen, Dept Pediat, Ctr Liver Digest & Metab Dis, Gz Groningen, Netherlands. [Luegering, Andreas] Med Care Ctr Portal 10, Munster, Germany. [Heidemann, Jan] Klinikum Bielefeld, Dept Gastroenterol, Bielefeld, Germany. [Nofer, Jerzy-Roch] Univ Hosp Munster, Ctr Lab Med, Munster, Germany. RP Nowacki, TM (reprint author), Univ Hosp Munster, Dept Med B, Albert Schweitzer Campus 1,Gebaude A1, D-48149 Munster, Germany. EM tobias.nowacki@ukmuenster.de FU Innovative Medizinische Forschung Munster (IMF) [111017] FX We thank Ms. Sonja Dufentester, Ms. Elke Weber and Ms. Beate Schulte for the excellent technical assistance. This work was supported by Innovative Medizinische Forschung Munster (IMF) (No. 111017 to T.M.N., J.-R.N. and J.H.). NR 62 TC 0 Z9 0 U1 5 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1188 EI 1476-5381 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD SEP PY 2016 VL 173 IS 18 BP 2780 EP 2792 DI 10.1111/bph.13556 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DV9KJ UT WOS:000383259000007 PM 27425846 ER PT J AU Fehringer, G Kraft, P Pharoah, PD Eeles, RA Chatterjee, N Schumacher, FR Schildkraut, JM Lindstrom, S Brennan, P Bickeboller, H Houlston, RS Landi, MT Caporaso, N Risch, A Al Olama, AA Berndt, SI Giovannucci, EL Gronberg, H Kote-Jarai, Z Ma, J Muir, K Stampfer, MJ Stevens, VL Wiklund, F Willett, WC Goode, EL Permuth, JB Risch, HA Reid, BM Bezieau, S Brenner, H Chan, AT Chang-Claude, J Hudson, TJ Kocarnik, JK Newcomb, PA Schoen, RE Slattery, ML White, E Adank, MA Ahsan, H Aittomaki, K Baglietto, L Blomquist, C Canzian, F Czene, K dos-Santos-Silva, I Eliassen, AH Figueroa, JD Flesch-Janys, D Fletcher, O Garcia-Closas, M Gaudet, MM Johnson, N Hall, P Hazra, A Hein, R Hofman, A Hopper, JL Irwanto, A Johansson, M Kaaks, R Kibriya, MG Lichtner, P Liu, JJ Lund, E Makalic, E Meindl, A Muller-Myhsok, B Muranen, TA Nevanlinna, H Peeters, PH Peto, J Prentice, RL Rahman, N Sanchez, MJ Schmidt, DF Schmutzler, RK Southey, MC Tamimi, R Travis, RC Turnbull, C Uitterlinden, AG Wang, ZM Whittemore, AS Yang, XHR Zheng, W Buchanan, DD Casey, G Conti, DV Edlund, CK Gallinger, S Haile, RW Jenkins, M Le Marchand, L Li, L Lindor, NM Schmit, SL Thibodeau, SN Woods, MO Rafnar, T Gudmundsson, J Stacey, SN Stefansson, K Sulem, P Chen, YA Tyrer, JP Christiani, DC Wei, YY Shen, HB Hu, ZB Shu, XO Shiraishi, K Takahashi, A Bosse, Y Obeidat, M Nickle, D Timens, W Freedman, ML Li, QY Seminara, D Chanock, SJ Gong, J Peters, U Gruber, SB Amos, CI Sellers, TA Easton, DF Hunter, DJ Haiman, CA Henderson, BE Hung, RJ AF Fehringer, Gordon Kraft, Peter Pharoah, Paul D. Eeles, Rosalind A. Chatterjee, Nilanjan Schumacher, Fredrick R. Schildkraut, Joellen M. Lindstrom, Sara Brennan, Paul Bickeboller, Heike Houlston, Richard S. Landi, Maria Teresa Caporaso, Neil Risch, Angela Al Olama, Ali Amin Berndt, Sonja I. Giovannucci, Edward L. Gronberg, Henrik Kote-Jarai, Zsofia Ma, Jing Muir, Kenneth Stampfer, Meir J. Stevens, Victoria L. Wiklund, Fredrik Willett, Walter C. Goode, Ellen L. Permuth, Jennifer B. Risch, Harvey A. Reid, Brett M. Bezieau, Stephane Brenner, Hermann Chan, Andrew T. Chang-Claude, Jenny Hudson, Thomas J. Kocarnik, Jonathan K. Newcomb, Polly A. Schoen, Robert E. Slattery, Martha L. White, Emily Adank, Muriel A. Ahsan, Habibul Aittomaki, Kristiina Baglietto, Laura Blomquist, Carl Canzian, Federico Czene, Kamila dos-Santos-Silva, Isabel Eliassen, A. Heather Figueroa, Jonine D. Flesch-Janys, Dieter Fletcher, Olivia Garcia-Closas, Montserrat Gaudet, Mia M. Johnson, Nichola Hall, Per Hazra, Aditi Hein, Rebecca Hofman, Albert Hopper, John L. Irwanto, Astrid Johansson, Mattias Kaaks, Rudolf Kibriya, Muhammad G. Lichtner, Peter Liu, Jianjun Lund, Eiliv Makalic, Enes Meindl, Alfons Muller-Myhsok, Bertram Muranen, Taru A. Nevanlinna, Heli Peeters, Petra H. Peto, Julian Prentice, Ross L. Rahman, Nazneen Sanchez, Maria Jose Schmidt, Daniel F. Schmutzler, Rita K. Southey, Melissa C. Tamimi, Rulla Travis, Ruth C. Turnbull, Clare Uitterlinden, Andre G. Wang, Zhaoming Whittemore, Alice S. Yang, Xiaohong R. Zheng, Wei Buchanan, Daniel D. Casey, Graham Conti, David V. Edlund, Christopher K. Gallinger, Steven Haile, Robert W. Jenkins, Mark Le Marchand, Loic Li, Li Lindor, Noralene M. Schmit, Stephanie L. Thibodeau, Stephen N. Woods, Michael O. Rafnar, Thorunn Gudmundsson, Julius Stacey, Simon N. Stefansson, Kari Sulem, Patrick Chen, Y. Ann Tyrer, Jonathan P. Christiani, David C. Wei, Yongyue Shen, Hongbing Hu, Zhibin Shu, Xiao-Ou Shiraishi, Kouya Takahashi, Atsushi Bosse, Yohan Obeidat, Ma'en Nickle, David Timens, Wim Freedman, Matthew L. Li, Qiyuan Seminara, Daniela Chanock, Stephen J. Gong, Jian Peters, Ulrike Gruber, Stephen B. Amos, Christopher I. Sellers, Thomas A. Easton, Douglas F. Hunter, David J. Haiman, Christopher A. Henderson, Brian E. Hung, Rayjean J. CA OCAC PRACTICAL Consortium Hereditary Breast Ovarian Canc Res Colorectal Transdisciplinary African Amer Breast Canc African Ancestry Prostate Canc TI Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations SO CANCER RESEARCH LA English DT Article ID SUSCEPTIBILITY LOCI; IDENTIFIES 2; GENETIC POLYMORPHISMS; AGGRESSIVE PROSTATE; AFRICAN ANCESTRY; COMMON VARIANTS; GASTRIC-CANCER; CELL CARCINOMA; RISK LOCI; METAANALYSIS AB Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus atCDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer, and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression. (C) 2016 AACR. C1 [Fehringer, Gordon; Gallinger, Steven; Hung, Rayjean J.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, 60 Murray St, Toronto, ON M5T 3L9, Canada. [Kraft, Peter; Lindstrom, Sara; Giovannucci, Edward L.; Willett, Walter C.; Eliassen, A. Heather; Christiani, David C.; Wei, Yongyue; Hunter, David J.] Harvard TH Chan Sch Publ Hlth, Boston, MA USA. [Pharoah, Paul D.; Tyrer, Jonathan P.; Easton, Douglas F.] Univ Cambridge, Cambridge, England. [Eeles, Rosalind A.; Houlston, Richard S.; Kote-Jarai, Zsofia] Inst Canc Res, London, England. [Chatterjee, Nilanjan; Landi, Maria Teresa; Caporaso, Neil; Berndt, Sonja I.; Figueroa, Jonine D.; Garcia-Closas, Montserrat; Wang, Zhaoming; Yang, Xiaohong R.; Seminara, Daniela; Chanock, Stephen J.] NCI, Bethesda, MD 20892 USA. [Schumacher, Fredrick R.; Casey, Graham; Conti, David V.; Edlund, Christopher K.; Schmit, Stephanie L.; Gruber, Stephen B.; Haiman, Christopher A.; Henderson, Brian E.] Univ So Calif, Los Angeles, CA USA. [Schildkraut, Joellen M.] Univ Virginia, Charlottesville, VA USA. [Brennan, Paul; Johansson, Mattias] Int Agcy Res Canc, Lyon, France. [Bickeboller, Heike] Univ Gottingen, Sch Med, Gottingen, Germany. [Risch, Angela] Salzburg Univ, Div Canc Genet Epigenet, Dept Mol Biol, Salzburg, Austria. [Risch, Angela] DKFZ German Canc Res Ctr, Div Epigenom & Canc Risk Factors, Heidelberg, Germany. [Risch, Angela] German Ctr Lung Res DZL, Translat Lung Res Ctr Heidelberg TLRCH, Heidelberg, Germany. [Al Olama, Ali Amin] Univ Cambridge, Cambridge, England. [Gronberg, Henrik; Wiklund, Fredrik; Czene, Kamila; Hall, Per] Karolinska Inst, Stockholm, Sweden. [Ma, Jing; Stampfer, Meir J.; Eliassen, A. Heather; Hazra, Aditi; Tamimi, Rulla] Harvard Univ, Sch Med, Boston, MA USA. Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Muir, Kenneth] Univ Manchester, Manchester, Lancs, England. [Muir, Kenneth] Univ Warwick, Coventry, W Midlands, England. [Stevens, Victoria L.; Gaudet, Mia M.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Goode, Ellen L.; Thibodeau, Stephen N.] Mayo Clin, Rochester, MN USA. [Permuth, Jennifer B.; Reid, Brett M.; Chen, Y. Ann; Sellers, Thomas A.] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [Risch, Harvey A.] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Bezieau, Stephane] Serv Genet Med, Nantes, France. [Brenner, Hermann] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Brenner, Hermann] German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany. [Brenner, Hermann] German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany. [Chan, Andrew T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Chang-Claude, Jenny; Kaaks, Rudolf] Natl Ctr Tumor Dis, Heidelberg, Germany. [Chang-Claude, Jenny; Kaaks, Rudolf] German Canc Res Ctr, Heidelberg, Germany. [Hudson, Thomas J.] Ontario Inst Canc Res, Toronto, ON, Canada. [Kocarnik, Jonathan K.; Newcomb, Polly A.; White, Emily; Prentice, Ross L.; Gong, Jian; Peters, Ulrike] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Schoen, Robert E.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Slattery, Martha L.] Univ Utah, Hlth Sci Ctr, Salt Lake City, UT USA. [Adank, Muriel A.] Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands. [Ahsan, Habibul; Kibriya, Muhammad G.] Univ Chicago, Chicago, IL USA. [Aittomaki, Kristiina; Blomquist, Carl; Muranen, Taru A.; Nevanlinna, Heli] Univ Helsinki, Helsinki, Finland. [Aittomaki, Kristiina; Blomquist, Carl; Muranen, Taru A.; Nevanlinna, Heli] Univ Helsinki, Cent Hosp, Helsinki, Finland. [Baglietto, Laura; Southey, Melissa C.; Buchanan, Daniel D.; Jenkins, Mark] Univ Melbourne, Melbourne, Vic, Australia. [Canzian, Federico] German Canc Res Ctr, Gen Epidemiol Grp, Heidelberg, Germany. [dos-Santos-Silva, Isabel; Peto, Julian] London Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, London, England. [Flesch-Janys, Dieter] Univ Med Ctr HamburgEppendorf, Hamburg, Germany. [Fletcher, Olivia; Johnson, Nichola] Breakthrough Res Ctr, Inst Canc Res, London, England. [Hein, Rebecca] German Canc Res Ctr DKFZ Heidelberg, Div Canc Epidemiol, Heidelberg, Germany. [Hein, Rebecca] Univ Cologne, Inst Med Stat Informat & Epidemiol, Cologne, Germany. [Hofman, Albert; Uitterlinden, Andre G.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Hopper, John L.; Makalic, Enes; Schmidt, Daniel F.] Univ Melbourne, Melbourne Sch Populat Hlth, Melbourne, Vic, Australia. [Irwanto, Astrid; Liu, Jianjun] Genome Inst Singapore, Singapore, Singapore. [Johansson, Mattias] Umea Univ, Dept Biobank Res, Umea, Sweden. [Lichtner, Peter] German Res Ctr Environm Hlth, Neuherberg, Germany. [Lund, Eiliv] UiT Arctic Univ Norway, Inst Community Med, Tromso, Norway. [Meindl, Alfons] Tech Univ Munich, Munich, Germany. [Muller-Myhsok, Bertram] Max Planck Inst Psychiat, Munich, Germany. [Peeters, Petra H.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Dept Epidemiol, Utrecht, Netherlands. [Rahman, Nazneen; Turnbull, Clare] Inst Canc Res, Sutton, Surrey, England. [Sanchez, Maria Jose] Escuela Andaluza Salud Publ, Inst Invest Biosanitaria Ibs GRANADA, Granada, Spain. [Sanchez, Maria Jose] Univ Granada, Hosp Univ Granada, Granada, Spain. [Sanchez, Maria Jose] CIBER Epidemiol & Salud Publ CIBERESP, Madrid, Spain. [Schmutzler, Rita K.] Univ Cologne, Cologne, Germany. [Travis, Ruth C.] Univ Oxford, Nuffield Dept Populat Hlth, Canc Epidemiol Unit, Oxford, England. [Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Whittemore, Alice S.; Haile, Robert W.] Stanford Univ, Stanford, CA 94305 USA. [Zheng, Wei; Shu, Xiao-Ou] Vanderbilt Univ, 221 Kirkland Hall, Nashville, TN 37235 USA. [Le Marchand, Loic] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96822 USA. [Li, Li] Case Western Reserve Univ, Case Comprehens Canc Ctr, Cleveland, OH 44106 USA. [Li, Li] Case Western Reserve Univ, Mary Ann Swetland Ctr Environm Hlth, Cleveland, OH 44106 USA. [Lindor, Noralene M.] Mayo Clin, Scottsdale, AZ USA. [Woods, Michael O.] Mem Univ Newfoundland, St John, NF, Canada. [Rafnar, Thorunn; Gudmundsson, Julius; Stacey, Simon N.; Stefansson, Kari; Sulem, Patrick] Amgen Inc, DeCODE Genet, Reykjavik, Iceland. [Shen, Hongbing; Hu, Zhibin] Nanjing Med Univ, Sch Publ Hlth, Nanjing, Jiangsu, Peoples R China. [Shiraishi, Kouya] Natl Canc Ctr, Div Genome Biol, Tokyo, Japan. [Takahashi, Atsushi] RIKEN Ctr Integrat Med Sci, Lab Stat Anal, Yokohama, Kanagawa, Japan. [Bosse, Yohan] Univ Laval, Inst Univ Cardiol & Pneumol Quebec, Dept Mol Med, Quebec City, PQ, Canada. [Obeidat, Ma'en] Univ British Columbia, St Pauls Hosp, Ctr Heart Lung Innovat, Vancouver, BC, Canada. [Nickle, David] Merck & Co Inc, Merck Res Labs, Seattle, WA USA. [Timens, Wim] Univ Groningen, Univ Med Ctr Groningen, GRIAC Res Inst, Groningen, Netherlands. [Freedman, Matthew L.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Li, Qiyuan] Xiamen Univ, Xiamen, Peoples R China. [Amos, Christopher I.] Dartmouth Coll, Sch Med, Hanover, NH 03755 USA. RP Hung, RJ (reprint author), Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, 60 Murray St, Toronto, ON M5T 3L9, Canada. EM rayjean.hung@lunenfeld.ca RI Hung, Rayjean/A-7439-2013; Zheng, Wei/O-3351-2013; Brenner, Hermann/B-4627-2017; Risch, Angela/H-2669-2013; OI Zheng, Wei/0000-0003-1226-070X; Brenner, Hermann/0000-0002-6129-1572; Risch, Angela/0000-0002-8026-5505; Muranen, Taru/0000-0002-5895-1808; Houlston, Richard/0000-0002-5268-0242 FU Cancer Research UK [10119, 10124, A10118, A10119, A10124, A12014, A16561, A5660, A8339]; Medical Research Council [G0700491]; NCI NIH HHS [P30 CA023108, R01 CA050385, R01 CA055769, R01 CA074386, R01 CA092824, R01 CA121197, R01 CA127219, R01 CA133996, U01 CA137088, U01 CA164973, U19 CA148065, U19 CA148107, U19 CA148112, U19 CA148127, U19 CA148537, UM1 CA167551, UM1 CA176726]; NIH HHS [S10 OD020069] NR 47 TC 0 Z9 0 U1 5 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD SEP 1 PY 2016 VL 76 IS 17 BP 5103 EP 5114 DI 10.1158/0008-5472.CAN-15-2980 PG 12 WC Oncology SC Oncology GA DU6BU UT WOS:000382298900020 PM 27197191 ER PT J AU Gunzle, J Osterberg, N Saavedra, JE Weyerbrock, A AF Guenzle, Jessica Osterberg, Nadja Saavedra, Joseph E. Weyerbrock, Astrid TI Nitric oxide released from JS-K induces cell death by mitotic catastrophe as part of necrosis in glioblastoma multiforme SO CELL DEATH & DISEASE LA English DT Article ID POLY(ADP-RIBOSE) POLYMERASE CLEAVAGE; ANTINEOPLASTIC ACTIVITY; ACID SPHINGOMYELINASE; INHIBITS APOPTOSIS; MALIGNANT GLIOMAS; TUMOR-CELLS; PATHWAYS; ACTIVATION; DONOR; DAMAGE AB The nitric oxide (NO) donor JS-K is specifically activated by glutathione S-transferases (GSTs) in GST-overexpressing cells. We have shown the induction of cell death in glioblastoma multiforme (GBM) cells at high JS-K doses but the mechanism remains unclear. The aim of this study was to determine whether NO-induced cell death is triggered by induction of apoptotic or necrotic pathways. For the first time, we demonstrate that NO induces cell death via mitotic catastrophe (MC) with non-apoptotic mechanisms in GBM cells. Moreover, the level of morphological changes indicating MC correlates with increased necrosis. Therefore, we conclude that MC is the main mechanism by which GBM cells undergo cell death after treatment with JS-K associated with necrosis rather than apoptosis. In addition, we show that PARP1 is not an exclusive marker for late apoptosis but is also involved in MC. Activating an alternative way of cell death can be useful for the multimodal cancer therapy of GBM known for its strong anti-apoptotic mechanisms and drug resistance. C1 [Guenzle, Jessica; Osterberg, Nadja; Weyerbrock, Astrid] Univ Freiburg, Dept Neurosurg, Med Ctr, Breisacher Str 64, D-79106 Freiburg, Germany. [Guenzle, Jessica] Univ Freiburg, Fac Biol, Schaenzlestr 1, D-79104 Freiburg, Germany. [Saavedra, Joseph E.] NCI, Canc Inflammat Program, Ctr Canc Res, Bldg 567,Room 254, Frederick, MD 21702 USA. RP Weyerbrock, A (reprint author), Univ Freiburg, Dept Neurosurg, Med Ctr, Breisacher Str 64, D-79106 Freiburg, Germany. EM weyerbrock@uniklinik-freiburg.de OI Weyerbrock, Astrid/0000-0001-9060-4462 NR 46 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-4889 J9 CELL DEATH DIS JI Cell Death Dis. PD SEP PY 2016 VL 7 AR e2349 DI 10.1038/cddis.2016.254 PG 10 WC Cell Biology SC Cell Biology GA DU6LR UT WOS:000382326800009 PM 27584787 ER PT J AU Staunton, JR Vieira, W Fung, KL Lake, R Devine, A Tanner, K AF Staunton, Jack R. Vieira, Wilfred Fung, King Leung Lake, Ross Devine, Alexus Tanner, Kandice TI Mechanical Properties of the Tumor Stromal Microenvironment Probed In Vitro and Ex Vivo by In Situ-Calibrated Optical Trap-Based Active Microrheology SO CELLULAR AND MOLECULAR BIOENGINEERING LA English DT Article DE Microrheology; Optical traps; Biomaterials; Tissue mechanics; Hydrogels; Biopsy ID PARTICLE-TRACKING MICRORHEOLOGY; AMPLITUDE OSCILLATORY SHEAR; COLLAGEN FIBRIL FORMATION; SOFT GLASSY MATERIALS; EXTRACELLULAR-MATRIX; CELL-MIGRATION; BREAST-CANCER; 2ND-HARMONIC GENERATION; BIOPOLYMER NETWORKS; COMPLEX FLUIDS AB One of the hallmarks of the malignant transformation of epithelial tissue is the modulation of stromal components of the microenvironment. In particular, aberrant extracellular matrix (ECM) remodeling and stiffening enhances tumor growth and survival and promotes metastasis. Type I collagen is one of the major ECM components. It serves as a scaffold protein in the stroma contributing to the tissue's mechanical properties, imparting tensile strength and rigidity to tissues such as those of the skin, tendons, and lungs. Here we investigate the effects of intrinsic spatial heterogeneities due to fibrillar architecture, pore size and ligand density on the microscale and bulk mechanical properties of the ECM. Type I collagen hydrogels with topologies tuned by polymerization temperature and concentration to mimic physico-chemical properties of a normal tissue and tumor microenvironment were measured by in situ-calibrated Active Microrheology by Optical Trapping revealing significantly different microscale complex shear moduli at Hz-kHz frequencies and two orders of magnitude of strain amplitude that we compared to data from bulk rheology measurements. Access to higher frequencies enabled observation of transitions from elastic to viscous behavior that occur at similar to 200-2750 Hz, which largely was dependent on tissue architecture well outside the dynamic range of instrument acquisition possible with SAOS bulk rheology. We determined that mouse melanoma tumors and human breast tumors displayed complex moduli similar to 5-1000 Pa, increasing with frequency and displaying a nonlinear stress-strain response. Thus, we show the feasibility of a mechanical biopsy in efforts to provide a diagnostic tool to aid in the design of therapeutics complementary to those based on standard histopathology. C1 [Staunton, Jack R.; Vieira, Wilfred; Fung, King Leung; Devine, Alexus; Tanner, Kandice] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. [Lake, Ross] NCI, Lab Genitourinary Canc Pathogenesis, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Tanner, K (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM kandice.tan-ner@nih.gov RI Staunton, Jack/G-3786-2010 OI Staunton, Jack/0000-0001-9773-8025 FU Intramural Research Program of the National Institutes of Health; National Cancer Institute FX This effort was supported by the Intramural Research Program of the National Institutes of Health, the National Cancer Institute. We thank Ben Blehm for helpful technical discussions and George Leiman for critical reading of the manuscript. We also thank Daniel Blair, and Xinran Zhang of Georgetown University for assistance with bulk rheometry. NR 106 TC 1 Z9 1 U1 19 U2 19 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1865-5025 EI 1865-5033 J9 CELL MOL BIOENG JI Cell. Mol. Bioeng. PD SEP PY 2016 VL 9 IS 3 BP 398 EP 417 DI 10.1007/s12195-016-0460-9 PG 20 WC Cell & Tissue Engineering; Biophysics; Cell Biology SC Cell Biology; Biophysics GA DT6LC UT WOS:000381594700009 PM 27752289 ER PT J AU Kos, A Loohuis, NO Meinhardt, J van Bokhoven, H Kaplan, BB Martens, GJ Aschrafi, A AF Kos, Aron Loohuis, Nikkie Olde Meinhardt, Julia van Bokhoven, Hans Kaplan, Barry B. Martens, Gerard J. Aschrafi, Armaz TI MicroRNA-181 promotes synaptogenesis and attenuates axonal outgrowth in cortical neurons SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Article DE Neurodevelopment; Neuronal morphology; Cortex; Non-coding RNA; Post-transcriptional regulation ID FLUORESCENCE MICROSCOPY IMAGES; PLURIPOTENT STEM-CELLS; MESSENGER-RNA; OXIDATIVE-PHOSPHORYLATION; SYMPATHETIC NEURONS; HIPPOCAMPAL-NEURONS; NEURAL DEVELOPMENT; PREFRONTAL CORTEX; TEMPORAL CORTEX; AUTISM AB MicroRNAs ( miRs) are non-coding gene transcripts abundantly expressed in both the developing and adult mammalian brain. They act as important modulators of complex gene regulatory networks during neuronal development and plasticity. miR-181c is highly abundant in cerebellar cortex and its expression is increased in autism patients as well as in an animal model of autism. To systematically identify putative targets of miR-181c, we repressed this miR in growing cortical neurons and found over 70 differentially expressed target genes using transcriptome profiling. Pathway analysis showed that the miR-181c-modulated genes converge on signaling cascades relevant to neurite and synapse developmental processes. To experimentally examine the significance of these data, we inhibited miR-181c during rat cortical neuronal maturation in vitro; this loss-of miR-181c function resulted in enhanced neurite sprouting and reduced synaptogenesis. Collectively, our findings suggest that miR-181c is a modulator of gene networks associated with cortical neuronal maturation. C1 [Kos, Aron; Loohuis, Nikkie Olde; Meinhardt, Julia; van Bokhoven, Hans; Aschrafi, Armaz] Radboud Univ Nijmegen, Dept Cognit Neurosci, Med Ctr, NL-6500 HB Nijmegen, Netherlands. [Martens, Gerard J.] Radboud Univ Nijmegen, Dept Mol Anim Physiol, Nijmegen, Netherlands. [van Bokhoven, Hans] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6500 HB Nijmegen, Netherlands. [Kos, Aron; Loohuis, Nikkie Olde; Meinhardt, Julia; van Bokhoven, Hans; Martens, Gerard J.; Aschrafi, Armaz] Donders Inst Brain Cognit & Behav Ctr Neurosci, NL-6525 AJ Nijmegen, Netherlands. [Kaplan, Barry B.; Aschrafi, Armaz] NIMH, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Aschrafi, A (reprint author), Donders Inst Brain Cognit & Behav Ctr Neurosci, NL-6525 AJ Nijmegen, Netherlands. EM armaz.aschrafi@gmail.com FU Intramural NIH HHS [Z99 MH999999] NR 64 TC 1 Z9 1 U1 5 U2 5 PU SPRINGER BASEL AG PI BASEL PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND SN 1420-682X EI 1420-9071 J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD SEP PY 2016 VL 73 IS 18 BP 3555 EP 3567 DI 10.1007/s00018-016-2179-0 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DU7JP UT WOS:000382390600009 PM 27017280 ER PT J AU Satin, LS Ha, J Sherman, AS AF Satin, Leslie S. Ha, Joon Sherman, Arthur S. TI Islets Transplanted Into the Eye: Do They Improve Our Insight Into Islet Adaptation to Insulin Resistance? SO DIABETES LA English DT Editorial Material ID BETA-CELL MASS; MOUSE; MODEL; PREVENTION; METABOLISM; MECHANISMS; SECRETION; FAILURE; BIOLOGY C1 [Satin, Leslie S.] Univ Michigan, Sch Med, Dept Pharmacol, Ann Arbor, MI 48109 USA. [Satin, Leslie S.] Univ Michigan, Sch Med, Brehm Ctr Diabet Res, Ann Arbor, MI 48109 USA. [Satin, Leslie S.] Uppsala Univ, Dept Med Cell Biol, Uppsala, Sweden. [Ha, Joon; Sherman, Arthur S.] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. RP Satin, LS (reprint author), Univ Michigan, Sch Med, Dept Pharmacol, Ann Arbor, MI 48109 USA.; Satin, LS (reprint author), Univ Michigan, Sch Med, Brehm Ctr Diabet Res, Ann Arbor, MI 48109 USA.; Satin, LS (reprint author), Uppsala Univ, Dept Med Cell Biol, Uppsala, Sweden. EM lsatin@umich.edu FU NIDDK NIH HHS [R01 DK046409] NR 17 TC 0 Z9 0 U1 3 U2 3 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD SEP PY 2016 VL 65 IS 9 BP 2470 EP 2472 DI 10.2337/dbi16-0025 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DU3GW UT WOS:000382099800002 PM 27555572 ER PT J AU Gilgun-Sherki, Y Eliaz, RE McCann, DJ Loupe, PS Eyal, E Blatt, K Cohen-Barak, O Hallak, H Chiang, N Gyaw, S AF Gilgun-Sherki, Yossi Eliaz, Rom E. McCann, David J. Loupe, Pippa S. Eyal, Eli Blatt, Kathleen Cohen-Barak, Orit Hallak, Hussein Chiang, Nora Gyaw, Shwe TI Placebo-controlled evaluation of a bioengineered, cocaine-metabolizing fusion protein, TV-1380 (AlbuBChE), in the treatment of cocaine dependence SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Cocaine; Addiction; Dependence; TV-1380; AlbuBChE; Butyrylcholinesterase ID HUMAN BUTYRYLCHOLINESTERASE; MUTATED BUTYRYLCHOLINESTERASE; CONTINGENCY MANAGEMENT; HYDROLASE; ADDICTION; THERAPY; TOXICITY; SAFETY; MUTANT; USERS AB Background: TV-1380 (AlbuChE) is a novel recombinant fusion protein of mutated butyrylcholinesterase (BChE) that has increased catalytic efficiency for cocaine metabolism compared to wild-type BChE. Methods: Intra-muscular injections of TV-1380 (150 mg or 300 mg) or placebo were administered once weekly to participants (n = 66-69 per group) in a randomized, double-blind study to evaluate the ability of TV-1380 to facilitate abstinence in treatment-seeking, cocaine-dependent individuals. The primary endpoint was the proportion of participants achieving abstinence from cocaine during the last three weeks of the 12 week treatment phase, based on daily self-report of "no use" confirmed by urine testing. Results: Although there were no significant differences between the TV-1380 treatment groups and placebo for the primary endpoint, 6% of participants in the 150 mg and 300 mg TV-1380 groups and no participants in the placebo group achieved abstinence. For the only declared secondary endpoint, there was a dose-dependent increase in the group mean percentage of urine samples testing negative for cocaine metabolites during weeks 5-12 (8.1% and 14.6% for the 150 mg and 300 mg TV-1380 groups, respectively, compared to 4.7% for the placebo group; p = 0.0056 for 300 mg vs. placebo). No meaningful differences in adverse events were seen between treatment groups. Conclusions: While the apparent reduction in cocaine use may be of insufficient magnitude to justify further trials of TV-1380 in cocaine dependence, the results argue for development of improved enzymes with greater catalytic activity. (C) 2016 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY-NC-ND license C1 [Gilgun-Sherki, Yossi] Teva Pharmaceut, Clin Dev & Med Sect, Petah Tiqwa, Israel. [Eliaz, Rom E.] Teva Pharmaceut, Innovat Project Leadership Res & Dev, Petah Tiqwa, Israel. [McCann, David J.; Chiang, Nora; Gyaw, Shwe] NIDA, Div Therapeut & Med Consequences, Bethesda, MD 20892 USA. [Loupe, Pippa S.] Teva Pharmaceut, Res & Sci Affairs, Res & Dev, 11100 Nall Ave, Overland Pk, KS 66047 USA. [Eyal, Eli] Teva Pharmaceut, Biostat Res & Dev, Petah Tiqwa, Israel. [Blatt, Kathleen] Teva Pharmaceut, Global Clin Operat Res & Dev, Frazer, PA USA. [Cohen-Barak, Orit] Teva Pharmaceut, Phase & Clin Pharmacol Res & Dev 1, Petah Tiqwa, Israel. [Hallak, Hussein] Teva Pharmaceut, Nonclin DMPK Res & Dev, Petah Tiqwa, Israel. RP Loupe, PS (reprint author), Teva Pharmaceut, Res & Sci Affairs, Res & Dev, 11100 Nall Ave, Overland Pk, KS 66047 USA. EM ygilgun@gmail.com; rom.eliaz@teva.co.il; DMCCANN@NIH.GOV; pippa.loupe@tevapharm.com; eli.eyal@teva.co.il; kathleen.blatt@tevapharm.com; orit.cohen-barak@teva.co.il; Hussein.Hallak@teva.co.il; nchiang@nida.nih.gov; shwe.gyaw@nih.gov FU Teva Pharmaceutical Industries; National Institute on Drug Abuse (NIDA); NIDA support through the U.S. Department of Veterans Affairs Cooperative Studies Program [ADA12009] FX The clinical study was jointly funded by Teva Pharmaceutical Industries and the National Institute on Drug Abuse (NIDA), with NIDA support provided through the U.S. Department of Veterans Affairs Cooperative Studies Program (Interagency Agreement # ADA12009). Teva and NIDA were jointly responsible for the study design, statistical analysis plan, and the writing of this report. Teva was responsible for regulatory filings and data acquisition, and NIDA was responsible for providing oversight by an independent Data Safety Monitoring Board. NR 19 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD SEP 1 PY 2016 VL 166 BP 13 EP 20 DI 10.1016/j.drugalcdep.2016.05.019 PG 8 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA DU6QJ UT WOS:000382339400003 PM 27394932 ER PT J AU Kim, C Seow, WJ Shu, XO Bassig, BA Rothman, N Chen, BSE Xiang, YB Hosgood, HD Ji, BT Hu, W Wen, CJ Chow, WH Cai, QY Yang, G Gao, YT Zheng, W Lan, Q AF Kim, Christopher Seow, Wei Jie Shu, Xiao-Ou Bassig, Bryan A. Rothman, Nathaniel Chen, Bingshu E. Xiang, Yong-Bing Hosgood, H. Dean, III Ji, Bu-Tian Hu, Wei Wen, Cuiju Chow, Wong-Ho Cai, Qiuyin Yang, Gong Gao, Yu-Tang Zheng, Wei Lan, Qing TI Cooking Coal Use and All-Cause and Cause-Specific Mortality in a Prospective Cohort Study of Women in Shanghai, China SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID HOUSEHOLD AIR-POLLUTION; LUNG-CANCER RISK; POLYCYCLIC AROMATIC-HYDROCARBONS; RETROSPECTIVE COHORT; STOVE IMPROVEMENT; LIFE EXPECTANCY; BIOMASS FUELS; UNITED-STATES; XUANWEI; EXPOSURE AB Background: Nearly 4.3 million deaths worldwide were attributable to exposure to household air pollution in 2012. However, household coal use remains widespread. Objectives: We investigated the association of cooking coal and all-cause and cause-specific mortality in a prospective cohort of primarily never-smoking women in Shanghai, China. Methods: A cohort of 74,941 women were followed from 1996 through 2009 with annual linkage to the Shanghai vital statistics database. Cause-specific mortality was identified through 2009. Use of household coal for cooking was assessed through a residential history questionnaire. Cox proportional hazards models estimated the risk of mortality associated with household coal use. Results: In this cohort, 63% of the women ever used coal (n = 46,287). Compared with never coal use, ever use of coal was associated with mortality from all causes [hazard ratio (HR) = 1.12; 95% confidence interval (CI): 1.05, 1.21], cancer (HR = 1.14; 95% CI: 1.03, 1.27), and ischemic heart disease (overall HR = 1.61; 95% CI: 1.14, 2.27; HR for myocardial infarction specifically = 1.80; 95% CI: 1.16, 2.79). The risk of cardiovascular mortality increased with increasing duration of coal use, compared with the risk in never users. The association between coal use and ischemic heart disease mortality diminished with increasing years since cessation of coal use. Conclusions: Evidence from this study suggests that past use of coal among women in Shanghai is associated with excess all-cause mortality, and from cardiovascular diseases in particular. The decreasing association with cardiovascular mortality as the time since last use of coal increased emphasizes the importance of reducing use of household coal where use is still widespread. C1 [Kim, Christopher; Seow, Wei Jie; Bassig, Bryan A.; Rothman, Nathaniel; Ji, Bu-Tian; Hu, Wei; Wen, Cuiju; Lan, Qing] NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Rockville, MD USA. [Shu, Xiao-Ou; Cai, Qiuyin; Yang, Gong; Zheng, Wei] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Chen, Bingshu E.] Queens Univ, Queens Canc Res Inst, Kingston, ON, Canada. [Xiang, Yong-Bing; Gao, Yu-Tang] Shanghai Jiao Tong Univ, Sch Med, Renji Hosp, Shanghai Canc Inst, Shanghai, Peoples R China. [Hosgood, H. Dean, III] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, New York, NY USA. [Chow, Wong-Ho] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. RP Seow, WJ (reprint author), 9609 Med Ctr Dr.,Room 6E632, Rockville, MD 20850 USA.; Lan, Q (reprint author), 9609 Med Ctr Dr,Room 6E136, Rockville, MD 20850 USA. EM weijie.seow2@nih.gov; qingl@mail.nih.gov RI Zheng, Wei/O-3351-2013 OI Zheng, Wei/0000-0003-1226-070X FU National Institutes of Health (NIH) intramural research program; NIH [N02 CP1101066]; NIH research grant [R01 CA70867] FX This work was supported by the National Institutes of Health (NIH) intramural research program, NIH grant contract N02 CP1101066, and NIH research grant R01 CA70867. NR 35 TC 0 Z9 0 U1 6 U2 6 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD SEP PY 2016 VL 124 IS 9 BP 1384 EP 1389 DI 10.1289/EHP236 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA DU9IM UT WOS:000382530200017 PM 27091488 ER PT J AU Stephen, J Vilboux, T Haberman, Y Pri-Chen, H Pode-Shakked, B Mazaheri, S Marek-Yagel, D Barel, O Di Segni, A Eyal, E Hout-Siloni, G Lahad, A Shalem, T Rechavi, G Malicdan, MCV Weiss, B Gahl, WA Anikster, Y AF Stephen, Joshi Vilboux, Thierry Haberman, Yael Pri-Chen, Hadass Pode-Shakked, Ben Mazaheri, Sina Marek-Yagel, Dina Barel, Ortal Di Segni, Ayelet Eyal, Eran Hout-Siloni, Goni Lahad, Avishay Shalem, Tzippora Rechavi, Gideon Malicdan, May Christine V. Weiss, Batia Gahl, William A. Anikster, Yair TI Congenital protein losing enteropathy: an inborn error of lipid metabolism due to DGAT1 mutations SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article ID DIACYLGLYCEROL ACYLTRANSFERASE; TRIGLYCERIDE SYNTHESIS; FAMILY; FAT AB Protein-losing enteropathy (PLE) is a clinical disorder of protein loss from the gastrointestinal system that results in hypoproteinemia and malnutrition. This condition is associated with a wide range of gastrointestinal disorders. Recently, a unique syndrome of congenital PLE associated with biallelic mutations in the DGAT1 gene has been reported in a single family. We hypothesize that mutations in this gene are responsible for undiagnosed cases of PLE in infancy. Here we investigated three children in two families presenting with severe diarrhea, hypoalbuminemia and PLE, using clinical studies, homozygosity mapping, and exome sequencing. In one family, homozygosity mapping using SNP arrays revealed the DGAT1 gene as the best candidate gene for the proband. Sequencing of all the exons including flanking regions and promoter regions of the gene identified a novel homozygous missense variant, p.(Leu295Pro), in the highly conserved membrane-bound O-acyl transferase (MBOAT) domain of the DGAT1 protein. Expression studies verified reduced amounts of DGAT1 in patient fibroblasts. In a second family, exome sequencing identified a previously reported splice site mutation in intron 8. These cases of DGAT1 deficiency extend the molecular and phenotypic spectrum of PLE, suggesting a re-evaluation of the use of DGAT1 inhibitors for metabolic disorders including obesity and diabetes. C1 [Stephen, Joshi; Vilboux, Thierry; Pri-Chen, Hadass; Mazaheri, Sina; Malicdan, May Christine V.; Gahl, William A.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Vilboux, Thierry] Inova Translat Med Inst, Div Med Genom, Fairfax, VA USA. [Haberman, Yael; Lahad, Avishay; Shalem, Tzippora; Weiss, Batia] Edmond & Lily Safra Childrens Hosp, Sheba Med Ctr, Div Pediat Gastroenterol Hepatol & Nutr, Tel Hashomer, Israel. [Haberman, Yael] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Pri-Chen, Hadass; Pode-Shakked, Ben; Rechavi, Gideon; Weiss, Batia; Anikster, Yair] Tel Aviv Univ, Sackler Fac Med, Tel Aviv, Israel. [Pode-Shakked, Ben; Marek-Yagel, Dina; Anikster, Yair] Edmond & Lily Safra Childrens Hosp, Sheba Med Ctr, Metab Dis Unit, Tel Hashomer, Israel. [Pode-Shakked, Ben] Sheba Med Ctr, Dr Pinchas Borenstein Talpiot Med Leadership Prog, Tel Hashomer, Israel. [Barel, Ortal; Di Segni, Ayelet; Eyal, Eran; Hout-Siloni, Goni; Rechavi, Gideon] Sheba Med Ctr, Sheba Canc Res Ctr, Tel Hashomer, Israel. [Malicdan, May Christine V.; Gahl, William A.] NHGRI, NIH Undiagnosed Dis Program, NIH, 10C-103 10 Ctr Dr 9000,Rockville Pike, Bethesda, MD 20892 USA. [Gahl, William A.] NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA. RP Malicdan, MCV (reprint author), NHGRI, NIH Undiagnosed Dis Program, NIH, 10C-103 10 Ctr Dr 9000,Rockville Pike, Bethesda, MD 20892 USA. EM malicdanm@mail.nih.gov FU Intramural Research Programs of the National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA; I-CORE program [41/11]; Gene and Protein Expression core of the NIH Cincinnati Children's Hospital Research Foundation Digestive Health Center [1P30DK078392-01] FX This research was supported by the Intramural Research Programs of the National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA; the I-CORE program (grants No. 41/11); and the Gene and Protein Expression core of the NIH-supported Cincinnati Children's Hospital Research Foundation Digestive Health Center (1P30DK078392-01). We thank the patients and their families for their kind assistance. NR 21 TC 2 Z9 2 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1018-4813 EI 1476-5438 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD SEP PY 2016 VL 24 IS 9 BP 1268 EP 1273 DI 10.1038/ejhg.2016.5 PG 6 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA DU6FV UT WOS:000382310600006 PM 26883093 ER PT J AU O'Brien, KM Shi, M Sandler, DP Taylor, JA Zaykin, DV Keller, J Wise, AS Weinberg, CR AF O'Brien, Katie M. Shi, Min Sandler, Dale P. Taylor, Jack A. Zaykin, Dmitri V. Keller, Jean Wise, Alison S. Weinberg, Clarice R. TI A family-based, genome-wide association study of young-onset breast cancer: inherited variants and maternally mediated effects SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article ID FALSE DISCOVERY RATE; CASE-PARENT TRIADS; SUSCEPTIBILITY LOCI; BIRTH-WEIGHT; RISK; AGE; REPLICATION; DISEASE; WHITES; GENES AB Young-onset breast cancer shows certain phenotypic and etiologic differences from older-onset breast cancer and may be influenced by some distinct genetic variants. Few genetic studies of breast cancer have targeted young women and no studies have examined whether maternal variants influence disease in their adult daughters through prenatal effects. We conducted a family-based, genome-wide association study of young-onset breast cancer (age at diagnosis o50 years). A total of 602 188 single-nucleotide polymorphisms (SNPs) were genotyped for 1279 non-Hispanic white cases and their parents or sisters. We used likelihood-based log-linear models to test for transmission asymmetry within families and for maternally mediated genetic effects. Three autosomal SNPs (rs28373882, P=2.8 x 10(-7); rs879162, P=9.2 x 10(-7); rs12606061, P=9.1 x 10(-7)) were associated with risk of young-onset breast cancer at a false-discovery rate below 0.20. None of these loci has been previously linked with young-onset or overall breast cancer risk, and their functional roles are unknown. There was no evidence of maternally mediated, X-linked, or mitochondrial genetic effects, and no notable findings within cancer subcategories defined by menopausal status, estrogen receptor status, or by tumor invasiveness. Further investigations are needed to explore other potential genetic, epigenetic, or epistatic mechanisms and to confirm the association between these three novel loci and youngonset breast cancer. C1 [O'Brien, Katie M.; Shi, Min; Zaykin, Dmitri V.; Wise, Alison S.; Weinberg, Clarice R.] NIEHS, Biostat & Computat Biol Branch, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. [Sandler, Dale P.; Taylor, Jack A.] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Keller, Jean] Westat Corp, Durham, NC USA. RP Weinberg, CR (reprint author), NIEHS, Biostat & Computat Biol Branch, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM weinber2@niehs.nih.gov OI O'Brien, Katie/0000-0002-1931-1349; taylor, jack/0000-0001-5303-6398 FU Intramural Research Program of the NIH; National Institute of Environmental Health Sciences [Z01-ES044005, Z01-ES102245]; Susan G Komen for the Cure [FAS0703856] FX This work was supported by the Intramural Research Program of the NIH, the National Institute of Environmental Health Sciences (project Z01-ES044005 to DPS and project Z01-ES102245 to CRW) and Susan G Komen for the Cure (grant FAS0703856 to CRW). We thank the Center for Inherited Disease Research, the Genetics Coordinating Center at the University of Washington (Cecelia Laurie, Quenna Wong, Sarah Nelson, and Cathy Laurie), and Jing Dong and Lauren Wilson from NIEHS for reviewing earlier drafts of this paper. NR 42 TC 1 Z9 1 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1018-4813 EI 1476-5438 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD SEP PY 2016 VL 24 IS 9 BP 1316 EP 1323 DI 10.1038/ejhg.2016.11 PG 8 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA DU6FV UT WOS:000382310600013 PM 26883092 ER PT J AU Willems, SM Cornes, BK Brody, JA Morrison, AC Lipovich, L Dauriz, M Chen, YN Liu, CT Rybin, DV Gibbs, RA Muzny, D Pankow, JS Psaty, BM Boerwinkle, E Rotter, JI Siscovick, DS Vasan, RS Kaplan, RC Isaacs, A Dupuis, J van Duijn, CM Meigs, JB AF Willems, Sara M. Cornes, Belinda K. Brody, Jennifer A. Morrison, Alanna C. Lipovich, Leonard Dauriz, Marco Chen, Yuning Liu, Ching-Ti Rybin, Denis V. Gibbs, Richard A. Muzny, Donna Pankow, James S. Psaty, Bruce M. Boerwinkle, Eric Rotter, Jerome I. Siscovick, David S. Vasan, Ramachandran S. Kaplan, Robert C. Isaacs, Aaron Dupuis, Josee van Duijn, Cornelia M. Meigs, James B. TI Association of the IGF1 gene with fasting insulin levels SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article ID RARE-VARIANT ASSOCIATION; GROWTH-FACTOR-I; SEQUENCING DATA; POPULATION-GROWTH; WIDE ASSOCIATION; AGING RESEARCH; LOW-FREQUENCY; OLDER-ADULTS; DISEASE; MUTATIONS AB Insulin-like growth factor 1 (IGF-I) has been associated with insulin resistance. Genome-wide association studies (GWASs) of fasting insulin (FI) identified single-nucleotide variants (SNVs) near the IGF1 gene, raising two hypotheses: (1) these associations are mediated by IGF-I levels and (2) these noncoding variants either tag other functional variants in the region or are directly functional. In our study, analyses including 5141 individuals from population-based cohorts suggest that FI associations near IGF1 are not mediated by IGF-I. Analyses of targeted sequencing data in 3539 individuals reveal a large number of novel rare variants at the IGF1 locus and show a FI association with a subset of rare nonsynonymous variants (P-SKAT=5.7 x 10(-4)). Conditional analyses suggest that this association is partly explained by the GWAS signal and the presence of a residual independent rare variant effect (P-conditional=0.019). Annotation using ENCODE data suggests that the GWAS variants may have a direct functional role in insulin biology. In conclusion, our study provides insight into variation present at the IGF1 locus and into the genetic architecture underlying FI levels, suggesting that FI associations of SNVs near IGF1 are not mediated by IGF-I and suggesting a role for both rare nonsynonymous and common functional variants in insulin biology. C1 [Willems, Sara M.; Isaacs, Aaron; van Duijn, Cornelia M.] Erasmus MC, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands. [Cornes, Belinda K.; Dauriz, Marco; Meigs, James B.] Massachusetts Gen Hosp, Div Gen Internal Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. [Cornes, Belinda K.; Dauriz, Marco; Meigs, James B.] Harvard Med Sch, Dept Med, Boston, MA USA. [Brody, Jennifer A.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Morrison, Alanna C.; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Houston, TX 77030 USA. [Lipovich, Leonard] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. [Lipovich, Leonard] Wayne State Univ, Sch Med, Dept Neurol, Detroit, MI 48201 USA. [Dauriz, Marco] Univ Verona, Dept Med, Div Endocrinol Diabet & Metab, Sch Med, Verona, Italy. [Dauriz, Marco] Hosp Trust Verona, Verona, Italy. [Chen, Yuning; Liu, Ching-Ti; Dupuis, Josee] Boston Univ, Dept Biostat, Sch Publ Hlth, Boston, MA USA. [Rybin, Denis V.] Boston Univ, Data Coordinating Ctr, Boston, MA 02215 USA. [Gibbs, Richard A.; Muzny, Donna] Univ Texas Hlth Sci Ctr Houston, Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Pankow, James S.] Univ Minnesota, Div Epidemiol & Community Hlth JSP, Minneapolis, MN 55455 USA. [Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Los Angeles Biomed Res Inst, Torrance, CA 90509 USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90509 USA. [Siscovick, David S.] New York Acad Med, New York, NY USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Prevent Med & Epidemiol, Cardiol Sect, Boston, MA 02118 USA. [Vasan, Ramachandran S.; Dupuis, Josee] NHLBI, Framingham Heart Study, Framingham, MA USA. [Kaplan, Robert C.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, New York, NY USA. RP Meigs, JB (reprint author), Massachusetts Gen Hosp, Div Gen Internal Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM jmeigs@mgh.harvard.edu RI Dauriz, Marco/S-5843-2016; OI Dauriz, Marco/0000-0002-5542-5941; Ramachandran, Vasan/0000-0001-7357-5970 FU U.S. CHARGE Consortium by the 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]; NHLBI; Boston University [N01 HC 25195]; Affymetrix, Inc. [N02-HL-6-4278]; NHLBI [HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393]; National Institute of Neurological Disorders and Stroke (NINDS); National Institute on Aging (NIA) [1R01AG031890, R01AG023629]; National Center for Advancing Translational Sciences, CTSI [UL1TR000124]; National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) [DK063491]; Netherlands Organization for Scientific Research NWO Investments [175.010.2005.011, 911-03-012]; Research Institute for Diseases in the Elderly [014-93-015]; Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO) [050-060-810, 242244]; Erasmus Medical Center and Erasmus University, Rotterdam; Netherlands Organization for the Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly (RIDE); Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; European Commission (DG XII); Municipality of Rotterdam; [R01 DK078616]; [K24 DK080140] FX 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' were provided by Eric Boerwinkle on behalf of the Atherosclerosis Risk in Communities (ARIC) Study, L Adrienne Cupples, principal investigator for the Framingham Heart Study, and Bruce Psaty, principal investigator for the Cardiovascular Health Study. Sequencing was carried out at the Baylor Genome Center (U54 HG003273). The ARIC Study is 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). The Framingham Heart Study is conducted and supported by the NHLBI in collaboration with Boston University (Contract No. 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 Clusters for Genetic Analysis (LinGA) computing resources at Boston University Medical Campus. Also supported by R01 DK078616 (Dr Meigs) and K24 DK080140 (Dr Meigs). This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086; and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, and R01HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through 1R01AG031890 and R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI Grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) Grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The generation and management of GWAS genotype data for the Rotterdam Study is supported by the Netherlands Organization for Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO) project nr. 050-060-810, CHANCES (nr 242244). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 40 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1018-4813 EI 1476-5438 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD SEP PY 2016 VL 24 IS 9 BP 1337 EP 1343 DI 10.1038/ejhg.2016.4 PG 7 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA DU6FV UT WOS:000382310600016 PM 26860063 ER PT J AU Kunutsor, SK Laukkanen, JA Bluemke, DA Butler, J Khan, H AF Kunutsor, Setor K. Laukkanen, Jari A. Bluemke, David A. Butler, Javed Khan, Hassan TI Baseline and long-term gamma-glutamyltransferase, heart failure and cardiac arrhythmias in middle-aged Finnish men: Prospective study and pooled analysis of published evidence SO EUROPEAN JOURNAL OF PREVENTIVE CARDIOLOGY LA English DT Article DE Gamma-glutamyltransferase; heart failure; ventricular arrhythmias; atrial fibrillation ID FATTY LIVER-DISEASE; ATRIAL-FIBRILLATION; CARDIOVASCULAR-DISEASE; OXIDATIVE STRESS; ATHEROSCLEROSIS RISK; ENZYMES; METAANALYSIS; MORTALITY; COHORT; EPIDEMIOLOGY AB Aim To assess the associations of baseline and long-term gamma-glutamyltransferase (GGT) activity with risk of heart failure (HF), ventricular arrhythmias (VAs) and atrial fibrillation (AF). Methods GGT measurements were made in a prospective cohort of 1780 men free of HF and cardiac arrhythmias at baseline. Correction for within-person variability was made using data from repeat measurements taken several years apart. Results During an average follow-up of 22 years, 222 HF, 56 VA and 336 AF events occurred. The regression dilution ratio of log(e) GGT was 0.68 (95% confidence interval (CI): 0.61-0.74). Serum GGT was log-linearly associated with risk of HF, VAs and AF. In analyses adjusted for established risk factors, the hazard ratios (HRs) (95% CIs) for HF, VAs and AF per 1 SD higher baseline log(e) GGT values were 1.25 (1.07-1.45), 1.37 (1.04-1.80) and 1.04 (0.92-1.18), respectively. After correction for within-person variability, the corresponding HRs were 1.38 (1.11-1.73), 1.58 (1.06-2.37) and 1.06 (0.88-1.27), respectively. These findings remained consistent in analyses accounting for incident coronary heart disease and the development of impaired renal function. In a meta-analysis of five population-based studies, the fully adjusted relative risks for HF per 1 SD higher baseline and long-term GGT values were 1.28 (1.20-1.35) and 1.43 (1.31-1.56), respectively. In a pooled analysis of two studies, the corresponding risks for AF were 1.09 (1.02-1.16) and 1.14 (1.03-1.25), respectively. Conclusion GGT is positively and log-linearly associated with future risk of HF, VAs and AF. Further research is needed in order to assess the causal relevance of these findings. C1 [Kunutsor, Setor K.] Univ Bristol, Sch Clin Sci, Southmead Hosp, Learning & Res Bldg,Level 1,Southmead Rd, Bristol BS10 5NB, Avon, England. [Laukkanen, Jari A.] Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Joensuu, Finland. [Bluemke, David A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Butler, Javed] SUNY Stony Brook, Hlth Sci Ctr, Div Cardiol, Stony Brook, NY 11794 USA. [Khan, Hassan] Emory Univ, Sch Med, Atlanta, GA USA. RP Kunutsor, SK (reprint author), Univ Bristol, Sch Clin Sci, Southmead Hosp, Learning & Res Bldg,Level 1,Southmead Rd, Bristol BS10 5NB, Avon, England. EM skk31@cantab.net OI Bluemke, David/0000-0002-8323-8086 FU Academy of Finland, Helsinki, Finland; Finnish Foundation for Cardiovascular Research, Helsinki, Finland; Finnish Cultural Foundation, Helsinki, Finland FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Academy of Finland, Helsinki, Finland, the Finnish Foundation for Cardiovascular Research, Helsinki, Finland, and the Finnish Cultural Foundation, Helsinki, Finland. NR 33 TC 4 Z9 4 U1 1 U2 2 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 2047-4873 EI 2047-4881 J9 EUR J PREV CARDIOL JI Eur. J. Prev. Cardiol. PD SEP PY 2016 VL 23 IS 13 BP 1354 EP 1362 DI 10.1177/2047487316644086 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DV1BO UT WOS:000382655100001 PM 27084895 ER PT J AU Gore, AV Weinstein, BM AF Gore, Aniket V. Weinstein, Brant M. TI DNA methylation in hematopoietic development and disease SO EXPERIMENTAL HEMATOLOGY LA English DT Review ID ACUTE MYELOID-LEUKEMIA; X-CHROMOSOME INACTIVATION; EMBRYONIC STEM-CELLS; TET PROTEINS; DEFINITIVE HEMATOPOIESIS; PROGENITOR CELLS; REPRESSES TRANSCRIPTION; METHYLTRANSFERASE 1; DNMT3A MUTATIONS; SELF-RENEWAL AB DNA methylation is an important epigenetic modification that can have profound and widespread effects on gene expression and on cellular fate and function. Recent work has indicated that DNA methylation plays a critical role in hematopoietic development and hematopoietic disease. DNA methyltransferases and Ten-eleven translocation enzymes are required to add and remove methyl "marks" from DNA, respectively, and both sets of genes have been found necessary for proper formation and maintenance of hematopoietic stem cells and for differentiation of downstream hematopoietic lineages during development. DNA methylation and demethylation enzymes have also been implicated in hematopoietic disorders such as acute myeloid leukemia and myelodysplastic syndrome. Here, we review some of the recent literature regarding the role of DNA methylation in hematopoietic health and disease. Published by Elsevier Inc. on behalf of ISEH - International Society for Experimental Hematology. C1 [Gore, Aniket V.; Weinstein, Brant M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Dev Biol, NIH, Bethesda, MD 20892 USA. RP Weinstein, BM (reprint author), NICHD, Div Dev Biol, NIH, Bldg 6B,Room 413,6 Ctr Dr, Bethesda, MD 20892 USA. EM bw96w@nih.gov FU intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development FX The Weinstein lab is supported by the intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. We apologize to authors whose work we could not cite because of space limitations. NR 74 TC 0 Z9 1 U1 9 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X EI 1873-2399 J9 EXP HEMATOL JI Exp. Hematol. PD SEP PY 2016 VL 44 IS 9 BP 783 EP 790 DI 10.1016/j.exphem.2016.04.013 PG 8 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA DU4LQ UT WOS:000382184500003 PM 27178734 ER PT J AU Chen, JC Kang, JG Keyvanfar, K Young, NS Hwang, PM AF Chen, Jichun Kang, Ju-Gyeong Keyvanfar, Keyvan Young, Neal S. Hwang, Paul M. TI Long-term adaptation to hypoxia preserves hematopoietic stem cell function SO EXPERIMENTAL HEMATOLOGY LA English DT Article ID CORONARY-HEART-DISEASE; BONE-MARROW; SUPPRESSED ERYTHROPOIESIS; COMMITTED PROGENITORS; HIGH-ALTITUDE; CFU KINETICS; DNA-DAMAGE; OXYGEN; MICE; MORTALITY AB Molecular oxygen sustains aerobic life, but it also serves as the substrate for oxidative stress, which has been associated with the pathogenesis of disease and with aging. Compared with mice housed in normoxia (21% O-2), reducing ambient oxygen to 10% O-2 (hypoxia) resulted in increased hematopoietic stem cell (HSC) function as measured by bone marrow (BM) cell engraftment onto lethally irradiated recipients. The number of BM c-Kit(+)Sca-1(+)Lin(-) (KSL) cells as well as the number of cells with other hematopoietic stem and progenitor cell markers were increased in hypoxia mice, whereas the BM cells' colony-forming capacity remained unchanged. KSL cells from hypoxia mice showed a decreased level of oxidative stress and increased expression of transcription factor Gatal and cytokine receptor c-Mpl, consistent with the observations of increased erythropoiesis and enhanced HSC engraftment. These observations demonstrate the benefit of a hypoxic HSC niche and suggest that hypoxic conditions can be further optimized to preserve stem cell integrity in vivo. Published by Elsevier Inc. on behalf of ISEH - International Society for Experimental Hematology. C1 [Chen, Jichun; Keyvanfar, Keyvan; Young, Neal S.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Kang, Ju-Gyeong; Hwang, Paul M.] NHLBI, Ctr Mol Med, NIH, NIH Bldg 10,CRC Room 5-5330, Bethesda, MD 20814 USA. RP Hwang, PM (reprint author), NHLBI, Ctr Mol Med, NIH, NIH Bldg 10,CRC Room 5-5330, Bethesda, MD 20814 USA.; Chen, JC (reprint author), NIH, Hematol Branch, NIH Bldg 10,10 Ctr Dr,Room 3E-5272, Bethesda, MD 20892 USA. EM chenji@nhlbi.nih.gov; hwangp@mail.nih.gov FU Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health FX We thank Ping-yuan Wang for constructive comments and advice. This work was supported by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health. NR 38 TC 1 Z9 1 U1 6 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X EI 1873-2399 J9 EXP HEMATOL JI Exp. Hematol. PD SEP PY 2016 VL 44 IS 9 BP 866 EP 873 DI 10.1016/j.exphem.2016.04.010 PG 8 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA DU4LQ UT WOS:000382184500013 PM 27118043 ER PT J AU Kim, S AF Kim, Sunghwan TI Getting the most out of PubChem for virtual screening SO EXPERT OPINION ON DRUG DISCOVERY LA English DT Review DE PubChem; cheminformatics; virtual screening; computer-aided drug discovery; computational toxicology; polypharmacology; biological assay; data mining; database; quantitative structure-activity relationship (QSAR) ID CHEMICAL UNIVERSE DATABASE; SUPPORT VECTOR MACHINES; OVER-SAMPLING TECHNIQUE; PROTEIN DATA-BANK; DRUG DISCOVERY; COMBINATORIAL CHEMISTRY; CLASSIFICATION MODELS; MOLECULAR DOCKING; BENCHMARKING SETS; KINASE INHIBITORS AB Introduction: With the emergence of the 'big data' era, the biomedical research community has great interest in exploiting publicly available chemical information for drug discovery. PubChem is an example of public databases that provide a large amount of chemical information free of charge. Areas covered: This article provides an overview of how PubChem's data, tools, and services can be used for virtual screening and reviews recent publications that discuss important aspects of exploiting PubChem for drug discovery. Expert opinion: PubChem offers comprehensive chemical information useful for drug discovery. It also provides multiple programmatic access routes, which are essential to build automated virtual screening pipelines that exploit PubChem data. In addition, PubChemRDF allows users to download PubChem data and load them into a local computing facility, facilitating data integration between PubChem and other resources. PubChem resources have been used in many studies for developing bioactivity and toxicity prediction models, discovering polypharmacologic (multi-target) ligands, and identifying new macromolecule targets of compounds (for drug-repurposing or off-target side effect prediction). These studies demonstrate the usefulness of PubChem as a key resource for computer-aided drug discovery and related area. C1 [Kim, Sunghwan] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Dept Hlth & Human Serv, Bethesda, MD 20894 USA. RP Kim, S (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Dept Hlth & Human Serv, Bethesda, MD 20894 USA. EM kimsungh@ncbi.nlm.nih.gov RI Kim, Sunghwan/A-6738-2008 OI Kim, Sunghwan/0000-0001-9828-2074 FU Intramural Research Program of the National Library of Medicine, NIH FX This work was supported by the Intramural Research Program of the National Library of Medicine, NIH. NR 118 TC 1 Z9 1 U1 18 U2 19 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1746-0441 EI 1746-045X J9 EXPERT OPIN DRUG DIS JI Expert. Opin. Drug Discov. PD SEP PY 2016 VL 11 IS 9 BP 843 EP 855 DI 10.1080/17460441.2016.1216967 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DU6RO UT WOS:000382342500004 PM 27454129 ER PT J AU Martins, KA Jahrling, PB Bavari, S Kuhn, JH AF Martins, Karen A. Jahrling, Peter B. Bavari, Sina Kuhn, Jens H. TI Ebola virus disease candidate vaccines under evaluation in clinical trials SO EXPERT REVIEW OF VACCINES LA English DT Review DE Candidate vaccine; clinical trial; Ebola virus; Ebola virus disease; ebolavirus; EBOV; EVD; Filoviridae; filovirus; MCM; medical countermeasure; vaccine ID VESICULAR-STOMATITIS-VIRUS; ADENOVIRUS-BASED VACCINE; T-CELL RESPONSES; PROTECTS NONHUMAN-PRIMATES; FILOVIRUS-LIKE PARTICLES; IMMUNE-RESPONSES; PREEXISTING IMMUNITY; MARBURG VIRUSES; DOUBLE-BLIND; NEUTRALIZING ANTIBODIES AB Filoviruses are the etiological agents of two human illnesses: Ebola virus disease and Marburg virus disease. Until 2013, medical countermeasure development against these afflictions was limited to only a few research institutes worldwide as both infections were considered exotic due to very low case numbers. Together with the high case-fatality rate of both diseases, evaluation of any candidate countermeasure in properly controlled clinical trials seemed impossible. However, in 2013, Ebola virus was identified as the etiological agent of a large disease outbreak in Western Africa including almost 30,000 infections and more than 11,000 deaths, including case exportations to Europe and North America. These large case numbers resulted in medical countermeasure development against Ebola virus disease becoming a global public-health priority. This review summarizes the status quo of candidate vaccines against Ebola virus disease, with a focus on those that are currently under evaluation in clinical trials. C1 [Martins, Karen A.; Bavari, Sina] US Army Med Res Inst Infect Dis, Frederick, MD USA. [Jahrling, Peter B.; Kuhn, Jens H.] NIAID, Integrated Res Facil Ft Detrick, Div Clin Res, NIH, Frederick, MD 21702 USA. RP Kuhn, JH (reprint author), NIAID, Integrated Res Facil Ft Detrick IRF Frederick, Div Clin Res, NIH, B-8200 Res Plaza, Frederick, MD 21702 USA. EM kuhnjens@mail.nih.gov FU NIAID [HHSN272200700016I] FX We thank Laura Bollinger (Integrated Research Facility at Fort Detrick) for providing Technical Writing Services in critically editing this manuscript on behalf of Battelle Memorial Institute through Battelle Memorial Institute's prime contract with NIAID under Contract No. HHSN272200700016I. NR 105 TC 6 Z9 6 U1 19 U2 25 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1476-0584 EI 1744-8395 J9 EXPERT REV VACCINES JI Expert Rev. Vaccines PD SEP PY 2016 VL 15 IS 9 SI SI BP 1101 EP 1112 DI 10.1080/14760584.2016.1187566 PG 12 WC Immunology SC Immunology GA DV2TX UT WOS:000382775700006 PM 27160784 ER PT J AU DeGrazia, D AF DeGrazia, David TI Ethical Reflections on Genetic Enhancement with the Aim of Enlarging Altruism SO HEALTH CARE ANALYSIS LA English DT Article DE Altruism; Enhancement; Genetic enhancement; Moral enhancement; Embryo selection; Addressing human need ID MORAL ENHANCEMENT; FREEDOM AB When it comes to caring about and helping those in need, our imaginations tend to be weak and our motivation tends to be parochial. This is a major moral problem in view of how much unmet need there is in the world and how much material capacity there is to address that need. With this problem in mind, the present paper will focus on genetic means to the enhancement of a moral capacity-a disposition to altruism-and of a cognitive capacity that facilitates use of the moral capacity: the ability to grasp vividly the needs of individuals who are unknown and not present. I will address two questions, with more extensive attention to the first question. First, assuming we had excellent reason to believe that the enhancements were safe, effective, and available to all who desired them, would seeking these enhancements be inherently morally acceptable-that is, free of inherent wrongness? Second, would it be wise for a society to pursue these enhancements? I will defend an affirmative answer to the first question while leaving the second question open. C1 [DeGrazia, David] NIH, Dept Bioeth, Bldg 10,Rm 1C118, Bethesda, MD 20892 USA. [DeGrazia, David] George Washington Univ, Dept Philosophy, Washington, DC 20052 USA. RP DeGrazia, D (reprint author), NIH, Dept Bioeth, Bldg 10,Rm 1C118, Bethesda, MD 20892 USA.; DeGrazia, D (reprint author), George Washington Univ, Dept Philosophy, Washington, DC 20052 USA. EM david.degrazia@nih.gov FU Wellcome Trust; Monash University; National Institutes of Health Clinical Center FX A draft of this paper was presented in Prato, Italy at a workshop, "Translational Bodies: Ethical, Legal, and Social Issues," sponsored by the Wellcome Trust and Monash University on 24 April 2014. I thank attendees for their helpful feedback. I also thank David Lawrence and three anonymous reviewers for further suggestions. This work was supported, in part, by intramural funds from the National Institutes of Health Clinical Center. The views expressed are the author's own. They do not represent the position of the NIH, the US Public Health Service, or the Department of Health and Human Services. NR 31 TC 1 Z9 1 U1 10 U2 10 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1065-3058 EI 1573-3394 J9 HEALTH CARE ANAL JI Health Care Anal. PD SEP PY 2016 VL 24 IS 3 BP 180 EP 195 DI 10.1007/s10728-015-0303-1 PG 16 WC Ethics; Health Policy & Services; Social Sciences, Biomedical SC Social Sciences - Other Topics; Health Care Sciences & Services; Biomedical Social Sciences GA DU1OG UT WOS:000381977100002 PM 26246070 ER PT J AU Sun, X Liu, AY Li, ZH AF Sun, Xian Liu, Aiyi Li, Zhaohai TI Maximizing an ROC-type measure via linear combinations of biomarkers SO HEALTH SERVICES AND OUTCOMES RESEARCH METHODOLOGY LA English DT Article DE Biomarkers; Diagnostic accuracy; Linear combinations ID IMPROVE DIAGNOSTIC-ACCURACY; GOLD STANDARD; MARKERS; TESTS AB The receiver operating characteristic curve is a popular tool to describe and compare the diagnostic accuracy of biomarkers when the binary-scale gold standard is available. There are, however, many examples of diagnostic tests whose gold standards are continuous. Hence, several extensions are proposed to evaluate the diagnostic potential of biomarkers when the gold standard is continuous-scale. In practice, there may exist more than one biomarkers and diagnostic accuracy can be improved by combining multiple biomarkers. In this paper, an explicit form of diagnostic accuracy index and the corresponding linear combination that maximizes the diagnostic accuracy are derived under elliptical distribution assumption. Simulations are conducted to evaluate the performance of the diagnostic accuracy and the optimal linear combination under different distribution assumptions. The methodology is applied to a behavioral intervention study for families of youth with type 1 diabetes. C1 [Sun, Xian; Li, Zhaohai] George Washington Univ, Dept Stat, Washington, DC 20052 USA. [Liu, Aiyi] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Bethesda, MD USA. RP Liu, AY (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Bethesda, MD USA. EM xiansun@gwu.edu; liua@mail.nih.gov; zli@gwu.edu OI Liu, Aiyi/0000-0002-6618-5082 NR 23 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1387-3741 EI 1572-9400 J9 HEALTH SERV OUTCOME JI Health Serv. Outcomes Res. Methodol. PD SEP PY 2016 VL 16 IS 3 SI SI BP 103 EP 116 DI 10.1007/s10742-016-0150-z PG 14 WC Health Care Sciences & Services SC Health Care Sciences & Services GA DT4DK UT WOS:000381430100003 ER PT J AU Xu, B Sandrini, M Wang, WT Smith, JF Sarlls, JE Awosika, O Butman, JA Horwitz, B Cohen, LG AF Xu, Benjamin Sandrini, Marco Wang, Wen-Tung Smith, Jason F. Sarlls, Joelle E. Awosika, Oluwole Butman, John A. Horwitz, Barry Cohen, Leonardo G. TI PreSMA stimulation changes task-free functional connectivity in the fronto-basal-ganglia that correlates with response inhibition efficiency SO HUMAN BRAIN MAPPING LA English DT Article DE concurrent; TMS; fMRI; task-free; stop-signal ID TRANSCRANIAL MAGNETIC STIMULATION; SUPPLEMENTARY MOTOR AREA; DEEP BRAIN-STIMULATION; STOP-SIGNAL INHIBITION; PARKINSONS-DISEASE; COGNITIVE CONTROL; DIFFUSION TENSOR; SUBCORTICAL INTERACTIONS; INDIVIDUAL-DIFFERENCES; NEUROIMAGING DATA AB Previous work using transcranial magnetic stimulation ( TMS) demonstrated that the right presupplementary motor area ( preSMA), a node in the fronto-basal-ganglia network, is critical for response inhibition. However, TMS influences interconnected regions, raising the possibility of a link between the preSMA activity and the functional connectivity within the network. To understand this relationship, we applied single-pulse TMS to the right preSMA during functional magnetic resonance imaging when the subjects were at rest to examine changes in neural activity and functional connectivity within the network in relation to the efficiency of response inhibition evaluated with a stop-signal task. The results showed that preSMA-TMS increased activation in the right inferior-frontal cortex ( rIFC) and basal ganglia and modulated their task-free functional connectivity. Both the TMS-induced changes in the basal-ganglia activation and the functional connectivity between rIFC and left striatum, and of the overall network correlated with the efficiency of response inhibition and with the whitematter microstructure along the preSMA-rIFC pathway. These results suggest that the task-free functional and structural connectivity between the rIFCop and basal ganglia are critical to the efficiency of response inhibition. (C) 2016 Wiley Periodicals, Inc. C1 [Xu, Benjamin; Sandrini, Marco; Awosika, Oluwole; Cohen, Leonardo G.] NINDS, Human Cort Physiol & Neurorehabil Sect, NIH, 7D51 Bldg 10 Ctr Dr, Bethesda, MD 20892 USA. [Xu, Benjamin; Sandrini, Marco; Wang, Wen-Tung; Butman, John A.] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. [Smith, Jason F.] Univ Maryland, Dept Psychol, College Pk, MD 20742 USA. [Butman, John A.] NIH, Radiol & Imaging Sci, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Sarlls, Joelle E.] NINDS, NIH MRI Res Facil, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Horwitz, Barry] Natl Inst Deafness & Other Commun Disorders, Sect Brain Imaging & Modeling, NIH, Bethesda, MD 20892 USA. RP Xu, B (reprint author), NINDS, Human Cort Physiol & Neurorehabil Sect, NIH, 7D51 Bldg 10 Ctr Dr, Bethesda, MD 20892 USA. EM benxu1@mail.nih.gov RI Sandrini, Marco/J-2276-2014 OI Sandrini, Marco/0000-0002-1664-5722 FU Department of Defense through the Center for Neuroscience and Regenerative Medicine [G189AN, G189BK]; National Institute of Neurological Disorders and Stroke; National Institute on Deafness and Other Communication Disorders, National Institutes of Health FX Contract grant sponsor: Department of Defense through the Center for Neuroscience and Regenerative Medicine; Contract grant numbers: G189AN and G189BK; Contract grant sponsor: Intramural Research Program of the National Institute of Neurological Disorders and Stroke; Contract grant sponsor: National Institute on Deafness and Other Communication Disorders, National Institutes of Health NR 80 TC 2 Z9 2 U1 5 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1065-9471 EI 1097-0193 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD SEP PY 2016 VL 37 IS 9 BP 3236 EP 3249 DI 10.1002/hbm.23236 PG 14 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DU8SL UT WOS:000382484600012 PM 27144466 ER PT J AU Xiao, WB Chen, WW Sorbara, L Davies-Hill, T Pittaluga, S Raffeld, M Jaffe, ES AF Xiao, Wenbin Chen, Wayne W. Sorbara, Lynn Davies-Hill, Theresa Pittaluga, Stefania Raffeld, Mark Jaffe, Elaine S. TI Hodgkin lymphoma variant of Richter transformation: morphology, Epstein-Barr virus status, clonality, and survival analysis-with comparison to Hodgkin-Like lesion SO HUMAN PATHOLOGY LA English DT Article DE Richter transformation; Chronic lymphocytic leukemia; Hodgkin lymphoma; Epstein-Ban virus; Clonality; ZAP-70; Reed-Sternberg cell ID CHRONIC-LYMPHOCYTIC-LEUKEMIA; B-CELL LYMPHOMA; STERNBERG CELLS; SOMATIC HYPERMUTATION; REED/STERNBERG-CELLS; ZAP-70 EXPRESSION; DISEASE; ORIGIN; CLL; FLUDARABINE AB Hodgkin/Reed-Sternberg (HRS) cells in the setting of chronic lymphocytic leukemia (CLL) exist in 2 forms: type I with isolated HRS cells in a CLL background (Hodgkin-like lesion) and type II with typical classic Hodgkin lymphoma, a variant of Richter transformation (CHL-RT). The clinical significance of the 2 morphological patterns is unclear, and their biological features have not been compared. We retrospectively reviewed 77 cases: 26 of type I and 51 of type II CHL-RT; 3 cases progressed from type I to type II. We examined clinical features, Epstein Barr virus (EBV) status, and clonal relatedness after microdissection. Median age for type I was 62 years versus 73 years for type II (P = .01); 27% (type I) versus 73% (type II) had a history of CLL. HRS cells were positive for EBV in 71% (55/77), similar in types I and II. Clonality analysis was performed in 33 cases (type I and type II combined): HRS cells were clonally related to the underlying CLL in 14 and unrelated in 19. ZAP-70 expression of the CLL cells but not EBV status or morphological pattern was correlated with clonal relatedness: all 14 clonally related cases were ZAP-70 negative, whereas 74% (14/19) of clonally unrelated cases were ZAP-70 positive. Overall median survival (types I and II) after diagnosis was 44 months. Advanced age was an adverse risk factor for survival, but not histologic pattern, type I versus type II. HRS-like cells in a background of CLL carries a similar clinical risk to that of CHL-RT and may progress to classic Hodgkin lymphoma in some cases. Published by Elsevier Inc. C1 [Xiao, Wenbin; Chen, Wayne W.; Davies-Hill, Theresa; Pittaluga, Stefania; Jaffe, Elaine S.] NCI, Hematopathol Sect, Pathol Lab, NIH, Bldg 10,Room 3S235,MSC 1500, Bethesda, MD 20892 USA. [Sorbara, Lynn; Raffeld, Mark] NCI, Mol Diagnost Unit, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Chen, Wayne W.] Neogen Labs, Irvine, CA USA. RP Jaffe, ES (reprint author), NCI, Hematopathol Sect, Pathol Lab, NIH, Bldg 10,Room 3S235,MSC 1500, Bethesda, MD 20892 USA. EM ejaffe@mail.nih.gov FU intramural research program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health; Lymphoma Disease Discovery and Definition [ZIA SC 000550] FX This study was supported by the intramural research program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. Intramural financial support is provided under the following project: ZIA SC 000550: Lymphoma Disease Discovery and Definition. NR 37 TC 4 Z9 4 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0046-8177 EI 1532-8392 J9 HUM PATHOL JI Hum. Pathol. PD SEP PY 2016 VL 55 BP 108 EP 116 DI 10.1016/j.humpath.2016.04.019 PG 9 WC Pathology SC Pathology GA DT5RW UT WOS:000381541300015 PM 27184478 ER PT J AU Kumar, NP Moideen, K Viswanathan, V Kornfeld, H Babu, S AF Kumar, Nathella P. Moideen, Kadar Viswanathan, Vijay Kornfeld, Hardy Babu, Subash TI Effect of standard tuberculosis treatment on naive, memory and regulatory T-cell homeostasis in tuberculosis-diabetes co-morbidity SO IMMUNOLOGY LA English DT Article DE bacterial; diabetes; T cells ID PULMONARY TUBERCULOSIS; INSULIN-RESISTANCE; MELLITUS; METABOLISM; COINCIDENT; CARE; CD4 AB Perturbations in CD4(+) and CD8(+) T-cell phenotype and function are hallmarks of tuberculosis-diabetes co-morbidity. However, their contribution to the pathogenesis of this co-morbidity and the effect of anti-tuberculosis treatment on the phenotype of the T-cell subsets is poorly understood. In this study, we examined the frequency of different T-cell subsets in individuals with pulmonary tuberculosis (PTB) with diabetes mellitus (DM) or without coincident diabetes mellitus (NDM) before, during and after completion of anti-tuberculosis chemotherapy. PTB-DM is characterized by heightened frequencies of central memory CD4(+) and CD8(+) T cells and diminished frequencies of naive, effector memory and/or effector CD4(+) and CD8(+) T cells at baseline and after 2months of treatment but not following treatment completion in comparison with PTB-NDM. Central memory CD4(+) and CD8(+) T-cell frequencies exhibited a positive correlation with fasting blood glucose and glycated haemoglobin A1c levels, whereas the frequencies of naive and effector memory or effector CD4(+) and CD8(+) T cells exhibited a negative correlation. However, the frequencies of CD4(+) and CD8(+) T-cell subsets in individuals with PTB exhibited no significant relationship with bacterial burdens. Finally, although minor alterations in the T-cell subset compartment were observed at 2months of treatment, significantly decreased frequencies of central memory and significantly enhanced frequencies of naive CD4(+) and CD8(+) T cells were observed at the completion of treatment. Our data reveal a profound effect of coexistent diabetes on the altered frequencies of central memory, effector memory and naive T cells and its normalization following therapy. C1 [Kumar, Nathella P.; Moideen, Kadar; Babu, Subash] NIRT, Natl Inst Hlth, Int Ctr Excellence Res, Madras, Tamil Nadu, India. [Viswanathan, Vijay] Prof M Viswanathan Diabet Res Ctr, Madras, Tamil Nadu, India. [Kornfeld, Hardy] Univ Massachusetts, Sch Med, Worcester, MA USA. [Babu, Subash] NIAID, Parasit Dis Lab, NIH, Bethesda, MD USA. RP Babu, S (reprint author), NIRT, Natl Inst Hlth, Int Ctr Excellence Res, Madras, Tamil Nadu, India. EM sbabu@mail.nih.gov FU Indian Department of Biotechnology; Indian Council of Medical Research; National Institute for Allergy and Infectious Diseases, National Institutes of Health; CRDF Global [USB1-31149-XX-13]; Division of Intramural Research, NIAID, NIH FX We thank the staff of Department of Clinical Research and the Department of Bacteriology, NIRT for valuable assistance in bacterial cultures and radiology and the staff of MVDRC for valuable assistance in recruiting the patients for this study; we are grateful to R. Anuradha, Prabha Chandran and Gokul Raj of the NIH-ICER for technical assistance. We would also like to thank Thomas Nutman of NIAID for his valuable guidance. This work was jointly sponsored by the Indian Department of Biotechnology; the Indian Council of Medical Research; and the National Institute for Allergy and Infectious Diseases, National Institutes of Health, and administered by CRDF Global (grant USB1-31149-XX-13). This work was also funded by the Division of Intramural Research, NIAID, NIH. NR 30 TC 1 Z9 1 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0019-2805 EI 1365-2567 J9 IMMUNOLOGY JI Immunology PD SEP PY 2016 VL 149 IS 1 BP 87 EP 97 DI 10.1111/imm.12632 PG 11 WC Immunology SC Immunology GA DV2UR UT WOS:000382778000008 PM 27289086 ER PT J AU Narasimhan, PB Bennuru, S Meng, ZJ Cotton, RN Elliott, KR Ganesan, S McDonald-Fleming, R Veenstra, TD Nutman, TB Semnani, RT AF Narasimhan, Prakash Babu Bennuru, Sasisekhar Meng, Zhaojing Cotton, Rachel N. Elliott, Kathleen R. Ganesan, Sundar McDonald-Fleming, Renee Veenstra, Timothy D. Nutman, Thomas B. Semnani, Roshanak Tolouei TI Microfilariae of Brugia malayi Inhibit the mTOR Pathway and Induce Autophagy in Human Dendritic Cells SO INFECTION AND IMMUNITY LA English DT Article ID MAMMALIAN-TARGET; MYCOBACTERIUM-TUBERCULOSIS; T-CELLS; RAPAMYCIN; DEATH; DIFFERENTIATION; INFECTION; INNATE; EXPRESSION; MATURATION AB Immune modulation is a hallmark of patent filarial infection, including suppression of antigen-presenting cell function and downmodulation of filarial antigen-specific T cell responses. The mammalian target of rapamycin (mTOR) signaling pathway has been implicated in immune regulation, not only by suppressing T cell responses but also by regulating autophagy (through mTOR sensing amino acid availability). Global proteomic analysis (liquid chromatography-tandem mass spectrometry) of microfilaria (mf)-exposed monocyte-derived dendritic cells (DC) indicated that multiple components of the mTOR signaling pathway, including mTOR, eIF4A, and eIF4E, are downregulated by mf, suggesting that mf target this pathway for immune modulation in DC. Utilizing Western blot analysis, we demonstrate that similar to rapamycin (a known mTOR inhibitor), mf downregulate the phosphorylation of mTOR and its regulatory proteins, p70S6K1 and 4E-BP1, a process essential for DC protein synthesis. As active mTOR signaling regulates autophagy, we examined whether mf exposure alters autophagy-associated processes. mf-induced autophagy was reflected in marked upregulation of phosphorylated Beclin 1, known to play an important role in both autophagosome formation and autolysosome fusion, in induction of LC3II, a marker of autophagosome formation, and in induced degradation of p62, a ubiquitin-binding protein that aggregates protein in autophagosomes and is degraded upon autophagy that was reduced significantly by mf exposure and by rapamycin. Together, these results suggest that Brugia malayi mf employ mechanisms of metabolic modulation in DC to influence the regulation of the host immune response by downregulating mTOR signaling, resulting in increased autophagy. Whether this is a result of the parasite-secreted rapamycin homolog is currently under study. C1 [Narasimhan, Prakash Babu; Bennuru, Sasisekhar; Cotton, Rachel N.; Elliott, Kathleen R.; McDonald-Fleming, Renee; Nutman, Thomas B.; Semnani, Roshanak Tolouei] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20817 USA. [Meng, Zhaojing; Veenstra, Timothy D.] Frederick Natl Lab, Canc Res Technol Program, Frederick Natl Lab Canc Res, Leidos Biomed Res Inc, Frederick, MD USA. [Ganesan, Sundar] NIAID, Biol Imaging Sect, Res Technol Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Cotton, Rachel N.] Harvard Med Sch, Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Boston, MA USA. [McDonald-Fleming, Renee] SUNY Downstate Coll Med, Brooklyn, NY USA. [Veenstra, Timothy D.] Maranatha Baptist Univ, Dept Appl Sci, Watertown, WI USA. RP Semnani, RT (reprint author), NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20817 USA. EM rsemnani@niaid.nih.gov FU Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 59 TC 0 Z9 0 U1 4 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD SEP PY 2016 VL 84 IS 9 BP 2463 EP 2472 DI 10.1128/IAI.00174-16 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DU6JH UT WOS:000382320300007 PM 27297394 ER PT J AU Weber, MM Faris, R van Schaik, EJ McLachlan, JT Wright, WU Tellez, A Roman, VA Rowin, K Case, ED Luo, ZQ Samuel, JE AF Weber, Mary M. Faris, Robert van Schaik, Erin J. McLachlan, Juanita Thrasher Wright, William U. Tellez, Andres Roman, Victor A. Rowin, Kristina Case, Elizabeth Di Russo Luo, Zhao-Qing Samuel, James E. TI The Type IV Secretion System Effector Protein CirA Stimulates the GTPase Activity of RhoA and Is Required for Virulence in a Mouse Model of Coxiella burnetii Infection SO INFECTION AND IMMUNITY LA English DT Article ID NUCLEOTIDE-EXCHANGE FACTOR; LEGIONELLA-PNEUMOPHILA; HOST-CELL; INTRACELLULAR REPLICATION; SALMONELLA-TYPHIMURIUM; VACUOLE FORMATION; IDENTIFICATION; TOXIN; ACTIN; TRAFFICKING AB Coxiella burnetii, the etiological agent of Q fever in humans, is an intracellular pathogen that replicates in an acidified parasitophorous vacuole derived from host lysosomes. Generation of this replicative compartment requires effectors delivered into the host cell by the Dot/Icm type IVb secretion system. Several effectors crucial for C. burnetii intracellular replication have been identified, but the host pathways coopted by these essential effectors are poorly defined, and very little is known about how spacious vacuoles are formed and maintained. Here we demonstrate that the essential type IVb effector, CirA, stimulates GTPase activity of RhoA. Overexpression of CirA in mammalian cells results in cell rounding and stress fiber disruption, a phenotype that is rescued by overexpression of wild-type or constitutively active RhoA. Unlike other effector proteins that subvert Rho GTPases to modulate uptake, CirA is the first effector identified that is dispensable for uptake and instead recruits Rho GTPase to promote biogenesis of the bacterial vacuole. Collectively our results highlight the importance of CirA in coopting host Rho GTPases for establishment of Coxiella burnetii infection and virulence in mammalian cell culture and mouse models of infection. C1 [Weber, Mary M.; Faris, Robert; van Schaik, Erin J.; McLachlan, Juanita Thrasher; Wright, William U.; Tellez, Andres; Rowin, Kristina; Case, Elizabeth Di Russo; Samuel, James E.] Texas A&M Hlth Sci Ctr, Dept Microbial Pathogenesis & Immunol, Coll Med, Bryan, TX 78665 USA. [Roman, Victor A.; Luo, Zhao-Qing] Purdue Univ, Dept Biol Sci, W Lafayette, IN 47907 USA. [Weber, Mary M.] NIAID, Bacteriol Lab, NIH, Rocky Mt Labs, Hamilton, MT USA. [Faris, Robert] NIAID, Persistent Viral Dis Lab, NIH, Rocky Mt Labs, Hamilton, MT USA. RP Samuel, JE (reprint author), Texas A&M Hlth Sci Ctr, Dept Microbial Pathogenesis & Immunol, Coll Med, Bryan, TX 78665 USA. EM jsamuel@medicine.tamhsc.edu OI Faris, Robert/0000-0003-0855-7041; Case, Elizabeth/0000-0002-9129-3894 FU HHS \ NIH \ National Institute of Allergy and Infectious Diseases (NIAID) [K02AI085403, AI090142, AI088430]; DOD \ Defense Threat Reduction Agency [HDTRA1-13-1-0003] FX This work, including the efforts of Zhao-Qing Luo, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (K02AI085403). This work, including the efforts of James E. Samuel, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (AI090142). This work, including the efforts of James E. Samuel, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (AI088430). This work, including the efforts of James E. Samuel, was funded by DOD vertical bar Defense Threat Reduction Agency (HDTRA1-13-1-0003). NR 59 TC 1 Z9 1 U1 4 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD SEP PY 2016 VL 84 IS 9 BP 2524 EP 2533 DI 10.1128/IAI.01554-15 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DU6JH UT WOS:000382320300012 PM 27324482 ER PT J AU Butler, J Hernandez, AF Anstrom, KJ Kalogeropoulos, A Redfield, MM Konstam, MA Tang, WHW Felker, GM Shah, MR Braunwald, E AF Butler, Javed Hernandez, Adrian F. Anstrom, Kevin J. Kalogeropoulos, Andreas Redfield, Margaret M. Konstam, Marvin A. Tang, W. H. Wilson Felker, G. Michael Shah, Monica R. Braunwald, Eugene TI Rationale and Design of the ATHENA-HF Trial Aldosterone Targeted Neurohormonal Combined With Natriuresis Therapy in Heart Failure SO JACC-HEART FAILURE LA English DT Review DE acute heart failure; aldosterone; heart failure; hospitalization; mineralocorticoid receptor antagonist; natriuretic peptides ID SODIUM RETENTION; CLINICAL-COURSE; EVEREST TRIAL; ESCAPE TRIAL; HOSPITALIZATION; ANTAGONIST; ASSOCIATION; OUTCOMES; DISEASE; CONGESTION AB Although therapy with mineralocorticoid receptor antagonists (MBAs) is recommended for patients with chronic heart failure (HF) with reduced ejection fraction and in post-infarction HF, it has not been studied well in acute HF (AHF) despite being commonly used in this setting. At high doses, MRA therapy in AHF may relieve congestion through its natriuretic properties and mitigate the effects of adverse neurohormonal activation associated with intravenous loop diuretics. The ATHENA-HF (Aldosterone Targeted Neurohormonal. Combined with Natriuresis Therapy in Heart Failure) trial is a randomized, double-blind, placebo-controlled study of the safety and efficacy of 100 mg/day spironolactone versus placebo (or continued low-dose spironolactone use in participants who are already receiving spironolactone at baseline) in 360 patients hospitalized for AHF. Patients are randomized within 24 h of receiving the first dose of intravenous diuretics. The primary objective is to determine if high-dose spironolactone, compared with standard care, will lead to greater reductions in N-terminal pro B-type natriuretic peptide levels from randomization to 96 h. The secondary endpoints include changes in the clinical congestion score, dyspnea relief, urine output, weight change, loop diuretic dose, and in-hospital worsening HF. Index hospital length of stay and 30-day clinical outcomes will be assessed. Safety endpoints include risk of hyperkalemia and renal function. Differences among patients with reduced versus preserved ejection fraction will be determined. (Study of High-dose Spironolactone vs. Placebo Therapy in Acute Heart Failure [ATHENA-HF]; NCT02235077) (C) 2016 by the American College of Cardiology Foundation. C1 [Butler, Javed] SUNY Stony Brook, Dept Med, Stony Brook, NY USA. [Hernandez, Adrian F.; Anstrom, Kevin J.; Felker, G. Michael] Duke Univ, Dept Med, Durham, NC USA. [Kalogeropoulos, Andreas] Emory Univ, Dept Med, Atlanta, GA 30322 USA. [Redfield, Margaret M.] Mayo Clin, Dept Cardiovasc Dis, Rochester, MI USA. [Konstam, Marvin A.] Tufts Univ, Dept Med, Boston, MA 02111 USA. [Tang, W. H. Wilson] Cleveland Clin, Dept Cardiovasc Med, Cleveland, OH 44106 USA. [Shah, Monica R.] NHLBI, Div Cardiovasc Sci, Baltimore, MD USA. [Braunwald, Eugene] Brigham & Womens Hosp, Dept Med, Harvard Med Sch, Boston, MA 02115 USA. RP Butler, J (reprint author), SUNY Stony Brook, Div Cardiol, Hlth Sci Ctr, T-16,Room 080, Stony Brook, NY 11794 USA. EM javed.butler@stonybrookmedicine.edu NR 42 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2213-1779 EI 2213-1787 J9 JACC-HEART FAIL JI JACC-Heart Fail. PD SEP PY 2016 VL 4 IS 9 BP 726 EP 735 DI 10.1016/j.jchf.2016.06.003 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DV4OV UT WOS:000382905800006 PM 27522631 ER PT J AU Jasniewski, AJ Engstrom, LM Vu, VV Park, MH Que, L AF Jasniewski, Andrew J. Engstrom, Lisa M. Vu, Van V. Park, Myung Hee Que, Lawrence, Jr. TI X-ray absorption spectroscopic characterization of the diferric-peroxo intermediate of human deoxyhypusine hydroxylase in the presence of its substrate eIF5a SO JOURNAL OF BIOLOGICAL INORGANIC CHEMISTRY LA English DT Article DE Nonheme diiron enzymes; Oxygen activation; Peroxo intermediates; Deoxyhypusine hydroxylase; Cell death ID METHANE MONOOXYGENASE HYDROXYLASE; COLI RIBONUCLEOTIDE REDUCTASE; METHYLOCOCCUS-CAPSULATUS BATH; METHYLOSINUS-TRICHOSPORIUM OB3B; TOLUENE/O-XYLENE MONOOXYGENASE; CARRIER PROTEIN DESATURASE; IRON-CARBOXYLATE PROTEINS; NONHEME DIIRON PROTEINS; ACTIVE-SITE STRUCTURE; FE-FE SEPARATION AB Human deoxyhypusine hydroxylase (hDOHH) is an enzyme that is involved in the critical post-translational modification of the eukaryotic translation initiation factor 5A (eIF5A). Following the conversion of a lysine residue on eIF5A to deoxyhypusine (Dhp) by deoxyhypusine synthase, hDOHH hydroxylates Dhp to yield the unusual amino acid residue hypusine (Hpu), a modification that is essential for eIF5A to promote peptide synthesis at the ribosome, among other functions. Purification of hDOHH overexpressed in E. coli affords enzyme that is blue in color, a feature that has been associated with the presence of a peroxo-bridged diiron(III) active site. To gain further insight into the nature of the diiron site and how it may change as hDOHH goes through the catalytic cycle, we have conducted X-ray absorption spectroscopic studies of hDOHH on five samples that represent different species along its reaction pathway. Structural analysis of each species has been carried out, starting with the reduced diferrous state, proceeding through its O-2 adduct, and ending with a diferric decay product. Our results show that the Feai-Fe distances found for the five samples fall within a narrow range of 3.4-3.5 , suggesting that hDOHH has a fairly constrained active site. This pattern differs significantly from what has been associated with canonical dioxygen activating nonheme diiron enzymes, such as soluble methane monooxygenase and Class 1A ribonucleotide reductases, for which the Feai-Fe distance can change by as much as 1 during the redox cycle. These results suggest that the O-2 activation mechanism for hDOHH deviates somewhat from that associated with the canonical nonheme diiron enzymes, opening the door to new mechanistic possibilities for this intriguing family of enzymes. C1 [Jasniewski, Andrew J.; Engstrom, Lisa M.; Vu, Van V.; Que, Lawrence, Jr.] Univ Minnesota, Dept Chem, 207 Pleasant St SE, Minneapolis, MN 55455 USA. [Jasniewski, Andrew J.; Engstrom, Lisa M.; Vu, Van V.; Que, Lawrence, Jr.] Univ Minnesota, Ctr Met Biocatalysis, 207 Pleasant St SE, Minneapolis, MN 55455 USA. [Vu, Van V.] Natl Inst Dent & Craniofacial Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Vu, Van V.] Nguyen Tat Thanh Univ, NTT Hitech Inst, 298-300A Nguyen Tat Thanh St,Ward 13,Dist 4, Ho Chi Minh City, Vietnam. RP Que, L (reprint author), Univ Minnesota, Dept Chem, 207 Pleasant St SE, Minneapolis, MN 55455 USA.; Que, L (reprint author), Univ Minnesota, Ctr Met Biocatalysis, 207 Pleasant St SE, Minneapolis, MN 55455 USA. EM larryque@umn.edu FU National Institutes of Health [GM-38767, 5F32GM106612-02]; Intramural Research Program of the National Institute of Dental and Craniofacial Research; Vietnam Education Foundation; US Department of Energy (DOE), Office of Science, Office of Basic Energy Sciences [DE-AC02-76SF00515]; DOE Office of Biological and Environmental Research; National Institutes of Health, National Institute of General Medical Sciences [P41GM103393]; DOE Office of Science by Brookhaven National Laboratory [DE-AC02-98CH10886] FX This work was supported by the National Institutes of Health grant GM-38767 to L. Q. and postdoctoral fellowship 5F32GM106612-02 to L. M. E. and by the Intramural Research Program of the National Institute of Dental and Craniofacial Research. V. V. V. is grateful to the Vietnam Education Foundation for providing him with a predoctoral fellowship. XAS data were collected on Beamline 7-3 at the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory and at Beamline X3B of the National Synchrotron Light Source (NSLS). SLAC is supported by the US Department of Energy (DOE), Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515. Use of Beamline 7-3 is supported by the DOE Office of Biological and Environmental Research, and by the National Institutes of Health, National Institute of General Medical Sciences (including P41GM103393). NSLS is a DOE Office of Science User Facility operated for the DOE Office of Science by Brookhaven National Laboratory under Contract No. DE-AC02-98CH10886. We thank Dr. Caleb Allpress for helpful discussions. NR 127 TC 3 Z9 3 U1 9 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0949-8257 EI 1432-1327 J9 J BIOL INORG CHEM JI J. Biol. Inorg. Chem. PD SEP PY 2016 VL 21 IS 5-6 BP 605 EP 618 DI 10.1007/s00775-016-1373-8 PG 14 WC Biochemistry & Molecular Biology; Chemistry, Inorganic & Nuclear SC Biochemistry & Molecular Biology; Chemistry GA DU3QL UT WOS:000382127000004 PM 27380180 ER PT J AU Hershman, DL Till, C Wright, JD Awad, D Ramsey, SD Barlow, WE Minasian, LM Unger, J AF Hershman, Dawn L. Till, Cathee Wright, Jason D. Awad, Danielle Ramsey, Scott D. Barlow, William E. Minasian, Lori M. Unger, Joseph TI Comorbidities and Risk of Chemotherapy-Induced Peripheral Neuropathy Among Participants 65 Years or Older in Southwest Oncology Group Clinical Trials SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID BREAST-CANCER; DIABETES-MELLITUS; MONOCLONAL GAMMOPATHY; PACLITAXEL; TOXICITY; PREDICTORS; PREVENTION; THERAPY AB Background Neuropathy is a debilitating toxicity associated with various chemotherapy agents. We evaluated the association between common comorbid conditions and the development of peripheral neuropathy in patients treated with taxane-based chemotherapy. Methods We examined the Southwest Oncology Group database to identify phase II and III trials that included taxane therapy from 1999 to 2011. We linked the Southwest Oncology Group clinical records to Medicare claims data according to Social Security number, sex, and date of birth. The following disease conditions potentially associated with peripheral neuropathy were evaluated: diabetes, hypothyroidism, hypercholesterolemia, hypertension, varicella zoster, peripheral vascular disease, and autoimmune diseases. Multivariate logistic regression was used to model the odds of experiencing grade 2 to 4 neuropathy. Results A total of 1,401 patients from 23 studies were included in the analysis. Patients receiving paclitaxel were more likely to experience grade 2 to 4 neuropathy compared with docetaxel (25% v 12%, respectively; OR, 2.20; 95% CI, 1.52 to 3.18; P < .001). The inclusion of a platinum agent was also associated with greater neuropathy (OR, 1.68; 95% CI, 1.18 to 2.40; P = .004). For each increase in age of 1 year, the odds of neuropathy increased 4% (P = .006). Patients with complications from diabetes had more than twice the odds of having neuropathy (OR, 2.13; 95% CI, 1.31 to 3.46; P = .002) compared with patientswith no diabetes. In contrast, patientswith autoimmune disease were half as likely to experience neuropathy (OR, 0.49; 95% CI, 0.24 to 1.02; P = .06). The other conditions were not associated with neuropathy. Conclusion We found that in addition to drug-related factors, age and history of diabetes were independent predictors of the development of chemotherapy-induced peripheral neuropathy. Interestingly, we also observed that a history of autoimmune disease was associated with reduced odds of neuropathy. Patients with diabetic complications may choose to avoid paclitaxel or taxane plus platinum combination therapies if other efficacious options exist. (C) 2016 by American Society of Clinical Oncology C1 [Hershman, Dawn L.; Wright, Jason D.; Awad, Danielle] Columbia Univ, Med Ctr, 161 Ft Washington Ave,10-1068, New York, NY 10032 USA. [Till, Cathee; Ramsey, Scott D.; Unger, Joseph] Fred Hutchinson Canc Res Ctr, Seattle, WA USA. [Barlow, William E.] Univ Washington, Seattle, WA 98195 USA. [Minasian, Lori M.] NCI, Bethesda, MD 20892 USA. RP Hershman, DL (reprint author), Columbia Univ, Med Ctr, 161 Ft Washington Ave,10-1068, New York, NY 10032 USA. EM dlh23@columbia.edu FU National Cancer Institute Community Oncology Research Program Research Base [1UG1CA189974-01]; American Society of Clinical Oncology; Breast Cancer Research Foundation; National Cancer Institute, Division of Cancer Prevention [NCI R01CA134964, NCI R01CA169121-01A1] FX D.L.H. (NCI R01CA134964) and J.D.W. (NCI R01CA169121-01A1) are recipients of grants from the National Cancer Institute, Division of Cancer Prevention, National Cancer Institute Community Oncology Research Program Research Base Grant No. 1UG1CA189974-01. D.L.H. is the recipient of a grant from the American Society of Clinical Oncology and the Breast Cancer Research Foundation. NR 26 TC 2 Z9 2 U1 4 U2 4 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 1 PY 2016 VL 34 IS 25 BP 3014 EP + DI 10.1200/JCO.2015.66.2346 PG 13 WC Oncology SC Oncology GA DU8NJ UT WOS:000382470100012 PM 27325863 ER PT J AU Lagmay, JP Krailo, MD Dang, H Kim, A Hawkins, DS Beaty, O Widemann, BC Zwerdling, T Bomgaars, L Langevin, AM Grier, HE Weigel, B Blaney, SM Gorlick, R Janeway, KA AF Lagmay, Joanne P. Krailo, Mark D. Dang, Ha Kim, AeRang Hawkins, Douglas S. Beaty, Orren, III Widemann, Brigitte C. Zwerdling, Theodore Bomgaars, Lisa Langevin, Anne-Marie Grier, Holcombe E. Weigel, Brenda Blaney, Susan M. Gorlick, Richard Janeway, Katherine A. TI Outcome of Patients With Recurrent Osteosarcoma Enrolled in Seven Phase II Trials Through Children's Cancer Group, Pediatric Oncology Group, and Children's Oncology Group: Learning From the Past to Move Forward SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID REFRACTORY SOLID TUMORS; RESPONSE EVALUATION CRITERIA; FREE SURVIVAL; MURAMYL TRIPEPTIDE; OSTEOGENIC-SARCOMA; PROGNOSTIC-FACTORS; PROGRESSION-FREE; RECIST CRITERIA; CLINICAL-TRIALS; CHEMOTHERAPY AB Purpose The use of radiographic response as the primary end point in phase II osteosarcoma trials may limit optimal detection of treatment response because of the calcified tumor matrix. We performed this study to determine if time to progression could be used as an end point for subsequent studies. Patients and Methods We performed a retrospective analysis of outcome for patients with recurrent/refractory osteosarcoma enrolled in one of seven phase II trials conducted by the Children's Oncology Group and predecessor groups from 1997 to 2007. All trials used RECIST or WHO radiographic response criteria and the primary end point of response rate. The following potential prognostic factors-age, trial, number of prior chemotherapy regimens, sex, and race/ethnicity-were evaluated for their impact on event-free survival (EFS). We used data from a phase II study (AOST0221) of patients with osteosarcoma who were given inhaled granulocyte-macrophage colony-stimulating factor with first pulmonary recurrence who had an EFS as well as biologic end point to determine the historical disease control rate for patients with fully resected disease. Results In each included trial, the drugs tested were determined to be inactive on the basis of radiographic response rates. The EFS for 96 patients with osteosarcoma and measurable disease was 12% at 4 months (95% CI, 6% to 19%). There was no significant difference in EFS across trials according to number of prior treatment regimens or patient age, sex, and ethnicity. The 12-month EFS for the 42 evaluable patients enrolled in AOST0221 was 20% (95% CI, 10% to 34%). Conclusion The EFS was uniformly poor for children with recurrent/refractory osteosarcoma in these single-arm phase II trials. We have now constructed baseline EFS outcomes that can be used as a comparison for future phase II trials for recurrent osteosarcoma. (C) 2016 by American Society of Clinical Oncology C1 [Lagmay, Joanne P.] Univ Florida, Shands Hosp Children, Gainesville, FL USA. [Krailo, Mark D.; Dang, Ha] Univ Southern Calif, Los Angeles, CA USA. [Krailo, Mark D.; Dang, Ha] Childrens Oncol Grp, Monrovia, CA USA. [Zwerdling, Theodore] Miller Childrens & Womens Hosp, Jonathan Jaques Childrens Canc Ctr, Long Beach, CA USA. [Kim, AeRang] Childrens Natl Med Ctr, Ctr Canc & Blood Disorders, Washington, DC 20010 USA. [Hawkins, Douglas S.] Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle Childrens Hosp, Seattle, WA 98195 USA. [Beaty, Orren, III] Mission Hosp, Zeiss Childrens Canc Ctr, Asheville, NC USA. [Widemann, Brigitte C.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Bomgaars, Lisa; Blaney, Susan M.] Baylor Coll Med, Texas Childrens Canc Ctr, Houston, TX 77030 USA. [Langevin, Anne-Marie] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Grier, Holcombe E.; Janeway, Katherine A.] Boston Childrens Canc & Blood Disorders Ctr, Dana Farber Canc Inst, Boston, MA USA. [Weigel, Brenda] Univ Minnesota, Minneapolis, MN USA. [Gorlick, Richard] Yeshiva Univ, Albert Einstein Coll Med, Childrens Hosp Montefiore, New York, NY 10033 USA. RP Lagmay, JP (reprint author), Univ Florida, Shands Hosp Children, Div Pediat Hematol Oncol, 1600 SW Archer Rd,HD 204, Gainesville, FL 32610 USA. EM jplagmay@peds.ufl.edu FU National Clinical Trials Network (NCTN) Operations Center, from the National Cancer Institute [U10CA180886]; NCTN Statistics and Data Center, from the National Cancer Institute [U10CA180899, U10CA98543, U10CA98413]; QuadW Foundation FX Supported by National Clinical Trials Network (NCTN) Operations Center Grant No. U10CA180886, NCTN Statistics and Data Center Grant No. U10CA180899, Chair Grant No. U10CA98543, and Statistics and Data Center Grant No. U10CA98413, all from the National Cancer Institute. Additional research support was provided by a grant from the QuadW Foundation to the Children's Oncology Group. NR 32 TC 2 Z9 2 U1 2 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 1 PY 2016 VL 34 IS 25 BP 3031 EP + DI 10.1200/JCO.2015.65.5381 PG 9 WC Oncology SC Oncology GA DU8NJ UT WOS:000382470100014 PM 27400942 ER PT J AU Shiovitz, TM Bain, EE McCann, DJ Skolnick, P Laughren, T Hanina, A Burch, D AF Shiovitz, Thomas M. Bain, Earle E. McCann, David J. Skolnick, Phil Laughren, Thomas Hanina, Adam Burch, Daniel TI Mitigating the Effects of Nonadherence in Clinical Trials SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE nonadherence; professional subjects; duplicate subjects; adherence; clinical trials ID PLACEBO RUN-IN; METHAMPHETAMINE DEPENDENCE; PROFESSIONAL SUBJECTS; MEDICATION ADHERENCE; HEALTHY-VOLUNTEERS; PATIENT ADHERENCE; DOSING HISTORIES; RESPONDERS; EFFICACY; PILL AB Accounting for subject nonadherence and eliminating inappropriate subjects in clinical trials are critical elements of a successful study. Nonadherence can increase variance, lower study power, and reduce the magnitude of treatment effects. Inappropriate subjects (including those who do not have the illness under study, fail to report exclusionary conditions, falsely report medication adherence, or participate in concurrent trials) confound safety and efficacy signals. This paper, a product of the International Society for CNS Clinical Trial Methodology (ISCTM) Working Group on Nonadherence in Clinical Trials, explores and models nonadherence in clinical trials and puts forth specific recommendations to identify and mitigate its negative effects. These include statistical analyses of nonadherence data, novel protocol design, and the use of biomarkers, subject registries, and/or medication adherence technologies. C1 [Shiovitz, Thomas M.] Calif Neurosci Res Med Grp, Sherman Oaks, CA USA. [Shiovitz, Thomas M.] CTSdatabase LLC, Beverly Hills, CA USA. [Bain, Earle E.] AbbVie Inc, Global Pharmaceut Res & Dev, N Chicago, IL USA. [McCann, David J.; Skolnick, Phil] NIDA, Div Therapeut & Med Consequences, NIH, Bethesda, MD 20892 USA. [Laughren, Thomas] Massachusetts Gen Hosp Clin Trial Network & Inst, Regulatory Affairs, Boston, MA USA. [Hanina, Adam] AiCure, New York, NY USA. [Burch, Daniel] Pharmaceut Prod Dev LLC, Wilmington, NC USA. RP Shiovitz, TM (reprint author), 4835 Van Nuys Blvd, Sherman Oaks, CA 91403 USA. EM thomas@shiovitz.com NR 54 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0091-2700 EI 1552-4604 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD SEP PY 2016 VL 56 IS 9 BP 1151 EP 1164 DI 10.1002/jcph.689 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DV2JO UT WOS:000382746900013 PM 26634893 ER PT J AU Frawley, RP Smith, MJ White, KL Elmore, SA Herbert, R Moore, R Staska, LM Behl, M Hooth, MJ Kissling, GE Germolec, DR AF Frawley, Rachel P. Smith, Matthew J. White, Kimber L., Jr. Elmore, Susan A. Herbert, Ron Moore, Rebecca Staska, Lauren M. Behl, Mamta Hooth, Michelle J. Kissling, Grace E. Germolec, Dori R. TI Immunotoxic effects of sodium tungstate dihydrate on female B6C3F1/N mice when administered in drinking water SO JOURNAL OF IMMUNOTOXICOLOGY LA English DT Article DE Cell-mediated immunity; cytotoxic T-lymphocyte; sodium tungstate dihydrate ID MURINE BONE-MARROW; ENHANCED HISTOPATHOLOGY; IMMUNE-RESPONSES; DNA-DAMAGE; EXPOSURE; CELLS; MODULATION; APOPTOSIS; LYMPHOCYTES; EXPRESSION AB Tungsten is a naturally occurring, high-tensile strength element that has been used in a number of consumer products. Tungsten has been detected in soil, waterways, groundwater, and human tissue and body fluids. Elevated levels of tungsten in urine were reported for populations exposed to tungstate in drinking water in areas where natural tungsten formations were prevalent. Published reports indicated that sodium tungstate may modulate hematopoiesis, immune cell populations, and immune responses in rodent models. The objective of this study was to assess potential immunotoxicity of sodium tungstate dihydrate (STD), a drinking water contaminant. Female B6C3F1/N mice received 0-2000mg STD/L in their drinking water for 28 d, and were evaluated for effects on immune cell populations in spleen and bone marrow, and humoral-mediated, cell-mediated, and innate immunity. Three different parameters of cell-mediated immunity were similarly affected at 1000mg STD/L. T-cell proliferative responses against allogeneic leukocytes and anti-CD3 were decreased 32%, and 21%, respectively. Cytotoxic T-lymphocyte activity was decreased at all effector:target cell ratios examined. At 2000mg STD/L, the absolute numbers of CD3(+) T-cell progenitor cells in bone marrow were increased 86%, but the alterations in B-lymphocyte and other progenitor cells were not significant. There were no effects on bone marrow DNA synthesis or colony forming capabilities. STD-induced effects on humoral-mediated immunity, innate immunity, and splenocyte sub-populations were limited. Enhanced histopathology did not detect treatment-related lesions in any of the immune tissues. These data suggest exposure to STD in drinking water may adversely affect cell-mediated immunity. C1 [Frawley, Rachel P.; Elmore, Susan A.; Herbert, Ron; Behl, Mamta; Hooth, Michelle J.; Germolec, Dori R.] NIEHS, Div Natl Toxicol Program, 111 TW Alexander Dr,MD K2-15, Res Triangle Pk, NC 27709 USA. [Smith, Matthew J.; White, Kimber L., Jr.] Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, Richmond, VA USA. [Moore, Rebecca] Expt Pathol Labs Inc, Res Triangle Pk, NC USA. [Staska, Lauren M.] WIL Res, Hillsborough, NC USA. [Kissling, Grace E.] NIEHS, Div Intramural Res, POB 12233, Res Triangle Pk, NC 27709 USA. RP Frawley, RP (reprint author), NIEHS, Div Natl Toxicol Program, 111 TW Alexander Dr,MD K2-15, Res Triangle Pk, NC 27709 USA. EM frawleyr@niehs.nih.gov FU NIH, National Institute of Environmental Health Sciences, NTP [N01-ES-55538, N01-ES-05456] FX This research was supported by the NIH, National Institute of Environmental Health Sciences, NTP Contract N01-ES-55538, and the NTP Chemistry Support Services Contract N01-ES-05456. NR 52 TC 0 Z9 0 U1 4 U2 4 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1547-691X EI 1547-6901 J9 J IMMUNOTOXICOL JI J. Immunotoxicol. PD SEP PY 2016 VL 13 IS 5 BP 666 EP 675 DI 10.3109/1547691X.2016.1154118 PG 10 WC Toxicology SC Toxicology GA DU9NF UT WOS:000382543800006 PM 27223060 ER PT J AU Yucesoy, B Talzhanov, Y Barmada, MM Johnson, VJ Kashon, ML Baron, E Wilson, NW Frye, B Wang, W Fluharty, K Gharib, R Meade, J Germolec, D Luster, MI Nedorost, S AF Yucesoy, Berran Talzhanov, Yerkebulan Barmada, M. Michael Johnson, Victor J. Kashon, Michael L. Baron, Elma Wilson, Nevin W. Frye, Bonnie Wang, Wei Fluharty, Kara Gharib, Rola Meade, Jean Germolec, Dori Luster, Michael I. Nedorost, Susan TI Association of MHC region SNPs with irritant susceptibility in healthcare workers SO JOURNAL OF IMMUNOTOXICOLOGY LA English DT Article DE Genetics; healthcare workers; irritant contact dermatitis; MHC ID TRIM FAMILY PROTEINS; PATCH TEST REACTIONS; CONTACT-DERMATITIS; HAND ECZEMA; BENZALKONIUM CHLORIDE; PREVALENCE; GENE; POPULATION; TOOL; POLYMORPHISMS AB Irritant contact dermatitis is the most common work-related skin disease, especially affecting workers in wet-work occupations. This study was conducted to investigate the association between single nucleotide polymorphisms (SNPs) within the major histocompatibility complex (MHC) and skin irritant response in a group of healthcare workers. 585 volunteer healthcare workers were genotyped for MHC SNPs and patch tested with three different irritants: sodium lauryl sulfate (SLS), sodium hydroxide (NaOH) and benzalkonium chloride (BKC). Genotyping was performed using Illumina Goldengate MHC panels. A number of SNPs within the MHC Class I (OR2B3, TRIM31, TRIM10, TRIM40 and IER3), Class II (HLA-DPA1, HLA-DPB1) and Class III (C2) genes were associated (p<0.001) with skin response to tested irritants in different genetic models. Linkage disequilibrium patterns and functional annotations identified two SNPs in the TRIM40 (rs1573298) and HLA-DPB1 (rs9277554) genes, with a potential impact on gene regulation. In addition, SNPs in PSMB9 (rs10046277 and ITPR3 (rs499384) were associated with hand dermatitis. The results are of interest as they demonstrate that genetic variations in inflammation-related genes within the MHC can influence chemical-induced skin irritation and may explain the connection between inflamed skin and propensity to subsequent allergic contact sensitization. C1 [Yucesoy, Berran; Kashon, Michael L.; Frye, Bonnie; Wang, Wei; Fluharty, Kara] NIOSH, Hlth Effects Lab Div, CDC, Morgantown, WV USA. [Talzhanov, Yerkebulan; Barmada, M. Michael] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA. [Johnson, Victor J.] BRT, Morrisville, NC USA. [Baron, Elma; Nedorost, Susan] Case Western Reserve Univ, Univ Hosp Case Med Ctr, Cleveland, OH 44106 USA. [Wilson, Nevin W.] Univ Nevada, Sch Med, Dept Pediat, Reno, NV 89557 USA. [Gharib, Rola] West Virginia Univ, Sch Med, Dept Dermatol, Morgantown, WV USA. [Meade, Jean] NIOSH, Off Director, CDC, Morgantown, WV USA. [Germolec, Dori] NIEHS, Toxicol Branch, DNTP, POB 12233, Res Triangle Pk, NC 27709 USA. [Luster, Michael I.] West Virginia Univ, Sch Publ Hlth, Morgantown, WV USA. RP Yucesoy, B (reprint author), NIOSH, Hlth Effects Lab Div, Morgantown, WV 26505 USA. EM berranyucesoy@gmail.com FU NIOSH [AES12007001-1-0-6]; NIEHS [AES12007001-1-0-6] FX This study was supported in part by an inter-agency agreement between NIOSH and NIEHS (AES12007001-1-0-6) as a collaborative National Toxicology Program research activity. NR 39 TC 1 Z9 1 U1 1 U2 1 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1547-691X EI 1547-6901 J9 J IMMUNOTOXICOL JI J. Immunotoxicol. PD SEP PY 2016 VL 13 IS 5 BP 738 EP 744 DI 10.3109/1547691X.2016.1173135 PG 7 WC Toxicology SC Toxicology GA DU9NF UT WOS:000382543800013 PM 27258892 ER PT J AU Merchant-Borna, K Lee, H Wang, D Bogner, V van Griensven, M Gill, J Bazarian, JJ AF Merchant-Borna, Kian Lee, Hyunhwa Wang, Dan Bogner, Viktoria van Griensven, Martijn Gill, Jessica Bazarian, Jeffrey J. TI Genome-Wide Changes in Peripheral Gene Expression following Sports-Related Concussion SO JOURNAL OF NEUROTRAUMA LA English DT Article DE gene network; IPA; longitudinal study; mild traumatic brain injury; mTBI; PBMC; sports-related concussion ID TRAUMATIC BRAIN-INJURY; NF-KAPPA-B; BLOOD MONONUCLEAR-CELLS; ACTIVATION; IMMUNITY; INNATE; INTERLEUKIN-12; PROFILES; CYTOKINE; IMPACT AB We conducted a prospective study to identify genome-wide changes in peripheral gene expression before and after sportsrelated concussion (SRC). A total of 253 collegiate contact athletes underwent collection of peripheral blood mononuclear cells (PBMCs) before the sport season (baseline). Sixteen athletes who subsequently developed an SRC, along with 16 non-concussed teammate controls, underwent repeat collection of PBMCs within 6 h of injury (acutely). Concussed athletes underwent additional sample collection at 7 days post-injury (sub-acutely). Messenger RNA (mRNA) expression at baseline was compared with mRNA expression acutely and sub-acutely post-SRC. To estimate the contribution of physical exertion to gene changes, baseline samples from athletes who subsequently developed an SRC were compared with samples from uninjured teammate controls collected at the acute time-point. Clinical outcome was determined by changes in post-concussive symptoms, postural stability, and cognition from baseline to the sub-acute time-point. SRC athletes had significant changes in mRNA expression at both the acute and sub-acute time-points. There were no significant expression changes among controls. Acute transcriptional changes centered on interleukins 6 and 12, toll-like receptor 4, and NF-kappa B. Sub-acute gene expression changes centered on NF-kappa B, follicle stimulating hormone, chorionic gonadotropin, and protein kinase catalytic subunit. All SRC athletes were clinically back to baseline by Day 7. In conclusion, acute post-SRC transcriptional changes reflect regulation of the innate immune response and the transition to adaptive immunity. By 7 days, transcriptional activity is centered on regulating the hypothalamic-pituitary-adrenal axis. Future efforts to compare expressional changes in fully recovered athletes with those who do not recover from SRC could suggest putative targets for therapeutic intervention. C1 [Merchant-Borna, Kian; Bazarian, Jeffrey J.] Univ Rochester, Sch Med & Dent, Dept Emergency Med, Rochester, NY USA. [Lee, Hyunhwa] Univ Nevada, Sch Nursing, Las Vegas, NV 89154 USA. [Wang, Dan; Gill, Jessica] NINR, NIH, Bethesda, MD 20892 USA. [Bogner, Viktoria] Univ Munich, Munich, Germany. [van Griensven, Martijn] Tech Univ Munich, Klinikum Rechts Isar, Dept Trauma Surg, Munich, Germany. RP Bazarian, JJ (reprint author), Univ Rochester, Sch Med & Dent, 265 Elmwood Ave, Rochester, NY 14642 USA. EM jeff_bazarian@urmc.rochester.edu RI van Griensven, Martijn/F-5808-2012 OI van Griensven, Martijn/0000-0001-5104-9881 FU NCATS NIH HHS [UL1 TR000042]; NICHD NIH HHS [K24 HD064754] NR 54 TC 1 Z9 1 U1 2 U2 5 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD SEP 1 PY 2016 VL 33 IS 17 BP 1576 EP 1585 DI 10.1089/neu.2015.4191 PG 10 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA DU6EH UT WOS:000382306300003 PM 27035221 ER PT J AU Navarrete, CT Wrage, LA Carlo, WA Walsh, MC Rich, W Gantz, MG Das, A Schibler, K Newman, NS Piazza, AJ Poindexter, BB Shankaran, S Sanchez, PJ Morris, BH Frantz, ID Van Meurs, KP Cotten, CM Ehrenkranz, RA Bell, EF Watterberg, KL Higgins, RD Duara, S AF Navarrete, Cristina T. Wrage, Lisa A. Carlo, Waldemar A. Walsh, Michele C. Rich, Wade Gantz, Marie G. Das, Abhik Schibler, Kurt Newman, Nancy S. Piazza, Anthony J. Poindexter, Brenda B. Shankaran, Seetha Sanchez, Pablo J. Morris, Brenda H. Frantz, Ivan D., III Van Meurs, Krisa P. Cotten, C. Michael Ehrenkranz, Richard A. Bell, Edward F. Watterberg, Kristi L. Higgins, Rosemary D. Duara, Shahnaz CA Eunice Kennedy Shriver Natl Inst C TI Growth Outcomes of Preterm Infants Exposed to Different Oxygen Saturation Target Ranges from Birth SO JOURNAL OF PEDIATRICS LA English DT Article ID NEONATAL RESEARCH NETWORK; INTENSIVE-CARE-UNIT; WEIGHT INFANTS; BRONCHOPULMONARY DYSPLASIA; INTRAUTERINE GROWTH; CONTROLLED-TRIAL; PULSE OXIMETRY; RETINOPATHY; HYPOXEMIA; GESTATION AB Objective To test whether infants randomized to a lower oxygen saturation (peripheral capillary oxygen saturation [SpO(2)]) target range while on supplemental oxygen from birth will have better growth velocity from birth to 36 weeks postmenstrual age (PMA) and less growth failure at 36 weeks PMA and 18-22 months corrected age. Study design We evaluated a subgroup of 810 preterm infants from the Surfactant, Positive Pressure, and Oxygenation Randomized Trial, randomized at birth to lower (85%-89%, n = 402, PMA 26 +/- 1 weeks, birth weight 839 +/- 186 g) or higher (91%-95%, n = 408, PMA 26 +/- 1 weeks, birth weight 840 +/- 191 g) SpO(2) target ranges. Anthropometric measures were obtained at birth, postnatal days 7, 14, 21, and 28; then at 32 and 36 weeks PMA; and 18-22 months corrected age. Growth velocities were estimated with the exponential method and analyzed with linear mixed models. Poor growth outcome, defined as weight <10th percentile at 36 weeks PMA and 18-22 months corrected age, was compared across the 2 treatment groups by the use of robust Poisson regression. Results Growth outcomes including growth at 36 weeks PMA and 18-22 months corrected age, as well as growth velocity were similar in the lower and higher SpO(2) target groups. Conclusion Targeting different oxygen saturation ranges between 85% and 95% from birth did not impact growth velocity or reduce growth failure in preterm infants. C1 [Navarrete, Cristina T.; Duara, Shahnaz] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Wrage, Lisa A.; Gantz, Marie G.] RTI Int, Social Stat & Environm Sci Unit, Res Triangle Pk, NC USA. [Carlo, Waldemar A.] Univ Alabama Birmingham, Div Neonatol, Birmingham, AL USA. [Walsh, Michele C.] Case Western Reserve Univ, Rainbow Babies & Childrens Hosp, Dept Pediat, Cleveland, OH 44106 USA. [Rich, Wade; Newman, Nancy S.] Univ Calif San Diego, Div Neonatol, San Diego, CA 92103 USA. [Das, Abhik] RTI Int, Social Stat & Environm Sci Unit, Rockville, MD USA. [Schibler, Kurt] Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Cincinnati, OH 45229 USA. [Schibler, Kurt] Univ Cincinnati, Cincinnati, OH USA. [Piazza, Anthony J.] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA. [Piazza, Anthony J.] Childrens Healthcare Atlanta, Atlanta, GA USA. [Poindexter, Brenda B.] Indiana Univ Sch Med, Dept Pediat, Indianapolis, IN 46202 USA. [Shankaran, Seetha] Wayne State Univ, Dept Pediat, Detroit, MI 48202 USA. [Sanchez, Pablo J.] Univ Texas Southwestern Med Ctr Dallas, Dept Pediat, Dallas, TX USA. [Morris, Brenda H.] Univ Texas Med Sch Houston, Dept Pediat, Houston, TX USA. [Frantz, Ivan D., III] Floating Hosp Children, Tufts Med Ctr, Dept Pediat, Div Newborn Med, Boston, MA USA. [Van Meurs, Krisa P.] Stanford Univ, Sch Med, Dept Pediat, Div Neonatal & Dev Med, Palo Alto, CA 94304 USA. [Van Meurs, Krisa P.] Lucile Packard Childrens Hosp, Palo Alto, CA USA. [Cotten, C. Michael] Duke Univ, Dept Pediat, Durham, NC 27706 USA. [Ehrenkranz, Richard A.] Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06510 USA. [Bell, Edward F.] Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA. [Watterberg, Kristi L.] Univ New Mexico, Hlth Sci Ctr, Albuquerque, NM 87131 USA. [Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Navarrete, CT (reprint author), POB 016960,R-131, Miami, FL 33136 USA. EM cnavarrete@med.miami.edu OI Ambalavanan, Namasivayam/0000-0003-0731-9092 FU National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Heart, Lung, and Blood Institute FX The National Institutes of Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Heart, Lung, and Blood Institute provided grant support for the Neonatal Research Network's SUPPORT Trial. Additional funding information is available at www.jpeds.com (Appendix). Participating sites collected data and transmitted it to RTI International, the data coordinating center for the network, which stored, managed, and analyzed the data for this study. The authors declare no conflicts of interest. NR 34 TC 0 Z9 0 U1 2 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD SEP PY 2016 VL 176 BP 62 EP + DI 10.1016/j.jpeds.2016.05.070 PG 11 WC Pediatrics SC Pediatrics GA DU5NM UT WOS:000382258500013 PM 27344218 ER PT J AU Milligan, KL Mann, D Rump, A Anderson, VL Hsu, AP Kuhns, DB Zerbe, CS Holland, SM AF Milligan, Ki Lee Mann, Daphne Rump, Amy Anderson, Victoria L. Hsu, Amy P. Kuhns, Douglas B. Zerbe, Christa S. Holland, Steven M. TI Complete Myeloperoxidase Deficiency: Beware the "False-Positive" Dihydrorhodamine Oxidation SO JOURNAL OF PEDIATRICS LA English DT Article ID DYSFUNCTION AB Myeloperoxidase deficiency is the most common inherited phagocyte disorder (1:2000) and causes an abnormal dihydrorhodamine oxidation test, which also is seen in chronic granulomatous disease. A patient with Candida meningitis and low dihydrorhodamine oxidation signal was diagnosed with chronic granulomatous disease but actually had compound heterozygous myeloperoxidase deficiency. C1 [Milligan, Ki Lee] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Mann, Daphne; Rump, Amy; Anderson, Victoria L.; Hsu, Amy P.; Zerbe, Christa S.; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Mann, Daphne; Rump, Amy] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Clin Monitoring Res Program, Frederick, MD USA. [Kuhns, Douglas B.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Clin Serv Program, Frederick, MD USA. RP Milligan, KL (reprint author), NIH, CRC, B3-4141 MSC 1684, Bethesda, MD 20892 USA. EM milligank@live.com FU Division of Intramural Research; National Institute of Allergy and Infectious Diseases; National Cancer Institute/National Institutes of Health [HHSN261200800001E] FX Supported by the Division of Intramural Research, the National Institute of Allergy and Infectious Diseases and, the National Cancer Institute/National Institutes of Health (HHSN261200800001E). The content of this report does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does it imply endorsement by the US Government. The authors declare no conflicts of interest. NR 12 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD SEP PY 2016 VL 176 BP 204 EP 206 DI 10.1016/j.jpeds.2016.05.047 PG 3 WC Pediatrics SC Pediatrics GA DU5NM UT WOS:000382258500037 PM 27301573 ER PT J AU Ransome, Y Gilman, SE AF Ransome, Yusuf Gilman, Stephen E. TI The Role of Religious Involvement in Black-White Differences in Alcohol Use Disorders SO JOURNAL OF STUDIES ON ALCOHOL AND DRUGS LA English DT Article ID NATIONAL EPIDEMIOLOGIC SURVEY; INTERVIEW SCHEDULE AUDADIS; OLDER AFRICAN-AMERICANS; UNITED-STATES; GENDER-DIFFERENCES; MENTAL-HEALTH; GENERAL-POPULATION; ETHNIC-DIFFERENCES; DRINKING PATTERNS; CARIBBEAN BLACKS AB Objective: To date, a paradox in the social epidemiology of alcohol use disorders (AUDs) remains unresolved: non-Hispanic Blacks experience higher socioeconomic disadvantage, stressor exposures, and individual stress-prominent AUD risk factors, yet have lower than expected AUD risk compared with non-Hispanic Whites. Religious involvement is associated with lower AUD risk. Non-Hispanic Blacks are highly religiously involved. Together, those facts may account for Black-White differences in AUD risk. Method: We used Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) (N = 26,784) to examine whether (a) religious involvement accounts for Black-White differences in AUD risk, and (b) race moderates the association between religious involvement and AUD. Religious involvement indicators were service attendance, social interaction, and subjective religiosity and spirituality. Twelve-month AUD prevalence as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, was the outcome. Covariates were age, education, income, marital status, and U.S.-born versus foreign-born nativity. Results: Blacks were significantly less likely than Whites to have an AUD (adjusted odds ratio [aOR] for men = 0.70, 95% CI [0.59, 0.83]; aOR for women = 0.71, 95% CI [0.57, 0.89]). An adjusted model with all three religious involvement indicators explained 17% of race differences among men (OR = 0.82) and 45% among women (OR = 1.03). There was no evidence that the association between religious involvement and AUD differed between Blacks and Whites. Conclusions: Religious service attendance, subjective religiosity, and spirituality account for a meaningful share of the Black-White differences in AUD. Future research is needed to conduct more fine-grained analyses of the aspects of religious involvement that are potentially protective against AUD, ideally differentiating between social norms associated with religious involvement, social support offered by religious participation, and deeply personal aspects of spirituality. C1 [Ransome, Yusuf; Gilman, Stephen E.] Harvard TH Chan Sch Publ Hlth, Dept Social & Behav Sci, 677 Huntington Ave,Kresge 7th Floor, Boston, MA 02115 USA. [Gilman, Stephen E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Hlth Behav Branch, Div Intramural Populat Hlth Res, Bethesda, MD USA. RP Ransome, Y (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Social & Behav Sci, 677 Huntington Ave,Kresge 7th Floor, Boston, MA 02115 USA. EM yransome@hsph.harvard.edu FU Alonzo Smythe Yerby Fellowship at the Harvard T.H. Chan School of Public Health; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This work was supported in part by the Alonzo Smythe Yerby Fellowship at the Harvard T.H. Chan School of Public Health, and the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 84 TC 0 Z9 0 U1 6 U2 6 PU ALCOHOL RES DOCUMENTATION INC CENT ALCOHOL STUD RUTGERS UNIV PI PISCATAWAY PA C/O DEIRDRE ENGLISH, 607 ALLISON RD, PISCATAWAY, NJ 08854-8001 USA SN 1937-1888 EI 1938-4114 J9 J STUD ALCOHOL DRUGS JI J. Stud. Alcohol Drugs PD SEP PY 2016 VL 77 IS 5 BP 792 EP 801 PG 10 WC Substance Abuse; Psychology SC Substance Abuse; Psychology GA DU7UM UT WOS:000382420100018 PM 27588538 ER PT J AU Norton, JM Moxey-Mims, MM Eggers, PW Narva, AS Star, RA Kimmel, PL Rodgers, GP AF Norton, Jenna M. Moxey-Mims, Marva M. Eggers, Paul W. Narva, Andrew S. Star, Robert A. Kimmel, Paul L. Rodgers, Griffin P. TI Social Determinants of Racial Disparities in CKD SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Review ID CHRONIC KIDNEY-DISEASE; STAGE RENAL-DISEASE; QUALITY-OF-LIFE; DIETARY-SODIUM RESTRICTION; AFFORDABLE CARE ACT; NEIGHBORHOOD SOCIOECONOMIC-STATUS; CONVERTING ENZYME-INHIBITORS; URBAN HEMODIALYSIS-PATIENTS; SOUTHEASTERN UNITED-STATES; 3RD NATIONAL-HEALTH AB Significant disparities in CKD rates and outcomes exist between black and white Americans. Health disparities are defined as health differences that adversely affect disadvantaged populations, on the basis of one or more health outcomes. CKD is the complex result of genetic and environmental factors, reflecting the balance of nature and nurture. Social determinants of health have an important role as environmental components, especially for black populations, who are disproportionately disadvantaged. Understanding the social determinants of health and appreciating the underlying differences associated with meaningful clinical outcomes may help nephrologists treat all their patients with CKD in an optimal manner. Altering the social determinants of health, although difficult, may embody important policy and research efforts, with the ultimate goal of improving outcomes for patients with kidney diseases, and minimizing the disparities between groups. C1 [Norton, Jenna M.; Moxey-Mims, Marva M.; Eggers, Paul W.; Narva, Andrew S.; Star, Robert A.; Kimmel, Paul L.] NIDDK, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD 20892 USA. [Rodgers, Griffin P.] NIDDK, Off Director, NIH, Bethesda, MD 20892 USA. [Norton, Jenna M.; Moxey-Mims, Marva M.; Eggers, Paul W.; Narva, Andrew S.; Star, Robert A.; Kimmel, Paul L.; Rodgers, Griffin P.] NIDDK, NIH, 6707 Democracy Blvd,Off 611, Bethesda, MD 20892 USA. RP Kimmel, PL (reprint author), NIDDK, NIH, 6707 Democracy Blvd,Off 611, Bethesda, MD 20892 USA. EM KimmelP@extra.niddk.nih.gov NR 348 TC 0 Z9 0 U1 10 U2 11 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD SEP PY 2016 VL 27 IS 9 BP 2576 EP 2595 DI 10.1681/ASN.2016010027 PG 20 WC Urology & Nephrology SC Urology & Nephrology GA DU5SB UT WOS:000382270500007 PM 27178804 ER PT J AU Heyer, CM Sundsbak, JL Abebe, KZ Chapman, AB Torres, VE Grantham, JJ Bae, KT Schrier, RW Perrone, RD Braun, WE Steinman, TI Mrug, M Yu, ASL Brosnahan, G Hopp, K Irazabal, MV Bennett, WM Flessner, MF Moore, CG Landsittel, D Harris, PC AF Heyer, Christina M. Sundsbak, Jamie L. Abebe, Kaleab Z. Chapman, Arlene B. Torres, Vicente E. Grantham, Jared J. Bae, Kyongtae T. Schrier, Robert W. Perrone, Ronald D. Braun, William E. Steinman, Theodore I. Mrug, Michal Yu, Alan S. L. Brosnahan, Godela Hopp, Katharina Irazabal, Maria V. Bennett, William M. Flessner, Michael F. Moore, Charity G. Landsittel, Douglas Harris, Peter C. CA HALT PKD CRISP Investigators TI Predicted Mutation Strength of Nontruncating PKD1 Mutations Aids Genotype-Phenotype Correlations in Autosomal Dominant Polycystic Kidney Disease SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID MOLECULAR DIAGNOSTICS; VOLUME PROGRESSION; RENAL-DISEASE; GENE; SEVERITY; POSITION; OUTCOMES; DOSAGE; TRIALS; ADPKD AB Autosomal dominant polycystic kidney disease (ADPKD) often results in ESRD but with a highly variable course. Mutations to PKD1 or PKD2 cause ADPKD; both loci have high levels of allelic heterogeneity. We evaluated genotype-phenotype correlations in 1119 patients (945 families) from the HALT Progression of PKD Study and the Consortium of Radiologic Imaging Study of PKD Study. The population was defined as: 77.7% PKD1, 14.7% PKD2, and 7.6% with no mutation detected (NMD). Phenotypic end points were sex, eGFR, height adjusted total kidney volume (htTKV), and liver cyst volume. Analysis of the eGFR and htTKV measures showed that the PKD1 group had more severe disease than the PKD2 group, whereas the NMD group had a PKD2-like phenotype. In both the PKD1 and PKD2 populations, men had more severe renal disease, but women had larger liver cyst volumes. Compared with nontruncating PKD1 mutations, truncating PKD1 mutations associated with lower eGFR, but the mutation groups were not differentiated by htTKV. PKD1 nontruncating mutations were evaluated for conservation and chemical change and subdivided into strong (mutation strength group 2 [MSG2]) and weak (MSG3) mutation groups. Analysis of eGFR and htTKV measures showed that patients with MSG3 but not MSG2 mutations had significantly milder disease than patients with truncating cases (MSG1), an association especially evident in extreme decile populations. Overall, we have quantified the contribution of genic and PKD1 allelic effects and sex to the ADPKD phenotype. Intrafamilial correlation analysis showed that other factors shared by families influence htTKV, with these additional genetic/environmental factors significantly affecting the ADPKD phenotype. C1 [Heyer, Christina M.; Sundsbak, Jamie L.; Torres, Vicente E.; Hopp, Katharina; Irazabal, Maria V.; Harris, Peter C.] Mayo Clin, Div Nephrol & Hypertens, 200 First St,SW, Rochester, MN 55905 USA. [Abebe, Kaleab Z.; Landsittel, Douglas] Univ Pittsburgh, Sch Med, Ctr Res Hlth Care, Pittsburgh, PA USA. [Bae, Kyongtae T.] Univ Pittsburgh, Sch Med, Dept Radiol, Pittsburgh, PA USA. [Chapman, Arlene B.] Univ Chicago, Nephrol Sect, Chicago, IL 60637 USA. [Grantham, Jared J.; Yu, Alan S. L.] Univ Kansas, Med Ctr, Kidney Inst, Kansas City, KS 66103 USA. [Schrier, Robert W.; Brosnahan, Godela] Univ Colorado, Hlth Sci Ctr, Div Nephrol, Denver, CO USA. [Perrone, Ronald D.] Tufts Med Ctr, Div Nephrol, Boston, MA USA. [Braun, William E.] Cleveland Clin, Glickman Urol & Kidney Inst, Cleveland, OH 44106 USA. [Steinman, Theodore I.] Beth Israel Deaconess Med Ctr, Div Nephrol, Boston, MA 02215 USA. [Mrug, Michal] Univ Alabama Birmingham, Div Nephrol, Birmingham, AL USA. [Bennett, William M.] Legacy Good Samaritan Hosp, Legacy Transplant Serv, Portland, OR USA. [Flessner, Michael F.] NIDDK, Bethesda, MD 20892 USA. [Moore, Charity G.] Carolinas HealthCare Syst, Dickson Adv Analyt, Charlotte, NC USA. RP Harris, PC (reprint author), Mayo Clin, Div Nephrol & Hypertens, 200 First St,SW, Rochester, MN 55905 USA. EM harris.peter@mayo.edu FU National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) [DK062410S1, DK056957S1, DK058816]; Mayo Translational Polycystic Kidney Disease Center [DK090728]; NIDDK [DK056943, DK056956, DK056957, DK056961, DK062410, DK062408, DK062402, DK082230, DK062411, DK062401]; National Center for Research Resources General Clinical Research Centers Cooperative Agreements [RR025008, TR000454, RR024150, TR00135, RR025752, TR001064, RR025780, TR001082, RR025758, TR001102, RR033179, TR000001] FX Mutation analysis of the HALT PKD Study and the CRISP Study populations was supported by National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) Grants DK062410S1, DK056957S1, and DK058816 and Mayo Translational Polycystic Kidney Disease Center Grant DK090728. MRC-Holland is thanked for providing multiplex ligation-dependent probe amplification kits at a discount. The CRISP Study and the HALT PKD Study were supported by NIDDK Cooperative Agreements DK056943, DK056956, DK056957, DK056961, DK062410, DK062408, DK062402, DK082230, DK062411, and DK062401; National Center for Research Resources General Clinical Research Centers Cooperative Agreements RR000039, RR000585, RR000054, RR000051, RR023940, and RR001032; and National Center for Advancing Translational Sciences Clinical and Translational Science Awards Cooperative Agreements RR025008, TR000454, RR024150, TR00135, RR025752, TR001064, RR025780, TR001082, RR025758, TR001102, RR033179, and TR000001 to the participating centers. NR 35 TC 3 Z9 3 U1 2 U2 2 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD SEP PY 2016 VL 27 IS 9 BP 2872 EP 2884 DI 10.1681/ASN.2015050583 PG 13 WC Urology & Nephrology SC Urology & Nephrology GA DU5SB UT WOS:000382270500031 PM 26823553 ER PT J AU Tempero, M AF Tempero, Margaret TI Hillary and Donald, Our Patients Are Watching SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Editorial Material C1 [Tempero, Margaret] UCSF Pancreas Ctr, Med, San Francisco, CA 94158 USA. [Tempero, Margaret] NCI, Clin Oncol Study Sect, Bethesda, MD 20892 USA. [Tempero, Margaret] Canc Prevent & Res Inst Texas, Clin & Translat Study Sect, Austin, TX 78701 USA. [Tempero, Margaret] UNMC Eppley Canc Ctr, Omaha, NE 68198 USA. [Tempero, Margaret] UCSF, Div Med Oncol, San Francisco, CA 94143 USA. [Tempero, Margaret] UCSF Helen Diller Family Comprehens Canc Ctr, Res Programs, San Francisco, CA 94143 USA. RP Tempero, M (reprint author), UCSF Pancreas Ctr, Med, San Francisco, CA 94158 USA.; Tempero, M (reprint author), Canc Prevent & Res Inst Texas, Clin & Translat Study Sect, Austin, TX 78701 USA.; Tempero, M (reprint author), UNMC Eppley Canc Ctr, Omaha, NE 68198 USA.; Tempero, M (reprint author), UCSF, Div Med Oncol, San Francisco, CA 94143 USA.; Tempero, M (reprint author), UCSF Helen Diller Family Comprehens Canc Ctr, Res Programs, San Francisco, CA 94143 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU HARBORSIDE PRESS PI COLD SPRING HARBOR PA 37 MAIN ST, COLD SPRING HARBOR, NY 11724 USA SN 1540-1405 EI 1540-1413 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD SEP PY 2016 VL 14 IS 9 BP 1047 EP 1047 PG 1 WC Oncology SC Oncology GA DV4OC UT WOS:000382903900001 PM 27587617 ER PT J AU DiNapoli, SR Hirsch, VM Brenchley, JM AF DiNapoli, Sarah R. Hirsch, Vanessa M. Brenchley, Jason M. TI Macrophages in Progressive Human Immunodeficiency Virus/Simian Immunodeficiency Virus Infections SO JOURNAL OF VIROLOGY LA English DT Review ID CD4(+) T-CELLS; CENTRAL-NERVOUS-SYSTEM; ACTIVE ANTIRETROVIRAL THERAPY; AIDS DEMENTIA COMPLEX; PREFERENTIALLY HARBORS HIV-1; CD16(+) MONOCYTE SUBSET; REPLICATION IN-VIVO; NEUROCOGNITIVE DISORDERS; IMMUNE ACTIVATION; RHESUS MACAQUES AB The cells that are targeted by primate lentiviruses (HIV and simian immunodeficiency virus [SIV]) are of intense interest given the renewed effort to identify potential cures for HIV. These viruses have been reported to infect multiple cell lineages of hematopoietic origin, including all phenotypic and functional CD4 T cell subsets. The two most commonly reported cell types that become infected in vivo are memory CD4 T cells and tissue-resident macrophages. Though viral infection of CD4 T cells is routinely detected in both HIV-infected humans and SIV-infected Asian macaques, significant viral infection of macrophages is only routinely observed in animal models wherein CD4 T cells are almost entirely depleted. Here we review the roles of macrophages in lentiviral disease progression, the evidence that macrophages support viral replication in vivo, the animal models where macrophage-mediated replication of SIV is thought to occur, how the virus can interact with macrophages in vivo, pathologies thought to be attributed to viral replication within macrophages, how viral replication in macrophages might contribute to the asymptomatic phase of HIV/SIV infection, and whether macrophages represent a long-lived reservoir for the virus. C1 [DiNapoli, Sarah R.; Brenchley, Jason M.] NIAID, Parasit Dis Lab, Bethesda, MD 20892 USA. [Hirsch, Vanessa M.] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Brenchley, JM (reprint author), NIAID, Parasit Dis Lab, Bethesda, MD 20892 USA. EM jbrenchl@mail.nih.gov OI DiNapoli, Sarah/0000-0002-3675-9030 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX Funding for this work was provided in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 112 TC 1 Z9 1 U1 7 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD SEP PY 2016 VL 90 IS 17 BP 7596 EP 7606 DI 10.1128/JVI.00672-16 PG 11 WC Virology SC Virology GA DU6EM UT WOS:000382306800001 PM 27307568 ER PT J AU Tran, EEH Nelson, EA Bonagiri, P Simmons, JA Shoemaker, CJ Schmaljohn, CS Kobinger, GP Zeitlin, L Subramaniam, S White, JM AF Tran, Erin E. H. Nelson, Elizabeth A. Bonagiri, Pranay Simmons, James A. Shoemaker, Charles J. Schmaljohn, Connie S. Kobinger, Gary P. Zeitlin, Larry Subramaniam, Sriram White, Judith M. TI Mapping of Ebolavirus Neutralization by Monoclonal Antibodies in the ZMapp Cocktail Using Cryo-Electron Tomography and Studies of Cellular Entry SO JOURNAL OF VIROLOGY LA English DT Article ID NIEMANN-PICK C1; IMMUNODEFICIENCY-VIRUS TYPE-1; GLYCOPROTEIN; INFECTION; BINDING; REQUIRES; PROTECTION; RESIDUES; ENVELOPE; RECEPTOR AB ZMapp, a cocktail of three monoclonal antibodies (MAbs; c2G4, c4G7, and c13C6) against the ebolavirus (EBOV) glycoprotein (GP), shows promise for combatting outbreaks of EBOV, as occurred in West Africa in 2014. Prior studies showed that Fabs from these MAbs bind a soluble EBOV GP ectodomain and that MAbs c2G4 and c4G7, but not c13C6, neutralize infections in cell cultures. Using cryo-electron tomography, we extended these findings by characterizing the structures of c2G4, c4G7, and c13C6 IgGs bound to native, full-length GP from the West African 2014 isolate embedded in filamentous viruslike particles (VLPs). As with the isolated ectodomain, c13C6 bound to the glycan cap, whereas c2G4 and c4G7 bound to the base region of membrane-bound GP. The tomographic data suggest that all three MAbs bind with high occupancy and that the base-binding antibodies can potentially bridge neighboring GP spikes. Functional studies indicated that c2G4 and c4G7, but not c13C6, competitively inhibit entry of VLPs bearing EBOV GP into the host cell cytoplasm, without blocking trafficking of VLPs to NPC1(+) endolysosomes, where EBOV fuses. Moreover, c2G4 and c4G7 bind to and can block entry mediated by the primed (19-kDa) form of GP without impeding binding of the C-loop of NPC1, the endolysosomal receptor for EBOV. The most likely mode of action of c2G4 and c4G7 is therefore by inhibiting conformational changes in primed, NPC1-bound GP that initiate fusion between the viral and target membranes, similar to the action of certain broadly neutralizing antibodies against influenza hemagglutinin and HIV Env. IMPORTANCE The recent West African outbreak of ebolavirus caused the deaths of more than 11,000 individuals. Hence, there is an urgent need to be prepared with vaccines and therapeutics for similar future disasters. ZMapp, a cocktail of three MAbs directed against the ebolavirus glycoprotein, is a promising anti-ebolavirus therapeutic. Using cryo-electron tomography, we provide structural information on how each of the MAbs in this cocktail binds to the ebolavirus glycoprotein as it is displayed-embedded in the membrane and present at high density-on filamentous viruslike particles that recapitulate the surface structure and entry functions of ebolavirus. Moreover, after confirming that two of the MAbs bind to the same region in the base of the glycoprotein, we show that they competitively block the entry function of the glycoprotein and that they can do so after the glycoprotein is proteolytically primed and bound to its intracellular receptor, Niemann-Pick C1. These findings should inform future developments of ebolavirus therapeutics. C1 [Tran, Erin E. H.; Subramaniam, Sriram] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Nelson, Elizabeth A.; Bonagiri, Pranay; Simmons, James A.; White, Judith M.] Univ Virginia, Sch Med, Dept Cell Biol, Charlottesville, VA 22908 USA. [Shoemaker, Charles J.; Schmaljohn, Connie S.] United States Army Med Res Inst Infect Dis, Div Virol, Ft Detrick, MD USA. [Kobinger, Gary P.] Univ Manitoba, Dept Med Microbiol, Publ Hlth Agcy Canada, Special Pathogens Program,Natl Microbiol Lab, Winnipeg, MB, Canada. [Zeitlin, Larry] Mapp Biopharmaceut, San Diego, CA USA. RP White, JM (reprint author), Univ Virginia, Sch Med, Dept Cell Biol, Charlottesville, VA 22908 USA. EM jw7g@virginia.edu FU HHS \ National Institutes of Health (NIH) [T32AI007046, R21 AI103601, RO1 AI114776]; National Cancer Institute (NCI) (Intramural Research Program) FX This work, including the efforts of James A. Simmons, was funded by HHS vertical bar National Institutes of Health (NIH) (T32AI007046). This work, including the efforts of Judith Miriam White, was funded by HHS vertical bar National Institutes of Health (NIH) (R21 AI103601 and RO1 AI114776). This work, including the efforts of Sriram Subramaniam, was funded by National Cancer Institute (NCI) (Intramural Research Program). NR 42 TC 1 Z9 1 U1 3 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD SEP PY 2016 VL 90 IS 17 BP 7618 EP 7627 DI 10.1128/JVI.00406-16 PG 10 WC Virology SC Virology GA DU6EM UT WOS:000382306800003 PM 27279622 ER PT J AU Yuan, Z Kang, GB Ma, FR Lu, WX Fan, WJ Fennessey, CM Keele, BF Li, QS AF Yuan, Zhe Kang, Guobin Ma, Fangrui Lu, Wuxun Fan, Wenjin Fennessey, Christine M. Keele, Brandon F. Li, Qingsheng TI Recapitulating Cross-Species Transmission of Simian Immunodeficiency Virus SIVcpz to Humans by Using Humanized BLT Mice SO JOURNAL OF VIROLOGY LA English DT Article ID RESTRICTION FACTORS; NONPANDEMIC HIV-1; CHIMPANZEES; AIDS; REPLICATION; ADAPTATION; INFECTION; ORIGIN; LENTIVIRUSES; EVOLUTION AB The origins of human immunodeficiency virus type 1 (HIV-1) have been widely accepted to be the consequences of simian immunodeficiency viruses from wild chimpanzees (SIVcpz) crossing over to humans. However, there has not been any in vivo study of SIVcpz infection of humans. Also, it remains largely unknown why only specific SIVcpz strains have achieved cross-species transmission and what transmission risk might exist for those SIVcpz strains that have not been found to infect humans. Closing this knowledge gap is essential for better understanding cross-species transmission and predicting the likelihood of additional cross-species transmissions of SIV into humans. Here we show that humanized bone marrow, thymus, and liver (hu-BLT) mice are susceptible to all studied strains of SIVcpz, including the inferred ancestral viruses of pandemic and nonpandemic HIV-1 groups M (SIVcpzMB897) and N (SIVcpzEK505) as well as strains that have not been found in humans (SIVcpzMT145 and SIVcpzBF1167). Importantly, the ability of SIVcpz to cross the interspecies barrier to infect humanized mice correlates with their phylogenetic distance to pandemic HIV-1. We also identified mutations of SIVcpzMB897 (Env G411R and G413R) and SIVcpzBF1167 (Env H280Q and Q380R) at 14 weeks postinoculation. Together, our results have recapitulated the events of SIVcpz cross-species transmission to humans and identified mutations that occurred during the first 16 weeks of infection, providing in vivo experimental evidence that the origins of HIV-1 are the consequence of SIVcpz crossing over to humans. This study also revealed that SIVcpz viruses whose inferred descendants have not been found in humans still have the potential to cause an HIV-1-like zoonosis. IMPORTANCE It is believed that the origins of HIV-1 are the consequence of SIV from wild chimpanzees crossing over to humans. However, the origins of HIV-1 have been linked back to only specific SIVcpz strains. There have been no experiments that directly test the in vivo cross-species transmissibility of SIVcpz strains to humans. This is the first in vivo study of SIVcpz cross-species transmission. With the humanized-BLT mouse model, we have provided in vivo experimental evidence of multiple SIVcpz strains crossing over to humans and identified several important mutations of divergent SIVcpz strains after long-term replication in human cells. We also found that the cross-species transmission barrier of SIVcpz to humans correlates with their phylogenetic distance to pandemic HIV-1 group M. Importantly, this work provides evidence that SIVcpz viruses, whose inferred descendants have not been found in humans, still have the potential to cause a future HIV-1-like zoonotic outbreak. C1 [Yuan, Zhe; Kang, Guobin; Ma, Fangrui; Lu, Wuxun; Fan, Wenjin; Li, Qingsheng] Univ Nebraska, Sch Biol Sci, Nebraska Ctr Virol, Lincoln, NE 68588 USA. [Fennessey, Christine M.; Keele, Brandon F.] Leidos Biomed Res Inc, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Li, QS (reprint author), Univ Nebraska, Sch Biol Sci, Nebraska Ctr Virol, Lincoln, NE 68588 USA. EM qli@unl.edu FU HHS \ NIH \ National Cancer Institute (NCI) [HHSN261200800001E]; HHS \ National Institutes of Health (NIH) [P30GM103509, R01 DK087625] FX This work, including the efforts of Brandon F. Keele, was funded by HHS vertical bar NIH vertical bar National Cancer Institute (NCI) (HHSN261200800001E). This work, including the efforts of Qingsheng Li, was funded by HHS vertical bar National Institutes of Health (NIH) (P30GM103509). This work, including the efforts of Qingsheng Li, was funded by HHS vertical bar National Institutes of Health (NIH) (R01 DK087625). NR 36 TC 0 Z9 0 U1 6 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD SEP PY 2016 VL 90 IS 17 BP 7728 EP 7739 DI 10.1128/JVI.00860-16 PG 12 WC Virology SC Virology GA DU6EM UT WOS:000382306800013 PM 27307566 ER PT J AU Liu, RK Moss, B AF Liu, Ruikang Moss, Bernard TI Opposing Roles of Double-Stranded RNA Effector Pathways and Viral Defense Proteins Revealed with CRISPR-Cas9 Knockout Cell Lines and Vaccinia Virus Mutants SO JOURNAL OF VIROLOGY LA English DT Article ID EARLY MESSENGER-RNAS; HINDIII-D FRAGMENT; N-TERMINAL DOMAIN; HUMAN HELA-CELLS; GENE-EXPRESSION; INFECTED-CELLS; HOST-RANGE; E3L GENE; TRANSLATION INITIATION; TRANSCRIPTION PRODUCTS AB Vaccinia virus (VACV) decapping enzymes and cellular exoribonuclease Xrn1 catalyze successive steps in mRNA degradation and prevent double-stranded RNA (dsRNA) accumulation, whereas the viral E3 protein can bind dsRNA. We showed that dsRNA and E3 colocalized within cytoplasmic viral factories in cells infected with a decapping enzyme mutant as well as with wild-type VACV and that they coprecipitated with antibody. An E3 deletion mutant induced protein kinase R (PKR) and eukaryotic translation initiation factor alpha (eIF2 alpha) phosphorylation earlier and more strongly than a decapping enzyme mutant even though less dsRNA was made, leading to more profound effects on viral gene expression. Human HAP1 and A549 cells were genetically modified by clustered regularly interspaced short palindromic repeat-Cas9 (CRISPR-Cas9) to determine whether the same pathways restrict E3 and decapping mutants. The E3 mutant replicated in PKR knockout (KO) HAP1 cells in which RNase L is intrinsically inactive but only with a double knockout (DKO) of PKR and RNase L in A549 cells, indicating that both pathways decreased replication equivalently and that no additional dsRNA pathway was crucial. In contrast, replication of the decapping enzyme mutant increased significantly (though less than that of wild-type virus) in DKO A549 cells but not in DKO HAP1 cells where a smaller increase in viral protein synthesis occurred. Xrn1 KO A549 cells were viable but nonpermissive for VACV; however, wild-type and mutant viruses replicated in triple-KO cells in which RNase L and PKR were also inactivated. Since KO of PKR and RNase L was sufficient to enable VACV replication in the absence of E3 or Xrn1, the poor replication of the decapping mutant, particularly in HAP1 DKO, cells indicated additional translational defects. IMPORTANCE Viruses have evolved ways of preventing or counteracting the cascade of antiviral responses that double-stranded RNA (dsRNA) triggers in host cells. We showed that the dsRNA produced in excess in cells infected with a vaccinia virus (VACV) decapping enzyme mutant and by wild-type virus colocalized with the viral E3 protein in cytoplasmic viral factories. Novel human cell lines defective in either or both protein kinase R and RNase L dsRNA effector pathways and/or the cellular 5' exonuclease Xrn1 were prepared by CRISPR-Cas9 gene editing. Inactivation of both pathways was necessary and sufficient to allow full replication of the E3 mutant and reverse the defect cause by inactivation of Xrn1, whereas the decapping enzyme mutant still exhibited defects in gene expression. The study provided new insights into functions of the VACV proteins, and the well-characterized panel of CRISPR-Cas9-modified human cell lines should have broad applicability for studying innate dsRNA pathways. C1 [Liu, Ruikang; Moss, Bernard] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. EM bmoss@nih.gov OI Moss, Bernard/0000-0002-2154-8564 FU HHS \ NIH \ National Institute of Allergy and Infectious Diseases (NIAID), Division of Intramural Research [1 ZIA AI000979 10] FX This work, including the efforts of Bernard Moss, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID), Division of Intramural Research (1 ZIA AI000979 10). NR 69 TC 1 Z9 1 U1 4 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD SEP PY 2016 VL 90 IS 17 BP 7864 EP 7879 DI 10.1128/JVI.00869-16 PG 16 WC Virology SC Virology GA DU6EM UT WOS:000382306800024 PM 27334583 ER PT J AU Alfano, N Michaux, J Morand, S Aplin, K Tsangaras, K Lober, U Fabre, PH Fitriana, Y Semiadi, G Ishida, Y Helgen, KM Roca, AL Eiden, MV Greenwood, AD AF Alfano, Niccolo Michaux, Johan Morand, Serge Aplin, Ken Tsangaras, Kyriakos Lober, Ulrike Fabre, Pierre-Henri Fitriana, Yuli Semiadi, Gono Ishida, Yasuko Helgen, Kristofer M. Roca, Alfred L. Eiden, Maribeth V. Greenwood, Alex D. TI Endogenous Gibbon Ape Leukemia Virus Identified in a Rodent (Melomys burtoni subsp.) from Wallacea (Indonesia) SO JOURNAL OF VIROLOGY LA English DT Article ID C-TYPE VIRUS; KOALA RETROVIRUS; HAMSTER-CELLS; MUS-CAROLI; RECEPTOR; SEQUENCE; INFECTION; RATES; GAMMARETROVIRUSES; TRANSMISSION AB Gibbon ape leukemia virus (GALV) and koala retrovirus (KoRV) most likely originated from a cross-species transmission of an ancestral retrovirus into koalas and gibbons via one or more intermediate as-yet-unknown hosts. A virus highly similar to GALV has been identified in an Australian native rodent (Melomys burtoni) after extensive screening of Australian wildlife. GALV-like viruses have also been discovered in several Southeast Asian species, although screening has not been extensive and viruses discovered to date are only distantly related to GALV. We therefore screened 26 Southeast Asian rodent species for KoRV- and GALV-like sequences, using hybridization capture and high-throughput sequencing, in the attempt to identify potential GALV and KoRV hosts. Only the individuals belonging to a newly discovered subspecies of Melomys burtoni from Indonesia were positive, yielding an endogenous provirus very closely related to a strain of GALV. The sequence of the critical receptor domain for GALV infection in the Indonesian M. burtoni subsp. was consistent with the susceptibility of the species to GALV infection. The second record of a GALV in M. burtoni provides further evidence that M. burtoni, and potentially other lineages within the widespread subfamily Murinae, may play a role in the spread of GALV-like viruses. The discovery of a GALV in the most western part of the Australo-Papuan distribution of M. burtoni, specifically in a transitional zone between Asia and Australia (Wallacea), may be relevant to the cross-species transmission to gibbons in Southeast Asia and broadens the known distribution of GALVs in wild rodents. IMPORTANCE Gibbon ape leukemia virus (GALV) and the koala retrovirus (KoRV) are very closely related, yet their hosts neither are closely related nor overlap geographically. Direct cross-species infection between koalas and gibbons is unlikely. Therefore, GALV and KoRV may have arisen via a cross-species transfer from an intermediate host whose range overlaps those of both gibbons and koalas. Using hybridization capture and high-throughput sequencing, we have screened a wide range of rodent candidate hosts from Southeast Asia for KoRV- and GALV-like sequences. Only a Melomys burtoni subspecies from Wallacea (Indonesia) was positive for GALV. We report the genome sequence of this newly identified GALV, the critical domain for infection of its potential cellular receptor, and its phylogenetic relationships with the other previously characterized GALVs. We hypothesize that Melomys burtoni, and potentially related lineages with an Australo-Papuan distribution, may have played a key role in cross-species transmission to other taxa. C1 [Alfano, Niccolo; Tsangaras, Kyriakos; Lober, Ulrike; Greenwood, Alex D.] Leibniz Inst Zoo & Wildlife Res, Berlin, Germany. [Michaux, Johan] Univ Liege, Conservat Genet Unit, Inst Bot, Liege, Belgium. [Michaux, Johan] CIRAD, Campus Int Baillarguet, Montpellier, France. [Morand, Serge] Ctr Infectiol Christophe Merieux Laos, CIRAD CNRS, Viangchan, Laos. [Aplin, Ken; Fabre, Pierre-Henri; Helgen, Kristofer M.] Smithsonian Inst, Natl Museum Nat Hist, Washington, DC 20560 USA. [Fabre, Pierre-Henri] Univ Montpellier, ISEM, UM2, IRD,CNRS,UMR 5554, Montpellier, France. [Fitriana, Yuli; Semiadi, Gono] Indonesian Inst Sci LIPI, Museum Zoologicum Bogoriense, Biol Res Ctr, Cibinong, Indonesia. [Ishida, Yasuko; Roca, Alfred L.] Univ Illinois, Dept Anim Sci, Urbana, IL USA. [Eiden, Maribeth V.] NIMH, Sect Directed Gene Transfer, Lab Cellular & Mol Regulat, NIH, Bethesda, MD 20892 USA. [Greenwood, Alex D.] Free Univ Berlin, Dept Vet Med, Berlin, Germany. [Tsangaras, Kyriakos] Cyprus Inst Neurol & Genet, Nicosia, Cyprus. RP Greenwood, AD (reprint author), Leibniz Inst Zoo & Wildlife Res, Berlin, Germany.; Greenwood, AD (reprint author), Free Univ Berlin, Dept Vet Med, Berlin, Germany. EM greenwood@izw-berlin.de FU HHS \ NIH \ National Institute of General Medical Sciences (NIGMS) [R01GM092706]; HHS \ NIH \ National Institute of Mental Health (NIMH) [ZIAMH002592]; International Max Planck Research School for Infectious Diseases and Immunology (IMPRS-IDI) at the Interdisciplinary Center of Infection Biology and Immunity (ZIBI) of Humboldt University Berlin (HU); Marie Curie Fellowship [PIOF-GA-2012-330582-CANARIP-RAT]; Center for Macroecology Evolution and Climate, University of Copenhagen, Copenhagen, Denmark FX This work, including the efforts of Yasuko Ishida, Kristofer Helgen, Alfred Roca, and Alex David Greenwood, was funded by HHS vertical bar NIH vertical bar National Institute of General Medical Sciences (NIGMS) (R01GM092706). This work, including the efforts of Maribeth Eiden, was funded by HHS vertical bar NIH vertical bar National Institute of Mental Health (NIMH) (ZIAMH002592). Niccolo Alfano was supported by the International Max Planck Research School for Infectious Diseases and Immunology (IMPRS-IDI) at the Interdisciplinary Center of Infection Biology and Immunity (ZIBI) of Humboldt University Berlin (HU). Pierre-Henri Fabre was funded by a Marie Curie Fellowship (PIOF-GA-2012-330582-CANARIP-RAT). He also acknowledges Carsten Rahbek (Center for Macroecology Evolution and Climate, University of Copenhagen, Copenhagen, Denmark) for generously funding part of his recent field research in the Moluccas. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 64 TC 2 Z9 2 U1 4 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD SEP PY 2016 VL 90 IS 18 BP 8169 EP 8180 DI 10.1128/JVI.00723-16 PG 12 WC Virology SC Virology GA DU6HD UT WOS:000382314100013 PM 27384662 ER PT J AU Okada, K Ito, N Yamaoka, S Masatani, T Ebihara, H Goto, H Nakagawa, K Mitake, H Okadera, K Sugiyama, M AF Okada, Kazuma Ito, Naoto Yamaoka, Satoko Masatani, Tatsunori Ebihara, Hideki Goto, Hideo Nakagawa, Kento Mitake, Hiromichi Okadera, Kota Sugiyama, Makoto TI Roles of the Rabies Virus Phosphoprotein Isoforms in Pathogenesis SO JOURNAL OF VIROLOGY LA English DT Article ID PML NUCLEAR-BODIES; P-PROTEIN; INTERFERON ANTAGONIST; MATRIX PROTEIN; NUCLEOPROTEIN; GENE; INVOLVEMENT; ACTIVATION; BINDING; STAT1 AB Rabies virus (RABV) P gene mRNA encodes five in-frame start codons, resulting in expression of full-length P protein (P1) and N-terminally truncated P proteins (tPs), designated P2, P3, P4, and P5. Despite the fact that some tPs are known as interferon (IFN) antagonists, the importance of tPs in the pathogenesis of RABV is still unclear. In this study, to examine whether tPs contribute to pathogenesis, we exploited a reverse genetics approach to generate CE(NiP)Delta P2- 5, a mutant of pathogenic CE(NiP) in which the P gene was mutated by replacing all of the start codons (AUG) for tPs with AUA. We confirmed that while CE(NiP) expresses detectable levels of P2 and P3, CE(NiP)Delta P2-5 has an impaired ability to express these tPs. After intramuscular inoculation, CE(NiP)Delta P2-5 caused significantly lower morbidity and mortality rates in mice than did CE(NiP), indicating that tPs play a critical role in RABV neuroinvasiveness. Further examinations revealed that this less neuroinvasive phenotype of CE(NiP)Delta P2-5 correlates with its impaired ability to replicate in muscle cells, indicative of the importance of tPs in viral replication in muscle cells. We also demonstrated that CE(NiP)Delta P2-5 infection induced a higher level of Ifn-beta gene expression in muscle cells than did CE(NiP) infection, consistent with the results of an IFN-beta promoter reporter assay suggesting that all tPs function to antagonize IFN induction in muscle cells. Taken together, our findings strongly suggest that tPs promote viral replication in muscle cells through their IFN antagonist activities and thereby support infection of peripheral nerves. IMPORTANCE Despite the fact that previous studies have demonstrated that P2 and P3 of RABV have IFN antagonist activities, the actual importance of tPs in pathogenesis has remained unclear. Here, we provide the first evidence that tPs contribute to the pathogenesis of RABV, especially its neuroinvasiveness. Our results also show the mechanism underlying the neuroinvasiveness driven by tPs, highlighting the importance of their IFN antagonist activities, which support viral replication in muscle cells. C1 [Okada, Kazuma; Ito, Naoto; Yamaoka, Satoko; Masatani, Tatsunori; Nakagawa, Kento; Mitake, Hiromichi; Okadera, Kota; Sugiyama, Makoto] Gifu Univ, United Grad Sch Vet Sci, Gifu, Japan. [Ito, Naoto; Goto, Hideo; Sugiyama, Makoto] Gifu Univ, Lab Zoonot Dis, Fac Appl Biol Sci, Gifu, Japan. [Yamaoka, Satoko; Ebihara, Hideki] NIAID, Mol Virol & Host Pathogen Interact Unit, Virol Lab, Div Intramural Res,NIH,Rocky Mt Labs, Hamilton, MT USA. [Masatani, Tatsunori] Kagoshima Univ, Joint Fac Vet Med, Transboundary Anim Dis Res Ctr, Kagoshima, Japan. RP Sugiyama, M (reprint author), Gifu Univ, United Grad Sch Vet Sci, Gifu, Japan.; Sugiyama, M (reprint author), Gifu Univ, Lab Zoonot Dis, Fac Appl Biol Sci, Gifu, Japan. EM sugiyama@gifu-u.ac.jp FU Ministry of Education, Culture, Sports, Science and Technology, Japan; Japan Society for the Promotion of Science (JSPS) [23380179, 24580424, 15K07720]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases (DIR, NIAID) FX This work, including the efforts of Makoto Sugiyama, was funded by Ministry of Education, Culture, Sports, Science and Technology, Japan. This work, including the efforts of Makoto Sugiyama, was funded by Japan Society for the Promotion of Science (JSPS) (23380179). This work, including the efforts of Naoto Ito, was funded by Japan Society for the Promotion of Science (JSPS) (24580424). This work, including the efforts of Naoto Ito, was funded by Japan Society for the Promotion of Science (JSPS) (15K07720). This work, including the efforts of Satoko Yamaoka and Hideki Ebihara, was funded by Division of Intramural Research, National Institute of Allergy and Infectious Diseases (DIR, NIAID). NR 27 TC 0 Z9 0 U1 4 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD SEP PY 2016 VL 90 IS 18 BP 8226 EP 8237 DI 10.1128/JVI.00809-16 PG 12 WC Virology SC Virology GA DU6HD UT WOS:000382314100017 PM 27384657 ER PT J AU Brown, P Juarez, B AF Brown, Patricia Juarez, Bernadette TI A word from USDA and OLAW SO LAB ANIMAL LA English DT Editorial Material C1 [Brown, Patricia] NIH, OLAW, OER, OD,HHS, Bethesda, MD USA. [Juarez, Bernadette] USDA, APHIS, AC, Miami, FL USA. RP Brown, P (reprint author), NIH, OLAW, OER, OD,HHS, Bethesda, MD USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0093-7355 EI 1548-4475 J9 LAB ANIMAL JI Lab Anim. PD SEP PY 2016 VL 45 IS 9 BP 328 EP 328 PG 1 WC Veterinary Sciences SC Veterinary Sciences GA DU4LO UT WOS:000382184300016 PM 27551800 ER PT J AU de Villiers, TJ Hall, JE Pinkerton, JV Perez, SC Reese, M Yang, C Pierroz, DD AF de Villiers, T. J. Hall, J. E. Pinkerton, J. V. Perez, S. Cerdas Reese, M. Yang, C. Pierroz, D. D. TI Revised global consensus statement on menopausal hormone therapy SO MATURITAS LA English DT Article ID WOMEN AB The following Consensus Statement is endorsed by The International Menopause Society, The North American Menopause Society, The Endocrine Society, The European Menopause and Andropause Society, The Asia Pacific Menopause Federation, The International Osteoporosis Foundation and The Federation of Latin American Menopause Societies. (C) 2016 International Menopause Society and Elsevier Ireland Ltd. All rights reserved. C1 [de Villiers, T. J.] Univ Stellenbosch, Mediclin Panorama, ZA-7500 Cape Town, Parow, South Africa. [de Villiers, T. J.] Univ Stellenbosch, Dept Gynecol, ZA-7500 Cape Town, Parow, South Africa. [Hall, J. E.] NIH, Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. [Pinkerton, J. V.] Univ Virginia Hlth Syst, Dept Obstet & Gynecol, Charlottesville, VA USA. [Perez, S. Cerdas] Hosp Cima, Dept Endocrinol, San Jose, Costa Rica. [Reese, M.] Univ Oxford, Oxford OX1 2JD, England. [Yang, C.] Mt Alvernia Hosp, Singapore, Singapore. [Pierroz, D. D.] Univ Geneva, CH-1211 Geneva 4, Switzerland. RP de Villiers, TJ (reprint author), Univ Stellenbosch, Mediclin Panorama, ZA-7500 Cape Town, Parow, South Africa.; de Villiers, TJ (reprint author), Univ Stellenbosch, Dept Gynecol, ZA-7500 Cape Town, Parow, South Africa. EM tobie@iafrica.com OI Hall, Janet/0000-0003-4644-3061 NR 6 TC 0 Z9 0 U1 4 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-5122 EI 1873-4111 J9 MATURITAS JI Maturitas PD SEP PY 2016 VL 91 BP 153 EP 155 DI 10.1016/j.maturitas.2016.06.001 PG 3 WC Geriatrics & Gerontology; Obstetrics & Gynecology SC Geriatrics & Gerontology; Obstetrics & Gynecology GA DT2QP UT WOS:000381325800021 PM 27389038 ER PT J AU Noone, AM Lund, JL Mariotto, A Cronin, K McNeel, T Deapen, D Warren, JL AF Noone, Anne-Michelle Lund, Jennifer L. Mariotto, Angela Cronin, Kathleen McNeel, Timothy Deapen, Dennis Warren, Joan L. TI Comparison of SEER Treatment Data With Medicare Claims SO MEDICAL CARE LA English DT Article DE SEER; Medicare; treatment; validation; chemotherapy ID BREAST-CANCER; UNITED-STATES; REGISTRY DATA; CHEMOTHERAPY CLAIMS; LINKED MEDICARE; HORMONE-THERAPY; CLINICAL-DATA; VALIDITY; HEALTH; VALIDATION AB Background: The population-based Surveillance, Epidemiology, and End Results (SEER) registries collect information on first-course treatment, including surgery, chemotherapy, radiation therapy, and hormone therapy. However, the SEER program does not release data on chemotherapy or hormone therapy due to uncertainties regarding data completeness. Activities are ongoing to investigate the opportunity to supplement SEER treatment data with other data sources. Methods: Using the linked SEER-Medicare data, we examined the validity of the SEER data to identify receipt of chemotherapy and radiation therapy among those aged 65 and older diagnosed from 2000 to 2006 with bladder, female breast, colorectal, lung, ovarian, pancreas, or prostate cancer and hormone therapy among men diagnosed with prostate cancer at age 65 or older. Treatment collected by SEER was compared with treatment as determined by Medicare claims, using Medicare claims as the gold standard. The kappa, sensitivity, specificity, positive predictive values, and negative predictive values were calculated for the receipt of each treatment modality. Results: The overall sensitivity of SEER data to identify chemotherapy, radiation, and hormone therapy receipt was moderate (68%, 80%, and 69%, respectively) and varied by cancer site, stage, and patient characteristics. The overall positive predictive value was high (> 85%) for all treatment types and cancer sites except chemotherapy for prostate cancer. Conclusions: SEER data should not generally be used for comparisons of treated and untreated individuals or to estimate the proportion of treated individuals in the population. Augmenting SEER data with other data sources will provide the most accurate treatment information. C1 [Noone, Anne-Michelle; Mariotto, Angela; Cronin, Kathleen] NCI, Div Canc Control & Populat Sci, Surveillance Res Program, 9609 Med Ctr Dr, Bethesda, MD 20850 USA. [Lund, Jennifer L.] Univ North Carolina Chapel Hill, Dept Epidemiol, Gillings Sch Publ Hlth, Chapel Hill, NC USA. [McNeel, Timothy] Informat Management Serv Inc, Calverton, MD USA. [Deapen, Dennis] Univ Southern Calif, Los Angeles Canc Surveillance Program, Keck Sch Med, Los Angeles, CA USA. [Warren, Joan L.] NCI, Div Canc Control & Populat Sci, Appl Res Program, Bethesda, MD 20850 USA. RP Noone, AM (reprint author), NCI, Div Canc Control & Populat Sci, Surveillance Res Program, 9609 Med Ctr Dr, Bethesda, MD 20850 USA. EM noonea@mail.nih.gov FU California Department of Public Health [103885]; National Cancer Institute's Surveillance, Epidemiology and End Results Program [HH5N261201000140C, HHSN261201000035C, HHSN261201000034C]; Centers for Disease Control and Prevention's National Program of Cancer Registries [U58DP003862-01] FX D.D. would like to acknowledge the following funding sources: The collection of cancer incidence data used in this study 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; the National Cancer Institute's Surveillance, Epidemiology and End Results Program under contract HH5N261201000140C awarded to the Cancer Prevention Institute of California, contract HHSN261201000035C awarded to the University of Southern California, and contract HHSN261201000034C awarded to the Public Health Institute; and the Centers for Disease Control and Prevention's National Program of Cancer Registries, under agreement U58DP003862-01 awarded to the California Department of Public Health. NR 28 TC 5 Z9 5 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0025-7079 EI 1537-1948 J9 MED CARE JI Med. Care PD SEP PY 2016 VL 54 IS 9 BP E55 EP E64 DI 10.1097/MLR.0000000000000073 PG 10 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA DU5JJ UT WOS:000382247700001 PM 24638121 ER PT J AU Melamed, S Peer, A Faigenbaum-Romm, R Gatt, YE Reiss, N Bar, A Altuvia, Y Argaman, L Margalit, H AF Melamed, Sahar Peer, Asaf Faigenbaum-Romm, Raya Gatt, Yair E. Reiss, Niv Bar, Amir Altuvia, Yael Argaman, Liron Margalit, Hanah TI Global Mapping of Small RNA-Target Interactions in Bacteria SO MOLECULAR CELL LA English DT Article ID GCVB SMALL RNA; ESCHERICHIA-COLI; MESSENGER-RNA; COMPARATIVE GENOMICS; SOLUBLE-RNA; ACID RESISTANCE; STRESS-RESPONSE; ANTISENSE RNAS; NONCODING RNAS; IN-VIVO AB Small RNAs (sRNAs) associated with the RNA chaperon protein Hfq are key posttranscriptional regulators of gene expression in bacteria. Deciphering the sRNA-target interactome is an essential step toward understanding the roles of sRNAs in the cellular networks. We developed a broadly applicable methodology termed RIL-seq (RNA interaction by ligation and sequencing), which integrates experimental and computational tools for in vivo transcriptome-wide identification of interactions involving Hfq-associated sRNAs. By applying this methodology to Escherichia coli we discovered an extensive network of interactions involving RNA pairs showing sequence complementarity. We expand the ensemble of targets for known sRNAs, uncover additional Hfq-bound sRNAs encoded in various genomic regions along with their trans encoded targets, and provide insights into binding and possible cycling of RNAs on Hfq. Comparison of the sRNA interactome under various conditions has revealed changes in the sRNA repertoire as well as substantial re-wiring of the network between conditions. C1 [Melamed, Sahar; Peer, Asaf; Faigenbaum-Romm, Raya; Gatt, Yair E.; Reiss, Niv; Bar, Amir; Altuvia, Yael; Argaman, Liron; Margalit, Hanah] Hebrew Univ Jerusalem, Fac Med, Inst Med Res Israel Canada, Dept Microbiol & Mol Genet, IL-9112102 Jerusalem, Israel. [Melamed, Sahar] NICHD, Div Mol & Cellular Biol, NIH, 18 Lib Dr MSC 5430, Bethesda, MD 20892 USA. RP Altuvia, Y; Argaman, L; Margalit, H (reprint author), Hebrew Univ Jerusalem, Fac Med, Inst Med Res Israel Canada, Dept Microbiol & Mol Genet, IL-9112102 Jerusalem, Israel. EM yaelal@md.huji.ac.il; liron.argaman@mail.huji.ac.il; hanahm@ekmd.huji.ac.il FU European Research Council [322920]; I-CORE Programs of the Planning and Budgeting Committee; Israel Science Foundation [1796/12, 41/1, 1411/13] FX This study was supported by the European Research Council Advanced Grant #322920, I-CORE Programs of the Planning and Budgeting Committee and The Israel Science Foundation (grants 1796/12 and 41/1), and the Israel Science Foundation administered by the Israeli Academy for Sciences and Humanities (grant 1411/13). We thank T. Kaplan for his helpful advice, R. Rehani for her contribution to the experiments, H. Aiba for the hfq-Flag strain, O. Pines for the Saccharomyces cerevisiae strain, S. Pearl-Mizrahi, O. Shechter, and M. Nitzan for technical assistance, G. Storz for work conducted by S. M. in her lab and for very helpful advice, S. Altuvia, E. Holmqvist, I. Rosenshine, and S. Ben-Yehuda for their very useful comments, and K. McDowall and J. Wade for data sharing. NR 55 TC 8 Z9 8 U1 10 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 EI 1097-4164 J9 MOL CELL JI Mol. Cell PD SEP 1 PY 2016 VL 63 IS 5 BP 884 EP 897 DI 10.1016/j.molcel.2016.07.026 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DU9MO UT WOS:000382542000016 PM 27588604 ER PT J AU Canela, A Sridharan, S Sciascia, N Tubbs, A Meltzer, P Sleckman, BP Nussenzweig, A AF Canela, Andres Sridharan, Sriram Sciascia, Nicholas Tubbs, Anthony Meltzer, Paul Sleckman, Barry P. Nussenzweig, Andre TI DNA Breaks and End Resection Measured Genome-wide by End Sequencing SO MOLECULAR CELL LA English DT Article ID DOUBLE-STRAND BREAKS; V(D)J RECOMBINATION; CELL-CYCLE; NUCLEOTIDE-RESOLUTION; TRANSCRIPTION; NUCLEASES; CANCER; DAMAGE; GENES; TRANSLOCATIONS AB DNA double-strand breaks (DSBs) arise during physiological transcription, DNA replication, and antigen receptor diversification. Mistargeting or misprocessing of DSBs can result in pathological structural variation and mutation. Here we describe a sensitive method (END-seq) to monitor DNA end resection and DSBs genome-wide at base-pair resolution in vivo. We utilized END-seq to determine the frequency and spectrum of restriction-enzyme-, zincfinger- nuclease-, and RAG-induced DSBs. Beyond sequence preference, chromatin features dictate the repertoire of these genome-modifying enzymes. END-seq can detect at least one DSB per cell among 10,000 cells not harboring DSBs, and we estimate that up to one out of 60 cells contains off-target RAG cleavage. In addition to site-specific cleavage, we detect DSBs distributed over extended regions during immunoglobulin class-switch recombination. Thus, END-seq provides a snapshot of DNA ends genome-wide, which can be utilized for understanding genome-editing specificities and the influence of chromatin on DSB pathway choice. C1 [Canela, Andres; Sridharan, Sriram; Sciascia, Nicholas; Tubbs, Anthony; Nussenzweig, Andre] NCI, Lab Genome Integr, NIH, Bethesda, MD 20892 USA. [Meltzer, Paul] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. [Sleckman, Barry P.] Weill Cornell Med Coll, Dept Pathol & Lab Med, New York, NY 10065 USA. RP Nussenzweig, A (reprint author), NCI, Lab Genome Integr, NIH, Bethesda, MD 20892 USA. EM andre_nussenzweig@nih.gov FU Intramural Research Program of the NIH, the National Cancer Institute; Center for Cancer Research FLEX Program; NIH [R01 AI074953] FX We thank Avinash Bhandoola, Ferenc Livak, Sam John, and Nicola Crosetto for stimulating discussions, and Robert L. Walker, Marbin Pineda, Gustavo Gutierrez-Cruz, Stefania Dell'Orso, and Jack Zhu for help on sequencing and data handling. This work was supported by the Intramural Research Program of the NIH, the National Cancer Institute, and by the Center for Cancer Research FLEX Program. B.P.S. was supported by NIH grant R01 AI074953. NR 58 TC 5 Z9 5 U1 14 U2 15 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 EI 1097-4164 J9 MOL CELL JI Mol. Cell PD SEP 1 PY 2016 VL 63 IS 5 BP 898 EP 911 DI 10.1016/j.molcel.2016.06.034 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DU9MO UT WOS:000382542000017 PM 27477910 ER PT J AU Dutzan, N Konkel, JE Greenwell-Wild, T Moutsopoulos, NM AF Dutzan, N. Konkel, J. E. Greenwell-Wild, T. Moutsopoulos, N. M. TI Characterization of the human immune cell network at the gingival barrier SO MUCOSAL IMMUNOLOGY LA English DT Article ID INNATE LYMPHOID-CELLS; DENDRITIC CELLS; T-CELLS; PERIODONTAL-DISEASE; BONE LOSS; IN-VIVO; PORPHYROMONAS-GINGIVALIS; LANGERHANS CELLS; ORAL-MUCOSA; MEMORY AB The oral mucosa is a barrier site constantly exposed to rich and diverse commensal microbial communities, yet little is known of the immune cell network maintaining immune homeostasis at this interface. We have performed a detailed characterization of the immune cell subsets of the oral cavity in a large cohort of healthy subjects. We focused our characterization on the gingival interface, a particularly vulnerable mucosal site, with thin epithelial lining and constant exposure to the tooth adherent biofilm. In health, we find a predominance of T cells, minimal B cells, a large presence of granulocytes/neutrophils, a sophisticated network of professional antigen-presenting cells (APCs), and a small population of innate lymphoid cells (ILCs) policing the gingival barrier. We further characterize cellular subtypes in health and interrogate shifts in immune cell populations in the common oral inflammatory disease periodontitis. In disease, we document an increase in neutrophils and an upregulation of interleukin-17(IL-17) responses. We identify the mainsource of IL-17 in health and Periodontitis within the CD4(+) T-cell compartment. Collectively, our studies provide a first view of the landscape of physiologic oral immunity and serve as a baseline for the characterization of local immunopathology. C1 [Dutzan, N.; Greenwell-Wild, T.; Moutsopoulos, N. M.] NIDCR, Oral Immun & Inflammat Unit, NIH, Bethesda, MD 20892 USA. [Konkel, J. E.] Univ Manchester, Fac Life Sci, Manchester Immunol Grp, Manchester, Lancs, England. RP Moutsopoulos, NM (reprint author), NIDCR, Oral Immun & Inflammat Unit, NIH, Bethesda, MD 20892 USA. EM nmoutsop@mail.nih.gov FU NIDCR; Wellcome Trust [097820/Z/11/B, 105610/Z/14/Z]; Manchester Collaborative Centre for Inflammation Research FX This study was funded in part by the intramural program of NIDCR (to N.M.M.), by the Wellcome Trust (097820/Z/11/B and 105610/Z/14/Z; to J.E.K.), and by the Manchester Collaborative Centre for Inflammation Research (to J.E.K.). We also thank Kal Shastri and the OP1 clinical team who provided surgical discard tissue for assay development. NR 50 TC 4 Z9 4 U1 4 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1933-0219 EI 1935-3456 J9 MUCOSAL IMMUNOL JI Mucosal Immunol. PD SEP PY 2016 VL 9 IS 5 BP 1163 EP 1172 DI 10.1038/mi.2015.136 PG 10 WC Immunology SC Immunology GA DU6IY UT WOS:000382319200006 PM 26732676 ER PT J AU Watanabe, T Sadakane, Y Yagama, N Sakurai, T Ezoe, H Kudo, M Chiba, T Strober, W AF Watanabe, T. Sadakane, Y. Yagama, N. Sakurai, T. Ezoe, H. Kudo, M. Chiba, T. Strober, W. TI Nucleotide-binding oligomerization domain 1 acts in concert with the cholecystokinin receptor agonist, cerulein, to induce IL-33-dependent chronic pancreatitis SO MUCOSAL IMMUNOLOGY LA English DT Article ID INNATE LYMPHOID-CELLS; STELLATE CELLS; TH2 CELLS; MICE; INTERLEUKIN-33; INFLAMMATION; ACTIVATION; FIBROSIS; CARCINOGENESIS; TRYPSINOGEN AB Nucleotide-binding oligomerization domain 1 (NOD1) fulfills important host-defense functions via its responses to a variety of gut pathogens. Recently, however, we showed that in acute pancreatitis caused by administration of cholecystokinin receptor (CCKR) agonist ( cerulein) NOD1 also has a role in inflammation via its responses to gut commensal organisms. In the present study, we explored the long-term outcome of such NOD1 responsiveness in a new model of chronic pancreatitis induced by repeated administration of low doses of cerulein in combination with NOD1 ligand. We found that the development of chronic pancreatitis in this model requires intact NOD1 and type I IFN signaling and that such signaling mediates a macrophage-mediated inflammatory response that supports interleukin (IL)-33 production by acinar cells. The IL-33, in turn, has a necessary role in the induction of IL-13 and TGF-beta 1, factors causing the fibrotic reaction characteristic of chronic pancreatitis. Interestingly, the Th2 effects of IL-33 were attenuated by the concomitant type I IFN response since the inflammation was marked by clear increases in IFN-gamma and TNF-alpha production but only marginal increases in IL-4 production. These studies establish chronic pancreatitis as an IL-33-dependent inflammation resulting from synergistic interactions between the NOD1 and CCKR signaling pathways. C1 [Watanabe, T.; Chiba, T.] Kyoto Univ, Grad Sch Med, Dept Gastroenterol & Hepatol, Kyoto, Kyoto, Japan. [Watanabe, T.; Sadakane, Y.; Yagama, N.; Ezoe, H.] Kyoto Univ, Grad Sch Med, Ctr Innovat Immunoregulat Technol & Therapeut, Kyoto, Kyoto, Japan. [Watanabe, T.; Strober, W.] NIAID, Mucosal Immun Sect, Lab Host Defenses, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Sakurai, T.; Kudo, M.] Kinki Univ, Grad Sch Med, Dept Gastroenterol & Hepatol, Osaka, Osaka, Japan. RP Watanabe, T (reprint author), Kyoto Univ, Grad Sch Med, Dept Gastroenterol & Hepatol, Kyoto, Kyoto, Japan.; Watanabe, T (reprint author), Kyoto Univ, Grad Sch Med, Ctr Innovat Immunoregulat Technol & Therapeut, Kyoto, Kyoto, Japan.; Watanabe, T (reprint author), NIAID, Mucosal Immun Sect, Lab Host Defenses, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM tmhrwtnb@kuhp.kyoto-u.ac.jp FU Japan Society for the Promotion of Science [25293172, 15K15370]; Japanese Society of Gastroenterology; Kato Memorial Trust for Nambyo Research; Ministry of Education, Culture, Sports, Science and Technology of Japan; Ministry of Health, Labor and Welfare, Japan; Astellas Pharma. in Creation of Innovation Centers for Advanced Interdisciplinary Research Areas Program FX This work was supported by Grant-in-Aid for Scientific Research (25293172, 15K15370) from the Japan Society for the Promotion of Science, the Japanese Society of Gastroenterology, the Kato Memorial Trust for Nambyo Research, and the Special Coordination Funds by the Ministry of Education, Culture, Sports, Science and Technology of Japan and Astellas Pharma. in Creation of Innovation Centers for Advanced Interdisciplinary Research Areas Program, and the Health and Labor Sciences Research Grants for Research on Intractable Diseases from the Ministry of Health, Labor and Welfare, Japan. NR 48 TC 1 Z9 1 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1933-0219 EI 1935-3456 J9 MUCOSAL IMMUNOL JI Mucosal Immunol. PD SEP PY 2016 VL 9 IS 5 BP 1234 EP 1249 DI 10.1038/mi.2015.144 PG 16 WC Immunology SC Immunology GA DU6IY UT WOS:000382319200012 PM 26813347 ER PT J AU Minster, RL Hawley, NL Su, CT Sun, G Kershaw, EE Cheng, H Buhule, OD Lin, J Reupena, MS Viali, S Tuitele, J Naseri, T Urban, Z Deka, R Weeks, DE McGarvey, ST AF Minster, Ryan L. Hawley, Nicola L. Su, Chi -Ting Sun, Guangyun Kershaw, Erin E. Cheng, Hong Buhule, Olive D. Lin, Jerome Reupena, Muagututia Sefuiva Viali, Satupditea Tuitele, John Naseri, Take Urban, Zsolt Deka, Ranjan Weeks, Daniel E. McGarvey, Stephen T. TI A thrifty variant in CREBRF strongly influences body mass index in Samoans SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; SAMPLE-SIZE REQUIREMENTS; HAPLOTYPE STRUCTURE; POSITIVE SELECTION; INSULIN-RESISTANCE; AMERICAN-SAMOA; OBESITY; ADIPOGENESIS; ADIPOSITY; GENE AB Samoans are a unique founder population with a high prevalence of obesity(1-3), making them well suited for identifying new genetic contributors to obesity(4). We conducted a genome-wide association study (GWAS) in 3,072 Samoans, discovered a variant, rs12513649, strongly associated with body mass index (BMI) (P = 5.3 x 10(-14)), and replicated the association in 2,102 additional Samoans (P = 1.2 x 10(-9)). Targeted sequencing identified a strongly associated missense variant, rs373863828 (p.Arg457Gln), in CREBRF (meta P = 1.4 x 10(-20)). Although this variant is extremely rare in other populations, it is common in Samoans (frequency of 0.259), with an effect size much larger than that of any other known common BMI risk variant (1.36-1.45 kg/m(2) per copy of the risk-associated allele). In comparison to wild-type CREBRF, the Arg457Gln variant when overexpressed selectively decreased energy use and increased fat storage in an adipocyte cell model. These data, in combination with evidence of positive selection of the allele encoding p.Arg457Gln, support a 'thrifty' variant hypothesis as a factor in human obesity. C1 [Minster, Ryan L.; Su, Chi -Ting; Lin, Jerome; Urban, Zsolt; Weeks, Daniel E.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA. [Hawley, Nicola L.] Yale Univ, Sch Publ Hlth, Dept Epidemiol Chron Disease, New Haven, CT USA. [Sun, Guangyun; Cheng, Hong; Deka, Ranjan] Univ Cincinnati, Coll Med, Dept Environm Hlth, Cincinnati, OH 45267 USA. [Kershaw, Erin E.] Univ Pittsburgh, Dept Med, Div Endocrinol, Pittsburgh, PA USA. [Buhule, Olive D.; Weeks, Daniel E.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. [Reupena, Muagututia Sefuiva] Govt Samoa, Bur Stat, Apia, Samoa, New Zealand. [Viali, Satupditea] Samoa Natl Hlth Serv, Apia, Samoa, New Zealand. [Tuitele, John] Amer Samoa Govt, Dept Hlth, Pago Pago, AS USA. [Naseri, Take] Govt Samoa, Minist Hlth, Apia, Samoa, New Zealand. [McGarvey, Stephen T.] Brown Univ, Sch Publ Hlth, Dept Epidemiol, Int Hlth Inst, Providence, RI 02912 USA. [McGarvey, Stephen T.] Brown Univ, Dept Anthropol, Providence, RI 02912 USA. [Su, Chi -Ting] Natl Taiwan Univ Hosp, Yun Lin Branch, Dept Internal Med, Yunlin, Taiwan. [Buhule, Olive D.] Eunice Kennedy Shrivel Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, US NIH, Bethesda, MD USA. RP McGarvey, ST (reprint author), Brown Univ, Sch Publ Hlth, Dept Epidemiol, Int Hlth Inst, Providence, RI 02912 USA.; McGarvey, ST (reprint author), Brown Univ, Dept Anthropol, Providence, RI 02912 USA. EM stephen_mcgarvey@brown.edu OI Weeks, Daniel/0000-0001-9410-7228 FU NIH [R01-HL093093, R01-AG09375, R01-HL52611, R01-DK59642, P30 ES006096, R01-DK55406, R01-HL090648, R01-DK090166]; Brown University student research funds; American Samoan Department of Health; Samoan Ministry of Health; Samoan Bureau of Statistics FX The authors would like to thank the Samoan participants of the study, and local village authorities and the many Samoan and other field workers over the years. We acknowledge the Samoan Ministry of Health and the Samoan Bureau of Statistics, and the American Samoan Department of Health for their support of this research. We also acknowledge S.S. Shiva and C.G. Corey at the University of Pittsburgh Center for Metabolism and Mitochondrial Biology for assistance with cellular bioenergetic profiling. This work was funded by NIH grants R01-HL093093 (S.T.M.), R01-AG09375 (S.T.M.), R01-HL52611 (I. Kamboh), R01-DK59642 (S.T.M.), P30 ES006096 (S.M.Ho), R01-DK55406. (R.D.), R01-HL090648 (Z.U.), and R01-DK090166 (E.E.K.) and by Brown University student research funds. Genotyping was performed in the Core Genotyping Laboratory at the University of Cincinnati, funded by NIH grant P30 ES006096 (S.M. Ho). Illumina sequencing was conducted at the Genetic Resources Core Facility, Johns Hopkins Institute of Genetic Medicine (Baltimore). NR 68 TC 4 Z9 4 U1 5 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD SEP PY 2016 VL 48 IS 9 BP 1049 EP + DI 10.1038/ng.3620 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA DU7MQ UT WOS:000382398800016 PM 27455349 ER PT J AU Notarangelo, LD Holland, SM AF Notarangelo, Luigi D. Holland, Steven M. TI Friendly fire: anti-cytokine antibodies elicited by microbes SO NATURE MEDICINE LA English DT Editorial Material ID NONTUBERCULOUS MYCOBACTERIAL INFECTIONS; IFN-GAMMA AUTOANTIBODIES; MENDELIAN SUSCEPTIBILITY AB A recent study suggests that exposure to the mold Aspergillus induces the production of antibodies that neutralize interferon-gamma (IFN-gamma), which increases the risk of mycobacterial disease. C1 [Notarangelo, Luigi D.] Harvard Med Sch, Boston Childrens Hosp, Div Immunol, Boston, MA 02115 USA. [Holland, Steven M.] NIAID, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Notarangelo, LD (reprint author), Harvard Med Sch, Boston Childrens Hosp, Div Immunol, Boston, MA 02115 USA. EM luigi.notarangelo@childrens.harvard.edu; sholland@niaid.nih.gov NR 11 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD SEP PY 2016 VL 22 IS 9 BP 973 EP 975 PG 4 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA DU9MW UT WOS:000382542800006 PM 27603131 ER PT J AU Ran, C Hoon, MA Chen, XK AF Ran, Chen Hoon, Mark A. Chen, Xiaoke TI The coding of cutaneous temperature in the spinal cord SO NATURE NEUROSCIENCE LA English DT Article ID TRPM8-EXPRESSING SENSORY NEURONS; IN-VIVO; RESPONSE CHARACTERISTICS; CAPSAICIN RECEPTOR; CELLULAR BASIS; TRP CHANNELS; ION-CHANNEL; COLD; PAIN; THERMOSENSATION AB The spinal cord is the initial stage that integrates temperature information from peripheral inputs. Here we used molecular genetics and in vivo calcium imaging to investigate the coding of cutaneous temperature in the spinal cord in mice. We found that heating or cooling the skin evoked robust calcium responses in spinal neurons, and their activation threshold temperatures distributed smoothly over the entire range of stimulation temperatures. Once activated, heat-responding neurons encoded the absolute skin temperature without adaptation and received major inputs from transient receptor potential (TRP) channel V1 (TRPV1)-positive dorsal root ganglion (DRG) neurons. By contrast, cold-responding neurons rapidly adapted to ambient temperature and selectively encoded temperature changes. These neurons received TRP channel M8 (TRPM8)-positive DRG inputs as well as novel TRPV1(+) DRG inputs that were selectively activated by intense cooling. Our results provide a comprehensive examination of the temperature representation in the spinal cord and reveal fundamental differences in the coding of heat and cold. C1 [Ran, Chen; Chen, Xiaoke] Stanford Univ, Dept Biol, Stanford, CA 94305 USA. [Hoon, Mark A.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. RP Chen, XK (reprint author), Stanford Univ, Dept Biol, Stanford, CA 94305 USA. EM xkchen@stanford.edu FU intramural research program of NIDCR; Whitehall Foundation; Terman Fellowship; Stanford University FX We thank L. Luo for his generous support during the entire project, Z. Shen for initial experiments and G. Kamalani for assistance; and B. Barres (Stanford University) and D. Julius (University of California, San Francisco) for Mgfap-cre and Trpal knockout mice. We are grateful to X. Gao, C. Guenthner, B. Weissbourd and members of the Chen laboratory for comments on the manuscript. This work was supported by grants from the intramural research program of NIDCR (M.A.H.), and the Whitehall Foundation, Terman Fellowship and start-up funding from Stanford University (X.C.). NR 50 TC 4 Z9 4 U1 7 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 EI 1546-1726 J9 NAT NEUROSCI JI Nat. Neurosci. PD SEP PY 2016 VL 19 IS 9 BP 1201 EP 1209 DI 10.1038/nn.4350 PG 9 WC Neurosciences SC Neurosciences & Neurology GA DU5SA UT WOS:000382270400019 PM 27455110 ER PT J AU Castle, PE Katki, HA AF Castle, Philip E. Katki, Hormuzd A. TI A risk-based framework to decide who benefits from screening SO NATURE REVIEWS CLINICAL ONCOLOGY LA English DT Editorial Material ID CERVICAL-CANCER; PREVENTION AB We believe that current controversies surrounding screening might be better approached by shifting the question from 'does screening work?' to 'for whom does screening work?' We propose a 'rule-out/rule-in' principle as an intellectual basis and starting point for screening. Finally, we advocate the 'equal management of equal risks' principle as an unifying framework for developing simplified and consistent screening guidelines and practice. C1 [Castle, Philip E.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, 1300 Morris Pk Ave, Bronx, NY 10461 USA. [Castle, Philip E.] Global Coalit Cerv Canc, 3800 Fairfax Dr, Arlington, VA 22203 USA. [Katki, Hormuzd A.] NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr, Rockville, MD 20850 USA. RP Castle, PE (reprint author), Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, 1300 Morris Pk Ave, Bronx, NY 10461 USA.; Castle, PE (reprint author), Global Coalit Cerv Canc, 3800 Fairfax Dr, Arlington, VA 22203 USA. EM castle.philip@gmail.com NR 11 TC 0 Z9 0 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4774 EI 1759-4782 J9 NAT REV CLIN ONCOL JI Nat. Rev. Clin. Oncol. PD SEP PY 2016 VL 13 IS 9 BP 531 EP 532 DI 10.1038/nrclinonc.2016.101 PG 2 WC Oncology SC Oncology GA DU4HS UT WOS:000382174300002 PM 27323876 ER PT J AU Keutgen, XM Hammel, P Choyke, PL Libutti, SK Jonasch, E Kebebew, E AF Keutgen, Xavier M. Hammel, Pascal Choyke, Peter L. Libutti, Steven K. Jonasch, Eric Kebebew, Electron TI Evaluation and management of pancreatic lesions in patients with von Hippel-Lindau disease SO NATURE REVIEWS CLINICAL ONCOLOGY LA English DT Review ID RENAL-CELL CARCINOMA; ENETS CONSENSUS GUIDELINES; TUMOR-SUPPRESSOR GENE; BILE-DUCT OBSTRUCTION; NEUROENDOCRINE-TUMORS; LIVER METASTASES; CLINICAL UTILITY; CHROMOGRANIN-A; JAPANESE PATIENTS; IMAGING FEATURES AB von Hippel-Lindau (VHL) disease is a heritable cancer-predisposition syndrome with multiorgan involvement. Pancreatic lesions are detected in approximately two-thirds of patients with VHL disease at some point during their lifetime. In these patients, cystic pancreatic lesions are almost exclusively benign and, unless symptomatic, do not require surgical or endoscopic intervention; however, solid pancreatic lesions can often be recognized through imaging screens, and are commonly found to be nonfunctioning pancreatic neuroendocrine tumours (pNETs) with malignant potential. The natural history of these VHL-associated pNETs is variable, and lacks clinical or imaging features that predict disease progression or metastatic potential, and generally needs to be managed more conservatively than their sporadic counterparts. Treatment options for such lesions, which range from active surveillance to surgical intervention, can nevertheless be associated with considerable morbidity and even mortality. Of note, although several guidelines have been established for the management of tumours associated with VHL syndrome, none of these have specifically focused on pancreatic lesions. Thus, we aim to characterize the types of pancreatic lesions associated with VHL disease and their natural history, to identify particular lesions that necessitate treatment, and to define what forms of treatment should be undertaken. C1 [Keutgen, Xavier M.; Kebebew, Electron] NCI, Endocrine Oncol Branch, Ctr Canc Res, NIH, Bldg 10,Room 4-5940, Bethesda, MD 20891 USA. [Hammel, Pascal] Beaujon Univ Hosp, AP HP, PRES Paris Diderot 7, Dept Digest Oncol, 100 Blvd Gen Leclerc, F-92110 Clichy, France. [Choyke, Peter L.] NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bldg 10,Room B3B69F, Bethesda, MD 20892 USA. [Libutti, Steven K.] Montefiore Med Ctr, Dept Surg, 111 East 210th St, Bronx, NY 10467 USA. [Libutti, Steven K.] Albert Einstein Coll Med, 1300 Morris Pk Ave, Bronx, NY 10461 USA. [Jonasch, Eric] Univ Texas MD Anderson Canc Ctr, Div Canc Med, Dept Genitourinary Med Oncol, 1155 Pressler St,Unit 1374, Houston, TX 77030 USA. RP Kebebew, E (reprint author), NCI, Endocrine Oncol Branch, Ctr Canc Res, NIH, Bldg 10,Room 4-5940, Bethesda, MD 20891 USA. EM kebebewe@mail.nih.gov FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health, USA FX We would like to thank the patients with von Hippel-Lindau disease who participated in our clinical protocols and their families. The work of the authors is supported in part by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health, USA. NR 89 TC 2 Z9 2 U1 4 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4774 EI 1759-4782 J9 NAT REV CLIN ONCOL JI Nat. Rev. Clin. Oncol. PD SEP PY 2016 VL 13 IS 9 BP 537 EP 549 DI 10.1038/nrclinonc.2016.37 PG 13 WC Oncology SC Oncology GA DU4HS UT WOS:000382174300005 PM 27030075 ER PT J AU Shieh, Y Eklund, M Sawaya, GF Black, WC Kramer, BS Esserman, LJ AF Shieh, Yiwey Eklund, Martin Sawaya, George F. Black, William C. Kramer, Barnett S. Esserman, Laura J. TI Population-based screening for cancer: hope and hype SO NATURE REVIEWS CLINICAL ONCOLOGY LA English DT Review ID SERVICES TASK-FORCE; CARCINOMA-IN-SITU; HIGH-VALUE CARE; BREAST-CANCER; PROSTATE-CANCER; COLORECTAL-CANCER; CERVICAL-CANCER; LUNG-CANCER; RECOMMENDATION STATEMENT; UNITED-STATES AB Several important lessons have been learnt from our experiences in screening for various cancers. Screening programmes for cervical and colorectal cancers have had the greatest success, probably because these cancers are relatively homogenous, slow-growing, and have identifiable precursors that can be detected and removed; however, identifying the true obligate precursors of invasive disease remains a challenge. With regard to screening for breast cancer and for prostate cancer, which focus on early detection of invasive cancer, preferential detection of slower-growing, localized cancers has occurred, which has led to concerns about overdiagnosis and overtreatment; programmes for early detection of invasive lung cancers are emerging, and have faced similar challenges. A crucial consideration in screening for breast, prostate, and lung cancers is their remarkable phenotypic heterogeneity, ranging from indolent to highly aggressive. Efforts have been made to address the limitations of cancer-screening programmes, providing an opportunity for cross-disciplinary learning and further advancement of the science. Current innovations are aimed at identifying the individuals who are most likely to benefit from screening, increasing the yield of consequential cancers on screening and biopsy, and using molecular tests to improve our understanding of disease biology and to tailor treatment. We discuss each of these concepts and outline a dynamic framework for continuous improvements in the field of cancer screening. C1 [Shieh, Yiwey] Univ Calif San Francisco, Dept Med, Div Gen Internal Med, 1545 Divisadero St, San Francisco, CA 94115 USA. [Eklund, Martin] Karolinska Inst, Dept Med Epidemiol & Biostat, Nobels Vag 12A, S-17177 Stockholm, Sweden. [Sawaya, George F.] Univ Calif San Francisco, Sch Med, Dept Obstet, 550 16th St, San Francisco, CA 94158 USA. [Sawaya, George F.] Univ Calif San Francisco, Sch Med, Dept Gynecol, 550 16th St, San Francisco, CA 94158 USA. [Sawaya, George F.] Univ Calif San Francisco, Sch Med, Dept Reprod Sci, 550 16th St, San Francisco, CA 94158 USA. [Black, William C.] Dartmouth Hitchcock Med Ctr, Geisel Sch Med Dartmouth, Dept Radiol, 1 Med Ctr Dr, Lebanon, NH 03756 USA. [Kramer, Barnett S.] NCI, Div Canc Prevent, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. [Esserman, Laura J.] Univ Calif San Francisco, Dept Surg, 1600 Divisadero St,Box 1710, San Francisco, CA 94115 USA. [Esserman, Laura J.] Univ Calif San Francisco, Dept Radiol, 1600 Divisadero St,Box 1710, San Francisco, CA 94115 USA. RP Esserman, LJ (reprint author), Univ Calif San Francisco, Dept Surg, 1600 Divisadero St,Box 1710, San Francisco, CA 94115 USA.; Esserman, LJ (reprint author), Univ Calif San Francisco, Dept Radiol, 1600 Divisadero St,Box 1710, San Francisco, CA 94115 USA. EM laura.esserman@ucsfmedctr.org FU NCI [R011CA169093] FX M.E. is named on four patents applications for prostate-cancer diagnostics. G.F.S. is Principal Investigator of an NCI-funded grant that aims to identify the range of reasonable options for cervical-cancer screening from a patient-centred and economic perspective (R011CA169093). Y.S., W.C.B., B.S.K., and L.J.E. declare no competing interests. NR 147 TC 2 Z9 2 U1 8 U2 16 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4774 EI 1759-4782 J9 NAT REV CLIN ONCOL JI Nat. Rev. Clin. Oncol. PD SEP PY 2016 VL 13 IS 9 BP 550 EP 565 DI 10.1038/nrclinonc.2016.50 PG 16 WC Oncology SC Oncology GA DU4HS UT WOS:000382174300006 PM 27071351 ER PT J AU Outterson, K Rex, JH Jinks, T Jackson, P Hallinan, J Karp, S Hung, DT Franceschi, F Merkeley, T Houchens, C Dixon, DM Kurilla, MG Aurigemma, R Larsen, J AF Outterson, Kevin Rex, John H. Jinks, Tim Jackson, Peter Hallinan, John Karp, Steve Hung, Deborah T. Franceschi, Francois Merkeley, Tyler Houchens, Christopher Dixon, Dennis M. Kurilla, Michael G. Aurigemma, Rosemarie Larsen, Joseph TI Accelerating global innovation to address antibacterial resistance: introducing CARB-X SO NATURE REVIEWS DRUG DISCOVERY LA English DT Editorial Material AB A global response to the chronic shortfall in antibiotic innovation is urgently needed to combat antimicrobial resistance. Here, we introduce CARB-X, a new global public-private partnership that will invest more than US$350 million in the next 5 years to accelerate the progression of a diverse portfolio of innovative antibacterial products into clinical trials. C1 [Outterson, Kevin] Boston Univ, Sch Law, Boston, MA 02215 USA. [Outterson, Kevin] Chatham House, London SW1Y 4LE, England. [Rex, John H.] AstraZeneca, Waltham, MA 02451 USA. [Rex, John H.] Univ Texas Houston, Sch Med, Houston, TX 77225 USA. [Jinks, Tim] Wellcome Trust Res Labs, London NW1 2BE, England. [Jackson, Peter] AMR Ctr, Alderley Pk, Macclesfield SK10 4TG, Cheshire, England. [Hallinan, John] Mass Bio, Cambridge, MA 02139 USA. [Karp, Steve] Calif Life Sci Inst, San Francisco, CA 94080 USA. [Hung, Deborah T.] Broad Inst, Cambridge, MA 02142 USA. [Hung, Deborah T.] Harvard Med Sch, Boston, MA 02215 USA. [Hung, Deborah T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Franceschi, Francois; Dixon, Dennis M.; Kurilla, Michael G.; Aurigemma, Rosemarie] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Merkeley, Tyler; Houchens, Christopher; Larsen, Joseph] Biomed Adv Res & Dev Author, Washington, DC 20201 USA. RP Outterson, K (reprint author), Boston Univ, Sch Law, Boston, MA 02215 USA.; Outterson, K (reprint author), Chatham House, London SW1Y 4LE, England. EM mko@bu.edu NR 4 TC 3 Z9 3 U1 5 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1776 EI 1474-1784 J9 NAT REV DRUG DISCOV JI Nat. Rev. Drug Discov. PD SEP PY 2016 VL 15 IS 9 BP 589 EP 590 DI 10.1038/nrd.2016.155 PG 2 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA DU9JI UT WOS:000382532500001 PM 27469032 ER PT J AU Feigin, VL Norrving, B George, MG Foltz, JL Roth, GA Mensah, GA AF Feigin, Valery L. Norrving, Bo George, Mary G. Foltz, Jennifer L. Roth, Gregory A. Mensah, George A. TI Prevention of stroke: a strategic global imperative SO NATURE REVIEWS NEUROLOGY LA English DT Review ID RANDOMIZED-CONTROLLED-TRIAL; CARDIOVASCULAR-DISEASE PREVENTION; COMPARATIVE RISK-ASSESSMENT; AMERICAN-HEART-ASSOCIATION; LOW-INCOME COUNTRIES; HEALTHY LIFE-STYLE; SMARTPHONE APPLICATION; ATRIAL-FIBRILLATION; MOBILE PHONE; SYSTEMATIC ANALYSIS AB The increasing global stroke burden strongly suggests that currently implemented primary stroke prevention strategies are not sufficiently effective, and new primary prevention strategies with larger effect sizes are needed. Here, we review the latest stroke epidemiology literature, with an emphasis on the recently published Global Burden of Disease 2013 Study estimates; highlight the problems with current primary stroke and cardiovascular disease (CVD) prevention strategies; and outline new developments in primary stroke and CVD prevention. We also suggest key priorities for the future, including comprehensive prevention strategies that target people at all levels of CVD risk; implementation of an integrated approach to promote healthy behaviours and reduce health disparities; capitalizing on information technology to advance prevention approaches and techniques; and incorporation of culturally appropriate education about healthy lifestyles into standard education curricula early in life. Given the already immense and fast-increasing burden of stroke and other major noncommunicable diseases (NCDs), which threatens worldwide sustainability, governments of all countries should develop and implement an emergency action plan addressing the primary prevention of NCDs, possibly including taxation strategies to tackle unhealthy behaviours that increase the risk of stroke and other NCDs. C1 [Feigin, Valery L.] Auckland Univ Technol, Natl Inst Stroke & Appl Neurosci, Sch Rehabil & Occupat Studies, Sch Publ Hlth & Psychosocial Studies,Fac Hlth & E, North Shore Campus,AA254,90 Akoranga Dr, Auckland 1142, New Zealand. [Norrving, Bo] Lund Univ, Dept Clin Sci, Neurol, Paradisgatan 2, Lund, Sweden. [George, Mary G.; Foltz, Jennifer L.] Ctr Dis Control & Prevent, Div Heart Dis & Stroke Prevent, 600 Clifton Rd, Atlanta, GA 30333 USA. [Roth, Gregory A.] Univ Washington, Inst Hlth Metr & Evaluat, 2301 5th Ave,Suite 600, Seattle, WA 98121 USA. [Roth, Gregory A.] Univ Washington, Sch Med, Div Cardiol, 2301 5th Ave,Suite 600, Seattle, WA 98121 USA. [Mensah, George A.] NHLBI, CTRIS, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Mensah, George A.] NHLBI, Div Cardiovasc Sci, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Feigin, VL (reprint author), Auckland Univ Technol, Natl Inst Stroke & Appl Neurosci, Sch Rehabil & Occupat Studies, Sch Publ Hlth & Psychosocial Studies,Fac Hlth & E, North Shore Campus,AA254,90 Akoranga Dr, Auckland 1142, New Zealand. EM valery.feigin@aut.ac.nz FU Health Council of New Zealand; Brain Research New Zealand Centre of Research Excellence; "Ageing Well" Programme of the National Science Challenge; Ministry of Business, Innovation and Employment of New Zealand; US National Institute on Ageing and Medtronic Philanthropy FX V.L.F. was partly funded by the Health Council of New Zealand, the Brain Research New Zealand Centre of Research Excellence, the "Ageing Well" Programme of the National Science Challenge, and the Ministry of Business, Innovation and Employment of New Zealand. G.A.R. has grant funding from the US National Institute on Ageing and Medtronic Philanthropy. We would like to thank Barbara Bowman at the Centers for Disease Control and Prevention for her valuable comments on early version of the manuscript. The views expressed in this article are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; NIH; Centers for Disease Control and Prevention; or the U.S. Department of Health and Human Services. NR 175 TC 5 Z9 5 U1 11 U2 14 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4758 EI 1759-4766 J9 NAT REV NEUROL JI Nat. Rev. Neurol. PD SEP PY 2016 VL 12 IS 9 BP 501 EP 512 DI 10.1038/nrneurol.2016.107 PG 12 WC Clinical Neurology SC Neurosciences & Neurology GA DU2BW UT WOS:000382017000004 PM 27448185 ER PT J AU Joyce, MG Zhang, BS Ou, L Chen, M Chuang, GY Druz, A Kong, WP Lai, YT Rundlet, EJ Tsybovsky, Y Yang, YP Georgiev, IS Guttman, M Lees, CR Pancera, M Sastry, M Soto, C Stewart-Jones, GBE Thomas, PV Van Galen, JG Baxa, U Lee, KK Mascola, JR Graham, BS Kwong, PD AF Joyce, M. Gordon Zhang, Baoshan Ou, Li Chen, Man Chuang, Gwo-Yu Druz, Aliaksandr Kong, Wing-Pui Lai, Yen-Ting Rundlet, Emily J. Tsybovsky, Yaroslav Yang, Yongping Georgiev, Ivelin S. Guttman, Miklos Lees, Christopher R. Pancera, Marie Sastry, Mallika Soto, Cinque Stewart-Jones, Guillaume B. E. Thomas, Paul V. Van Galen, Joseph G. Baxa, Ulrich Lee, Kelly K. Mascola, John R. Graham, Barney S. Kwong, Peter D. TI Iterative structure-based improvement of a fusion-glycoprotein vaccine against RSV SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID RESPIRATORY SYNCYTIAL-VIRUS; MONOCLONAL-ANTIBODY; NEUTRALIZING ANTIBODY; MEMBRANE-FUSION; F GLYCOPROTEIN; PREFUSION FORM; HIV-1 ENV; HALF-LIFE; PROTEIN; INFECTION AB Structure-based design of vaccines, particularly the iterative optimization used so successfully in the structure-based design of drugs, has been a long-sought goal. We previously developed a first-generation vaccine antigen called DS-Cav1, comprising a prefusion-stabilized form of the fusion (F) glycoprotein, which elicits high-titer protective responses against respiratory syncytial virus (RSV) in mice and macaques. Here we report the improvement of DS-Cav1 through iterative cycles of structure-based design that significantly increased the titer of RSV-protective responses. The resultant second-generation 'DS2'-stabilized immunogens have their F subunits genetically linked, their fusion peptides deleted and their interprotomer movements stabilized by an additional disulfide bond. These DS2 immunogens are promising vaccine candidates with superior attributes, such as their lack of a requirement for furin cleavage and their increased antigenic stability against heat inactivation. The iterative structure-based improvement described here may have utility in the Optimization of other vaccine antigens. C1 [Joyce, M. Gordon; Zhang, Baoshan; Ou, Li; Chen, Man; Chuang, Gwo-Yu; Druz, Aliaksandr; Kong, Wing-Pui; Lai, Yen-Ting; Rundlet, Emily J.; Yang, Yongping; Georgiev, Ivelin S.; Lees, Christopher R.; Pancera, Marie; Sastry, Mallika; Soto, Cinque; Stewart-Jones, Guillaume B. E.; Thomas, Paul V.; Van Galen, Joseph G.; Mascola, John R.; Graham, Barney S.; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Tsybovsky, Yaroslav; Baxa, Ulrich] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Electron Microscopy Lab, Canc Res Technol Program, Frederick, MD USA. [Guttman, Miklos; Lee, Kelly K.] Univ Washington, Dept Med Chem, Seattle, WA 98195 USA. RP Kwong, PD (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM pdkwong@nih.gov FU Intramural Research Program of the Vaccine Research Center; National Institute of Allergy and Infectious Diseases; National Institutes of Health; Gates Foundation Global Health Vaccine Accelerator Platform (GH-VAP) [OPP1126258]; Federal funds from Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E]; Leidos Biomedical Research, Inc.; US Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-76SF00515, W-31-109-Eng-38] FX We thank M. Moore and A. Hotard (Department of Pediatrics, Emory University, and Children's Healthcare of Atlanta) for engineered RSVs used in neutralization assays and protocols. We thank J. Stuckey for assistance with figures, and L. Shapiro and members of the Structural Biology Section, the Structural Bioinformatics Core Section, the Virology Core Section of the Virology Laboratory and the Viral Pathogenesis Laboratory, Vaccine Research Center, NIAID, NIH for discussions and comments on the manuscript. Funding was provided by the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health for M.G.J., B.Z., L.O., M.C., G.-Y.C., A.D., W.-P.K., E.J.R., Y.T., Y.Y., I.S.G., C.R.L., M.P., M.S., C.S., G.B.E.S.-J., P.V.T., J.G.V.G., J.R.M., B.S.G. and P.D.K., and by the Gates Foundation Global Health Vaccine Accelerator Platform (GH-VAP), no. OPP1126258, to M.G. and K.K.L. This project was funded in part by Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E. Leidos Biomedical Research, Inc. provided support in the form of salaries for Y.T. and U.B. Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory by M.G. and K.K.L. was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract no. DE-AC02-76SF00515. Use of sector 22 (Southeast Region Collaborative Access team) at the Advanced Photon Source by M.G.J. and P.D.K. was supported by the US Department of Energy, Basic Energy Sciences, Office of Science, under contract no. W-31-109-Eng-38. NR 51 TC 4 Z9 4 U1 19 U2 21 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 EI 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD SEP PY 2016 VL 23 IS 9 BP 811 EP 820 DI 10.1038/nsmb.3267 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA DV1WL UT WOS:000382712700009 PM 27478931 ER PT J AU Sousa, R Liao, HS Cuellar, J Jin, SP Valpuesta, JM Jin, AJ Lafer, EM AF Sousa, Rui Liao, Hsien-Shun Cuellar, Jorge Jin, Suping Valpuesta, Jose M. Jin, Albert J. Lafer, Eileen M. TI Clathrin-coat disassembly illuminates the mechanisms of Hsp70 force generation SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID MOLECULAR CHAPERONE HSC70; SHOCK COGNATE PROTEIN; STRUCTURAL BASIS; AUXILIN; ATP; BINDING; HSP110; DISAGGREGATION; ASSOCIATION; DYNAMICS AB Hsp70s use ATP hydrolysis to disrupt protein-protein associations and to move macromolecules. One example is the Hsc70-mediated disassembly of the clathrin coats that form on vesicles during endocytosis. Here, we exploited the exceptional features of these coats to test three models Brownian ratchet, power-stroke and entropic pulling proposed to explain how Hsp70s transform their substrates. Our data rule out the ratchet and power-stroke models and instead support a collision-pressure mechanism whereby collisions between clathrin-coat walls and Hsc70s drive coats apart. Collision pressure is the complement to the pulling force described in the entropic pulling model. We also found that self-association augments collision pressure, thereby allowing disassembly of clathrin lattices that have been predicted to be resistant to disassembly. These results illuminate how Hsp70s generate the forces that transform their substrates. C1 [Sousa, Rui; Jin, Suping; Lafer, Eileen M.] Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, San Antonio, TX 78229 USA. [Sousa, Rui; Jin, Suping; Lafer, Eileen M.] Univ Texas Hlth Sci Ctr San Antonio, Ctr Biomed Neurosci, San Antonio, TX 78229 USA. [Liao, Hsien-Shun; Jin, Albert J.] Natl Inst Biomed Imaging & Bioengn, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD USA. [Cuellar, Jorge; Valpuesta, Jose M.] CSIC, CNB, Dept Macromol Struct, Madrid, Spain. [Liao, Hsien-Shun] Natl Taiwan Univ, Dept Mech Engn, Taipei, Taiwan. RP Sousa, R (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, San Antonio, TX 78229 USA.; Sousa, R (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Ctr Biomed Neurosci, San Antonio, TX 78229 USA. EM sousa@uthscsa.edu OI Cuellar, Jorge/0000-0002-7789-807X; Valpuesta, Jose/0000-0001-7468-8053 FU NIH Intramural Research Program (NIBIB); Spanish Ministry of Economy and Innovation [BFU2013-44202]; Madrid Regional Government [S2013/MIT-2807]; Taiwan National Science Council [NSC103-2917-I-564-072]; [NS029051]; [GM118933] FX We thank L. Wang of UTHSCSA for technical assistance; T. Kirchhausen of HMS for CHC cDNA; C. Brantner and D. Sackett of NICHD, the NHLBI EM Core Facility for help with EM at an early stage of the work; and D. Sackett and R. Nossal at NICHD, D. Luque from ISCIII and J. Stachowiak from UT-Austin for helpful discussions. This work was supported by NS029051 (to E.M.L.) and GM118933 (to E.M.L. and R.S.); the NIH Intramural Research Program (NIBIB); and by grants BFU2013-44202 from the Spanish Ministry of Economy and Innovation and S2013/MIT-2807 from the Madrid Regional Government to J.M.V. H.-S.L. was supported in part by a scholarship from the Taiwan National Science Council (NSC103-2917-I-564-072). NR 48 TC 2 Z9 2 U1 7 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 EI 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD SEP PY 2016 VL 23 IS 9 BP 821 EP 829 DI 10.1038/nsmb.3272 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA DV1WL UT WOS:000382712700010 PM 27478930 ER PT J AU Bjorn-Yoshimoto, WE Underhill, SM AF Bjorn-Yoshimoto, Walden E. Underhill, Suzanne M. TI The importance of the excitatory amino acid transporter 3 (EAAT3) SO NEUROCHEMISTRY INTERNATIONAL LA English DT Article DE EAAT3; Glutamate transporter ID OBSESSIVE-COMPULSIVE DISORDER; NEURONAL GLUTAMATE TRANSPORTER; CYSTINE/GLUTAMATE EXCHANGE TRANSPORTER; FAMILY-BASED ASSOCIATION; HAN CHINESE POPULATION; RAT-BRAIN; GENE SLC1A1; CEREBRAL-ISCHEMIA; MEMBRANE TOPOLOGY; ANION CONDUCTANCE AB The neuronal excitatory amino acid transporter 3 (EAAT3) is fairly ubiquitously expressed in the brain, though it does not necessarily maintain the same function everywhere. It is important in maintaining low local concentrations of glutamate, where its predominant post-synaptic localization can buffer nearby glutamate receptors and modulate excitatory neurotransmission and synaptic plasticity. It is also the main neuronal cysteine uptake system acting as the rate-limiting factor for the synthesis of glutathione, a potent antioxidant, in EAAT3 expressing neurons, while on GABAergic neurons, it is important in supplying glutamate as a precursor for GABA synthesis. Several diseases implicate EAAT3, and modulation of this transporter could prove a useful therapeutic approach. Regulation of EAAT3 could be targeted at several points for functional modulation, including the level of transcription, trafficking and direct pharmacological modulation, and indeed, compounds and experimental treatments have been identified that regulate EAAT3 function at different stages, which together with observations of EAAT3 regulation in patients is giving us insight into the endogenous function of this transporter, as well as the consequences of altered function. This review summarizes work done on elucidating the role and regulation of EAAT3. Published by Elsevier Ltd. C1 [Bjorn-Yoshimoto, Walden E.] Univ Copenhagen, Fac Hlth & Med Sci, Dept Drug Design & Pharmacol, Univ Pk 2, DK-2100 Copenhagen O, Denmark. [Underhill, Suzanne M.] NIMH, NIH, 35 Convent Dr Room 3A 210 MSC3742, Bethesda, MD 20892 USA. RP Underhill, SM (reprint author), NIMH, NIH, 35 Convent Dr Room 3A 210 MSC3742, Bethesda, MD 20892 USA. EM smunderhill@yahoo.com OI Bjorn-Yoshimoto, Walden Emil/0000-0003-1019-9239 FU Danish Medical Research Council; NIMH Division of Intramural Research FX This work is supported in part by The Danish Medical Research Council (W.E.B.) and the NIMH Division of Intramural Research (S.M.U.) This work was written as part of Suzanne Underhill's official duties as a Government employee. The views expressed in this article do not necessarily represent the views of the NIMH, NIH, HHS, or the United States Government. NR 97 TC 1 Z9 1 U1 8 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0197-0186 EI 1872-9754 J9 NEUROCHEM INT JI Neurochem. Int. PD SEP PY 2016 VL 98 SI SI BP 4 EP 18 DI 10.1016/j.neuint.2016.05.007 PG 15 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA DT5QH UT WOS:000381537200002 PM 27233497 ER PT J AU Cohen, MS Chen, YQ McCauley, M Gamble, T Hosseinipour, MC Kumarasamy, N Hakim, JG Kumwenda, J Grinsztejn, B Pilotto, JHS Godbole, SV Chariyalertsak, S Santos, BR Mayer, KH Hoffman, IF Eshleman, SH Piwowar-Manning, E Cottle, L Zhang, XC Makhema, J Mills, LA Panchia, R Faesen, S Eron, J Gallant, J Havlir, D Swindells, S Elharrar, V Burns, D Taha, TE Nielsen-Saines, K Celentano, DD Essex, M Hudelson, SE Redd, AD Fleming, TR AF Cohen, M. S. Chen, Y. Q. McCauley, M. Gamble, T. Hosseinipour, M. C. Kumarasamy, N. Hakim, J. G. Kumwenda, J. Grinsztejn, B. Pilotto, J. H. S. Godbole, S. V. Chariyalertsak, S. Santos, B. R. Mayer, K. H. Hoffman, I. F. Eshleman, S. H. Piwowar-Manning, E. Cottle, L. Zhang, X. C. Makhema, J. Mills, L. A. Panchia, R. Faesen, S. Eron, J. Gallant, J. Havlir, D. Swindells, S. Elharrar, V. Burns, D. Taha, T. E. Nielsen-Saines, K. Celentano, D. D. Essex, M. Hudelson, S. E. Redd, A. D. Fleming, T. R. CA HPTN 052 Study Team TI Antiretroviral Therapy for the Prevention of HIV-1 Transmission SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID SERODISCORDANT COUPLES; RANDOMIZED-TRIAL; VIRAL LOAD; HPTN 052; INFECTION; POPULATION; CHALLENGES; INITIATION AB BACKGROUND An interim analysis of data from the HIV Prevention Trials Network (HPTN) 052 trial showed that antiretroviral therapy (ART) prevented more than 96% of genetically linked infections caused by human immunodeficiency virus type 1 (HIV-1) in serodiscordant couples. ART was then offered to all patients with HIV-1 infection (index participants). The study included more than 5 years of follow-up to assess the durability of such therapy for the prevention of HIV-1 transmission. METHODS We randomly assigned 1763 index participants to receive either early or delayed ART. In the early-ART group, 886 participants started therapy at enrollment (CD4+ count, 350 to 550 cells per cubic millimeter). In the delayed-ART group, 877 participants started therapy after two consecutive CD4+ counts fell below 250 cells per cubic millimeter or if an illness indicative of the acquired immunodeficiency syndrome (i.e., an AIDS-defining illness) developed. The primary study end point was the diagnosis of genetically linked HIV-1 infection in the previously HIV-1-negative partner in an intention-to-treat analysis. RESULTS Index participants were followed for 10,031 person-years; partners were followed for 8509 person-years. Among partners, 78 HIV-1 infections were observed during the trial (annual incidence, 0.9%; 95% confidence interval [CI], 0.7 to 1.1). Viral-linkage status was determined for 72 (92%) of the partner infections. Of these infections, 46 were linked (3 in the early-ART group and 43 in the delayed-ART group; incidence, 0.5%; 95% CI, 0.4 to 0.7) and 26 were unlinked (14 in the early-ART group and 12 in the delayed-ART group; incidence, 0.3%; 95% CI, 0.2 to 0.4). Early ART was associated with a 93% lower risk of linked partner infection than was delayed ART (hazard ratio, 0.07; 95% CI, 0.02 to 0.22). No linked infections were observed when HIV-1 infection was stably suppressed by ART in the index participant. CONCLUSIONS The early initiation of ART led to a sustained decrease in genetically linked HIV-1 infections in sexual partners. (Funded by the National Institute of Allergy and Infectious Diseases; HPTN 052 ClinicalTrials.gov number, NCT00074581.) C1 [Cohen, M. S.; Hosseinipour, M. C.; Hoffman, I. F.; Eron, J.] Univ North Carolina Chapel Hill, Dept Med, Chapel Hill, NC USA. [Chen, Y. Q.; Zhang, X. C.] Fred Hutchinson Canc Res Ctr, Div Vaccine & Infect Dis, 1124 Columbia St, Seattle, WA 98104 USA. [Chen, Y. Q.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Cottle, L.] Fred Hutchinson Canc Res Ctr, Stat Ctr HIV AIDS Res & Prevent, 1124 Columbia St, Seattle, WA 98104 USA. [Fleming, T. R.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [McCauley, M.] FHI 360, Washington, DC USA. [Gamble, T.] FHI 360, Durham, NC USA. [Kumarasamy, N.] YR Gaitonde Ctr AIDS Res & Educ, Madras, Tamil Nadu, India. [Godbole, S. V.] Natl AIDS Res Inst, Pune, Maharashtra, India. [Hakim, J. G.] Univ Zimbabwe, Harare, Zimbabwe. [Kumwenda, J.] Johns Hopkins Project, Coll Med, Blantyre, Malawi. [Grinsztejn, B.] Inst Pesquisa Clin Evandro Chagas, Rio De Janeiro, Brazil. [Pilotto, J. H. S.] Hosp Geral Nova Iguacu, Rio De Janeiro, Brazil. [Pilotto, J. H. S.] Fiocruz MS, IOC, Lab AIDS & Imunol Mol, Rio De Janeiro, Brazil. [Santos, B. R.] Hosp Nossa Senhora Conceicao GHC, Serv Infectol, Porto Alegre, RS, Brazil. [Chariyalertsak, S.] Chiang Mai Univ, Res Inst Hlth Sci, Chiang Mai, Thailand. [Mayer, K. H.] Fenway Inst, Boston, MA USA. [Essex, M.] Harvard Sch Publ Hlth, Boston, MA USA. [Eshleman, S. H.; Piwowar-Manning, E.; Hudelson, S. E.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Redd, A. D.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Taha, T. E.] Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Celentano, D. D.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Elharrar, V.; Burns, D.] NIAID, Div Aids, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Redd, A. D.] NIAID, Immunoregulat Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Makhema, J.] Botswana Harvard AIDS Inst, Gaborone, Botswana. [Mills, L. A.] Ctr Dis Control & Prevent CDC, Div HIV AIDS Prevent, KEMRI CDC Res & Publ Hlth Collaborat HIV Res Bran, Kisumu, Kenya. [Panchia, R.] Univ Witwatersrand, Perinatal HIV Res Unit, Johannesburg, South Africa. [Faesen, S.] Univ Witwatersrand, Clin HIV Res Unit, Dept Med, Fac Hlth Sci, Johannesburg, South Africa. [Gallant, J.] Southwest CARE Ctr, Santa Fe, NM USA. [Havlir, D.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Swindells, S.] Univ Nebraska Med Ctr, Omaha, NE USA. [Nielsen-Saines, K.] David Geffen UCLA Sch Med, Div Infect Dis, Los Angeles, CA USA. RP Cohen, MS (reprint author), Univ N Carolina, Inst Global Hlth & Infect Dis, Bioinformat Bldg,2nd Fl,130 Mason Farm Rd, Chapel Hill, NC 27599 USA. EM mscohen@med.unc.edu FU National Institute of Allergy and Infectious Diseases [HPTN 052] FX Funded by the National Institute of Allergy and Infectious Diseases; HPTN 052 ClinicalTrials.gov number, NCT00074581. NR 29 TC 28 Z9 29 U1 9 U2 10 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 1 PY 2016 VL 375 IS 9 BP 830 EP 839 DI 10.1056/NEJMoa1600693 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA DU9HA UT WOS:000382526000006 PM 27424812 ER PT J AU Chaturvedi, AK D'Souza, G Gillison, ML Katki, HA AF Chaturvedi, Anil K. D'Souza, Gypsyamber Gillison, Maura L. Katki, Hormuzd A. TI Burden of HPV-positive oropharynx cancers among ever and never smokers in the US population SO ORAL ONCOLOGY LA English DT Article DE HPV; Oropharynx cancers; Smoking; NHANES ID SQUAMOUS-CELL CARCINOMA; HUMAN-PAPILLOMAVIRUS INFECTION; UNITED-STATES; NECK-CANCER; SEXUAL-BEHAVIORS; ORAL-CANCER; HEAD; SURVIVAL; RISK; ASSOCIATION AB Background: HPV-positive oropharynx cancer is frequently characterized as a disease of never-smokers due to higher HPV prevalence in oropharynx tumors among never-smokers than ever-smokers. We sought to estimate the burden (incidence rates and case counts) of HPV-positive oropharynx cancers among never, former, and current smokers in the US population by combining data from several sources. Methods: We decomposed the SEER population-level incidence of oropharynx cancers into rates among never-, former-, and current-smokers using a formula based upon rate ratios (RR) for the smoking-oropharynx cancer association (NIH-AARP cohort study) and smoking prevalence in the U.S. population (NHANES 2007/2008). These rates were multiplied by smoking strata-specific HPV prevalence in oropharynx cancer patients (RTOG0129) to estimate incidence of HPV-positive and HPV-negative oropharynx cancers, which were applied to the US population of smokers to calculate annual case counts. Analyses were conducted overall and gender-stratified. Results: The incidence of HPV-positive oropharynx cancers was significantly higher among ever versus never- smokers in the US population aged 20+ years during 2007/2008 (RR = 1.81; 95%CI = 1.32-2.47), including significantly higher incidence in current smokers (RR = 2.26; 95% CI = 1.60-3.21) and former smokers (RR = 1.38; 95% CI = 1.02-1.85). Of the estimated 6677 (5418 in men and 1259 in women) annually incident HPV-positive oropharynx cancers in the U.S during 2007/2008, 63.3% arose among ever smokers and 36.7% among never- smokers (p < 0.001). In both men and women, incidence rates and annual cases of HPV-positive oropharynx cancers were higher in ever smokers versus never smokers. Conclusions: The population-level burden of HPV-positive oropharynx cancers is significantly higher among ever-smokers than never- smokers in the U.S. Published by Elsevier Ltd. C1 [Chaturvedi, Anil K.; Katki, Hormuzd A.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [D'Souza, Gypsyamber] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Gillison, Maura L.] Ohio State Univ, Columbus, OH 43210 USA. RP Chaturvedi, AK (reprint author), NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr,Rm 6-E238, Rockville, MD 20850 USA. EM chaturva@mail.nih.gov FU Intramural Research Program of the National Cancer Institute FX This work was supported in part by the Intramural Research Program of the National Cancer Institute. NR 37 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1368-8375 EI 1879-0593 J9 ORAL ONCOL JI Oral Oncol. PD SEP PY 2016 VL 60 BP 61 EP 67 DI 10.1016/j.oraloncology.2016.06.006 PG 7 WC Oncology; Dentistry, Oral Surgery & Medicine SC Oncology; Dentistry, Oral Surgery & Medicine GA DU5DP UT WOS:000382232700010 PM 27531874 ER PT J AU Shridhar, K Walia, GK Aggarwal, A Gulati, S Geetha, AV Prabhakaran, D Dhillon, PK Rajaraman, P AF Shridhar, Krithiga Walia, Gagandeep Kaur Aggarwal, Aastha Gulati, Smriti Geetha, A. V. Prabhakaran, Dorairaj Dhillon, Preet K. Rajaraman, Preetha TI DNA methylation markers for oral pre-cancer progression: A critical review (vol 53, pg 1, 2015) SO ORAL ONCOLOGY LA English DT Correction C1 [Shridhar, Krithiga; Walia, Gagandeep Kaur; Aggarwal, Aastha; Gulati, Smriti; Geetha, A. V.; Prabhakaran, Dorairaj; Dhillon, Preet K.] Publ Hlth Fdn India, Ctr Chron Condit & Injuries, 4th Floor,Plot 47,Sect 44, Gurgaon 122002, Haryana, India. [Prabhakaran, Dorairaj] Ctr Chron Dis Control, Gurgaon, Haryana, India. [Prabhakaran, Dorairaj] London Sch Hyg & Trop Med, London, England. [Rajaraman, Preetha] NCI, Ctr Global Hlth, NIH, DHHS, Bethesda, MD 20892 USA. RP Shridhar, K (reprint author), Publ Hlth Fdn India, Ctr Chron Condit & Injuries, 4th Floor,Plot 47,Sect 44, Gurgaon 122002, Haryana, India. EM g.krithiga@phfi.org NR 1 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1368-8375 EI 1879-0593 J9 ORAL ONCOL JI Oral Oncol. PD SEP PY 2016 VL 60 BP E1 EP E1 DI 10.1016/j.oraloncology.2016.07.011 PG 1 WC Oncology; Dentistry, Oral Surgery & Medicine SC Oncology; Dentistry, Oral Surgery & Medicine GA DU5DP UT WOS:000382232700001 ER PT J AU Harun, A Oh, ES Bigelow, RT Studenski, S Agrawal, Y AF Harun, Aisha Oh, Esther S. Bigelow, Robin T. Studenski, Stephanie Agrawal, Yuri TI Vestibular Impairment in Dementia SO OTOLOGY & NEUROTOLOGY LA English DT Article DE Cognitive impairment; Dementia; Vestibular dysfunction ID MILD COGNITIVE IMPAIRMENT; ALZHEIMERS ASSOCIATION WORKGROUPS; SPATIAL MEMORY; VESTIBULOOCULAR REFLEX; DIAGNOSTIC GUIDELINES; VISUOSPATIAL ABILITY; NATIONAL INSTITUTE; VIDEO-OCULOGRAPHY; OLDER INDIVIDUALS; MENTAL-IMAGERY AB Objective: Recent studies suggest an association between vestibular and cognitive function. The goal of the study was to investigate whether vestibular function was impaired in individuals with mild cognitive impairment (MCI) and Alzheimer's disease (AD) compared with cognitively normal individuals. Study Design: Cross-sectional study. Setting: Outpatient memory clinic and longitudinal observational study unit. Patients: Older individuals >= 55 years with MCI or AD. Age, sex, and education-matched normal controls were drawn from the Baltimore Longitudinal Study of Aging (BLSA). Intervention: Saccular and utricular function was assessed with cervical and ocular vestibular-evoked myogenic potentials (c- and oVEMPs) respectively, and horizontal semicircular canal function was assessed with video head impulse testing. Main Outcome Measures: Presence or absence of VEMP responses, VEMP amplitude, and vestibular ocular reflex (VOR) gain were measured. Results: Forty-seven individuals with cognitive impairment (MCI N = 15 and AD N = 32) underwent testing and were matched with 94 controls. In adjusted analyses, bilaterally absent cVEMPs were associated with an over three-fold odds of AD (OR 3.42, 95% CI 1.33-8.91, p = 0.011). One microvolt increases in both cVEMP and oVEMP amplitudes were associated with decreased odds of AD (OR 0.28, 95% CI 0.09-0.93, p = 0.038 and OR 0.92, 95% CI 0.85-0.99, p = 0.036, respectively). There was no significant difference in VOR gain between the groups. Conclusions: These findings confirm and extend emerging evidence of an association between vestibular dysfunction and cognitive impairment. Further investigation is needed to determine the causal direction for the link between peripheral vestibular loss and cognitive impairment. C1 [Harun, Aisha; Bigelow, Robin T.; Agrawal, Yuri] Johns Hopkins Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, Baltimore, MD 21205 USA. [Oh, Esther S.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Oh, Esther S.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Oh, Esther S.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Studenski, Stephanie] NIA, Longitudinal Studies Sect, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. RP Harun, A (reprint author), Dept Otolaryngol Head & Neck Surg, 601 N Caroline St Suite 6210, Baltimore, MD 21287 USA. EM aisha@jhmi.edu FU NIH [5T32DC000027-25, 5K23DC013056-02]; AAO-HNSF Core Grant [349386]; NIH/NIDCD [5T32DC000030-1]; NIA/NIH [1K23AG043504-01]; Roberts Gift Fund; Ossoff Family Fund; NIA award [3P50AG005146-32S1, 1ZIAAG000015-57] FX AH was funded by a NIH T32 Award (5T32DC000027-25) and an AAO-HNSF Core Grant (349386). RB was funded by a T32 Award (NIH/NIDCD 5T32DC000030-1). YA was funded by a NIH K23 Award (5K23DC013056-02). EO was funded by a NIA/NIH K23 Award (1K23AG043504-01), the Roberts Gift Fund, and the Ossoff Family Fund. The Alzheimer's disease Research Council is supported by an NIA award (3P50AG005146-32S1). The Baltimore Longitudinal Study of Aging is supported by an NIA award (1ZIAAG000015-57). NR 50 TC 3 Z9 3 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1531-7129 EI 1537-4505 J9 OTOL NEUROTOL JI Otol. Neurotol. PD SEP PY 2016 VL 37 IS 8 BP 1137 EP 1142 DI 10.1097/MAO.0000000000001157 PG 6 WC Clinical Neurology; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA DU5FE UT WOS:000382236800036 PM 27466890 ER PT J AU Kenner, BJ Chari, ST Maitra, A Srivastava, S Cleeter, DF Go, VLW Rothschild, LJ Goldberg, AE AF Kenner, Barbara J. Chari, Suresh T. Maitra, Anirban Srivastava, Sudhir Cleeter, Deborah F. Go, Vay Liang W. Rothschild, Laura J. Goldberg, Ann E. TI Early Detection of Pancreatic Cancer-a Defined Future Using Lessons From Other Cancers A White Paper SO PANCREAS LA English DT Article DE early detection; pancreatic ductal adenocarcinoma; screening; high-risk group; new-onset diabetes ID STATISTICS; BIOMARKERS AB The implementation of effective early detection programs has significantly improved treatment, prognosis, and life expectancy in breast, prostate, and colorectal cancers. Early-detection methods need to be developed for pancreatic ductal adenocarcinoma (PDAC), where progress during the past decades has remained slow. Addressing this need, the forum "Early Detection: Lessons Learned from Other Cancers" was held in November 2015 and presented by the Kenner Family Research Fund in partnership with the American Pancreatic Association. Leading experts from breast, prostate, and colorectal cancers described the development of early detection methods in their respective fields. Emerging opportunities for scientific advancement were subsequently identified that hold the greatest promise for the future of early detection in PDAC, including a 4-part strategic map of necessary actionable items. Knowledge from other fields must be applied to achieve large-scale change within the arena of PDAC. A major breakthrough in early detection of PDAC will occur only through a definitive interdisciplinary collaborative effort involving a critical mass of committed academic research institutions, government agencies, industry leaders, and philanthropies. C1 [Kenner, Barbara J.; Rothschild, Laura J.; Goldberg, Ann E.] Kenner Family Res Fund, 39 East 78th St,Suite 501, New York, NY 10075 USA. [Chari, Suresh T.] Mayo Clin, Dept Med, Rochester, MN USA. [Maitra, Anirban] Univ Texas MD Anderson Canc Ctr, Sheikh Ahmed Bin Zayed Ctr Pancreat Canc Res, Houston, TX 77030 USA. [Srivastava, Sudhir] NCI, Canc Biomarkers Res Grp, Canc Prevent Div, Rockville, MD USA. [Cleeter, Deborah F.] Sawgrass Leadership Inst, Ponte Vedra Beach, FL USA. [Go, Vay Liang W.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. RP Kenner, BJ (reprint author), Kenner Family Res Fund, 39 East 78th St,Suite 501, New York, NY 10075 USA.; Chari, ST (reprint author), Mayo Clin, Div Gastroenterol & Hepatol, 200 1st St SW, Rochester, MN 55905 USA. EM drbkenner@kennerfamilyresearchfund.org; chari.suresh@mayo.edu NR 31 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 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD SEP PY 2016 VL 45 IS 8 BP 1073 EP 1079 DI 10.1097/MPA.0000000000000701 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DU6JZ UT WOS:000382322200004 PM 27518362 ER PT J AU Miller, MS Allen, P Brentnall, TA Goggins, M Hruban, RH Petersen, GM Rao, CV Whitcomb, DC Brand, RE Chari, ST Klein, AP Lubman, DM Rhim, AD Simeone, DM Wolpin, BM Umar, A Srivastava, S Steele, VE Rinaudo, JAS AF Miller, Mark Steven Allen, Peter Brentnall, Teresa A. Goggins, Michael Hruban, Ralph H. Petersen, Gloria M. Rao, Chinthalapally V. Whitcomb, David C. Brand, Randall E. Chari, Suresh T. Klein, Alison P. Lubman, David M. Rhim, Andrew D. Simeone, Diane M. Wolpin, Brian M. Umar, Asad Srivastava, Sudhir Steele, Vernon E. Rinaudo, Jo Ann S. TI Pancreatic Cancer Chemoprevention Translational Workshop Meeting Report SO PANCREAS LA English DT Article DE pancreatic cancer; chemoprevention; biomarkers; early detection; high-risk patient cohorts; clinical trials ID PAPILLARY MUCINOUS NEOPLASMS; ENGINEERED MOUSE MODELS; INTRAEPITHELIAL NEOPLASIA; DUCTAL ADENOCARCINOMA; HIGH-RISK; HEREDITARY PANCREATITIS; INVASIVE-CARCINOMA; DELAY PROGRESSION; WHOLE-EXOME; STEM-CELLS AB Pancreatic cancer is the fourth leading cause of cancer related deaths in the United Stateswith a 5-year survival rate of less than 10%. The Division of Cancer Prevention of the National Cancer Institute sponsored the Pancreatic Cancer Chemoprevention Translational Workshop on September 10 to 11, 2015. The goal of the workshop was to obtain information regarding the current state of the science and future scientific areas that should be prioritized for pancreatic cancer prevention research, including early detection and intervention for high-risk precancerous lesions. The workshop addressed the molecular/genetic landscape of pancreatic cancer and precursor lesions, high-risk populations and criteria to identify a high-risk population for potential chemoprevention trials, identification of chemopreventative/immunopreventative agents, and use of potential biomarkers and imaging for assessing short-term efficacy of a preventative agent. The field of chemoprevention for pancreatic cancer is emerging, and this workshop was organized to begin to address these important issues and promotemulti-institutional efforts in this area. The meeting participants recommended the development of an National Cancer Institute working group to coordinate efforts, provide a framework, and identify opportunities for chemoprevention of pancreatic cancer. C1 [Miller, Mark Steven; Umar, Asad; Srivastava, Sudhir; Steele, Vernon E.; Rinaudo, Jo Ann S.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Allen, Peter] Mem Sloan Kettering Canc Ctr, Dept Surg, David M Rubenstein Ctr Pancreat Canc Res, 1275 York Ave, New York, NY 10021 USA. [Brentnall, Teresa A.] Univ Washington, Div Gastroenterol, Seattle, WA 98195 USA. [Goggins, Michael; Hruban, Ralph H.] Johns Hopkins Univ, Dept Pathol, Sol Goldman Pancreat Canc Res Ctr, Baltimore, MD USA. [Petersen, Gloria M.] Mayo Clin, Dept Epidemiol, Hlth Sci Res, Rochester, MN USA. [Rao, Chinthalapally V.] Univ Oklahoma, Hlth Sci Ctr, Dept Med, Ctr Canc Prevent, Oklahoma City, OK USA. [Rao, Chinthalapally V.] Univ Oklahoma, Hlth Sci Ctr, Drug Dev Program, PC Stephenson Oklahoma Canc Ctr, Oklahoma City, OK USA. [Whitcomb, David C.; Brand, Randall E.] Univ Pittsburgh, Med Ctr, Div Gastroenterol Hepatol & Nutr, Pittsburgh, PA USA. [Chari, Suresh T.] Mayo Clin, Dept Med, Rochester, MN USA. [Klein, Alison P.] Johns Hopkins Univ, Dept Oncol, Natl Familial Pancreas Tumor Registry, Sol Goldman Pancreat Canc Res Ctr, Baltimore, MD USA. [Lubman, David M.] Univ Michigan, Dept Surg, Pancreat Canc Ctr, Ann Arbor, MI 48109 USA. [Rhim, Andrew D.] Univ Michigan, Dept Internal Med, Pancreat Canc Ctr, Ann Arbor, MI 48109 USA. [Simeone, Diane M.] Univ Michigan, Dept Surg, Translat Oncol Program, Pancreat Canc Ctr, Ann Arbor, MI 48109 USA. [Wolpin, Brian M.] Harvard Med Sch, Dana Farber Canc Inst, Pancreat Tumor Ctr, Dept Med, Cambridge, MA USA. RP Miller, MS (reprint author), Canc Prevent Div, Chemoprevent Agent Dev Res Grp, 9609 Med Ctr Dr,MSC9787,Room 5E546, Bethesda, MD 20892 USA. EM mark.miller5@nih.gov FU Division of Cancer Prevention, National Cancer Institute; Office of Disease Prevention, National Institutes of Health FX The Pancreatic Cancer Chemoprevention Translational Workshop was jointly funded by the Division of Cancer Prevention, National Cancer Institute and the Office of Disease Prevention, National Institutes of Health. NR 108 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 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD SEP PY 2016 VL 45 IS 8 BP 1080 EP 1091 DI 10.1097/MPA.0000000000000705 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DU6JZ UT WOS:000382322200005 PM 27518363 ER PT J AU Wolff-Hughes, DL McClain, JJ Dodd, KW Berrigan, D Troiano, RP AF Wolff-Hughes, Dana L. McClain, James J. Dodd, Kevin W. Berrigan, David Troiano, Richard P. TI Number of accelerometer monitoring days needed for stable group-level estimates of activity SO PHYSIOLOGICAL MEASUREMENT LA English DT Article DE physical activity assessment; accelerometer; measurement; bias ID MEASURED PHYSICAL-ACTIVITY; YOUTH; BEHAVIOR; CHILDREN; ADULTS AB To determine the number and distribution of days required to produce stable group-level estimates of a 7 d mean for common accelerometer-derived activity measures. Data from the 2003-2006 NHANES were used in this analysis. The sample included 986 youth (6-19 year) and 2532 adults (>= 20 year) with 7 d of >= 10 h of wear. Accelerometer measures included minutes of inactive, light physical activity, moderate-to-vigorous physical activity (MVPA); and total activity counts/d. Twenty-five alternative protocols were bootstrapped with 50 000 samples drawn for each protocol. Alternative protocols included: 1-6 random days, Saturday plus 1-5 random weekdays (WD), Sunday plus 1-5 random WD, 1 random weekend day (WE) plus 1-5 WD, and both WE plus 1-4 random WD. Relative difference was calculated between the 7 d mean and alternative protocol mean (((alternative protocol mean - 7 d mean)/7 d mean) * 100). Adult MVPA is used as an example; however, similar trends were observed across age groups and variables except adult inactive time, which was stable across protocols. The 7 d mean for adult MVPA was 44.1(0.9) min d(-1). The mean bias for any 1-6 random days ranged from -0.0(0.3) to 0.0(0.2) min d-1 with a relative difference of -0.1 to 0.0%. For protocols with non-random components, bias ranged from -1.4(0.2) to 0.6(0.1) min d(-1) with relative difference ranging from -7.2 to 3.1%. Simulation data suggest that stable estimates of group-level means can be obtained from as few as one randomly selected monitoring day from a sampled week. On the other hand, estimates using non-random selection of weekend days may be significantly biased. Purposeful sampling that disproportionally forces inclusion of weekend data in analyses should be discouraged. C1 [Wolff-Hughes, Dana L.; McClain, James J.; Berrigan, David; Troiano, Richard P.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Dodd, Kevin W.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Wolff-Hughes, DL (reprint author), NIH, Off Behav & Social Sci Res, 31 Ctr Dr,RM B1C19, Bethesda, MD 20892 USA. EM dana.wolff@nih.gov NR 26 TC 0 Z9 0 U1 2 U2 3 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0967-3334 EI 1361-6579 J9 PHYSIOL MEAS JI Physiol. Meas. PD SEP PY 2016 VL 37 IS 9 BP 1447 EP 1455 DI 10.1088/0967-3334/37/9/1447 PG 9 WC Biophysics; Engineering, Biomedical; Physiology SC Biophysics; Engineering; Physiology GA DU5OT UT WOS:000382261800008 PM 27510765 ER PT J AU Stamm, M Forrest, LR AF Stamm, Marcus Forrest, Lucy R. TI Structure alignment of membrane proteins: Accuracy of available tools and a consensus strategy (vol 83, pg 1720, 2015) SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Correction C1 [Stamm, Marcus; Forrest, Lucy R.] Max Planck Inst Biophys, Computat Struct Biol Grp, Frankfurt, Germany. [Forrest, Lucy R.] NINDS, Computat Struct Biol Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Forrest, LR (reprint author), NINDS, Computat Struct Biol Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM lucy.forrest@nih.gov FU Intramural NIH HHS [ZIA NS003139-02, ZIA NS003139-01] NR 1 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0887-3585 EI 1097-0134 J9 PROTEINS JI Proteins PD SEP PY 2016 VL 84 IS 9 BP 1333 EP 1333 DI 10.1002/prot.25098 PG 1 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA DV3HZ UT WOS:000382812900015 PM 27516158 ER PT J AU Wald, I Fruchter, E Ginat, K Stolin, E Dagan, D Bliese, PD Quartana, PJ Sipos, ML Pine, DS Bar-Haim, Y AF Wald, I. Fruchter, E. Ginat, K. Stolin, E. Dagan, D. Bliese, P. D. Quartana, P. J. Sipos, M. L. Pine, D. S. Bar-Haim, Y. TI Selective prevention of combat-related post-traumatic stress disorder using attention bias modification training: a randomized controlled trial SO PSYCHOLOGICAL MEDICINE LA English DT Article DE Attention bias modification training; combat; post-traumatic stress disorder; prevention; stress ID MENTAL-HEALTH PROBLEMS; PSYCHOMETRIC PROPERTIES; PTSD; ANXIETY; SYMPTOMS; SOLDIERS; IRAQ; INTERVENTIONS; VARIABILITY; PSYCHOTHERAPY AB Background Efficacy of pre-trauma prevention for post-traumatic stress disorder (PTSD) has not yet been established in a randomized controlled trial. Attention bias modification training (ABMT), a computerized intervention, is thought to mitigate stress-related symptoms by targeting disruptions in threat monitoring. We examined the efficacy of ABMT delivered before combat in mitigating risk for PTSD following combat. Method We conducted a double-blind, four-arm randomized controlled trial of 719 infantry soldiers to compare the efficacy of eight sessions of ABMT (n = 179), four sessions of ABMT (n = 184), four sessions of attention control training (ACT; n = 180), or no-training control (n = 176). Outcome symptoms were measured at baseline, 6-month follow-up, 10 days following combat exposure, and 4 months following combat. Primary outcome was PTSD prevalence 4 months post-combat determined in a clinical interview using the Clinician-Administered PTSD Scale. Secondary outcomes were self-reported PTSD and depression symptoms, collected at all four assessments. Results PTSD prevalence 4 months post-combat was 7.8% in the no-training control group, 6.7% with eight-session ABMT, 2.6% with four-session ABMT, and 5% with ACT. Four sessions of ABMT reduced risk for PTSD relative to the no-training condition (odds ratio 3.13, 95% confidence interval 1.01-9.22, p < 0.05, number needed to treat = 19.2). No other between-group differences were found. The results were consistent across a variety of analytic techniques and data imputation approaches. Conclusions Four sessions of ABMT, delivered prior to combat deployment, mitigated PTSD risk following combat exposure. Given its low cost and high scalability potential, and observed number needed to treat, research into larger-scale applications is warranted. The ClinicalTrials.gov identifier is NCT01723215. C1 [Wald, I.; Bar-Haim, Y.] Tel Aviv Univ, Sch Psychol Sci, IL-69978 Tel Aviv, Israel. [Fruchter, E.; Ginat, K.; Stolin, E.; Dagan, D.] Israel Def Forces, Div Mental Hlth, Med Corps, Tel Aviv, Israel. [Bliese, P. D.] Univ South Carolina, Darla Moore Sch Business, Columbia, SC 29208 USA. [Quartana, P. J.; Sipos, M. L.] US Army Med Res & Mat Command, Ctr Mil Psychiat & Neurosci, Walter Reed Army Inst Res, Ft Detrick, MD USA. [Pine, D. S.] NIMH, Bethesda, MD USA. [Bar-Haim, Y.] Tel Aviv Univ, Sagol Sch Neurosci, Tel Aviv, Israel. RP Wald, I (reprint author), Tel Aviv Univ, Sch Psychol Sci, IL-69978 Tel Aviv, Israel. EM ilanwald@013net.net FU US Army Medical Research and Materiel Command (USAMRMC) [W81XWH-13-1-0003]; Iranian American Jewish Federation of New York FX The study was supported by US Army Medical Research and Materiel Command (USAMRMC), Award W81XWH-13-1-0003, and by the Iranian American Jewish Federation of New York. NR 35 TC 3 Z9 3 U1 8 U2 8 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0033-2917 EI 1469-8978 J9 PSYCHOL MED JI Psychol. Med. PD SEP PY 2016 VL 46 IS 12 BP 2627 EP 2636 DI 10.1017/S0033291716000945 PG 10 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA DU9WA UT WOS:000382567600015 PM 27377418 ER PT J AU Park, J Bevans, MF AF Park, Jumin Bevans, Margaret F. TI Use of biomarkers in research on caregivers' health: A systematic review SO PSYCHONEUROENDOCRINOLOGY LA English DT Meeting Abstract CT 46th Annual Conference of the International-Society-of-Psychoneuroendocrinology - Personalized Medicine in the Neurosciences - Genetics, Imaging, and Hormones CY SEP 08-11, 2016 CL Miami, FL SP Int Soc Psychoneuroendocrinol C1 [Park, Jumin; Bevans, Margaret F.] NIH, Ctr Clin, Bethesda, MD USA. EM jumin.park@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4530 J9 PSYCHONEUROENDOCRINO JI Psychoneuroendocrinology PD SEP PY 2016 VL 71 SU S BP 57 EP 57 DI 10.1016/j.psyneuen.2016.07.150 PG 1 WC Endocrinology & Metabolism; Neurosciences; Psychiatry SC Endocrinology & Metabolism; Neurosciences & Neurology; Psychiatry GA DV0FX UT WOS:000382594500138 ER PT J AU Wang, HW Pittaluga, S Jaffe, ES AF Wang, Hao-Wei Pittaluga, Stefania Jaffe, Elaine S. TI Multicentric Castleman disease: Where are we now? SO SEMINARS IN DIAGNOSTIC PATHOLOGY LA English DT Article DE Castleman disease; Kaposi sarcoma-associated herpesvirus; Human herpesvirus type-8; Interleukin-6; TAFRO syndrome; Acquired immune deficiency syndrome ID SARCOMA-ASSOCIATED HERPESVIRUS; PRIMARY EFFUSION LYMPHOMA; PROTEIN-COUPLED RECEPTOR; SYSTEMIC LYMPHOPROLIFERATIVE DISORDER; GROWTH-FACTOR EXPRESSION; DENDRITIC CELL-SARCOMA; REGULATORY FACTOR 4; NF-KAPPA-B; KAPOSIS-SARCOMA; NODE HYPERPLASIA AB Multicentric Castleman disease (MCD) encompasses a spectrum of conditions that give rise to overlapping clinicopathological manifestations. The fundamental pathogenetic mechanism involves dysregulated cytokine activity that causes systemic inflammatory symptoms as well as lymphadenopathy. The histological changes in lymph nodes resemble in part the findings originally described in the unicentric forms Castleman disease, both hyaline vascular and plasma cell variants. In MCD caused by Kaposi sarcoma-associated herpesvirus/human herpesvirus-8 (KSHV/HHV8), the cytokine over activity is caused by viral products, which can also lead to atypical lymphoproliferations and potential progression to lymphoma. In cases negative for KSHV/HHV8, so-called idiopathic MCD, the hypercytokinemia can result from various mechanisms, which ultimately lead to different constellations of clinical presentations and varied pathology in lymphoid tissues. In this article, we review the evolving concepts and definitions of the various conditions under the eponym of Castleman disease, and summarize current knowledge regarding the histopathology and pathogenesis of lesions within the MCD spectrum. Published by Elsevier Inc. C1 [Wang, Hao-Wei; Pittaluga, Stefania; Jaffe, Elaine S.] NCI, Hematopathol Sect, Pathol Lab, Ctr Canc Res,NIH, Bldg 10,Room 3S 235,MSC 1500, Bethesda, MD 20892 USA. RP Jaffe, ES (reprint author), NCI, Hematopathol Sect, Pathol Lab, NIH, Bldg 10,Room 3S 235,MSC 1500, Bethesda, MD 20892 USA. EM ejaffe@mail.nih.gov FU Intramural NIH HHS [Z01 BC011070-01, ZIA BC011070-08] NR 129 TC 4 Z9 4 U1 4 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0740-2570 EI 1930-1111 J9 SEMIN DIAGN PATHOL JI Semin. Diagn. Pathol. PD SEP PY 2016 VL 33 IS 5 BP 294 EP 306 DI 10.1053/j.semdp.2016.05.006 PG 13 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA DV4NX UT WOS:000382903400007 PM 27296355 ER PT J AU Allio, T AF Allio, Theresa TI Product Development Under FDA's Animal Rule: Understanding FDA's Expectations and Potential Implications for Traditional Development Programs SO THERAPEUTIC INNOVATION & REGULATORY SCIENCE LA English DT Review DE Animal Rule; data extrapolation; efficacy; pharmacokinetics; dose selection AB In 2002 the US Food and Drug Administration (FDA) established a regulatory pathway for drug and biological products targeting indications for which human efficacy studies are not feasible or ethical. These regulations (21 CFR 314.600 for drugs and 21 CFR 601.90 for biologics), commonly referred to as the "Animal Rule," were the result of many years of thinking about how to make such products available to people who might need them. A handful of products have been approved under the Animal Rule, and several others are in development. This article reviews how different products met the requirements for licensure under the Animal Rule, based on information publicly available on FDA's website. The primary aim of this manuscript is to offer an understanding of FDA's interpretation of relevant regulations and guidances in the context of this licensure pathway. Some of the methods used for Animal Rule approvals may also have potential application in more traditional development programs. Thus, this article may also offer insight into methods for accelerating product development in general. C1 [Allio, Theresa] NIAID, Div Allergy Immunol & Transplantat, NIH, 5601 Fishers Lane,Room 7B35, Bethesda, MD 20892 USA. RP Allio, T (reprint author), NIAID, Div Allergy Immunol & Transplantat, NIH, 5601 Fishers Lane,Room 7B35, Bethesda, MD 20892 USA. EM theresa.allio@nih.gov NR 26 TC 1 Z9 1 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 2168-4790 EI 2168-4804 J9 THER INNOV REGUL SCI JI Ther. Innov. Regul. Sci. PD SEP PY 2016 VL 50 IS 5 BP 660 EP 670 DI 10.1177/2168479016641717 PG 11 WC Medical Informatics; Pharmacology & Pharmacy SC Medical Informatics; Pharmacology & Pharmacy GA DV1VU UT WOS:000382711000018 ER PT J AU Yanagiba, Y Suzuki, T Suda, M Hojo, R Gonzalez, FJ Nakajima, T Wang, RS AF Yanagiba, Yukie Suzuki, Tetsuya Suda, Megumi Hojo, Rieko Gonzalez, Frank J. Nakajima, Tamie Wang, Rui-Sheng TI Cytochrome P450 2EI is responsible for the initiation of 1,2-dichloropropane-induced liver damage SO TOXICOLOGY AND INDUSTRIAL HEALTH LA English DT Article DE 1,2-Dichloropropane; CYP2EI; metabolism; hepatotoxicity; DNA damage ID KAPPA-B ACTIVATION; OXIDATIVE STRESS; PRINTING WORKERS; METABOLISM; TOXICITY; RATS; 1,2-DIBROMOETHANE; HEPATOTOXICITY; MICE; DNA AB 1,2-Dichloropropane (1,2-DCP), a solvent, which is the main component of the cleaner used in the offset printing companies in Japan, is suspected to be the causative agent of bile duct cancer, which has been recently reported at high incidence in those offset printing workplaces. While there are some reports about the acute toxicity of I,2-DCP, no information about its metabolism related to toxicity in animals is available. As part of our efforts toward clarifying the role of I,2-DCP in the development of cancer, we studied the metabolic pathways and the hepatotoxic effect of I,2-DCP in mice with or without cytochrome P450 2EI (CYP2EI) activity. In an in vitro reaction system containing liver homogenate, I,2-DCP was only metabolized by liver tissue of wild-type mice but not by that of cyp2e I-null mice. Furthermore, the kinetics of the solvent in mice revealed a great difference between the two genotypes; I,2-DCP administration resulted in dose-dependent hepatic damage, as shown biochemically and pathologically, but this effect was only observed in wild-type mice. The nuclear factor kappa B p52 pathway was involved in the liver response to I,2-DCP. Our results clearly indicate that the oxidative metabolism of I,2-DCP in mice is exclusively catalyzed by CYP2EI, and this step is indispensable for the manifestation of the hepatotoxic effect of the solvent. C1 [Yanagiba, Yukie; Suzuki, Tetsuya; Suda, Megumi; Hojo, Rieko; Wang, Rui-Sheng] Natl Inst Occupat Safety & Hlth, Div Hlth Effects Res, 6-21-1 Nagao, Kawasaki, Kanagawa 2148585, Japan. [Gonzalez, Frank J.] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. [Nakajima, Tamie] Chubu Univ, Coll Life & Hlth Sci, Kasugai, Aichi, Japan. RP Wang, RS (reprint author), Natl Inst Occupat Safety & Hlth, Div Hlth Effects Res, 6-21-1 Nagao, Kawasaki, Kanagawa 2148585, Japan. EM wang@h.jniosh.go.jp NR 34 TC 0 Z9 0 U1 4 U2 4 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0748-2337 EI 1477-0393 J9 TOXICOL IND HEALTH JI Toxicol. Ind. Health PD SEP PY 2016 VL 32 IS 9 BP 1589 EP 1597 DI 10.1177/0748233714568801 PG 9 WC Public, Environmental & Occupational Health; Toxicology SC Public, Environmental & Occupational Health; Toxicology GA DU1FP UT WOS:000381953900006 PM 25681370 ER PT J AU Rozov, A Demeshkina, N Westhof, E Yusupov, M Yusupova, G AF Rozov, Alexey Demeshkina, Natalia Westhof, Eric Yusupov, Marat Yusupova, Gulnara TI New Structural Insights into Translational Miscoding SO TRENDS IN BIOCHEMICAL SCIENCES LA English DT Review ID AMINOACYL-TRANSFER-RNA; CODON-ANTICODON INTERACTION; 30S RIBOSOMAL-SUBUNIT; WATSON-CRICK GEOMETRY; COGNATE TRANSFER-RNA; MESSENGER-RNA; GENETIC-CODE; ESCHERICHIA-COLI; ANGSTROM RESOLUTION; BACTERIAL RIBOSOME AB The fidelity of translation depends strongly on the selection of the correct aminoacyl-tRNA that is complementary to the mRNA codon present in the ribosomal decoding center. The ribosome occasionally makes mistakes by selecting the wrong substrate from the pool of aminoacyl-tRNAs. Here, we summarize recent structural advances that may help to clarify the origin of missense errors that occur during decoding. These developments suggest that discrimination between tRNAs is based primarily on steric complementarity and shape acceptance rather than on the number of hydrogen bonds between the molding of the decoding center and the codon-anticodon duplex. They strengthen the hypothesis that spatial mimicry, due either to base tautomerism or ionization, drives infidelity in ribosomal translation. C1 [Rozov, Alexey; Demeshkina, Natalia; Yusupov, Marat; Yusupova, Gulnara] Univ Strasbourg, Dept Integrated Struct Biol, Inst Genet & Mol & Cellular Biol, CNRS,UMR7104,INSERM, Strasbourg, France. [Westhof, Eric] Univ Strasbourg, Architecture & React RNA, Inst Mol & Cellular Biol, CNRS,UPR9002, Strasbourg, France. [Demeshkina, Natalia] NHLBI, Biochem & Biophys Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Yusupova, G (reprint author), Univ Strasbourg, Dept Integrated Struct Biol, Inst Genet & Mol & Cellular Biol, CNRS,UMR7104,INSERM, Strasbourg, France. EM gula@igbmc.fr RI Yusupov, Marat/I-6126-2013 OI Yusupov, Marat/0000-0001-5544-0597 FU French National Research Agency [ANR-15-CE11-0021-01]; LABEX [ANR-10-LABX-0036_NETRNA]; European Research Council [294312] FX This work was supported by the French National Research Agency ANR-15-CE11-0021-01 (to G.Y. and E.W), the LABEX ANR-10-LABX-0036_NETRNA (to E.W.), and the European Research Council advanced grant 294312 (to M.Y.). M.Y. thanks the Russian Government Program of Competitive Growth of Kazan Federal University. NR 80 TC 2 Z9 2 U1 10 U2 10 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0968-0004 J9 TRENDS BIOCHEM SCI JI Trends Biochem.Sci. PD SEP PY 2016 VL 41 IS 9 BP 798 EP 814 DI 10.1016/j.tibs.2016.06.001 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DU7TG UT WOS:000382416900010 PM 27372401 ER PT J AU Lujan, SA Williams, JS Kunkel, TA AF Lujan, Scott A. Williams, Jessica S. Kunkel, Thomas A. TI DNA Polymerases Divide the Labor of Genome Replication SO TRENDS IN CELL BIOLOGY LA English DT Review ID OKAZAKI FRAGMENT MATURATION; IMBALANCED DNTP POOLS; SACCHAROMYCES-CEREVISIAE; RIBONUCLEOTIDE INCORPORATION; MISMATCH REPAIR; CATALYTIC DOMAINS; ESCHERICHIA-COLI; POL EPSILON; IN-VITRO; DELTA AB DNA polymerases synthesize DNA in only one direction, but large genomes require RNA priming and bidirectional replication from internal origins. We review here the physical, chemical, and evolutionary constraints underlying these requirements. We then consider the roles of the major eukaryotic replicases, DNA polymerases alpha, delta, and epsilon, in replicating the nuclear genome. Pol alpha has long been known to extend RNA primers at origins and on Okazaki fragments that give rise to the nascent lagging strand. Taken together, more recent results of mutation and ribonucleotide incorporation mapping, electron microscopy, and immunoprecipitation of nascent DNA now lead to a model wherein Pol epsilon and Pol delta, respectively, synthesize the majority of the nascent leading and lagging strands of undamaged DNA. C1 [Lujan, Scott A.; Williams, Jessica S.; Kunkel, Thomas A.] NIEHS, Genome Integr & Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Kunkel, TA (reprint author), NIEHS, Genome Integr & Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. EM kunkel@niehs.nih.gov FU Division of Intramural Research of the National Institute of Environmental Health Sciences, a member of the National Institutes of Health [Z01 ES065070] FX We thank Roel Schaaper, Daniel Menendez, and Rachel Krasich for critical reading of the manuscript. This work was supported by Project Z01 ES065070 to T.A.K. from the Division of Intramural Research of the National Institute of Environmental Health Sciences, a member of the National Institutes of Health. The authors apologize to the many colleagues whose primary research articles could not be cited owing to space limitations. NR 88 TC 0 Z9 0 U1 10 U2 15 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0962-8924 J9 TRENDS CELL BIOL JI Trends Cell Biol. PD SEP PY 2016 VL 26 IS 9 BP 640 EP 654 DI 10.1016/j.tcb.2016.04.012 PG 15 WC Cell Biology SC Cell Biology GA DU6SI UT WOS:000382344500003 PM 27262731 ER PT J AU Wess, J AF Wess, Jurgen TI Use of Designer G Protein-Coupled Receptors to Dissect Metabolic Pathways SO TRENDS IN ENDOCRINOLOGY AND METABOLISM LA English DT Editorial Material ID BETA-CELL FUNCTION; G(Q)-COUPLED RECEPTOR; IN-VIVO; ACTIVATION; TARGETS; DREADDS; AGRP AB G protein-coupled receptors (GPCRs) regulate virtually all metabolic processes, including glucose and energy homeostasis. Recently, the use of designer GPCRs referred to as designer receptors exclusively activated by designer drug (DREADDs) has made it possible to dissect metabolically relevant GPCR signaling pathways in a temporally and spatially controlled fashion in vivo. C1 [Wess, Jurgen] NIDDK, Mol Signaling Sect, Lab Bioorgan Chem, NIH, Bldg 8A,8 Ctr Dr MSC 0810, Bethesda, MD 20892 USA. RP Wess, J (reprint author), NIDDK, Mol Signaling Sect, Lab Bioorgan Chem, NIH, Bldg 8A,8 Ctr Dr MSC 0810, Bethesda, MD 20892 USA. EM jurgenw@helix.nlh.gov FU Intramural NIH HHS NR 14 TC 2 Z9 2 U1 3 U2 3 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1043-2760 J9 TRENDS ENDOCRIN MET JI Trends Endocrinol. Metab. PD SEP PY 2016 VL 27 IS 9 SI SI BP 600 EP 603 DI 10.1016/j.tem.2016.04.001 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DU6SE UT WOS:000382344100002 PM 27381463 ER PT J AU Xiao, CY Reitman, ML AF Xiao, Cuiying Reitman, Marc L. TI Bombesin-Like Receptor 3: Physiology of a Functional Orphan SO TRENDS IN ENDOCRINOLOGY AND METABOLISM LA English DT Editorial Material ID OBESITY; MICE AB Bombesin-like receptor 3 (BRS-3) is an X-linked orphan. Gq-coupled receptor that regulates food intake, metabolic rate, body temperature, heart rate, blood pressure, and insulin secretion. Most BRS-3 actions occur via the brain, through mechanisms including regulating sympathetic outflow. Ablation of Brs3 causes obesity, while synthetic agonists produce weight loss. C1 [Xiao, Cuiying; Reitman, Marc L.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. RP Reitman, ML (reprint author), NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. EM marc.reitman@nih.gov OI Reitman, Marc/0000-0002-0426-9475 FU Intramural NIH HHS NR 14 TC 1 Z9 1 U1 2 U2 2 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1043-2760 J9 TRENDS ENDOCRIN MET JI Trends Endocrinol. Metab. PD SEP PY 2016 VL 27 IS 9 SI SI BP 603 EP 605 DI 10.1016/j.tem.2016.03.003 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DU6SE UT WOS:000382344100003 PM 27055378 ER PT J AU Babu, S Nutman, TB AF Babu, Subash Nutman, Thomas B. TI Helminth-Tuberculosis Co-infection: An Immunologic Perspective SO TRENDS IN IMMUNOLOGY LA English DT Review ID NEGLECTED TROPICAL DISEASES; HUMAN LYMPHATIC FILARIASIS; T-CELL RESPONSES; MYCOBACTERIUM-TUBERCULOSIS; LATENT TUBERCULOSIS; INTESTINAL HELMINTH; IMMUNE-RESPONSE; ACTIVE TUBERCULOSIS; SCHISTOSOMA-MANSONI; BCG VACCINATION AB Over 2 billion people worldwide are infected with helminths (worms). Similarly, infection with Mycobacterium tuberculosis (Mtb) occurs in over a third of the world's population, often with a great degree of geographical overlap with helminth infection. Interestingly, the responses induced by the extracellular helminths and those induced by the intracellular Mtb are often mutually antagonistic and, as a consequence, can result in impaired (or cross-regulated) host responses to either of the infecting pathogens. In this review, we outline the nature of the immune responses induced by infections with helminths and tuberculosis (TB) and then provide data from both experimental models and human studies that illustrate how the immune response engendered by helminth parasites modulates Mtb-specific responses in helminth-TB coinfection C1 [Babu, Subash] NIH NIRT ICER, Madras, Tamil Nadu, India. [Babu, Subash; Nutman, Thomas B.] NIAID, Helminth Immunol Sect, Parasit Dis Lab, Bethesda, MD 20892 USA. RP Babu, S (reprint author), NIH NIRT ICER, Madras, Tamil Nadu, India.; Babu, S (reprint author), NIAID, Helminth Immunol Sect, Parasit Dis Lab, Bethesda, MD 20892 USA. EM sbabu@mail.nih.gov FU Intramural NIH HHS [Z99 AI999999] NR 87 TC 1 Z9 1 U1 6 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4906 EI 1471-4981 J9 TRENDS IMMUNOL JI Trends Immunol. PD SEP PY 2016 VL 37 IS 9 BP 597 EP 607 DI 10.1016/j.it.2016.07.005 PG 11 WC Immunology SC Immunology GA DV0FZ UT WOS:000382594700005 PM 27501916 ER PT J AU Ershow, AG Goodman, G Coates, PM Swanson, CA AF Ershow, Abby G. Goodman, Gay Coates, Paul M. Swanson, Christine A. TI Assessing iodine intake, iodine status, and the effects of maternal iodine supplementation: introduction to articles arising from 3 workshops held by the NIH Office of Dietary Supplements SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article; Proceedings Paper CT Workshop 1 on Assessment of Iodine Intake - Foods and Supplements CY APR 22-23, 2014 CL NIH, Off Dietary Supplements, Rockville, MD HO NIH, Off Dietary Supplements DE biomarkers; clinical studies; iodine nutrition; neurodevelopment; supplementation ID REPRODUCTIVE-AGE WOMEN; UNITED-STATES; PREGNANCY; DEFICIENCY; LACTATION; NUTRITION; EXCESS; RISK; MILK AB The NIH Office of Dietary Supplements (ODS) convened 3 workshops on iodine nutrition in 2014, each held in Rockville, Maryland. These workshops were part of the ongoing ODS Iodine Initiative, begun in 2011 in response to concerns that US pregnant women may be at risk of iodine deficiency and that a high fraction of prenatal dietary supplements do not contain the recommended amounts of iodine. The primary purpose of the workshops was to consider the data and resources necessary to evaluate the clinical and public health benefits and risks of maternal iodine supplementation in the United States. The first workshop focused on the assessment of iodine intake, the second focused on the assessment of iodine status, and the third focused on the design and interpretation of clinical trials of maternal iodine supplementation. Here we provide the background of the ODS Iodine Initiative, summarize the 3 workshops held in 2014, and introduce the articles that arose from the workshops and are published in this supplement issue. C1 [Ershow, Abby G.; Coates, Paul M.; Swanson, Christine A.] NIH, Off Dietary Supplements, Bldg 10, Bethesda, MD 20892 USA. [Goodman, Gay] Human Hlth Risk Res, Seattle, WA USA. RP Ershow, AG (reprint author), NIH, Off Dietary Supplements, Bldg 10, Bethesda, MD 20892 USA. EM abby.ershow@nih.gov NR 37 TC 3 Z9 3 U1 8 U2 10 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD SEP PY 2016 VL 104 IS 3 SU S BP 859S EP 863S DI 10.3945/ajcn.115.111161 PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DU7UW UT WOS:000382421100001 PM 27534646 ER PT J AU Pehrsson, PR Patterson, KY Spungen, JH Wirtz, MS Andrews, KW Dwyer, JT Swanson, CA AF Pehrsson, Pamela R. Patterson, Kristine Y. Spungen, Judith H. Wirtz, Mark S. Andrews, Karen W. Dwyer, Johanna T. Swanson, Christine A. TI Iodine in food- and dietary supplement-composition databases SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article; Proceedings Paper CT Workshop 1 on Assessment of Iodine Intake - Foods and Supplements CY APR 22-23, 2014 CL NIH, Off Dietary Supplements, Rockville, MD HO NIH, Off Dietary Supplements DE DSID; FDA; NHANES; Total Diet Study; USDA ID NUTRIENT ANALYSIS PROGRAM; UNITED-STATES; AMERICA-NHANES; NATIONAL FOOD; WOMEN; NUTRITION; MILK; SALT; EAT; AGE AB The US Food and Drug Administration (FDA) and the Nutrient Data Laboratory (NDL) of the USDA Agricultural Research Service have worked independently on determining the iodine content of foods and dietary supplements and are now harmonizing their efforts. The objective of the current article is to describe the harmonization plan and the results of initial iodine analyses accomplished under that plan. For many years, the FDA's Total Diet Study (TDS) has measured iodine concentrations in selected foods collected in 4 regions of the country each year. For more than a decade, the NDL has collected and analyzed foods as part of the National Food and Nutrient Analysis Program.; iodine analysis is now being added to the program. The NDL recently qualified a commercial laboratory to conduct iodine analysis of foods by an inductively coupled plasma mass spectrometry (ICP-MS) method. Co-analysis of a set of samples by the commercial laboratory using the ICP-MS method and by the FDA laboratory using its standard colorimetric method yielded comparable results. The FDA recently reviewed historical TDS data for trends in the iodine content of selected foods, and the NDL analyzed samples of a limited subset of those foods for iodine. The FDA and the NDL are working to combine their data on iodine in foods and to produce an online database that can be used for estimating iodine intake from foods in the US population. In addition, the NDL continues to analyze dietary supplements for iodine and, in collaboration with the NIH Office of Dietary Supplements, to publish the data online in the Dietary Supplement Ingredient Database. The goal is to provide, through these 2 harmonized databases and the continuing TDS focus on iodine, improved tools for estimating iodine intake in population studies. C1 [Pehrsson, Pamela R.; Patterson, Kristine Y.; Andrews, Karen W.] ARS, Nutr Data Lab, Beltsville Human Nutr Res Ctr, USDA, Beltsville, MD 20705 USA. [Spungen, Judith H.; Wirtz, Mark S.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Dwyer, Johanna T.; Swanson, Christine A.] NIH, Off Dietary Supplements, Bldg 10, Bethesda, MD 20892 USA. RP Pehrsson, PR (reprint author), ARS, Nutr Data Lab, Beltsville Human Nutr Res Ctr, USDA, Beltsville, MD 20705 USA. EM pamela.pehrsson@ars.usda.gov NR 37 TC 5 Z9 5 U1 10 U2 10 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD SEP PY 2016 VL 104 IS 3 SU S BP 868S EP 876S DI 10.3945/ajcn.115.110064 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DU7UW UT WOS:000382421100003 PM 27534627 ER PT J AU Carriquiry, AL Spungen, JH Murphy, SP Pehrsson, PR Dwyer, JT Juan, W Wirtz, MS AF Carriquiry, Alicia L. Spungen, Judith H. Murphy, Suzanne P. Pehrsson, Pamela R. Dwyer, Johanna T. Juan, WenYen Wirtz, Mark S. TI Variation in the iodine concentrations of foods: considerations for dietary assessment SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article; Proceedings Paper CT Workshop 1 on Assessment of Iodine Intake - Foods and Supplements CY APR 22-23, 2014 CL NIH, Off Dietary Supplements, Rockville, MD HO NIH, Off Dietary Supplements DE food composition; iodine; nutrient content; statistical distribution; variability AB Background: Food-composition tables typically give measured nutrient concentrations in foods as a single summary value, often the mean, without providing information as to the shape of the distribution. Objective: Our objective was to explore how the statistical approach chosen to describe the iodine concentrations of foods affects the proportion of the population identified as having either insufficient or excessive iodine intakes. Design: We used food intake data reported by the 2009-2010 NHANES and measured iodine concentrations of Total Diet Study (TDS) foods from 4 US regions sampled in 2004-2011. We created 4 data sets, each by using a different summary statistic (median, mean, and 10th and 90th percentiles), to represent the iodine concentration distribution of each TDS food. We estimated the iodine concentration distribution of each food consumed by NHANES participants as the 4 iodine concentration summary statistics of a similar TDS food and used these, along with NHANES food intake data, to develop 4 estimates of each participant's iodine intake on each survey day. Using the 4 estimates in turn, we calculated 4 usual iodine intakes for each sex- and age-specific subgroup. We then compared these to guideline values and developed 4 estimates of the proportions of each subgroup with deficient and excessive usual iodine intakes. Results: In general, the distribution of iodine intakes was poorly characterized when food iodine concentrations were expressed as mean values. In addition, mean values predicted lower prevalences of iodine deficiency than did median values. For example, in women aged 19-50 y, the estimated prevalence of iodine deficiency was 25% when based on median food iodine concentrations but only 5.8% when based on mean values. Conclusion: For nutrients such as iodine with highly variable concentrations in important food sources, we recommend that food composition tables provide useful variability information, including the mean, SD, and median. C1 [Carriquiry, Alicia L.] Iowa State Univ, Dept Stat, Ames, IA 50011 USA. [Spungen, Judith H.; Juan, WenYen; Wirtz, Mark S.] US FDA, College Pk, MD 20740 USA. [Murphy, Suzanne P.] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. [Pehrsson, Pamela R.] ARS, Nutr Data Lab, Beltsville Human Nutr Res Ctr, USDA, Beltsville, MD 20705 USA. [Dwyer, Johanna T.] NIH, Off Dietary Supplements, Bldg 10, Bethesda, MD 20892 USA. RP Carriquiry, AL (reprint author), Iowa State Univ, Dept Stat, Ames, IA 50011 USA. EM alicia@iastate.edu NR 20 TC 4 Z9 4 U1 6 U2 6 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD SEP PY 2016 VL 104 IS 3 SU S BP 877S EP 887S DI 10.3945/ajcn.115.110353 PG 11 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DU7UW UT WOS:000382421100004 PM 27534633 ER PT J AU Juan, W Trumbo, PR Spungen, JH Dwyer, JT Carriquiry, AL Zimmerman, TP Swanson, CA Murphy, SP AF Juan, WenYen Trumbo, Paula R. Spungen, Judith H. Dwyer, Johanna T. Carriquiry, Alicia L. Zimmerman, Thea P. Swanson, Christine A. Murphy, Suzanne P. TI Comparison of 2 methods for estimating the prevalences of inadequate and excessive iodine intakes SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article; Proceedings Paper CT Workshop 1 on Assessment of Iodine Intake - Foods and Supplements CY APR 22-23, 2014 CL NIH, Off Dietary Supplements, Rockville, MD HO NIH, Off Dietary Supplements DE dietary surveys; food content; iodine; Total Diet Study; urinary iodine; variability ID URINARY IODINE; MASS SPECTROMETRY; NATIONAL-HEALTH; UNITED-STATES; TOTAL DIET; NUTRITION; POPULATION; SODIUM; FOOD; EXCRETION AB Background: Prevalences of iodine inadequacy and excess are usually evaluated by comparing the population distribution of urinary iodine concentration (UIC) in spot samples with established UIC cutoffs. To our knowledge, until now, dietary intake data have not been assessed for this purpose. Objective: Our objective was to compare 2 methods for evaluating the prevalence of iodine inadequacy and excess in sex- and life stage specific subgroups of the US population: one that uses UIC cutoffs, and one that uses iodine intake cutoffs. Design: By using the iodine concentrations of foods measured in the US Food and Drug Administration's Total Diet Study (TDS), dietary intake data from the NHANES 2003-2010, and a file that maps each NHANES food to a TDS food with similar ingredients, we estimated each NHANES participant's iodine intake from each NHANES food as the mean iodine concentration of the corresponding TDS food in samples gathered over the same 2-y period. We calculated prevalences of iodine inadequacy and excess in each sex and life stage specific subgroup by both the UIC cutoff method and the iodine intake cutoff method using the UIC values and dietary intakes reported for NHANES participants who provided both types of data and compared the prevalences across methods. Results: We found lower prevalences of iodine inadequacy across all sex- and life stage specific subgroups with the iodine intake cutoff method than with the UIC cutoff method; for pregnant females, the respective prevalences were 5.0% and 37.9%. For children aged y, the prevalence of excessive iodine intake was high by either method. Conclusions: The consideration of dietary iodine intake from all sources may provide a more complete understanding of population prevalences of iodine inadequacy and excess and thus better inform dietary guidance than consideration of UIC alone. Methods of adjusting UIC for within-person variation are needed to improve the accuracy of prevalence assessments based on UIC. C1 [Juan, WenYen; Trumbo, Paula R.; Spungen, Judith H.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Dwyer, Johanna T.; Swanson, Christine A.] NIH, Off Dietary Supplements, Bldg 10, Bethesda, MD 20892 USA. [Carriquiry, Alicia L.] Iowa State Univ, Dept Stat, Ames, IA 50011 USA. [Zimmerman, Thea P.] Westat Corp, Rockville, MD 20850 USA. [Murphy, Suzanne P.] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. RP Juan, W (reprint author), US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. EM wenyen.juan@fda.hhs.gov NR 38 TC 3 Z9 3 U1 5 U2 5 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD SEP PY 2016 VL 104 IS 3 SU S BP 888S EP 897S DI 10.3945/ajcn.115.110346 PG 10 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DU7UW UT WOS:000382421100005 PM 27534630 ER PT J AU Troendle, JF AF Troendle, James F. TI Statistical design considerations applicable to clinical trials of iodine supplementation in pregnant women who may be mildly iodine deficient SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article; Proceedings Paper CT Workshop 3 on Maternal Iodine Supplementation - Clinical Trials and Assessment of Outcomes CY SEP 22-23, 2014 CL NIH, Off Dietary Supplements, Rockville, MD HO NIH, Off Dietary Supplements DE clinical trials; iodine supplementation; outcomes measurement; pregnancy; statistical methods ID URINARY IODINE; MISSING DATA AB No large, randomized, placebo-controlled trial of iodine supplementation in pregnant women in a region of mild or moderate iodine deficiency has been completed in which a primary outcome measure was an assessment of the neurobehavioral development of the offspring at age >= 2 y. In this article, I discuss considerations for the design of such a trial in a region of mild iodine deficiency, with a focus on statistical methods and approaches. Exposure and design issues include the ethics of using a placebo, the potential for overexposure to iodine, and the possibility of community randomization. The main scientific goal of the trial is important in determining the follow-up period. If the goal is to determine whether iodine supplementation during pregnancy improves neurobehavioral development in the offspring, then follow-up should continue until a reasonably reliable assessment can be conducted, which might be at age y. Once the timing of assessment is decided, the impact of potential loss to follow-up should be considered so that appropriate statistical methods can be incorporated into the design. The minimum sample size can be calculated by using a sample size formula that incorporates noncompliance and assumes that a certain proportion of study participants do not have any outcome observed. To have sufficient power to detect a reasonably modest difference in neurobehavioral development scores using an assessment tool with an SD of 15, a large number of participants (>500/group) is required. The minimum adequate number of participants may be even larger (>1300/group) depending on the magnitude of the difference in outcome between the supplementation and placebo groups, the estimated proportion of the iodine-supplementation group that fails to take the supplement, and the estimated proportion of pregnancies that do not produce outcome measurements. C1 [Troendle, James F.] NHLBI, Off Biostat Res, Div Cardiovasc Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Troendle, JF (reprint author), NHLBI, Off Biostat Res, Div Cardiovasc Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. EM jt3t@nih.gov NR 20 TC 2 Z9 2 U1 1 U2 1 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD SEP PY 2016 VL 104 IS 3 SU S BP 924S EP 927S DI 10.3945/ajcn.115.110403 PG 4 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DU7UW UT WOS:000382421100011 PM 27534639 ER PT J AU Ershow, AG Goodman, G Coates, PM Swanson, CA AF Ershow, Abby G. Goodman, Gay Coates, Paul M. Swanson, Christine A. TI Research needs for assessing iodine intake, iodine status, and the effects of maternal iodine supplementation SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article; Proceedings Paper CT Workshop 3 on Maternal Iodine Supplementation - Clinical Trials and Assessment of Outcomes CY SEP 22-23, 2014 CL NIH, Off Dietary Supplements, Rockville, MD HO NIH, Off Dietary Supplements DE clinical trials; iodine deficiency; iodine excess; neurobehavioral development; prenatal supplementation ID THYROID-FUNCTION; PREGNANT-WOMEN; PERCHLORATE; THIOCYANATE; MILK; NITRATE; HYPOTHYROXINEMIA; ASSOCIATION; CHILDHOOD; NUTRITION AB The Office of Dietary Supplements of the NIH convened 3 workshops on iodine nutrition in Rockville, Maryland, in 2014. The purpose of the current article is to summarize and briefly discuss a list of research and resource needs developed with the input of workshop participants. This list is composed of the basic, clinical, translational, and population studies required for characterizing the benefits and risks of iodine supplementation, along with related data, analyses, evaluations, methods development, and supporting activities. Ancillary studies designed to use the participant, biological sample, and data resources of ongoing and completed studies (including those not originally concerned with iodine) may provide an efficient, cost-effective means to address some of these research and resource needs. In the United States, the foremost question is whether neurobehavioral development in the offspring of mildly to moderately iodine-deficient women is improved by maternal iodine supplementation during pregnancy. It is important to identify the benefits and risks of iodine supplementation in all population subgroups so that supplementation can be targeted, if necessary, to avoid increasing the risk of thyroid dysfunction and related adverse health effects in those with high iodine intakes. Ultimately, there will be a need for well-designed trials and other studies to assess the impact of maternal supplementation on neurodevelopmental outcomes in the offspring. However, 2 basic information gaps loom ahead of such a study: the development of robust, valid, and convenient biomarkers of individual iodine status and the identification of infant and toddler neurobehavioral development endpoints that are sensitive to mild maternal iodine deficiency during pregnancy and its reversal by supplementation. C1 [Ershow, Abby G.; Coates, Paul M.; Swanson, Christine A.] NIH, Off Dietary Supplements, Bldg 10, Bethesda, MD 20892 USA. [Goodman, Gay] Human Hlth Risk Res, Seattle, WA 98103 USA. RP Ershow, AG (reprint author), NIH, Off Dietary Supplements, Bldg 10, Bethesda, MD 20892 USA. EM abby.ershow@nih.gov NR 49 TC 2 Z9 2 U1 2 U2 2 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD SEP PY 2016 VL 104 IS 3 SU S BP 941S EP 949S DI 10.3945/ajcn.116.134858 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DU7UW UT WOS:000382421100014 PM 27534640 ER PT J AU Clarke, SLN Pellowe, EJ de Jesus, AA Goldbach-Mansky, R Hilliard, TN Ramanan, AV AF Clarke, Sarah L. N. Pellowe, Elizabeth J. de Jesus, Adriana A. Goldbach-Mansky, Raphaela Hilliard, Tom N. Ramanan, Athimalaipet V. TI Interstitial Lung Disease Caused by STING-associated Vasculopathy with Onset in Infancy SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Letter ID STIMULATOR C1 [Clarke, Sarah L. N.; Pellowe, Elizabeth J.; Hilliard, Tom N.; Ramanan, Athimalaipet V.] Bristol Royal Hosp Children, Bristol, Avon, England. [Clarke, Sarah L. N.] Univ Bristol, Bristol, Avon, England. [de Jesus, Adriana A.; Goldbach-Mansky, Raphaela] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Clarke, SLN (reprint author), Bristol Royal Hosp Children, Bristol, Avon, England.; Clarke, SLN (reprint author), Univ Bristol, Bristol, Avon, England. NR 11 TC 2 Z9 2 U1 1 U2 1 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD SEP 1 PY 2016 VL 194 IS 5 BP 639 EP 642 PG 4 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DU7SY UT WOS:000382416100021 PM 27585386 ER PT J AU Gaynor, JW Stopp, C Wypij, D Andropoulos, DB Atallah, J Atz, AM Beca, J Donofrio, MT Duncan, K Ghanayem, NS Goldberg, CS Hovels-Gurich, H Ichida, F Jacobs, JP Justo, R Latal, B Li, JS Mahle, WT McQuillen, PS Menon, SC Pemberton, VL Pike, NA Pizarro, C Shekerdemian, LS Synnes, A Williams, I Bellinger, DC Newburger, JW AF Gaynor, J. William Stopp, Christian Wypij, David Andropoulos, Dean B. Atallah, Joseph Atz, Andrew M. Beca, John Donofrio, Mary T. Duncan, Kim Ghanayem, Nancy S. Goldberg, Caren S. Hovels-Gurich, Hedwig Ichida, Fukiko Jacobs, Jeffrey P. Justo, Robert Latal, Beatrice Li, Jennifer S. Mahle, William T. McQuillen, Patrick S. Menon, Shaji C. Pemberton, Victoria L. Pike, Nancy A. Pizarro, Christian Shekerdemian, Lara S. Synnes, Anne Williams, Ismee Bellinger, David C. Newburger, Jane W. CA ICCON Investigators TI Impact of Operative and Postoperative Factors on Neurodevelopmental Outcomes After Cardiac Operations The International Cardiac Collaborative on Neurodevelopment (ICCON) Investigators SO ANNALS OF THORACIC SURGERY LA English DT Article; Proceedings Paper CT 52nd Annual Meeting of the Society-of-Thoracic-Surgeons CY JAN 23-27, 2016 CL Phoenix, AZ SP Soc Thorac Surg ID HYPOTHERMIC CIRCULATORY ARREST; CARDIOPULMONARY BYPASS; SINGLE VENTRICLE; HEART-SURGERY; HEALTH OUTCOMES; CHILDREN; INFANTS; TRIAL; AGE; PREDICTORS AB Background. Neurodevelopmental disability is common after operations for congenital heart defects. We previously showed that patient and preoperative factors, center, and calendar year of birth explained less than 30% of the variance for the Psychomotor Development Index (PDI) and the Mental Development Index (MDI) of the Bayley Scales of Infant Development-Second Edition. Here we investigate how much additional variance in PDI and MDI is contributed by operative variables and postoperative events. Methods. We analyzed neurodevelopmental outcomes after operations with cardiopulmonary bypass at age 9 months or younger between 1996 and 2009. We used linear regression to investigate the effect of operative factors (age, weight, and cardiopulmonary bypass variables) and postoperative events on neurodevelopmental outcomes, adjusting for center, type of congenital heart defect, year of birth, and preoperative factors. Results. We analyzed 1,770 children from 22 institutions with neurodevelopmental testing at age 13.3 months (range, 6 to 30 months). Among operative factors, longer total support time was associated with lower PDI and MDI (p < 0.05). When postoperative events were added, use of either extracorporeal membrane oxygenation or ventricular assist device support, and longer postoperative length of stay were associated with lower PDI and MDI (p < 0.05). Longer total support time was not a significant predictor in these models. After adjusting for patient, preoperative, intraoperative, and postoperative factors, measured intraoperative and postoperative factors accounted for 5% of the variances in PDI and MDI. Conclusions. Operative factors may be less important than innate patient and preoperative factors and postoperative events in predicting early neurodevelopmental outcomes after cardiac operations in infants. Neurodevelopmental outcomes improved over calendar time when adjusted for patient and medical variables. (C) 2016 by The Society of Thoracic Surgeons C1 [Gaynor, J. William] Childrens Hosp Philadelphia, 34th & Civ Ctr Blvd, Philadelphia, PA 19104 USA. [Stopp, Christian; Wypij, David; Bellinger, David C.; Newburger, Jane W.] Boston Childrens Hosp, Boston, MA USA. [Andropoulos, Dean B.] Texas Childrens Hosp, Houston, TX 77030 USA. [Atallah, Joseph] Stollery Childrens Hosp, Edmonton, AB, Canada. [Atallah, Joseph] Western Canadian Complex Pediat Therapies Follow, Edmonton, AB, Canada. [Atz, Andrew M.] Med Univ S Carolina, Div Pediat Cardiol, Charleston, SC 29425 USA. [Beca, John] Starship Childrens Hosp, Auckland, New Zealand. [Donofrio, Mary T.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Duncan, Kim] Childrens Hosp & Med Ctr, Omaha, NE USA. [Ghanayem, Nancy S.] Med Coll Wisconsin, Childrens Hosp Wisconsin, Milwaukee, WI 53226 USA. [Goldberg, Caren S.] Univ Michigan, CS Mott Childrens Hosp, Ann Arbor, MI 48109 USA. [Hovels-Gurich, Hedwig] Univ Hosp Aachen, Aachen, Germany. [Ichida, Fukiko] Toyama Univ Hosp, Toyama, Japan. [Jacobs, Jeffrey P.] Johns Hopkins All Childrens Heart Inst, St Petersburg, FL USA. [Justo, Robert] Univ Queensland, Brisbane, Qld, Australia. [Latal, Beatrice] Univ Childrens Hosp Zurich, Zurich, Switzerland. [Li, Jennifer S.] Duke Univ, Med Ctr, Durham, NC USA. [Mahle, William T.] Childrens Healthcare Atlanta, Atlanta, GA USA. [McQuillen, Patrick S.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Menon, Shaji C.] Primary Childrens Med Ctr, Salt Lake City, UT 84103 USA. [Pemberton, Victoria L.] NHLBI, Bldg 10, Bethesda, MD 20892 USA. [Pike, Nancy A.] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Pizarro, Christian] Alfred I duPont Hosp Children, Wilmington, DE USA. [Shekerdemian, Lara S.] Royal Childrens Hosp, Melbourne, Vic, Australia. [Synnes, Anne] Univ British Columbia, Vancouver, BC, Canada. [Williams, Ismee] New York Presbyterian Morgan Stanley Childrens Ho, New York, NY USA. RP Gaynor, JW (reprint author), Childrens Hosp Philadelphia, 34th & Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM gaynor@email.chop.edu RI Justo, Robert/D-4708-2011 NR 18 TC 0 Z9 0 U1 5 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-4975 EI 1552-6259 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD SEP PY 2016 VL 102 IS 3 BP 843 EP 849 DI 10.1016/j.athoracsur.2016.05.081 PG 7 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA DU6EG UT WOS:000382306200054 ER PT J AU Qian, Y Culton, DA Jeong, JS Trupiano, N Valenzuela, JG Diaz, LA AF Qian, Ye Culton, Donna A. Jeong, Joseph S. Trupiano, Nicole Valenzuela, Jesus G. Diaz, Luis A. TI Non-infectious environmental antigens as a trigger for the initiation of an autoimmune skin disease SO AUTOIMMUNITY REVIEWS LA English DT Review DE Pemphigus foliaceus; Autoantibodies; Environmental antigens; IgG4; IgE ID ENDEMIC PEMPHIGUS FOLIACEUS; ALLERGEN-SPECIFIC IMMUNOTHERAPY; ATOPIC-DERMATITIS PATIENTS; MEMBRANE ZONE ANTIBODIES; CELL-ADHESION MOLECULES; EXPERT PANEL WORKSHOP; MEMORY B-CELLS; FOGO-SELVAGEM; IGE AUTOANTIBODIES; IMMUNOGLOBULIN-E AB Pemphigus represents a group of organ specific autoimmune blistering disorders of the skin mediated by pathogenic autoantibodies with well-defined antigenic targets. While most of these diseases are sporadic, endemic forms of disease do exist. The endemic form of pemphigus foliaceus (also known as fogo selvagem, FS) exhibits epidemiological features that suggest exposure to hematophagous insect bites are a possible precipitating factor of this autoimmune disease, and provides a unique opportunity to study how environmental factors contribute to autoimmune disease development. FS patients and healthy individuals from endemic regions show an autoreactive IgM response that starts in early childhood and becomes restricted to IgG4 autoantibodies in FS patients. In searching for triggering environmental antigens, we have found that IgG4 and IgE autoantibodies from FS patients cross-react with a salivary antigen from sand flies. The presence of these cross-reactive antibodies and antibody genetic analysis confirming that these antibodies evolve from the same naive B cells provides compelling evidence that this non-infectious environmental antigen could be the initial target of the autoantibody response in FS. Consequently, FS serves as an ideal model to study the impact of environmental antigens in the development of autoimmune disease. (C) 2016 Elsevier B.V. All rights reserved. C1 [Qian, Ye; Culton, Donna A.; Jeong, Joseph S.; Trupiano, Nicole; Diaz, Luis A.] Univ N Carolina, Dept Dermatol, CB 7287, Chapel Hill, NC 27599 USA. [Valenzuela, Jesus G.] NIAID, Vector Mol Biol Sect, LMVR, NIH, Rockville, MD 20852 USA. RP Qian, Y (reprint author), Univ N Carolina, Dept Dermatol, CB 7287, Chapel Hill, NC 27599 USA. EM ye_qian@med.unc.edu FU NIH [K01-AR056378, R01 AR067315, R01-AR32599] FX This work was supported by NIH grants, K01-AR056378, R01 AR067315 (to YQ) and R01-AR32599 (to LAD). NR 108 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-9972 EI 1873-0183 J9 AUTOIMMUN REV JI Autoimmun. Rev. PD SEP PY 2016 VL 15 IS 9 BP 923 EP 930 DI 10.1016/j.autrev.2016.07.005 PG 8 WC Immunology SC Immunology GA DU6TE UT WOS:000382346700010 PM 27396816 ER PT J AU Reider, L Beck, T Alley, D Miller, R Shardell, M Schumacher, J Magaziner, J Cawthon, PM Barbour, KE Cauley, JA Harris, T AF Reider, Lisa Beck, Thomas Alley, Dawn Miller, Ram Shardell, Michelle Schumacher, John Magaziner, Jay Cawthon, Peggy M. Barbour, Kamil E. Cauley, Jane A. Harris, Tamara CA Hlth ABC Study TI Evaluating the relationship between muscle and bone modeling response in older adults SO BONE LA English DT Article DE Femoral stress; Bone modeling response; Muscle ID PROXIMAL FEMUR GEOMETRY; HIP FRACTURE; FEMORAL-NECK; CORTICAL BONE; AGE; STRENGTH; RISK; DENSITY; HEALTH; WOMEN AB Bone modeling, the process that continually adjusts bone strength in response to prevalent muscle-loading forces throughout an individual's lifespan, may play an important role in bone fragility with age. Femoral stress, an index of bone modeling response, can be estimated using measurements of DXA derived bone geometry and loading information incorporated into an engineering model. Assuming that individuals have adapted to habitual muscle loading forces, greater stresses indicate a diminished response and a weaker bone. The purpose of this paper was to evaluate the associations of lean mass and muscle strength with the femoral stress measure generated from the engineering model and to examine the extent to which lean mass and muscle strength account for variation in femoral stress among 2539 healthy older adults participating in the Health ABC study using linear regression. Mean femoral stress was higher in women (9.51, SD = 1.85 Mpa) than in men (8.02, SD = 1.43 Mpa). Percent lean mass explained more of the variation in femoral stress than did knee strength adjusted for body size (R-2 = 0.187 vs. 0.055 in men; R-2 = 0237 vs. 0.095 in women). In models adjusted for potential confounders, for every percent increase in lean mass, mean femoral stress was 0.121 Mpa lower (95% CI: 0.138, 0.104; p < 0.001) in men and 0.139 Mpa lower (95% CI: 0.158, 0.121; p < 0.001) in women. The inverse association of femoral stress with lean mass and with knee strength did not differ by category of BMI. Results from this study provide insight into bone modeling differences as measured by femoral stress among older men and women and indicate that lean mass may capture elements of bone's response to load. (C) 2016 Elsevier Inc. All rights reserved. C1 [Reider, Lisa] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD USA. [Beck, Thomas] Beck Radiol Innovat Inc, Catonsville, MD USA. [Alley, Dawn] Ctr Medicare & Medicaid Serv, Ctr Medicare & Medicaid Innovat, Baltimore, MD USA. [Miller, Ram] Novartis Inst Biomed Res, Cambridge, MA USA. [Miller, Ram] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD USA. [Shardell, Michelle] NIA, Longitudinal Study Sect, Bethesda, MD USA. [Schumacher, John] Univ Maryland Baltimore Cty, Dept Sociol & Anthropol, Baltimore, MD USA. [Magaziner, Jay] Univ Maryland, Sch Med, Baltimore, MD USA. [Cawthon, Peggy M.] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. [Cawthon, Peggy M.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA USA. [Barbour, Kamil E.] Ctr Dis Control, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA USA. [Cauley, Jane A.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Harris, Tamara] NIA, Lab Epidemiol & Populat Sci, Intramural Res Program, Bethesda, MD USA. RP Reider, L (reprint author), 415 N Washington St,Room 351, Baltimore, MD 21231 USA. EM lsemani1@jhu.edu FU [P30 AG028747]; [R37 AG009901] FX Magaziner: During the past year Jay Magaziner consulted with or served on advisory boards for: Ammonett; Novartis; Regeneron; Sanofi; Viking; partially supported by grants P30 AG028747; R37 AG009901. NR 33 TC 1 Z9 1 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 EI 1873-2763 J9 BONE JI Bone PD SEP PY 2016 VL 90 BP 152 EP 158 DI 10.1016/j.bone.2016.06.012 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DT1MK UT WOS:000381246600019 PM 27352990 ER PT J AU Tian, Q Ferrucci, L Resnick, SM Simonsick, EM Shardell, MD Landman, BA Venkatraman, VK Gonzalez, CE Studenski, SA AF Tian, Qu Ferrucci, Luigi Resnick, Susan M. Simonsick, Eleanor M. Shardell, Michelle D. Landman, Bennett A. Venkatraman, Vijay K. Gonzalez, Christopher E. Studenski, Stephanie A. TI The effect of age and microstructural white matter integrity on lap time variation and fast-paced walking speed SO BRAIN IMAGING AND BEHAVIOR LA English DT Article DE Diffusion tensor imaging; White matter integrity; Lap time variation; Fast-paced walking speed ID OLDER-ADULTS; GAIT VARIABILITY; MULTIPLE-SCLEROSIS; DIFFUSION; BRAIN; DISEASE; PERFORMANCE; MOBILITY; LESIONS; HEALTH AB Macrostructural white matter damage (WMD) is associated with less uniform and slower walking in older adults. The effect of age and subclinical microstructural WM degeneration (a potentially earlier phase of WM ischemic damage) on walking patterns and speed is less clear. This study examines the effect of age on the associations of regional microstructural WM integrity with walking variability and speed, independent of macrostructural WMD. This study involved 493 participants (n = 51 young; n = 209 young-old; n = 233 old-old) from the Baltimore Longitudinal Study of Aging. All completed a 400-meter walk test and underwent a concurrent brain MRI with diffusion tensor imaging. Microstructural WM integrity was measured as fractional anisotropy (FA). Walking variability was measured as trend-adjusted variation in time over ten 40-meter laps (lap time variation, LTV). Fast-paced walking speed was assessed as mean lap time (MLT). Multiple linear regression models of FA predicting LTV and MLT were adjusted for age, sex, height, weight, and WM hyperintensities. Independent of WM hyperintensities, lower FA in the body of the corpus callosum was associated with higher LTV and longer MLT only in the young-old. Lower FA in superior longitudinal, inferior fronto-occipital, and uncinate fasciculi, the anterior limb of the internal capsule, and the anterior corona radiate was associated with longer MLT only in the young-old. While macrostructural WMD is known to predict more variable and slower walking in older adults, microstructural WM disruption is independently associated with more variable and slower fast-paced walking only in the young-old. Disrupted regional WM integrity may be a subclinical contributor to abnormal walking at an earlier phase of aging. C1 [Tian, Qu; Ferrucci, Luigi; Simonsick, Eleanor M.; Shardell, Michelle D.; Studenski, Stephanie A.] NIA, Longitudinal Studies Sect, Translat Gerontol Branch, 251 Bayview Blvd,Suite 100,Rm 04B316, Baltimore, MD 21224 USA. [Resnick, Susan M.; Venkatraman, Vijay K.; Gonzalez, Christopher E.] NIA, Lab Behav Neurosci, Baltimore, MD 21224 USA. [Landman, Bennett A.] Vanderbilt Univ, Sch Engn, Nashville, TN 37212 USA. RP Tian, Q (reprint author), NIA, Longitudinal Studies Sect, Translat Gerontol Branch, 251 Bayview Blvd,Suite 100,Rm 04B316, Baltimore, MD 21224 USA. EM qu.tian@nih.gov RI Tian, Qu/E-5266-2015 OI Tian, Qu/0000-0003-2706-1439 FU Intramural Research Program of the National Institute on Aging FX This research was supported by the Intramural Research Program of the National Institute on Aging. Authors would like to thank the National Institutes of Health Editorial Fellows Editorial Board. NR 54 TC 2 Z9 2 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1931-7557 EI 1931-7565 J9 BRAIN IMAGING BEHAV JI Brain Imaging Behav. PD SEP PY 2016 VL 10 IS 3 BP 697 EP 706 DI 10.1007/s11682-015-9449-6 PG 10 WC Neuroimaging SC Neurosciences & Neurology GA DU7IL UT WOS:000382387300009 PM 26399234 ER PT J AU Sacks, DB AF Sacks, David B. TI Hemoglobin A(1c) and Race: Should Therapeutic Targets and Diagnostic Cutoffs Differ among Racial Groups? SO CLINICAL CHEMISTRY LA English DT Article ID HISPANIC WHITE ADULTS; A1C; METAANALYSIS; DISPARITIES C1 [Sacks, David B.] NIH, Dept Lab Med, Bldg 10,Rm 2C306,10 Ctr Dr, Bethesda, MD 20892 USA. RP Sacks, DB (reprint author), NIH, Dept Lab Med, Bldg 10,Rm 2C306,10 Ctr Dr, Bethesda, MD 20892 USA. EM sacksdb@mail.nih.gov FU Intramural Research Program of the National Institutes of Health FX Intramural Research Program of the National Institutes of Health. NR 15 TC 1 Z9 1 U1 2 U2 2 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 EI 1530-8561 J9 CLIN CHEM JI Clin. Chem. PD SEP PY 2016 VL 62 IS 9 BP 1199 EP 1201 DI 10.1373/clinchem.2016.255166 PG 3 WC Medical Laboratory Technology SC Medical Laboratory Technology GA DU7VH UT WOS:000382422200008 PM 27386851 ER PT J AU Venables, MJ Navarro-Martin, L Basak, A Baum, BR Zhang, DP Trudeau, VL AF Venables, Maddie J. Navarro-Martin, Laia Basak, Ajoy Baum, Bernard R. Zhang, Dapeng Trudeau, Vance L. TI Characterization of multiple nestin isoforms in the goldfish brain SO COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY D-GENOMICS & PROTEOMICS LA English DT Article DE Antibody generation; Goldfish; Hypothalamus; Nestin; Neurogenesis and Telencephalon ID CENTRAL-NERVOUS-SYSTEM; NEURAL STEM-CELLS; INTERMEDIATE-FILAMENTS; ADULT NEUROGENESIS; PROGENITOR CELLS; SUBVENTRICULAR ZONE; TELEOST FISH; RADIAL GLIA; ZEBRAFISH; REGENERATION AB Nestin is an intermediate filament protein involved in neurogenesis in fish, mice, and humans. In this study we used rapid amplification of cDNA ends PCR to isolate goldfish nestin (nes). PCR analysis and sequencing revealed three different nes transcripts of 4003, 2446, and 2126 nucleotides, which are predicted to generate proteins of 860, 274, and 344 amino acids in length. Sequence analysis suggests that these nes transcripts are likely a result of alternative splicing. We next applied a multiple-antigenic peptide strategy to generate a goldfish-specific nestin antibody. Western blotting with this antibody together with mass spectrometry verified the presence of major nestin protein isoforms with differing molecular weights (similar to 70, 40 and 30 kDa). We further examined expression patterns of these nestin protein isoforms in different parts of the goldfish brain and pituitary and found the telencephalon to express all three isoforms at a distinct level and abundance. We report that multiple nestin isoforms are present indicating another level of complexity for the regulation of intermediate filaments in comparison to mammals. Studying the differential roles and regulation of these nestins could lead to a better understanding of cellular remodeling during neurogenesis and the unparalleled regenerative abilities after damage in the teleost CNS. (C) 2016 Elsevier Inc. All rights reserved. C1 [Venables, Maddie J.; Navarro-Martin, Laia; Baum, Bernard R.; Trudeau, Vance L.] Univ Ottawa, Dept Biol, Ctr Adv Res Environm Genom, 30 Marie Curie, Ottawa, ON K1N 6N5, Canada. [Basak, Ajoy] Univ Ottawa, Fac Hlth Sci, Interdisciplinary Sch Hlth Sci, Ottawa, ON K1H 8M5, Canada. [Zhang, Dapeng] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [Navarro-Martin, Laia] IDAEA CSIC, Inst Environm Assessment & Water Res, Jordi Girona 18, Barcelona 08034, Spain. RP Trudeau, VL (reprint author), Univ Ottawa, Dept Biol, Ctr Adv Res Environm Genom, 30 Marie Curie, Ottawa, ON K1N 6N5, Canada. EM trudeauv@uottawa.ca RI Navarro-Martin, Laia/A-3588-2011 OI Navarro-Martin, Laia/0000-0001-6554-8833 FU NSERC [RGPIN-2016-04182]; University of Ottawa Research Chair in Neuroendocrinology FX This research was supported by the NSERC Discovery program (VT) (RGPIN-2016-04182) and the University of Ottawa Research Chair in Neuroendocrinology (VT). The authors greatly appreciate the help of the Animal Care and Veterinary Services at the University of Ottawa for nestin antibody generation. We would like to acknowledge the help of Bill Fletcher and Christine Archer for maintenance and care of the goldfish and Wei Seah for his help with experiments and fish husbandry. We would also like to thank Dr. A. Poulin and Dr. P. Walsh for use of the chemiluminescence detector systems for western blot imaging. The authors declare no competing interests. NR 37 TC 0 Z9 0 U1 4 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1744-117X EI 1878-0407 J9 COMP BIOCHEM PHYS D JI Comp. Biochem. Physiol. D-Genomics Proteomics PD SEP PY 2016 VL 19 BP 8 EP 17 DI 10.1016/j.cbd.2016.05.002 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA DU7TA UT WOS:000382416300002 PM 27254106 ER PT J AU Sudhindra, P Wang, GQ Schriefer, ME McKenna, D Jian, ZG Krause, PJ Marques, AR Wormser, GP AF Sudhindra, Praveen Wang, Guiqing Schriefer, Martin E. McKenna, Donna Jian Zhuge Krause, Peter J. Marques, Adriana R. Wormser, Gary P. TI Insights into Borrelia miyamotoi infection from an untreated case demonstrating relapsing fever, monocytosis and a positive C6 Lyme serology SO DIAGNOSTIC MICROBIOLOGY AND INFECTIOUS DISEASE LA English DT Article DE Borrelia; Borrelia Miyamotoi; Lyme disease; C6 serology; Monocytosis; Relapsing fever ID UNITED-STATES; DISEASE; MENINGOENCEPHALITIS; BURGDORFERI; SYPHILIS; VECTOR; EUROPE; JAPAN; ASSAY AB We describe a patient from the United States with PCR- and serology-confirmed Borrelia miyamotoi infection who recovered without antibiotics. Our findings suggest that B. miyamotoi infection may cause relapsing fever, blood monocytosis and antibody reactivity to the C6 peptide. Further studies are required to better define the spectrum of clinical and laboratory findings for this emerging tick-transmitted infection. (C) 2016 Elsevier Inc. All rights reserved. C1 [Sudhindra, Praveen; Wormser, Gary P.] New York Med Coll, Div Infect Dis, Valhalla, NY 10595 USA. [Wang, Guiqing; Jian Zhuge] New York Med Coll, Dept Pathol, Valhalla, NY 10595 USA. [Wang, Guiqing; Jian Zhuge] Westchester Med Ctr, Dept Pathol & Clin Labs, Valhalla, NY 10595 USA. [Schriefer, Martin E.] Ctr Dis Control & Prevent, Ft Collins, CO USA. [Krause, Peter J.] Yale Univ, Yale Sch Publ Hlth, New Haven, CT USA. [Krause, Peter J.] Yale Univ, Yale Sch Med, New Haven, CT USA. [Marques, Adriana R.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Wormser, GP (reprint author), New York Med Coll, Div Infect Dis, Valhalla, NY 10595 USA. EM gwormser@nymc.edu FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX The authors thank Denise Cooper, Carol Scavarda, Julia Singer, Sophia Less, Artemio Zavalla, Lisa Giarratano, Chris Sexton, Adam Replogle, Luke Kingly and Cecilia Dumouchel for their assistance. This work was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (ARM). NR 26 TC 1 Z9 1 U1 7 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0732-8893 EI 1879-0070 J9 DIAGN MICR INFEC DIS JI Diagn. Microbiol. Infect. Dis. PD SEP PY 2016 VL 86 IS 1 BP 93 EP 96 DI 10.1016/j.diagmicrobio.2016.06.015 PG 4 WC Infectious Diseases; Microbiology SC Infectious Diseases; Microbiology GA DU7TB UT WOS:000382416400020 PM 27412815 ER PT J AU Miles, A Iqbal, Z Vauterin, P Pearson, R Campino, S Theron, M Gould, K Mead, D Drury, E O'Brien, J Rubio, VR MacInnis, B Mwangi, J Samarakoon, U Ranford-Cartwright, L Ferdig, M Hayton, K Su, XZ Wellems, T Rayner, J McVean, G Kwiatkowski, D AF Miles, Alistair Iqbal, Zamin Vauterin, Paul Pearson, Richard Campino, Susana Theron, Michel Gould, Kelda Mead, Daniel Drury, Eleanor O'Brien, John Rubio, Valentin Ruano MacInnis, Bronwyn Mwangi, Jonathan Samarakoon, Upeka Ranford-Cartwright, Lisa Ferdig, Michael Hayton, Karen Su, Xin-zhuan Wellems, Thomas Rayner, Julian McVean, Gil Kwiatkowski, Dominic TI Indels, structural variation, and recombination drive genomic diversity in Plasmodium falciparum SO GENOME RESEARCH LA English DT Article ID COPY NUMBER VARIATION; LOW-COMPLEXITY REGIONS; DROSOPHILA-MELANOGASTER; CHLOROQUINE-RESISTANCE; MEIOTIC RECOMBINATION; MALARIA PARASITES; GENE DUPLICATION; SEQUENCING DATA; NON-CROSSOVER; HOT-SPOTS AB The malaria parasite Plasmodium falciparum has a great capacity for evolutionary adaptation to evade host immunity and develop drug resistance. Current understanding of parasite evolution is impeded by the fact that a large fraction of the genome is either highly repetitive or highly variable and thus difficult to analyze using short-read sequencing technologies. Here, we describe a resource of deep sequencing data on parents and progeny from genetic crosses, which has enabled us to perform the first genome-wide, integrated analysis of SNP, indel and complex polymorphisms, using Mendelian error rates as an indicator of genotypic accuracy. These data reveal that indels are exceptionally abundant, being more common than SNPs and thus the dominant mode of polymorphism within the core genome. We use the high density of SNP and indel markers to analyze patterns of meiotic recombination, confirming a high rate of crossover events and providing the first estimates for the rate of non-crossover events and the length of conversion tracts. We observe several instances of meiotic recombination within copy number variants associated with drug resistance, demonstrating a mechanism whereby fitness costs associated with resistance mutations could be compensated and greater phenotypic plasticity could be acquired. C1 [Miles, Alistair; Vauterin, Paul; Pearson, Richard; Kwiatkowski, Dominic] Univ Oxford, MRC Ctr Genom & Global Hlth, Oxford OX3 7BN, England. [Miles, Alistair; Pearson, Richard; Campino, Susana; Theron, Michel; Gould, Kelda; Mead, Daniel; Drury, Eleanor; Rayner, Julian; Kwiatkowski, Dominic] Wellcome Trust Sanger Inst, Malaria Programme, Hinxton CB10 1SA, England. [Iqbal, Zamin; McVean, Gil] Univ Oxford, Welkome Trust Ctr Human Genet, Oxford OX3 7BN, England. [O'Brien, John] Bowdoin Coll, Brunswick, ME 04011 USA. [Rubio, Valentin Ruano; MacInnis, Bronwyn] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. [Mwangi, Jonathan] Mt Kenya Univ, Sch Med, Dept Biochem, Thika 01000, Kenya. [Mwangi, Jonathan] Univ Glasgow, Coll Med Vet & Life Sci, Inst Infect Immun & Inflammat, Glasgow G12 8QQ, Lanark, Scotland. [Samarakoon, Upeka; Ferdig, Michael] Univ Notre Dame, Dept Biol Sci, Eck Inst Global Hlth, Notre Dame, IN 46556 USA. [Hayton, Karen; Su, Xin-zhuan; Wellems, Thomas] NIAID, Lab Malaria & Vector Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [McVean, Gil] Univ Oxford, Dept Stat, Oxford OX1 3LB, England. RP Miles, A (reprint author), Univ Oxford, MRC Ctr Genom & Global Hlth, Oxford OX3 7BN, England.; Miles, A (reprint author), Wellcome Trust Sanger Inst, Malaria Programme, Hinxton CB10 1SA, England. EM alistair.miles@well.ox.ac.uk OI Miles, Alistair/0000-0001-9018-4680; Rayner, Julian/0000-0002-9835-1014; Su, Xinzhuan/0000-0003-3246-3248; Ranford-Cartwright, Lisa/0000-0003-1992-3940; Kwiatkowski, Dominic/0000-0002-5023-0176; Iqbal, Zamin/0000-0001-8466-7547; Mead, Daniel/0000-0001-7717-4330 FU Wellcome Trust [090770/Z/09/Z, 098051, 091791]; Medical Research Council UK; DFID [MR/M006212/1]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Wellcome Trust (090770/Z/09/Z; 098051) and Medical Research Council UK & DFID (MR/M006212/1) and by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. Research in L.R.-C.'s laboratory was supported by the Wellcome Trust (091791). NR 79 TC 4 Z9 4 U1 11 U2 14 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1088-9051 EI 1549-5469 J9 GENOME RES JI Genome Res. PD SEP PY 2016 VL 26 IS 9 BP 1288 EP 1299 DI 10.1101/gr.203711.115 PG 12 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA DU7UV UT WOS:000382421000014 PM 27531718 ER PT J AU Cotter, EW Hamilton, NS Kelly, NR Harney, MB Greene, L White, KA Mazzeo, SE AF Cotter, Elizabeth W. Hamilton, Natia S. Kelly, Nichole R. Harney, Megan B. Greene, LaShaun White, Kelly A. Mazzeo, Suzanne E. TI A Qualitative Examination of Health Barriers and Facilitators Among African American Mothers in a Subsidized Housing Community SO HEALTH PROMOTION PRACTICE LA English DT Article DE Black; African American; qualitative research; obesity; health disparities; community intervention ID LOW-INCOME; SOCIOECONOMIC-STATUS; VEGETABLE CONSUMPTION; OBESITY PREVENTION; ADOLESCENT FEMALES; PHYSICAL-ACTIVITY; GO GIRLS; FRUIT; OVERWEIGHT; FOOD AB Although African American families are at particular risk for obesity and its associated health comorbidities, few interventions have directly targeted low-income members of this group living in subsidized public housing. Using a consensual qualitative research approach, we conducted 11 interviews with African American mothers living in two public housing communities to enhance understanding of their perceived barriers and facilitators to health. Five primary domains emerged, including barriers (access, financial, personal, and neighborhood concerns), resources (personal and community), current behaviors (diet, physical activity, and program participation), definition of health (mental well-being, physical well-being, and health behaviors), and needs/interests in programming (health behavior-specific programs, non-health-related programs, child-focused programming, and qualities of programs and their leaders). Results demonstrate the complex interaction among social, environmental, and personal factors on health behaviors for this priority population, and highlight the need for community members' involvement in the development of community-based obesity prevention programming. C1 [Cotter, Elizabeth W.] Amer Univ, Washington, DC 20016 USA. [Hamilton, Natia S.] Virginia State Univ, Petersburg, VA 23806 USA. [Kelly, Nichole R.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Kelly, Nichole R.] Colorado State Univ, Ft Collins, CO 80523 USA. [Harney, Megan B.] Univ North Carolina Chapel Hill, Chapel Hill, NC USA. [Greene, LaShaun] Family & Adolescent Serv, Richmond, VA USA. [White, Kelly A.; Mazzeo, Suzanne E.] Virginia Commonwealth Univ, Richmond, VA USA. RP Cotter, EW (reprint author), Amer Univ, Dept Hlth Studies, 4400 Massachusetts Ave NW, Washington, DC 20016 USA. EM cotter@american.edu NR 39 TC 0 Z9 0 U1 5 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1524-8399 EI 1552-6372 J9 HEALTH PROMOT PRACT JI Health Promot. Pract. PD SEP PY 2016 VL 17 IS 5 BP 682 EP 692 DI 10.1177/1524839916630504 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DU9NB UT WOS:000382543300008 PM 27091605 ER PT J AU Tollanes, MC Strandberg-Larsen, K Eichelberger, KY Moster, D Lie, RT Brantsaeter, AL Meltzer, HM Stoltenberg, C Wilcox, AJ AF Tollanes, Mette C. Strandberg-Larsen, Katrine Eichelberger, Kacey Y. Moster, Dag Lie, Rolv Terje Brantsaeter, Anne Lise Meltzer, Helle Margrete Stoltenberg, Camilla Wilcox, Allen J. TI Intake of Caffeinated Soft Drinks before and during Pregnancy, but Not Total Caffeine Intake, Is Associated with Increased Cerebral Palsy Risk in the Norwegian Mother and Child Cohort Study SO JOURNAL OF NUTRITION LA English DT Article DE Cerebral palsy; antenatal caffeine exposure; caffeine consumption; caffeinated soft drinks; pregnancy; prospective cohort study ID DIETARY PATTERNS; CONSUMPTION; DISORDER; THERAPY; BIRTH; MOBA; PREMATURITY; PREVALENCE; EXPOSURE; BEHAVIOR AB Background: Postnatal administration of caffeine may reduce the risk of cerebral palsy (CP) in vulnerable low-birth-weight neonates. The effect of antenatal caffeine exposure remains unknown. Objective: We investigated the association of intake of caffeine by pregnant women and risk of CP in their children. Methods: The study was based on The Norwegian Mother and Child Cohort Study, comprising >100,000 live-born children, of whom 222 were subsequently diagnosed with CP. Mothers reported their caffeine consumption in questionnaires completed around pregnancy week 17 (102,986 mother child pairs), week 22 (87,987 mother child pairs), and week 30 (94,372 mother child pairs). At week 17, participants were asked about present and prepregnancy consumption. We used Cox regression models to estimate associations between exposure [daily servings (1 serving = 125 mL) of caffeinated coffee, tea, and soft drinks and total caffeine consumption] and CP in children, with nonconsumers as the reference group. Models included adjustment for maternal age and education, medically assisted reproduction, and smoking, and for each source of caffeine, adjustments were made for the other sources. Results: Total daily caffeine intake before and during pregnancy was not associated with CP risk. High consumption (>= 6 servings/d) of caffeinated soft drinks before pregnancy was associated with an increased CP risk (HR: 1.9; 95% CI: 1.2, 3.1), and children of women consuming 3-5 daily servings of caffeinated soft drinks during pregnancy weeks 13-30 also had an increased CP risk (HR: 1.7; 95% CI: 1.1, 2.8). A mean daily consumption of 51-100 mg caffeine from soft drinks during the first half of pregnancy was associated with a 1.9-fold increased risk of CP in children (HR: 1.9; 95% CI: 1.1, 3.6). Conclusions: Maternal total daily caffeine consumption before and during pregnancy was not associated with CP risk in children. The observed increased risk with caffeinated soft drinks warrants further investigation. C1 [Tollanes, Mette C.; Moster, Dag; Lie, Rolv Terje; Stoltenberg, Camilla] Univ Bergen, Dept Global Publ Hlth & Primary Care, Bergen, Norway. [Tollanes, Mette C.; Moster, Dag] Norwegian Inst Publ Hlth, Domain Hlth Data & Digitalisat, Bergen, Norway. [Strandberg-Larsen, Katrine] Univ Copenhagen, Dept Publ Hlth, Copenhagen, Denmark. [Eichelberger, Kacey Y.] Univ South Carolina, Sch Med Greenville, Greenville Hlth Syst, Dept Obstet & Gynecol, Greenville, SC USA. [Moster, Dag] Haukeland Hosp, Dept Pediat, Bergen, Norway. [Brantsaeter, Anne Lise; Meltzer, Helle Margrete] Norwegian Inst Publ Hlth, Domain Infect Control & Environm Hlth, Oslo, Norway. [Stoltenberg, Camilla] Norwegian Inst Publ Hlth, Oslo, Norway. [Wilcox, Allen J.] NIEHS, Durham, NC USA. RP Tollanes, MC (reprint author), Univ Bergen, Dept Global Publ Hlth & Primary Care, Bergen, Norway.; Tollanes, MC (reprint author), Norwegian Inst Publ Hlth, Domain Hlth Data & Digitalisat, Bergen, Norway. EM mette.tollanes@uib.no RI Brantsaeter, Anne Lise/H-7014-2016; OI Brantsaeter, Anne Lise/0000-0001-6315-7134; Wilcox, Allen/0000-0002-3376-1311; Meltzer, Helle Margrete/0000-0002-3591-7017 FU NIH, National Institute of Environmental Health Sciences (NIEHS); Norwegian Ministry of Health; Ministry of Education and Research; NIH/NIEHS [N01-ES-75558]; NIH/National Institute of Neurological Disorders and Stroke [UO1 NS 047537-01, UO1 NS 047537-06A1] FX Supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (NIEHS) The Norwegian Mother and Child Cohort Study is supported by the Norwegian Ministry of Health and the Ministry of Education and Research, NIH/NIEHS (contract N01-ES-75558), NIH/National Institute of Neurological Disorders and Stroke (grants UO1 NS 047537-01 and UO1 NS 047537-06A1). NR 35 TC 0 Z9 0 U1 7 U2 15 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 EI 1541-6100 J9 J NUTR JI J. Nutr. PD SEP PY 2016 VL 146 IS 9 BP 1701 EP 1706 DI 10.3945/jn.116.232272 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DU7VN UT WOS:000382422800011 PM 27489007 ER PT J AU Bowers, KA Olsen, SF Bao, W Halldorsson, TI Strom, M Zhang, CL AF Bowers, Katherine A. Olsen, Sjurdur F. Bao, Wei Halldorsson, Thorhallur I. Strom, Marin Zhang, Cuilin TI Plasma Concentrations of Ferritin in Early Pregnancy Are Associated with Risk of Gestational Diabetes Mellitus in Women in the Danish National Birth Cohort SO JOURNAL OF NUTRITION LA English DT Article DE iron; biomarkers; pregnancy; gestational diabetes mellitus; plasma ferritin ID SERUM FERRITIN; IRON OVERLOAD AB Background: Evidence from experimental studies has demonstrated that higher than normal iron concentrations can lead to pancreatic beta cell dysfunction and impaired glucose metabolism. Studies on body iron stores in early pregnancy and subsequent gestational diabetes mellitus (GDM) risk are sparse. Objective: Our objective was to determine whether biomarkers of body iron stores measured in early pregnancy are associated with GDM risk. Methods: A case-control study of 350 GDM cases and 349 non-GDM controls was conducted in participants from the Danish National Birth Cohort. Blood was collected at a mean +/- SD gestational age of 9.4 +/- 3.2 wk. Plasma biomarkers of iron stores, including ferritin and soluble transferrin receptor (sTfR), were measured. Logistic regression was used to estimate the OR of GDM associated with quintiles of plasma biomarkers of body iron stores, controlling for maternal age, family history of diabetes, exercise in pregnancy, parity, and prepregnancy body mass index (BM). Results: Cases were older (mean +/- SD age: 32.2 +/- 4.3 compared with 29.9 +/- 4.2 y) and had a higher BMI (in kg/m(2); mean SD: 28.7 +/- 6.0 compared with 24.1 +/- 4.6) than controls. Plasma concentrations of both ferritin and sTfR in early pregnancy were significantly higher in GDM cases than in controls [means +/- SDs: 80.6 +/- 56.0 compared with 71.8 +/- 50.1 mu g/L (P = 0.03) and 1.5 +/- 0.7 compared with 1.4 +/- 0.6 mg/L (P = 0.002) for ferritin and sTfR, respectively]. Ferritin was positively and significantly associated with GDM risk even after adjustment for major risk factors of GDM, including prepregnancy BMI. ORs across increasing quintiles of ferritin were 1.00 (reference), 1.25 (95% CI: 0.70, 2.22), 1.89 (95% CI: 1.06, 3.37), 0.82 (95% CI: 0.46, 1.48), and 2.34 (95% CI: 1.30, 4.21) (P-linear trend = 0.02). Conclusion: These findings suggest that plasma ferritin measured in early pregnancy is significantly and positively associated with GDM risk. C1 [Bowers, Katherine A.] Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Div Biostat & Epidemiol, Cincinnati, OH 45229 USA. [Olsen, Sjurdur F.; Halldorsson, Thorhallur I.; Strom, Marin] Statens Serum Inst, Dept Epidemiol Res, Ctr Fetal Programming, Copenhagen, Denmark. [Olsen, Sjurdur F.; Zhang, Cuilin] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA. [Bao, Wei] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, Rockville, MD USA. [Bao, Wei] Univ Iowa, Coll Publ Hlth, Dept Epidemiol, Iowa City, IA USA. [Halldorsson, Thorhallur I.] Univ Iceland, Fac Food Sci & Nutr, Raykjavik, Iceland. [Strom, Marin] Univ Faroe Islands, Fac Nat & Hlth Sci, Torshavn, Faroe Islands, Denmark. RP Bowers, KA (reprint author), Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Div Biostat & Epidemiol, Cincinnati, OH 45229 USA.; Zhang, CL (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA. EM katherine.bowers@cchmc.org; zhangcu@mail.nih.gov OI Bao, Wei/0000-0002-7301-5786 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH [HHSN275201000020C]; NIH Office of Dietary Supplements FX Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH (contract no. HHSN275201000020C), and NIH Office of Dietary Supplements. NR 24 TC 2 Z9 2 U1 4 U2 6 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 EI 1541-6100 J9 J NUTR JI J. Nutr. PD SEP PY 2016 VL 146 IS 9 BP 1756 EP 1761 DI 10.3945/jn.115.227793 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DU7VN UT WOS:000382422800018 PM 27511926 ER PT J AU Loftfield, E Freedman, ND Dodd, KW Vogtmann, E Xiao, Q Sinha, R Graubard, BI AF Loftfield, Erikka Freedman, Neal D. Dodd, Kevin W. Vogtmann, Emily Xiao, Qian Sinha, Rashmi Graubard, Barry I. TI Coffee Drinking Is Widespread in the United States, but Usual Intake Varies by Key Demographic and Lifestyle Factors SO JOURNAL OF NUTRITION LA English DT Article DE coffee; usual intake; population survey; National Cancer Institute method; diet ID DOSE-RESPONSE METAANALYSIS; CHRONIC LIVER-DISEASE; BASAL-CELL CARCINOMA; PROSPECTIVE COHORT; ENDOMETRIAL CANCER; CARDIOVASCULAR-DISEASE; DECAFFEINATED COFFEE; RECOVERY BIOMARKERS; COLORECTAL-CANCER; CAFFEINE INTAKE AB Background: Despite widespread popularity and possible health effects, the prevalence and distribution of coffee consumption in US adults are poorly characterized. Objective: We sought to estimate usual daily coffee intakes from all coffee-containing beverages, including decaffeinated and regular coffee, among US adults according to demographic, socioeconomic, and health-related factors. Methods: Dietary intake data from <= 2 nonconsecutive 24-h dietary recalls and a food-frequency questionnaire administered during the NHANES 2003-2006 were used to estimate the person-specific probability of consuming coffee on a particular day and the usual amount consumed on consumption days. Trends in population mean coffee consumption over time were evaluated by using multiple linear regression and 1-d 24-h recall data from NHANES 2003-2012. Analyses were weighted to be representative of the US adult population aged >= 20 y. Results: An estimated 154 million adults, or 75% of the US population, aged >= 20y reported drinking coffee; 49% reported drinking coffee daily. Prevalence did not vary by sex, education, income, or self-reported general health (all P >= 0.05) but did vary by age, race/ethnicity, smoking status, and alcohol drinking (all P < 0.05). Among coffee drinkers, the mean +/- SE usual intake was 14.1 +/- 0.5 fluid ounces/d (417 +/- 15 mL/d). Mean usual intakes were higher in men than women, in older age groups than in those aged 20 to <30 y, in non-Hispanic whites than in non-Hispanic blacks or Hispanic/other races, in smokers than in never smokers, and in daily alcohol consumers than in nonconsumers (all P < 0.05). Population mean coffee consumption was stable from 2003 to 2012 (P-trend = 0.09). Conclusions: Coffee is widely consumed in the United States, with usual intakes varying by lifestyle and demographic factors, most notably by age. Longitudinal studies are needed to determine whether observed differences by age reflect birth cohort effects or changes in drinking patterns over the lifetime. C1 [Loftfield, Erikka; Freedman, Neal D.; Vogtmann, Emily; Xiao, Qian; Sinha, Rashmi; Graubard, Barry I.] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA. [Dodd, Kevin W.] NCI, Canc Prevent Div, Rockville, MD USA. RP Loftfield, E (reprint author), NCI, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA. EM erikka.loftfield@nih.gov FU Intramural Research Program of the NIH; Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH; Department of Health and Human Services FX Supported by the Intramural Research Program of the NIH; Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH; and the Department of Health and Human Services. NR 43 TC 0 Z9 0 U1 10 U2 10 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 EI 1541-6100 J9 J NUTR JI J. Nutr. PD SEP PY 2016 VL 146 IS 9 BP 1762 EP 1768 DI 10.3945/jn.116.233940 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DU7VN UT WOS:000382422800019 PM 27489008 ER PT J AU Deac, OM Mills, JL Gardiner, CM Shane, B Quinn, L Midttun, O McCann, A Meyer, K Ueland, PM Fan, RZ Lu, ZH Brody, LC Molloy, AM AF Deac, Oana M. Mills, James L. Gardiner, Clair M. Shane, Barry Quinn, Louise Midttun, Oivind McCann, Adrian Meyer, Klaus Ueland, Per M. Fan, Ruzong Lu, Zhaohui Brody, Lawrence C. Molloy, Anne M. TI Serum Immune System Biomarkers Neopterin and Interleukin-10 Are Strongly Related to Tryptophan Metabolism in Healthy Young Adults SO JOURNAL OF NUTRITION LA English DT Article DE tryptophan; kynurenine; cytokines; neopterin; interleukin-10 ID C-REACTIVE PROTEIN; VITAMIN-B-6 STATUS; KYNURENINE PATHWAY; INTERFERON-GAMMA; LYMPHOCYTE-PROLIFERATION; FOLATE CONCENTRATIONS; MULTIPLE-SCLEROSIS; T-CELLS; INFLAMMATION; MARKERS AB Background: Changes in tryptophan metabolism through the vitamin B-6 dependent kynurenine pathway have been linked to activation of the immune system. Objective: We hypothesized that blood concentrations of tryptophan and its catabolites were associated with biomarkers relevant to inflammatory processes in healthy noninflamed subjects. Methods: Healthy young adults (n = 737) aged 18-28 y without any known diseases or clinical evidence of inflammation provided blood samples for analysis of serum tryptophan/kynurenine metabolites, neopterin, C-reactive protein (CRP), and plasma pyridoxal 5'-phosphate (PLP) with LC tandem mass spectrometry methodologies. A panel of cytokines was measured in serum by using high-sensitivity ELISA assays. Anthropometric and lifestyle data were collected by questionnaire. Multiple linear regression analysis to determine the effect of measured serum cytokine concentrations as predictors of tryptophan metabolites was performed on inverse normal-rank transformations of the data, adjusted for sex, body mass index, smoking, alcohol intake, and contraceptive use in women. Results: Median serum CRP and neopterin concentrations were well below established clinical cutoffs for inflammation. We observed significant positive associations between serum interleukin-10 (IL-10) and serum kynurenine (P= 0.0002), the kynurenine-to-tryptophan ratio (KTR) (P = 0.003), 3-hydroxykynurenine (P = 0.01), and 3-hydroxyanthranilic acid (P = 0.04). Serum neopterin was positively associated with kynurenine, the KTR (both P < 0.0001), and anthranilic acid (P = 0.004), and was negatively associated with serum tryptophan (P = 0.01) and PLP (P < 0.0001). Serum tumor necrosis factor a was also negatively associated with tryptophan (P < 0.001). Conclusions: In healthy young adults with no apparent inflammatory conditions, serum tryptophan metabolites are significantly associated with key immune system biomarkers. The observed association between IL-10 and kynurenine is unexpected and suggests that kynurenine-linked mechanisms promoting negative regulation of inflammatory responses are associated with normal immune homeostasis. C1 [Deac, Oana M.; Molloy, Anne M.] Trinity Coll Dublin, Sch Med, Dublin, Ireland. [Gardiner, Clair M.; Quinn, Louise; Molloy, Anne M.] Trinity Coll Dublin, Sch Biochem & Immunol, Dublin, Ireland. [Mills, James L.; Fan, Ruzong; Lu, Zhaohui] Eunice Kennedy Shriner Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Bethesda, MD USA. [Brody, Lawrence C.] NHGRI, Mol Pathogenesis Sect, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Shane, Barry] Univ Calif Berkeley, Nutr Sci & Toxicol, Berkeley, CA 94720 USA. [Midttun, Oivind; McCann, Adrian; Meyer, Klaus] Bevital AS, Bergen, Norway. [Ueland, Per M.] Univ Bergen, Inst Med, Pharmacol Sect, Bergen, Norway. [Ueland, Per M.] Haukeland Hosp, Bergen, Norway. RP Molloy, AM (reprint author), Trinity Coll Dublin, Sch Med, Dublin, Ireland.; Molloy, AM (reprint author), Trinity Coll Dublin, Sch Biochem & Immunol, Dublin, Ireland. EM amolloy@tcd.ie FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD [N01HD33348]; Health Research Board, Ireland FX Supported by the Health Research Board, Ireland, and the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD (contract no. N01HD33348). NR 44 TC 0 Z9 0 U1 3 U2 3 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 EI 1541-6100 J9 J NUTR JI J. Nutr. PD SEP PY 2016 VL 146 IS 9 BP 1801 EP 1806 DI 10.3945/jn.116.230698 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DU7VN UT WOS:000382422800024 PM 27489009 ER PT J AU Tanumihardjo, SA Russe, RM Stephensen, CB Gannon, BM Craft, NE Haskell, MJ Lietz, G Schulze, K Raiten, DJ AF Tanumihardjo, Sherry A. Russe, Robert M. Stephensen, Charles B. Gannon, Bryan M. Craft, Neal E. Haskell, Marjorie J. Lietz, Georg Schulze, Kerry Raiten, Daniel J. TI Biomarkers of Nutrition for Development (BOND)-Vitamin A Review SO JOURNAL OF NUTRITION LA English DT Article DE BOND; vitamin A biomarkers; vitamin A review; breast milk; dose response tests; dried blood spot; isotope dilution; retinol-binding protein; serum retinol; xerophthalmia ID VITAMIN-A STATUS; RETINOL-BINDING-PROTEIN; DOSE-RESPONSE TEST; BETA-CAROTENE SUPPLEMENTATION; ACUTE-PHASE RESPONSE; CLUSTER-RANDOMIZED-TRIAL; STABLE-ISOTOPE-DILUTION; GERBILS MERIONES-UNGUICULATUS; DEPENDENT DIABETES-MELLITUS; PREGNANT INDONESIAN WOMEN AB The Biomarkers of Nutrition for Development (BOND) project is designed to provide evidence-informed advice to anyone with an interest in the role of nutrition in health. The BOND program provides information with regard to selection, use, and interpretation of biomarkers of nutrient exposure, status, function, and effect, which will be especially useful for readers who want to assess nutrient status. To accomplish this objective, expert panels are recruited to evaluate the literature and to draft comprehensive reports on the current state of the art with regard to specific nutrient biology and available biomarkers for assessing nutritional status at the individual and population levels. Phase I of the BOND project includes the evaluation of biomarkers for 6 nutrients: iodine, folate, zinc, iron, vitamin A, and vitamin B-12. This review of vitamin A is the current article in this series. Although the vitamin was discovered >100 y ago, vitamin A status assessment is not trivial. Serum retinol concentrations are under homeostatic control due in part to vitamin A's use in the body for growth and cellular differentiation and because of its toxic properties at high concentrations. Furthermore, serum retinol concentrations are depressed during infection and inflammation because retinol-binding protein (RBP) is a negative acute-phase reactant, which makes status assessment challenging. Thus, this review describes the clinical and functional indicators related to eye health and biochemical biomarkers of vitamin A status (i.e., serum retinol, RBP, breast-milk retinol, dose-response tests, isotope dilution methodology, and serum retinyl esters). These biomarkers are then related to liver vitamin A concentrations, which are usually considered the gold standard for vitamin A status. With regard to biomarkers, future research questions and gaps in our current understanding as well as limitations of the methods are described. C1 [Tanumihardjo, Sherry A.; Gannon, Bryan M.] Univ Wisconsin, Dept Nutr Sci, Interdept Grad Program Nutr Sci, 1415 Linden Dr, Madison, WI 53706 USA. [Russe, Robert M.] Tufts Univ, Boston, MA 02111 USA. [Stephensen, Charles B.] USDA, Western Human Nutr Res Ctr, Davis, CA USA. [Craft, Neal E.] Craft Technol Inc, Wilson, NC USA. [Haskell, Marjorie J.] Univ Calif Davis, Davis, CA 95616 USA. [Lietz, Georg] Newcastle Univ, Newcastle Upon Tyne, Tyne & Wear, England. [Schulze, Kerry] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Raiten, Daniel J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. RP Raiten, DJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. EM raitend@mail.nih.gov OI Gannon, Bryan M./0000-0003-1781-9242 FU Bill & Melinda Gates Foundation; PepsiCo; Division of Nutrition Research Coordination (DNRC, NIH); Office of Dietary Supplements (ODS, NIH); Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD, NIH) FX Published in a supplement to The Journal of Nutrition The Biomarkers of Nutrition for Development (BOND) project was developed by the nutrition program staff of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) of the NIH within the US Department of Health and Human Services (DHHS). The initial 6 nutrients selected, iodine, vitamin A, iron, zinc, folate, and vitamin B-12, were chosen for their high public health importance. Expert panels on each nutrient were constituted and charged with developing comprehensive reviews for publication in the BOND series. The BOND program received its core funding from the Bill & Melinda Gates Foundation, PepsiCo, the Division of Nutrition Research Coordination (DNRC, NIH), the Office of Dietary Supplements (ODS, NIH), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD, NIH). The Supplement Coordinator for this supplement was Daniel J Raiten (NICHD, NIH). Supplement Coordinator disclosures: no conflicts of interest. Publication costs for this supplement were defrayed in part by the payment of page charges. This publication must therefore be hereby marked "advertisement" in accordance with 18 USC section 1734 solely to indicate this fact. The opinions expressed in this publication are those of the authors and are not attributable to the sponsors or the publisher, Editor, or Editorial Board of The Journal of Nutrition.; The BOND project was funded in part by the Bill & Melinda Gates Foundation, PepsiCo, the Office of Dietary Supplements (ODS, NIH), the Division of Nutrition Research Coordination (DNRC, NIH), and the Eunice Kennedy Shnver National Institute of Child Health and Human Development (NICHD, NIH). The vitamin A review was written in response to an invitation from the NICHD of the NIH within the US Department of Health and Human Services (DHHS). This is a free access article, distributed under terms (http://www.nutrition.org/publications/guidelinesand-policies/license/) that permit unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited. NR 313 TC 7 Z9 7 U1 7 U2 13 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 EI 1541-6100 J9 J NUTR JI J. Nutr. PD SEP PY 2016 VL 146 IS 9 BP 1816 EP 1848 DI 10.3945/jn.115.229708 PG 33 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DU7VN UT WOS:000382422800028 PM 27511929 ER PT J AU Sorokin, AV Yang, ZH Vaisman, BL Thacker, S Yu, ZX Sampson, M Serhan, CN Remaley, AT AF Sorokin, Alexander V. Yang, Zhi-Hong Vaisman, Boris L. Thacker, Seth Yu, Zu-Xi Sampson, Maureen Serhan, Charles N. Remaley, Alan T. TI Addition of aspirin to a fish oil-rich diet decreases inflammation and atherosclerosis in ApoE-null mice SO JOURNAL OF NUTRITIONAL BIOCHEMISTRY LA English DT Article DE Atherosclerosis; Inflammation; Fish oil; Omega-3 fatty acids; Aspirin ID ENDOTHELIAL PROGENITOR CELLS; CORONARY-HEART-DISEASE; N-3 FATTY-ACIDS; LIPID MEDIATORS; EICOSAPENTAENOIC ACID; BASIC MECHANISMS; KO MICE; OMEGA-3-FATTY-ACIDS; CHOLESTEROL; RESOLUTION AB Aspirin (ASA) is known to alter the production of potent inflammatory lipid mediators, but whether it interacts with omega-3 fatty acids (FAs) from fish oil to affect atherosclerosis has not been determined. The goal was to investigate the impact of a fish oil-enriched diet alone and in combination with ASA on the production of lipid mediators and atherosclerosis. ApoE(-/-) female mice were fed for 13 weeks one of the four following diets: omega-3 FA deficient (OD), omega-3 FA rich (OR) (1.8 g omega-3 FAs/kg.diet per day), omega-3 FA rich plus ASA (ORA) (0.1 g ASA/kg.diet per day) or an omega-3 FA deficient plus ASA (ODA) with supplement levels equivalent to human doses. Plasma lipids, atherosclerosis, markers of inflammation, hepatic gene expression and aortic lipid mediators were determined. Hepatic omega-3 FAs were markedly higher in OR (9.9-fold) and ORA (7-fold) groups. Mice in both OR and ORA groups had 40% less plasma cholesterol in very low-density lipoprotein-cholesterol and low-density lipoprotein fractions, but aortic plaque area formation was only significantly lower in the ORA group (5.5%) compared to the OD group (2.5%). Plasma PCSK9 protein levels were approximately 70% lower in the OR and ORA groups. Proinflammatory aortic lipid mediators were 50%-70% lower in the ODA group than in the OD group and more than 50% lower in the ORA group. In summary, less aortic plaque lesions and aortic proinflammatory lipid mediators were observed in mice on the fish oil diet plus ASA vs. just the fish oil diet. (C) 2016 Elsevier Inc. All rights reserved. C1 [Sorokin, Alexander V.; Yang, Zhi-Hong; Vaisman, Boris L.; Thacker, Seth; Remaley, Alan T.] NHLBI, Lipoprot Metab Sect, Cardiopulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Yu, Zu-Xi] NHLBI, Pathol Core, NIH, Bldg 10, Bethesda, MD 20892 USA. [Sampson, Maureen] NIH, Ctr Clin, Dept Lab Med, Bethesda, MD 20892 USA. [Serhan, Charles N.] Brigham & Womens Hosp, Harvard Inst Med, Dept Anesthesiol Perioperat & Pain Med, Ctr Expt Therapeut & Reperfus Injury, 75 Francis St, Boston, MA 02115 USA. [Serhan, Charles N.] Harvard Med Sch, Boston, MA USA. RP Remaley, AT (reprint author), NHLBI, Lipoprot Metab Sect, Cardiopulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM aremaley1@nhlbi.nih.gov OI Vaisman, Boris/0000-0003-0495-2220 FU National Heart, Lung, and Blood Institute; National Institutes of Health [R01GM038765, P01GM095467] FX This study is supported by intramural research funding of the National Heart, Lung, and Blood Institute. LC-MS-MS profiling was supported by the National Institutes of Health (R01GM038765 and P01GM095467) to Charles N. Serhan. NR 46 TC 1 Z9 1 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0955-2863 EI 1873-4847 J9 J NUTR BIOCHEM JI J. Nutr. Biochem. PD SEP PY 2016 VL 35 BP 58 EP 65 DI 10.1016/j.jnutbio.2016.05.012 PG 8 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA DU7TX UT WOS:000382418600006 PM 27394692 ER PT J AU Ordonez, AE Loeb, FF Zhou, XP Shora, L Berman, RA Broadnax, DD Gochman, P Liu, SY Rapoport, JL AF Ordonez, Anna E. Loeb, Frances F. Zhou, Xueping Shora, Lorie Berman, Rebecca A. Broadnax, Diane D. Gochman, Peter Liu, Siyuan Rapoport, Judith L. TI Lack of Gender-Related Differences in Childhood-Onset Schizophrenia SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE childhood-onset schizophrenia; gender differences; cortical volumes ID PERVASIVE DEVELOPMENTAL DISORDERS; AUTISM SPECTRUM DISORDERS; SURFACE-BASED ANALYSIS; SEX-DIFFERENCES; BRAIN VOLUME; EPISODE SCHIZOPHRENIA; SEGMENTATION; ADOLESCENCE; PREVALENCE; PSYCHOSIS AB Objective: Gender differences, including younger age of onset and greater premorbid deficits in men, have been reported in adult-onset schizophrenia. This study comprehensively evaluated gender differences in childhood-onset schizophrenia (COS), a rare variant of the disorder. Method: Demographic, premorbid, clinical, familial, and cognitive characteristics, presence of chromosomal abnormalities, and brain magnetic resonance imaging cortical volumes were evaluated in 133 patients with COS. Cortical analyses included age- and gender-matched healthy volunteers (n = 124). Results: Males with COS (n = 72) had a slightly but significantly younger age of onset than females with COS (mean age 9.51 +/- 2.28 versus 10.29 +/- 1.63 years, t(131) = 2.21, p = .03), higher verbal IQ scores (83.00 +/- 15.97 versus 75.58 +/- 15.10, t(89) = 2.24, p = .03), and higher rates of comorbid pervasive developmental disorder (28.17% versus 6.90%, chi(2)(1) = 9.54, p < .01) and attention-deficit/hyperactivity disorder (43.86% versus 21.43%, chi(2)(i) = 5.40, p = .02). There were no significant gender differences across other demographic, IQ, or clinical measurements, frequency of chromosomal abnormalities, family clinical measurements, premorbid functioning, or in gender-by-disorder interactions for magnetic resonance imaging brain measurements. Conclusion: The present comprehensive examination found few remarkable gender differences in COS. Although less striking than that seen in adult-onset schizophrenia, males with COS had a younger age of onset. Attentiondeficit/hyperactivity disorder and pervasive developmental disorder rates were high in COS overall, suggesting greater neurodevelopmental vulnerability in COS. However, the gender ratios of these comorbidities in COS mirror those of the general populations, indicating that these gender differences might be unrelated to COS. C1 [Loeb, Frances F.; Zhou, Xueping; Shora, Lorie; Berman, Rebecca A.; Broadnax, Diane D.; Gochman, Peter; Liu, Siyuan; Rapoport, Judith L.] NIMH, Child Psychiat Branch, Res Grp, NIH, Bldg 10, Bethesda, MD 20892 USA. [Ordonez, Anna E.] NIMH, Child Psychiat Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Ordonez, Anna E.] NIMH, Off Clin Res, NIH, Bethesda, MD 20892 USA. RP Ordonez, AE (reprint author), 6001 Execut Blvd,MSC 9669, Bethesda, MD 20892 USA. FU Intramural Research Program of the NIMH [ZIAMH002581, 84-M-0050] FX This research was supported by the Intramural Research Program of the NIMH (annual report number ZIAMH002581, protocol ID 84-M-0050). NR 80 TC 0 Z9 0 U1 6 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0890-8567 EI 1527-5418 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD SEP PY 2016 VL 55 IS 9 BP 792 EP 799 DI 10.1016/j.jaac.2016.05.022 PG 8 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA DU9CU UT WOS:000382514600009 PM 27566120 ER PT J AU Waciar, SN Bonomi, PD Govindan, R Hirsch, FR Riely, GJ Papadimitrakopoulou, V Kazandjian, D Khozin, S Larkins, E Dickson, DJ Malik, S Horn, L Ferris, A Shaw, AT Janne, PA Mok, TSK Herbst, R Keegan, P Pazdur, R Blumenthal, GM AF Waciar, Saiama N. Bonomi, Philip D. Govindan, Ramaswamy Hirsch, Fred R. Riely, Gregory J. Papadimitrakopoulou, Vassiliki Kazandjian, Dickran Khozin, Sean Larkins, Erin Dickson, Dane J. Malik, Shakun Horn, Leora Ferris, Andrea Shaw, Alice T. Janne, Pasi A. Mok, Tony S. K. Herbst, Roy Keegan, Patricia Pazdur, Richard Blumenthal, Gideon M. TI Clinician Perspectives on Current Issues in Lung Cancer Drug Development SO JOURNAL OF THORACIC ONCOLOGY LA English DT Review DE Lung cancer; Clinical trials; Targeted therapy; Immunotherapy ID TYROSINE KINASE INHIBITORS; RANDOMIZED PHASE-3 TRIAL; 1ST-LINE TREATMENT; ACQUIRED-RESISTANCE; PERFORMANCE STATUS; EGFR MUTATIONS; OPEN-LABEL; CHEMOTHERAPY; THERAPY; ERLOTINIB AB Recent advances in molecularly targeted therapy and immunotherapy offer a glimmer of hope for potentially realizing the dream of personalized therapy for lung cancer. This article highlights current questions in clinical trial design, enrollment strategies and patient focused drug development, with particular emphasis on unique issues in trials of targeted therapy and immunotherapy. Published by Elsevier Inc. on behalf of International Association for the Study of Lung Cancer. C1 [Waciar, Saiama N.; Govindan, Ramaswamy] Washington Univ, Sch Med, Div Oncol, St Louis, MO USA. [Bonomi, Philip D.] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Hirsch, Fred R.] Univ Colorado, Ctr Canc, Denver, CO 80262 USA. [Riely, Gregory J.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Papadimitrakopoulou, Vassiliki] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Kazandjian, Dickran; Khozin, Sean; Larkins, Erin; Keegan, Patricia; Pazdur, Richard; Blumenthal, Gideon M.] US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20903 USA. [Dickson, Dane J.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Malik, Shakun] NCI, Bethesda, MD 20892 USA. [Horn, Leora] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Ferris, Andrea] LUNGev Fdn, Bethesda, MD USA. [Shaw, Alice T.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Janne, Pasi A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Mok, Tony S. K.] Chinese Univ Hong Kong, Hong Kong, Hong Kong, Peoples R China. [Herbst, Roy] Yale Sch Med, New Haven, CT USA. RP Blumenthal, GM (reprint author), US FDA, Div Oncol Prod 2, OHOP, OND, 10903 New Hampshire Ave, Silver Spring, MD 20903 USA. EM Gideon.Blumenthal@fda.hhs.gov FU NCI/NIH [K12 CA167540] FX Dr. Waciar reports grant K12 CA167540 from the NCI/NIH during the conduct of the study, and grant PI on the 1 UM1 CA186704-01 from NIH/NCI outside the submitted work. Dr. Bonomi reports serving on advisory boards of Astra Zeneca, Clovis, Merck, Biodesics, Trovagene, and Eli Lilly and on data monitoring committees of Roche Genentech and Pfizer outside the submitted work. Dr. Govindan reports consulting fees from Boehringer Ingelheim, GlaxoSmithKline, Celgene, Roche, Bayer, Genentech, Clovis, Helsinn Healthcare, and honoraria from Baxalta, and Roche outside the submitted work. Dr. Hirsch reports participation in advisory boards of Bristol-Myers Squibb, Merck, Genentech/Roche, AstraZeneca, and Lilly outside the submitted work. Dr. Riely reports personal fees from Novartis and Roche and grants from Novartis, Millennium, GlaxoSmithKline, Pfizer, Infinity. Pharmaceuticals, and Ariad outside the submitted work. Dr. Papadimitrakopoulou is a scientific advisory committee member for Clovis Oncology and Genentech, reports consulting fees from Merck, AstraZeneca, Bristol-Myers Squibb, and ARIAD Pharmaceuticals and grants from the following: AstraZeneca; Bristol-Myers Squibb; the American Association for Cancer Research; the National Cancer Institute, National Institutes of Health; Cancer Prevention and Research Institute of Texas; and Hope Foundation outside the submitted work. Dr. Horn reports participation in paid advisory board for Lilly Genentech, and Merck, serving as an unpaid advisory board member and steering committee member at Bristol-Myers Squibb and an upaid advisory board member at Boehringer Ingelheim, performing unpaid consulting work for Xcovery, and serving as an uncompensated steering committee member at Bayer outside the submitted work. Dr. Shaw is a consulting and scientific advisory board member for Blueprint medicine and reports consulting fees from Novartis, Genentech/Roche, Ariad, Daiich-Sankyo, Ignyta, Taiho, EMD Serono, and Pfizer outside the submitted work. Dr. Janne reports grants and personal fees from AstraZeneca; consulting fees from Boehringer Ingelheim, Pfizer, Merrimack Pharmaceuticals, Chugai, and Roche; grants from Astellas; consulting fees from Ariad; and stock ownership in Gatekeeper Pharmaceuticals during the conduct of the study. In addition, Dr. Janne receives postmarketing royalties from Dana-Farber Cancer Institute-owned intellectual property on epidermal growth factor receptor mutations licensed to Lab Corp. Dr. Mok reports personal fees from AstraZeneca, Roche/Genentech, Pfizer, Lilly, Boeh, ringer Ingelheim, Merck Serono, Merck Sharp and Dohme, Janssen, Clovis Oncology, BioMarin, GlaxoSmithKline, Novartis, SFJ Pharmaceuticals, ACEA Biosciences, Vertex Pharmaceuticals, Bristol-Myers Squibb, AVEO and Biodesix, Prime Oncology, Amgen, Sanomics Ltd., and geneDecode outside the submitted work. Dr. Herbst reports personal fees from Diatech, Kolltan, AstraZeneca, Boehringer Ingelheim, Eli Lilly, and Pfizer and grants and personal fees from Genentech/Roche and Merck outside the submitted work. The remaining authors declare no conflict of interest. NR 54 TC 0 Z9 0 U1 5 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1556-0864 EI 1556-1380 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD SEP PY 2016 VL 11 IS 9 BP 1387 EP 1396 DI 10.1016/j.jtho.2016.05.009 PG 10 WC Oncology; Respiratory System SC Oncology; Respiratory System GA DU7UN UT WOS:000382420200005 ER PT J AU Madan, RA Gulley, JL Dahut, WL AF Madan, Ravi A. Gulley, James L. Dahut, William L. TI Radium-223 in prostate cancer: emitting the right signals SO LANCET ONCOLOGY LA English DT Editorial Material C1 [Madan, Ravi A.; Gulley, James L.; Dahut, William L.] NCI, Genitourinary Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Madan, RA (reprint author), NCI, Genitourinary Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM madanr@mail.nih.gov NR 7 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 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD SEP PY 2016 VL 17 IS 9 BP 1186 EP 1187 DI 10.1016/S1470-2045(16)30248-0 PG 3 WC Oncology SC Oncology GA DU7MP UT WOS:000382398700027 PM 27473889 ER PT J AU Marcinkiewcz, CA Mazzone, CM D'Agostino, G Halladay, LR Hardaway, JA DiBerto, JF Navarro, M Burnham, N Cristiano, C Dorrier, CE Tipton, GJ Ramakrishnan, C Kozicz, T Deisseroth, K Thiele, TE McElligott, ZA Holmes, A Heisler, LK Kash, TL AF Marcinkiewcz, Catherine A. Mazzone, Christopher M. D'Agostino, Giuseppe Halladay, Lindsay R. Hardaway, J. Andrew DiBerto, Jeffrey F. Navarro, Montserrat Burnham, Nathan Cristiano, Claudia Dorrier, Cayce E. Tipton, Gregory J. Ramakrishnan, Charu Kozicz, Tamas Deisseroth, Karl Thiele, Todd E. McElligott, Zoe A. Holmes, Andrew Heisler, Lora K. Kash, Thomas L. TI Serotonin engages an anxiety and fear-promoting circuit in the extended amygdala SO NATURE LA English DT Article ID STRIA TERMINALIS; BED NUCLEUS; RECEPTORS; FLUOXETINE; CITALOPRAM; NEURONS AB Serotonin (also known as 5-hydroxytryptamine (5-HT)) is a neurotransmitter that has an essential role in the regulation of emotion. However, the precise circuits have not yet been defined through which aversive states are orchestrated by 5-HT. Here we show that 5-HT from the dorsal raphe nucleus (5-HTDRN) enhances fear and anxiety and activates a subpopulation of corticotropin-releasing factor (CRF) neurons in the bed nucleus of the stria terminal's (CRFBNST,) in mice. Specifically, 5-HTDRN projections to the BNST, via actions at 5-HT2C receptors (5-HT(2C)Rs), engage a CRFBNST inhibitory microcircuit that silences anxiolytic BNST outputs to the ventral tegmental area and lateral hypothalamus. Furthermore, we demonstrate that this CRFBNST inhibitory circuit underlies aversive behaviour following acute exposure to selective serotonin reuptake inhibitors (SSRIs). This early aversive effect is mediated via the corticotrophin-releasing factor type 1 receptor (CRF1R, also known as CRHR1), given that CRF1R antagonism is sufficient to prevent acute SSRI-induced enhancements in aversive learning. These results reveal an essential 5-HTDRN -> CRFBNST circuit governing fear and anxiety, and provide a potential mechanistic explanation for the clinical observation of early adverse events to SSRI treatment in some patients with anxiety disorders(1,2). C1 [Marcinkiewcz, Catherine A.; Mazzone, Christopher M.; Hardaway, J. Andrew; DiBerto, Jeffrey F.; Dorrier, Cayce E.; Tipton, Gregory J.; Thiele, Todd E.; McElligott, Zoe A.; Kash, Thomas L.] Univ North Carolina Chapel Hill, Bowles Ctr Alcohol Studies, Chapel Hill, NC 27599 USA. [Mazzone, Christopher M.; Kash, Thomas L.] Univ North Carolina Chapel Hill, Sch Med, Curriculum Neurobiol, Chapel Hill, NC 27599 USA. [D'Agostino, Giuseppe; Cristiano, Claudia; Heisler, Lora K.] Univ Aberdeen, Rowett Inst Nutr & Hlth, Aberdeen AB25 2ZD, Scotland. [Halladay, Lindsay R.; Holmes, Andrew] NIAAA, NIH, Rockville, MD 20852 USA. [Navarro, Montserrat; Burnham, Nathan; Thiele, Todd E.; Kash, Thomas L.] Univ North Carolina Chapel Hill, Coll Arts & Sci, Dept Psychol & Neurosci, Chapel Hill, NC 27599 USA. [Ramakrishnan, Charu; Deisseroth, Karl] Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA. [Kozicz, Tamas] Tulane Univ, Hayward Genet Ctr, New Orleans, LA 70112 USA. [Kozicz, Tamas] Radboud Univ Nijmegen, Med Ctr, Dept Anat, NL-6500 HB Nijmegen, Netherlands. [McElligott, Zoe A.] Univ North Carolina Chapel Hill, Sch Med, Dept Psychiat, Chapel Hill, NC 27599 USA. [Kash, Thomas L.] Univ North Carolina Chapel Hill, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA. RP Marcinkiewcz, CA (reprint author), Univ North Carolina Chapel Hill, Bowles Ctr Alcohol Studies, Chapel Hill, NC 27599 USA. OI Heisler, Lora/0000-0002-7731-1419 FU NIH [AA019454, AA011605, K01AA023555]; Wellcome Trust [098012]; Biotechnology and Biological Sciences Research Council [BB/K001418/1]; Alcohol Beverage Medical Research Fund; NIAAA [AA021319-02, F31AA023440] FX We acknowledge B. Roth for providing DREADD viral constructs and SertCre mice, and B. Lowell for providing CrfCre mice. We also thank A. Lopez, D. Perron, and A. Kendra for technical assistance with stereotaxic surgeries on mice, B. Geenen for technical assistance with immunohistochemistry and E. Dankoski for technical assistance with the FSCV. This work was supported by NIH grants AA019454, AA011605 (T.L.K.), the Wellcome Trust (098012) and the Biotechnology and Biological Sciences Research Council grant (BB/K001418/1) (L.K.H.) and by NIH grant K01AA023555 and the Alcohol Beverage Medical Research Fund (Z.A.M.). C.A.M. was supported by a postdoctoral NIAAA F32 fellowship (AA021319-02). C.M.M. is supported by a predoctoral NIAAA F31 fellowship (F31AA023440). NR 20 TC 7 Z9 7 U1 18 U2 20 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD SEP 1 PY 2016 VL 537 IS 7618 BP 97 EP 101 DI 10.1038/nature19318 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DU7XC UT WOS:000382426900046 PM 27556938 ER PT J AU Job, MO AF Job, Martin O. TI Injection of Cocaine-Amphetamine Regulated Transcript (CART) peptide into the nucleus accumbens does not inhibit caffeine-induced locomotor activity: Implications for CART peptide mechanism SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE CART peptide; CART 55-102; Caffeine; Cocaine, dopamine; Locomotion; Nucleus accumbens ID ADENOSINE A(2A) RECEPTORS; GLUTAMATE RELEASE; DOPAMINE RELEASE; MESSENGER-RNA; BODY-WEIGHT; ADULT RATS; NGFI-B; STIMULATION; MICE; SHELL AB Much evidence suggests that intra-nucleus accumbens (NAc) CART peptide (CART 55-102) injection inhibits locomotor activity (LMA) when there is an increase in the release and activity of dopamine (DA) in the NAc. However, this hypothesis has not been fully tested. One way to examine this is to determine if there is a lack of effect of intra-NAc CART peptide on LMA that does not involve increases in DA release in the NAc. Several studies have suggested that caffeine-induced LMA does not involve extracellular DA release in the NAc core. Therefore, in this study, we have examined the effect of injections of CART peptide (2.5 mu g) into the NAc core on the locomotor effects of caffeine in male Sprague-Dawley rats. Several LMA relevant doses of caffeine were used (0, 10, 20 mg/kg i.p.), and an inverted U response curve was found as expected. We determined, in the same animals, that intra-NAc CART peptide had no effect on caffeine-induced LMA whereas it blunted cocaine-mediated LMA, as shown by other reports. We also extended a previous observation in mice by showing that at a LMA activating dose of caffeine there is no alteration of CART peptide levels in the NAc of rats. Our study supports the hypothesis that the inhibitory effects of CART peptide in the NAc may be exerted only under conditions of increased extracellular DA release and activity in this region. Our results also suggest that intra-NAc CART 55-102 does not generally inhibit increases in LMA due to all drugs, but has a more specific inhibitory effect on dopaminergic neurotransmission. Published by Elsevier Inc. C1 [Job, Martin O.] NIDA, Psychobiol Sect, Mol Neuropsychiat Res Branch, Intramural Res Program,NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. RP Job, MO (reprint author), NIDA, Psychobiol Sect, Mol Neuropsychiat Res Branch, Intramural Res Program,NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM femijob@gmail.com FU National Center for Research Resources [P51RR165]; Office of Research Infrastructure Programs/OD [P51OD11132]; NIH/NIDA [DA15040]; Georgia Research Alliance FX This project was funded by the National Center for Research Resources P51RR165 and supported by the Office of Research Infrastructure Programs/OD P51OD11132. It was also supported by NIH/NIDA DA15040 and the Georgia Research Alliance. These funding sources had no role in the direction of this research or publication. The author wishes to acknowledge the support of his mentor Dr. M.J. Kuhar who also assisted with the writing of the manuscript. The author also wishes to acknowledge the technical input of Ms. Li L Shen. The work was carried out at the Yerkes National Primate Research Center of Emory University. NR 55 TC 0 Z9 0 U1 2 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD SEP PY 2016 VL 148 BP 8 EP 14 DI 10.1016/j.pbb.2016.05.001 PG 7 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA DU6TP UT WOS:000382347800002 PM 27168116 ER PT J AU Zhang, XX Xue, XJ Xian, L Guo, ZJ Ito, Y Sun, WJ AF Zhang, Xinxin Xue, Xuanji Xian, Liang Guo, Zengjun Ito, Yoichiro Sun, Wenji TI Potential neuroprotection of protodioscin against cerebral ischemia-reperfusion injury in rats through intervening inflammation and apoptosis SO STEROIDS LA English DT Article DE Protodioscin; Middle cerebral artery occlusion; Caspase-3; Bax/Bcl-2 ratio; Pro-inflammatory cytokines; NF-kappa B ID NF-KAPPA-B; CELL-DEATH; ARTERY OCCLUSION; IN-VIVO; STROKE; MECHANISMS; BRAIN; PROTECTS; NECROSIS; PENUMBRA AB The aim of the current research is to investigate the cerebral-protection of protodioscin on a transient cerebral ischemia-reperfusion (I/R) model and to explore its possible underlying mechanisms. The rats were preconditioned with protodioscin at the doses of 25 and 50 mg kg(-1) prior to surgery. Then the animals were subjected to right middle cerebral artery occlusion (MCAO) using an intraluminal method by inserting a thread (90 min surgery). After the blood flow was restored in 24 h via withdrawing the thread, some representative indicators for the cerebral injury were evaluated by various methods including. TTC-staining, TUNEL, immunohistochemistry, and Western blotting. As compared with the operated rats without drug intervening, treatment with protodioscin apparently lowered the death rate and improved motor coordination abilities through reducing the deficit scores and cerebral infarct volume. What's more, an apparent decrease in neuron apoptosis detected in hippocampus CM and cortex of the ipsilateral hemisphere might attribute to alleviate the increase in Caspase-3 and Bax/Bc1-2 ratio. Meanwhile, concentrations of several main pro-inflammatory cytokines (TNF-alpha, IL-1 beta and IL-6) in the serum were also significantly suppressed. Finally, the NF-kappa B and I kappa Ba protein expressions in the cytoplasm of right injured brain were remarkably up-regulated, while NF-kappa B in nucleus was down-regulated. Therefore, these observed findings demonstrated that protodioscin appeared to reveal potential neuroprotection against the I/R injury due to its anti-inflammatory and anti-apoptosis properties. This therapeutic effect was probably mediated by the inactivation of NF-kappa B signal pathways. (C) 2016 Published by Elsevier Inc. C1 [Zhang, Xinxin; Xue, Xuanji; Xian, Liang; Guo, Zengjun] Xi An Jiao Tong Univ, Coll Pharm, 76 Yanta Rd, Xian 710061, Peoples R China. [Sun, Wenji] Northwest Univ, Biomed Key Lab Shaanxi Prov, 229 Taibai North Rd, Xian 710069, Peoples R China. [Ito, Yoichiro] NHLBI, Lab Bioseparat Technol, Biochem & Biophys Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Guo, ZJ (reprint author), Xi An Jiao Tong Univ, Coll Pharm, 76 Yanta Rd, Xian 710061, Peoples R China.; Sun, WJ (reprint author), Northwest Univ, Biomed Key Lab Shaanxi Prov, 229 Taibai North Rd, Xian 710069, Peoples R China. EM guozj@mail.xjtu.edu.cn; cxbm1360@126.com FU Scientific Research Supporting Project for New Teachers of Xi'an Jiaotong University [1191320023]; China Postdoctoral Science Foundation FX This study was financially supported by Scientific Research Supporting Project for New Teachers of Xi'an Jiaotong University (No. 1191320023) and China Postdoctoral Science Foundation (First-class). The authors sincerely thank the Guge Biological Technology Co., Ltd (Hubei, China) for the analysis of various indicators, such as Nissl staining, determination of the inflammatory cytokines, and Western blotting. NR 46 TC 2 Z9 2 U1 5 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-128X EI 1878-5867 J9 STEROIDS JI Steroids PD SEP PY 2016 VL 113 BP 52 EP 63 DI 10.1016/j.steroids.2016.06.008 PG 12 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA DU6RD UT WOS:000382341400008 PM 27343977 ER PT J AU Zhang, XX Xue, XJ Zhao, J Guo, ZJ Ito, Y Sun, WJ AF Zhang, Xinxin Xue, Xuanji Zhao, Jing Guo, Zengjun Ito, Yoichiro Sun, Wenji TI Quantitative determination of gracillin by HPLC-MS/MS after oral administration and its application to a pharmacokinetic study SO STEROIDS LA English DT Article DE Gracillin; Ginsenoside Rb-1; HPLC-MS/MS; Multiple reaction monitoring; Pharmacokinetic behaviors ID PERFORMANCE LIQUID-CHROMATOGRAPHY; RAT PLASMA; SIMULTANEOUS QUANTIFICATION; FINGERPRINT ANALYSIS; DIOSCOREA-NIPPONICA; MASS-SPECTROMETRY; UPLC-MS/MS; SAPONINS; CURCUMIN AB A sensitive and credible high performance liquid chromatography hyphenated to mass spectrometry (HPLC-MS/MS) was established to quantify the concentration of gracillin in rat plasma. The plasma samples were subjected to a direct protein precipitation process with acetonitrile as a precipitant in a single-step. Ginsenoside Rb-1 was selected as an internal standard (IS). The chromatographic separation of analyte and IS were carried out on an Inersil ODS-3 C-18 column (250 x 4.6 mm, 5 mu m) with a binary solvent system containing acetonitrile and 0.1% formic acid in water at a flow rate of 1 mL min(-1) under a gradient elution mode. Mass spectrometric detection was performed on a triple quadrupole tandem mass spectrometer by the multiple reaction monitoring (MRM) mode to examine the precursor-to-daughter ion transitions of 1110.3 -> 948.2 for IS and 886.1 -> 739.9 for gracillin, respectively, in a positive electrospray ionization mode. The calibration curve showed a promising linearity over a concentration range of 0.065-800 ng mL(-1) with a better regression coefficient of r(2) = 0.9960. The intra- and inter-day precisions (as relative standard deviation) of the assay at three quality control levels were all less than 3.48%, while the intra- and inter-day accuracies (as relative error) ranged from -8.43% to 9.74%, whose data were within the acceptable limits. The mean extraction recoveries of analyte from rat plasma were all more than 74.11%, and no notable matrix effect was observed. Stability experiments revealed that gracillin remained stable throughout the analytical procedure under various stored conditions. The above validated method was successfully used to investigate the pharmacokinetic behaviors of gracillin orally administrated to rats at three proportion doses. The pharmacokinetic analysis would pave the way for understanding the pharmacological actions and provide a meaningful foundation for further development and application in preclinical and clinical use of gracillin in the near future. (C) 2016 Elsevier Inc. All rights reserved. C1 [Zhang, Xinxin; Xue, Xuanji; Zhao, Jing; Guo, Zengjun] Xi An Jiao Tong Univ, Coll Pharm, 76 Yanta Rd, Xian 710061, Peoples R China. [Sun, Wenji] Northwest Univ, Biomed Key Lab Shaanxi Prov, 229 Taibai North Rd, Xian 710069, Peoples R China. [Ito, Yoichiro] NHLBI, Lab Bioseparat Technol, Biochem & Biophys Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Guo, ZJ (reprint author), Xi An Jiao Tong Univ, Coll Pharm, 76 Yanta Rd, Xian 710061, Peoples R China.; Sun, WJ (reprint author), Northwest Univ, Biomed Key Lab Shaanxi Prov, 229 Taibai North Rd, Xian 710069, Peoples R China. EM guozj@mail.xjtu.edu.cn; cxbm1360@126.com FU Scientific Research Supporting Project for New Teacher of Xi'an Jiaotong University [1191320023]; China Postdoctoral Science Foundation FX This study was financially supported by Scientific Research Supporting Project for New Teacher of Xi'an Jiaotong University (No. 1191320023) and China Postdoctoral Science Foundation (First-class). The authors sincerely thank the Guge Biological Technology Co., Ltd (Hubei, China) for the analysis of various indicators, such as Nissl staining, determination of the inflammatory cytokines, and Western blotting. NR 21 TC 0 Z9 0 U1 13 U2 16 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-128X EI 1878-5867 J9 STEROIDS JI Steroids PD SEP PY 2016 VL 113 BP 78 EP 86 DI 10.1016/j.steroids.2016.07.002 PG 9 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA DU6RD UT WOS:000382341400011 PM 27394958 ER PT J AU Zhang, XX Xue, XJ Zhao, J Qian, CX Guo, ZJ Ito, Y Sun, WJ AF Zhang, Xinxin Xue, Xuanji Zhao, Jing Qian, Chunxiang Guo, Zengjun Ito, Yoichiro Sun, Wenji TI Diosgenin attenuates the brain injury induced by transient focal cerebral ischemia-reperfusion in rats SO STEROIDS LA English DT Article DE Diosgenin; Ischemia-reperfusion injury; Middle cerebral artery occlusion; Anti-apoptosis; Anti-inflammation; NF-kappa B ID NF-KAPPA-B; STEROIDS; STROKE; MICE AB The aim of the present study is to explore the potential cerebroprotection of diosgenin against the transient focal cerebral ischemia-reperfusion (I/R) injury and its possible underlying mechanisms. The diosgenin at two dose levels, namely 100 and 200 mg kg(-1), was intragastrically administrated once daily for 7-day period prior to the surgery. Then, the rats were subjected to middle cerebral artery occlusion (MCAO) using the intraluminal thread for 90 min. After 24 h reperfusion, several diagnostic indicators were evaluated and all animals were sacrificed to harvest their brains and blood for subsequent biochemical analyses. The results indicated that diosgenin treatment significantly inhibited the death rate and improved the impaired neurological functions along with neurological deficit scores and cerebral infarct size as compared with the rats exposed to I/R insult without agents administration. The increase in the number of apoptotic cells determined by TUNEL in the hippocampus CA1 and cortex was also apparently attenuated in the diosgenin treatment group, which was closely correlated with suppression of Caspase-3 activity and Bax/Bcl-2 ratio. In addition the elevated concentrations of pro-inflammatory cytokines (TNF-alpha, IL-1 beta, and IL-6) in blood serum of the I/R treated rats were reduced almost to their normal level. Further results obtained from the Western blotting analysis revealed that the protein expression of I kappa B alpha, in the injured brain was up-regulated, while the p65 subunit of NF-kappa B was down-regulated in nucleus after the treatment. Collectively, this neuroprotection of diosgenin against I/R injury may be attained through its anti-apoptosis, anti-inflammation and intervening the NF-kappa B signal pathway properties. Due to the satisfactory findings, diosgenin might be a powerful therapeutic agent to combat the similar disease in future clinic. (C) 2016 Elsevier Inc. All rights reserved. C1 [Zhang, Xinxin; Xue, Xuanji; Zhao, Jing; Qian, Chunxiang; Guo, Zengjun] Xi An Jiao Tong Univ, Coll Pharm, 76 Yanta Rd, Xian 710061, Peoples R China. [Sun, Wenji] Northwest Univ, Biomed Key Lab Shaanxi Prov, 229 Taibai North Rd, Xian 710069, Peoples R China. [Ito, Yoichiro] NHLBI, Lab Bioseparat Technol, Biochem & Biophys Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Guo, ZJ (reprint author), Xi An Jiao Tong Univ, Coll Pharm, 76 Yanta Rd, Xian 710061, Peoples R China.; Sun, WJ (reprint author), Northwest Univ, Biomed Key Lab Shaanxi Prov, 229 Taibai North Rd, Xian 710069, Peoples R China. EM guozj@mail.xjtu.edu.cn; cxbml360@126.com FU Scientific Research Supporting Project for New Teacher of Xi'an Jiaotong University [1191320023]; China Postdoctoral Science Foundation FX This study was financially supported by Scientific Research Supporting Project for New Teacher of Xi'an Jiaotong University (NO. 1191320023) and China Postdoctoral Science Foundation (First-class). The authors sincerely thank the Guge Biological Technology Co., Ltd (Hubei, China) for the analysis of various indicators, such as Nissl staining, determination of the inflammatory cytokines, and Western blotting. NR 22 TC 0 Z9 0 U1 4 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-128X EI 1878-5867 J9 STEROIDS JI Steroids PD SEP PY 2016 VL 113 BP 103 EP 112 DI 10.1016/j.steroids.2016.07.006 PG 10 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA DU6RD UT WOS:000382341400014 PM 27425638 ER PT J AU Lambert, C Rua, R Gessain, A Buseyne, F AF Lambert, Caroline Rua, Rejane Gessain, Antoine Buseyne, Florence TI A new sensitive indicator cell line reveals cross-transactivation of the viral LTR by gorilla and chimpanzee simian foamy viruses SO VIROLOGY LA English DT Article DE Foamy viruses; Gorilla; Zoonotic infection; Viral transcription; Long terminal repeat ID LONG TERMINAL REPEAT; FUNCTIONAL-CHARACTERIZATION; SPECIES TRANSMISSION; GENE-EXPRESSION; BEL-1 TRANSACTIVATOR; NUCLEAR-LOCALIZATION; TRANSCRIPTION FACTOR; MOLECULAR VIROLOGY; CENTRAL-AFRICA; IN-VITRO AB The majority of currently identified simian foamy virus (SFV)-infected Cameroonian and Gabonese individuals harbor SFV from the gorilla lineage. We constructed an indicator cell line for the quantification of gorilla SFVs, in which the U3 sequence of a gorilla SFV directs the expression of the beta-galactosidase protein. The gorilla foamy virus activated beta-galactosidase (GFAB) cells efficiently quantified two zoonotic primary gorilla isolates and SFVs from three chimpanzee subspecies. Primary gorilla SFVs replicated more slowly and at lower levels than primary chimpanzee SFVs. Analysis of previously described motifs of Tas proteins and U3 LTRs involved in viral gene synthesis revealed conservation of such motifs in Tas proteins from gorilla and chimpanzee SFVs, but little sequence homology in the LTR regions previously shown to interact with viral and cellular factors. (C) 2016 Elsevier Inc. All rights reserved. C1 [Lambert, Caroline; Rua, Rejane; Gessain, Antoine; Buseyne, Florence] Inst Pasteur, Unite Epidemiol & Physiopathol Virus Oncogenes, 28 Rue Dr Roux, F-75015 Paris, France. [Lambert, Caroline; Gessain, Antoine; Buseyne, Florence] Inst Pasteur, UMR CNRS 3569, F-75015 Paris, France. [Lambert, Caroline] Univ Paris Diderot, Sorbonne Paris Cite, Cellule Pasteur, Inst Pasteur, F-75015 Paris, France. [Rua, Rejane] NINDS, Viral Immunol & Intravital Imaging Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Buseyne, F (reprint author), Inst Pasteur, Unite Epidemiol & Physiopathol Virus Oncogenes, 28 Rue Dr Roux, F-75015 Paris, France. EM florence.buseyne@pasteur.fr FU French government program Investissement d'Avenir, laboratory of excellence, Integrative biology of emerging infectious diseases (LabEx IBEID); Institut Pasteur, Paris, France; Program Transversal de Recherche 437 from the Institut Pasteur; Agence Nationale de la Recherche [ANR-10-LABX-62-IBEID, ANR 15-CE-15-0008-01] FX C. Lambert was personally supported by a doctoral Grant from the French government program Investissement d'Avenir, laboratory of excellence, Integrative biology of emerging infectious diseases (LabEx IBEID). This work was supported by the Institut Pasteur, Paris, France, by the Program Transversal de Recherche 437 from the Institut Pasteur, and by the Agence Nationale de la Recherche (Grant ANR-10-LABX-62-IBEID; REEMFOAMY project, ANR 15-CE-15-0008-01). Funding agencies had no role in study design, the generation of results, or writing. NR 58 TC 1 Z9 1 U1 7 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD SEP PY 2016 VL 496 BP 219 EP 226 DI 10.1016/j.virol.2016.06.010 PG 8 WC Virology SC Virology GA DT1IU UT WOS:000381235700025 PM 27348053 ER PT J AU Wang, JQ Mi, P Lin, G Wang, YXJ Liu, G Chen, XY AF Wang, Junqing Mi, Peng Lin, Gan Wang, Yi Xiang J. Liu, Gang Chen, Xiaoyuan TI Imaging-guided delivery of RNAi for anticancer treatment SO ADVANCED DRUG DELIVERY REVIEWS LA English DT Review DE Molecular imaging; Cancer; Nanocarrier; siRNA; RNA interference; Gene delivery; Theranostics ID MEDIATED SIRNA DELIVERY; POSITRON-EMISSION-TOMOGRAPHY; ENDOTHELIAL GROWTH-FACTOR; TARGETED DRUG-DELIVERY; ADVANCED SOLID TUMORS; IN-VIVO; GENE DELIVERY; SYSTEMIC DELIVERY; CANCER-THERAPY; CONTRAST AGENTS AB The RNA interference (RNAi) technique is a new modality for cancer therapy, and several candidates are being tested clinically. In the development of RNAi-based therapeutics, imaging methods can provide a visible and quantitative way to investigate the therapeutic effect at anatomical, cellular, and molecular level; to noninvasively trace the distribution; to and study the biological processes in preclinical and clinical stages. Their abilities are important not only for therapeutic optimization and evaluation but also for shortening of the time of drug development to market. Typically, imaging-functionalized RNAi therapeutics delivery that combines nanovehicles and imaging techniques to study and improve their biodistribution and accumulation in tumor site has been progressively integrated into anticancer drug discovery and development processes. This review presents an overview of the current status of translating the RNAi cancer therapeutics in the clinic, a brief description of the biological barriers in drug delivery, and the roles of imaging in aspects of administration route, systemic circulation, and cellular barriers for the clinical translation of RNAi cancer therapeutics, and with partial content for discussing the safety concerns. Finally, we focus on imaging-guided delivery of RNAi therapeutics in preclinical development, including the basic principles of different imaging modalities, and their advantages and limitations for biological imaging. With growing number of RNAi therapeutics entering the clinic, various imaging methods will play an important role in facilitating the translation of RNAi cancer therapeutics from bench to bedside. Published by Elsevier B.V. C1 [Wang, Junqing; Mi, Peng; Lin, Gan; Liu, Gang] Xiamen Univ, State Key Lab Mol Vaccinol & Mol Diagnost, Xiamen 361102, Peoples R China. [Wang, Junqing; Mi, Peng; Lin, Gan; Liu, Gang] Xiamen Univ, Ctr Mol Imaging & Translat Med, Sch Publ Hlth, Xiamen 361102, Peoples R China. [Wang, Junqing; Wang, Yi Xiang J.] Chinese Univ Hong Kong, Prince Wales Hosp, Fac Med, Dept Imaging & Intervent Radiol, Shatin, Hong Kong, Peoples R China. [Mi, Peng] Tokyo Inst Technol, Div Polymer Chem, Chem Resources Lab, Midori Ku, R1-11,4259 Nagatsuta, Yokohama, Kanagawa 2268503, Japan. [Liu, Gang] Xiamen Univ, Sch Life Sci, Innovat Ctr Cell Biol, State Key Lab Cellular Stress Biol, Xiamen 361102, Peoples R China. [Liu, Gang] Xiamen Univ, Coll Chem & Chem Engn, MOE Key Lab Spectrochem Anal & Instrumentat, Xiamen 361005, Peoples R China. [Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. RP Liu, G (reprint author), Xiamen Univ, State Key Lab Mol Vaccinol & Mol Diagnost, Xiamen 361102, Peoples R China.; Liu, G (reprint author), Xiamen Univ, Ctr Mol Imaging & Translat Med, Sch Publ Hlth, Xiamen 361102, Peoples R China.; Wang, YXJ (reprint author), Chinese Univ Hong Kong, Prince Wales Hosp, Fac Med, Dept Imaging & Intervent Radiol, Shatin, Hong Kong, Peoples R China.; Liu, G (reprint author), Xiamen Univ, Sch Life Sci, Innovat Ctr Cell Biol, State Key Lab Cellular Stress Biol, Xiamen 361102, Peoples R China.; Liu, G (reprint author), Xiamen Univ, Coll Chem & Chem Engn, MOE Key Lab Spectrochem Anal & Instrumentat, Xiamen 361005, Peoples R China.; Chen, XY (reprint author), Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. EM yixiang_wang@cuhk.edu.hk; gangliu.cmitm@xmu.edu.cn; shawn.chen@nih.gov OI Wang, Junqing/0000-0002-9091-9891; Mi, Peng/0000-0003-3790-4663 FU Major State Basic Research Development Program of China (973 Program) [2014CB744503, 2013CB733802]; National Natural Science Foundation of China (NSFC) [81422023, 81101101, 81371596, U1505221, 51273165]; Key Project of Chinese Ministry of Education [212149]; Fundamental Research Funds for the Central Universities, China [20720160065, 20720150141]; Program for New Century Excellent Talents in University [NCET-13-0502]; Shenzhen municipal government project [ICY:120130401164750006]; Research of CUHK [4054012, 4054087]; focused investments scheme of CUHK [1902062]; Hong Kong RGC CRF [CUHK4/CRF/12G]; Intramural Research Program, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health FX This study was supported in part by the Major State Basic Research Development Program of China (973 Program) (grant nos. 2014CB744503 and 2013CB733802), the National Natural Science Foundation of China (NSFC) (grant nos. 81422023, 81101101, 81371596, U1505221 and 51273165), the Key Project of Chinese Ministry of Education (grant no. 212149), the Fundamental Research Funds for the Central Universities, China (grant nos. 20720160065 and 20720150141), the Program for New Century Excellent Talents in University (NCET-13-0502), the Shenzhen municipal government project no. ICY:120130401164750006, Research of CUHK (ref. nos. 4054012 and 4054087), the focused investments scheme of CUHK (ref. no. 1902062), the Hong Kong RGC CRF (ref. no. CUHK4/CRF/12G), and the Intramural Research Program, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health. NR 170 TC 8 Z9 8 U1 23 U2 42 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-409X EI 1872-8294 J9 ADV DRUG DELIVER REV JI Adv. Drug Deliv. Rev. PD SEP 1 PY 2016 VL 104 BP 44 EP 60 DI 10.1016/j.addr.2016.01.008 PG 17 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DT1JX UT WOS:000381239300005 PM 26805788 ER PT J AU Zhou, Y Yang, JH Zhang, LX Zhou, XD Cisar, JO Palmer, RJ AF Zhou, Yuan Yang, Jinghua Zhang, Luxia Zhou, Xuedong Cisar, John O. Palmer, Robert J., Jr. TI Differential Utilization of Basic Proline-Rich Glycoproteins during Growth of Oral Bacteria in Saliva SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID 2-DIMENSIONAL GEL-ELECTROPHORESIS; SUBMANDIBULAR-SUBLINGUAL SALIVA; DENTAL PLAQUE; STREPTOCOCCUS-ORALIS; ALPHA(1)-ACID GLYCOPROTEIN; VIRIDANS STREPTOCOCCI; ACTINOMYCES-VISCOSUS; MASS-SPECTROMETRY; MUCIN; IDENTIFICATION AB Although saliva is widely recognized as a primary source of carbon and nitrogen for growth of the dental plaque biofilm community, little is known about how different oral bacteria utilize specific salivary components. To address this question, 32 strains representing 16 genera commonly isolated from early plaque biofilms were compared for growth over two transfers in stimulated (by chewing Parafilm) whole saliva that was stabilized by heat treatment and dialysis. The cell densities, measured by quantitative PCR (qPCR), ranged from similar to 1 x 10(6) to 1 x 10(7)/ml for strains of Streptococcus gordonii, Streptococcus oralis, and Streptococcus mitis and one strain of Streptococcus sanguinis. Strains of Streptococcus mutans, Gemella haemolysans, and Granulicatella adiacens reached similar to 1 x 10(5) to 1 x 10(6)/ml. In contrast, little or no growth was noted for three other strains of S. sanguinis, as well as for strains of Streptococcus parasanguinis, Streptococcus salivarius, Streptococcus vestibularis, Streptococcus sobrinus, Actinomyces spp., Abiotrophia defectiva, and Rothia dentocariosa. SDS-PAGE, lectin blotting, and two-dimensional gel electrophoresis of saliva from cultures of S. gordonii, S. oralis, and S. mitis revealed species-specific differences in the degradation of basic proline-rich glycoproteins (PRG). In contrast, saliva from cultures of other bacteria was indistinguishable from control saliva. Species-dependent differences in the utilization of individual host sugars were minor. Thus, differences in salivary glycan foraging between oral species may be important to cross-feeding and cooperation between organisms in dental plaque biofilm development. IMPORTANCE Bacteria in the mouth use saliva for nutrition. How each of the many types of bacteria uses saliva is not clear. We show that a major protein in saliva, called PRG, is an important nutrition source for certain bacteria but not for others. PRG has many sugar molecules linked in chains, but the sugar is not available for bacteria until the chains are degraded. The bacteria that can grow by digesting this protein break the sugar chains into parts which not only support their own growth but could also be available to support the growth of those bacteria that cannot use the intact protein. C1 [Zhou, Yuan; Yang, Jinghua; Zhang, Luxia; Cisar, John O.; Palmer, Robert J., Jr.] NIH, Microbial Receptors Sect, Lab Cell & Dev Biol, Bldg 10, Bethesda, MD 20892 USA. [Zhou, Yuan; Zhou, Xuedong] Sichuan Univ, West China Hosp Stomatol, State Key Lab Oral Dis, Chengdu, Peoples R China. [Yang, Jinghua] Chinese Acad Sci, State Key Lab Mycol, Inst Microbiol, Beijing, Peoples R China. RP Palmer, RJ (reprint author), NIH, Microbial Receptors Sect, Lab Cell & Dev Biol, Bldg 10, Bethesda, MD 20892 USA. EM rjpalmer@dir.nidcr.nih.gov OI Yang, Jinghua/0000-0001-7140-5548 FU Intramural Research Program of the NIDCR, NIH; State Key Laboratory of Oral Diseases FX This work was supported by the Intramural Research Program of the NIDCR, NIH. Y.Z. received support from the State Key Laboratory of Oral Diseases. NR 39 TC 1 Z9 1 U1 2 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 EI 1098-5336 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD SEP PY 2016 VL 82 IS 17 BP 5249 EP 5258 DI 10.1128/AEM.01111-16 PG 10 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA DT5DI UT WOS:000381500700019 PM 27316966 ER PT J AU Yang, JH Zhou, Y Zhang, LX Shah, N Jin, C Palmer, RJ Cisar, JO AF Yang, Jinghua Zhou, Yuan Zhang, Luxia Shah, Nehal Jin, Cheng Palmer, Robert J., Jr. Cisar, John O. TI Cell Surface Glycoside Hydrolases of Streptococcus gordonii Promote Growth in Saliva SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID PROLINE-RICH PROTEINS; WHEAT-GERM-AGGLUTININ; PNEUMONIAE; SPECIFICITY; BINDING; BACTERIA; GENE; EXOGLYCOSIDASES; GLYCOPROTEINS; PURIFICATION AB The growth of the oral commensal Streptococcus gordonii in saliva may depend on a number of glycoside hydrolases (GHs), including three cell wall-anchored proteins that are homologs of pneumococcal beta-galactosidase (BgaA), beta-N-acetylglucosaminidase (StrH), and endo-beta-N-acetylglucosaminidase D (EndoD). In the present study, we introduced unmarked in-frame deletions into the corresponding genes of S. gordonii DL1, verified the presence (or absence) of the encoded proteins on the resulting mutant strains, and compared these strains with wild-type strain DL1 for growth and glycan foraging in saliva. The overnight growth of wild-type DL1 was reduced 3- to 10-fold by the deletion of any one or two genes and approximately 20-fold by the deletion of all three genes. The only notable change in the salivary proteome associated with this reduction of growth was a downward shift in the apparent molecular masses of basic proline-rich glycoproteins (PRG), which was accompanied by the loss of lectin binding sites for galactose-specific Erythrina cristagalli agglutinin (ECA) and mannose-specific Galanthus nivalis agglutinin (GNA). The binding of ECA to PRG was also abolished in saliva cultures of mutants that expressed cell surface BgaA alone or together with either StrH or EndoD. However, the subsequent loss of GNA binding was seen only in saliva cocultures of different mutants that together expressed all three cell surface GHs. The findings indicate that the growth of S. gordonii DL1 in saliva depends to a significant extent on the sequential actions of first BgaA and then StrH and EndoD on N-linked glycans of PRG. IMPORTANCE The ability of oral bacteria to grow on salivary glycoproteins is critical for dental plaque biofilm development. Little is known, however, about how specific salivary components are attacked and utilized by different members of the biofilm community, such as Streptococcus gordonii. Streptococcus gordonii DL1 has three cell wall-anchored glycoside hydrolases that are predicted to act on host glycans. In the present study, we introduced unmarked in-frame deletions in the corresponding genes, verified the presence (or absence) of encoded proteins on the resulting mutant strains, and compared these strains with wild-type DL1 for growth and glycan foraging in saliva. The results indicate that the growth of S. gordonii DL1 depends to a significant extent on sequential action of these cell surface GHs on N-linked glycans of basic proline-rich salivary glycoproteins, which appears to be an essential first step in salivary glycan foraging. C1 [Yang, Jinghua; Zhou, Yuan; Zhang, Luxia; Shah, Nehal; Palmer, Robert J., Jr.; Cisar, John O.] NIH, Microbial Receptors Sect, Lab Cell & Dev Biol, Bldg 10, Bethesda, MD 20892 USA. [Yang, Jinghua; Jin, Cheng] Chinese Acad Sci, State Key Lab Mycol, Inst Microbiol, Beijing, Peoples R China. [Zhou, Yuan] Sichuan Univ, West China Hosp Stomatol, State Key Lab Oral Dis, Chengdu, Peoples R China. RP Yang, JH (reprint author), NIH, Microbial Receptors Sect, Lab Cell & Dev Biol, Bldg 10, Bethesda, MD 20892 USA.; Yang, JH (reprint author), Chinese Acad Sci, State Key Lab Mycol, Inst Microbiol, Beijing, Peoples R China. EM jinghuay98@gmail.com OI jin, cheng/0000-0002-1514-6374 FU HHS \ National Institutes of Health (NIH); Intramural Research Program of the NIH, NIDCR FX This work, including the efforts of John O. Cisar, was funded by HHS vertical bar National Institutes of Health (NIH).; This work was supported the Intramural Research Program of the NIH, NIDCR. NR 35 TC 1 Z9 1 U1 5 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 EI 1098-5336 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD SEP PY 2016 VL 82 IS 17 BP 5278 EP 5286 DI 10.1128/AEM.01291-16 PG 9 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA DT5DI UT WOS:000381500700022 PM 27316967 ER PT J AU Degrazia, D AF Degrazia, David TI SENTIENT NONPERSONS AND THE DISVALUE OF DEATH SO BIOETHICS LA English DT Article DE harm of death; persons; sentient nonpersons; prudential value theory; time-relative interest account; death AB Implicit in our everyday attitudes and practices is the assumption that death ordinarily harms a person who dies. A far more contested matter is whether death harms sentient individuals who are not persons, a category that includes many animals and some human beings. On the basis of the deprivation account of the harm of death, I argue that death harms sentient nonpersons (whenever their lives would be worth continuing). I next consider possible bases for the commonsense judgment that death ordinarily harms persons more than it harms sentient nonpersons. Contrary to what some philosophers believe, it is doubtful that the familiar resources of prudential value theory can vindicate this judgment. I show that the approach that at first glance seems most promising for supporting this judgment - namely, invoking an objective account of well-being - faces substantial challenges, before arguing that McMahan's time-relative interest account supplies the needed theoretical basis. I then go on to extract a significant practical implication of the first thesis, that death ordinarily harms sentient nonpersons: We should find a way to discontinue the routine killing of animal subjects following their use in experiments. C1 [Degrazia, David] George Washington Univ, Dept Bioeth, Natl Inst Hlth, Washington, DC USA. [Degrazia, David] George Washington Univ, Philosophy, Washington, DC USA. RP Degrazia, D (reprint author), George Washington Univ, Dept Philosophy, Phillips 525 801 22nd St NW, Washington, DC 20052 USA. EM ddd@gwu.edu FU National Institutes of Health Clinical Center FX This work was supported in part by intramural funds from the National Institutes of Health Clinical Center. The views expressed are my own. They do not represent the position or policy of the NIH, the US Public Health Service, or the Department of Health and Human Services. A draft of this article was presented at Oslo University on 21 June 2015 for a workshop entitled 'Saving Lives from the Badness of Death.' I thank the University of Bergen for sponsoring the workshop and attendees for their feedback. I also thank two anonymous reviewers for the journal for their animadversions. NR 20 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-9702 EI 1467-8519 J9 BIOETHICS JI Bioethics PD SEP PY 2016 VL 30 IS 7 BP 511 EP 519 DI 10.1111/bioe.12250 PG 9 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA DS7FL UT WOS:000380948300006 PM 26833656 ER PT J AU Deibel, SH Weishaupt, N Regis, AM Hong, NS Keeley, R Balog, RJ Bye, CM Himmler, SM Whitehead, SN McDonald, RJ AF Deibel, S. H. Weishaupt, N. Regis, A. M. Hong, N. S. Keeley, Rd. Balog, R. J. Bye, C. M. Himmler, S. M. Whitehead, S. N. McDonald, R. J. TI Subtle learning and memory impairment in an idiopathic rat model of Alzheimer's disease utilizing cholinergic depletions and beta-amyloid SO BRAIN RESEARCH LA English DT Article DE Alzheimer's disease; Cofactor theory; Hippocampus; Rat; Cholinergic depletions; beta-amyloid ID NUCLEUS BASALIS MAGNOCELLULARIS; MILD COGNITIVE IMPAIRMENT; ACETYLCHOLINE-RELEASE; MEDIAL SEPTUM; TG2576 MICE; IN-VIVO; INFLAMMATORY RESPONSES; PERSISTENT IMPAIRMENTS; HIPPOCAMPAL ATROPHY; PHOTOPERIOD SHIFTS AB Alzheimer's disease (AD) is a disease of complex etiology, involving multiple risk factors. When these risk factors are presented concomitantly, cognition and brain pathology are more severely compromised than if those risk factors were presented in isolation. Reduced cholinergic tone and elevated amyloid-beta (A beta) load are pathological hallmarks of AD. The present study sought to investigate brain pathology and alterations in learning and memory when these two factors were presented together in rats. Rats received either sham surgeries, cholinergic depletions of the medial septum, intracerebroventricular A beta(25-35) injections, or both cholinergic depletion and A beta(25-35) injections (A beta+ACh group). The A beta+ACh rats were unimpaired in a striatal dependent visual discrimination task, but had impaired acquisition in the standard version of the Morris water task. However, these rats displayed normal Morris water task retention and no impairment in acquisition of a novel platform location during a single massed training session. A beta+ACh rats did not have exacerbated brain pathology as indicated by activated astroglia, activated microglia, or accumulation of A beta. These data suggest that cholinergic depletions and A beta injections elicit subtle cognitive deficits when behavioural testing is conducted shortly after the presentation of these factors. These factors might have altered hippocampal synaptic plasticity and thus resemble early AD pathology. (C) 2016 Elsevier B.V. All rights reserved. C1 [Deibel, S. H.; Hong, N. S.; Keeley, Rd.; Balog, R. J.; Bye, C. M.; Himmler, S. M.; McDonald, R. J.] Univ Lethbridge, Dept Neurosci, Canadian Ctr Behav Neurosci, Lethbridge, AB T1K 3M4, Canada. [Weishaupt, N.; Regis, A. M.; Whitehead, S. N.] Univ Western Ontario, Schulich Sch Med & Dent, Dept Anat & Cell Biol, Vulnerable Brain Lab, London, ON N6A 3K7, Canada. [Balog, R. J.] NIDA, NIH, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. RP Deibel, SH (reprint author), Univ Lethbridge, Dept Neurosci, Canadian Ctr Behav Neurosci, Lethbridge, AB T1K 3M4, Canada. EM deibel@uleth.ca FU Natural Sciences and Engineering Research Discovery Grant [RGPIN-2015-06347, 418489]; Canadian Institutes of Health Research, team grant [CBG-101925]; Alzheimer's Society of Canada [12-120]; Canadian Institutes of Health Research operating Grant [126127]; Ontario Mental Health Foundation; Natural Sciences and Engineering Research Council PGSD-3 scholarship; Natural Sciences and Engineering Research Council CREATE BIP PhD fellowship FX We would like to thank Sophia Liu, Amelia Hunter, Angela Zhang and Lynn Wang for their technical assistance. This experiment was supported by Grants awarded to RJM from Natural Sciences and Engineering Research Discovery Grant (RGPIN-2015-06347), Canadian Institutes of Health Research, team grant (CBG-101925) and Alzheimer's Society of Canada (12-120). This work was also supported by a Natural Sciences and Engineering Research Discovery Grant (418489), and Canadian Institutes of Health Research operating Grant (126127) awarded to SNW. NW is supported by an Ontario Mental Health Foundation Postdoctoral Fellowship and SHD currently holds a Natural Sciences and Engineering Research Council PGSD-3 scholarship and Natural Sciences and Engineering Research Council CREATE BIP PhD fellowship. NR 84 TC 0 Z9 0 U1 12 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 EI 1872-6240 J9 BRAIN RES JI Brain Res. PD SEP 1 PY 2016 VL 1646 BP 12 EP 24 DI 10.1016/j.brainres.2016.05.033 PG 13 WC Neurosciences SC Neurosciences & Neurology GA DT9TH UT WOS:000381844700002 PM 27208489 ER PT J AU Kwok, M Wu, SP Mo, C Summers, T Roschewski, M AF Kwok, Mary Wu, S. Peter Mo, Clifton Summers, Thomas Roschewski, Mark TI Circulating Tumor DNA to Monitor Therapy for Aggressive B-Cell Lymphomas SO CURRENT TREATMENT OPTIONS IN ONCOLOGY LA English DT Review DE Diffuse large B-cell lymphoma; Circulating tumor DNA; Minimal residual disease; MRD; Next-generation sequencing; Liquid biopsy; Surveillance imaging; Response-adapted ID NON-HODGKIN-LYMPHOMA; RESIDUAL DISEASE DETECTION; COMPLETE REMISSION; CANCER-PATIENTS; EPOCH-RITUXIMAB; FDG-PET; BLOOD; CHOP; POPULATION; RADIATION AB The goal of therapy for aggressive B-cell lymphomas such as diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL) is to achieve cure. Combination chemotherapy with rituximab cures most patients, but those with recurrent disease have a poor prognosis. Medical imaging scans such as computed tomography (CT) and positron emission tomography (PET) are the principal methods to assess response and monitor for disease relapse after therapy but are fundamentally limited by risks of radiation, cost, and a lack of tumor specificity. Novel sequencing-based DNA monitoring methods are capable of quantifying small amounts of circulating tumor DNA (ctDNA) before, during, and after therapy for mature B-cell lymphomas. Detection of ctDNA encoding clonal rearranged variable-diversity-joining (VDJ) receptor gene sequences has demonstrated improved analytical sensitivity and enhanced tumor specificity compared to imaging scans in DLBCL, offering broad clinical applicability across a range of aggressive B-cell lymphomas. Molecular monitoring of ctDNA has vaulted into the spotlight as a promising non-invasive tool with immediate clinical impact on monitoring for recurrence after therapy prior to clinical symptoms. As these clinical observations are validated, ctDNA monitoring needs to be investigated as a tool for response-adapted therapy and as a marker of minimal residual disease upon completion of therapy in aggressive B-cell lymphomas. Molecular monitoring of ctDNA holds tremendous promise that may ultimately transform our ability to monitor disease in aggressive B-cell lymphomas. C1 [Kwok, Mary; Mo, Clifton] Walter Reed Natl Mil Med Ctr, Hematol Oncol Dept, John P Murtha Canc Ctr, 4954 N Palmer Rd, Bethesda, MD 20889 USA. [Wu, S. Peter] NYU, Langone Med Ctr, Perlmutter Canc Ctr, Internal Med Dept, 560 E 34th St, New York, NY 10016 USA. [Summers, Thomas] Uniformed Serv Univ Hlth Sci, Dept Pathol, 4301 Jones Bridge Rd, Bethesda, MD 20895 USA. [Roschewski, Mark] NCI, Lymphoid Malignancies Branch, Ctr Canc Res, NIH, 9000 Rockville Pike,Bldg 10,Room 4N-115, Bethesda, MD 20892 USA. RP Roschewski, M (reprint author), NCI, Lymphoid Malignancies Branch, Ctr Canc Res, NIH, 9000 Rockville Pike,Bldg 10,Room 4N-115, Bethesda, MD 20892 USA. EM mark.roschewski@nih.gov FU NIH FX The authors would like to acknowledge support from the intramural research program of the NIH including all patients and providers. NR 50 TC 0 Z9 0 U1 7 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1527-2729 EI 1534-6277 J9 CURR TREAT OPTION ON JI Curr. Treat. Options Oncol. PD SEP PY 2016 VL 17 IS 9 AR 47 DI 10.1007/s11864-016-0425-1 PG 12 WC Oncology SC Oncology GA DS9BJ UT WOS:000381076500003 PM 27461036 ER PT J AU Putnick, DL Bornstein, MH AF Putnick, Diane L. Bornstein, Marc H. TI Measurement invariance conventions and reporting: The state of the art and future directions for psychological research SO DEVELOPMENTAL REVIEW LA English DT Article DE Comparative psychology; Measurement invariance; Structural equation modeling; Confirmatory factor analysis; Multiple-group analysis ID CONFIRMATORY FACTOR-ANALYSIS; ITEM-RESPONSE-THEORY; TESTING MEASUREMENT INVARIANCE; STRUCTURAL EQUATION MODELS; CROSS-CULTURAL RESEARCH; FACTORIAL INVARIANCE; MEASUREMENT EQUIVALENCE; FIT INDEXES; SPECIFICATION SEARCHES; COVARIANCE-STRUCTURES AB Measurement invariance assesses the psychometric equivalence of a construct across groups or across time. Measurement noninvariance suggests that a construct has a different structure or meaning to different groups or on different measurement occasions in the same group, and so the construct cannot be meaningfully tested or construed across groups or across time. Hence, prior to testing mean differences across groups or measurement occasions (e.g., boys and girls, pretest and posttest), or differential relations of the construct across groups, it is essential to assess the invariance of the construct. Conventions and reporting on measurement invariance are still in flux, and researchers are often left with limited understanding and inconsistent advice. Measurement invariance is tested and established in different steps. This report surveys the state of measurement invariance testing and reporting, and details the results of a literature review of studies that tested invariance. Most tests of measurement invariance include configural, metric, and scalar steps; a residual invariance step is reported for fewer tests. Alternative fit indices (AFIs) are reported as model fit criteria for the vast majority of tests; chi(2) is reported as the single index in a minority of invariance tests. Reporting AFIs is associated with higher levels of achieved invariance. Partial invariance is reported for about one-third of tests. In general, sample size, number of groups compared, and model size are unrelated to the level of invariance achieved. Implications for the future of measurement invariance testing, reporting, and best practices are discussed. Published by Elsevier Inc. C1 [Putnick, Diane L.; Bornstein, Marc H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, 6705 Rockledge Dr,Suite 8030, Bethesda, MD 20892 USA. RP Putnick, DL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, 6705 Rockledge Dr,Suite 8030, Bethesda, MD 20892 USA. EM putnickd@mail.nih.gov OI Putnick, Diane/0000-0002-6323-749X FU Intramural Research Program of the NIH, NICHD FX This research was supported by the Intramural Research Program of the NIH, NICHD. Many thanks to Charlene Hendricks and Patrick S. Malone for feedback on early drafts. NR 72 TC 2 Z9 2 U1 9 U2 11 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0273-2297 EI 1090-2406 J9 DEV REV JI Dev. Rev. PD SEP PY 2016 VL 41 BP 71 EP 90 DI 10.1016/j.dr.2016.06.004 PG 20 WC Psychology, Developmental SC Psychology GA DT9TM UT WOS:000381845200004 PM 27942093 ER PT J AU Nguyen, TT Tchetgen, EJT Kawachi, I Gilman, SE Walter, S Glymour, MM AF Nguyen, Thu T. Tchetgen, Eric J. Tchetgen Kawachi, Ichiro Gilman, Stephen E. Walter, Stefan Glymour, M. Maria TI Comparing Alternative Effect Decomposition Methods The Role of Literacy in Mediating Educational Effects on Mortality SO EPIDEMIOLOGY LA English DT Article ID HEALTH OUTCOMES; PATHWAYS; INTELLIGENCE; DISPARITIES; POPULATION; MECHANISMS; EXPOSURE AB Background: Inverse odds ratio weighting, a newly proposed tool to evaluate mediation in exposure-disease associations, may be valuable for a host of research questions, but little is known about its performance in real data. We compare this approach to a more conventional Baron and Kenny type of decomposition on an additive hazards scale to estimate total, direct, and indirect effects using the example of the role of literacy in mediating the effects of education on mortality. Methods: Health and Retirement Study participants born in the United States between 1900 and 1947 were interviewed biennially for up to 12 years (N = 17,054). Literacy was measured with a brief vocabulary assessment. Decomposition estimates were derived based on Aalen additive hazards models. Results: A 1 standard deviation difference in educational attainment (3 years) was associated with 6.7 fewer deaths per 1000 personyears (beta = -6.7, 95% confidence interval [CI]: -7.9, -5.4). Of this decrease, 1.3 fewer deaths (beta = -1.3, 95% CI: -4.0, 1.2) were attributed to the literacy pathway (natural indirect), representing 19% of the total effect. Baron and Kenny estimates were consistent with inverse odds ratio weighting estimates but were less variable ( natural indirect effect: -1.2 [95% CI: -1.7, -0.69], representing 18% of total effect). Conclusion: In a cohort of older Americans, literacy partially mediated the effect of education on mortality. See Video Abstract at http://links.lww.com/EDE/B78. C1 [Nguyen, Thu T.; Walter, Stefan; Glymour, M. Maria] Univ Calif San Francisco, Dept Epidemiol & Biostat, 550 16th St,2nd Floor, San Francisco, CA 94158 USA. [Tchetgen, Eric J. Tchetgen] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Tchetgen, Eric J. Tchetgen; Gilman, Stephen E.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Kawachi, Ichiro; Gilman, Stephen E.; Glymour, M. Maria] Harvard TH Chan Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA USA. [Gilman, Stephen E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Bethesda, MD USA. RP Nguyen, TT (reprint author), Univ Calif San Francisco, Dept Epidemiol & Biostat, 550 16th St,2nd Floor, San Francisco, CA 94158 USA. EM Thu.Nguyen@ucsf.edu OI Gilman, Stephen/0000-0002-8331-6419 FU National Institutes of Health (NIH) [AI113251, ES020337]; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development FX Dr. Tchetgen Tchetgen's work was funded by the National Institutes of Health (NIH) grants AI113251 and ES020337. Dr. Gilman's work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 38 TC 0 Z9 0 U1 4 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1044-3983 EI 1531-5487 J9 EPIDEMIOLOGY JI Epidemiology PD SEP PY 2016 VL 27 IS 5 BP 670 EP 676 DI 10.1097/EDE.0000000000000517 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DS8CR UT WOS:000381011000015 PM 27280331 ER PT J AU Jukic, AMZ McConnaughey, DR Weinberg, CR Wilcox, AJ Baird, DD AF Jukic, Anne Marie Z. McConnaughey, D. Robert Weinberg, Clarice R. Wilcox, Allen J. Baird, Donna D. TI Long-term Recall of Time to Pregnancy SO EPIDEMIOLOGY LA English DT Article ID CARDIOVASCULAR-DISEASE; TO-PREGNANCY; FECUNDABILITY; PREECLAMPSIA; RISK; QUESTIONNAIRE; METAANALYSIS; INFERTILITY; VALIDITY AB Background: Despite the widespread use of retrospectively reported time to pregnancy to evaluate fertility either as an outcome or as a risk factor for chronic disease, only two small studies have directly compared prospective data with later recall. Methods: The North Carolina Early Pregnancy Study (1982-1986) collected prospective time-to-pregnancy data from the beginning of participants' pregnancy attempt. In 2010, (24-28 years later) women were sent a questionnaire including lifetime reproductive history that asked about all prior times to pregnancy. Of the 202 women with prospective time-to-pregnancy data, 76% provided recalled time to pregnancy. Results: A lower proportion of women with times to pregnancy >= 3 cycles provided a recalled time to pregnancy than women with times to pregnancy < 3 cycles. Also, high gravidity or parity was associated with a lower likelihood of providing a recalled time to pregnancy. Women with very short or very long times to pregnancy (1 cycle or >= 13 cycles) had good recall of time to pregnancy. Positive predictive values of 1 or >= 13 cycles were 73% and 68%, respectively, while positive predictive values for other categories of time to pregnancy ranged from 38% to 58%. The weighted kappa statistic for recalled versus prospective time to pregnancy was 0.72 (95% confidence interval: 0.65, 0.79). Conclusions: Recalled time to pregnancy showed good agreement with prospective time to pregnancy. Informative missingness must be considered when imputing recalled time to pregnancy. Associations observed in future studies can be corrected for misclassification. C1 [Jukic, Anne Marie Z.] Yale Sch Publ Hlth, Chron Dis Epidemiol, New Haven, CT USA. [McConnaughey, D. Robert] Westat Corp, Durham, NC USA. [Weinberg, Clarice R.] NIEHS, Biostat Branch, Durham, NC USA. [Wilcox, Allen J.; Baird, Donna D.] NIEHS, Epidemiol Branch, Durham, NC USA. RP Jukic, AMZ (reprint author), One Church St,6th Floor, New Haven, CT 06510 USA. EM annemarie.jukic@yale.edu RI Baird, Donna/D-5214-2017; OI Baird, Donna/0000-0002-5544-2653; Wilcox, Allen/0000-0002-3376-1311 FU National Institute of Health, National Institute of Environmental Health Sciences; Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health [R00HD079659] FX Supported in part by the intramural research program of the National Institute of Health, National Institute of Environmental Health Sciences. Research reported in this publication was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health under award number R00HD079659. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 22 TC 1 Z9 1 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1044-3983 EI 1531-5487 J9 EPIDEMIOLOGY JI Epidemiology PD SEP PY 2016 VL 27 IS 5 BP 705 EP 711 DI 10.1097/EDE.0000000000000506 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DS8CR UT WOS:000381011000020 PM 27487038 ER PT J AU Whitworth, KW Haug, LS Sabaredzovic, A Eggesbo, M Longnecker, MP AF Whitworth, Kristina W. Haug, Line S. Sabaredzovic, Azemira Eggesbo, Merete Longnecker, Matthew P. TI Plasma Concentrations of Perfluorooctane Sulfonamide and Time-to-pregnancy Among Primiparous Women SO EPIDEMIOLOGY LA English DT Article ID SELF-REPORTED TIME; PERFLUORINATED COMPOUNDS; POLYFLUOROALKYL SUBSTANCES; PERFLUOROALKYL SUBSTANCES; SERUM CONCENTRATIONS; NORWEGIAN MOTHER; CHILD COHORT; CHEMICALS; VALIDITY; SUBFECUNDITY AB Background: A previous study reported a negative association between perfluorooctane sulfonamide (PFOSA) concentrations and fecundability. Methods: We examined this association among women enrolled in the Norwegian Mother and Child Cohort Study (MoBa), in 20032004. This analysis was restricted to 451 primiparous women to avoid bias due to previous pregnancy. Self-reported time-topregnancy (TTP) and plasma were obtained around 18 weeks of gestation. Approximately half of the women had measurable PFOSA levels; missing values were multiply imputed. We used the logistic analogue of discrete-time survival analysis to examine the adjusted association between PFOSA, other perfluoroalkyl substances, and TTP. Results: The median-measured PFOSA concentration was 0.03 ng/ml (interquartile range = 0.02, 0.07). The age and body mass index-adjusted association between an interquartile distance increase in PFOSA and TTP was 0.91 (95% confidence interval = 0.71, 1.17). Imputation of missing PFOSA resulted in similar estimates. No association was observed with other perfluoroalkyl substances. Conclusion: Based on a weakly decreased fecundability odds ratio, we found only limited support for an association between plasma PFOSA concentrations and TTP among primiparous women. See Video Abstract at http://links.lww.com/EDE/B79. C1 [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. [Haug, Line S.; Sabaredzovic, Azemira; Eggesbo, Merete] Norwegian Inst Publ Hlth, Oslo, Norway. [Longnecker, Matthew P.] NIEHS, Dept Hlth & Human Serv, NIH, Durham, NC USA. RP Whitworth, KW (reprint author), Univ Texas Sch Publ Hlth, San Antonio Reg Campus,7411 John Smith Dr, San Antonio, TX 78216 USA. EM Kristina.w.whitworth@uth.tmc.edu FU Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences; Norwegian Ministry of Health; NIH/NIEHS [N01-ES-85433]; NIH/NINDS [1 UO1 NS 047537-01]; Norwegian Research Council/FUGE [151918/S10] FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. The Norwegian Mother and Child Cohort Study is supported by the Norwegian Ministry of Health, NIH/NIEHS (Contract No. N01-ES-85433), NIH/NINDS (Grant No. 1 UO1 NS 047537-01), and the Norwegian Research Council/FUGE (Grant No. 151918/S10). NR 23 TC 0 Z9 0 U1 6 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1044-3983 EI 1531-5487 J9 EPIDEMIOLOGY JI Epidemiology PD SEP PY 2016 VL 27 IS 5 BP 712 EP 715 DI 10.1097/EDE.0000000000000524 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DS8CR UT WOS:000381011000021 PM 27276029 ER PT J AU Upson, K Harmon, QE Laughlin-Tommaso, SK Umbach, DM Baird, DD AF Upson, Kristen Harmon, Quaker E. Laughlin-Tommaso, Shannon K. Umbach, David M. Baird, Donna D. TI Soy-based Infant Formula Feeding and Heavy Menstrual Bleeding Among Young African American Women SO EPIDEMIOLOGY LA English DT Article ID PITUITARY-GONADAL RELATIONS; NEONATAL EXPOSURE; UTERINE LEIOMYOMATA; FEMALE RATS; GENISTEIN; ESTROGEN; ACTIVATION; BETA; PHYTOESTROGENS; PREVALENCE AB Background: Phytoestrogen exposure from soy formula feeding during infancy may disrupt reproductive system development, resulting in altered menstrual bleeding in adulthood. Methods: We investigated this relationship in a cohort of 1,696 young African American women using enrollment data from the Study of Environment, Lifestyle, & Fibroids (2010-2012). Questionnaire data on soy formula feeding were available for 1,553 participants, 89% based on mother's report. Menstrual bleeding outcomes including those indicative of heavy menstrual bleeding were ascertained by interview. We estimated relative risks (RRs) and 95% confidence intervals (CI) for associations between soy formula feeding and menstrual bleeding outcomes using log-binomial regression and log-multinomial regression, comparing participants ever fed and never fed soy formula. Results: We observed associations between soy formula feeding and variables indicating a history of heavy menstrual bleeding, including ever experiencing heavy, gushing-type bleeding (RR: 1.2, 95% CI: 1.0, 1.4), ever use of nonsteroidal anti-inflammatory drugs for heavy bleeding (RR: 1.3, 95% CI: 1.0, 1.6), and ever use of a contraceptive method for heavy bleeding (RR: 1.2, 95% CI, 0.9, 1.6). Among the subset of participants with menses in the past year who did not use medication that may alter menstrual flow (n = 762), our data suggested that soy formula feeding was associated with heavier flow and the adverse impact of menstrual bleeding on quality of life, but CIs were wide. Conclusions: Our data suggested that soy formula feeding is associated with heavy menstrual bleeding. Our results support the idea that infancy is a susceptible developmental window for female reproductive function. C1 [Upson, Kristen; Harmon, Quaker E.; Baird, Donna D.] NIEHS, Epidemiol Branch, NIH, 111 TW Alexander Dr,Rall Bldg 101,MD A3-05, Res Triangle Pk, NC 27709 USA. [Laughlin-Tommaso, Shannon K.] Mayo Clin, Dept Obstet & Gynecol, Rochester, MN USA. [Laughlin-Tommaso, Shannon K.] Mayo Clin, Dept Surg, Rochester, MN USA. [Umbach, David M.] NIEHS, Biostat & Computat Biol Branch, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RP Upson, K (reprint author), NIEHS, Epidemiol Branch, NIH, 111 TW Alexander Dr,Rall Bldg 101,MD A3-05, Res Triangle Pk, NC 27709 USA. EM kristen.upson@nih.gov RI Upson, Kristen/D-4504-2017; Baird, Donna/D-5214-2017 OI Upson, Kristen/0000-0001-9598-8776; Baird, Donna/0000-0002-5544-2653 FU Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences [1Z1A ES049013-10]; American Recovery and Reinvestment Act FX Supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences (1Z1A ES049013-10), and in part by funds allocated for health research by the American Recovery and Reinvestment Act. NR 47 TC 1 Z9 1 U1 2 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1044-3983 EI 1531-5487 J9 EPIDEMIOLOGY JI Epidemiology PD SEP PY 2016 VL 27 IS 5 BP 716 EP 725 DI 10.1097/EDE.0000000000000508 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DS8CR UT WOS:000381011000022 PM 27196806 ER PT J AU Olerud, HM Toft, B Flatabo, S Jahnen, A Lee, C Thierry-Chef, I AF Olerud, Hilde M. Toft, Benthe Flatabo, Silje Jahnen, Andreas Lee, Choonsik Thierry-Chef, Isabelle TI Reconstruction of paediatric organ doses from axial CT scans performed in the 1990s-range of doses as input to uncertainty estimates SO EUROPEAN RADIOLOGY LA English DT Article DE Tomography scanners, X-ray computed; Radiologic health; Paediatrics; Dose-response relationship, radiation; Radiation dosage ID RADIATION RISKS; TOMOGRAPHY; DOSIMETRY; PHANTOMS AB To assess the range of doses in paediatric CT scans conducted in the 1990s in Norway as input to an international epidemiology study: the EPI-CT study, http://epi-ct.iarc.fr/. National Cancer Institute dosimetry system for Computed Tomography (NCICT) program based on pre-calculated organ dose conversion coefficients was used to convert CT Dose Index to organ doses in paediatric CT in the 1990s. Protocols reported from local hospitals in a previous Norwegian CT survey were used as input, presuming these were used without optimization for paediatric patients. Large variations in doses between different scanner models and local scan parameter settings are demonstrated. Small children will receive a factor of 2-3 times higher doses compared with adults if the protocols are not optimized for them. For common CT examinations, the doses to the active bone marrow, breast tissue and brain may have exceeded 30 mGy, 60 mGy and 100 mGy respectively, for the youngest children in the 1990s. The doses children received from non-optimised CT examinations during the 1990s are of such magnitude that they may provide statistically significant effects in the EPI-CT study, but probably do not reflect current practice. aEuro cent Some organ doses from paediatric CT in the 1990s may have exceeded 100 mGy. aEuro cent Small children may have received doses 2-3 times higher compared with adults. aEuro cent Different scanner models varied by a factor of 2-3 in dose to patients. aEuro cent Different local scan parameter settings gave dose variations of a factor 2-3. aEuro cent Modern CTs and age-adjusted protocols will give much lower paediatric doses. C1 [Olerud, Hilde M.; Flatabo, Silje] NRPA, POB 55, NO-1332 Osteras, Norway. [Olerud, Hilde M.] HSN Univ, Coll Southeast Norway, POB 235, NO-3603 Kongsberg, Norway. [Toft, Benthe] Gjovik Univ Coll, Teknologivn 22, NO-2815 Gjovik, Norway. [Jahnen, Andreas] LIST, 29 Ave John F Kennedy, L-1855 Luxembourg, Luxembourg. [Lee, Choonsik] NCI, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr, Rockville, MD 20850 USA. [Thierry-Chef, Isabelle] Int Agcy Res Canc, 150 Cours Albert Thomas, F-69008 Lyon, France. RP Olerud, HM (reprint author), NRPA, POB 55, NO-1332 Osteras, Norway.; Olerud, HM (reprint author), HSN Univ, Coll Southeast Norway, POB 235, NO-3603 Kongsberg, Norway. EM hilde@olerud.net FU European Community [269912]; EURATOM program of the Norwegian Research Council FX The scientific guarantors of this publication are Hilde M. Olerud and Isabelle Thierry-Chef. The authors of this manuscript declare no relationships with any companies, whose products or services may be related to the subject matter of the article. The research leading to these results has received funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement number 269912 - EPI-CT: Epidemiological study to quantify risks for paediatric computed tomography and to optimize doses, http://epi-ct.iarc.fr/. The Norwegian part of the EPI-CTstudy was funded by the EURATOM program of the Norwegian Research Council. Acknowledgements to Astrid Liland who administrated the EPI-CT project for the Norwegian Radiation Protection Authority, and to Deborah H Oughton, Norwegian University of Life Sciences, who was co-supervisor for Benthe Toft (second author). No complex statistical methods were necessary for this paper. Institutional Review Board approval was obtained from the International Agency for Research on Cancer (IARC) Ethics Committee. Some previous results were reported at ECR 2014 as an oral presentation. Methodology: retrospective, experimental, multicenter. NR 31 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0938-7994 EI 1432-1084 J9 EUR RADIOL JI Eur. Radiol. PD SEP PY 2016 VL 26 IS 9 BP 3026 EP 3033 DI 10.1007/s00330-015-4157-6 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DS9SA UT WOS:000381122400019 PM 26803507 ER EF